TW201211053A - 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

201211053 VI. Description of the invention: [Technical field to which the invention belongs]

The present invention relates to a method for preventing, treating, and improving a disease which is characterized by having an adiponectin receptor affinity and/or an agonist effect, which is effective for adiponectin receptor activation. Further, the present invention relates to a metabolic syndrome containing an agent having an action of an agonist of an adiponectin receptor as an active ingredient, particularly a metabolic syndrome caused by obesity or diabetes, and prevention of arteriosclerosis. Or a therapeutic drug. [Prior Art] Adiponectin is a kind of adipocytokine which is a physiologically active substance secreted by fat cells. Although the role of adiponectin has been a possibility, as the most important role, it is considered as a defensive factor to prevent tissue from acquiring insulin resistance diabetes. In fact, there are reports indicating insulin resistance indicators and blood. The adiponectin concentration is inversely correlated φ (see, for example, Non-Patent Document 1). Further, as the detailed action, the sugar absorption in the adipose tissue or the muscle tissue is directly stimulated, and the insulin resistance can be improved by increasing the fatty acid oxidation in the liver or muscle tissue and reducing the fatty acid or neutral fat content in the cell (for example, Non-patent documents 2, 3, and 4). Considering this effect, adiponectin may improve the risk of obesity through the improvement of insulin resistance. In fact, it has been reported that the degree of obesity is inversely proportional to the concentration of adiponectin in the blood (for example, refer to the non-patent literature). 5). Moreover, adiponectin has a therapeutically effective possibility for improving the diabetes mellitus or obesity, a metabolic syndrome associated with these complex pathological syndromes -5 - 201211053 (metabolic syndrome).

It is known that adiponectin functions as an adiponectin receptor (hereinafter sometimes referred to as AdipoR). There are two subtypes of AdipoR 1 and AdipoR2 in AdipoR. AdipoRl is distributed in the whole body tissues. The stimulation mainly shows the activation of AMP kinase (sugar regeneration inhibition). On the one hand, it has been reported that Adip〇R2 is mainly distributed in the liver. It mainly shows the /3 oxidation hyperactivity of the activated fatty acids via PPARa. The AMP kinase system is a kinase that is an important enzyme for the metabolism of sugars and lipids such as ACC or HMG-CoA, and regulates the metabolic pathways of sugar transport or saccharification, such as lipid metabolism. The activated AMP kinase and the activated fatty acid 3 oxidize to a metabolic pathway such as fatty acid decomposition or saccharification, inhibit lipid synthesis, and the like, thereby exerting an insulin resistance improving effect.

Moreover, it has been reported that adiponectin can reduce glycogen content by reducing the activity of glycogen synthase in the liver. Other reports have also indicated that adiponectin can also protect against inflammation or coronary artery disease, non-alcoholic steatohepatitis, liver fibrosis or malignant tumors (for example, refer to Non-Patent Documents 6, 7, and 8). As described above, a compound having an affinity for an adiponectin receptor and/or an agonist is a disease effective for adiponectin receptor activation, such as for diabetes, because it exhibits an action such as adiponectin. Obesity, metabolic syndrome, arteriosclerosis, coronary artery disease, nonalcoholic steatohepatitis, liver fibrosis, or malignant tumors are particularly effective for prevention, treatment, and improvement of diabetes. As a low molecular compound that exhibits the action of an adiponectin receptor agonist, although 8 -6- 201211053

Rigel has reported (see Patent Documents 1 to 4), and it is expected that further pharmaceutical development will be possible. [Advanced Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2008/083 1 24 [Patent Document 2] International Publication No. 2009/065 1 3 1 [Patent Document 3] International Publication No. 2009/07663 1 [Patent Document 4] International Publication No. 2009/1 32 1 36 [Non-Patent Document] [Non-Patent Document 1] Circ J. 2004, 68(11), 975-981. Adiponectin as a biomarker of the metabolic syndrome.

[Non-Patent Document 2] Nat. Med. 2002, 8(11), 1288-1295. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating A ΜP-activated protein kinase.

[Non-Patent Document 3] Proc. Natl. Acad. Sci. USA. 2002, 99(25), 16309-16313. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase Activation.

[Non-Patent Document 4] Diabetes. 2003, 52(6), 1355-1363. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes.

[Non-Patent Document 5] Arterioscler. Thromb. Vase. Biol. 2000, 20(6), 1 5 9 5- 1 599. Plasma concentrations of a novel, adipose- 201211053 specific protein, adiponectin, in type 2 diabetic patients.

[Non-Patent Document 6] Arterioscler. Thromb. Vase. Biol· 2003, 23(1), 85-89. Coronary artery disease. Association of hypoadiponectinemia with coronary artery disease in men.

[Non-Patent Document 7] Hepatology. 2008, 47(4), 1167-77· Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH.

[Non-Patent Document 8] Proc. Natl. Acad. Sci. USA. 2004, 101(8), 2476-2 4 8 1. Adiponectin-induced antiangiogenesis and antitumor activity involved caspase-mediated endothelial cell apoptosis. The problem to be solved by the present invention is to provide metabolic syndrome and agonist effects, metabolic syndrome caused by metabolic syndrome, particularly obesity or diabetes, and arteriosclerosis. A novel medicine that is useful for prevention or treatment is a subject. The inventors of the present invention conducted a detailed review of the above problems and found that the compound represented by the general formula (1) exhibits an excellent adiponectin receptor agonist action to complete the present invention. That is, the present invention relates to the following.

Formula (I) 201211053 【化1】

[in the formula (I),

£ represents an oxygen atom or a sulfur atom, L 1 represents a single bond, a Cm alkyl group, a Cw extended alkenyl group or a C2·3 extended alkynyl group (the Cl-3 alkylene group, the C2·3 extended alkenyl group and the c : 2_3 an alkynyl group is unsubstituted or substituted by a cyclopropyl group), L represents a single bond 'Cl-3 alkylene group, C2 3 extended alkenyl group or C: 2 3 extended alkynyl group (the Cl-3 alkylene group) , C2·3 alkenyl and c:2_3 alkynyl are unsubstituted or substituted by cyclopropyl),

X represents a C3-M cycloalkylene group, a Cy t ring-extended alkenyl group (the Cn t ring-extension base group and the C3-U ring-extended alkenyl group are unsubstituted or independently selected from the Ci-3 yard group, C2·3 olefin Substituted by 丨 〇Ri6 and cyano groups of more than one substituent), C6.1Q aryl or 5~10 member heteroaryl (the C6_1() extended aryl and 5~1〇 The heteroaryl group is unsubstituted or independently selected from a halogen atom, a nitro group, a cyano group, a Ci-3 alkyl group (the oxime:, -3 alkyl group is unsubstituted or independently selected from a halogen atom and -OR16) Substituted by more than one substituent), C2_3 alkenyl, c2.3 alkynyl, -OR16, -〇(C2.3 alkenyl), -0(c3-4 cycloalkyl), -n( R16)c( = o)or17, -N(R16)C(=0)R17, -n(R16)C(=0)H, -n(r16)r17, -nh2, -N(R16)S( =0) 2R17, -C( = 0)NR16R17 201211053, -c( = o)nh2, -C( = 〇)R16, -s( = o)2r17, -s( = o)2nr16r17, -s( = o) Substituted by more than one substituent in groups of 2nh2), Z1 represents formula (II-1) to (Π-8)

J1 ~人ιΛ R3 R4 (ΙΙ-4) RVS," into R3 R4 (N-5) R 2 , G1

(II-6)

(In the formula, J1 each independently represents an oxygen atom or a sulfur atom, G1 represents a single bond, an oxygen atom or a sulfur atom, R1 and R3 are, R1 represents a hydrogen atom, OR11, NR11. 2, CU9 alkyl group (this Cl.9) The alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3), Ciu cycloalkyl or 4 to 11 membered heterocycloalkyl (the C3.M cycloalkyl group and 4 to 11) A heterocycloalkyl group may be bonded to a C6-10 aryl group or a 5 to 10 membered heteroaryl group (the C6.1G aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from the group consisting of -10-201211053 substituent groups The substitution of one or more substituents in which A2 and C4·6 alkyl groups are substituted) is condensed, and the ChH cycloalkyl group and the 4 to 1 membered heterocycloalkyl group are unsubstituted or independently selected from substituents. Group 1 and C4_6 alkyl groups are substituted with one or more substituents), R3 represents a hydrogen atom or a Ci.3 alkyl group, or R1 and R3 are combined with a nitrogen atom to which they are bonded. 11 member heterocycloalkyl (the 4 to 11 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a substituent group A! and a C4-6 alkyl group), R2 Represents Ci.9 alkyl (the CL9 alkyl is not taken Or substituted by one or more substituents independently selected from the substituent group A3), (^.^cycloalkyl or 4 to 11 membered heterocycloalkyl (the (3: η cycloalkyl group and 4 to 11) A heterocycloalkyl group may be bonded to a C6-10 aryl group or a 5 to 10 membered heteroaryl group (the C6-10 aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from the group of substituents VIII and c4). The -6-alkyl group is substituted with one or more substituents), and the C3_M cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are unsubstituted or independently selected from the substituent group % A! And one or more substituents in which C4_6 alkyl groups are substituted), R4 and R5 each independently represent a hydrogen atom or an alkyl group, m represents an integer of 1 or 2, and R6 each independently represents a hydrogen atom. , C!_3 alkyl or cyclopropyl, or two R6 present on the same carbon atom are combined with the carbon atom to which they are bonded to form a C3-6 cycloalkane, η represents an integer from 〇 to 4, and R7 is each Independently represents an alkyl group, -11 - 201211053 T represents a formula (V 〖-1) to (VI-3) [Chemical 3] /xl^lv /sy\s (VI-1) (VI-2) J2 (ν, .3) (wherein L4 represents Cu alkyl group, and L·5 represents a single bond, an oxygen atom, a sulfur atom, S ( = Q), s( = 〇h, C = 0 or C = NOR12, R8 represents aryl or 5~Π) heteroaryl (the c6iq aryl and 5 to 10 membered heteroaryl are unsubstituted or Independently selected from the group of substituents ^ and C4 (substituted by more than one substituent of the group of alkyl groups), J2 represents an oxygen atom or a sulfur atom, G2 represents an oxygen atom, a sulfur atom or NR11, and R9 represents C, -9 An alkyl group (this Cl_9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), c6 i. An aryl group (the C6.1Q aryl group is unsubstituted or substituted by one or more substituents independently selected from the group of substituents and C4.6 alkyl groups), C3-n cycloalkyl group (the Cy t The cycloalkyl group may be a heteroaryl group with a Ce_1Q aryl group or a 5- to oxime aryl group (the c6_1G aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from the group of substituents a2 and C4·6) Substituting a group of more than one substituent) to carry out a condensed ring, and the Cm ring is substituted by an unsubstituted or substituted by one substituent of -12-201211053 or more independently selected from the substituent group 2) or Cld alkyl (the Ci-3 alkyl group represents a C6-10 aryl group or a C3-H cycloalkyl group (the c6-1Q aryl group and the Cm cycloalkyl group are unsubstituted or independently selected from the group of substituents A2 and c4_6) Substituted by one or more substituents in which the alkyl group is substituted))

R1G represents a C-9 alkyl group which may be substituted with a Ci-9 alkyl group (the mountain-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), Cm 〇 aryl group, 5 to 10 member hetero aryl group a group (the c6-1() aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the group consisting of a substituent group of octa 2 and a C4-6 alkyl group), and a ring Alkyl (the c3,,, cycloalkyl group may be substituted with a c6-10 aryl group or a 5 to 10 membered heteroaryl group (the C6-1Q aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by an independent one) The group octa 2 and the C4-6 alkyl group are substituted with one or more substituents) to carry out condensed ring, and the C3.H cycloalkyl group is unsubstituted or one independently selected from the substituent group A2 Substituted by the above substituent) or C,-3 alkyl (the C alkyl group may be a C3-H cycloalkyl group (the C3_n cycloalkyl group is unsubstituted or one or more independently selected from the substituent group hexa-2) Any one of the substituents A) substituted with a substituent), represents a C, "alkyl group (the Cu alkyl group is unsubstituted or one or more substituents selected from the substituent group A3) Substituted) and the substituent group consisting of the substituent group A3, The group A3 is a C3-u cycloalkyl group, a 4 to 11 membered heterocycloalkyl group (the (^-^cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are available as a C6_1Q aryl group or a 5 to 10 member heteroaryl group). a group (the C6_iQ aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by i or more substituents independently selected from the group consisting of a substituent ^ A2 and a C4_6 alkyl group) - 13-201211053 condensed ring And the Cn, cycloalkyl group and 4 to 11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent group 2 and the C4.6 alkyl group), C6_1() aryl, 5 to 10 membered heteroaryl (the C6-1Q aryl group and 5 to 10 membered heteroaryl group are available as a 4- to n-membered heterocycloalkane (the 4 to η member heterocycloalkane is unsubstituted) Or condensed by a substituent selected from one or more substituents independently selected from the substituent group Α2, and the C6.1Q aryl group and the 5~1 member heteroaryl group are unsubstituted or independently selected from the group of substituents Substituted by one or more substituents of a group of human 2 and C4-6 alkyl groups), -C(= 〇)〇R13, -c(=o)nr12r13, -〇(=〇)11丨3, _C ( = N〇R12)r13, _s( = 〇)r13 _s( = 〇)2Rl3, 〇r13, -SR13, -N(R12)C( = 0)0R13, _n(r12)c( = o)r13, a group of substituents consisting of -n(r12)r13, a halogen atom, a cyano group, a nitro group, a thiol group, -C(=N〇r12)h, _N(R12)c(=〇)h, or a hydroxyl group , in the substituent group A2,

a group of substituents consisting of a Cl-3 alkyl group (the C, _3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A4, and the substituent group A4 is a _ atom, a nitro group, Cyano, _Qr14, _sR14, _c( = 〇)〇r14

C(-0)NR14R丨5, -c(=〇)R丨5, -c( = n〇R15)Rm, -CpNOR'H S(~0)R -S( = 0)2R14 ' -N( R15)C( = 〇)〇Ri4 , -N(R15)C( = 〇)r14 , or a group of substituents formed by RU, each independently representing a hydrogen atom or a CU6 building group,

Rl2 is independently represented by a hydrogen atom or a CU3 fluorenyl group, and R 3 is an independent representation.

Ci-6 alkyl (the c, 4 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent-14-201211053 group A4), C3-11 ring yard base, 4 to 11 members Heterocyclic compound, C6-10 aryl, or 5 to 10 membered heteroaryl (the C3-ii ring, 4 to 11. heterocyclic, 06.1 aryl and 5 to 10 heteroaryl) Substituted as unsubstituted or substituted by one or more substituents independently selected from the group consisting of a substituent group a2 and C4.6 alkyl), R14 represents a C^3 alkyl group (the C:.3 alkyl group is unsubstituted) Or replaced by more than one halogen atom),

R15 represents a hydrogen atom or a Cl" group (the Cu group is unsubstituted or substituted by one or more halogen atoms), R16 represents a hydrogen atom or a Ci-3 alkyl group, and R17 represents a Cu alkyl group. a cyclic compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (2) Formula (1) [Chemical 4]

[In the formula (1), E represents a non-oxygen atom or a sulfur atom, -15-201211053 L1 represents a single bond, C, -3 alkylene group, C2-3 extended alkenyl group or C2.3 extended alkynyl group (the C10 alkylene group) , c2_3 alkenyl and C2.3 ankynyl are unsubstituted or substituted by cyclopropyl), L2 represents a single bond, Cu alkyl, C2-3 extended alkenyl or C2-3 extended alkynyl (the Cu An alkyl group, a c2.3 alkenyl group and a C2.3 alkynyl group are unsubstituted or substituted by a cyclopropyl group, X is a 7pc C3-II ring-extension base group, and a C3-11 ring stretching base group (the c __丨丨cycloalkyl and Cm cycloalkenyl are unsubstituted or substituted by one or more groups independently selected from the group consisting of Ci.3 alkyl, C:2·3 alkenyl, -ORR16 and cyano Substituted by a group, a C6-1Q aryl group or a 5 to 10 member heteroaryl group (the C6.iq aryl group and the 5 to 10 member heteroaryl group are unsubstituted or independently selected from a halogen atom, a nitro group a cyano 'Ci-3 alkyl group (the C, -3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR16), a C2.3 alkenyl group, C2.3 alkynyl, _〇R16, -〇(C2.3 alkenyl), -〇(C3.4 cycloalkyl), -N(R16)c( = 〇)〇r17, -n(r16)c ( = o)r17, -n(r16)c( = o )h, -N(R16)r", -nh2, -n(r16)s( = o)2r17, -c( = o)nr16r17, -C( = 〇)NH2, -C( = 〇)R16, -S( = 〇) 2R17, -S( = 〇hNR16R17, -S( = 0)2NH2 is replaced by one or more substituents, and Z1 represents formula (II-1) to (Π-8) 201211053

【化5】

(11-6) (11-7) (11-8) (wherein J is an independent oxygen atom or a sulfur atom, and G1 represents a single bond, an oxygen atom or a sulfur atom,

In R1 and R3,

R1 represents a hydrogen atom, OR11, NRUR12, C, -9 alkyl (the Cw alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3), (: 3-11 naphthenic) Or a 4 to 11 membered heterocycloalkyl group (the (^-^cyclodecyl group and the 4 to 11 membered heterocycloalkyl group may be bonded to Cl, an aryl group or a 5 to 1 member heteroaryl group). The () aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the fluorene ring is formed, and the 〇3-ιι ring fluorenyl group and 4~ 11 is a heterocyclic compound which is unsubstituted or substituted by one or more substituents independently selected from the substituent group A 1 ), and r 3 represents a hydrogen atom or -17-201211053

Ci-3 alkyl, or R1 and R3 are bonded to the nitrogen atom to which they are bonded to represent a 4 to 11 membered heterocycloalkyl group (the 4 to 11 membered heterocycloalkyl group is unsubstituted or independently selected from substituents). Substituted by more than one substituent of group A i ), R 2 represents c, -9 alkyl (the C. 9 alkyl group is unsubstituted or substituted by more than one substituent selected independently from the substituent group As ), cycloalkyl or 4 to 11 membered heterocycloalkyl (the c3.μ cycloalkyl and 4 to 11 membered heterocycloalkyl are available as C6-1C (aryl or 5 to 1 member heteroaryl) The c6.1G aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the Cn, cycloalkyl group and 4~ are substituted. 1 1 member heterocyclic compound is unsubstituted or substituted by one or more substituents independently selected from the group of substituents, and R and R5 are each independently represent a hydrogen atom or a Ci3 alkyl group), m An integer representing 1 or 2, r6 is independently a hydrogen atom, a Ci 3 alkyl group or a cyclopropyl group, or two Han 6 present on the same carbon atom are combined with the carbon atom to which they are bonded to form a C3_6 Cycloalkane, η represents an integer from 〇 to 4, r 7 is an independent representation of a Cl3 alkyl group, and T represents a formula (VI-1) to (VI-3) 201211053 person [Chem. 6]

(VI-1) Person R1. (VI-2) (wherein L4 represents a Cm alkyl group, L5 represents a single bond, an oxygen atom, a sulfur atom, S(= 〇), sb (1) 2, Ca C = 〇 or C = NOR12, and R8 represents C6- 1Q aryl or 5 to 10 membered heteroaryl (the aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by more than 1 substituent selected independently from the substituent group ~), and J2 represents an oxygen atom Or a sulfur atom, G2 represents an oxygen atom, a sulfur atom or NRn,

VR represents a C..9-membered group (the Cl_9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4) 'C6_1Q aryl group (the C6-10 aryl group is unsubstituted) Or substituted by one or more substituents independently selected from the substituent group A2), a Cm cycloalkyl group (the cycloalkyl group may be a C6-10 aryl group or a 5-10 member heteroaryl group (the C6-1G) The aryl group and the 5 to 1 member heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2) and the C3.U cycloalkyl group is unsubstituted or Substituted from one or more substituents independently selected from the substituent group A2), or c, 3 alkyl groups (the Cu alkyl group represents a C6-l() aryl group or a Cn, a cycloalkyl group (the C6-1G aryl group) And the Cs-u cycloalkyl group is unsubstituted or substituted by a substituent independently selected from the substituent group 2, substituted by a substituent on -19-201211053),

R1() represents a C?9 alkyl group (the C alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), a C6_1Q aryl group, and a 5 to 10 membered heteroaryl group (this The C6.1()aryl group and the 5-10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group 2), Cm t cycloalkyl group (the cycloalkyl group is And the <^·ια aryl or 5~10 membered heteroaryl (the C6_lc aryl group and the 5~10 membered heteroaryl group are unsubstituted or one or more substituents independently selected from the substituent group A2) Substituting) a condensed ring, and the cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the group VIII of the substituent), or a Ci_3 alkyl group (the C alkyl group is derived from a C3.u cycloalkane) Any one of the groups (the C3-H cycloalkyl group being unsubstituted or substituted by one or more substituents independently selected from the substituent group a2)), the substituent group A, representing an alkyl group (the Cu) The alkyl group is a group of substituents which are unsubstituted or substituted by one or more substituents independently selected from the substituent group A3) and the substituent group A3,

Substituent group A3 represents 匕-^cycloalkyl, 4 to 11 membered heterocycloalkyl (the (^-^cycloalkyl group and 4 to 11 membered heterocycloalkyl group can be mixed with C6_1Q aryl or 5 to 10 members) An aryl group (the C6-1D aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the c3-n ring is substituted And a 4 to 11 membered heterocycloalkyl group which is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), a C6-1G aryl group, and a 5 to 10 membered heteroaryl group (the C6- 1G aryl and 5 to 10 membered heteroaryl are available as 4 to 11 membered heterocycloalkanes (the 4 to 11 membered heterocycloalkanes are unsubstituted or independently selected from the group of substituents A 2 to 1-20-8) The above substituent is substituted) to carry out condensed ring, and the Ce-io aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), - C( = 0)0R13, -C( = 〇)NR12R13, -C( = 0)R13, -C( = NOR12)R13, -S( = 0)R13, -S( = 〇)2R13, -OR13, -SR13, -n(r12)c( = o)or13, -N(R12)C( = 〇)R", -N(R12)R13 'Halogen, cyano, nitro, formazan, -C (= NOR12;) H, -n(r12)c( = o)h, or a group of substituents composed of a hydroxyl group,

Substituent group a2

a group of substituents consisting of a Cl-3 alkyl group (which is unsubstituted or substituted by more than one halogen atom) and a substituent group A4, and a substituent group A4 represents

Halogen atom, nitro group, cyano group, -OR14, -SR14, -Ci = 〇>〇R14 -C(=0)NR14R'5 ' -C( = 0)R15 ' -C(=NOR15)R14 ' - C( = NORIS)H , -S( = 0)R14, -S(=〇)2R14, -N(R15)C( = 〇)〇R14, _N(R15)C( = 〇)r丨4 , or a group of substituents consisting of -n(r15)c( = 0)h, R11 is independently represented by a hydrogen atom or (^.6), R12 is independently represented by a hydrogen atom or cU3, and R13 is an independent representation.

Ci-6 alkyl (the c!.6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A*), 匸3-11 cycloalkyl group, 4 to 11 member hetero a cycloalkyl group, a c6_1Q aryl group, or a 5 to 10 membered heteroaryl group (the (^.cycloalkylene group, 4 to 11 membered heterocycloalkyl group, a nonyl group, and a 5 to 10 membered heteroaryl group) are unsubstituted or Substituted by one or more substituents independently selected from the group of substituents), -21 - 201211053 R14 represents c,.3 alkyl (the Ci.3 alkyl group is unsubstituted or substituted by one or more halogen atoms) R15 represents a hydrogen atom or a C, _3 alkyl group (the alkyl group is unsubstituted or substituted by one or more halogen atoms), R16 represents a hydrogen atom or C, -3 alkyl group, and R17 represents a Ci-3 yard group. The spiro compound described in the above (1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (3) X represents Cn, a cyclic alkyl group or (^~ ring extension) Alkenyl group (the c3·, ring-extension and C3-11 ring-extension group is unsubstituted or consists of a group independently selected from the group consisting of Ci-3, C2-3 alkenyl, -OR16 and cyano Substituted by one or more substituents). The spirocyclization described in the above (2) a compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (4) X represents c6.1() aryl or 5 to 10 member heteroaryl (this (^(一)) And a 5 to 10 membered heteroaryl group is unsubstituted or independently selected from a halogen atom, a nitro group, a cyano group, or a (3- 3 alkyl group (the CU3 alkyl group is unsubstituted or independently selected from a halogen atom and Substituted by one or more substituents of OR16), C2-3 dilute group, C2-3 alkynyl group, -〇R 6 , -〇(C2_3 dilute group), -0(C3-4 cycloalkyl group) , -n(r16)c(=o)or17, -n(r16)c(=0)r", ·ν(κ16)(:(=0)η -22- 201211053 , -n(r16)r17, · νη2, -n(r16)s( = o)2r17, -c( = o)nr16r17 ' -C( = 0)NH2 ' -C( = 0)R16 ' -S( = 0)2R17 ' -S( = 0) 2NR16R17, -S (=O) 2 is substituted by one or more substituents of the group of NH 2). The spiro compound described in the above (2), the tautomer of the compound, or Pharmaceutically acceptable salts. (5)

L1 represents a Cu alkyl group, a C2-3 alkenyl group or a C2.3 alkynyl group (the Ch alkyl group, the C2_3 alkenyl group, and the C2.3 alkynyl group are unsubstituted or substituted by a cyclopropyl group). The spiro compound described in the above (4), the tautomer of the compound or a pharmaceutically acceptable salt thereof. (6) Z1 expressions (ll-ι) to (11_8)

201211053

(wherein \ is independently an oxygen atom or a sulfur atom, and G represents a single bond, an oxygen atom or a sulfur atom,

In R1 and R3, R represents a hydrogen atom, OR11, NR hr12, C, .5 alkyl (the Cm alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3. m represents i 'when both R6 represent a hydrogen atom, the Cl-5 group is substituted by one or more substituents independently selected from the substituent group VIII), C0.9 alkyl (the C6-9 alkane) The group is unsubstituted or substituted by one or more substituents independently selected from the substituent group a3), C3.H cycloalkyl or 4 to 11 membered heterocycloalkyl (the Cm cycloalkyl group and 4 to 11 members) Heterocycloalkyl is a C6-10 aryl group or a 5 to 10 membered heteroaryl group (the C6_lc aryl group and the 5 to 10 membered heteroaryl group are 8-24-201211053 unsubstituted or independently selected from the substituent group A2 The cyclization is carried out by substituting one or more substituents, and the Cm cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from the group of substituents! Substituted), R3 represents a hydrogen atom or a CL3 alkyl group, or R1 and R3 are bonded to a nitrogen atom to which they are bonded to represent a 4 to 11 membered heterocycloalkyl group (the 4 to 11 membered heterocycloalkyl group is unsubstituted or 1 independently selected from the substituent group A i The substituents on the group),

R2 represents a Ci-5 alkyl group (the alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3. However, m represents 1, and when both R6 represent a hydrogen atom, the C! .5 alkyl is substituted by one or more substituents independently selected from the substituent group As), C6_9 alkyl (the C6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3) Substituted by a group), a Cm cycloalkyl group or a 4 to 11 membered heterocycloalkyl group (the c3_n cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are available as a Cl IG aryl group or a 5 to 1 member heteroaryl group). (The C6-ia aryl group and the 5-10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the ":^^ cycloalkyl group And the 4 to 11 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A), and R4 and R5 each independently represent a hydrogen atom or a Cu alkyl group. The spiro compound described in the above (5), a tautomer of the compound, or a pharmaceutically acceptable salt thereof. L1 represents Cu alkyl group, -25- (7) 201211053 L2 is a single bond, and Z1 represents a formula (II-l), (II-4) or (II-7) d3 j1 jl [Chemical 8]

Γλ «, human ^ into RlG1% into J1 R3 R4 r4 (wherein R1, R2, R3, R4, J1 and G1 represent the same as defined in (2) above) (2) or ( 3) A spiro compound as described, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (8) L1 represents C!.3 alkyl, L2 is a single bond, and Z1 represents a formula (ll-ι), (II-4) or (II-7).

(11-1) (IW) (II-7) (wherein R1, R2, R3, R4, J1, and G1 represent the same as defined in -26-201211053 described in (6) above) 6) A spiro compound as described, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (9) The spiro compound described in any one of the above (2) to (8), or the tautomer of the compound, wherein E is an oxygen atom, m is 1, and η is 〇, or pharmaceutically acceptable thereof Salt.

(10) The spiro compound described in any one of the above (2) to (8), or the tautomer of the compound, wherein Ε is an oxygen atom, and m is 2' η is 〇 or it is pharmaceutically acceptable Salt. (11) Τ Expression (VI-1) or (VI-2)

Person L4〆1·5'# person R1. (VI-1) (VI-2) (wherein, L4 represents Cu alkyl group, L5 represents a single bond, and R8 and R1Q represent the same as defined in the above (2)) (1) The spiro compound described in any one of the items, the tautomer of the compound, or the pharmaceutically acceptable salt thereof, -27 - 201211053. (12) Z1 represents formula (II-1), (II-4) or (II-7)

(In the formula, R1 and R3, R1 represents a Cu-based group (the Ci.6 yard is replaced by a 4- to 7-membered oxygen-containing heterocyclic or -NHChC^CKCi.6 alkyl)). R3 represents a hydrogen atom. Or R1 represents a Cu alkyl group (the C alkyl group is a C6.1() aryl group or a 5~1 杂 heteroaryl group (the Ce-io aryl group and the 5 to 10 membered heteroaryl group are available with 4 to η a heterocycloalkane (the 4 to 11 membered heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the C6 1 aryl group and 5 to 10 are condensed. The heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group As), and the c" can be independently selected from the group consisting of a trans group, a halogen atom and a cyanogen. Substituted by more than one substituent in the group) 'R3 represents a hydrogen atom, or R1 represents a 4~η member nitrogen-containing heterocyclic compound (the 4~u member nitrogen-containing heterocyclic-28-201211053 Ci_3 院基(The Cl·3 fluorenyl group is a phenyl group (this group is unsubstituted or independently selected from -c(=o)och3, cyano, nitro, -sch3, -ocf3, -〇ch3, chlorine Substituted by one or more substituents of a group of -CF3 and -CH3) or cyanide Any of a group) or - 0 (= 0) 0 ((^ - C6 alkyl) any - are substituted), R3 represents a hydrogen atom, or

R1 and R3 are combined with the nitrogen atom to which they are bonded, and represent a 4 to n member nitrogen-containing heterocycloalkyl group (the 4 to 11 member nitrogen-containing heterocycloalkyl group is independently selected from one or more substituent groups A i Substituted by a substituent), R2 represents a Cu alkyl group (the Q.6 alkyl group is substituted by 4 to 7 members of an oxygen-containing heterocycloalkyl group or -NHCfC^CKCu alkyl group), R4 represents a hydrogen atom, and J1 represents oxygen. The spiro compound, the tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of the above items (2) to (11), wherein the atom, G1 represents a single bond or an oxygen atom. . (13) Z1 represents the formula (11-1), (II-4) or (II-7) [Chemical 1 2]

201211053 (wherein, R1 and R3 indicate that the R table is not 0丨_6垸 base (the Ci·6 yard base can be 4~7 members of the oxygen-containing heterocyclic base or - NHC(= 〇)〇(Ci-6) Substituted), r3 represents a hydrogen atom, or R1 represents a 5 to 7 membered nitrogen-containing heterocycloalkyl group (the 5 to 7 membered nitrogen-containing heterocycloalkyl group may be derived from a phenyl group (the Cl_3 alkyl group may be derived from a phenyl group) The phenyl group is unsubstituted or one or more groups selected from the group consisting of -C(= 〇)〇CH3, cyano, nitro, -SCH3, -〇CF3, -OCH3, chlorine atom, -CF3 and -CH3 Substituted by a substituent) substituted), R3 represents a hydrogen atom, or R1 and R3 are combined with a nitrogen atom to which they are bonded to represent a 5 to 7 member nitrogen-containing heterocycloalkyl group (the 5 to 7 member) The nitrogen-containing heterocycloalkyl group is substituted by one or more substituents independently selected from the substituent group Ai), and R represents a C丨_6 yard base (the Ci-β yard group is composed of 4 to 7 members of an oxygen-containing gas Any one of the above (2) to (12), which is substituted by a cycloalkyl group or a -NHCbCOCKC^alkyl group, wherein R4 represents a hydrogen atom, and J1 represents an oxygen atom, and G1 represents a single bond or an oxygen atom. a spiro compound, a tautomer of the compound, or a pharmaceutically acceptable Accepted salt. (14) Z1 expression (II-1) or (II-4) -30- 201211053 [Chemical 1 3]

(wherein, in R1 and R3, R1 represents a Cm alkyl group (the Cl-6 alkyl group is a c6-1() aryl group or a 5~u member heteroaryl group (the C6-1Q aryl group and 5 to 10 member hetero The aryl group is condensed with 4 to 7 membered oxacyclohexanes (the 4 to 7 membered oxacyclohexanes are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2) And the C6-1G aryl group and the 5-10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the Ci 6 yard group can be independently selected Substituted by one or more substituents in a group of a hydroxyl group, a halogen atom and a cyano group, R3 represents a hydrogen atom, or R1 represents a 4-11 member nitrogen-containing heterocycloalkyl group (the 4_n member nitrogen-containing heterocycloalkyl group) Substituted by -C( = 〇)〇(Cl_6 alkyl)), R3 represents a hydrogen atom, or R1 and R3 are bonded to the nitrogen atom to which they are bonded to represent a tetrahydroindenyl group (the tetrahydroindenyl group) To be substituted by one or more substituents independently selected from the substituent group Αι, R4 represents a hydrogen atom,

The spiro compound-31 - 201211053 according to any one of the above (2) to (12), the tautomer of the compound, or the pharmaceutically acceptable salt thereof (15) T represents formula (VI-1) or (VI-2) [chemical 1 4] person L4〆1^ person#. (VM) (VI-2) (wherein L4 represents (^-3 alkylene, L5 represents a single bond, and R8 and R1Q are each independently represented as C 6 · 1 0 aryl or 5 -1 含 aza-containing The aryl group (c 6 - i aryl group and 5-1 member nitrogen-containing heteroaryl group is unsubstituted or independently selected from a fluorine atom, C, -3 alkyl group (the C 3 alkyl group is composed of one or more) The spiro compound according to any one of the above items (2) to (1), wherein the fluorine atom is substituted by a fluoro group, and the cyano group is substituted with one or more substituents, a tautomer of a compound, or a pharmaceutically acceptable salt thereof. (16) T represents a formula (VI-1) or (VI-2) [Chem. 15] /nv, l5v human R1. (VI-1 (VI-2) • 32- 201211053 (wherein L4 represents Cu alkyl group, L5 represents a single bond, and R8 and R10 each independently represent a phenyl or pyridyl group (the phenyl and pyridyl groups are unsubstituted or Any one selected from the group consisting of a fluorine atom 'Ci -3 alkyl group (the Cl-3 alkyl group is substituted by one or more fluorine atoms) and one or more substituents in which the cyano group is substituted)) (2) The spiro compound described in any one of (I5), the tautomer of the compound, or It can be pharmacologically acceptable salt thereof.

(17) T represents formula (VI-1) or (VI-2) [Chem. 1 6] Human L4〆1^ Person R1. (VI-1) (VI-2)

(wherein, L4 represents a Cw alkyl group, and L5 represents a single bond 'R8 and Ri〇 are each independently represented by a phenyl group (the phenyl group is composed of 1 or 2 c, -3 alkyl groups (the Cl. 3 A spiro compound according to any one of the above items (2) to (16), or a tautomer of the compound, or a cyano group substituted by one or more cyano groups, or a cyano group, or Its pharmaceutically acceptable salt. T represents the formula (VI-1) or (VI-2) -33- (18) 201211053 [Chem. 1 7] Human R1. (VI-2) Person I 4〆1·5,

LV (VI-1) (where L4 denotes c ^ t mountain class one #其(9)~丨, 3 extension yard base, L5 denotes single bond, R8 and R丨Q each stand alone = this base is one The above phenyl group substituted by a fluorine atom is substituted by a Cm alkyl group [兮p ^ C, -3 alkyl group substituted by more than one fluorine atom) or a cyano group (substituted)) (2) to ( 16) A spirocyclic Q material contained in any one of the above, a tautomer of the compound, or a salt acceptable for the drug. (19) Z1 represents Formula (II-1) or (II-4) [Chem. 1 8]

(wherein, in R1 and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded, and 5 to 7 members are contained in -34-201211053. The nitrogen-containing heterocycloalkyl group is independently selected from phenyl group, The aryl group is unsubstituted or consists of a monoazinocycloalkylene group (the 5 5-10 membered heteroaryl group (the phenyl group and the 51 fluorene group are selected from an alkyl group (the cm alkyl group is unsubstituted or consists of more than one) Substituted by a fluorine atom, one or more substituents of a group of dentate atoms and cyano groups) -c( = 〇)〇R13 > -C( = 0)R", -OR1 -NR12R13, halogen atom And substituted by more than one substituent of a group of cyano groups), R12 represents a hydrogen atom,

R represents a C 6 alkyl group (the alkyl group is unsubstituted or substituted by more than one fluorine atom), a Cho aryl group or a 5 to 10 membered heteroaryl group (the C 6-1 aryl group and 5 〜 1 〇 杂 芳The group is unsubstituted or substituted by one or more selected from the group consisting of Ci3 alkyl (the h·3 fluorenyl group is unsubstituted or substituted by more than one fluorine atom), halogen atom, cyano group and -ORl4 Any one of the substituents, R14 represents a CL3 alkyl group (the d-3 alkyl group is unsubstituted or substituted by one or more halogen atoms),

The spiro compound according to any one of the above (2) to (1 3 ) ' or (1 5) to (1 8), or a tautomer of the compound, or A pharmaceutically acceptable salt. (20) Z1 expression (II-1) or (II-4) -35- 201211053 [Chemical 1 9]

(wherein, in R1 and R3, R represents a Ci·3 fluorenyl group (the Ci·3 yard group is composed of a phenyl group, a fluorene d group, a furyl group or a decyl group (the phenyl group, the fluorene group, the thiol group, The furyl group and the iso-D-decyl group are condensed by an oxocycloalkane independently selected from 4 to 7 members, and the phenyl 'pyridyl group, furyl group and isoxazolyl group are unsubstituted or halogen atoms, a cyano group, a Cl_3 alkyl group (which is substituted by one or more fluorine atoms) and one or more substituents in which _0 (Ci3 alkyl group) is substituted), R3 Represents a gas atom, or R1 represents a Ci3 subunit (the Ct-3 alkyl group is a phenyl, pyridyl or furyl group (the phenyl, pyridyl and furyl groups are compatible with 4 to 7 members of an oxygen-containing heterocyclic ring). The alkane is condensed, and the phenyl, pyridyl and furyl groups are unsubstituted or independently selected from a halogen atom, a cyano group and a Ci.3 alkyl group (the Ci.3 alkyl group is substituted by one or more fluorine atoms) Any one of the substituents substituted by one or more of the groups is substituted, and the α·3 alkyl group is substituted by one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group. ), R3 means a hydrogen atom, R4 represents a hydrogen atom, and J1 represents an oxygen atom, and any of the above (2) to (12) or (Μ) to (1S) is a spiro compound of any of the items -36 to 201211053, A tautomer of the compound, or a pharmaceutically acceptable salt thereof. (21) Z1 expression (Π-1) or (II-4) [化2 0]

(where, R1 and R3

R1 and R3 are the nitrogen atom to which they are bonded, and represent a piperidinyl group, a thiol group, a homologous piperidinyl group or a homologous piperazine (the piperidinyl group, piperazinyl group, homologous piperidinyl group and homologous piperazine). The group is substituted by one or more substituents independently selected from the group consisting of _c(= 〇)〇Ri3, -C(=0), R13, -OR", -Nr12r13, a halogen atom and a cyano group), R12 Represents a hydrogen atom' R13 represents C, -6 alkyl (the C, -6 alkyl group is unsubstituted or substituted by more than one fluorine atom), phenyl or azo π group (the phenyl group and the phenyl group) Substituted or substituted by one or more substituents selected from the group consisting of Ci_3, which is unsubstituted or substituted by more than one fluorine atom, halogen atom, cyano group and alkyl group Any one of -37-201211053 R4 represents a hydrogen atom, and J1 represents an oxygen atom), the spiro compound described in the above (19), a tautomer of the compound, or a pharmaceutically acceptable thereof. Salt (22) Z1 indicates

Formula (II-1) or (II-4) [Chem. 2 1]

R3

R1V (IM) (where R1 and R3,

R1 and R3 are combined with the nitrogen atom to which they are bonded to represent piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl (the piperidinyl, piperazinyl, homopiperidinyl and homopyrazine) The base is a phenyl group, a pyridyl group, an oxadiazolyl group, a benzimidazolyl group, a benzoisoxazolyl group or a quinolyl group (the phenyl group, pyridyl group, chemodiazole group, benzimidazolyl group, benzohistylene group). The oxazolyl quinolinyl group is unsubstituted or is grouped by an alkyl group independently selected from C..3 alkyl (the d-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom and a cyano group. The spiro compound described in the above (19), which is substituted by one or more substituents, wherein R4 represents a hydrogen atom, -38-201211053 j1 represents an oxygen atom, and the mutual mutation of the compound A construct, or a pharmaceutically acceptable salt thereof. (23) Z1 represents formula (II-1) or (II-4)

[Chemical 2 2]

(wherein, in R1 and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded to represent a tetrahydroindolyl group (the tetrahydroindenyl group is unsubstituted or independently selected from -C( = 0) 0R13, -c(= 0)n13' _OK13> _NR12R13, one or more substituents in which a halogen atom and a cyano group are substituted), R12 represents a hydrogen atom, and R13 represents a C, -6 alkyl group, benzene Or pyridyl (the phenyl and pyridyl groups are unsubstituted or are selected from the group consisting of C^3, which is unsubstituted or substituted by more than one fluorine atom)' halogen atom, cyano group And any one of (2) to any one of _0 ((: 13 alkyl) substituted by one or more substituents), R4 represents a hydrogen atom, -39-201211053 j 1 represents an oxygen atom) The spiro compound described in any one of (2), the tautomer of the compound, or a pharmaceutically acceptable salt thereof (24) L1 is a Cm alkyl group,

L2 is a single bond, E is an oxygen atom, m is an integer of 1 or 2' R6 is a hydrogen atom, η is 〇, τ is a formula (νι-υ or (VI-2) [Chem. 2 3] Human L4/L5\ R8 Λ (V1-1) R10 (VI-2)

(wherein, L4 represents a Ci-3 alkylene group, L5 represents a single bond, and R8 and r1<) represent the spiro compound described in the above (1) in the same meaning as defined in the above (1). a tautomer of the compound, or a pharmaceutically acceptable salt thereof. 8 -40 - 201211053 (25) Z1 is expressed by (II-l) or (II-4) [Chem. 2 4]

R3

R1V

(丨丨-1) (II-4) (wherein, in R1 and R3, R1 represents C!-3 alkyl (the C^3 alkyl group is derived from a phenyl group or a pyridyl group (the phenyl group and the fluorenyl group) Substituted by C.6.), r3 represents a hydrogen atom, or R1 represents a piperidinyl group (the piperidinyl group is substituted by a C4-6 alkyl group), R3 represents a hydrogen atom, or R1 R3 is a nitrogen atom bonded to the same, and represents a piperidinyl group which is one or more substituents grouped independently of -C(=0)R13, -OR13 and _NR12R13. Substituting), R12 represents a hydrogen atom, R13 represents a phenyl or pyridyl group (the phenyl and pyridyl group is unsubstituted or substituted by a C4-6 alkyl group), R4 represents a hydrogen atom, and J1 represents an oxygen atom) The spiro compound according to any one of the above (1) or (24), a tautomer of the compound, or a pharmaceutically acceptable salt thereof. -41 - 201211053 (26) Z1 means Formula (II-l) or (II-4) [Chem. 2 5]

(wherein, in R1 and R3, R1 represents a Cm building group (the C1-6 alkyl group is substituted by 4 to 7 members of an oxygen-containing heterocycloalkyl group or a -= alkyl group), R3 represents a hydrogen atom, or R represents a Cm institute. The group (the Cl_6 alkyl group is independently selected from the group consisting of c6_1() aryl or 5 to 10 membered heteroaryl (the (:6·1() aryl group and the 5~1 杂 heteroaryl group is available with 4 to 7 members) The oxocycloalkane is condensed, and the c6.1Q aryl group and the 5~1 fluorene heteroaryl group are unsubstituted or independently selected from a halogen atom, a cyano group, and a Ci3 yard group (the 匕.3 alkyl group is Substituted in any of the substituents which are unsubstituted or substituted by more than one fluorine atom), -〇 (<^-3 alkyl), and (: 4/6 alkyl group is replaced by more than one substituent) And the Cl 6 alkyl group may be substituted by one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group, R 3 represents a hydrogen atom, or R represents a 4-11 member nitrogen-containing heterocycloalkyl group ( The 4_n member nitrogen-containing heterocyclic fluorenyl group is substituted by -0:(=0)0 (0:,.6 alkyl), R3 represents a hydrogen atom, or R1 and R3 are a nitrogen atom bonded to them.倂 represents tetrahydroindenyl or 5 to 7 membered nitrogen-containing heterocycloalkyl (the tetrahydroindenyl group and 5 to 7) Nitrogen-42-Fire 201211053 Heterocycloalkyl is selected from the group consisting of an independent glucone group, a 5·10 membered heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group), which is unsubstituted or Independently selected from the group consisting of a Cl-3 alkyl group (the Ci 3 alkyl group is unsubstituted or Φ, , , ^ _ or more than a fluorine atom), a halogen atom, and a cyano group in groups of more than one substituent Substituting), -C(=0)0R", COR 3 ' _0Rl3 ' _nr12r13, one or more substituents in which a halogen atom and a cyano group are substituted), R12 represents a hydrogen atom,

R is not a cu^-based (the Ci0-based group is unsubstituted or substituted by more than one fluorine atom), phenyl or pyridyl (the phenyl and pyridyl groups are unsubstituted or independently selected from C!·) Any one of a 3 alkyl group (the Cl-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom or a cyano group) substituted with one or more substituents, and R4 represents The spiro compound described in the above (1) or (24), wherein the hydrogen atom or J1 represents an oxygen atom, or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (27) T represents formula (VI-1) or (VI-2) [Chem. 2 6 ]

R1Q (VI-1) (VI-2) -43- 201211053 (wherein, L4 represents Cm alkyl, 15 represents a single bond, and R8 and R1Q each independently represent a phenyl or pyridyl group (the phenyl group and The pyridyl group is unsubstituted or substituted by one or more substituents independently selected from a fluorine atom, a Ci-3 alkyl group (the C1-3 alkyl group is substituted by one or more fluorine atoms), and a cyano group. The spiro compound according to any one of the above (1), (24) to (6), or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (28) T represents formula (VI-1) or (VI-2) [Chem. 2 7] Person L4'LV person R1. (VI-1) (VI-2) (wherein, L4 represents Cu alkyl group, L5 represents a single bond, and R8 and R1() each independently represent a phenyl group (the phenyl group is substituted by a C4-6 alkyl group) The spiro compound described in any one of the above (1), (2 4) to (6), or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (29) A spirocyclic compound according to any one of the above (2) to (23), wherein R6 is a hydrogen atom, or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. -44- (30) 201211053 X is a spiro compound as described in any one of the above items (1) to (3), (7), (9) to (29), and tautomerism of the compound. Or a pharmaceutically acceptable salt thereof. (31)

X is any of the above (1) or (2), (4) to (6), (8) to (29) which is a phenylene group, a pyridyldiyl group, a pyrazinediyl group, a thiophenediyl group or a thiophenediyl group. The spiro compound described in the above item, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (32) A spirocyclic compound according to any one of the above (1) to (3 1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, which is an adiponectin Activator. φ (33) The prevention, treatment, and improvement of a disease effective for adiponectin receptor activation by the adiponectin receptor-activated drug described in the above (32) as an active ingredient. (34) A metabolic syndrome of adiponectin receptor-activated drug according to the above (32), and a preventive or therapeutic agent for arteriosclerosis. -45-201211053 (35) A pharmaceutical containing a spiro compound described in any one of the above (1) to (3), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, as an active ingredient MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below. In the present specification, "η-" means positive, "s_ indicates second, "b" and "tert-" indicate third, and "0_" means adjacent m-" Indicates that 'p-' means that 'rac_' means racemate Ph' means phenyl'. "Py" means pyridyl, and "Me" means that "Et" is not ethyl. "Pr" is not. Base, "bu" means butyl Bocj means tert-butoxycarbonyl' "Ms" means methylsulfonyl, "P-toluenesulfonyl", "Tf" means trifluoromethanesulfonyl. "Halogen atom" indicates a fluorine atom, a chlorine atom, a desert atom, and a sec-substrate T: or iodine. The "4 to 11 membered heterocycloalkane" in the specification means 1) the atom constituting the ring is 4 to 11 2) The atom constituting the ring contains one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and 3) Is saturated or partially unsaturated, 4) may contain 1 to 3 carbonyl or thiocarbonyl groups in the ring, 5) when the atom constituting the ring contains a sulfur atom, the sulfur atom may be sub-46-201211053 sulfonyl Or the sulfonic acid group 6) represents a monocyclic system, a condensed ring system, a crosslinked ring system or a spiro ring system non-aromatic heterocyclic ring. Specific examples of the "4 to 1 1 membered heterocycloalkane" include, for example, [Chem. 2 8].

Wait. 47-201211053 m stomach-to-gastric sputum 4 to 11-membered heterocycloalkyl" means a monovalent substituent of one hydrogen hydrazine taken out from "4 to 11-membered heterocycloalkyl j." "In the above-mentioned definition, the heterocyclic alkyl group of the 11-membered heterocycloalkyl group" is a type in which the hetero atom contained in the atom constituting the ring is one type of oxygen atom. The specific example of the group is exemplified by [Chem. 2 9] 9 ° 99 9 47 broken and so on. The "4 to 7 member oxygen-containing heterocycloalkyl group" is a group of 4 to 7 atoms constituting the ring in the above definition "4 to 11 member oxygen-containing heterocycloalkyl group". The "4- to 4-membered nitrogen-containing heterocycloalkyl group" is a group of the "4 to 11 membered heterocycloalkyl group" defined above, and the hetero atom contained in the atom constituting the ring is a nitrogen atom. A specific example of the base 'is exemplified by [Chemical 3 0 ]

-48 - 201211053

The "5 to 7 member nitrogen-containing heterocyclic compound group" means the "4 to 11 member nitrogen-containing heterocycloalkyl group" defined above, and the atom constituting the ring is 5 to 7. The "4 to 11 member oxygen-containing nitrogen-containing heterocycloalkyl group" is a member of the above-mentioned definition "4 to 11 membered heterocycloalkyl group", and the hetero atom contained in the atom constituting the ring is an oxygen atom and a nitrogen atom. Specific examples of the base include, for example,

The "4 to 11 member sulfur-containing nitrogen-containing heterocycloalkyl group" is a member of the above-mentioned definition "4 to 11 membered heterocycloalkyl group", and the hetero atom contained in the atom constituting the ring is a sulfur atom and a nitrogen atom. Further, the "4 to 11 member sulfur-containing nitrogen-containing heterocycloalkyl group" means a mono-oxide body and a dioxide body which also contain a sulfur atom. Specific examples of the base include, for example, -49-201211053 [Chemical 3 2] n v° by '9' and the like. The "5 to 10 membered heteroaryl group" means 1) the atom constituting the ring is 5 to 1 ' ' 2), and the atom constituting the ring contains one or more selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Heteroatom '3) A monocyclic or bicyclic aromatic heterocyclic ring. Specific examples of the "5 to 10 membered heteroaryl group" include, for example, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, benzotriazole, pyrazole, and imidazole. ,benzimidazole, anthracene, isoindole, pyridazine, anthracene, oxazole, quinoline, isoquinoline 'pyridazine, pyridazine, quinoxaline, oxazoline, porphyrin, pteridine, imidazolium [l,5-a][l,3,5]triazine, pyrazino[2,3-d]pyridazine, imidazo[4,5-b]pyridine, imidazo[l,2-a] Pyrimidine, pyrazolo[l,5-a]pyrimidine, furan, pyran, benzofuran, isobenzofuran, thiophene, benzothiophene, thiazole, isothiazole, benzothiazole, benzothiadiazole, iso Oxazole, oxazole, benzoxazole, oxadiazole, pyrazolo[3,4 · d μoxan, imidazo[4,5-d]thiazole, thieno[3,2_b]furan, thiophene [2,3-c] pyrazole, [1,4] dioxo[2,3-b]pyridine, etc. Further, when the "5 to 10 membered heteroaryl group" has a C=n double bond, it also contains The N-oxide body. The "5 to 10 membered heteroaryl group" means a monovalent substituent in which one hydrogen atom is removed from the "5 to 1 member heteroaryl group" defined above. -50- 201211053 The so-called "C6-10 square base" does not 1) The atoms constituting the ring are 6 to 10 ' 2) The atoms constituting the ring are all carbon atoms, 3) Monocyclic or bicyclic aromatic hydrocarbons ring. Specific examples of the "C6-1G aryl group" include benzene, pentylene, naphthalene, anthracene and the like.

The "C6-1Q aryl group" means a monovalent substituent in which one hydrogen atom is removed by the above definition "C6-1Q aryl group". In the present specification, the "C^3 alkyl group" means a methyl group, an ethyl group, a propyl group or an isopropyl group. The "Ci-6 alkyl group" means a monovalent substituent having 1 to 6 carbon atoms and one hydrogen atom removed by a linear or branched saturated hydrocarbon. Specific examples of the group include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a new one. Pentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpyridylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethyl Butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-B Alkyl-1-methylpropyl, 1-ethyl-2-methylpropyl, and the like. The "Ci-9 alkyl group" means a monovalent substituent having 1 to 9 carbon atoms in which one hydrogen atom is removed by a linear or branched saturated hydrocarbon. The "(^-5 alkyl group) represents a monovalent substituent in which one hydrogen atom is removed by a linear or branched saturated hydrocarbon in the range of 1 to 5 carbon atoms. -51 - 201211053 The so-called "c4_6 alkyl group" means The number of carbon atoms is 4 to 6, and a monovalent substituent of one hydrogen atom is removed by a linear or branched saturated hydrocarbon. The "C6-9 alkyl group" means a carbon number of 6 to 9 and is composed of a linear chain. A monovalent substituent in which one hydrogen atom is removed by a saturated hydrocarbon. The so-called "C3-6 ring" means that 1) atoms constituting the ring are 3 to 6, and 2) atoms constituting the ring are carbon atoms, 3 ) An aliphatic hydrocarbon ring of "single ring system" or "crosslinked ring system". Specific examples of the "C3.6 naphthene" include cyclopropane, cyclobutane, cyclopentane, and cyclohexane. The "C30! naphthenic acid" means that the atoms constituting the ring are 3 to 11 in the U, 2) the atoms constituting the ring are all carbon atoms, and 3) the "monocyclic system", the "condensed ring system", and the "crosslinked ring system". Or a "spirocyclic hydrocarbon" aliphatic hydrocarbon ring. Specific examples of the "C3-M naphthenic acid" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloglycan. Alkane, cyclooctane, adamantane, bicyclo[3.1.0]octane, bicyclo[2.2.1]heptane, spiro[5.5]undecane, and the like. The "C3-M cycloalkyl group" means a monovalent substituent in which one hydrogen atom is removed by the above-mentioned "C3.H cycloalkane". The "C3_4 cycloalkyl group" means that the "C3-u cycloalkyl group J" has 3 to 4 atoms constituting the ring. The "C2-3 alkenyl group" means vinyl group, prop-1-ene-1. -Based 'C-2-52-201211053 Dil-1-yl or propan-1-iso-2-yl. The "c2-6 alkenyl group" means 1) a carbon number of 2 to 6 and 2) a monovalent substituent having one or more double bonds and one hydrogen atom removed from a linear or branched unsaturated hydrocarbon. .

Specific examples of the group include, for example, a vinyl group, a prop-1-en-1-yl group, a propan-2-iso-1-yl group, a prop-1-yl-2-yl group, and a butyl-1-iso- 1-yl, but-2-zil-1-yl, but-3-zhen-1-yl'pent-1-yept-1-yl, pent-4-iso-1-yl, hex-1-fuel- 1-yl, hex-5-pyring-1-yl, 4-methylpent-3-y-1-1-ylpenta-2,4-di-di-1-yl and the like. The term "Cn! cycloalkane" means 1) the atoms constituting the ring are 3 to 11, 2) the atoms constituting the ring are all carbon atoms, 3) have one or more double bonds, and 4) "single ring system", An aliphatic hydrocarbon ring of "condensed ring system", "crosslinked ring system" or "spirocyclic system". Specific examples of the "cycloalkenes" include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexane. Alkene, cycloheptene, cyclooctene, anthracene, 4·cyclooctadiene, 1,2,3,3a,4,6a-hexahydropentene, (1R,4S)_bicyclo[2.2.1] Hept-2-ene, spiro[5.5]undec-2-ene, and the like. The "C^h cycloalkenyl group" means the above-mentioned definition "C3. anthracene olefin". A monovalent substituent which removes one hydrogen atom - 53 - 201211053 The so-called "c2.3 alkynyl group" means ethynyl group, propan-1- Alkyn-1-yl, alkyn-1-yl. The "(^.3 alkylene group)" means a divalent substituent which further removes one hydrogen atom at an arbitrary position in the above-mentioned "C, .3 courtyard. To cite a specific example of the base, Examples of the methyl group, the group, the propyl-1,3-diyl'propane-2,2-diyl group, etc. The so-called "C, -6 alkylene group" means the above definition "(^.6 alkane further) A divalent substituent of a hydrogen atom at an arbitrary position is removed. Specific examples of the group include methyl, extens, propane-1,3-diyl and propane-2,2-di. Base, 2,2-dimethyl-propan-1,3-dihexane-1,6-diyl, 3-methylbutane-1,2-diyl, etc. "C3-H cyclohexane The "base" represents a divalent enthalpy of further removing a hydrogen atom at an arbitrary position from the above-mentioned "C3·alkyl group". Specific examples of the group include cyclopropane-1,1_ and a ring. Propane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,4-, cyclohexane-1,1-diyl, bicyclo[2.2.1]heptane- 2,5-diyl, [3.3.0]octane-2,5-diyl, spiro[5.5]undecane-3,9-diyl, etc. The so-called "C3-u cycloalkenyl group" means "C3-alkenyl" as defined above Further, the removal of a hydrogen atom at an arbitrary position is referred to as "C6-1() extended aryl group", and the "C6-l0" defined above is used to remove one hydrogen atom at any position. The specific example of the divalent substituent is exemplified by a phenyl group, a naphthyl-2-yl group, an ethylidene group, and a 1 1 cycloalkyldiyldiyl ring TUU 1 . 1 Cycloalkylaryl 0-2,6--54- 201211053 Diyl, etc. The so-called "5 to 10 member heteroaryl" means that one of the "5 to 10 membered heteroaryl groups" defined above is further removed. A divalent substituent of a hydrogen atom at an arbitrary position. Specific examples of the group include pyridine-2,5-diyl, pyrimidine-2,4-diyl, pyridazine-3,6. - Diji and so on.

The "C2-3 extended alkenyl group" means a divalent substituent in which one hydrogen atom at an arbitrary position is further removed from the "C2_3 alkenyl group" defined above. The "C2-3 alkynyl group" is a divalent substituent in which one hydrogen atom at an arbitrary position is further removed from the above-mentioned definition "C2-3 alkynyl group". Next, preferred configurations of the respective substituents in the present invention are given. Preferred in E is an oxygen atom. In L1, Cyalkyl, C2-3 extended alkenyl or C2-3 extended alkynyl (the Cw alkyl, C2-3 extended alkenyl and C2-3 extended alkynyl are unsubstituted or by cyclopropyl) Substituting) is preferred, preferably C, -3 alkylene, more preferably methyl. In L2, a single bond or a C, _3 alkyl group is preferred, and a single bond or a methyl group is preferred, and a single bond is more preferred. A preferred example of X is a C3-U cycloalkyl group, preferably a cyclohexanediyl group, more preferably a cyclohexane-1,4-diyl group. As another preferable example of X, a C6_1G extended aryl group (the C6.10 aryl group is unsubstituted or substituted by a methoxy group) or a 5~10 member heteroaryl group is preferable. Or a thiophenediyl group or a pyridyldiyl group, more preferably a phenylene group. A hydrogen atom is preferred in R4. R6 is preferably each independently represented by a hydrogen atom or a C!_3 alkyl group, and preferably -55 to 201211053 is a hydrogen atom or a methyl group, more preferably a hydrogen atom. In R7, it is preferred to independently represent a methyl group. Preferable examples of τ include the formula (VI-1) or (VI-2). (VI-1) (VI-2)

(wherein L4 represents Cu alkyl group, L5 represents a single bond, and R8 represents a phenyl or pyridyl group (the phenyl and pyridyl groups are unsubstituted or independently selected from C!-6 alkyl, fluorine atom, C) • a 3 alkyl group (the C alkyl group is substituted by one or more fluorine atoms) and one or more substituents in a group of cyano groups, and R 1 G represents a phenyl group and a pyridyl group (the phenyl group and the pyridine group). The group is unsubstituted or one or more groups independently selected from the group consisting of <^_6 alkyl group, fluorine atom, Cu alkyl group (the C!_3 alkyl group is substituted by i or more fluorine atoms) and a cyano group. Any one of the C3-11 ring groups in which the substituent is substituted or the C6_l aryl group is condensed. Preferred examples of Z1 include the formula (ΙΠ-1), (in-2) or (III-3).

(111-3) 8 -56 - 201211053 (wherein, in R1 and R3, R1 represents a Cu-based group (the CUe alkyl group is substituted by a 4-h-membered heterocycloalkyl group or a -NHChWWCu alkyl group), R3 Any one of a hydrogen atom and G1 represents a single bond or an oxygen atom. Preferably, it is a formula (111·), (111_2) or (ΙΠ_3)

[化3 5] R1

P-1) (川-2) (HJ-3) (wherein, in R1 and R3, R1 represents a Cu alkyl group (the C, _6 alkyl group is composed of 4 to 7 members of an oxygen-containing heterocycloalkyl group or -NHCbC^) CUC, .6 alkyl) is substituted, R3 represents a hydrogen atom, and (1) represents either a single bond or an oxygen atom. As another preferable example of Z 1 , a formula (11丨_ i _ 2) or

(川-1) (HI-2) (III-3) (wherein, R1 and R3, R1 represents a 4 to 11 membered heterocycloalkyl group (the 4 to 11 membered heterocycloalkyl group is a C3-alkyl group) (The C,-3 alkyl group is derived from a phenyl group (the phenyl group is unsubstituted or independently selected from _-57-201211053 C(=0)0CH3' cyano, nitro, _SCH3, _OCF3, _OCH3, chlorine atom And one or more substituents of -CF3 and -CH3 are substituted by a substituent), R3 represents a hydrogen atom, and G1 represents a single bond or an oxygen atom. Preferably, it is a formula (111-1), (III-2) or (III-3).

(wherein, in R1 and r3, R1 represents a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered azacycloalkane c^3 alkyl group (the Ci3 alkyl group is a phenyl group (the phenyl group is Substituted or substituted by one or more substituents selected from the group consisting of _c( = 〇)och3, cyano, nitro, _sch3, -ocf3, -och3 'chlorine, -CF3 and -ch3 Substituted by)), R3 represents a hydrogen atom, and G1 represents a single bond or an oxygen atom. In particular, as a more preferable 5- to 7-membered nitrogen-containing heterocycloalkyl group, an MD group may be used, and a piperazinyl group may be used. , the homologous piperidinyl or homologous piperazinyl. As another preferable example of Z1, a formula (ΙΙΙ-1) or (ΙΙΙ-2) can be cited.

58- 201211053 (wherein R1 and y, -, R is a nitrogen atom bonded to them, and 4 to 11 members of the heterocyclic alkyl group are represented by the heterocyclic alkyl group. An alkyl group, a phenyl group, a 5-10 membered heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or are independently selected from a Cl.3 alkyl group (the Ci-3 alkyl group is unsubstituted or consists of one) Substituted by the above gas atom), substituted by one or more substituents of a group of a halogen atom and a cyano group), -C(=0)0R13, -C(=0)R13, -OR13, -NR12R13, dentate Substituted by one or more substituents of a group of atoms and cyano groups, R represents a nitrogen atom, and Rl3 represents a C6.1G aryl group or a 5 to 10 membered heteroaryl group (the C6-1Q aryl group and 5 to 10) a heteroaryl group which is unsubstituted or independently selected from (^.3) (the C--3 alkyl group is substituted by more than one fluorine atom), Ci6 alkyl group, dentate atom and cyano group Any one of the above-mentioned substituents is substituted by any of the above substituents. Preferably, it is a formula (m) or (ΙΠ_2)

[化3 9]

(wherein, in R1 and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded, and are represented by independently selected from tetrahydroindenyl, 5 to 7 membered nitrogen-containing heterocycloalkyl or 4 to 11 members. Oxygen nitrogen-containing heterocycloalkyl (the tetrahydroindenyl group, 5 to 7 membered nitrogen-containing heterocyclic group, and 4 to 11 membered oxygen-containing nitrogen-containing heterocycloalkyl group independently selected from Ci-6 alkyl group, phenyl group 5-10 member-59-201211053 Heteroaryl (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or independently selected from C..3 alkyl (the Cl.3 alkyl group is unsubstituted or Substituted by one or more fluorine atoms, one or more substituents in which a halogen atom and a cyano group are grouped), -C(=0)0R13, = -〇Rl3, nr12r13, halogen oxime and cyano group Substituted by more than one substituent in the group), R12 represents a hydrogen atom, and R13 represents a C6.1G aryl group or a 5-10 membered heteroaryl group (the c6.1Q aryl group and the 5-10 membered heteroaryl group are Unsubstituted or substituted by one or more substituents independently selected from the group consisting of a C3 alkyl group (the C.3 alkyl group is substituted by one or more fluorine atoms), a (^-6 alkyl group, a halogen atom, and a cyano group) Any one of them) and preferably of formula (III-1) (III-2) [Formula 40]

(111-1) (111-2) (wherein, in Ri and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded to represent a tetrahydroindenyl group or a 5 to 7 membered nitrogen-containing heterocycloalkyl group. (The tetrahydroindenyl group and the 5-7 membered nitrogen-containing heterocycloalkyl group are independently selected from the group consisting of q alkyl, phenyl, 5-10 membered heteroaryl (the phenyl group and the 5-10 membered heteroaryl group are none Substituting, or substituted by one or more substituents independently selected from the group consisting of Ci3 alkyl (the C!·3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom and a cyano group; _C( = 0)0Ri3, -C( = 0)W3, -OR13, _nr12r13, halogen atom and cyano group -60- 201211053

Substituted by one or more substituents), R12 represents a hydrogen atom, and R13 represents a Cl.3 alkyl group (the C,-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) 'C6-1Q aryl group Or a 5 to 10 membered heteroaryl group (the Cu. aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from (^_3 alkyl group (the Q.3 alkyl group consists of more than one fluorine atom) Any of the substituted), (^-6 alkyl, halogen atom, and one or more substituents in which the cyano group is substituted), as a particularly preferred 5- to 7-membered nitrogen-containing heterocycloalkyl group. Specific examples include piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl. Other preferred examples of Z1 include formula (111_1) or (111_2). -1)

(where R1 and R3,

R1 represents a <^.6 alkyl group (the Cu alkyl group is composed of a C6_1() aryl group or a 5 to 10 membered heteroaryl group (the C6-1Q aryl group and the 5 to 10 membered heteroaryl group are available with 4 to 7). The oxocycloalkane is condensed, and the C 6-1Q aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from a C 4-6 alkyl group, a halogen atom, a cyano group, a Cm alkyl group (the C10) The alkyl group is unsubstituted or substituted by one or more fluorine atoms) and substituted with one or more substituents of a group of -(Cu3 alkyl), and the C, 6 alkyl group may be independently selected. Substituted by one or more substituents in which a group of a hydroxyl group, a halogen atom, and a cyano group is substituted, and R3 represents a hydrogen atom) -61 - 201211053. Preferably, it is a formula (ΙΙΙ-l) or (III-2) [Chemical 4 2]

0 R3 Η (111-1) (III-2) (wherein R1 and R3, R represents not Ci.3 yard base (the Ci.3 焼 base is derived from phenyl, lyophilyl, fluorenyl or Isoxazolyl (the phenyl, pyridyl, furyl and isoxazolyl groups are condensed with 4 to 7 members of the oxacyclohexane, and the phenyl, pyridyl, furyl and isoxazolyl groups Is unsubstituted or independently selected from C4_6 alkyl, halogen atom, cyano, C, . . . alkyl) (the Cl 3 alkyl is unsubstituted or substituted by more than one fluorine atom) and -0 ((^- Any one of the three alkyl groups substituted by one or more substituents, and the C 3 -3 alkyl group may be one or more selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Substituted by a substituent), R3 represents a hydrogen atom). As another preferred example of Z1, a formula can be cited.

(111-1) (III-2) (wherein R1 and R3, -62 - 201211053 R1 represents a 4- to 11-membered heterocycloalkyl group (the 4-n-membered heterocycloalkyl group is derived from -C (= 0) ) 0 (Ci·6 yard base) can be substituted for ''R3 represents a hydrogen atom). Preferably, it is of formula (III-1) or (III-2)

[4 4]

(111-1)

(wherein, in R1 and R3, R1 represents a 4-11 member nitrogen-containing heterocycloalkyl group (the 4-11 member nitrogen-containing heterocycloalkyl group is derived from - (: ( = 0) 0 (0, -6 alkyl group) And R3 represents a hydrogen atom. Any of the more preferable examples of the 4-11 member nitrogen-containing heterocycloalkyl group is a tetrahydroindenyl group, a pyrrolidinyl group or a piperidinyl group. Base, homologous piperidinyl or homologous piperazine.

Examples of preferred compounds of the spiro compound of the present invention include the structures shown below. (1) Formula (1) [Chem. 4 5]

-63 - 201211053 [In the formula (I), E represents an oxygen atom, L1 represents a Cu alkyl group, a C2-3 alkylene group or a C2-3 alkynyl group, L2 represents a single bond or a Cu alkyl group, and X represents Cm. Cycloalkylene 'C6-1G extended aryl (the C6_1G extended aryl is unsubstituted or substituted by methoxy) or 5 to 10 membered heteroaryl, Z1 represents formula (III-1), (III -2) or (III-3) [Chem. 4 6]

(III-1) (111-2) (111-3) (In the formula, R1 and R3, 111 is not awkward: 1.6 yard base (the 0:1-6 yard base is composed of 4 to 7 members containing oxygen a cycloalkyl group, a C6.1Q aryl group, a 5 to 10 membered heteroaryl group (the C6.1Q aryl group and the 5 to 10 membered heteroaryl group are condensed with a 4 to 7 membered oxacyclohexane), and The C6_1 fluorenyl group and the 5~10 membered heteroaryl group are unsubstituted or independently selected from the group consisting of c4_6, dentate atom, cyano group, Cl.3 hospital base (the Cl.3 hospital base is unsubstituted or one by one) The above-mentioned fluorine atom is substituted) and - 〇 (Ci·3) is substituted by one or more substituents) or -NHC(=0)0((^-6 alkyl) Taking π, and the (^_6 alkyl group may be substituted by one or more substituents independently selected from the group consisting of a hydroxyl group and a halogen atom), R3 represents a hydrogen atom, or -64 - 201211053 R represents 4 to 11 members a nitrogen-containing heterocycloalkyl group (the 4- to n-membered nitrogen-containing heterocyclic compound is derived from a C 3 alkyl group (the C | 3 alkyl group is derived from a phenyl group (the phenyl group is unsubstituted or independently selected from -C) ( = 〇) 〇CH3, cyano, nitro, -SCH3, -〇CF3, -0CH3, .chlorine, -CF3 and -CH3 are replaced by one or more substituents) Or substituted by any of the substituted phenyl groups), R3 represents a hydrogen atom, or R and R are combined with a nitrogen atom to which they are bonded, and 4 to 11 members of the φ nitrogen-containing heterocyclic compound are used. (The 4-11 member nitrogen-containing heterocycloalkyl group is independently selected from Ci_6, phenyl, 5-10 membered heteroaryl (the phenyl and 5_1 member heteroaryl is unsubstituted) or is independently Substituted from a Cbs alkyl group (the Ci-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), substituted with one or more substituents in which a halogen atom and a cyano group are grouped), -C(= 〇) 〇R", _c(= 〇)r13, _〇r13, -NR 12R13, dentate atom and one or more substituents of a group of cyano groups are substituted), R12 represents a hydrogen atom, and ri3 represents a c6_1 fluorene group. Or 5~1 杂 heteroaryl (the C6.1G aryl group and the 5~1 杂 heteroaryl group are unsubstituted or independently φ selected from the Cl·3 yard group (the Ci-3 alkyl group is more than one) Any one of the substituents substituted by a fluorine atom, a G-6 group, a halogen atom, and a cyano group, and G1 represents a single bond or an oxygen atom), m represents 1, and R6 represents Hydrogen atom, η represents 0, Τ Expression (VI-1) or (νι·2) -65- 201211053 [Chem. 4 7] Person R1. (VI-2)

/xl^lV (VI-1)

(wherein, L4 represents no C i _3 stretching base group L5 represents a single bond, and r8 represents a phenyl or pyridyl group (the phenyl and pyridyl groups are unsubstituted or independently selected from the group consisting of Cl_6, fluorine atom, C, a -3 alkyl group (the C 3 alkyl group is substituted by one or more fluorine atoms) and one or more substituents in a group of cyano groups, and r1q represents a phenyl group or a pyridyl group (the phenyl group) And the pyridyl group is unsubstituted or one or more substituents independently selected from the group consisting of a Cu alkyl group, a fluorine atom, a Cu alkyl group (the C alkyl group is substituted by one or more fluorine atoms), and a cyano group. Substituting) or C6-1Q aryl for condensed ring C3.U cycloalkyl)]. The spiro compound is shown. (2) The spiro compound described in the above (1), wherein (3) is a spiro compound described in the above (1).

(4) The spiro compound described in any one of the above (1) to (3) wherein L2 is a single bond or a methyl group. (5) The spiro compound described in any one of the above (1) to (3), wherein L2 is a single bond. (6) The spiro compound described in any one of the above (1) to (5) wherein X is a cyclohexanediyl group (7) X is the above-mentioned (1) of cyclohexane-1,4-diyl The spiro compound described in any one of (5). 8 -66- 201211053 (8) X is the above-mentioned (1) to (5) of the pyridyldiyl group! The spiro compound described in the item. (9) The spiro compound described in any one of the above (1) to (5), wherein X is a thiophene-based group. (10) X is a spiro compound described in any one of the above items (1) to (5). (11) If R6 is a gas atom or a methyl group, it is recorded in any one of (1) to (1〇).

a spiro compound. (12) The spiro compound according to any one of the above (1) to (1), wherein R6 is a hydrogen atom. (13) T represents a spiro compound as described in any one of the above (1) to (12).

-67- 201211053 【化4 8】

Ch3 ch9

(wherein, in R1 and R3, R1 represents a Cu alkyl group (the C, -6 alkyl group is substituted by 4 to 7 members of an oxygen-containing heterocycloalkyl group or -NHChC^CKCM alkyl group), and R3 represents a hydrogen atom. The snail-68-201211053 ring compound according to any one of the above (1) to (13), wherein G1 represents a single bond or an oxygen atom. (15) 21 is a spiro compound described in the above (14), which is any of the structures shown below. [化5 0]

=丫.丫 〇 ch3 o ch3

(Ιό)Ζ1 indicates the formula (ΙΠ-1), (III-2) or (III-3) [Chemical 5 1]

(IN-1) (ΙΙΙ-2) (ΙΙΙ-3) wherein, in R1 and R3, R1 represents a 5 to 7 member nitrogen-containing heterocycloalkyl group (the 5 to 7 member nitrogen-containing heterocycloalkyl-69-201211053 Ei·3 hospital base (the Ci3 alkyl group is composed of a phenyl group (the phenyl group is unsubstituted or independently selected, C(= 〇)〇CH3, cyano, nitro, -SCHs, -ocf3, -och3, (1) to (13) in which a chlorine atom, a substituent of a group of -CF3 and -ch3 is substituted by one or more substituents), (a) is substituted with a hydrogen atom, and G1 represents a single bond or an oxygen atom) The spiro compound described in any one of the items. (17) The 5- to 7-membered nitrogen-containing heterocycloalkyl group is a spirocyclic compound described in the above (16), which is a piperidinyl group, a piperazinyl group, a homologous piperazine group or a homologous azine group.

(18) Z is a spiro compound described in the above (16), which is not in the following structure. [化5 2]

8 -70- 201211053 【化5 3】

(in-1)

(where R1 and R3,

R and R3 are combined with the nitrogen atom to which they are bonded, and represent a tetrakile fluorenyl group or a 5 to 7 membered nitrogen-containing heterocycloalkyl group (the tetrahydroindenyl group and the 5 to 7 membered nitrogen-containing heterocyclic fluorenyl group). Independently selected from C!-6, phenyl, 5-1, heteroaryl (the phenyl and 5-10 membered heteroaryl are unsubstituted, or independently selected from Ci3) (the 3 alkane) The group is unsubstituted or substituted by more than one fluorine atom. 'The halogen atom and one or more substituents of the cyano group are substituted.), _C(=0)〇R13, _C(=0)R13, _〇 Rl3, _nr12r13 _ atom and one or more substituents of a group of cyano groups are substituted), Rl2 represents a hydrogen atom '13' private, Cu alkyl (the Cu alkyl is unsubstituted or consists of more than one fluorine atom) Substituted), c6-1()aryl or 5~10 membered heteroaryl (the c6_10 aryl and 5~1 杂 heteroaryl are unsubstituted or independently selected from Cl-3 alkyl (the cumene) Any one of the above (1) to (13) in which any one of the substituents is substituted by one or more fluorine atoms, a Cl_6 alkyl group, a halogen atom or a group of cyano groups; The spiro compound described in any one of the items. (2〇) The 5- to 5-membered nitrogen-containing heterocycloalkyl group is a spirocyclic compound described in the above (19), which is a pyrrolidinyl group, a piperidinyl group, a piperazinyl 'homo-piperidinyl group or a homologous piperazinyl group. (2) UZ1 is a compound of the spiro-71 - 201211053 described in the above (19), which is any of the following structures. [Chemical 5 4]

(22) Zi represents formula (III-1) or (III-2)

(in the formula, R1 and R3, 8 -72- 201211053

R1 represents the Ci-6 yard base (the Ci-6 yard base consists of C6-10 aryl or 5~l 杂 heteroaryl (the C6-1G aryl and 5~10 member heteroaryl are available with 4~) a 7-membered oxacycloalkane is subjected to condensed ring' and the aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from a C4-6 alkyl group, a halogen atom, a cyano group, a c!-3 alkyl group (the mountain) .3 alkyl is substituted or substituted by one or more fluorine atoms) and substituted with one or more substituents of the group -(C^3 alkyl), and the C!-6 The group may be substituted by one or more substituents independently selected from the group consisting of a trans group, a halogen atom and a cyano group, and R3 represents a hydrogen atom, as described in any one of the above items (1) to (1 3). Spiro compound. (23) 1 represents Cm alkyl (the (^.3 alkyl group is derived from phenyl, pyridyl, furyl or isoxazolyl (the phenyl, pyridyl, furyl and isoxazolyl are 4 ~7 members of the oxacycloalkane are condensed, and the phenyl, pyridyl, furyl and isoxazolyl are unsubstituted or independently selected from C4-6 alkyl, halogen atom, cyano group, alkyl group (the alkane Any one of the substituents substituted by one or more fluorine atoms and substituted by one or more alkyl groups), and the C, .3 alkyl group may also be independently selected from The spiro compound described in the above (22), which is substituted by one or more substituents in which a group of a hydroxyl group, a halogen atom and a cyano group are substituted. (2WZ1 is a spiro compound described in the above (22) in any of the structures shown below. -73- 201211053 [Chem. 5 6]

(25)21 represents the formula (III-1) or (ΠΙ-2)

(wherein, in R1 and R3, R is not a 4-11 shell nitrogen-containing heterocyclic compound (the 4'-member nitrogen-containing heterocyclic compound is replaced by -C(= 〇)0(Cl_6 alkyl)) The spiro compound described in any one of the above (1) to (13), wherein R3 represents a hydrogen atom. (26) The 4-11 member nitrogen-containing heterocycloalkyl group is a tetrahydroindenyl group, a pyrrole group, a piperidinyl group, a piperazinyl group, a homologous piperidinyl group or a homologous piperazinyl group. The spiro ring described in the above (25) Compound. (27) 21 represents the spiro compound described in the above (25), which is any of the structures shown below. -74- 201211053

【化5 8】

In the present invention, the compound of the formula (I) of the present invention, for example, exists in the ring or the ring, in addition to the tautomerism or geometric isomerism, and also contains the mixture or a mixture of the respective isomers. Existence. Further, when there is an asymmetric center or as a result of isomerization, when an asymmetric center is generated, each optical isomer and a mixture of any ratio exist. Further, in the case of a compound having φ 2 asymmetric centers, there are further diastereomers by optical isomerism. The compounds of the present invention contain all of these types in any ratio. For example, the diastereomer can be isolated by a method well known to those skilled in the art, for example, by a crystal separation method or the like, and an optically active substance can be obtained by this purpose by a widely known organic chemical method. The compound of the formula (I) of the present invention or the pharmaceutically acceptable salt may have any crystal form by the production conditions, and may exist as any water and substance 'but these crystal forms or water and substances and These mixtures are also included in the scope of the invention of -75-201211053. Further, it may be present as a solvate containing an organic solvent such as acetone, ethanol or tetrahydrofuran, and these forms are all included in the scope of the present invention.

The compound of the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt, if necessary, or can be freed from the salt formed. 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.), manganese, organic bases, and amino acids. . Further, it may be combined with inorganic acids (hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, P-). a salt of toluenesulfonic acid or the like.

The "inhibition of adiponectin receptor activation" which contains the "adiponectin receptor activator" of the present invention as an active ingredient. The treatment can be used as a general tablet, capsule, powder, or granule. The agent, the nine-agent, the syrup, and the like are administered by an oral administration agent, a rectal administration agent, a transdermal absorption agent or an injection. The agent can be administered as a therapeutic agent or as a mixture with other therapeutic agents. These can be administered as a monomer, but are usually administered in the form of a pharmaceutical composition. These preparations may be added according to a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, an additive such as a general excipient, a slip agent, a binder, a breaker, a wetting agent, a plasticizer, or a coating agent can be used as the oral preparation. The oral liquid preparation can be in the form of an aqueous or oily suspension, a solution, an emulsion, a syrup, an elixir, or the like, or as a dry syrup prepared by using water or other suitable solvent before use. The above liquid preparations may contain a general additive such as a suspending agent, a perfume, a diluent or an emulsifier. It can be administered as a suppository when administered intrarectally. The suppository is 8 -76- 201211053 cocoa butter, lauric fat, polyethylene glycol, glycerin gelatin, Witepsol, sodium stearate or a mixture thereof. The appropriate substance is used as a base, and emulsifier and suspension may be added as necessary. Chemical agents, preservatives, etc. As the injection, a preparation component such as a distilled water for injection, a physiological saline solution, a 5% glucose solution or a propylene glycol such as a dissolution aid, a dissolution aid, a pH adjuster, an isotonic agent or a stabilizer can be used.

When the agent of the present invention is administered to a human, the administration amount may be determined according to the age, state, and the like of the patient, but in the case of an adult, the oral administration or intrarectal administration is 0.1 to 1000 mg/human/day. It is 0.05 mg to 500 mg/human/day at the time of injection. These numbers are only examples, and the amount of administration must be determined in accordance with the symptoms of the patient. In the case of using the present invention, it is possible to expect an improvement in the pathological state by using a compound having an adiponectin receptor activating action. Specifically, S ' is set as a metabolic syndrome, particularly for metabolic syndrome (metab〇nc φ syndrome) caused by obesity, diabetes, high blood pressure, etc., and prevention and treatment of arteriosclerosis; myocardial infarction or cardiac hypertrophy, etc. Prevention and treatment of cardiovascular diseases, prevention of liver diseases such as nonalcoholic steatohepatitis or hepatic fibrosis; treatment of malignant tumors such as gastric cancer, rectal cancer, breast cancer, and myeloid leukemia; treatment; other anti-inflammatory effects The systemic lupus erythematosus caused by renal dysfunction, prevention of acute pulmonary disorders, treatment, etc., but is not limited thereto. The compound of the present invention can be synthesized by the method shown below, but the following production method can also be exemplified by a general production method, and the production method is not limited. The compound of the present invention can be generally purified by column chromatography, thin layer chromatography, -77-201211053 high-speed liquid chromatography (HPLC), etc., if necessary, by recrystallization or solvent washing to obtain high purity. By.

Examples of the base described in the general production method of the compound of the present invention include sodium acetate, potassium acetate, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planing, potassium hydroxide, sodium hydroxide, and potassium tert-butylate. , alkali metal salts such as sodium tributoxide, sodium decylamine, sodium hydride, lithium hydride, lithium diisopropyl decylamine, lithium bis(trimethylammonium) decylamine, η-butyllithium, pyridine, triethylamine An amine such as diisopropylethylamine, hydrazine-methylmorpholine, hydrazine-methylpiperidine or bis(trimethylammonium)amine.

The solvent described in the general production method of the compound of the present invention is stable under the reaction conditions, and is not particularly limited as long as it does not interfere with the reaction under inert conditions. For example, an yttrium-based solvent represented by dimethyl hydrazine: a guanamine-based solvent represented by hydrazine, hydrazine-dimethylformamide or hydrazine, hydrazine-dimethylacetamide; , dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether as a representative ether solvent; halogen represented by dichloromethane, chloroform or 1,2-dichloroethane a solvent; a nitrile solvent represented by acetonitrile or propionitrile: an aromatic hydrocarbon solvent represented by benzene or toluene; a hydrocarbon solvent represented by η-hexane, η-heptane or cyclohexane: Ethyl acetate or n-butyl acetate as a representative ester solvent; an alcohol solvent represented by methanol, ethanol, 1-propanol '2-propanol or ethylene glycol; or water. Further, the reaction can be carried out under conditions in which the above solvent can be optionally mixed or in the absence of a solvent. The reaction temperature in the general production method of the compound of the present invention may be selected from -78 ° C as the appropriate temperature in the range of the boiling point of the solvent used for the reaction, and the method of the present invention can be carried out under normal pressure under the pressure of 8 - 78 - 201211053. It is carried out under microwave irradiation. The general formula for the compounds of the present invention shown below, the general formula of the intermediates and final products in each step, but these intermediates and final products also contain their precursors. The term "precursor" means a compound which can be derivatized to a target by deprotection, hydrolysis, reduction, oxidation, alkylation or the like as necessary, for example, which contains a protecting group which chemically permits the compound to be protected by organic synthesis. . Protection and deprotection can be carried out by

A known protective reaction and deprotection reaction [for example, refer to Protective Groups in Organic Synthesis, Fourth edition, T.W. Greene

Implemented by John Wiley & Sons Inc. (2006), etc. Among the compounds contained in the compound (I) of the present invention, the compound of the formula (I) can be produced, for example, by the following method. [化5 9 ]

Wherein P1 represents a protecting group of an amine group, and P2 represents a protecting group of a carboxyl group, 'v, Vlb and V2 each independently represent a leaving group, and other symbols are the same as defined above-79-201211053 (Step 1) This step is a The C〇fey_Chaykovsky reaction of the method for producing the compound (2) by converting the reaction of the carbonyl group of the compound (1) with a sulfinane to an epoxide. The compound (1) used in this step can be obtained from a commercially available compound. The compound or the easily available compound is obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. In the reaction in this step, the sulfinium ion generated by the action of the base can be reacted with the compound (1) for the cerium ion such as trimethylsulfonium iodide or the cerium oxide ion such as trimethylsulfoxonium iodide. And proceed. The equivalent amount of trimethylsulfonium iodide or trimethylphosphonium iodide used in this step is generally from 1 to 5 equivalents, preferably from 1 to 3 equivalents, per equivalent of the compound (1)1. Examples of the base used in the present step include sodium hydroxide, potassium hydroxide, sodium hydride, lithium hexamethyldiamine, and the like, and sodium hydroxide is preferred. The amount of the base is related to the compound (1). In terms of 1 equivalent, it is usually 1 to 1 equivalent, preferably 1 to 5 equivalents. The reaction solvent is not particularly limited as long as it is barrier-free to the reaction, and examples thereof include tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol, water, dimethyl hydrazine, and N,N-dimethyl group. The indoleamine or the like is preferably methanol, acetonitrile or water. The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 30 ° C. The reaction time is usually from 1 to 240 hours, preferably from 0.1 to 120 hours. (Step 2) This step is a method for producing an amine alcohol compound (4) by reacting the oxide moiety of the ring 201211053 of the compound (2) obtained in the above step 1 with the amine group of the compound (3). The compound (3) used in this step can be obtained from a commercially available compound, a known compound, or a compound which can be easily obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include tetrahydrofuran, 1,4-dioxane, methanol 'ethanol, water, and the like, and more preferably methanol or water.

The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 30 ° C. The reaction time is usually from 0.1 to 24 hours, preferably from 0.1 to 120 hours. (Step 3) This step is a process for producing a compound (6) by reacting the compound (4) obtained in the above step 2 with a carbonylating agent or a thiocarbonylating agent represented by the compound (5). Examples of the compound (5) to be used include 1,1'-carbonyldiimidazole, P-nitrophenyl chloroformate, 1,1'-thiocarbonyldiimidazole, triphosgene, % thiophosgene, and the like. Preferably, it is a plant-carbonyl diimidazole, P-nitrophenyl chloroformate, 1, P-thiocarbonyldiimidazole. The amount of the compound (5) is usually from 1 to 20 equivalents, preferably from 1 to 6 equivalents, per equivalent of the compound (4). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, etc., preferably 1,4-dioxane or chloroform. . The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 〇 to 120. . . The reaction time is generally 〇 1 to 1 〇 〇 hours, preferably 0.1 to 7 2 small -81 - 201211053 hours. (Step 4) This step is a method in which the ester group of the compound (6) obtained in the above step 3 is hydrolyzed in a base to produce the compound (7). As the base used in the step, for example, hydrogen peroxide is exemplified. Sodium or potassium hydroxide, etc. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 10 equivalents, per equivalent of the compound (6).

The reaction solvent is not particularly limited as long as it is barrier-free to the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxacarb, N,N-dimethylformamide, and the like. Preferably, it is methanol. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 24 hours. (Step 5) This step is carried out by subjecting the carboxyl group of the compound (7) obtained in the above step 4 to the amine moiety of the compound (8). A method of producing a compound (9) by reacting to form a guanamine bond. The compound (8) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The indole bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (7) or a reactive derivative thereof. Examples of the reactive derivative of the compound (7) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard C). Larock,

John Wiley & Sons Inc. (1 999) 1 94 1- 1 949 pages). Further, in the above reaction, when the carboxylic acid represented by the compound (7) is used, it may be, for example, ι, ι'· carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-B. 3-(3-dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, ruthenium-(7-azabenzotriazole The reaction is carried out in the presence of a condensing agent such as -1-yl)-fluorene, hydrazine, hydrazine, hydrazine-tetramethyltetramethyl hexafluorophosphate, PyBOP (registered trademark), or PyBroP (registered trademark). The amount of the condensing agent is from 1 to 5 equivalents, preferably from 1 to 2 equivalents per equivalent of the compound (7).

Further, the amount of the compound (8) is from 0.5 to 5 equivalents, preferably from 1 to 2 equivalents, per equivalent of the compound (7). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, hydrazine, hydrazine-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 60 ° C. The reaction time is usually from 0.1 to 24 hours, preferably from 0.1 to 1400 hours. (Step 6) This step is a method of producing a compound (1) by removing the protective group of the amine group of the compound (9) obtained in the above step 5. The reaction in this step is a reaction for removing an amine group protecting group, and can be carried out according to methods described in the literature [for example, Protective Groups in Organic Synthesis, Fourth edition, TW Greene, John Wiley & Sons Inc. (2006). Etc.] or combine this with the usual method. (Step 7) This step is a method for producing a compound (1_1} or a precursor of -83-201211053 by reacting the compound (10) obtained in the above step 6 with a compound (1) in the presence of a base. The compound (11) to be used can be obtained from a compound obtained by a commercially available compound, a known compound or a compound which can be easily obtained by various organic synthesis methods known to those skilled in the art. As the base used in this step, for example, there can be mentioned Potassium carbonate, sodium carbonate, carbonic acid planing, triethylamine, hydrazine, hydrazine-diisopropylethylamine, etc., preferably potassium carbonate. The amount of the base is generally from 1 to 10 for 1 equivalent of the compound (10). The equivalent weight is preferably from 1 to 3 equivalents.

The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, hydrazine, hydrazine-dimethylformamide, and the like, preferably tetrahydrofuran. Ν, Ν-dimethylformamide. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 0.1 to 48 hours.

Further, in the compound (11) used in the present step, when the carbon atom to which V2 is bonded may be substituted by 1 to 2 hydrogen atoms, even an aldehyde compound or a ketone compound which is a carbonyl group by combining with V 2 and 1 hydrogen atom Reductive amination can also produce compound (1-1). The reducing agent to be used in this step may, for example, be sodium triacetate borohydride-zinc chloride-sodium cyanide hydride or the like, and preferably sodium triacetate borohydride. The amount of the reducing agent is usually from 1 to 30 equivalents, preferably from 1 to 10 equivalents, per equivalent of the compound (10). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and 8-84-201211053 acetic acid, and preferably chloroform. Methanol. The reaction temperature is usually from 〇 t to the reflux temperature of the reaction solvent, preferably from 0 to 30 °C. The reaction time is generally from 0.1 to 1 hour, preferably from 0.1 to 48 hours. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (1-2) can be produced, for example, by the following method.

[化60]

La R, V, X Ο The compound of the formula (10) obtained in the step 6

[wherein, V3 represents a leaving group, and other symbols are the same as defined above]. (Step 8) This step is a method of producing the compound (1-2) or these precursors by reacting the φ amine moiety of the compound (10) obtained in the above step 6 with the compound (12) or the compound (13). The compound (12) or the compound (13) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (1-3) can be produced, for example, by the following method. -85- 201211053 【化6 1】

Compound represented by formula (10)

Ri,nY (1-3)

Λ R10a

[In the formula, V4a represents a halogen atom or a halogen atom equivalent, Rlh represents a C6-1Q aryl group, a 5-10 membered heteroaryl group (the c6.1{) aryl group and a 5-10 membered heteroaryl group are unsubstituted. Or substituted by one or more substituents independently selected from the substituent group a2), the other symbols are the same as defined above.] (Step 9) This step is a compound obtained in the above step 6 in the presence of a transition metal catalyst. (1) A method of producing a compound (1-3) or a precursor thereof after reacting with the compound (14), a so-called Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained from a commercially available compound, a known compound, or a compound which can be easily obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. The reaction in this step can be carried out by a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, vol. 37, page 2046-2067 or Acc. Chem. Res., 1998). In the 31st volume, 805-8 1 8), a combination of the transition metal catalysts used in the present step, for example, palladium acetate, ginseng (diphenylideneacetone) palladium, etc., may be mentioned as the transition metal complex. The ligand may, for example, be 2,2'-bis(diphenylphosphinobiphthalene or the like. Examples of the base include carbonic acid planing, potassium phosphate, and third sodium butoxide. The amount of the base is 10) In terms of 1 equivalent, it is generally 1 to 1 〇〇 when 8 - 86 - 201211053, preferably 1 to 10 equivalents. The reaction solvent is not particularly limited as long as it is unobstructed, for example, Toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, etc., preferably toluene, I,4-dioxane. The reaction temperature is generally 20 °. The reflux temperature of C to the reaction solvent is preferably from 50 to 180 ° C. The reaction time is usually from 1 to 48 hours, preferably from 0.1 to 24 hours.

Further, in this step, the compound (1-3) can be produced without using a transition metal catalyst as necessary. In this case, examples of the base used in the present step include potassium carbonate, sodium carbonate, carbonic acid, triethylamine, hydrazine, hydrazine-diisopropylethylamine, and the like, and potassium carbonate is preferred. The amount of the base is usually from 1 to 10 equivalents, preferably from 1 to 3 equivalents, per equivalent of the compound (10). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane 'oxime, fluorene-dimethylformamide, and the like, and preferably tetrahydrofuran. , hydrazine, hydrazine-dimethylformamide. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 〇 to 180 ° C. The reaction time is usually from 1 to 24 hours, preferably from 1 to 4 8 hours. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (I-4) can be produced, for example, by the following method. -87- 201211053 [Chem. 6 2] R3 |Λ/1Ά 7)n 化合物 Compound represented by formula (10) obtained in step 6 (10) ^-ΝΗ

Wherein v4b represents a leaving group, R1Qb represents a Ch9 alkyl group (the Ci-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), C3-M cycloalkyl group (The C3-u cycloalkyl group may be a C6_1Q aryl group or a 5-10 member heteroaryl group (the C6-1Q aryl group and the 5-10 member heteroaryl group are unsubstituted or independently selected from the substituent group A2) Substituting one or more substituents to carry out a condensed ring, and the C3_u cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2) or a C! alkyl group (the cumene The base is substituted by a C3_u cycloalkyl group (the C3_u cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the other symbols are the same as defined above].

(Step 10) This step is a method of producing the compound (1_4) or these precursors by reacting the compound (10) obtained in the above step 6 with the compound (15) in the presence of a base. The base to be used in this step may, for example, be potassium carbonate, sodium carbonate, triethylamine or N,N-diisopropylethylamine, and is preferably potassium carbonate. The amount of the base is generally from 丨 to the equivalent, more preferably from 1 to 3 equivalents per equivalent of the compound (10). The reaction solvent is not particularly limited as long as it is barrier-free to the reaction, and examples thereof include acetonitrile, tetrahydrofuran, hydrazine, 4-dioxane, and N,N-:methylmethyl 8-88-201211053 decylamine. Preferably, it is tetrahydrofuran, N,N-dimethylacetamide. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 0 to 1 to 240 hours, preferably from 1 to 4 8 hours. Further, in the compound (15) used in the present step, when the carbon atom to which V4b is bonded may be substituted by 1 to 2 hydrogen atoms, the aldehyde compound or ketone which becomes a carbonyl group by combining with v4b and 1 φ hydrogen atoms Compound (1-4) can also be produced by reductive amination of the compound. The reducing agent to be used in this step may, for example, be sodium triacetate borohydride, zinc chloride-boron sodium cyanide hydride, 2-pyridylborane conjugate or the like, preferably triacetate boron hydride. sodium. The amount of the reducing agent is generally from 1 to 30 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound 00). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 14-dioxane, and #acetic acid, and chloroform or methanol is preferred. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 30 ° C. The reaction time is usually from 0 1 to 100 hours, preferably from 1 to 4 8 hours. Further, the compound represented by the above formula (1-1) can also be produced from the above compound (6) by the following method. -89 - 201211053 【化6 3】

[In the formula, the symbol is the same as defined above].

(Step 11) This step is a method of producing a compound (16) by removing the protective group of the amine group of the compound (6) obtained in the above step 3. The reaction in this step is a reaction in which the protecting group of the amine group is removed, and can be carried out according to methods described in the literature (for example, Protective Groups in Organic Synthesis, Fourth editi ο η, T. W. G reene 'J ohn Wi 1 ey &amp ; S on s In c · (2006), etc.) or combination of these and the common law. (Step 12) This step is a method for producing the compound (17) by reacting the compound (16) obtained in the above step U with the compound (11) in the presence of a base. The compound (11) used in this step may be Commercially available compounds, known compounds, or readily available compounds are obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. The base to be used in this step may, for example, be potassium carbonate, sodium carbonate, triethylamine or N,N-diisopropylethylamine, and is preferably potassium carbonate. The amount of the base is usually from 1 to 10 equivalents, preferably from 1 to 3 equivalents, per equivalent of the compound (16). The reaction solvent is not particularly limited as long as it is unobstructed for the reaction, and examples thereof include, for example, acetonitrile, tetrahydrofuran, I, 4·diox, N,N-dimethylformamide, and the like. Preferred is tetrahydrofuran, N,N-dimethylformamide. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 1 to 48 hours.

And the carbon atom to which V2 is bonded in the compound (U) used in the present step may be substituted by 1 to 2 hydrogen atoms, even if it is combined with ν2 and 1 hydrogen atom to form a carbonyl group or a ketone compound. Reductive amination can also produce compound (17). The reducing agent to be used in this step may, for example, be sodium triacetate borohydride, zinc chloride-boron sodium cyanide hydride, 2-pyridylborane conjugate or the like, preferably triacetate boron hydride. sodium. The amount of the reducing agent is usually from 1 to 30 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound (16). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and acetic acid, and chloroform or methanol is preferred. The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 30 〇 c 0 . The reaction time is usually from 1 to 1 Torr, preferably from 1 to 4 8 hours. (Step 13) This step is a method in which the ester group of the compound (17) obtained in the above step 12 is hydrolyzed in a base to produce a compound (18). The base to be used in this step may, for example, be sodium hydroxide or hydrogen-91 - 201211053 potassium oxide or the like. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 10 equivalents, per equivalent of the compound (17). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Methanol. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 〇 · i to 2 4 hours. (Step 14) This step is a method of producing a compound (1-1) or a precursor by reacting a carboxyl group of the compound (18) obtained in the above step 13 with an amine moiety of the compound (8) to form a guanamine bond. The compound (8) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The indole bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (18) or the reactive derivative. Examples of the reactive derivative of the compound (18) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard). C. Larock, John Wiley & Sons Inc. (1 999) 1 94 1 - 1 949 pages) Obtained. Further, in the above reaction, when the carboxylic acid represented by the compound (18) is used, for example, 1,1'-carbonyldiimidazole, anthracene, fluorene-dicyclohexylcarbodiimide or 1-ethyl-3-( 3-dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, 0-(7-azabenzotriazol-1-yl 201211053 The reaction is carried out in the presence of a condensing agent such as -N,N,N', N'-tetramethyltetramethylhexafluorophosphate, PyBOP (registered trademark) or PyBroP (registered trademark). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 60 ° C.

The reaction time is usually from 0.1 to 24 hours, preferably from 0.1 to 100 hours. Further, the compound represented by the above formula (1-2) can also be produced from the above compound (16) by the following method.

【化6 4】

H0 R1 , ΝΗ (8) I Step 16

R9 Step 17

[In the formula, the symbol is the same as defined above]. (Step I5) This step is a method of producing the compound (19) by reacting the amine moiety of the compound (16) obtained in the above step 11 with the compound (12) or the compound (13). The compound (12) or the compound (13)-93-201211053 used in the present step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art (step 16). This step is a method of producing the compound (20) by subjecting the ester group of the compound (19) obtained in the above step 15 to hydrolysis in a base.

The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound (19). The reaction solvent is not particularly limited as long as it is barrier-free to the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Methanol is preferred. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 〇 to 1 800 °c. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 24 hours. (Step 17) In this step, the carboxyl group of the compound (20) obtained in the above step 16 is reacted with the amine moiety of the compound (8) to form a guanamine bond, and the compound (I-2) or the precursor thereof is produced. method. The compound (8) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The indole bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (20) or the reactive derivative. Examples of the reactive derivative of the compound (20) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, 8-94-201211053).

Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley & Sons Inc. (1 999) 1 941 -1 949 pages). Further, in the above reaction, when the carboxylic acid represented by the compound (20) is used, for example, 1,1'-carbonyldiimidazole, anthracene, fluorene fluorene-dicyclohexyl carbon can be used.

Diimine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, 0-( a condensing agent such as 7-azabenzotriazol-1-yl)-fluorene, hydrazine, hydrazine, Ν'-tetramethyltetramethyl hexafluorophosphate, PyBOP (registered trademark), PyBroP (registered trademark) The reaction is carried out in the presence. The amount of the condensing agent is from 1 to 5 equivalents, preferably from 1 to 2 equivalents, per equivalent of the compound (20). Further, the compound (8) is used in an amount of from 0.5 to 5 equivalents, preferably from 1 to 2 equivalents, per equivalent of the compound (20). The reaction solvent is not particularly limited as long as it is unobstructed by the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably 〇 to 60 〇 c 0 , and the reaction time is usually from 0.1 to 240 hours, preferably from ο1 to io hours. Further, the compound represented by the above formula (1-3) can also be produced from the above compound (16) by the following method. -95- 201211053 【化6 5】

[wherein the symbols are the same as defined above]. (Step 18) This step is a method for producing a compound (21) by reacting the compound (16) obtained in the above step 11 with a compound (14) in the presence of a transition metal catalyst, so-called Buchwald-Hartvey Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The reaction in this step can be carried out by a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, vol. 37, page 2046-2067 or Acc. Chem. Res., 1998, 31). Vol., pp. 805-818) The combination of the transition metal catalyst used in this step, for example, as a transition metal complex, an acetic acid pin, a ginseng (diphenylene methyl propyl fluorene), etc. The ligand may, for example, be 2,2'-bis(diphenylphosphinobiphthalene or the like. Examples of the test include carbonic acid, potassium phosphate, and sodium tributoxide. The amount of the ruthenium is for the compound (16). In the case of 1 equivalent, it is usually 1 to 1 equivalent, preferably 1 to 10 equivalents. The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include toluene, tetrahydrofuran, and 1 4 - dioxane, N, N_: methylmethyl-96- 201211053 decylamine, N-methylpyrrolidone, etc., preferably toluene, 1,4-dioxane. The reaction temperature is generally 20 ° C to the reaction The reflux temperature of the solvent is preferably from 50 ° C to 180 ° C. The reaction time is usually from 1 to 48 hours, preferably from 1 to 24 hours.

Further, in this step, the compound (21) may be produced without using a transition metal catalyst as the case may be. In this case, examples of the base used in the present step include potassium carbonate, sodium carbonate, carbonic acid planing, triethylamine, N,N-diisopropylethylamine, and the like, and potassium carbonate is preferred. The amount of the base is usually from 1 to 10 equivalents, preferably from 1 to 3 equivalents, per equivalent of the compound (16). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, and preferably tetrahydrofuran. N,N-dimethylformamide. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C.

The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 48 hours. (Step 19) This step is a method of producing the compound (22) by hydrolyzing the ester group of the compound (21) obtained in the above step 18. The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound (21). The reaction solvent is not particularly limited as long as it is barrier-free to the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N-di-97-201211053 methylformamide. Preferably, it is methanol. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 0.1 to 240 hours, preferably from 1 to 24 hours. (Step 20) This step is a step of producing a compound (1-3) or a precursor thereof by reacting a carboxyl group of the compound (22) obtained in the above step 15 with an amine moiety of the compound (8) to form a guanamine bond. Methods. The compound (8) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The indole bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (22) or the reactive derivative. Examples of the reactive derivative of the compound (22) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard C). Larock, John Wiley & Sons Inc. (1999) 1941-1949 pages. Further, 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, diphenyl azide, dipyridyl disulfide-triphenylphosphine, anthracene-(7-azabenzotriazol-1-yl) The reaction is carried out in the presence of a condensing agent such as hydrazine, hydrazine, hydrazine, hydrazine--tetramethyltetramethyl hexafluorophosphate, PyBOP (registered trademark), or PyBroP (registered trademark). The amount of the condensing agent is from 1 to 5 equivalents per 1 equivalent of the compound (22), preferably 1 201211053. Further, the compound (8) is used in an amount of from 0.5 to 5 equivalents per equivalent of the compound (22). Preferably it is from 1 to 2 equivalents. The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, hydrazine, hydrazine-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 60 °C. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 100 hours. Further, the compound represented by the above formula (1-4) can also be produced from the above compound (16) by the following method. [6 6]

[wherein the symbols are the same as defined above]. (Step 21) This step is a step of producing a compound (2 3) by reacting the compound (16) obtained in the above step 11 with the compound (15) in the presence of a base. The base used in the present step is, for example, a base. Potassium carbonate, sodium carbonate, triethylamine, hydrazine, hydrazine-diisopropylethylamine or the like is preferably potassium carbonate. The amount of the base -99 to 201211053 is usually from 1 to 10 equivalents, preferably from 1 to 3 equivalents, per equivalent of the compound (16). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, and preferably tetrahydrofuran. N,N-dimethylformamide. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 0.1 to 48 hours. Further, in the compound (13) used in the present step, when the carbon atom to which V4b is bonded may be substituted by 1 to 2 hydrogen atoms, the aldehyde compound which becomes a carbonyl group by hydrazine with 乂41> and 1 hydrogen atom or Compound (23) can also be produced by reductive amination of a ketone compound. Examples of the reducing agent used in this step include sodium triacetate borohydride, zinc chloride-boron sodium cyanide hydride, 2-pyridylborane conjugate, and the like, and triacetate boron hydride is preferred. sodium. The amount of the reducing agent is usually from 1 to 30 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound (16). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1, cardiodioxane, and acetic acid, and chloroform or methanol is preferred. The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 30 ° C. The reaction time is usually from 0.1 to 100 hours, preferably from 0.1 to 48 hours. -100-201211053 (Step 22) This step is a method in which the ester group of the compound (23) obtained in the above step 21 is hydrolyzed to produce the compound (24). The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 100 equivalents, preferably from i to 1 equivalent, per equivalent of the compound (23). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include methanol, ethanol, tetrahydrofuran, hydrazine, 4-dioxane, and N,N_: φ methylformamide. Methanol. The reaction temperature is usually from 〇 t to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 0.1 to 24 hours. (Step 23) In this step, the residue of the compound (24) obtained in the above step 22 is reacted with the amine moiety of the compound (8) to form a guanamine bond to produce a compound (1-4) or a precursor thereof. The method of things. The φ compound (8) used in this step can be obtained from a compound obtained by a commercially available compound, a known compound, or a readily available compound, by various organic synthesis methods known to those skilled in the art. The indole bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (24) or the reactive derivative. Examples of the reactive derivative of the compound (24) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard C). Laroc, John Wiley & Sons Inc. (1999) 1 941 -1 949 pages). Further, in the above reaction, when the carboxylic acid is represented by the compound (24) -101 - 201211053, for example, 1,1'-carbonyldiimidazole, hydrazine, Ν'-dicyclohexylcarbodiimide, 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, 0-(7-azabenzotriazole-1 The reaction can be carried out in the presence of a condensing agent such as -, hydrazine, hydrazine, hydrazine, hydrazine-tetramethyltetramethyl hexafluorophosphate, PyBOP (registered trademark), or PyBroP (registered trademark). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 60 ° C. The reaction time is usually from 0.1 to 24 hours, preferably from 0.1 to 100 hours. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (1-5) can be produced, for example, by the following method. 【化6 7】

The symbol in the formula is the same as defined above. (Step 24) This step is a carbonyl group of the compound (ΐ_υ, compound (1_2), compound (13) or compound (I-4) obtained in the aforementioned step 7, 8, 9, 1 , 14, 17, 20 or 23. The compound of the compound (15) is converted into a thiocarbonyl group. The method of the compound (15) 201211053. The reaction in this step can be carried out by using a Lawesson reagent or phosphorus pentasulfide. The amount of Lawesson reagent or phosphorus pentasulfide used in this step is for the compound (1). 1 equivalent of any one of -1) to (1-4) is 1 to 10 〇 equivalent, preferably 1 to 1 〇 equivalent. The reaction solvent is not particularly limited as long as it is barrier-free, for example, Give tetrahydrofuran and the like.

The reaction temperature is usually from 20 to 200 ° C, preferably 50. (: to the reflux temperature of the reaction solvent. The reaction time is generally from 1 to 48 hours, preferably from 1 to 24 hours, and in the compound of the compound (I) of the present invention, the formula (I-6) The compound shown can be produced, for example, by the following method.

_ . 2 P0X —-—► 9

Base Step 28 [wherein, v5 represents a leaving group, and other symbols are the same as defined above]. (Step 25) A method in which an anion is produced at the α position of the ester group of the compound (25) in the presence of a base, and the carbonyl group of the compound (1) is reacted to produce the compound-103-201211053 compound (26). . The compound (1) and the compound (25) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The base to be used in this step may, for example, be lithium diisopropyl decylamine or lithium hexamethyldiamine. The amount of the base used in this step is generally from 0.9 to 2 equivalents, preferably from 1 to 1.5 equivalents, per equivalent of the compound (25). The reaction solvent is not particularly limited as long as it is barrier-free to 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 from 0.1 to 48 hours, preferably from 1 to 24 hours. (Step 26) This step is a method in which the ester group of the compound (26) obtained in the above step 25 is hydrolyzed to produce the compound (27). The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 1 equivalent, preferably from 1 to 10 equivalents, per equivalent of the compound (26). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Methanol. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 1 to 24 hours. -104-201211053 (Step 27) This step is a method in which the carboxyl group of the compound (27) obtained in the above step 26 is converted into an isocyanate by a transposition reaction, and the compound (28) is produced by directly cyclizing in a molecule. The reaction in this step is 'based on the methods described in the literature (eg Comprehensive Organic Transformations, Second Edition, by Richard C. Larock,

John Wiley & Sons Inc. (1999) pp. 868-869, etc.) may be combined with conventional methods.

(Step 28) This step is a process for producing a compound (30) by reacting the compound (28) obtained in the above step 27 with the compound (29) under a base. The compound (29) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. Examples of the base used in this step include sodium hydride, potassium hydride, potassium butoxide, fluorination, lithium diisopropyl decylamine, lithium hexamethyldiamine, and hexamethyldiene. Sodium guanidine or the like is preferably sodium hydride or potassium third potassium hydride. The amount of the base is usually from 1 to 10 equivalents, preferably from 1 to 2 equivalents, per equivalent of the compound (28). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, hydrazine, and hydrazine-dimethyl hydride. The acetamide, N-methylpyrrolidone, tert-butanol or the like is preferably tetrahydrofuran, hydrazine or hydrazine-dimethylformamide. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is generally 0.1 to 2,400 hours, preferably 0. 1 to 4 8 small - 105 - 201211053 The conversion of the compound represented by the formula (1-6) by the compound (30) can be carried out by any combination. The method of the same method as the above steps 4 to 7, 8, 9, 10, 11 to 14, 15 to 17, 18 to 20, 21 to 23, and 24, according to the method or the combination of the methods of the conventional method . Further, the compound represented by the formula (1-7) in the compound of the compound (1) of the present invention can be produced, for example, by the following method. 【化6 9】

[wherein the symbols are the same as defined above]. (Step 29) This step is a method in which an anion is produced at the α position of the cyano group of the compound (31) in the presence of a base, and the compound (3 2) is produced by reacting the carbonyl group of the compound (1). The compound (1) and the compound (3 使用 used in the present step can be obtained from a commercially available compound, a known compound, or a readily available compound by using a compound synthesized by various organic synthesis methods known to those skilled in the art. The base may, for example, be lithium diisopropyl decylamine or lithium hexamethyldiamine. The amount of the base used in the present step is generally 0.9 to 1 equivalent of the compound (31). The amount of the reaction solvent is not particularly limited as long as it is unobstructed for the reaction, and examples thereof include tetrahydrofuran, etc. The reaction temperature is usually -78 to 1 Torr. Preferably, it is -78 to 30. (: The reaction time is generally from 0.1 to 48 hours, preferably from 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 above step 29 and converting it into an aminomethyl group in the presence of a base. The reactions in this step are those documented in the literature (for example, Comprehensive Organic Transformations, Second Edition,

Richard C. Larock, John Wiley & Sons Inc. (1 999) pp. 875-878, etc.), according to this method or may be combined with the conventional method (step 31), this step is obtained from the aforementioned step 30 Compound (33) φ A method of producing a compound (34) by reacting a carbonylating agent or a thiocarbonylating agent represented by the compound (5). The compound (5) to be used may, for example, be 1,1'-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1'-thiocarbonyldiimidazole, triphosgene or thiophosgene. The amount of the compound (5) is usually from 1 to 20 equivalents, preferably from 1 to 6 equivalents, per equivalent of the compound (33). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, etc., and preferably 1,4-dioxane or chloroform. . The reaction temperature is usually 〇 t: the reflux temperature to the reaction solvent is preferably -107 - 201211053 〇 to 1 2 〇 °c. The reaction time is usually from 0 to 1 to 1,000 hours, preferably from 〇 to 7 2 hours. (Step 32) This step is a method in which the compound (35) is produced by reacting the π compound (34) obtained in the above step 31 with the compound (21 2) under the presence of a base. The compound (29) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The base used in this step is exemplified by sodium hydride, third potassium pentoxide or the like. Examples of the base used in the present step include sodium hydride, potassium hydride, potassium t-butoxide, fluorinated planer, lithium diisopropyl decylamine, lithium hexamethyldiamine, and hexamethyl-di Sodium guanidine or the like is preferably sodium hydride or potassium third potassium hydride. The amount of the base is usually from 1 to 10 equivalents, preferably from 1 to 2 equivalents, per equivalent of the compound (34). The reaction solvent is not particularly limited as long as it is unobstructed for the reaction, and examples thereof include acetonitrile, tetrahydrofuran 'I, 4·dioxin, ν, ν-dimethylformamide, hydrazine, hydrazine-dimethyl methacrylate. The acetaminophen, the oxime-methyl sulphate, the third butanol and the like are preferably tetrahydrofuran, hydrazine or hydrazine-dimethylformamide. The reaction temperature is usually from 0 ° C to the reaction temperature of the reaction glutinous agent, preferably from 〇 to 180 ° C. The reaction time is generally 0.1 g for 240 hours, preferably 〇.] to 48 hours, the compound (35) is converted to the formula (Bu 7), and the compound can be converted into any combination with the aforementioned steps 4 to 8 1 9 . 10' 11 to 14, 15 to 17, 2 to 108 - 201211053 18 to 20, 21 to 23, and 24, the same method, or the method according to the same, and the method of the conventional method. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (1-8) can be produced, for example, by the following method. 【化7〇

I

I P3 ?S, N. s R4(38) ^ Λ1-, step π ΤΓ

An NH X is obtained by the formula (36) obtained in steps 3, 28, 32. Rf (39) 1 p1 I. Step 35 (4〇) Nv (42) Η Step 37 LV \ (43)

7) π is the same as steps 7, 8, 9, 10 R4 〇

X

(1-8) H [wherein pl and p3 represent a protecting group of an amino group, and p2 represents a protecting group of a carboxyl group. ’V6 represents a leaving group, and other symbols are the same as defined above]. (Step 3 3) This step is a method of producing a compound (37) by subjecting the ester group of the compound (36) obtained in the above step 3, 28 or 32 to hydrolysis. The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 10 equivalents, per equivalent of the compound (36). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N_: -109 - 201211053 methylformamide. Methanol is preferred. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 24 hours. (Step 34) This step is a method of producing a compound (39) by reacting a carboxyl group of the compound (37) obtained in the above step 33 with an amine moiety of the compound (38) to form a hydrazone bond. The compound (37) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. The oxime bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (37) or the reactive derivative. Examples of the reactive derivative of the compound (37) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard). C. Larock, John Wiley & Sons Inc. (1999), pages 1941-1949). Further, in the above reaction, when the carboxylic acid represented by the compound (37) is used, for example, 1,1'-carbonyldiimidazole, :^,:^-dicyclohexylcarbodiimide, 1-ethyl-3 can be used. -(3-dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, 0-(7-azabenzotriazole-1- The reaction is carried out in the presence of a condensing agent such as N,N,N', N'-tetramethyltetramethylhexafluorophosphate, PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is from 1 to 5 equivalents, preferably from 1 to 2 equivalents per equivalent of the compound (37). Further, the compound (38) is used in an amount of from -10 to 5,100 equivalents per 1 equivalent of the compound (37), preferably from 1 to 2 equivalents. The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 〇 ° C to the reflux temperature of the reaction solvent, preferably from 0 to 60 ° C. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 1 Torr.

hour. (Step 35) This step is a method of producing a compound (40) by selectively removing the group (P3: a protecting group for an amine group) in which the thiol group of the compound (39) obtained in the above step 34 is protected. The reaction in this step is a reaction in which the protecting group of the amine group is removed, as described in the literature (for example, Protective

Groups in Organic Synthesis, Fourth edition, T.W. Greene, 'John Wiley & Sons Inc. (2000), etc., according to this method or may be combined with these conventional methods. (Step 36) This step is a method of producing a compound (42) by reacting the oxime moiety of the compound (40) obtained in the above step 35 with the compound (41). The compound (4 1) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. (Step 37) This step is a method of producing a compound (43) by removing the protective group of the amine group of the compound (42) obtained in the above step 36. The reaction in this step is a reaction for removing an amine group protecting group by a method described in the literature (for example, Protective Groups in Organic Synthesis, -111 - 201211053).

Fourth edition, TW Greene, John Wiley & Sons Inc. (2006), etc., according to the method or the combination of these and the conventional method, the compound (43) is a compound of the formula 88) The conversion can be carried out by the same method as the above-mentioned step 7' 8, 9 or 1 、, according to the method or the combination of them and the method of the conventional method. Further, the compound represented by the above formula (1-8) can be produced, for example, by the following method. 【化7 1】

[wherein, P1 and P3 represent a protecting group of an amino group, and P2 represents a protecting group of a carboxyl group.] V6 represents a leaving group, and other symbols are the same as defined above]. (Step 3 8) This step is a method of producing a compound (44) by removing the protecting group (P1) having an amine group of the compound (36) obtained in the above step 3' 28 or 32. The reaction in this step is to remove the reaction of the protecting group of the amine group by the method described in the literature (for example, Protective GrouPs in

Organic Synthesis, Fourth edition, T.W. Greene, John -112- 201211053

Wiley & Sons Inc. (2006), etc., according to this method, may be combined with these conventional methods. The conversion of the compound (45) from the compound (44) can be carried out by the same method as the above-mentioned step 12, 15, 18 or 23, the method according to the method, or the combination of the methods of the conventional method. (Step 39) This step is a method of producing a compound (46) by hydrolyzing an ester group of the compound (45).

The base to be used in this step may, for example, be sodium hydroxide or potassium hydroxide. The amount of the base is usually from 1 to 100 equivalents, preferably from 1 to 1 equivalent, per equivalent of the compound (45). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Methanol. The reaction temperature is usually from 〇 ° c to the reflux temperature of the reaction solvent, preferably from 0 to 180 ° C. The reaction time is usually from 1 to 240 hours, preferably from 0.1 to 24 hours. (Step 40) This step is a method for producing a compound (47) by reacting a carboxyl group of the compound (46) obtained in the above step 39 with an amine moiety of the compound (38) to form a hydrazone bond. The compound (38) used in this step can be obtained from a commercially available compound, a known compound, or a compound which can be easily obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. The hydrazine bond formation reaction in this step is carried out using the carboxylic acid represented by the compound (46) or the reactive derivative. Examples of the reactive derivative of the compound (46) include a mixed acid anhydride, an active ester, an active decylamine, an acid halide, and the like, which can be, for example, a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley & Sons Inc. (1999) 1 941 - 1 949 pages). Further, in the above reaction, when the carboxylic acid represented by the compound (46) is used, for example, ruthenium-carbonyldiimidazole, ruthenium, Ν'-dicyclohexylcarbodiimide, 1-ethyl-3-(3) may be used. - dimethylaminopropyl)carbodiimide, diphenyl azide, dipyridyl disulfide-triphenylphosphine, 0-(7-azabenzotriazol-bu)-oxime The reaction is carried out in the presence of a condensing agent such as hydrazine, hydrazine, hydrazine, hydrazine-tetramethyltetramethyl hexafluorophosphate, PyBOP (registered trademark), or PyBroP (registered trademark). The reaction solvent is not particularly limited as long as it is unobstructed, and examples thereof include dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, and the like, and chloroform is preferred. The reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from 〇 to 60 ° C. The reaction time is usually from 0.1 to 240 hours, preferably from 0.1 to 100 hours. (Step 41) This step is a method of producing a compound (48) by removing the group (P3: protecting group for an amine group) in which the thiol group of the compound (47) obtained in the above step 40 is protected. The reaction in this step is a reaction in which the protecting group of the amine group is removed, as described in the literature (for example, pr〇tective Groups in

Organic Synthesis, Fourth edition, T. W. Greene, John Wiley & Sons Inc. (2 006), etc., may or may be combined according to the method. -114-201211053 (Step 42) This step is a method in which the oxime moiety of the compound (48) obtained in the above step 41 is reacted with the compound (41) to produce the compound (1-8) or the same. The compound (4?) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. Further, among the compounds contained in the compound (I) of the present invention, the compound of the formula (1-9) can be produced, for example, by the following method. [化 7 2 ]

^ [wherein, P1 represents a protecting group of an amine group, and V7 represents a leaving group, and other symbols are the same as defined above]. (Step 43) This step is a method of producing a compound (5 1) by reacting the oxime moiety of the compound (40) obtained in the above step 35 with the compound (49) or the compound (50). The compound (49) or the compound (5?) used in this step can be obtained from a commercially available compound, a known compound, or a compound which can be easily obtained by using a compound synthesized by various organic synthesis methods known to those skilled in the art. (Step 4 4) This step is a method of producing a compound (52) by removing the protective group of the amine group of the compound (5 1) -115 - 201211053 obtained in the above step 43. The reaction in this step is a reaction for removing an amine group protecting group by a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition, TW Greene, John Wiley & Sons Inc. (2006), etc.) According to this method, it is possible to combine these with the conventional method. The conversion of the compound of the formula (1-8) by the compound (52) is carried out by the same method as the above-mentioned step 7, 8, 9 or 10, the method according to the method or the combination thereof, and the method of the conventional method. Further, the compound represented by the above formula (1-9) can be produced, for example, by the following method. [化7 3] V L2丄1, person H X start R (48), -N,

The compound represented by the formula («) obtained in the step (wherein 'V7 represents a leaving group, and the other symbols are the same as defined above]. (Step 45) This step is a method of producing a compound (1-9) or a precursor thereof by reacting the brewed portion of the compound (48) obtained in the above step 41 with the compound (49) or the compound (50). The compound (49) or the compound (5〇) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. Further, among the compounds of the compound (I) of the present invention, the compounds represented by the formulae -116 to 201211053 (1-10), the formula (IH), the formula (1-12) and the formula (1-13) can be, for example, by the following method. Manufacturing.

【化7 4】

[V8 and V9 represent a leaving group, and other symbols are the same as defined above] (Step 46) This step is a step of converting the carboxyl group of the compound (46) obtained in the above step 39 into an amine group by transposition reaction to produce a compound (5). 3) The method. As the translocation reaction which can be utilized in this step, a translocation reaction via samarium nitrogen (so-called Curtius translocation and Schmidt translocation), via the first guanamine The translocation reaction (so-called Hofmann translocation) and the translocation reaction of hydroxamic acid (so-called Lossen translocation) and the like. These reactions can be performed by methods described in the literature (for example, Comprehensive Organic)

Transformations, Second Edition, Richard C. Larock, -117- 201211053

John Wiley & Sons Inc. (1999) pp. 868-869, etc., may or may not be combined with these methods. (Step 47) This step is a method of producing a compound (i-io) or a precursor thereof by reacting the amine moiety of the compound (53) obtained in the above step 46 with the compound (41). The compound (41) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art.

(Step 48) This step is a method in which the amine moiety of the compound (53) obtained in the above step 46 is reacted with the compound (49) or the compound (50) to produce a compound (?-11) or a precursor thereof. The compound (49) or the compound (50) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art.

(Step 49) This step is a method in which the amine moiety of the compound (53) obtained in the above step 46 is reacted with the compound (5 4) to produce the compound (1-12) or a precursor thereof. The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. (Step 50) This step is a method of producing a compound (1-1 3) or a precursor thereof by reacting the amine moiety of the compound (53) obtained in the above step 46 with the compound (55). The compound (5 5) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. Further, the compound represented by the above formula (1-10) can be produced, for example, by the following method. 8-118-201211053

【化7 5】

(37) The formula (37) obtained by the step 33 is the same as the compound R2' G1.

(58) 1

Same as steps 7, 8, 9, . , 10 Λ -►

[wherein the symbols are the same as defined above]. (Step 51) This step is a method for producing a compound (56) by subjecting a carboxyl group of the compound (37) obtained in the above step 33 to an amine group by a transposition reaction. As the translocation reaction usable in this step, a translocation reaction via samarium nitrogen (so-called Curtius translocation and Schmidt translocation), via the first guanamine The translocation reaction (so-called Hofmann to Φ position) and the translocation reaction via hydroxamic acid (so-called Lossen translocation) and the like. These reactions can be performed by methods described in the literature (for example, Comprehensive

Organic Transformations, Second Edition, Richard C.

Larock, John Wiley & Sons Inc. (1999) pp. 868-869, etc., may or may be combined according to this method. (Step 52) This step is a method of producing the compound (57) by reacting the amine moiety of the compound (56) obtained in the above step 51 with the compound (41). The compound (4 1) used in this step can be obtained from a commercially available compound, a known compound, or a compound which can be easily obtained by using a compound synthesized by various methods known in the art from the organic group -119-201211053. (Step 53) This step is a method of producing a compound (58) by removing the protective group of the amine group of the compound (57) obtained in the above step 52. The reaction in this step is a reaction of removing the protecting group of the amine group by the method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition, TW Greene, John Wiley & Sons Inc. (2006), etc.) According to this method, it is possible to combine these with the conventional method. The conversion of the compound of the formula (1-10) from the compound (58) can be carried out by the same method as the above-mentioned step 7, 8, 9 or 10, the method according to the method, or the combination thereof. Further, the compound represented by the above formula (1-11) can be produced, for example, by the following method. 【化7 6】

Step 55

[wherein the symbols are the same as defined above]. (Step 54) This step is a method in which the amine moiety of the compound (56) obtained in the above step 51 is reacted with the compound (49) or the compound (5) to produce the compound (59). The compound (49) or the compound (5〇)-120-201211053 used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art (steps). 55) This step is a method of producing the compound (60) by removing the protective group of the amine group of the compound (59) obtained in the above step 54. The reaction in this step is a reaction in which the protecting group of the amine group is removed, as described in the literature (for example, Protective Groups in Organic Synthesis, Fourth

Edition, T · W · G re en e, J 〇 hn W i 1 ey & S ο ns I nc · (2006), etc., according to this method or can be combined with these common methods . The conversion of the compound represented by the formula (1-11) from the compound (60) can be carried out by the same method as the above-mentioned steps 7, 8, 9 or 10, the method according to the method or the combination thereof, and the method of the conventional method. Further, the compound represented by the above formula (I - 12) can be produced, for example, by the following method. 【化7 7】

A1, h2n

I

, (P7)n (just 'X-M* step 56) The compound represented by the formula (56 > 1 ) obtained in the step 51 is a step 56 (61) P1 Step 57

Same as steps 7, 8, and 9, where the symbols are the same as defined above. (Step 56) This step is a process for producing a compound (61) by reacting an amine moiety of the compound (56)-121 - 201211053 obtained in the above step 51 with a compound (54). The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. (Step 57) This step is a method of producing the compound (62) by removing the protective group of the amine group of the compound (61) obtained in the above step 56. The reaction in this step is a reaction for removing an amine group protecting group by a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition, TW Greene, John Wiley & Sons Inc. (2006), etc.) According to this method, it is possible to combine these with the conventional method. The conversion of the compound represented by the formula (I.12) by the compound (62) can be carried out by the same method as the above-mentioned step 7, 8, 9 or 1 oxime, the method according to the method or the combination thereof, and the method of the conventional method. Further, the compound represented by the above formula (I-13) can be produced, for example, by the following method. [化7 8]

By the steps: ) Hemp compound

(1-13) [wherein the symbols are the same as defined above]. -122-201211053 (Step 58) This step is a method for producing a compound (63) by reacting the amine moiety of the compound (56) obtained in the above step 51 with the compound (55). The compound (5 5) used in this step can be obtained from a commercially available compound, a known compound, or a readily available compound using a compound synthesized by various organic synthesis methods known to those skilled in the art. (Step 59) This step is a method of producing the compound (64) by removing the protective group of the amine group of the compound (63) obtained in the above step 58. The reaction of φ in this step is a reaction for removing the protecting group of the amine group by a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition, TW Greene, John Wiley & Sons Inc. (2006), etc. ), according to this method or may be combined with the conventional method. The conversion of the compound of the formula (1-13) from the compound (64) can be carried out by the same method as the above-mentioned step 7, 8, 9 or 10, the method according to the method or the combination thereof, and the method of the conventional method. [Embodiment] [Examples] Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples, Synthesis Examples, Test Examples, and Preparation Examples, but the present invention is not limited to the examples. The NMR (nuclear magnetic resonance) spectrum was measured at room temperature using a spectrometer of 300 MHz (JNM-ECP300; manufactured by JEOL Co., Ltd., or JNM-ECX3 00; manufactured by JEOL Co., Ltd.). The chemical shift 本 in this specification can also be used as an internal reference material when using any of heavy chloroform (CDC13), heavy dimethyl hydrazine (DMSO-d6), or heavy methanol (CD3OD). -123- 201211053 The hospital will be fully represented by Ppm (parts per million). Further, for the description of the NMR spectrum, s represents a singlet, d represents a doublet state, dd represents a doublet state of a doublet state, dt represents a triplet state of a doublet state, dq represents a quadruple state of a doublet state, and ddd represents a doublet state of a doublet state. The doublet state, t represents the triplet state, tt represents the triplet state of the triplet state, q represents the quartet state, sep represents the quaternary state, quin represents the quaternary state, m represents the multiplet state, br represents the multistate, br represents the broad state, J represents the coupling constant, Hz represents Hertz . The LC-MS (Liquid Chromatography Mass Spectrometry) spectrum was measured using the following conditions and apparatus. Condition 1:

Device: Waters micromass ZQ Column: Waters SunFire C18 (3.5pm, 4.6><30mm)

Column temperature: 4 (TC dissolved solution composition: acetonitrile / hydrazine · 1% by mass aqueous formic acid (volume ratio: 1 0/90 - 85/15) Condition 2

Device: Waters micromass ZQ Column: Waters SunFire 018 (3·5μιη, 2.1x20mm)

Column temperature: 40 ° C Composition of the eluent: acetonitrile / hydrazine · 1% by mass aqueous formic acid (volume ratio: 15/85 - 85/15) When purifying with HP LC, the following conditions were used.

Device: Waters micromass ZQ Column: Waters S unF ire C 1 8 (5.0 μηι '1 9 χ 1 00mm) -124- 201211053

Column temperature: 2 3 ± 2 °C Composition of the eluent: acetonitrile / 0.1% by weight aqueous formic acid (volume ratio: 20/80 - 95/5) Flow rate: 20 mL / min, and if the mixed solvent in the relevant examples is described When the mixing ratio is 'when not specified, the mixing ratio of the tables indicates the volume ratio. [化7 9]

Reference Example 1 -1 Production of 1-Ethyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester

1-(t-Butoxycarbonyl)-4-piperidone (purchased from Wako Pure Chemical Industries, Ltd.) (5.1 g, 26 mmol) was dissolved in acetonitrile (50 mL), and trimethylsulfoxonium iodide was added. (6.6 g, 30 mmol) and potassium hydroxide (2.1 g, 38 mmol) were vigorously stirred and mixed at room temperature for 3 days. After the completion of the reaction, the insoluble material in the obtained reaction mixture was taken out, and hexane/ethyl acetate (2/1, 75 mL) and water (25 mL) were added thereto, and the mixture was shaken and allowed to stand to separate the clear liquid. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to give 1-butyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (4.3 g, yield 78%) Colorless solid lH-NMR (300MHz, CDCl3) 5: 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, -125 - 201211053 3.3 Hz), 3-63-3.80 (2H, m). [化8 0]

Reference Example 1-2 3-[4-(Methoxycarbonyl)benzyl]-2-oxo-1-carbo-3,8-diazospiro[4.5]decane-8-carboxylic acid tertidine Preparation of the ester The 1-butyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (17 g, 80 mmol) obtained from Reference Example 1-1 and methyl 4-aminomethyl benzoate (purchased from Aldrich (stock)) (17 g, 86 mmol), suspended in methanol (340 mL), water (30 mL) and 1 M aqueous sodium hydroxide (86 mL, 86 mol), stirred at room temperature for 3 days, and then decompressed. The methanol was distilled off. Water (200 mL) was added to the obtained mixture and the mixture was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 4-hydroxy-4-{[4-(methoxycarbonyl)benzylamino]methyl}piperidine-indole-carboxylic acid. Tributyl ester (37 g, yield quantitative) of a yellow oil. It was used in the next stage of the reaction without purification. The obtained 4-hydroxy-4-{[4-(methoxycarbonyl)benzylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (34 g, 75 mmol) was dissolved in 1,4-two Oxane (300 mL) was added with 1,1'-carbonyldiimidazole (46 g, 300 mmol), and the mixture was stirred and mixed at 90 ° C for 2 days. The reaction mixture was cooled and concentrated under reduced pressure, -126-201211053

Under ice cooling, ethyl acetate (0 mL) was added and water (2 mL) was evaporated. Ethyl acetate (300 mL) and water (200 mL) were evaporated. The obtained residue was purified by silica gel column chromatography [塡 !! 1 : Merck GMBH 矽 60 60 (0.040-0.063 mm), developing solvent: chloroform / ethyl acetate = 10/1]. Recrystallization from chloroform/ethyl acetate/hexane gave 3-[4-(methoxycarbonyl)benzyl]-2-oxo-1-oxo-3,8-diazaspiro[4.5]indole. A white solid of alkane-8-carboxylic acid tert-butyl ester (llg, 29%). 1H-NMR (300MHz, CDCl3) 5: 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), 3.8 1 (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]: Hold 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 Manufacture of 4-[(2-oxo-oxy-1-oxo-3,8-diazaspiro[4.5]decan-3-yl)methyl]benzoic acid methyl ester hydrochloride 3-[4-(Methoxycarbonyl)benzyl]-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tributyl phthalate obtained in 1-2 The ester (5.0 g, -127-201211053 12 mmol) was dissolved in methanol (70 mL), and 4M hydrogen chloride-dioxane solution (3 1 mL, 120 mmol) was added and the mixture was allowed to stand at room temperature for 16 hours. The precipitated solid was collected by filtration, and dried under reduced pressure at 50 ° C to give 4-[(2-oxo-l-oxo-3,8-diazaspiro[4.5]decane-3-yl)methyl. ] A benzoic acid methyl ester hydrochloride (4.0 g, yield 95%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) 5: 1. 85-2.07 (4H, m), 2.97-3.25 (4H, m), 3.3 1 (2H, s), 3.84 (3H, s), 4.44 ( 2H, s), 7.41 (2H, d, J = 8.2H z), 7.95 (2Η, 8.8 2(2H, brs). LC/MS [Condition 1]: Hold time 0.88 min; m/z 305.0 [M + H]+ (ESI positive ion mode) [Chem. 8 2]

Example 1 4-({2-Sideoxy-8-[4-(trifluoromethyl)phenylmethyl]-indole-oxo-3,8-diazospin[4.5] 癸院-3-基}甲Preparation of methyl benzoate (Compound No. 1) 4 - [(2 - oxo-1 -oxa-3,8-diazosuro[4.5] 癸-3-yl) obtained in Reference Example 1-3 Methyl]benzoic acid methyl acetate hydrochloride (4. 〇g, llmmol) was dissolved in N,N-dimethylformamide (40 mL), triethylamine (4.9 mL, 35 mmol), 4- 4- Fluoromethyl)benzyl bromide (purchased from Tokyo Chemical Industry Co., Ltd.) (3.4 g, Mmmol) was added at room temperature, and then mixed for 3 hours. The reaction mixture was added dropwise to water (200 mL), and the precipitated solid was filtered and washed with water from -128 to 201211053. The obtained solid was dried under reduced pressure at 50 ° C to give 4-({2-oxo-8-[4-(trifluoromethyl)phenylmethyl) 1-oxo-3,8-diazo snail. [4.5] decane-3-yl}methyl)benzoic acid methyl ester (5.2 g, yield 95%) as a white solid. IH-NMR (300 MHz, CDCl3) 5: 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 = 8.3Hz), 7.42(2H,d ,J = 8.3Hz ), 7.56 (2H, d, J = 8.3 Hz), 8.03 (2H, d, J = 8.3 Hz).

LC/MS [Condition 1]: Hold time 3.25 minutes; m/z 462.9 [M + H] + (ESI positive ion mode) ' m/z 507.1 [M + HCO〇r (ESI negative ion mode) 3]

Reference Example 2-1 (Production of lr, 4〇-4-(aminomethyl)cyclohexanecarboxylic acid methyl hydrochloride

Dis-4-aminomethyl-1-cyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (3.9 g, 25 mmol) was dissolved in methanol (60 mL), and hydrogen chloride-methanol (39 mL, 75 mm 〇l) was added. ) 'mix at room temperature for 7 hours. After the reaction was completed, the reaction solvent was distilled off under reduced pressure. After the precipitated solid was dissolved in chloroform, cyclopentyl methyl ether (2 mL) was added, and the precipitate was separated again, and then the solid was filtered to give (lr, 4 〇-4-(aminomethyl)cyclohexanecarboxylic acid. Methyl hydrochloride (5.5 g, quantitative) of colorless solid. 'H-NMR (300 MHz, CDCl3) 5: 1.08 (2H, q, J = l 1.9 Hz), 1.48 (2H,q, J = 12.7 Hz ), 1.68-1.87( 1 H,m), 1.8 8-2.12(4H,m), 2.26(lH,tt,J = 12.3, 3.3 -129- 201211053

Hz), 2.76-2.95 (2H, brm), 3.66 (3H, s), 8.36 (2H, brs). [化8 4]

Reference Example 2 - 2 3- {[(11",4〇-4-(methoxycarbonyl)cyclohexyl]methyl}-2-oxo-oxo-oxa-3,8-diazo snail [4.5] Preparation of tert-butyl-8-carboxylic acid tert-butyl ester The 1-butyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (3.2 g, 15 mmol) obtained in Reference Example 1-1. (lr, 4r)-4-(aminomethyl)cyclohexanecarboxylic acid methyl hydrochloride (3.4 g, 17 mmol) obtained in Reference Example 2-1 was dissolved in a methanol-water mixed solvent (1:1). 96 mL), 1 M aqueous sodium hydroxide solution (15 mL, 15 mmol) was added, and the mixture was stirred and stirred at room temperature for 6 days. After the reaction was completed, methanol was distilled off under reduced pressure, and then chloroform (80 mL) and water (20 mL) were added. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-hydroxy-4-({[(1Γ,4〇- 4- (methoxy). a light yellow oil of the carbonyl group of cyclohexyl]methylamino}methyl)piperidine-1-carboxylic acid. The resulting 4-hydroxy-4-({[(lr,4〇-) 3-(Methoxycarbonyl)cyclohexyl]methylamino}methyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 1,4-dioxane (20 mL), and 1,1'-carbonyl was added. two Imidazole (1 g, 66 mmol) was stirred at 90 ° C for 2 days. After the reaction was completed, the reaction solvent was distilled off under reduced pressure to give water (50 mL), 1 M hydrochloric acid (100 mL) and chloroform. (200 mL), the organic layer was separated by shaking and standing, and the organic layer obtained from -130-201211053 was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-{[(lr, 4r)-4. -(methoxycarbonyl)cyclohexyl]methyl b 2-oxo-1.ox-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.3 g, yield 54 %) pale yellow amorphous lH-NMR (3 00MHz, CDCl3) 5: 1.03 (2H, dq, J = 3.3, l 2.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.5 2-l .62 (lH, m), 1.66 (2H, ddd, J = l 1.9, 12.2, 4.6 Hz), 1.77 (2H, brd, J = 13.2 Hz), 1.88 (2H) ,brd,J = 13.2Hz), Lu 2.02(2H,brd,J=13.5Hz), 2.26(lH,tt,J=12.2,3.3Hz),3.10(2H,d,J = 7.3

Hz), 3.26 (2H, s), 3.27 (2H, brt, J = U.6 Hz), 3.67 (3H, s), 3.75-3.97 (2 H, b rm) 〇

Φ Reference Example 2-3 (11*,4〇-4-{[8-〇-butoxycarbonyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3 Preparation of -yl]methyl}cyclohexanecarboxylic acid 3-{[(lr,4r)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-side oxygen obtained in Reference Example 2-2 1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.9 g, 4.5 mmol) dissolved in 1,4-dioxane (40 mL), 1 M hydr Aqueous sodium (6.8 m L, 6 · 8 mm ο 1 ) was mixed at room temperature for 3 hours. After the completion of the reaction, the 1,4-dioxane was distilled off under reduced pressure, and then 1 M hydrochloric acid (6.8 mL) and ethyl acetate (40 mL) were added to the residue mixture, and the organic layer was separated from -131 - 201211053. . The obtained organic layer was concentrated to dryness under reduced pressure to give (1. 4 〇-4-{[8-(^butoxycarbonyl)-2-oxooxy-1-oxo-3,8-diazo snail. [4.5] Colorless amorphous material of decane-3_yl]methyl}cyclohexanecarboxylic acid (1. 9 g, quantitative). 1H-NMR (3 00 MHz, CDCl3) 5: 1.03 (2H, dq, J =3.3,12.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.5 2-1.62 (lH, m), 1.66 (2Hiddd, J=l 1.9, 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 (lH, tt, J = 12.2, 3.3) Hz), 3.10(2H, d, J = 7.3Hz)>3.26(2H,s), 3.27(2H,brt,J = l 1.6Hz), 3.75-3.97(2H,brra )0

LC/MS [Condition 1]: Hold time 3.65 min; m/z 395 [M-Hr (ESI negative ion mode)

Example 2 2-Sideoxy-3-([(lr,4r)-4-{[(tetrahydrofuran-2-yl)methyl]aminemethanyl}cyclohexyl)methyl]-1-oxo-3, Manufacture of 8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 2) will be obtained in Reference Example 2-3 (丨!",41:)-4-{[8- (1-Butoxycarbonyl)-2_ sideoxy·1_oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid-132- 201211053 (700 mg, 1.7 Methyl) was dissolved in chloroform (14 mL), tetrahydrofurfurylamine (0.26 mL, 2.5 mmol), 1-benzobenzotriazine (230 mg, 1.7 mol) and 1-ethyl-3-(3-) Methylaminopropyl)carbodiimide hydrochloride (480 mg, 2.5 mmol) was stirred and mixed at room temperature for 4 days. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and chloroform was evaporated, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the organic layer was separated. The organic layer is decompressed

Concentrated to dryness to give 2-oxooxy-3-[((lr,4r)-4-{[(tetrahydrofuran-2-yl)methyl]aminemethanoyl}cyclohexyl)methyl]-1-oxole a colorless amorphous material of -3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (87 Omg, quantitative).

1H-NMR (300MHz, CDCl3) 5: 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 (1 H, m), 3.26 (2H, s), 3.26-3.32 (2H, m), 3.54-3.62 (lH, m), 3.72-3.78 (lH, m), 3.82 - 3.98 (4H, m).

Example 3 (11:,4〇-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran- Preparation of 2-yl)methyl]cyclohexanecarbamamine hydrochloride (Compound No. 3) 2-sided oxo-3-[((lr,4r)-4-{[(tetrahydrofuran) obtained in Example 2 -2-yl)methyl]amine-carbamoyl}cyclohexyl)methyl]-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (l.: 2 g , 2.4mmol) dissolved in methanol (2〇mL) -133- 201211053 'Add 4 Μ hydrogen chloride-dioxane solution (3 · 〇m L, 丨 2 mm〇1) at room temperature, 1 at 5 °C After stirring for a day, the reaction was completed, and concentrated to dryness under reduced pressure to give (lr, 4r)-4-[(2-oxo-oxo-oxa-3,8-diazospiro[45]decane_3_ Methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexylcarbamidine hydrochloride, quantitative) colorless amorphous material. ^-NMRiSOOMHZjDMSO-deiSrO.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 = 6.6Hz), 3.08-3.16(6H,m), 3.40(2H,s), 3.45-3.62(3H,m),7.8 l(lH,brs),9.23-9.32(2H, Brm). [化8 8]

Example 4 (lr,4r)-4-{[2-Sideoxy-8-(pyridin-3-ylmethyl)-1-oxo-3,8-diazospiro[4·5]nonane-3 Preparation of -yl]methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 4) (lr, 4r)-4-[(2) obtained in Example 3. -Side oxy-1 -oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamidine hydrochloride The salt (50 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), and triethylamine (5 mL, 0.33 mmol) and 3-(bromomethyl)pyridine were added at room temperature. The hydrogen bromide (49 mg, 0.17 mmol) was stirred and mixed at room temperature for 1 day. After the completion of the reaction, ethyl acetate was added, and the mixture was washed with water, and dried over anhydrous sodium sulfate - 134 - 201211053 and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [塡 剂: FUJI SILYSIA FL100D, developing solvent: chloroform / methanol = 30/1] to obtain (lr, 4r)-4-{[2- side Oxy-8-(pyridin-3-ylmethyl)-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}-N-[(tetrahydrofuran-2-yl)- A colorless amorphous material of cyclohexanecarbamide (2.9 mg, yield 4%). 1H-NMR (300MHz, CDCl3) 6: 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 (lH, m), 3.73-3.78 (lH, m), 3.84-3.8 6 (lH, m), 3.92-3.94 (lH, m), 5.81 (lH, brs), 7.25 (lH, Dd, J = 7.7, 5.1 Hz), 7.64 (lH, d, J = 7.7 Hz), 8.5 1 (lH, d, J = 5.1 Hz), 8_56 (lH, s).

[化8 9] Ο

Example 5 (lr,4r)-4-({8-[2-(ethylthio)ethyl]-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3 -Methyl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (Compound No. 5) was produced by substituting 3-(bromomethyl)pyridine hydrobromide using 2- The same reaction as in Example 4 was carried out, except for the bromoethylethyl sulfide, to give the title compound 135-201211053 (3.1 mg, yield 7%) as a colorless powder. 1H-NMR (300 MHz, CDC13) 6: 0.96-1.08 (2H, m), 1.27 (3H, t, J = 7.2 Hz) 1.43-1 · 60 (4 Η, 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 (lH, m), 3.25 (2H, s ), 3.55-3.63 (lH, m), 3.7 1- 3.98 (3H, m), 5.8 1 (lH, brs). [化9 0]

Reference Example 6-1 (lr, 4r)-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4·5]decan-3-yl)methyl]cyclohexanecarboxylate The production of acid methyl hydrochloride will be described in Reference Example 2-2 for 3-{[(lr,4r)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-oxan-1-one-3. 8-Diazanespiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.4 g, 5-8 mmol) was dissolved in methanol (30 mL), and 4 M hydrogen chloride-di chewing solution (15 mL, 58 mmol) was added at 0 °C. After warming to room temperature, stirring was carried out for 1 day, followed by concentration and concentration under reduced pressure to obtain (lr, 4r)-4-[(2-oxo-oxo-oxa-3,8-diazoxil [4.5] A white powder of decyl-3-yl)methyl]cyclohexanecarboxylic acid methyl hydrochloride (2. lg, quantitative). i-NMRpOOMHz.CDClW] .02 (2H, q, J = 12.3 Hz), l .42 (2H, q, J = 12·7Ηζ), 1.5 1-1.66 (1 H, m), 1.76 (2H, d , J=ll, 5Hz), 1.97-2.15( 4H,m), 2.19-2.41(3H,m), 3.11(2H,d,J = 7.4Hz),3.21-3.40(4H,m ),3.4h3. 55 (2H, m), 3.67 (3H, s), 9.75 (2H, brs). LC/MS [Condition 1]: Hold time 0.82 min; m/z 311.0 [M + H] + -136- 201211053 (ESI positive ion mode) [Chem. 9 1]

Reference example 6 - 2

(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- The production of methyl}methyl)cyclohexanecarboxylic acid methyl group will be referred to the (lr, 4r)-4-[(2-oxo-1,oxan-3,8-diazoxan] obtained in Synthesis Example 6-1. 4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid methyl hydrochloride (2. lg, 5.9 mmol) was dissolved in N,N-dimethylformamide (22 mL) at room temperature 4-(Trifluoromethyl)benzyl bromide (1.6 g, 6.5 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 to obtain (lr,4〇-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3). , white powder of methyl 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylate (2.6 g, yield 94%). 1H-NMR (300 MHz, CDCl3) 5: 0.93 -l.ll(2H,m),1.3 3- 1.49(2H, m), l .50-1.66(lH,m),1.70-1.86(4H,m),1.8 8-2.08(4H)m), 2.25 (lH, tt, J = 12.1, 3.5 Hz), 2.57 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.5 8 (2H, brs), 3.66 ( 3H, s), 7.33-7.72 (4H, brm). LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 469.2 [M + H] + (ESI positive ion mode), m/z 512.9 [M + HC〇0] _ (ESI negative ion mode) - 137 201211053 【化9 2】

Reference Example 6-3 (1>*, 4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ 4.5] Production of decyl-3-yl}methyl)cyclohexanecarboxylic acid (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoro)) obtained in Reference Example 6-2 Methyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylate (2.6 g, 5.6 mmol) was dissolved in methanol ( After 28 mL), a 1 M aqueous sodium hydroxide solution (8.4 mL, 84 mmol) was added at room temperature, and the mixture was mixed at 60 ° C for 1 hour. Thereafter, the mixture was concentrated under reduced pressure, and then methanol was evaporated and water (25 mL) was added. 1M hydrochloric acid was added to pH 6 in the day, and the precipitated solid was filtered to obtain (lr, 4r)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxole a white powder of 3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (2.38, yield 90%). 1H-NMR (300 MHz, CDC 13) 6: 0.94 1,13(2H,m),1.33-l .5 1(2H,m),1 .51-1 .68(lH,m), 1.72-2:14(8H,m), 2.20-2.35(lH , m), 2.61 (4 H, brs), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.61 (2H, brs), 7.45 (2 H, d, J = 7.4 Hz) , 7, 59 (2H, d, J = 8.2 Hz) LC/MS [Condition 1]: Keep Between 2.90 minutes: m / z454.8 [M + H] + (ESI positive ion mode), m / z452.9 [M-H] - (ESI negative ions to the mode) -138-201211053 of [93]

Example 6 4-[(lr,4r)-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5 Manufacture of decyl-3-yl}methyl)cyclohexanecarbamide]piperidine-1-carboxylic acid third φ butyl ester (Compound No. 6) (lr, 4r) obtained in Reference Example 6-3 -4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) Cyclohexanecarboxylic acid (92 mg, 0.20 mmol) and 4-aminopiperidine-carboxylic acid tert-butyl ester (45 mg, 0.22 mm 〇l), and 1-hydroxybenzotriazole (27 mg, 0.20 mol) After dissolving in chloroform (1.0 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.22 mmol) was added at room temperature. Stir and mix for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure. chloroform was evaporated, and ethyl acetate and saturated aqueous sodium The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-[(lr, 4r)-4-({2-s. ]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine] piperidine-1-carboxylic acid tert-butyl ester (120 mg, yield 89 %) of white powder. 1H-NMR (3 00MHz, CDCl3) 5: 1.01 (2H, qd, J = 13.1, 3.3 Hz), 1.27 (2H, qd, J = 1.9, 4.1 Hz), 1.39-1.67 (1 3H, 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 - 139 - 201211053 (2H, s), 3.81-3.98 (lH, m), 3.97-4.12 (2H, brm), 5.42 (lH, 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]: Hold time 3.46 minutes; m/z 636.9 [M + H] + (ESI positive ion mode), m/z 681.0 [M + HCO〇r (ESI negative ion mode) 9 4]

Example 7 (11:, 4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Manufacture of alk-3-yl}methyl)-N-(piperidin-4-yl)cyclohexanecarbamamine 2 hydrochloride (Compound No. 7) 4·[(1γ,4) obtained in Example 6. 〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl Cyclohexanecarbamamine] piperidine-1-carboxylic acid tert-butyl ester (49 mg, 0.077 mmol) was dissolved in methanol (0.50 mL), and 4 M hydrogen chloride-dioxane solution (0.19 mL, 0.7) was added at room temperature. 7 mmol), stirred at room temperature for 1 day, and then concentrated and concentrated under reduced pressure to give (lr, 4r)-4-({2-s. Benzyl]-1·oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)-N-(piperidin-4-yl)cyclohexanecarbamamine 2 hydrochloride (47 mg, quantitative) of white powder. LC/MS [Cond. 1]: retention time 1.10 min; m/z 536.8 [M + H] + (ESI positive ion mode), m/z 581. 〇 [M + HCO 〇r (ESI negative ion mode) -140 - 201211053 [Chem. 9 5]

Example 8 4-[(11',4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]_1-oxa-3,8-heavy] 4.5] 癸院-3-基}methyl) Cycloheximide methamine]Methylpyrrolidine-methyl decanoate (Compound No. 8) was produced in Example 7 (lr, 4r)-4-( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)-N-( Piperidin-4-yl)cyclohexanecarbamide 2 hydrochloride (20 mg, 〇. 〇33 mmol) was dissolved in ethyl acetate (1.0 mL), and then triethylamine (? 17.17 mmol) and methyl chloroformate (〇.〇38 mL, 0.050 mmol) were stirred and mixed at room temperature for 1 day. Thereafter, water was added and the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate. Concentration and concentration under reduced pressure gave 4-[(lr,4r)-4-({2- oxo- 8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- White powder of methyldiazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine]piperidine-1-carboxylate (4.3 mg, yield 22%). 1H-NMR (300 MHz , CDCl3) 6: 1.00 (2H, qd, J = 12.7, 2.5 Hz), 1.20 - 1.38 8 (2H, m), 1.3 9-1.6 7 (3H, m), 1. 7 0-2.06 (1 lH, 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 (2 H, s), 3.69 (3H, s), 3.82-4.00 (lH, m), 4.00-4.24 ( 2H, m), 5.46 (lH, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) » -141 - 201211053 LC/MS [Conditions 1]: Hold time 3·16 minutes; m/z 595.0 [M + H] + (ESI positive ion mode),

Example 9 (1Bu 4〇-1^-[1-(cyanomethyl)piperidine-4-yl]-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene) Manufacture of methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 9) (lr, 4r)-4-({2·Sideoxy_8_[4-(trifluoromethyl)benzyl}]oxan-3,8-diazospiro[4.5]decane-3-yl}methyl ->^-(piperidin-4-yl)cyclohexanecarbamide 2 hydrochloride (15 mg, 0.024 mm 〇l) was suspended in ethyl acetate (1.0 mL). The amine (〇.〇17 mL, 0.12 mmol) and bromoacetonitrile (0.020 mL, 0.029 mmol) were stirred and stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure and the residue was obtained. Purification by ruthenium column chromatography [塡 :: FUJI SILYSIA FL 1 00D, developing solvent: chloroform/methanol = 1 0/1] gave (11*,4〇->1-[1-(cyanide) Methyl)piperidin-4-yl]-4-({2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5 a white powder of decyl-3-yl}methyl)cyclohexanecarbamide (1.8 mg, yield 13%). 1H-NMR (300 MHz, CDC 13) 6: 1.01 (2H,q,J=l 2 .7Hz), 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 -142- 201211053 ,2·5Ηζ), 2.6 l (4H, brs), 2.72-2.82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.2 5 (2H, s), 3.50 (2H, s), 3.57 (2H, s) , 3.72-3.90 (lH, m), 5.3 0 (lH, 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]: Hold time 2.92 minutes; m/z 575.9 [M + H] (ESI positive ion mode), m/z 620.0 [M + HCOO]- (ESI negative ion mode) [Chem. 9 7]

Example 1 〇(11*,41〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 10)

(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (41 mg, 0.090 mmol) and tetrahydrofurfurylamine (〇.〇〇9〇mL, 0.090 mmol)' and 1-hydroxybenzotriene After azole (12 mg, 0.090 mol) was dissolved in chloroform (1.0 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, O) was added at room temperature. .llmmol), stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated under reduced pressure and the chloroform was evaporated. The organic layer was separated from ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (lr, 4r) -4- ({2- s. - cacao - -143- 201211053 3,8-diazospiro[4.5]nonan-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine ( 41 mg, yield 85%) of a white powder. 'Η-ΝΜΚ(300ΜΗζ,α〇αΐ3)δ: 1.02 (2Η,ς(1,Ι=11.5,2.0Ηζ), 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)s3.52-3.63 (3H,m),3.69-3.80( 1H,m),3.88- 3.80 (1 Η, m), 3.99-3.89 (lH, m), 5.8 l (lH, s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC/MS [Condition 1]: Hold time 2.98 min; m/z 53 7.8 [M + H] + (ESI positive ion mode), m/z 5 82_0 [M + HCOO] _ (ESI negative ion mode) [Chem. 9 8]

Example 1 1

(lr,4r)-N-(l-methoxybutan-2-yl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxole Preparation of 3-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 11) Substituted tetrahydrofurfurylamine using 2-amino-1-lane The title compound (20 mg, yield 78%) was obtained as white powder. IH-NMR (300 MHz, CDCl3) 5: 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), 3.3 1- 3.44 ( 144- 201211053 5H,m),3.57(2H,s),3.89-4.01(lH,m), 5.60 (lH,d,J = 9.0Hz), 7.44 (2H,d,J = 8.2Hz),7.57( 2H, <i, J = 8.2 Hz). LC/MS [Condition 1] ··Retention time 3.16 min; m/z 539.8 [M + H] + (ESI positive ion mode), m/z 584.0 [M + HCOO] _ (ESI negative ion mode)

[化9 9]

Example 1 2 2-[(1. 4〇-4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [ Preparation of 4.5]decane-3-yl}methyl)cyclohexanecarbonyl]diamine carboxylic acid tert-butyl ester (Compound No. 12) Substituted tetrahydrofurfurylamine, using ethyl methacrylate The same reaction as in Example 1 was carried out to give the title compound (140 mg, yield 95%) as white powder. 1H-NMR (300 MHz, CDCl3) 5: 1.03 (2H, q, J = 12.7 Hz) , 1.42- 1.64( 1 2H,m),1.72-1 · 84(4H,m),1.89-2.01(4H,m),2.02-2.16(1 H,m) ,2.56(4H,brs),3.10( 2H,d,J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 6.44 (lH, s), 7.18 (lH, s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H,d,J = 8.2 Hz) o LC/MS [Condition 1]: Hold time 3.16 min; m/z 5 68.8 [M + H] + (ESI positive ion mode), m/z 567.0 [MH] _(ESI negative ion mode) -145- 201211053 【化1 ο ο】

Example 13 (lr, 4r)-4-({2-Sideoxy-8-(4-(dimethyl))methyl]_1_oxo-3,8-diazospiro[4.5]decane Manufacture of 3-[(lr,4r)-4-({2-lateral oxygen-8-) obtained in Example 12, _3-yl}methyl)cyclohexanecarbazide hydrochloride (Compound No. 13) [4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]diaminecarboxylic acid tert-butyl The ester (63 mg, 0.11 mmol) was dissolved in methanol (0.50 mL), and 4M hydrogen chloride-dioxane solution (.28 mL, 1.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. Thereafter, it was concentrated to dryness under reduced pressure to give (lr, 4r)-4-({2-s.s.s.s. A white powder of diazanespiro[4.5]decane-3-yl}methyl)cyclohexanecarbazide hydrochloride (60 mg, quantitative). LC/MS [Condition 1]: Hold time 3.24 minutes; m/z 468.8 [M + H] + (ESI positive ion mode) [Chemical 1 0 1]

Reference Example 1 4 - 146 201211053 Manufacture of 2-(tetrahydrofuran-2-yl)acetic acid

Ethyl 2-(tetrahydrofuran-2-yl)acetate (purchased from Tokyo Chemical Industry Co., Ltd.) (〇.94 g, 6.0 mmol) was dissolved in methanol (6.0 inL), and a 1 M aqueous sodium hydroxide solution (9.0 mL, 9.0) was added. Methyl), mixed at room temperature for 3.5 hours. After 1 M hydrochloric acid (9.0 mL) was added to the reaction mixture and neutralized, 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 (MgSO4). H-NMR (300MHz, CDCl3) S: 1.58 (lH, dq, J = 12.3, 7.8 Hz), 2.02-1.84 (2H, m), 2.U (lH, dtt, J = 11.9, 7.4, 6.1 Hz) ), 2.56 (lH, dd, J = 15.6, 5.7 Hz), 2.62 (lH, dd, J = 15.6, 7.4 Hz), 3.80 (lH, dt, J = 8.6, 7.0 Hz), 3.92 (lH, dt, J = 8.2, 7.0 Hz), 4.26 (lH, tt, J = 6.5, 6.5 Hz) » LC/MS [Condition 1]: Hold time 0.73 min; m/zl 30.9 [M + H] + (ESI positive ion Mode) 【化1 0 2

Example 1 4 (lr, 4r)-4_({2_Sideoxy-8_[4-(trifluoromethyl)benzyl]]indole-oxo-3,8-diazospiro[4.5]decane- Manufacture of 3-hexane}methyl)-oxime-[2-(tetrahydrofuran-2-yl)ethenyl]cyclo-147-201211053 hexane carbaryl (Compound No. 14) obtained in Example 13 (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Cyclohexylcarbazide hydrochloride (42 mg, 0.077 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid (15 mg, 0.12 mmol) obtained in Reference Example 14 and 1-hydroxybenzotriazole ( 10 mg, 0.077 mmol) was dissolved in chloroform (1.0 mL), and triethylamine (〇.〇 54 mL, 0.39 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) were added at room temperature. The carbodiimide hydrochloride (16 mg, 0.085 mmol) was stirred and mixed at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. chloroform was evaporated. Thereafter, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give (11 ", 4 〇 -4- ({2- s. ]]-1-oxo-3,8-diazospiro[4_5]decane-3-yl}methyl)-Ν'-[2-(tetrahydrofuran-2-yl)ethenyl]cyclohexane (25 mg, yield 55%) of white powder. 1H-NMR (3 00 MHz, CDC 13) 6: 1.02 (2H, q, J = 12.7 Hz), 1.43-1, 67 (4H, m), l.71- 1.8 5(4H,m),2.17-1.86(8H,m),2.41-2.62(6H,m),3.09( 2H,d,J = 7.4Hz),3.2 5(2H,s),3.57(2H, s), 3.81 (lH, q, J = 6.5 Hz), 3.96 (lH, q, J = 7.0 Hz), 4.10-4.22 (lH, m), 7.43 (2H, d, J = 8.2 Hz), 7.56 ( 2H,d,J = 8.2Hz), 8.05 ( lH,d,J = 4.5Hz), 9.08 ( lH,d,J = 4.5Hz) LC/MS [Condition 1]: Hold time 2.81 minutes; m/z5 80.9 [M + H] + (ESI positive ion mode), m/z 579.1 [MH]-(ESI negative ion mode) -148- 201211053 [Chemical 1 0 3]

Example 1 6 3-{[(lr,4r)-4-(piperidin-1-carbonyl)cyclohexyl]methyl}_8_[4_(trifluoromethyl)benzyl]-1-cax-3, Lu manufacturing of 8-diazospiro[4.5]decane-2-one (compound number 16)

(ir, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (66 mg, 0.15 mm 〇l) with piperidine (〇.〇i 6 mL, 0.16 mmol), and 1-hydroxybenzotriazole (20 mg, After dissolving in chloroform (1.0 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) was added at room temperature. Stirring was carried out for 3 days at room temperature. After the reaction mixture was concentrated under reduced pressure, chloroform was evaporated, and ethyl acetate and saturated aqueous sodium hydrogen The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (purification: FUJI SILYSIA FL100D, developing solvent: chloroform/methanol = 10/1). After purification, 3-{[(lr,4r)-4-(piperidin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo- 3,8-diazospiro[4.5]nonane-2-one (4411^, yield 57%) of white powder " 1H-NMR (300MHz, CDCl3) 6:1.04 (2H,q,J=l 1.9 Hz), 1.46-1.70( -149- 201211053 9H,m),l.70- 1.86(6H,m),l.88-2.00(2H,m),2.3 8-2.5 1(1 H,m), 2.56(4H5brs), 3.10(2H,d,J = 7.4Hz), 3.25(2H,s), 3.41(2H,t,J = 5.1 Hz), 3.49-3.62(4H,m),7.43(2H,d , J = 7.8Hz), 7.56 (2H, d, J = 8.2

Hz) 〇LC/MS [Condition 1]: Hold time 3.30 minutes; m/z 521.9 [M + H] + (ESI positive ion mode), m/z 566.0 [M + HCOO]- (ESI negative ion mode) [化1 0 4]

Reference Example 1 7 -1 (lr, 4r)-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane- Preparation of 3-yl]methyl}cyclohexanecarboxylic acid methyl group (lr,4r)-4-[(2-Sideoxy-1-oxo-3,8-diazo snail) obtained in Reference Example 6-1 [4.5] decyl-3-yl)methyl]cyclohexanecarboxylic acid methyl hydrochloride (91 Omg, 2.6 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature 4-Cyanobenzyl bromide (570 mg, 2.9 mmol) and triethylamine (1.1 mL, 7.9 mmol) were added, and the mixture was stirred at room temperature for 1 day. Thereafter, 100 mL of water was added, and the precipitated solid was collected by filtration to obtain (lr, 4r)-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8- A white powder of methyl diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylate (1.0 g, yield 92%).

'H-NMR (300MHz, CDC13) 5: 1 .〇2(2H,q,J= 12.3Hz), 1.41(2 H,q,J =1 2·3Ηζ), 1.49-1.66(1H,m) , 1.70-1.85 (4H,m) , 1.88-2.07 (4 H,m), 2.25 (lH,tt,J=12.3,4.5Hz), 2.50-2.61(4H,brm),3.09(2H,d,J = 7.4 Hz -150 - 201211053 ), 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]: Hold time 2.61 min; m/z 425.9 [M + H] (ESI positive ion mode), m/z 47 〇.l [M + HCO〇r (ESI negative ion mode)

[化1 〇 5]

Reference Example 1 7 - 2 (1]:, 4〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4_5]癸Manufacture of alk-3-yl]methyl}cyclohexanecarboxylic acid

(lr, 4r)-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]癸 obtained in Reference Example 17-1 Methyl alk-3-yl]methyl}cyclohexanecarboxylate (1.0 g, 2.4 mmol) was dissolved in methanol (10 mL), and 1M aqueous sodium hydroxide (3.6 mL, 3.6 mm 〇1) was added at room temperature. Mix at 3 °C for 3 hours. After the reaction mixture was concentrated under reduced pressure, methanol was evaporated, and water (4.0mL). 1M hydrochloric acid was added to pH 6, and the precipitated solid was filtered to give (lr, 4r)-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-weight A white powder of N. sulph[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid (1.0 g, quantitative) 0 1H-NMR (300 MHz, DMSO-d6) 5: 0.92 (2H, q, J= 13.1 Hz), 1.27( 2H,q,J=12.7Hz), l .42-2.2 0(10H,m),2.3 0-2.5 9(6H,brm),2.97( 2H,d,J = 7.0 Hz), 3.34 (2H, s), 7.33 - 8.12 (4H, m), 12.02 (lH, s). -151 - 201211053 LC/MS [Condition 1]: Hold time 1.04 minutes; m/z41 1.9 [M + H] (ESI positive ion mode) [Chemical 1 0 6]

Example 1 7 4-((lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4·5] Manufacture of decyl-3-yl]methyl}cyclohexanecarbamamine) piperidine-1-carboxylic acid tert-butyl ester (Compound No. 17) (lr, 4r)-4 obtained in Reference Example 17-2 -{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid ( llOmg, 0.26 mmol), 4-aminopiperidin-1-carboxylic acid tert-butyl ester (58 mg, 0.29 mmol), and 1-p-benzobenzotriazine (35 mg, 0.26 mol) were dissolved in N,N- After dimethylformamide (1.0 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg, 0.29 mmol) was added at room temperature. Stir and mix for 1 day. Thereafter, chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 4-, 4-,,,,,,,,,,,,,,,,, , 8 - Diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbazide) piperidine-1-carboxylic acid tert-butyl ester (70 mg, yield 45%) as a white solid. 1H-NMR (300MHz, CDCl3) 6: 1.01 (2H, qJJ = 11.5 Hz), 1.19-1.36 (-152-201211053 2H, m), 1.38-1.68 (1 3H, m), 1.69-2.06 (1) OH, m), 2.56 (4H, brs), 2.84 (2H, t, J = 12.9HZ), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, S), 3.57 (2H, S), 3.82-4.13(3H,m), 5.29 (lH,d,J = 8.2Hz), 7.44 (2H,d,J = 7.4Hz), 7·6 1 (2H,d,J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.16 min: m/Z 594.0 [M + H] + (ESI positive ion mode), m/z 638.2 [M + HCOO] - (ESI negative ion mode) 0 7]

Reference Example 1 8 (lr, 4〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4·5]decane- Manufacture of 3-yl]methyl}-N-(piperidin-4-yl)cyclohexanecarbendamine 2 hydrochloride

4-((lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-oxo- 3,8-diazo snail [4.5] obtained in Example 17. Decyl-3-yl]methyl}cyclohexanecarbamamine) piperidine-1-carboxylic acid tert-butyl ester (64 mg, 0.1 mmol) was dissolved in methanol, and 4 M hydrogen chloride-dioxane was added at room temperature. The solution (〇28 mL, 1.1 mmol) was mixed at 60 ° C for 1 hour. Thereafter, concentration and drying under reduced pressure gave (11:,4〇-4-{[8-(4-cyanobenzyl)-2-sideoxy-1_oxo-3,8-diazo snail [ 4. 5] decyl-3-yl]methyl}-N-(piperidine-4-yl)cyclohexanecarbamimidamine 2 hydrochloride (64 mg, quantitative) of a green solid. -153- 201211053 LC/ MS [Condition 1]: Hold time 0.53 min; m/z 493.9 [M + H] + (ESI positive ion mode), m/z 528.1 [M + Cir (ESI negative ion mode) [Chem. 1 0 8]

Example 1 8 4-((11*,4〇-4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazo snail [4·5 Production of methyl decyl-3-yl]methyl}cyclohexanecarbamamine) piperidine-1-carboxylate (Compound No. 18) (lr, 4r)-4-{[ 8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}-N-(piperidin-4- Base Cyclocaramine 2 hydrochloride (17 mg, 0.030 mmol) was dissolved in N,N-dimethylformamide (〇.50 mL), and triethylamine (〇.〇 21 mL, 0.15 mmol) and methyl chloroformate (40 mL, 0.045 mmol) were mixed at 60 ° C for 3 hours. Chloroform and water were added to the reaction mixture, and the organic layer was separated. After drying, the mixture was concentrated to dryness under reduced pressure to give 4-((1]*,4〇-4-{[8-(4-cyanobenzyl)-2-oxoxy-1-oxo-3,8 - diazaspiro[4.5]decane-3-yl]methyl}cyclohexanecarbamamine) piperidine-1-carboxylic acid methyl ester (6.2 mg, yield 36%) as a white solid. 300MHz, CDCl3) 5: 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), l .83-2.05(7H,m) -154- 201211053 ,2.55 (4H, brs), 2.89 (2H, t, J = 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 (lH, m), 4.08 (2H, brs), 5.30 (lH, 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]: Hold time 2.69 minutes; m/z 551.9 [M + H] + (ESI positive ion mode)

[化1 Ο 9]

Example 1 9 (11*,4〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3 Manufacture of -methyl]methylcyanomethyl)piperidin-4-yl]cyclohexanecarboxamide (Compound No. 19)

Substituting the methyl chloroformate, the same reaction as in Example 18 was carried out, except using bromoacetonitrile, to give the title compound (2.4 m, yield: 13%) as a white solid. 1H-NMR (3 00MHz, CDC13) 6: 1 .〇1 (2H, qs J = 1 3.1 Hz), 1.38-1.65 (5H, m), 1.70-1.84 (4H, m), 1.84-2.06 (7H, m), 2.45 (2H, t, J = l 1,0 Hz), 2.5 6 (4 H, brs), 2.71-2.82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H) ,s), 3.5〇(2H,s),3.56(2H,s),3.74-3.89(lH,m),5.27(lH,d,J = 7.8Hz),7.43(2H, d,J = 7.8Hz ), 7.60 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 1.08 min; m/z 5 3 2.7 [M + H] + -155- 201211053 (ESI positive ion mode), m/z 567.0 [M + Cir (ESI negative ion mode) [ 1 1 0]

Example 2 0 (lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3- Preparation of methyl imino}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 20) substituted 4-aminopiperidine-1-carboxylic acid tert-butyl ester, used The title compound (13 mg, yield 32%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 5: 1.02 (2H, q, J = 11.6Hz), 1.66-1.39 (4H, m), 1.7 1-2.1 0 (1 2H, 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 (lH, m), 3.80-3.89 (lH, m), 3.8 9- 3.99 (lH, m), 5.79 (lH, t, J = 5.3 Hz), 7.44 (2H, d, J = 8_2 Hz), 7·6 1 (2H, d, J = 8 · 2Ηζ). LC/MS [Condition 1]: Hold time 1.42 minutes; m/z 494.9 [M + H] + (ESI positive ion mode), m/z 5 3 9.0 [M + HCOO] - (ESI negative ion mode) 1 1]

-156- 201211053 Reference Example 2 1 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene-1-oxa-3,8-diazospiro[4.5]decane-3 -Based on the manufacture of methyl benzoic acid

4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- obtained in Example 1. Methyl methicone methyl ester (5.2 g, ll mmol) was dissolved in a solvent mixture of methanol-tetrahydrofuran (25 mL - 25 mL), and 1 M sodium hydroxide aqueous solution (56 mL, 56 mmol) was added, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled, EtOAc (EtOAc) Water (20 mL) and 1 M hydrochloric acid (56 mL, 56 mmol) were added to the obtained pale yellow liquid. After the precipitated solid was collected by filtration, dried at 50 ° C under reduced pressure to give 4-({2-s.s. 8- Diazospiro[4.5]decane-3-yl}methyl)benzoic acid (4.7 g, yield 94%) as a white solid.

1H-NMR (300MHz, DMSO-d6) 5:1.67-1.85 (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 = 8.2H z), 7.5 1 (2H, d, J = 8.2Hz), 7.67 (2H, d, J = 8.2Hz), 7.92 (2H, d, J = 8. 2Hz). LC/MS [Condition 1]: Hold time 2.89 minutes; m/Z 448.8 [M + H] + (ESI positive ion mode), m/z 446.9 [MH] — (ESI negative ion mode) -157- 201211053 1 1 2]

Example 2 1 4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)phenylmethyl)-oxa-3,8-diazospiro[4.5]decane-3- Manufacture of tert-butyl methacrylate] piperidine-1-carboxylic acid tert-butyl ester (Compound No. 21) 4-({2- Side Oxygen-8-[4-(III) obtained in Reference Example 21. Fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (50 0m g, 1.1 mmol), 4-amino group Piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol), and 1-hydroxybenzotriazole (1 5 Omg, 1.1 mol) were dissolved in chloroform (6.0 ml) at room temperature After adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg, 1.2 mmol), the mixture was stirred for 1 day. After the reaction mixture was concentrated under reduced pressure, chloroform was evaporated, and ethyl acetate (20 mL) was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-[4-({2-s.s. A white powder of 3,8-diazospiro[4·5]decane-3-yl}methyl)benzamide = piperidine-1-carboxylic acid tert-butyl ester (680 mg, yield 97%). 'H-NMR (300MHz, CDC13) 5: 1.5 1-1.33 (1 lH, 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=12.1Hz),3.11(2H,s),3.55(2H,s),4.02-4.21(3H,m),4.46 -158- 201211053 (2H, s) , 6.00 ( lH, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.4 1 (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]: Hold time 3.46 minutes; m/z 631.0 [M + H] + (ESI positive ion mode), m/z 675.2 [M + HCOO] - (ESI negative ion mode)

[1 1 3]

Reference example 22

4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)- Preparation of N-(piperidin-4-yl)benzamide 2 hydrochloride The 4 - [ 4 - ({ 2 - side oxo-8 - [ 4 - (trifluoromethyl)) obtained in Example 2 1 Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide>piperidine-1-carboxylic acid tert-butyl ester (680 mg, 1 -1 mmol) Dissolved in methanol (5.0 mL), and added 4 M hydrogen chloride-dioxane solution (2.7 mL, 1 1 mmol) at room temperature. Thereafter, the mixture was concentrated to dryness under reduced pressure to give 4-({2-s-oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5]. A white powder of decyl-3-yl}methyl)-N-(piperidin-4-yl)benzamide 2 hydrochloride (650 mg, quantitative). LC/MS [Condition 1]: Hold time 0.94 min; m/z 5 3 0.9 [M + H] + (ESI positive ion mode) ' m/z 575.1 [M + HCO〇] - (ESI negative ion mode) -159 - 201211053

[1 1 4] H3C

Example 22 4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Preparation of methyl}methyl)benzamide]piperidine-1-carboxylate (Compound No. 22) 4-({2-Sideoxy-8-[4-(trifluoromethyl) obtained in Reference Example 22 Phenylmethyl-1-pyro-3,8-diazospiro[4-5]nonan-3-yl}methyl)-> 1-(piperidin-4-yl) benzamide 2 salt The acid salt (213 mg, 〇.35 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), and triethylamine (0.25 mL, 1.8 mmol) and methyl chloroformate were added at room temperature. 〇 54 mL, 0.7 1 mm 〇 l), and 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 concentrated under reduced pressure to give 4-[4-({2-s.s. Methyl 3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide]piperidine-1-carboxylate (150 mg, yield 71%) as a white solid. ^-NMRiSOOMHz.CDCljja: 1.33-1.5 l(2H,m), 1.65- 1,79(2H,m), 1.84-1.96(2H,brm),l.99-2.1 0(2H,brm), 2.42-2.61 (4H, brm), 2.97 (2H, t, J = 11.9 Hz), 3.11 (2H, s) s 3.55 (2H, s), 3.70 (3H, s), 4.04-4.27 (3H, m ), 4.46(2H, s), 5.97 (lH, 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 = 8.2Hz), 7.73(2H,d,J = 8.2Hz -160- 201211053 LC/MS[Condition 1] ··Retention time 3.20 minutes; m/z588.9[M + H] (ESI positive ion mode ), m/z 633.1 [M + HCOO] _ (ESI negative ion mode) [Chemical 1 1 5]

Example 23: gas cyanomethyl hydrazine-cardiac 丨 丨 mouth-side oxygen ^-^^ trifluoromethyl) * methyl]-1-oxo-3,8-diazo snail [4.5 Production of decyl-3-yl}methyl)benzamide (Compound No. 23) Substituted methyl chloroformate 'Substantially reacted with Example 22 except 'bromoacetonitrile' to give the title compound (3 〇) Mg, yield 80%) of a white solid. LC/MS [Condition 1]: Hold time 2.92 minutes; m/z 569.9 [M + H] + (ESI positive ion mode), m/Z 614.0 [M + HCO〇r (ESI negative ion mode) 1 6]

-161 - 201211053 Example 24 &(1-Ethylpiperidin-4-yl)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1- Production of cacao-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 24) Substituting methyl chloroformate, substantially using an ethyl chloroformate The title compound (31 mg, yield 82%) was obtained as white solid. LC/MS [Condition 1]: Hold time 2.90 minutes; m/; z572.8 [M + H] 4 (ESI positive ion mode), m/Z6 16.9 [M + HCO〇r (ESI negative ion mode) 1 7]

Example 25 Heart [1-(Methylsulfonyl)piperidin-4-yl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxole Preparation of -3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 25) Substituting methyl chloroformate, using substantially methanesulfonyl chloride The same reaction as in Example 22 gave the title compound (3Omg, yield 75%) as a white solid. LC/MS [Condition 1]: Hold time 3.08 minutes; m/z 608.8 [M + H] + (ESI positive ion mode), m/z 652.9 [M + HCOO] _ (ESI negative ion mode) -162- 201211053 【化1 1 8】

Example 26 N-[l-(4-Chlorobenzyl)piperidin-4-yl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1 -Production of cacao-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (φ compound number 26) substituted methyl methyl chloroformate using 4-chlorobenzyl bromide The title compound (1 8 mg, yield 41%) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.08 min; m/z 654.9 [M + H] + (ESI positive ion mode) ' m/z 699.0 [M + HCOO] - (ESI negative ion mode)

Example 27 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of )-Ν-{1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}benzamide (Compound No. 27) Substituting methyl chloroformate, using 4-(three The fluoromethyl)benzyl bromide was reacted in the same manner as in Example 22 to give the title compound (27 mg, yield 60%) as a white solid. LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 689.0 [M + H] + (ESI positive ion mode), m/z 73 3_0 [M + HCOO] _ (ESI negative ion mode) 0]

Example 2 8 N-[ 1-(3-Methylbenzyl)piperidin-4-yl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl] Manufacture of 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 28) in place of methyl chloroformate using α-bromo-m- The title compound (22 mg, yield 51%) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.02 minutes; m/z 63 5.0 [M + H wide (ESI positive ion mode), m/z 679.1 [M + HCOO] - (ESI negative ion mode) [Chemical 1 2 1 】

-164- 201211053 Example 29 N-(l-Ethylpiperidin-4-yl)-4-({2-sideoxy- 8-[4-(dimethylmethyl)benzyl]_ 1 - Production of cacao-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 29) Substituting methyl chloroformate, using substantially other ethyl bromide The title compound (7.4 mg 'yield 20%.

LC/MS [Condition 1]: Hold time 1 · 1 6 minutes m/z 558.9 [M + H] (ESI positive ion mode) [Chem. 1 2 2] Ο

Example 3 0 φ 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl }Methyl)-NU-[4-(trifluoromethoxy)benzyl]piperidin-4-yl}benzamide (Compound No. 30) was produced by substituting methyl chloroformate, using 4-(three The title compound (30 mg, yield 66%) was obtained as a white solid, m. LC/MS [Condition 1]: Hold time 3.30 minutes; m/z 7 〇 5.3 [M + H] + (ESI positive ion mode), m/z 749.1. [M + HCO 〇r (ESI negative ion mode) - 165- 201211053 【化1 2 3】

Example 31 N - { 1 - [ 2 -(diethylamino)-2-oxoethyl]indole-4 -yl} - 4 - ({ 2 - side oxygen-8-[4-(three Manufacture of fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 31) will be obtained in Reference Example 2 4 - ({2 - oxo-8-[4-(trifluoromethyl)benzyl]-1-che- 3,8-diazo snail [4.5] 癸院-3-yl}methyl) -N-(峨dt-4-yl)benzamide 2 hydrochloride (40 mg, .0.066 mmol) was dissolved in n,N-dimethylformamide (4.0 mL), and then added at room temperature The amine (〇.〇46 mL, 0.33 mmol) and N,N-diethyl chloroacetamide (0.01 8 mL, 〇·13 mmol) were stirred and mixed at 40 °C. After the reaction mixture was concentrated under reduced pressure, N,N-dimethylformamide was evaporated. The obtained residue was purified by HP LC to give Ν-{1-[2-(diethylamino)-2-oxoethyl]piperidin-4-yl}-4-( {2- Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (17 mg, Yield 40%) of yellow solid aim. LC/MS [Condition 1]: Hold time 2.73 minutes; m/z 643.9 [M + H] + (ESI positive ion mode), m/z688.1 [M + HCOO] - (ESI negative ion mode) -166- 201211053 【化1 2 4 ]

Example 32 Ν-{1-[4-(Methylthio)benzyl]piperidin-4-yl}-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzene) Manufacture of N-N-diethyl chloroacetate by the preparation of 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzene φ carbamide (Compound No. 32) The title compound (13 mg, yield 30%) was obtained as a yellow solid, m. m. LC/MS [Condition 1]: Hold time 3.20 minutes; m/z 666.9 [M + H] + (ESI positive ion mode), m/z 7 10.9 [M + HCO〇r (ESI negative ion mode) [Chem. 1 2 5]

Example 33 N-[l-(Naphthalene-2-ylmethyl)piperidin-4-yl]-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]- Preparation of dioxa-3,8-diazospiro[4.5]nonan-3-yl}methyl)benzamide (Compound No. 3 3 ) in place of N,N-diethyl chloroacetamide, The title compound -167-201211053 (16 mg, yield 36%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3.34 minutes; m/z671 · 1 [M + H] + (ESI positive ion mode), m/z 715.0 [M + HCO〇r (ESI negative ion mode) 2 6]

Example 3 4 N-[l-(3-Nitrobenzyl)piperidin-4-yl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl] Manufacture of -1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 34) in place of N,N-diethyl chloroacetamide The title compound (14 mg, yield 32%) was obtained 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) 2 7]

Example 3 5 N-[ 1-(3-Chlorobenzyl)piperidin-4-yl]-4-( {2-o-oxo-8-[4-(trifluoromethyl)-168- 201211053 benzene Manufacture of methyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 35) substituted Ν,Ν·diethyl chloroacetate The title compound (13 mg, yield 30%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 654_9[M + H]+ (ESI positive ion mode), m/z 699.0 [M + HCO〇r (ESI negative ion mode) [Chem. 1 2 8 】

Example 3 6

N-[l-(3-methoxybenzylmethyl)oxime--4-yl]-4-({2-sideoxy-8-[4-(dimethylmethyl)benzyl]-1- Preparation of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 3 6) Substituting N,N-diethyl chloroacetamide, using 3- The title compound (14 mg, yield 33%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3.02 minutes; m/z 650.9 [M + H]+ (ESI positive ion mode), m/z 695.1 [M + HCOO] _ (ESI negative ion mode) -169- 201211053 【化1 2 9】

Example 3 7 N-[l-(3-Cyanobenzyl)piperidin-4-yl]-4-({2-Sideoxy-8-(4-trifluoromethyl)benzyl] Manufacture of -1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 37) in place of N,N-diethyl chloroacetamide The title compound (12 mg, yield 28%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 2.90 minutes; m/z 646.0 [M + H]+ (ESI positive ion mode), m/z 690.2 [M + HCOO]- (ESI negative ion mode) 3 0]

H3C

Example 3 8 4-(4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]癸Preparation of ethyl alk-3-yl}methyl)benzamide]piperidin-1-yl)butanoate (Compound No. 38) Substituting N,N-diethyl chloroacetamide, using 4-bromo The ethyl acetate of the title compound (63 mg, yield 61%) was obtained. LC/MS [Condition 1]: Hold time 2.79 minutes; m/Z645.0 [M + H]+ (ESI positive ion mode), m/z689.2 [M + HCOO]- (ESI negative ion mode)

【化1 3 1】

Example 3 9 3-({4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] Preparation of methyl decane-3-yl}methyl)benzamide]piperidine-1-yl}methyl)benzoate (Compound No. 39) substituted hydrazine, hydrazine-diethyl chloroacetamide, used A white solid of the title compound (73 mg, yield: 67%) was obtained from m.p. LC/MS [Condition 1]: Hold time 2.98 minutes; m/z679.1 [M + H]+ (ESI positive ion mode), m/z 723.1 [M + HCO〇r (ESI negative ion mode) 3 2]

Example 40 -171 - 201211053 4-({4-[4-({2-Sideoxy-8-(4-trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of N,N-diethylchloroacetic acid by the manufacture of methyl decyl-3-yl}methyl)benzamide]piperidine-1-yl}methyl)benzoate (Compound No. 40) The title compound (84 mg, yield 77%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 2.98 minutes; m/z679.1 [M + H]+ (ESI positive ion mode), m/z 723.2 [M + HCOO]- (ESI negative ion mode) 3 3]

Example 4 1 4-({4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] Manufacture of decyl-3-yl}methyl)benzamide]piperidine-1-yl}methyl)benzoic acid (Compound No. 41) 4-({4-[4_({) obtained in Example 40 2-sided oxygen-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide] Methyl piperidine-l-yl}methyl)benzoate (33, mg, 0.048 mmol) was dissolved in methanol, and 1 M aqueous sodium hydroxide (〇.〇 88 mM, 0.48 mm 〇l) was added at room temperature at 60 Mix at °C for 10 hours. After the reaction mixture was concentrated under reduced pressure, methanol was distilled off, and then hydrochloric acid was added to pH. Thereafter, the organic layer was separated by adding chloroform, and the obtained organic layer was dried over anhydrous sodium sulfate - 172 - 201211053, and concentrated to dryness under reduced pressure to give 4-({4_[4-({2_ side oxygen). 8-(4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide]piperidine-1 -Based on methyl) benzoic acid (5.2 mg, yield 16%) as a white solid. LC/MS [Condition 1]: Hold time 2.61 min; m/z 665, l [M + H]+ (ESI positive ion mode), m/z 663.1 [M-H]- (ESI negative ion mode)

【化1 3 4】

F Example 42 N-(1-(2-ethylbutyl)piperidin-4-yl)-4-((2-oxo-o-8-(4-(trifluoromethyl)phenylmethyl)- Manufacture of 1-oxo-3,8-diazospiro[4.5]nonan-3-yl)methyl)benzamide (Compound No. 42)

4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- obtained in Reference Example 22. Methyl}methyl)-indole-(piperidin-4-yl) benzamide 2 hydrochloride (38xng, 0_063mmol) was dissolved in methanol, and acetic acid (0_01 lmL, 0.19mmoI) and 2-B were added at room temperature. The butyl aldehyde (0.045 mL, 0.38 mm 〇l) was mixed at room temperature for 3 hours. Sodium triacetate borohydride (70 mg, 0.32 mmol) was added to the reaction mixture, and the mixture was stirred for 3 days. After that, chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture, and the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel-173-201211053 column chromatography [塡-filling agent: NH-DM1 020, manufactured by FUJI SILYSIA, developing solvent: hexane/ethyl acetate = 1/4] to obtain N- [l-(2-ethylbutyl)piperidin-4-yl]-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8- Diazospiro[4.5]decane-3-yl}methyl)benzamide (24 mg, yield 62%) as a white solid. 1H-NMR (300 MHzs CDCl3) 5: 0.86 (6HJt, J = 7.4 Hz ) J1.2 1-1.45 (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), 3.1 l (2H, s), 3.55 (2H, s), 3.90-4.06 (1 H, m), 4.45 (2H, s), 5.97 (1 H, 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 = 8.2Hz) 〇LC/MS [Condition 1]: Hold time 3.00 minutes; m/z 615.0 [M + H]+ (ESI positive ion mode), m/z 659.2 [M + HCO〇r ( ESI negative ion mode) [Chem. 1 3 5]

Example 4 3 Heart [1-(cyclohexylmethyl)piperidin-4-yl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxole Preparation of -3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 43) Substituting 2-ethylbutyl aldehyde, using cyclohexanecarboxyaldehyde, substance The title compound (2.8 mg, -174 - 201211053 yield 11%) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3-12 minutes; m/z 627.0 [M + H]+ (ESI positive ion mode), m/z 671.2 [M + HCO〇r (ESI negative ion mode) 3 6] Ο

Example 4 4 Heart (2-morpholinoethyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 44) 4-({2-Sideoxy-8-[4-(trifluoromethyl) obtained in Reference Example 21 Benzyl]_〗-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (4〇mg, 0.089mmol) and 4-(2-aminoethyl) ) morpholine (0 · 0 2 3 m L, 0.1 8 mmo 1) φ , and 1-hydroxybenzotriazole (12 mg, 0.089 mol) dissolved in hydrazine, hydrazine-dimethylformamide (4. OmL) After adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (〇_〇 32 mL, 0.18 mmol) at room temperature, the mixture was stirred and mixed at 40 ° C for 1 day. After the reaction mixture was concentrated under reduced pressure, N,N-dimethylformamide was evaporated, and chloroform and saturated aqueous sodium hydrogencarbonate were added and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. chloroform was evaporated, and the residue was purified by HPLC to give N-(2-morpholinoethyl)-4-( -Sideoxy-8-[4-(trifluoromethyl)benzyl]-l-oxa-3,8-diazospiro[4·5]nonane_3_yl}methyl)benzamide (38 mg, yield -175 - 201211053 95%) of a yellow solid. LC/MS [Condition 1]: Hold time 1.04 min; m/z 561.2 [M + H]+ (ESI positive ion mode), m/z 605.0 [M + HCO〇r (ESI negative ion mode) 3 7]

Example 45 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of 4-(3-(2-oxopyrrolidin-1-yl)propyl]benzamide (Compound No. 45) for the replacement of 4-(2-aminoethyl)morpholine The title compound (4 1 mg, quantitative) of a brown oil was obtained from the compound obtained in the same manner as in Example 44, except for 1-(3-aminopropyl)-2-pyrrolidone. LC/MS [Condition 1]: Hold time 2.94 minutes; m/z 572.9 [M + H]+ (ESI positive ion mode), m/z 617. 〇 [M + HCO〇r (ESI negative ion mode) 3 8]

Example 46 N-(1-Methoxybutan-2-yl)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene 201211053)]-1-carbo-3 , 8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 46) was produced by substituting 4-(2-aminoethyl)morpholine, using 2-amino group- The title compound (35 mg, quantitative) was obtained as a yellow solid. LC/MS [Condition 1]: Hold 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 4 7

4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)- Production of N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 47) was substituted for 4-(2-aminoethyl)morpholine, and substantially the same was carried out except using tetrahydrofurfurylamine. The title compound (3 5 mg, quantitative) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.04 min; m/z 531.8 [M + H] + (ESI positive ion mode) ' m/z 575.9 [M + HCOO] - (ESI negative ion mode) -177- 201211053 [化1 4 0]

:FF Example 4 8 Heart cyclooctyl-4-({2-o-oxo-8_[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Production of alkyl-3-yl}methyl)benzamide (Compound No. 48) Substituting 4-(2-aminoethyl)morpholine, substantially the same as Example 44 except using cyclooctylamine The title compound (37 mg, quantitative) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3.62 minutes; m/z5 5 7_9[M + H]+ (ESI positive ion mode), m/z 602.0 [M + HCOO]-(ESI negative ion mode) 4 1]

Example 49 (S)-N-(l-Hydroxy-4-methylpentan-2-yl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl] Manufacture of 4-(2-aminoethyl)morpholine, 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 49) The title compound (33 mg, yield 94%) was obtained as white solid. -178- 201211053 LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 547.8 [M + H]+ (ESI positive ion mode), m/z 592.0 [M + HCO〇r (ESI negative ion mode) ) 【化1 4 2】

φ Example 5 0 1^-(1-adamantylmethyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 50) Substituting 4-(2-aminoethyl)morpholine, using 1-adamantanemethylamine The title compound (39 mg, quantitative) was obtained as a yellow solid. LC/MS [Condition 1] ··Retention time 3.78 min; m/z 595.8 [M + H]+ (φ ESI positive ion mode), m/z 640_0 [M + HCO〇r (ESI negative ion mode) 4 3]

Example 5 1 Third butyl 5-[4-({2· sideoxy-8-[4-(trifluoromethyl)benzyl]]- oxa] 3,8-diazo snail [4.5] Preparation of decyl-3-yl}methyl)benzamide]pentylaminocarboxylic acid-179-201211053 ester (Compound No. 51) Substituting 4-(2-aminoethyl)morpholine, using N-( The title compound (41 mg, quantitative) of a brown oil was obtained from m.p. LC/MS [Condition 1]: Hold time 3.44 minutes; m/z 63 2.8 [M + H]+ (ESI positive ion mode), m/z 677.0 [M + HCO〇r (ESI negative ion mode) [Chem. 1 4 4]

Example 5 2 Third butyl 6-[4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Preparation of decane-3_yl}methyl)benzamide]hexylaminoformate (Compound No. 52) Substituting 4-(2-aminoethyl)morpholine, using N-(t-butoxy The title compound (43 mg, quantitative) was obtained as a white solid, m. m. LC/MS [Condition 1]: Hold time 3 54 minutes; m/z 646.9 [M + H]+ (ESI positive ion mode), m/z691〇[M + HC〇〇]-(ESI negative ion mode) 8 -180- 201211053 【化1 4 5】

Example 5 3 3-[4-(Thiomorpholin-4-carbonyl)benzyl]_8_[4-(trifluoromethyl)benzyl]_ 1-oxa-3,8-diazospiro[4.5 Manufacture of decane-2-one (Compound No. 53)

Substituting 4-(2-aminoethyl)morpholine, the title compound (35 mg, quantitative) was obtained as a white solid. LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 53 3.7 [M + H]+ (ESI positive ion mode), m/z 578.0 [M + HCO〇r (ESI negative ion mode) [Chem. 1 4 6]

Example 5 4 3_{4-[4-(pyrrolidin-1-yl)piperidin-1-carbonyl]benzyl}_8-[4-(trifluoromethyl)benzyl]-1-oxo_ Preparation of 3,8-diazospiro[4.5]decane-2-one (Compound No. 54) Substituting 4-(2-aminoethyl)morpholine' using 4 - (卩比卩院-1 _ base The title compound (28 mg, yield 72%) was obtained as a yellow solid. -181 - 201211053 LC/MS [Condition 1]: Hold time ι·ΐ2 min; m/z 5 84.7 [M + H]+ (ESI positive ion mode), m/z 629.0 [M + HCOO]_ (ESI negative ion Mode) [Chem. 1 4 7]

Example 5 5 3_[4-(4-Benzylmercaptopiperidin-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-2-one (Compound No. 55) in place of 4-(2-aminoethyl)morpholine, using 4-benzylpyridinium hydrochloride and triethylamine The title compound (41 mg, quantitative) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.46 minutes; m/z 619.8 [M + H]+ (ESI positive ion mode), m/z 664.0 [M + HCO〇r (ESI negative ion mode) 4 8]

Example 56 Heart (Benzo[(^[1,3]dioxazole-5-ylmethyl)-4-({2-Sideoxy-8-[4-(trifluoro-182- 201211053 methyl)) Manufacture of benzyl-l-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 56) in place of 4-(2-aminoethyl) The title compound (38 mg, quantitative) of a yellow solid was obtained from the morpholine in the same manner as in Example 44. LC/MS [Cond. 1]: retention time 3.32 minutes; m/ Z58 1 ·8[Μ + Η]+ (ESI positive ion mode), m/z625.9[M + HCOO]-(ESI negative ion mode) [Chem. 1 4 9]

Example 57 N-(2,3-Dihydro-1H-indol-1-yl)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxole -3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (combination φ material number 57) was produced by substituting 4-(2-aminoethyl)morpholine, using 1 In the same manner as in Example 44, the title compound (37 mg, quantitative) was obtained. LC/MS [Condition 1]: Hold time 3.50 minutes; m/z 563_8 [M + H]+ (ESI positive ion mode), m/z 607.9 [M + HCO〇r (ESI negative ion mode) -183- 201211053 [ 1 5 0]

Example 5 8

Ν-(naphthalen-1-ylmethyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8-diazo snail [4 Preparation of 5]nonan-3-yl}methyl)benzamide (Compound No. 58) Substituting 4-(2-aminoethyl)morpholine, using 1-naphthylmethylamine, substantially The title compound (38 mg, quantitative) was obtained as a yellow solid. LC/MS [Condition 1]: Hold time 3.56 minutes; m/z 587.8 [M + H]+ (ESI positive ion mode), m/z 632.0 [M + HCOO]- (ESI negative ion mode) 5 1]

Example 59 N-(2,3-Dihydro-1H-indol-2-yl)-4-((2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxole Preparation of 3-,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 59) Substituting 4-(2-aminoethyl)morpholine, using 2-amine The title compound (i 〇mg - 184 - 8 201211053, yield 27%) was obtained as a yellow solid, which was obtained in the same manner as in Example 44. LC/MS [Cond. 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) [Chem. 1 5 2]

Example 60 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of N-phenylethylbenzamide (Compound No. 60) Substituting 4-(2-aminoethyl)morpholine, substantially the same reaction as in Example 44 except using phenethylamine The title compound (3O mg, yield 81%) ^ LC/MS [Condition 1]: Hold time 3.40 minutes; m/z 551.8 [M + H]+ (ESI positive ion mode), m/z 596.0 [M + HCO〇r (ESI negative ion mode) 1 5 3]

Example 6 1 Heart isopropyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-heavy-185-201211053 nitrogen snail [ 4.5] Production of decyl-3-yl}methyl)benzamide (Compound No. 61) Substituting 4-(2-aminoethyl)morpholine, substantially using isopropylamine, and examples The title compound (39 mg, yield 88%) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.08 min: m/z 489.7 [M + H]+ (ESI positive ion mode), m/z 533.9 [M + HCO〇r (ESI negative ion mode)

Example 62

1^-cyclohexyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decane- The production of 3-yl}methyl)benzamide (Compound No. 62) was substituted for 4-(2-aminoethyl)morpholine, and substantially the same reaction as in Example 44 was carried out except that cyclohexylamine was used. The title compound (47 mg, quantitative) was obtained as white solid. LC/MS [Condition 1]: Hold time 3.42 minutes; m/z 529.7 [M + H]+ (ESI positive ion mode), m/z 573.9 [M + HCO〇r (ESI negative ion mode) 8 -186 - 201211053 【化1 5 5】

Example 63

4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)- Ν-[1-(Pyridin-4-yl)piperidin-4-yl]benzamide (Compound No. 63) was produced by substituting 4-(2-aminoethyl)morpholine, using 4-(4- The title compound (51 mg, yield 79%) was obtained as a white solid. 1H-NMR (300 MHz, CDC13) 8: 1.49-1.65 (2H, m), 1.65-1, 78 (2H, m), 1.85-1.96 (2H, brm), 2.1 0-2.21 (2H, brm ), 2.62-2.42 (4H, brm), 2.98 - 3.15 (4H, m), 3.55 (2H, s), 3.86-3.97 (2H, brm), 4.1 8-4.3 3 (lH, m), 4.46 (2H , s), 6.01 (lH, d, J = 7.8 Hz), 6.69 (2H, dd, J = 5.3, 1.6 Hz), 7.34 (2 H, 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). 【化1 5 6】

NH2 3HCI Reference Example 64 Manufacture of 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride -187- 201211053 Nicotinal aldehyde (purchased from Tokyo Chemical Industry Co., Ltd.) (1.3 g , 12 mmol) was dissolved in chloroform (50 ml), and 4-(t-butoxycarbonylamino)piperidine (Sigma purchased from Aldrich) (2.4 g, 12 mmol) was added at room temperature, followed by stirring for 2 minutes. mixing. Sodium triacetoxyborohydride (3.2 g, 15 mmol) was slowly added to the reaction mixture, followed by mixing at room temperature for 4 hours. After a 1 M aqueous sodium hydroxide solution was added to the reaction mixture, the organic layer was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated A white solid of pyridine. The compound was dissolved in methanol (5.0 ml) without further purification, and 4 M hydrogen chloride-dioxane solution (25 ml) was added at room temperature, and mixed for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and methanol and ethyl acetate were added to the residue, and then stood overnight. The precipitated solid was collected by filtration, and dried under reduced pressure for 5 hours to give 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride (2.9 g, yield 81). %) White solid. 1H-NMR (3 00 MHz JCD3 〇D) 5: 2.03-2.22 (2H, m), 2.28 (2H, d, J = 13.0 Hz), 3.25-3.4 5 (2H, m), 3.49- 3.62 (lH, m), 3.67 (2H, d, J = 12.6 Hz), 4.6 8 ( 2H, s), 8.19 (lH, dd, J = 8.2, 5.8 Hz), 8.94 (lH, dt, J = 8.2) , l .7 Hz), 8.98 ( lH, d, J = 5.8 Hz), 9.26 (lH, d, J = 1.7 Hz) [Chem. 1 5 7]

188-201211053 Example 64 4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of benzyl}methyl)-N-[l-(pyridin-3-ylmethyl)piperidine-4-yl]benzamide (Compound No. 64)

4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3 obtained in Reference Example 2 _yl}methyl)benzoic acid (2 31^, 0 · 0 5 1 mm ο 1 ), 4-amino-1 -(pyridin-3-ylmethyl)piperidine trihydrochloride obtained in Reference Example 6 The salt (18 mg, 0.062 mmol) and triethylamine (35 mL, 0.26 mmol) were suspended in chloroform (1.5 mL), and 1-mercaptobenzotriazole (6.8 mg, 0.051 mmol) and 1-ethyl- After 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.076 mmol), it was mixed at room temperature for 16 hours. To the reaction mixture were added chloroform (1.0 mL) and EtOAc (EtOAc). The organic layer of 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 (purifying agent: manufactured by FUJI SILYSIA, NH-DM1 020, developing solvent: acetic acid The title compound (25 mg, yield 80%) was obtained as white solid.

1H-NMR (300MHz, CDCl3) 6: 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 (4H, d, J = 5.8 Hz), 3.93-4.1 0( lH,m), 4.46(2H,s) , 6.0 1(1 H,d,J = 7.4Hz), 7.26( 3H,dd,J = 7.4,5.0Hz),7.3 3(2H,d,J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7_56 (2H, d, J = 8.0 Hz), 7.66 (lH, dt, J = 7_7, 1.9 Hz), 7.74 (2H, d, J) -189- 201211053 = 8.3 Hz), 8.5 1 (lH, dd, J = 4.7, 1.7 Hz), 8'56 (lH, d, J = 1.9 Hz). LC/MS [Condition 1]: Hold time 1.19 min; + (ESI positive ion mode), m/z 620_0 [M-Hr (ESI negative ion mode) [Chem. 1 5 8]

Example 65 N-[3-(Dimethylamino)propyl]-4-({2-sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, Preparation of 8-diazospiro[4.5]decane-3-yl}methyl)benzimidamide formate (Compound No. 65) Substituting 4-(2-aminoethyl)morpholine, using hydrazine, hydrazine The title compound (43 mg, yield: 79%) was obtained as a pale yellow oil from m.p. 1H-NMR (300MHz, CDCl3) 5: 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 = 6.8Hz), 3.15(2H,s), 3.58(2H,q,J = 6.1Hz), 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 (lH, t, J = 5.5 Hz), 8.40 (2H, s). LC/MS [Condition 1]: Hold time 1.07 minutes; m/z 53 2.8 [M + H]+ (ESI positive ion mode), m/z 577.0 [M + HCOO] - (ESI negative ion mode) -190 - 201211053 【化1 5 9】

Ο

F Example 6 6

3-[4-(morpholine-4-carbonyl)benzyl]-8_[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- The production of 2-ketoformate (Compound No. 66) was carried out in the same manner as in Example 44 except that 4-(2-aminoethyl)morpholine was replaced with morpholine (purchased from Pure Chemicals Co., Ltd.). The title compound (38 mg, yield 76%) 1H-NMR (3〇〇MHz, CDC13) 5: 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), 7.3 l (2H, d, J = 8.2 Hz), 7.4 1 (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 [Conditional 丨]: Hold time 2.91 min; m/z 517.8 [M + H]+ (ESI positive ion mode), m/z 561.9 [M + HCO〇r (ESI negative ion mode)

Example 6 7 N-Benzyl-4_({2_sideoxy-8_[4-(trifluoromethyl)benzyl]- oxa- 3,8-diazospiro[4.5]decane-3- Manufacture of 4-(2-aminoethyl)morpholine, using benzylamine (by Tokyo Chemical Industry Co., Ltd.) for the manufacture of benzyl benzyl carbamide (Compound No. 67) -191 - 201211053 The title compound (1 Omg, yield 21%) was obtained as a white solid. 'H-NMR (300MHz, DMSO-d6) 5: 1.64-1.90 (3H, brm), 2.33-2.56 (2H, brm), 3.21 (2H, s), 3.75-3.3 8 (5H, m), 4.39(2H, s), 4.46(2H,d,J = 5.8Hz), 7.1 8-7.33(5H,m), 7.34(2H,d,J = 8.2Hz), 7.47-7.61(2H,m), 7.63 -7.76(2H,m),7_88(3H,d,J = 8.2Hz), 9.04 ( lH,t,J = 5.5Hz). LC/MS [Condition 1]: Hold time 3.37 min; m/z 53 7.8 [M + H]+ (ESI positive ion mode), m/z 53 5.9 [M-H]- (ESI negative ion mode)

Example 68 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of 4-N-(pyridin-3-ylmethyl)benzamide (Compound No. 68) Substituting 4-amino-1 -(pyridin-3-ylmethyl)piperidine trihydrochloride for use The title compound (17 mg, yield 70%) was obtained as white solid. -192- 201211053 1H-NMR (300MHz, CDCl3) 6: 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 (lH, t, J = 5.5 Hz), 7.29 (lH, 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 (lH, dt, J = 7.8, 2.0 Hz), 7.79 (2H, d, J = 8.2 Hz), 8.55 (lH, dd, J = 4.8, 1.7 Hz), 8.6 1 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 1.21 minutes; ιη/ζ53 6.9[Μ-ΗΓ(

ESI negative ion mode) [Chem. 1 6 2]

Example 69

4-([4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl} Manufacture of methylaminobenzamide]methyl)benzoic acid methyl ester (Compound No. 69) substituted amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride using 4-(amino group) Methyl) benzoic acid methyl ester hydrochloride (purchased from Aldrich) was reacted in the same manner as in Example 64 to give the title compound (140 mg, quantitative) as a white solid. 1H-NMR (300MHz, CDCl3) 5: 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) -193- 201211053 , 3.91 (3H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.52 (lH, 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), 7.8 0 (2H, d, J = 8.5 Hz), 8.02 (2H, d, J = 8.4 Hz). LC/MS [Condition 1]: Hold time 3.41 minutes; m/z 595.8 1 [M + H]+ (ESI positive ion mode), m/z 593.9 [M-Hr (ESI negative ion mode) [Chem. 1 6 3]

H3C Η Example 70 Third butyl 2-[4-({2- oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5 Manufacture of decyl-3-yl}methyl)benzamide]ethylcarbamate (Compound No. 70) substituted 4-amino-1-(pyridin-3-ylmethyl)piperidine III The title compound (1 l mg, yield) was obtained from m. m. 43%) white solid. 1H-NMR (300MHz, CDCl3) 5: 1.43 (9H, s), 1.7 1 (2H, ddd, J = 14.0, 6.5, 5.8 Hz), 1.84-1.97 (2H, m), 2.42-2.6 l ( 4H,m),3.1 1 (2H,s),3.4 1 ( 2H,q,J = 5.5Hz), 3.5 5-3.5 7(4H,m), 4.46(2H,s),4.96(lH,brs) , 7.3 2 ( 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). -194- 201211053 LC/MS [Condition 1]: Hold time 3.27 minutes; m/z 5 90.9 [M + H]+ (ESI positive ion mode), m/z 634.9 [M + HCO〇r (ESI negative ion mode) 【化1 6 4】

Example 7 1 Third butyl 4-[4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4· Preparation of 5]decane-3-yl}methyl)benzamide]butylcarbamate (Compound No. 71) Substituted 4-amino-1-(pyridin-3-ylmethyl)piperidine The same reaction as in Example 64 was carried out to give the titled compound (25 mg), using the title compound (3). , yield 80%) of a white solid. *H-NMR (300MHz, CDC13) 6: 1.44 (9H, s), 1.54-1.67 (4 H, m), 1.72 (2H, ddd, J = 14.0, 7.2, 6.8 Hz), 1.9 1 (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 (2 Η, s), 4.46 (2H, s), 4.65 (1 H, brs), 6.57 (1 H'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]: Hold time 3.41 minutes; m/z 618.9 [M + H] + (ESI positive ion mode), m/z 663.0 [M + HCO〇r (ESI negative ion mode) -195- 201211053 【化1 6 5】

Example 72

1<[-butyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decane Manufacture of 4-amino}methyl)benzamide (Compound No. 72) Substituted 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride using butylamine (by The title compound (17 mg, yield 76%) was obtained as white solid. 'Η-ΝΜΚ(300ΜΗζ,0〇αΐ3)δ: 0.96(3Η,1,Ι = 7.2Ηζ), 1.43(2Η,11,Ι =1 0.0,5.0Hz), 1.66- 1.54(2H,m),1.72 (2H, ddd, 1 = 13.8, 7.0, 6.5 Hz), 1.9 1 (2H, dt, J = 13.3, 3.7 Hz), 2.44-2.62 (4HJm), 3.12 (2H, s), 3.46 (2H, q, J = 6.5 Hz), 3.55 (2H, s), 4.46 (2H, s), 6.10 (lH, 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]: Hold time 3.31 minutes; m/z 5 03.9 [M + H]+ (ESI positive ion mode), m/z 547.9 [M + HCO〇r (ESI negative ion mode) 8 -196- 201211053 【化1 6 6】

Example 73 N-(2-Methoxyethyl)-4-({2-oxo-oxy-8-(4-trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)benzamide (Compound No. Φ 73) in place of 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride, The title compound (15 mg, yield: 64%) was obtained as white solid, m. m.

1H-NMR (3 00MHz, CDCl3) 6: 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, in), 3.12 ( 2H, s), 3.39 (3H, s), 3.55 (2H, s), 3.5 7 (2H, t, J = 5.0 Hz), 3.66 (2H, q, J = 5.2 Hz), 4.4 7 (2H, s ), 6.51 ( lH, brs), 7.3 3 (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 = 8.0Hz) » LC/MS [Condition 1]: Hold time 2.95 minutes; m/z 505.8 [M + H]+ (ESI positive ion mode), m/z 503.9 [M-Hr (ESI Negative ion mode) [Chem. 1 6 7]

F

C-197 201211053 Example 74 3-[4-(Piperidine-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl; _ 3,8-diazo snail [4.5] Production of decane-2·one (Compound No. 74) was substituted for 4-amino-]-(pyridin-3-ylmethyl)piperidine trihydrochloride, except that piperidine (purchased from pure chemical (share)) was used. The title compound (12 mg, yield 52%) was obtained as white solid. IH-NMR (300MHz, CDC) 3) 5: 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), 3.5 6 ( 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) o LC/MS [Condition 1]: Hold 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 (11*,4〇-4-{[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazo snail Manufacture of [4_5]decane-3-yl}methyl)benzamide]methyl}cyclohexanecarboxylic acid methyl ester (Compound No. 75) -198- 201211053 Substituted 4-amino-1-(pyridine- 3-methylmethyl)piperidine trihydrochloride was substantially the same as that of Example 64 except that trans-4-aminomethylcyclohexanecarboxylic acid methyl hydrochloride obtained in Reference Example 2-1 was used. Reaction gave the title compound as a white solid (m.

1H-NMR (300MHz, CDCl3) 5: 1.05 (2H, dq, J = 3.4, 12.3Hz), 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(lH,tt,J=11.9,3.7Hz),2.62-2.43(4H,ra),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 (lH, 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]: Hold time 3.37 minutes; m/z 601.9 [M + H]+ (ESI positive ion mode), m/z 600.0 [MH]- (ESI negative ion mode) [Chem. 1 6 9 】

Ο

Example 76 1-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Manufacture of 4-amino-1-pyridyl-3-ylmethyl)piperidine trihydrochloride The same reaction as in Example 64 was carried out using substantially hexahydroisonicotinic acid methyl (purchased from Tokyo Chemical Industry Co., Ltd.) to give the title compound (2 mg, yield: 75%) as colorless. Oily. 1H-NMR (300MHz, CDCl3) 6: 1.59-2.12 (8H, m), 2.46-2.58 (4H, m), 2.60 (lH, 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 (lH, tn), 3.7 1 (3H, s), 4.61-4.38 (lH, 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]: Hold time 3.21 minutes; m/z 573.8 [M + H]+ (ESI positive ion mode), m/Z 617.9 [M + HCOO]- (ESI negative ion mode) 7 0] 〇

F

Example 77 2-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Manufacture of 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride with ethyl methacrylate The title compound was obtained as a white solid (20 mg, yield: 75%). 1H-NMR (300MHz, CDCl3) 8: 1.32 (3H, t, J = 7.4 Hz), 1.65- 1.79 (8 -200-201211053 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 (2 H, s), 6.62 (lH, 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]: Hold time 3·〇7 min; m/z 533.7 [M + H]+ (ESI positive ion mode), m/z 532.0 [MH]. (ESI negative ion mode) I: 1 7 1]

〇

Example 78

(lr,4r)-N-(2-isopropoxyethyl)·4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, Manufacture of 8-diazospiro[4·5]decane-3-yl}methyl)cyclohexanecarbamide (Compound No. 78) Substituted tetrahydrofurfurylamine using 2-aminoethylisopropyl The title compound (32 mg, yield: 88%) was obtained as white solid. 'Η-ΝΜΚ(300ΜΗζ, α〇αΐ3) δ: 1.03 (2Η, άς, Ι = 3.3, 12.3Hz), 1.16( 6H,d,J = 6.1Hz), 2.08-1.3 9(12H,m), 2.50 -2.61(4H,m), 3.09 (2H,d,J = 7.4Hz), 3.26(2H,s),3.3 8(4H,s),3.4 1 (2H,q,J = 4.9Hz),3.44- 3.5 1 (2H, m), 3.52-.63 (3H, m), 5.85 (lH, t, J = 4.9 Hz), 7.44 (2H, d, J = 8.2

Hz), 7.57 (2H, d, J = 8.2 Hz). -201 - 201211053 LC/MS [Condition 1]: Hold time 3.16 minutes: m/z 539.8 [M + H]+ (ESI positive ion mode), m/z 584.0 [M + HCOO]_ (ESI Negative ion mode) [Chem. 1 7 2]

Example 79 (lr,4r)-N-(furan-2-ylmethyl)-4-({2-Sideoxy-8-[4-(trimethylmethyl)benzyl]-1-oxo- Production of 3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 79) Substituted tetrahydrofurfurylamine, substantially in addition to mercaptoamine The title compound (35 mg, yield 96%)yield 'H-NMR (300MHz, CDC13) 5:1. 〇1 (2H, dq, J = 3.3, 12.7 Hz), 1.50 (2H, dq, J = 3.3, 12.3 Hz), 1.60-1.68 (lH, m), 1.70-1.8. 5 (4H, m), 1.8 6-1.98 (4H, m), 2.04 (lH, tt, J = l 1.9, 3.7 Hz), 2.4 8-2.61 (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 (l H, tsJ = 5.1 Hz), 6.21 (lH) , d, J = 3.3 Hz), 6.32 (lH, dd, J = 3.3, 1.6 Hz), 7.35-7.35 (lH, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2Hz) o LC/MS [Condition 1]: Hold time 3_21 minutes; m/z53 3.8 [M + H]+ (ESI positive ion mode), m/z 578.1 [M + HCO〇r (ESI negative ion) Mode) -202- 201211053 【化1 7 3】

Example 8 0

(lr,4r)-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxan-3,8-diazospiro[4.5]decane-3- Production of methyl}methyl)-N-(tetrahydro-2H-pyran-4-yl)cyclohexanecarbamamine (Compound No. 80) Substituted tetrahydrofurfurylamine using 4-amino-tetrahydro- The title compound (31 mg, yield 84%) was obtained as a pale yellow solid. 1H-NMR (300MHz, CDCl3) 6: 1.0 1 (2H, dq, J = 3.3, 12.7 Hz), 1.35-2.06 (16H, m), 2.49-2.62 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.46 (2H, td, J = l 1.7, 2.0 Hz), 3.57 (2H, s), 3.8 8-4.06 (3H, m), 5.32 (lH, 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]: Hold time 2.97 minutes; m/z 53 7.9 [M + H]+ (ESI positive ion mode), m/z 582. 〇 [M + HCOO] _ (ESI negative ion mode) 1 7 4]

F Example 8 1 -203 201211053 (11",4〇-4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Replacement of spiro[4·5]decane-3-yl}methyl)-N-[(tetrahydro-2H-pyran-4-yl)methyl]cyclohexanecarboxamide (Compound No. 81) The title compound (31 mg, yield 84%) was obtained as a pale yellow solid, m. m.

1H-NMR (3 00MHz, CDC13) 6:1.02 (2H, tdd, J-13.1, 13. l, 3.0 Hz), 1.3 0 (2H, tdd, J = 1 1.9, 11.9, 5.3 Hz), l_4 1-1.99 (1 4H, m), 2.02 (lH, tt, J = 1.1, 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 (2 H, 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]: Hold time 3.07 minutes; m/z 551.8 [M + H]+ (ESI positive ion mode), m/z 596.0 [M-H]- (ESI negative ion mode)

Example 8 2 Third butyl 4-({2. oxo-8-[4-(trifluoromethyl)benzyl]-1 oxa-3,8-diazospiro[4.5]decane- Manufacture of 3-yl}methyl)phenylcarbamate (Compound No. 82) 8-204-201211053

4-( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxa-3,8-diazospiro[4.5]decan-3-yl obtained in Reference Example 21. }methyl)benzoic acid (19〇11^, 0.42mmol) 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) was stirred and mixed at room temperature for 30 minutes, and then mixed at 80 ° C for 6 hours. The reaction mixture was cooled to room temperature, then ethyl acetate (5. EtOAc) was evaporated. The aqueous layer was extracted with EtOAc. The obtained residue was subjected to silica gel column chromatography [塡 剂: FUJI SILYSIA amine ruthenium dioxide NH-DM1020, developing solvent: η-hexane/ethyl acetate = 2/1 to 1/1] Purification to give the title compound (160 mg, yield: 64%)

1H-NMR (300 MHz, CDC13) 5: 1.5 2 (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),4.3 6(2H,s),6.49(lH,brs),7.19(2H,d,J = 8.5Hz • ) , 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]: Hold time 3.55 min; m/z 5 19.8 [M + H] + (ESI positive ion mode), m/z 5i 8.0 [M-H]- (ESI negative ion mode) [Chem. 1 7 6]

-205- 201211053 Example 8 3 Tert-butyl 3-{3-[4-({2-Sideoxy-8_[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of Diazospiro[4.5]decane-3-yl}methyl)phenyl]ureido}propylaminocarbamate (Compound No. 83) 4-({2- Side Oxygen) obtained in Reference Example 21 -8-[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4-5]nonan-3-yl}methyl)benzoic acid (43 mg, 0.096 mmol) suspended Toluene (1. 〇mL), triethylamine (33 mL, 0.24 mmol) and diphenyl azide (31 mL, 0-14 mmol) were added and stirred at room temperature for 30 minutes. Mixing was carried out 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 directly added, and the mixture was mixed at 80 ° C for 4 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (3.0 mL) and water (3.0 mL) were evaporated. The organic layer was evaporated. The combined organic layers were dried with anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (purified: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> %) of a colorless oil. IH-NMR (300MHz, CDCl3) 5: 1.44 (9H, s), 1.59-1.77 (4H, m), 1.89 (2H, dt, J = 13.0, 3.4 Hz), 2.43-2.60 (4H, m), 3.11 (2H, s), 3.2 1 (2H, q, J = 6.5Hz), 3.29 (2H, q, J = 5.8Hz), 3.54(2H, s), 4.36(2H, s), 4.87 (lH, t , J = 6.5 Hz), 5.58 (lH, t, J = 6.5 Hz), 6.7 1 (lH, brs), 7.16 (2Hsd, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H,d,J = 8.5Hz), 7.56 (2H, d, J = 8.5Hz). -206- 201211053 LC/MS [Condition 1] ··Retention time 3.43 minutes; m/z 619.9[M + H]+ (ESI positive ion mode), m/z 618.0 [M-Hr (ESI negative ion mode) [化1 7 7]

F

Example 8 4 1-(1-Benzylpiperidin-4-yl)-3-[4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1- Preparation of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl]urea (Compound No. 84) substituted N-(t-butoxycarbonyl)-1,3-di The title compound (7.7 mg) was obtained by the same reaction as in Example 8 except that 4-amino-1-phenylmethylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) was used. Rate 1 1%) of a white solid. 1H-NMR (300MHz, CDCl3) 5: 1.46 (2H, dq, J = 3.7, 11.6 Hz), 1.79-1.5 8 (2H, m), 1.83-2.02 (4H, m), 2.13 (2H, t , J = l 0.9Hz), 2.42 - 2.59 (4H, m), 2.8 1 (2H, d, J = 11.6Hz), 3.12 (2H, s), 3.49 (2H, s), 3.54 (2 H, s ), 3.61-3.80 (lH, m), 4.36 (2H, s), 4.68 (lH, d, J = 7.8 Hz), 6.43 (lH, s), 7.16 (2H, d, J = 8.5 Hz), 7.22 -7.3 5(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 63 5.9 [M + H]+ (ESI positive ion mode), m/z 634.0 [M-Hr (ESI negative ion mode) -207- 201211053 1 7 8]

Example 85 1-Benzylpiperidin-4-yl 4-({2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)phenylcarbamate (Compound No. 85) Substituting N-(t-butoxycarbonyl)-1,3-diaminopropane, using 4- A hydroxy-1-phenylmethylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) was used to give the title compound (4.9 mg, yield 8%). 1H-NMR (300MHz, CDCl3) 5: 2.03-1.61 (8H, m), 2.28 (2H, t &gt; 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 (lH, m), 6.60 (lH, 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]: Hold time 3.13 minutes; m/z 637.02 [M + H]+ (ESI positive ion mode), m/z 635.07 [MH]-(ESI negative ion mode) -208- 201211053 1 7 9] H3C h3c4^ h3c

Example 8 6

3-(t-butoxycarbonylamino)propyl 4_({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ Preparation of 4.5]decane-3-yl}methyl)phenylcarbamate (Compound No. 86) Substituting N-(t-butoxycarbonyl)-1,3-diaminopropane, using hydrazine- The title compound (16 mg, yield 27%) was obtained from the title compound (16 mg, yield: 27%). Colorless oil. 1H-NMR (300MHz, CDCl3) 5: 1.44 (9H, s), 1.5 9- 1.95 (6H, m), 2.43-2.63 (4H, m), 3.10 (2H, s), 3.24 (2H, q, J = 6.0Hz), 3.5 5(2H, s), 4.23 (2H, t, J = 6.3Hz) 4.3 7(2H,s), 4.68(lH,brs),6.75(lH,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]: Hold time 3.55 min; m/z 621. 〇[M + H]+ (ESI positive ion mode), m/z 619.0 [MH]-(ESI negative ion mode) -209- 201211053 1 8 0] again

Example 8 7 1-Cyclohexyl-3-[4-({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazo snail [4.5 Manufacture of decyl-3-yl}methyl)phenyl]urea (Compound No. 87) substituted N-(t-butoxycarbonyl)-1,3-diaminopropane using cyclohexylamine (by Tokyo) The title compound (I7 mg, yield 34%) was obtained as white solid. h-NMROOOMHz'CDCIM] .06-1 _47(6H,m),1.64-1.8 1(4H, m),l.83-2.03 (4H,m),2.42-2.61(4H,m),3.13(2H , s), 3.5 5 (2H, s), 3.58-3.73 ( lH, m), 4.36 (2H, s), 4.72 (lH, d, J = 7.7 Hz), 6.47 ( lH, s), 7.16 (2H , d, J = 8.3 Hz), 7.29 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.3 H z), 7 · 5 6 (2 H, d, J = 8.3 H z) . LC/MS [Condition 1]: Hold time 3.41 minutes; m/z 544.9 [M + H]+ (ESI positive ion mode), m/z 543.0 [MH]- (ESI negative ion mode) [Chem. 1 8 1 】

-210- 201211053 Example 8 8 cyclohexyl 4_({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazospiro[4.5]decane Manufacture of -3_yl}methyl)phenylcarbamate (Compound No. 88)

Substituting N-(t-butoxycarbonyl)-1,3-diaminopropane in the same manner as in Example 83 except that cyclohexanol (purchased from Kanto Chemical Co., Ltd.) was used to obtain the title compound. (3.Omg, yield 6%) of colorless oil H-NMR (300MHz, CDC13) 6: 1.8 1-1.35 (10H, m), 1.83-2.00 (4H, m), 2.42-2.62 (4H, m), 3.10 (2H, s), 3.5 5 (2H, s), 4.37 (2H, s), 4.69-4.80 (1 H, m), 6.56 ( lH, 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]: Hold time 3.67 min; m/z 545.8 [M + H]+ (ESI positive ion mode), m/z 544.0 [M-H], (ESI negative ion mode)

Example 8 9 1-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1_|]oxa-3,8-diazospiro[4_5]decane- Preparation of 3-yl}methyl)phenyl]-3-[(tetrahydrofuran-2-yl)methyl]urea (Chemical 211 - 201211053 Compound No. 89) substituted N-(t-butoxycarbonyl)-1 , 3-diaminopropane, which was obtained by the same reaction as Example 83, except for the use of tetrahydrofurfurylamine (purified from Tokyo Chemical Industry Co., Ltd.) to give the title compound (20 mg, yield 38%). Oily. 1H-NMR (300MHz, CDCl3) 5: 1.59- 1.77 (3H, m), 1.84-2.04 (5H, m), 2.40-2.62 (4H, m), 3.11 (2H, s), 3.15 (lH, ddd, J=14.3#6.5,5.3Hz), 3.56(2H,s), 3.58(lH,ddd,J=14.7,7.0,2.9Hz), 3.78(lH,dt,J=8.2,7.0Hz),3.88(lH , dt, J = 8.2, 6.5 Hz), 3.98-4.08 (lH, m), 4.36 (2H, s), 5.23 (lH, t, J = 5.3 Hz), 7.17 (2H, d, J = 8.2 Hz) , 7.30 (lH, brs), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.17 minutes; m/z 546.8 [M + H]+ (ESI positive ion mode), m/z 545.0 [M-Hr (ESI negative ion mode) [Chem. 1 8 3 】

Example 9 0 (tetrahydrofuran-2-yl)methyl 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [ 4.5] Manufacture of decyl-3-yl}methyl)phenylcarbamate (Compound No. 90) -212-201211053 Substituted N-(t-butoxycarbonyl)-1,3-diaminopropane The title compound (30 mg, yield: 6%) was obtained as a colorless oil, which was obtained in the same manner as in Example 303, using THF (purified from Tokyo Chemical Industry Co., Ltd.). .

1H-NMR (300MHz, CDC13) 6: 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 (lH, dt, J = 8.2, 7.0 Hz), 3.91 (lH, dt, J = 8.6, 6.5 Hz), 4.05 (lH, dd, J=ll.l, 7.4 Ηζ), 4·21-4.10(lH,m), 4.29(1 H,dd,J=ll. 1,2 ·9Ηζ), 4· 3.7(2H,s ), 6.78(lH,s), 7.20(2H,d , J = 8.2 Hz), 7.36 (2H, 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]: Hold time 3.25 minutes; m/z 547.7 [M + H]+ (ESI positive ion mode), m/z 545.9 [M-H]- (ESI negative ion mode)

[化1 8 4]

F Example 9 1 1-[(11',4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexyl]-3-[(tetrahydrofuran-2-yl)methyl]urea (Compound No. 91) substituted N-(t-butoxycarbonyl) -1,3-Diaminopropane, using tetrahydrofurfurylamine (purchased by Tokyo Chemical Industry Co., Ltd.) to replace 4-({2- side oxygen-8-[4-( -213- 201211053 trifluoromethyl) (Benzene)-1-phenoxy-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using (1 r, 4 r) obtained in Reference Example 6-3 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) ring The title compound (39 mg, yield 71%) was obtained as a pale yellow solid, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), 1.50-2.08 (13H, m), 2.46-2.63 (4H, m), 3.03 (lH, ddd, J = 14.3, 7.0, 5.3 Hz), 3.08 (2H, d, J = 7.0 Hz), 3.27 ( 2H, s), 3.41 - 3.5 2 (2H, m), 3.57 (2H, s), 3.74 (lH5dt, J = 8.2, 7.0 Hz), 3.83 (lH, dt, J = 7.8, 6.5 Hz) 53.91-4.01 (lH, m), 4.53-4.72 (2H, brm), 7.44 (2H, d, J = 8.2 Hz), 7 .57(2H,d,J = 8.2Hz) LC/MS [Condition 1]: Hold time 3.02 minutes; m/z5 52.8[M + H]+ (ESI positive ion mode), m/z597.0[M + HCOO]-(ESI negative ion mode) [Chem. 1 8 5]

Example 92 (Tetrahydrofuran-2-yl)methyl(lr,4r)-4-({2-sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8 -Preparation of N-(t-butoxycarbonyl)-i,3-diamine by the manufacture of diazospiro[5]nonane-3-yl}methyl)cyclohexylcarbamate (Compound No. 92) Propane, using tetrahydroanthracene-214- 201211053 base alcohol (purchased by Tokyo Chemical Industry Co., Ltd.) to replace 4-({2-sialoxy-8-(4-trifluoromethyl)benzyl]- 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using (lr, 4r)-4-({2-side oxygen-) obtained in Reference Example 6-3 8-

Substituting and carrying out [4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid The title compound (24 mg, yield 41%) was obtained. 1H-NMR (300MHz, CDC13) 6:1.〇〇-1 19(4H,m), 1.48-2.09(1 3H ,m), 2.48-2.64(4H,m),3.08(2H,d,J = 7. 〇 Hz), 3.26 (2H, s), 3.35-3.48 (lH, m), 3.57 (2H, s), 3.80 (lH, dt, J = 7.8, 6.5 Hz), 3.85-3.95 (2H, m ), 4.1 4-4.03 ( 1 H, m), 4 · 18 (1 H, dd, J = ll.i, 3.3 Hz), 4.63 (1 Η, 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]: Hold time 3.07 minutes; m/z 553.4 [M + H]+ (ESI positive ion mode), m/z 597.9 [M + HCOO]- (ESI negative ion mode)

[化1 8 6] 0

Reference Example 93 3-(4-Aminobenzyl)-8-[4-(trifluoromethyl)benzyl]-1-oxa-3,8-diazospiro[4.5]decane-2-one 2 salt Preparation of the acid salt The third butyl 4-({2-oxo-8-[4-(trifluoromethyl)benzyl]]-oxa-3,8-diazo snail obtained in Example 82. [4.5] decyl-3-yl}methyl)phenyl-215- 201211053 Amino carboxylic acid vinegar (160 mg, 0.31 mmol) dissolved in 1,4-two chews (4.0 mL), added 4] hydrogen chloride - two The methane solution (3. 1111) and methanol (4. 1111 〇, mixed at 50 ° C for 3 hours. Concentrated under reduced pressure to dry to give 3-(4-aminophenylmethyl)- A yellow solid of 8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]nonan-2-one 2 hydrochloride (200 mg, quantitative). 1H-NMR (300MHz, CD3〇D) 6: 2.13-2.29 (4H, m), 3.42-3.3 1 (2H, m), 3.37 (2H, brs), 3.49 (2H, d, J = 12.7 Hz), 4.49 (4Hss), 7.42 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.77-7.8 7 (4H, m). LC/MS [Condition 1]: Hold time 1 ·〇6 minutes; m/z419.4[M + H]+ (ESI positive ion mode) [Chem. 1 8 7]

Example 93 1^-[4-({2-Sideoxy-8-[4-(dimethylmethyl)benzyl]-1-indolyl-3,8-diazospiro[4.5]decane- Preparation of 3-yl}methyl)phenyl]cyclohexanecarbamamine (Compound No. 93) 3-(4-Aminobenzyl)-8-[4-(trifluoromethyl) obtained in Reference Example 93 Benzyl)-1-oxo-3,8-diazospiro[4.5]decane-2-one 2 hydrochloride (23 mg, 0.047 mmol)' triethylamine (0.015 mL, O.llmmol) dissolved In dichloromethane (2.0 mL), add cyclohexane carbonyl chloride (0.010 mL, 0.074 mmol) -216- 201211053

Mix at 4 °C for 4 hours. Chloroform (4.0 mL) and a saturated aqueous solution of sodium hydrogencarbonate (4.0 mL) were added to the mixture, and the organic layer was evaporated. The obtained residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 77%) colorless oil. 1H-NMR (300MHz, CDCl3) 6: 1.21-2.01 (14H, m), 2.23 (lH, 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 (lH, s), 7.22 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.5 1 (2H, d , J = 8.3 Hz), 7.56 (2H, d, J = 7.9 Hz). LC/MS [Condition 1]: Hold time 3.51 min; m/z 529.8 [M + H]+ (ESI positive ion mode), m/z 529.7 [M-Hr (ESI negative ion mode)

【化1 8 8】

Example 94 Second butyl 4-side oxo 4- [4-({2 - oxo-8-[4-(trifluoromethyl)benzyl]] benzyl-3,8-diazo snail [4.5] Manufacture of decane-3-yl}methyl)phenylamino]butylcarbamate (Compound No. 94) in place of 4-({2-sideoxy-8-[4-(difluoro) (Methyl)benzyl]_1_che-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using 4_(bubutyloxycarbonyl-217- 201211053 amino group Butylcarboxylic acid (purchased from Aldrich), substituted 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride, using 3-(4-amine obtained in Reference Example 93) In addition to benzylidene-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-2-one 2 hydrochloride, substantially The title compound (16 mg, yield: 6 1%)

1H-NMR (300MHz, CDCl3) 5: 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 = 5.9Hz), 3.55(2H,s), 4.38(2H,s), 4.79(lH,t,J = 5.3Hz) , 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 (1 H, s). LC/MS [Condition 1]: Hold time 3.39 minutes; m/z 604.9 [M + H]+ (ESI positive ion mode), m/z 603.0 [MH]_ (ESI negative ion mode) [Chem. 1 8 9 】

Example 95 4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Manufacture of tert-butyl ester of methyl}methyl)phenylamine-mercapto]piperidine-1-carboxylate (Compound No. 95) 8-218-201211053 Substituting 4-({2-lateral oxygen_8_[4-( Trifluoromethyl)benzyl]·oxo_3,8-diazospiro[4.5]decane_3_yl}methyl)benzoic acid, using i_(t-butoxy-oxocarbonyl)piperidine-4 -carboxylic acid (purchased by sigma Aldrich Japan Co., Ltd.), substituted 4-amino-1-(pyridin-3-ylmethyl)piperidine trihydrochloride, using 3-(4-aminobenzene) obtained in Reference Example 93 The title compound was obtained by substantially the same reaction as in Example 64 except for the methyl group of _8_[4_(trifluoromethyl)benzyl]diazospiro[4·5]nonane-2-one 2 hydrochloride. (1 7 mg, yield 93%)

1H-NMR (3 00MHz, CDCl3) 5: 1.47 (9H, s), 1.64 - 1.8 2 (4H, m), 1.83 - 1.95 (4H, m), 2.39 (lH, tt, J = 11.5, 3.7 Hz) , 2.46-2.58(4H,m), 2.79 (2H,t,J=11.9Hz), 3.11(2H,s),3.54(2H,s),4.19(2H,d,J=11.9Hz),4.3 8 (2H, s), 7.22 (2H, d, J = 8.6 Hz), 7.29 (lH, 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) 〇 LC/MS [Condition 1]: Hold time 3.57 minutes; m/z 63 0.9 [M + H]+ (ESI positive ion mode) ' m/z629.1 [M-Hr (ESI negative ion mode) [Chem. 1 9 0]

Reference Example 96-1 Third butyl (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene i-chew-3, 8-diazo! Snail [4.5] 癸____ 丨 methyl) cyclohexyl carbazate -219- 201211053 Manufacture of substituted 4-({2- oxo-8-[4-(trifluoromethyl) phenyl (lr, 4r)-4-({2-) In addition to oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, The same reaction as in Example 82 was carried out to give the title compound (8. 1H-NMR (300 MHz, CDCl3) 6: 0.98-1.17 (4H, m), 1.44 (9H, s), 1.63-1.48 (lH, m), 1.68-1.83 (4H, m), 1.87 -2.08(4H,m), 2.48-2.59(4 H,m),3.07(2H,d,J = 7.0Hz), 3.26(2H,s), 3.30-3.43(lH,m),3.57 (2H, s), 4.36 (lH, brs), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, t, J = 8.0 Hz). LC/MS [Condition 1]: Hold 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-{[(lr,4r)-4-Aminocyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of Diazospiro[4.5]decane-2-one 2 hydrochloride The use of the third butyl (lr, 4r)-4- ({2- side-220-201211053 Oxygen-8) obtained in Reference Example 96-1 was used. -[4-(Trifluoromethyl)phenylmethyl]_丨_oxo-3,8-diazospiro[4.5]decane-3_yl}methyl)cyclohexylcarbamate to replace the third 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-;[_oxa-3,8-diazospiro[45]decane-3-yl}methyl In the same manner as in Reference Example 93, the title compound (5.0 mg, quantitative) was obtained to give a pale yellow liquid. 1H-NMR (300MHz, CD3OD) 6: 1.12 (2H, q, J = l 2.7Hz), 1.26-1.5 1

(3H, m), 1.57-1.77 (lH, m), 1.84 (2H, d, J = 12.3 Hz), 2.06 (2H, d, J = ll.lHz), 2.14 - 2.33 (4H, m), 2.97 -3.12 (lH, m), 3.12 (2H, d, J = 7·4 Hz), 3.72-3.3 5 (4H, m), 4.49 (2H, s), 7.81 (4H, s). LC/MS [Condition 1]: Hold time 〇 88 minutes; m/z 426.0 [M + H]+ (ESI positive ion mode)

Example 9 6 N-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [ 4.5] decane_3_yl}methyl)cyclohexyl]_2_(tetrahydrofuran-2-yl)acetamide (Compound No. 96) was produced by substituting 4-({2-lateral oxygen-8-[4-(three) Fluoromethyl)benzyl]-oxazo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using 2-221-201211053 2-221-201211053 2-(tetrahydrofuran- 2-Sub)acetic acid 'substituted 4-amino-indole-(pyridin-3-ylmethyl)piperidine trihydrochloride' 3-{[(lr,4r)-4- obtained using Reference Example 96-2 Aminocyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl bromide-oxa-3,8-diazospiro[4.5]decane-2-one 2 hydrochloride, Substantially the same reaction as in Example 64 gave the title compound (4·················· ), 1.45-2.1 5(1 3H , m), 2.36 (lH, dd, J = 15.1, 7.8 Hz), 2.46 (lH, 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(lH,m),3.77(lH,dt,J = 7.4,7.4Hz) , 3.88 (lH, dt, J = 8.6, 7.0 Hz), 4.05-4.15 (lH, m), 6.30 (lH, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.5 7 ( 2H, d, J = 7.8 Hz) ). LC/MS [Condition 1]: Hold time 3.05 min; m/z 537.8 [M + H]+ (ESI positive ion mode), m/z 582.0 [M + HCO〇r (ESI negative ion mode) 9 3]

Example 97 (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5] Manufacture of decyl-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanemethylthioguanamine (Compound No. 97) -222-201211053

(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazosudene obtained in Example 1 4.5]decane-3-yl}methyl)-heart [(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (21 mg, 0.038 mol) was dissolved in toluene (2.0 mL), and Lawson's reagent was added. 18 mg, 0.045 m〇l), mixed at 110 ° C for 2 hours. After cooling, ethyl acetate (5.0 mL) and aq. After the aqueous layer was extracted with ethyl acetate (5 mL), the organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [ 塡 : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU / / / / / / / (2.4 mg, yield 7%) of a white solid. 1H-NMR (300MHz, CDCl3) 5: 1.07 (2H, dq, J = 3.3, 12.7 Hz), 1.62-2.08 (15H, m), 2.43 (lH, tt, J = 12.3 &gt; 3.3 Hz), 2.49- 2.6 8(4H,m), 3.10 (2H,d,J = 7.4Hz), 3.25(2H,s), 3.45 (lH,ddd,J=14.3,9.0,3.7Hz), 3.5 7(2H,s) , 3.78 (lH, dt, J = 8.2, 6.5 Hz), 3.8 9 (lH, 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), 7.5 8 (1 H, s). LC/MS [Condition 1]: Hold time 3.38 min; m/z 5 5 3.8 [M + H]+ (ESI positive ion mode), m/z 551.9 [M-H]- (ESI negative ion mode)

-223- 201211053 Reference Example 9 8 (11*,4〇-1^-(1-Benzylpiperidin-4-yl)-4-[(2-flaxo-1-oxo-3,8-weight Preparation of azaspiro[4.5]decane-3-yl)methyl]cyclohexanecarbamide hydrochloride 3-{[(lr,4r)-4-(l-benzyl) obtained in Example 123 Piperidin-4-ylfee-glycolyl)cyclohexyl]methyl}-2-sideoxy-1-indole-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (〇 .35g, 0.62mmol) was dissolved in a mixed solvent of 1,4-dioxane (7.0mL) and methanol (4.0mL), and added 4M chlorinated gas - 卩 卩院 solution (0.62mL, 2.5mmol) at room temperature After standing at room temperature for 1 day, it was concentrated to dryness under reduced pressure. Acetone (5. 〇mL) was added to the residue and allowed to stand for 3 days, and then concentrated to dryness under reduced pressure to give (lr , 4r)-N-(l-Benzylpiperidin-4-yl)-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4-5]nonan-3-yl) a white solid of methyl]cyclohexanecarbamide hydrochloride (〇35g, yield in quantitative). [Chem. 1 9 5]

Example 98 (lr,4r)-4-[(8-Benzyl-2-oxooxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]-N -(l-Benzylpiperidin-4-yl)cyclohexanecarbamamine (Compound No. 98) -224-201211053

(lr,4r)-N-(l-Benzylpiperidin-4-yl)-4-[(2_sideoxy-1-oxo-3,8-diazoxil][4.5] obtained in Reference Example 98 ]] decyl-3-yl)methyl]cyclohexanecarbamide hydrochloride (20 mg, 〇. 〇 37 mmol) was suspended in N,N-dimethylformamide (0.40 mL), and triethylamine was added. 〇.〇 21 mL, 〇.15 minol), benzyl bromide (0.0050 mL, 〇. 〇 41 mmol), and stirred at room temperature for 3 days. Water (1.0 mL) and chloroform (2.0 mL) were added to the mixture, and the organic layer was separated and washed with water (1.OmL). After concentrating the organic layer under reduced pressure, the obtained residue was subjected to silica gel column chromatography [塡 : : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU The title compound (15 mg, yield 72%) was obtained as white solid. H-NMR (300MHz, CDCl3) 5: 1.0 1 (2H, dq, J = 3.7, 11.9 Hz), 1.34-1.56 (5H, m), 1.69-2.03 (UH, m), 2.11 (2H, t, J =11.6Hz), 2.46-2.65(4H,m), 2.80(2H,d,J=11.6Hz), 3.08(2H,d,J=7.2Hz), 3.24( 2H,s), 3.49(2H,s ), 3.53 (2H, s), 3.69-3.87 (lH, m), 5.28 (lH, d, J = • 7.8 Hz), 7_3 7-7.22 (l OH, m). LC/MS [Condition 1] ··Retention time ι·ΐ5 minutes; m/z5 5 9.1 [M + H]+ (ESI positive ion mode), m/z6〇3.1[M + HCOO]-(ESI negative ion mode) [化1 9 6] 〇

225 _ 201211053 Example 99 3-{[(11*,4〇-4-(1-Benzylpiperidin-4-ylaminocarbamoyl)cyclohexyl]methyl}_ 2 - sideoxy-1- Preparation of oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid benzyl (Compound No. 99) Substituted benzyl bromide 'Use benzyl chloroformate to replace N,N_: methyl Methionamine, except for chloroform, was used to give the title compound (1 5 mg, yield 68%) as a white solid (1H-NMR (3 00 MHz, CDCl3) 5:1.0. 1 (2H, dq, J = 3.0, 12.2 Hz), 1.95-1.33 (15H, m), 1.97 (lH, tt, J = 12.9, 3.3 Hz), 2.10 (2H, t, J = 11.2 Hz), 2.80 (2HJd, J = 11.6 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.25 (2H, s), 3.33 (2H, t, J = 11.6 Hz) &gt; 3.48 (2H, s), 3.70- 3.86 (lH, m), 3.87-4.06 (2H, m), 5 · 1 3 (2H, s), 5.29 ( lH, d, J = 7.6 Hz), 7.3 1- 7.36 (1 OH, m). /MS [Condition 1]: Hold time 3_35 minutes; m/z 603.0 [M + H]+ (ESI positive ion mode), m/z 647.1 [M + HCOO] — (ESI negative ion mode) [Chemical 1 9 7]

Example 100 (11*,4〇-1^-(1-Benzylpiperidin-4-yl)-4-{[8-(4-cyanobenzyl)-2-side-226- 201211053 Preparation of oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbamamine (Compound No. 100) Substituted benzyl bromide using 4-cyano The title compound (1 l mg, yield 51%) was obtained as a white solid, m.p. 2H, dq, J = 3.6, 12.6Hz), 1.3 5-

2.03 (16H, m), 2.11 (2H, t, J = 10.9 Hz), 2.48 - 2.63 (4H &gt; m), 2.8 1 (2 H, 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 (1 H, m), 5.27 (1 H, 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]: Hold time 1.07 min; m/z 5 8 3.9 [M + H] + (ESI positive ion mode), m/z 628.0 [M + HCOO] _ (ESI negative ion mode)

[化1 9 8] 〇

Example 1 0 1 (11:,41:)-1^-(1-Benzyl succinyl]- -4-yl)-4-({8-[(3,5-dimethyl oxime) - 4-yl)methyl]-2-oxo-oxo-oxa-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 101) The same reaction as in Example 98-227-201211053 was carried out except that the substituted benzyl bromide was produced using 4-(chloromethyl)_3,5-dimethylisoxazole (purchased from Aldrich). The title compound (18 mg, yield 85%) was obtained as a white solid (1H-NMR (300 MHz, CDC13) 6: 1.01 (2H,q,J=l 3.2 Hz), 1.80 -1.9 1 (16H,m), 2.11 (2H, t, J = 11.2 Hz), 2.24 (3H, s), 2.33 (3H, s), 2.40-2.60 (4H, m), 2.80 (2H, 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 (lH, m), 5.29 (lH, d, J = 8.3 Hz), 7.43 - 7.23 (5H, m). LC/MS [Condition 1]: Hold time 0.69 min; m/z 578.0 [M + H]+ (ESI positive ion mode), m/z 622.1 [M + HCOO]- (ESI negative ion mode) 9 9]

Example 1 0 2 (lr,4r)-N-(l-Benzylacridin-4-yl)-4-{[8-(3-methoxybenzyl)-2-oxo-1 -Dox-3,8-diazo snail [4.5] 癸-3--3-yl]methyl}cyclohexylcarboxamide (Compound No. 102) Manufactured Substituted Benzyl bromide 'Use 3-methoxy The title compound (13 mg, yield 61%) was obtained as a white solid. 1 H-NMR ( 3 00 MHz , CDC 13 ) δ : 1.01 (2H, dq, 1 = 3.0, 11.9 Hz), 2.03 - -228 - 201211053 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), 3.5 0 ( 2H, s), 3.71 - 3.8 5 (lH, m), 3.81 (3H, s), 5.28 (lH, d, J = 7.3 Hz), 6.80 (l H, dd, J = 7.6, 3_0Hz), 6.85 -6.94 (2H, m), 7.19-7.37 (6H, m). LC/MS [Condition 1]: Hold time 1.25 minutes; m/z 589.0 [M + H]+ (ESI positive ion mode), m/z 633.0 [M + HCOO]_ (ESI negative ion mode)

[化2 0 0]

Example 103 4-[(3-{[(lr,4r)-4-(l-Benzylpiperidin-4-ylaminocarbamoyl)cyclohexyl]methyl}-2-oxanoxy-1- Preparation of oxa-3,8-diazospiro[4.5]decane-8-yl)methyl]benzoate Φ methyl ester (Compound No. 103) Substituted benzyl bromide using 4-(bromomethyl)benzoin The title compound (30 mg, yield: 65%) was obtained as a white solid. 1H-NMR (3 00MHz, CDCl3) 5: 1.0 1 (2H, q, J = 12.2Hz), 1.3 3 - 2.03 ( 16H, m), 2.U (2H, t, J=ll.lHz), 2.48 -2.62 (4H, m), 2.80 (2H, d, J = 11.6 Hz), 3.09 (2H, d, J = 7.3 Hz), 3.25 (2H, s), 3.49 (2H, s), 3.57 (2 H , s), 3.70-3.85 (lH, m), 3.91 (3H, s), 5.29 (lH, d, J = 7.6 Hz), 7.3 5- 7.22 (5H, m), 7.39 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz). -229- 201211053 LC/MS [Condition 1]: Hold time 1.09 minutes; m/z 617.0 [M + H]+ (ESI positive ion mode), m/z 661.0 [M + HCOO]- (ESI negative ion mode ) 【化2 0 1】

Example 104 4-[(3-{[(1γ,4〇-4-(1-Benzylpiperidin-4-ylaminocarbamoyl)cyclohexyl]methyl}_2_ sideoxy-1-oxole - Preparation of 3,8-diazospiro[4-5]nonane-8-yl)methyl]benzoic acid (Compound No. 104) Substituting ethyl 2-(tetrahydrofuran-2-yl)acetate, using Example 103 4-[(3-{[(lr,4r)-4-(l-Benzylpiperidin-4-ylaminecarbamoyl)cyclohexyl]methyl}-2 - oxo-1-oxo-3 The title compound (1.2 mg, yield 5%) was obtained by the same reaction as the title compound (1). White solid. 1H-NMR (300MHz, CDCl3) 5: 0.98 (2H, q, J = 13.1 Hz), 1.43 (2H, q, J = 13.5 Hz), 1.46-1.65 (lH, m), 1.77- 1.93(1 3H,m), 2.33(2H, t,J = ll.lHz), 2.5 5-2.8 1(4H,m),3.07(2H,d,J = 7.0Hz), 3.13(2H ,d, J = 11.5 Hz), 3.25 (2H, s), 3.70 (2H, s), 3.76-3.93 (lH, m), 3_78 (2H, s), 5.70 (1 H, d, J = 7.8 Hz), 7.30 -7.43 (7H, m), 8.02 (2H, d, J = 8.2 Hz). -230- 201211053 LC/MS [Cond. i]: Hold time 0.93 min; m/z 602,6[M + H]+ ( ESI Positive ion mode), m/z 601.1 [MH]-(ESI negative ion mode [202] billion of

Example 1 0 5 (11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl]-1-oxo-3,8-diazospirite [4.5] Preparation of methyl decyl-3-yl}methyl)cyclohexanecarboxylate (Compound No. 1〇5) (11*,41')-4-[(2- Side Oxygen) obtained in Reference Example 6-1 Dehydrogenation of 1-oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid methyl hydrochloride to give (lr,4r)-4-[(2 - side oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid methyl. Under nitrogen, the resulting (lr, 4r)- Methyl 4-[(2-oxo-1-oxo-3,8-diazaspiro[4.5]decan-3-yl)methyl]cyclohexanecarboxylate (100 mg, 0.32 mmol), acetate ( 7.2 mg, 0.03 2 mmol), 2,2'-bis(diphenylphosphinobiphthalene (20 mg, 0.032 mmol), carbonic acid (210 mg, 0.64 mmol) and 4-bromobenzotrifluoride (72 mg, 0.32 mmol) Dissolved in 1,4-dioxane (3.0 mL), and mixed at 100 ° C for 19 hours in a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added thereto, and the mixture was stirred and mixed for 20 minutes. The diatomaceous stone was filtered to remove 'the organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. After the solid was concentrated to dryness - 231 - 201211053, the obtained residue was purified by silica gel column chromatography (Purif-Pack ΝΗ60μιη, hexane/ethyl acetate). 10 mg, yield 77%) of white solid. 'H-NMR (300 MHz, CDC 13) 6: 0.94-1.13 (2H, m), 1.32-1.5 1 (2H, m), 1.52-1.66 (lH, m), 1.73-1.91 (4H, m), 1.95-2.11 (4H5m), 2.l8-2.34 (lH, m), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.3 1- 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]: Hold time 4.51 minutes; m/z 45 5.0 [M + H]+ (ESI positive ion mode) [Chemical 2 0 3]

Reference Example 1 0 6 (lr, 4r)-4-({2-Sideoxy-8-(4-(trifluoromethyl)phenyl)-1-oxo-3,8-diazospiro[4.5]癸Preparation of alk-3-yl}methyl)cyclohexanecarboxylic acid (lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl) obtained in Example 105 ]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid methyl vinegar (110 mg, 0.25 mmol) dissolved in methanol (1.5 mL) and tetrahydroanthracene A mixed solvent of hexane (1.5 mL) was added to a 5M aqueous solution of sodium hydroxide (60 mL), and the mixture was stirred at room temperature for 9 hours. After cooling to 0 ° C, 5M hydrochloric acid, -232 - 201211053 was added and the pH was adjusted to 4. The precipitated white solid was filtered, and the title compound (tetrahydrofuran-methanol) (m.

[化2 0 4]

Example 1 〇6 (lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl]-1-oxo-3,8-diazospiro[4.5]癸Manufacture of alk-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 106)

(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl]-1-oxo-3,8-diazospin [4.5] obtained in Reference Example 106. 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 After chloroform, triethylamine (12 mg, O.llmmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg, 0.17 mmol) were added at room temperature. Mix for 11 hours. The organic layer was separated by adding water, and the mixture was washed with saturated sodium hydrogen carbonate solution and 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 [Purif-Pack ΝΗ60 μιη, manufactured by Moritex Co., Ltd., developing solvent: chloroform / ethyl acetate = 3/1 - -233 - 201211053 chloroform / methanol = = 10/1]. The title compound (39 mg, mp. 65%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 5: 1.04 (2H, q, J = l 1.7 Hz), 1.40-1 · 67 (3H, m), 1.72-2.1 2 (1 3H, m), 3.03-3 18(1 H,m), 3.12(2H,d,J = 7.4Hz), 3.29(2H,s),3.32-3.44(2H,m),3.53-3.65(3H,m),3.7〇-4.01 (3H, m), 5.75-5.89 (1 H, brm), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz). [化2 0 5]

Example 107 (11*,4〇-:^-cyclohexyl-4-({2-o-oxo-8-[4-(trifluoromethyl)phenyl]- oxa-3,8-diazo snail [4.5] Manufacture of decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 107) (lr, 4r)-4-({2- Side Oxygen-8-[ 4-(Trifluoromethyl)phenyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (10 mg, 0.023 mmol), cyclohexyl After the amine (2.3 mg, 0.023 mmol) and 1-hydroxybenzotriazole (5.7 mg, 0.030 mmol) were dissolved in chloroform, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added. The amine hydrochloride (5.7 mg, 0.03 mmol) was stirred and mixed at room temperature for 3 days. The organic layer was separated by adding water, and the solution was washed with saturated sodium hydrogen carbonate solution and saturated brine. There was -234-201211053 The layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained residue was subjected to thin layer chromatography (manufactured by Merck, Inc., PLC glass plate, 6 〇F 2 54 , developing solvent: ethyl acetate) Purification to give the title compound ( 7.6 mg, yield: 63%) as a white solid. </RTI> H-NMR (300 MHz, CDCl3) 5: 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 (lH, m), 5.28 (lH, d, J = 7.4 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz). [化2 0 6]

H3c, 〇 Reference Example 1 0 8 · 1 3-, [3-(Methoxycarbonyl)benzyl]-2-oxo-1-oxa-3,8-diazospiro[4.5]decane-8 -Production of tert-butyl carboxylic acid After dissolving 3-(aminomethyl)benzoic acid methyl ester hydrochloride (950 mg, 0.47 mm ο 1 ) in water (1.0 m L), a 5 Μ aqueous sodium hydroxide solution was added. (0.094 mL, 0.47 mmol) of 1-butyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (100 mg, 0-47 mmol) obtained in Reference Example 1-1 (m. The solution was stirred and mixed at room temperature for 10 days. Concentrate under reduced pressure and distill off methanol. Chloroform was added to the residue reaction mixture to separate the organic layer, which was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate - 235 - 201211053 and concentrated to dryness. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI 60 pm, developed solvent: hexane/ethyl acetate) to give 3-{[(4-hydroxypiperidin-4-yl). Methylamino]methyl}benzoic acid methyl ester (96 mg, yield 54%) as a colorless oil. This was dissolved in chloroform (2.0 mL), and 1,1,-carbonyldiimidazole (82 mg, 0.51 mmol) was added, followed by mixing at 5 (TC for 3 hours. Further addition of 1,1,_carbyl-methane ( 82 mg, 〇.51 mmol), and the mixture was mixed at 50 ° C for 3 hours. After adding water, the mixture was mixed at room temperature for 10 minutes to stop foaming, and the organic layer was separated and washed with saturated brine. The layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI 60 pm, developed solvent: hexane/ethyl acetate). The title compound (55 mg, yield 9%) was obtained.

H3C〆. Reference Example 1 0 8 - 2 3-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 -Methyl}methyl benzoate methyl ester. The 3-[3-(methoxycarbonyl)benzyl]-2-oxo-1-oxo-3,8-weight obtained in Reference Example 108-1 After the third butyl sulphate [4.5] decane-8-carboxylic acid (50 mg, 〇. 12 mmol) was dissolved in methanol (0.1 mL), 4M hydrogen chloride-dioxo-236-201211053 was added.

The alkane solution (1.5 mL) was stirred and mixed at room temperature for 40 minutes. The reaction mixture was concentrated to dryness under reduced pressure, and further azeotroped three times in methanol to give 3-[(2-oxo-1-oxo-3,8-diazaspiro[4.5]decan-3-yl) A white solid of the hydrochloride salt of methyl]benzoate. The hydrochloride salt was suspended in N,N-dimethylformamide (1.0 mL), and 1-(bromomethyl)-4-(trifluoromethyl)benzene (3 6 mg '0.15 mmol) and three were added. After ethylamine (30 mg, 0.30 mmol), it was stirred and mixed at room temperature for 4 days. Water and ethyl acetate were added, and the organic layer was separated, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The obtained residue was purified by silica gel column chromatography (Purif-Pack ΝΗ60 μιη, hexane/ethyl acetate), to give the title compound (3 4 mg, yield 50%) as colorless. Oily.

[化2 0 8]

Reference Example 1 0 8 - 3 3·({2 - oxo-8-[4-(difluoromethyl)benzyl] 丨 恶-3,8-diazospiro[4 5] decane- The production of 3-yl}methyl)benzoic acid will be based on the 3-({2-s. Methyl benzospiro[4·5]nonane-3_yl)methyl)benzoate (34 mg, 〇.〇78 mmol) was dissolved in methanol (1 mL), then 5M aqueous sodium hydroxide solution (〇.25mL) ), mixing at room temperature for 15 hours. After yc cold-237- 201211053, add 5M hydrochloric acid to adjust the pH to 4 » Add a mixed solvent of chloroform and 2-propanol (1〇: 1), separate the organic layer, and add chloroform and 2-propyl to the water layer again. A mixed solvent of alcohol (1〇: 1), and the organic layer was separated. The organic layer was combined and dried over anhydrous sodium sulfate. [化2 0 9]

Example 1 0 8 Third butyl 3-[3-({2- oxo-8-[4-(trifluoromethyl)phenylmethyl)-1 oxa-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)benzamide] propylcarbamate (Compound No. 1 〇 8) will be obtained by referring to Example 1 〇8 - 3 of 3 · ({ 2 · side oxygen - 8-[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3_ylindolemethyl)benzoic acid (10 mg, 0.02 2 mmol), N -(t-butoxycarbonyl) 4,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3 6 mg, 〇.〇27 mmol) dissolved in chloroform (1. 〇mL) After adding '1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.lmg, 〇.〇27 mmol), stirring at room temperature for 3 days . Triethylamine (2.7 mg, 0.02 7 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. After adding -238- 201211053, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by a thin layer chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate 1%) to give the title compound (8.4 mg, yield 63%). a colorless oil. 1H-NMR (300MHz, CDCl3) 5: 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), 3.5 1 (2H, q, J = 6.4 Hz), 3.55 ( 2H, s), 4.47 (2H, s), 4.8 5-4.89 ( lH, brm), 7.33 (lH, brs), 7.38-7.49 (4H, m), 7.56 (2H, d, J = 8.2 Hz), 7.77 (2H, s). LC/MS [Condition 2]: Hold time 3.30 min; m/z 6 〇 4.8 [M + H]+ (ESI positive ion mode)

[化2 1 0]

Example 1 0 9 N-(l-Benzylpiperidin-4-yl)-3-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1-snail - 3,8-diazo snail [4.5] phenyl-3-yl}methyl)benzamide (Compound No. 109) Manufactured in Reference Example 108_3 3-({2 - Side Oxygen^-[" (three-win methyl) benzyl]-1-indole-3, 8-diazospiro [4.5] brothel-3-yl}methyl) benzoic acid-239- 201211053 (10mg, 0.022mmol), 4- Amino-i-benzylphenystamine (4.7 mg, 0.025 mmol), 1-hydroxybenzotriazole (3.6 mg, 〇.〇27 mmol) was dissolved in chloroform (1.0 mL), then 1 -ethyl-3 was added. -(3-Dimethylaminopropyl)carbodiimide hydrochloride (5.1 mg, 0.027 mmol), stirred at room temperature for 3 days, and triethylamine (2.7 mg, After 0.027 mmol), the mixture was further stirred at room temperature for 2 days. The organic layer was separated by adding water to dryness over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purification by the method [Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate 1%) gave the title compound (14 mg, yield 82%) Colorless oil 〇1H-NMR (300MHz, CDCl3) 5: 1.49- 1.79 (4H, m), 1.85-1.97 (2H, m), 1.97-2.07 (2H, m), 2.12-2.26 (2H, m), 2.44-2.5 9(4H,m), 2.82-2.90(2H,m), 3.14(2H,s)s3.52(2H,s),3.55(2H,s),3.91-4.08 (lH, m), 4.47 (2H, s), 5.97 (lH, 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]: Hold time 2.84 minutes; m/z 620.9 [M + H]+ (ESI positive ion mode) [Chem. 2 1 1]

Example 11 〇-240- 201211053 3_({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazospiro[4.5]decane-3 Manufacture of -yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 1 1 0) The 3-({2-side oxygen-) obtained in Reference Example 108-3 8-[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid

(10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol), dissolved in chloroform (1.0 mL), and added 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (5.1 mg, 0.027 mm) was mixed at room temperature for 12 hours. The organic layer was separated with water, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by fractional chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: chloroform/methanol = 10 / 1 ) to give the title compound (4.0 mg, yield 3). 4%) of a colorless oil. 1H-NMR (300MHz, CDCl3) 5: 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 (lH , m), 3.5 5 (2H, s), 3.7 1- 3.94 (3H, m), 4.01-4.13 (lH, m), 4.47 (2H, s), 6.48-6.5 8 (lH, 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]: Hold time 5.42 min; m/z 53 2.2 [M + H]+ (ESI positive ion mode) -241 - 201211053 [Chem. 2 1 2]

Reference Example 1 1 1 -1 2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester was produced by the method described in JP 2008-546820. [Chem. 2 1 3]

Reference Example 1 Production of 1 1 - 2 6-(hydroxymethyl)nicotinic acid ethyl A pyridine-2,5-dicarboxylic acid diethyl (purchased from Tokyo Chemical Industry Co., Ltd.) (350 mg, 1.6 mmol) After dissolving in tetrahydrofuran (3_3 mL) and ethanol (6.7 mL), it was cooled at 〇 °C. After the chlorination consumption (690 mg, 6.25 mmol) was added, sodium borohydride (150 mg, 4.0 mmol) was slowly added thereto, and the mixture was mixed at the same temperature for 1 hour. After adding a saturated aqueous solution of manganese chloride, the mixture was stirred for 40 minutes at 〇t. After adding chloroform and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. -242- 201211053 [Chem. 2 1 4]

Reference example 1 1 1 - 3

3-{[5-(ethoxycarbonyl)pyridine-2.yl]methyl}-2-sideoxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid III Preparation of butyl ester The 6-(hydroxymethyl)nicotinic acid ethyl ester (100 mg, 0.55 mmol) obtained in Reference Example 1 1 I-2 was dissolved in tetrahydrofuran (4.0 mL), and after cooling at 〇 ° C, chlorination was added. Methanesulfonyl (75 mg, 0.66 mmol) and triethylamine (73 mg, 0.72 mmol) were stirred and mixed for 30 minutes. Further, methanesulfonyl chloride (38 mg, O.33 mmol) and triethylamine (37 mg, O.36 mmol) were added, and the mixture was 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 evaporated to dryness. The 2-butoxy-2-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was dissolved in hydrazine, hydrazine- Dimethylformamide (1.0 mL), sodium hydride (&gt; 55%, dispersed in mobile paraffin, purchased from Kanto Chemical Co., Ltd.) (19 mg, 0.43 mmol) at 0 ° C 'at the same temperature Stirring was carried out for 20 minutes. After adding a solution of 6-[(methylsulfonyloxy)methyl]nicotinic acid ethyl ester (11 Omg) in N,N-dimethylformamide (1.0 mL) to the obtained reaction mixture, Mix at room temperature overnight at 243-201211053. Further, sodium hydride (&gt; 5 5%, dispersed in flowing paraffin, purchased from Kanto Chemical Co., Ltd.) (9 mg, 0.22 mmol) was added, and the mixture was mixed at room temperature for 1 hour. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The resulting residue was recrystallized from ethyl acetate / hexanes to give the title compound (86 mg), 2- 2- s. a mixture of third butyl esters. [Chem. 2 1 5]

Reference Example 1 1 1 - 4 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1 oxa-3,8-diazospiro[4.5] decane-3 -Methyl}methyl)nicotonic acid ethyl 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-oxan-1 obtained in Reference Examples 11 to 1-3 -oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (86 mg) was dissolved in 1,4-dioxane (〇_50 mL), then 4 M hydrogen chloride-dioxane was added. The solution (2.0 mL) was mixed at room temperature for 1 hour. After the reaction suspension was added with ethanol (〇. 20 mL), the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped three times with methanol to give 6-[(2-oxo-oxo-1 -oxa-3,8-diazospiro[4.5]decane-3-yl a white solid of methyl]nicotinic acid ethyl ester hydrochloride. The hydrochloride salt was suspended in 201211053 N,N-dimethylformamide (1.0 mL), and 4-(trifluoromethyl)benzyl bromide (62 mg, 0-26 mmol) and triethylamine (52 mg, After 0.52 mmol), the mixture was stirred and stirred at room temperature for 24 hours. The organic layer was separated by adding water and ethyl acetate. This was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (Puri f-Pack SI 60 pm, solv. chloroform/methanol) to give the title compound (49 mg, yield

[Chem. 2 1 6]

Reference Example 1 1 1 - 5 Φ 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5] decane- Preparation of 3-yl}methyl)nicotinic acid 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxole obtained in Reference Example 1 1 1 - 4 -3,8-diazospiro[4_5]nonan-3-yl}methyl)nicotinic acid ethyl ester (49 mg, 0.1 mmol) was dissolved in methanol (1.0 mL), then 5M sodium hydroxide solution was added ( 0.1 0 m L, 0.5 1 mm ο 1), stirring at room temperature overnight. After cooling the reaction mixture to 〇 ° C, 5 M hydrochloric acid was added to adjust the pH to 5. After water was added, the title compound (12 mg, 27%) was obtained. After adding a mixed solvent of chloro-245-201211053 iodo/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 the salt to the aqueous layer, the extraction was carried out once in a mixed solvent of chloroform/isopropyl alcohol (5/1). The combined organic layer was dried over anhydrous sodium sulfate and evaporated. [Chem. 2 1 7]

Example 1 1 1 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl Manufacture of <methyl)-N-[(tetrahydrofuran-2-yl)methyl]nicotinium amide (Compound No. 1 U) 6-({2- Side Oxygen-8) obtained in Reference Example 1 1 1-5 -[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)nicotinic acid (10 mg, 0.022 mmol), four Hydroxydecylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mm 〇U dissolved in chloroform (1.0 mL), then added 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (5.1 mg, 0.027 mm) was mixed at room temperature for 15 hours. The organic layer was separated by water and the aqueous layer was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained fractions were taken in a thin layer -246 - 201211053 The title compound (8.4 mg, yield: 72%) was obtained by chromatography (PLC: EtOAc, EtOAc: EtOAc: As a yellow oil.

1H-NMR (300MHz, CDCl3) 5: 1.54- 1.67 (2H, m), 1.70- 1.86 (2H, m), 1.88-2.1 2 (4H, m), 2.48-2.6 1 (4H, m), 3.27- 3.37(1 H ,m),3.33 (2H,s),3.56(2H,s),3.73-3.95(3H,m),4.02-4.1 4( lH,m),4.59( 2H,s),6.47- 6.54 ( lH, brm), 7.38 (1 H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 8.08 (lH, dd, J = 7.8, 2.4 Hz), 8.93 (1 H, d, J = 2.4 Hz). LC/MS [Condition 2]: Hold time 5 · 19 minutes; m/z 53 3.3 [M + H]+ (ESI positive ion mode)

[2 2 8

Reference Example U2-1 Production of 6-(hydroxymethyl)pyridinecarboxylic acid methyl group Diethyl pyridine-2,6-dicarboxylate (purchased from Tokyo Chemical Industry Co., Ltd.) (l.〇g, 5.1 mmol) After dissolving in dichloromethane (35 mL) and methanol (15 mL), it was cooled to 〇 °C. Sodium borohydride (195 mg, 5.2 mmol) was slowly added and mixed at room temperature for 3 hours. After adding a saturated aqueous solution of manganese chloride, the mixture was stirred and mixed at 〇 ° C for 40 minutes. After adding chloroform and water, the organic layer was separated and washed with saturated brine. After drying the organic layer with anhydrous sodium sulfate, the mixture was concentrated to dryness by subtracting from -247 to 201211053. The obtained residue was purified by silica gel column chromatography (Purif-pack. [Chem. 2 1 9]

Reference Example 1 1 2 - 2 3-{[6-(Methoxycarbonyl)pyridin-2-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane Preparation of -8-carboxylic acid tert-butyl ester The 6-(hydroxymethyl)pyridinecarboxylic acid methyl group (100 mg, 0.60 mmol) obtained in Reference Example 112-1 was dissolved in tetrahydrofuran (4.0 mL) and cooled to 0 ° C. Thereafter, methanesulfonyl chloride (75 mg, 0.66 mmol) and triethylamine (73 mg, 0.72 mmol) were added and mixed for 30 minutes. Further, a thiol group (38 mg, 0.33 mmol) and triethylamine (37 mg, 0-36 mmol) were added, and the mixture was stirred and mixed 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 evaporated to dryness. The 2-butoxy-2-oxo-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was dissolved in N,N- Dimethylformamide (1.0 mL), sodium hydride (&gt; 55%, dispersed in mobile paraffin, purchased from Kanto Chemical Co., Ltd.) (19 mg, 〇.43 mmol) -248-201211053 after adding at 0 °C 'Agitate and mix at 2 minutes for the same temperature. After adding a solution of 6-[(methylsulfonyloxy)methyl]pyridinecarboxylic acid methyl (110 mg) in N,N-dimethylformamide (1 mL) to the obtained reaction mixture, Mix overnight at night with warming. 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 concentrated to dryness. The obtained residue was purified by silica gel column chromatography (purif_pack ΝΗ60 μιη, hexane, hexane/ethyl acetate) to give the title compound (93 mg, yield: 60%). [化2 2 0] Ο

Reference example 1 12-3

6-({2-Sideoxy-8[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)pyridine The production of the carboxylic acid methyl group will be based on the 3-{[6-(methoxycarbonyl)pyridin-2-yl]methyl}-2-oxan-1-oxo-3,8-weight obtained in Reference Example 112-2. After dissolving the third butyl sulphide [4·5]nonane-8-carboxylic acid (93 mg) in methanol (0.20 mL), a solution of 4 Μ hydrogen chloride-dioxane (2.0 mL) was added and the mixture was allowed to stand at room temperature for 1 hour. mixing. The reaction mixture was concentrated to dryness under reduced pressure, and further azeotroped three times with methanol to give 6-[(2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl a white solid of the hydrochloride salt of methyl]pyridinecarboxylic acid methyl. The hydrochloride salt was suspended in hydrazine, hydrazine-dimethyl-249-201211053 decylamine (2.0 mL), and 4-(trifluoromethyl)benzyl bromide (60 mg, 0.25 mmol) and triethylamine were added. After (51 mg, 0-51 mmol), it was stirred and mixed at room temperature for 24 hours. Water and ethyl acetate were added, and the organic layer was separated, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The obtained residue was purified by silica gel column chromatography ( Purif-Pack SI 60 pm, solv. chloroform/methanol) to give the title compound (4 8 m g, yield: 45%). [化 2 2 1]

Reference Example 1 1 2 - 4 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 Preparation of -yl}methyl)pyridinecarboxylic acid 6_({2·Sideoxy-8-[4-(trimethylmethyl)benzyl]-1-oxo-3 obtained in Reference Example 1 I2·3, 8-Diazospiro[4.5]decane-3-yl}methyl)pyridinecarboxylic acid methyl (48 mg, 0.1 mmol) was dissolved in methanol (1.0 mL) and then poured into a 5M sodium hydroxide solution (〇 l〇mL, 0.51 mmol) 'After stirring at room temperature overnight. After cooling the reaction mixture to 〇 ° C, 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). After adding salt to the aqueous layer, extraction was carried out once with a mixed solvent of chloroform/2-propanol (5/1). The combined organic layer was dried over anhydrous sodium sulfate (MgSO4) [Chemical 2 2 2]

Example 1 1 2 Φ 6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of benzyl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]pyridinium amide (Compound No. 112)

6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane obtained in Reference Example 112-4 3-yl}methyl)pyridinecarboxylic acid (1 Omg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) were dissolved in chloroform (l After .OmL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mg, 0.027 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The organic layer was separated by water and the aqueous layer was extracted with chloroform. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The obtained residue was purified by a thin-layer chromatography (PLC, glass, silica gel, 6OF254, hexane, chloroform/methanol = 1 0/1) to give the title compound (5.9 mg, yield 50). %) of colorless oil > 1H-NMR (300MHz, CDCl3) 6: 1.53-1.68 (2H, m), 1.7 1- 2.09 (6H, m), 2.48-2.63 (4H, m), 3.3 1 (2H ,s),3.3 3 -3.46(lH,m)53.57(2H, -251 - 201211053 s), 3.69-3.80(2H,m),3.85-3 ·94(1Η,ιη),4.02-4.1 3( lH , m), 4.60 (2H, s), 7.42 (3H, t, J = 7.0 Hz), 7.5 7 (2H, d, J = 7.8 Hz), 7.85 (lH, t, J = 7.7 Hz), 8.13 ( lH,d,J = 7.2HZ), 8. 1 7-8.25 ( 1 H,m). LC/MS [Condition 2]: Hold time 5.35 min; m/z 53 3.2 [M + H]+ (ESI positive ion mode)

Example 1 1 3 Third butyl 3_[4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]] oxime] 3,8-diazo snail [4· Manufacture of 5] nonane-3-yl}methyl)benzamide] propylcarbamate (Compound No. 113) 4-({2 - side oxygen_8-[4] obtained in Reference Example 21. -(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (1〇1118, 0.022 mmol), N-( T-butoxycarbonyl)-indole, 3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol), dissolved in chloroform (1.0 mL), -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.111^, 0.027111111〇1), stirred at room temperature for 3 days, adding water to separate the organic layer, After drying over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure. The residue was purified by fractional chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA) to give the title compound (12 mg, yield: 90%) as a white solid. -252- 201211053 1H-NMR (300 MHz, CDCl3) 5: 1.4 5 (9H, s), 1.65-1.80 (4H, m), 1.85-1.96 (2H, m), 2.44-2.6 1 (4H, m), 3.12 (2H, s), 3.25 (2H, q, J = 6.0 Hz), 3.5 1 (2H, q, J = 6.0 Hz), 3.55 (2H, s), 4.47 (2H, s), 4.80 -4.92 (lH , m), 7.30 (lH, 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) , 7.8 5 (2H, d, J = 8.0 Hz). [化2 2 4] 0

Example 1 1 4 N-(l-Benzylpiperidin-4-yl)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 1 14)

4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- obtained in Reference Example 21. }]methyl)benzoic acid (l〇mg, 0.022mmol), 4-amino-1-benzylmethyl sulfonate (5.1mg, 0.027mmol), 1-hydroxybenzotriazole (3.6mg, 0.027mmol) After dissolving in chloroform (i.〇mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mg, 0.027 mmol) was added at room temperature Mix for 15 hours. The organic layer was separated with water, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by fractional chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate oxime%) - 253 - 201211053 to obtain the title compound (9 · 9 mg) , yield 73%) of white solid 〇 'H-NMRiSOOMHz^DCbia : 1.48- 1.78 (4H, m), 1.8 6 - 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.U (2H, s), 3.52 (2H, s), 3.55 (2H, s), 3.93 - 4.09 ( lH,m), 4.46(2H,s)&gt;5.93-6.01(lH,m),7.2 3-7.34(5H,m),7.32(2H,d,J = 8.3Hz), 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]: Hold time 4.93 minutes; m/z 621.3 [M + H]+ (ESI positive ion mode) [Chem. 2 2 5]

H3c, 0 Reference Example 1 1 5 - 1 3-[2-Methoxy-4-(methoxycarbonyl)benzyl]_2_sideoxy-^-- 3,8-diazo snail [4.5]癸Production of alkane-8-carboxylic acid tert-butyl ester The 2-butyloxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester obtained in Reference Example 111-1. (200 mg, 0.78 mmol) dissolved in N,N-dimethylformamide (5 mL), sodium hydride (&gt; 55%, dispersed in mobile paraffin, purchased from Kanto Chemical Co., Ltd.) (41 mg, 0.78 mmol) After stirring for 30 minutes, add methyl 4-(bromomethyl)-3-methoxybenzoate (trans world -254- 201211053)

Chemicals inc (200 mg, 0.78 mmol) were stirred at room temperature for 17 hours. After the reaction was stopped, a saturated aqueous solution of manganese chloride (2.0 mL) and ethyl acetate (2.0 mL) were added to the mixture. The mixture was extracted twice with ethyl acetate (10 mL), and brine (10 mL) was added to the organic layer, and liquid separation was carried out. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by ruthenium column chromatography [grave charge: FL100D manufactured by FUJI SILYSIA, developing solvent: n-hexane/ethyl acetate = 1/1] to obtain 3-[2-methoxy 4-(methoxycarbonyl)benzyl]-2-oxo-1,oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (240 mg, yield 71%) white solid. W-NMRpOOMHz'CDClW: 1.45 (9H, s), 1.60 (2H, dt, J = 5.1, 1 3.0 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), 7.3 1 (lH , d, J = 7.8 Hz), 7.55 (lH, d, J = 1.4 Hz), 7.64 (lH, dd, J = 1.4, 7.8 Hz). ^ LC/MS [Condition 1]: Hold time 4.23 minutes; m/z 434.8 [M + H]+ (ESI positive ion mode), m/z 479.0 [M + HCOO]- (ESI negative ion mode) 2 2 6] o^CH3 ?

Reference Example 1 1 5 - 2 3 -Methoxy- 4- [(2-Sideoxy-1-noise-3,8-diazosuro[4.5] 癸-3-yl)methyl-255- 201211053 ] Preparation of benzoic acid methyl ester hydrochloride. Reference will be made to 3-[2-methoxy-4-(methoxycarbonyl)benzyl]-2-oxo-1-oxo-3 obtained in Example 115-1. 8 - Diazo snail [4.5] decane-8-carboxylic acid tert-butyl vinegar (220 mg, 0.50 mmol) was dissolved in chloroform (1. 〇mL), force D into 4M hydrogen chloride-dioxane solution (3 mL), Stirring was carried out for 1 hour at room temperature. After the reaction was stopped, the reaction mixture was concentrated to dryness under reduced pressure to give 3-methoxy-

4 - [(2-oxo-oxy-1 -oxa-3,8-diazospiro[4 · 5 ]decane-3-yl)methyl]benzoic acid methyl ester hydrochloride (180 mg, yield 97%) White solid. , H-NMR (300MHz, CDCl3) 6: 1.93-2.32 (4H, m), 3.14-3.52 (6H, m), 3.90 (3H, s), 3.93 (3H, s), 4.49 (2H, s), 7.3 1 (lH, d, J = 7.8 Hz), 7 • 56 (lH, d, J = 1.4 Hz), 7.63 (lH, dd, J = 1.4, 7.8 Hz). [2 2 7]

Reference Example 1 1 5 _ 3 3 -Methoxy-4- ({2-Sideoxy-8-(4-(trifluoromethyl)phenylmethyl)_i_Dox_3,8-diazo snail [4.5] Preparation of methyl decane-3-yl}methyl)benzoate. 3-methoxy-4-[(2-oxo-oxo-oxa-3,8-diazo) obtained in Reference Example 1 15-2 Snail [4.5] 癸-3-yl)methyl]benzoate methyl ester hydrochloride (180 mg, 0.48 mmol) was dissolved in chloroform (i. 〇mL), then ν, Ν-dimethylformamide ( l.OmL). Add 4-(trifluoromethyl)benzyl bromide (13〇mg 8 -256- 201211053, 0.52mmol), triethylamine (0.20mL, 1.4mmol) in the order of 16 hours at room temperature Stir. After the reaction was stopped, the reaction mixture was concentrated under reduced pressure and chloroform was evaporated. The precipitated solid was filtered, and then dried at 50 ° C under reduced pressure to give 3-methoxy-4-({2--oxo-8-[4-(difluoromethyl)benzyl). ]-1-Boxo-3,8-diazospiro[4.5]decane-3-yl}methyl)methyl benzoate (190 mg, yield 80%) as a white solid.

'H-NMR (300MHz, CDC13) 6: 1.79-1.66 (2H, m), 1.85-1.96 (2H, m), 2.59-2.48 (4H, brm), 3.16 (2H, s), 3.5 5 ( 2H, brs), 3.89 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 7.3 0 (lH, d, J = 7.5 Hz), 7.42 (2H, d, J = 7.8 Hz) , 7.5 1- 7.60 (3H, m), 7.63 (lH, dd, J = 7.8, 1.4 Hz). LC/MS [Condition 1]: Hold time 3.28 minutes; m/z 492.8 [M + H]+ (ESI positive ion mode), m/z 536.9 [M + HCO〇r (ESI negative ion mode)

[2 2 8]

Reference Example 1 1 5 - 4 3-methoxy-4-( {2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro [ 4.5] Manufacture of decyl-3-yl}methyl)benzoic acid 3-methoxy-4-({2-trioxo-8-[4-(trifluoromethyl)) of Reference Example 115-3 Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)an-257- 201211053 Methyl benzoate (170 mg, 0.35 mmol) dissolved in 1,4 After dioxane (1.5 mL), 1 M aqueous sodium hydroxide solution (1.4 mL) was added and stirred at room temperature. After 21 hours, 1 M hydrochloric acid (1.3 mL) was added and the reaction was stopped. The reaction mixture was extracted twice with ethyl acetate (10 mL), and the organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The precipitated solid was washed with diisopropyl ether to give 3-methoxy-4-({2-trioxo-8-[4-(trifluoromethyl)benzyl]-1-oxo_ 3,8- Diazospiro[4.5]decane-3-yl}methyl)benzoic acid (140.0 mg, yield 84%) as a white solid. 1H-NMR (300MHz, CDCI3) 5: 1.94 (4H, m), 2.77 (2H, t, J = 10.2Hz), 2.98-3 · 1 5 (4H, m), 3.88 (3H, s), 3.90 ( 2 H, s), 4.49 (2H, s), 7.27 ( lH, d, J = 7_8 Hz), 7.50-7.65 (6H, m). LC/MS [Condition 1]: Hold time 3.04 min; m/z 478.8 [M + H]+ (ESI positive ion mode), m/z 476.9 [M-Hr (ESI negative ion mode) [Chem. 2 2 9 】

Example 1 1 5 3 -Methoxy-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 115) -258- 201211053

3-methoxy-4_({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro] obtained in Reference Example 115-4 4.5]decane-3-yl}methyl)benzoic acid (30 mg, 0.063 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg, hydrazine) .l3mmol) and 1-hydroxybenzotriazole (17mg, 0.13mmol) were dissolved in chloroform (l.〇mL), then tetrahydrofurfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) (〇.〇13mL, 0.13 mmol) and triethylamine (0.018 mL, 0.13 mmol) were added at room temperature, and stirred for 20 hours. After the reaction was stopped, 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 (1 mL), and the organic layer was combined with saturated brine. 1 OmL) Wash. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was washed with hexane and dried at 5 (TC) under reduced pressure to give 3-methoxy-4-({2-s. ]-1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide (23 mg, produced) White solid with a yield of 66%) 1H-NMR (300MHz, CDCl3) 6: 1.54- 1.79 (3H, m), 1.84- 1.98 (4H, m), 1.98-2.11 (lH, m), 2.53 (4H, brs ), 3.15 (2H, s), 3.34 (lH, 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 (lH, dq, J = 3.4, 7.2 Hz), 4.4 8 (2H, s), 6.5 1 (lH, t, J = 5.5 Hz), 7.22 (1 H, dd, J = 7.8, 1 · 7 Ηζ) , 7.28 (1 H, d, J = 7.8 Hz), 7.39-7.48 (3H, m), 7.57 (2H, d, J = 7.8 Hz) LC/MS [Condition 1]: Hold time 3.18 minutes; m/ Z561.8[M + H]+ (ESI positive ion mode), m/z 606.0 [M + HCO〇r (ESI negative ion mode) -259- 201211053 [Chem. 2 3 0]

Example 11 6

4-[3-methoxy-4-({2-o-oxo-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane Manufacture of -3-yl}methyl)benzamide = piperidine-1-carboxylic acid tert-butyl ester (Compound No. 116) Substituted tetrahydrofurfurylamine using 4-aminopiperidine-1-carboxylic acid The same reaction as in Example 115 was carried out to give the title compound as a white solid (1 mg, yield: 84%).

1H-NMR (3 00MHz, CDCl3) 5: 1.40 (2H, td, J = 12.3, 3.7 Hz), 1.47 (9H5s), 1.64 - 1.79 (2H, brm), 1.89 (2H, d, J-13.0 Hz) , 2.02 (2Hsdd, J = 12.6, 2.7 Hz), 2.4 1- 2.63 (4H, brm), 2.9 1 (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 (lH, d, J = 8.2 Hz), 7.17 (lH, 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]: Hold time 3.58 minutes; m/z 660.9 [M + H]+ (ESI positive ion mode), m/z 705.0 [M + HCOO]_ (ESI negative ion mode) -260- 201211053 【化2 3 1】.CH3

Reference example 1 1 7

• Preparation of a nitrogen snail [4.5] decane-3 yl}methyl)-N-(piperidin-4-yl)benzamide 2 hydrochloride The 4-fluorofluorocarbon obtained in Example 1 16 Base) methyl]-1-chew- 3,8-diazo snail [4.5] brothel _3_yl}methyl) benzalamine] piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.090 mm 〇 1) was dissolved in a 4 M 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-s.s.s.s. -3,8-diazo φ spiro[4·5]decane-3-yl}methyl)-N-(piperidine-4-yl)benzamide 2 hydrochloride (63 mg, yield 1 〇) 〇%) white solid. LC/MS [Condition 1]: Hold time 1.40 min; m/z 5 60.8 [M + H]+ (ESI positive ion mode) [Chem. 2 3 2]

-261 - 201211053 Example 11 7 N-[l-(#lylmethyl)indole-4-yl]-3-methoxy·4·((2-side oxygen_8_[4-(=r Manufacture of fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 117) will be obtained in Reference Example 117. 3-methoxy-4-((2. oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane_3_yl} Methyl)_N_(piperidin-4-yl)benzamideamine hydrochloride (32 mg, 〇.〇5〇mmol) was dissolved in hydrazine, hydrazine dimethylformamide (1.0 mL) Bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.0067 mL, 0.1 Ommol) and triethylamine (0·02 1 mL '0.1 5 mmo 1) were added in this order, and stirred at room temperature for 1 day. After adding saturated aqueous solution of manganese chloride (2.0 mL) and ethyl acetate (2.0 mL), the mixture was extracted twice with ethyl acetate (10 mL), and the 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 subjected to thin layer chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., Development solvent: ethyl acetate] was purified to give N-[l-(cyanomethyl)piperazin-4-yl]-3-methoxy ""-o-oxo-^-"trifluoromethylhydrazine Benzyl dipyridyl-oxo-^"-diazospiro[4.5]decane-3-yl}methyl)benzamide (18 mg, yield 60%) as a white solid. 1H-NMR (300 MHz, CDCl3) ) 6:1.55-1.79(4H,m), 1.89 (2H, dJJ = 13.3Hz), 2.10(2H,dd,J=13.0,3.1Hz), 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) s 3.89 (3H, s), 3.94-4.11 (lH, m), 4.48 (2H ,s),6.08(lH,d,J = 7.8 -262- 201211053

Hz), 7.19 (lH, dd, J = 7.8, 1.4 Hz), 7.28 (lH, d, J = 7.8 Hz), 7.39-7.46 (3 Η, m), 7 · 5 6 (2 Η, d, J = 8 · 2 Η z). LC/MS [Condition 1]: Hold time 3·〇2 minutes; m/z5 99.9 [M + H]+ (ESI positive ion mode), m/z 644.1 [M + HCOO] — (ESI negative ion mode)

[化2 3 3]

F Example 1 1 8 4-[3-Methoxy-4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Manufacture of spiro [4.5]decane-3-yl}methyl)benzamide]piperidine-1-carboxylic acid methyl ester (Compound No. 1 18)

The title compound was obtained as a white solid (20 mg, yield: 64%), which was obtained from the crude compound of the compound (1). 1H-NMR (300MHz, CDCl3) 6: 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 (lH, d, J = 7.8 Hz), 7.19 (lH, dd, J = 7.8, 1.4 Hz), 7.28 (lH, d, J = 7.8 Hz), 7.41 (lH, d, J = 1.4 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, -263- 201211053 d, J = 8.2 Hz) » LC/MS [Condition i]: Hold time 3.22 minutes; m/z 618.9 [M + H]+ (ESI positive ion mode), m/z663.i [M + HCO〇r (ESI negative ion mode) [ 2 3 4]

Reference Example 1 Production of 1 9 -1 4-(1-ethoxy-1-oxopropan-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 1 M hexamethyldifluoride A solution of lithium aluminide tetrahydrofuran (purchased from Aldrich) (9.9 mL, 9.9 mmol) in tetrahydrofuran (25 mL) was slowly added dropwise to ethyl propionate at -7 8 ° C under air atmosphere (by Tokyo) Chemical industry (stock) purchase) (l.lmL, 9.9mmol). After stirring at the same temperature for 1 minute, a solution of Ι-t-butoxycarbonyl-4-piperidine (purchased from Wako Pure Chemical Industries, Ltd.) (1.8 g, 9.0 mmol) in tetrahydrofuran (5.0) was slowly added. mL). While stirring to room temperature, the mixture was stirred for 1 day, and then a saturated aqueous solution of sodium chloride (10 mL) and ethyl acetate (10 mL) were added. The reaction mixture was extracted twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and then reduced to -264-201211053 under reduced pressure to give 4-(1-ethoxy-1-oxopropan-2-yl)-4-pyridylpiperidine. Yellow oil of 1-carboxylic acid tert-butyl ester (2.5 g). The reaction was used directly in the next stage without purification. [Chemical 2 3 5]

Reference Example 1 Production of 1 9 - 2 2_[l-(t-butoxycarbonyl)-4-hydroxypiperidin-4-yl]propionic acid

The solution of 4-(1-ethoxy-1-oxopropan-2-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester obtained in Reference Example 119-1 was added to methanol (36 m L). A 1 M aqueous sodium hydroxide solution (3 6 mL) was stirred at room temperature for 3 days. After the reaction temperature was 〇 ° C, 1 M hydrochloric acid (30 mL) was added, and the mixture was adjusted to pH 8. Then ethyl acetate (2OmL) was added and the aqueous layer was washed twice. 1 M hydrochloric acid was added to the obtained aqueous layer, and the mixture was adjusted to pH 4, and then extracted three times with ethyl acetate (20 mL), and the organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated to dryness. (7 9Omg). It is used directly in the next stage of the reaction without purification. -265- 201211053 【化2 3 6】HN Ο人 Ό

〇^°XcchH3 H3C ch3 Reference Example 1 1 9 - 3 4-Methyl-2-oxo-oxo-3,8-diazospiro[4·5]decane-8-carboxylic acid tert-butyl ester Triethylamine (0.45 mL) was added to a toluene solution (15 mL) of 2-[l-(t-butoxycarbonyl)-4-hydroxypiperidin-4-yl]propanoic acid obtained in Reference Example 119-2. 3.2 mmol) and diphenylphosphoryl azide (〇.81 mL, 3.8 mmol) were stirred at 70 ° C for 30 minutes, and then the reaction solution was heated under reflux. After 6 hours, a saturated aqueous solution of sodium hydrogencarbonate (10 mL) was added and the mixture was adjusted to pH 8 and then ethyl acetate (20 mL) was added and extracted five times, and the organic layer was washed with saturated brine (50 mL) . The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The obtained residue was subjected to silica gel column chromatography [塡剂: Shanshan Hi-FLASH column size L (4 (^m, 3〇g), developing solvent: hexane/ethyl acetate = 1/1 40 Purification with 0 mL, followed by ethyl acetate (300 mL) gave 4-methyl-2-oxo-oxo-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (310 mg) , a yellowish solid with a yield of 13%) in the 3rd order. 1H-NMR (300MHz, CDCl3) 5: 1.19 (3H, d, J = 6.5Hz), 1.46 (9H, s) 9 1.61 (2H, ddd, J = 3 1.0, 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 (lH, q, J = 6.5 Hz), 4.02 (2H, brs) s5.04 ( • 266- 201211053 1 H, brs). [Chem. 2 3 7]

Ο Reference Example 1 1 9 - 4 4-(Bromomethyl) benzoic acid methyl vinegar

Add 4-indole hydrogen chloride-methanol solution (1 〇m L) to 4-(bromomethyl)benzoic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (5 〇 0 mg, 2.3 mm 〇I) at 60 ° C Stir the sample. After 2 hours, the reaction was stopped, and a saturated aqueous solution of sodium hydrogencarbonate (2 mL) was added at room temperature. Ethyl acetate (2 mL) was added for 2 extractions. The combined organic layers were washed with saturated brine (40 mL). The organic layer was separated and dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give a mixture of methyl 4-(bromomethyl)benzoate and 2:3 of methyl 4-(chloromethyl)benzoate. Yellow solid (39 Omg). It is used directly in the next stage of the reaction without purification. 4_(Bromomethyl)benzoate methyl ester 1H-NMR (300 MHz, CDC13) 5: 3.92 (3H, s), 4.50 (2H, s), 7.46 (2H, d, J = 8 · Ο Η z), 8.0 1 (2 Η,d,J = 8 · Ο Η z). 4·(Chloromethyl) benzoic acid methyl ester 1H-NMR (300MHz, CDC13) 5: 3.92 (3H, s), 4.62 (2H, s), 7.46 (2H, d, J = 8.0 Hz), 8.04 (2H , d, J = 8.0Hz). -267- 201211053 【化2 3 8】 Ο

Reference Example 1 1 9 -5 3-[4-(Methoxycarbonyl)benzyl]-4-methyl-2-oxo-1-oxa-3,8-diazospiro[4.5]decane- Production of 8-carboxylic acid tert-butyl ester 4-methyl-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid obtained in Reference Example 119-3 Tributyl ester (200 mg, 〇.74 mmol) was dissolved in N,N-dimethylformamide (4.0 mL), and sodium hydride (&gt;55%, dispersed in mobile paraffin, purchased from Kanto Chemical Co., Ltd.) was added ( 39 mg, 〇.89 iximol), after stirring for 30 minutes, a 2:3 mixture of methyl 4-(bromomethyl)benzoate and methyl 4-(chloromethyl)benzoate obtained in Reference Example 1 19-4 was added. (180 mg, 0.89 mmol), stirring at room temperature. After 28 hours, a saturated aqueous solution of manganese chloride (5. 〇mL) and ethyl acetate (5.0 mL) were added. The mixture was extracted twice with ethyl acetate (10 mL), and the 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 [塡 剂: Shanshan Hi-FLASH column size L (40 pm, 30 g), developing solvent: hexane/ethyl acetate = 1/1]. [4_(Methoxycarbonyl)benzyl; 1-4-methyl-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (290.Omg 'yield 95%) of colorless oil. -268 - 201211053 1H-NMR (300MHz, CDCl3) 5: 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 (lH, q, J = 6.5 Hz), 3.92 (3H, s ), 3.94 - 4.11 (2H, m), 4.16 (lH, d, J = 15.7 Hz), 4.80 (lH, d, J = 15.7 Hz), 7.36 (2H, d, J = 8.2 Hz), 8.03 (2 H, d, J = 8.2 Hz).

[化 2 3 9]

Reference Example 1 1 9 - 6 4-[(4-Methyl-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl] benzoic acid methyl ester salt The acid salt was produced in 3-[4-(methoxycarbonyl)benzyl]-4-methyl-2-oxo-1-oxo-3,8-diazo snail obtained in Reference Example 119-5. 4.5] decane-8-carboxylic acid tert-butyl ester Φ (28〇11^, 0.67111111〇1) was added 41^hydrogen chloride-dioxane solution (31111〇, stirred at room temperature for 3 hours. After the reaction was stopped) The reaction mixture was concentrated to dryness under reduced pressure to give 4-[(4-methyl-2-oxo-1-oxo-3,8-diazaspiro[4.5]decane-3-yl)methyl ] benzoic acid methyl ester hydrochloride (260 mg, yield 100%) as a white solid.] H-NMR (300 MHz, CDC 13) 5:1 .1 5 (3H, d, J = 6.5 Hz), l.94 ( 2H, dd, J = 35.6, 14.3 Hz), 2.09-2.3 1 (2H, m), 3.17-3.38 (3H, m), 3.38-3.55 (2H, m), 3.93 (3H, s), 4.14 (lH) , d, J = 15.6 Hz), 4.79 (lH, 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 ) -269- 201211053 【化2 4 0】 Ο

F Reference Example 1 19-7 4-({4-Methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1 oxa-3,8-diazo snail [4.5 [4-Methyl-2-oxo-oxo-oxa-3,8-diazo snail obtained by the preparation of methyl benzoate-3-yl}methyl)benzoate. [4.5] decyl-3-yl)methyl]benzoic acid methyl ester hydrochloride (200 mg, 0.56 mmol) was added N,N-dimethylformamide (2.0 mL). 4-(Trifluoromethyl)benzyl bromide (150 mg, 0-61 mmol), triethylamine (0.23 mL, 1.7 mmol) was added in this order, and stirred at room temperature. After 21 hours, the reaction was stopped and water (3.0 mL) was added. The precipitated solid was filtered, dried under reduced pressure at 50 ° C to give 4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]- Methyl 1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoate (240 mg, yield 88%) as a white solid. ^-NMRiSOOMHz.CDClsja: 1.10(3H,d,J = 6.5Hz), 1.53-1.87 (4H,m), 2.38-2.55(2H,m), 2.70(2H,t,J=11.5Hz)53.27(lH ,q,J = 6.5Hz),3.57(2H,s),3.92(3H,s),4.15(lH,d,J-15.6Hz),4.79( lH,d,J=15.6Hz),7.35(2H , d, J = 8.2 Hz), 7.43 (2H, d, J = 7.8 Hz) s 7.56 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz). -270- 201211053 【化2 4 1】

Reference example 1 1 9 - 8

4-({4-methyl-2-oxo-8-[4-(difluoromethyl)benzyl]]ιιυ - 3,8-diazospiro[4.5]decane-3-yl}A Preparation of benzoic acid 4-({4-methyl·2_sideoxy·8_[4·(trifluoromethyl)benzyl]-1-oxo-3,8 obtained in Reference Example 119-7 - a mixture of diazospiro[4.5]decane-3-yl}methyl)benzoic acid methyl ester (240 mg, 0.49 mmol) dissolved in 1,4-dioxane (3.0 m L) and methanol (2.0 mL) After the solvent, a 1 M aqueous sodium hydroxide solution (3.0 mL·) was added, and the mixture was stirred at room temperature. After 2 hours, 1 M hydrochloric acid (3.0 mL) was added to leave the reaction. The reaction mixture was extracted twice with ethyl acetate (1 mL). The organic layer was washed with saturated brine (1OmL). The organic layer was separated and dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1 - oxa- 3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (i 70 mg, yield 77%) as a white solid. LC/MS [Condition 1]: Hold time 3.10 minutes; m/z 462.7 [M + H]+ (ESI positive ion mode), m/z 46 〇.9 [M-Hr (ESI negative ion mode) -271 - 201211053 [Chem. 2 4 2]

EXAMPLES 4 9 4_({4-Methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]癸Preparation of alk-3-yl}methyl)-indole-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 119) 4-({4-methyl) obtained in Reference Example 119-8 -2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (40 mg , 0.086 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mm 〇l) and 1-hydroxybenzotriazole (23 mg, 0.17) After dissolving in chloroform (1.0 mL), tetrahydrofurfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) (〇.〇18 mL, 0.17 mmol) and triethylamine (0.024 mL, 0.17 mmol) were placed in the chamber. Add by warming and stir for 3 days. Water (2. 〇mL) and ethyl acetate (2.0 mL) were added to the mixture, and the mixture was extracted twice with ethyl acetate (10 mL), and the organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography [塡 剂: FUJI SILYSIA FL100D, developing solvent: ethyl acetate / methanol = 1 〇Π] to give 4-({4-methyl-2- side Oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)-:^[(tetrahydrofuran-2) -yl)methyl]benzamide (43 mg, yield 91%) of white powder. -272 - 201211053 1H-NMR (3 00 MHz, CDCl3) S: 1.09 (3H, d, J = 6.5 Hz), 1.59 - 1.8 5( 5H,m),1 .87 -1 ·98 (2Η,m) ,1.98-2.10(1 H,m),2.3 8-2.54(2H,m) ,2.69(2H,t,J= l 1.9 Hz), 3.24 (1 H, q, J = 6.5 Hz), 3.27-3 .38 (1 H, m ), 3.56 (2H, brs), 3.72-3.94 (3H, m), 4.07 (lH, Dq, J = 2.9, 7.4 Hz), 4.12 (lH, d, J = 15.6 Hz), 4.79 (lH, d, J = 15.6 Hz), 6.48 (lH, 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), 7.76 (2H, d, J = 7.8 Hz).

LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 545.9 [M + H]+ (ESI positive ion mode), m/z 590.1 [M + HCO〇r (ESI negative ion mode) 4 3] Ο

• Example 1 2 0 4-[4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1_oxo-3,8-diazo Spirulina [4.5] brothel _3_ yl} methyl) benzyl hydrazide] piper steep acid third vinegar (compound number 1 20) was produced by substituting tetrahydrofurfurylamine using 4-aminopiperidine- The title compound was obtained as a white solid (1 50 mg, yield 89%) 1H-NMR (300 MHz). , CDCl3) 6: 1.09 (3H, d, J = 6.5 Hz), 1.32- 1.49 (-273-201211053 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=12.7Hz), 2.91(2H,t,J=12.7Hz), 3.24 (1 H,q,J = 6.5Hz) , 3.56 (2H, s), 4.02-4.2 l (3H, brm), 4.1 3 (1 H, d, J = 5.6 Hz), 4.79 (lH, d, J = l 5.6 Hz), 5.93 (lH, d, J = 8.2 Hz), 7.3 5 (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 = 8_2Hz). LC/MS [Condition 1]: Hold time 3.62 minutes; m/z 645.0 [M + H]+ (ESI positive ion mode), m/Z643.1 [MH]- (ESI negative ion mode) 4 4]

Reference Example 1 2 1 4-({4-Methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Preparation of alk-3-yl}methyl)-N-(piperidin-4-yl)benzamide 2 hydrochloride The 4-[4-({4-methyl-2-) obtained in Example 120. Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide]piperidine The butyl carboxylic acid tert-butyl ester (110 mg, 0.18 mmol) was dissolved in a 4 M 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 to give 4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1--- 3,8-diazospiro-274-201211053 [4.5]decane-3-yl}methyl)-N-(piperidin-4-yl)benzamide 2 hydrochloride (130 mg) as a white solid. Directly used in the next stage of the reaction without purification

Example 1 2 1 Heart [1-(cyanomethyl)piperidin-4-yl]-4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzene) Manufacture of keto-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. m)

4-({4-Methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] obtained in Reference Example 121 Decane-3-yl}methyl)-N-(piperidin-4-yl)benzamide 2 hydrochloride (54 mg, 0.08 8 mm) dissolved in hydrazine, hydrazine-dimethylformamide (l .OmL) was added in the order of bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.01 2 mL, 0.18 mmol) and triethylamine (0.03 7 mL, 0.26 mmol), and stirred at room temperature for 2 days. After adding water (2.0 mL) and ethyl acetate (2.0 mL), the mixture was extracted twice with ethyl acetate (10 mL), and the organic layer was combined with saturated aqueous sodium hydrogen carbonate (10 mL) The order of water (1 〇 mL) was washed. The organic layer was separated and dried over anhydrous magnesium sulfate. After adding hexane/ethyl acetate (4/1, 5.0 mL) to the resulting solid and shaking, the solid-275-201211053 body was filtered and dried at 50 ° C under reduced pressure to obtain N-[l- (cyanomethyl)piperidin-4-yl]-4-({4-methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, A white powder of 8-diazospiro[4.5]decane-3-yl}methyl)benzamide (3 5 mg, yield 68%). 1H-NMR (300MHz, CDCl3) 8:1.10 (3H,d,J = 6.5Hz), 1.56 -1.86 (6H,m), 2.06-2.16(2H,m), 2.39-2.5 8(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 (lH, q, J = 6.5 Hz), 3.54 (2H, s), 3.58 (2H5brs), 3.96-4.10 (lH, m), 4.13 (lH, d, J = 15.6 Hz), 4.79 (lH, d, J = 15.6 Hz), 5.96 (lH, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.40-7.5 1 (2H, brm), 7.53 - 7.63 (2H, brm), 7.73 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.00 min; m/z 5 83.8 [M + H]+ (ESI positive ion mode), m/z 582.1 [M-Hr (ESI negative ion mode) [Chem. 2 4 6]

Example 1 2 2 4-[4-({4-Methyl-2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ 4.5] Preparation of methyl decyl-3-yl}methyl)benzamide]piperidine-1-carboxylate (Compound No. 122) Substituted bromoacetonitrile, using methyl chloroformate (by Tokyo Chemical Industry Co., Ltd.) Purchased -276- 201211053

The same reaction as in Example 1 2 1 was carried out, and the title compound was obtained as white powder (46 mg, yield: 87%). 1H-NMR (300MHz, CDCl3) 5:1.10 (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), 3.2 5 (lH, q, J = 6.5 Hz), 3.57 (2H, brs), 3.70 (3H, s), 4.05-4.26 (3H, m), 4.13 (lH, d, J = 15.3 Hz), 4.78 (lH, d, J = 15.3 Hz), 5.96 (lH, d, J = 7.8 Hz), 7.3 5 (2H, d, J = 8.6 Hz), 7.3 9-7.49 (2H, brm), 7.52-7.62 (2H, brm), 7.73 (2H, d, J = 7.8 Hz ). LC/MS [Condition 1]: Hold time 3.22 min; m/z 602_9 [M + H]+ (ESI positive ion mode), m/z 601.0 [M-Hr (ESI negative ion mode)

[化2 4 7] Ο

Example 1 2 3 3-{[(11&quot;,4〇-4-(1-Benzylpiperidin-4-ylaminemethanyl)cyclohexyl]methyl}-2-sideoxy-1 - evil Manufacture of -3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 123) (lr, 4r)-4-{[8-(t - Butoxy oxy)-2-oxooxy-1 -oxa-3,8-diazospiro[4 · 5 ]decane-3-yl]methyl}cyclohexanecarboxylic acid-277- 201211053 (0.29g , 0.73 mmol) dissolved in chloroform (3.0 mL), 4-amino-indole, lysylmethylpiperidine (〇.21 g, 1.1 mmol), 1-hydroxybenzotriazole (30 mg, • 2 2 mmol) And 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride _ (0.21 g, 1.1 mmol), stirred and mixed at room temperature for 4 days. Water (5.0 mL) was added to the mixture, the organic layer was separated, and the organic layer was washed with water (1 mL) and then evaporated to dryness. OmL), after sufficient vibration, the insoluble matter was filtered to give 3-{[(lr,4r)-4-(l-benzylpiperidin-4-ylaminecarboxamyl)cyclohexyl]methyl}- 2-sided oxy-1-oxo-3, 8-diazospiro[4.5]decane-8-carboxylic acid third Ester (0.35 g, yield 83%) as a white solid. 1H-NMR (300 MHz, CDCl3) 5: 1.02 (2H, dq, J = 2.9512.7 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 (lH, 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 (lH, d, J = 8.2 Hz), 7.21-7.36 (5H, m). [Chem. 2 4 8]

Example 124 (lr,4r)-N-(l-Benzylpiperidin-4-yl)-4-({2. sideoxy_8-[4-(trifluoromethyl)benzyl]- Manufacture of decylamine (Compound No. 124) 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexane-278-201211053

(lr, 4r)-4-({2-Sideoxy-8·[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (91 mg, 0.20 mmol), 4-amino-1-benzylpiperidine (57 mg, 0.30 mmol) and 1-p-benzoyl After triterpenoids (8 mg, 0.060 mol) were dissolved in chloroform (2.0 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol) was stirred and mixed 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 after sufficiently vibrating, the insoluble material was filtered. This was purified by a ruthenium column chromatography method [塡 剂 : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 , , , -benzyl-1-piperidin-4-yl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5 ] decyl-3-yl}methyl)cyclohexanecarbamide (i 9 mg, yield 87%) as a white solid. • 1H-NMR (300MHz, CDCl3) 5: 1.01 (2Hsdq, J = 3.7, 12.3Hz)) 1.33 - 1.64 (5H, m), 1.69-1.83 (4H, m), 1.83-2.03 (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 ( lH, m), 5.27 (lH, 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]: Hold time 3.16 minutes; m/z 314.2 [M + 2H]2 + , 627.4 [M + H]+ (ESI positive ion mode) -279- 201211053 [Chem. 2 4 9]

HsC&gt;r〇^N H3C Ο

Example 125 Third Butyl 3-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-Heavy Substituting 4-Amino-1-benzylpiperidine for the manufacture of azaspiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine]propylcarbamate (Compound No. 125) The title compound (〇23 g, yield 84%) was obtained as a white solid. 1H-NMR (3 00MHz, CDCl3) 5: 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(4 H,m),2.05( lH,tt,J=l 2.7,3.3Hz), 2.43-2.7 l(4H,m), 3.09(2H, d,J = 7_4Hz ), 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 (lH, br s), 6.19 (lH, br s), 7.44 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.2 Hz) » LC/MS [Condition 2]: Hold time 3_64 minutes; m/ Z611.4[M + H]+ (ESI positive ion mode), m/z 655.8 [M + HCO〇r (ESI negative ion mode) [Chem. 2 5 0]

-280- 201211053 Example 1 2 6 (1!',4〇-1^-cyclohexyl-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1- Manufacture of oxa-3, 8-diazospiro[4.5]nonan-3-yl}methyl)cyclohexanecarbamamine (Compound No. 126)

(lr, 4r)-4-({2-Sideoxy-8-[4.(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (0.42 g, 0.93 mm 〇l), cyclohexylamine (〇.16 mL, 1.4 mmol), and 1-hydroxybenzotriazole (38 mg) , 〇.28mol) after dissolving in chloroform (8.0mL), adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature (〇.27g, 1.4) Mm〇l), stirred at room temperature for 1 day. After sufficiently adding water (8.0 m L), the organic layer was separated and concentrated under reduced pressure to dryness. After adding water (20 mL) to the residue and shaking well, the insoluble matter was filtered to give (lr, 4r)-N-cyclohexyl-4- ({2- side oxo-8-[4-(trifluoro) Methyl) benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (〇.45 g, yield 89%) of white solid. 'H-NMRQOOMHz, CDC13)3: 0.8 9 - 1.24 (5 H, 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 = 7.4 Hz), 3.25 (2H, br s), 3.5 7 (2H, br s), 3.6 5 - 3.8 3 ( 1 H, m), 5.26 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.5 7 (2H, d, J = 8.2 Hz). LC/MS [Condition 2]: Hold time 3.62 min; m/z 536.2 [M + H]+ (ESI positive ion mode) 281 - 201211053 [Chem. 2 5 1]

Example 1 2 7 (1!^,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ 4.5] Manufacture of decyl-3-yl}methyl)-N-[l-(pyridine-3-ylmethyl)piperidine-4-yl]cyclohexanecarbamide (Compound No. 127) Reference Example (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5]癸-alkyl-3-yl}methyl)cyclohexane decanoic acid (0.36 g, O_79 mmol), 4-amino-1-(hydroxypyridin-3-ylmethyl)pipertrinium salt obtained in Reference Example 64 After the acid salt, triethylamine (0.66 mL, 4.8 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) were dissolved in chloroform (2 mL), 1-ethyl-3 was added at room temperature. - (3-dimethylaminopropyl)carbodiimide hydrochloride (0-23 g, 1.2 mmol) 'The mixture was stirred and stirred at room temperature for 1 day. After adding water (8.0 mL), the organic layer was separated and the organic layer was separated. The mixture was concentrated to dryness under reduced pressure. After ethyl acetate (2 mL) was added to the residue and shaken thoroughly, the insoluble material was filtered to give (lr, 4r)-4-({2- side oxygen-8- [4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4-5]nonan-3-yl}methyl)-heart [1-(pyridine -3-ylmethyl)piperidin-4-yl]cyclohexanecarbamide (0.44 g, yield 89%) as a white solid. 1H-NMR (300 MHz, CDCl3) 5: 1.01 (2H, dq, J = 3.3,12.7Hz),1.3 1-1.64(5H,m),1.68- 1.84(4H,m),1.84-2.04(7H,m),2.13(2H,dt, J=1 ·6,11.9Hz) , 2.40-2.67 (4H, m), 2.78 (2H, d, J = 11.9 Hz), 3.09 (-282-201211053 2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.49 (2H, s ), 3.57 (2H, s), 3.69-3.88 (lH, m), 5.3 l (lH, d, J = 8.6 Hz), 7.25 (1 H, 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 (lH, dt, J = 7.8, 2.0 Hz), 8.50 (lH, dd, J = 4.9, 1.6 Hz), 8.54 ( lH,d,J = 2.5 Hz) LC/MS [Condition 1]: Hold time 1.22 minutes; m/z 628.0 [M + H]+ (ESI positive ion mode) ' m/z 672.1 [M + HCOO ] — (ESI negative ion mode) [Chem. 2 5 2]

Example 1 2 8

(lr,4〇-N-(3-Aminopropyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of Diazospiro[4.5]nonan-3-yl}methyl)cyclohexanecarbamide hydrochloride (Compound No. 128) The third butyl 3-[(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl} A ) 环 院 醯 醯 ] ] ] ] ] ] ] 27 27 (27 mg, 0.044 mmol) dissolved in methanol (1.0 mL), 2M hydrogen chloride-methanol solution (〇.20mL, 0.40mmol) was added at room temperature, The mixture was allowed to stand at room temperature for 5 hours, and after standing at 40 ° C for 2 hours, it was concentrated to dryness under reduced pressure. ethyl acetate (2.0 mL) was added to the residue. , 4r)-N-(3-Aminopropyl)-4-((2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Spirulina-283- 201211053 [4.5] decane-3-yl}methyl)cyclohexanecarbamide hydrochloride (27 mg, yield y.) as a white solid. 1H-NMR (3 00 MHz, DMSO-d6 ) 5: 0.89 (2H, q, J = 11.9 Hz), 1.3 3 ( 2H, q, J = 12.7 Hz), 1.44-1.61 (lH, 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 = 3.7Hz), 7.5 9-8.09 ( 8H, m), l 1.03-1 1.47 (lH, m) LC/MS [Condition 2]: Hold time 〇·98 min; m/z 511.3 [M + H]+ (ESI positive ion mode)

Example 1 2 9 methyl 3-[(lr,4r)-4-({2-o-oxo-8-(4-trifluoromethyl)benzyl]-1-oxo-3,8-weight Preparation of aziridine [4.5]decane-3-yl}methyl)cyclohexanecarbamamine]propylaminoformate (Compound No. 129) The (lr,4r)-N- obtained in Example 128. (3-aminopropyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane - 3-yl}methyl)cyclohexanecarbamide hydrochloride (10 mg, 0.017 mmol) was suspended in ethyl acetate (1.0 mL), and then triethylamine (0.012 mL, 0.086 mmol) A solution of methyl chloroformate (〇.〇〇16 mL, 0.021 mmol) in ethyl 2-284-201211053 acid ethyl ester (〇_10 mL) was placed at room temperature. After stirring at room temperature for 40 minutes, water (1.0 mL) was added to separate the organic layer, and concentrated to dryness under reduced pressure to give methyl 3-[(11:, 41')-4- ({2- side Oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamide] A urethane (9.0 mg, 93% yield) of a white solid.

lH-NMR (300MHz, CDCl3) 5: 1.02 (2H, dq, J = 2.9, 12.3Hz), 1,48 (2H, dq, J = 2.9, 12.3Hz), 1.54- 1.69 (3H, m) , 1.69- 1.85 (4H, m), 1.85-1.98 (4H, m), 2.04 (lH, 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 (2 H, dt, J = 5.7, 6.1 Hz), 3.57 (2H, s), 3.67 (3H) , s), 5.18 (lH, br s), 6.07 (lH'br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz) » LC/MS [Condition 2 ]: Hold time 3.26 minutes; m/z 569.3 [M + H]+ (ESI positive ion mode), m/z 613.6 [M + HCO〇r (ESI negative ion mode)

[化2 5 4] Ο

Example 1 3 0 (lr,4r)-N-methyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-weight Preparation of azaspiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 1 30) (lr, 4r)-4-({2-) obtained in Reference Example 6-3 Lateral oxygen-8-[4-(trifluoromethyl-285- 201211053

Benzo) benzyl]-oxazo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (20 mg, 0.044 mmol), methylamine hydrochloride (5 mg , 0.066 mmol), triethylamine (0.03 6 mL, 0.26 mmol) and 1-hydroxybenzotriazole (2 mg, 0.013 mmol) suspended in chloroform (〇.40 mL) and N,N-dimethylformamide (0-40 mL) After the solvent mixture was mixed, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg, 0.078 mmol) was added at room temperature. After stirring and stirring for 1 day at room temperature, the mixture was concentrated to dryness, and then evaporated to dryness, and then, to the obtained residue, water (1.0 mL) and ethyl acetate (2.0 mL) were added, and the organic layer was separated. This was concentrated to dryness under reduced pressure to give (l,,,,,,,,,,,,,,,,,,,,,,,,,, 3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamide (21 mg, yield quantitative) of white solid 1H-NMR (300 MHz, CDCl3) 6: 1.02 ( 2H, dq, J = 3.3, 12.3Hz), 1.48 (2H, dq, J = 2.9, 1 2.7Hz), 1.52- 1.68( lH,m), 1.69- 1.8 5(4H,m),

1.85-1.98(4H,m), 2.01(lH,tt,J = l 1.5,3.7Hz),2.44-2.72(4H,m ), 2.80(3H,d,J = 4.9Hz),3.09(2H , d, J = 7.0 Hz), 3.25 (2H, s), 3.57 (2H, s), 5.43 (lH, br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2Hz). LC/MS [Condition 2]: Hold time 3.08 min; m/z 468.2 [M + H]+ (ESI positive ion mode)

[Chemical 2 5 5] 2HCI σχχ; Reference Example 1 3 1 8 -286- 201211053 Manufacture of 1-benzyl-N-methylpiperidin-4-amine 2 hydrochloride

1) 4-Amino-1-benzylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) (1.0 g, 5.3 mmol) was dissolved in chloroform (5.0 mL), and dibutyl carbonate was added at 〇 °C. A solution of the ester (1.3 g, 5.8 mm 〇l) in chloroform (5 mL). After allowing to stand at room temperature for 5 minutes, it was concentrated to dryness under reduced pressure to give white crystals of butyl benzyl benzyl </RTI> <RTIgt; 1H-NMR (300MHz, CDCl3) 6:1.3 5- 1.50 (lH, 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 (lH, br s), 7.18-7.37 (5H, m). 2) The obtained third butyl 1-benzylpiperidin-4-ylcarbamate (0.10 g, 0.34 mmol) was dissolved in N,N-dimethylformamide (1.0 mL). After adding potassium tributoxide (43 mg, 0.38 mmol), the mixture was stirred at room temperature for 10 minutes, and then methyl iodide (24 mL, 0.38 mmol) was added for 1 day, and stirred at room temperature for 1 day. Water (2.0 mL), η-hexane (2.0 mL), and ethyl acetate (2.0 mL) were added, and the organic layer was separated, washed with water (2.0 mL×l) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [塡 剂 : NH FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU 己烷 己烷 己烷 己烷a colorless oil of benzyl piperidin-4-yl(methyl)carbamate (64 mg, yield 61%). !H-NMR (300MHz, CDC13) 5: 1.45 (9 H, s), 1.53-1.64 (2 H, m), 1.72 (2H, dq, J = 3.7, 12.7 Hz), 2.03 (2H, t, J =ll.lHz), 2.73(3H)s), 2.87

-2.98 (2H, m), 3.49 (3H, s), 3.55-4.2 l (lH, br m), 7.3 7 - 7 . 1 8 ( 5 H , m) » 3 ) The resulting third butyl group 1 -Benzyl piperidin-4-yl(methyl)amino-287-201211053 Formate (56 mg, 〇.i9 mmol) dissolved in methanol (2.5 mL). Add 2M hydrogen chloride-methanol solution (0.50 mL 'l. Ommol) ' After standing at 50 ° C for 3 hours, concentrated and concentrated under reduced pressure to give 1-benzyl-N-methylpiperidinamine 2 hydrochloride (50 mg, yield) White solid. [Chem. 2 5 6]

Example 1 3 1 (11*,4〇-1^-(1-Benzylpiperidin-4-yl)-:^-methyl-4-({2- sideoxy-8-[4-( Manufacture of trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 131)

(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (20 mg, 0.044 mmol), 1-benzyl-N-methylpiperidin-4-amine dihydrochloride obtained in Reference Example 131 (15mg, 0.053mmol), triethylamine (0.018mL, 0.13mmol) and 1-diabase benzotriazine (2mg, 0.013mol) were dissolved in chloroform (〇.40mL), then added 1-B at room temperature The benzyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg, 0,066 mmol) was stirred and mixed at room temperature for 10 days. After adding water (1. 〇 mL) and shaking well, ethyl acetate (2.0 mL) was added, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [塡 剂 : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU ( ( ( ( ( ( )-N-(l-Benzylpiperidin-4-yl)-N-methyl-4_({2• sideoxy·8_[4·(trifluoromethyl)benzyl]-1-oxo- 3,8- Diazospiro[4.5]decane-3-yl}methyl) Cyclohexanecarbamide (24 mg, yield 86%) as a colourless oil. 'H-NMRPOOMHz, CDC13) 3: 0.93-1.17 (2H, m), 1.42-2 15 (15H, m), 2.42 (lH, tt, J = 11.9, 2.9 Hz), 2.48-2.65 (4H, m) , 2.8 1 &amp; 2.87 (total 3H, each 5), 2.87-3.03 (21111), 3.10&amp; 3.11 (total of 21 each (1, each

J = 7.4 Hz, J = 7.0 Hz), 3.25 (2H, s), 3.49 (1.2H, s), 3.53 (0.8H, 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 decylamine isomers) LC/MS [Condition 2]: Hold time 3.30 min; m/z 321.2 [M + 2H] 2 + , 641.4 [M + H] + (ESI cation mode)

Reference Example 1 3 2 - 1 (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)cyclohexanecarboxylic acid methyl

(lr,4r)-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexane obtained in Reference Example 6-1 The carboxylic acid methyl hydrochloride (5Omg, 0.14mmol) was suspended in ethyl acetate (2.5 mL), triethylamine (0.080 mL - 289 - 201211053, 0.58 mmol) was added and chlorinated 4-( Trifluoromethyl)benzhydryl (0.024 mL, 0.16 mmol) was mixed at room temperature for 20 minutes. After water (1 mL) was shaken well, the organic layer was separated, and concentrated under reduced pressure to give (lr, 4r) -4- ({2 - s. A white solid of methyl-1-bromo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylate (71 mg yield). 1H-NMR (300MHz, CDCl3) 6: 1.03 (2Hsdq, J = 3.3, 12.7 Hz), 1.41 (2H, dq, J = 3.7, 13.5 Hz), 1.50-2.16 (9H, m), 2.26 (lH, tt , J = 12.3, 3.7 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.18-3.63 (5Hsm), 3.66 (3H, s), 4.4 4.67 (lH, br m), 7.52 (2H, d , J = 8.2 Hz), 7.69 (2H, d, J = 8.2 Hz). LC/MS [Condition 2]: Hold time 4.39 min; m/z 48 3.2 [M + H] + (ESI positive ion mode), m/z 527.6 [M + HCOO] _ (ESI negative ion mode) [Chem. 2 5 8】

Reference Example 1 3 2 - 2 (11*, 4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (lr,4r)-4-({2- sideoxy-8-[4-() obtained in Reference Example 132-1 Methyl trifluoromethyl)benzylidene]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylate (62 mg, 0.13 mmol) was dissolved in 1,4-Dioxane (3.0 -290 - 201211053 mL), add water (0.60 mL) and 1 M aqueous sodium hydroxide solution (0.19 mL), stir at room temperature for 4 hours, then add water (im L), minus The mixture was concentrated under reduced pressure, and dioxane was evaporated. Water (1. 〇mL) and 1M hydrochloric acid (0.30 mL) were added to the residue to adjust to pH 2, and extracted with ethyl acetate (4.0 mL). After concentration and concentration, (1 r, 4 r) - 4 - ({2 - oxo-8 ·[ 4 -(trifluoromethyl) benzylidene]- oxa-3,8-diazo snail [4.5] decyl-3-yl}methyl)cyclohexanecarboxylic acid (58 mg, yield 96%) as a white solid.

Example 1 3 2

(11*,4〇-~(1-Benzylpiperidin-4-yl)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzylidene]-1- Production of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 132) (ir, 4r)-4 obtained in Reference Example 132-2 -({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene]-1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl Cyclohexylamine decanoic acid (28mg, 0.060mmol) and 4-amino-1-benzylphenyridin (16mg, 0-090mmol) were dissolved in N,N-dimethylformamide (〇.30mL), added 1 -Phenylbenzotriazine (3 mg, O. 〇 18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, O.〇9〇mm The mixture was stirred and stirred for 11 days at room temperature. Water (1.OmL) and ethyl acetate-291 - 201211053 (2.OmL) were added and shaken well, then the organic layer was separated and concentrated to dryness under reduced pressure. Ethyl acetate (1. 〇m L) was added to the residue, and after sufficiently vibrating, 'insoluble matter was filtered off to obtain (lr, 4r)-N-(l-benzylpiperidin-4-yl)- 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzylidene]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) a yellowish solid of cyclohexanecarbamide (12 mg, yield 32%). 1H-NMR (300 MHz, CDCl3) 5: 1.02 (2H, dq, J = 2.5, 12.3 Hz), 1.33-2.05 (3H, m ), 1.97 (lH, 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 (5 H, m), 3.49 (2H, s), 3.69-3.88 (lH, m), 4.42-4.68 (lH, br m), 5.27 (1 Η , 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]: Hold time 3.48 minutes; m /z641.4[M + H] + (ESI positive ion mode), m/z 685.6 [M + HCOO]_ (ESI negative ion mode) [Chem. 2 6 0]

Cis-reverse mixture Reference Example 1 3 3 -1 4-Aminocyclohexanecarboxylic acid methyl hydrochloride salt Production 4-Aminocyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (2〇 g, 14 mmol) dissolved in 2M hydrogen chloride-methanol solution (5 〇mL), allowed to stand at room temperature for 1 day, and then concentrated to dryness under reduced pressure to obtain 4-aminocyclohexane decanoic acid methyl hydrochloride ( 2.6 g, yield 96%) of white solid · -292- 201211053 1H-NMR (CDCl3) 5: 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 1 3 3 - 2 3-[4-(Methoxycarbonyl)cyclohexyl]-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid III Production of butyl ester 1) 4-Aminocyclohexanecarboxylic acid methyl hydrochloride (0.25 g, 1.3 mmol) obtained in Reference Example 133-1, 1-ox-6-nitrogen obtained in Reference Example 1-1 Heterospiro[2.5]octane-6-carboxylic acid tert-butyl ester (〇25g, 1.2mmol) was suspended in water (2.5mL), and methanol (4.0mL) and 1M sodium hydroxide solution (i.2mL, 1.2 mm 〇 1), after stirring and mixing for 3 days at room temperature, methanol was distilled off under reduced pressure. Water (1.0 mL) and chloroform (5. 〇mL) were added to the residue, and the organic layer was separated and concentrated to dryness to give 4-hydroxy-4 -{[4-(methoxycarbonyl) ring. A crude color of hexylamino]methyl}piperidine-1 -carboxylic acid tert-butyl ester (〇. 4 3 g) as a colorless oil. 2) Dissolving a crude product (〇.43g) of 4-butyl-4-[[4-(methoxyl)cyclohexylamino]methyl)piperidine-1-carboxylic acid tert-butyl ester in 于.43g l,4-Dioxane-293- 201211053 (7_0mL) ' Add 1,1 carbonyldiimidazole (0.57g, 3.6mmol), stir at 90 °C for 2 days, then cool to room temperature, under reduced pressure Concentrated and dried. Water (5.0 mL), 1 M hydrochloric acid (6.0 mL), ethyl acetate (5. 〇1111 〇, 11-hexane (2.OmL) was added, and the organic layer was separated and concentrated to dryness under reduced pressure. Purification by ruthenium column chromatography [塡 :: FUJI SILYSIA FL100D, development solvent: η-hexane/ethyl acetate = 1/1] gave 3-[4-(methoxycarbonyl)cyclohexyl] -2-oxo-1-oxo-3, 8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (6 8 mg, yield 14%, cis-trans-form about 1 : 1 mixture of colorless oil. 1 H-NMR (CDC13) 5: 1.3 0-1.7 5 (8 H, m), 1.46 (9H, s), 1.78-1.97 (3 H, m ), 2.03- 2.14 (lH, m), 2.14-2.30 (1.5H, m), 2.66 (0.5H, br s), 3.20 (lH, s), 3.2 l (lH, 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) [Chem. 2 6 2]

Reference Example 1 3 3 - 3 4-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of a cyclohexanecarboxylic acid methyl group 1) 3-[4-(methoxycarbonyl)cyclohexyl]-2-sideoxy-1 -oxa-3,8-weight obtained in Reference Example 133-2 Aziridine [4 · 5 ]decane-8-carboxylic acid tert-butyl ester (6 8 mg, 〇_17 mmol, 1:1 mixture of cis-trans-form) dissolved in methanol-294-201211053 (l .OmL), into a 2M hydrogen chloride-methanol solution (0.30mL, 0_60mmol), allowed to stand at room temperature for 3 days, then concentrated under reduced pressure to dry to obtain 4 - (2-oxo-1 - oxa-3 , 8_ Diazospiro[4.5]decane-3-yl)cyclohexanecarboxylic acid methyl ester (5 7|1^, yield is quantitative).

2) Dissolving the obtained methyl 4-(2-oxo-1 -oxa-3,8-diazospiro[4.5]decane-3-yl)cyclohexanecarboxylate (57 mg, 0.17 mmol) in N , N-dimethylformamide (1.0 mL), triethylamine (〇.〇72 mL, 0.51 mmol) and 4-(trifluoromethyl)benzyl bromide (45 mg, 0.19 mmol, from Tokyo A solution of ethyl acetate (〇.2〇mL) obtained by Chemical Industry Co., Ltd. was added at room temperature, and then stirred and mixed at room temperature for 1 day. After adding water (2m L) to the reaction mixture, the insoluble matter was filtered to give 4-{2- side-oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - White solid of diazospiro[4.5]decane-3-yl}cyclohexanecarboxylate (6 51^, 2 step yield: 83%). 'Η-ΝΜΚ(α〇€ΐ3)δ: 1.32-2.00 (1 0Η, πι), 2.01-2.14 (0.8Η, ιη), 2.14 -2.33 (1.6H, m), 2.43-2.62 (4H, m) , 2.62-2.70 (0.6H, m), 3.19 &amp; 3.2 1 (total 2H, each s), 3.56 (2H, br s), 3.65 -3.8 0 (lH, m), 3.67 &amp; 3.71 (total 3H, Each 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]: Hold time 3.40 min; m/z 45 5.2 [M + H]+ (ESI positive ion mode) [Chem. 2 6 3]

-295 201211053 Reference Example 133-4 4-{2-Sideoxy-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 Production of -yl}cyclohexanecarboxylic acid 4-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- obtained in Reference Example 133-3 Methyldiazospiro[4.5]decane-3-yl}cyclohexanecarboxylate (60 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.50 mL) and 1M EtOAc. The sodium aqueous solution (20 mL, 0.20 mmol) was stirred at room temperature for 10 days, and then concentrated under reduced pressure and 1,4-dioxane was evaporated. 1M hydrochloric acid (〇_25mL, 0.25mmol) was added to the residue, and adjusted to pH 6, and the precipitated solid was filtered to obtain 4-{2- sideoxy-8-[4-(trifluoromethyl)benzene. Methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}cyclohexanecarboxylic acid (37 mg, yield 65%) as a white solid. [Chem. 2 6 4]

Example 133 N-(l-Benzylpiperidin-4-yl)-4·{2-sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo_3,8 - Preparation of Diazospiro[4.5]decane-3-yl}cyclohexanecarbamamine (Compound No. 133) 4-{2- Side Oxygen-8-[4-(III) obtained in Reference Example 133-4 Fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4,5]decane-3-yl}cyclohexanecarboxylic acid (19mg, -296- 201211053)

0.043111111〇1) Suspension in 1-heart dimethylformamide (0.401111 〇, adding 4-amino-1-benzylhydrazine (12 mg·, 0.065 mmol) in chloroform (0.30 mL) and 1-hydroxybenzene After triazole (3 mg, 0.022 mm 〇l), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg, 0.06 5 mmol) was added at room temperature. After stirring for 8 days at room temperature, water (2.0 mL) and ethyl acetate (4.0 mL) were added, and the organic layer was separated and concentrated to dryness under reduced pressure. [Tanning agent: NH-DM1 020, manufactured by FUJI SILYSIA, developing solvent: chloroform / ethyl acetate = 2 / 1], and purifying to obtain N-(l-benzylpiperidin-4-yl)-4-{2 -Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}cyclohexanecarbamidine (14 mg, Yield 54%) of a white solid. H-NMR (CDCl3) 5: 1.33-2.06 (1 6.2H, m), 2.11 (2H, t, J = l 1.9 Hz) 2.36 (0.8H, brs), 2.43- 2.66 (4H, m), 2.82 (2H, br d, J = l 1.9 Hz), 3.20 (0.4H, s), 3.23 (1.6H, s), 3.49 (2H, s), 3.55 (2H, brs) ), 3.62-3.89 ( 2H, m), 5.25 (0.2H, d, J = 8.2Hz), 5.33 (0.8H, d, J = 7.8Hz), 7.19-Lu 7.36 (5H, m), 7.43 (2H, d, J = 8_0Hz), 7.57 (2H, d, J = 8.0 Hz). (Approximately 4:1 mixture of cis-trans-form) LC/MS [Condition 1]: Hold time 3.00 min; m/z3〇7.1[M + 2H]2 + , 613.0[M + H]+(ESI positive ion mode) [Chem. 2 6 5]

-297- 201211053 Example 1 3 4 Tert-butyl 3-(4-{2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}cyclohexanecarbamamine)propylaminoformate (Compound No. 134) Substituting 4-amino-1-benzylpiperidine, using N-( The title compound (22 mg, yield: 92%) was obtained as a white solid (yield::::::::::::::: 1H-NMR (CDCl3) 8: 1.44 (9H, br s), 1.49-2.20 (14.2H, 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 «&amp; 3.25 (combined 2H, each 8), 3.30 (21^, (^, 6.5, 5.71^), 3.56 (211, 1^3), 3.65· 3.83(1 H,m), 4.72-4.93 (1 H,m), 6.3 1-6.57 (1 H,m), 7.44 (2H,d,J = 8.2 Hz), 7.57 (2H,d,J = 8.2 Hz) (about 4: 1 mixture of cis-trans-body) LC/MS [Condition 1]: hold time 3.52 min; m/z 596.9 [M + H]+ (ESI positive ion mode) , m/z 641.2 [M + HCO〇r (ESI negative ion mode) [Chem. 2 6 6] ^γΝΗ2

H3c^Y

HCI Reference Example 1 3 5 Preparation of 4-aminopiperidine-1-carboxylic acid methyl hydrochloride salt Third ester of piperidin-4-ylaminocarbamate (790 mg, 3.9 mmol) was dissolved in chloroform (l? (mL), methyl chloroformate (0.31 mL, 3.9 mmol) and triethylamine (0.55 mL, 3.9 mmol) were added under ice-cooling at room temperature for 1-298-201211053

Stir and mix for the day. After the reaction was completed, the reaction mixture was diluted with chloroform and water was added, and the organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then evaporated to give 4-(t-butoxycarbonylamino)piperidine-1-carboxylic acid methyl ester (800 mg). ). Methyl 4-(t-butoxycarbonylamino)piperidine-1-carboxylate (800 mg) was dissolved in methanol (2.0 mL) and 4M hydrogen chloride-dioxane (8.0 mL) at room temperature Mix for 3 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals 4-(t-Butoxycarbonylamino)piperidine-1-carboxylic acid methyl 1H-NMR (CDC13) 5: 1.1 9-1.37 (2H, m), 1.44 (9H, s), 1.87-2.01 ( 2H,m),2.82-2.99(2H,m), 3.49-3.72(1 H,m),3.69(3 H,s),3.9 1-4.19(2H,m),4.34-4.52(lH,brm) . φ 4-Aminopiperidine-1-carboxylic acid methyl hydrochloride 1H-NMR (CDCl3) 5: 1.60-1.9 1 (2H, m), 1.8 3 (2H, s), 2.04-2.25 ( 2H, m ), 2.73 - 3.03 (2H, m), 3.24 - 3.47 (lH, m), 3.70 (3H, s), 4.03-4.39 (2H, m), 8_49 (3H, brs). -299- 201211053 【化2 6 7】

Example 1 3 5 4-[6-({2-Sideoxy 8-[4-(trifluoromethyl)benzyl]]indole-oxa-3,8-diazospiro[4.5]decane- Preparation of 3-methyl}methyl)nicotiniumamine]piperidine-i-carboxylic acid methyl ester (Compound No. 135) Substituted tetrahydrofurfurylamine, 4-aminopiperidine obtained using Reference Example 1 3 5 The title compound (14 mg, quantitative) of an amorphous solid was obtained by the same reaction as in Example 1 1 1 except for 1-carboxylic acid methyl hydrochloride and triethylamine. 1H-NMR (CDCl3) 6: 1.3 7-1.54 (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), 3.3 3 (2H, s), 3.56 (2H, s), 3.69 (3H, s), 4.04-4.27 (3H, m), 4.57 (2H, s), 6.48 (1 H, Br m), 7.3 5 (lH, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz), 8.10 (lH, dd, J = 8.0) , 2.2 Hz), 8.93 (lH, d, J = 2.2 Hz). LC/MS [Condition 1]: Hold time 4.68 min; m/z 590.3 [M + H]+ (ESI positive ion mode) -300- 201211053 [Chem. 2 6 8]

Example 1 3 6

4-[(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl]-1-oxo-3,8-diazospiro[4.5]decane) Preparation of methyl-3-methyl}methyl)cyclohexanecarbamamine]piperidine-1-carboxylate (Compound No. 136) Substituted cyclohexylamine, 4-aminopiperidine-1 obtained in Reference Example 135 The title compound (1 1 mg, yield 83%) was obtained as a colorless solid, m.p. 0.95-1.12 (2H, m), 1.22-1.37 (2H, m), 1.41-1.67 (3H, m), 1.73-2.08 (1 lH, m), 2.90 (2H, t, J = 12.1 Hz), 3.12 (2 • H, d, J = 7.4 Hz), 3.29 (2H, s), 3.3 1- 3.43 (2H, m), 3.53-3.64 (2H, m), 3.69 (3H, s), 3.85-4.00 ( 1 H, m), 4.00-4.23 (2H, m), 5.35-5.48 (lH, br m), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz). /MS [Condition 1]: Hold time 5.8 minutes; m/z 582.4 [M + H] + (ESI positive ion mode), m/z 625.6 [M + HCOO] - (ESI negative ion mode) -301 - 201211053 [Chem. 2 6 9]

Example 1 3 7 3-{[5-(4-Benzylmercaptopiperidin-1-carbonyl)pyridin-2-yl]methyl}-8-[4-(trifluoromethyl)benzyl] Manufacture of 1-oxa-3,8-diazaspiro[4.5]decane-2-one (Compound No. 137) in place of tetrahydrofurfurylamine, other than 4-benzylidenepiperidine hydrochloride and triethylamine The title compound (14 mg, yield 80%) was obtained as a white solid. 1H-NMR (CDCl3) 6: 1.7 1- 2.10 (8H, m), 2.49-2.62 (4H, m), 3.02-3.32 (2H, m), 3.35 (2H, s), 3.52-3.65 (lH, m ), 3.56 (2H, s), 3.73-3.95 (lH, m), 4.53-4.73 (lH, m), 4.58 (2H, s), 7.34-7.64 (8H, m), 7.76 (lH, dd, J = 7.8, 2.0 Hz), 7.95 (2H, dd, J = 8.4, 1.2 Hz), 8.62 (l H, d, J = 2.0 Hz) » LC/MS [Condition 1]: Hold time 3.35 min; m/z 621 .〇[M + H]+ ( ESI positive ion mode), m/z 655.2 [M + Cl]- (ESI negative ion mode) [Chem. 2 7 0]

Plant NH 0° -302- 201211053 Example 1 3 8 l-[6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-weight Manufacture of azaspiro[4.5]decane-3-yl}methyl)pyridin-3-yl]-3-[(tetrahydrofuran-2-yl)methyl]urea (Compound No. 138)

Substituting 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl) As the benzoic acid, 6-((2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro) obtained using Reference Example 1 1 1-5 [ 4.5] decyl-3-yl}methyl)nicotinic acid, substituted for ]^-(^-butoxycarbonyl)-1,3-diaminopropane, substantially carried out and implemented using tetrahydrofurfurylamine The title compound (1.9 mg, yield 5%) was obtained as crystals. , 2.45-2.61 (4H, m), 2.66-2.85 (lH, m), 3.1 2-3.23 (1 H, m), 3_28 (2H, s), 3.5 1- 3.62 (lH, m), 3.55 (2H ,s),3.73-3.95(2H,m),3.99-4.09(Lu lH,m),4.47(2H,s),5.24-5.3 7(lH,brm),7.19(lH,d,J = 8.4Hz ), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.92 (lH, dd, J = 8.4, 2.6 Hz), 8.39 (lH, d, J = 2.6 Hz) LC/MS [Condition 1]: Hold time 2.79 minutes; m/z 547.6 [M + H]+ (ESI positive ion mode), m/z 546.1 [M-Hr (ESI negative ion mode) -303- 201211053 【化2 7 1】

Reference Example 1 3 9 -1 3_{Bu [4-(methoxycarbonyl)phenyl]ethyl}-2-oxo-1-oxa-3,8-diazospiro[4.5]decane-8- The production of the third butyl carboxylate was substituted for the 6-(hydroxymethyl)nicotinic acid ethyl group, and the same reaction as in Reference Example 111-3 was carried out except that methyl 4-(1-hydroxyethyl)benzoate was used. The title compound (22 mg, yield 27%) was obtained as a coloured oil. 1H-NMR (CDCl3) 5: 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 (lH, d, J = 8.5 Hz), 3.19 (lH, d, J = 8.5 Hz), 3.19-3.36 (2H, m), 3.65-3.91 ( 2H, m), 3.92 (3H, s), 5.28 (lH, 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]: Hold time 4.42 min; m/z 441.0 [M + Na] + (ESI positive ion mode) [Chem. 2 7 2]

0 H3C Reference Example 1 3 9 - 2 304- 201211053 4-(1-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-i-oxo-3,8-diazo [4.5] Manufacture of methyl decane-3-yl}ethyl) benzoate

Substituting 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid Tributyl ester, using 3-{1-[4-(methoxycarbonyl)phenyl]ethyl}-2-oxo-oxo-oxa-3,8-diazospiro obtained from Reference Example 131-1 [ 4.5. The title compound (26 mg, yield: 56%) was obtained as a colorless oil from the title compound (1%). 1H-NMR (CDC13) 6: 1.5 9 (3 Η, (1, Ι = 7.2 Ηζ), 1 - 61-1.84 (2H, m), 1.88-1.98 (lH, m), 2.43-2.60 (4H, m) , 2.83 (lH, d, J = 8.5 Hz), 3.19 (lH, d, J = 8.5 Hz), 3.54 (2H, s), 3.92 (3H, s), 5.27 (lH, q, J = 7.2 Hz) , 7.39 (2H, d, J = 8.2 Hz), 7.4 l (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]: Hold time 3.14 minutes; m/z 477.0 [M + H]+ (ESI positive ion mode)

Reference Example 1 3 9 - 3 4-(1-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane Manufacture of -3-yl}ethyl)benzoic acid-305-201211053 Substituted 6-({2-o-oxo-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8- Diazospiro[4.5]nonan-3-yl}methyl)nicotinic acid ethyl, 4-(1-{2- sideoxy-8-[4-(three) obtained using Reference Example 139-2 In addition to methyl fluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}ethyl)benzoate, substantially the same as Reference Example 11 I-5 The title compound (24 mg, quantitative) was obtained as a colorless oil. [化2 7 4]

Example 1 3 9 3- {1-[4-(4-Benzylmercaptopiperidin-1-carbonyl)phenyl]ethyl b- 8-[4-(trifluoromethyl)benzyl]-1-oxole -3,8-diazospiro[4.5]decane-2-one (compound No. 139) was produced by substituting 6-({2-oxo-8-[4-(trifluoromethyl)phenylmethyl) - cacao-3,8-diazospiro[4.5]decane-3-yl}methyl)nicotinic acid, 4-(1-{2- sideoxy-8-[4] obtained using Reference Example 139-3 -(Difluoromethyl)-methyl]-1-che- 3,8-diazospiro[4.5]decane-3-yl}ethyl)benzoic acid, substituted tetrahydrofurfurylamine, 4-phenylene The title compound (9·3 mg, yield: 85%) was obtained as a colorless oil. 1H-NMR (CDC13) 5: 1.47-1.71 (5H, m), 1.70-2.09 (6H, m), 2.39--306-201211053 2.63 (4H, m), 2.87 (lH, d, J = 8.5 Hz) , 3.00-3.24(2H,m), 3.18(lH ,d,J = 8.5Hz) , 3.46-3.63(1 H,m),3.55(2H,s) , 3.70-3.97(1 H,m ),4.54 -4.82 ( lH,m), 5.24 ( lH,q,J = 7.2 Hz), 7.33 - 7.63 (1 lH, m), 7.91 - 7.98 (2H, m). LC/MS [Condition 1]: Hold time 3.54 minutes; m/z 634.0 [M + H]+ (ESI positive ion mode), m/z 678.3 [M + HCO〇r (ESI negative ion mode)

[化2 7 5]

Example 1 4 0 4-(l-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 -Substituted ethyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide ( φ compound number 140) for the preparation of 4-benzylpyridylpiperidine hydrochloride and triethylamine The title compound (6.8 mg, yield 73%) was obtained as a colorless oil. 'Η-ΝΜΚ (€0€13) δ: 1.53-1.65 (5Η, ηι), 1.72-1.84 (2Η, ηι), 1.88-2.11 (4H, m), 2.41-2.61 (4H, m), 2.82 ( lH,d,J = 8.5Hz), 3.18 (lH, d, J = 8.5Hz), 3.27 -3.3 9(lH,m), 3.5 5(2H,s),3.72-3.95(3H,m), 4.01 -4.13(lH,m), 5.26(lH,q,J = 7.2Hz),6.43-6.54(lH,brm), 7.3 8(2H,d,J = 8.2Hz), 7.42(2H,d,J = 8.2 Hz), 7.56 (2H, d, J = 8.2 -307- 201211053

Hz), 7.77 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 546.0 [M + H]+ (ESI positive ion mode), m/z 580.2 [M + Cl]- (ESI negative ion mode) 7 6]

Example 1 4 1 4-[4-(1-{2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Manufacture of methyl alk-3-yl}ethyl)benzamide]piperidine-1-carboxylate (Compound No. 141)

The 4-phenylpyridylpiperidine hydrochloride was used in the same manner as in Example 139 except that the 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 was used. Compound (8.6 mg, yield 82%) as a colourless solid. 1H-NMR (CDCl3) 5: 1.33-1.65 (6H, m), 1.71-1.82 (2H, m), 1.88-1.97 (lH, m), 2.00-2.09 (2H, m), 2.3 9-2.60 (4H , m), 2.82 (lH, d, J = 8.5 Hz), 2.97 (2H, t, J = 12.3 Hz), 3.19 (lH, d, J = 8.5 Hz), 3.54 (2H, s), 3.70 (3H) , s), 4.04-4.26 (3H, m), 5.25 (lH, q, J = 7.2 Hz), 5.93-6.03 (lH, 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]: Hold time 3.2 min; m/z 603.0 [M + H] + (ESI 8 -308 - 201211053 positive ion mode), m/z 637.2 [M + Cl] — (ESI negative ion mode)

[化2 7 7] 0 H3C

Reference Example 1 Production of 4 2 -1 5-(chloromethyl)thiazole-2-carboxylic acid ethyl

Ethyl 2-amino-2-thioacetate (1. g, 7.5 mmol) and 1,3-dichloropropan-2-one (1. lg, 8.5 mmol) were dissolved in toluene (15 mL). At 11 baht.进行 Mix for 5 hours and a half. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate and a saturated aqueous The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography [Purif-Pack 2L 40 pm from Moritex Co., Ltd., solvent: hexane / ethyl acetate = 6 /1]. The title compound (0.3 g, mp. 1H-NMR (CDCl3) 5: 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]: Hold time 3.62 min; m/z 2 〇 6.0 [M + H]+ (ESI positive ion mode)

N=N+-N' -309- 201211053 Reference Example 142-2 Manufacture of ethyl 5-(azidomethyl)thiazole-2-carboxylate

The ethyl 5-(chloromethyl)thiazole-2-carboxylate (1.3 g, 6.1 mmol) obtained in Reference Example 142-1 was dissolved in N,N-dimethylformamide (20 mL), and then az. Sodium (440 mg, 6.7 mmol) was stirred and mixed at room temperature for 3 days. After the reaction mixture was diluted with ethyl acetate, water was added. The organic layer was separated, washed with water and saturated brine and dried over anhydrous sodium sulfate. After the organic layer solution was concentrated to about 10 mL under reduced pressure, EtOAc was evaporated. The residual solution was used directly in the next stage of the reaction: 1H-NMR (CDCl3) 5: 1.45 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 7_55 ( 1 H, s).

Reference Example 1 Preparation of 4 2 -3 5-(aminomethyl)thiazole-2-carboxylic acid ethyl group 5-(Azidomethyl)thiazole-2-carboxylic acid ethyl group obtained in Reference Example 142-2 After adding ethanol (10 mL) to an ethyl acetate solution (about 10 mL), 10% by weight of palladium-carbon (300 mg) was added under an argon atmosphere. After the reaction system was again filled with argon gas, it was replaced with hydrogen gas, and stirred at room temperature for stirring overnight. Will reverse 8 -310- 201211053

After replacing with argon in the system, the reaction mixture was filtered through diatomaceous earth to remove insolubles. After the filtrate was concentrated under reduced pressure, 10% by weight of palladium-carbon (600 mg) was added under argon. After the reaction system was again filled with argon gas, it was replaced with hydrogen, and mixed at room temperature for 5 hours. After the reaction system was replaced with argon gas, the reaction mixture was filtered through diatomaceous stone to remove insolubles. After distilling the solvent to a solution to about 15 mL, 0.06 mL was taken and concentrated under reduced pressure to give the title compound. The residual solution is used directly in the next stage of the reaction. 1H-NMR (CDCl3) 5: 1.44 (3H5t, J = 7.2 Hz) 94.08 (2H, s), 4.49 (2H, q, J = 7.2 Hz), 7.42 (lH, s).

Reference Example 1 4 2 - 4 % 5-({[l-(t-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methylamino}methyl)thiazole-2-carboxylic acid ethyl A solution of 5-(aminomethyl)thiazole-2-carboxylic acid ethyl ester obtained in Reference Example 142-3 in ethanol (about 15 mL), water (10 mL) and 1-? After the addition of 啰-6-azaspiro[2.5] xinyuan-6-haloic acid terpene vinegar (1.2 §, 5.4111111 〇1), it was stirred and mixed at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. [化2 8 1]

H3C

Reference Example 1 4 2 -5 3-{[2-(ethoxycarbonyl)thiazol-5-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane Manufacture of -8-carboxylic acid tert-butyl ester

The 5-({[l-(t-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methylamino}methyl)thiazole-2-carboxylic acid B obtained in Reference Example 142-4 The base mixture (2.58) was dissolved in tetrahydrofuran (3〇1111〇, 1,1'-carbonyldiimidazole (1.58, 9.3 mmol) was added, and the mixture was mixed at 70 ° C for 2 hours, and stirred 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 again mixed at 70 ° C for 3 hours. After cooling the reaction mixture, water was added and stirred to stop foaming. After the mixture was diluted with ethyl acetate, a saturated aqueous solution of sodium hydrogencarbonate was added, and the organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (Purif-Pack 2L 40 pm, mp. NMR (CDCl3) 6: 1.44 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.55-1.73 8 -312 - 201211053 (2H, m), 1.80- 1.95 (2H, m), 3.29 ( 2H,t,J=ll.lHz), 3.39(2H,s), 3.72-3.89(2H,m),4.49(2H,q,J = 7.2Hz), 4.64(2H,s),7.5 5(lH , s) LC/MS [Condition 1]: Hold time 4·〇2 minutes; m/z 448.0 [M + Na]+ (ESI positive ion mode)

[化2 8 2]

Reference Example 1 4 2 - 6 5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5] decane_3 Manufacture of _ yl}methyl)thiazole-2-carboxylic acid ethyl

Substituting 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid Tributyl ester, 3-{[2-(ethoxycarbonyl)thiazol-5-yl]methyl}-2-oxo-1-oxo-3,8-diazo snail obtained using Reference Example 142-5 The title compound (140 mg, yield 63%) was obtained from the title compound (1. 'Η-ΝΜΙΙ(〇0(:13)δ:1_44(3Η, ί,; = 7.2Ηζ), 1.67-1·86(2Η,ιη),1·86-2.00(2H,m),2.4 1- 2.63 (4H,m),3_ 3 8(2H,s),3.56(2H,s), 4.48( 2H,q,J = 7.1Hz),4.63(2H,s),7.43(2H,d,J = 8.3 Hz), 7.54 (lH, s), 7.57 (2H, d, J = 8.3 Hz) LC/MS [Condition 1]: Hold time 2.36 minutes; m/z 48 3.8 [M + H]+ ( -313- 201211053 ESI positive ion mode) 【化2 8 3】

F Reference Example 1 4 2 - 7 5-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-indole_oxo_38 Diazospiro[45]decane-3-yl The manufacture of the methyl]thrazole-2-carboxylic acid replaces 6-({2-sideoxy-8-[4-(trifluoromethyl)benzyl]]indole_spiro_3,8-diazospiro [ 4.5] decyl-3-yl}methyl)nicotinic acid ethyl group, 5-({2-trifluoromethyl-8-[4-(trifluoromethyl)phenylmethyl pi-acean) obtained using Reference Example 142_6 The title compound (110 mg, the title compound (lOmg, m. Yield 81%). 1H-NMR (DMSO-d6) 5: 1.7 1-1.89 (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 (lH, s), and piperinidine 2H are peaks and cannot be observed. LC/MS [Condition 1]: Hold time 2.36 minutes; m/z 45 5.9 [M + H]+ (ESI positive ion mode), m/z 45 3.0 [M-H]_ (ESI negative ion mode) [Chem. 2 8 4]

-314- 201211053 Example 142 3-{[2-(4-Benzylmercaptopiperidin-1-carbonyl)thiazol-5-yl]methyl}-8-[4-(trifluoromethyl)benzene Manufacture of keto-1-oxo-3,8-diazosuro[4.5]decane-2-one (Compound No. 142)

Substituted 6 - ({2 - oxo-8-[4-(trifluoromethyl)benzyl]-1 -oxa-3,8-diazospiro[4.5]decane-3-yl}methyl) Nicotinic acid, 5-({2-oxo-8-[4-(trifluoromethyl)benzyl) 1-oxo-3,8-diazospin [4.5] obtained using Reference Example 142-7. Cycloalkyl-3-yl}methyl)thiazole-2-carboxylic acid, substituted tetrahydrofurfurylamine, substantially using and carrying out 1 2 3 4-benzylidene piperidine hydrochloride and triethylamine The title compound (1 4 mg, yield 73%) was obtained after the same reaction of the title compound (1).

Example 143 -315-1 H-NMR (CDCl3) 6: 1.68-2.10 (8H, m), 2.46-2.60 (4H, m), 3. O3- 2 3.28 (lH, m), 3.3l (2H, s), 3.40-3.68 (2H, m), 3.55 (2H, s), 4.5 1-4.73 (lH, m), 4.56 (2H, d, J = 2.7 Hz), 5.20-5.43 (lH, m), 7.36-7.67 • (8H, m), 7.95 (2H, d, J = 7.2Hz). 3 LC/MS [Condition 1]: Hold time 3.45 minutes; m/z 627.1 [M + H]+ (4 ESI positive ion mode), m/z 661.3 [M + Cir (ESI negative ion mode) 201211053 Heart ( Benzo[&lt;1][1,3]dioxazol-5-ylmethyl)-6-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1- Production of oxa-3,8-diazospiro[4·5]decane-3-yl}methyl)nicotinium amide (Compound No. 143) Substituted tetrahydrofurfurylamine, substantially other than piperonylamine The title compound (7.1 mg, yield 68%)yield 1H-NMR (CDCl3) 6: 1.70-1.82 (2H, m), 1.90-2.0 1 (2H, m), 2.46-2.60 (4H, m), 3.3 2 (2H, s), 3.56 (2H, s) , 4.55 (2H, d, J = 5.8 Hz), 4.57 (2H, s), 5.96 (2H, s), 6.3 7 (lH, brs), 6.75-6.86 (3H, m), 7.3 7 (lH, d , J = 8.2Hz), 7.43 (2H, d, J = 8.2Hz), 7.56 (2H, d, J = 8.2Hz), 8.09 ( lH, dd, J = 8.2, 2.0Hz), 8.92 (lH, d , J = 2.0Hz). LC/MS [Condition 1]: Hold time 3.2 min; 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-Fluorobenzylidinyl)piperidin-1-carbonyl]pyridin-2-yl}methyl)-8-[4-(trifluoromethyl)benzene Production of methyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 144) Substituted tetrahydrofurfurylamine using 4-(4-fluorobenzhydryl) In the same manner as in Example 1 1 1 except that the piperidine hydrochloride and triethylamine were reacted in the same manner to give the title compound (4.9 mg, yield 43%) as a colorless oil. 1H-NMR (CDCl3) 5: 1.69-2.08 (8H, m), 2.45-2.65 (4H, m), 3.01-3.27 (2H, m), 3.3 5 (2H, s), 3.4 1- 3.65 (lH, m), 3.5 7(2H, s), 4.47-4.76 (lH, m), 4.57 (2H, s), 7.17 (2H, t, J = 8.5 Hz), 7.36 (lH, d, J = 7.8 Hz), 7.43 ( 2H,d,J = 8.2Hz), 7.57(2H,d,J = 8.2Hz), 7.76(lH,dd,J = 7.8,2.0Hz),7.94-8.02(2H,m),8.61(lH,d , J = 2.0Hz). 1 Hinvisible(broad)

LC/MS [Condition 1]: Hold time 3_4 minutes; m/z 63 9.1 [M + H] + (ESI positive ion mode), m/z 673.3 [M + Cir (ESI negative ion mode) [Chem. 2 8 7]

Preparation of methyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]nonanone (Compound No. 145) Substituted tetrahydroindenyl The title compound (7.6 mg, yield 66) was obtained from m. %) of a colorless oil. 1H-NMR (CDCl3) 5: 1.40-1.60 (lH, m), 1.72-1.87 (2H, m), 1.91-2.3 1 (6H, m), 2.46-2.65 (4H, m), 3.09-3.47 (4H ,m), 3.35 (2H, s),

3.57 (2H, s), 4.5 8 (2H, s), 7.09 (lH, td, J = 8.9, 2.0 Hz), 7.3 8 (2H, d, J -317 - 201211053 = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.63 (lH, dd, J = 8.7, 4.9 Hz), 7.78 (lH, dd, J = 8.2, 2.0 Hz), 8.65 ( lH,d,J=1.4Hz) 〇LC/MS [condition lp hold time 3.47 minutes; m/z 652.1 [M + H]+ (ESI positive ion mode), m/z 686.3 [M + Cl]- (ESI negative ion mode) [Chem. 2 8 8]

Reference example 1 4 6

3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1 -Production of oxa-3,8-diazospiro[4.5]decane-2-one substituted piperidine using phenyl (piperidin-4-yl)methanone hydrochloride (purchased) and triethylamine The same reaction as in Example 16 was carried out to give the title compound (37 mg, yield: 59%) as white powder. </RTI> NMRCSOO </ RTI> &gt; CD C13) δ : 1 . 0 5 (2 H, q, J = 1 1.9 H z), 1.4 6 -1 . 7 1 (4Hsm), 1.71-1.87 (7H, m), 1.87-2.00 (4H, m), 2.46 (lH, tt, J = 11.9, 3.3 Hz), 2.56 (4H, br s), 2.8 1 ( 1 H, t, J = 1 1.4 Hz), 3 .1 1 (2H, d, J = 8.2 Hz), 3.13 - 3.29 (3H, m), 3.51 (lH, Tt, J = 11.0, 4.5 Hz), 3.57 (2H5s), 3.98 (lH, d, J = 13.5 Hz), 4.60 (lH, d, J = 13.1 Hz), 7.39-7.62 (7H, m), 7.93 ( 2H,d,J = 6.5Hz). LC/MS [Condition 1]: Hold time 3.56 minutes; m/z626_0[M + H]+ (ESI positive ion mode), m/z 670.2 [M + HCOO]-(ESI negative ion mode) 8 -318- 201211053 [化2 8 9]

Example 1 4 6

3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidine-i-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1 -Production of cacao-3,8-diazospiro[4.5]decane-2-one hydrochloride (Compound No. 146) 3-{[(lr,4r)-4-(4-) obtained in Reference Example 146 Benzylpyridinylpiperidine-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4_5]decane 2-ketone (17 mg, 0.028111111 〇1) was dissolved in methanol (1. 〇1111 ' 'Add 4M hydrogen chloride-dioxane solution (purchased) (0.02 lmL, 0.083 mmol) at room temperature at 60 ° C After 5 hours of mixing, it was concentrated to dryness under reduced pressure to give 3-{[(lr,4r)-4-(4-benzopyridylpiperidine-1-carbonyl)cyclohexyl]methyl}-8. -[4-(Trifluoromethyl)benzyl]_1-oxo-3,8-diazospiro[4.5]nonan-2-one hydrochloride (19 mg, quantitative) of white powder. W-NMRpOOMHz , CDCl3)S: 1.04 (2H, q, J=ll.4Hz), 1.46-1.99 (llH, m), 2.05 (2H, d, J = 13.9Hz), 2.46 (lH, 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 (lH, tt, J-11.0, 3.7 Hz ), 3.97 (lH, br s), 4.17 (2H, d, J = 5.3 Hz)} 4.57 (1 H, br s), 7.42 - 7.52 (2 H, m), 7.53 - 7.63 (lH, m), 7.73 (2H, d, J = 8.2 Hz), 7.8 5 (2H, d, J = 8.2 Hz), 7.89-7.97 (2H, m), 13.26 ( lH,s -319- 201211053 【化2 9 0】

Example 1 4 7 3-({(lr,4r)-4-[4-(tetrahydrofuran-2-carbonyl)piperazine-1-carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl) Preparation of phenylmethyl]-1-oxo-3,8-diazaspiro[4.5]nonan-2-one (Compound No. 147) substituted piperidine using piperazin-1-yl (tetrahydrofuran- The title compound (48 mg, yield 72%) was obtained as white powder. 1H-NMR (300MHz 'CD C13) δ : 1.0 5 (2 H, q, J= 1 1.9 Η z), 1.4 5 -1.7 0 (3Η, m), 1.70- 1.86 (6Η, m), 1.87-2 Ll(5H,m),2.24-2.5 l(2H,m) ,2.56(4H,br s),3.11(2H,d,J = 7.4Hz), 3.26(2H,s),3.33-3.63(7 H, m), 3.64 - 3.9 8 (5H, m), 4.5 9 (lH, 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]: Hold time 3·ι〇 min; m/z 620.9 [M + H]+ (ESI positive ion mode), m/z 665.2 [M + HCO〇r (ESI negative ion mode) [化2 9 1]

-320- 201211053 Example 1 4 8 4-[(lr,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]丨_恶_3 8_ Preparation of Diazospiro[4.5]nonan-3-ylmethyl)}cyclohexanecarbonyl]piperazine-indole-carboxylic acid tert-butyl ester (Compound No. 148) Substituted piperidines using piperazine-1 - The same reaction as in Example 16 was carried out to give the title compound (137 mg, yield: 92%) as a white powder. iH-NMRGOOMHz, CDCl3)5 : 1.04 (2H, q, J = 11.9 Hz), 1.47 (9H, s), 1.5 1-1.69 (3H, m), 1.70-1.86 (6H, m), 1.87-2.02 (2H, m), 2.42 ( lH, 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]: Hold time 3.42 minutes; m/z 622.9 [M + H]+ (ESI positive ion mode) 'm/z 667.1 [M + HCO〇r (ESI negative ion mode)

Reference Example 1 4 9 3-{[(lr,4r)-4-(piperazin-1-carbonyl)cyclohexyl]methyl b-8-[4-(trifluoromethyl)benzyl]-1-oxo- Preparation of 3,8-diazospiro[4.5]decane-2-one dihydrochloride salt 4-[(lr,4r)-4-({2- sideoxy-8-[4] obtained in Example 148 -(三-321 - 201211053 fluoromethyl)benzyl]-1_oxo-3,8-diazospiro[4.5]decane-3-ylmethyl)}cyclohexanecarbonyl]piperazine-1- The carboxylic acid tert-butyl ester (89 mg, 〇. 14 mmol) was dissolved in methanol (1.0 mL), and 4M hydrogen chloride-dioxane solution (purchased) (0.36 mL, 1.4 mmol) was added at 60 ° C at room temperature. Mix for 4 hours. Thereafter, the residue was concentrated to give 3-{[(lr,4r)-4-(piperazin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzene. A white powder of methyl]-1-oxo-3,8-diazospiro[4·5]nonan-2-one dihydrochloride (83 mg, quantitative).

LC/MS [Condition 1]: Hold time 〇·96 min; m/z 523.0 [M + H]+ (ESI positive ion mode [Chem. 2 9 3] Example 149

4-[(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]癸Manufacture of methyl alk-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carboxylate (Compound No. 149) 3-{[(lr,4r)-4-(pi) obtained in Reference Example 149 Pyrazin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one Hydrochloride (26 mg, 0.044 mmol) was dissolved in dimethylformamide (0.5 mL), and triethylamine (0.031 mL, EtOAc. After stirring for 3 days at room temperature, chloroform (3.0 mL) and saturated aqueous sodium carbonate 8-32-201211053 (3.0 mL) were added to the mixture, and the organic layer was separated. After drying over sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- }}methyl)cyclohexanide base] piperidine-1-decanoate (16mg, 63% yield) of a white powder

'H-NMR (3 00MHz ' CDC13) 5: 1.05 (2H, q, J = l 1. 6Hz), l .45-1 .69 (3H, m), 1.78 (6H, d, J=11.4) Hz) s1.94 (2H, d, J = 13.1 Hz), 2.42 (lH, tt, J = l 1.9, 2.9 Hz), 2.5 5 (4H, 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 = 8.2Hz). LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 580.9 [M + H]+ (ESI positive ion mode), m/z 625.1 [M + HCOO]- (ESI negative ion mode)

[化2 9 4]

Example 1 5 0 2-{4-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]ι_ox-3,8-weight Preparation of alkalose [4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-1 -yl}acetonitrile (Compound No. 150) Substituted methyl chloroformate using 2-bromoacetonitrile (purchased) The title compound (7 〇rng, yield 33%) was obtained as a colorless oil. *H-NMR (300 MHz &gt; CDC13) 6: 1. 〇 4 (2H, dqsJ-3.7, 12.3 Hz), 1.46-

1.69(3H,m), 1.79(6H,d,J=11.4Hz),l.88-2.01(2H,m),2.42(lH

, tt, J = 10.6, 2.5 Hz), 2.57 (8H, br s), 3.l 〇 (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) o LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 562.3 [M + H] + ( ESI Positive ion mode), m/z 606.1 [M + HC〇〇]-(ESI negative ion mode) [Chem. 2 9 5]

Example 1 5 1 3-{[(lr,4r)-4-(4-Ethylpiperazine_1-carbonyl)cyclohexyl]methyl}_8_[4-(trifluoromethyl)benzyl]- Production of 1-oxo-3,8-diazospiro[4·5]nonane-2-ketone (Compound No. 151) Substituting methyl chloroformate, substantially the same as Example 149 except using ethyl hydrazine chloride The same reaction gave the title compound (9 mg, yield 36%) as white powder. lH-NMR (300MHz ' CD C13 ) δ : 1 . 〇 5 (2 H , q, J = 1 2.0 Η z), 1.47 -1.7 0 (3H,m), 1.79 (6H,d,J=11.0Hz) , 1.94 (2H, d, J = 13.1 Hz), 2.12 (3H, s), 2.36-2.51 (lH, m), 2.56 (4H, br s), 3 .1 1 (2H, d, J = 7.4 Hz ), 3.26 (2 -324- 201211053 H, s), 3.3 8-3.53 (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]: Hold time 2.98 minutes; m/z 564.9 [M + H]+ (ESI positive ion mode), m/z 609.2 [M + HCOO]- (ESI negative ion mode)

[化2 9 6]

Example 1 5 2 4-[(1]:,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-weight Manufacture of ethyl siro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine]piperidine-1-carboxylate (Compound No. 152)

The title compound (58 mg, yield: 92%) was obtained from m. White powder. ^-NMRiSOOMHz ' CD C13) δ : 1.0 1 (2 H, dq, J = 2.9,1 2.3 H z), 1. 18 -1.36 (5H, m), 1.38-1.66 (3H, m), 1.67- 2.06(llH,m),2.55(4H,br s) ,2.89(2H,t,J=11.9Hz),3.09(2H,d,J = 7.4Hz), 3.25(2H,s),3.57( 2H, s), 3.82-4.00 (lH, m), 4.01-4.19 (4H, m), 5.29 (lH, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.4 Hz), 7.57 (2H, d , J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 608.9 [M + H]+ (ESI positive ion mode), m/z653_2 [M + HCO〇r (ESI negative ion mode) -325- 201211053 [ 2 9 7]

Example 1 5 3 (11:,4〇-1^-butyl-4-{[8-(4-cyanobenzyl)-2-oxo-oxo-oxa-3,8-diazo snail [4.5] Manufacture of decane-3-yl]methyl}cyclohexanecarbamamine (Compound No. 153) Substituted (1 r, 4r)-4-( {2- Side Oxygen - 8·[4-(3 Fluoromethyl)benzyl]-1 -oxan 3.8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, used in Reference Example 17-2 (lr, 4r) )-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3.8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid Substituting piperidine, using η-butylamine (commercially available), substituting chloroform, and using the same procedure as in Example 16 to give the title compound (23 mg, yield 37 %) of white powder. j-NMROOOMHz, CDCl3) 5: 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, br s), 3.09 (2H, d, J = 7.4 Hz), 3.16-3.30 (4H, m), 3.59 (2H, s), 5.39 (lH, 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]: Hold time 2.96 min; m/z 466.9 [M + H]+ (ESI positive ion mode), m/z 511.l [M + HCO〇r (ESI negative ion mode) -326- 201211053 [Chem. 2 9 8] Example 1 5 4 4-[(3-{[(lr,4r)-4-(4-Benzylmercaptopiperidin-indole-carbonyl)cyclohexyl]methyl b 2 - Preparation of oxo-oxo-3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (combination number 154) in place of η-butylamine 'using phenyl ( The same reaction as in Example 153 was carried out in the same manner as in Example 153 to give the title compound (3, 7 mg, yield: 6%) of white powder. . ^-NMRCSOOMHz ' CDCl3) 6: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.43 - 2.06 (15H, m), 2.47 (lH, tt, J = 11.4, 2.9 Hz), 2.55 (4H, br s), 2.8 1( lH,t,J=11.9Hz), 3.11(2H,d,J = 5.7Hz), 3.20(lH,t,J=12.7Hz), 3.26(2H,s),3.44-3.56 (lH,m), 3.57(2H,s), 3.98 (lH,d,J=12.7Hz • ), 4.59 (lH,d,J = 12.7Hz),7.3 9-7.53(4H,m),7.54- 7.65 (3H&gt;m), 7.93 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3 2 8 minutes; m/z 5 82 9 [M + H]+ (ESI positive ion mode), m/z 627.2 [M + HCO〇r (ESI negative ion mode) [ 2 9 9]

-327- 201211053 Example 1 5 5 (lr,4r)-N-(Benzo[d][l,3]dioxazole-5-ylmethyl)-4-{[8-(4-cyano) Manufacture of benzyl-)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbamamine (Compound No. 155) The title compound (21 mg, yield) was obtained from the title compound (yield: yyyyyyyyyyyy 30%) of a colorless oil. 'H-NMR (300MHz 'CDCl3) 5: 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 (lH, 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 (lH, 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]: Hold time 3.06 minutes; m/z 544.9 [M + H]+ (ESI positive ion mode), m/z 589.2 [M + HCO〇r (ESI negative ion mode) 0 0]

Example 1 5 6 (lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3 -Based on the manufacture of methyl b-n-(2,3-dihydro-1H-indol-2-yl)cyclohexanecarbamamine (Compound No. 156) in place of η-butylamine, using 2,3-di Hydrogen-1H-indol-2-amine (commercially available) - 328 - 201211053 'The same reaction as in Example 1 5 3 was carried out to give the title compound (26 mg, yield: 48%) as a yellow powder. Η-ΝΜΙΙ (300ΜΗζ, CDCl3) 5: 0.98 (2H, dq, J = 3.7, 13. IHz), l.36-1.65 (3H, m), 1.66-2.01 (9H, m), 2.55 (4H, Br s), 2.76 (2H, dd, J=l 6.8, 4.5

Hz), 3.07 (2H, d, J = 7.4 Hz), 3.24 (2H, s), 3.3 1 (2H, dd, J = 15.9, 7.8 Hz), 3.56 (2H, s), 4.73 (lH, dtt, J = 7.8, 7.0, 4.1 Hz), 5.64 (lH, 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

LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 526.9 [M + H]+ (ESI positive ion mode), m/z 571.1 [M + HCO〇r (ESI negative ion mode) 〇1]

Example 1 5 7 (lr,4r)-N-methoxy-N-methyl-4_({2_sideoxy 1[4_(difluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazane snail [4.5] decane _3_ yl} methyl) cyclohexylcarbamide (Compound No. 157) substituted piperidine using N, fluorene-dimethyl-amine hydrochloride (purchased In the same manner as in Example 16 except that triethylamine was used, a white powder of the same compound (140 mg, yield: 77%) was obtained. 'h-nmr(3〇omhz ' CDci3)s: 1 07(2H5dci>J = 2-6&gt;12-6Hz^1 ·41 -1.6 8(3H,m), 1.69-2.00(8 H,m)52 -57(4H&gt;br s), 2.65( 1 H,t,J-1 0.6Hz -329- 201211053 ),3.1 1(2 H, d,J = 7.3 Hz), 3.17(3 H, s), 3.2 6 (2 H, s), 3.5 7 (2 H, s), 3.69 (3H, s), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz). MS [Condition 1]: Hold time 3.18 minutes; m/z 498.4 [M + H]+ (ESI positive ion mode) [Chemical 3 0 2]

Reference Example 1 5 8 4-{[8-(t-Butoxycarbonyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}benzoin The acid is replaced by 3-{[(lr,4r)-4-(methoxycarbonyl)cyclohexyl]methyl b 2-oxo-1-oxo-3,8-diazospiro[4.5]decane- 8-carboxylic acid tert-butyl ester, using 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo as obtained in Example 1. The title compound (900 mg, yield 93%) was obtained as white powder, m. m. • H-NMRiSOOMHz ' CDC13) 5: 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), 4.5 1 (2H, s), 7.3 7 (2H, d, J = 8.2 Hz), 8.09 ( 2H, d, J = 8.6Hz). LC/MS [Condition 1]: Hold time 3.88 minutes; m/z3 89.0 [M-H]-(ESI negative ion mode) -330- 201211053 [Chem. 3 0 3]

Example 1 5 8 3-[4-(4-Benzylmercaptopiperidin-1-carbonyl)benzyl]-2-oxo-1-oxo-3,8-heavy φ snail [4·5 Manufacture of tert-butyl-8-carboxylic acid tert-butyl ester (Compound No. 158) substituted (lr,4r)-4-{[8-(t-butoxycarbonyl)-2-oxo-l-oxo- 3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid, 4-{[8-(1-butoxymethylene)-2- obtained using Reference Example 158 Side oxy-1-che-3,8-diazospiro[4.5]decane-3-yl]methyl}benzoic acid' substituted tetrahydrofurfurylamine using phenyl(piperidin-4-yl)methanone The title compound (1·1 g, yield 88%) was obtained as a white powder.隹 'Η-ΝΜΚ (300ΜΗζ ' CDCl3) 6: 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 (lH, m), 3.66-4.00 (3 H, m), 4.45 (2H, s), 4.68 (1 H, br s), 7.30 (2H,d,J = 8.2Hz), 7.36-7.53 (4H,m), 7.54-7.63 (lH,m), 7.94 (2H,d,J = 7_8Hz). LC/MS [Condition 1]: Hold time 4.39 minutes; m/z 606.2 [M + HCOO]·( ESI negative ion mode) -331 - 201211053 [Chem. 3 0 4]

Example 1 5 9 3-[4-(4-oxopiperidin-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-2-one (Compound No. 159) Substituting (lr, 4r)-4-({2-Sideoxy-S-[4-(trifluoromethyl)benzyl) ]-1-oxo-3,8-diazospiro[4·5]nonane_3_yl}methyl)cyclohexanecarboxylic acid, using 4-({2-side oxygen-8) obtained in Reference Example 21. -[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4·5]decane-3-yl}methyl)benzoic acid, substituted 4-aminopiperidine The title compound was obtained by substantially the same reaction as in Example 6 except that the piperidin-4-carboxylic acid tert-butyl ester was reacted with piperidin-4-one-water and the hydrochloride salt (complex) and triethylamine. (240 mg, yield 99%) of a yellow powder. *Η-ΝΜΚ(300ΜΗζ 'CDCl3)5:1.74(2H,dt,J= 1 3.5,7.0Hz), 1.92(2H,d,J=13.1Hz),2.34-2.68(8H,br m),3.1 5 (2H, s), 3.5 6(2H, s), 3.8 8 (4H, br s), 4.46(2H, s), 7.34 (2H, d, J = 8.2Hz), 7.42 (2H, d, J = 7.8 Hz), 7.46 (2 H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time min; m/z 529.9 [M + H]+ (ESI positive ion mode), m/z 574.2 [M + HCOO]- (ESI negative ion mode) [Chemical 3 0 5 ]

-332- 201211053 Example 1 6 0 1-(Benzo[d][l,3]dioxazole-5-ylmethyl)-3-[4-({2- sideoxy- 8-[4- Manufacture of (trifluoromethyl)benzyl]-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl]urea (Compound No. 160) in place of N-(t -butoxycarbonyl)-1,3-diaminopropane, substantially using benzo[d][l,3]dioxazole-5-ylmethylamine (purchased) The same reaction gave the title compound (24 mg, yield 20% 'H-NMR (300MHz ' CDC13) 5: 1.49- 1.79 (2H, m), 1.78- 1 , 93 (2H, m), 2.50 (4H, br s), 3.1 1 (2H, s), 3.54 (2H, s), 4.26-4.3 8(4H, m), 5.23 (lH, t, J = 5.7Hz), 5.9 1(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]: Hold time 3.64 minutes; m/z 596.9 [M + H]+ (φ ESI positive ion mode), m/z 64 1 . 1 [M + HCOO] — (ESI negative ion mode) 3 0 6]

Example 1 6 1 4-Benzyldecyl-N-[4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4·5]decane-3_ylindolemethyl)phenyl]piperidine-carboxamide (combination-333-201211053, material number 161) 3-(4-amino group) obtained in Reference Example 93 Benzyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one dihydrochloride (7 7 mg, 0.16) Mm〇l) was dissolved in chloroform (i.0 mL), and pyridine (〇. 〇9 0 m L, 1.1 mmol) and 4-nitrophenyl chloroformate (38 mg, 0.19 mmol) were added at 0 ° C. Stir and mix for 1 day at a temperature. Thereafter, triethylamine (〇.〇56 mL, 0.40 mm〇l) and phenyl(piperidin-4-yl)methanone hydrochloride (purchased) (4 3 mg, 0.19 mm〇l) were added in the room. Stir and mix for 1 day at a temperature. Chloroform (3.0 mL) and a saturated aqueous solution of sodium hydrogen sulfate (3 mL) were evaporated. The obtained residue was purified by silica gel chromatography [塡 剂 : 胺 FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU 、 、 、 、 、 、 、 、 、 、 、 、 、 、 乙酸乙酯 乙酸乙酯 乙酸乙酯 , , 4- 4- 4- 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzene A white powder of piperidine-1-carboxamide (23 mg, 23% yield). 1 H-NMR (300 MHz &gt; CD C13) δ : 1.6 2 - 1 . 7 7 (2 H, m), 1.7 6 - 2.0 3 (6 Η , m), 2.50 (4H, br s), 3 · 1 Ο(2Η, s), 3.1 3 (4H, dt, J = 2 · 9, 1 2.7 Hz), 3. 5 1 (lH, tt, J = 11.0, 4.1 Hz), 3.54 (2H, br s), 4.1 1 (2 H , dt, J = 1 3.2, 3.5 Hz), 4.36 (2H, s), 6.44 (lH, 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]: Hold time 3.82 minutes; m/z 63 5_0[M + H]+ ( ESI positive ion mode), m/z 633.2 [MH]_ (ESI negative ion mode) -334- 201211053 [Chem. 3 0 7]

Example 162 3-{4-[4-(4-Fluorobenzylidinyl)piperidine-1-carbonyl]benzyl}_8-[4-(trifluoromethyl)benzyl]-1-oxole -3,8-diazospiro[4.5]decane-2-one (compound number)

Preparation of 162) Substituting 4-(2-aminoethyl)morpholine, using (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (purchased), substantially carried out and carried out The title compound (41 mg, yield 72%) of the title compound (H-NMR (3 00 MHz 'CDC13) 5: 1. 63-2.1 1 (8H, m), 2.54 (4H) , br s) , 2.98-3.26(2H, br m ), 3 . 1 4 (2 H , s ) , 3.3 9 - 3.6 8 ( 3 H, brm), 3.84 (1 H, br s), 4.44 (2H , s), 4.67 (lH, br s), 7.1 5 (2H, t, J = 8, 2 Hz), 7.3 0 (2H, d, Lu 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]: Hold time 3_54 minutes; m/z 63 8.1 [M + H]+ (ESI positive ion mode), m/z 682.3 [M + HCO〇r (ESI negative ion mode) [Chemical 3 0 8 ]

-335- 201211053 Example 1 6 3 3-[4-(4-Hydroxy-4-phenylpiperidin-1-carbonyl)benzyl]8-[4-(trifluoromethyl)benzyl] Manufacture of 4-(2-aminoethyl)morpholine, using 4-phenylpiperidine, in the manufacture of 1-oxa-3,8-diazospiro[4.5]decane-2-one (Compound No. 163) A yellow amorphous substance of the title compound (41 mg, yield 76%) was obtained. j-NMRpOOMHz, CDCl3) 8: 1.48-2.02 (8H, m), 2.15 (lH, br s), 2.57 (4H, br s) s 3 . 1 4 ( 2 Η, s), 3 . 3 5 ( 1 Η, brs), 3.4 7 - 3.7 3 (4 H, brm) , 4.44 (2H, s), 4.67 (lH, br s), 7.26-7.33 (3H, m), 7.33 - 7.51 (8H, m), 7.57(2H,d,J = 8.2Hz) 0 LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 608.1 [M + H]+ (ESI positive ion mode), m/z 652.3 [M + HCO〇r (ESI negative ion mode) [Chemical 3 Ο 9]

Example 164 1-[4-({2_Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Manufacture of 4-(2-aminoethyl)morpholine, using piperidine-4·nitrile (purchased), in the preparation of methyl}methyl)benzimidyl]piperidine-4-carbonitrile (Compound No. 164) The title compound -336 - 201211053 (38 mg, yield 79%) ofyield of yellow crystals was obtained from the title compound. *Η-ΝΜΚ(300ΜΗζ ' CD C13) δ : 1 . 5 3 - 2.0 7 (8 H, m), 2.5 9 (4 H, brs) , 2.94 (lH, tt, J = 7.0, 4.5 Hz), 3.15 (2H, s), 3.28-4.01 (6H, br m), 4.44 ( 2H, s), 7.3 1 (2H, d, J = 8.2 Hz), 7.3 8 (2H, d, J = 8.6 Hz), 7.4 1- 7.5 1(2 H,m ), 7.58 (2H,d,J = 7.8 Hz). LC/MS [Condition 1]: Hold 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 1 6 5

4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of benzylidene]piperazine-1-carboxylic acid tert-butyl ester (Compound No. 165) in place of 4-(2-aminoethyl)morpholine, using piperazine-1·carboxylic acid tert-butyl The title compound (37 mg, yield 66%) of yellow amorphous material was obtained from the title compound (yield: 66%). • H-NMROOOMHz 'CDC13) 5: 1.46 (9H, S), 1.64-1.84 (2H, m), 1.92 (2H, d, J = 12.7 Hz), 2.54 (4H, br s), 3.1 4 (2H, s), 3.22-3.84 ( 1 0H, br m), 4.44 (2H, s), 7.3 1 (2H, d, J = 7.8 Hz), 7.35-7.49 (4H, m), 7.57 (2H, d, J =7.4Hz). LC/MS [Condition 1]: Hold time 3.46 minutes; m/z 617.1 [M + H]+ (-337-201211053 ESI positive ion mode), m/z 661.3 [M + HCOO]' (ESI negative ion mode) ) 【化3 1 1】

Example 1 6 6 3-[4-(4-Methoxypiperidine-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Production of Diazospiro[4.5]decane-2-one (Compound No. 166) Substituting 4-(2-aminoethyl)morpholine, using 4-methoxypiperidine (purchased) The title compound (33 mg, yield 68%) ofyield of yellow crystal 'H-NMR (3 00 MHz ' CDCl3) 6: 1.41-2.07 (8Hsm)) 2.55 (4H, br s) , 3.13 (2H, s), 3.21 (lH, br s), 3.3 6 (3H, s), 3.40-3.74(5H,m), 3.47( lH,tt,J = 7.4,3.7Hz), 3.99(lH,br s),4.44(2H,s), 7.29(2H,d,J = 8.2 Hz), 7.3 3-7.49 (4H, m), 7.57 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 546.1 [M + H]+ (ESI positive ion mode), m/z 590.3 [M + HCO〇r (ESI negative ion mode) 1 2]

-338- 201211053 Example 1 6 7 N-[(6-chloropyridin-3-yl)methyl]-4-({2-o-oxo- 8-[4-(trifluoromethyl)benzyl] Manufacture of -1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 167)

Substituting 4-(2-aminoethyl)morpholine (6-chloropyridin-3-yl)methylamine (p.), the title compound (34 mg, Yield 67%) of yellow amorphous material. 1H-NMR (300MHz &gt; CDC13) 6: 1.6 1 -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 (lH, t, J = 5.7 Hz), 7.30 (lH, 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 (lH, dd, J = 8.2, 2.5 Hz), 7.77 (2H, d, J = 8.2 Hz), 8.3 7 (lH , d, J = 2.5Hz). LC/MS [Condition 1]: Hold time 3.26 min; m/z 573.0 [M + H]+ (ESI positive ion mode), m/z 571.2 [M-H]- (ESI negative ion mode)

[化3 1 3]

Reference Example 1 6 8 -1 Preparation of 4-[Methoxy(methyl)amine-carbamoyl]piperidine-1-carboxylic acid tert-butyl ester 1-(t-butoxycarbonyl)piperidine-4 -carboxylic acid (purchased) (i.g, 4.4 mmol) and N,0-dimethylhydroxylamine hydrochloride (purchased) (470 mg, 4.8 mmol), 1-phenylbenzotriazine (600 mg, After 4.4 mol) and triethylamine (i.8 mL, -339-201211053 13 mmol) were dissolved in chloroform (10 ml), 1-ethyl-3-(3-dimethylaminopropyl) was added at room temperature. The carbodiimide hydrochloride (46 mg, 〇. 22 mmol) was stirred and mixed at room temperature for 3 days. Thereafter, chloroform (10 mL) and a saturated aqueous sodium hydrogencarbonate solution (5.0 mL) were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-[Methyl(methyl)amine-carbamoyl]piperidine-1-carboxylic acid tert-butyl ester (1.2 g, quantitative a colorless oil.

lH-NMR (300MHz ' CDC13) 6 : 1.46 (9H, s), 1.6 1 -1 .7 7 (4H, m) , 2.66-2.89 (3H, br m), 3.18 (3H, s), 3.71 (3H , s), 4.03-4.24 (2H, br m). [化3 1 4]

Reference Example 1 Production of 6 8 - 2 4-Ethylpiperidine-1-carboxylic acid tert-butyl ester

A solution of 1.1 Μ methylmagnesium bromide-tetrahydrofuran (purchased) (0.68 mL, 0.68 mmol) was dissolved in tetrahydrofuran under nitrogen atmosphere, and 4-[methoxy] obtained in Reference Example 168-1 was added at 0 °C. Tert-butyl (meth)amine indolyl]piperidine-1-carboxylate (93 mg, 0.34 mmol), stirred at room temperature for 1 day. Then, acetic acid B was added to the reaction mixture. The organic layer was separated from the ester (2. OmL) and a saturated aqueous solution of sodium chloride (2.0 mL). The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel chromatography (purine: FL100D, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: hexane/ethyl acetate = 2/1) to give 4-ethylmercaptopiperidin-1- Carboxylic acid No. 340- 8 201211053 Tributyl ester (45 mg, yield 59%) as a colorless oil. 'Η-ΝΜΚ(300ΜΗζ ' CDCl3) 5: 1.45 (9H, s), 1.42 - 1.63 (2H, m), 1.83 (2H, dd, J = 1.3, 2.5 Hz), 2.16 (3H, s), 2.45 (1 H, tt, J = l 1.4, 3.7 Hz), 2.78 (2H, td, J = 13.1, 2_9 Hz), 4.10 (2H, dt, J = 13.1, 3.3 Hz). [化3 1 5]

Reference Example 1 Preparation of 6 8 -3 1-(piperidin-4-yl)ethanone hydrochloride The third butyl 4-ethylhydrazine piperidine-1-carboxylate obtained in Reference Example 168-2 (45 mg) 0.20 mmol) was dissolved in methanol (0.50 mL), and a 10% hydrogen chloride-methanol solution (purchased) (0.30 mL, 〇.70 mmol) was added at room temperature, and the mixture was mixed at 50 ° C for 3 hours. Thereafter, the mixture was concentrated to dryness under reduced pressure to give a yellow powder of &lt;RTIgt;&lt;/RTI&gt;&gt;(&lt;/RTI&gt; LC/MS [Condition 1]: Hold time 0.61 min; m/zl 28.0 [M + H]+ (ESI positive ion mode) [Chem. 3 1 6]

Example 1 6 8 3-[4-(4-Ethylpiperidine-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzene-341 - 201211053 base]-1- Production of oxa-3,8-diazospiro[4.5]decane-2-one (Compound No. 168) was substituted for 4-(2-aminoethyl)morpholine, using the reference 168-3 obtained. The title compound (36 mg, yield 73%) of a yellow amorphous material was obtained from the residue of the title compound. 1H-NMR (300MHz, CDCl3) 5: 1.62-2.09 (8H, m), 2.19 (3H, s), 2.39-2.72 (5H, m), 3.00 (2H, br s), 3 .1 4 (2 Η , s), 3.5 8 ( 2 Η, br s), 3.78 (lH, br s), 4.44 (2H, s), 4.62 (lHsbr s), 7.29 (2H, d, J = 8.2 Hz), 7.38 (2 H, d, J = 8.2 Hz), 7.40-7.50 (2H, br m), 7.57 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 5 5 8.0 [M + H]+ (ESI positive ion mode), m/z 602_3 [M + HCO〇r (ESI negative ion mode) [Chem. 3 1 7 】

Reference Example 1 Preparation of 6 9 -1 4-(thiophene-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester In place of a 1.1 M methylmagnesium bromide-tetrahydrofuran solution, 1.0 M 2-thiophene lithium was used. The title compound (92 mg, yield 80%) was obtained as a brown oil.

'H-NMRCSOOMHz ' CDC13) 6: 1.47 (9H, s), 1.66-1.92 (4H, m), 2.87 ( 2H, td, J = 11.9, 3.7 Hz), 3.24 (lH, tt, J = 10.8, 4.0 Hz), 4.17 (2H, dt, J 201211053 = 13.1, 2.9 Hz), 7.14 (lH, t, J = 4.5 Hz), 7.65 (lH, d, J = 4.9 Hz), 7.73 (lH, d, J = 3.9 Hz).

[Chemical 3 1 8] 〇 HCI ΛΙη Reference Example 1 6 9 - 2

Preparation of piperidin-4-yl(thiophen-2-yl)methanone hydrochloride Substituting tert-butyl 4-ethenylpiperidine-1-carboxylate using 4-(thiophene-2-carbonyl)piperidine In the same manner as in the above-mentioned Example 168-3, the title compound (72 mg, quantitative) of brown powder was obtained. LC/MS [Condition 1]: Hold time 0.65 min; ηι/ζ196·0[Μ + Η]+ (ESI positive ion mode)

Example 169 3-{4-[4-(Thien-2-carbonyl)piperidine-1-carbonyl]benzyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo- Preparation of 3,8-diazospiro[4.5]decane-2-one (Compound No. 169) Substituting 4-(2-aminoethyl)morpholine, using -343-201211053 by reference example 169-2 The title compound (43 mg, yield 76%) was obtained from the title compound (yield: 76%). ^-NMRCSOOMHz 'CDCl3) δ: 1.62-2.1 9(8H,m), 2.5 3 (4H,br s), 2.92-3.23(2H,m)53.13(2H,s),3.3 0-3.47(lH,m ), 3.5 6(2H, br s), 3.8 5( lH, br s), 4.44 (2H, s), 4.68 (lH, br s), 7.1 5 (1 H, dd, J = 4.9, 3.7 H z ), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.48 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.67 (lH, dd, J = 4.9, 1.2 Hz), 7.75 (lH, dd, J = 3.7, 1.2 Hz)» LC/MS [Condition 1]: Hold time 3.44 minutes; m/z 626.1 [M + H]+ (ESI positive ion mode), m/z 670.3 [ M + HCOO]-(ESI negative ion mode). [Chemical 3 2 0]

Reference Example 170-1 Preparation of tert-butyl 4-(dimethylaminocarbamimidyl)piperidine-1-carboxylate Substituting N,0-dimethylhydroxylamine hydrochloride, using dimethylamine hydrochloride The title compound (24 mg, quantitative) was obtained as a yellow oil. 'H-NMR (300MHz ' CDC13) 6: 1.46 (9H, s), 1.60-l. 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]: Hold time 3.64 minutes; m/z25 7.1 [M + H]+ (ESI positive ion mode) -344- 201211053 [Chem. 3 2 1] h»s\^hc,

0Hj k^NH Reference Example 1 7 0 - 2 N,N-Dimethylpiperidine-4_Proline Hydrochloride Salt Manufacture

In place of the tert-butyl 4-ethylhydrazinylpiperidine-1-carboxylate, except for the tert-butyl 4-(dimethylaminocarbazyl)piperidine-1-carboxylate obtained in Reference Example 170-1, The title compound (181 mg, quantitative) was obtained as a colorless powder. LC/MS [Condition 1]: Hold time 0.59 min; m/zl 57.0 [M + H]+ (ESI positive ion mode) [Chem. 3 2 2]

Example 170 N,N-Dimethyl-l-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)benzhydryl]piperidine-4-carboxamide (Compound No. 170) Substituting 4-(2-aminoethyl)morpholine, using reference example The title compound (35 mg, yield 68%) was obtained from the title compound (35 mg, yield: 68%), m. m. Shaped object. -345- 201211053 ^-NMRCSOOMHz ' CDC13) 6: 1.62-2.00 (8H, m), 2.53 (4H, br s), 2.72 - 2.85 (lH, 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 ), 3.8 0 (1 H, br s ), 4.44 (2 H , s), 4.6 8 (1 H , 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]: Hold time 3.04 minutes; m/z 587.1 [M + H]+ (ESI positive ion mode), m/Z 631.4 [M + HCOO]- (ESI negative ion mode) twenty three】

Reference Example 1 7 1 -1 4-{[8-(4-cyanobenzyl)_2-sideoxy-1-oxo-3,8-diazospiro[4·5]nonan-3-yl] Methyl}methyl benzoate methyl ester was substituted for 4-(trifluoromethyl)benzyl bromide, and the same reaction as in Example 1 was carried out except that 4-cyanobenzyl bromide (commercially available) was used. The title compound (820 mg, yield 95%) was obtained. LC/MS [Condition 1]: Hold time 1.36 minutes; m/z 420.0 [M + H]+ (ESI positive ion mode [Chem. 3 2 4]

-346- 201211053 Reference Example 171-2 4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl Substitution of methyl}benzoic acid to replace 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo- 3,8-diazospiro[4.5]癸Methyl alk-3-yl}methyl)benzoate, 4-{[8-(4-cyanobenzyl)-2-oxo-I-oxa-3,8 obtained using Reference Example 171-1 - a colorless amorphous form of the title compound (730 mg, yield: 92%) Things. lH-NMR (300MHz, CD C13) δ : 1 · 7 4 -1 · 9 8 (4H, br m), 2.5 4 - 2 · 7 9 (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]: Hold time i_i4 min; m/z 405.9 [M + H]+ (^ ESI positive ion mode), m/z 4 〇 4.1 [MH]-(ESI negative ion mode) [Chemical 3 2 5]

Example 1 7 1 4-[(3-{4-[4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-carbonyl]benzyl}-2-sideoxy Manufacture of -1-oxa-3,8-diazospiro[4 5 ]decane _8-yl)methyl]benzonitrile (Chemical-347-201211053 Compound No. 171) replaces 4-({2-side Oxy-8-[4-(trifluoromethyl)benzyl]-indolyl-3,8-diazaspiro[4.5]decane-3-yl}methyl)benzoic acid, using Reference Example 171- 2 4-{[8-(4-Cyanobenzyl)-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-3-yl]methyl}benzoic acid Substituting 4-(2-aminoethyl)morpholine, using 6·fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (purchased) and triethylamine The title compound (36 mg, yield 60%) was obtained as the colourless crystals. 1 H-NMR (3 00 MHz ' CDC13 ) δ : 1.62- 1 . 8 2 (2 Η, m), 1. 8 3 -2.3 6 (6Η, m), 2.52 (4H, br s), 3.0 1 - 3 . 3 0 (2 Η , brm), 3 .1 4 (2 Η, s), 3.3 7 (1 Η, tt, J=10.6, 4.1 Hz), 3.55 (2H, s), 3.91 (lH, br s ), 4.4 5 (2 Η, s), 4.7 2 (lH, br s), 7.08 (lH, td, J = 8.2, 2.5 Hz), 7.26-7.3 5 (3H, m), 7.3 6-7.48 ( 4H , m), 7.5 3-7.67 (3 H, m). LC/MS [Condition 1]: Hold time 3.34 minutes; m/z 608.1 [M + H]+ (ESI positive ion mode)

Example 172 N-(Benzo[dni,3]dioxazole-5-ylmethyl)_4-{[8-(4-cyanobenzyl)-2-oxoxy-1-oxo-3, Manufacture of 8-diazospiro[4-5]nonan-3-yl]methyl}benzamide (Compound No. 172) -348-201211053 Substituted 6-fluoro-3-(piperidin-4-yl)benzo [d] Isoxazole, the same reaction as in Example 1 7 1 was carried out, except that benzo[d Π 1,3 ]dioxazol-5-ylmethylamine (available from the product) was obtained. 4 mg, yield 45%) of a colorless amorphous material. ^-NMRCSOOMHz ' CDC 13) δ : 1. 6 3 - 1 . 7 9 (2 H, m), 1. 8 4 - 1 .9 7 (2 Η, m), 2.49-2.52 (4H, brm), 3.11(2H)s), 3.54(2H,s), 4.45(2H,s), 4.54 (2H,d,J = 5.7Hz), 5.95(2H,s),6.30(lH,t,J = 5.1Hz ), 6.77 (lH, d, spring J = 7.4 Hz), 6.8 1 (lH, dd, J = 8.0, 1.4 Hz), 6.84 (lH, 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]: Hold time 3.00 minutes; m/z 539.0 [M + H]+ (ESI positive ion mode) [Chem. 3 2 7]

Example 1 7 3 4-{[8-(4-Cyanobenzyl)-2-oxo-oxo-3,8-diazospiro[4.5]decane·3-yl]methyl} Preparation of -N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 173) Substituted 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole, used A colorless amorphous material of the title compound (22 mg, yield 46%) was obtained from the title compound (yield: 46%). -349- 201211053 W-NMROOOMHz, CDC13)S: 1.51-1.80 (3H, m), 1.82-2.12 (5H, m), 2.3 9-2.6 6(4H, br m), 3.11 (2H, s) , 3.31 (lH, ddd, J = 13.8, 7.7, 4.8 Hz), 3.55 (2H, br s), 3.72 - 3.9 5 (3 H, m), 4.0 6 (1 H, dq, J = 3.3, 7.4 Hz ), 4.46(2H, s), 6.47 (l H, br t, 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]: Hold time 0.61 min; m/z 489.0 [M + H]+ (ESI positive ion mode) [Chem. 3 2 8]

Example 174 4-(4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl Manufacture of methyl benzoguanamine) piperidine-1-carboxylate (Compound No. 174) in place of 6-fluoro-3-(峨D-1,4-yl)benzo[d]isoindole, use reference The title compound (29 mg, yield: 54%) was obtained from the title compound (29 mg, yield: 54%). 'H-NMR (300MHz ' CDCl3) 6: 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 = 2.9,1 1 · 9H z ), 2.51(4H,br s), 2.97(2H,t,J= 1 1.4Hz),3.1 2(2H,s),3.55 (2H,s) , 3.70 (3H, s), 4.04-4.26 (3Hsm), 4.46 (2H, s), 5.95 (lH, d, J = 7.8 Hz), 7.32 (-350-201211053 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) 〇LC/MS [Condition 1]: Hold time 2.15 minutes ;m/z546.1 [M + H]+ (ESI positive ion mode) [Chem. 3 2 9]

Example 1 7 5 4 - ( { 3 - [ 4 - (4 - Benzyl hydrazinopiperidine - hydrazine - carbonyl) benzyl] _ 2 _ side oxy - _ _ _ _ 3,8 -diazo snail [ 4.5]Manufacture of decane-8-yl}methyl)benzonitrile (Compound No. 175)

Substituting 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole, using phenyl (piperidin-4-yl)methanone hydrochloride (purchased), substantially The title compound (3 4 ml, yield 60%) was obtained as a colorless amorphous material. *Η-ΝΜΚ(300ΜΗζ ' CDC13) 6:1.6 1-2.09(8H,m),2.55(4H,br s),2.99 -3.26(2H,br m), 3 . 1 3 (2 H , s), 3.4 2 - 3.6 8 (3 H, m), 3.8 4 (1 H, br s), 4.44 (2 H, 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]: Hold time 3.24 minutes; m/z577_l[M + H]+ (ESI positive ion mode), m/z 611.3 [M + Cl]-(ESI negative ion mode) -351 - 201211053

Example 176 4-({2-Sideoxy- 8-[4-(difluoromethyl)phenylmethylpyridinium-oxaxime] Diazospira] 癸院-3-yl}methyl)-N -(2,2,3,3,3-pentafluoropropyl)benzamide (Compound No. 176) was produced by substituting 4-(2-aminoethyl)morpholine using 2,2,3,3 The title compound (10 mg, yield 20%) of white powder was obtained after the reaction was carried out in the same manner as in Example 44. ^-NMRiSOOMHz &gt; CD C13) δ : 1. 6 5 - 1 . 8 2 (2 H , m), 1.8 5 - 2.0 1 ( 2H , m), 2.53 (4H, br s), 3.1 4 (2 Η , s), 3.5 6 (2 Η, br s), 4.1 9 (2H, td, J = 14.6, 6.4 Hz), 4.47 (2H &gt; s), 6.29 (lH, t, J = 6.1 Hz), 7.3 5 -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]: Hold Time 3.42 minutes; m/z5 80.0 [M + H]+ (ESI positive ion mode), m/z 578_2 [MH]- (ESI negative ion mode) [Chem. 3 3 1]

Example 1 7 7 352- 201211053 N-methoxy-N-methyl-4-({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-1-oxo-3, Manufacture of 8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 17 7)

Substituted (11&quot;,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- 3-yl}methyl)cyclohexanecarboxylic acid, 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxan-3 obtained in Reference Example 21, The same reaction as in Example 157 was carried out to give the title compound (2400 mg, yield: 5%). Colorless amorphous. ^-NMRCBOOMHz ' CD C13) δ : 1.6 4 -1 . 8 1 ( 2 H, m), 1.9 2 ( 2 H , brd, 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 (2 H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz) » LC/MS [Condition 1]: Hold time 3 · 〇 6 minutes; m/z 492.0 [ M + H]+ (ESI positive ion mode)

Cl [Chemical 3 3 2] Example 1 7 8 (2-chloroethyl)-3-[4-({2-o-oxo- 8-[4-(trifluoromethyl)benzyl]-1 -Production of cacao-3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl]urea hydrochloride (Compound No. 178) -353-201211053 3-(I obtained from Reference Example 93) 4-aminobenzylmethyl-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one dihydrochloride ( 44111 layer, 0.090 mmol) was dissolved in toluene (i. 〇mL), and 1-chloro-2-isocyanate ethane (commercially available) (0.024 mL '0.30 mmol) was added at room temperature at 100. (: Mixing was carried out for 3 hours. Hexane (1.0 mL) was added to the reaction mixture, and the precipitated solid was filtered, dried under reduced pressure at room temperature to give 1-(2-chloroethyl)-3-[4 -({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl Urea hydrochloride (48 mg, quantitative) of white powder. • H-NMRiSOOMHz 'DMSO-d6) 5: 2.04 (4H, br s), 2.9 9 - 3.3 7 (6 Η, m) s 3.40 (2H , qsJ = 6.0Hz), 3.64 (2H, t, J = 6.1Hz), 4.25 (2H, s), 4.33 - 4.52 (2H, m), 6.46 (lH, t, J = 6.1Hz), 7.12 (2H , d, J = 8.6 Hz), 7.3 7 ( 2H, d, J = 8.2 Hz), 7.72 - 7.89 (4H, m), 8.77 (lH, s), 10.77 (lH, br s) o LC/MS [ Condition 1]: Hold time 3.16 minutes; m/z 524.9 [M + H] + (ESI positive ion mode), m/z 559.2 [M + Cir (ESI negative ion mode) [Chem. 3 3 3]

Example 179 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Manufacture of -N-(2,2,2-trifluoroethyl)benzamide (Compound No. -354 - 201211053 179) The 4-({2· side oxygen-8-[ 4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (50 mg, O.llmmol) dissolved in dichloro Methane (1, 〇1^), 2,2,2-trifluoroethylamine (purchased) (0.013 mL, 〇.17 mmol) and 0-(benzotriazin-1-yl) were added at room temperature. -N,N,N,N-tetramethylurea hexahydro acid salt (63 mg, 0.17 mmol), and diethylamine (0.030 mL, 〇_22 mmol) were stirred at room temperature for 1 day. Ethyl acetate (2.0 mL) and saturated aqueous sodium hydrogencarbonate (2 mL) were evaporated. The organic layer was dried with anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [Hybrid: HI-FLASH (registered trademark) COLUMNs Uicagel 40 pin, development solvent: ethyl acetate / methanol = 10/1]. -({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)-1 A white powder of ^-(2,2,2-trifluoroethyl)benzamide (41 mg, yield 70%). • W-NMR pOOMHz, CDCl3) 5: 1.67-1.8 5 (2H, m), l_8 6- 1.97 (2H, m), 2.55 (4H, br s), 3. 3 (2 Η, s), 3 . 5 7 (2 Η , brs), 4.1 3 (2 Η , dq , J = 6.5, 8.6 Hz), 4_47 (2H, s), 6'3 5 ( lH, t, J = 6_lHz), 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 ]: Hold time 3.02 minutes; m/z5 3 0.0[M + H]+ (ESI positive ion mode), m/z 528.1 [M-Hr (ESI negative ion mode) -355- 201211053 [Chem. 3 3 4]

Example 1 80 N-(4-cyanobenzyl)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-che-3,8- Preparation of Diazo snail [4.5] 癸院-3-yl}methyl)benzamide (Compound No. 180) 4 - ({ 2 - oxo-8 - [ 4 - (three) obtained in Reference Example 2 1 Fluoromethyl)benzyl]-1_oxo-3,8-diazospiro[45]decane_3_yl}methyl)benzoic acid (47 mg, 0.1 mmol) and 4-(amino group A) Benzomidonitrile hydrochloride (purchased) (19rng, O.llmmol), 1-hydroxybenzotriazole (7. 〇mg, 〇.〇5〇mol), and triethylamine (〇.〇42mL) , 0.30 mmol) was dissolved in chloroform (1.0 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 1 mg, 0.1 1 ) was added at room temperature. Methyl), stirred at room temperature for 1 day. Thereafter, ethyl acetate (2.0 mL) and water (2.0 mL) were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Hybrid: HI-FLASH (registered trademark) COLUMNsilicage MOpm, developed solvent: ethyl acetate/methanol = 10/1] to obtain N. -(4-cyanobenzyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4- 5] Colorless amorphous material of decyl-3-yl}methyl)benzamide (41 mg, yield 73%). 'H-NMRiSOOMHz ' CD C13) δ : 1.6 4 - 1 . 8 2 (2 H, m), 1. 8 5 - 1.9 8 (2 Η , m), 2.52 (4H, br s), 3 · 1 3 (2Η, s), 3 · 56 (2H, br s), 4.46 (2H, s), 4.7 1 ( -356- 201211053 2H, d, J = 6.1 Hz), 6.54 (lH, t, J = 5.7 Hz) ), 7.34 (2H, d, J = 8.2 Hz), 7.3 7-7.49 (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]: Hold time 3.41 minutes; ^/2562.8 ^ + 1^+ ( Ε S I positive ion mode)

Example 1 8 1 '-(Oral-side Oxygen^-^-trifluoromethyl hydrazinyl-dioxa-oxime--diazo snail).]] decane-3-yl}methyl)-N -[4_(Trifluoromethyl)benzyl]benzamide (Compound No. 181) was produced by substituting 4-(aminomethyl)benzonitrile hydrochloride using [4_(trifluoromethyl) φ The title compound (47 mg, yield 76%) was obtained as a colorless crystals of the title compound (yield: mp. - 1 .8 0(2H,m), 1.84- 1.96(2H ,m), 2.5 1 (4H,br s),3 .1 2(2H,s),3 ·5 5 (2H,br s), 4.46(2H,s),4·70 (2H,d,J = 5.7Hz), 6.50 (lH,t,J = 5.3Hz), 7.34(2H,d,J = 8.2Hz),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]: Hold time 3,96 minutes; m/z 605.9 [M + H]+ (ESI positive ion mode) -357- 201211053 [Chem. 3 3 6]

Reference Example 1 Production of 8 2 -1 (tetrahydrofuran-2-yl)methylaminocarboxylic acid tert-butyl ester Tetrahydroindenylamine (〇.86 g, 8.5 mmol) was dissolved in chloroform (9 mL), and dicarbonate was added. The third butyl group (2.04 g, 9.3 mmol) was mixed at room temperature for 1 hour. After that, the reaction mixture was evaporated to dryness crystals crystals 1H-NMR (300MHz, CDCl3) 5: 1.44 (9H, s), 1.51-1.67 (lH, m), 1.83-2.02 (3H, m) 53.06 (lH,ddd,J=13.5,5.7,5.7 Hz), 3.38 (lH, ddd, J = 13.5, 6.1 s3.7 Hz), 3.74 (lH, dt, J = 8.2, 6.5 Hz), 3.85 (lH, dt, J = 8.2, 6.5 Hz), 3.90-4.00 (lH, m), 4.88 (lH, br s) » LC/MS [Condition 1]: Hold time 3.38 minutes; m/zl01.78 [M-Boc] + (ESI positive ion mode) [Chem. 3 3 7]

Reference Example 1 Production of 8 2 - 2 methyl butyl [(tetrahydrofuran-2-yl)methyl]carbamic acid tert-butyl ester (tetrahydrofuran-2-yl)methylcarbamic acid obtained in Reference Example 182-1 358- 201211053 The third butyl ester (132mg, 0.66mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (2mL), and the third potassium pentoxide (81mg, 0.72mmol), methyl iodide (0.045) mL, 〇.72 mmol) was mixed at room temperature for 3 hours. Thereafter, third cesium oxide (81 mg, 0.72 mmol) and methyl iodide (0.045 mL, 0.72 mmol) were added, and the mixture was mixed at room temperature for 2 hours. Thereafter, water (5.0 mL) and ethyl acetate (5.0 m L) were added to the reaction mixture, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and then purified by silica gel column chromatography [Hybrid: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Purification was carried out to give the title compound (9Omg, yield: 64%) as pale yellow oil. 1H-NMR (3 00MHz, CDCl3) 5: 1.45 (9H, s), 1.48-1.70 (lH, m), 1.78-2.0 1 (3H, m), 2.93 (3H, s), 3.01-3.60 (2H, m), 3.74 (lH, q, J-7.4 Hz), 3.85 (lH, q, J = 7_2 Hz), 3.96-4.11 (lH, m). LC/MS [Condition 1]: Hold time 3.78 minutes; m/zll5.91 [M-Boc] + (ESI positive ion mode)

[化3 3 8]

H-CI Reference Example 182-3 Preparation of N-methyl-1-(tetrahydrofuran-2-yl)methylamine hydrochloride The methyl [(tetrahydrofuran-2-yl)methyl] obtained in Reference Example 182-2 Aminobutyric acid terpene vinegar (9 〇 mg, 0.66 mmol) was dissolved in methanol (1.0 mL), and 4 M hydrogen chloride-dioxane solution (2.0 mL) was added at room temperature for 12-359-201211053. mixing. After the reaction mixture was concentrated to give the title compound (m. 'H-NMR (300MHz, CDC13) 5: 1.55- 1.69 (1 H, m), 2.2 1-1. 8 1 (3Η, m), 2.80 (3H, t, J = 5.3 Hz), 2.84-2.98 ( 1 H,m) , 3.07-3.20 ( lH,m), 3.80 (lH,dt,J = 7.8,7.0 Hz), 3.96 (lH,dt,J = 8.2,7.0 Hz), 4.36-4.47 ( 1 H, m), 9.29 ( lH, brs), 9.53 ( lH, brs).

Example 182 (11*,4〇-1^-methyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl)-1-oxo-3,8-weight Preparation of alkalo[4.5]decane-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 182) Substituted tetrahydrofurfurylamine, used The title compound (6 8 mg, yield) was obtained from m. 8 5 %) of a colorless oil. h-NMROOOMHz 'CDChWO.95-1.14 (2H, m), 1.42-2.03 (1 5H, m), 2.47 (lH, tt, J = 11.9, 3.1 Hz) , 2.49-2.65 (4H, m), 2.97 (1.05H, s), 3.05-3.17 (4.6H, 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, -360-201211053 m), 4.09-3.95 (lH, m), 7.43 (2H, d , J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz) LC/MS [condition i]: hold time 3.06 min; m/z 551.9 [M + H]+ (ESI positive ion mode), m/z596.〇[M + HCO〇r (ESI negative ion mode) [Chem. 3 4 0] Ο

Example 1 8 3 1-Methyl-3-[4-({2·Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ Manufacture of 4 _5]decal-3-yl}methyl)phenyl]-1-[(tetrahydrofuran-2-yl)methyl]urea (Compound No. 183)

In place of N-(t-butoxycarbonyl)-1,3-diaminopropane, N-methyl-1-(tetrahydrofuran-2-yl)methylamine hydrochloride obtained in Reference Example 182-3 was used. The title compound (24 mg, yield 39%) was obtained as white solid. W-NMRGOOMHz^DClOS: 1.62- 1.76 (3 H, m), 1.89 (2H, br d, J = 1 3.1), 1.94-2.09 (3H, m), 2.42-2.59 (4H, m), 3.02 (3H, s), 3.09 (2 H, s), 3.34 (lH, dd, J = 16.0, 6.5 Hz), 3.55 (2H, s), 3.58 (lH, dd, J = 16.0, 1.6 Hz), 3.90 (lH, dt, J = 8.2, 6.1 Hz), 3.98 (lH, dt, J = 8.2, 7.0 Hz), 4.08-4.18 (lH, m), 4.3 5 (2H, s), 7.15 (2H, d5J = 8.6 Hz), 7.3 1 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.54 (l -361 - 201211053 H, Br s). LC/MS [Condition 1]: Hold time 3.35 minutes; m/z 56 〇 9 [M + H] + (ESI positive ion mode), m/z 559.1 [MH; T (ESI negative ion mode) [Chem. 3 4 1 】

Example 1 8 4 3-{[(lr,4r)-4-(4-morpholinopiperidin-1-carbonyl)cyclohexyl]methyl b-[4-(trifluoromethyl)benzyl Production of 1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 184) Substituted tetrahydrofurfurylamine, substantially in addition to 4-morpholinopiperidine The title compound (23 mg, yield 53%) lH-NMR (300 MHzs CDCl3) 5: 1.04 (2H, q, J = l 2.3 Hz), 1.3 1-1.68 (5H, m), 1.7 1-2.00 (1 OH, m), 2.30-2.65 (1 1 H, m), 3.02 (1 H, t, J = 12.3 Hz), 3.10 (2H, d5J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.68-3.75 (4H, m), 3.93 (lH, d, J = 13.5 Hz), 4.63 (lH, 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]: Hold time 1.34 minutes; m/z 606.7 [M + H]+ (ESI positive ion mode), m/z 65 1.2 [M + HCOO]- (ESI negative ion mode) -362- 201211053 [Chemical 3 4 2] Example 1 8 5

3 - ( {(1 r,4 r) - 4 - [ (1,1 -dioxa-thiomorpholin-4-yl)carbonyl]cyclohexyl}methyl)-8-[4-(three gas Methyl)benzylidene] chew_3,8-diazospiro[4.5] brothel __ 2-ketone (Compound No. 185) was produced by substituting tetrahydrofurfurylamine using thiomorpholine 1, 1 - two The title compound (23 mg, yield 48%) was obtained as white solid.

F 1H-NMR (300 MHz, CDCl3) 5: 1.06 (2H, qd, J = 12.7, 2.5 Hz), 1.48-1.71 (3H, m) 51.72-1.87 (6H, m), 1.94 (2H, d, J =12.7 Hz), 2.46 (lH, 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), 3.5 7 (2H, s), 3.9 1- 4.18 (4H, br m), 7.44 (2H, d, J = 8.2 Hz), 7.5 7 (2H, d, J = 8.2 Hz). L C / M S [Condition 1]·Retention time 3_03 minutes; m/z 571.8[M + H]+ (ESI positive ion mode), m/z 616.1 [M + HCO〇r (ESI negative ion mode)

Reference Example 1 8 6 -1 -363- 201211053 Manufacture of 2-[(tetrahydrofuran-3-yl)methyl]isoindan-1,3-dione

(Tetrahydrofuran-3-yl)methanol (950 mg, 9.3 mmol), phthalimide (1.37 g, 9.3 mmol) and triphenylphosphine (2.7 g, 10 mmol) were dissolved in tetrahydrofuran (0.9 mL). Diisopropyl azodicarboxylate (2.0 mL, 1 O mmol) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The resulting residue was added to 2-propanol (24 mL). Further, 2-propanol (10 mL) was added to the obtained solid, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (l. 'H-NMR (30 0 MHz, CDC13) 5: 1.72 (lH, ddt, J = 13.9, 6.5, 6.5 Hz), 2.01 (lH, dtd, J = 12.7, 7.8, 5.3 Hz), 2.73 (lH, tt, J = 7.4, 7.4 Hz), 3.61 (lH, dd, J = 9.0, 5.7 Hz), 3.69 (lH, dd, J = 13.5, 7.0 Hz), 3.80-3.72 (2H, m), 3.83 (lH, dd) , J = 9.0, 7.2 Hz), 3.94 (lH, ddd, J = 8.2, 8.2, 5.7 Hz), 7.70-7.77 (2H, m), 7.8 3-7.90 (2H, m). [化3 4 4]

Reference Example 1 Production of 8 6 - 2 (tetrahydrofuran-3-yl)methylamine 2 -[(tetrahydrofuran-3-yl)methyl]isoindan-1,3- obtained in Reference Example 1 8 6 -1 The diketone (1.3 g, 5.8 mmol) was dissolved in ethanol (i3 mL), and hydrazine monohydrate (〇4 mL) was added, and the mixture was mixed at 85 ° C for 2 hours. Thereafter, the reaction mixture was concentrated to give the title compound (yield: </ RTI> </ RTI> <RTIgt; lH-NMR (300MHz, CDCh) 5: 1.58 (lH, ddt, J = 11.9, 7.3, 7.3 Hz), 2.04 (lH, dtd, J = 12.9, 7.9, 5.3 Hz), 2_29 (lH, ttt, J = 7.3, 7.3, 7.3 Hz), 2.72 (2H, d, J = 6.9 Hz), 3.5 1 (lH, dd, J = 8.6, 5.9 Hz), 3.74 (lH, dt, J = 8.3, 7.6 Hz), 3.84 (lH, dd, J = 8.3, 5.3 Hz), 3.8 7 (lH, dt, J = 8.6, 7.3 Hz)

Example 1 8 6

(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 Preparation of -yl}methyl)-N-[(tetrahydrofuran-3-yl)methyl]cyclohexanecarbamide (Compound No. 186) Substituted tetrahydrofurfurylamine, obtained using Reference Example 1 8 6-2 The title compound (44 mg, yield 75%) was obtained as a white solid. m.p. 2H, qd, J = 12.9, 3.0 Hz), 1.39-1.68 (4H, m), 1.7 1-1.85 (4H, m), 1.85-2.09 (6H, m), 2.39-2.6 1 (5 H, m) , 3.09 (2H, d, J = 7.3 Hz), 3.20-3.34 (4H, m), 3.52 (lH, dd, J = 8.9, 5.3z), 3.57 (2H, s), 3.73 (lH, dd, J =15.9, 8.3 Hz), 3.80 (lH, dd, J = 8.9, 7.3 Hz), 3.88 (lH, ddd, J = 8.3, 8.3, 5.3 Hz), 5.69 (lH, t, J = 5.6 -365- 201211053)

Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8_3 Hz). LC/MS [Condition 1]: Hold time 2.99 minutes; m/z 53 7.9 [M + H]+ (ESI positive ion mode), m/z 582.1 [M + HCOO]- (ESI negative ion mode) [Chem. 3 4 6]

Example 1 8 7 (1]:,4〇-:^-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-4-({2- side Oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (compound) The production of the number 187) was carried out in place of the tetrahydrofurfurylamine, and the same reaction as in Example 1 was carried out except that 2,2-dimethyl-1,3-dioxapentane-4-methylamine was used, and the title was obtained. Compound (28 mg, yield 69%) as a white solid. 1H-NMR (300 MHz, CDCl3) 6: 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 (4 H,m) ,2.06(1 H,tt,J=l 2.2,3.3Hz), 2.49-2.61 (4H , m), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.32 (lH, ddd, J = 13.9, 5.9, 5.9 Hz), 3.53 (lH, ddd, J = 14.2, 5.9 , 3.6 Hz), 3.57 (2H, s), 3.61 (lH, dd, J = 8.3, 6.3 Hz), 4.03 (1 H, dd, J = 8.4, 6.4 Hz), 4.26-4.1 8 (1 H, qd , J = 6.3, 3.3 Hz), 5.79 (1 H, t, J = 5.8 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz). -366- 201211053 LC/MS [Condition 1] · Hold time 3.19 minutes; m/Z 567.8 [M + H]+ (ESI positive ion mode), m/z 612.1 [M + HCO〇r (ESI negative ion mode) [Chem. 3 4 7] Ο

Example 1 8 8 N -Methyl-l-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, Preparation of 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidine-4-carboxamide (Compound No. 188) Substituted tetrahydrofurfurylamine using piperidine-4 The title compound (2 2 mg, yield: 7%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 8: 1.04 (2H, q5J = l 2.6Hz), 1.46-1.71 (5H, m), 1.72-1.99 (1 0H, m), 2.3 1 (lH, tt, J=11.2) , 3.6 Hz), 2.3 8-2.67 (6H, m), 2.82 (3H, d, J = 5.0 Hz), 3.04 (lH, t, J = 11.9 Hz), 3.10 (2H, d) J = 6.9 Hz) , 3.26 (2H, s), 3.57 (2H, s), 3.94 (lH, d, J = 12.9 Hz), 4.62 (lH, d, J = 12.2 Hz), 5.43-5.52 (lH, m), 7.44 ( 2H, d, J = 8.3 Hz), 7_57 (2H, d, J = 7.9 Hz). LC/MS [Condition 1]: Hold time 3_〇2 minutes; m/z5 78.9 [M + H]+ (ESI positive ion mode), m/z 623.1 [M + HCOO]_ (ESI negative ion mode) - 367- 201211053 【化3 4 8】 Ο

Example 189 l-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]丨_嚼_3 8_重重

Preparation of a nitrogen snail [4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidine·_4-carbonitrile (Compound No. 189), in place of tetrahydrofurfurylamine, using 4-cyanopyridinium, The title compound (27 mg, yield 71%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 6: 1.04 (2H, q, J = l 2.9 Hz), 1.45-1.68 (3H, m), 1.7 1- 2.00 (l2H, m), 2.42 (lH, tt, J = 11.7, 3.0 Hz), 2.48-2.65 (4H, m), 2.89 (lH, tt, J = 7.3, 4.6 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.3 8 -3.87 (4H, m), 3.5 7 (2H, s), 7.44 (2H, d, J = 8.3 Hz), 7.5 7 (2H, d, J = 7.9 Hz). LC/MS [Condition 1]: Hold time 3.19 minutes; m/z 546.8 [M + H]+ (ESI positive ion mode), m/z 59i.l [M + HCO〇r (ESI negative ion mode) 4 9]

8-369-201211053 Example 190 3-{[(lr,4r)-4-(4-oxopiperidin-1-carbonyl)cyclohexyl]methyl}-8-[4·(trifluoromethyl) Manufacture of benzylidene-1-one-3,8-diazospiro[4.5]decane-2-one (Compound No. 190) in place of tetrahydrofurfurylamine, using piperidin-4-one monohydrate The title compound (39 mg, yield 99%) was obtained as a white solid.

1H-NMR (300MHz, CDCl3) 6: 1.07 (2H, qd &gt; 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), 2.4 1-2.66 (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, JT = 7.9 Hz). LC/MS [Condition 1]: Hold time 3.05 min; m/z 53 5.87 [M + H]+ (ESI positive ion mode), m/z 580.1 [M + HCOO]- (ESI negative ion mode)

Example 1 9 1 3-{[(lr,4r)-4-(4-Benzylpiperidin-1-carbonyl)cyclohexyl]methyl b8_[4_(difluoromethyl)benzyl]- 1-Chewing · 3,8-diazospirulin [4.5] brothel-2-one (compound number 191) production Substituting tetrahydrofurfurylamine 'substantially and in addition to 4-benzyl thiophene Example 1 The same reaction of hydrazine gave the title compound (3 5 mg, yield - 369 - 201211053 78%) as a white solid. IH-NMR (300MHz, CDCl3) 5: 0.92- 1.23 (4H, m), 1.43-1.86 (12H, m), 1.94 (2H, d, J = 13.1Hz), 2.37-2.65 (8H, m), 2.93 (lH, t, J = 12.3 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.85 (lH, d, J = 12.3 Hz) 54.60 ( lH, 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]: Hold time 3.83 minutes; m/z 612_0 [M + H]+ (ESI positive ion mode), m/z 656.2 [M + HCOO]- (ESI negative ion mode) [Chemical 3 5 1 】

Example 192 (11&quot;,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Manufacture of alk-3-yl}methyl)-N-(tetrahydro-2H-pyran-4-yl)cyclohexanemethylthioguanamine (Compound No. 192) (lr, 4r) obtained in Example 80 -4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-11-oxa-3,8-diazospiro[4.5]癸院-3-yl}methyl -N-(tetrahydro-2^1-pyran-4-yl)cyclohexanecarbamamine (161112, 〇.〇3〇111111〇1) was dissolved in toluene (2.0 mL), and Lawson's reagent was added ( 25 mg, 0.061 mmol), and the mixture was stirred at 80 ° C for 3 hours. After cooling, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate (3.0 mL) were added and the organic layer was separated. After the layer was extracted with ethyl acetate (5. 〇mL), the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography. The title compound (9.3 mg, yield 55%) of white solid was obtained from the title compound (9.3 mg, yield: 55%).

1H-NMR (300MHz, CDCl3) 5:1.06 (2H,q,J=l 1.9Hz), 1.54 (2H, qd, J = 1 2.3,4·5Ηζ), 1.62-2.00 (1 1 H,m), 2.08(2H,d,J = 10.6Hz), 2.3 6(lH,tt,J=11.9,4.1Hz), 2.45-2.66(4H,m),3.10(2H,d,J = 7.4Hz), 3.25( 2H, s), 3.5 1 (2H, ddd, J = l 1.5, 1 1.5, 2.0 Hz), 3.57 (2 H, s), 3.92-4.04 (2H, m), 4.65 (lH, dtt, J = 15.1) , 7.4, 4.1 Hz), 7.2 1-7.28 (lH, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.39 minutes; m/z 55 3.8 [M + H]+ (ESI positive ion mode), m/z 588.1 [M + HCO〇r (ESI negative ion mode) [Chem. 3 5 2】

Ο

Example 1 9 3 3-({(lr,4r)-4-[4-(6-fluorobenzo[d]iso Doxan-3-yl)indole D-1,4-indenyl]cyclohexyl} Production of methyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 193) Indoleamine, using 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (purchased from Wako Pure Chemical Industries, Ltd.), substantially in the same manner as in Example 10 -371 - 201211053 The same reaction gave the title compound (26 mg, yield 70%) (3H,m), 1.72-2.03 (1 OH,m), 2.07-2.25 (2H,m), 2.50 (lH,tt,J = 11.9,3.3 Hz), 2.50-2.64 (4H,m),2.88 ( lH, t, J = 12.7 Hz), 3.11 (2 H, d, J = 7.4 Hz), 3.20-3_41 (lH, m), 3.27 (2H, s), 3.33 (lH, tt, J = 1 1.1, 3 ·7Ηζ), 3.58(2H, s), 4.05(1 H,d,J = l 3.5Hz), 4.67( lH,d,J = 13.1Hz),7.08(lH,td,J = 8.8,2.0Hz ), 7.26 (lH, dd, J = 8.2, 2.0 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.62 (lH, dd, J = 8.6, 4.9Hz) » LC/MS [Condition 1]: Hold time 3.8 1 minute; m/z65 7.0[M + H]+ (ESI positive ion mode), m/z701.2[M + HCOO] — (ESI negative ion mode ) 【化3 5 3】

Example 194 (11*,4〇-1^-[1-(isoxazol-5-yl)ethyl]-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene) Production of methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 194) Substituted tetrahydrofurfurylamine, using 1 - (isoxazole-5-yl)ethylamine (synthesis was carried out by the method described in PCT/JP2008/07062 1), and the same reaction as in Example 1 was carried out in substantially -372-201211053 to obtain the title compound (7.1). Mg, yield 34%) of light yellow oil.

1H-NMR (300MHz, CDCl3) 6: 1.02 (2H, q, J = l 2.3Hz), 1.40-1.64 (3H, m), 1.54 (3H, d, J = 7.0Hz), 1.7 1-1.99 (8H , m), 2.05 (lH, tt, J = 12.3, 3.3 Hz), 2.50-2.63 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2 H, s), 3.58 (2H) , s), 5.36 (lH, qd, J = 7.4, 7.4 Hz), 5.84 (lH, d, J = 8.2 Hz), 6.11 (lH, d, J = 1.6 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.17 (lH, d, J = 1.6 Hz). LC/MS [Condition 1]: Hold time 3.33 minutes; m/z 54 8.8 [M + H]+ (ESI positive ion mode), m/z 593.1 [M + HCOO]_ (ESI negative ion mode) [Chemical 3 5 4]

φ Reference Example 1 9 5 3-Isopropyl 5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride was produced using Journal of Medicinal Chemistry (2008, 51, 5172-5) 175) The method described is carried out for synthesis. [化3 5 5] Ο

-373- 201211053 Example 1 9 5 3-({(lr,4〇-4-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1- Carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (compound number 195) The production of the substituted tetrahydrofurfurylamine was carried out substantially using the 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride obtained in Reference Example 195. The title compound (3 9 mg, yield 73%) was obtained as a white solid. </RTI> <RTIgt; </RTI> NMR (300 MHz, CDCl3) 5: 1.05 (2H,q,J=l 1.9 Hz), 1.33 (6H) , d, J = 6.9Hz), 1.46- 1.70(3H,m), 1.71-2.00(10H,m), 2.03-2.2 1(2H, m), 2.46(lH,tt,J=11.9,3.0Hz) , 2.49-2.62 (4H, m), 2.88 (lH, t, J = 11.9 Hz), 3.01-3.28 (5H, m), 3.26 (2H, s), 3.57 (2H, s), 3.94 (lH, d , J = 13.2 Hz), 4.52 (lH, 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] : Hold time 3.64 minutes; m/z 63 1 ·9[Μ + Η]+ (ESI positive ion mode), m/z 676.2 [M + HCOO]- (ESI negative ion mode) [Chem. 3 5 6]

Example 196 -374-201211053 3-{[(lr,4r)-4-(4-methoxypiperidine-indole-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzene Production of methyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 196) Substituting tetrahydrofurfurylamine, using 4-methoxypiperidine, substantially The title compound (34 mg, yield: 87%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 5: 1.04 (2H, q, J = 12.3Hz), 1.43-2.00 • (15H, m), 2.45 (lH, tt, J=ll.5, 2.9Hz), 2.5 1 - 2.63(4H,m), 3.10(2 H,d,J = 7.4Hz), 3.18-3.3 3(4H,m), 3.36(3H,s),3.43(lH,tt,J = 7.4,3.7Hz ), 3.57 (2H, s), 3.62-3.74 (lH, m), 3.84-3.99 (lH, m), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) . LC/MS [Condition 1]: Hold time 3.23 minutes; m/z 551.8 [M + H]+. (ESI positive ion mode), m/z 596.0 [M + HCOO]- (ESI negative ion mode) 3 5 7] 〇

Example 1 9 7 3-{[(11',4〇-4-(4-methoxypiperidine-1-carbonyl)cyclohexyl]methyl}_8_[4-(trifluoromethyl)benzyl] Manufacture of 1-{[(lr,4r)-4 obtained in Example 196, -1-oxa-3,8-diazospiro[4.5]decane-2-one hydrochloride (Compound No. 197) -(4-methoxypiperidine-1-37-201211053 carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8· Nitrospiro[4.5] oxacin-2-one (2.3 mg, 0.0042 mmol) was dissolved in methanol (1.0 mL), and a 1% by weight hydrogen chloride-methanol solution was added and mixed at room temperature for 1 hour. Thereafter, The reaction mixture was concentrated under reduced pressure to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssss ), 2.05 (2H, d, J = 13.5 Hz), 2.44 (lH, t, J = 11.9 Hz), 2.75 (2 H, t, J = 12.7 Hz), 3.01-3.50 (14H, m), 3.55- 3.97 (2H, m), 4.18 (2 H, s), 7.73 (2H, d, J = 7.8 Hz), 7.8 5 (2H, d, J = 7.8 Hz), 13.18 (lH, br LC/MS [conditions 1]: Hold time 3.36 minutes; m/z 551.9 [M + H]+ (ESI positive ion mode), m/z 586.2 [M + Cir (ESI negative ion mode) [Chem. 3 5 8]

Reference Example 1 9 8 -1 4-methyl-3-(3-trifluoromethyl)benzoic acid methyl ester production 4-methyl-3-(trifluoromethyl)benzoic acid (purchased) (i. 3 g 6.2 mmol) was dissolved in methanol (6.0 mL), concentrated sulfuric acid (〇. 5 mL) was added, and mixed at 60 ° C for 10 hours. After the reaction mixture was cooled to room temperature, water (15 mL) and ethyl acetate (15 m. The obtained organic-376-201211053 layer was washed once with a saturated aqueous solution of sodium hydrogencarbonate, brine, and water, and then evaporated. , the yield is quantitative) of a colorless liquid. 1H-NMR (300MHz, CDCl3) 5: 2.56-2.53 (3H, m), 3.94 (3H, s), 7.37 (lH, d, J = 7.8 Hz), 8.09 (lH, d, J = 7.8 Hz), 8.28 (lH, s).

[化3 5 9] F

Reference Example 1 9 8 - 2 3-[4-(Methoxycarbonyl)-2-(trifluoromethyl)benzyl]-2-oxo-1-oxo-3,8-diazo snail [4.5] Manufacture of decane-8-carboxylic acid tert-butyl ester

4-methyl-3-(trifluoromethyl)benzoic acid obtained in Reference Example 198-1

The methyl ester (1 10 mg, 0.50 mm 〇l) was dissolved in chloroform (2.0 mL), and after heating to 80 ° C, N-bromosuccinimide (179 mg, 1.0 mmol) and azobisisobutyronitrile were added. 17 mg, 0.1 mmol) was mixed 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 evaporated. The organic layer was dried over anhydrous magnesium sulfate and evaporated.

The obtained residue was purified by silica gel column chromatography [塡 剂 : M M M M M M M 60 60 60 60 60 60 60 60 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 A pale yellow oil (156 mg) was obtained. -377- 201211053 Reference to Example 1-1, 2-sided oxy-1-oxo-3,8-diazospiro[4·5] 癸院-8-residual acid third butyl vinegar (130 mg, 0.50 mmol) Dissolve in hydrazine, hydrazine-dimethylformamide (2.0 mL), and force in the third sodium sulphate (53 mg, 0.55 mmol). After stirring for 30 minutes, add the previously obtained pale yellow oil (156 mg). A solution of N,N-dimethylformamide (2.0 mL) was mixed for 3 hours. Thereafter, water (10 mL) and ethyl acetate (10 mL) were added, and then organic layer was separated. The obtained organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography [purifying agent: silica gel 60 (0.040-0.063 mm) manufactured by Merck, and solvent: hexane/ethyl acetate = 3/1] to give the title compound. (120 mg, yield 49%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) 5: 1.45 (9H5s), 1.52-1.70 (2H, m), 1.8 1-1.93 (2H, m), 3.16 (2H, s) 53.22-3.3 5 (2H, m) , 3.75-3.8 9 (2H, m), 3.96 (3H, s), 4.69 (2H, s), 7.61 (lH, d, J = 8.2 Hz), 8.23 (lH, d, J = 8.2 Hz), 8.35 (lH, s). LC/MS [Condition 1]: Hold time 3.36 min; m/z 494.8 [M + Na]+ (ESI positive ion mode)

[化3 6 0] F

-378- 201211053 Reference Example 1 9 8 - 3 4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]-3-(trifluoro Manufacture of methyl benzoic acid methyl ester hydrochloride

3-[4-(Methoxycarbonyl)-2-(trifluoromethyl)benzyl]-2· sideoxy-1-oxo-3,8-diazospin obtained in Reference Example 198-2. 4.5] decane-8-carboxylic acid tert-butyl ester (120 mg, 0.025 mmol) was dissolved in 1,4-dioxane (2·0 ml), methanol (0.50 mL), and 4 M hydrogen chloride-dioxane solution was added ( l.OmL), stirring at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was evaporated. LC/MS [Condition 1]: Hold time 2.33 minutes; m/z3 73.0 [M + H]+ (ESI positive ion mode)

[化3 6 1] F

Reference Example 198-4 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl Manufacture of methyl methyl]-3-(trifluoromethyl)benzoate The 4-[(2-oxo-oxo-3,8-diazoxil][4.5] obtained in Reference Example 198-3 Cycloalkyl-3-yl)methyl]-3-(trifluoromethyl)benzoic acid methyl ester hydrochloride-379-201211053 (100 mg, 〇_24 mmol) suspended in N,N-dimethylformamide 2.0 mL), triethylamine (0.1 mL, 0.73 mmol) and 4-(trifluoromethyl)benzyl bromide (64 mg, 〇.27 mmol) were added and mixed at room temperature for 7 hours. Thereafter, water (10 ml) and ethyl acetate (i 〇 mL) were added to the reaction mixture, and 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 [塡 剂 : 胺 FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU / / / / / / / Compound (10 mg, yield 85%) as a colorless oil. 'H-NMRiSOOMHz^DChia:!.67-1.85(2H,m),l.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), 7.69-7.3 9 (5H, m), 8.2 1 (lH, d, J = 7.8 Hz), 8.3 5 (lH, s) 0 LC/MS [Condition 1]: Hold time 3.56 minutes; m/z 530.9 [M + H]+ (ESI positive ion mode)

[化3 6 2] F

Reference Example 198-5 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-indole-oxo-3,8-diazospiro[4.5] -380- 201211053 decane Manufacture of -3-yl}methyl)-3 _(trifluoromethyl)benzoic acid 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzene) obtained in Reference Example 198-4 Methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)-3-(trifluoromethyl)methyl benzoate (71 mg, 〇.13 mmol) was suspended in Methanol (2.0 mL) 'When heated and dissolved at 50 ° C, 1 Μ aqueous sodium hydroxide solution (〇. 6 8 m L, 0.68 mmol) was added and mixed at 50 ° C for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then methanol was distilled off under reduced pressure. Remnant of income

Water was added to the separated material to dilute hydrochloric acid (0.68 mL, 0.68 mmol). The precipitated white solid was filtered. 1H-NMR (300MHz, CDCl3) 5: 1.60-2.08 (4H, m), 2.67-2.8 1 (2H, m), 2.94-3.07 (4H, m), 3.8 8 (2H, s), 4.67 (2H, s), 7.48-7.55 (3H, m), 7.62 (2H, d, J = 8.2 Hz), 8.2 1 (lH, d, J = 8.2 Hz), 8.37 (lH, s). LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 516.9 [M + H]+ (ESI positive ion mode), m/z 515.1 [M-H]_ (ESI negative ion mode)

Example 1 9 8 4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazosole-381 - 201211053 [4 Preparation of 5]nonane-3-yl}methyl)-3-(trifluoromethyl)benzamide>piperidine-1-carboxylic acid methyl ester (Compound No. 198) will be obtained in Reference Example 198-5. 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) -3-(trifluoromethyl)benzoic acid (25 mg, 0.048 mmol), 4-amino-based scorch-l-residual acid methyl hydrochloride (llmg, 0.073 mmol) obtained in Reference Example 135, triethylamine

(9.9 μί, 0.073 mmol) and 1-pyridylbenzotriazine (6_4 mg, 0.048 mmol) were dissolved in chloroform (1.0 mL), then 1-ethyl-3-(3-dimethylaminopropyl) was added. Carbodiimide hydrochloride (14 mg, 0.073 mmol) was mixed at room temperature for 60 hours. After that, water (2.0 mL) was added to the reaction mixture, and the organic layer was evaporated. The obtained residue was purified by a silica gel column chromatography [purification agent: NH-DM 1 020 'developing solvent: hexane/ethyl acetate = 1/1 by FUJI SILYSIA Co., Ltd.' to obtain the title compound (2) 5 mg, yield 80%) of a pale yellow solid. 1H-NMR (300MHz, CDCl3) 5: 1.37- 1.52 (2H, m), 1.68-1.8 1 (2H, m), 1.87- 1.98 (2H, m), 2.00-2.11 (2H, m) s2.48- 2.59(4H,m), 2.97(2H5t,J=12.6Hz), 3.15(2H,s),3.56(2H,s),3.7 1(3H,s), 4.07-4.25(3H,m),4.67( 2H, s), 6.09 (lH, d, J = 7.6 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.54-7.62 (3H, m), 7.91 (lH, d, J = 8.3 Hz), 8.08 (lH, s). LC/MS [Condition 1]: Hold time 3.41 minutes; m/z657_l[M + H]+ (ESI positive ion mode), m/z 655.3 [M-Hr (ESI negative ion mode) 8 -382- 201211053 3 6 4]

Example 1 9 9

3-[4-(4-Benzylmercaptopiperidin-1-carbonyl)-2-(trifluoromethyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1 -Production of oxa-3,8-diazospiro[4.5]nonan-2-one (Compound No. 1 99) Substituting 4-aminopiperidine-1-carboxylic acid methyl hydrochloride, using 4-benzyl The title compound (9.0 mg, yield 84%) was obtained as a colorless oil. lH-NMR (300MHz, CDCl3) 6 : 1.63 - 2.13 (8H, m), 2.42 - 2.64 (4H, m), 3.03-3 · 26 (2Η, m), 3. 17(2H, s), 3.43- 3.88(4H,m), 4.52-4.72 (lH,m),4.65(2H,s),7.3 8-7.53(4H,m),7.53-7.64(5H,m),7.74 (lH,s),7.98 -7'91 (2H, m). LC/MS [Condition 1]: Hold time 3.71 min; m/z 68 8.0 [M + H]+ (ESI positive ion mode), m/z 732.3 [M + HCOO]- (ESI negative ion mode)

〇 【化3 6 5】

F -383- 201211053 Example 2 0 0 Ν-(Benzo[d][l,3]dioxazole-5-ylmethyl)-4-({2- Side Oxygen-8-[4-(III Fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4_5]decane-3-yl}methyl)-3-(trifluoromethyl)benzamide (Compound No. 200 Manufacturing

Substituting 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine, the title compound (9.5 mg, yield 93%) a colorless oil. 1H-NMR (300MHz, CDCl3) 5: 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 (lH, 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 (lH, d, J = 8.2 Ηζ), 8·1 l (lH, s). LC/MS [conditional hold time 3.61 min; m/z 650.0 [M + H] + (ESI positive ion mode), m/z 648.2 [M-H]- (ESI negative ion mode)

[化3 6 6]

Example 201 4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-indolyl-3,8-diazospiro[4 5]decane-3-yl} Methyl)-N-[(tetrahydrofuran-2-yl)methyl]·3·(trifluoromethyl) 8 •384- 201211053 Manufacture of benzamide (Compound No. 201)

Substituting 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine, the same reaction as in Example 1 98 was carried out to give the title compound (2.6 mg). A colorless oil of 28%). 'H-NMROOOMHz/DChW: 1.5 1-1.8 l(3H,m), 1.87-2.13(5H, m), 2.46-2.64(4H,m), 3.14(2H,s),3.3 1(lH, Ddd, J=13.9, 7.9, 4.6 Hz), 3.56 (2H, s), 3.74-3.97 (3H, m), 4.07 (lH, qd5J = 7.3, 3.0 Hz), 4.67 (2H, s), 6.55 (lH) , t, J = 5.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.54 - 7.62 (3H, m), 7.93 (lH, dd, J = 7.9, 2.0 Hz), 8.11 (lH, d, J = 2.0Hz). LC/MS [Condition 1]: Hold time 3.37 minutes; m/z 600.0 [M + H]+ (ESI positive ion mode), m/z 598.2 [M-Hr (ESI negative ion mode) [Chem. 3 6 7 】

Example 202 4-[3-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Preparation of methyl}methyl)benzamide) piperidine-1-carboxylate (Compound No. 202) 3-({2- Side Oxygen-8_[4-() obtained in Reference Example 1〇8-3 Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (28 mg, 〇.〇 62 mmol), Reference Example 1 3 5 obtained 4-amino-based D-l-residual acid methyl hydrochloride (15 mg, 〇.〇75 mmol), triethylamine (13pL, 0.094-385-201211053 mmol) and 1-p-benzotriene After dissolving hydrazine (8.4 mg, 0.062 mmol) in chloroform (1.0 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18 mg, 0.094 mmol) was added. Mix for 36 hours at room temperature. After the completion of the reaction, water (3.0 mL) was added, and the organic layer was separated, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography [purification: NH-DM1020, manufactured by FUJI SILYSIA, developed solvent: hexane / ethyl acetate = 1 / 1] to give the title compound (3 1 mg , yield 83%) of a white solid. 'H-NMR (300MHz, CDC13) 5: 1.36 - 1.53 (2H, m), 1.67-1.8 1 (2H, m), 1.86- 1.99 (2H, m), 1.99-2.12 (2H, m), 2.47- 2.61(4H,m), 2.9 7(2H,t,J=11.9Hz), 3.14(2H,s),3.5 5(2H,s),3.71(3H,s),4.08-4.24(3H,m) , 4.46 (2H, s), 6.03 (lH, 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]: Hold time 3.01 min; m/z 589.1 [M + H]+ (ESI positive ion mode), m/z 623.2 [M + Cl]- (ESI negative ion mode) 6 8]

F Example 203 3-[3-(4-Benzyl phenylpiperidine-l-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 -Triazospiro[4.5]decane-2-one (Compound No. 203) -386- 201211053 Manufacture of substituted 4-aminopiperidine-1-carboxylic acid methyl hydrochloride using 4-benzylidenepiperidine The title compound (4.8 mg, yield 17%) was obtained as a colorless oil. 1H-NMR (300MHz, CDCl3) 6: 1.67-2.05 (8H, m), 2.42-2.65 (4H, m), 3.00-3.29 (4H, m), 3.49-3.62 (3H, m), 3.75-4.0 1 (1 H,br m),

4.44 (2H, s), 4.58-4.77 (1 H, br m), 7.28-7.63 (1 1 H, m), 7.88-8.01 (2H, m). LC/MS [Condition 1]: Hold time 3.51 min; m/z 620.2 [M + H]+ (ESI positive ion mode), m/z 654.4 [M + Cir (ESI negative ion mode)

Example 204 Heart (Benzo[(1][1,3]dioxazole-5-ylmethyl)-3-({2- sideoxy-8-[4-(trifluoromethyl)benzyl) Manufacture of 4-oxo-3, 8-diazospiro[4-5]nonan-3-yl}methyl)benzamide (Compound No. 204) Substituted 4-Aminopiperidine-1 -carboxylic acid A The title compound (17 mg, yield: 65%) as a white solid was obtained from the title compound (m.p. 6:1.66- 1.78(2H,m),1.85- 1.95(2H, -387- 201211053 m), 2.45-2.5 8(4H,m), 3.14(2H,s),3.5 5(2H,s), 4.46(2H, s), 4.54 ( 2H, d, J = 5.7 Hz), 5.94 (2H, s), 6.40 (lH, 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 [Cond. 1]: Hold time 3.37 min; m/z 582. 〇 [M + H] + (ESI positive ion mode), m/z 616.3 [M + Cir (ESI negative ion mode)

Reference Example 2 0 5 -1 3-[3-Methoxy-4-(methoxycarbonyl)benzyl]-2-oxo-1-oxa-3,8-diazospiro [4·5] Preparation of tert-butyl-8-carboxylic acid tert-butyl ester Methyl 2-methoxy-4-methylbenzoate (purchased) (120 mg, 0.64 mmol) was dissolved in chloroform (2.0 mL) and heated to 80 ° After C, N-bromosuccinimide (172 mg, 〇.96 mmol) and azobisisobutyronitrile (21 mg, 0.13 mmol) were added, and the mixture was mixed at 80 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, aqueous saturated sodium hydrogen sulfate (5. The obtained organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was subjected to a silica gel column chromatography [塡 剂 :: M GMBH 6 6 6 6 6 6 6 6 6 6 6 6 6 / / / / / / / / / / / / / / / / / / Purification to obtain a colorless oil-388-201211053 (1 99 mg) 2- 2-sided oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid obtained in Reference Example 111-1 Tributyl ester (164 mg, 0.64 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (2.0 mL), and sodium tributoxide (68 mg, 〇. 70 mmol) was added thereto, and after stirring for 30 minutes, the previously obtained was added. A light yellow oil (199 mg) of hydrazine, hexane-dimethylformamide (2.0 mL) Thereafter, water and ethyl acetate were added, the organic layer was separated, and the organic layer was washed twice with saturated φ brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (purifying agent: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane The title compound (120 mg, 45%) was obtained as a pale yellow oil. 1H-NMR (300MHz, CDCl3) 5: 1.45 (9H, s), 1.54-1.68 (2H, m), 1.79-1.90 (2H, m), 3.13 (2H, s), 3.22-3.3 6 (2H, m ), 3.70-3.8 6(2H,m), 3.8 9(3H,s),3.90(3H,s),4.44(2H,s),6.81-6.92(2H,m),7.7 7(lH,d , J = 7.8Hz). LC/MS [Condition 1]: Hold time 4.03 min; m/z 457.0 [M + Na]+ (ESI positive ion mode) [Chem. 3 7 1]

389- 201211053 Reference Example 205-2 2-Methoxy-4-[(2-oxo-1-cax-3,8-diazospiro[4.5] 癸-3-yl)methyl]benzoate A Production of the ester hydrochloride salt 3-[3-methoxy-4-(methoxycarbonyl)benzyl]-2-sideoxy-1-oxo-3,8-weight obtained in Reference Example 205-1 N-butyl sulphate [4.5] decane-8-carboxylic acid (120 mg, 0.029 mmol) was dissolved in methanol (i. 〇mL), and 4 M hydrogen chloride-dioxane solution (2.0 m L) was added. Stir for 1 hour. After that, the residue was concentrated to dryness crystals crystals crystals crystals crystals IH-NMR (300MHz, CD3OD) 5: 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 (lH, dd, J = 8.2, 1.4 Hz), 7.04-7.06 (1 H, m), 7.72-7.78 (lH, m). LC/MS [Condition U: holding time 0.58 min; m/z3 3 5.1 [M + H]+ (E S I positive ion mode) [Chem. 3 7 2]

Reference Example 2 Ο 5 - 3 2-Methoxy-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazospiro[ 4.5] Production of decane-3_yl}methyl)benzoic acid methyl ester The 2-methoxy-4-[(2-sideoxy-1-oxo--390-201211053 3) obtained in Reference Example 205-2 , 8-diazospiro[4.5]decane-3-yl)methyl]benzoic acid methyl ester hydrochloride (110 mg, 〇.29 mmol) was suspended in N,N-dimethylformamide (2.0 mL). Triethylamine (0.12 mL, 0.85 mmol) and 4-(trifluoromethyl)benzyl bromide (82 mg, 〇.34 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. After adding water and ethyl acetate, the organic layer was separated and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [塡 剂 : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU , , , , , , , , , , , , , , , , , , , , , , , , The title compound (8 8 mg, yield 63%) 1H-NMR (300MHz, CDCl3) 5: 1.65- 1.79 (2H, m), 1.85-1.96 (2H, m), 2.46-2.60 (4H, m), 3.13 (2H, s), 3.5 5 (2H, s ), 3.8 9 (6H, s), 4.43 (2 H, 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 (lH, d, J = 7.6 Hz). LC/MS [Condition 1]: Hold time 3 〇 2 minutes; m/z 492_9 [M + H]+ ( φ ESI positive ion mode) [Chem. 3 7 3]

Reference Example 2 0 5 - 4 2-Methoxy-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-weight-391 - 201211053 Preparation of azaspiro[4.5]decane-3-yl}methyl)benzoic acid The 2-methoxy-4-(4-(2-oxo-8-[4-()) of Reference Example 205-3) Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) benzoic acid methyl ester (88 mg, 0.18 mmol) was suspended in methanol (2. OmL) After heating to 50 ° C and dissolving, 1 M aqueous sodium hydroxide solution (〇.36 mL, 0.36 mm ο 1 ) was added, and the mixture was mixed at 50 ° C for 2 hours. Thereafter, the reaction mixture is cooled

However, to room temperature, 1 M hydrochloric acid (〇.36 mL, 0.36 mmol) was added dropwise. After adding ethyl acetate (5.0 mL) and water (5 mL),EtOAc. 1H-NMR (300MHz, CDCl3) 5: 1.68-1.82 (2H, m), 1.85- 1.98 (2HJ 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 (lH) , d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 2.42 minutes; m/z 479.1 [M + H]+ (ESI positive ion mode), m/z 477.1 [M-H]- (ESI negative ion mode)

[化3 7 4]

Example 205 3-[4-[4-Benzylmercaptopiperidin-1-yl)-3-methoxybenzyl]_8-[4-(trifluoromethyl)benzyl]-1 -Production of cacao-3,8-diazospiro[4.5]decane-2-one (Compound No. 8-392-201211053, code 205) 2-methoxy-4-({) obtained in Reference Example 205-4 2-sided oxygen-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid (8.3 mg , 0.017 mmol), 4-benzylidene piperidine hydrochloride (4.7 11^, 0.021111111〇1), triethylamine (3.641^, 0.026111111〇1) and 1-hydroxybenzotriazole (2.3 mg, 0.027) After dissolved in chloroform (1.0 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.1 mg, 〇. 〇 17 mmol) was added. Stirring was carried out for 3 days at room temperature. After that, water (2.0 mL) was added to the mixture, and the organic layer was evaporated. The obtained residue was purified by fractional chromatography (Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate 100%) to give the title compound (8.4 mg, yield: 75 %) Light yellow solid. 1H-NMR (300 MHz, CDCl3) 5: 1.69-2.08 (8H, m), 2.47-2.62 (4H, m), 2.99-3.25 (4H, m), 3.45-3.65 (4H, m), 3.8 1- 3.87(3H,m), 4.28 φ -4.56(2H,m), 4.70-4.80(lH,m),6.79-6.9 1(2H,m),7.19-7.26 (lH,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]: Hold time 3.31 minutes; m/z 65 0.2 [M + H]+ (ESI positive ion mode), m/z684 3 [M + C1]-(ESI negative ion mode) -393- 201211053 3 7 5]

HaC 丫 Ο

FF Example 206 4-[2-methoxy-4-({2-sideoxy- 8-[4-(trifluoromethyl)benzyl]] oxime- 3,8-diazo snail [4 ·5] decyl-3-yl}methyl)benzamide = piperidine-residic acid methyl ester (Compound No. 206) was produced by substituting 4-benzylidene hydrazide D hydrochloride, using reference examples The title compound (8·7 mg, yield 81%) was obtained by substantially the same reaction as in Example 20.5 except for the 4-aminopyridin-1-resin acid methyl hydrochloride obtained from 丨3 5 Light yellow oil" 1H-NMR (300 MHz, CDCl3) 6: 1.3 7-1.6l (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),3.7 1(3H,s),3.94(3H , s), 3.96-4.25 (3 H, m), 4.43 (2H, s), 6.90 (lH, s), 6.95 (lH, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz) ), 7.56 (2H, d, J = 8.2 Hz), 7.75 (lH, d, J = 7.8 Hz), 8.17 (lH, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 3.07 min; m/z 619.2 [M + H]+ (ESI positive ion mode), m/z 653.4 [M + Cir (ESI negative ion mode) 201211053 [Chem. 6]

F Example 2 0 7

2-methoxy-4-({-o-oxo-8-[4-(trifluoromethyl)benzyl]- oxa-3,8-diazospiro[4.5]decane-3-yl} Preparation of methyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 207) Substituting 4-benzylidene piperidine hydrochloride with triethylamine, using tetrahydroindenyl The title compound (6.5 mg, yield 67%) was obtained as a pale yellow oil. 1H-NMR (300MHz, CDCl3) 5: 1.80-1.60 (3H, m), 2.08-1.85 (5H, m), 2.45-2.66 (4H, m), 3.13 (2H, s), 3.45 (lH, ddd, J = 13.9, 6.8, 5.5 Hz), 3.55 (2H, s), 3.74 (lH, ddd, J = 13.5, 5.7, 3.3 Hz), 3.79 (lH, dt, J = 8.2, 6.5 Hz), 3.90 (lH) , dt, J = 8.2, 6.5 Hz), 3.95 (3H, s), 4.08 (lH, 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 (lH, t, J = 5.7 Hz), 8.17 (lH, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 2.99 minutes; m/z 562.0 [M + H]+ (ESI positive ion mode), m/z 596_l [M + Cl]- (ESI negative ion mode) -395- 201211053 3 7 7]

Example 2 0 8 N-(Benzo[d][l,3]dioxazole-5-ylmethyl)-2-methoxy- 4-({2-Sideoxy-8-4-(4- Manufacture of trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 208) The title compound (9.1 mg, yield 86%) was obtained as a pale yellow oil from m. 1H-NMR (300MHz, CDCl3) 6: 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 (2Η, 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 = 8.2 Hz), 8.05 (lH, t, J = 6.1 Hz), 8.21 (lH, 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) 7 8] Ο

396-201211053 Example 209 4-(4-Fluorobenzylidene)-1[3_({2-Sideoxy-8_[4-(trifluoromethyl)benzyl]] 1-oxo-3,8- Manufacture of Diazospiro[4.5]decane-3-yl}methyl)phenyl]piperidine-1-carboxamide (Compound No. 209)

3-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane obtained in Reference Example 108-3 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 (〇〇i4niL, 0.13 mmol) were added. ), stirring and mixing for 4 days at room temperature. 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, This oil (37 mg) was dissolved in toluene (3. 〇mL) at 1 1 0. (: Mixing was carried out for 2 hours. Thereafter - 4-(4-fluorobenzhydryl)piperidine hydrochloride (27 mg, 0.11 mmol) and triethylamine (〇.〇i 5 mL, O.) were added to the reaction mixture. Limmol) in toluene (1.0 mL) solution was mixed for 5 hours. The reaction mixture was cooled to room temperature. After adding ethyl acetate (3.0 mL) and water (3.0 mL) and separating organic layer, the aqueous layer was The ester (3 mL) was extracted. The organic layer of the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographic column chromatography [塡 剂 胺 胺 FU FU FU FU FU FU FU FU FU FU FU FU FU FU The title compound (2.3 mg, yield 7%) was obtained as a colorless oil. </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; m), 2.47-2.60 (4H, m), 3.12 (2H, ddd, J-13.5, 11.5, 2.9 Hz), 3.16 (2H, s), 3.47 (lH, tt, -397-201211053 J = 1 ll, 4.1 Hz), 3.55 (2H, s), 4.07-4.l6 (2H, m), 4.3 8 (2H, s), 6.44 (lH, s), 6.91-6.96 (lH, 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]: Hold time 3.43 minutes; m/z 653.1 [M + H]+ (ESI positive ion mode), m/z 651.1 [M-Hr (ESI negative ion mode)

Example 2 1 0 1-[3-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- Preparation of 3-yl}methyl)phenyl]-3-[(tetrahydrofuran-2-yl)methyl]urea (Compound No. 210) 3-({2- Side Oxygen-8) obtained in Reference Example 108-3 -[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)benzoic acid (50 mg, O.llmmol) suspended in Toluene (1. 〇 mL), triethylamine (0.023 mL, 0.22 mmol) and diphenylphosphoryl azide (14 mL, 0.13 mmol) were added and stirred at room temperature for 4 days. After the organic layer was separated (3 mL), EtOAc (EtOAc m. 3.0 m L), mixing was carried out for 2 hours at 110 ° C. Thereafter, tetrahydrofurfurylamine (〇.〇1 2 mL, 0.1 1 mmol) was added to the reaction solution for 5 hours to mix. -398- 201211053

The reaction mixture was cooled to room temperature, ethyl acetate (3 mL) and water (3 mL). The combined organic layers were dried with anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [塡: FU] IS IL YS IA company, amine cerium oxide NH-DM 1 020, developing solvent: ethyl acetate], and further divided into Purification by thin layer chromatography [Chromatorex NH-PLC05, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate 100%] to give the title compound (1 1 mg, yield: 5%) . 1H-NMR (300MHz, CDCl3) 6: 1.64- 1.79 (3H, m), 1.85-2.05 (5H, m), 2.45-2.62 (4H, m), 3.1 5 (2H, s), 3.15 (1 H, Ddd, 1 = 14.3, 6.5, 5.3 Hz), 3.55 (2H, s), 3.57 (lH, ddd, J = 14.3, 6.5, 2.9 Hz), 3.78 (lH, dt, J = 8.2 s7.0 Hz), 3.88 (lH, dt, J = 8.2, 6.5 Hz), 4.02 (lH, qd, J = 7.0, 3.3 Hz), 4.3 8 (2H, s), 5.07 (lH, t, J = 5.7 Hz), 6.90-6.96 (lH,m), 7.27-7.3 1(4H,m), 7.42 (2H,d,J = 7.8Hz), 7.56(2H,d,J = 8.2Hz) o LC/MS[Condition 1]: Hold time 2.99 minutes; m/z 547.0 [M + H]+ (ESI positive ion mode), m/z 545.1 [MH]_ (ESI negative ion mode) [Chem. 3 8 0]

OH 0 Reference Example 2 1 1 - 1 (ls, 4s) -4-(hydroxymethyl)cyclohexanecarboxylic acid methyl group - 399 - 201211053 cis-4-(hydroxymethyl)cyclohexanecarboxylic acid (purchased by Tokyo Chemical Industry Co., Ltd.) (500 mg, 3.2 mmol) dissolved in methanol (10 mL), followed by concentrated sulfuric acid (after 17 μΙ〇 addition), heated and stirred at 80 ° C for 2 hours. Saturated hydrogen carbonate was added to the reaction mixture. After the sodium aqueous solution (5. 〇mL) and ethyl acetate (5.0 mL) were shaken, the organic layer was separated. Next, the aqueous layer was extracted twice with ethyl acetate (10 mL), and then the organic layer was saturated. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (s, 4s) of methyl 4-(hydroxymethyl)cyclohexanecarboxylate. (522 mg, yield 96%) as a colorless oil. The obtained oil was used directly in the next step without purification. 1 H-NMR (300 MHz, C DC13 ) δ: 1.19-1.73 (lH, br s), 1.2 2 -1 .3 8 (2 Η, m), 1.50-1.70 (5H, m), 1.94-2.09 (2H, m), 2.58 (lH5tt, J = 4.9, 4.1 Hz), 3.50 (2H) , d, J = 5.9 Hz), 3.69 (3H, s). [Chem. 3 8 1]

Reference Example 2 1 1 - 2 (ls, 4s) -4-[(trifluoromethylsulfonyloxy)methyl]cyclohexanecarboxylic acid methyl group Preparation of Reference Example 211-1 (ls, 4s) Methyl 4-(hydroxymethyl)cyclohexanecarboxylate (200 mg, 1.16 mmol) and pyridine (187 μί, 2.32 mmol) were dissolved in dichloromethane (1 mL), and then the reaction solution was cooled to -78 ° C, followed by slowly -400-201211053, added trifluoromethanesulfonic anhydride (purchased by Tokyo Chemical Industry Co., Ltd.;) (343 pL, 2.1 mmol). After stirring at the same temperature for one and a half hours, water (5 mL) and ethyl acetate (5 mL) were added to the mixture and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (10 mL), and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (1OmL) and saturated aqueous sodium chloride (10 mL).

Drying over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (1 s, 4 s) - 4 -[(trifluoromethylsulfonyloxy)methyl]cyclohexanecarboxylic acid methyl ester (266 mg, yield 75%) of a colorless oil. The resulting product was used in the next stage of the reaction without further purification. 1H-NMR (300MHz, CDCl3) 5: 1.22-1.42 (2H, m), 1.5 1-1.75 (4H, m), 1.84-2.14 (3H, m), 2.64 (lH, tt, J = 4.5, 4.5 Hz) ), 3.70 (3H, s), 4.35 (2H, d, J = 7.4 Hz).

[化3 8 2] Ο

Reference Example 2 1 1 - 3 3-{[(13,43)-4-(methoxycarbonyl)cyclohexyl]methyl}-2_sideoxy-1-oxo-3,8-diazo snail [4.5 [Production of tert-butyl-8-carboxylic acid tert-butyl ester] 2-sided oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid obtained in Reference Example 1 1 1-1 The third butyl ester (O.llg, 〇.43mmol) was dissolved in tetrahydrofuran-401 - 201211053

After (1.0 mL), sodium hydride (&gt; 55 wt%, dispersed in flowing paraffin, purchased from Kanto Chemical Co., Ltd.) (23 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for one hour. Next, the methyl ester of (ls, 4s)-4-[(trifluoromethylsulfonyloxy)methyl]cyclohexanecarboxylate (0.28 g, 0.85) obtained in Reference Example 2 1 1 - 2 was added to the reaction mixture. After adding a solution of tetrahydrofuran (i.0 mL) and sodium iodide (purchased from Kanto Chemical Co., Ltd.) (6.5 mg, 0.04 mmol), the mixture was stirred at 80 ° C for one hour. Thereafter, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the mixture, and the organic layer was separated, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained colorless oil was purified by silica gel column chromatography [purifying agent: FL100D, manufactured by FUJI SILYSIA, developing solvent: hexane/ethyl acetate = 2/1] to obtain 3-{[(ls, 4s)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-oxo-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.10 g, yield 57%) of a white solid.

1H-NMR (300MHz, CDCl3) 5: 1.20-1.3, 5 (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), 2.52-2.6 1 (lH,m), 3.13(2H,d,J = 7.6Hz), 3.20-3.34(4H,m)s3.68(3H,s), 3.77-3.92( 2H, br m). [化3 8 3] Ο

8 201211053 Reference Example 2 1 1 - 4 (ls, 4s)-4-({2-Sideoxy-8-[4-(difluoromethyl)benzyl]-1-che- 3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid methyl substituted 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-oxo 1-oxa-3,8-diazosuro[4.5]decane-8-carboxylic acid tert-butyl ester' use reference example

3-{[(ls,4s)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-oxo-1-oxa-3,8-diazospiro[4.5]癸 obtained from 211-3 The title compound was obtained as a white solid (1 3 mg, yield: 1 1 / / / / / / / / / / / / / / / . 'H-NMRCSOOMHz^DChiS: 1.1 8-1.34(2H,m), 1.46-1.62(4H, m), 1.67-1.83(3H,m), 1.93(2H,d,J = 13.5Hz) , l.98-2.10(2H,m) , 2.49-2.6 1(5H,m), 3.12(2H,d,J = 7.4Hz), 3.26(2H,s), 3.56(2H, brs), 3.67( 3H, s), 7.43 (2H, d, J = 8.2Hz), 7.57 (2H, d, J = 8.2Hz) »

Reference Example 2 1 1 - 5 (13,43)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro [ Preparation of 4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid Substituted (lr,4r)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl] -1-ox_-403- 201211053 3,8- Diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid methyl group, obtained using Reference Examples 21 1-4 (ls, 4s) )-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl In the same manner as in Reference Example 6-3, the title compound was obtained as a white solid (1 1 mg, yield: 90%). LC/MS [Condition 1]: Hold time 3.04 minutes; m/z 454.8 [M + H]+ (ESI positive ion mode), m/z 453.0 [MH]- (ESI negative ion mode) [Chem. 3 8 5 】

Example 2 1 1 (18,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Production of decyl-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 21 1) Substituted (lr, 4r)-4-({2 -Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, (ls, 4s)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo as obtained in Reference Example 21 1-5 The title compound was obtained as a colorless oil (7.3 mg, m. m. m. , yield 57%). 'H-NMRCBOOMHz^DChia:!.40 - 1.69(7H,m), 1.70-2.04(1 0H, -404- 201211053 m), 2.30 (lH,tt,J = 7.8,3.7 Hz), 2.55 (4H, br s), 3.12 (lH, ddd, J = 13.5, 7.4, 4.5 Hz), 3.20 (2H, d, J = 8.2 Hz), 3.27 (2H, s), 3.57 (2H, s), 3.59 (lH, ddd, J = 13.5, 6.5, 3.3 Hz), 3.75 (lH, dt, J = 8.2, 7.0 Hz), 3.85 (lH, dt, J = 8.2, 7.0 Hz), 3.94 (lH) , dq, J = 3.3, 7.0Hz), 6.00 (lH, 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]: Hold time 3.15 min; m/z 53 7.9 [M + H]+ (ESI positive ion mode), m/z582_l [M + HCO〇r (ESI negative ion mode) [Chem. 3 8 6] Ο

Example 2 1 2 φ 4-[(18,43)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]_1-oxa-3,8·diazo snail [4.5] Manufacture of decane-3-yl}methyl)cyclohexanecarbamamine]piperidine-1-carboxylic acid tert-butyl ester (Compound No. 212) Substituted tetrahydrofurfurylamine using 4-amino group -1 - t - Butoxycarbonylpiperidine (purchased from Aldrich) - Substantially reacted in the same manner as in Example 211 to give the title compound as a white solid (48 mg, yield 69%) 〇1H-NMR (CDCl3) 6: 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 (lH, tt, J = 7.4, 4.1 Hz), 2.47- -405 - 201211053 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), 3.9 1 (lH, dtt, J = 7.4, 11.5, 3.7 Hz), 3.93-4.15 (2H, m), 5.39 (lH, 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]: Hold time 3.62 min; m/z 63 6.9 [M + H]+ (ESI positive ion mode), m/z 681_l [M + HCOO] _ (ESI negative ion mode) [Chem. 3 8 7]

Example 2 1 3 (ls, 4s)-N-[l-(cyanomethyl)piperidin-4-yl]-4-({2-sideoxy-8-[4-(trifluoromethyl)) Preparation of Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 21 3) -[(ls,4s)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- 3-butyl}methyl)cyclohexanecarbamamine] piperidine-1-carboxylic acid tert-butyl ester (16 mg, 〇.〇25 mmol) dissolved in 4M hydrogen chloride-dioxane solution (1 mL) at room temperature After stirring for 1 hour, the reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (1.0 mL), bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (6·7 μί, 0.1 mmol) and triethylamine (2IpL). Add 0.15 mmol) in sequence and stir at room temperature for 1 day. In reaction mixing -406- 201211053

A saturated aqueous solution of manganese chloride (2.0 mL) and ethyl acetate (2.0 mL) were added and the mixture was shaken, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (1 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (purified solvent: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Yield 47%). 1H-NMR (300MHz, CDCl3) 6: 1.40-1.70 (8H, m), 1.70-2.03 (9H, m), 2.26 (lH, tt, J = 7.8, 4.1 Hz), 2.46 (2H) td, J = Ll.l, 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) , 3.5 1 (2H, s), 3.57 (2H, br s), 3.82 (lH, dtt, J = 7.8, 10.4, 4.0 Hz), 5.3 7 (lH, d, J = 7.4 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

[化3 8 8] H3C

F Example 2 1 4 4-[(ls,4s)-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine]piperidine-1-carboxylic acid methyl ester (Compound No. 214) substituted bromoacetonitrile using methyl chloroformate (formed by Tokyo) The same reaction as in Example 2 1 3 was carried out to give the title compound as a white solid (1 mg, yield 68%). 1H-NMR (300MHz, CDCl3) 5: 1.29 (2H, dq, J = 4.9, 11.8 Hz), 1.4 1. 1.72 (6H, m), 1.72- 1.99 (9H, m), 2.25 (lH, 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 (lH, dtt, J = 7.4, 11.5, 3.7 Hz), 4.00-4.1 3 (2H, br m), 5.38 (lH, d, J = 8.2 Hz) ), 7.44 (2H, d, J = 8.2)

Hz), 7_57 (2H, d, J = 8.2 Hz). [化3 8 9]

Example 2 1 5 3-(4-{4-[(methoxyimino)(phenyl)methyl]piperidine-1-carbonyl}benzyl)-8-[4-(trifluoromethyl) Manufacture of benzyl-3-]-oxa-3,8-diazaspiro[4-5]nonan-2-one (Compound No. 215) 3-[4-(4-Benzamethylene oxime) obtained in Example 55 Isopiperidin-1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decane-2- Ketone (30 mg, 0.049 mmol), methoxylamine hydrochloride (purchased from Aldrich) (8.2 mg, 0.098 mmol) and sodium acetate (purchased from pure chemical (stock)) (8_0 mg, 0-098 mmol) dissolved in ethanol (l.OmL), at 100 ° C -408- 201211053

Stir for 28 hours. Thereafter, water (5.0 m L) and ethyl acetate (5.0 m L) 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 solution of sodium chloride (10 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography [塡剂: FL100D, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate/methanol = 20/1] to obtain (4-{4-[(A) Oxyimine)(phenyl)methyl]piperidine-1-carbonyl}benzyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Snail [4.5] decane-2-one (14 mg, yield 44%) as a colourless oil. 1H-NMR (DMSO-d6) 5: 1.41 (lH, br q, J = l 1.9 Hz), 1.54-1. 89 (7H, br m), 2.34 - 2.47 (4H, br m), 2.7 1 - 2.8 9 &amp; 3.3 4 - 3.4 8 ( 1 H, ea ch m ), 2.71-3. 1 5 (2H, br m), 3, 22 (2H, br s), 3.5 7 (2 H, s), 3.5 8 ( 1 H, br s ), 3.70&amp; 3.87 (3H, each s), 4.3 8 (2 H , s), 4.4 8 (1 H , brs), 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]: Hold time 3.82 minutes; m/z 649.0 [M + H]+ (ESI positive ion mode), m/z 693.2 [M + HCO〇r (ESI negative ion mode) [ 3 9 Ο

F Example 2 1 6 3-[4-(4-Benzylguanidinopiperidinylcarbonyl)_2-methoxybenzyl]-8-[4-(tri-409- 201211053 fluoromethyl)benzyl Manufacture of 1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 216) Substituted tetrahydrofurfurylamine using 4-benzylpyridylpiperidine hydrochloride (by

The same reaction as in Example 1 to 5 was carried out to give the title compound as a colorless oil (1 6 mg, yield 54%) 〇1H-NMR (300 MHz, CDCl3) :1.58-2.06(8H5m),2.44-2.63(4H, m), 2.99-3.26(2H,m), 3.16(2H,s),3.50-3.63(lH9m),3.56(2H, s ),3.86(3H , s), 3.89 (lH, br s), 4.4 7 (2 H, s), 4.6 9 (1 H , brs), 6.90 -7.03 (2H, m), 7.26 (lH5d, J = 7.0Hz), 7.36 -7.65 (7H, m), 7.95 (2H, d, J = 7.4 Hz). LC/MS [Condition 1]: Hold time 3.54 minutes; m/z 650.2 [M + H]+ (ESI positive ion mode), m/z 694.3 [M + HCO〇r (ESI negative ion mode) [ 3 9 1]

Reference Example 2 1 7 -1 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was produced from acetonitrile (purchased from Kanto Chemical Co., Ltd.) (1.4 mL, 25 mmol) Tetrahydrofuran solution (50 mL), a solution of lithium hexamethyldiamine in 1.0 M tetrahydrofuran (purchased from Aldrich) (28 mL, 28 mmol) -410 - 201211053

The mixture was slowly added dropwise at -78 ° C, and stirred at the same temperature for 30 minutes. Next, 15 mL of a tetrahydrofuran solution of N-(t-butoxycarbonyl)piperidine-4-one (purchased from Wako Pure Chemical Industries Co., Ltd.) was added, and the reaction solution was stirred for 12 hours while gradually raising the temperature to room temperature. . Then, water (30 mL) and ethyl acetate (30 mL) were added to the mixture and the mixture was shaken, and the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The organic layer of the combined organic layer was dried over anhydrous magnesium sulfate. After concentration and dried under reduced pressure, the obtained orange oil was chromatographic column chromatography [塡 剂 : FL FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU Purification of the title compound (2.Og, yield 32%). 1H-NMR (300MHz, CDC13) 5: 1.46 (9H, s), 1.55-1.79 (4H, m), 1.99 ( lH, br s), 2.53 (2H, s), 3.15 (2H, t, J = 12.3 Hz), 3.90 (2H, d, J = 14.3 Hz) [Chemical 3 9 2

Ο T heart o ch3 - Reference Example 2 1 7 - 2 2-oxo-oxo-oxa-3,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester was produced in Reference Example 2 4- 7-(cyanomethyl)-4-hydroxypiperidine-1 -decanoic acid tert-butyl ester (〇.50g, 2.1mmol) obtained from 1 7 -1 and chlorinated (II) hexahydrate and -411 - 201211053

A methanol solution (20 ml) of (〇.99 g, 4.2 mm) was obtained from Aldrich, and sodium borohydride (purchased from pure chemical (manufactured)) (0.79 g, 21 mmol) was added in three portions at 0 °C. After confirming the disappearance of the foaming, the reaction mixture was warmed to room temperature, and further stirred for 120 hours. Thereafter, the reaction mixture was cooled at 〇 ° C, 1M hydrochloric acid (15 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Next, diethyl ether (5 OmL) was added and shaken to separate the organic layer. After adding 28% by weight of aqueous ammonia (6_0 mL) to the aqueous layer, the mixture was extracted three times with ethyl acetate (50 mL). The combined organic layer was washed with a saturated aqueous solution of sodium chloride (100 mL) and dried over anhydrous magnesium sulfate. The obtained residue was dissolved in 1,4-dioxane (1 mL), and carbonyldiimidazole (purchased from Tokyo Chemical Industry Co., Ltd.) (〇36 g, 2.2 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Thereafter, a saturated aqueous solution of manganese chloride (5.0 mL) was added to the reaction mixture, and then extracted twice with ethyl acetate (10 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (20 mL) and dried over anhydrous magnesium sulfate. The resulting yellow oil was added to diisopropyl ether (1 mL). 1H-NMR (300MHz, CDCl3) 6: 1.46 (9H, s), 1.59 (2H, td, J = 13.3, 4.7 Hz), 1.80- 1.9 5 (4H, m), 3.29 (2H, t, J = 13.1) Hz), 3.4 1 (2H, td, J = 6.4, 2.4 Hz), 3.74 - 3.95 (2H, m), 5.27 (lH, br s). -412 201211053 【化3 9 3】 Η〆0

Reference Example 2 1 7 -3 3-[4-(Methoxycarbonyl)benzyl]-2-oxo-1-oxa-3,9-diazospiro[5.5]undecane-9-carboxylic acid Manufacture of third butyl ester

2 - side oxy-1 -oxa-3,9-diazospiro[5 · 5 ]undecane-9-carboxylic acid tert-butyl ester obtained in Reference Example 2 1 7 - 2 (〇.12g, 〇. 46 mmol) of hydrazine, hydrazine-dimethylformamide solution (1.5 mL) was added sodium hydride (55 wt%, dispersed in mobile sarcophagus) (purchased from Kanto Chemical Co., Ltd.) (24 mg, 0.55 mmol), After stirring for 1 hour at room temperature, methyl 4-(bromomethyl)benzoate (purchased from Tokyo Chemical Industry Co., Ltd.) (〇.13 g, 0.55 mmol) was added and stirred at room temperature for 4 hours. Water (1. 〇 mL) was added to the reaction mixture, and the mixture was stirred for 30 min. 1H-NMR (300MHz, CDCl3) 6: 1.45 (9H, s), 1.49-1.62 (2HJm), 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), 3.76-3.9 1 (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]: Hold time 4.23 minutes; m/z 418.9 [M + H]+ (ESI positive ion mode) -413- 201211053 [Chem. 3 9 4]

Reference Example 217-4 4-({2-Sideoxy-9-[4-(trifluoromethyl)benzyl]-1-che-3,9-diazospiro[5.5]undecane-3- Preparation of methyl 4-methyl-2-oxo-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester by using methyl ethyl benzoate as a reference 3-[4-(Methoxycarbonyl)benzyl]-2-oxo-1-oxo-3,9-diazospiro[5.5]undecane-9-carboxylic acid obtained in Example 217-3 The title compound was obtained as a yellow oil (48 mg, yield: 5%). iH-NMRpOOMHz'CDCIM: 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 = 8.2Hz), 7.45(2H,d,J = 7.8Hz), 7.5 6(2H,d,J = 7.8Hz),7.9 9( 2H,d , J = 8.2Hz) » LC/MS [Condition 1]: Hold time 3.50 minutes; m/z476.9 [M + H]+ (ESI positive ion mode) [Chem. 3 9 5]

-414 201211053 Reference Example 2 1 7 · 5 4-({2-Sideoxy-9-[4-(trifluoromethyl)benzyl]-1-oxo-3,9-diazo snail [5.5] Manufacture of monoalkyl-3-yl}methyl)benzoic acid

Substituting 4-({2-oxo-8-[4-(trifluoromethyl)benzyl]-1-che- 3,8-diazospiro[4·5]decane-3-yl} Methyl benzoate, 4-({2-oxo-9-[4-(trifluoromethyl)benzyl]]oxan-3,9-diazo as obtained using Reference Example 217-4 The title compound was obtained as a colorless solid (3 2 mg, yield, m.p. 69%). LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 462.9 [M + H] + (ESI positive ion mode), m/z 461.1 [MH]- (ESI negative ion mode) [Chem. 3 9 6 )

Example 2 1 7 3-[4-(4-Benzylmercaptopiperidinyloxy)benzyl]_9_[4-(trifluoromethyl)benzyl]-1-che-3,9- Substitution of diazospiro[5.5]undecane-2-one (Compound No. 217) for the replacement of 4-((2-oxo-8-[4-(trifluoromethyl)benzylsulfonyl][4.5]癸Alkyl-3-yl}methyl)benzoic acid, 4-U2· side oxo-9-[4-(trifluoromethyl)benzyloxy-3-3,9-diazo snail [5.5] obtained using Reference Example 217_5. Idecan-3-yl}methyl)benzoic acid (5.41^, 〇〇121^111〇1) other than -415-201211053, substantially the same reaction as in Example 55 was carried out to give the title compound as a colorless oil. (2.7 mg, yield 36%) ° 'H-NMRCSOOMHz. CDChiS: 1.63-1.95 (1 0H, 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 (lH, br m), 3.59 (2H, s), 3.85 (lH, br s), 4.59 (2H, s), 4.62 ( 1 H, br s), 7.3 2 (2 H , d, J = 8.4 Hz), 7.3 6-7.63 (9H, m), 7.95 (2H, d, J = 8.2 Hz) » LC/MS [condition lp hold time 3.78 min; m/z 634 .0[M + H]+ (ESI positive ion mode), m/z 678.2 [M + HCOO]_ (ESI negative ion mode) [Chem. 3 9 7]

Example 2 1 8 4-({2-Sideoxy-9-[4-(trifluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5.5]undecane-3- Preparation of 4-methyl)-N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 218) Substituting 4-benzimidylpiperidine hydrochloride using tetrahydrofurfurylamine ( The title compound was obtained as a yellow solid (1 lmg, yield: 75%). 〇1H-NMR (3 00 MHz, CDCl3) 6:1.5 8- 1.75(3H,m), 1.76-2.08(7H,m), 2.49-2.6 6(4H,br m),3.1 8(2H,t, J = 6.1 Hz),3.3 2( 1 H,ddd, 1 3.9 , 7.8, 4.9 Hz), 3.58 (2H, s), 3.72-3.96 (3H, m), 4.02-4.13 (lHsm), 4.60 -416-201211053 (2H, s), 6.44-6.48 (lH, brm), 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]: Hold time 3.42 minutes; m/z 545.9 [M + H]+ (ESI positive ion mode)

Example 2 1 9 Heart (Benzo[(1][1,3]dioxazole-5-ylmethyl)-4-({2-Sideoxy-9-[4-(trifluoromethyl)benzene) Preparation of methyl]-1-oxo-3,9-diazospiro[5.5]undecano-3-yl}methyl)benzamide (Compound No. 21 9) Substituted 4-benzylidenepiperidine The hydrochloride was substantially the same as that of Example 2 17 except that piperonylamine (purchased by Tokyo Chemical Industry Co., Ltd.) was used.

The title compound was obtained as a colorless solid (5.3 mg, yield: 33%). 1H-NMR (300MHz, CDCl3) 5: 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), 6.3 1 (lH, t, J = 4.9 Hz), 6.77 (1 H , d, J = 8.0 Hz), 6.8 l (lH, dd, J = 8.0, 1.2 Hz), 6.85 (1 H, 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]: Hold time 3.68 minutes; m/z 5 96.0 [M + H]+ (ESI positive ion mode), m/z 594.2 [MH]_ (ESI negative ion mode) -417- 201211053 3 9 9] h3c 〆0

Example 220 々-[々-(mouth-side oxygen-^^gas trifluoromethyl^phenylmethylpyrazine-oxo-)-diazospiro[5.5]undec-3-yl}methyl)benzene Preparation of methylamine] piperidine-indole-carboxylate (Compound No. 220) Substituted 4-benzylidene piperidine hydrochloride, 4-aminopiperidine-1-carboxyl synthesized using Reference Example 135 The title compound was obtained as a yellow oil (9·4 mg, yield: 61%) of the title compound, except for the acid methyl salt. 1H-NMR (3 00 MHz, CDCl3) 6:1.34- 1.52(2H,m), 1.5 7- 1.75 (2H, m), 1.77-1.89 (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), 4.00-4.3 l (3H, br m), 4.60 (2H, s), 6.12 (lH, 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]: Hold time 3.14 minutes; m/z 603.0 [M + H]+ (ESI positive ion mode) , m/z601.2[MH]-(ESI negative ion mode) -418- 201211053 【化4 0 0】 H3cy^ Ο

FF Example 221 3_{4·[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-carbonyl]benzyl}_9-[4-(three Fluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5.5]undecane-2·

Preparation of a ketone (Compound No. 221) in place of 4-benzylpyridylpiperidine hydrochloride using 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride The same reaction as in Example 2 1 7 was carried out to give the title compound as a colorless oil (1 9 mg, yield: 42%). 1H-NMR (300MHz, CDCl3) 5: 1.34 (6H, d, J = 6.8 Hz), 1.6 1-1.77 (2H, m), 1.77-1.99 (6H, m), 2.01-2.2 8 (2H, Br m), 2.49-2.69 (4H, br m), 3.08 (lH, sep, J = 6.8 Hz), 3.10-3.26 (5H, m), 3.59 (2H, s), 3.85 (lH, Lu br s) , 4.59 (lH, 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]: Hold time 3.22 minutes; m/z 640.1 [M + H]+ (ESI positive ion mode), m/z 684.2 [M + HCO〇r (ESI negative ion mode) 0 1] H3Cv^〇

Nt°Ych33 0 ch3 -419- 0 201211053 Reference Example 2 2 2 -1 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-sideoxy-1-oxo-3, Preparation of 9-diazospiro[5.5]undecane-9-carboxylic acid tert-butyl ester in place of 2-sided oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid Tributyl ester, 2-tert-oxy-1-oxo-3,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (0.218, 0.78!11111〇) obtained in Reference Example 217-2. In the same manner as in Reference Example 111-3, the title compound was obtained as a yellow oil (yield: 20%). 1H-NMR (300MHz, CDCl3) 6: 1.41 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.52-1.67 (2H, m), 1.84-1.99 (4H, m), 3.3 1 ( 2H,t,J=12.7Hz), 3.47(2H,t,J=6.1Hz),3.74-3.98(2H,m),4.41(2H,q,J=7.4Hz), 4.7 l(2H,s) , 7.42 (1 H, d, J = 7.8 Hz), 8.27 (1 H, dd, J = 8.2, 1.6 Ηζ), 9.13 (lH, s). [化4 0 2]

Reference Example 2 2 2 - 2 6-({2-Sideoxy-9-[4-(trifluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5_5]undecane- Preparation of 3-yl}methyl)nicotinic acid ethyl substituted 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2-oxyloxy-1-oxo-3,8- Diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester, using 3-{[5-(ethoxycarbonyl)pyridin-2-yl]methyl}-2- obtained in Reference Example 222-1 Side oxygen - -420- 201211053 1-oxo-3,9-diazospiro[5.5]undecane-9-carboxylic acid tert-butyl ester (77.〇11^, 0.18mmol), substantially The title compound was obtained as a colorless oil (j. 'H-NMR (300MHz, CPCl3) 5: 1.40 (3H, t, J-7.4Hz), 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), 4.7 1 (2H, s), 7.41 (lH, d,

J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7_57 (2H, d, J = 8.2 Hz), 8.26 (1 Η , dd, J = 8.2, 2.0 Hz), 9.12 (lH, d , J = 2.0Hz) ο LC/MS [Condition 1]: Hold time 2.98 minutes; m/z 491.9 [M + H]+ (ESI positive ion mode)

Reference Example 2 2 2 _ 3 6-({2-Sideoxy-9-[4-(trifluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5.5]undecane- Production of 3-yl}methyl)nicotinic acid substituted 6-({2-oxo-8-[4-(trifluoromethyl)benzyl]-1 -oxa-3,8-diazospiro [ 4.5] decyl-3-yl}methyl)nicotinic acid ethyl, using 6-({2- sideoxy_9-[4-(trifluoromethyl)benzyl) obtained in Reference Example 222-2 -1-oxa-3,9-diazospiro[5.5]undecyl-3-yl}methyl)nicotinic acid ethyl ester (361118, 〇.〇7〇111111〇1) other than 'substantially with reference The title compound was obtained as a colorless solid (3lmg, yield 91%). -421 - 201211053 1H-NMR (300MHz, CD3〇D) 5: 1.80- 1.93 (2H, m), 1.96-2.08 (4H, m), 2.70 (2H, t, J = 11.6Hz), 2.77-2.90 ( 2H,m), 3.45 (2H, t, J = 6.3 Hz), 3.83 (2H, s), 4.67 (2H, s), 7.36 (lH, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 8.27 (lH, dd, J = 8.3, 2.0 Hz), 9_01 (lH, s) 〇 LC/MS [Condition 1]: Hold time 1.00 min :m/z463.9[M + H]+ (ESI positive ion mode), m/z4 62.0 [M-Hr (ESI negative ion mode) [Chemical 4 0 4]

Example 222 3-({5-[4-(4-Fluorobenzylidyl)piperidin-1-carbonyl]pyridin-2-yl}methyl)[4-(trifluoromethyl)benzyl] -1. Production of oxa-3,9-diazaspiro[5.5]undecyl-2-one (Compound No. 222) Substituted 6-({2-oxo-8-[4-(trifluoromethyl)) Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)nicotinic acid, 6-((2-sided oxygen) obtained using Reference Example 222-3 9-[4-(Trifluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5.5] eleven-yard-3-yl}methyl) niacin (14 mg, 0.030 mmol) The same reaction as in Example 1 1 1 was carried out, except that 4-(4-fluorobenzylidene)piperidine hydrochloride and triethylamine were used, to give the title compound as a colorless oil. (13 mg, yield 66%).

1H-NMR (300MHz, CDCl3) 6: 1.60-2.01 (10H, m), 2.50-2.68 (4H - 422 - 201211053 m), 2.98-3.3 1 (2H, br m), 3.43 (2H, t, J = 6.1 Hz), 3.47-3.62 (lH, m), 3.59 (2H, s), 3.84 (lH, br s), 4.66 (lH, br s), 4.68 (2H, s), 7.17 (2H, t, J = 8.2 Hz), 7.39 (lH, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2 H, d, J = 8.2 Hz), 7.73 (lH, dd, J = 8.2, 2.0 Hz), 7.98 (2H, dd, J = 8.2, 5.3 Hz), 8.59 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.18 min; τη/ζ65 3·1[Μ + Η]+ (ESI positive ion mode), m/z 697.2 [M + HCO〇r (ESI negative ion mode)

Example 223 3-({5-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-carbonyl]pyridin-2-yl}methyl)- Manufacture of 9-[4-(trifluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5.5] φ undecane-2-one (Compound No. 223) -Fluorobenzylidene)piperidine hydrochloride, substantially carried out and carried out using 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride The title compound was obtained as a colorless oil (14 mg, yield: 1H-NMR (300MHz, CDCl3) 5: 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(lH,sep,J=7.2Hz),3.14-3.3 1(3H,m),3.43(2H,t,J = 6.5Hz ),3.59(2H,s),3.81 (lH, br s), 4.58 (l H, br s) , 4.6 8 (2H, s), 7.40 ( 1 H, -423- 201211053 d, J = 8.2 Hz), 7_44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.72 (1 H, dd, J = 8.2, 2.1 Hz), 8.59 (1 H, d, J = 2.0 Hz) » LC/MS [Condition 1] : Hold time 3 · 1 2 minutes; m / z 641 · 2 [Μ + Η] + ( ESI positive ion mode), m / z 685.2 [M + HCOO] _ (ESI negative ion mode) [Chemical 4 0 6]

Example 224 (lr,4r)-4-{[8-(2-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl Manufacture of methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (Compound No. 224) substituted 3-(bromomethyl)pyridine hydrobromide using 2-cyano The title compound (21. 7 mg, yield 63%) was obtained as white powder. 1H-NMR (300MHz, CDCl3) 5: 1.01 (2H, dq, J = 3.7, 13.1Hz) 51.38-1.69 (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 (1 H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.25 (2H, s), 3.58 ( 1 H,ddd,J=1 3.9,6.5,3.3 Hz), 3.7 l(2H,s), 3.74 (lH,dt,J = 8.2,6.5 Hz), 3.85 (lH, dt, J = 8.2, 6.5 Hz) ), 3.94 (lH, dq, J = 3.3, 7.1 Hz), 5.8 0 (lH, br t, J = 5 · 3 Hz), 7.3 6 (1 H, t, J = 7.4 Hz), 7·48 (1 H, d, J = 7.4 Hz), 7.55 (lH, t, J = 7.4 Hz), 7.66 (lH, d, J = 7.4 Hz). -424- 201211053 LC/MS [Condition 1]: Hold time 1.48 minutes; m/z 495.0 [M + H]+ (ESI positive ion mode), m/z 493.0 [MH]·, 529.1 [M + C1 ]·, 539.3[M + HCO〇r (ESI negative ion mode) [化 4 0 7]

Example 2 2 5 (11*,4〇-4-{[8-(3-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane- Preparation of 3-yl]methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 21 2 3 5) Substituting 3-(bromomethyl)pyridine hydrocyanate The title compound (23.9 mg, yield 69%) was obtained as a colorless oil.

-425- 1 H-NMR (300 MHz, CDCl3) 5: 1.02 (2HJdq, J = 3.0512.7 Hz), 1.40 - 2 1.69 (4H, m), 1.7 1-1.84 (4H, m), 1.84-2.11 ( 8H,m), 2.42-2.70(4H, br m), 3.09 (2H,d,J = 7.4Hz), 3.11 (lH,ddd,J=13.9,7.6,4.5Hz), 3 3.26(2H,s) , 3.5 5(2H, s), 3.58 (lH, ddd, J = 13.9, 6.5, 3.3 Hz), 3.74 (lH, dt, J = 8.2, 7.0 Hz), 3.85 (lH, dt, J-8.2, 6.5) Hz), 3.94 (lH, dq, J = 3.3, 7.1 Hz), 5.82 (lH, br t, J = 5.3 Hz), 7.4 2 (1 H, t, J = 7.8 H z), 7.5 5 ( 2H, Br d, J = 7.8 Hz), 7.67 (lH, s) ° 4 LC/MS [Condition 1]: Hold time 1.62 min; m/z 494.9 [M + H] + 201211053 (ESI positive ion mode), m /z493.2[MH]·, 5 39.1 [M + HCOO]-( ESI Negative Ion Mode) [Chemical 4 0 8]

Example 226. (11:,4〇-4-{[8-(Cyclohexylmethyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decan-3-yl] Preparation of methyl b-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 226) Substituting 3·(bromomethyl)pyridine hydrobromide, using (bromomethyl) The title compound (32.7 mg, yield 98%) was obtained as a white powder, m.p. 2H, br q, J = 11.9 Hz), 1.02 (2H, dq, J = 3.3, 2.9 Hz), 1.1 0-1.3 5 (3H, m), 1.37-2.1 1 (22H, m), 2.08- 2.24( 2H,br m),2.33-2.68(4H,br m) ,3.09(2H,d, J = 7.6Hz), 3.1 1 (1 H, ddd , J = 13.9, 7.6, 4.5Hz), 3.24 ( 2H, s), 3.59 (lH, ddd, J = 13.9, 6.5, 3.3 Hz), 3.75 (lH, dt, J = 8.2, 6.9 Hz), 3.86 (1 H, dt, J = 8.2, 6.5 Hz), 3 · 94 (lH, dq, J = 3.3, 6.9 Hz), 5.80 (lH, br t, J = 5.3 Hz) LC/MS [Condition 1]: hold time 2,77 min; m/z 476.0 [ M + H]+ (ESI positive ion mode), m/z 474.3 [MH; T, 510.1 [M + C1]-, 520.2 [M + HCOO]- (ESI negative ion mode) -426- 201211053 [Chemical 4 Ο 9】

Example 227 (11*,41*)-4-{[8-(4-methylbenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane- Preparation of 3-yl]methyldipyridyl-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (Compound No. 227) Substituting 3-(bromomethyl)pyridine hydrobromide, using 4 The title compound (15.8 mg, yield: 65%) was obtained as a colorless oil. LC/MS [Condition 1]: Hold time 2.78 min; m/z 483.9 [M + H] + (ESI positive ion mode), m/z 482.0 [MH]·, 518.1 [M + C1]·, 528.2 [M + HCOO]_ (ESI negative ion mode)

Example 228 (lr,4r)-4-[(8-Benzyl-2-oxooxy-1-oxo-3,8-diazospiro[4.5]decan-3-yl)methyl]-N -[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Chemical-427-201211053 Compound No. 228) was produced by substituting 3-(bromomethyl)pyridine hydrobromide using benzyl The title compound (5.6 mg, yield 24%) was obtained as a colorless oil. 1H-NMR (300MHz, CDCl3) 5: 1.01 (2H, dq, J = 2.9, 12.7 Hz), 1.3 8-1.66 (4H, m), 1.66-2.1 2 (1 2H, m), 2.44-2.79 (4H , br m), 3.08 (2H, d, J = 7.4 Hz), 3.11 (lH, ddd, J = 13.5, 7.4, 4.9 Hz), 3.25 (2H, s), 3.58 (2H, br s), 3.58 ( lH,ddd,J = 13.5,7.0,3.3 Hz), 3.74 (lH9dt, J=8.6, 6.5 Hz), 3.85 (lH, dt, J = 8.6, 6.5 Hz), 3.94 (lH, dq, J = 3.3, 7.0 Hz), 5.79 (lH, br t, J = 5.3 Hz), 7.25-7_39 (5H, m). [化 4 1 1]

Example 2 2 9 (U,4〇-4-{[8-(3-methoxybenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane- Preparation of 3-(methylidene)methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 229) Substituting 3-(bromomethyl)pyridinylhydrochloride for use The title compound (5.6 mg, yield 22%) was obtained as a colorless oil, m.p. ) 5: 1.01 (2H, dq, J = 3.3, 12.3 Hz), 1.39· 428- 201211053 1 · 67 (4Η, m), 1.70-1.84 (4H, m), 1.84-2. ll (8H, m) , 2.43 - 2.7 1 (4 H, br m), 3_09 (2H, d, J = 7.4 Hz), 3.11 (lH, ddd, J = 13.9, 7_4, 4.9 Hz), 3.25 (2H, s), 3.52 ( 2H, br s), 3.5 8 (1H , ddd, J = 1 3.9, 6.5, 3.3 Hz), 3.7 5 ( lH, dt, J = 8.2, 6.5 Hz), 3.81 (3H, s), 3.85 (lH, Dt, J = 8.2, 6.5 Hz), 3.94 (l H, dq, J = 3.3, 7.1 Hz), 5.8 0 (lH, br t, J = 5.7 Hz), 6.8 1 (lH, dd, J = 8.2, 2.5 Hz), 6.89 (lH, d, J = 2.5 Hz), 6.89 (lH, d, J = 8.2 Hz), 7.23 (lH, t, J = 8.2 Hz).

LC/MS [Condition 1]: Hold time 2.75 minutes; m/z 499.9 [M + H]+ (ESI positive ion mode), ηι/ζ498·0 [Μ·ΗΓ, 53 4.3 [M + C1]·, 544.3 [M + HCOO]-(ESI Negative Ion Mode) [Chem. 4 1 2]

Example 2 3 0 (11*,41:)-4-({8-[3-fluoro-5-(trifluoromethyl)benzyl]-2-oxo-1-oxo-3,8- Production of Diazospiro[4.5]decane-3-yl}methyl)·Ν-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 23〇) The title compound (2 4.9 mg) was obtained in the same manner as in Example 4 except that the pyridine bromohydrobronic acid salt was used in the same manner as the fluoro-5-(trifluoromethyl)benzyl bromide (sold). , yield 90%) of a pale yellow oil. -429- 201211053

1H-NMR (300MHz, CDCl3) 5: 1.01 (2H, dq, J = 2.8, 12.7 Hz), 1.39-1.68 (4H, m), 1.68-2.1 5 (1 2H, m), 2.44-2.76 (4H, Br m), 3.09 (2H, d, J = 7.8 Hz), 3.10 (lH, ddd, J = 13.9, 7.6, 4.5 Hz), 3.2 6 (2H, s), 3.5 8 (lH, ddd, J = 13.9) , 6.5, 3.3 Hz), 3.58 (2H, s), 3.74 (lH, dt, J = 8.2, 6.5 Hz), 3.85 (lH, dt, J = 8.2, 6.5 Hz), 3.93 (lH, dq, J = 3.3, 7.1 Hz), 5.80 (lH, br t, J = 5.3 Hz), 7.22 (lH, d, J = 8.6 Hz), 7.29 (lH, d, J = 8.4 Hz), 7.3 9 (lH, s) °

LC/MS [Condition 1]: Hold time 3.08 min; m/z 5 5 5.8 [M + H]+ (ESI positive ion mode) [Chem. 4 1 3]

Example 2 3 1

(11:,4〇-4-{[8-(4-〖-butylbenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane·3-yl Production of methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 231) Substituting 3-(bromomethyl)pyridine hydrobromide, using 4-t A pale yellow powder of the title compound (26.3 mg, yield: 61%) was obtained from the title compound (26.3 mg, yield 61%). Hold time 3.34 minutes; m/z 525.9 [M + H]+ (ESI positive ion mode), m/z 560.1 [M + Cl]-, 570.2 [M + HCOO]-( 8 -430- 201211053 ESI anion mode)

【化4 1 4】

Example 232 (lr,4r)-4 - {[8-(4-Fluorophenethyl)-2-oxooxo-3,8-diazospiro[4.5]decane-3-yl]methyl} Preparation of -N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (Compound No. 232) Substituting 3-(bromomethyl)pyridine hydrobromide '4-fluorophenethyl bromide The title compound (13.6 mg, yield 54%) was obtained as a pale yellow oil.

LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 502.0 [M + H]+ (ESI positive ion mode), m/z 536.2 [M + Cl]·, 546·2 [Μ + Η (:00)·( ESI negative ion mode) 【化 4 1 5】 Ο

Example 23 3 (lr,4r)-4-{[8-(4-fluorobenzyl)-2_sideoxy-1 - chewing-3,8-heavy snail-431 - 201211053 [4.5] decane Manufacture of -3-yl]methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 233) in place of 3-(bromomethyl)pyridine hydrobromide, The title compound (14.6 mg, yield 60%) was obtained as a white powder, which was obtained in the same manner as in Example 4, except for using 4-fluorobenzyl bromide (purified). 1H-NMR (300MHz, CDCl3) 5: 1.01 (2H, dq, J = 3.3, 13.1Hz), 1.39-1.67 (4H, m), 1.67-1.83 (4H, m), 1.83-2.09 ( 8H,m), 2.40-2.70(4 H,br m),3.08(2H,d,J = 7.8Hz), 3.10(lH,ddd,J=13.9,7.6,4.5Hz),3.24(2H,s) , 3.49 (2H, s), 3.58 (lH, ddd, J = 13.9, 6.5, 3.3 Hz), 3.7 4 (lH, dt, J = 8.2, 6.5 Hz), 3.85 (lH, dt, J = 8.2, 6.5 Hz), 3.93 (lH, dq, J = 3.3, 7.1 Hz), 5.79 (lH, br t, J = 5.3 Hz), 6.99 (2H, t, J = 8.6 Hz), 7.27 (4H, dd, J = 8.6, 4.8 Hz). LC/MS [Condition 1]: Hold time 1.26 minutes; m/z 487.9 [M + H]+ (ESI positive ion mode) [Chem. 4 1 6]

Example 2 3 4 (lr,4〇-4-({8-[4-(methylthio)benzyl)] 2 oxo-1 _oxo-3,8-diazospiro[4.5]decane- Preparation of 3-yl}methyl)_N_[(tetrahydrofuran-2-yl)methyl]cyclohexylcarbamide (Compound No. 234) Substituting 3-(bromomethyl)pyridine hydrobromide, using 4 _ (methylthio)benzene 201211053

The same reaction as in Example 4 was carried out, except for the methyl bromide (purified) to give the title compound (16.1 mg &gt; yield 62%) as white powder. 1H-NMR (300MHz, CDC13) 6: 1.01 (2H, br q, J = 12.2Hz), 1.38-2.11 (16H, m), 2.43-2.71 (4H, br m), 2.48 (3H, s), 3.08 (2H,d,J = 6.9Hz), 3.1 l(2H,ddd,J=13.5,7.5,4.6Hz), 3.2 4(2H,s), 3.49(2H,s),3.5 8(l H ,ddd , J = 13.5, 6.8, 3.3 Hz), 3.74 (lH, dt, J = 8.3, 6.6 Hz), 3.85 (lH, dt, J = 8.3, 6.6 Hz), 3.94 (lH, dq, J = 3.3, 6.9 Hz), 5.81 (lH, br t, J = 4.6 Hz), 7.22 (4H, s). LC/MS [Condition 1]: Hold time 2.96 min; m/z 516.0 [M + H] + (ESI positive ion mode), m/z 514.1 [M-Hr (ESI negative ion mode) 5 5 0.3 [M + C1]-(ESI negative ion mode) [Chem. 4 1 7]

Example 235 (11&quot;, 4〇-4-({8-[3,5-bis(trifluoromethyl)benzyl)-2-oxo-oxo-3,8-diazospiro[ 4.5] decane-3-yl}methyl)-1^-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (Compound No. 23 5) was produced in Example 3 (11*) ,41')-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)- Cyclohexanecarbamide 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(trifluoro) was added at room temperature. A-433-201211053 base benzaldehyde (purchased) (11.5pL, 〇.〇7mmol) and borane-2-carbamazepine steep complex (purchased by Pure Chemical Company) (7.5mg, 0.07mmol) The mixture was stirred and mixed at room temperature for 1 day. After the completion of the reaction, the reaction mixture was distilled off under reduced pressure. The obtained reaction residue was subjected to silica gel column chromatography [塡 剂 : FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU Purification by methanol = 20/1] gave (lr, 4r)-4-({8-[3,5-bis(trifluoromethyl)benzyl]-2-oxo-l-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)-&gt;^-[ White powder of (tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide (23.3 mg 'yield 7 7%). 1H-NMR (300 MHz, CDCl3) 6: 1.02 (2H, dqiJ = 3.0, 12.6 Hz ) 51.36-

1.69(4H,m), 1.69-2.1 5(1 2H,m),2.53-2.68(4H,br m),3.10(2H ,d,J = 7.3Hz), 3.1 l(lH,ddd,J=13.9 , 7.3, 4.6 Hz), 3.27 (2H, s), 3.58 (lH, ddd, J = 13.9, 6.9, 3.3 Hz), 3.63 (2H, s), 3.75 (lH, dt, J = 8.3, 6.8 Hz) , 3.85 (lH, dt, J = 8.3, 6.6 Hz), 3.94 (lH, dq, J = 3.3, 7.1 Hz), 5.82 (lH, br t, J = 5.6 Hz), 7.78 (lH, br s), 7.80 (2H, br s). LC/MS [Condition 1]: Hold time 3.60 min; m/z 6 〇 6. 〇 [M + H] + (ESI positive ion mode) ' m/z 640.2 [M + Cl]·, 650.2 [M + HCO 〇H ESI negative ion mode) [Chem. 4 1 8]

-434- 201211053 Example 2 3 6 (lr,4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1 - Ester- Manufacture of 3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 236)

The same reaction as in Example 23 5 was carried out, except that 3,5-bis(trifluoromethyl)benzaldehyde was substituted, and 6-(trifluoromethyl)pyridine-3-pyridinecarboxyaldehyde (available) was used. The title compound (U. 7 mg, yield 43%) was obtained as white powder. 1H-NMR (300MHz, CDCl3) 5: 1.02 (2H, dq, J = 3.7, 12.8Hz), 1.3 9-1.65 (4H, m), 1.69- 1.84 (4H, m), 1.84-2.12 (8H, m ), 2.46-2.70(4H, br m)s3.09(2H,d,J = 7.4Hz), 3.11 (lH,ddd,J=13.9,7.4,4.5Hz), 3.26(2H,s),3.5 8 (lH,ddd,J=13.9,6.5,3.3 Hz), 3.6 1 (2H, s), 3.74 (lH, dt, J = 8.2, 6.5 Hz), 3.85 (lH, dt, J = 8.2, 6.5 Hz) , 3.94 (lH, dq, J = 3.3, 7.1 Hz), 5.80 (lH, br t, J = 5.3 H z), 7.6 5 (1 H, d, J = 7.8 H z), 7.85 ( lH, br d , J = 7.8 Hz), 8.68 (lH, s). LC/MS [Condition 1]: Hold time 3:00 min; m/z 5 3 8.9 [M + H]+ (ESI positive ion mode), m/z 5 7 3.1 [M + Cir, 5 8 3.2 [M + HCOO ]-( ESI Negative Ion Mode) [Chem. 4 1 9] ο

Reference Example 2 3 7 -435- 201211053 3-[4-(4-Benzylhydrazinopiperidine-i-carbonyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane_ Production of 2-ketone hydrochloride replaces 2-oxo-3-[((lr,4r)-4-{[(tetrahydrofuran-2-yl)methyl]aminemethanyl}cyclohexyl)methyl]- 3-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester, using 3-[4-(4-benzoylpiperidine-1-carbonyl) obtained in Example 158 The same reaction as in Example 3 was carried out except that benzylidene-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester was obtained. A colorless amorphous material of the compound (1.lg, quantitative). 'H-NMR (300MHz ' CDC13) δ : 1.70-2.1 4(6H,m), 2.25 (2H, t, J = 9.8 Hz), 2.92-4.02 (1 OH, m), 4.44 (2H, s), 4.67 (1 H, br s), 7.30 (2H, d, J = 7.4 Hz), 7.36-7.54 (4H, m), 7.59 (lH, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.0 Hz), 9.70 (lH, s). LC/MS [Condition 1]: Hold time 3.16 min; m/z 461.9 [M + H]+ (ESI positive ion mode) [Chem. 4 2 0] Fork

Example 237 3-[4-(4-Benzylmethyl-piperidine-1.carbonyl)-benzyl]-8-(4-nitro-benzyl)-1-oxo-3,8- Manufacture of diaza-spiro[4.5]decane-2-one (compound number 2 3 7)-436- 201211053

3_[4_(4-Benzylmercaptopiperidinylcarbonyl)benzyl]-1-oxo-3,8-diaza-spiro[4.5]decane-2-one hydrochloride obtained in Reference Example 237 (24.9 mg, 0.05 mmol) was dissolved in n,N-dimethylformamide (1.0 mL), and 4-nitrobenzyl bromide (purchased) (^ mg, 0.07 mmol) was added at room temperature. Triethylamine (20.9 μί, 0.1 5 mmol) was stirred and mixed at room temperature for 1 day. After the completion of the reaction, ethyl acetate was added, and the mixture was washed with water, dried over anhydrous sodium sulfate and evaporated. The obtained reaction residue was purified by silica gel column chromatography [塡 剂 :: FL100D, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate/methanol = 20/1] to obtain 3-[4-(4-phenylene). Mercapto-piperidin-1-carbonyl)-benzyl]_8-(4-nitro-benzyl)-1-oxo-3,8-diazospiro[4.5]decane-2-one (20.4 Mg, yield 68%) of light yellow oil. 1H-NMR (300MHz, CDC13) 5 : 1.61 - 2. ^(δΗ, ηι)^.40-2.66(4H, br m), 2.95-3.29(2H, br m), 3.14(2H, s), 3.48 -3.62 (lH, m), 3.60 (2 H, s), 3.65-4.07 (lH, br m), 4.44 (2H, s), 4.49-4.85 (lH, br m), Lu 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 (lH, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 8.0 H z), 8 · 1 7 (2 H, d, J = 8.6 H z) » LC/MS [Condition 1]: Hold time 3.30 min; m /z597.1[M + H]+ (ESI positive ion mode), m/z 595.4 [MH]-, 631.3 [M + C1]- (ESI negative ion mode) -437- 1 201211053 [Chem. 4 2 1]

Example 2 3 8 3-[4-(4-Benzyl fluorenyl-?] has its own, male ^ 甘, ., ^ — 瓜u疋-i_carbonyl)·本 methyl]_8_(4_二Preparation of fluoromethoxy-methionyl-l-oxa-3'8-diazaspiro[4.5]decane-2-ketone (Compound No. 23 8) Substituted 4-nitro-substituted benzyl bromide The title compound (278 mg, yield: 87%) was obtained as white powder, m. m.

1H-NMR (300 MHz, CDC13) 6: 1.68-2.1 3 (8 H, m), 2.3 8-2.63 (4H, br m), 2.95-3.25 (2H, br m), 3 .1 2 (2 H , s), 3.4 9 (2 H , s), 3.4 9 - 3.6 1 ( lH, m), 3.65-4.05 (lH, br m) , 4.44 (2H, s), 4.4 7-4.8 3 ( 1 H , Br m), 7.14(2H,d,J = 7.8Hz), 7.30(2H,d,J = 8.2Hz), 7.32(2H,d,J = 7.8Hz), 7.41(2H,d,J = 8.2Hz ), 7.48 (lH, t, J = 7.8 Hz), 7.58 (lH, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 3.50 minutes; m/z 636.2 [M + H]+ (ESI positive ion mode), m/z 670.2 [M + Cl]·, 68 0·3 [Μ + Η(:ΟΟ]·( ESI negative ion mode) 8 -438- 201211053 【化4 2 2】

Example 239 3 -[4-(4-Benzylfluorenyl-piperidine-fluorenylcarbonyl)-phenylmethyl b. (4-bromo-benzyl)-1-spiro-3,8-diaza - Spirulina [4.5] decane-2 ketone (Compound No. 239) • Manufacture

Substituting the 4-nitro-substituted benzyl bromide, using the same reaction as in Example 23 7 except that 4-bromobenzyl bromide (supplied) was used to give the title compound (1 4 9 · 8 mg, Yield 9 5 %) of a colorless oil. 1H-NMR (300MHz, CDCl3) 6: 1.64-2.18 (8H, m), 2.36-2.61 (4H, br m), 2.94-3.27 (2H, br m), 3.1 2 (2 Η, s), 3.4 5 (2 ,, s), 3.4 8 - 3.6 3 ( lH, m), 3.64 - 4.05 (lH, br m), 4.44 (2H, br s), 4.4 8 - 4.9 2 ( 1 H, br m ), 7.17 (2H,d,J = 8.4Hz), 7.30(2H,d,J = 8.2Hz), 7.41(2H,d,J = 8.2Hz), 7.42(2H,d,J = 8.4Hz),7.49(2H , t, J = 7.8 Hz), 7.59 (lH, tt, J-7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.40 minutes; m/z 63 0.1 [M + H]+ (ESI positive ion mode), m/z 664.3 [M + C!r (ESI negative ion mode) [Chem. 4 2 3] 0

201211053 Example 240 3-[4-(4-Benzyldecyl-piperidine-carbonyl)-benzyl]_8-(4-chloro-benzyl)-1·oxa-3,8-diaza- Manufacture of spiro[4.5]decane-2-ketone (Compound No. 240)

Substituting the 4-nitro-substituted benzyl bromide, and using the same procedure as in Example 237 to give the title compound (9.5 mg, yield 31%). Light yellow oil 1H-NMR (3 00 MHz &gt; CDCl3) 6: 1.64-2.20 (8H, m), 2.37-2.65 (4H, br m), 2.97-3.29 (2H, br m), 3 .1 2 (2 Η, s), 3.4 6 (2 Η, s) , 3.48-3.65 (lH, m), 3.65 -4.07 (lH, br m), 4.44 (2 H, s), 4.46-4.8 4 ( 1 H , 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 (lH, tt, J = 7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC/MS [Condition 1]: Hold 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/ Z630.3[M + HCO〇]-(ESI negative ion mode) [Chem. 4 2 4] 1

Example 24 1 8 -440- 201211053 2-{3-[4-(4-Benzylmethyl-piperidine-hydrazinylcarbonyl)-benzyl]-2_sideoxy-boxa-3,8- Manufacture of diaza-spiro-μ.5] 癸-8-ylmethylbenzonitrile (Compound No. 241)

Substituting the 4-nitro-substituted benzyl bromide and using 2-cyanobenzyl bromide (commercially available) to carry out the same reaction as in Example 2 3 7 to give the title compound (2 6.5 mg. Rate 9 2 %) of light yellow oil. 1H-NMR (300MHz, CDC13) 6: 1.67-2.17 (8H, m), 2.43-2.72 (4H, m), 2.95-3.26 (2H, br m), 3.1 3 (2H, s), 3.46-3.63 ( 1 H, m), 3.67-4.1 2 ( lH, br m), 3.69 (2H, s), 4.44 (2H, s), 4.47-4.88 (lH, br m), 7.30 ( 2H, d, J = 8.2 Hz), 7.3 5 (lH, dt, J = 1.2, 7.8 Hz), 7.4 1 (2H, d, J = 8.2 Hz), 7.44 - 7.61 (5H, m), 7.63 (lH, d, J = 7.8 Hz) ), 7.94 (2H, d, J = 7.8 Hz) LC/MS [Condition 1]: Hold time 3.28 minutes; m/z 576.7 [M + H]+ (ESI positive ion mode)

Example 242 3_ {3-[4-(4-Benzylmercapto-piperidin-1 -carbonyl)-benzylidene 2·Sideoxy-1 -oxa-3,8-diaza-spiro[45癸_8_ylmethylbenzonitrile (Compound No. 242) Manufactured -441 - 201211053 Substituted 4-nitro substituted benzyl bromide, other than 3-cyanobenzyl bromide (purchased) The title compound (2 1.3 mg, yield 74%) was obtained as a pale yellow oil. 1H-NMR (300MHz, CDCl3) 5: 1.68-2.17 (8H, m), 2.40-2.65 (4H, br m), 2.96-3.3 0 (2 H, br m), 3.1 3 (2Η, s), 3.4 7 - 3.6 2 (1 Η ,m), 3.5 3 ( 2H,s), 3.63 -4.05 (lH,br m), 4.4 5 (2 Η, s), 4.5 1 - 4.8 7 (1 Η ,brm), 7.3 0 (2H, d, J = 8.2 Hz), 7.40 (lH, 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 (lH, tt, J = 7.4, 1.2 Hz), 7.64 (lH, br s), 7.94 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3 28 minutes; m/z 577.1 [M + H] + (ESI positive ion mode), m/z 611.3 [M + Cir, 621.4 [M + HCOO]. ESI negative ion mode)

Example 2 4 3 3 - [4 - (4-Benzyl fluorenyl-piperidine-hydrazino-carbonyl)-benzyl]_ 2 _ side oxo-oxime_oxo_3,8-diaza-spiro[ 4.5] Preparation of decane-8 carboxylic acid (4-cyano-phenyl)-decylamine (Compound No. 243) Substituting 4-nitro substituted benzyl bromide using 4-cyanophenyl isothio The cyanate ester (purchased) is substantially the same as the embodiment 2 3 7 -442- 201211053

The reaction gave the title compound (2 7.2 mg, yield: 1H-NMR (300MHz, CDCl3) 5: 1.74-2.11 (8H, m), 2.95-3.26 (2H, brm), 3.18 (2H, s), 3.54 (2H, t, J = 11.9 Hz), 3.55-3.63 (lH,m), 3.64-3.99 (lH, br m), 4.4 6 (2H, s), 4.4 8 (1 H , brd, J = l 4.3 Hz), 4.54-4.78 (lH'br m), 7.30 (2H,d,J = 8.2Hz), 7.3 1(2H,d,J = 8.5Hz), 7.40(2H, d,J = 8.2Hz), 7.49(2H,t,J = 7.4Hz), 7.56( 2H, d, J = 8.5 Hz), 7.60 (l H, tt, J = 7.0, 1.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 7.97 (lH, br s). LC/MS [Condition 1]: Hold time 4.33 minutes; m/z 622.2 [M + H]+ (ESI positive ion mode), m/z 620.3 [MH]·, 656.2 [M + Cir (ESI negative ion mode) )

[化 4 2 7]

Example 2 4 4 3 - [4 - (4-Benzyl fluorenyl-piperidine-hydrazino-carbonyl)-benzyl]_ 2 _ oxo-oxime _ oxa _ 3,8 diaza-spiro [ 4.5] Preparation of decane-8-carboxylic acid (4-cyano-phenyl)-decylamine (Compound No. 244) Substituting 4-nitro substituted benzyl bromide using 4-cyanophenyl isocyanate The title compound (27.4 mg, yield 90%) was obtained as a colorless oil from &lt;RTI ID=0.0&gt;&gt;&gt; 6:1.65-2.14(8H,m), 2.93-3.28(2H, br m), 3.16(2H,s),3.3 6(2H,t,J=l 2.7Hz),3.50-3.65( lH,m) , 3.69-3.95 (lH, br m), 3, 92 (2H, br d, J = 1 3.9 Hz), 4.45 (2H, s), 4.4 8-4.8 0 (lH, br m), 7.30 (2H&gt; d, J = 8.2 Hz), 7.34 (lH, br s ), 7.4 0 (2 H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.50 (4H, s), 7.59 (lH, tt, J = 7.8, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 4.03 min; m/z 606.1 [M + H]+ (ESI positive ion mode), m/z 604.2 [MH]-, 640.2 [M + C1]- (ESI) Negative ion mode) 【化4 2 8】 1

Example 245 3 - [ 4 -(4-Benzylmercapto-piperidine-1 carbonyl)-benzyl]_ 2 -sideoxy·丨-chew_3,8-_aza-spiro[4_5] Production of broth-8-residual acid (3-cyano-phenyl)-decylamine (Compound No. 245) Substituting 4-nitro-substituted benzyl bromide using 3-cyanophenyl isocyanate (purchased) The same reaction as in Example 237 was carried out to give the title compound (38.1 mg, yield 100%) as a colorless oil. 'H-NMR (300MHz, CDC13) 5: 1.63-2.1 l(8H, m), 2.98-3.3 〇(2H, br m), 3. 6 (2H, s), 3.36 (2H, br t, J = 1 2.7Hz), 3.49 - 3.6 5 (ihm) -444 - 201211053 , 3.73-4.05(lH,br m),3,90(2H,br d, J= 1 3.9 Hz), 4.46 (2 H, s ), 4.5 1-4.81(lH,br m), 7.1 8 (1 H, brs), 7.2 6 (1 H, dd d, J = 7.4,1 . 6,1 . 2 H z) , 7.3 1 (2H , d, J = 8.2 Hz), 7.34 (lH, t, J = 7.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1 H, Tt, J = 7.4, 1.2 Hz), 7.63 (2H, ddd, J = 7.8, 2.0, 1.2 Hz), 7.70 (lH, t, J = 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 4.01 min; m/z 606_2 [M + H]+ (ESI positive ion mode), m/z 604.2 [M-H] — (ESI negative ion mode)

[化 4 2 9]

Example 2 4 6 3-[4-(4-Benzylmercapto-piperidin-1-carbonyl)-benzyl]-8-(2,5-dimethoxy-oxyl-benzyl)-1 -Production of oxa-3,8-diaza-spiro[4.5]nonan-2-one (Compound No. 246) Substituting 4-nitro-substituted benzyl bromide using 2,5-dimethoxybenzene The title compound (7.7 mg 'yield 25%) was obtained as a colorless oily substance, m.p.

1H-NMR (300MHz, CDCl3) 6: 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 (lH,m),3.54(lH,s),3.7 1-3.99( 1 H,br m),3.77(6H,s),4.44(2H,s),4.5 1-4.84( 1H ,br m -445 - 201211053 ), 6.74 (lH, dd, J = 9.0, 2.9 Hz), 6.78 (lH, d, J = 9.0 Hz), 6.93 (lH, d, J = 2.9 Hz), 7.3 0 (2H, d, J) = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.48 (2H, t, J = 8.2 Hz), 7.58 (lH, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8Hz). LC/MS [Condition 1]: Hold time 4.01 min; m/z 606.2 [M + H]+ (ESI positive ion mode), m/z 604.2 [MH]- (ESI negative ion mode) [Chem. 4 3 0 】

Example 247 3-[4-(4-Benzylmercapto-piperidin-1-carbonyl)-benzyl]-8-(2-trifluoromethyl-benzyl)-1-oxo-3, Preparation of 8-diaza-spiro[4.5]decane-2-one (Compound No. 247) Substituting 4-nitro-substituted benzyl bromide using 2-trifluoromethylbenzyl bromide (purchased In the same manner as in Example 237, the title compound (20.5 mg, yield 66%) was obtained as a colorless oil. </RTI> 1H-NMR (300 MHz, CDCl3) 5: 1.70-2.13 (8H, m) , 2.40-2.55 (2H, br m), 2.63 (2H, br t, J = 9.0 Η z), 3.0 1 - 3.3 5 (2 H , brm), 3.15 (2H , s), 3.47-3.64 ( lH, m), 3.65-4.07 (lH, br m), 3.66 (2H, s), 4.45 (2H, 8), 4.47-4.90 (lH, br m), 7.27-7.37 (3H, m), 7.41 (2H, d, J = 8.2 Hz - 446 - 201211053 ), 7.44 - 7.54 (3H, m), 7.59 (lH, tt, J = 7.4, 1.6 Hz), 7.6 1 (lH, br d, J = 7 · 8 H z ), 7.7 3 (2 H, brd, J = 8.2 H z), 7.9 4 (2 H, d, J = 8 · 2 H z). LC/MS [Condition 1]: Hold 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) [Chem. 4 3 1] 1

Example 248 3-[4-(4-Benzylmethyl-piperidine-1-carbonyl)-benzyl]-8-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1-oxo-3,8-diaza-spiro[4.5]decane-2-one

The compound No. 248) was produced by substituting the 4-nitro substituted benzyl bromide, and the same reaction as in Example 237 was carried out except that 4-trifluoromethylphenethyl bromide (commercially available) was used to obtain the title. Compound (20.5 mg, 65% yield) as a pale yellow oil. *H-NMR (300MHz, CDC13)5: 171- 2. ll(6H,br m), 2 . 1 3 - 2.3 9 (2 H ,br m),2.82-3,02(4H,br m), 3.0 2 - 3.2 5 (6 H, brm), 3.2 2 (2 H, s), 3.57 (lH, tt, J = 9.8, 4.1 Hz), 3.65-4.05 (lH, br m), 4.4 5 (2 H , s), 4.4 9 -4.87(lH,br m),7.3 1(2H,d,J = 8.2Hz), 7.35(2H,d,J = 8.2Hz),7.43 -447- 201211053 (2H,d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.59 (lH, tt, J = 7.4, 1.2 Hz), 7.95 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 3.34 minutes; m/z 634.3 [M + H]+ (ESI positive ion mode), m/z 668.4 [M + Cl]·, 678.4 [M + HCO〇r (ESI negative ion mode) [Chem. 4 3 2]

Example 249 8-(4-Ethyl-benzyl)-3-[4-(4-benzylidene-piperidin-1-carbonyl)·benzyl]-1-oxo-3,8- Preparation of diaza-spiro[4.5]nonan-2-one (Compound No. 249) 3-[4-(4-Benzylfluorenyl-piperidin-1-carbonyl)-benzene obtained in Example 23 Methyl]-8-(4-bromo-benzyl)-indole·3,8-diazospiro[4.5]decane-2-one (102.3 mg, 〇. 2 mmol) was dissolved in tetrahydrofuran (2.0 mL) Adding tributyl(1-ethoxyvinyl)tin (purchased by Aldrich) (13 5.bL, 0.4mm〇l) and bis(triphenylphosphine)palladium(II) chloride at room temperature (7.9 mg, 0.01 mmol) was mixed under heating for 15 hours. After cooling, 0.1 M hydrochloric acid (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the mixture was washed with water, and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [-448 - 201211053 oxime: FL1 00D, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: ethyl acetate-ethyl acetate/methanol = 20/1]. -(4-Ethyl-benzyl)-3-[4-(4-benzylidenyl-piperidine-1-carbonyl)-benzyl]-1-oxa-3,8-diaza a white powder of spiro[4.5]nonan-2-one (28.3 mg, yield 24%).

j-NMROOOMHz.CDCh"].64-2.2 l(8H,m),2.3 5-2·65(4Η, brm), 2.5 8 ( 3 Η, s ), 2.9 3 - 3 · 2 8 (2 Η, Brm), 3 . 1 3 (2 Η , s ), 3 · 4 9 - 3.6 1 (lH, m), 3.56 (2H, s), 3.70-4.04 (lH, br m), 4.4 4 (2 H, s), 4.4 9 - 4.8 6 ( lH, br m), 7.30 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.4 1 (2H, d, J = 7.8 Hz) ), 7.49 (2H, t, J = 7.8 Hz), 7.59 (lH, 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]: Hold time 3.26 minutes; m/z 594.1 [M + H]+ (ESI positive ion mode), m/z 592.1 [MH; T, 628.2 [M + C1]·, 638.2 [M + HCO〇r (ESI negative ion mode)

[化4 3 3]

Example 2 5 0 3-{4-[(Benzo[1.3]dioxazol-5-ylmethyl)-aminemethylmercapto]-benzyl}-2-oxyloxy-1-oxo-3, Manufacture of 8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 25 0) - 449- 201211053 Substituting 4-benzylidene piperidine hydrochloride, using piperonylamine The title compound (905.2 mg, yield 70%) was obtained as a colorless oil. iH-NMR (300MHz, CDC13) 5: 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, l 1·5, 2·5Ηζ ), 3.78 (2H, br d, J = 1 3 . 5 Η ζ), 4.4 5 (2 Η, s), 4.5 4 (2 Η, d , J = 5.7 Η ζ), 5.94 (2H, s), 6.42 (lH, br s), 6.77 ( 1 H, d, J = 7.8 Hz), 6.8 1 (1 Η, dd, J = 7.8, 1.6 Hz) , 6.84 (lH, 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]: Hold time 4.10 min; m/z 424.1 [M-isobutene-C02 + H]+, 468.1 [M-isobutene + H]+, 5 2 4.2 [ M + H ] + (ESI Positive ion mode), m/z 522.2 [MH]·, 568.2 [M + HCO〇r (ESI negative ion mode) [Chem. 4 3 4]

Example 2 5 1 3-(4-{4-[Hydroxy(phenyl)methyl]piperidine-1-carbonyl}benzyl)-8-[4-(trifluoromethyl)benzyl]- Preparation of 1-oxa-3,8-diazaspiro[4·5]nonan-2-one (Compound No. 251) 3-[4-(4-Benzylmercaptopiperidine) obtained in Example 55 1-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane--450- 201211053 2-ketone ( A solution of 20 mg, 0.03 mmol of methanol (1.0 mL) was added to sodium borohydride (2.0 mg, 0 to 48 mmol). After stirring at room temperature for 30 minutes, acetic acid (5 pL, 0.09 mmol) was added and concentrated to dryness under reduced pressure. Water (1 mL) and ethyl acetate (2 mL) were added to the residue, and the organic layer was evaporated. .

IH-NMR (300MHz, CDCl3) 8: 1.10-i.52 (3H, br m), 1.72 (2H, ddd, J = 1 3.9, 7.8, 6. 1 Hz), 1.80-2.2 1 (5H, br m ), 2.4 2 - 2.6 0 (4 H , brm) , 2.60-2.82 (lH, br m), 2.8 2 - 3.0 7 ( 1 H, br m), 3 . 1 1 (2 H, s), 3 . 5 5 ( 2H, s), 3.5 5-3.90 (lH, br m) , 4.36-4.52 (3H, m), 4.52-4.92 (1 H, br m), 7.24-7.40 (9H, m), 7.42 ( 2H,d,J = 8.2Hz), 7.56(2H,d,J = 8.2 Hz LC/MS [Condition 1]: Hold time 3_66 minutes; m/z622.0[M + H]+ (ESI positive ion mode) , m/z 666.2 [M + HCOO]-(ESI negative ion mode)

Example 252 3-{[(lr,4r)-4-(4-Benzylmercaptopiperidine-1-carbonyl)cyclohexyl]methyl b- 2-oxo-1-oxo-3, 8-diazo (r, 4r)_4_{[8-(t-butoxycarbonyl)_2- 451 - 201211053

Side oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid (1.6 3 g '4.11 mmol), 1-c- benzobenzotriazine ( a solution of 0.17 g, 1.2 mmol) and 4-benzylpyridylpiperidine hydrochloride (available) (1 g, 4.5 mmol) in chloroform (50 mL), triethylamine (1. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 g, 6.2 mm〇l), after standing at room temperature for 2 days, water (5) OmL) and vigorously stirred for 2 hours. The organic layer was separated, washed with EtOAc EtOAc EtOAc (EtOAc)

'H-NMR (300MHz, CDCl3) 5: 1.05 (2H, br q, J = 12.7 Hz), 1.46 (9H, s), 1.49-1.99 (1 5H, m), 2.47 (lH, tt, J = 11.9) , 2.9 Hz), 2.82 (lH, br t, J = 12.7 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.21 (lH, br t, J = 13.1 Hz), 3.26 (2H, s), 3.28 (2H, br t, J = 13.0 Hz), 3.5 1 (lH, tt, J = l 0.6, 4.1 Hz), 3.85 (2H, br d, J = 13.0 Hz), 3.98 (lH, br d, J =13.5 Hz), 4.59 (lH, br d, J = 13.1 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (lH, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.4 Hz). LC/MS [Condition 1]: Hold time 4.47 minutes: m/z 590.1 [M + Na] + (ESI positive ion mode), m/z 612.4 [M + HCOO] - (ESI negative ion mode) 3 6]

4 Example 253 8 -452-201211053 3-[4-(4-Benzylpiperidinyl-p-carbonyl)benzyl]|[4(trifluoromethyl)benzyl]-1-che-3, Manufacture of 8-diazospiro[45]decane-2-ketone (Compound No. 253)

4_({2_Sideo_8_[4-(trifluoromethyl)benzyl]-1-che-3,8-diazospiro[4.5]decane-3-yl} obtained in Reference Example 21 Methyl)benzoic acid (221^, 0.049mmol), 1-hydroxybenzotriazole (2mg, 〇〇lmm〇1) &amp; 4-benzylidene (purchased) (llpL, 〇.〇64mmol) Dissolved in chloroform (1 mL), added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.074 mmol), and allowed to stand at room temperature for 7 days. A solution of citric acid (3 mg) in water (2 mL) was added. The organic layer was separated, dried and evaporated to dryness crystals crystals crystals 1H-NMR (300MHz, CDCl3) 8: 1.02- 1.42 (2H, br m), 1.63-1.87 (5H, m), 1.9 1 (2H, br d, J = 1 3 . 5 Η z), 2.4 4 - 2.6 4 (4 Η, brm), 2.5 4 (2 H , d, J = 7.4 Hz), 2.60-2.8 5 (lH, br m), 2.8 0 - 3.0 5 ( 1 H , brm), 3.12 (2H, s), 3.53-3.83 (lH, brm), 3.56 (2H, s), 4.43 (2H, s), 4.52-4.84 (lH, br m), 7.13 (2H, dd, J = 7.4) 1.6 Hz), 7.20 (lH, tt, J = 7.4, 1.6 Hz), 7.25 - 7.34 (4H, m), 7.3 7 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 ( 2H,d,J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.52 minutes; m/z 606.2 [M + H]+ (ESI positive ion mode), m/z 650.2 [M + HCO〇r (ESI negative ion mode) 3 7]

F-453-201211053 Example 254 4-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] Preparation of ethyl decyl-3-yl}methyl)benzamide]piperidine-i-carboxylate (Compound No. 254) Substituted 4-benzyl substituted piperidine using 4-aminopiperidine-1 The title compound (m.p. 1H-NMR (300MHz, CDCl3) 5: 1.27 (3H, t, J = 7.4 Hz), 1.43 (2H, dq, J = 4.1, 1 1.5 Hz), 1.71 (2H, ddd, J = 14.3, 8.2, 6.1 Hz), 1.9 0 (2H, br d, J = 1 2.7 Hz), 2.05 (2H, br d, J = 1 2.7 H z), 2.4 2 - 2.6 4 (4 H , brm), 2.96 ( 2H, br t, J = 12.7 Hz), 3.11 (2H, s), 3.55 (2H, s), 4.0 1-4.29 (3H, br m), 4.14 (2H, q, J = 7.4 Hz)} 4.4 6 (2H, s), 5.9 6 (lH, 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_74 (2H, d, J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 603.2 [M + H] + (ESI positive ion mode), m/z 601.3 [MH]_ (ESI negative ion mode) [Chem. 4 3 8 】

Reference Example 255 3-{[(11&quot;,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazo snail [4.5 Manufacture of decane-2-one hydrochloride 201211053 Substituted 2-oxo-oxy-3-[((lr,4r)-4-{[(tetrahydrofuran-2-yl)methyl]aminemethanyl}cyclohexyl Methyl]-1-oxo-3,8-diazospiro[4.5]decane-8-residual acid tert-butyl ester '3-{[(lr,4r)-4-) obtained using Example 252 4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl-sideoxy-1-oxo-3,8-diazospiro[4.5] decane-8-carboxylic acid tert-butyl ester, substance The same reaction as in Example 3 was carried out to obtain a white powder of the title compound (20 g, quantitative).

1H-NMR (CD3〇D) 5:1.10 (2H,q,J=11.2Hz), 1.36-2.22 (15H,m), 2.68 (lH,t,J = 11.2Hz), 2.88 (lH,t,J =13.2 Hz), 3.11 (2H, d, J = 8.1 Hz), 3.28-3.38 (lH, m), 3.48 (2H, s), 3.67-3.80 (lH, m), 4.11 (lH, d, J= 11.9 Hz), 4.53 (lH, d, J = 13.9 Hz), 7.52 (lH, t, J = 7.9 Hz), 7.62 (lH, t, J = 7.9 Hz), 8.01 (2H, d,; T = 7.9) Hz). LC/MS [Condition 1]: Hold time 2.82 minutes; m/z 467.9 [M + H]+ (ESI positive ion mode), m/Z502.1 [M + C!r (ESI negative ion mode)

[化 4 3 9]

Example 255 3-{[(11&quot;,4〇-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl b8_[2,4-bis(trifluoromethyl)benzene Production of methyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (compound No. 255) substituted (lr, 4r)-4-[(2_sideoxy-b. 3,8-diazospiro[4.5]decane-3_yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide hydrochloride, -455- 201211053 Reference example 3-{[(lr,4r)-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}-1•oxa-3,8-diazosole[4.5] Hydrane-2-one hydrochloride, and substituted 3-(bromomethyl)pyridine hydrobromide using 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (purchased) The same reaction as in Example 4 was carried out to give the title compound (14 mg, yield: 25%) as a white powder. <H-NMR (CDCl3) 6: 1.06 (2H, q, J = 12.7 Hz), 1.44 -2.02(1 5H,m), 2.47(1 H,t,J=l 1.9Hz) , 2.50-2.71 (4H,br m), 2.8 2 ( 1 Η, t, J = 1 1 .5 Hz), 3.11(2H,d,J = 6.5Hz), 3.20(lH,t,J=13.0Hz), 3.28(2H,s), 3.43 -3.59(lH,m),3.73(2H,s),3.98(lH ,d,J=13.1Hz), 4.60 (lH d, J = 12.7 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (lH, t, J = 7.4 Hz), 7.78 (lH, d, J = 7.8 Hz), 7.8 8 (lH, br s), 7.94 (2H, d, J = 7.4 Hz), 7.97 (lH, d, J = 7.8 Hz) LC/MS [Condition 1]: Hold time 4·01 min; m/z 694.0 [M + H]+ (ESI positive ion mode)' m/z738.0[M + HCOO]-(ESI negative ion mode) [Chem. 4 4 0]

Example 2 5 6 4-[(3-{[(1]:, 4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}_ 2_ sideoxy-1 -Production of oxa-3,8-diazospiro[4.5]decane-8-yl)methyl]-3-fluorobenzonitrile (Compound No. 256) substituted!-(Bromomethyl)-2,4- Bis(trifluoromethyl)benzene was reacted in the same manner as in Example 25 5 except that 4-(bromomethyl-456-201211053-)-3-fluorobenzonitrile (p-purified) was used to give the title compound (23 mg, yield 55%) of white powder 1H-NMR (CDCl3) 6: 1.05 (2H, q, J = l 1.6 Hz), 1.39-2.02 (1 5H, m), 2.47 (lH, t, J = 10.9 Hz), 2.54-2.69 (4H, br m), 2.81 (lH, t, J = 12.5 Hz),

3.11 (2H, d, J = 5.9 Hz), 3.20 (lH, t, J = 12.2 Hz), 3.26 (2H, s), 3.45-3.58 (lH, m), 3.64 (2H, s), 3.98 (lH) , d, J = 11.9 Hz), 4.60 (lH, d, J = l 2.9 Hz), 7.34 (lH, d, J = 9.2 Hz), 7.44 (lH, d, J = 9.2 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.5 1- 7.58 (lH, m), 7.59 (lH, t, J = 7.3 Hz), 7.95 (2H, d, J = 7.3 Hz). LC/MS [Condition 1]: Hold time 3.16 minutes; m/z 601.0 [M + H]+ (ESI positive ion mode), m/z 645.1 [M + HCOO]_ (ESI negative ion mode)

[化44 1]

Example 257 3-[(3-{[(11',4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}_ 2-sided oxo-1-oxo- 3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. 257) was produced in Reference Example 25 5 3-{[(lr, 4r)_4_(4_ Benzamethylene sulfhydryl _ 1-carbyl)cyclohexyl]methyl hydrazine-hydrazine-11 oxa-3,8·diazo snail [4.5] brothel-2 ketone hydrochloride (1 6 mg, 0.03 2 mmol) N,N-dimethylformamide (〇5〇mL) suspension -457- 201211053 Add triethylamine (11μί, 0.079mmol) and 3-(bromomethyl)benzonitrile (purchased) (7mg After being allowed to stand at room temperature for 2 days, water (0.5 mL) was added, and the resulting solid was filtered to give the title compound (yield: 7 mg, yield 94%) as a white solid. • H-NMRCSOOMHz, CDC13) 5: 1.05 (2 H, dq, J = 4.1, 12.3 Hz), 1.49- 1.71 (4H, br m), 1. 7 1 -1 . 8 7 (7 H, brm), 1 . 8 7 - 2.0 1 (4 H} brm), 2.47 (lH, tt, J = 11.5, 2.9 Hz), 2.49-2.65 (4H, m), 2.82 (lH, br t, J = l 1.5 Hz) , 3.11 (2H, d, J = 7.4 Hz), 3.21 (lH, br t, J = 1 3.9 Hz), 3.2 7 (2 H, s), 3.51 (lH, tt, J = 10.6, 3.7 Hz), 3.55(2H, s), 3.98 (lH, br d, J = 12.7 Hz), 4.59 (lH, br d, J = 1 3.1 Hz), 7.3 6-7.6 3 (6H , m), 7.6 6 ( 1 H , brs), 7.94 (2H, d, J = 7.8Hz). LC/MS [Condition 2]: Hold time 3.58 min; m/z 583.6 [M + H]+ (ESI positive ion mode), m/z 627.6 [M + HCOO]- (ESI negative ion mode) 4 2]

Example 2 5 8 2_[(3-{[(11&quot;,4〇-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}_ 2- Side Oxy-1-Derivative -3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. 25 8) was produced by substituting 3-(bromomethyl)benzonitrile using 2_(bromomethyl) The same reaction as in Example 257 was carried out to give the title compound (19 mg, yield yield) as a white solid. - 458 - 201211053 1H-NMR (30 0 MHz, CDCl3) : 1.05 (2H, dq, J = 4.1, 11.9 Hz) 51.48-1.70 (4H, br m), 1. 7 〇-1 . 8 7 (7 H, brm), 1. 8 7 - 2.0 1 (4 H , brm), 2.46 (lH, tt, J = l 1.5, 2.9 Hz), 2.54-2.74 (4H, br m), 2.82 ( 1 H, br t, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.20 (lH, brt, J = 11.9 Hz), 3.26 (2H, s), 3.51 (lH, tt, J = l〇.2, 3.7 Hz), 3.72 (2H, s), 3.97 ( lH, br d, J=14.3

Hz), 4.59 (lH, br d, J = 13.9 Hz), 7.3 6 (lH, dt, J = 1.2, 7.4 Hz), 7.41 - 7.62 (5H'm), 7.65 (lH, d, J = 7.8 Hz) ), 7.94 (2H, d, J = 8.6 Hz).

LC/MS [Condition 2]: Hold time 3.56 minutes; m/z 5 83.6 [M + H]+ (ESI positive ion mode), ηι/ζ627·6[Μ + Η(:00]·(Ε3Ι negative ion mode) 4 4 3]

Example 259

4-{3-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- The ethyl 4-methyl)phenyl]ureido}piperidine-1-carboxylate (Compound No. 25 9) was produced in Reference Example 21 4-({2- Side Oxygen-8-[4-(3) a solution of fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4_5]nonane_3_yl}methyl)benzoic acid (100 m g, 0.22 mmol) in chloroform (2 mL) Triethylamine (62 μί, 0.45 mmol) and diphenyl azide (72 μ [, 〇. 33 mmol) were added, and after standing at room temperature for 18 hours, water (2 mL) was added, and the organic layer was separated. The organic layer was depressurized to a volume of 1 part by volume, toluene (2 ml) was added, and after stirring at 110 ° C for -2 hours to 2,011,0100, 2 hours, 4-aminopiperidine-1 -carboxylate was added. (57 μί, 0.33 mmol) was purchased and cooled to room temperature. After water (2 mL) was added to the mixture, the organic layer was evaporated and evaporated. The residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> White solid. 1H-NMR (300MHz, CDCl3) 6: 1.25 (3H, t, J = 7.0Hz), 1.3 1 (2H, dq,

J = 4.1, 11.5 Hz), 1.7 1 (2H, dt, J = 13.5, 7.4 Hz), 1.83-2.04 (4H, brm), 2.41-2.61 (4H, br m ), 2.9 5 ( 2 Η, brt, J = 1 2.3 Η ζ) , 3 . 1 5 ( 2 Η , s ) , 3.54 ( 2H, s), 3.77-3.95 (lH, m), 3.98-4.13 (2H, br m), 4.12 (2H, q , J = 7.0 Hz), 4.35 (2H, s), 4.89 (lH, br d, J = 7.8 Hz), 6.72 (lH, 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 = 8.2 Hz) 〇 LC/MS [Condition 2]: Hold 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 2 6 0 -1 2-(4-{[8-(〖-butoxy)-2-oxo-1-oxa-3,8-diazospiro[4.5]decane-3- Preparation of 2-methyl}phenyl)acetic acid The 2-sided oxo-oxime-oxa-3,8-diazospiro[4.5] 8 460- 201211053 decane-8-carboxylic acid obtained in Reference Example 111-1 A solution of tributyl acrylate (20 mg, 〇. 〇 78 mmol) in N,N-dimethylformamide (0.60 mL) was added to a solution of sodium succinate (19 mg, 0.20 mmol) and stirred at room temperature for 3 min. . 2-{4-(Bromomethyl)phenyl}acetic acid (purchased) (18 mg, 0.078 mmol) was added to the reaction mixture, and after stirring for 4 days at room temperature, water (2 mL) and 1 M hydrochloric acid (0.12) were added. (mL) and ethyl acetate (2 mL). A solution of sodium hydrogencarbonate (33 mg) in water (2.4 mL) was added to the organic layer, and the aqueous layer was separated. Add 1M salt to the water layer

After the acid (0.50 mL) and ethyl acetate (3 mL),EtOAc. 1H-NMR (300MHz, CDCl3) 5: 1.44 (9H, s), 1.59 (2H, ddd, J = 13.1, 10.2, 4.9 Hz), 1.85 (2H, br d, J = 1 3 . 1 Η z), 3 . 1 2 (2 Η, s), 3.2 8 (2 Η, brt , J=11.9 Hz), 3.65 (2H, s), 3.79 (2H, br d, J=l 1.9 H z), 4.4 1 ( 2 H , s ) , 7.22 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz).

LC/MS [Condition 2]: Hold time 4.02 min; m/z 427.3 [M + Na]+, 349.3 [M-isobutene + H]+ ' 3 0 5.3 [Mi sobut en eC 02+ H ]+ (ESI Positive ion mode) 【化4 4 5】

Reference Example 2 6 0 - 2 -461 - 201211053 2 - Side Oxygen-3 - (4- {2 -Sideoxy-2 -[(tetrahydrofuran-2-yl)methylamino]ethyl} benzyl)- Preparation of 1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester 2-(4-{[8-(t-butoxy) obtained in Reference Example 260-1 Carbonyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}phenyl)acetic acid (24 mg, 0.059 mmol), 1-hydroxybenzotriene Addition of 1-ethyl-3-(3-dimethylaminopropyl) to azole (3 mg, 0.02 mmol) and tetrahydrofurfurylamine (purchased) (12 pL, 0.12 mmol) in chloroform (1 mL) After the carbodiimide hydrochloride (17 mg, 0.08 9 mmol) was allowed to stand at room temperature for 8 days, water (1 mL) was added and the organic layer was separated. The organic layer was washed with EtOAc (EtOAc) (EtOAc) 1H-NMR (300MHz, CDCl3) 5: 1.41-1.53 (lH, m), 1.4 5 (9H, s), 1.53-1.68 (2H, m), 1.74-2.0 1 (5H, m), 3.13 (2H, s), 3.14 (lH, ddd, J = 13.5, 7.4, 5.3 Hz), 3.28 (2H, ddd, J = 13.9, 11.0, 2.9 Hz), 3.54 (lH, d dd, J = 13.5, 6.5, 3.3 Hz) ), 3.56 (2H, s), 3.63 - 3.8 0 (2H, m), 3.80 (2H, brd, J = 12.3 Hz), 3.91 (lH, dq, J = 3.3, 7.0 Hz), 4.42 (2H, s ), 5.67-5.88 (lH, br m), 7.23 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.99 minutes; m/z 510.0 [M + Na]+ ( Ο ESI positive ion mode), m/z 486.3 [M-H]_ (ESI negative ion mode)

-462- 201211053 Example 2 6 0 2-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5 Manufacture of decyl-3-yl}methyl)phenyl]-indole-[(tetrahydrofuran-2-yl)methyl]acetamide (Compound No. 260)

2-sided oxo-3-(4·{2- side oxy-2-[(tetrahydrofuran-2-yl)methylamino]ethyl}benzyl)_methane-- obtained from Reference Example 260-2 3,8_ Diazo snail [45] 癸院-8- decanoic acid second vinegar (26 mg, 0.053 mmol) of 1,4-two chewing compound (1.3 m L) was added with 10% by mass hydrogen chloride methanol solution (〇 .13 mL), after standing at room temperature for 16 hours, concentrated and dried under reduced pressure. The residue was dissolved in N,N-dimethylformamide (imL), and triethylamine (22 μM and 4-(trifluoromethyl)benzyl bromide (9 μM) was added at room temperature. After 4 days, water (3 mL) and ethyl acetate (4 mL) were added to the reaction mixture, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by column chromatography. The title compound (1), 2 mg (yield: 52%) of white solid was obtained as the title compound (1M) (M.p., EtOAc, EtOAc, EtOAc, EtOAc) , m), 1.65-2.01 (7H, m), 2.43-2.61 (4H, br m), 3.1 3 (2 H, s), 3.1 4 ( 1 H ,ddd, J= 1 3.5, 7.4, 4.9 Hz) , 3.53 (lH, ddd, J = 13.9, 6.5, 3.3 Hz), 3.55 (4H, s), 3.63-3.78 (2H, m), 3.91 (lH, dq, J-3.7, 7.0 Hz), 4.41 (2H) , s), 5.78 (lH, 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 = 8.2Hz) 〇LC/MS [Condition 1]: Hold time 2.86 minutes; m/z 546.0 [M + H] + (ESI positive ion mode), m/z 590.2 [M + HCOO ]-(ESI Negative Ion Mode) -463- 201211053 [Chem. 4 4 7]

Example 2 6 1

4-({3-[((lr,4r)-4-{4-[hydroxy(phenyl)methyl)piperidin-1-carbonyl}cyclohexyl)methyl]-2-oxyloxy-1-oxole Manufacture of -3,8-diazospiro[4.5]nonane-8-yl}methyl)benzonitrile (Compound No. 261)

4-[(3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxan-1-) obtained in Example 154 Methanol - 3,8-diazospiro[4_5]nonane-8-yl)methyl]benzonitrile (3〇11^, 0.051111111〇1) in methanol (1.〇1111_tetrahydrofuran (〇.5mL) Add sodium borohydride (2.0 mg, 0.051 mmol) to the solution, stir at room temperature for 30 minutes, then add acetic acid (6 μM, concentrate to dryness under reduced pressure) and add methanol (1 mL) to the residue. The mixture was concentrated to dryness, and cyclopentyl methyl ether (2 mL) and water (1 mL) were added to the residue, and the organic layer was separated and concentrated to dryness under reduced pressure. Purification of the title compound (21 mg, yield 70%) as a colorless amorphous material (yield: EtOAc: EtOAc: EtOAc: 300MHz, CDC13) 6:0.87 - 1.40(5H,m), 1.40-2.1 3(1 3H, m), 2.27-2.5 1 (2H,m), 2.47-2.65 (4H,br m), 2.8 9 (0.5 Η , brt, J =

12.7 Hz), 2.96 (0.5H, 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 = 1 3.5 H z), 3.9 3 (0.5 H, brd, J = 8 -464- 201211053 13.1Hz), 4.3 9(lH,d,J = 7.4Hz), 4.5 8(0.5H,br d,J= 13.5 Hz), 4.69 (0.5H, br d, J = 13.1 Hz), 7.26-7.40 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz) . LC/MS [Condition 1]: Hold time 2.98 min; m/z 5 8 5.0 [M + H]+ (ESI positive ion mode), m/z 629.2 [M + HCO〇r (ESI negative ion mode)

Example 262 (lr,4〇-N-(4-cyanobenzyl)-4-((2-oxo-8-[4-(trifluoromethyl)benzyl]-1--- Manufacture of 3,8-diazospiro[4 ·5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 262)

(lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail obtained in Reference Example 6-3 [4.5]decane-3-yl}methyl)cyclohexane residual acid (20 mg, 0.044 mmol), 1-p-benzobenzotrimole (2 mg, 0.01 mmol) and 4-(aminomethyl)benzene The nitrile hydrochloride (purchased) (9.0 mg, 0.053 mmol) was dissolved in chloroform (1 mL), triethylamine (12 μί, 0.088 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (13 mg, 0.06 6 mmol) was allowed to stand at room temperature for 8 days. Water (1 mL) was added to the reaction mixture, and the organic layer was evaporated. The residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Colorless amorphous. 'H-NMR (300MHz, CDCl3) 6: 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 (lH, 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 (lH, br t, J = 5.7 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.43 (2H, dsJ = 8.2 Hz), 7.57 (2H,d,J = 8.2Hz), 7.61 (2H, d, J = 8.2Hz).

LC/MS [Condition 1]: Hold time 3.08 min; m/z 569.1 [M + H]+ (ESI positive ion mode), m/z 603.2 [M + Cir (ESI negative ion mode) [Chem. 4 4 9 Example 263

(lr,4r)-N-(4-cyanobenzyl)-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazo snail [4.5] decyl-3-yl]methyl}cyclohexanecarbamamine (Compound No. 263) Manufactured in Reference Example 17-2 (lr, 4r)-4-{ [8-(4-cyanide) Benzomethyl)-2-oxo-oxo-3,8-diazospiro[4·5]decan-3-yl]methyl}cyclohexanecarboxylic acid (0.10 g, 0.24 mmol) In a suspension of N,N-dimethylformamide (2 mL), triethylamine (0.1 mL, 0.72 mm), 1-hydroxybenzotriazole (10 mg, 0.072 mmol), 4- (Aminomethyl)benzonitrile hydrochloride (purchased) (48 mg, 0.29 mm 〇l) and 1-ethyl-3·(3-dimethylaminopropyl)carbodiimide salt 8 - 466- 201211053 Acid salt (6 9 mg, 0.33 mmol) was stirred at room temperature for 5 days. Water (4 mL) and chloroform (6 mL) were added to the mixture, and the organic layer was washed with water (5 mL?? The residue was purified by silica gel column chromatography (purified solvent: FL100D, manufactured by FUJI SILYSIA, developed solvent: chloroform/acetone = 2/1) to give the title compound (26 mg, yield 20%) as colorless. Shaped object

1H-NMR (300MHz, CDCl3) 5: 1.03 (2H, dq, J = 3.3s 12.5 Hz), 1.52 (2H, dq, J = 3.3, 12.5 Hz), 1.56-1.66 (lH, m), 1.69-1.85 (4H,m), 1.86-2.00(4H,m), 2.10(1 H,tt,J=l 1.9,3.3Hz),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 (l H, br t, J = 6.0 Hz), 7.3 6 (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]: Hold time 2.61 min; m/z 526.1 [M + H]+ (ESI positive ion mode), m/z 524.2 [M-HK (ESI negative ion mode)

[化4 5 0]

^ch3 Reference Example 264-1 Preparation of 4-(4-cyano basic oxy) hydrazine B-1,4-residual acid terpene vinegar The synthesis was carried out by the method described in WO20 0 7/1 067 05.

lH-NMR (300 MHz, CDCl3) 8: 1.47 (9H, s), 1.6 4-1.8 6 (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 (lH, tt, J = 7.4, 3.3 Hz), 6.95 (2H, d, J - 467 - 201211053 = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz). LC/MS [Condition 1]: Hold time 4.49 min; m/z 247.2 [M-isobutene + H]+, 203.2 [M-isobutene-CO2 + H] + (ESI positive ion mode) [Chem. 4 5 1]

Reference Example 264-2 Preparation of 4-(piperidin-4-oxy)benzonitrile hydrochloride The synthesis was carried out by the method described in WO2007/1 06705. 'H-NMR (300MHz, CDCl3) 5: 2.06-2.25 (2H, br m), 2.26-2.48 (2H, br m), 3 .1 8-3, 52 (4H, br m), 4.68-4.8 1 (1 H, br m), 6.96 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 9.0 Hz), 9.74 (2H, br s). LC/MS [Condition 1]: Hold time 0.49 min; m/z 203.2 [M + H]+ (ESI positive ion mode) [Chem. 4 5 2]

Example 2 6 4 4-{1-[4-({2-Sideoxy-8-[4-(trifluoromethyl)phenylmethyl]_1_spiro_3,8-diazospiro[4.5]癸Manufacture of alk-3-yl}methyl)benzhydryl]piperidine-4-oxindole benzonitrile. (Compound No. 264) 201211053 Substituted 4-benzyl substituted piperidine, using Reference Example 264-2 The title compound (20 mg, yield 68%) was obtained as colorless crystals. 1H-NMR (300MHz, CDCl3) 5: 1.73 (2H, ddd, J = 13.5, 8.6, 6.1 Hz), 1.74-2.1 3 (4H, br m), 1,92 (2H, br d, J = 1 3.5 Η z), 2.4 Ο - 2.6 5 (4 Η

, br m), 3. 14(2H, s), 3.26-4.03 (4H, br m), 3.5 5 (2 H, s), 4.4 5 (2 H, s), 4.67 (lH, 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]: Hold time 3.32 minutes; m/z 63 3.1 [M + H]+ (ESI positive ion mode), m/z 677.2 [M + HCOO]- (ESI negative ion mode) [Chemical 4 5 3]

Example 265 4-{1-[(11*,41')-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidine-4-yloxy}benzonitrile (Compound No. 265) Substituting 4-(aminomethyl)benzate The same reaction as in Example 262 was carried out to give the title compound (5 mg, m.p. Yield • 469- 201211053 54%) colorless amorphous. lH-NMR (300MHz, CDCl3) 6: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.46-1.68 (3H, br m), 1. 6 9 - 1 . 8 7 (8 Η, brm), 1 . 8 7 - 2.0 2 (4 Η, brm), 2.46 (lH, tt, J = 11.5, 3.3 Hz), 2.52-2.67 (4H, br m), 3.10 (2 H, d , J = 7.4

Hz), 3.26 (2H, s), 3.37-3.53 (lH, br m), 3.59 (2H, s), 3.60-3.83 (3H, br m), 4.62 (lH, tt, J = 6. l, 3.3 Hz), 6.95 (2H, d, J = 8 · 6 H z), 7.4 4 (2H, d, J = 8.2 Hz), 7.52-7.63 (4H, m). LC/MS [Condition 1]: Hold time 3.38 minutes; m/z 639.22 [M + H]+ (ESI positive ion mode), m/z 683.3 [M + HCO〇r (ESI negative ion mode) 5 4]

Example 2 6 6 4-[l-((lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[ Preparation of 4-(Aminomethyl)benzonitrile hydrochloride by the preparation of 4.5]decane-3-yl]methyl}cyclohexanecarbonyl)piperidin-4-yloxy]benzonitrile (Compound No. 266) The title compound (3 l mg, yield 43%) was obtained by the same procedure as the compound of 263. Colorless amorphous. *H-NMR (300MHz, CDCl3) 5: l. 〇 5 (2H, dq, J = 3.3, 12.3 Hz), 1.50-1.67 (3H, br m), 1.70-1.8 7 (8H, br m), 1.87 -2.01(4H,br m),2.47 -470- 201211053 (lH,tt,J=U.5,2.9Hz), 2.49-2.64(4H,br m),3.1 1 (2H,d,J = 7.4Hz ), 3.26 (2H, s), 3.38-3.53 (lH, br m), 3.57 (2H, s), 3.58-3.85 (3H, br ra), 4.63 (lH, 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_6 1 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 596.1 [M + H]+ (ESI positive ion mode), m/z 640.2 [M + HCO〇r (ESI negative ion mode) 5 5]

Example 267 4-[(3-{[(11:,4〇-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxyloxy-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-8-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 267)

3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidine-1-carbonyl)cyclohexyl]methyl b-oxo-3, 8-diazo snail obtained in Reference Example 25 [4.5] decane-2-one hydrochloride (20 mg, 0.040 mmol) and 3,5-difluoro-4-methanebenzonitrile (commercially available) (8.0 mg, 0.046 mmol) in methanol (1 mL) Add acetic acid (80 μM and borane-2-methylpyridine (5 mg, 0.05 mmol)' to the solution for 3 days at room temperature, then add borane-2-methylpyridine (2 mg ' 0.02 mmol) The mixture was further stirred for 2 6 days. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure, and the obtained residue was dissolved in methanol (ml). After adding chloroform (1 mL) and water (UmL) to the residue, the organic layer was separated and concentrated under reduced pressure -471 - 201211053. The obtained residue was purified by silica gel column chromatography (purified solvent: FL100D, manufactured by FUJI SILYSIA Co., Ltd., developing solvent: chloroform/acetone = 4/1) to give the title compound (18 mg, yield 72%). Colorless amorphous. , H-NMR (300MHz, CDC13) 6: 1.04 (2H.br q, J = 12.3Hz), 1.43-1.68 (4H, br m), 1.68- 1.86 (7H, br m), 1. 8 6 -2.0 0 (4H , br m), 2.46 (lH, tt, J = l 1.9, 2.5 Hz), 2.53-2.72 (4H, br m), 2.8 1 (1 H, br t, J = 12.3 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.20 (lH, br t, J = 1 2.3 H z), 3.2 2 (2 H, s), 3 . 5 1 (lH, tt, J = 10.6, 3.7 Hz), 3_75(2H, s), 3.98 (lH, brd, J = 13.5 Hz), 4_60 (lH, br d, J = 13.1 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.49 (2H) , dd, J = 8.2, 7.4 Hz), 7.59 (lH, t, J = 7.4 Hz), 7.94 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 619.0 [M + H]+ (ESI positive ion mode), m/z 663.1 [M + HCOO]- (ESI negative ion mode) 5 6]

Example 2 6 8 3-({(lr,4〇-4-[4-(4-cyanophenoxy)piperidin-1-carbonyl]cyclohexyl}methyl)-2-sideoxy-1- Production of oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 268) in place of 4-benzylidene piperidine hydrochloride, using Reference Example 2 6 4 - The same reaction as in the above-mentioned Example 472-201211053 Example 252 was carried out, except that the obtained 4-(piperidin-4-oxy)benzonitrile hydrochloride was obtained, to give the title compound (yield: 58 mg yield) 1H-NMR (CDCl3) 6: 1.06 (2H, q, J = 12.7 Hz), 1.46 (9H, s), 1.47-1.73 (5H, m), 1.73-2.09 (1 OH, m), 2.47 ( 1 H, br t, J = l 1.1 Hz), 3.07-3 .1 8 ( 2H, m), 3.26 (2H, s), 3.28 (2H, br t, J = 1 1 · 5 H z), 3.40 -3.5 7 ( 1 H , br m ), 3.56-4.04 (5H, br m), 4.63 (lH, 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 minutes; m/z 603.0 [M + Na]+ (ESI positive ion mode), m/z 625.2 [M + HC〇〇r (ESI negative ion mode) 4 5 7]

Example 269 φ 3-{[(lr,4r)-4-(4-cyanobenzylmethylcarbamoyl)cyclohexyl]methyl b 2-sided oxygen_1_oxo-3,8-diazo Preparation of spiro[4.5]decane-8-carboxylic acid dibutyl acrylate (Compound No. 269) in place of 4-benzylidene piperidine hydrochloride using 4-(aminomethyl)benzonitrile hydrochloride The same reaction as in Example 2 52 was carried out to give the title compound (5 5 mg, yield, yield) as a white solid. 1H-NMR (CDCl3) 6: 1.04 (2H, dq, J== 3-35l2, 3 Hz), 1-46 (9H, s) &gt; 1.49- 1.73 (5H, m), 1.73-2.02 (6H, n 〇, 2.1〇UH,tt,J = 12.3,3.3Hz), 3.1 l(2H,d,J = 7.8Hz), 3.26(2H,s),3-27(2H,br t, J-1 2.0Hz ), 3.8 6 -473 - 201211053 (2H, br d, J = 12.0 Hz), 4.49 (2H, d, J = 6.1 Hz), 5.88 (lH, 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]: Hold time 4.03 min; m/z 532.9 [M + Na]+ (ESI positive ion mode), m/z 509.1 [MH]-, 5 55.1 [M + HCO〇r ( ESI negative ion mode) [Chem. 4 5 8]

Example 2 7 0 l-[(lr,4r)-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazo snail [4.5] Manufacture of 4-(aminomethyl)benzonitrile hydrochloride by the manufacture of [decyl-3-yl}methyl)cyclohexanecarbonyl]-4-phenylpiperidin-4-carbonitrile (Compound No. 270) The title compound (26 mg, yield: 96%) was obtained as a colorless crystals of the title compound (yield: 1H-NMR (CDCl3) 5: 1.07 (2H, qJJ = 12.3 Hz) s1.44- 1.69 (3H, m),

1.72-2.04 (1 0Hsm), 2.1 9 (2H, br t, J = 1 2.3 Hz), 2.4 6 - 2.6 8 (4 H , br m ), 2.49 (lH, br t, J = 1 1.9 Hz), 3.0 2 (1 H , brt, J = 1 3 . 1 Hz), 3 .1 1 (2H, d , J = 7.4 Hz), 3.2 6 (2H, s), 3.55 (lH, br t, J = 1 3 _ 5 Hz), 3.5 8 (2 H, s), 4 · 〇 5 (lH, br d, J = 14.7 Hz), 4.85 (lH, br d, J = 14.3 Hz), 7.32 - 7.51 (7H, m), 7.57 (2H, d, J = 8_2 Hz). -474- 201211053 LC/MS [Condition 1]: Hold time 3.40 minutes; m/z 623.1 [M + H]+ (ESI positive ion mode), m/z 667.1 [M + HCO〇r (ESI negative ion mode) ) 【化4 5 9】

Example 2 7 1

1-((11*,4〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of 4-(aminomethyl)benzonitrile hydrochloride by using 4-methylcyclohexanecarbonyl)-1 2 3 4-phenylpiperidin-4-carbonitrile (Compound No. 271) The title compound (52 mg, yield 93%) was obtained as a colorless amorphous material - 475-1H, from phenylpiperidine-4-carbonitrile hydrochloride (purified). NMR (CDCl3) 6: 1.06 (2H, q, J = 11.9 Hz), 1.46-1.70 (3H, m), 2 1.71 - 2.01 (10H, m), 2.19 (2H, br, J = 11.9 Hz), 2.44-2.68(4H,br m ), 2.48(lH,br t,J=l 1,9Hz), 3.02(lH,br t, J= 1 3.1 Hz),3.1 1 (2H, d, J = 7.4Hz ), 3.26 (2H, s), 3.55 (lH, br t, J = 13.9 Hz), 3.57 (2H, s), 4.05 (lH, d, J = 14.3 Hz), 4.86 (lH, br d, J = l 3.5Hz), 7.3 1-7.50(7H,m), 7.6 1 ( 3 2H,d,J = 8.2Hz) 4 LC/MS[Condition 1]: Hold time 3.18 minutes; m/z5 8 0.0[M + H]+ (ESI positive ion mode), m/z 624.1 [M + HCOO]-(ESI negative ion mode) 201211053 [Chem. 4 6 0]

Reference Example 2 7 2 -1 4-[(cyclohexylmethylamino)methyl]- 4-hydroxypiperidine-carboxylic acid tert-butyl ester was produced in Reference Example 1-1. A solution of azapyr-[2.5]octane-6-carboxylic acid tert-butyl ester (〇.70g, 0.33mmol) in methanol (1.5mL) was added cyclohexylmethylamine (purchased) (85μί, 0.66mm〇) l) Stir with water (1.5 mL) at room temperature for 8 days. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. The residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> a colorless oil. 1H-NMR (CDCl3) 5: 0.90 (2H, q, J = l 1.5 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, br t, J = 11.9 Hz), 3.75 - 3.97 (2H, br m). [chemical 4 6 1] abc,, Reference Example 2 7 2 - 2 3-(cyclohexylmethyl)-2-oxo-oxo- 3,8-diazospiro[4.5]decane-8-carboxylate Manufacture of acid tert-butyl ester -476- 201211053

4-[(cyclohexylmethylamino)methyl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (86 mg, 0.26 mmol) obtained in Reference Example 2 72-1 To the solution of the oxane (3 mL), 1,1 carbonyldiimidazole (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), η-hexane (2 mL) and ethyl acetate (2 mL) were evaporated. The residue was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (CDCl3) 6: 0.96 (2H, q, J = 11.5 Hz), l.ll-1.3 2 (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). [化 4 6 2]

φ Reference Example 272-3 3-(cyclohexylmethyl)-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride was obtained in Reference Example 272-2. (cyclohexylmethyl)-2-oxo-l-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (59 mg, 0.17 mmol) in methanol (3 mL) 'After adding 10% by mass of hydrogen chloride in methanol (〇.4〇mL), the reaction mixture was allowed to stand at room temperature for 42 hours, and was allowed to stand at 4 (TC for 6 hours). Thereafter, the reaction mixture was concentrated to dryness under reduced pressure. The title compound (5 3 mg, yield, yield) was obtained as a yellow solid. - 477 - 201211053 LC/MS [condition 2]: retention time 〇·82 min; m/z 253.1 [M + H]+ ( ESI Positive ion mode) [Chem. 4 6 3]

Example 272 3-{4-[3-(Cyclohexylmethyl)-2-oxo-oxo-oxa-3,8-diazaspiro[4-5]nonane-8-carbonyl]benzyl}-8 -[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-2-one (Compound No. 272) was prepared by substituting 4-benzyl substituted pipe The pyridine was substantially the same as the Example except that 3-(cyclohexylmethyl)-1-oxo-3, 8-diazospiro[4.5]nonane-2-one hydrochloride obtained in Reference Example 272-3 was used. The same reaction of 253 gave the title compound (19 mg, yield: 90%) as colorless. 1H-NMR (CDCl3) 5: 0.96 (2H, q, J = 11.5 Hz), 1.08-1.35 (3H, m), 1.50-2.1 5 (1 3H, 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, brm), 3.29 (2H, s), 3.56 (2H, s), 4.36-4.65 (lH, br m ), 4.45(2H, br s), 7.3 1 (2 H, d, J = 8.2 H z), 7.4 0 (2 H, 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]: Hold time 3_42 minutes; m/z 683.2 [M + H]+ (ESI positive ion mode), m/z 727.2 [M + HCO〇r (ESI negative ion mode) -478- 201211053 【化4 6 4】

Reference Example 2 7 3 -1 - Production of 1-oxa-3,8-diazospiro[4-5]nonan-2-one hydrochloride

The 2-tert-oxy-1-oxo-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (95 mg, 〇.37 mmol) obtained in Reference Example 111-1 (MeOH) (2 mL) After adding 1 〇 mass% hydrogen chloride methanol solution (1 mL) to the solution, the reaction mixture was allowed to stand at room temperature for 3 days. After that, the reaction mixture was concentrated to dryness to dryness crystall 1H-NMR (DMSO-d6) 5: 1.85-2.06 (4H, m), 2.98-3.13 (2H, m), 3.13-3.24 (2H, m), 3.32 (2H, s), 7.65 (lH, br s ), 8.8 2 (2 Η, brs) » [化4 6 5]

Manufacture of [4-(difluoromethyl)benzyl]]i_oxo_3,8-diazospirol-2-one The 4-({2_ side oxygen_8_[4_() obtained in Reference Example 21 Trifluoromethyl)benzyl]-1-noise-3,8-diazospiro[4.5]decane_3_yl}methyl)benzoic acid (51 mg -479- 201211053, O.llmmol), 1- Hydroxybenzotriazole (5 mg, 0.03 mmol) and 1-oxo-3,8-diazospiro[4.5]nonan-2-one hydrochloride (24 mg, 0.12 mmol) obtained in Reference Example 273-1 were suspended in Chloroform (1 mL), triethylamine (63 μM, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbonated monoimine hydrochloride (33 mg, 0.17 mmol). Stirring was carried out for 21 days at 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 [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Colorless amorphous. 1H-NMR (CDC13) 5: 1.54-2.2 2 (4H, br m), 1.73 (2H, dt, J = 13.5, 7.0

Hz), l .92 (2H, d, J = 13.1 Hz), 2.41-2.65 (4H, br m), 3.1 4 (2H, s), 3.26 - 3.80 (3H, br m), 3. 3 9 ( 2 H, brs), 3.5 5 (2 H, s), 4.3 3 - 4.6 2 (1 H , brm ), 4.45 (2H, br s), 5 .1 0 ( 1 H, br s), 7.3 2 ( 2 H, d, J = 7.8 H z), 7.4 0 ( 2 H , 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]: Hold time 1.9 to 2.4 minutes; m/z 587.0 [M + H]+ (ESI positive ion mode), m/z 631.0 [M + HCO〇r, 5 8 5.1 [MH ] —(ESI Negative Ion Mode) [Chem. 4 6 6]

Example 273 3-[4-(3-Ethyl-2-oxo-l-oxo-3,8-diazospiro[4.5]decane-8-carbonyl)benzene-480- 201211053 methyl]-8 -[4-(Trifluoromethyl)benzyl]-1-che- 3,8-diazaspiro[4.5]valer-2-one (Compound No. 273) was produced in Reference Example 273-2 3-[4-(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-8-carbonyl)benzyl]-8-[4-(trifluoromethyl)benzene 1,2-oxo-3,8-diazospiro[4.5]decane-2-one (20111§, 0.0341^11〇丨)]^,1^-dimethyl

Potassium butyrate (5 mg, 0.05 mm 〇i) was added to the solution of carbamide (ImL), and the mixture was stirred at room temperature for 1.5 hours. Thereafter, ethyl iodide (4 μL) was added, and the mixture was stirred at room temperature for 4 hours. Acetic acid (6 μM, water (2 mL), and chloroform (4 mL) was added, and the organic layer was separated and evaporated to dryness. The residue was concentrated and dried, and the residue was purified by silica gel column chromatography (purified by: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The title compound (10 mg, EtOAc, EtOAc: EtOAc (EtOAc) 1,92(2H,br d, J= 1 3 .1 Hz), 2.4 3 - 2.6 5 (4 H ,br m), 3.14(2H,s ), 3.26-3.76(3 H,br m), 3 . 3 0 (2 H, s), 3.3 4 (2 H , q, J = 7.4 H z), 3 . 5 6 ( 2H, s), 4.3 3 - 4.62 (l H, br m), 4.4 5 ( 2 H, brs), 7.3 2 (2 H , 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]: Hold time 2.96 minutes; m/z 615.0 [M + H]+ (ESI positive ion mode), m/z 659.1 [M + HCO〇r (ESI Negative ion mode) -481 - 201211053 [Chem. 4 6 7]

Example 274 4-(3-{[(11*,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxanthoxy-1-oxo-3 , 8--diazospiro[4.5]decane-8-yl)-3-nitrobenzonitrile (Compound No. 274) was produced in Reference Example 255, 3-{[(lr, 4r)-4-( 4-benzylidene piperidine-bucarbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride (20 mg, 0.040 mmol) and 4 To a suspension of chloro-3-nitrobenzonitrile (7 mg, 0.040 mmol) in 1,4-dioxane (1 m L), N,N-diisopropylethylamine (21 μί, 0·12ιηιη) After 〇1), the reaction mixture was stirred at EtOAc EtOAc (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography (purification: FL100D, manufactured by FUJI SILYSIA, developed solvent: chloroform/acetone = 3/1) to give the title compound (23 mg, yield: 96%). 1H-NMR (CDCl3) 6: 1.07 (2H, q, J = 12.7 Hz) s1.5 1-1.72 (3H, m), I. 73-2.1 l (12H, m), 2.48 (lH, Br t, J = 1 1 .1 Η z), 2.8 2 (1 Η, brt, J = II. 9Hz) , 3.14 (2H, d, J = 7.4 Hz), 3.19-3.3 1 (3H, m), 3.35 (2H, s), 3.36-3.47 (2H, m), 3.52 (1 H, tt, J = l 0.6 , 3.7 Hz), 3.99 ( 1 H, br d, J = 13.5 Hz), 4.61 (lH, br d, J = 13.1 Hz), 7·14 (1 H, d, J = 9.0 Hz), 7.49 ( 2H ,t,J = 7.4Hz),7_59(lH,tt,J = 7.4,l_2Hz), 7.68(lH,dd,J = 8.6, -482- 201211053 2.0Hz), 7.95(2H,d,J = 7.4Hz ), 8.12 (lH, d, J = 2.0 Hz) LC/MS [Condition 1]: Hold time 4.31 min; m/z 614.1 [M + H]+ (ESI positive ion mode), m/z 658.2 [M + HCOO]_(ESI negative ion mode) [Chem. 4 6 8]

Example 275 3-(4-{2-[4.(4-Cyanophenoxy)piperidin-1-yl]-2-oxoethyl}benzyl)-2-oxan-1- The production of the third ester of oxa-3,8-diazosuccinyl[4.5]decane-8-carboxylic acid (Compound No. 275) was obtained by the 2-(4-{[8-(t-) obtained in Reference Example 260-1. Butoxycarbonyl)-2-oxo-1-carbo-3,8-diazospiro[4.5]decane-3-yl]methyl}phenyl)acetic acid (60 mg, 0.15 mm 〇l), 1- a suspension of 4-(piperidin-4-oxy)benzonitrile hydrochloride (35 mg, 0.15 mmol) in chloroform, obtained from benzotriazine (6 mg, 0.05 mmol) Triethylamine (62 μί, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg, 0.22 mmol) were taken at room temperature Stir for 19 days. 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 [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Shaped object. , H-NMR (CDCl3) 5: 1.44 (9H &gt; s), 1.59 - 1.99 (8H, m), 3.13 (2H, s), -483 - 201211053 3.27 (2H, t, J = 12.3Hz), 3.40- 3.52 (lH, m), 3.67 (lH, ddd, J = 13.9, 7.8, 4.1 Hz), 3.70-3.9 1 (4H, m), 3.75 (2H, s), 4.41 (2H, s), 4.59 (l H, 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 = 9.0Hz). LC/MS [Condition 1]: retention time 4.27 minutes; m/z 610.8 [M + Na] +, 532.9 [M-isobutene + H] + ' 4 8 8.9 [ Μ - isobut en e - C Ο 2 + Η ] + (ESI positive ion mode), m/z 633.1 [M + HCO〇]- (ESI negative ion mode) [Chem. 4 6 9]

Example 2 7 6 (11*,4]:)-1^-(Benzo[(1][1,3]dioxazole-5-ylmethyl)-4-({2- Side Oxy-8 -[4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[45]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 276) The substitution of 4-(aminomethyl)benzonitrile hydrochloride was carried out in the same manner as in Example 262 except that benzo[du],3]dioxazol-5-ylmethylamine (purchased) was used. The reaction gave the title compound (1 7 mg, yield: 65%) as a colorless amorphous material. 1H-NMR (CDCl3) 6: 1.01 (2H, br q, J = 12.9 Hz), 1.41-1.67 (3H, m ), 1.69 -1 · 87(4H,m),1 ·87-2.1 4(5H,m),2.43-2.66(4H,m) ,3.09( 2H,d,J = 7.4Hz), 3.25(2H, s), 3.57 (2H, s), 4.3 3 (2H, d, J = 5.7 Hz), 5.65 (lH, br t, J = 5.3 Hz), 5.95 (2H, s), 6.67-6.8 1 (3H, m), 7.44 (2H, d, -484- 201211053 J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz) LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 5 8 7.9 [ M + H]+ (ESI positive ion mode), m/z 632.1 [M + HCOO]- (ESI negative ion mode)

Reference Example 2 7 7 -1 [Chemical 4 7 0 ]

Preparation of 3-hydroxy-4-({[(1!*,4〇-4-(methoxycarbonyl)cyclohexyl]methylamino}methyl)piperidine-1-carboxylic acid tert-butyl ester (lr, 4r)-4-(aminomethyl)cyclohexanecarboxylic acid methyl hydrochloride (0.10 g, 0.48 mmol) obtained in Reference Example 2-1 and 1-oxo obtained in Reference Example 1-1 A solution of 6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.10 g, 0.48 mmol) in methanol (1.5 mL)-water (1 mL) was added 1M aqueous sodium hydroxide (0.48 mL) The reaction mixture was stirred at room temperature for 5 days. After the insoluble material was filtered and removed, 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 crystals crystals crystals crystals crystalssssssssssssssssssssssssss , 12.3 Hz), 1.32-1.56 (3H, m), 1.46 (9H, s), 1.86 (2H, br d, J = 12·7Ηζ), 1.92-2.15 (6H, m), 2.24 (lH, tt, J = 12.3, 3.3 Hz), 2.44-2.56 (4H, m), 3.16 (2H, br t, J = 1 1.9 Hz), 3.67 (3H, s), 3.75-3.99 (2H, br m) -485 - 201211053 【化4 7 1】

Reference Example 2 7 7 - 2 3-{[(lr,4r)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-thio-1-oxo-3,8-diazospiro[4 5] 4-Hydroxy-4-({[(lr, 4r)-4-(methoxycarbonyl)cyclohexyl]) obtained from the decane-8-carboxylic acid tert-butyl ester obtained in Reference Example 277-1. Addition of 1,1,-thiocarbonyl to a solution of methylamino}methyl)piperidine-1-carboxylic acid tert-butyl ester (0.1 〇g, 0-26 mmol) in 1,4-dioxane (2 m L) The diimidazole (0.12 g, 0.68 mmol) was allowed to stand at 90 ° C for 43 hr. Hexane (2 ml), ethyl acetate (2 mL) and water (2 mL) were evaporated. The residue was purified by silica gel column chromatography (purified solvent: FL100D, product: chloroform/ethyl acetate = 6/1), to give the title compound (6 8 mg, yield 61%) White solid. 1H-NMR (CDCl3) 8: 1.12 (2H, dq, J = 3.3512.3 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 (lH, tt, J = 11.9, 3.7 Hz), 3.37 ( 2H, br t, J = 11.9 Hz), 3.46 (2H, s), 3.5 1 (2H, d, J = 7.0 Hz), 3.67 (3H, s), 3.82 (2H, br d, J = 11.9 Hz). LC/MS [Condition 2]: Hold time 4.61 min; m/z 449.2 [M + Na] +, 42 7·2 [Μ + Η]+, 371.1 [M-isobutene + H] + (ESI positive ion mode ) -486- 201211053 【化4 7 2】

Reference example 2 7 7 - 3

(lr,4r)-4-{[8-(t-butoxycarbonyl)-2-thioxo- 3,8-diazospiro[4.5]decane-3-yl]methyl} The cyclohexanecarboxylic acid was produced in the 3-{[(lr,4r)-4-(methoxycarbonyl)cyclohexyl]methyl}-2-thio-1-oxo obtained in Reference Example 2 77-2. 3,8-diazospiro[4.5]decane-8-carboxylic acid terpene vinegar (68 mg, 0.16 mmol) in a solution of 1,4-dicholine (1.4 mL), water (0.50 mL) and 1 M An aqueous sodium hydroxide solution (0.18 mL) was stirred at room temperature for 1 day. After adding acetic acid (1 μίί) to adjust the pH to 7, the reaction mixture was concentrated to dryness under reduced pressure. Water (2 mL) and chloroform (4 mL) and EtOAc (EtOAc (EtOAc) LC/MS [Condition 1]: Hold time 5.56 min; m/z 43 5.0 [M + Na] + (ESI positive ion mode), m/z 411. 〇 [MH]- (ESI negative ion mode) [Chem. 4 7 3]

Example 277 -487- 201211053 3-({(lr,4r)-4-[4-(4-Cyanophenoxy)piperidin-1-carbonyl]cyclohexyl}methyl)-2-thio- Manufacture of 1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 277)

(lr,4r)-4-{[8-(t-butoxycarbonyl)-2-thio-1-oxo-3,8-diazospiro[4.5]decane obtained in Reference Example 277-3 -3-yl]methyl}cyclohexanecarboxylic acid (65 mg, 0.16 mmol), 1-p-benzobenzotriazine (6 mg, 0.05 mmol) and 4-(piperidine-4-4) obtained in Reference Example 264-2 To a suspension of oxy)benzonitrile hydrochloride (41 mg, 0.17 mmol) in chloroform, triethylamine (66 μί, 0.47 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) The carbodiimide hydrochloride (45 mg, 0.24 mmol) was allowed to stand at room temperature for 26 days. Thereafter, water (3 m L) was added, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Shaped object.

1H-NMR (CDCl3) 6: 1.18 (2H, q5J = 12.7 Hz), 1.46 (9H, s), 1.49-2.10 (15H, m), 2.50 (lH, br, J = 11.9 Hz), 3.28-3.54 (3H, m), 3.45 (2H, s), 3.55 (2H, d, J = 7.0 Hz), 3.5 9-3.95 (5H, m), 4.57-4.69 (lH, m), 6.96 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz) » LC/MS [Condition 1]: Hold 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) [Chem. 4 7 4]

8 201211053 Reference 278 -1 Manufacture of 4-(quinoline-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Add N to a solution of 4-chloromorpholine (0.20 g, 1.2 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.34 g, 1.8 mmol) in N,N-dimethylformamide (2 mL) N-Diisopropylethylamine (0.43 mL, 2.4 mmol). The reaction mixture was placed at 100 ° C for 22 hr. Ethyl acetate (2 mL) and water (2 mL) were added to the residue. The residue was purified by silica gel column chromatography (purified solvent: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc Amber oil. 1H-NMR (CDC13) 5: 1.5 l (9H, s), 3.1 3-3.25 (4H, m), 3.68-3.78 (4H, m), 6.85 (lH, d, J = 4.9 Hz), 7.5 1 ( lH,ddd,J = 8.2,7.0,1.2 Hz), 7.68 (lH,ddd,J = 8.2,7.0,1.6 Hz), 8.02 (lH,dd,J = 8.2,1.2 Hz), 8.07 (l H,d , J = 8.2 Hz), 8_75 (lH, d, J = 4_9 Hz). [化 4 7 5]

n^nh 2HCI Reference Example 2 7 8 - 2 4-(piperazin-1-yl)quinoline dihydrochloride salt Manufactured as 4-(quinolin-4-yl)piperazine obtained in Reference Example 278-1 After a solution of hydrazine-carboxylic acid tert-butyl ester (〇27 g, 0.86 mmol) in methanol (6 mL) was added 1% by mass of hydrogen chloride in methanol (2 mL), the reaction mixture was at 55. (:3, 下, -489-201211053, while standing to dryness under reduced pressure to give the title compound (0 25 g, yield) as a white solid. LC/MS [condition 1]: retention time 〇 45 minutes; m/z2l4.1[M + H]+ (ESI positive ion mode) [Chem. 4 7 6]

Example 2 7 8 4-{[2-Sideoxy-3-({(lr,4r)-4-[4-(porphyrin-4-yl)piperazine-1-carbonyl)cyclohexyl]methyl} Preparation of 1-oxa-3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. 278) Substituting 4-(aminomethyl)benzonitrile hydrochloride, The title compound (25 mg, yield: 86%) was obtained as colorless, m. m. Amorphous. 1H-NMR (CDCl3) 5: 1.08 (2H, q, J = 12.3 Hz), 1.5 3- 1.65 (lH, m), 1.61 (2H, q, J = 13.1 Hz), 1.71-1.90 (6H, m) , 1.95 (2H, br d, J = l 3.5 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 (lH, d, J = 4.9 Hz), 7.45 (2H, d, J = 8.2 Hz) , 7.53 (lH, t, J = 7.0 Hz), 7.6 1 (2H, d, J = 8.2 Hz), 7.69 (lH, dt, J = 1.2, 7.6 Hz), 8.03 (lH, d, J = 8.2 Hz) ), 8.08 (lH, d, J = 8.2 Hz), 8.77 (lH, d, J = 4.9 Hz). -490- 201211053 LC/MS [Condition 1]: Hold time 0.51 min; m/z606_9[M + H]+ (ESI positive ion mode) ' m/z 651.1 [M + HCOO]-(ESI negative ion mode) 4 7 7]

Example 2 7 9 3-{4-[4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-carbonyl]benzyl}-8-[4-(trifluoro) Preparation of methyl) benzyl pi-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 279) Substituted 4-benzyl substituted piperidine using 6-fluoro-3- The same reaction as in Example 2W was carried out to give the title compound (3Omg, yield as quantitative) as a colorless amorphous material, except (p-piperidin-4-yl)benzo[d]isoxazole (purified). . 1 H-NMR (CDCl 3 ) 6 : 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 · 3 7-2 · 6 9(4H,br m),3 · Ο 3 - 3 · 3 2 (2H,br m),3_14(2H,s),3.38(lH,tt,J=ll.l,4.1 Hz), 3.56 (2H, s), 3.71-4.13 (lH, br m), 4.4 6 (2 H , s), 4.5 5 -4.9 4 ( 1 H, brm), 7.09 ( lH, dt, J = 2.0 , 8.6 Hz), 7.2 7 (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 Hz), 7_64 (lH, dd, J = 8.6, 5.3 Hz). LC/MS [Condition 1]: Hold time 3.46 minutes; m/z 65 0.9 [M + H]+ (ESI positive ion mode), m/z 695.0 [M + HCO〇r (ESI negative ion mode) -491 - 201211053 Example 4 8 Ο 4-{[3-({(1!^,41:)-4-[4-(6-fluorobenzo[(1]isoxazol-3-yl) Piperidine-1-carbonyl]cyclohexyl}methyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (compound number) Manufacture of 280) in place of 4-(aminomethyl)benzonitrile hydrochloride, using 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (purchased), substantially The title compound (41 mg, yield 91%) was obtained as a colorless crystals of the title compound (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3H,m)s 1.71-2.04(10H,m),2.08-2.25 (2H,br m), 2.4 7 - 2.6 8 (4 Η , brm), 2.50 (lH,br t, J= 1 1.5 Hz), 2.8 8 (1 H , brt, J = 1 1 . 5 H z), 3 . 1 1 (2 H, d , J = 7.8 Hz), 3.18-3.3 l(lH, br m), 3.27 (2H, s ), 3.33 (lH, tt, J = 11.5, 3.7 Hz), 3.57 (2H, s), 4.05 (lH, d, J = 13.9 Hz), 4.67 (lH, br d, J = 13.9)

Hz), 7.08 (lH, dt, J-2.0, 8.6 Hz), 7.27 (lH, dd, J = 8.2, 2.5 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.6 1 (2H, d, J = 8.2 Hz), 7.63 (lH, d, J = 8.6 Hz). LC/MS [Condition 1]: Hold time 3·24 minutes; m/z614_0[M + H]+ (ESI positive ion mode), m/z 658.1 [M + HCO〇r (ESI negative ion mode) -492- 201211053 【化4 7 9】

Reference Example 2 Production of 8 1 -1 4-(3-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester The synthesis was carried out by the method described in WO2007/1 06705.

1 H-NMR (CDC13) 5: 1.47 (9H, s), 1.67-1.8 l (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 (lH, tt, J = 7.4, 3.3 Hz), 7.10-7.18 (2H, m), 7.24 ( 1 H, dt, J = 7.4 , 0.8 Hz), 7.3 8 ( lH, td, J = 7 · 8, 0.8 Hz). LC/MS [Condition 1]: Hold time 4.59 minutes; m/z 247.0 [M-isobutene + H]+, 203.0 [M-isobutene-C02 + H] + (ESI positive ion mode) [Chem. 4 8 0]

Reference Example 281-2 Preparation of 3-(piperidin-4-oxy)benzonitrile hydrochloride The synthesis was carried out by the method described in W〇2〇07/1 067 05. 4- and 11 (〇河3〇-(16)3:1,74].9 1(21111), 2.03-2.19(21111), 2.97-3.14(2H,m),3.16-3.3 2(2H,m ), 4.74 (lH, tt, J = 7.8, 3.7 Hz), 7.35 (lH, d, J = 7.8 Hz), 7.43 (lH, d, J = 7.8 Hz), 7.5 1 (lH, t, J = 7.8) Hz), 7.54 - 7.56 (lH, m), 8.88 (2H, br s) LC/MS [Cond. 1]: Hold time 0.55 min; m/z 203.1 [M + H] + ( -493 - 201211053 ESI Positive ion mode) [Chemical 4 8 Example 2 8 1 ' 3-{1-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxa-3, Preparation of 8_diazospiro[4_5]decane-3-yl}methyl)benzhydryl]piperidine-4-oxo}benzonitrile (Compound No. 281) Substituted 4-benzyl-substituted piperidine The title compound (3 〇 mg, yield) was obtained from the title compound. To a quantitative basis, a colorless amorphous material. 1H-NMR (CDC13) 6: 1.65-2.17 (8H, m), 2.39-2.64 (4H, m), 3.14 (2H, s), 3.29-3.52 (lH, m) , 3.56 (2H, s), 3.5 8-4.06 (3H, m), 4.45 (2 H, s), 4.56-4.66 (lH, m), 7.11-7.18 (2H, m), 7.22-7.29 (lH, m, overlappedbyCHC13), 7.32 (2H, d, J = 8.2 Hz), 7.39 (lH, 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]: Hold time 3.42 minutes; m/z 63 3.0 [M + H]+ (ESI positive ion mode), m/z 677.0 [M + HCOO]_ (ESI negative ion mode) -494- 201211053 [Chem. 4 8 2] Example 2 8 2

3-{l-[(lr,4r)-4-({2-Sideoxy-8-[4-(difluoromethyl)benzyl]-1-che-3,8-diaza snail [4 _5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidin-4-yl}benzonitrile (Compound No. 2 82) was produced by substituting 4-(aminomethyl)benzonitrile hydrochloride The title compound (3 2 mg, yield was obtained from the title compound Quantitative) colorless amorphous material.

1H-NMR (CDC13) 5: 1.06 (2H, br q, J - 1 2.7 Η z), 1.4 7 - 1 . 6 9 (2 Η , m , overlappedbyH20), 1.69-l_87 (8H, m), L.87-2.06(4H,m), 2.47( lH,tt,J = l 1.9,2.9Hz), 2.49-2.6 5(4H,m),3.1 l(2H,d,J = 7.4Hz), 3.26 (2H, s), 3.38-3.5 1 (lH, m), 3.52-3.89 (3H, m), 3.57 (2H, s), 4.50-4.62 (1H, m), 7.10-7.1 8 (2H, m) , 7.23 - 7.29 ( lH, m, overlappedbyCHC13 ), 7.39 (lH, t, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.42 minutes; m/z 63 9.0 [M + H]+ (ESI positive ion mode), m/z 683.1 [M + HCOO]- (ESI negative ion mode) -495- 201211053 [化4 8 3]

Example 2 8 3 6-(3-{[(11*,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxan-1-one -3,8-diazospiro[4·5]nonane-8-yl)nicotinonitrile (Compound No. 283) was produced in Reference Example 255, 3-{[(lr, 4r)-4-(4- Benzylpyridinyl-1-carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride (20 mg, 0.040 mmol) and 6- After adding triethylamine (22 pL, 0.16 mmol) to a suspension of chloronicotinonitrile (purchased) (7 mg, 0.05 mmol) in ethanol (1 mL), the reaction mixture was stirred at 70 ° C for 33 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (purified product: FL100D, manufactured by FUJI SILYSIA, developing solvent: chloroform/acetone = 3/1) to give the title compound (16 mg, yield 70%). 1H-NMR (CDCl3) 5: 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 (2H, br d, J = 13.9 Hz), 2.48 (lH, br t, J = 1 1.9 Hz), 2.8 2 (1 H, br t, J = 1 1.9 Hz), 3.1 3 ( 2H,d,J = 7.0Hz), 3.21(lH,br t,J = 12.4Hz), 3.29(2H,s),3.42-3.61( 3H,m),3.99(lH,br d,J=13.9Hz ), 4.25 (2H, br d, J = 13.5 Hz), 4.61 (lH, br d, J = 13.9 Hz), 6.65 (lH, d, J = 9.0 Hz), 7.49 (2H, t, J = 7.4 Hz) s 7.60 (lH, t , J = 7.4 Hz), 7.62 (lH, dd, J = 9.0, 2.5 Hz), 7.95 (2H, d, J = 7.8 Hz), 8_41 (lH, d, J = 2.0 Hz) -496- 201211053 LC /MS [Condition 1]: Hold time 4.11 minutes; m/z 569.9 [M + H]+ (ESI positive ion mode), m/z 614.0 [M + HCO〇r (ESI negative ion mode)

HCI Reference Example 2 8 4

(11*,4〇-heart (4-cyanobenzyl)-4-[2- sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl] Preparation of cyclohexanecarbamide hydrochloride 3-{[(lr,4r)-4-(4-cyanobenzylaminecarbamyl)cyclohexyl]methyl}-2 obtained in Example 269 - side oxy-1-oxo-3,8-diazospiro[4.5]decane-8-residual acid tert-butyl ester (51 mg, 0-10 mmol) in a solution of two chews (lmL) - acetonitrile (1 mL), added A 10 mass% hydrogen chloride methanol solution (0.20 mL) was allowed to stand at room temperature for 1 day. 1H-NMR (DMSO-d6) 8: 0.9 1 (2H, q, J = 12.3 Hz), 1.37 (2H, q, J = 13.1 Hz), 1.46-1.6 1 (1 H, m), 1 . 69(2H,br d, J = 1 2.3 Η z), 1. 7 9 (2 H ,brd, J=13.5H), 1.89-2.07(4H,m), 2.16(lH,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 (lH, t, J = 5.7 Hz), 8.92 (2H, br s). LC/MS [Condition 1]: Hold time 0.5 to 1.1 minutes; m/z 410.9 [M + H] + (ESI positive ion mode), m/z 454.9 [M + HCO〇r (ESI negative ion mode) 497- 201211053 【化4 8 5】

Example 2 8 4 (11*,41')-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-weight Stomach substitution of 3-[[11',41')-4-(N-[[[11],41')-4-) 4-Benzylmercaptopiperidine-1 -carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride, obtained using Reference Example 284 (lr,4r)-N-(4-cyanobenzyl)-4-[(2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-3-yl)methyl In the same manner as in Example 267, the title compound (3 mg, yield: 3%) was obtained as white solid. 1H-NMR (CDCl3) 5: 1.02 (2H, dq, J = 2.9, 12.3 Hz), 1.52 (2H, dq, J = 2.9, 13.5 Hz), 1.57-1.66 (lH, m), 1.69 -1.84 (4H, m), 1.85-2.01 (4H, m), 2.09 (lH, tt, J = 12.3, 2.9 Hz), 2.50-2.74 (4Hsm), 3.08 (2H, d, J = 7.8 Hz), 3.22(2H,s),3.7 5(2H5s), 4.49(2H,d5J = 6.1Hz), 5.8 7(l H,br t,J = 6.1Hz), 7.22(2H,d,J = 6.1Hz), 7.36 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 2.86 minutes; m/z 561.9 [M + H]+ (ESI positive ion mode), m/zm/z 560.0 [MH]·, 606.1 [M + HCOO ]_(ESI negative ion mode) -498- 201211053 【化4 8 6】

HCI Reference Example 2 8 5

4-(l-{(lr,4r)-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decan-3-yl)methyl]cyclohexanecarbonyl} 3-({(lr,4r)-4-[4-(4-Cyanophenoxy)piperidin-1-) obtained in Production Example 268, <RTIgt; Carbonyl]cyclohexyl}methyl)_2_sideoxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (54 mg, 0.093 mmol) in acetonitrile (2 mL) Into a 10 mass% hydrogen chloride methanol solution (〇. 20 mL), the mixture was allowed to stand at room temperature for 1 day, and then concentrated to dryness under reduced pressure. The residue was washed with ethyl acetate (2 mL) toield 'H-NMR (DMSO-d6) 5: 0.99 (2H, q, J = l 1.9 Hz), l. 3 6 (2H, q, J = l 1.5 Hz), l .44-1 · 75 (7 Η, m), l · 85-2.0 7 (6 Η, m), 2.58 (lH, 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 (lH, 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]: Hold time 2.88 minutes; m/z 480.9 [M + H]+ (ESI positive ion mode), m/z 525_0 [M + HCO〇]- (ESI negative ion mode) -499- 201211053 [化4 8 7]

Example 285 4-{[3-({(lr,4r)-4-[4-(4-Cyanophenoxy)piperidine-1-carbonyl)cyclohexyl]methyl}-2 - sideoxy- Production of 1-oxo-3,8-diazospiro[4.5]decane-8-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 285) in place of 3-{[(lr, 4r) -4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride, used Reference Example 28 5 4-(1-{(11*,4〇-4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl))) The title compound (14 mg, yield: 58%) was obtained as a white solid, m. m. m. -NMR (CDCl3) 5: 1.04 (2H, q, J = 12.7. Hz), 1.45 - 1.67 (3H, m), 1.67-2.02 (1 2H, m), 2.46 (1 H, br, J = 11.5) Hz), 2.54-2.78(4H,m), 3.09(2H,d,J=7.0Hz), 3.23(2H,s), 3.37-3.55(lH,br m),3.56-3.86 (3H,m), 3.76 (2H, s), 4.5 6-4.69 (lH, m), 6.9 6 (2H, d, J = 8.6 Hz), 7.2 3 (2H, d, J = 6.1 Hz), 7.59 (2H, d, J = 8.6 Hz) LC/MS [Condition i]: Hold time 3.30 min; m/z 632.0 [Μ + Η]+ (ESI positive ion mode), m/z 676 .1[M + HCOO]-(ESI Negative Ion Mode) [Chem. 4 8 8]

-500- 201211053 Reference Example 2 8 6 - 1 4-(2-Chlorophenylamino)piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-oxo piperidine-1-carboxylic acid tert-butyl ester (〇.38g, 1.9mm〇l) in 1,2-dichloroethane (4mL) was added 2-chloroaniline (0.1 mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetate sodium hydride (0.60 g, 2.8 mmol), and the reaction mixture was stirred at room temperature for 1 day. Thereafter, a saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture, and the mixture was stirred for 30 minutes and then 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 (purifying agent: FL100D, manufactured by FUJI SILYSIA, developing solvent: η-hexane/ethyl acetate = 3/1). The title compound (0.29 g, yield) was obtained as a colourless oil. 1H-NMR (CDC13) 5: 1.35-1.5 l (2H, m), 1.46 (9H, s), 1.96-2.11 (2 H, m), 2.97 (2H, t, J = 11.9 Hz), 3.38-3.55 (lH,m), 3.91-4.13 (2H, ^ br m), 4.20 (lH, br d, J = 6.9 Hz), 6.62 (lH, td, J = 7.3, 1.3 Hz), 6.68 (lH, d, J = 7.9 Hz), 7.12 (lH, ddd, J = 7.9, 7.3, 1.3 Hz), 7.25 (lH, dd, J = 7.6, 1.7 Hz). LC/MS [Condition 2]·• Hold time 4.83 min; m/z 310.9 [M + H]+, 254.9 [M-isobutene + H] + (ESI positive ion mode)

[Chemical 4 8 9] 2HCI -501 - 201211053 Reference Example 2 8 6 - 2 N-(2-Chlorophenyl)piperidin-4-amine dihydrochloride salt was produced in place of 4-(quinoline-4-yl) Piperazine-1-carboxylic acid tert-butyl ester, except using 4-butyl 2-(2-chlorophenylamino)piperidine-1-carboxylate obtained in Reference Example 286-1, was substantially carried out with reference examples. The same reaction of 27-8-2 gave the title compound (m. LC/MS [Condition 2]: Hold time 1.74 min; m/z 211. 〇 [M + H]+ (ESI positive ion mode) [Chem. 4 9 0]

Example 2 8 6 4-{[3-({(1!*,4〇-4-[4-(2-chlorophenylamino))piperidine-1-carbonyl]cyclohexyl}methyl)-2 -Side-oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 2 8 6) was substituted for 4-(aminomethyl)benzene The same reaction as in Example 263 was carried out in the same manner as in Example 263, to give the title compound, using the N-(2-chlorophenyl)piperidin-4-amine dihydrochloride salt obtained from Reference Example 28 6-2. (24 mg, yield 83%) of colorless amorphous material. 1H-NMR (CDCl3) 5: 1.05 (2H, q, J = 11.5 Hz), 1.32-1.69 (5H, m) J 1.70-1.87 (6H, m ), 1.94 (2H, d, J = 12.7 Hz), 2.03-2.2 1 (2H, m), 2.47-2.66 (4H, br m), 2.47 (lH, tt, J = 11.9, 2.9 Hz), 2.92 ( lH, br t, -502- 201211053 J=11.9Hz), 3.11 (2H, d, J = 7.8Hz), 3.22 (lH, br t, J = 1 2.3 Η z), 3.2 6 (2H, s), 3.47-3.63(lH,m),3.57(2H,s),3.88(lH,br d,J=13.5Hz), 4.2 1(lH,d,J = 7.8Hz), 4.46(lH,br d,J = 13.5 Hz), 6.64 (lH, dt, J = 1.2, 7.8 Hz), 6.68 (lH, d, J = 8.6 Hz), 7.14 (lH, dt, J = 1.2, 7.8 Hz), 7.26 (lH, 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]: Hold time 3.36 minutes; m/z 603.8 [M + H]+ (ESI positive ion mode), m/z 648_0 [M + HCOO]- (ESI negative ion mode) [Chem. 4 9 1 】

Reference Example 2 8 7 -1 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester was produced in 4,6-dichloropyran (0-50 §, 3.4111111 〇1) Acetonitrile (251111^) solution ^ Piperazine-1 -carboxylic acid tert-butyl ester (〇.63g, 3.4mmol) and triethylamine (1.4mL, 10.1mmol) were added, and the reaction mixture was stirred at 80 ° C for 4 hours. After concentration, it was concentrated to dryness under reduced pressure. Ethyl acetate (5 mL) and water (5 mL) were added to the residue. The organic layer was evaporated. The title compound (〇64 g, yield: 64%) 1H-NMR (CDC13) 5: 1.49 (9H, s), 3.4 8-3.5 9 (4H, m), 3.5 9-3.70 (4H, m), 6.50 (1H, s), 8.39 (lH, s). -503- 201211053 【化4 9 2】

Reference Example 2 Preparation of 8 7 - 2 4-(pyrimidin-4-yl)piperazine-1-carboxylic acid terpene vinegar 4-(6-chloropurine, steep _4-yl obtained in Reference Example 287-1 a solution of piperazine-1-decanoic acid in the third butyl group (0.30 g, 1.0 mmol) in ethanol (15 mL) under a nitrogen atmosphere, 10% by mass of palladium on carbon (60 mg), triethylamine (2.1 mL, 15 mmol) and formic acid (0.28 mL, 7.5 mmol) were stirred and mixed at room temperature for 1 day, and then the catalyst was filtered and removed, and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (1 mL) and aq. EtOAc (EtOAc) 6491%) of a white solid. [Chem. 4 9 3] Reference Example 2 8 7 - 3 4-(piperazin-1-yl)pyrimidine dihydrochloride was produced in place of 4-(quinolin-4-yl)piperazine-1-carboxylic acid The butyl ester was subjected to the same reaction as in Reference Example 278-2 except that 4-(pyrimidin-4-yl)piperazine-1 -carboxylic acid tert-butyl ester obtained in Reference Example 2 8 7 - 2 was used to give the title. Compound (76 mg, yield in quantitative) of white solid. H-NMR (DMSO-d6) 5: 3.18-3.30 (4H, br m), 3.99-4.1 9 (4H, m), -504 - 201211053 7.27 (lH, d, J = 7.6 Hz), 8.44 (lH, d, J = 7.3 Hz), 8.90 (lH, s), 9.65 (2 H, br s) 〇 [4 4 4]

Example 287

3-({(11&quot;,41')-4-[4-(pyrimidin-4-yl)piperazine-1-carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl)benzene Preparation of methyl]-1-oxo-3,8-diazaspiro[4.5]decane-2-one (Compound No. 287) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using reference example In the same manner as in the Example 2 6 3 except for the obtained 4-(piperazin-1-yl)pyrimidine dihydrochloride, the title compound (1 9 mg, yield: solid. 1H-NMR (CDCl3) 5: 1.07 (2H, q, J = 12.7 Hz), 1.49- 1.70 (3H, m), 1.70-1.8 8 (6H, m), l, 94 (2H, br d, J = 13.1 Hz), 2.47 (lH, 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), 3.55-3.67 (4H, br m), 3.5 7 (2 H, s), 3.6 6 - 3.8 2 (4 H, brm), 6.52 (lH, dd &gt; J = 6.1, 1.5 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 8.25 (lH, d, J = 6.1 Hz), 8.63 (lH, br s). LC/MS [Condition 1]: Hold time 〇_92 min; m/z 600.8 [M + H]+ (ESI positive ion mode), m/z 645.1 [M + HCOO]- (ESI negative ion mode) - 505- 201211053 【化4 9 5】

Reference Example 2 8 8 Preparation of 4-chloro-6-(piperazine-indolyl)pyrimidine dihydrochloride Replacement of tert-butyl 4-(quinolin-4-yl)piperazine-1-carboxylate The same reaction as in Reference Example 278-2 was carried out in the same manner as in the above-mentioned 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester obtained in Example 287. .2lg, yield is a quantitative white solid. 1H-NMR (DMSO-d6) 6: 3.08-3.2 1 (4H, m), 3.84-3.95 (4H, m), 7. 〇9 (1H, s), 8.42 (1H, s), 9.33 (2H, s). [化4 9 6]

Example 2 8 8 3-({(lr,4r)-4-[4-(6-chloropyrimidin-4-yl)piperazine-1-carbonyl]cyclohexyl}methyl)-8-[4-( Preparation of trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 288) Substituting 4-(aminomethyl)benzonitrile The title compound (20 mg, yield) was obtained from mjjjjjjjj 91%) white solid. -506- 201211053 1H-NMR (CDCl3) 5: 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 = 1 3.1 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), 3.5 8 (2 H, s), 3.6 4 - 3.8 7 (4 H, brm), 6.5 2 (1 H, s), 7.44 (2H,d,J = 7.4 Hz), 7.57 (2H, d, J = 7.4HZ), 8.4 1 (lH, s). LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 634.8 [M + H]+ (ESI positive ion mode), m/z 678.9 [M + HCO〇r (ESI negative ion mode)

Reference Example 2 8 9 4-[1-(2-{4-[(2-Sideoxy-1-oxa-3,8-diazosuro[4.5]decane-3-yl)methyl]] 3-(4-{2-[4-(4-Cyanophenoxy)piperidine) was obtained from the compound of Example 275. 1-yl]-2-oxoethyl}benzyl)_2_sideoxy_1_oxo_3,8-diazospiro[45]decane-8-carboxylic acid tert-butyl ester (28 mg, hydrazine) Add 1 〇 mass to a methanol (imL) solution of 〇48mmc&gt;1). /. After a solution of the title compound (24 mg, yield, quantitative) was obtained as a white solid. H NMR (CDC13) 5: 1.65 - 2.3 9 (8H, br m), 2.9 9 - 4.0 0 (1 2 Η, brm), 4.42 (2H, br s), 4.50-4.69 (1 H, br m), 6.94 (2H, d, J = 8.0HZ), 7.1 8- 7.31 (4H, m), 7.59 (2H, d, J = 8.0 Hz), 9.43 - 9.99 (2H, br m). -507- 201211053

LC/MS [Condition 1]: Hold time 2.94 minutes; m/z 488.7 [M + H]+ (ESI positive ion mode), m/z 532.9 [M + HCOO]·, 487.0 [MH]_ (ESI) Negative ion mode) [Chem. 4 9 8]

Example 2 8 9 3-(4·{2-[4-(4-Cyanophenoxy)piperidin-1-yl]-2-oxoethyl}benzyl)-2-oxooxy Manufacture of ethyl-1-oxa-3,8-diazosuccinyl[4.5]decane-8-carboxylate (Compound No. 289) in Reference Example 2 8 9 - [ 1 - (2 - {4 - [(2-oxo-1,oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]phenyl}ethenyl)piperidin-4-yloxy]benzonitrile Triethylamine (32 μί, 0.23 mmol) was added to a solution of EtOAc (1 mL). After taking out the ice bath and allowing to stand for 3 days, a solution of citric acid (44 mg) in water (1 mL) was added, and the organic layer was separated and concentrated to dryness. The residue was purified by silica gel column chromatography [lubricant: FL100D, manufactured by FUJI SILYSIA, developed solvent: chloroform/acetone = 4/1] to give the title compound (16 mg, yield 62%) as colorless. Shaped object. 1H-NMR (CDCl3) 5: 1.25 (3H, t5J = 7.0 Hz), 1.53-2.01 (8H, m), 3.14 (2H, s), 3.31 (lH, br, J = 1 1.9 Hz), 3.46 ( 1 H, ddd, J = 1 3.5, 6.1, 4.1 Hz), 3.67 (lH, ddd, J = 13.5, 8.2, 3.7 Hz), 3.70-3.80 (2H, m), 3.75 - 508 - 201211053 (2H, s ), 3.78-4.0 l(2H, br m), 4.13 (2H, q, J = 7.0 Hz), 4.42 (2H, s), 4.5 9 (lH, 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]: Hold time 4.01 min; m/z 5 60.8 [M + H]+ (ESI positive ion mode), m/z 605.0 [M + HCOO] _ (ESI negative ion mode) [Chem. 4 9 9】

S

Reference Example 2 9 0 4-(1-{(11*,4〇-4-[(2-thio-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl) Manufacture of cyclohexanecarbonyl}piperidin-4-yloxy)benzonitrile hydrochloride

3-({(lr,4r)-4-[4-(4-cyanophenoxy)piperidine-1-carbonyl]cyclohexyl}methyl)-2-thio-1 obtained in Example 277 - oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (82 mg, 〇.14 mmol) in methanol (2 mL) - chloroform (0.5 mL) The reaction mixture was allowed to stand at room temperature for 3 days, and the title compound was obtained (yield: y. 1H-NMR (CDCl3) 6: 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),4.5 9-4.69(lH,m),6.96(2H,d,J = 9.0Hz), 7.60(2H ,d,J = 9.0Hz), 9.64-10.16(2H,br m) 〇

LC/MS [Condition 1]: retention time 3.12; m/z 496.8 [M + H] + (ESI - 509 - 201211053 positive ion mode), m/z 540.9 [M + HCO〇r (ESI negative ion mode) ) 【化5 0 0】

Example 290 3-({(lr,4r)-4-[4-(4-Cyanophenoxy)piperidine-1-carbonyl]cyclohexyl}methyl)-2-thio-1-oxo- Preparation of 3,8-diazospiro[4.5]decane-8-carboxylic acid ethyl ester (Compound No. 290) 4-(l-{(lr,4r)-4-[(2-) obtained in Reference Example 290 Thio-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarbonyl}piperidin-4-yloxy)benzonitrile hydrochloride (20 mg, 0.03) Triethylamine (26 μί, 〇.19 mmol) was added to a suspension of 8 mmol) of chloroform (1 mL), and ethyl chloroformate (4 pL, O. 〇 4 mm 〇l) was added to TC. Take out the ice bath for 3 days. After standing, a solution of citric acid (37 mg) in water (1 mL) was evaporated. : 1.18 (2H, q, J = 12.3 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.45-1.66 (3H, m), 1.66-1.89 (8H, m), 1.97 (2H, br d, J = 14.0 Hz), 2.41-2.58 (lH, m), 3.3 7-3.52 (lH, br m), 3.4 1 (2H, t, J = 1 1.1 Hz), 3.46 (2H, s), 3.56 (2H) , d, J = 7.4 Hz), 3.59-3.83 (3H, m), 3.8 1-4.01 (2H, br m), 4.15 (2H, q, J = 7.0 Hz), 4.63 (1 H, tt, J = 6.1, 3:3 Hz), 6.96 (2 H, d, J = 8 _6Hz), 7.59 (2H, d, J = 8.6Hz) LC/MS [Condition 1]: Hold time 4.23 minutes; m/z5 68.8 [M + H]+ ( -510- 201211053 ESI positive ion mode), m /z612.9[M + HCO〇r (ESI negative ion mode) [Chemical 5 0 1]

Example 291

4-[l-((lr,4r)-4-{[8-(4-cyanobenzyl)-2-thio-1-oxo-3,8-diazospiro[4.5]decane- 3-(l-{(lr,4r)-4-), which is obtained by the preparation of Reference Example 290, 3-ethyl]methyl}cyclohexanecarbonyl)piperidin-4-yloxy]benzonitrile (Compound No. 291) [(2-Thio-1-oxo 3, 8-diazospiro-μ.5]decane-3-yl)methyl]cyclohexanecarbonyl}piperidin-4-yloxy)benzonitrile hydrochloride Add a suspension of the salt (20 mg, 0.03 8 mmol) of N,N-dimethylformamide (0.60 mL), and add triethylamine (Ι6μί, O.llmmol) and 4-(bromomethyl)benzonitrile (purchased () (8mg, 0.041 mmol). After stirring for 3 days at room temperature, water (1 mL) was added. The title compound (17 mg, yield 74%) was obtained as white solid. 1H-NMR (CDCl3) 6: 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 (lH, 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]: Hold time 3.34 minutes; m/z 611.9 [M + H]+ (ESI positive ion mode), m/z 656.0 [M + HCO〇r (ESI negative ion mode) -511 - 201211053 [Chem. 5 0 2] Reference Example 292-1 Preparation of tert-butyl 4-(2-methoxyphenylamino)piperidine-1-carboxylic acid

To a solution of 4-oxo piperidine-1-carboxylic acid tert-butyl ester (〇.38g, 1.9mmol) in 1,2-dichloroethane (4mL) was added 2-methoxyaniline (O.11mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetate hydride (0.60 g, 2.8 mmol), and the reaction mixture was stirred at room temperature for 2 hours. Thereafter, a saturated aqueous solution of sodium hydrogencarbonate (5 mL) was added to the mixture, and the mixture was stirred for 30 minutes and then 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 (purification: FL100D, manufactured by FUJI SILYSIA, developing solvent: η-hexane/ethyl acetate = 3/1). The title compound (0.31 g, yield) was obtained as a white solid. 1H-NMR (CDCl3) 5: 1.36 (2H, dddJJ=13.0510.9, 4.3 Hz), 1.47 (9H, s), 2.04 (2H, br dd, J = 12.6, 3.3 Hz), 2.95 (2H, t, J=12.6Hz), 3.36-3.50(lH,m), 3.84(3H,s),3.94-4.12(2H,br m), 4.1 1-4.1 7 (1 H ,br m ),6.63(lH,td , J = 7.9, 1.5 Hz), 6.67 (lH, dd, J = 7.6, 1.5 Hz), 6.78 (l H, dd, J = 7.9, 1.5 Hz), 6.86 (l H, td, J = 7.6, l ·5Ηζ) o LC/MS [Condition 2]: Hold time 2.81 minutes; m/z3 07.0[M + H] +, 251.0[M-isobutene + H] + (ESI positive ion mode) 8 -512- 201211053

[Chemical 5 Ο 3 ] HJC'^Oh 2HCI Reference Example 292-2 Preparation of N-(2-methoxyphenyl)piperidin-4-amine dihydrochloride

Substituting tert-butyl 4-(quinolin-4-yl)piperazine-1-carboxylate, using 4-(2-methoxyphenylamino)piperidine-1·carboxylic acid obtained in Reference Example 292_1 In the same manner as in Reference Example 27.8, except for the tributyl vinegar, the title compound (〇_2 9 g, yield was quantitative) was obtained as a gray solid. LC/MS [Condition 2]: Hold time 〇.55 min; m/z 207.0 [M + H]+ (ESI positive ion mode) [Chemical 5 0 4] Λ

Example 292 4-{[3-({(lr,4r)-4-[4-(2-methoxyphenylamino)piperidin-1-carbonyl]cyclohexyl}methyl)-2- side Preparation of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 292) Substituting 4-(aminomethyl)benzonitrile hydrochloride The title compound (2 9 mg) was obtained from mjjjjjjjjjjjjjjjjjjj , yield is a quantitative white solid. -513- 201211053 1H-NMR (CDCl3) 5: 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) , l .94 (2H, br d, J = 1 3.9 Hz), 2. 〇〇. 2.22 (2H, m), 2.47 (lH, t, J = ll.lHz), 2.48-2.66 (4H, m) , 2.89 (2H, br t, J = 12.3 Hz), 3.1 l (2H, d, J = 7.4 Hz), 3.20 (2H, br t, J = 12.3 Hz), 3.26 (2H, s), 3.43 - 3.62 (1 H, br m), 3.57 (2H, s), 3.83 (3H, s), 3.87 (lH, br d, J = 13.5 Hz), 4.09-4.19 (lH, br m), 4.46 (lH, br d, J = 13.5 Hz), 6.63 (1 H, dd, J = 7.8, 1.2 Hz), 6.67 (lH, dt, J = 1.2, 7. 8 Ηζ), 6.78 (lH, dd, J = 7.8, 1.2 Hz), 6.86 (lH, dt, J = 1.2, 7.8 Hz), 7.44 (2H, d, Ja 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz) » LC/MS [Condition 1]: Hold Time 2.86 minutes; m/z 599.8 [M + H]+ (ESI positive ion mode), 111/2 6 44.0 [^1 + 11(:〇〇]- (Ugly 31 negative ion mode) [Chemical 5 0 5]

Reference Example 2 9 3-1,3-(4-cyanopyridine-2-oxy)piperidine-1-carboxylic acid tert-butyl ester was produced from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( A solution of (0.20 g, 0.99 mmol) in tetrahydrofuran (2.0 mL) was added, and sodium hydride (55% by mass, dispersed in mobile paraffin) (44 mg, 0.99 mmol) was added at room temperature over 13 minutes. After stirring at room temperature for 20 minutes, a solution of 6-chloronicotinonitrile (purchased) (O.llg, 0.79 mmol) in tetrahydrofuran (2.0 mL) was added and stirred for 3 hours. Add acetic acid (23 μ! 〇, concentrate to dryness under reduced pressure. After ethyl acetate (2 mL) and water (1 mL) was added to the residue, the organic layer was separated and concentrated under reduced pressure -514 - 201211053. The residue was purified by silica gel column chromatography (purified solvent: FL100D, manufactured by FUJI SILYSIA, developing solvent: chloroform/ethyl acetate = 10/1) to give the title compound (0.27 g, solid

1H-NMR (CDCl3) 6: 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 (lH, tt, J = 8.2, 4.1 Hz), 6.79 (lH, d, J = 9.0 Hz), 7.78 (lH, dd, J) = 9.0, 2.5 Hz), 8.45 (lH, d, J = 2.5 Hz). [化5 0 6]

Reference Example 2 Production of 9 3 - 2 6-(piperidin-4-oxy)nicotinonitrile hydrochloride 4-(5-Cyanopyridin-2-oxy)piperidine obtained in Reference Example 293-1 - Φ. carboxylic acid tert-butyl ester (〇26g, 0.86mm〇l) was dissolved in methanol (2mL), 10% by mass hydrogen chloride methanol solution (2mL) was added, and after standing at 50 ° C for 4 hours, the reaction was carried out. The solution was concentrated to dryness crystals crystals crystals crystals 1H-NMR (DMSO-d6) 5: 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 (lH, tt, J = 7.8, 3.7 Hz), 7.03 (lH, d, J = 9.0 Hz), 8.19 (l H, dd, J = 9.0, 2.5 Hz) , 8.70 (lH, d, J = 2.5 Hz), 8.77 (2H, br s). LC/MS [Condition 1]: Hold time 0.54 min; m/z 204.1 [M + H]+ (-515-201211053 ESI positive ion mode) [Chemical 5 Ο 7]

Example 293 6-{1-[(11&quot;,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]-oxa-3,8-weight Preparation of 4-(aminomethyl)benzonitrile salt by the preparation of azathio[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidin-4-yl}nicotinonitrile (Compound No. 293) The title compound (26 mg, yield 93%) was obtained from m. White solid. 1H-NMR (CDCl3) 5: 1.06 (2HJq, J = 11.9 Hz) s 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 (lHstt, J = 11.9, 2.9 Hz), 3.11 (2H, d, J = 7.4 Hz) , 3.26(2H, s), 3.3 2-3.5 2 (2H, br m), 3.5 7 (2 H, s), 3.6 7-3.83 (lH, br m), 3.8 9 - 4.0 5 ( 1 H , brm ), 5.3 6 (1 H , 11, J = 7.8, 3.7 H z ), 6.80 (lH, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.79 (lH, dd, J = 8.8, 2.5 Hz), 8.46 (lH, d, J = 2.5 Hz) LC/MS [Condition 1]: Hold time 3.30 min; m/z 639_9 [M + H]+ (ESI positive ion mode), m/z6 8 4.1[M + HCOO]-(ESI negative ion mode -516-201211053 of [508]

Example 2 9 4

6-{1-[4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazospiro[4.5]decane-3- Preparation of 4-methylbenzylidene]piperidin-4-oxy}nicotinonitrile (Compound No. 294) Substituting 4-benzyl substituted piperidine, using the 6-(piperider) obtained in Reference Example 2 93-2 The title compound (29 mg, yield was quantitative) of a colorless amorphous material was obtained from the title compound (29 mg, yield). 1H-NMR (CDC13) 6: 1.72-2.29 (4H, br m), 1.7 (2 Η, dt, J = 1 3.5, 7.0 Hz), 1.92 (2H, br d, J = 1 3.5 Η z), 2.3 9-2.6 4 (4 Η, brm), 3.14 (2H, s ), 3.24 - 3.51 (lH, br m), 3.4 8 - 3.8 5 ( 2 H , brm), 3.5 6 ( 2H, s), 3.8 8-• 4.22(lH,br m),4.4 5 (2 H,s), 5.40 ( 1 H, tt, J = 7.0, 3.7 Hz), 6.8 1 (1 H, 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 (lH , dd, J = 9.0, 2.0 Hz), 8.45 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 633.9 [M + H]+ (ESI positive ion mode), m/z 677.9 [M + HCO〇r (ESI negative ion mode) -517- 201211053 【化5 0 9】

Example 295 3-[l-((lr,4r)-4-{[8-(4-Cyanobenzyl)-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane Preparation of -3-yl]methyl}cyclohexanecarbonyl)piperidin-4-yloxy]benzonitrile (Compound No. 295) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using reference example The title compound (23 mg, yield: 79%) was obtained as white solid. 1H-NMR (CDCl3) 5: 1.05 (2H, q, J = 13.1 Hz), 1.45- 1.68 (3H, m), 1.70-1.87 (8H, m), 1.87-2.03 (4H, m), 2.47 (lH) , br t, J = l 1. 1 Hz), 2.49-2.62 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2 H, s), 3.37-3.5 1 (lH, m), 3.52-3.86 (3H, m), 3.57 (2H, s), 4.56 (lH, tt, J = 6.5, 3.3 Hz), 7. 10-7_19 (2H, m), 7.22-7.28 (1 H , m), 7.39 ( lH, 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]: Hold time 3.18 minutes; m/z 595.9 [M + H]+ (ESI positive ion mode), m/z 640.0 [M + HCO〇r (ESI negative ion mode) 1 0]

-518- 201211053 Example 296 4-{[3-({(lr,4r)-4-[4-(4-Cyanophenoxy)piperidine-1-carbonyl]cyclohexyl}methyl)-2 -Production of thio-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 296)

Substituting 3-{[(11',41*)-4-(4-benzimidylpiperidine-1-carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospir [4· 5] decane-2-one hydrochloride, using 4-(1-{(1]*, 41')-4-[(2-thio-1-che-3,8-) obtained in Reference Example 290 The same reaction as in Example 267 was carried out except for the diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarbonyl}piperidin-4-yloxy)benzonitrile hydrochloride. Compound (23 mg, 94% yield) as a white solid. 1H-NMR (CDC13) 8: 1.07- 1.28 (2H, m), 1.40-2.09 (1 5H, m)} 2.49 (lH, t, J = 11.5 Hz), 2.53-2.82 (4H, m), 3.40- 3.59 (lH, br m), 3.41 (2H, s), 3.52 (2H, d, J = 7.0 Hz), 3.59-3.90 (3H, br m), 3.7 5 ( 2 H , s) , 4.56-4.69 ( lH, 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]: Hold time 3.56 minutes; m/z 647.9 [M + H]+ (ESI positive ion mode), m/z 692. 〇 [M + HCO〇r (ESI negative ion mode)

Example 297 -519-201211053 3·({5-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-carbonyl]pyridine. 2-Base} Production of methyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 297) The mercaptoamine was substantially carried out and used in addition to 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride obtained in Reference Example 195 and triethylamine. The title compound (25 mg, quantitative) was obtained as a colorless oil.

1H-NMR (CDCl3) 6: 1.34 (6H, dsJ = 6.0 Hz) 5 1.66- 1.85 (2H, m), 1.88-2.03 (4H, m), 2.06-2.26 (2H, m), 2.45-2.64 (4H , m), 3.0 1-3· 1 5 (1 H, septet, J = 6.0 Hz), 3.1 7-3.30 (3H, m), 3.35 (2H, s), 3.57 (2H, s), 3.69-3.8 8( lH,brm), 4.50-4.6 l(lH,brm),4.58(2H,s), 7.3 7(lH,d,J = 7.8Hz), 7.44(2H,d,J = 8.2Hz),7.57 (2H, d, J = 8.2 Hz), 7.76 (lH, dd, J = 7.8, 2.0 Hz), 8.61 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.19 minutes; m/z627_0[M + H]+ (ESI positive ion mode), m/z 671.1 [M + HCO〇r (ESI negative ion mode)

【化5 1 2】

Example 298 N-(4-cyanobenzyl)·6_({2·Sideoxy-8_[4-(trifluoromethyl)benzyl]oxa-3, 8-diazospiro[4.5]decane Manufacture of -3-yl}methyl)nicotinamide (Compound No. 29 8 ) 8-520-201211053

The title compound (25 mg, quantitative) was obtained after the same reaction as in Example 1 1 1 except that the 4-(hydrocarbylmethyl) benzonitrile hydrochloride and triethylamine were used. a colorless oil. 'Η-ΝΜΚ(ΟΟ€13)δ: 1.69- 1.83(2Η,ιη), 1.90-2.0 1(2Η,ιη)52.47-2.59(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 (lH, brm), 7.37 (lH, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.5 Hz), 7.5 7 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.5 Hz), 8.13 (lH, dd, J = 7.8) , 2.4Hz), 8.96 (lH, d, J = 2.4Hz). LC/MS [Condition 1]: Hold time 3.06 min; m/Z 563.9 [M + H]+ (ESI positive ion mode), m/z 562.1 [M-Hr (ESI negative ion mode) [Chem. 5 1 3 】

φ Example 299 4-[5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3 Preparation of methyl 4-methyl thiazol-2-carboxamide] piperidine-1-carboxylate (Compound No. 299) Substituting 4-benzylidene piperidine hydrochloride, using the reference 135 An oily substance of the title compound (9.1 mg, yield: y. 'H-NMR(CDC13)6: 1.43- 1.54(2H,m), 1.70- 1.84(2H,m), 1.88- -521 - 201211053 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), 3.7 1 (3H, s), 4.01-4.27 (3H, m), 4.56 (2H, s), 7.07 (lH,d,J = 8.0 Hz), 7.42 (lH, s), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). LC/MS [Condition 1]: Hold time 3.02 minutes; m/z 595.9 [M + H]+ (ESI positive ion mode), m/z 594.0 [MH]- (ESI negative ion mode) [Chem. 5 1 4 】

Example 300 1(4-cyanobenzyl)-5-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)thiazole-2-carboxamide (Compound No. 300) Substituting 4-benzylidylpiperidine hydrochloride using 4-(aminomethyl)benzene The title compound (7.9 mg, yield: 64%) of white solid was obtained from the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ), 1.87- 1.98 (2H, m), 2.45-2.62 (4H, m), 3.25 (2H, s), 3.56 (2H&gt;s), 4.56 (2H, s), 4.69 (2H, d, J = 6.3) Hz), 7.43 (2H, d, J = 8.3 Hz), 7.46 (lH, s), 7.46 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.61-7.68 ( lH,m), 7.64 (2H,d,J = 8.0Hz) ο LC/MS[Condition 1]: Hold time 3.19 minutes; m/z569.8[M + H]+ ( -522- 201211053 ESI positive ion mode ), m/z 568.0 [MH]. (ESI negative ion mode) [Chemical 5 1 5]

Example 3 0 1 φ 5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of 4-benzylidene piperidine hydrochloride and triethyl ethane by methyl}-N-[(tetrahydrofuran-2-yl)methyl]thiazole-2-carboxamide (Compound No. 3 0 1 ) The title compound (8.0 mg, yield 68%) was obtained. 1H-NMR (CDCl3) 5: 1.60-1.67 (lH, m), 1.70- 1.83 (2H, m), 1.86-2.10 (5H, m), 2.48-2.60 (4H, m), 3.3 2 (2H, s ),3.34-3.43(lH,m) Spring, 3.57(2Η,s), 3.68-3.80(2H,m), 3.83-3.93(lH,m), 4.01-4.12( lH,m),4.56( 2H, s), 7.40-7.52 (lH, m), 7.42 (lH, s), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). LC/MS [Condition 1]: Hold time 2.91 minutes; m/z 538_9 [M + H]+ (ESI positive ion mode), m/z 537.0 [M-Hr (ESI negative ion mode) [Chem. 5 1 6 ]

-523- 201211053 Example 302 4-{1-[6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ Manufacture of 4.5-decane-3-yl}methyl)nicotinyl]piperidin-4-yloxy}benzonitrile (Compound No. 3 02) Substituted tetrahydrofurfurylamine using 4-(piperidine- The title compound (14 mg, 96%) was obtained as a colorless oil from the title compound (1H-NMR (CDCl3)5. :1.71-2.13(8H,brm),2.4 5-2.66(4H,m), 3.29-4.00(4H,brm),3.35(2H,s)s3.57(2H,s),4.58(2H,s) , 4.66-4.77 (lH, m), 6.97 (2H, d, J = 8.9 Hz), 7.37 (lH, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz) 57.57 (2H, d , J = 8.2 Hz), 7.60 (2H, d5J = 8.9 Hz), 7.76 (lH, dd, J = 7.8, 2.0 Hz), 8.62 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 634.0 [M + H]+ (ESI positive ion mode), m/z 678.1 [M + HCOO]- (ESI negative ion mode) 1 7 ]

Example 3 0 3 4-{1-[5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]] oxime-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)thiazole-2-carbonyl]piperidine-4-oxy}benzonitrile (Compound No. 3 03 )-524-201211053

The title compound (5.8 mg) was obtained by substituting the same reaction with Example 142, except for the 4-(----- </RTI> </RTI> <RTIgt; , yield 41%) of a colorless oil. 1H-NMR (CDCl3) 5: 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(lH,m),6.97(2H,d,J = 8.9 Hz),7.39(lH,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]: Hold time 3.39 minutes; m/z 640.0 [M + H]+ (ESI positive ion mode), m/z 684.0 [M + HCO〇K (ESI negative ion mode) 1 8] 0

Reference Example 3 0 4 -1 4-[(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decan-3-yl)methyl]benzoic acid methyl ester production Reference Example 1 - 2 -3 -(4-methoxycarbonyl)benzyl]-2-ylo-oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (16〇1^, 〇.40mmol) was dissolved in methanol (〇.40 mL). A 4M hydrogen chloride-dioxane solution (2_0 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated to dryness under reduced pressure, the obtained solid was dissolved in chloroform, and aqueous sodium carbonate - 525 - 201211053 was added and neutralized. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained solid was dissolved in ethyl acetate (yield: hexane). [化5 1 9]

Reference Example 3 Production of 0 4 - 2 1-[4-(trifluoromethyl)phenyl]ethanol 1-[4-(Trifluoromethyl)phenyl]ethanone (a commercially available reagent) (190 mg, l .Ommol) was dissolved in methanol (5.0 mL), sodium borohydride (38 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After water and manganese chloride were added to the reaction mixture, 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 give the title compound (l. 1H-NMR (CDCl3) 5: 1.5 1 (3HJdJJ = 6.8 Hz), 1.9 1 (lH, brs), 4.97 (1H, q, J = 6.8 Hz), 7.49 (2H, d, J = 8_2 Hz), 7.61 ( 2H,d,J = 8.2Hz). [化5 2 0]

-526- 201211053 Reference Example 3 0 4 - 3 4-[(2-Sideoxy-8-{1-[4-(trifluoromethyl)phenyl]ethyl ug-3,8-diazo snail [ 4.5] Preparation of methyl decyl-3-yl)methyl]benzoate (13 mg) The methanesulfonyl chloride (0.014 mL, 0.17 mmol) and triethylamine (24 mL, φ O.lYmmol) were added under ice cooling, and the mixture was stirred for 30 minutes. After further stirring and mixing for 15 minutes at room temperature, the reaction mixture was added with ethyl acetate and water under ice-cooling, and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. . The 4-[(2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]benzoic acid methyl ester (52 mg, 0.17 mmol) obtained in Reference Example 3044 was dissolved. After N,N-dimethylformamide (1.0 mL), the above obtained methanesulfonic acid [4-(trifluoromethyl)phenyl]ethyl and diethylamine (17 mg) were added under ice cooling. 0.17 mmol) was added and stirred at room temperature for 1 day. After water was added to the reaction mixture, the obtained white solid was filtered. 'Η-ΝΜΚ(€0€ΐ3)δ: 1.34 (3Η, (1,Ι = 6.5Η2), 1.49-1.95(4Η,ιη), 2.38-2.63(4H,m), 3.10(2H,s), 3.49 (lH, 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]: Hold time 3.14 minutes; m/z 476.9 [M + H]+ (- 527- 201211053 ESI positive ion mode) 【化5 2 1】

Reference Example 304-4 4-[(2-Sideoxy-8-{1-[4-(trifluoromethyl)phenyl]ethyldip-oxa-3,8-diazospiro[4_5]decane Manufacture of -3-yl)methyl]benzoic acid in place of 3-({2-o-oxo-8-[4-(trifluoromethyl)phenylmethyl]-indole-oxo-3,8-diazospiro[ 4,5]decane-3-yl}methyl)benzoic acid methyl ester, using 4-[(2-oxo-8-{1-[4-(trifluoromethyl)) obtained from Reference Example 3 04-3 The same reaction as in Reference Example 108-3 was carried out except that phenyl]ethyl bromide-3,8-diazospiro[4.5]decane-3-yl)methyl]benzoate methyl ester was obtained. The title compound (19 mg, yield 73%) 1H-NMR (CDCl3) 5: 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 (lH,m), 3.17(2H,s), 3.41-3.59(lH,m),4.06(lH,q,J=6.1Hz), 4.42(lH,d,J=15.1Hz),4.50(lH, d, J = 15.1 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.6 1- 7.72 (4H, m), 8.03 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 2.84 minutes; m/z 462.8 [M + H]+ (ESI positive ion mode), m/z 461. 〇 [MH]-(ESI negative ion mode) 528- 201211053 5 2 2]

Example 304

3-[4-(4-Benzylhydrazinopiperidine-1-carbonyl)benzyl]_8_{1_[4_(trifluoromethyl)phenyl]ethyl}-1-oxo-3,8-weight Preparation of azaspiro[4.5]decane-2-one (Compound No. 304) in place of 6-({2-oxo-8-[4-(trifluoromethyl)benzyl]]丨_恶-3,8 - Diazospiro[4.5]decane-3-yl}methyl)nicotinic acid, 4-[(2-oxo-8-{1-[4-(trifluoro)) obtained using Reference Example 3〇4_4 Phenyl]ethyl bromide-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]benzoic acid, substituted tetrahydrofurfurylamine, 4-benzylidenepiped The title compound (6. 〇mg, yield: 5%) was obtained by the reaction of the title compound (1. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3H,d,J = 6.8Hz), 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 (lH, Brm), 3.50 (lH, q, J = 6.8 Hz), 3.73-3.96 (lH, brm), 4.44 (2H, s), 4.58-4.77 (lH, 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]: Hold time 3.39 minutes; m/z 63 3.7 [M + H]+ (ESI positive ion mode), m/z 678.0 [M + HCOO]_ (ESI negative ion mode) -529- 201211053 [化5 2 3 ]

Example 3 0 5 4-(l-{4-[(2-Sideoxy-8-l-[4-(trifluoromethyl)phenyl]ethyl}-l-oxo-3,8-weight Preparation of alkalose [4.5]decane-3-yl)methyl]benzhydryl}piperidin-4-yloxy)benzonitrile (Compound No. 305) Substituting 6-({2- Side Oxygen-8- [4-(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)nicotinic acid, obtained using the test example 304-4 4-[(2-Sideoxy-8-{1-[4-(trifluoromethyl)phenyl]ethyl}-1-oxo-3,8-diazospiro[4_5]decan-3-yl Methyl]benzoic acid, substituted tetrahydrofurfurylamine, substantially the same reaction as in Example 111 except that 4-(piperidin-4-oxy)benzonitrile hydrochloride and triethylamine were used. The title compound (7.5 mg, yield 61%). 1H-NMR (CDCl3) 5: 1.35 (3H, d, J = 6.5 Hz), 1.62-2.07 (8H, m), 2.3 5 - 2.63 (4H, m), 3. 1 l (2H, s), 3.36 -3.92 (4H, br m), 3.50 (lH, q, J = 6.5 Hz), 4.44 (2H, s), 4.63-4.73 ( lH'm), 6.96 (2H, d, J = 8.9 Hz), 7.3 1 (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 = 8.9Hz). LC/MS [Condition i]: Hold time 3.44 min; m/z 647.0 [M + H] + (ESI positive ion mode), m/z 691.0 [M + HCO〇r (ESI negative ion mode) -530- 201211053 【化5 2 4】

Reference Example 3 0 6 -1 4-[(4-Bromophenethylamino)methyl]-4-hydroxypiperidine-bucarboxylic acid tert-butyl ester

The 1-butyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (lg, 4.7 mmol) obtained in Reference Example 1-1 was suspended in methanol (10 mL) and water (l? After mL), 4-bromophenethylamine (purchased) (940 mg, 4.7 mm) was added and mixed at room temperature for 45 hours. After the chloroform was added to the reaction mixture, the organic layer was separated and washed with a saturated aqueous solution of sodium chloride and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was dissolved in a small amount of ethyl acetate, and then hexane was added to crystallize. The title compound (1.6 g, yield 81%) was obtained. 1H-NMR (CDCl3) 5: 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 = 7.0Hz), 3.03 -3.34(2H,m), 3.6 9-4.02(2H,m),7.06(2H,d,J = 8.2Hz), 7.42(2H,d,J = 8.2Hz) (NH ' OH invisible) LC/MS [Condition 1]. Hold time 3.22 minutes; m/z 412.9, 414.8 [M + H] + (ESI positive ion mode), hold time 3.81 minutes; m/z 446.9, 449.2 [M + HCO〇r (ESI negative ion mode) -531 - 201211053 【化5 2 5】

Reference Example 3 Manufacture of 0 6 - 2 3-(4-bromophenethyl)-2-oxo-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester The tert-butyl 4-[(4-bromophenethylamino)methyl]-4-hydroxypiperidine-1-carboxylate (1.5 g, 3.6 mmol) obtained in Reference Example 3 06-1 was dissolved in tetrahydrofuran. After (20 mL), 1,1'-carbonyldiimidazole (1.2 g, 7.3 mmol) was added, and the mixture was stirred and mixed at room temperature for 48 hours. After water was added to the reaction mixture, it was mixed for 1 hour until the foaming was 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 then hexane was added to crystallize. The obtained white solid was collected, dried, m. 'H-NMR (CDCl3) 5: 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 = 8.5Hz). LC/MS [Condition 1] · Hold time 4.65 min; m/z 460.7, 462.7 [M + Na] + (ESI positive ion mode) -532- 201211053 [Chem. 5 2 6]

Reference Example 3 0 6 - 3 2-oxo-3-(4-vinylphenethyl)-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester Manufacturing

3-(4-Bromophenethyl)-2-oxo-l-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester obtained in Reference Example 3 06-2 (l〇〇mg, 0.2 3 mmol), tributyl(vinyl)tin (87 mg, 0.27 mm〇l) and hydrazine (triphenylphosphine) palladium complex (27 mg, 0.023 mmol) suspended in toluene, · Mix at 110 degrees for 3 hours. After the reaction mixture was cooled to room temperature, a 5 % aqueous potassium fluoride solution was added, and the mixture was mixed at room temperature for 1 hour. After adding ethyl acetate to the reaction mixture, it was filtered through diatomaceous earth 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 [Purif-Pack SI 60 pm, development solvent hexane-ethyl acetate]. The title compound (54 mg, yield 62%) 1H-NMR (CDCl3) 5: 1.45 (9H, s), 1.50-1.59 (2H, m), 1.72-1.8 1 (2H, m), 2.8 8 (2H, t, J = 7.2 Hz), 3.07 (2H) , s), 3.17-3.3 1(2H,m), 3.52(2H,t,J = 7.2Hz), 3.66-3.84(2H,br m), 5.2 4 (1 Η, d, J = 1 0.9 Η z ), 5.73 (1 H, d, J = 1 7.4 Hz), 6.69 ( lH, dd, J = l 7.4, 10.9 Hz), 7.18 (2 - 533 - 201211053 H, d, J = 8.2 Hz), 7.3 6 (2H,d,J = 8.2Hz). LC/MS [Condition 1]: Hold time 4 47 minutes; m/z 4 〇 8 8 [M + H]+ (ESI positive ion mode) [Chem. 5 2 7]

Reference Example 306-4 Manufacture of 3-(4-carbophenethylethyl)-2-oxo-1-oxo-3, 8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester The 2-butyloxy-3-(4-vinylphenethyl)-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester obtained in Reference Example 306-3 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2.0 mL), and then forced into tetraoxide (microencapsulated, content 10 ο/p purchased from Wako Pure Chemical Industries Co., Ltd.) (46 mg, 0.10 mmol) 'water (l .OmL) was mixed with sodium periodate (83 mg, 0.39 mmol) 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 ethyl acetate was added, the insoluble matter was removed, and the organic layer of the filtrate was separated. The organic layer was washed with EtOAc EtOAc. The resulting solid was used directly in the next stage of the reaction without purification. iH-NMR (CDC13) 6: 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.U (2H) , s), 3.17-3.29(2H,m), -534- 201211053 3.58(2H,t,J = 7.2Hz),3.72-3.8 9(2H,m), 7.40(2H,d,J = 8.2Hz) , 7.85 (2H, d, J = 8.2 Hz), 10.00 (lH, s). LC/MS [Condition 1]: Hold time 4.02 minutes; m/z 410.9 [M + Na]+ (ESI positive ion mode) [Chem. 5 2 8]

Reference Example 3 0 6 -5 4-{2-[8-(t-Butoxycarbonyl)-2-oxo-1-oxo-3,8-diazospiro[45]decane-3-yl] Manufacture of ethyl}benzoic acid

3-(4-Methylphenylphenethyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid obtained in Reference Example 3 06-4 Butyl ester (60 mg) was suspended in tert-butyl alcohol (1.5 mL) and water (1.0 mL), 2-methyl-2-butene (0.14 mL, 1.3 mmol), sodium dihydrogen phosphate (78 mg, 0.65) Methyl) was mixed with sodium perchlorate (35 mg, 0.39 mmol) at room temperature for 24 hours with stirring. Dimethylhydrazine (0.50 ml) was added to the reaction mixture, and the mixture was further stirred and stirred at room temperature for 24 hours. Sodium perchlorate (35 mg, 0.39 mmol), sodium dihydrogen phosphate (78 mg, 〇_65 mmol) and 2-methyl-2-butene (〇.14 mL, 1-3 mmol) were added to the reaction mixture, and then chloroform (i) was added. .5 mL), stirred and mixed at room temperature for 24 hours. After 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. After the combined organic layer was washed with saturated brine, the aqueous layer separated from -535 to 201211053 was extracted once again with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. Diethyl ether was added to the residue, and the precipitated white solid was collected, and dried under reduced pressure for 30 hours to give the title compound (28 mg, yield 53% (2 steps)). LC/MS [Condition 1]: Hold time 3.81 minutes; m/z 403.0 [M-H]-(ESI negative ion mode) [Chem. 5 2 9]

Reference Example 3 0 6 - 6 3-{4-[4-(4-Cyanophenoxy)piperidine-1-carbonyl]phenethyl}_2_sideoxy-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-8-carboxylic acid tert-butyl ester 4-{2-[8-(t-butoxycarbonyl)-2-sideoxy-1 obtained in Reference Example 3 06-5 Oxy-3,8-diazospiro[4.5]decane-3-yl]ethyl}benzoic acid (2511^, 0.062 mmol), 4-(piperidin-4-oxy) obtained in Reference 264-2 After the benzonitrile hydrochloride (15 mg, 0.062 mmol) and 1-p-benzobenzotriazine (2.5 mg, 0-019 mmol) were dissolved in chloroform (2.0 mL), triethylamine (0.0090 mL, 0.062 mmol) and 1 - Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg, 0.062 mmol) was mixed at room temperature for 20 hours. After the water was added, the organic layer was separated by shaking. The organic layer was washed with an aqueous solution of citric acid, aqueous sodium hydroxide, water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The residue was purified by fractional chromatography - </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , yield 60%) of a white solid.

1H-NMR (CDC13) 5: 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), 3.17-3.3 0 (2H, m), 3.48-3.96 (6H, m), 3.53 (2H, t, J = 7.2 Hz), 4.62-4.72 (lH, m) &gt; 6.96 (2H, d , J = 9.2 Hz) &gt; 7.27 (2H, d, J = 8.0 Hz) s7.38 (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/Z6 33.0 [M + HCO〇r (ESI negative ion mode) [Chemical 5 3 0] Reference Example 3 0 6 - 7 4-(1-{4-[2-(2-Sideoxy-1-oxo-3,8-diazospiro[4.5]decan-3-yl)ethyl] Preparation of benzhydryl}piperidin-4-yloxy)benzonitrile 3-{4-[4-(4-cyanophenoxy)piperidine-1-carbonyl obtained in Reference Example 3 06-6 ]Phenylethyl}_2·Sideoxy-1-oxo-3,8-diazospiro[4.5]indole-8-carboxylic acid tert-butyl ester (22 mg, 0.03 7 mm〇l) was immersed in dioxane (1) After 〇mL), 4 Μhydrogen chloride-dioxane solution (2. 〇ml) was added and mixed at room temperature for 3 hours. Further, the reaction solution was mixed at 50 °C for 4 hours, and then cooled to room temperature, and methanol (0.1 mL) was added thereto, and the mixture was mixed at room temperature for 12 hours. -537-201211053 Thereafter, a 4 M hydrogen chloride-dioxane solution (20 mL) was added to the reaction solution, followed by mixing at 50 °C for 4 hours. After concentration and concentration under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added and shaken. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The residue was concentrated to dryness crystals crystals crystals crystals crystals The white solid obtained was used directly in the next stage of the reaction without purification. LC/MS [Condition 1]: Hold time 2.94 minutes; m/z 48 8.8 [M + H]+ (ESI positive ion mode), m/z 532.9 [M + HCO〇r (ESI negative ion mode) [Chem. 5 3 1】

Example 306 4-[(3-{4-[4-(4-Cyanophenoxy)piperidine-indole-carbonyl]phenethyl}_2· side oxygen_1-oxo-3,8-diazo Manufacture of spiro[4.5]decyl)methyl]-3,5-difluorobenzonitrile (Compound No. 306) 4-(1-{4-[2-(2) obtained in Example 306-7 -Phenoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)ethyl]benzhydryl}piperidin-4-yloxy)benzonitrile (15 mg) with 3, 5-Difluoro-4-methylindenylbenzonitrile (5.5 mg, 0.033 mmol) dissolved in dichloromethane (1. 〇m L) 'Added sodium triacetate borohydride (9.5 mg, 0.045 mm )l)' Mix and mix at room temperature for 1 Torr. The material was observed by thin-layer chromatography [TLC glass pan 60 60F2 5 4 manufactured by Merck, developing solvent: chloroform/methanol = 10/1] to the disappearance, and triacetate was added -538-201211053

Sodium borohydride and 3,5-difluoro-4-methylindenylbenzonitrile were stirred and mixed at room temperature. After confirming the disappearance of the starting material, a saturated aqueous sodium hydrogencarbonate solution and water were added to the reaction mixture, and then chloroform was added thereto, and the mixture was shaken vigorously. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and the obtained residue was subjected to thin-layer chromatography (PLC glass plated silica gel 60 F 2 5 4 manufactured by Merck, developing solvent: chloroform/methanol = 10 Π). The crude product (27 mg) containing the title compound as a main component was obtained. The crude product was recrystallized from diethyl ether, and the precipitated solid was collected and dried under reduced pressure at room temperature for 3 hours to give the title compound (9. 7 mg, yield 40%, step 2). 1H-NMR (CDC13) 5: 1.59-2.09 (8H, m), 2.50-2.67 (4H, m), 2.89 (2H, t, J = 7.0 Hz), 3.12 (2H, s), 3.3 6-3.98 ( 4H,m), 3.50 (2H, t, J = 7.0 Hz), 3.7 1 (2H, s), 4.60-4.73 (lH, m), 6.96 (2H, d, J = 8.8 Hz), 7.18-7_28 ( 4H,m), 7.36 (2H'd, J = 7.7Hz), 7.60 (-2H, d, J = 8.8Hz) • LC/MS [Condition 1]: Hold time 3.29 minutes: m/z640.0[M + H]+ (ESI positive ion mode), m/z 684.2 [M + HCOO]-(ESI negative ion mode) [Chemical 5 3 2

H-CI

Preparation of NH H3CT0, Reference Example 3 0 7 1,2,5-oxadiazepine-5-carboxylic acid methyl hydrochloride The substituted tert-butyl piperidin-4-ylcarbamic acid, used by Watanabe In addition to the 12,5-oxadiazepine-2carboxylic acid tert-butyl ester hydrochloride (23 0 mg, 0.97 mm〇l) purchased by Chem.-539-201211053, substantially the same as Reference Example 135 The reaction was carried out to give the title compound (1 mg, yield: 54%) as pale yellow solid. 1H-NMR (CDCl3) 6: 3.57-3.68 (2H&gt;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]: Hold time 0.59 minutes; m/zl60.9[M + H]+ (ESI positive ion mode)

Example 307 2-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4· Manufacture of methyl decane-3-yl}methyl)cyclohexanecarbonyl]-I,2,5-oxadiazepine-5-carboxylate (Compound No. 307) Substituted tetrahydrofurfurylamine Using the same reaction as in Example 10 except that 1,2,5-oxadiazepine-5-carboxylic acid methyl hydrochloride obtained in Reference Example 307 and triethylamine were used, the title compound was obtained. 8.3 mg 'yield 2 1%) of a colorless solid. 1 H-NMR (CDCl3) 5: 1.05 (2H, dq, J ==3·3.12.3 Hz), 1.36-2.41 (12 H, br m), 2.51-3.04 (4H, br m), 3.1 〇 (2H , d, J = 7 4Ηζ), 3·29 (2Η, s), 3.54-3.96 (8H, m), 3.72 (3H, s), 3.95-4.08 (2H, br m), 7.5 1-7.67 (- 540- 201211053 4H, br m) ° LC/MS [Condition 1]: Hold time 3.09 minutes; m/z 596.9 [M + H]+ (ESI positive ion mode), m/z 641.0 [M + HCO〇 r (ESI negative ion mode)

Example 3 0 8 [Chemical 5 3 4] 0

5-[(Bu, 4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane Manufacture of -3-yl}methyl)cyclohexanecarbonyl; 1-12,5-oxadiazepine heptane-2-carboxylic acid tert-butyl ester (Compound No. 308) in place of tetrahydrofurfurylamine, using Watanabe The title compound was obtained by substantially the same reaction as in Example 10 except that t-butyl hydrochloride of 1,2,5-oxadiazepine-2-carboxylate purchased from Chemical Company and triethylamine. (89 mg, 94% yield) of colorless solid.

1H-NMR (CDCl3) 5: 0.95-1.14 (2H, br m), 1.48 (9H, s), 1.37-2.03 (llH, br m), 2.3 1-2.49 (1 H, m), 2.49-2.78 ( 4H, br m), 3.1 〇 (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]: Hold time 3.32 minutes; m/z 639.0 [M + H]+ (ESI positive ion mode), m/z 683.1 [M + HCO〇r (ESI negative ion mode) -541 - 201211053 【化5 3 5】

Example 309

3-{4·[4-(3-isopropyl-1,2,4-oxadiazole-5-yl)piperidine-indole-carbonyl]benzyl}_8-[4-(trifluoromethyl) Substituting .4-(Aminomethyl)benzonitrile hydrochloride for the manufacture of phenylmethyldipyridyl-oxa-3,8-diazospiro[45]decane-2.one (Compound No. 3 09) The same reaction as in Example 180 was carried out except that 3-isopropyl-5-(piperidin-4-yl)-i,2,4-oxadiazole hydrochloride obtained in Reference Example 195 was used. The title compound (14 mg, yield 19%) was obtained as colorless.

丨H-NMR (300MHz, CDC13) S: 1.34 (6H, d, J = 7.0 Hz), 1.65- 1.80 ( 2H, br m), 1. 82- 1.99 (4H, br m), 2.1 3 (2 H, brs), 2.5 2 (4 H, brs), 2.99-3.28 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 3.79 (lH, brs), 4.45 ( 2H , s), 4.57 (lH, br s), 7.3 1 (2 H, d, J = 8.2 H z), 7.3 6 - 7.4 6 (4 H, m), 7.56 (2 H, d, J = 8.4 Hz 0 LC/MS [Condition 1]: Hold time 3.02 minutes; m/z 626.0 [M + H]+ (ESI positive ion mode), m/z 670.1 [M + HCOO]- (ESI negative ion mode) 5 3 6]

8 -542- 201211053 Reference Example 3 1 0 1-[4-({2-Sideoxy-8-[4_(trifluoromethyl)phenylmethylpyrazine-oxo_3,8 Diazo snail [4.5]癸Manufacture of alk-3-yl}methyl)benzimidyl]piperidine-4-carboxylic acid

1-[4-({2_Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane obtained in Example 76. -3-yl}methyl)benzhydryl]piperidine D 疋-4-residual acid methyl vinegar (〇.i3g, 〇.23mmol) was dissolved in 1,4-dioxin (1.5ml) and '1M hydrogen was added An aqueous solution of sodium oxide (〇.35 mL, 0.35 mm )l) was mixed at room temperature for 4 hours. After the completion of the reaction, the 1,4-dioxane was evaporated under reduced pressure, and then the mixture was evaporated to ethyl ether (0.3 mL) and chloroform (3 mL). The obtained organic layer was concentrated to dryness to dryness crystall LC/MS [Condition 1]: Hold time 2.78 minutes; m/z 560.0 [M + H]+ (ESI positive ion mode), m/z 558_l [M-Hr (ESI negative ion mode)

Example 3 1 0 3-{4-[4-(Piperidine-1-carbonyl)piperidin-1-carbonyl]benzyl}_8_[4-(trifluoromethyl)benzyl]-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-2-one (Compound No. 310) 1 - [ 4 - ({ 2 - Side Oxygen-8 - [ 4 · (3) Fluoromethyl) -543- 201211053 Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzhydryl]piperidin-4-residate (29mg, 0_052mmol) and piperazine (O.OlOmL, O.lmmol), 1-p-benzobenzotriazine (7_0mg, 0.052mmol), and triethylamine (0.022mL, 0.16mmol) were dissolved in chloroform (1. After OmL), the addition of phenethyl-3-(3·dimethylaminopropyl)carbodiimide hydrochloride (20 mg, 0.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [Hybrid: HI-FLASH (registered trademark) COLUMNsilicagel 40 pm, developed solvent: ethyl acetate / methanol = 10/1]. Compound (6.4 mg, yield 19%) of colorless amorphous. 1H-NMR (300MHz 'CD C13) δ : 1.4 7 -1.9 7 (1 4 H , m), 2.5 3 (4 H, brs ), 2.7 1- 2.84 (lH, m), 2.96 (2H, br s) , 3.13 (2H, s), 3.38-3.49 (2H, br m), 3.56 (4H, s), 3.79 ( 1 H, s s), 4.4 4 (2 H, s), 4.6 8 (1 H, brs ), 7.29 (2H, d, J = 8.2 Hz), 7.3 5-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz) o 1^/1^3 [Condition 1]: Hold time 2.84 Minutes; 111/2627.0 [1^ + 1^+ (ESI positive ion mode), m/z 671.1 [M + HCOO]- (ESI negative ion mode)

-544 - 201211053 Example 3 1 1 3-{4-[4-(l-Methyl-1H-imidazol-5-yl)piperidin-1-carbonyl]benzyl (trifluoromethyl)benzyl Preparation of 1-oxa-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 1 1) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using 4- (1-methyl-1H-imidazole-5-yl)piperidine (purchased), the title compound (27 mg, yield 52%) . • H-NMRCSOOMHz ' CDC13) 5: 1.43 -2.09 (8 H, m), 2.60 (4H, br s) , 2.78 (lH, tt, J = l 1.9, 2.5 Hz), 2.8 8-3.1 7 ( 2H, br m), 3.1 5(2H, s), 3.6 1 (5H, s), 3.85 (l H, br s), 4.4 5 (2 H, s), 4.8 0 (1 H, brs), 6.8 1 (1 H, s ), 7.3 1 (2H, d, J = 7.8 Hz), 7.37-7.49 (5H, m), 7.57 (2H, d, J = 7.4 Hz) o LC/MS [Condition 1]: Hold time 0.51 min; m/z 298.6 [M + 2H]2 + , 59 5.9 [M + H] + (ESI positive ion mode), m/z 640.1 [M + HCO〇]- ( φ ESI negative ion mode ) 【化5 3 9】

Example 3 1 2 N-(4-Nitrobenzyl)-4-( {2-oxo-8-[4-(trifluoromethyl)benzyl]don-3,8-diazo snail [4_5]Production of 癸-3-yl}methyl)benzamide (Compound No. -545-201211053 312) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using (4_nitro The title compound (27 mg, yield 52%) of the title compound (2. 7 mg, yield 52%) was obtained from the phenylamine hydrochloride (purified). 6: 1.64- 1.80(2H,br m), 1. 8 4 -1.9 6 ( 2H,br m),2.52(4H,br s), 3 . 1 3 (2 H , s), 3.5 5 (2 H , s), 4.4 6 (2 H, s), 4.75 (2H, d, J = 5.7 Hz), 6.73 (lH, t, J = 6.1 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.37 -7.60(6H,m),7.8 1(2H,d,J = 8.6Hz), 8.19(2H5d, J = 8.6Hz) o

LC/MS [Condition 1]: Hold time 2.86 min; m/z 582.9 [M + H] + (ESI positive ion mode), m/z 581.0 [MH]., 627.0 [M + HCOO]- (ESI) Negative ion mode) [Chemical 5 4 0]

Example 313 N-[4-(Methylsulfonyl)benzyl]-4-({2-trioxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3 , 8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 313) was produced by substituting 4-(aminomethyl)benzonitrile hydrochloride, using [4- The title compound (3 3 mg, yield 5 9 ) was obtained after the same reaction as the compound of 546-201211053 1 0 0 (m). %) of white powder. *Η-ΝΜΚ(300ΜΗζ ' CD C13) δ : 1.7 4 (2 H, br s), 1. 8 4 - 1.9 6 (2 Η, brm), 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 (lH, t, J = 6.1 Hz), 7.3 5 (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] _ Hold time 2.65 min; m/z 616.0 [M + H]+ (ESI positive ion mode), m/z 614.1 [MH]·, 660.1 [M + HCOO] (ESI anion mode)

[化5 4 1]

-547- 201211053 ),6·52( lH,t,J = 5.9Hz), 7.33(2H,d,J = 8.6Hz), 7.40-7.50(3H,m), 7.52-7,62(5H,m ), 7.79 (2H, d, J = 8.6 Hz). LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 605.9 [M + H]+ (ESI positive ion mode), m/z 604.1 [MH]·, 650.1 [M + HCOO]- (ESI Negative ion mode) [Chemical 5 4 2]

Example 3 1 5 '(Oral-Side Oxygen^-)-Gatrifluoromethylhydrazinyl-dioxa-oxime--diazospiro[^]decane-3-yl}methyl)-N-[ Preparation of 2-(Aminomethyl)benzonitrile hydrochloride by 2-(trifluoromethyl)benzyl]benzamide (Compound No. 3 15), using [2_(trifluoromethyl) A colorless amorphous material of the title compound (32 mg, yield: 59%) was obtained. • H-NMRCBOOMHz ' CDCl3) 5: 1.72-1.98 (4H, br m), 2.62 (4H, br s ), 3.12 (2H, s) 53.63 (2H, s), 4.45 (2H, s), 4.82 (2H , d, J = 6.1 Hz), 6.46 (lH, t, J = 5.9 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.36-7.48 (3H, m), 7.49-7.6 1 (3H, m ), 7.66 (2H, t, J = 8.0 Hz), 7.75 (2H, d, J = 8.2 Hz) » LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 605.9 [M + H]+ (ESI positive ion mode), m/z 604.1 [MH]-, 65 0.1 [M + HCO〇r (ESI negative ion mode) -548- 201211053 [Chemical 5 4 3]

Example 3 1 6

N-(4-t-butylbenzyl)-4-({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazo [4.5] Manufacture of decyl-3-yl}methyl)benzamide (Compound No. 316) Substituting 4-(aminomethyl)benzonitrile hydrochloride using (4-t-butylphenyl) The title compound (37 mg, yield 6.9 %) of white powder was obtained after the reaction of the same procedure as in Example 180. 1H-NMR (3 00 MHz ' CDC 13) δ : 1 . 3 1 (9 H, s ), 1.6 3 - 1.7 7 (2 H, brm) , 1. 8 5- 1,95 (2H, br m), 2.5 1 (4 H , brs), 3 .1 1 (2 H , s), 3.5 5 (2 H, s), 4.45 (2H, s), 4.61 (2H, d, J = 5.3 Hz), 6.3 1 (lH, t, J = 5.1 Hz), 7.29 (2 H, d, J = 8.2 Hz), 7.32 (2H, d, J = 7.4 Hz), 7.38 (2H, dt, J = 8.2, 2.0 Hz), 7.4 1 (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]: Hold time 3.46 minutes; m/z 594.0 [M + H]+ (ESI positive ion mode), m/z 592.2 [MH]·, 63 8.1 [M + HCOO]-( ESI negative ion mode) -549- 201211053 【化5 4 4】

Example 3 1 7 4-({2-Sideoxy- 8-[4-(trifluoromethyl)benzyl]]丨_恶_3,8 Diazo snail [4·5] 癸院-3- Manufacture of 4-(Aminomethyl)benzonitrile hydrochloride and trisin by the manufacture of methyl}methyl)-indole-[4-(trifluoromethoxy)benzyl]benzamide (Compound No. 317) The title compound (28 mg, yield 52%) was obtained from the titled compound (yield: EtOAc (m. Yellow powder "H-NMRiSOOMHz ' CDC13) 6:1.65-1.98 (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 (lH, t, J = 5.5 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.3 0-7.50 (6H, m), 7.57 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.28 minutes; m/z 621.9 [M + H]+ (ESI positive ion mode), ηι/ζ620·1 [Μ-ΗΓ, 666_2[M + HCOO]-(ESI Negative ion mode) [Chem. 5 4 5]

-550- 201211053 Example 3 1 8 N-[3,5-Bis(trifluoromethyl)benzyl]-4-({2-Sideoxy-8-(4-trifluoromethyl)benzene Manufacture of keto-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 318)

Substituting 4-(aminomethyl)benzonitrile hydrochloride and triethylamine, using [3,5·bis(trifluoromethyl)phenyl]methylamine (purchased), substantially The title compound (30 mg, yield 50%) was obtained as a colourless crystal. • H-NMRiSOOMHz ' CDC13) 5: 1.72-1.97 (4H, br m), 2.62 (4H, br s ), 3.14 (2H, s), 3.63 (2H, s), 4.46 (2H, s), 4.7 7 (2H, d, J = 6.1 Hz), 6.68 (l H, 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), 7.77-7.8 3 (5H, m).

LC/MS [Condition 1]: Hold time 3.52 minutes; m/z 674.0 [M + H]+ (ESI positive ion mode), m/z 672_0 [MH] -, 718.1 [M + HCO〇r (ESI negative ion mode) )

Example 3 1 9 N-(4-chlorobenzyl)-4-({2-o-oxo-8-(4-trifluoromethyl)benzyl]-1-oxo-3,8-weight Manufacture of azaspiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 319) -551 - 201211053 Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethylamine, A white powder of the title compound (3 1 mg, yield 61%) was obtained. 'H-NMR (300MHz ' CDC13) 5: 1.63 - 1.79 (2H, br m), 1. 8 2 - 1.9 8 ( 2H, br m), 2.5 1 (4H, br s), 3. 1 1 (2 H, s), 3.5 5 (2 H, s), 4.4 6 (2 H, s ), 4.61 (2H, d, J = 5.7 Hz)) 6.41 (lH, t, J = 5.1 Hz), 7.22 -7.36(6H,m), 7.4 1(2H,d,J = 7.4Hz), 7.56(2H,d,J = 7.8Hz),7.77(2H,d,J = 8.2Hz )0 LC/MS[conditions 1]: Hold time 3 12 minutes; m/z 571.9 [M + H]+ (ESI positive ion mode), m/zsyouM.H]-, 616.1 [M + HCOO; T (ESI negative ion mode) 4 7]

Example 3 2 Ο Ν-(4-methylbenzyl)-4-({2- sideoxy_8·[4-(trifluoromethyl)benzyl]-1- chew-3,8- Preparation of Diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 320) Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethylamine, using p- A white powder of the title compound (31 mg, yield: 63%) was obtained. 'H-NMRiSOOMHz ' CD C13) δ : 1.6 2 -1 . 7 7 (2 H, brm), 1.83-1.96 -552- 201211053 (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 (lH, t, J = 4.5 Hz), 7.16 ( 2H,d,J = 7.8Hz), 7.24(2H,d,J = 7_0Hz), 7.32(2H,d,J = 8.2Hz), 7.4 l(2H,d,J = 7.8Hz),7.55(2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz) 〇

LC/MS [Condition 1]: Hold time 3.02 min; m/z 552.0 [M + H] + (ESI positive ion mode), m/Z5 50.1 [M-H]-, 596.1 [M + HCOO]- (ESI

Negative ion mode) [Chem. 5 4 8]

Example 3 2 1 N-(4-Methoxybenzyl)4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-Φ 丨·Evil, 8- Preparation of Diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 321) Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethylamine, using (4 A white powder of the title compound (24 mg, yield 47%) was obtained. 1H-NMR (300MHz 'CDCl3) 5: 1.62-1.79 (2H, br m), 1.83-1.97 (2H, br m), 2.5 1 (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 (lH, t, J = 4.9 Hz), 6.88 ( 2H, dt, J = 8.6 , 2.5Hz), 7.23-7.35(4H,m), 7.41(2H,d,J = 7.8Hz), -553- 201211053 7.55(2H,d,J = 7.8Hz),7.76(2H,d,J = 8.2 Hz). LC/MS [Condition 1]: Hold time 2.86 min; m/z 568.0 [M + H]+ (ESI positive ion mode), m/Z566.1 [MH]-, 612.1 [M + HCO〇r (ESI Negative ion mode) [Chem. 5 4 9]

Example 3 2 2 N-(3,4-Dimethoxybenzyl)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-Chew- Preparation of 3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 3 22) Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethyl The title compound (16 mg, yield 30%) was obtained from the title compound (1 6 mg, yield 30%). powder. 'H-NMRCSOOMHz ' CDC13) 5: 1. 6 3 - 1.78 (2H, br m), 1.83-1.97 (2H, br m), 2.5 1 (4H, br s), 3 . 1 1 (2 H, s ), 3.5 4(2 H, s), 3.8 8 (6 H, s ), 4.45 (2H, s), 4.58 (2H, d, J = 5.3 Hz), 6.3 1 (lH, 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 (2 H, d, J = 7.8 Hz), 7.76 ( 2H,d,J = 8.2Hz).

LC/MS [Condition 1]: Hold time 2.71 minutes; m/z 597.9 [M + H]+ (ESI positive ion mode), m/z 596.1 [MH]-, 642.1 [M + HCOO]- (ESI -554- 201211053 Negative ion mode) 【化5 5 0】

Example 3 2 3 Φ heart [(2,3-dihydrobenzo[1^[1,4]dioxine-6-yl)methyl]-4-({2- sideoxy-8-[4-( Manufacture of trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 323) Substituting 4-(amine Methyl)benzonitrile hydrochloride and triethylamine, using (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methylamine (purchased), substantially Example 1 After the same reaction of 80%, the title compound (16 mg, yield 29%)

lH-NMR (300MHz, CDCl3) 5: 1.63-1.79 (2H, br m), 1.84-1.97 (2H, br m), 2.51 (4H, br s), 3 .1 0 ( 2 H , s ) , 3 5 5 (2 H , s ), 4.2 5 (4 H , s ), 4.45 (2H, s), 4.53 (2H, d, J = 5.7 Hz), 6.27 (lH, t, J = 4.9 Hz), 6.76-6.88(3H,m),7.3 1(2H,d,J = 8.2Hz), 7.4 1(2H,d,J = 7.8Hz), 7.55(2 H,d,J = 7.8Hz),7.76( 2H,d,J = 8.6Hz).

LC/MS [Condition 1]: Hold time 2.80 minutes; m/z 5 95.9 [M + H]+ (ESI positive ion mode), m/z 594.1 [MH]·, 640.1 [M + HCOO]. (ESI negative ion Mode) -555- 201211053 【化5 5 1】

Example 324 N-(furan-2-ylmethyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 324) Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethylamine, using furan-2- A white powder of the title compound (2 mg, yield 41%) was obtained. 'H-NMRCSOOMHz ' CDC13) 5: 1.62- 1.79 (2H, br m), 1. 8 4 -1.9 7 (2H, br m), 2.5 1 (4H, br s), 3 .1 1 (2 H, s), 3.5 5 (2 H, s ), 4.4 6 (2 H, s) , 4.64 (2H, d, J = 5.3 Hz), 6.27-6.36 (2H, m), 6.36 (lH, t, J = 4.9 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.3 6-7.39 (lH, m), 7.4 1 (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]: Hold time 2.63 min; m/z 527.8 [M + H] + (ESI positive ion mode), m/z 526.0 [MH]·, 571.9 [M + HCOO]- (ESI Negative ion mode) [Chemical 5 5 2]

201211053 Example 325 4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8-diazospiro[4_5]decane_3-yl} Manufacture of methyl)_N-(tetrahydro-2H-pyran-4-yl)benzamide (Compound No. 3 25)

Substituting 4-(aminomethyl)benzonitrile hydrochloride, using tetrahydro-2H-pyran-4-amine hydrochloride (purchased), substantially the same reaction as in Example 180 gave the title Compound (28 mg, yield 59%) of a white powder. *H-NMR (300MHz ' CDC 13) δ : 1.4 8 -1 . 8 0 ( 4 H ,br m), 1. 8 3 - 2.0 8 ( 4H,br m),2.52(4H,br s), 3 .1 2 (2 Η , s), 3.4 5 - 3.6 2 (4 Η, m), 3.9 4-4.05 (2H, br m), 4.11-4.28 (lH, m), 4.46 (2H, s), 5.95 (lH,d,J = 7.0

Hz), 7.3 3 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.5 6 (2H, d, J = 7.4 Hz), 7.74 (2H, d, J = 8.2) Hz).

LC/MS [Condition 1]: Hold time 2.37 minutes; m/z 531.9 [M + H] + (ESI positive ion mode), m/z 530.1 [MH]_' 576.1 [M + HCO〇r (ESI Negative ion mode)

Example 326 3-{4-[3-(4-Chlorobenzylidene)piperidin-1-carbonyl]benzylidene-8-[4-(trifluoromethyl)benzyl]-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-2-one (Compound No. 326) - 557- 201211053 Substituting 4-(aminomethyl)benzonitrile hydrochloride, using (4-chlorophenyl) The title compound (49 mg, yield: 84%) was obtained as a colorless crystals of the title compound (yield: EtOAc). W-NMROOOMHz, CDCl3) 5: l'39-2.21 (8H, br m), 2.53 (4H, br s ), 2.8 1-3.1 9 (2H, br m), 3 .1 4 ( 2 Η , s) , 3.3 1 (1 Η, br s ), 3.5 6 (2 H, s) , 3.67-3.93 (lH, br m) , 4.4 5 (2H, s) , 4.5 5-4.92 (1 H, br m), 7.31( 2H,d,J = 6.5Hz), 7.35-7.5 1(6H,m), 7.56(2H,d,J = 8.2Hz),7.6 1- 8.06(2H,br m) 〇

LC/MS [Condition 1]: Hold time 3.50 minutes; m/z 653.9 [M + H]+ (ESI positive ion mode), m/z 652.1 [MH]·, 698.1 [M + HCO〇r (ESI negative ion mode) [Chemical 5 5 4]

Example 3 2 7 [4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 Manufacture of 4-(aminomethyl)benzonitrile hydrochloride by using 4-phenyl-methylbenzylbenzylidene]- 4-phenylpiperidine-4-carbonitrile (Compound No. 3 27) The title compound (41 mg, yield 75%) of colorless amorphous material - 558 - 201211053 Η </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -ΝΜΚ(300ΜΗζ ' CDC13)6:1.63-2.34(8H,br m), 2.5 3 (4H ,br s ), 3.14(2H,s), 3.28(lH,br s), 3 . 5 5 (3 H , s), 3.9 1 (1 H, brs), 4.45 ( 2H, s), 4.93 (lH, br s), 7.28-7.50 (llH, m), 7.56 (2H, d, J = 7.8 Hz) o LC /MS [Condition 1]: Hold time 3.42 minutes; m/z 617.0 [M + H]+ (ESI positive ion mode), m/z 66 1 .l [M + HCO〇r (ESI negative ion mode)

【化5 5 5】

Example 3 2 8 3-{4-[4-(3,5-Dimethyl-1H-pyrazol-1-yl)piperidine-1-carbonyl]benzylidene 8-[4-(trifluoro Methyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (

Compound No. 328) was substituted for 4-(aminomethyl)benzonitrile hydrochloride and triethylamine using 4-(3,5-dimethyl-1H-pyrazol-1-yl)piperidine (purchased) The title compound (42 mg, yield 76%) was obtained as a white powder. 1 H-NMR (3 00 MHz ' CD C13) δ : 1 . 6 4 -1 . 8 1 (2 Η, brm), 1. 8 3 - 2.0 0 ( 4 Η , brm), 2.14 - 2.31 (2H, m ), 2.22 (3H, s), 2.25 (3H, s), 2.53 (4H, br s), 2.8 0-3 .1 5 ( 2H , br m), 3 . 1 3 (2Η , s ), 3 . 5 5 (2Η, s), 3.9 1 (1 Η, br s), 4.13 (lH, tt, J = 11.4, 4.1 Hz), 4.44 (2H) s), 4.84 (lH, br s), 5.79 201211053 ( lH, s), 7.29 (2H, dJ = 7.8 Hz), 7.3 6-7.47 (4H, m), 7.56 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold 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) [Chemical 5 5 6]

Example 3 2 9 3-{4-[4-(morpholine-4-carbonyl)piperidine-1-carbonyl]benzylidene 8-[4-(trifluoromethyl)benzyl]-1- Production of cacao-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 29) was substituted for piperidine, and the same reaction as in Example 3 10 was carried out except that morpholine (purchased) was used. The title compound (2 mg, yield 59%) was obtained as colorless amorphous. • H-NMRCSOOMHz ' CDCl3) 6: 1.61-2.00 (8H, br m), 2.53 (4H, br s ), 2.66-2.83 (lH, br m), 2.8 3 - 3 .1 5 (2 H , brm) , 3 .1 3 (2H, s), 3.44. 3.75 (10H, m), 3.81 (lH, br s), 4.44 (2H, s), 4.68 ( 1 H, 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]: Hold time 2.90 minutes; m/z 629.1 [M + H]+ (ESI positive ion mode), m/z 673.2 [M + HCO〇r (ESI negative ion mode) -560- 201211053 【化5 5 7】

Example 3 3 0 Ν-cyclohexyl-1-[4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl]- oxa] 3,8-diazo snail [4.5 Manufacture of decyl-3-yl}methyl)benzhydrazinyl]piperidine _4-formamide ( φ compound number 3 3 0) in place of 峨Π定' using a ring body (purchased) The title compound (2 mg, yield 59%) was obtained as a colourless crystals. • h-NMRCSOOMHz ^ CDCl3) 5:1.10 (2H, dq, 1 = 2.5, 1 1.4HZ), 1.20 - 1.46 (2H, m), 1.49-1.99 (14H, br m), 2.30 (lH, tt, J = l 1·4,3·7Ηζ ), 2.52(4H,br s), 2.7 6 - 3 . 1 1 (2 Η , brm), 3 . 1 3 (2 Η, s ), 3 . 5 5 (2H , s), 3.67-3.8 7 (2H, m), 4.44 (2H, s), 4.67 (lH, br s), 5.2 9 (1 Η, d, J = 7.8 Η z • ), 7.29 (2H, d , J = 8.2 Hz), 7.3 3 - 7.47 (4H, m), 7.56 (2H, d, J = 7.4 Hz) ° LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 641.0 [M + H]+ (ESI positive ion mode), m/z 685.2 [M + HCOO]- (ESI negative ion mode) [Chemical 5 5 8]

-561 - 201211053 Example 331 N-Tertibutyl-l-[4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl)-1-oxo-3,8- Preparation of Diazospiro[4.5]decane-3-yl}methyl)benzylidene]piperidine-4-carboxamide (Compound No. 331) Substituted piperidine using 2-methylpropan-2-amine The title compound (2 1 mg, yield 62%) was obtained as a colorless amorphous material. • H-NMRiSOOMHz 'CD C13) δ : 1 . 3 5 (9 H, s), 1. 6 1 -1.9 9 ( 8 H , brm) , 2.24 (1 H, tt, J = l 1.0, 3.7 Hz) , 2.52 (4H, br s), 2.7 8 - 3.0 7 (2 H, brm ), 3.13 (2H, s), 3.55 (2H, s), 3.76 (lH, br s), 4.44 (2H, s), 4.67 (lH, br s), 5.25 (lH, s), 7.2 9 (2H, d, J = 8.2 Hz), 7.33 - 7.4 8 (4H, m), 7.56 (2 H, d, J = 8.0 Hz) . LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 615.1 [M + H]+ (ESI positive ion mode), m/z 659.2 [M + HCO〇r (ESI negative ion mode) 5 9]

Example 3 3 2 N-(furan-3-ylmethyl)-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of diazospiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 3 3 2) Substituting 4-(aminomethyl)benzonitrile hydrochloride with triethylamine, used The title compound (37 mg, yield 78%) was obtained as a white powder. m. m. 'H-NMR (3 00 MHz &gt; CDC13) 5: 1. 6 1-1, 79 (2H, br m), 1.82-1.98 (2H, br m), 2.51 (4H, br s), 3 .1 1 (2 H, s), 3.5 5 (2 H , s), 4.4 6 (2 H , s) , 4.49 (2H, d, J = 5.3 Hz), 6.21 (lH&gt;t, J = 4.5 Hz), 6.42 (lH, s), 7.32 (2 H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.75 (2 H, dt, J = 8.6 , 2.0Hz) 〇

LC/MS [Condition 1]: Hold time 3.04 min; m/z 527.8 [M + H] + (ESI positive ion mode), m/z 526.0 [MH]·, 572.0 [M + HCO〇r (ESI Negative ion mode) 【化5 6 0】 0

Reference example 3 3 3 -1

Preparation of 4_(4-t-butylbenzylidenyl)piperidine-1-carboxylic acid tert-butyl ester Substituting 1.1 M methylmagnesium bromide·tetrahydrofuran solution using 2.0 M (4-t-butylphenyl) The title compound (8 1 mg, yield 71%) was obtained as a colorless oil. LC/MS [Condition 1]: Hold time 5_38 minutes; m/z 290.0 [M-isobutene + H] + (ESI positive ion mode) -563- 201211053 [Chem. 5 6 1]

Reference Example 3 Preparation of 3 3 - 2 (4-tert-butylphenyl)(piperidin-4-yl)methanone hydrochloride Substituting tert-butyl 4-aceticylpiperidine-1-carboxylate The same reaction as in Reference Example 1 68-3 was carried out, except that the tert-butyl 4-(4-t-butylbenzylidene)piperidine-1-carboxylate obtained in Reference Example 3 3 3 -1 was used. The title compound (61 mg, quant.) was obtained as a purple powder. LC/MS [Condition 1]: Hold time 2.82 min; m/z 246.1 [M + H]+ (ESI positive ion mode) [Chem. 5 6 2]

Example 3 3 3 3-{4-[4-(4-Tertiary benzylbenzylidene)piperidine-hydrazine-carbonyl]benzyltrifluoromethyl)benzyl]-1-oxo-3 Preparation of 8-diazospiro[4.5]decane-2-one (Compound No. 3 3 3) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using Reference Example 33 3_2 (4_ The title compound -564 - 201211053 (5 7 mg, yield 95%) was obtained by the same reaction as in Example 1 80 except for the title compound of the butyl phenyl) (piperidin-4-yl) ketone hydrochloride. Colorless amorphous. 'H-NMR (300MHz ' CDC13) 8: 1.35 (9H, s), 1.6 3 -2.08 (8 H, br m) , 2.52 (4H, br s), 2.9 6 - 3.2 5 (2 H , brm ), 3 . 1 3 (2 H, s), 3.4 6 - 3.6 1 (1 H, br m), 3.55 (2H, s), 3.82 (lH, br s), 4 44 (2H, s), 4.66 (1H, br s) , 7.3 0 (2H, d, J = 8.2 Hz), 7.3 6-7.45 (4H, n1) &gt; 7-49 (2H &gt; dt5j = 8·6, 1 -6 Hz), 7 · 5 6 (2 H,d,J = 7 · 4 H z), 7.8 9 (2 H,dt, J = 8 · 6,1 · 6 H z).

LC/MS [Condition 1]: Hold time 3.70 min; 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) [Chemical 5 6 3]

^ch3 Reference Example 3 Manufacture of 3 4 -1 4-(cyclohexanecarbonyl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained by substituting the same reaction with Reference Example 1 8 8 - 2 except that the solution of the methyl propyl bromide-tetrahydrofuran (1M) was used.丨7 mg, yield 15%) as a colorless oil. LC/MS [Condition 1]. Hold time 4.87 minutes; m/z 240.1 [M -isobutene + H] + (ESI positive ion mode) -565 - 201211053 [Chem. 5 6 4]

NH

HCI Reference Example 334-2 Preparation of cyclohexyl (piperidin-4-yl)methanone hydrochloride Substituting tert-butyl 4-ethylhydrazine piperidine-1-carboxylate, using Reference Example 3 34-1 A white powder of the title compound (13 mg, quantitative) was obtained from the title compound (yield: hexane). LC/MS [Condition 1]: Hold time 0.74 min; m/zl 96.1 [M + H]+ (ESI positive ion mode) [Chem. 5 6 5]

Example 334 3-{4-[4-(Cyclohexanecarbonyl)piperidine-1-carbonyl]benzyl}_8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-2-one (Compound No. 3 34) Substituting 4-(aminomethyl)benzonitrile hydrochloride, using the cyclohexyl group obtained in Reference Example 3 3 4-2 ( The title compound (2 2 mg, yield -566 - 201211053 80%) was obtained as a white powder. ^-NMRiSOOMHz ' CDC13) 5: 1.1 1 -1,42(6H,br m), 1.4 7 - 2.0 〇( 12H,br m),2.40-2.64(5H,br m),2.6 8-2.8 3 (1 H , m ), 2.9 6 (2 H , br s ), 3.13 (2H, s), 3.57 (2H, s), 3.74 (lH, br s), 4.44 (2H, s), 4.65 (lH, 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 H z), 7.5 6 (2 H, d, J = 7.8) H z ). LC/MS [Condition 1]··Retention time 3.48 minutes; m/z 626.0 [M + H]+ (ESI positive ion mode), m/z 670.1 [M + HCO〇r (ESI negative ion mode) 5 6 6]

Example 3 3 5 3-{4-[4-(4-Chlorobenzylidinyl) piperidine_1-carbonyl]benzylidene 8-[4-(trifluoromethyl]phenyl)benzyl]- Manufacture of 1_(8-diazosuccinyl) A white powder of the title compound (5 2 mg, yield: 9%) was obtained. 1H-NMR (300 MHz ^ CDCl3) 5:1.64-2.08 (8H, br m), 2.5 2 (4H, brs), 2.96-3.28 (2H, br m), 3. 1 3 (2H, s) , 3.42-3.57( lH,m) , 3.55(2 H,s),3.83(lH,br s),4.44(2H,s),4.67(lH,br s),7.30(2H,d,J = -567 - 201211053 8.2Hz), 7.35-7.50(6H,m), 7.56(2H,d,J = 8.6Hz),7.88(2H,d,J = 8·2Ηζ) » LC/MS[Condition 1]: Hold time 3.50 minutes; m/z653_9[M + H]+ (ESI positive ion mode), m/z698.〇[M + HC〇〇r (ESI negative ion mode)

[化5 6 7] HjC

Reference Example 3 Preparation of 3 6 -1 4-(4-methoxybenzylidene)piperidine-1-carboxylic acid tert-butyl ester Substituting 1.1 M methylmagnesium bromide-tetrahydrofuran solution, using l. (4-methoxyphenyl)magnesium bromide-tetrahydrofuran solution (purchased), the title compound (113 mg, yield: 88%) . LC/MS [Condition 1]: Hold time 4.45 min; m/z 264.0 [M-isobutene + H] + (ESI positive ion mode) [Chem. 5 6 8]

Reference Example 3 Preparation of 3 6 - 2 (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride Substituting tert-butyl 4-ethylhydrazine piperidine-1-carboxylate, used Reference Example 3 3-(4-Methoxybenzylidene)piperidine-1-carboxylic acid tert-butyl ester-36-201211053 obtained in the same manner as in Reference Example 1 68-3 The title compound (83 mg, quantitative) of blue amorphous material was obtained after the reaction. LC/MS [Condition 1]: Hold time 〇·53 min; m/z 220.0 [M + H]+ (ESI positive ion mode)

【化5 6 9】

Example 3 3 6 3-{4-[4-(4-Methoxybenzhydryl)piperidine-i-carbonyl]phenylmethyl 8_[4·(trifluoromethyl)benzyl]- Preparation of 1-oxa-3,8-diazaspiro[4.5]nonan-2-one (Compound No. 3 3 6) Substituting 4-(aminomethyl)benzonitrile hydrochloride, Reference Example 3 3 6-2 (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride, the title compound (59 mg, yield 70%) Colorless amorphous. iH-NMRpOOMHz, CDCl3)5: 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 (lH, m ), 3.55(2H, s ), 3.84 (lH, br s), 3.88 (3H, s), 4.44 (2H, s), 4.68 (lH, br s), 6.95 ( 2H, dt, J = 9.0, 2.0 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.94 (2H, dt, J = 9.0, 2.0 Hz). LC/MS [Condition 1]: Hold time 3.32 minutes; m/z 649.9 [M + H]+ (ESI positive ion mode), m/z 694.0 [M + HCOO]- (ESI negative ion mode) -569- 201211053 【化5 7 0】 ^Ϊ^Η; Reference Example 3 3 7 -1 4-(2-methylbenzimidyl)piperidine-i-carboxylic acid tert-butyl ester was replaced by 1.1 Μ bromide The title compound (20 mg, yield 27%) was obtained from the title compound (20 mg, yield: 27%), m. m. Colorless oil. LC/MS [Condition 1]: Hold time 4.63 min; m/z 248.0 [M-isobutene + H] + (ESI positive ion mode) [Chem. 5 7 0 1]

CCP

NH HCI Reference Example 3 Preparation of 3 7 -2 piperidin-4-yl(indole-tolyl)methanone hydrochloride Substituting 4-3-ethenylpiperidine-1-carboxylic acid tert-butyl ester, Reference Example 33 was used. In the same manner as in Reference Example 1 68-3, the title compound (16 mg, m. Quantitative) white powder. LC/MS [Condition 1]: Hold time 0.68 min; m/z 204.1 [M + H]+ (-570-201211053 ESI positive ion mode) [Chem. 5 7 2]

Example 3 3 7 Φ 3-{4-[4-(2-methylbenzimidyl)piperidine-i-carbonyl]benzyl}·8·[4_(trifluoromethyl)benzyl] Manufacture of 4-(aminomethyl)benzonitrile hydrochloride by using -1-oxa-3,8-diazospiro[4.5]decane-2-one (compound No. 3 3 7), using Reference Example 3 A colorless amorphous form of the title compound (26 mg, yield 69%) was obtained from the compound obtained in the same manner as in Example 180, except for the obtained piperidin-4-yl(indole-methyl) ketone hydrochloride. Things.

'H-NMROOOMHz, CDCl3) 5: 1.62-2.09 (8H, br m), 2.43 (3H, s), 2.52 (4H, br s), 2.89-3.2 Ο (2Η, br m), 3. 13 (2Η , s), 3.26-3.43 ( lH, m), 3.55 (2H, s), 3.8 1 (lH, br s), 4.4 4 (2 Η , s), 4.6 4 (1 Η, brs), 7.2 1- 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/z634.0[M + H]+ (ESI positive ion mode), m/z 678.1 [M + HCO〇r (ESI negative ion mode) [Chem. 5 7 3] h3c,

X -571 - 201211053 Reference Example 3 3 8 -1 Preparation of piperazine-1,4-dicarboxylic acid (1-tert-butyl) 4-methyl group Piperazine-1-carboxylic acid tert-butyl ester (4.1 g, 22 mmol) was dissolved in chloroform (12 mL), and triethylamine (9.2 mL, 66 mmol) was added at 0 ° C, then methyl chloroformate (3.4 mL, 66 mmol) dissolved in chloroform (8.0 mL) at 0 ° C The mixture was slowly added dropwise, and after warming to room temperature, it was mixed for 12 hours. Then, water (40 mL) and chloroform (40 mL) were added, and the organic layer was evaporated. *H-NMR (300 MHz 'C D C13) δ : 1.4 7 ( 9 H, s), 3.3 5 - 3.4 8 ( 8 H , b r m) , 3.71 (3H, s). LC/MS [Condition 1]: Hold time 3.66 min; m/zl 45.0 [M-isobutene -C02 + H] + (ESI positive ion mode) [Chem. 5 7 4] H, c, 〇 lp

HCI Reference Example 338-2 Preparation of piperazine-1-carboxylic acid methyl hydrochloride Substituting tert-butyl 4-ethylhydrazine piperidine-1 -carboxylate using piperazine obtained in Reference Example 3 3 8- 1 A white powder of the title compound (3.9 g, quantitative) was obtained after the reaction was carried out in the same manner as the compound of 168. -572- 201211053 LC/MS [Condition 1]: Hold time 0.51 min; m/zl45.0 [M + H]+ (ESI positive ion mode) [Chem. 5 7 5]

Example 33 8 4-[4·({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 Preparation of methyl 4-methylbenzylidene]piperazine-1-carboxylate (Compound No. 3 3 8 ) Substituting 4-(aminomethyl)benzonitrile hydrochloride, Reference Example 3 3 The title compound (49 mg, yield 57%) was obtained as a colorless crystals. 'H-NMR (300MHz ' CDC13) 5: 1.65-1.8 l (2H, br m), 1.85-2.00 (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), 7.3 1 (2H, d, J = 8.2 Hz), 7.39 (2 H, 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]: Hold time 2.96 minutes; m/z 5 74.9 [M + H]+ (ESI positive ion mode), m/z 619.0 [M + HCO〇r (ESI negative ion mode) -573- 201211053 Η#-.义 [化5 7 6]

SN Example 3 3 9 4-((11:,41&quot;)-4-{[8-(4-Cyanobenzyl)-2-oxo-oxo-oxa-3,8-diaza snail [ 4.5] Preparation of methyl decyl-3-yl]methyl}cyclohexanecarbonyl)piperazine-1-carboxylate (Compound No. 3 3 9) Substituting 4-({2- Side Oxygen-8-[4- (Trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, which was obtained using Reference Example 17-2 (11: 4-〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexane Alkanecarboxylic acid, substituted 4-(aminomethyl)benzonitrile hydrochloride, substantially the same as the examples except that the piperazine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 3 3 8-2 was used. The title compound (14 mg, yield 34%) of white powder was obtained after the same reaction of 1 to 80. iH-NMRpOOMHz, CDCl3) 5: 1.05 (2H, q, J = 11.4 Hz), 1.45-1.68 (3H, br m) , 1.69- 1.86(6H,br m),l.87-2.〇〇(2H,br m),2.43(1 H,t,J=ll_7Hz), 2.56(4H,br s),3.11(2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.40-3.64 (8H, br m), 3.5 7 (2H, s), 3.72 (3H, s), 7.44 (2H, d, J = 8.2 Hz ), 7.61 (2H, d, J = 7.8Hz)LC/MS [Condition 1]: Hold time 1.40 min; m/z 53 7.9 [M + H]+ (ESI positive ion mode), m/z 582.1 [M + HCO〇r (ESI negative ion mode) -574- 201211053 [化5 7 7]

Example 3 4 0

4·(4·{[8-(4-Cyanobenzyl)-2-oxo-poxa-3,8-diazospiro[4.5]decane-3-yl]methyl}benzamide Production of ethylamine piperidine-indole-carboxylate (Compound No. 3 40) in place of 4-({2-oxo-8-[4-(trifluoromethyl)phenylmethyl]_1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using 4-{[8-(4-cyanobenzyl)-2- side oxygen obtained in Reference Example 1 71-2 -丨_恶-3,8-diazospiro[4.5]decane-3-yl]methyl}benzoic acid 'substituted 4-(aminomethyl)benzonitrile hydrochloride' using 4-aminopiperidine A white powder of the title compound (24 mg, yield: 57%) was obtained. • W-NMROOOMHz, CDCl3)5: 1.27 (3H5t5J = 7.2Hz), 1.42 (2H, dq, J = 3.3, 12.1Hz), 1.63 - 1.78(2H, br m), 1. 8 3 - 1.9 6 (2 Η , brm), 1.98-2.1 0(2H,br m), 2.4 0 - 6 0 (4 H , brm), 2.9 6 (2 H, t, J = 1 2.5 H z ), 3.11 (2H, s) , 3.55 (2H, s), 4.04-4.26 (3H, br m), 4.1 4 (2 H , q, J = 7.1 Hz), 4.46 (2H, s), 5.96 (lH, d, J = 7.8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.5 9 (2H, d, J = 8.2 Hz), 7.7 3 (2H, d, J = 8.2) Hz

LC/MS [Condition 1]: Hold time 2.78 min; m/z 559.9 [M + H] + (ESI positive ion mode), m/z 558.1 [M-Hr, 604.1 [M + HCOO]- (ESI -575- 201211053 Negative ion mode)

Example 3 4 1

4-((11*,4〇-4-{[8-(4-cyanobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3- Manufacture of ethyl (e-cyclohexanecarbamamine) piperidine-1-carboxylate (Compound No. 341)

Substituting the same reaction as in Example 3 3 9 except for the use of ethyl 4-aminopiperidine-1-carboxylate (purchased), the title compound was obtained. (3 Omg, yield 63%) of a white powder. 'H-NMR (3 00 MHz ' CDC13) 5: 1.0 1 (2H, dq, J = 2.9, 1 2.7 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), l .48 - 1.65 (lH, br m), 1. 7 0 - 2.0 5 (1 1 H, brm), 2.55 (4H sbr s )&gt;2.89(2H,t,J=12.3Hz), 3.09(2H,d,J=7.4Hz), 3.25 (2H, s), 3.56(3H,s),3.84-3.9 8 (lH,m) , 4.01-4.20 (2H, br m), 4.12 (2H, q, J = 7.1 Hz), 5.29 (lH, d, J = 8.2 Hz) s7.44 (2H, d, J = 8.2 Hz), 7.60 ( 2H, t, J = 4.1 Hz). LC/MS [Condition 1]: Hold time 2.82 minutes; m/z 5 6 5.9 [M + H]+ (ESI positive ion mode), m/z564.i [MH]·, 610.1 [M + HCOO; T (ESI Negative ion mode) 8 -576- 201211053 【化5 7 9】

Example 342 3-{[(11*,4〇-4-(3,5-Dimethylpiperidine-1-carbonyl)cyclohexyl]methyl}_8_[4-(difluoromethyl)benzyl] -1_oxo_3,8_diazospiro[4 5]decane-2-ketone (combination φ material number 342) was produced in place of 4-({2-lateral oxygen-8-[4-(trifluoromethyl) (Benzyl)-1-phenoxy-3,8-diazospiro[4.5]decane-3-yl}methyl)benzoic acid, using (lr, 4r)-4-({) obtained in Reference Example 6_3 2-sided oxygen-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid Substituting 4-(aminomethyl)benzonitrile hydrochloride, the title compound (22 mg, m. Yield 61%) of white powder. • 'Η-ΝΜΚ (300ΜΗζ ' CDCl3) 6: 0.84-0.94 (6H, m), 1.05 (2H, q, J = 1 2.4Hz), 1.40- 1. 65 (6H ,br m), 1. 6 9 - 1 . 8 7 (7 H , brm), 1.88-2.00 (3H, br m), 2.3 8 -2.56 (l.85H, m), 2.56 (4H, br s) , 3 . 1 0 (2 H, 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 (0.85H, d, J = 12. 7 Hz), 4.58 (0.85H, d, J = 12.7 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.6 Hz). LC/MS [Condition 1]: Hold time 3.40 minutes; m/z 549.8 [M + H]+ (ESI positive ion mode) ' m/z 593.9 [M + HCO〇r (ESI negative ion mode) -577- 201211053 [Chem. 5 8 0]

Example 343 3-{[(lr,4r)-4-(4-Isopropylpiperidin-1-carbonyl)cyclohexyl]methyl}-8-[4.(trifluoromethyl)benzyl] Preparation of 1-oxa-3,8-diazaspiro[4.5]nonan-2-one (Compound No. 3 43 ) Substituting 3,5-dimethyl substituted piperidine using 4-isopropyl piperazine A white powder of the title compound (27 mg, yield: 73%) was obtained. 'H-NMR (3 00 MHz &gt; CDCl3) 6: 0.88 (6H, d, J = 6.5 Hz), 0.94-1.33 (6H, m), 1.3 6-1.8 5 (1 lH, br m), 1. 8 6 - 2.0 0 (2 Η , brm), 2.3 7 - 2.5 1 ( 2H,m), 2.55(4H,br s), 2.94(lH)t,J=11.7Hz),3.10(2H,d,J = 7.4

Hz), 3.25 (2H, s), 3.57 (2H, s), 3.89 (lH, d, J = 13.1 Hz), 4.66 (lH, d, J = 13 Hz), 7_43 (2H, d, J = 7.8 Hz) ), 7.57 (2H, d, J = 7.6 Hz). LC/MS [Condition 1]: Hold time 3.54 minutes; m/z 563.9 [M + H]+ (ESI positive ion mode), m/z 608.0 [M + HCOO]- (ESI negative ion mode) 8 1]

-578-201211053 Example 344 3-{[(lr,4r)-4-(decahydroisoquinolin-2-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzene Manufacture of keto-1-oxo-3, 8-diazospiro[4.5]decane-2-one (Compound No. 344)

Substituting 3,5-dimethyl-substituted piperidine, the title compound (26 mg, yield 68%) of white powder. • H-NMRiSOOMHz ' CDC 13) δ : 0.9 2 -1 . 1 6 (3 H, brm), 1. 1 9 - 2.1 5 ( 22H, br m), 2.36-2.55 (lH, br m), 2.5 6 (4H, s), 2 · 8 1 - 3.2 8 (2 H, 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]: Hold time 3.52 minutes; m/z 575.9 [M + H]+ (ESI positive ion mode), m/z 620.1 [M + HCO〇r (ESI negative ion mode)

[化5 8 2]

Example 345 8-[4-(Trifluoromethyl)benzyl]-3-({(lr,4r)-4-[4-(trifluoromethyl)piperidin-1-carbonyl]cyclohexyl} Production of methyl)-1-oxo-3,8-diazospiro[4.5]decane-2-one (compound No. 3 4 5) substituted 3,5-dimethyl substituted piperidine, using 4-(three The title compound (30 g, yield 77%) was obtained as a white powder, m. m. *Η-ΝΜΚ(300ΜΗζ &gt; CD C13) δ : 1 . 0 4 (2 H, q, J = 1 2.0 H z), 1 . 3 5 -1 . 6 8 (5H,br m), 1.69- 1 .85(6H,br m), 1. 8 5 - 2.0 1 (4H,br m),2.15-2.35 (lH,m), 2.36-2.54(2H,br m),2.55(4H,br s), 3.02 (1 H, t, J = 1 2.9 Hz), 3.1 0 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.5 7 (2H, s), 3.99 (lH, d, J = 13.1 Hz), 4.75 (lH, 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]: Hold time 3.36 minutes; m/z 5 8 9.8 [M + H]+ (ESI positive ion mode), m/z 634.0 [M + HCOO]- (ESI negative ion mode) 8 3]

Example 346 3-({(11:,4〇-4-[4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl]cyclohexyl}methyl)-8-[4-(three Production of fluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 46) substituted 3,5-dimethyl substituted piperidine, used A white powder of the title compound (3 Om g, yield: 78%) was obtained from the compound obtained in the same manner as in Example 342, except for 2-((piperidin-4-yl)propane-2-ol. H-NMR (300MHz, CDCl3) 5: 1.04 (2H, q, J = 12.3 Hz), 1.17 (3H, s), 1.19 (3H, s), 1.20- 1.68 (6H, br m), 1.6 8-2.00 ( 1 OH, br m), 2.36- -580- 201211053 2.52 (2H, m), 2.55 (4H, br s), 2.96 (1 H, t, J = 12.1 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.96 (lH, d, J = 12.3 Hz)} 4.74 ( lH, d, J-13_9 Hz), 7.43 (2H, d, J = 7.8) Hz), 7.57 (2H, d, J = 8_2Hz) LC/MS [Condition 1]: Hold time 3.04 minutes; m/z579_9[M + H]+ (ESI positive ion mode), m/z 624.0 [M + HCOO]-(ESI negative ion mode)

HjC

【化5 8 4】 〇

Example 347 4-[(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1 oxa-3,8-diazo snail [ 4.5] Preparation of ethyl decyl-3-yl}methyl)cyclohexanecarbonyl]piperazine-indole-carboxylate (Compound No. 347) Substituting 3,5-dimethyl substituted piperidine using piperazine-oxime A white powder of the title compound (32 mg, yield 81%) was obtained from the title compound (yield: 81%).

'H-NMR (300MHz ' CD C13) δ : 1.0 4 (2 H, q, J = 1 1 . 7 Η z), 1. 2 7 (3 Η, 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 (lH, t, J = l 1.7 Hz), 2.55 (4H, br s), 3 .1 0 (2 H , 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]: Hold time 3 · ΐ 2 minutes; m / z 594.7 [M + H] + (ESI positive ion mode), m / z 639.0 [M + HCOO] - (ESI negative ion mode) - 581 - 201211053 【化5 8 5】

Example 348 4-[(1 r,4r)-4-( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[ Manufacture of 4_5]decane-3-yl}methyl)cyclohexanecarbonyl]-1,4-diazocycloheptane-1-carboxylic acid tert-butyl ester (Compound No. 348) in place of 3,5-dimethyl The title compound (3 7 mg, yield) was obtained from the title compound (m. 89%) of white powder. 'H-NMR (3 00 MHz ' CDCl3) 5: 1.04 (2H, q, J = 12.3 Hz), 1.38-1.48 (9H, m), 1.48- 1.68 (3H, br m), 1.6 8 - 1.8 8 (8 Η, brm), 1. 8 7 - 2.0 1 ( 2H, br m), 2.40 (l H, t, J = l 2.3 Hz), 2.55 (4H, br s), 3.0 5 - 3 .1 4 ( 2 H, br m), 3.25 (2H, s), 3.28-3.66 (8H, br m), 3.5 7 (2 H, s), 7.4 3 (2 H, d, J = 7.4 Hz), 7.57 ( 2H,d,J = 7.6Hz). LC/MS [Condition 1]: Hold time 3.32 min; m/z 63 6.8 [M + H]+ (ESI positive ion mode), m/z 68l_0 [M + HCO〇r (ESI negative ion mode) [Chem. 5 8 6]

Reference Example 349 - 582 - 201211053 Preparation of i,4-diazacycloheptane-1-carboxylic acid methyl hydrochloride salt Substituted tert-butyl piperidin-4-ylaminocarbamate using 1,4-diazo The title compound (524 mg, quantitative) was obtained as a pale-yellow solid (yield: 530 mg, EtOAc). 1H-NMR (CDCl3) 5: 2.17-2.37 (2H, br m), 3. 6 6-3.3 7 (4H, br m), 3.57-3.69 (2H, m), 3.74-3.86 (2H, m), 3.74 (3H, s), 9.8 1 (2H, br s)

LC/MS [Condition 1]: Hold time 0·49 minutes; m/zl 59·0[Μ + Η]+ (ESI positive ion mode) [Chem. 5 8 7]

φ Example 3 4 9 4-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)phenylmethylhh-3,8-diazosud[ 4.5]Methyl decyl-3-yl}methyl)cyclohexanecarbonyl]-1,4-diazacycloheptane-1-carboxylate (Compound No. 3 49) was substituted for 3,5-dimethyl The title compound (17 mg) was obtained after the same reaction as in Example 3 42 except for the THF. Rate 43%) of white powder. 'H-NMR (300MHz ' CD Cl3 ) δ : 1 . 04(2H,q, J= 1 1 . 7Hz), 1.46-1.69 -583- 201211053 (3H,br m), 1.69-2.00(1 OH , br m), 2.4 1 ( 1 H, t, J = 1 1.7 H z ), 2.58 (4H, br s), 3.1 〇 (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]: Hold time 3.02 min; m/z 594.7 [M + H]+ (ESI positive ion mode), m/z 638.9 [M + HCO〇r (ESI negative ion mode) 8 8]

Example 3 5 0 4-[(11:,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo Preparation of spiro-[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carboxylic acid 2-methoxyethyl (Compound No. 3 50) for the replacement of methyl chloroformate using chloroformic acid A white powder of the title compound (6.4 mg, yield 22%) was obtained.

'Η-ΝΜΚ(300ΜΗζ &gt; CDC13)6:1.04(2H,q,J=l 1.0Ηζ), 1.46-1.69 (3 Η,brm),1 · 7 1 -1 · 8 7 (6 Η,brm) , 1 · 8 8 - 2.0 0 (2 Η,brm),2 · 4 2 ( lH,t,J=l 1 .9Hz), 2.56(4H,br s),3.10(2H,d,J = 8.2Hz ), 3.26 (2H, s), 3.38 (3H, s), 3.41-3.54 (6H, br m), 3.53 - 3.66 (6H, m), 4.22 - 4.3 1 (2H, m), 7.43 (2H, d , J = 7.8Hz), 7.57(2H,d,J = 7.8Hz)» LC/MS[Condition 1]: Hold time 3.02 minutes; m/z624.9[M + H]+ ( -584- 201211053 ESI 正Ion mode), m/z 669.0 [M + HCO〇r (ESI negative ion mode) [Chemical 5 8 9]

Example 3 5 1 φ 4-[(1. 4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carboxylic acid isopropyl (Compound No. 351) substituted methyl chloroformate using isopropyl chloroformate A white powder of the title compound (7.3 mg, yield: 27%) was obtained.

'H-NMR (300MHz ' CDC13) 5: 1,04 (2H, q, J=l 1,9Hz), 1.25(6H, d, J= 6.1 Hz), 1.43-1,67(3H,br m) , 1. 7 0 -1 · 8 6 (6 H,brm),1 . 8 7-• 2.02(2H,br m), 2.4 3 (1 H , t, J = 1 2 . 1 H z), 2.5 6 (4 H , brs), 3.1 〇 (2H , d, J = 7.4 Hz), 3.26 (2H, s), 3.47 (6H, br s), 3, 57 (4H, br s), 4.94 (lH, Qq, J = 6.1, 6.1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) o LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 608 .8[M + H]+ (ESI positive ion mode), m/z653_0[M + HCOO]_(ESI negative ion mode) -585- 201211053 [Chem. 5 9 0]

tX〇rcr^ Example 3 5 2 3-({(1~4〇-4-[4-(methylsulfonyl)piperazine-1-carbonyl]cyclohexyl}methyl)-8-[4- Preparation of (trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 52) Substituting methyl chloroformate, using methyl sulfonate A white powder of the title compound (18 mg, yield 70%) was obtained from the title compound (m.p. q, J = 11.9 Hz), 1.47-I.68 (3H, br m), 1.71-1.85 (6H, br m), 1.87-2.01 (2H, br m), 2.42 (lH, t, J = 11.9 Hz) ), 2_56(4H, br s), 2.79 (3H, s), 3.11 (2H, d, J = 7_4Hz), 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]: Hold time 2.92 minutes: m/z 600.8 [M + H] + (ESI positive ion mode), m/z 645.0 [M + HCOO] - (ESI negative ion mode) [Chemical 5 9 1]

Example 3 5 3 -586- 201211053 3-sided oxygen-3-{4-[(1]*, 4〇-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene) Manufacture of 1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-yl}propanenitrile (Compound No. 3 53)

3-{[(lr,4r)-4-(piperazin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1 obtained in Reference Example 149 - oxa-3,8-diazospiro[4.5] valer-2-one dihydrochloride (28 mg, 0-047 mmol) and 2-cyanoacetic acid (purchased) (6.0 mg, 0.071 mmol), 1-hydroxyl Benzotriazole (3.0 mg, 0.024 mol), and triethylamine (0.033 mL, 0.24 mmol) were dissolved in chloroform (1. 〇mL), and 1-ethyl-3-(3-dimethyl) was added at room temperature. The aminopropyl)carbodiimide hydrochloride (14 mg, 0.071 mmol) was stirred and mixed at room temperature for 1 day. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the mixture and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [Hybrid: HI-FLASH (registered trademark) COLUMNsilicagel 40 pm, developed solvent: ethyl acetate / methanol = 1 0/1]. The title compound φ (20 mg, yield 71%) of white powder. &quot;H-NMRCSOOMHz ' CDC13) 5: 1-05 (2H, q, J = l 1.6Hz), 1.57 (2H, q, J = 12.7Hz), l .56-1,71 (lH, br m) , 1 · 7 2 -1 . 8 6 ( 6 H, br m), 1.88-2.00 (2H, br m ), 2.44 (1 H, t, J = 1 0.0 H z), 2.5 7 (4 H , brs ), 3.11 (2H, d, J = 7.0Hz), 3.26(2H, s), 3.3 8 -3.7 7( 1 2H, br m), 7.4 3 (2 H, d , J = 8.2Hz), 7.56 ( 2H,d,J= 8.2Hz). 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) -587- 201211053 [化5 9 2]

Example 354

L-{4-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5 Manufacture of decyl-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carbonyl}cyclopropanenitrile (Compound No. 3 54) Substituting 2-cyanoacetic acid using 1-cyanocyclopropanecarboxylic acid A white powder of the title compound (18 mg, yield 61%) was obtained. 'H-NMR (3 00 MHz 'CDCl3) 5: 1.05 (2H, q, J = 11.6 Hz), 1.48-1.68 (7H, m), 1. 7 1 -1.86 (6H, br m), 1. 8 6 - 2.0 2 (2 Η, brm), 2.44 ( 1 H, t, J = 1 1.9 Hz), 2.56 (4H, br s), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s) , 3.43

3.93 (8H, brm), 3.57 (2H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz). LC/MS [Condition 1]: Hold time 3.00 min; m/z 615.8 [M + H]+ (ESI positive ion mode), m/z 659.9 [M + HCO〇r (ESI negative ion mode) 9 3] Reference Example 3 5 5 - 1 5-(Hydroxymethyl)thiophene-2-carboxylic acid methyl group 8 -588- 201211053

5-(Methoxycarbonyl)thiophene-2-carboxylic acid (synthesis using the method described in US Pat. No. 26,094,694) (120 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2.0 mL), and 1 M borane tetrahydrofuran solution (1.2 mL) was added under ice cooling. 1.2 mmol), followed by mixing at 60 t 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 organic layer obtained was dried over anhydrous magnesium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography [purifying agent: silica gel 60 (0.040-0.063 mm), developed solvent: hexane / ethyl acetate = 2 / 1) to give the title compound. (1 l 〇mg, yield 98%) of colorless oil 1H-NMR (300MHz, CDCl3) 6: 2.00 (lH, t, J = 6.1 Hz), 3.88 (3H, s), 4.86 (2H, d , J = 5.7 Hz), 6.99 (lH, dt, J = 3.7, 0.8 Hz), 7.68 (lH, d, J = 3·7 Ηζ). [化5 9 4]

Reference Example 3 Production of 5 5 - 2 5-(chloromethyl)thiophene-2-carboxylic acid methyl group The 5-(hydroxymethyl)thiophene-2-carboxylic acid methyl group obtained in Reference Example 3 55-1 was dissolved in Dichloromethane (1.0 mL) was added triethylamine (0.066 mL, 〇.48 mmol) and methanesulfonyl chloride (〇.〇42 mL, 〇.52 mmol) under ice cooling for 2 hours at room temperature. Half agitation. Triethylamine (0.066 mL, 0.48 mmol) and methanesulfonyl chloride (0.042 mL, 〇.52 mmol) were added under ice cooling, and stirred overnight at room temperature -589 - 201211053. Water and chloroform were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [purifying agent: silica gel 60 (0.040-0.063 mm), developed solvent: hexane/ethyl acetate = 4/1] to give the title compound. (3 5 mg, yield 47%) of a colorless oil. 1H-NMR (300MHz, CDC13) 8: 3.88 (3H5s), 4.76 (2H, s), 7.07 (1H, d, J = 3 · 7 Η z), 7 · 6 5 (1 Η, d, J = 4 · 1 Η z). [化5 9 5]

Reference Example 3 5 5 - 3 3-{[5-(Methoxycarbonyl)thiophen-2-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane Production of -8-carboxylic acid tert-butyl ester The 2-butyloxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester obtained in Reference Example 111-1 ( 71 mg, 0.28 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (2.0 mL), and sodium tributoxide (30 mg, 〇.31 mmol) was added thereto, and after stirring for 30 minutes, reference example 3 5 5-2 was added. The obtained solution of methyl 5-(chloromethyl)thiophene-2-carboxylate (35 mg, 0.19 mmol) in N,N-dimethylformamide (2.0 mL) was mixed for 3 hours. Thereafter, water and ethyl acetate were added, and the organic layer was separated, 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 of -590-201211053 was obtained by the column chromatography of 矽 塡 : : M M M M 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 M M M M M M M M M The title compound (20 mg, yield 26%)yiel. 1H-NMR (300MHz, CDC13) 5: 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 (lH, d, J = 3.7 Hz), 7.68 (l H, d, J = 3 · 7Hz) 〇

LC/MS [Condition 1]: Hold time 4.1 1 min ESI positive ion mode) m/z 432.9 [M + Na]+ ( [5 5 6]

A

H-CI

Reference Example 3 5 5-4 5-[(2-oxo-oxy-1-cax-3,8-diazospiro[4.5] oxazol-3-yl)methyl]thiophene-2-carboxylic acid methyl hydrochloride Preparation of a salt to replace [(tetrahydrofuran-2-yl)methyl]aminocarbamic acid tert-butyl ester using 3-{[5-(methoxy- ortho-yl)-phenylen-2-yl]methyl}-2- The title was obtained by the same reaction as in Reference Example 182-3 except that the side oxy-1-[1 oxa-3,8-diazospiro[4.5]nonane-8-carbamic acid tert-butyl ester was substantially reacted. Compound (17 mg, yield in quantitative) of white solid. Ή-ΝΜΚ(3 00ΜΗζ,α〇3〇〇)δ:2.05-1.9 1(3Η,ιη), 2.15(2Η,(Ι,Ι = -591 - 201211053 14.3Hz), 3.44(2H,s),3.86 (3H, s), 4.66 (2H, s), 7.11 (lH, d, J = 3.7 Hz), 7.70 (lH, d, J = 3.7 Hz). 1^/1^13 [Condition 1]: Hold time 〇.59 minutes; 111/2311.〇[^4 + 11]+( ESI positive ion mode)

Reference Example 3 5 5 - 5 5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-che-3,8-diazospiro[4.5]decane-3 Preparation of -yl}methyl)thiophene-2-carboxylic acid methyl group 5-[(2-Sideoxy-1-oxo-3,8-diazosuro[4.5]癸 obtained in Reference Example 3 5 5 -4 Alkyl-methyl)thiophene-2-carboxylic acid methyl hydrochloride (17 mg, 0.049 mmol) was suspended in N,N-dimethylformamide (2.0 mL), triethylamine (0-020 mL, 0.15 mmol) And 4-(trifluoromethyl)benzyl bromide (14 mg, 0.058 mm ο 1), mixed at room temperature for 1 hour. After adding water and ethyl acetate, the organic layer was separated, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [塡 剂 : 胺 FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU / / / / / / / / / / / / The title compound (25 mg, yield) is a white solid. -592- 201211053 'H-NMR (300MHz, CDCl3) 5: 1.69- 1.84 (2H, m), 1.93 (2H, d, J = 12.9Hz), 2.61-2.49 (4H, brm), 3.24 (2H&gt;S ), 3.56 (2H, s), 3.88 (3, s), 4.61 (2H, s), 6.98 (lH, d, J = 4.0 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.5 7 ( 2H, d, J = 8.3 Hz), 7.68 (1 H, d, J = 3.6 Hz). LC/MS [Condition 1]: Hold time 3.04 minutes; m/z 468.8 [M + H]+ (ESI positive ion mode) [Chem. 5 9 8]

Reference Example 3 5 5 - 6 5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1_oxas-3,8-diazospiro[4.5] decane- Manufacture of 3-yl}methyl)thiophene-2-carboxylic acid

5 - ({2 - oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5] oxime obtained in Reference Example 3 5 5 -5 Methyl alk-3-yl}methyl)thiophene-2-carboxylate (25 mg, 0.052 mmol) was suspended in methanol (2.0 mL), and dissolved in vacuo at 60 ° C. .26 mmol), mixed at 6 ° C for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then 1M hydrochloric acid (〇_26 mL, 〇.26 mmol) was dropped. After further separating the organic layer by adding saturated brine and ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to dryness crystals crystals crystals -593- 201211053 1H-NMR (300MHz, CDCl3) 5: 1.88-2.03 (4H, m), 2.65-3.23 (6H, m), 3.93 (2H, s), 4.57 (2H, s), 6.93 (lH, 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) 9】

Example 3 5 5 3-({5-[4-(4-Fluorobenzylidinyl)piperidin-1-carbonyl]thiophen-2-yl}methyl)-8-[4-(trifluoromethyl) Manufacture of benzylmethyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 5 5) 5-({2) obtained in Reference Example 3 5 5-6 -Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)pyran-2-carboxylate Acid (4.011^, 0.008 8111111〇1), 4-(4-fluorobenzhydryl)piperidine hydrochloride (3.2 mg, 0.013 mmol), triethylamine (1·8 μί, 0.013 mmol) and 1-hydroxyl After benzotriazole (1.2 mg, 0.0088 mmol) was dissolved in chloroform (1.0 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.5 mg) was added. , 0.013 mmol), mixed at room temperature for 84 hours. After the completion of the reaction, the organic layer was separated from water, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by a thin layer chromatography (PLC05 Plate NH, manufactured by FUJI SILYSIA Co., Ltd., solvent: ethyl acetate) -594-201211053 to give the title compound (4.1 mg yield 73%) as a white solid.

IH-NMR (300MHz, CDCl3) 5: 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 (lH, 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]: Hold time 3.38 minutes; m/z 644.0 [M + H]+ (ESI positive ion mode), m/z 642_l [M-Hr (ESI negative ion mode)

Example 3 5 6

4-[5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}A Preparation of methyl thiophene-2-carbinamide] piperidine-1-carboxylate (Compound No. 3 56) Substituting 4-(4-fluorobenzhydryl)piperidine hydrochloride, using Reference Example 135 The title compound (3.6 mg, yield 6.9 %) was obtained as a colorless oil. 1H-NMR (300MHz, CDCl3) 6: 1.4 1 (2H, qd, J = 12.3, 3.3 Hz), 1.74 (2H, dt, J = 1 3.5, 7.2 Hz), 1.92 (2H, d, J = 13.1 Hz) ), 2.02 (2H, d, J = 13.9 Hz), -595- 201211053 2.49-2.57 (4H, m), 2.94 (2H, t, J = l 2.7 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 (lH, d, J = 7.4 Hz), 6.96 (lH&gt;d, J = 3.7 Hz) , 7.36 (lHsd, J = 3.7 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 2.31 minutes; m/z 594.9 [M + H]+ (ESI positive ion mode), m/z 593.0 [MH]- (ESI negative ion mode) [Chem. 6 0 1 】

Example 3 5 7 N-(Benzo[d][l,3]dioxazole-5-ylmethyl)-5-({2-Sideoxy-8-[4-(trifluoromethyl)benzene) Manufacture of methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)thiophene-2-carboxamide (Compound No. 3 5 7) in place of 4-(4- The fluorobenzhydryl)piperidine hydrochloride was reacted in the same manner as in Example 35 5 to give the title compound (3.8 mg, yield 74%) as a colorless oil. 1H-NMR (300MHz, CDCl3) 6: 1.74 (2H, dt, J = 14.1, 6.9 Hz), 1.92 (2H5dt, 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 (lH, t, J = 5.7 Hz), 6.73-6.8 5(3H,m), 6.96 (lH,d,J = 4.1Hz), 7.3 6(lH,d,J = 3.7Hz), 7.42(2H,d,J = 7.8Hz), 7.57(2H,d, J = 8.2 Hz). -596- 201211053 LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 5 8 7.9 [M + H]+ (ESI positive ion mode), m/z 586.0 [MH]- (ESI negative ion mode) 6 0 2]

Example 3 5 8 5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl Substitution of methyl)-N-[(tetrahydrofuran-2-yl)methyl]thiophene-2-carboxamide (Compound No. 358) to replace 4-(4-fluorobenzhydryl)piperidine hydrochloride, The title compound (2.9 mg, yield 60%) was obtained as a colorless oil. Lu 1H-NMR (300MHz, CDCl3) 6: 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 (lH,ddd, J = 13.9, 7.8, 4.9 Hz), 3.56 (2H, s), 3.70-3.83 (2H, m), 3.89 (lH, dt, J = 8.2, 7.0 Hz), 4.05 (lH, Qd, J = 7.4, 3.3 Hz) &gt; 4.59 (2H, s), 6.30 (lH, t, J = 5.7 Hz), 6.96 (lH, d, J = 3.7 Hz), 7.37 (lH, 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]: Hold time 2.90 min; m/z 53 7.8 [M + H]+ (ESI positive ion mode), m/z 536.1 [M-Hr (ESI negative ion mode) -597- 201211053 6 0 3]

Example 3 5 9

Ν-(4-cyanobenzyl)-5-({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-indole oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl}methyl)thiophene-2-carboxamide (Compound No. 3 59)

Substituting 4-(4-fluorobenzhydryl)piperidine hydrochloride, the same reaction as in Example 35 5 was carried out, except using 4-cyanobenzylamine hydrochloride. Mg, yield 48%) of a colorless oil. 1H-NMR (300MHzs CDCl3) 8: 1.53-1.87 (2H5ni), 1.93 (2H, ci, 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 (lH, t, J = 5.9 Hz), 6.98 (lH, d, J = 3.7 Hz), 7.42 (lH5d, J = 3.7) Hz), 7.44 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.5 8 (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 [M-Hr (ESI negative ion mode) 8 -598- 201211053 【化6 0 4】

Example 360 Ν-(4-cyanobenzyl)_3-({2-o-oxo-8-(4-(trifluoromethyl)benzyl)-1-# spiro-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)benzamide (Compound No. 3 60) Substituting 4-aminopiperidine-1-carboxylic acid methyl hydrochloride using 4-cyanobenzene The title compound (23 mg, yield 91%) was obtained as white solid. 1H-NMR (300MHz, CDCl3) 5: 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), 3.5 5 (2H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.67 (lH, t, J = 5.7 Hz) 57.38-7.50 (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]: Hold time min; m/z 562.9 [M + H]+ (ESI positive ion mode), m/z 561.0 [M-H]' (ESI negative ion mode) [Chem. 6 0 5]

201211053 Example 3 6 1 4-{l-[3-({2-Sideoxy-8-(4-trifluoromethyl)phenylmethylpyridinium-oxo_38diazospiro[4.5]decane- Preparation of 3-amino}methyl)benzhydryl]piperidine-4-yloxybenzonitrile (Compound No. 361) Substituted 4-aminopiperidine-1 -carboxylic acid methyl hydrochloride, use reference The title compound (3 lmg, yield was quantitative) white was obtained by the same procedure as the compound of Example 202, except for 4-(piperidine-4- oxy) solid. 1H-NMR (300 MHz, CDCl3) 8: 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 (lH, tt, J = 6.1, 3.7 Hz), 6.96 (2H, d, J = 9.3 Hz), 7.29-7.38 (3H, m), 7.40 (l H, d , J = 7.9 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.5 6 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 9.0 Hz). LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 633.0 [M + H]+ (ESI positive ion mode), m/z 677.1 [M + HCO〇r (ESI negative ion mode) [ 6 6 6]

Example 362 600-201211053 1-(4-Cyanobenzyl)-3-[4-({2-Sialoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl]urea (Compound No. 3 62)

Substituting N-(t-butoxycarbonyl)-1,3-diaminopropane, using 4-cyanobenzylamine (purification of commercially available 4-cyanobenzylamine hydrochloride by dehydrochlorination) The title compound (24 mg, yield 46%) was obtained as a colorless oil. 1H-NMR (300MHz, CDCl3) 6: 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), 4.5 1 (2H, d, J = 5.7 Hz), 5.43 (1 H, t, J = 6.1 Hz), 6.78 ( lH, 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) 〇 LC/MS [Condition 1] ··Retention time 3.18 minutes; m/z57 7.9M + H] + (ESI positive Ion mode), m/z 576.0 [MH]-(ESI negative ion mode)

【化6 0 7】

Example 3 6 3 Side Oxy-8-[4-(trifluoromethyl)benzyl]-oxazo-3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl] Manufacture of substituted -3-[(tetrahydro-2H-pyran-4-yl)methyl]-601 - 201211053 (Compound No. 363) substituted N-(t-butoxycarbonyl)-1,3-diamine The title compound (31 mg, yield 63%) was obtained as a white solid. 1H-NMR (300MHz, CDCl3) 5: 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 = 6.1Hz), 3.37(2H,td,J=l 1.7,1.9Hz), 3.5 5( 2H,s), 3.97( 2H, dd, J = 11.3, 3.1 Hz), 4.3 6 (2H, s), 4.99 (lH, t, J = 5.7 Hz), 6.58 (1 H, 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]: Hold time 2.94 minutes; m/z 560.9 [M + H]+ (ESI positive ion mode), m/z 559.0 [M-Hr (ESI negative ion mode) [Chem. 6 0 8 】

Example 364 1-(furan-2-ylmethyl)-3-[4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-3-yl}methyl)phenyl]urea (Compound No. 364) Substituting N-(t-butoxycarbonyl)-1,3-diaminopropane, using hydrazine In the same manner as in the above Example 8 except that the amine was reacted in the same manner to give the title compound: 602-201211053 (2 1 mg, yield 43%) as a yellow solid. 1H-NMR (300MHz, CDCl3) 5: 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 (lH, t, J = 5.3 Hz), 6.25 ( lH, d, J = 3.3 Hz) ), 6.32 (lH, dd, J = 3.3, 1.6 Hz), 6.46 (lH, s), 7.17 (2 H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.33 7.36 (lH, m), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 542.9 [M + H]+ (ESI positive ion mode), m/z 541.1 [MH]_ (ESI negative ion mode) [Chem. 6 0 9 】

φ Example 3 6 5 1-(Furan-3-ylmethyl)-3-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo- Preparation of 3,8-diazospiro[4.5]decane-3-yl}methyl)phenyl]urea (Compound No. 3 65) substituted N-(t-butoxycarbonyl)_ι,3-diamino The title compound (2 1 mg, yield 43%) was obtained as a pale yellow solid. 1H-NMR (300MHz, CDCl3) 5: 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, -603- 201211053 s), 4.30 (2H, d, J = 5.3 Hz), 4.36 (2H, s), 4.87-4.98 (lH, m), 6.40 (lH, s), 6.48 (lH, brs), 7.17 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.3 6 - 7.42 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.08 minutes; m/z 542.9 [M + H]+ (ESI positive ion mode), m/z 541_l [M-Hr (ESI negative ion mode) [Chem. 6 1 0]

Example 366 (lr,4r)-N-(3-Cyanobenzyl)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-I-Evil- Preparation of 3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamide (Compound No. 366) Substituted tetrahydrofurfurylamine using 3-(aminomethyl)benzene The title compound (19 mg, yield 73%) was obtained as a white solid. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m 1H-NMR (300MHz, CDCl3) 6: 1.03 (2H, qd, J = l 1.9, 2.9 Hz), 1.53 (2H, qd, J = 1 2.7, 2. 9 Ηζ), 1.62- 1.69 ( lH, m), L_79 (4H, d, J = l 0.6Hz), 1 · 95 (4Η, d, J = 15.1Hz), 2· 10 (lH, tt, J = 11.9, 3.7Hz), 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 (lH, t, J = 5.7 Hz) ), 7.39-7.62 (8H, m). -604- 201211053 LC/MS [Condition 1] ··Retention time 3·14 minutes; m/z568.7 [M + H]+ (ESI positive ion mode), m/z612.9[M + HCOO]-( ESI negative ion mode)

Reference Example 3 6 7 · 1 4-[4-(methylsulfonyl) benzhydryl]piperidine-1-carboxylic acid tert-butyl ester was produced by using W020〇5/〇5 9 1 07 Method synthesis. 【化6 1 2】

Φ Reference Example 3 67-2 Preparation of 4-[4-(methylsulfonyl)benzylidene]piperidine hydrochloride 4-[4-(methylsulfonate) obtained in Reference Example 3 67-1 Benzyl hydrazino] piped D-l-residual acid dibutyl ester (68 mg, 〇. 18 mmol) dissolved in methanol (2.0 mL) was added 4 M hydrogen chloride-dioxane solution (2.0 m L), Mix for 30 hours at room temperature. The reaction mixture was filtered, and the obtained solid was evaporated. 'Η-ΝΜΚ(300ΜΗζ, α〇3〇0) δ: 1.90 (2Η, (1ίά,;=15.1,11.ΐ,4.ΐΗ 605- ' · 201211053 , 2.14(2H,dd,J=14.9,2.7 Hz), 3.1 5 (1 H, dd, J = 7.4, 4.1 Hz), 3·17 (3 H, s), 3.21 (lH, dd, J = 12.3, 3.3 Hz), 3.47 (2H, dt, J =13.1, 4.2 Hz), 3.82 (lH, tt, J=ll.l, 3.7 Hz), 8.12 (2H, d, J = 8.6 Hz), 8.24 (2H, d, J = 9.0 Hz) 3]

Example 367 3-[((11',4〇-4-{4-[4-(methylsulfonyl)benzylidene]piperidine-1-carbonyl}cyclohexyl)methyl]-8- Production of [4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 67) Substituted tetrahydrofurfurylamine, used The title compound (3 O mg, m.p. Yield 97%) of white solid: 1H-NMR (300MHz, CDCl3) 6: 1.05 (2H, q, J = 12.7 Hz), 1.56 (2H, q, J = 13.1 Hz), 1.56 - 1.69 (2H, m ), l.72-1.87 (7H, m), l.88-2.00 (4H, m), 2.46 (lH, tt, J = 12.3, 3.3 Hz), 2.53-2.63 (4H, m), 2.84 (lH) ,t, J=11.9Hz), 3.09(3H,s),3.1 1 (2 H ,d, J = 8.2Hz), 3.22 (1 H, t, J= 1 3.5 H z) , 3.26(2H,s ), 3.5 1 (lH, tt, J = 10.6, 3.7 Hz), 3.57 (2H, s), 3.99 (lH, d, J = 13.5 Hz), 4.60 (lH, d, J = 13.1 Hz), 7.44 ( 2H,d,J = 7.8 Hz), 7.57 (-606-201211053 2H, d, J = 8.2 Hz), 8.07 (2H, d, J = 8.6 Hz), 8.11 (2H, d, J = 9.0 Hz). LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 703.8 [M + H]+ (ESI positive ion mode), m/z 747.9 [M + HCOO]- (ESI Negative ion mode)

【化6 1 4】 0

Example 3 6 8 3-{4-[4-(4-Fluorobenzylidinyl)piperidin-1-ylsulfonyl]benzylidene 2-sideoxy-1-oxo-3,8-weight Manufacture of a nitrogen snail [4.5] decane-8-carboxylic acid tert-butyl ester (Compound No. 3 68)

4-(Methylmethyl)benzene-propionic acid chloride (530 mg, 2.0 mmol) was dissolved in chloroform (5.OtnL). Under ice cooling, 4-(4-fluorobenzhydryl)piperidine hydrochloride (480 mg) was added. 2.0 mmol) and triethylamine (〇.55 mL, 4.0 mmol) were mixed at room temperature for 2 hours. After adding water (1 〇 mL) and chloroform (10 mL) to the reaction mixture, the organic layer was separated and filtered, and the resulting solution was concentrated under reduced pressure. The obtained residue was purified by a silica gel column chromatography [lubricant: sulphide 60 (0.040-0.063 mm), developed solvent: chloroform / ethyl acetate = 10/1] to give a colorless oil. (6Omg). The 2-sided oxy-1-oxo-3,8-diazospiro[4.5] brothel-8-residual acid third butyl vinegar (35 mg, 0-14 mmol) obtained in Reference Example 111-1 was dissolved in n,N-di A-607- 201211053

Base carbamide (1.0 mL), after adding sodium tributoxide (16 mg, 〇. 16 mmol) and stirring for 30 minutes, the previously obtained colorless oil (6 〇mg) of N,N-dimethyl A solution of carbamide (2.0 mL) was added and mixed for 5 hours. Thereafter, water and ethyl acetate were added, and the organic layer was separated. The obtained organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [塡 剂 : M M M M M M M M ( ( The title compound (75 mg, 6%) was obtained as white solid. 1H-NMR (300MHz JCDCl3) 5: 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 (lH) , tt, J = 10.2, 4.5 Hz), 3.2 1 (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, 5.5Hz).

LC/MS [Condition 1]: Hold time 4.59 minutes; m/z 615.8 [M + H]+ (ESI positive ion mode), m/z 659.9 [M + HCOO]. (ESI negative ion mode) 1 5]

Reference Example 3 6 9 3-{4-[4-(4-Fluorobenzylidene) acridine-1-ylsulfonyl]benzyl}_1_oxo - 8 -608- 201211053 3,8· Preparation of azaspiro[4.5]decane-2-one hydrochloride 3-{4-[4-(4-fluorobenzylidinyl)piperidin-1-ylsulfonyl group obtained in Example 3 6 8 ] Benzyl}-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (69 mg, 0.1 lmmol) dissolved in 1,4 - dioxins Alkane (2. Om L) was added to a 4M solution of hydrogen chloride in dioxane (2.0 mL) and mixed at room temperature for 3 hours. The reaction mixture was concentrated to dryness crystals crystals crystals

LC/MS [Condition 1]: Hold time 3.10 minutes; m/z 515_8 [M + H]+ (ESI positive ion mode), m/z 513.8 [M-H]- (ESI negative ion mode) [Chem. 6 1 6] 〇

φ Example 369 3,5-Difluoro-4-[(3-{4-[4-(4-fluorobenzylidinyl)piperidin-1-ylsulfonyl]benzyl}-2- side Preparation of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. 3 69) 3-{4-[4 obtained in Reference Example 369 -(4-fluorobenzhydryl)piperidine-buylsulfonyl]benzyl}-l-oxo-3,8-diazospiro[4.5]decane-2-ketone hydrochloride after desalting 3-{4-[4-(4-Fluorobenzylidene)piperidin-1-ylsulfonyl]benzylidene-1-oxo-3,8-diazospiro[4.5]decane- 2-ketone. 3-{4-[4-(4-Fluorobenzylidinyl)piperidin-1-ylsulfonyl]benzene-609 - 201211053 methyloxa-3,8-diazospiro[4.5]癸Alkan-2-one and 3,5-difluoro-4-carbamimidonitrile (6.9 mg, 0.041 mmol) were dissolved in dichloromethane (2. 〇mL), and sodium triacetate hydride (12 mg) was added. , 0.057 mmol), mixed at room temperature for 1 hour. Water and chloroform were added to the reaction mixture, and the organic layer was evaporated. The obtained residue was purified by EtOAc (EtOAc: EtOAc (EtOAc) iH-NMR (300MHz, CDC13) 6: 1.70-1.82 (2H, m), 1.82-1.99 (6H, m), 2.54-2.67 (6H, m), 3.17 (2H, s), 3.19 (lH, Tt, J = 9.6, 5.0 Hz), 3.74 (2H, s), 3.77 (2H, dt, J = 12.6, 3.3 Hz), 4.5 1 (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]: Hold time 3.58 min; m/z 666.7 [M + H]+ (ESI positive ion mode), m/z 711.0 [M + HCOO]- (ESI negative ion mode) 1 7]

Example 370 4-[(3-{4-[4-(4-Fluorobenzylidinyl)piperidin-1-ylsulfonyl]benzyl}-2-oxo-oxa- 3,8 - Substituted by the manufacture of diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. -610-201211053, code 370) (lr,4〇-N-(l-benzylpiperidine· 4·基)·4-[(2- Side Oxygen-1-Evil-

3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarbamide hydrochloride, using 3-{4-[4-(4-fluorophenyl) obtained in Reference Example 369 Mercapto)piperidin-1-ylsulfonyl]benzyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride, substituted benzyl bromide The title compound (1 2 mg, yield 66%) was obtained as a pale yellow solid.

, H-NMR (300MHz, CDCl3) 6: 1.73-2.01 (8H, m), 2.50-2.67 (6H, m), 3.19 (lH, tt, J = 9.8, 5.3 Hz), 3.20 (2H, s), 3.5 8(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), 7.6 1 (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]: Hold time 3.29 minutes; m/z 630.9 [M + H]+ (ESI positive ion mode), m/z 629.2 [M-H]- (ESI negative ion mode)

【化6 1 8】

Reference Example 3 7 1 -1 Preparation of 2-(methoxymethoxy)-4-methylbenzoic acid methyl ester 4-methylsalicylic acid methyl (426 mg, 2.6 mmol) was dissolved in N,N- -611 - 201211053 dimethylformamide (5. 〇mL), add sodium hydride (55 wt%, dispersed in flowing paraffin) U70 mg, 3.9 mmol) under ice cooling, and stir and mix for 20 minutes, then add chloromethyl group. Methyl ether (〇25 mL, 3.3 mmol) was mixed at room temperature for 15 hours. After a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and ethyl acetate (10 mL) were added to the mixture, the organic layer was separated and washed three times with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [purification: yttrium 60 (0.040-0.063 mm), hexane/ethyl acetate = oxime) to give the title compound. Colorless oil (4 80 mg &gt; yield 89%). 1H-NMR (300MHz) CDC13)5: 2.37 (3H, s) 53.53 (3H, s) 33.87 (3H, s), 5.25 (2H, s), 6.85 (lH, d, J = 8.2 Hz), 7.00 ( lH, s), 7.71 (lH, d, J = 7.8 Ηζ).

Reference Example 3 7 1 - 2 3_[4-(Methoxycarbonyl)-3-(methoxymethoxy)benzyl]_2· side oxygen_ΐ-oxa-3,8-diazo snail [4.5 [Production of tert-butyl-8-carboxylic acid tert-butyl ester] 2-(methoxymethoxy)-4-methyl-benzo-612-201211053 obtained in Reference Example 371-1

Methyl benzoate (48〇11^, 2.3111111〇1) was dissolved in chloroform (5.〇1111〇, heated at 80 °C), then added N-indimethalin (534 mg, 3.0 mmol) and azo Double isobutyronitrile (75 mg, 0.46 mmol) was mixed at 80 ° C for 3 hours. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (1 〇m L) and chloroform (10 mL) The dried magnesium sulfate was dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ 塡 : : M M M M M M M M M M M M M M M M M M / / / / / / =5/1] Purification afforded a colorless oil (694 mg). 2-2-oxo-oxo-3,8-diazaspiro[4.5] broth-8-decanoic acid obtained in Reference Example 111-1 The third butyl ester (591 mg, 2.3 mmol) was dissolved in n,N-dimethylformamide (6.0 mL), and third sodium butoxide (222 mg, 2.3 mmol) was added. After stirring for 30 minutes, the previously obtained The colorless oil (694 mg) was dissolved in N,N-dimethylformamide (4.0 mL), and added, and mixed for 2 hours. Thereafter, water and ethyl acetate were added, and the organic layer was separated and dried with saturated brine. Washed 3 times, no After drying with magnesium sulfate in water, it was concentrated under reduced pressure. The residue obtained was chromatographed on a silica gel column [mixing agent: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane/acetic acid) The title compound (5 4 2 mg, 5 1 %) was obtained as a colorless oil. <H-NMRiSOOMHz^DClsiSrl^SCPH^ilSS-l.69 (2H,m), 1.8 8(2 H,d,J=13.5Hz), 3.15(2H,s), 3.29(2H,t,J=ll.lHz), 3.5 1(3H,s ),3.81(2H,d,J = 12.3 Hz), 3.90 (3H, s), 4.45 (2H, s), 5.25 (2H, s), 6.94 (lH, dd, J = 7.8, 1.6 Hz), 7.07 (lH, d, J = 1.2 Hz) , 7.77 (lH, d, J = 8.2 Hz) -613- 201211053 LC/MS [Condition 1]: Hold time 4 〇 9 minutes; m/z 48 6.8 [M + Na]+ (ESI positive ion mode) 6 2 Ο 】

Reference Example 3 7 1 - 3 2-Hydroxy-4-[(2-oxo-oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl] benzoic acid methyl ester hydrochloride For the production of the salt, 3-[4-(methoxycarbonyl)-3-(methoxymethoxy)benzyl]-2-oxo-oxo-oxa-3,8 obtained in Example 371-2. - Diazospiro[4_5]nonane-8-carboxylic acid second butyl vinegar (542 mg, 0.029 mmol) was dissolved in methanol (5.0 mL), and 4M hydrogen chloride-dioxane solution (2.0 mL) was added at room temperature. Mix for 2 hours. After that, the obtained solid was filtered and washed with EtOAc EtOAc (EtOAc) W-NMRGOOMHz'CDCDSJ.t^pH'dJsl 3.5Hz), 2.17-2.3 1( 2H,m), 3.23(2H,s), 3.28(2H,t,J = 10.2Hz), 3.45(2H,d, J = 11.9 Hz), 3.96 (3H, s), 4.40 (2H, s), 6.7 7 (lH, dd, J = 8.2, 1.6 Hz), 6.84 (lH, d, J = 1.2 Hz), 7.83 (1) H, d, J = 8.2 Hz), 9.76 (2H, brs), l 0.82 (lH, s). LC/MS [Condition 1]: Hold time 0.74 min; m/z 321.0 [M + H]+ (ESI positive ion mode) -614- 201211053 [Chem. 6 2 1] Ο

Reference example 371-4

2-hydroxy-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl} Preparation of methyl benzoic acid methyl ester The 2-hydroxy-4-[(2-oxo-oxo-3,8-diazosuccinyl][4.5]decane-3-yl group obtained in Reference Example 371-3 Methyl] benzoic acid methyl ester hydrochloride (UOmg, 0.36 mmol) was suspended in N,N-dimethylformamide (3.0 mL), and triethylamine (0.15 mL, 1.1 mmol) and 4-( Trifluoromethyl)benzyl bromide (100 mg, 0.43 mmol) was mixed at room temperature for 2 hours. The organic layer was separated into water and ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [塡 剂 : 胺 FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU FU / / / / / / / / / / / / The title compound (1 42 mg, yield 82%) 1H-NMR (300MHz, CDCl3) 5: 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 (lH, dd, J = 8.2, 1.6 Hz), 6.85 (lH, d, J = 1.6 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.82 (lH, d, J = 8.2 -615- 201211053

Hz), 1 0.8 1 (1 H, s). LC/MS [Condition 1]: Hold time 3.10 minutes; m/z 478.8 [M + H]+ (ESI positive ion mode), m/z 477.0 [MH]- (ESI negative ion mode) [Chem. 6 2 2 】

Reference Example 3 7 1 -5 2-Hydroxy-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] Manufacture of decyl-3-yl}methyl)benzoic acid 2-hydroxy-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl) obtained in Reference Example 371-4 1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl) benzoic acid methyl ester (88 mg, 0.18 mmol) was suspended in methanol (5.0 mL), heated and dissolved at 50 ° C Thereafter, a 1 M aqueous sodium hydroxide solution (1.5 mL, 1.5 mmol) was added, and the mixture was allowed to stand at 50 ° C for 2 hours, at 60 ° C for 15 hours, and at room temperature for 16 hours. After that, 1 M hydrochloric acid (1.5 mL, EtOAc, EtOAc) 1H-NMR (300MHz, CD3OD) 8: 1.82- 1.96 (2H, m), 2.03 (2H, d, J = 14.3Hz), 2.82-2.98 (4H, m), 3.98 (2H, s), 4.38 (2H , s), 6.74 (2H, d sJ = 9.4 Hz), 7.6 1 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6 Hz), 7.83 (lH, d, J = 7.8 Hz) ). -616- 201211053 LC/MS [Condition 1] · Hold time 2.88 minutes; m/z 464.8 [M + H]+ (ESI positive ion mode), m/z 462.9 [M-H]- (ESI negative ion mode)

Example 3 7 1 [Chemical 6 2 3] Ο

4-[2-hydroxy-4-({2-trioxo-8-[4-(trifluoromethyl)phenylmethyl)-1-oxa-3,8-diazospiro[4·5] brothel- Manufacture of 3-ethyl}methyl)benzhydryl]piperazine-indolecarboxylic acid ethyl ester (Compound No. 371)

2-Hydroxy-4-((2-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospin [4.5] obtained in Reference Example 371-5 ]decane-3-yl}methyl)benzoic acid (20 mg, 0.043 mmol), 1-piperazinecarboxylic acid ethyl ester (〇.〇〇75 mL, 0.052 mmol) and 1-hydroxybenzotriazine (1.7 mg) 0. 〇3 1 mm ο 1) After dissolving in chloroform (1.0 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg, 0.068) was added. Mixing at room temperature for 84 hours. After the end of the reaction, water and citric acid (6 mg, 0 · 0 3 1 mm ο 1 ) were added, the organic layer was separated, concentrated under reduced pressure and ethyl acetate and water were added. The organic layer was separated from sodium hydrogencarbonate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography [PLCHI SILYSIA, PLC05 Plate NH, developing solvent: ethyl acetate Purification to give the title compound (8.5 mg, yield: 33%) as a white solid. -617-201211053 1H-NMR (300 MHz, CDCl3) 5: 1.29 (3H, t, J = 6.9 Hz ), 1.75 (2H, dt, J = ll.l, 6.6 Hz) s1.94 (2H, d, J = 13.9 Hz), 2.47-2.64 (4H, m), 3.18 (2H, s), 3.5 1- 3.62 (6H, m), 3.67-3.77 (4H, m), 4.18 (2H, q, J = 6.9 Hz), 4.39 (2H, s), 6.79 (lH, dd, J = 7.9, 1.3 Hz), 6.90 (lH,d,J = 1.3 Hz), 7.22 (lH,d,J = 7.9 Hz), 7.43 (2H,d,J = 7.9 Hz), 7.57 (2H,d,J = 8.1 Hz), 9.65 (lH) , brs) LC/MS [Condition 1]: Hold time 3.06 minutes; m/z 604.6 [M + H]+ (ESI positive ion mode), m/z 602.9 [M-Hr (ESI negative ion mode) [ 6 2 4]

Example 3 7 2 3-{4-[4-(6-chloropyrimidin-4-yl)piperazine-1-carbonyl]-3-hydroxybenzyl}-8-[4-(trifluoromethyl) Preparation of benzylidene-1-pyrene-3,8-diazospiro[4.5] oxazol-2-one (Compound No. 3 72) Substituting 1-piperazinecarboxylic acid ethyl ester, using Reference Example 28 8 The title compound (1 1 mg, yield 41%) was obtained from the title compound (1 1 mg), m. White solid.

1H-NMR (300MHz, CDCl3) 6: 1.76 (2H, dt5J = 13.2, 6.9 Hz), 1.94 (2H, d, J = 1 2.9 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 (lH, d, J - 618 - 201211053 = 0.7Hz) , 6.8 1 (lH, dd, J = 7.9, 1.7 Hz), 6.9 1 (lH, d, J = 1.7 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.5 7 (2H, d, J = 7.9 Hz), 8.42 (lH, d, J = 0.7 Hz), 9.68 (1 H, brs).

LC/MS [Condition 1]: Hold time 3.08 min; m/z 644.9 [M + H]+ (ESI positive ion mode), m/z 642.9 [M-Hr (ESI negative ion mode)

Example 3 7 3 2-Hydroxy-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5] Manufacture of decyl-3-yl}methyl)·Ν-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 3 73 )

The title compound (25 mg, yield quant.) was obtained as a white solid, m.p. 1H-NMR (300MHz, CDCl3) 5: 1.73 (2H, dt, J = 13.5, 6.9 Hz), 1.67-1.80 (2H, m), 1.87-2.12 (5H, m), 2.47-2.6 1 (4H, m ), 3.15 (2H, s), 3.3 1 (lH, ddd, J = 13.9, 7.9, 4.6 Hz), 3.56 (2H, s), 3.74-3.84 (2H, m), 3.90 (lH, dt, J = 8.6, 6.6 Hz), 4.07 (lH, dq, J = 3.0, 7.3 Hz), 4.3 8 ( 2H, s), 6.66 ( lH, t, J = 5.9 Hz), 6.77 (l H, dd, J = 8.3) , 1.7 Hz), 6.84 (1 H, d, J = 1.3 Hz), 7.37 (lH, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.56 - 619 - 201211053 (2H, d, J = 8.3 Hz), 12.45 (lH, s). LC/MS [Condition 1]: Hold time 3.06 minutes; m/z547 7[M + H]+ (ESI positive ion mode), m/Z545_9[M-H]-(ESI negative ion mode)

Example 374 4-[2-Hydroxy-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxa-3,8-diazospiro[4.5]decane Manufacture of -3-yl}methyl)benzhydryl]_1&gt;4-diazacycloheptane-indolecarboxylic acid methyl ester (Compound No. 3 74) Substituted 1-piperazinecarboxylic acid ethyl ester, use reference In the same manner as in Example 371, except that the 1,4-diazacycloheptane-1-carboxylic acid methyl hydrochloride salt obtained in Example 3 was obtained, the title compound (9·9 mg, yield 3 8 %) of a pale yellow solid. 'Η-ΝΜΚ(3 00ΜΗζ,α〇αΐ3)δ:1.7 1-2.03(6Η,ιη)52.5 0-2.64(4Η, m), 3.18(2H,s), 3.47-3.85(13H,m),4.38 (2H, s), 6.78 (lH, d, J = 7.6 Hz), 6.88 (lH, s), 7.25-7.32 (lH, m), 7.43 (2H, d, J = 7.6 Hz), 7·57 ( 2H,d,J = 8.9Hz), 9.47(1 H, brs). LC/MS [Condition 1]: Hold time 2.88 minutes; m/z 604.7 [M + H]+ (ESI positive ion mode), m/z 603.0 [M-Hr (ESI negative ion mode) -620- 201211053 [ 6 2 7]

Reference Example 3 7 5 - 1 3-{4·[4-(4-Fluorobenzylidyl)piperidine-1-carbonyl]benzylidene 2_sideoxy_1_oxo_3,8-diazo Manufacture of spiro[4_5]decane-8-carboxylic acid tert-butyl ester

Substituting (lr,4r)-4-{[8-(t-butoxycarbonyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl }cyclohexanecarboxylic acid, using 4-{[8-(1-butoxycarbonyl)-2-oxo-oxo-3,8-diazospiro[4.5]decane obtained in Reference Example 158. 3-yl]methyl}benzoic acid, substituted tetrahydrofurfurylamine, using (4.fluorophenyl)(piperidin-4-yl)methanone hydrochloride (purchased) and triethylamine, substantially The same reaction as in Example 2 was carried out to give the title compound (j. 1H-NMR (CDC13) 6: 1.45 (9H, s), 1.54-1.67 (2H, m), 1.71-2.09 (6 Lu H, br m), 2.97-3.22 (2H, m), 3.14 (2H, s ), 3.28 (2H, t, J = l 1.1 Hz), 3.43-3.60 (1 H, m), 3.74 - 3.94 ( 1 H, br m), 3. 8 1 (2 Η, d, J = 1 1 .5 Hz ), 4.46 (2H, s), 4.52-4.78 (lH, br m), 7.16 (2H, t, J = 8.6 Hz), 7.3 1 ( 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]: Hold 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) -621 - 201211053 [Chem. 6 2 8]

Reference Example 3 7 5 - 2 3-{4-[4-(4-Fluorobenzoguanidino)piperidin-1-carbonyl]benzylidene 1-oxo-3,8-diazospin[4.5]癸Production of alkan-2-one hydrochloride in place of 2-oxooxy-3-[((lr,4r)-4 - {[(tetrahydrofuran-2-yl)methyl]amine-methyl)-cyclohexyl)methyl ]-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester' used 3-{4-[4-(4-fluorobenzene) obtained in Reference Example 3 75- In addition to the tributyl butyl phthalate, piperidine-1-carbonyl]benzyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid, substantially The same reaction as in Example 3 was carried out to give the title compound (1.5 g, quantitative) as a white powder. LC/MS [Condition 1]: Hold 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) [Chem. 6 2 9]

Example 3 7 5 3-{4_[4-(4·气本甲基基)峨d定-i_羯基]Benzyl}_8_[4-(三气甲•622- 201211053 thio)benzene Production of methyl]-pox-3,8-diazospiro[4.5]decane-2-one (compound number 3 75) substituted (lr,4r)-4-[(2- sideoxy-1-oxole) -3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide hydrochloride, using Reference Example 3 7 5 - 2 of 3 - { 4 - [ 4 - (4-fluorobenzhydryl) piperidine-1 -

Carbonyl]benzyl}}oxan-3,8-diazospiro[4.5]decane-2-one hydrochloride, substituted 3-(bromomethyl)pyridine hydrobromide, using [4_( The title compound (3 5 mg, yield 99%) was obtained as white powder, except that bromomethyl) phenyl] (trifluoromethyl) sulane (purified) was obtained. 1H-NMR (DMSO-d6) 5: 1.5 l (2H, dq, J = 2.9, 11.9 Hz), 1.67 - 1.95 (6H, m), 2.32-2.49 (4H, br m ), 2.8 8 - 3 . 0 ( 1 Η , brm ) , 3 . 1 2 - 3.3 2 ( 2H, br m), 3.23 (2H, s), 3.55 (2H, s), 3.58-3.69 (lH, br m), 3.76 (lH, Tt, J = 11.5, 3.3 Hz), 4.39 (2H, s), 4.42-4.61 (lH, 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]: Hold time 3.48 minutes; m/z 669.9 [M + H]+ (ESI positive ion mode), m/z 704.0 [M + Cl]·, 714·1 [Μ + Η (:00]·( ESI negative ion mode) 【化6 3 0】

-623- 201211053 Example 376 3·{4-[4-(4-Fluorobenzylidene)piperidine-1-carbonyl]benzyl}-8-[4-(trifluoromethyl)phenethyl [-1-(Bromomethyl)phenyl](trifluoromethyl)sulfane is substituted for the production of 1-oxa-3,8-diazospiro[4.5]decane-2-one (Compound No. 3 76) The title compound (14 mg, yield 42%) was obtained from m. m. m. White powder. 1H-NMR (CDCl3) 6: 1.64-2.06 (8H, m), 2.49-2.7 1 (6H, m), 2.75-2.9 1 (2H, m), 2.98-3.23 (2H, m), 3.15 (2H, s), 3.44 - 3.60 (lH, m), 3.72-3.98 (lH, br m), 4 · 4 6 (2 Η, s), 4 · 5 7-4 · 8 2 (1 Η, br m), 7.17( 2H,t,J = 9.0Hz), 7.30(2H,d,J = 7.8Hz), 7.32(2H,d,J = 8.2Hz), 7.42( 2H,d,J = 8.2Hz),7.5 3 (2H,d,J = 7.8 Hz), 7.99 (2H, dd, J = 9.0, 5.3 Hz) ° LC/MS [Condition 1]: Hold time 3.40 min; m/z 651.8 [M + H]+ ( ESI positive ion mode), m/z 686.1 [M + Cir, 696.0 [M + HCO〇r (ESI negative ion mode) [Chem. 6 3 1

Example 377 3-[2-(3-{4-[4-(4-Fluorobenzylidinyl)pyridin-1-yl]benzyl}-2- side-624- 201211053 Oxygen-1 -[3,8-Diazanespiro[4.5]decane-8-yl)ethenyl]benzonitrile (Compound No. 3 77) was prepared by substituting [4-(bromomethyl)phenyl](trifluoro) The title compound (2.2 mg, yield 2.0%) was obtained from m. m. Light yellow amorphous. 1H-NMR (CDCl3) 6: 1.7 1-2.09 (8H, m), 2.57-2.8 1 (4H, br m), 2.99-

3.22(2H,m), 3.16(2H,s), 3.44-3.60(1 H,m), 3.75-3.96(1H,br m ),3.8 l(2H,s),4.46(2H,s),4.55 -4.8 l(lH,br m),7.1 7(2H,t,J = 8.6 Hz), 7.32 (2H,d,J = 8.2Hz), 7.42 (2H,d,J = 8.2Hz), 7.61 (lH , t, J = 7.8 Hz), 7.85 (lH, d, J = 7.8 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz), 8.22 (lH, d, J = 7.8 Hz), 8.31 (lH , s). LC/MS [Condition 1]: Hold time 3.20 minutes; m/z 622.9 [M + H]+ (ESI positive ion mode), m/z 621.1 [MH]_ (ESI negative ion mode) [Chem. 6 3 2 】

Reference Example 3 7 8 Production of 1-(bromomethyl)-4-(trifluoromethylsulfinyl)benzene and 1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene [4-(Bromomethyl)phenyl](trifluoromethyl)sulfane (purchased) (〇.27g, 1.0 mmol) was dissolved in acetonitrile (5.0 mL), and heptamanganate and heptahydrate were added. (0.12 g, 0.1 mmol) and 30% hydrogen peroxide water (〇.〇41 mL, 4.0 mmol) -625-201211053 'Agitated and mixed at room temperature for 7 hours and 30 minutes. After the reaction was completed, an aqueous sodium thiosulfate solution (4.0 mL) and ethyl acetate (10 mL). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography (purifying agent: FL100D, manufactured by FUJI SILYSIA, developing solvent: hexane/ethyl acetate = 10/1 - 2/1] Purification afforded 1-(bromomethyl)-4-(trifluoromethylsulfinyl)benzene (30 mg, yield 10%) as a colorless oil, 1-(bromomethyl)- 4-(Trifluoromethylsulfonyl)benzene (42 mg, yield 14%) as a colourless oil. 1_(Bromomethyl)-4-(trifluoromethylsulfinyl)benzene Data 1H-NMR (CDCl3) 8: 4.53 (2H, s), 7.64 (2H9Cl, J = 8.2 Hz), 7.78 (2Hs) d, J = 8.2 Η z). LC/MS [Condition 1]: Hold time 4.07 min; m/z 2 8 6.8 [M + H]+ (ESI positive ion mode) 1 · (bromomethyl)-4-(trifluoromethylsulfonyl)benzene Data 1H-NMR (CDCl3) 5: 4.53 (2H, s), 7.70 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz). 【化6 3 3】

Example 378 3-{4-[4-(4-Fluorobenzylidinyl)piperidine-1-carbonyl]benzyl}-8-[4-(trifluoromethylsulfinyl)benzyl Manufacture of 1-(4-(bromomethyl)phenyl](trifluoro) Methyl)sulfane was substantially reacted in the same manner as in Example 3 75 except that 1-(bromomethyl)-4-(trifluoromethylsulfinyl)benzene obtained in Reference Example 378 was used. The title compound (12 mg, yield 34%) was pale orange amorphous. 1H-NMR (CDC13) 5: 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 (lH, m), 3.60 (2H, s), 3.73

3.96 (lH, br m), 4.4 5 (2 H, s), 4.5 4 - 4.7 9 ( 1 H, brm), 7.1 6 (2 H , t, J = 8.6 Hz), 7.3 1 (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]: Hold time 3.26 minutes; m/z 68 6.0 [M + H]+ (ESI positive ion mode), m/z720_2 [M + Cl], 73 0.1 [M + HCOO] — (ESI negative ion Mode V (ESI negative ion mode)

【化6 3 4】

Example 379 3-{4-[4-(4-Fluorobenzylidinyl)piperidine-1-carbonyl]benzylidene-8-[4-(trifluoromethylsulfonyl)benzyl]-1 -Production of [4-(bromomethyl)phenyl](trifluoromethyl)sulfane in the manufacture of oxa-3,8-diazospiro[4.5]decane-2-one (compound No. 3 79), use reference The title compound (24 mg, yield) was obtained from m. m. m. 69%) colorless amorphous. 1H-NMR (CDCl3) 5: 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 (lH, tt, J = 7.3, 7.3 Hz), 3.64 (2H, s), 3.71-4.01 (lH, br m), 4.4 6 ( 2 H , s), 4.5 5 - 4.8 0 (1 H, brm), 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. 〇〇 (2H, d, J = 8.2 Hz) » LC/MS [Condition 1]: Hold time 3.48 minutes; m/z 702.0 [M + H]+ (ESI positive ion mode ), m/z 700.1 [MH; T, 746.1 [M + HCO 〇 K (ESI negative ion mode) [Chem. 6 3 5]

Reference Example 3 Manufacture of 1-(methoxymethyl)-4-(trifluoromethyl)cyclohexane (methoxymethyl)triphenylsulfonate (purchased) (14 g, 4.2) Ment) dissolved in tetrahydrofuran (8_〇mL), added n-butyllithium (about 15% hexane solution, 2.61111^, 4.〇111111〇1) under ice cooling, and stirred for 2 minutes under ice cooling. (Trifluoromethyl)cyclohexanone (purchased) (〇4〇g, 24min〇i) was stirred and mixed for 90 minutes under ice cooling. After completion of the reaction, the mixture was quenched with saturated aqueous sodium chloride (15 mL), and ethyl acetate (3 mL) was then evaporated. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> HI-FLASH (registered trademark) COLUMNsilicage MOpm, Purification solvent: hexane / ethyl acetate = 4 / 1 - 1 / 1] was purified to give the title compound (yel. 31 g, yield 67%) as white powder. 1H-NMR (CDCl3) 6: 1.28 (2H, dq5J = 4.5, 12.3 Hz), 1.65 (lH, dt, J = 5.7, 15.1 Hz), 1.82-2.03 (3H, m), 2.04-2.28 (2H, m ), 2.87 (lH, d, J = 13.9 Hz), 3.56 (3H, s), 5.80 (lH, s).

Example 3 8 0

3-{4-[4-(4-Fluorobenzylidene)piperidine-1-carbonyl]benzyl(trifluoromethyl)cyclohexyl]methyl}-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-2-one (Compound No. 380) Refer to Example 1-80 for 1-(methoxymethyl)- 4-(trifluoromethyl)cyclohexane (0.12 g, 0.62) Methyl acetate was dissolved in acetone (2.0 mL), and 1 M hydrochloric acid (.19 mL, 0.19 mmol) was added. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate (.OmL) was added, and methanol was evaporated under reduced pressure. chloroform (2 〇m) was added to the residue and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. This oil was combined with 3-{4-[4-(4-fluorobenzo-629-201211053 fluorenyl)piperidin-1-carbonyl]benzyl}-l--- obtained from Reference Example 375-2. 3,8-diazospiro[4.5]decane-2-one hydrochloride (2611^, 0.050111111〇1) was dissolved in methanol/acetic acid (10/1) (21«1〇, borane was added at room temperature a 2-methylpyridine complex (purchased from pure chemistry (stock)) (1 lmg, 0.1 mmol) was stirred and mixed at room temperature for 1 day. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and then obtained. The reaction residue was purified by silica gel column chromatography (purified solvent: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Amorphous. 1H-NMR (CDCl3) 5: 1.3 8-2.06 (1 8H, m), 2.27 (lH, d, J = 7.0 Hz), 2.36-2.59 (4H, br m), 3.00-3.24 (2H , m), 3.12 (2H, s), 3.45-3.5 8 ( lH, xn), 3.70-3.99 (lH, br m), 4.4 5 (2 Η, s), 4.5 4 - 4.7 9 ( 1 H , brm ), 7.17(2H,t,J = 8.6Hz), 7.3 1(2H,d,J = 8.2Hz), 7.42(2H,d,J = 8.2Hz),7.99(2H,dd,J = 8.6,5.3 Hz) LC/MS [Condition 1]: Hold time 3.36 minutes: m/z 643.9 [M + H]+ (ESI positive ion mode), m/z 688 .0[M + HCO〇r (ESI negative ion mode) [Chem. 6 3 7]

Reference Example 3 8 1 -1 Preparation of 3-(5-cyanopyridine-2-oxy)azetidin-1-carboxylic acid tert-butyl ester 3-hydroxyazetidin-1-carboxylate The acid tert-butyl ester (purchased) (0.87 g, 5.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and sodium hydride (&gt; 55%, dispersed in mobile paraffin, purchased from Kanto Chemical Co., Ltd.) was added at room temperature. (0.1 9g, -630- 201211053

After the addition of 5.O mmol), the mixture was stirred and mixed at the same temperature for 30 minutes, and then 6-chloronicotinonitrile (〇.66 g, 4.8 mmol) was added. After stirring and stirring for 150 minutes at room temperature, 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, and then subjected to silica gel column chromatography [塡 剂: HI-FLASH (registered trademark) COLUMNsilicage HOpm, developed solvent: The title compound (1.5 g, yield was quantitative) was obtained as white powder. 'Η-ΝΜΚ(ΟΟ€13)δ: 1.45(9Η,8), 3.98(2Η,ά(1,Ι = 10.6,4.1Ηζ)54.34 (2H,dd,J=10.6,6.7Hz)}5.36(lH , tt, J = 6.5, 4.1 Hz), 6.89 (lH, d, J = 8.8 Hz), 7.83 (1 H, dd, J = 8.8, 2·0 Ηζ), 8.44 (1 H, d, J = 2.0 Hz) LC/MS [Condition 1]: Hold time 4.17 minutes; m/z 276.0 [M + H]+, 220.0 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 3 8]

Reference Example 3 Production of 8 1 - 2 6-(azetidin-3-yloxy)nicotinonitrile The 3-(5-cyanopyridine-2-oxy)azacyclocycle obtained in Reference Example 381-1 Butane-1-carboxylic acid tert-butyl ester (〇36g, 1.3mmol) was dissolved in chloroform (2.0 mL), and trifluoroacetic acid (1.0 mL) was added. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate (3 mL) and then evaporated to ethyl acetate (60 mL), and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate (MgSO4jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH =10.2, 6.5 Hz), 3.98 (2H, dd, J = 10.2, 6.1 Hz), 5.50-5.52 (lH, m), 6.84 (lH, d, J = 8.6 Hz), 7.80 (lH, dd, J = 8.6, 2.5 Hz), 8.43 (lH, d, J = 2.5 Hz) » LC/MS [Condition 1]: Hold time 0·49 min; m/zl 76.0 [M + H]+ (ESI positive ion mode) [Chem. 6 3 9]

Example 3 8 1 6-{1-[4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diaza snail [4.5] Manufacture of 4-(2-aminoethyl)morpholine, using decane-3-yl}methyl)benzylidene]azetidin-3-yloxy}nicotinonitrile (Compound No. 381) The title compound (1 9 mg, yield 61%) was obtained from the compound obtained in the same manner as in Example 44, except for the 6-(azetidin-3-oxy)nicotinonitrile. a colorless amorphous material. 1 H-NMR (CDC13) 5: 1.66 - 1.79 (2H, m), 1.8 1-1.98 (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 (lH, tt, J = 6.6, 3.9-632-201211053)

Hz), 6.91 (lH, 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 (lH, dd, J = 8.6, 2.3 Hz), 8.43 (lH, d, J = 2.3 Hz). LC/MS [Condition 1]: Hold 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)

【化6 4 0】

Example 3 8 2 6-{l-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8- Manufacture of Diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]azetidin-3-yloxy}nicotinonitrile (Compound No. 3 82)

The title compound (20 mg, yield 66) was obtained from m.p. %) of white powder. 1H-NMR (CDCl3) 8: 1.0 1 (2H, q) J = 12.8 Hz), 1.39-2.00 (2H, m), 2.12 (lH, tt, J = 13.0, 3.3 Hz), 2.40-2.68 (4H, Br m), 3.0 9 (2 Η , d , J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.05 (lH, dd, J = 11.3, 4.1 Hz), 4.14 (1 H , dd, J = l 3.9, 4.1 Hz), 4.40 (1 H, dd, J = l 1.3, 7.2 Hz), 4.56 (1 H, dd, J = 9.2, 7.2 Hz), 5.42 (lH, tt, J = 6.1, 4.5 Hz), 6.90 (lH, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.85 (lH, dd5J = 8.6) , -633- 201211053 2.0Hz), 8.45 (lH, d, J = 2.0Hz). LC/MS [Condition 1]: Hold time 3.16 min; m/z 611.9 [M + H]+ (ESI positive ion mode), m/z 645.9 [M + Cl]-, 656·0 [Μ + Η 〇ΟΟ]·( ESI Negative Ion Mode) [Chem. 6 4 1]

Reference Example 3 Preparation of 8 3 -1 3-(4-cyanophenoxy)azetidin-1-carboxylic acid tert-butyl ester Substituting 6-chloronicotinonitrile, using 4-fluorobenzonitrile (purchased The same reaction as in Reference Example 3 8 1 -1 was carried out to give a white powder of the title compound (1·1 g ' yield 77%). 1H-NMR (CDCl3) 6: 1.45 (9H, s), 4.01 (2H, dd, J = 9.8, 4.1 Hz), 4.3 3 (2H, dd, J = 9.8, 6.5 Hz), 4.93 (lH, tt, J = 6.5, 4.1 Hz), 6.8 1 (2H, d, J = 9.4 Hz), 7.60 (2H, d, J = 9.4 Hz). LC/MS [Condition 1]: Hold time 4.29 minutes; m/z 219.0 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 4 2]

Reference Example 3 8 3 -2 -634- 201211053 Preparation of 4-(azetidin-3-yloxy)benzonitrile Substituted 3-(5-cyanopyridine-2-oxy)azetidine The tert-butyl ester of 1-carboxylic acid was substantially carried out using the third-butyl 3-(4-cyanophenoxy)azetidin-1-carboxylate obtained in Reference Example 3 8 3 -1 The same reaction as in Reference Example 381-2 gave the title compound (0.10 g, yield 31%) as white powder.

1H-NMR (DMSO-d6) 5: 3.20 (lH, dd, J = 6.1, 4.9 Hz), 3.61 (lH, t, J = 6 · 1 Hz), 4.87 ( 1 H, tt, J = 6.1, 4.9 Hz), 7.0 1 (2H, d, J = 8.6 Hz), 7.75 (2 H, d, J = 8.6 Hz) o LC/MS [Condition 1]: hold time 0.51 min; m/zl 75.0 [M- Isobutene + H] + (ESI positive ion mode)

【化6 4 3】

Example 3 8 3 4-{1-[(1]:,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3, Preparation of 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]azetidin-3-oxy}benzonitrile (Compound No. 383) Substituted piperidine, use reference In the same manner as in Example 16 except that the 4-(azetidin-3-yloxy)benzonitrile obtained in Example 3 3 - 2 was obtained, the title compound (6. Colorless amorphous material. 1H-NMR (CDCl3) 6: 1.02 (2H, qsJ = 12.6 Hz)) 1.46-1.62 (3H, m), -635 - 201211053 1.74-1.83 (6H, m), l_94 (2H , d, J = 13.1 Hz), 2.13 (lH, tt, J = 12.1, 3_lHz), 2_42-2.68 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s) , 3·57(2Η, s) , 4.05(1 H,dd,J=l 0.8,3.9Hz), 4.20(1 H,dd,J 2 9.2,3 .5 Hz), 4.40(lH,dd,J = 10.8, 6.3 Hz), 4.55 (lH, dd, J = 9.2, 6.5 Hz), 4.96 - 5.03 (1 H, m), 6.82 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 9.0 Hz).

LC/MS [Condition 1]: Hold time 3.32 minutes; m/z 611_0 [M + H]+ (ESI positive ion mode), m/z 644.9 [M + Cl]-, 65 5·2 [Μ + Η ( :00]·( ESI Negative Ion Mode) [Chem. 6 4 4]

Example 384

3-{[(lr,4r)-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}-8-{[6-(trifluoromethyl)pyridin-3-yl Substitution of methyl}-l-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 384) (11:,4〇-4-[(2-Sideoxy-1) - oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide hydrochloride, using reference example 25 5 3-{[(lr,4r)-4-(4-Benzylmercapyipiperidine-1-carbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazo snail [4.5癸 -2- -2- ketone hydrochloride, substituted 3,5-bis(trifluoromethyl)benzaldehyde, using 6-(trifluoromethyl)nicotinic aldehyde (purchased), substantially the same as the examples The same reaction of 23 5, got 8 -636- 201211053

To the title compound (1 4 mg, yield 28%) as a colorless amorphous material. 1H-NMR (CDCl3) 6: 1.05 (2H, q, J = l 1.5 Hz), 1.46-2.04 (1 5H, m), 2.47 (1 H, t, J = 16.0 Hz), 2.52-2.71 (4H, Br m), 2.8 2 (1 Η, t, J = 1 1.5 Hz), 3.11 (2H, d, J = 6.1 Hz), 3.20 (lH, t, J = 12.7 Hz), 3.27 (2H, s ), 3.52 (lH, tt, J = 11.5, 3.7 Hz), 3.62 (2H, s), 3.98 (lH, d, J = 13.1 Hz), 4.60 (lH, d, J = 12.7 Hz), 7.49 (1) H, t, J = 7.4 Hz), 7.5 9 ( lH, t, J = 7.4 Hz), 7.65 (lH, d, J = 8.2 Hz), 7.85 (lH, d, J = 8.2 Hz), 7.94 (2H , d, J = 7.4 Hz), 8.68 (lH, s). LC/MS [Condition 1]: Hold time 3.28 minutes; m/z 626.9 [M + H] + (ESI positive ion mode), m/z 661.4 [M + Cl], 671.0 [M + HCOO; T ( ESI negative ion mode)

【化6 4 5】

Example 385 3-{[(11:,41')-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-8-[2-fluoro-4-(trifluoro) Substituting 1-(bromomethyl)-2 for the production of methyl)benzyl]-1-oxo-3,8-diazospiro[4·5]nonan-2-one (compound No. 3 8 5 ) 4-bis(trifluoromethyl)benzene was obtained in the same manner as in Example 25 except that 1-(bromomethyl)-2-fluoro-4-yl (trifluoromethyl)benzene (purchased) was used. The title compound (34 mg, yield 67%) was obtained as white powder. - 637 - 201211053 1H-NMR (CDCl3) 5: 1.05 (2H, q, J = 11.3 Hz), 1.45-2.02 (1 5H, m), 2.46 (1H, t, J = 11.5 Hz), 2.53-2.69 ( 4H, br m), 2.8 2 ( 1 H, t, J = 1 2.7 Hz), 3.10 (2H, d, J = 5.7 Hz) s3.20 (lH, t, J = 13.5 Hz), 3.25 (2H, s), 3.44 -3.58 (lH, m), 3.64 (2H, s), 3.98 (lH, d, J = 12.7 Hz), 4.60 (lH, d, J = 14.3 Hz), 7.30 (2H, d, J) = 10.2 Hz), 7.3 9 (lH, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.52-7.57 (lH, m), 7.59 (lH, t, J = 7.6 Hz) , 7.94 (2H, d, J = 7.6 Hz).

LC/MS [Condition 1]: Hold 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) [Chem. 6 4 6]

Reference Example 3 Preparation of 8 6 6-(bromomethyl)nicotinonitrile 6-Methylnicotinonitrile (purchased) (0.30 g, 2.5 mmol) was dissolved in carbon tetrachloride (6.0 mL), and N-brominated amber was added. After the addition of the acid imine (0.50 g, 2.8 mmol) and azobisisobutyronitrile (4 lmg, 0.25 mmol), the mixture was stirred and mixed at 60 ° C for 2 days. After the reaction was completed, an aqueous sodium thiosulfate solution (8.0 mL) and ethyl acetate (2OmL) were evaporated. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and then subjected to silica gel column chromatography [塡 剂: HI-FLASH (registered trademark 8 - 638-201211053) COLUMNsilicagel 40 pm, The title compound (5 〇 mg, yield 10%) was obtained as a colourless oil. 1H-NMR (CDCl3) 5: 4.57 (2H, s), 7.60 (lH, d, J = 8.2 Hz), 7..99 (lH, dd, J = 8.2, 2_0 Hz), 8.8 5 (lH, d, J = 2.0Hz). LC/MS [Condition 1]: Hold time 2.35 minutes; m/zl96.8 [M + H]+ (ESI positive ion mode)

Example 3 8 6

6-[(3-{[(11:,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxyloxy-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-8-yl)methyl]nicotinonitrile (Compound No. 3 86) Substituted 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene, used The title compound (42 mg, yield: 90%) of white powder was obtained from the title compound (42 mg, yield: 90%). (2H,q,J= 12.1 Hz), 1.47-2.02(1 lH,m), 2.47(lH,tt,J=11.6,3.6Hz),2.54-2.74(4H,br m), 2.8 1 (1 H , td, J = 13.2, 2.3 Hz), 3.11 (2H, d5J = 7.6 Hz), 3.20 (lH, t, J-13.0 Hz), 3.28 (2H, s), 3.52 ( lH, tt, J = l 0.6 , 3.9 Hz), 3.76 (2H, s), 3.98 (1 H, d, J = l -639 - 201211053 3.2 Hz), 4.60 (lH, d, J = 13.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.58 (lH, d, J = 7.9 Hz), 7.59 (lH, t, J = 7.4 Hz), 7.90-7.98 (lH, m), 7.94 (lH, dd, J = 7.3, 1.6 Hz) , 8_84 (lH, d, J = 1.6 Hz) LC/MS [Condition 1]: retention time 3.04 minutes; m/z 5 8 3.9 [M + H]+ (ESI positive ion mode), ιη/ζ5 82.1 [Μ -ΗΓ, 627.9[M + HCOO]-(E SI negative ion mode) [Chem. 6 4 8]

Reference Example 3 8 7 Preparation of 5-(bromomethyl)methylpyridine nitrile Substituting 6-methylnicotinonitrile, using 5-methylmethylpyridine nitrile (purchased), substantially proceeded with Reference Example 3 8 6 The same reaction gave the title compound (0.59 g, yield: 71%) as white powder: 1H-NMR (CDCl3) 5: 4.52 (2H, s), 7.72 (1H, d, J = 8.2 Hz), 7.9 1 lH, dd, J = 8.2, 2.5 Hz), 8.74 (lH, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 2.94 minutes; m/zl96.9 [M + H]+ (ESI positive ion mode) [Chem. 6 4 9]

-640- 201211053 Example 3 8 7 5-[(3-{[(11*,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2- side Manufacture of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl)methyl]methylpyridonitrile (Compound No. 387)

Substituting 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene, using 5-(bromomethyl)methylpyridinecarbonitrile obtained in Reference Example 87, substantially the same as Example 25 The same reaction of 5 gave the title compound (25 mg, yield 53%) as white powder. 1H-NMR (CDCl3) 5: 1.05 (2H, q, J = 11.9 Hz), 1.45-2.01 (4H, m), 2.47 (1H, t, J = 11.9 Hz), 2.52-2.64 (4H, br m) , 2.8 1 (1 Η, t, J = 1 2.9 Hz), 3.11 (2H, d, J = 6.5 Hz), 3.20 (lH, t, J = 12.5 Hz), 3.27 (2H, s), 3.52 (lH) ,t,J=ll.lHz), 3.61(2H,s), 3.98(lH,d,J=13.5Hz), 4.60( lH,d,J=13.5Hz),7.49(2H,t,J = 7.4 Hz), 7.59 (lH, t, J = 7.4 Hz), 7.66 (lH, d, J = 7.8 Hz), 7.8 l (lH, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.4 Hz) ), 8.6 8 (lH, s). LC/MS [Condition 1]: Hold time 3.10 minutes; m/z 58 3.9 [M + H]+ (ESI positive ion mode), m/z 618.0 [M + Cl]·, 627.9 [M + HCOO]-( ESI negative ion mode) [Chem. 6 5 0]

-641 - 201211053 Example 3 8 8 3-{[(lr,4r)-4-(4-Benzylmercaptopiperidin-1-carbonyl)cyclohexyl]methyl}-8-[2-methoxy - 4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (compound number 3 8 8 ) was produced in place of 6-(trifluoromethyl) The nicotinic aldehyde was subjected to the same reaction as in Example 3 84 using 2-methoxy-4-(trifluoromethyl)benzaldehyde (supplied) to give the title compound (13 mg, yield 24). %) of a colorless amorphous material. 1H-NMR (CDCl3) 6: l. 〇 5 (2H, q, J = l 1.9 Hz), 1.45-2.03 (1 5H, m), 2.47 (1 H, t, J = 11.7 Hz), 2.54-2.73 (4H, br m ) , 2.8 1 ( 1 Η, t, J = 1 2.2 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.20 (lH, t, J = 11.9 Hz), 3.26 (2H, s), 3.52 (lH, tt, J = 10.9, 3.3 Hz), 3.61 (2H, s), 3.87 (3H, s), 3.98 (lH, d, J = 14.2 Hz), 4.60 (lH, d, J) =13.2 Hz), 7.06 (lH, s), 7.20 (lH, d, J = 7.6 Hz), 7.49 (3H, t, J = 7.6 Hz), 7.59 (1 H, t, J = 7.6 Hz), 7.94 (2H,d,J = 7.6Hz) o LC/MS [Condition 1]: Hold time 3.38 minutes; m/z65 5.8 [M + H]+ (ESI positive ion mode), m/z690.2 [M + Cl ]·, 699.6[M + HCOO]-( ESI Negative Ion Mode) [Chem. 6 5 1]

Reference Example 3 8 9 5-(Trifluoromethyl)methylpyridinaldehyde Production 5-(Trifluoromethyl)pyridinecarboxylic acid methyl (purchased) (1 〇g, 4 9 mm 〇1) -642- 201211053

Dissolved in dichloromethane (3 OmL), and added diisobutylaluminum hydride (17% toluene solution, about 1. 〇111〇1/]^) (15111 [, 15111111〇1) at -78 °C, -78.搅拌 Mix and mix for 20 minutes. After the completion of the reaction, a saturated aqueous solution of sodium potassium tartrate (50 mL) and chloroform (25 mL) were added and the mixture was vigorously stirred for one 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, and then purified by silica gel column chromatography [Hybrid: HI-FLASH (registered trademark) COLUMNsilicagel 40 pm, developing solvent: hexane / Ethyl acetate = 9/1 - 1 / 1] was purified to give the title compound (0.24 g, yield 28%) 1H-NMR (CDC13) 5: 8. 10 (lH, d, J = 8.2 Hz), 8.1 7 (1 H, dd, J = 8.2, 1.2 Hz), 9.07 (lH, d, J = 1.2 Hz), 10.15 (lH, s). LC/MS [Condition 1]: Hold time 2.69 minutes; m/zl75.9 [M + H]+ (ESI positive ion mode)

Example 3 8 9 3-{[(1!&quot;,4〇-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-8-{[5-(trifluoro Production of methyl)pyridin-2-yl]methyl}-1-oxo-3, 8-diazospiro[4.5]decane-2-one (compound No. 389) substituted 6-(trifluoromethyl The nicotinic aldehyde was reacted in the same manner as in Example 384, except that 5-(trifluoromethyl)methylpyridinaldehyde obtained in Reference Example 3 89, to give the title compound (1 2 mg). White powder with a rate of 1 9%) • H-NMR CCD Chia: 1.05 (2H, q, J = l 1.4 Hz), 1.40-2.03 (1 lH, m), 2.47 (lH, t, J = 11.7 Hz), 2.55 -2.73(4H,br m),2.82( 1 H,t, J= 1 1.4

Hz), 3.11 (2H, d, J = 6.6 Hz), 3.2 1 (lH, t, J = 12.9 Hz), 3.28 (2H, s), 3.52 (lH, tt, J = 10.5, 3.6 Hz), 3.76 (2H, s), 3.99 (lH, d, J = 12.9 Hz), 4.60 (lH, d, J = 13.2 Hz), 7.49 (4H, t, J = 7.6 Hz), 7.56 (lH, d, J = 8.3 Hz ), 7.59 ( lH, t, J = 7.6 Hz), 7.90 (1 H, dd, J = 8.3, 2.3 Hz), 7.95 (2H, d, J = 7.6 Hz), 8.83 (lH, s). LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 626.8 [M + H]+ (ESI positive ion mode), m/z 660.8 [M + Cir, 671.0 [M + HCOO]- (ESI Negative ion mode)

Reference Example 3 Production of 9 0 -1 3-(3-cyanophenoxy)azetidin-1-carboxylic acid tert-butyl ester Substituting 6-chloronicotinonitrile, using 3-fluorobenzonitrile (purchased The same reaction as in Reference Example 381-1 was carried out to give the title compound (yield: 66 g, yield: 83%) as a colorless oil. 1H-NMR (CDCl3) 5: 1.46 (9H, s), 4.00 (2H, dd, J = 9.8, 4.1 Hz) 54.34 (2H, dd, J = 9.8, 6.5 Hz), 4.90 (lH, tt, J = 6.5, 4.1 Hz), 6.99 (lH, br s ), 7.00 (lH, dd, J = 8.0, 2.0 Hz), 7.30 (lH, ddsJ = 7.4, 2.0 Hz), 7.40 (l H, t, J = 7_4 Hz) ). -644- 201211053 LC/MS [Condition 1]: Hold time 4.27 minutes; m/z 274.9 [M + H]+, 218.9 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 5 4]

Reference Example 3 9 0 - 2

Preparation of 3-(azetidin-3-yloxy)benzonitrile hydrochloride Substituted 2-oxooxy-3-[((lr,4〇-4-{[(tetrahydrofuran-2-yl)) Aminomethyl hydrazinyl}cyclohexyl)methyl]-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester, using 3-3% of Reference Example 390-1 The title compound (0.47 g, yield: 92%) of white was obtained from the title compound (m. 1H-NMR (CD3OD) 5: 4.16 (2H, dd, J = 12.7, 4.5 Hz), 4.58 (2H, dd, J = 12.7, 6.1 Hz), 5.21. (lH, tt, J = 6.1, 4.5 Hz ), 7.21 (lH, ddd, J = 8.2, 2.5, 1.2 Hz), 7.25 (lH, dd, J = 2.551.2 Hz), 7.41 (lH, dt, J = 7.7, 1.2 Hz), 7.52 (lH, t , J = 8.2 Hz) LC/MS [Condition 1] ··Retention time 〇·51 minutes; m/zl75.0[M + H]+ (ESI positive ion mode) [Chem. 6 5 5]

-645- 201211053 Example 3 9 0 3-{l-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo_ Preparation of 3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]azetidin-3-yloxy}benzonitrile (Compound No. 3 90) The title compound (3 6 mg) was obtained by the same reaction as in Example 16 except for using 3-(azetidine-3-oxy)benzonitrile hydrochloride obtained from Rate 73%) of white powder. 1H-NMR (CDC13) 5: 1,02 (2H, dq, J = 4.5, 1 1.9 Hz), 1.25 (2H, dq, J = 2.5, 11.5 Hz), 1.58-2.00 (9H, m), 2.14 (lH, tt, J = l 1.9, 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(lH,dd,J=11.3,3.9Hz), 4.19(lH,dd,J=9.4,3.9Hz), 4.39(l H,dd3J=10.6,6.5Hz),4.55(lH,dd,J = 8.6, 6.5 Hz), 4.96 (lH, tt, J = 6.5, 3.9 Hz), 6.99 (lH, d, J = 1.2 Hz), 7.01 (lH, ddd, J = 9.0, 2.9, 0.8 Hz), 7.32 ( lH, dt, J = 7.8, 1.2 Hz), 7.42 (lH, 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]: Hold time 3.30 minutes; m/z 610.7 [M + H]+ (ESI positive ion mode), m/z 654.9 [M + HCOO]-(ESI negative ion mode) 5 6]

Reference Example 3 9 1 -1 Preparation of tert-butyl 4-[4-(trifluoromethyl)phenylamino]piperidine-1-carboxylate 1-(t-butoxy)-4 - 峨 酮 ketone (l. 〇g, 5.0mmol) dissolved in -646- &quot; 201211053

1,2-Dichloroethane (10 mL), adding 4-(trifluoromethyl)aniline (0.97 g, 6.0 mmol) and acetic acid (1.2 mL, 20 mmol) at room temperature, at 80 ° C

Mix for 9 hours. After the reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (1.3 g, 6·0 m m ο 1 ) was added, and the mixture was mixed at room temperature for 12 hours. After the reaction was completed, water (1 〇 m L) and saturated aqueous sodium bicarbonate (20 mL) and chloroform (60 mL) were evaporated. The obtained organic layer was dried over anhydrous sodium sulfate (MgSO4). 62%) of white powder. lH-NMR (CDCl3) S: 1.35 (3H, dq, J = 4.9, 12.7 Hz), 1.47 (9H, s), 2·04 (2 Η, dd, J = 1 2.7, 3.3 Hz), 2.94 (2H, t, J = l 1.7 Hz), 3.39-3.54 ( lH, m), 3.87 (lH, d, J = 7.4 Hz), 4.07 (2H, d, J = 11.9 Hz), 6.59 (2H, d, J = 8.6 Hz), 7.3 9 (2H, d, J = 8.6 Hz) » LC/MS [Condition 1]: Hold time 4.85 min; m/Z 288.9 [M-iS〇butene + H] + (ESI positive ion mode )

Reference Example 391-2 Preparation of N-[4-(trifluoromethyl)phenyl]piperidin-4-amine dihydrochloride salt 4-[4-(trifluoromethyl) obtained in Reference Example 391-1 Phenylamino]piperidine-1-residual acid tert-butyl ester (1.lg, 3.1 mmol) was dissolved in acetonitrile (20 mL), -647-201211053 10% hydrogen chloride-methanol solution (6.2 mL) was added at room temperature. It was stirred and mixed at room temperature for 3 days. After the reaction was completed, the residue was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H-NMR (CD3OD) 6: 1.65-1.8 1 (2Hsm), 2.23 (2H, dd, J = 14.3, 3.7 Hz), 3.1 5 (2H, td, J = l 1.9, 2.9 Hz), 3.46 (2H, Dt, J = 13.0, 3.7 Hz), 3.72 (lH, 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]: Hold time 1.92 minutes; m/Z244.9 [M + H]+ (ESI positive ion mode) [Chem. 6 5 8] 〇

Example 3 9 1 8-[4-(Trifluoromethyl)benzyl]-3-[((1!*,4〇-4-{4-[4-(trifluoromethyl)phenylamine) Preparation of pipyridin-1-carbonyl}cyclohexyl)methyl]-1-oxo-3,8-diazaspiro[4.5]decane-2-one (Compound No. 391) Substituted piperidine, reference example The same reaction as in Example 16 was carried out except for the N-[4-(trifluoromethyl)phenyl]piperidin-4-amine dihydrochloride obtained from 391-2, and triethylamine to give the title compound. (4 1 mg, yield 73%) of a white powder. 1H-NMR (CDCl3) 5: 1.05 (2H, q, J = 12.2 Hz), 1.3 6 (2H, q, J = 12.6 Hz - 648 - 8 201211053 ), 1.46-1.90(9H,m), 1.94(2H,d,J=13.2Hz), 2.14(2H,d,J=12.9

Hz), 2.47 (lH, t, J = 11.7 Hz), 2.51-2.70 (4H, br m), 2.85 (l H, t, J = l 1.6

Hz), 3.11 (2H, d, J = 7.6 Hz), 3.20 (lH, t, J = 12.9 Hz), 3.26 (2H, s), 3.51-3.68 (lH, br m), 3.5 7 (2 H, s), 3.8 0 - 4.0 1 (2 H, m), 4.5 2 (1 H, 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]'· Hold time 3.68 min; m/z 680.9 [M + H]+ (ESI positive ion mode), m/z 725.0 [M + HCOO] — (ESI negative ion mode)

Reference Example 3 9 2 -1 φ 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-oxo-3,8-diazo snail [4.5] The decyl-3-yl]methyl}nicotinic acid ethyl group was produced in the 3-[{5-(ethoxycarbonyl)pyridin-2-yl}methyl]-2- side obtained in Reference Example 111-3. Oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.84 g, 2.0 mmol), 4 Μ hydrogen chloride-dioxane solution (10 mL), at room temperature Stir for 1 minute. After the reaction, the reaction mixture was concentrated, and dichloromethane and saturated aqueous ammonia was added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate. The obtained white solid was dissolved in 3,5-difluoro-4-methanebenzonitrile (〇.4〇, 2.4〇111111〇1) in -649-201211053 dichloromethane (6.0 mL), and added Sodium borohydride acetate (0.64 g, 3.0 mm 〇l) was stirred at room temperature for 10 minutes. After the reaction, water and aq. The residue was purified by silica gel column chromatography (purif-pack s s s s s s s s s s s. , H-NMR (300MHz, CDC13) 5: 1.41 (3H, t, J = 7.2 Hz), 1.68-1.80 (2H, m), 1.89-2.00 (2H, m), 2.62 (4H, brs), 3.3 1 (2H, s), 3.74 (2H, s), 4.4 1 (2H, q, J = 7_lHz), 4.5 8 (2H, s), 7.22 (2H, d, J = 6.1 Hz), 7_3 6 (lH, d, J = 8.0 Hz), 8_28 (lH, dd, J = 8.0, 1.8 Hz), 9.14 (lH, d, J = 1.8 Hz) ° LC/MS [Condition 1]: hold time 1.96 minutes; m/z 470 .8 [M + H]+ (ESI positive ion mode) [Chem. 6 6 0]

Reference Example 3 9 2 - 2 6-{[ 8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1.oxan-3,8-diazospiro[4.5]癸Alkyl-3-yl]methyl}nicotinic acid was produced in the 6-{[8-(4-cyano-2,6-difluorobenzyl-650- 201211053) obtained in Reference Example 3 92-1.

a solution of ethyl 2-oxo-oxo-3,8-diazaspiro[4.5]decane-3-yl]methyl}nicotinate (0.97 g, 2.05 mmol) in tetrahydrofuran (20 mL), Potassium trimethyl decanoate (0.53 g, 4.1 mmol) was added and stirred at room temperature for 3 hours. After the reaction, 4 M hydrogen chloride-dioxane solution (1.0 mL) was added, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Purif-Pack SI 60 pm, solv. %) of a white solid. 1H-NMR (300MHz, DMSO-d6) 5: 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 (lH, d, J = 8.2 Hz), 7.78 (2H, d, J = 6.3 Hz), 8.20 (lH, d, J = 8.2 Hz), 8.97 (lH, s). LC/MS [Condition 1]: Hold time 0.53 min; m/z 442.7 [M + H]+ (ESI positive ion mode), m/z 440.8 [M-Hr (ESI negative ion mode)

[6 6 1]

Example 392 3,5-Difluoro- 4-{[3-({5-[4-(4-fluorobenzylidinyl)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2 - side oxy-1-oxo- 3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 3 92) was produced in Reference Example 392-2. {[8_(4·Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl} Alkali acid (-651 - 201211053 20mg, 0.045mmol), 1-hydroxybenzotriazole (2mg, O.Olmmol) and (4-fluorophenyl) (piperidin-4yl)methanone hydrochloride (purchased Get) (13mg, 〇〇54

To a suspension of chloroform (imL), triethylamine (26 pL, 0-19 mm〇l) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 13 mg, 0.068 mmol), 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. A solution of ethyl acetate (1 mL) and sodium bicarbonate (3 mg) in water (1 mL) was evaporated. Amorphous 〇1H-NMR (CDCl3) 5: 1.66-2.09 (8H, m), 2.45-2.80 (4H, m), 2.97-3.36 (2H, m), 3.3 1 (2H, s), 3.45-3.61 (lH,m), 3.69-3.97(lH,br m ),3 _74(2H,s),4.55-4.78( lH,br m),4.56(2H,s),7.17(2H,t,J = 8.6 Hz), 7.22 (2H, d, J = 6_5Hz), 7_35 (lH, d, J = 8.2Hz), 7.76 (lH, dd, J = 7.8, 2.5Hz), 7.99 (2H, dd, J = 8.6, 5.7 Hz), 8.61 (lH, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 3.12 minutes; m/z 631.9 [M + H]+ (ESI positive ion mode), m/z 675.9 [M + HCOO]_ (ESI negative ion mode) 6 2]

Reference Example 3 9 3- 1 - 4-(methylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester Preparation l-(t-butoxycarbonyl)-4-hydroxypiperidine (by Tokyo Chemical Industry Co., Ltd. - 652-201211053, purchased (4.0g, 20mmol) dissolved in tetrahydrofuran (2〇ml), added with triethylamine (2.4g, 24mmol) and methanesulfonyl chloride (2.7g, 24mmol), The mixture was vigorously stirred for 3 hours at 〇 °C. After the completion of the reaction, ethyl acetate and hydrochloric acid were added and shaken, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-(methylsulfonyloxy)piperidine-1-carboxylic acid. The third butyl ester (5.0 g, yield 90%) was obtained as a colorless solid.

LC/MS [Condition 1]: Hold time 3.70 minutes; m/z 280.0 [M + H]+, 223.9 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 6 3]

Reference Example 3 Production of 93-2 4-[4-(trifluoromethyl)phenylthio]piperidine-1-carboxylic acid tert-butyl ester

The tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (0.60 g, 2.2 mmol) synthesized in Reference Example 3 93-1 was dissolved in N,N-dimethylformamide 4-(Trifluoromethyl)benzenethiol (0.50 g, 2.8111111〇1) and potassium carbonate (0.388, 2.8 mmol) were added, and vigorous stirring was carried out at 70 ° C for 3 hours. After the end of the reaction, ethyl acetate and 〇 5 Μ aqueous sodium hydroxide solution were added and shaken. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography [mixing agent: yttrium 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / hexane = 1/19] to give 4- [4-(Trifluoromethyl-653-201211053) phenylthio]piperidine-1-carboxylic acid tert-butyl ester (〇.55 g, yield 70%) as a colorless liquid. LC/MS [Condition 1] · Hold time 5.17 minutes; m/z 305.9 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 6 4]

Reference Example 3 9 3- 3 - 3-(3-fluorophenylthio)piperidine-1-carboxylic acid tert-butyl ester was produced by substituting 4-(trifluoromethyl)benzenethiol using 3-fluorobenzenethiol The title compound (0.62 g, yield 93%) was obtained as a colorless liquid. LC/MS [Condition 1]: Hold time 4.94 min; m/z 255.9 [M-isobutene + H] + (ESI positive ion mode)

[6 6 5]

Reference Example 3 9 3- 4 - 4-(3-Fluorophenylsulfonyl)piperidine-1-carboxylic acid tert-butyl ester Preparation 4-(3-fluorophenylsulfuric acid) synthesized in Reference Example 3 93 -3 Generation of piperidine-1-carboxylic acid tert-butyl ester (0.318, 0.99111111〇1) dissolved in methanol, adding 30% hydrogen peroxide water (0.45ml, 4_0mmol) and penta-molybdic acid hexa-manganese tetrahydrate (0.12g) , -654- 8 201211053 O.lOmmol), vigorously stirred for 4 days at room temperature. After the reaction was completed, sodium thiosulfate (0.63 g, 4.0 mm Qi), water and chloroform were added to the reaction mixture under ice cooling, and the mixture was shaken. After separating the organic layer, the aqueous layer was extracted three times with chloroform. After drying over anhydrous magnesium sulfate, the residue was evaporated to dryness crystals crystals. .

LC/MS [Condition 1]: Hold time 4.26 minutes; m/z 343.9 [M + H]+, 287_9 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 6 6]

Reference Example 3 9 3- 5 - 4-[4-(Trifluoromethyl)phenylsulfonyl]piperidine-1-carboxylic acid tert-butyl ester Preparation 4-[4] synthesized in Reference Example 393-2 -(trifluoromethyl)phenylthio]piperidin

The third butyl pyridine-1-carboxylate (〇.32g, 0.88mmol) was dissolved in methanol, and 30% hydrogen peroxide water (0.40ml, 3.5mmol) and hexahydrate tetrahydrogen tetrahydrate (0.1 lg, O.lOmmol), stirring vigorously at room temperature overnight. After the completion of the reaction, sodium thiosulfate (0.56 g, 3.5 2 mmol) was added to the reaction mixture with ice and stirred under ice cooling. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure. The filtrate obtained by filtration of the solid was extracted three times with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The previously obtained solid was combined to give 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine-1-carboxylic acid tert-butyl ester (0.31 g, yield 90%) as a colourless solid. -655- 201211053 LC/MS [Condition 1] · Hold time 4.54 minutes; m/z 337.9 [M-isobutene + H] + (ESI positive ion mode) [Chem. 6 6 7]

F F Reference Example 3 9 3 - 6

Preparation of 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine hydrochloride 4-[4-(Trifluoromethyl)phenylsulfonyl) synthesized according to Reference Example 3 93-5 The second butyl acid residue (0.18 g, 0.50 mmol) was dissolved in a 4 M hydrogen chloride-dioxane solution and stirred vigorously for 1 hour. After the 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 give 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine hydrochloride (0.20 g, yield: 100%).

LC/MS [Condition 1]: Hold time 〇_81 min; m/z 293.9 [M + H] + (ESI positive ion mode) [Chem. 6 6 8]

Reference Example 3 Production of 9 3 - 7 4-(3-fluorophenylsulfonyl)piperidine hydrochloride Substituted 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine-1-carboxylate Acid tributyl 8-656-201211053 ester, substantially the same as the tert-butyl 4-(3-fluorophenylsulfonyl)piperidine-1-carboxylate synthesized in Reference Example 3 93-4 The title compound (0.11 g,yield: 80%) LC/MS [Condition 1]: Hold time 0.54 min; m/z 243.9 [M + H]+ (ESI positive ion mode)

[6 6 9]

Example 3 9 3 3-({(lr,4r)-4-[4-(3-Fluorophenylsulfonyl)piperidin-1-carbonyl]cyclohexyl}methyl)-8-[4-( Preparation of trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 393) (lr, 4r) obtained in Reference Example 6-3 -4-({2-Sideoxy-8-[4-(trifluoromethyl)phenyl)]-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl Cyclohexanecarboxylic acid (40 mg, 0.090 mmol) was dissolved in N,N-dimethylformamide, and 4-(3-fluorophenylsulfonyl)piperidine hydrochloride obtained in Reference Example 393-7 was added. (25mg, 0.08 8mmol), diisopropylethylamine (3〇μ1, 〇·1 8mmol) and 2-(1Η-7-azabenzotriazol-1-yl)-1,1,3,3 - Tetramethylurea hexafluorophosphate melamamide gun (40 mg, O.llmmol), vigorously stirred overnight at room temperature. After the reaction was completed, citric acid (42 mg, 0.22 mmol), water and chloroform were added and shaken. After separating the organic layer, it was washed with a saturated aqueous solution of sodium hydrogen carbonate and evaporated to dryness. The obtained residue is subjected to silica gel column chromatography [塡剂: -657- 201211053

Purification by Merck GMBH 矽 60 (0.040-0.063mm), developing solvent · ethyl acetate / methanol = 9 / 1] to give 3-({(lr, 4r)-4-[4-(3-fluorobenzene) Sulfosyl)piperidin-1-carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸A colorless liquid of alkan-2-one (3.1 mg, yield 5.0%). 1H-NMR (300MHz, CDCl3) S: 1.04 (2H, q, J = 12.3Hz), 1.44-2.20 (1 5H, m), 2.34 - 2.55 (2H, m), 2.58 (4H, br m), 2.9 3 - 3.2 1 (4 H, m), 3.26 (2H, s), 3.5 9 (2H, s), 4.04 (lH, d, J = 12.6 Hz), 4.76 (lH, d, J = 12.6 Hz), 7.36-7.48 (3H, m), 7.55-7.70 (5H, m). LC/MS [Condition 1]: Hold time 3.29 minutes; m/z 679.9 [M + H]+ (ESI positive ion mode) [Chem. 6 7 0]

Example 394 8-[4-(Trifluoromethyl)benzyl]-3-[((11*,4〇-4-{4-[4-(trifluoromethyl)phenylsulfonyl]] Production of piperidine-1-carbonyl}cyclohexyl)methyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 394) in place of 4-(3-fluorophenyl) Sulfosyl) piperidine hydrochloride was substantially carried out in the same manner as in Example 393 except that 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine hydrochloride obtained in Reference Example 393-6 was used. After the reaction, the title compound (15 mg, yield: 23%) was obtained as a colorless liquid. - 658 - 201211053 'H-NMR (300 MHz 'CDCl3) 5: 1.04 (2H, q, J = 11.9 Hz), 1.43-1.88 (1 lH,m), 1.89-2.19(3H,m), 2.34-2.60(2H,m),2.56-2.59 (4H,brm),2.9 5-3.23(4H,m),3.2 6(2H,s), 3.5 9(2H, s), 4.05 (lH, d, J = 14.0 Hz), 4.77 (lH, 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]: Hold time 3.47 minutes; m/z 729.8 [M + H]+ (ESI positive ion mode) [Chem. 6 7 1]

Br Reference Example 3 9 5 -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) was added with benzammonium peroxide (〇.73 g, 3.0 mmol), and vigorously stirred at 85 ° C for 4 hours. After the completion of the reaction, the reaction solution was washed with a 1 Μ sodium hydroxide aqueous solution, a sodium thiosulfate aqueous solution, a manganese chloride aqueous solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue thus obtained was purified by silica gel column chromatography, eluent solvent: ethyl acetate /hexane = 1/1. After concentration under reduced pressure, a yellow liquid of 5-(bromomethyl)isoxazole (5.2 g, yield 53%) was obtained -659-201211053 [Chem. 6 7 2]

Reference Example 3 Manufacture of 9 5 - 2 2-(isoxazol-5-ylmethyl)isoindan-1,3-dione

5-(Bromomethyl)isoxazole (3.2 g, 20 mmol) synthesized in Reference Example 3 95-1 and potassium phthalimide (4.5 g, 24 mmol) were dissolved in hydrazine, hydrazine-dimethyl The carbamide (32 ml) was vigorously stirred at 90 ° C for 2 hours. After the completion of the reaction, water (200 ml) was added, and the precipitated solid was filtered to give 2-(isoxazole-5-ylmethyl)isoindan-1,3-dione (2.7 g, yield 60%) ) a brown solid. 'H-NMR (300 MHz &gt; CDCl3) 8: 5.03 (2H, s), 6.25-6.29 (lH, m), 7.72-7.80 (2H, m), 7.86-7.93 (2H, m), 8.67-8.68 ( lH, m).

LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 229.0 [M + H]+ (E S I positive ion mode) [Chem. 6 7 3]

Reference Example 3 95-3 Preparation of Isoxazole-5-ylmethylamine 2-(isoxazol-5-ylmethyl)isoindan-1,3-di which was synthesized in Reference Example 3 95-2 Ketone (91 mg, 0.40 mmol) and hydrazine 1 water (0.10 g, 2.0 mmol) were dissolved in ethanol (4 ml), and heated under reflux for 3 hours. After the reaction was completed -660 - 201211053, it was filtered with ethanol, and the filtrate was concentrated to dryness under reduced pressure. After the obtained residue was filtered over chloroform, the filtrate was concentrated under reduced pressure to give the crude product of the product of oxazol-5- propylamine (6 7 mg, yield: 85%). 【化6 7 4】

Reference Example 3 95-4 Preparation of 2-[(2-fluoropyridin-4-yl)methyl]isoindan-1,3-dione The synthesis was carried out according to the method described in WO2009057827. LC/MS [Condition 1]: Hold time 3.62 min; m/z 25 6.9 [M + H]+ (E S I positive ion mode) [Chem. 6 7 5]

Lu Reference Example 3 9 5 - 5 (2-Fluoropyridin-4-yl)methanamine is substituted for 2-(isoxazol-5-ylmethyl)isoindan-1,3-dione, use reference The reaction of the same reaction with Reference Example 3 5 5 - 3 was carried out except for 2-[(2-fluoropyridin-4-yl)methyl]isoindan-1,3-dione obtained in Example 395-4. The title compound (55 mg, yield 73%) LC/MS [Condition 1]: Hold time 0.49 min; m/zl 26.9 [M + H]+ (ESI positive ion mode) -661 - 201211053 [Chem. 6 7 6]

Example 3 9 5 (11*,4〇-!^-[(2-fluoropyridin-4-yl)methyl]-4-({2- sideoxy-8-[4_(trimethyl)methylbenzene) Preparation of methyl]-oxazo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexylcarbamide (Compound No. 395) will be obtained by reference to Example 395-5 (2) -Flupiride-4-yl)methylamine (iimg, 0-090 mmol) and (1 r,4 r) - 4 - ({ 2 - oxo-8 - [ 4 - (trifluoromethyl)] obtained in Reference Example 6 - 3 Benzyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl) Cyclohexanecarboxylic acid (40 mg, 0.090 mmol) dissolved in chloroform, diisopropyl Ethylethylamine (15μl, 0.090mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (17mg, 0.090mmol), intense at room temperature for 3 hours After the reaction was completed, water was added and shaken, and the organic layer was separated, and the aqueous layer was extracted three times with chloroform. The organic layer was concentrated and dried under reduced pressure. The obtained residue was chromatographed on a silica gel column. Purification by the method [塡 :: Merck GMBH 矽 60 60 (0.040-0.063 mm), developing solvent: ethyl acetate / methanol = 9 / 1] gave (lr, 4r)-N-[(2-fluoropyridine- 4-base) A ]-4-( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl a colorless liquid of cyclohexanecarbamide (2411^' yield 48%). 'H-NMRiSOOMHz 'CDCl3) 6: 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(lH,tt,J-662-201211053 = 11.9,3.3Hz),2.53-2.56(4H,br m), 3.10 (2H, d, J = 7.0 Hz), 3.2 8 (2H, s), 3.58 (2H, s), 4.47 (2H, d, J = 6.5 Hz), 6.76 (lH, t, J = 6.1 Hz), 6.82 (lH, s), 7.08 (lH, d, J = 4.9 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2 LC/MS [Condition 1]: Hold time 3.11 minutes ;m/z563.1 [M + H]+ (ESI positive ion mode)

【化6 7 7】

Example 3 9 6 (11&quot;,4〇-:1^-(isoxazol-5-ylmethyl)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene) ]]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxamidine

The production of the amine (Compound No. 3 96) was substituted for (2-fluoroU ratio D-1,4-yl)methylamine, and substantially the same was carried out except for the chewing oxime-5-methylamine obtained in Reference Example 3 9.5. The title compound (19 mg, yield 41%) ofyield W-NMROOOMHz, CDCl3)S: l.〇3 (2H, dq, J = 2.5, 12.7 Hz), 1.41-1.66 (3H, m), 1.7 1-1.86 (4H, m), 1.88-2.00 (4H, m), 2.12 (lH, tt, J = 3.3, 1 1.9 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 (lH, s), 6.30-6.41 (lH, br m), 7.45 (2H, d, J = 7.8 Hz ), 7.58 (2H, d, J = 8.2 Hz) -663- 201211053 LC/MS [Condition 1]: Hold time 2.81 minutes; m/z 534.8 [M + H]+ (ESI positive ion mode) 7 8]

Reference Example 3 9 7 -1 Production of 4-cyanophenethyl methanesulfonate

4-(2-Hydroxyethyl)benzonitrile (〇.50g, 3.4mm〇l) and triethylamine (0.60ml, 4.lmmol) were dissolved in tetrahydrofuran, and methylsulfonyl chloride (0.30ml) was added dropwise. , 4.1 mm〇l), vigorously stirred for 2 hours under ice cooling. After the completion of the reaction, ethyl acetate was added, and the organic layer was washed with water, 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-cyanophenethylethyl methanesulfonate (yield: 70 g, yield 93%) of colorless liquid. LC/MS [condition 1]: retention time 3.32 minutes; m/z 225.8 [M + H]+ (ESI positive ion mode) [Chem. 6 7 9]

Reference Example 3 9 7 - 2 Preparation of 4-[2-(1,3-dioxaisoxanthene-2-yl)ethyl]benzonitrile 8 -664- 201211053 Substituted 5-(bromomethyl) The isoxazole was subjected to the same reaction as in Reference Example 395-2 to give the title compound (2. 5 4 %) of a colorless solid. LC/MS [Condition 1]: Hold time 4 〇 4 minutes; m/z 276.9 [M + H]+ (ESI positive ion mode) [Chem. 6 8 0]

NHi

Reference Example 3 Production of 9 7 - 3 4-(2-aminoethyl)benzonitrile Substituted 2-(isoxazol-5-ylmethyl)isoindan-1,3-dione, use reference The same reaction as in Reference Example 3 95-3 was carried out except for 4-[2-(1,3-dioxaisoindan-2-yl)ethyl]benzonitrile obtained in Example 3 97-2. The title compound (80 g, yield 78%) was obtained as a yellow solid.

LC/MS [Condition 1]: Hold time 0.52 min; m/zl 47.0 [M + H]+ (E S I positive ion mode) [Chem. 6 8 1]

Example 3 9 7 (11:,4〇-^1-(4-cyanophenethyl)-4-({2- sideoxy-8-[4-(trifluoromethyl)benzene-665- 201211053 Production of methyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 3 97) Substituted (2-fluoropyridine-4 -Methylamine, the title compound (21 mg, yield 42) was obtained from m. m. %) of colorless solid 〇W-NMRpOOMHz, CDCl3)5:1.00 (2H, qsJ = 12.7 Hz), 1.45 (2H, dq, J = 3 ·3,1 2-7 Hz), 1.54- 1.67 ( 1 H,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 (lH, brs), 7.3 1 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.6 Hz) ), 7.54 - 7.64 (4H, m). LC/MS [Condition 1]: Hold time 3.21 minutes; m/z 582.8 [M + H]+ (ESI positive ion mode), m/z 627.0 [M + HCOO]- (ESI negative ion mode)

[6 8 2] I

Reference Example 3 9 8 -1 (1. 41:) _4_{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid methyl substituted 3_[{5·(ethoxycarbonyl)pyridin-2-yl}methyl]-2-oxo- 1-Chewing-3,8-heavy snail [4.5] decane-8-carboxylic acid tert-butyl ester, using Reference Example 2-2 -666 - 201211053

The resulting 3-[{(lr,4r)-4-(methoxycarbonyl)cyclohexyl}methyl]-2-oxooxa-1-oxo-3,8-diazospiro[4.5]decane-8 The title compound (2.13 g, yield: 92%) was obtained as white solid. 1H-NMR (300MHz, CDC13) 5: 1.01 (2H, qd, J = l 3.0, 3.3 Hz), 1.40 (2H, qd, J = 13.0, 3.3 Hz), 1.5 1-1.61 (lH, m), 1.69 -1.8 1(4H,m), 1.90-2.03(4H,m), 2.24(lH,tt,J=12.3,3.6Hz),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), 7.2 1 (2H, d, J = 6.5 Hz) 〇 LC/MS [Condition 1]: Hold time 2.76 minutes; m/z 461.8 [M + H]+ (ESI positive ion mode) [Chem. 6 8 3]

Reference Example 3 9 8 - 2 (lr, 4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-weight Preparation of azaspiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid (11*,4〇-4-{[8-(4-cyano)-) obtained in Reference Example 3 98-1 2,6-Difluorobenzyl)-2-sideoxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexylcarboxylate (2.13g) , 4.60 mmol) of a tetrahydrofuran solution (20 mL), adding potassium trimethyl decyl alcoholate (1.77 g, 13.80 mmol), and stirring at -667-201211053 for 3 hours at room temperature. After the reaction, a saturated aqueous solution of manganese chloride was added. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography [Purif-Pack 8 Ι 60 μιη, manufactured by Shouguang Scientific Co., Ltd. Solvent: chloroform/methanol = 10/ 1] Purification gave the title compound (1·3 6 g, yield 6 6 %) as a white solid. 1H-NMR (300 MHz, DMSO-d6) 5: 0.90 (2H, q, J = 9.9 Hz), 1.26 (2H,q,J = 9.9Hz), 1.40-1.55(lH,m),1.63(2H,d,J=12.2Hz),1.73-1.74(4H,m),1.88(2H,d,J=10.6 Hz), 2.12 (lH, 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), 7.8 1 (2H, dd, J = 12.4, 5.4 Hz), 12.02 (lH, brs)» LC/MS [Condition 1]: Hold time 0.70 minutes; m/z 447.8 [M + H]+ (ESI positive ion mode) [Chem. 6 8 4]

Example 3 9 8 (lr,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl]methyl}-N-(4-cyanophenethyl)cyclohexanecarboxamide (Compound No. 398) Substituted (2-fluoropyridin-4-yl)- Amine, using 4-(2-aminoethyl)benzonitrile obtained in Reference Example 397-3, substituting (ir, 4r)-4-({2- sideoxy-8-[4-(trifluoromethyl) Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclo-668- 201211053

Hexanecarboxylic acid, (lr, 4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2_sideoxy-1- obtained using Reference Example 3 98-2 The title compound (27 mg, produced in the same manner as in Example 3 95) was obtained from m.p. Rate 53%) of a colorless solid. W-NMR pOOMHz, CDCl3) 5: 0.99 (2H, dq, J = 3.3, 13.1 Hz), 1.44 (2H, dq, J = 2.9, 13.1 Hz), 1.52-1.64 (lH, m), 1.65-2.05 (9H , m), 2.54-2.7 1 (4H, m), 2.90 (2H, t, J = 7.4Hz), 3.07 (2H, d, J = 7.8Hz), 3.23 (2H, s), 3.52 (2H, q , J = 6.5 Hz), 3.7 5 (2H, s), 5.50-5.69 (lH, m), 7.23 (2H, d, J = 6.1 Hz), 7.3 1 (2H, d, J = 8.2 Hz), 7.60 (2H,d,J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.04 minutes; m/z 5 75.9 [M + H]+ (ESI positive ion mode), m/z 620.1 [M + HCOO]_ (ESI negative ion mode) [Chem. 6 8 5]

Preparation of (2-chlorothiazol-4-yl)methanamine hydrochloride The synthesis was carried out according to the method described in W〇2〇〇9〇57827. • H-NMROOOMHz ^ DMSO-d6) 5: 4.10 (2H) dd 5j = 11 9 5 7 Hz) 7 81 (lH, s), 8.55 (3H, br s). LC/MS [Condition U: Hold time 〇·5〇 Shovel; m/zM8 8[M + H]+ (ESI positive ion mode) -669- 201211053 [Chem. 6 8 6]

Example 3 9 9 (11*,4〇-;^-[(2-chlorothiazol-4-yl)methyl]-4-({2-Sideoxy-8-[4-(trifluoromethyl)) Manufacture of benzylidene]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexylcarbamide (Compound No. 3 99) (2-fluoropyridine) The title compound (20 mg, yield 38) was obtained from m.p. %) of a colorless solid. 'H-NMR (300MHz &gt; CDCl3) 6: 1.04 (2H, dq, J = 2.9, 12.7 Hz), 1.41 - 1.67 (3H, m), 1.70- 1.87 (4H, m), 1.89-2.0 1 (4H, m), 2.10 (lH, tt, J-11.9, 3.3 Hz), 2.55-2.59 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.27 ( 2H, s), 3.5 9(2H, s), 4.46 (2H, d, J = 5.7 Hz), 6.17 (lH, t, J = 5.3 Hz), 7.06 ( lH, s), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz) LC/MS [Condition 1]: Hold time 3.n minutes; m/z 584.6 [M + H]+ (ESI positive ion mode) 6 8 7]

F-670-201211053 Reference Example 4 0 (S)-2-(4-Fluorophenyl)pyrrolidine Production The synthesis was carried out in accordance with the synthesis method described in J.〇rg. Chem., 20 1 0, 75, 2263. LC/MS [Condition 1]: Hold time 0.56 min; ra/zl66.1 [M + H]+ (ESI positive ion mode)

【化6 8 8】

F Example 400

3-({(11*,4〇-4-[(3)-2-(4-fluorophenyl)pyrrolidin-1-carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl) Substituting 4-(3-fluorophenylsulfonyl)peridine for the production of benzyl)-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 4) The title compound (3 2.8 mg) was obtained by the same reaction as in Example 3 9 except for (S)-2-(4-fluorophenyl)pyrrolidine obtained in Reference Example 400. a yellow solid with a yield of 6 2 %) 'H-NMR (300 MHz, CDCl3) 5: 0.57 (0.6H, q, J = 12.3 Hz), 0.90 (0.6H, 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),2.1 6-2.45(1 H,m), 2.46-2.65(4H,br m) ,2.89-3.17 (2H, m), 3.2 1 (1.2H, s), 3.26 (0.8H, s), 3.57 (2H, br s), 3.61 - 3.8 1 ( -671 - 201211053 2H, m), 4.96 (0.6H, d, J = 7.2 Hz), 5.15 (0.4H, 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]: Hold time 3.44 minutes; m/z 601 · 8 [Μ + Η] + (ESI positive ion mode) [Chem. 6 8 9]

Reference Example 4 0 1 -1 4-Methylbenzenesulfonic acid (3-methoxyisoxazol-5-yl)methyl was produced from methyl 3-hydroxyisoxazol-5-carboxylate (purchased) A suspension of (6.0 g, 42 mmol) in tetrahydrofuran (60 mL) was added with potassium carbonate (6.4 g, 46 mmol) and dimethyl sulfate (4.3 g, 46 mmol) at room temperature, and stirred at 75 ° C for 21 hours. After adding a saturated aqueous solution of manganese chloride to the reaction mixture, the mixture was extracted twice with ethyl acetate. The organic layer of the combined organic layer was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography to give methyl 3-methoxyisoxazole-5. , yield 26%) solids. To a solution of the obtained methyl 3-methoxyisoxazole-5-carboxylate (0.50 g, 3.2 mmol) in ethanol (10 mL), sodium borohydride (〇.19 g, 4.9 mmol) was added at room temperature. After that, stirring was carried out for 1.5 hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. After a saturated aqueous solution of manganese chloride was added to the obtained residue, the mixture was extracted twice with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure. The residue (〇.47 g) was dissolved in tetrahydrofuran-672-201211053 (5.0 mL), and triethylamine (0.80 mL, 5.8 mmol) and 4-methylbenzenesulfonic acid chloride (0.82 g, 4.3 mmol) were added. Stirring was carried out for 15 hours at room temperature. After adding a saturated aqueous solution of manganese chloride and a saturated aqueous solution of sodium chloride, the mixture was extracted twice with ethyl acetate, and the organic layer was concentrated and evaporated to dryness. The obtained residue was purified by silica gel column chromatography [employing solvent: hexane / ethyl acetate = 3 / 1] to give 4-methylbenzenesulfonic acid (3-methoxyisoxazole - A 5-base) methyl (〇.51 g, yield 57%) white solid.

Reference Example 4 0 1 - 2

Preparation of 2-[(3-methoxyisoxazol-5-yl)methyl]isoindan-1,3-dione The 4-methylbenzenesulfonic acid obtained in Reference Example 401-1 (3) -Methoxyisoxazole-5-yl)methyl (0.50 g, 1.8 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and potassium phthalate was added (purchased (0.39 g, 2.1 mmol), stirred at 90 ° C for 1 hour. After cooling the reaction mixture to room temperature, the precipitated solid was collected by adding water (20 mL), and washed with water to give 2-[(3·methoxyisoxazole-5-yl)methyl]isoindole. A white solid of 1,3-1,3-diketone (〇.43 g, yield 93%). 【化6 9 1】

Nh2 673- 201211053 Reference Example 4 Production of 0 1 -3 (3-methoxyisoxazol-5-yl)methylamine Substituting 2-(isoxazole-5-ylmethyl)isoindan-1, The diketone was substantially the same as the 2-[(3-methoxyisoxazol-5-yl)methyl]isoindan-1,3-dione obtained in Reference Example 401-2. The title compound (46 mg, yield 90%) of m.j.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , s), 5 · 7 7 ( 1 Η , s). 【化6 9 2】

Example 401 (11,41〇-;^[(3-methoxyisoxazol-5-yl)methyl]-4-({2- sideoxy-8-[4-(trifluoromethyl)) Manufacture of benzyl-]-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamide (Compound No. 401) (2-fluoropyridine-4) -Methylamine, the title compound (1) was obtained after the same reaction as in Example 395, except for (3-methoxyisooxazol-5-yl)methylamine obtained in Reference Example 401-3. 8 mg, yield 37%) of a colorless solid. 'H-NMR (3 00 MHz &gt; CDCl3) 5: 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(lH,tt,J -674- 201211053 = 11.4,3.3Hz),2.54-2.57(4H,br m), 3.10 (2H, d, J = 7.0 Hz), 3.28 (2H, s), 3.59 (2H, s) 54.58 (2H, d, J = 5.7 Hz), 6.18 (lH, d, J = 1.2 Hz) ), 6.45-6.53 (1 H, brm), 7.45 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 7.8 Hz), 8. 18 (1 H, d, J = 1 · 6 Hz) ). LC/MS [Condition i]: Hold time 3·〇ι min; m/z 564.9 [M + H]+ (ESI positive ion mode)

【化6 9 3】

Example 4 0 2 6-[1-((11*,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-l-oxo-) Manufacture of 3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbonyl)piperidin-4-yloxy]nicotinonitrile (Compound No. 402)

Substituting 4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl) Benzoic acid, using the (11',4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1) oxalate obtained in Reference Example 3 98-2 - 3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid, substituted 4-(aminomethyl)benzonitrile hydrochloride, obtained using Reference Example 293-2 A white powder of the title compound (28 mg, yield 66%) was obtained from m. ' CD C13) δ : 1.0 4 (2 H, dq, J = 3.7, 1 1.9H z), 1.4 6- 1.66(3H,br m), 1. 6 9 - 1 . 8 5 (8 H, brm) , 1 . 8 6 - 2.1 1 (4 H, brm), 2.47 • 675- 201211053 (lH, tt, J=l 1.9, 2.9 Hz), 2.6 3 (4H, br s), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2 H, s), 3.31-3.53 (2H, br m), 3.6 6 - 3.8 0 ( 1 H , brm), 3.7 5 (2 H, s), 3.8 8 -4.05 (1 H, br m), 5.35 (lH, tt, J = 7.8, 3.7 Hz), 6.79 (lH, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.78 (lH, dd, J = 8.6, 2.0 Hz), 8.45 (lH, d, J = 2·5 Ηζ) 〇 LC/MS [condition: hold time 3.18 minutes; m/z 63 2 .8 [M + H]+ (ESI positive ion mode), m/z 676.9 [M + HCOO]_ (ESI negative ion mode) [Chem. 6 9 4]

Example 4 0 3 (11:,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl]methyl}-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 403) Substituted 6-(piperidin-4- The title compound (26 mg, yield 72%) of white powder was obtained from m.p. ' CD C13) δ : 1.0 0 (2 H , q, J = 1 2.3 H z), 1. 3 6 -1.6 6 (3H,m), 1.67- 1.82(4H,br m), 1. 8 2 - 2.1 0 (9 H, m), 2.6 3 (4 H, brs), 3.01-3.18 (lH, m), 3.07 (2H, d, J = 7.8 Hz), 3.22 (2H, s), 3.52- 3.63 (lH,m), 3.67-4.0 l(3H,m),3.75(2H,s), 5.79( lH,t,J = 5.3Hz), -676- 201211053 7.22(2H,d,J = 5.7Hz ). LC/MS [Condition 1]: Hold time 1.38 minutes; m/z 5 3 0.8 [M + H]+ (ESI positive ion mode), m/z 575.0 [M + HCO〇r (ESI negative ion mode) 9 5]

F Φ Example 404 4-{[3-({(1),4〇-4-[4-(6-chloropyrimidin-4-yl)piperazine-1-carbonyl]cyclohexyl}methyl)-2- Preparation of 2-oxo-oxa-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 404) Substituted 6-(piperidine) -4-oxy)nicotinonitrile hydrochloride, substantially the same reaction as in Example 402 except that 4-chloro-6-(piperazin-1-yl)pyrimidine dihydrochloride obtained in Reference Example 288 was used. The title compound (26 mg, yield 72%) was obtained as white powder.

1H-NMR (300MHz 'CDCl3) δ : 1.〇5(2H,dq, J = 4.5,1 1.4 Hz), 1.47-1.67(3H,br m) , 1.6 8 - 1. 8 6 (6 H, brm ), 1. 8 6 - 1.9 8 (2 H , brm), 2.46 (lH, 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), 3.7 5 (6 H , brs), 6.5 1 (1 H , s), 7.2 2 (2 H , d, J = 6.1 Hz), 8.40 (1H) , s). LC/MS [Condition 1]: Hold time 2.96 minutes; m/z 314.6 [M + 2H]2 + , 627.8 [M + H] + (ESI positive ion mode), ^/ζόΤΙ.ΜΜ + ΗεΟΟΓί ESI negative ion mode ) -677- 201211053 【化6 9 6】

F Example 4 0 5 3,5-Difluoro-4-{[2-Sideoxy-3-({(11*,4〇-4-[4-(quinolin-4-yl)piperazine-1 -Carbonyl]cyclohexyl}methyl)-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 405) was substituted for 6-(piperidine) -4-oxy)nicotinonitrile hydrochloride was obtained by substantially the same reaction as in Example 402 except that 4-(piperazin-1-yl)quinoline dihydrochloride obtained in Reference Example 278-2 was used. The title compound (38 mg, yield: 87%), mp. (2H,q,J= 12·7Ηζ), 1.70- 1.98(8 H,br m),2 · 5 1 (1 H,tt, J = 12.3,3.3Hz), 2.57-2.7 1(4H,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 (lH, d, J = 4.9 Hz), 7_22 (2H, d, J = 7.0 Hz), 7.53 (lH, t, J = 7.8 Hz), 7.70 (lH, t, J = 7.8 Hz) ), 8.02 (lH, dd, J = 8.2, 1.2 Hz), 8.11 (lH, d, J = 8.2 Hz), 8.75 (lH, d, J = 4.9 Hz). LC/MS [Condition 1]: Hold 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) -678- 201211053 【化6 9 7】

Example 4 0 6 3,5-Difluoro- 4-{[3-({(lr,4r)-4-[4-(6-fluorobenzo[d]isooxazol-3-yl)piperidine) -1-carbonyl]cyclohexyl}methyl)_2-sideoxy-1-oxo-3,8-diazospiro[4.5]indole® alkyl-8-yl]methyl}benzonitrile (Compound No. 4〇6 Manufactured in place of 6-(piperidin-4-yloxy)nicotinonitrile hydrochloride, using 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (purchased), The title compound (*19 mg, yield 43%) of white powder was obtained after the same reaction of the same procedure as Example 402.

*Η-ΝΜΚ(300ΜΗζ ' CD C13) δ : 1.0 5 (2 H, q, J= 1 2.3 Η ζ), 1.4 6 -1.6 8 (3H,br m), 1.70-2.06(1 OH,br m) , 2.0 7 - 2.2 5 (2 H, brm), 2.49 ( lH, t, J = 12.3 Hz), 2.63 (4H, br s), 2.8 7 (1 H, t, J = 1 1.4 Hz), 3.1 0 (2H, d, J = 7.4 Hz), 3.16-3.41 (2H, m), 3.23 (2H, s), 3.75 (2H, s), 4.04 (lH, d, J = 13.1 Hz), 4.67 (lH, d, J = 12.7 Hz), 7.07 (lH, td, J = 8.9, 2.2 Hz), 7.16-7.29 (3H, m), 7.61 (lH, dd, J = 8.6, 4.9 Hz). LC/MS [Condition 1]: Hold time 3.40 minutes; m/z 649.9 [M + H]+ (ESI positive ion mode), m/z 694.0 [M + HCOO]- (ESI negative ion mode) -679- 201211053 【化6 9 8】

Example 4 0 7 4-[(3-{[(lr,4r)-4-(4-Benzylpiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxyloxy-1-oxo- Preparation of 3,8-diazospiro[4.5]decane-8-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 407) Substituted 6-(piperidin-4-oxy) The title compound (35 mg, yield 86%) of white powder was obtained from the title compound (35 mg, yield: 86%). 'H-NMR (3 00 MHz ' CDC13) 5: 0.89-1.1 l (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. .8 5 - 1.99(2H,br m), 2.3 3 - 2.72 (8 H ,br m), 2.9 3 (1 H, t, J= 1 2.9 Hz), 3.08 (2H,d,J = 7.4 Hz), 3.21 (2H, s), 3.74 (2H, s), 3.84 (lH, d, J = 12.7 Hz), 4.60 (lH, d, J = 14.3 Hz), 7.08 -7.15 (2H, m), 7.15-7.33 (5H, m). LC/MS [Condition 1]: Hold time 3.56 minutes; m/z 604.9 [M + H]+ (ESI positive ion mode), m/z 649.2 [M + HCO〇r (ESI negative ion mode) [ 6 9 9]

-680- 201211053 Example 4 0 8 4-((lr,4r)-4-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-l-oxo- Manufacture of ethyl 3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbamamine)piperidine-1-carboxylate (Compound No. 408)

Substituting 6-(piperidin-4-oxy)nicotinonitrile hydrochloride, substantially the same reaction as in Example 402, except using ethyl 4-aminopiperidine-1-carboxylate (available from the product) The title compound (3 3 mg, yield 81%) was obtained as white powder. W-NMROOOMHz, CDCl3) 6: 1.00 (2H, dq, J = 2.9, 12.3 Hz), 1.25 (3H, t, J = 7.〇Hz), 1.27 (2H, dq, J = 4.1, 11.0 Hz), 1.46 - 1.65(1 H,br m), 1.47(2H,dq,J = 2.9,l 1.9Hz), 1.6 5 -1.8 2 (4H,br m), 1.82-2.06(7 H,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 (1 H, m), 4.00-4.2 1 (2H, brm), 4 · 1 2 (2 H, q, J = 7.2 H z), 5 · 3 4 (1 H, d, J = 7.8 H z), 7.2 2 (2 H, d, J = 5.7 Hz). LC/MS [Condition 1]: Hold time 2.92 minutes; m/z 601.8 [M + H]+ (ESI positive ion mode), m/z 646.1 [M + HCOO]- (ESI negative ion mode) 0 0]

F Example 409 l-((lr,4r)-4-{[8-(4-Cyano-2,6-difluorobenzyl)-2-sideoxy-1-oxo--681 - 201211053 3 , 8-diazospiro[4-5]nonan-3-yl]methyl}cyclohexanecarbonyl)piperidine-4-carbonitrile (Compound No. 409), substituted 6-(piperidin-4-yloxy) The title compound (33 mg, yield: 91%) of white powder was obtained from the title compound (yield: 91%). • H-NMRCSOOMHz ' CDC13) 6: 0.94-1 .14 (2H, br m), 1.4 4 -1 . 6 8 (3H, br m), 1.68-2.02 ( 1 2H, br m), 2.4 2 ( 1 H, t, J = 1 0.2 H z), 2.6 4 ( 4H, br s), 2.83 - 2.97 (lH, 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]: Hold time 1.48 minutes; m/z 539_8 [M + H]+ (ESI positive ion mode), m/z 583.8 [M + HCO〇r (ESI negative ion mode) [Chem. 7 0 1 】

Example 4 1 0 3,5-Difluoro-4-({3-[((11&quot;,4〇-4-{[-(2-methoxyphenylamino))piperidine-1-carbonyl] Manufacture of cyclohexyl}methyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 410) Substituted 6-( Piperidine-4-oxy)nicotinonitrile hydrochloride was substantially carried out and carried out using N-(2-methoxyphenyl)piperidin-4-amine dihydrochloride obtained in Reference Example 292-2. The title compound (3 2 mg, yield 74%) of white powder was obtained after the same reaction of Example 402. -682 - 201211053

• H-NMRiSOOMHz ' CDC13) 6: 1 .03 (2H,q, J= 1 3 .1 Hz), 1.27-1.47 (2H,br m), 1.47- 1,66(3H,br m), 1.6 7 - 1. 8 4 (6 H , br m), 1.86-1.97 (2H, br m), 2.11 (2H, t, J = 13.5 Hz), 2.46 (lH, tt, J = 11.9, 2.9 Hz), 2.53 -2.71 (4H, br m), 2.89 (lH, t, J = 11.4 Hz), 3.08 (2H, d, J = 7.4 Hz), 3.13 - 3.26 (lH, br m), 3.2 2 (2 H , s ), 3.5 1 (1 H, brs), 3.7 4 (2 H, s), 3.79-3.92 (1 H, br m), 3 . 8 4 ( 3 H , s), 4.1 3 (1 H, brs) , 4.4 6 (1 H, d, J = 14.3 Hz), 6.59-6.7 1 (2H, m), 6.78 (lH, dd, J = 7.4, 1.6 Hz), 6.86 (lH, td, J = 7.0, 1.6 Hz), 7.22 (2H, d, J = 5.7 Hz). LC/MS [Condition 1]: Hold time 2.98 minutes; m/z3 1 8·5 [Μ + 2Η] 2 + , 636.0 [M + H] + (ESI positive ion mode), m/z 680_0 [M + HCOO] -( ESI negative ion mode) [Chemical 7 0 2]

Example 4 1 1 4-((lr,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8- Production of methyl diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbonyl)piperazine-1-carboxylate (Compound No. 4 1 1) substituted 6-(piperidin-4-yloxy) The nicotinic acid hydrochloride was used in the same manner as in Example 402 except that the piperazine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 3 3 8-2 was used to give the title compound (23 mg). White powder with a rate of 59%) -683- 201211053 • H-NMROOOMHz, CDCl3) 5: 1.03 (2H, q, J = 12.7 Hz), 1.45-1.65 (3H, br m), 1.69-1.8 3 ( 6H, br m), 1.84 - 1.97 (2H, br m), 2.42 (lH, t, J = l 1.0 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 (3 H, s), 7.22 (2H, d, J = 5.7 Hz ). LC/MS [Condition 1]: Hold time 2.49 min: m/z 573.8 [M + H]+ (ESI positive ion mode), m/z 61 8.3 [M + HCOO]- (ESI negative ion mode)

[化7 0 3]

Example 4 1 2

3-{[(lr,4r)-4-(4,4-difluoropiperidin-1-carbonyl)cyclohexyl]methyl}-8-[4-(trifluoromethyl)benzyl]-1 -Production of cacao-3,8-diazosuro[4.5]nonan-2-one (compound number 412)

Substituting 3,5-dimethyl-substituted piperidine, using 4,4-difluoropiperidine hydrochloride (purchased), the title compound (28 mg, yield 76%) of white powder. !Η-ΝΜΚ(300ΜΗζ ' CDCl3) 5:1.05(2H,q,J=l 1.6Hz), 1.45-1.68 (3H,br m),l .71-1 .85(6H,br m), 1 . 8 5 - 2.0 8 (6 H, brm), 2.45 (lH , tt, J = l 1.9, 2.9 Hz), 2.55 (4H, br s), 3.1 l (2H, d, J = 7.4 Hz), 3.26 ( 2H, s), 3.59 (4H, br s), 3 · 7 2 (2H, br s), 7 · 43 (2H, d, J = 7 · 8 Hz), 7.5 7 ( 2 H, d, J = 7.8 Hz). 8 -684- 201211053 LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 557.8 [M + H]+ (ESI positive ion mode), m/z 601.9 [M + HCO〇r (ESI negative ion) Mode) 【化7 0 4】

Example 4 1 3 3-{[(lr,4r)-4-(4-nicotinium piperidine-1-carbonyl)cyclohexyl]methyl b8_[4_(trifluoromethyl)benzyl]- 1. Production of cacao-3,8-diazospiro[4·5]nonan-2-one (Compound No. 413). Substituting 3,5-dimethyl substituted piperidine, using piperidin-4-yl ( A white powder of the title compound (35 mg, yield 86%) was obtained from m.p. 1H-NMR (300MHz &gt; CD C13) δ : 1.0 5 (2 H, q, J = 1 1 . 9 H z), 1.4 7 -1 . 7 0 (4H, br m), 1. 72- 1 , 8 7(7H,br m), 1. 8 8 - 2.0 2 (2 H, brm), 2.46 (lH, tt, J = l 1.9, 2.5 Hz), 2.56 (4H, br s), 2.83 ( 1 H, t, J = 1 2.1 H z), 3 . 1 1 ( 2H,d,J = 7.4Hz), 3.22 (lH,t,J=l2.7Hz), 3.26(2H,s), 3.48( lH,tt,J=10.6,3.7Hz),3.57(2H,s),3.99(lH,d,J=13.5Hz),4.61(lH,d, J=1 2.7Hz),7.3 8-7.49(3H , m), 7.57 (2H, d, J = 8.2 Hz), 8.22 (1 H, dt, J = 7.8, 2.0 Hz), 8.75-8.84 (lH, m), 9.16 (lH, s). LC/MS [Condition 1]: Hold time 3.06 min; m/z 313.9 [M + 2H] 2 + , 626.8 [M + H] + (ESI positive ion mode), m/z 670.9 [M + HCOO; r (ESI negative ion mode) -685- 201211053 【化7 Ο 5】

Example 4 1 4 4-{[3-({(lr,4r)-4-[4-(2,4.-difluorobenzhydryl)piperidine-carbonyl]cyclohexyl}methyl)-2 -Side-oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}- φ 3,5-difluorobenzonitrile (Compound No. 4丨4) -(piperidin-4-yloxy)nicotinyl hydrochloride, substantially using (2,4-difluorophenyl)(piperidin-4-yl)methanone hydrochloride (purchased) The title compound (24 mg, yield 51%) was obtained as a yellow powder.

1 H-NMR (3 00 MHz ' CDC 13) δ : 1.03 (2Η, q, J = 1 2.3 Ηz) , 1.44- 1 . 6 5 (3H, br m), 1.65- 1.84 (6H, br m), 1.8 5 -2.03 (4H,br m),2,45 (lH ,t,J=l 1.7Hz), 2.51-2.6 9(4H,br m) ,2.77( 1 H, t, J= 11.9Hz),3.06 -3.23 ( lH, br m), 3.08 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.33 (lH, tt, J = 10.4, 3-3 Hz), 3.74 (2H, s), 3.94 (lH, d, J = 13.1 Hz), 4.5 6 (lH, d, J = 13.1 Hz), 6.82-6.93 (1H, m), 6.98 (1 H, td, J = 8.2, 2.5 Hz), 7 16-7.26(2H, m), 7.86 (lH, td, J = 8.6, 6.5 Hz). LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 654.8 [M + H]+ (ESI positive ion mode), m/z 698_9 [M + HCOO]_ (ESI negative ion mode) -686- 201211053 7 0 6] Q. HN-CH3 NH /—\ O^-CHa Reference Example 4 1 5 -1 4-[2-(pyridin-2-yl)biaminecarbonyl]piperidine-1-carboxylic acid III Preparation of butyl ester 2 - mercaptospira (520 mg, 4.8 mmol, sold), 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.4 mmol) and 1-hydroxyl After benzotriazole (180 mg, 1.3 mmol) was dissolved in chloroform (10 mL), 1-ethyl-3·(3-dimethylaminopropyl)carbodiimide hydrochloride (920 mg, 4.8 mmol) was added. ), mixing at room temperature for 27 hours. The organic layer was separated by adding water, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution, a 1.0 M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. After the obtained yellow residue was dissolved in diethyl ether (5.0 ml), hexane was added. Thereafter, the precipitated white solid was collected, and dried under reduced pressure at <RTI ID=0.0></RTI> <RTIgt; 1H-NMR (CDC13) 6: 1.46 (9H, s), 1.57-1.82 (2H, m), 1.82-1.95 (2H, m), 2.3 3-2.46 (lH, m), 2.6 8-2.8 6 (2H , m), 4.05-4.26 (2H, brm), 6.65 (lH, d, J = 8.5 Hz), 6.80 (lH, dd, J = 6.8, 4.4 Hz), 7.53 (lH, ddd, J = 8.5, 6.8 , 2.0 Hz), 8.16 (lH, dd, J = 4.4, 2.0 Hz). LC/MS [Condition 1]: Hold time ι·12 min; m/z 320.9 [M + H]+ (ESI positive ion mode) -687- 201211053 [Chem. 7 0 7]

Reference Example 4 Preparation of 1 5 - 2 4-([1,2,4]triazin[4,3-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester Reference Example 415 4-[2-(pyridin-2-yl)diaminecarbonyl]piperidine-1-carboxylic acid tert-butyl ester (700 mg, 2.2 mm) was dissolved in tetrahydrofuran (20 mL) and added to Burgess. Drug (Detailed reference to J. Am. Chem. Soc. 1 26, 2004, 6234.) (57Omg, 2.4mmol) &gt; 4 hours of hot mouth reflux was carried out, and mixing was carried out for 60 hours at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure. After the obtained residue was taken up in ethyl acetate, water was added. The organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (Purif-Pack SI 60 pm, solv. chloroform-methanol) to give the title compound (42 Omg, yield 64%) white solid. iH-NMR (CDC13) 5: 1.49 (9H, s), 1.99-2.14 (4H, m), 2.94-3.09 (2H, m), 3.17-3.29 (lH, m), 4.19-4.3 2 (2H, m ), 6.8 5 (lH, dd, J = 6.6, 7.2 Hz), 7.24 (lH, dd, J = 9.2, 6.6 Hz), 7.77 (lH, d, J = 9.2 Hz), 7.94 (lH, d, J) = 7.2Hz) 〇LC/MS [Condition 1]: Hold time 3.11 minutes; m/z3 02.9 [M + H]+ (ESI positive ion mode) -688- 201211053 [Chem. 7 0 8]

Reference Example 4 1 5 - 3 3-(piperidin-4-yl)-[1,2,4]triazinium [4,3-a]pyridine dihydrochloride

4-([1,2,4]triazin[4,3-a]pyridin-3-yl)piperazin-1-residual acid third butyl vinegar (420 mg, 1.4 mmol) obtained in Reference Example 415-2 After dissolving in methanol (2.0 mL), a 4 M hydrogen chloride-dioxane solution (6.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The precipitated white solid was collected and dried under reduced pressure at 30 deg. for 2 hours to give the title compound (3 20 mg, yield 84%).

1H-NMR (DMSO-d6) 5: 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, Br s), 7.4 7 ( 1 Η, dd, J = 6.7, 6.9 Hz), 7.94 (lH, dd, J = 9.1, 6.7 Hz), 8.05 (lH, d, J = 9.1 Hz), 9.03 (1 H , d, J = 6.9 Hz), 9.22 - 9.53 (2H, m). LC/MS [Condition 1]: Hold time 〇·47 min; m/z 203.0 [M + H]+ (ESI positive ion mode)

[Chemical 7 〇 9] ο Example 4 1 5 689- 201211053 3-({(11:,41*)-4-[4-([1,2,4]triazinium [4,34]pyridine- 3-yl) piperidine-1-carbonyl]cyclohexyl}methyl)-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5] Production of decane-2-one (Compound No. 415) Substituting 3,5-dimethyl substituted piperidine, using 3-(piperidin-4-yl)-[1,2,4 obtained in Reference Example 415-3 The title compound (13 mg, yield: 34%) of white powder was obtained from the title compound (yield: 34%).

'H-NMRCSOOMHz ' CDCl3) 5: 1.07 (2H, q, J = 13.1 Hz), 1.47-1.71 (3H, br m), 1. 7 1-2.0 1 (9H, br m), 2.0 4 - 2.3 0 ( 3 H, brm), 2.50 (lH , tt, J = 11.9, 4.1 Hz), 2.56 (4H, br s), 2.99 (lH, t, J = U.9 Hz), 3.07 - 3.16 (2H, m) , 3.24-3.40 (2H, m), 3.26 (2Hss), 3.58 (2H, s), 4.12 (lH, d, J = 7.4 Hz), 4.5 9 (lH, d, J = 13.5 Hz), 6.86 (lH) , t, J = 6.5 Hz), 7.19-7.30 (lH, m), 7.44 (2H, d, J = 8.2 Hz) s7.57 (2H, d, J = 8.2 Hz), 7.78 (l H, d, J = 9.4 Hz), 7.92 ( lH, d, J = 7.0 Hz). LC/MS [Condition 1]: Hold time 2.86 min; m/z 320.0 [M + 2H] 2 + , 63 8.9 [M + H] + (ESI positive ion mode), m/z 682.9 [M + HCO 〇r (ESI negative ion mode) [Chem. 7 1 0]

Reference Example 416-1 Preparation of butyl [(tetrahydrofuran-2-yl)methyl]carbamic acid tert-butyl ester (tetrahydrofuran-2-yl)methylcarbamic acid-690 obtained in Reference Example 182-1 - 201211053

The third butyl ester (0.10 g, 0.50 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), and sodium hydride (&gt; 63% by weight, dispersed in flowing paraffin) (36 mg, 1.5 mm) was added. After 〇l), it was mixed at room temperature for 1 hour. Thereafter, 2-iodopropane (〇25 mL, 2.5 mmol) was stirred at room temperature overnight. After water (2.0 mL) and ethyl acetate (2.0 mL) were added, the organic layer was separated and washed with water (2. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI 60 pm, hexanes: EtOAc/hexane) to give the title compound (3 5 mg, yield: Oily. LC/MS [Condition 1]: Hold time 4.31 minutes; m/zl 43.9 [M-isobutene -C02 + H] + (ESI positive ion mode) [Chem. 7 1 1] ch3 Η3〇γ〇Η WNhHc, Reference example Preparation of 4 1 6 - 2 N-[(tetrahydrofuran-2-yl)methyl]propane·2-amine hydrochloride The isopropyl [(tetrahydrofuran-2-yl)methyl] obtained in Reference Example 416-1] Aminobutyric acid terpene vinegar (35 mg, 0.14 mmol) was dissolved in methanol (1.0 mL), and 10% hydrogen chloride-methanol (〇.7 mL) was added at room temperature, and mixed at 50 ° C for 3 hours. Thereafter, the reaction solution was concentrated to dryness under reduced pressure to give the title compound (25 mg, quantitative) as a colorless oil. LC/MS [Condition 1]: Hold time 0.49 min; m/zl 44.0 [M + H]+ (ESI positive ion mode) -691 - 201211053 [Chem. 7 1 2]

Example 4 1 6 (lr,4r)-N-isopropyl-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]- oxa-3,8-weight Preparation of alkalose [4.5]decane-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarboxamide (Compound No. 416) Substituting 3,5-dimethyl The title compound was obtained by the same reaction as in Example 3 42 except that N-[(tetrahydrofuran-2-yl)methyl]propan-2-amine hydrochloride obtained in Reference Example 416-2 was used. (1 1 mg, yield 28%) of colorless oil "H-NMRiSOOMHz, CDCl3" 5: 1.05 (2H, dq, J = 3.7, 13.1 Hz), l.ll-1.21 (3.9H, m) , l.26 (2. lH, d, J = 6.5 Hz), l.41-1.67 (3H, br m), l .65-1.86 (7H, br m), 1. 8 5 -2.1 0 (5 H, br m), 2.47 ( 1 H, tt, J = 1 1.4, 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 - 3.3 9 (lH, 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 ( lH, m), 4.5 1 (0.35H, tt, J = 7.4, 7.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H , d, J = 8.2Hz). LC/MS [Condition 1]: Hold time 3.24 minutes; m/z 579.9 [M + H]+ (ESI positive ion mode), m/z 624.0 [M + HCO〇r (ESI negative ion mode) -692- 201211053 【化7 1 3】

Example 4 1 7

(11&quot;,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4 ·5 Manufacture of decyl-3-yl]methyl}-N-(furan-2-ylmethyl)cyclohexanecarbamamine (Compound No. 41 7) substituted 6-(piperidin-4-oxy) The title compound (1 9 mg, yield 55%) of white powder was obtained from the title compound (m. (3 00MHz ' CDC13) δ : 1.00 (2Η, dq, J = 3.3, 1 2.7Ηz), 1.49 (2H, dq, J = 2.9, 13.1Hz), 1.50-1.64 (lH, br m), 1.67 -1.84(4H,br m ),1.85-1.98(4H,br m),2.03 (1 Η,tt, J= 1 1.9,3.3 Hz), 2.62(4H,br s ),3.07(2H,d,J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H, s), 4.42 (2H, d, J = 5.3 Hz), 5.7 1 (lH, t, J = 4.9 Hz), 6.21 (lH, d, J-2.5 Hz), 6.3 1 (lH, dd, J = 3.3, 2.0 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.34 (lH, dd) J = 1.6, 0.8 Hz) LC/MS [ Condition 1]: Hold time 2.55 minutes; m/z 527.0 [M + H]+ (ESI positive ion mode), m/z 571.1 [M + HCOO]- (ESI negative ion mode) -693- 201211053 1 4]

Example 4 1 8 (11*,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl]methyl}-N-(furan-3-ylmethyl)cyclohexanecarbamamine (Compound No. 418) substituted 6-(piperidin-4-yloxy) The same was obtained as the title compound (1 7 mg, yield: 4 8 %). Powder. W-NMRpOOMHz, CDCl3)3: 1.00 (2H, dq, J = 3.3, 13.1 Hz), 1.49 (2H, dq, J = 2.5, 12.3 Hz), 1.51-1.63 (lH, br m), 1.6 8 -1.8 3 (4H,br m), 1. .8 5 - 1.99(4H,br m), 2.0 2 (1 H, 11, J = 1 1.9,3.3 H z ), 2.6 2 (4 H ,brs ), 3.07(2H,d,J = 7.4Hz), 3.22(lH,s),3.7 5(2H,s),4.2 7(2H,d,J = 5.3 Hz),5.57(lH,t,J = 4.9Hz ), 6.33 (lH, s), 7.22 (2H, d, J = 5.7 Hz), 7.33 - 7.38 (2H, m). LC/MS [Condition 1]: Hold time 2.27 minutes; m/z 526.9 [M + H]+ (ESI positive ion mode), m/Z 571.2 [M + HCO〇r (ESI negative ion mode) 1 5]

-694- 201211053 Example 4 1 9 (lr,4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8 -diazospiro[4.5]decane-3-yl]methyl}-N-[(3-methoxyisoxazol-5-yl)methyl]cyclohexanecarbamamine (Compound No. 419) Manufacturing

Substituting 6-(piperidin-4-oxy)nicotinonitrile hydrochloride, using (3-methoxyisoxazol-5-yl)methylamine obtained in Reference Example 401-3, substantially The title compound (26 mg, yield 70%) was obtained as white powder. 'H-NMR (300MHz ' CDCl3) 5: 1.01 (2H, dq, J = 2.9, 13.1 Hz), 1.48 (2 H, dq, J = 2.5, 13.1 Hz), 1.5 0- 1.63 (lH, br m) , 1.6 7 - 1 . 8 2 (4 H ,brm ),1.84- 1.98(4H,br m), 2.07( 1 H, tt, J= 1 1.9,3.3 Hz), 2.63 (4H ,br s ),3.07 (2H,d,J = 7.4Hz), 3.22(2H,s), 3.75(2H,s),3.94(3H,s),4.43(2 H, d, J = 5.7Hz), 5.78( lH,s ), 5.92 (lH,t,J = 5.7 Hz), 7.22 (2H,d,J = 6.1 Hz). ^ LC/MS [Condition 1]: Hold time 1.50 minutes; m/z 5 5 8.0 [M + H]+ (ESI positive ion mode), ηι/ζ5 56.1 [Μ-ΗΓ, 602.1 [M + HCOO] — (ESI Negative ion mode) [Chem. 7 1 6]

Example 420 -695- 201211053 (lr,4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-weight Preparation of aza-[4.5]decane-3-yl]methyl}-N-[(2-fluoropyridin-4-yl)methyl]cyclohexanecarboxamide (Compound No. 420) Pyridine-4-oxy)nicotinyl hydrochloride, the title compound was obtained after the same reaction as in Example 402, except that (2-fluoropyridin-4-yl)methylamine obtained from the compound of Example 395-5. 1 8 mg, yield 47 ° /.) white powder

i-NMRQOOMHz, CDCl3) 5: 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. 8 5-2.03 (4H , br m), 2.12 (lH, 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 (lH, t, J = 6.1 Hz), 6.79 (l H, s), 7.05 (lH, d, J = 4.9 Hz) 57.22 (2H, d, J = 5.3 Hz), 8.15 (lH, d, J = 4_9 Hz). LC/MS [Condition 1]: Hold time 1.40 minutes; m/z 27 8.6 [M + 2H] 2 + , 5 5 5.9 [M + H] + (ESI positive ion mode), m/z 5 54.2 [MH] _, 600.0 [M + HCOO]_ (ESI negative ion mode) [Chem. 7 1 7]

Example 42 1 4-[(3-{[(11*,4〇-4-(4,4-Difluoropiperidin-1-carbonyl)cyclohexyl]methyl}_2- sideoxy-1-oxo- Manufacture of 3,8-diazospiro[4.5]decane-8-yl)methyl]-3,5-difluorobenz-696- 201211053 nitrile (compound number 42 1)

Substituting 6-(piperidin-4-yloxy)nicotinonitrile hydrochloride, using the same reaction as in Example 402, except using 4,4-difluoropiperidine hydrochloride (sold) (4 6 mg, quantitative) of white powder. , H-NMR (300MHz ' CD C13) δ : 1.0 4 (2 H, q, J= 1 1 .9 Η z), 1.4 6 -1.6 7 (3H, br m), 1.67- 1.85 (6H, br m ), 1. 8 5 - 2.0 7 (6 H, br m), 2.45 (lH , tt, J = 12.7, 2.5 Hz), 2.5 1- 2.74 (4H, br m), 3.0 9 (2 H , d, J = 7.4 H z), 3.22 (2H, s), 3.57 (2H, br s), 3.7 1 (2 H, brs), 3.7 5 (2 H, s), 7.2 2 (2 H, d, J = 6.1 Hz). LC/MS [Condition 1]: Hold time 2.92 minutes; m/z 551.0 [M + H]+ (ESI positive ion mode), m/z 595.2 [M + HCO〇r (ESI negative ion mode) 1 8]

Example 4 2 2 3,5-Difluoro-4-{[2-Sideoxy-3-({(11*,41*)-4-[4-(trifluoromethyl))piperidine-1-carbonyl) Manufacture of cyclohexyl}methyl)-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 422) in place of 6-(piperidine-4) -oxy)nicotinyl hydrochloride, the title compound (5 3 mg, quantitative) was obtained after the same reaction as in Example 402, except using 4-(trifluoromethyl)piperidine hydrochloride (sold). White powder. k-NMROOOMHz, CDCl3)5: l_03 (2H, q, J=13_lHz), 1.36-1.65 - 697-201211053 (5H, br m), 1.67-1.84 (6H, br m), 1.85-2.01 (4H, br m), 2.16-2.34 (lH, m), 2.3 5-2.5 l(2H,m), 2.52-2·73(4H,br m), 3.〇l(lH,t,J = 12.7Hz), 3.09 (2H, d, J = 7-0Hz), 3.22 (2H, s), 3.75 (2H, s), 3.98 (l H, d, J = 12.3 Hz), 4.75 (lH, d, J = 13.5 Hz) ), 7.22 (2H, d, J = 6.1 Hz). LC/MS [Condition 1]: Hold time 3.18 minutes; m/Z5 83.1 [M + H]+ (ESI positive ion mode), m/z627_2 [M + HCO〇r (ESI negative ion mode) [Chem. 7 1 9]

Example 4 2 3 4-((lr,4r)-4-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8- Preparation of Ethyl Diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbonyl)piperazine-1-carboxylate (Compound No. 423) Substituted 6-(piperidin-4-oxy) The title compound (48 mg, quantitative) of white powder was obtained by the same reaction as in Example 402, except that the mixture was obtained from ethyl acetate (ethyl acetate). (300MHz ' CDCl3) 5: 1.03 (2H, q, J = 12.3Hz), 1.27 (3H, t, J = 7.4Hz), l .44-1.65 (3H, br m), 1.68-1.84 (6H, br m), l .84-1.97 (2H, br m), 2.42 (l H, tsJ = l 1,9 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 . 5 9 (2 H , brs), 3.75 (2H, s), 4.16 (2H, q, J = 6.5 Hz), 7.22 (2H, d , J = 5.9Hz). LC/MS [Condition 1]: Hold time 2.88 minutes; m/z 58 8.1 [M + H]+ (-698- 201211053 ESI positive ion mode), m/z 632.2 [M + HCOO]- (ESI negative ion mode) [化7 2 0]

F Example 424

4-((11*,41*)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-oxo-3,8-diazo snail [4.5] Manufacture of methyl decyl-3-yl]methyl}cyclohexanecarbonyl)-1,4-diazacycloheptane-1-carboxylate (Compound No. 424) substituted 6-(piperidin-4 -oxy)nicotinonitrile hydrochloride, substantially the same reaction as in Example 4〇2, except that the 1,4-diazacycloheptane-1-carboxylic acid methyl hydrochloride obtained in Reference Example 349 was used. The title compound (42 mg, quantitative) was obtained as white powder. ^-NMRCSOOMHz ' CD C13) δ : 1 . 0 3 (2 H, q , J = 1 1 . 6 Η z), 1 · 4 2 -1.6 8 (3H, br m), 1.6 7- 1.98 ( 1 0H , br m), 2.40 (lH, tsJ = 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]: Hold time 2.55 minutes; m/z 588.1 [M + H]+ (ESI positive ion mode), m/z 632.2 [M + HCOO]- (ESI negative ion mode) -699- 201211053 【化7 2 1 ]

Example 425

2-(( lr,4r)-4-{ [8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-l-oxa-3,8-diazo snail [4.5 Manufacture of methyl decyl-3-yl]methyl}cyclohexanecarbonyl)-1,2,5-oxadiazepine-5-carboxylate (Compound No. 425) Substituted 6-(piperidine- The 4-oxy)nicotinonitrile hydrochloride was substantially the same as that of Example 402 except that 1,2,5-oxadiazepine-5-carboxylic acid methyl hydrochloride obtained in Reference Example 307 was used. The title compound (19 mg, yield 48%) was obtained as white powder.

'H-NMR (300 MHz &gt; CDCl3) lH-NMR (CDC13) 6: 1.05 (2H, q, J = l 1.9 Hz), 1. 3 8- 1.66 (4H, br m), 1.6 8 - 2.04 (8 Η, brm), 2.63(4H, br s), 3.09(2H,d,J = 7.4Hz), 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]: Hold time 2.69 minutes; m/z 590.0 [M + H]+ (ESI positive ion mode), m/z 634.2 [M + HCOO]- (ESI negative ion mode) twenty two】

8 -700- 201211053 Example 4 2 6 3,5-Difluoro-4-[(3-{[(1!*,4〇-4-(4-nicotiniumpiperidin-1-carbonyl)cyclohexyl) Manufacture of methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-yl)methyl]benzonitrile (Compound No. 426) Substituted 6-(piperidine) -4-oxy)nicotinonitrile hydrochloride was obtained by substantially the same reaction as in Example 402 except that piperidin-4-yl(pyridin-3-yl)methanone hydrochloride (commercially available) was used. Compound (3 6 mg, yield 87%) of white powder

'H-NMRpOOMHz, CDCl3) S: 1.04 (2H, q, J = 11.6 Hz), l_45-1.67 (4H, br m), 1.68- 1.85 (7H, br m), 1.86-2.01 (4H , br m), 2.46 (lH, t, J = 1 1.9 Hz), 2.63 (4H, br s), 2.82 ( 1 H, t, J = 1 1 · 4 Ηζ), 3.09 (2H, d, J = 7.4) Hz), 3.13-3.28 (1 H, br m), 3.22 (2H, s), 3.48 (lH, tt, J = 10.6, 4.1 Hz), 3.75 (2H, s), 3.99 (lH, d, J = 13.9 Hz), 4.6 1 (lH, d, J = 14.3 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.45 (lH, dd, J = 8.2, 4.5 Hz), 8.22 (lH, dt , J = 7.9, 1.9 Hz), 8.80 (lH, dd, J = 4.9, 1.6 Hz), 9.15 (lH, d, J = 1.6 Hz)

LC/MS [Condition 1]: Hold time 2.65 min; 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) [Chemical 7 2 3]

-701 - 201211053 Example 427 4-[6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4·5 Manufacture of decane-3-yl}methyl)nicotinylsulfanyl]piperazine-1-carboxylic acid tert-butyl ester (Compound No. 427) Substituted tetrahydrofurfurylamine using piperazine-1-carboxylic acid The title compound (20 mg, yield 81%) of a yellow amorphous material was obtained from the title compound (yield: 81%). H-NMR (300MHz, CDCl3) 5: 1.47 (9H, s), 1.67- 1.87 (2H, br m), 1.9 1-2.05 (2H, br m), 2.5 5 (4 Η, brs), 3.2 9 - 3.6 1 (6 Η, brm), 3.35 (2H, s), 3.5 7 (2H, s), 3.74 (2H, s s), 4.5 7 (2H, s), 7.3 7 ( 1 H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (lH, dd, J = 8.0, 2.2 Hz), 8.59 (lH, d, J) = 2.0Hz). LC/MS [Condition 1]: Hold time 3.16 min; 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) 【化7 2 4】

Reference Example 428 3-{[(11&quot;,4〇-4-(1,2,5-oxadiazepine-5-carbonyl)cyclohexyl]methyl}- 8-[4-(trifluoromethyl) Benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one-702- 201211053 Preparation of ditrifluoroacetate salt 5-[(lr) obtained in Example 3 08 , 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4_5]decane-3-yl} Methyl)cyclohexanecarbonyl]-1,2,5-oxadiazepine heptane-2-carboxylic acid tert-butyl ester (49 mg, 0.077 mmol) dissolved in trifluoroacetic acid (1.0 mL) The mixture was stirred for 1 hour, and the title compound was obtained (yield: m.

LC/MS [Condition 1]: Hold time 2.21 minutes; m/z 53 8.9 [M + H]+ (ESI positive ion mode), m/z 582.9 [M + HCOO] _ (ESI negative ion mode) [Chem. 7 2 5 ]

Example 4 2 8 Φ 5-[(11*,4〇-4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-weight Azaspiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]-I,2,5-oxadiazepine heptane-2-carboxylic acid methyltrifluoroacetate (Compound No. 42 8) For the production of 3-{[(lr,4r)-4-(l,2,5-oxadiazepine-5-carbonyl)cyclohexyl]methyl}-8-[4- (Trifluoromethyl)benzyl]-l-oxo-3,8-diazospiro[4.5]decane-2-one ditrifluoroacetate (59 mg, 0.077 mmol) dissolved in chloroform (3. Triethylamine (0.054 mL, 0.39 mmol) and methyl chloroformate (12 mL, 0.012 mL) were added at 0 ° C, and mixed at room temperature for 1 hour. To the obtained reaction mixture was added chloroform (2) .OmL) -703- 201211053 The organic layer was separated with a 1.0 M aqueous citric acid solution (0.38 mL) and water (2.0 mL). The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The title compound (39 mg, yield: 84%) was obtained as a colorless crystals. </RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; ,br m),l .69- 1 .88(4H,br m), 1.96-2.1 1 (2H, br m), 2.26-2.50 (3H, br m), 2.98-3 . 1 6 (2H, br m), 3.1 0 (2H, d, J = 7.4 Hz), 3.3 6 ( 2 H, 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). 1 3 .87 (1 H, br s). LC/MS [Condition 1]: Hold time 2.88 minutes; m/z 597.0 [M + H]+ (ESI positive ion mode), m/z 641.1 [M + HCOO]- (ESI negative ion mode) 7 2 6]

Example 4 2 9 (lr,4r)-4-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-oxo-3,8-diazo snail [4.5] Manufacture of decyl-3-yl]methyl}-N-(3-cyanobenzyl)cyclohexanecarbamamine (Compound No. 429) substituted 6-(piperidin-4-oxy) Nicotinic acid hydrochloride, using 3-(aminomethyl)benzonitrile hydrochloride (manufactured according to the method described in WO200 7/002313), substantially the same reaction as in Example 402 except that -704-201211053 The title compound (13tng, yield 50%) was obtained as white solid.

丨H-NMR (300MHz, CDCl3) 5: 1.02 (2H, qd, J = 12.3, 2.9 Hz), 1.52 (2H, qd, J = 13.1, 3.3 Hz), 1.59-1.64 (lH, m), 1.69- 1.84(4H,m), 1.86- 1.99(4H,m),2.09(lH,tt,J = 12.3,3.7Hz),2.54-2.67(4H, m),3.09(2H,d,J = 7.4Hz) , 3.22 (2H, s), 3.75 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 5.87 (lH, t, J = 5.7 Hz), 7.22 (2H, d, J = 5.9 Hz) , 7.39-7.60 (4H, m). LC/MS [Condition 1]: Hold time 2.86 min; m/z 561.8 [M + H]+ (ESI positive ion mode), m/z 560.0 [MH]- (ESI negative ion mode) [Chem. 7 2 7 】

Example 430 3,5--Fluoro-4-({3-[((lr,4r)-4-{4-[4-(methyl))benzylidene]piperidin-1-carbonyl Manufacture of cyclohexyl)methyl]-2-oxo-1-oxo-3,8-diazospiro[4 5]decane-8-yl}methyl)benzonitrile (Compound No. 430) -(piperidin-4-oxy)nicotinonitrile hydrochloride, substantially using 4-[4-(methylsulfonyl)benzylidene]piperidine hydrochloride obtained in Reference Example 3 67_2 The title compound (20 mg, yield: 95%) was obtained as white solid. -705- 201211053 1H-NMR (300MHz, CDCl3) 6:1.04 (2H,q,J=i. 1.-9 Hz), 1.47 -1.70 (4H,m), 1.70- 1.87 (7H,m), 1.88 - 1.99(4H,m), 2.46(lH,tt,J = 10.0,3.3Hz),2.54-2.71(4H,m),2.83(lH,t,J=11.9Hz),3.09( 2H,d,J = 4_6Hz), 3.10(3H, s), 3.22 (lH, t, J = 12.2Hz), 3.23(2H, s), 3.51 (lH, tt, J=ll.l, 3.6Hz), 3.75 (2H, s), 3.99 (lH, d, J = 14.5 Hz), 4.60 (lH, d, J = 13.5 Hz), 7.23 (2H, d, J = 6.3 Hz), 8.07 (2H, d, J = 8.9 Hz) , 8.1 1 (2H, d, J = 8.9Hz). LC/MS [Condition 1]: Hold time 3.08 min; m/z 696.8 [M + H]+ (ESI positive ion mode), m/z 740.9 [M + HCO〇r (ESI negative ion mode) 2 8]

Reference Example 43 1-1 6-[(1,3-dioxaisoindan-2-yl)methyl]nicotinic acid ethyl was produced as a 6-(hydroxymethyl) smoke obtained in Reference Example 111_2 A solution of ethyl alkaliate (3.62 g, 20 mmol), triphenylphosphine (6.30 g, 24 mmol) and phthalimide (3_53 g, 24 mm) in tetrahydrofuran (10 mL) at 〇 ° C A toluene solution of isopropyl diazodicarboxylate (1.9 M, 12.70 mL, 24 mmol) was added dropwise, and stirred at room temperature for 30 minutes. After the completion of the reaction, water was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with a saturated aqueous solution of manganese chloride and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: ) a white solid. 1H-NMR (300MHz, CDCl3) 6: 1.38 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.07 (2H, s), 7.3 5 (lH, d, J = 8.3 Hz), 7.73-7.79 (2H, m), 7.87-7.92 (2H, m), 8.25 (lH, dd, J = 8.3, 2.2 Hz), 9.12 (lH, d, J = 1.4)

Hz).

LC/MS [Condition 1]: Hold time 3.97 minutes ESI positive ion mode) m/z3 1 0.9[M + H]+ (【化 7 2 9】

Reference Example 431-2 Preparation of 6-[(t-butoxycarbonylamino)methyl]nicotinic acid ethyl 6-[(1,3-dioxaisoindene-2-) obtained above A solution of ethyl (meth) nicotinic acid ethyl ester (2.58 g, 8.32 mm 〇l) in ethanol (30 mL) was added to hydrazine monohydrate (807·50 μί, 1 6.65 mmoL) and refluxed for 1 hour. After cooling, dichloromethane was added to the reaction solution to remove insoluble matter, and the filtrate was evaporated under reduced pressure. Dichloromethane was added to the obtained residue, and the insoluble material was separated by filtration. The filtrate was evaporated under reduced pressure to give a white solid. To the obtained white solid solution of dichloromethane (10 μm L), di-tert-butyl dicarbonate-707-201211053 (2.18 g, 9.99 mmol) was added, and the mixture was stirred at room temperature for 1 minute. After the completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystalsssssssssssssss %) of a white solid. LC/MS [Condition 1]: Hold time 3.87 minutes; m/z 280.9 [M + H]+ (ESI positive ion mode) [Chem. 7 3 0]

Reference Example 4 3 1 - 3 [5-(Hydroxymethyl)pyridin-2-yl]methylcarbamic acid tert-butyl ester was produced in the above-obtained 6-[(t-butoxycarbonylamino) A Sodium borohydride (0.19 g, 4.0 mm 〇L) was added to a solution of nicotinic acid ethyl ester (0.28 g, 1.0 mmol) in ethanol (4.0 mL) and refluxed for 30 min. After the end of the reaction, water and 1 M hydrochloric acid were added to make it acidic. After neutralizing with a saturated aqueous sodium hydrogencarbonate solution, ethyl acetate was evaporated. The obtained organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 'H-NMR (300MHz, CDCl3) 6: 1.45 (9H, s), 4.36 (2H, brs), 4.67 (2H, brs), 5.69 (lH, brs), 7.24 (lH, d, J = 8.0 Hz) , 7.67 (lH, d, J = 6.6 Hz), 8.38 (lH, s). -708- 201211053 LC/MS [Condition 1]: Hold time 0.61 min; m/z 23 9.0 [M + H]+ (ESI positive ion mode) [Chem. 7 3 1]

Reference Example 4 Preparation of 3 1-4 (3-cyanopyridin-2-yl)methylcarbamic acid tert-butyl ester [5-(Hydroxymethyl)pyridin-2-yl]methylamine obtained above A solution of tert-butyl carboxylic acid (94.70 mg, 0.40 mmol) in chloroform (2.0 mL) was added to manganese dioxide (〇.17 g, 2.0 mmoL), and refluxed for 30 minutes. After the reaction was completed, it was filtered through celite, and the filtrate was concentrated. Hydroxylamine hydrochloride (1 3 8.98 mg, 2.0 mmol) and pyridine (321.90 μΙ^, 4.0 mmol) were added to the obtained liquid ethanol solution (3.0 mL), and refluxed for 10 minutes. After cooling, the solvent was saturated, water and ethyl acetate were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and evaporated evaporated evaporated. To the obtained white solid and triethylamine (116.2 (^L, 1.2 mm 〇l) in dichloromethane (3.0 mL), methanesulfonyl chloride (61.9 (^1^, 0.80111111〇1) 0° (: After slowly adding, refluxing was carried out for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [developing solvent: hexane/ethyl acetate = 1 / 1] After purification, the title compound (7 1 · 30 mg, yield 76%) was obtained as colorless liquid - 709-201211053 1H-NMR (300 MHz, CDCl3) 8: 1.46 (9H, s), 4.5 1 (2H , d, J = 5.8 Hz) &gt; 5.47 (lH, s), 7.43 (lH, dd, J = 8.2, 0.7 Hz), 7.93 (lH, dd, J = 8.2, 2.1 Hz), 8.82 (l H ,d,J = 〇.7Hz) LC/MS [Condition 1]: Hold time 3.44 minutes; m/z234.0[M + H]+ (ESI positive ion mode) [Chem. 7 3 2 ] fi Mkl

Nh2 2HCI

Reference Example 4 Preparation of 3 1 -5 6-(aminomethyl)nicotinonitrile dihydrochloride (3 -Cyanopyridin-2-yl)methylcarbamic acid tert-butyl ester (71.30) A 4 M hydrogen chloride-dioxane solution (1.0 mL) was added to a solution of 1,4-dioxane (1· 〇m L) in mg, 0.30 mmol, and stirred at room temperature for 1 hour. After the reaction, the precipitated solid was filtered to give the title compound (37.5 Omg, yield 59%) as a white solid. φ LC/MS [Condition 1]: Hold time 0.47 min; m/zl 34.0 [M + H]+ (ESI positive ion mode) [Chem. 7 3 3]

8 -710- 201211053 Example 4 3 1 (11*,4〇-;1^-[(5-cyanopyridin-2-yl)methyl]-4-({2- sideoxy-8-[4 Manufacture of -(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 431)

Substituting (2-fluoropyridin-4-yl)methylamine, substantially the same reaction as in Example 395 except that 6-(aminomethyl)nicotinonitrile dihydrochloride obtained in Reference Example 431-5 was used. The title compound (23 mg, yield 47%) was obtained as a colourless liquid. ^-NMRCSOOMHz ' CDC13)5:1.05(2H,dq,J = 2.9,1 2.7Hz), 1.43-1.68 (3H,m),1.72-1.86(4H,m),1.88-2.03(4H,m) , 2.18 (lH, tt, J = 12.3, 3.3 Hz), 2.5 3 - 2.5 6 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.58 (2H, s), 4.6 1 (2H, d, J = 5.3 Hz), 6.7 1 (lH, t, J = 5.3 Hz), 7.39 (2 H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.92 (lH, dd, J = 8.2, 2.0 Hz), 8.80 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 2.92 minutes; m/z 569.7 [M + H]+ (ESI positive ion mode) [Chem. 7 3 4]

Reference Example 432-1 4-[1·(1,3-Dioxaisoindan-2-yl)ethyl]benzonitrile Production -711 - 201211053 Substituted 6-(hydroxymethyl)nicotinic acid The ethyl group was subjected to the same reaction as in Reference Example 431-1 except that 4-(1-hydroxyethyl)benzonitrile (synthesis by the method described in 73 5.90 mg, 5.0 mmol, W02006060461) was used. Compound (977.70 mg, 71% yield) as a white solid. 1H-NMR (300MHz, CDCl3) 5: 1.93 (3H, d, J = 7.4 Hz), 5.59 (lH, 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]: Hold time 3.89 minutes; m/z 276.9 [M + H]+ (ESI positive ion mode) [Chemical 7 3 5] \ )-NH2 h3c Reference Example 4 3 2 - 2 4- (1-Aminoethyl)benzonitrile was produced as described above for 4-[1-(1,3-dioxaisoindan-2-yl)ethyl]benzonitrile (276.30 mg, 1.0) Ethyl alcohol solution (5.0 mL) was added with hydrazine monohydrate (48.50 pL, 1.0 MmmoL) and refluxed for 1 hour. After cooling, chloroform was added to the reaction solution, and the insoluble material was separated by filtration, 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), and saturated aqueous ammonia was added to the aqueous layer to make the solution alkaline (pH &gt; The extraction was carried out twice with chloroform. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. NMR (300MHz, CDCl3) 6: 1.38 (3H, dd5J = 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]: Hold time 0·50 minutes; m/zi46_9[M + H]+ (ESI positive ion mode)

[化7 3 6]

Example 432 (lr, 4〇-N-[l-(4-cyanophenyl)ethyl]-4-({2- sideoxy-8-[4-(trifluoromethyl)benzyl] Manufacture of -1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 43 2)

Substituting (2-fluoropyridin-4-yl)methylamine, the same reaction as in Example 3 95 was carried out except that 4-(1-aminoethyl)benzonitrile obtained in Reference Example 432-2 was used. The title compound (1 1 mg, yield 21%) as a colorless solid, j-NMR, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, 3H,d,J = 7.0Hz), 1.66-2.00(8H,m), 2.10(lH,tt,J=11.9,3.3Hz),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 (lH, quin, J = 7.0 Hz), 6.14 (lH, d, J = 7_4 Hz), 7.37-7.48 (4H, m), 7.53 - 7.65 (4H, m). -713- 201211053 LC/MS [Condition 1]: Hold time 3.22 minutes; m/z 582.8 [M + H]+ (ESI positive ion mode), m/z 627.0 [M + HCOO]- (ESI negative ion mode ) 【化7 3 7】

Reference Example 4 3 3 -1 Preparation of 5-[(1,3-dioxaisoindan-2-yl)methyl]pyrazine-2-carboxylic acid ethyl 5-(bromomethyl)pyridinium Ethyl azine-2-carboxylate (2.45 g, 10 mmol, synthesized by the method described in WO 2005018557) and potassium phthalate (1.85 g, 10 mmol) in N,N-dimethylformamide After the reaction was completed, the reaction mixture was concentrated under reduced pressure. ethyl acetate and water were evaporated, and the organic layer was evaporated. Ethyl alcohol (50 mL) was added to the residue, and the mixture was evaporated to dryness. NMR (300MHz, CDCl3) 6: 1.43 (4H, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 5.13 (2H, s), 7.7 6-7.7 8 (2H, m), 7.90-7.92 (2H, m), 8.76 (l Η , s), 9.17 (lH, s) LC/MS [condition 1]: hold time 3.64 min; m/z 311.8 [M + H] + ( -714 - 201211053 ESI positive ion mode) [Chem. 7 3 8]

Reference example 4 3 3 - 2

Preparation of 5-(aminomethyl)pyrazine-2-carboxylic acid ethyl 5-[(1,3-dioxaisoindan-2-yl)methyl]pyrazine-2 obtained above A solution of ethyl carboxylate (1.56 g, 5.0 mmol) in ethanol (20 mL) was added with hydrazine monohydrate (48 5 μί, 10·0 ηηηη1) and refluxed for 1 hour. After cooling, dichloromethane was added to the reaction solution, and the insoluble material was separated by filtration, and the filtrate was evaporated under reduced pressure. Methylene chloride was added to the residue, and the insoluble material was separated by filtration. The filtrate was evaporated under reduced pressure to give the title compound (716.70 mg, yield: 80%). 1H-NMR (CDCl3) 5: 1.46 (3H, t, J = 7.1 Hz), 4.14 (2H, s), 4.5 1 (2H, q, J = 7.1 Hz), 8.73 (lH, d, J = 1.4 Hz) ), 9.24 (lH, d, J = 1.4 Hz). [化 7 3 9]

Example 433 -715- 201211053 5-{[(11:,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine]methyl}pyrazine-2-carboxylic acid ethyl ester (Compound No. 43 3) Substituted (2-fluoropyridine 4-methyl)methylamine was subjected to the same reaction as in Example 3 95 except that the ethyl 5-(aminomethyl)pyrazine-2-carboxylate obtained in Reference Example 43 3-2 was used. Compound (llmg, yield 21%) of colorless liquid. 'H-NMRCSOOMHz, CDC13) 6: 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 (lH, tt, J = 11.9, 3.7 Hz), 2.58 (4H, br m) , 3.12 (2H, d, J = 6.5 Hz), 3.28 (2H, s), 3.59 (2H, s), 4.52 (2H, q, J = 7.8 Hz), 4.70 (2 H, d, J = 5.3 Hz) ), 6.58 (lH, brs), 7.45 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 7_8 Hz), 8.70 (lH, s), 9.23 (lH, s). LC/MS [Condition 1]: Hold time 3.04 minutes: m/z617_7[M + H]+ (ESI positive ion mode) [Chem. 7 4 0]

Reference Example 434-1 Preparation of 1,1,1-trifluoro-2-(4-fluorophenyl)-3-nitropropan-2-ol from 1-bromo-4-fluorobenzene (5.25 g, 30 mmol) A tetrahydrofuran solution (50 mL) was slowly added dropwise at -78 °C to a hexane solution of η-butyllithium (2.66 M, 12.4 mL, -716-201211053).

33mmol). After stirring at -7 VC for 30 minutes, ethyl trifluoroacetate (4.64 mL, 45 mmol) was added at -78 ° C and warmed to room temperature. After adding nitromethane (3.25 mL, 60 mmol) to the reaction mixture at room temperature, stirring was carried out for 30 minutes. The reaction solution was poured into 1 M hydrochloric acid (75 mL), and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 1H-NMR (300 MHz, CDCl3) 5: 4.66 (lH, 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 4 Preparation of 3 4 - 2 3-amino-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol The above-obtained 1,1,1-trifluoro- 2-(4-Fluorophenyl)-3-nitropropan-2-ol (6.07 g, 24 mmol) in ethanol (25 mL), 10% by weight of palladium-carbon (1.0 g), under hydrogen atmosphere Stirring was carried out for 16 hours at room temperature. After the reaction was completed, the title compound (4.52 g, yield: 84%) ^-NMRCSOOMHz, CDCl3) 5: 2.97 (lH, d, J = 13.0 Hz), 3.57 (1 H, d, -717 - 201211053 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]: Hold time 0.54 min; m/z 224.0 [M + H]+ (ESI positive ion mode) [Chem. 7 4 2 】

Example 4 3 4 (11*,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo Spiro[4.5]decane-3-yl]methyl}-N-[3,3,3-trifluoro-2-(4-fluorophenyl)-2-hydroxypropyl]cyclohexanecarboxamide Preparation of Compound No. 434) Substituted (2-fluoropyridin-4-yl)methylamine, using 3-aminotrifluoro-2-(4-fluorophenyl)propan-2-ol obtained in Reference Example 434-2, Simultaneous substitution of (lr, 4r)-4-({2- sideoxy-8·[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- 3-yl}methyl)cyclohexanecarboxylic acid, using (lr, 4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)- obtained from Reference Example 398-2 The title was obtained in the same manner as in Example 3 95 except that 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid was obtained. Compound (32 mg, yield 54%) as a colorless solid. 'Η-ΝΜΚ(300ΜΗζ &gt; CDC13) 6: 0.81-1, 02 (2H, m), 1.24-2.07 (12Η, m), 2.5 3-2.71 ( 4H, br m), 3.03 (2H, d, J = 6.1 Hz), 3.23 (2H, s), 3.75 (2 Η, s ), 3.78 (lH, dd, J = 13.5, 5.7 Hz), 4.00 (lH, Dt, J = 13.5, 4.1 Hz), 6.13 - 718 - 201211053 6.66 (2H, brm), 7.06 (2H, t, J = 8. 6Hz), 7.23 (2H, d, J = 6.1Hz), 7.57 ( 2H, dd, J = 9.0, 4.9 Hz) LC/MS [Condition 1]: Hold time 3.39 minutes; m/z 652.9 [M + H]+ (ESI positive ion mode), m/z 650.9 [MH]_ (ESI negative ion mode)

[化 7 4 3]

Example 435 4-{[3-({(11*,4〇-4-[3-(4-cyanophenoxy)azetidin-1-carbonyl]cyclohexyl}methyl)-2 -Side-oxygen-poxa-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 43 5) Pyridin-4-yl)methylamine, using 4-(azetidin-3-yloxy)benzonitrile obtained in Reference Example 3 8 3 -2, while substituting (ir, 4r)-4-({2 - side ^ Oxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid Using (lr, 4r)-4_ {[8-(4-cyano-2,6-fluorobenzyl)-2-oxo-1-che-3,8 obtained in Reference Example 3 98-2 - The same reaction as in Example 3 5 5 except for the diazaspiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid afforded the title compound (1 _ 2 mg, yield 3). 0%) of a colorless liquid. j-NMROOOMHz, CDCl3) 6: 1.0 2 (2H, q, 1 = 12.7 Hz), 1.43-1.6 6 (3H, m), 1.70-1.87 (6H, m), 1.87- 1.98 (2H, m), 2.14 (lH, tt, J = 11.4, .λ 2.9 Hz), 2.6 1- 2.64 (4H, br m), 3.09 (2H, d, J = 6.5 Hz), 3.22 (2H, s ) -719- 201211053 , 3.76(2H, s), 4.06 (lH, dd, J = 4.1, l 1.0Hz) 4.21 (lH, dd, J = 9.0, 3.3 Hz), 4.41 (lH, dd, J = li. 4j6.lHz), 4.55 (lH, dd, J = 9.0, 6.5 Hz), 4.94 - 5.05 (lH, m ), 6.82 (2H, d, J = 9.4 Hz), 7.23 (2H, d, J = 6.5 Hz), 7.62 (2 H, d, J = 8.6 Hz). LC/MS [Condition 1]: Hold time 3.16 min; m/z 603.9 [M + H]+ (ESI positive ion mode), m/z 648.0 [M + HCO〇r (ESI negative ion mode) 4 4]

Example 436 4-{[3-({(11&quot;,4〇-4-[3-(3-Cyanophenoxy)azetidin-1-carbonyl]cyclohexyl}methyl)-2 Preparation of 2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 43 6) Fluoridin-4-yl)methylamine, using 3-(azetidin-3-yloxy)benzonitrile hydrochloride obtained in Reference Example 390-2, while substituting (lr, 4r)-4-( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl)cyclohexane For the alkanoic acid, (11:,41*)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1 was obtained using Reference Example 3 98-2. - The same reaction as in Example 3 95 was carried out in the same manner as the compound of the compound (3 mg). Rate 72%) of a colorless solid. 'H-NMRCSOOMHz ' CDC13) 6: 1 .02 (2H,q,J=l 1 .9Hz), 1.43-1.66 -720- 201211053 (3H,m),1.70-1.87 ( 6H,m), 1.87- 1.99(2H,m), 2.07-3.19(4H,br m), 2.15(lH,tt,J=ll.9,3.3Hz), 3.10(2H,d,J = 7.4Hz ), 3.23 (2H, s), 3.76 (2H, s), 4.05 (lH, dd, J) = 3.7, 11.0 Hz), 4.20 (lH, dd, J = 8.6, 3.3 Hz), 4.41 (lH, dd, J = l〇_6, 6.1 Hz), 4.57 (lH, dd, J = 9.0, 6.1 Hz) ), 4.91 -5.03 (lH, m), 6.98-7.05 (2H, m), 7.24 (2H, d, J = 6.1 Hz), 7.33 (lH, d, J = 7.4 Hz), 7.43 (lH, t, J = 7.8 Hz).

LC/MS [Condition 1]: Hold time 3·21 min; m/Z6〇3.9 [M + H]+ (ESI positive ion mode), m/z 648.1 [M + HCO〇r (ESI negative ion mode)

[化 7 4 5] F F

Reference Example 4 Preparation of 3 7 -1 1,1,1-trifluoro-2-(6-methoxypyridin-3-yl)-3-nitropropane-2-ol

The title compound (2.03 g, yield: 91%) was obtained as a colorless compound, m. liquid. 1H-NMR (3 00MHz, CDCl3) 5: 3.96 (3H5s), 5.04 (2H &gt; dd, J = 2 1.3, 13.2 Hz), 6.82 (lH, d, J-9.OHz), 7.78 (lH, dd, J = 9.0, 3.0 Hz), 8.38 (1 H, d, J = 3.0 Hz). -721 - 201211053

Reference Example 4 Production of 3 7 - 2 3 -aminotrifluoro 2 -(6-methoxypyridin-3-yl)propan-2-ol Substituted hydrazine, 1,1-trifluoro-2-(4- Fluorophenyl)-3-nitropropan-2-ol, using 1,1,1-trifluoro-2-(6-methoxypyridin-3-yl)-3-nitropropane-2 obtained above The title compound (1.52 g, yield 84%) was obtained as a colorless liquid. LC/MS [Condition 1]: Hold time 0.54 min; m/z 237.0 [M + H] + (ESI positive ion mode) [Chem. 7 4 7]

Example 437 (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane -3-yl}methyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxypyridin-3-yl)propyl]cyclohexanecarboxamide (compound The production of the number 43 7) was substituted for 4-(3-fluorophenylsulfonyl)piperidine hydrochloride, and the 3-amino-1,1,1-trifluoro-2- group obtained in Reference Example 437-2 was used. 6-methoxypyridin-3-yl)propane-722- 201211053

The title compound (5.1 mg, yield 9.0%) was obtained as a colorless solid. W-NMROOOMHz, CDC13) 5: 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 (lH, dd, J = 14.6, 6.5 Hz), 3.93 (3H, s), 4.00 (lH, dd, J =14.6, 5.4 Hz), 6.74 (lH, d, J = 8.5 Hz), 7.03 (lH, t, J = 6.1 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J) = 7.8 Hz), 7.8 1 (lH, dd, J = 8.5, 2.7 Hz), 8.34 (lH, d, J = 2'7 Hz). LC/MS [Condition 1]: Hold time 3.32 minutes; m/z 672.8 [M + H]+ (ESI positive ion mode) [Chem. 7 4 8]

Example 438 (11:,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]癸Alkyl-3-yl}methyl)-&gt;^-[3,3,3-trifluoro-2-(4-fluorophenyl)-2-hydroxypropyl]cyclohexanecarboxamide (Compound No. 438 The production of 4-(3-fluorophenylsulfonyl)piperidine hydrochloride was replaced by 3-amino-1,1,1-trifluoro-2-(4-) obtained in Reference Example 43 4-2. A yellow liquid of the title compound (28 mg, yield: 48%) was obtained from the compound obtained in the same manner as in Example 3 93, except for fluorophenyl)propan-2-ol. -723-201211053 'H-NMR (300 MHz ' CDC13 5:0.80-1 .〇1 (2H,m), 1.24- 1.46(2H 46-1.87(7H,m),l.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 (lH, dd, J = 6.5, 14.7 Hz), 4.00 (lH, dd, J = 5.8, 14.7 Hz), 6.27 (lH, br s), 6.59 (l H, br s ), 7.06 (2H, t, J = 8.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.5 1- 7.62 ( 4H,m) o LC/MS [Condition 1]: Hold time 3.51 minutes; m/z 659.8 [M + H]+ (ESI positive ion mode) [Chem. 7 4 9]

Reference Example 4 Production of 3 9 -1 2-(6-chloropyridin-3-yl)-1,1,1-trifluoro-3-nitropropan-2-ol Substituted 1-bromo-4-fluorobenzene, A yellow liquid of the title compound (4.93 g, yield: 67%) was obtained. 1H-NMR (300MHz, CDC13) 5: 4.96 (1H, brs), 5.06 (2H, s) s 7.45 (1H, d, J = 8.4 Hz), 7.92 (lH, dd, J = 8.4, 2.8 Hz), 8.62 (lH, d, J = 2.8 Hz) ο LC/MS [Condition 1]: Hold time 3.60 min; m/z 270.9, 272.8 [Μ + Η] + (ESI positive ion mode) -724- 201211053 7 5 0]

ΝΗ 2 Reference Example 4 3 9 - 2 3-Amino-1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol Manufactured from the above 2-(6-chloropyridine- a solution of 3-yl)-1,1,1-trifluoro-3-nitropropan-2-ol (2.53 g, 9.39 mmol) in tetrahydrofuran (20 mL), triethylamine (2.6.11.11. 〇 1) With 10% by weight of palladium-carbon (0.60 g), it was stirred at room temperature for 24 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Purif-Pack 8 ΐ 60 μιη, developed solvent: ethyl acetate / methanol / triethylamine = 9 / 1 / 1). , yield 47%) of white amorphous material. 1H-NMR (300MHz, CDCl3) S: 3.01 (1H, d, J = l 3.5Hz), 3.62 (1H, d, ru J = 13.5 Hz), 5.84 (lH, brs), 7.34 (lH, dd, J = 8.1, 4.8 Hz), 7.95 (lH, d, J = 8.1 Hz), 8.6 1 (lH, d, J = 4.8 Hz), 8.79 (lH, s). 【化7 5 1】

Example 4 3 9 (lr,4r)-4-({2-Sideoxy-8-(4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo-725- 201211053 Spiro[4·5]decane-3-yl}methyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(pyridin-3-yl)propyl]cyclohexaneformamidine Preparation of the amine (Compound No. 43 9) Substituting 4-(3-fluorophenylsulfonyl)piperidine hydrochloride, using 3-aminotrifluoro-2-(pyridine-3) obtained in Reference Example 43 9-2 The title compound (22 mg, yield 38%) was obtained as a colorless solid. 'H-NMR (3 00 MHz ' CDC13) 5: 0.79-1.00 (2H, m), 1.22- 1.42 (2H, m), 1.45-1.61 (lH, 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 = 7.2Hz), 3.26(2H,s),3.58(2H,s), 3.84(lH,dd,J =15.0, 6.5 Hz), 4.08 (lH, dd, J = 15.7, 5.8 Hz), 6.66-6.90 (1 H, m), 7.3 6 (lH, dd, J = 4.8, 7.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.5 8 ( 2H, d, J = 8.2 Hz), 8.04 (1 H, d, J = 7.5 Hz), 8.54-8.60 (lH, m), 8.7 1 (lH, s) . LC/MS [Condition 1]: Hold time 2.97 minutes; m/z 642.7 [M + H]+ (ESI positive ion mode) [Chem. 7 5 2]

Reference Example 4 Preparation of 4 0 -1 5-[(1,3-dioxaisoindan-2-yl)methyl]methylpyridine nitrile Substituted 5-(bromoethyl)pyrazine-2-carboxyl The acid ethyl group was reacted in the same manner as in Reference Example 43 3 -1 except for the 5-(bromomethyl)methylpyridinecarbonitrile obtained in Reference Example 38 to give the title compound (0. 63%) of -726- 201211053 white powder. , H-NMR (CDCl3) 6: 4.92 (2H, s), 7.66 (lH, d, J = 8.6 Hz), 7.7 6 (2H, dd, J = 5.3, 2.9 Hz), 7.88 (2H, dd, J = 5.3, 2.9 Hz), 7.9 1 (lH, dd, J = 8.6, 2.0 Hz), 8.81 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.58 min; m/z 263.9 [M + H]+ (E S I positive ion mode) [Chem. 7 5 3]

Reference Example 4 Production of 4 0 - 2 5-(aminomethyl)methylpyridine nitrile Substituted 5-[(1,3-dioxaisoindan-2-yl)methyl]pyrazine-2- The carboxylic acid ethyl group was substantially carried out in the same manner as in Reference Example 4 except that 5-[(1,3-dioxaisoindan-2-yl)methyl]methylpyridinecarbonitrile obtained in Reference Example 440-1 was used. The title compound (10 mg, yield 12%) was obtained as a pale yellow oil. 1H-NMR (CDCl3) 6: 4.02 (2H, s), 7.68 (1H, d, J = 8.0 Hz), 7.86 (lH, dd, J = 8.0, 2.0 Hz), 8.68 (lH, d, J = 2) .〇Hz). LC/MS [Condition 1]: Hold time 〇 49 minutes; m/zl33.8[M + H]+ (ESI positive ion mode) -727- 201211053 【化7 5 4】·

Example 440 (lr,4r)-N-[(6-Cyanopyridin-3-yl)methyl]-4-({2-o-oxo- 8-[4-(trifluoromethyl)benzyl) Preparation of 1-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 440) Substituted piperidine, using Reference Example 440-2 The title compound (1 1 mg, yield 26%) was obtained as a white powder, which was obtained in the same manner as in Example 16 except for 5-(aminomethyl)methylpyridonitrile. 1H-NMR (CDCl3) 5: 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 (l H, tt, J = 12.2, 3.3 Hz), 2.44-2.64 (4H, br m ) , 3.0 9 (2 Η, d, J = 7.3 Η z ), 3.26 (2H, s), 3.58 (2H, s), 4.50 (2H, d, J = 5.9 Hz), 6.3 7 (lH, t, J- 5.9 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.65 (lH, d, J = 7.9 Hz), 7.76 (1 H, dd, J = 7.9, 2.1 Hz), 8.62 (1 H, d, J = 2.1 Hz) ) LC/MS [Condition 1]: Hold 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) [Chem. 7 5 5]

-728- 201211053 Test Example 4 4 1 -1 Preparation of tert-butyl 4-(4-cyanophenylamino)piperidine-1-carboxylate Substituting 4-(trifluoromethyl)aniline, using 4- The title compound (0.84 g, yield: 56%) was obtained as white powder.

1H-NMR (CDCl3) 6: 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 (lH, 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]: Hold time 4.29 minutes; m/z 246.0 [M-isobutene + H]+ (ESI positive ion mode) [Chem. 7 5 6]

φ Reference Example 441-2 Preparation of 4-(piperidin-4-ylamino)benzonitrile dihydrochloride substituted 4-[4-(trifluoromethyl)phenylamino]piperidine-1-carboxylate The acid tert-butyl ester was substantially the same as that of Reference Example 391-2 except that the 4-butyl 4-(4-cyanophenylamino)piperidine-1-carboxylate obtained in Reference Example 441-1 was used. The reaction gave the title compound (0.73 g,yiel. 1H-NMR (CDCl3) 6: 1.56 (2H, dt, J = 27.0, 12.5 Hz), 1.93 (2H, d, J = 11.2 Hz), 2.89 (2H, q, J = 9.6 Hz), 3.20 (2H, d, J = 11.2 Hz), 3.55 (lH, tt, J = 10.2, 3.6 Hz), 6.63 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 8-729- 201211053 • 92-9.16(2H, br m). LC/MS [Condition 1]: Hold time 0.52 min; m/z 202.1 [M + H]+ (ESI positive ion mode) [Chem. 7 5 7]

Example 441 4-{l-[(lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidin-4-ylamino}benzonitrile (Compound No. 441) Substituted piperidine, using Reference Example 441-2 The title compound (26 mg, yield 51%) was obtained as white powder. , H-NMR (CDCl3) 6: 1.05 (2H, q, J = 11.5 Hz), 1.37 (2H, q, J = 11.3 Hz), 1.46-1.69 (3Hsm), 1.711-1.86 (6Hsm), 1.94 (2H,d,J=13.1Hz), 2.13(2H,d,J=13.9Hz), 2.46(lH,tt,J=U.9,3.3Hz),2.52-2.64 (4H,br m),2.83 (lH,t,J=l 1.9Hz), 3.1 l(2H,d,J = 7.4Hz), 3.19(1 H, t,J=12.7Hz), 3.26(2H,s), 3.48-3.65(lH , m), 3.57 (2H, s), 3.90 ( lH, d, J = 13.9 Hz), 4.12 (lH, d, J = 7.0 Hz), 4.53 (lH, d, J = 13.1 Hz), 6.56 (2H , d, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2 H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.36 minutes: m/z 63 7_8[M + H]+ (-730- 201211053 ESI positive ion mode), m/z 672.2 [M + Cir, 682.0 [M + HCOO] -( ESI negative ion mode) [Chem. 7 5 8]

Reference Example 4 4 2 - 1

Preparation of tert-butyl 4-(3-cyano-4-fluorophenylamino)piperidine-1·carboxylate Substituting 4-(trifluoromethyl)aniline using 5-amino-2-fluorobenzene The title compound (0.73 g, yield 96%) was obtained as white powder. 1H-NMR (CDCl3) 8: 1.22 - 1.42 (2H, m) J 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 (lH, br m), 3.76- 3.92 (1 H, br m), 4.06 (2H, d, J = 12.3 Hz), 6.7 1 (lH, dd, J = 4.9, 3.3

Hz), 6.77 (lH, ddd, J = 9.0, 4.5, 3.3 Hz), 7.00 (1 H, t, J = 8.6 Hz). LC/MS [Condition 1]: Hold time 4.43 min; 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) [Chemical 7 5 9

Reference Example 4 4 2 - 2 -731 - 201211053 Production of 2-fluoro-5-(piperidin-4-ylamino)benzonitrile dihydrochloride substituted 4-[4-(trifluoromethyl)phenyl Amino] piperidine-1-carboxylic acid tert-butyl ester 'T-butyl 4-(3-cyano-4-fluorophenylamino)piperidine-1-carboxylate obtained using Reference Example 442-1 The same reaction as in Reference Example 391-2 was carried out to give the title compound (yield: 63 g, yield: 50%) as white powder. 1H-NMR (DMSO-d6) 5: 1.54 (2H, dq, J = 4.1, l 1.9 Hz), 2.02 (2H, br d, J =1 3.9 Hz), 2.9 6 (2H, q, J = l l .lHz), 3.2 8 (2H, br d, J = 1 2.3 Hz), 3.41 - 3.66 (2H, br m), 6.92-7.00 (2H, m), 7.23 (lH, t, J = 9.8 Hz), 8.79 (2 H, br s). LC/MS [Condition 1]: Hold time 〇·67 min; m/z 220.0 [M + H]+ (ESI. positive ion mode) [Chem. 7 6 0]

Example 44·2 2-Fluoro-5-{1-[(1!*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-) Preparation of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperidin-4-ylamino}benzonitrile (Compound No. 442) substituted piperidine, The same reaction as in Example 16 was carried out except that 2-fluoro-5-(piperidin-4-ylamino)benzonitrile dihydrochloride obtained in Reference Example 442-2 and triethylamine were used to give the title. Compound (36 mg, yield 69%) of white powder. -732 - 201211053

IH-NMR (CDCl3) 5: 1.05 (2H, q, J = 11.5 Hz), 1.33 (2H, q! J = 11 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 (lH, tt, J = 11.5, 2.9 Hz), 2.52-2.63 (4H, br m), 2.83 (lH, t, J = 11.5 Hz) ), 3.11 (2H, d, J = 7.4 Hz), 3.l9 (lH, t, J = 12.7 Hz), 3.26 (2H, s), 3.36-3.52 (lH, m), 3.58 (2H, s) , 3.72 (lH, d, J = 7.8 Hz), 3.90 (lH, d, J = 13.5 Hz), 4.52 (lH &gt; d, J = 13.1 Hz), 6.72 (lH, dd, J = 4.9, 2.9 Hz) , 6.76 (lH, ddd, J = 8.8, 4.1, 2.9 Hz), 7.0 1 (lH, 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]: Hold time 3.44 minutes: m/z 655.8 [M + H]+ (ESI positive ion mode), m/z 690.2 [M + Cl]·, 700.0 [M + HCO〇r (ESI negative ion mode) [Chem. 7 6 1]

Reference Example 443-1 (6-Fluoropyridin-3-yl)methanol was produced by substituting 6-[(t-butoxycarbonylamino)methyl]nicotinic acid ethyl, using 6-fluoronicotinyl aldehyde, The same reaction as in Reference Example 43 1-3 was carried out to give the title compound (0.26 g, yield of 50%) as a colorless oil. 1H-NMR (CDCl3) 6: 4.71 (2H, s), 6.93 (lH, dd, J = 8.2, 2.5 Hz), 7.83 (lH, td, J = 8.2, 2.5 Hz), 8.15 (lH, br s) . LC/MS [Condition 1]: Hold time 〇 74 minutes: m/zi27.8 [M + H]+ (ESI positive ion mode) -733- 201211053 [Chem. 7 6 2]

Reference Example 4 Preparation of 4 3 - 2 2-[(6-fluoropyridin-3-yl)methyl]isoindan-i,3-dione Substituted 6-(hydroxymethyl)nicotinic acid ethyl, The title compound (0.36 g, yield: 69%) was obtained as white powder, which was obtained from the title compound (yield: 69%). , H-NMR (CDCl3) 5: 4.84 (2H, s) 56.89 (lH, dd, J = 8.6, 2.9 Hz), 7.71-7.78 (2H, m), 7.83-7.90 (3H, m), 8.33 (lH) ,d,J = 2.5Hz)» LC/MS[Condition 1]: Hold time 3.64 minutes; m/z256.9[M + H]+ (ESI positive ion mode) [Chem. 7 6 3]

Preparation of NHg Reference Example 443-1 (6-Fluoropyridin-3-yl)methylamine Substituted 5-[(1,3-dioxaisoindan-2-yl)methyl]pyrazine-2-carboxylate The acid ethyl group was substantially carried out in the same manner as in Reference Example 43 3 -2 except that 2-[(6-fluoropyridin-3-yl)methyl]isoindan-1,3-dione obtained in Reference Example 443-2 was used. The same as the -734-201211053-like reaction to give the title compound (24 mg, yield 24%) as a colorless oil, 1H-NMR (CDCl3) 6: 3.89 (2H, s), 6.90 (1H, dd, J = 8.2 , 2.9 Hz) 57.79 (lH, td, J = 8.2, 2.9 Hz), 8.13 (lH, br s). , LC/MS [Condition 1]: Hold time 0.49 minutes; m/zl26_9[M + H]+ (ESI positive ion mode)

【化7 6 4】

Example 4 4 3 (11:,4〇-&gt;^-[(6-fluoropyridin-3-yl)methyl]-4-({2- sideoxy-8-[4-(trifluoromethyl) Manufacture of benzylmethyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbamamine (Compound No. 443)

The title compound (24 mg, yield 53%) was obtained from the title compound (24 mg, yield: 53%). White powder. 1H-NMR (CDCl3) 5: 1.0 1 (2H, dq, J = 3.3, 13.0 Hz), 1.5 0 (2H, dq, J = 3.3, 12.3 Hz), 1.58-1.66 (lH, m), l .70-1.84(4H,m),1.87-1.98( 4H,m),2.08(lH,tt,J = 12.1,3.3Hz),2.47-2.62(4H,br m) ,3.08 (2 H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.43 (2H, d, J = 6.1 Hz), 6.09 (l H, t, J = 6.1 Hz), 6.89 (lH, dd , J = S.652.9Hz), 7.44 (2H, d, J = 8.2Hz), 7.57 (2H, d, J = 8.2Hz), 7.74 (lH, td, J = 8.6, 2.5Hz), 8.11 (lH ,d,J = -735- 201211053 2.5Hz).

LC/MS [Condition 1]: Hold time 3_00 minutes; m/z 562.7 [M + H]+ (ESI positive ion mode), m/z 560.8 [MH]-, 606.9 [M + HCOO]- (ESI Negative ion mode)

Reference Example 444-1 3-{[5-(Ethoxycarbonyl)pyrazin-2-yl]methyl}-2-oxo-1-oxo-3,8-diazospiro[4.5]decane- 8-carboxylic acid tert-butyl ester was produced according to Reference Example 111-1 2-sided oxy-1-oxo-3,8-diazospiro[4.5] brothel-8-carboxylic acid tert-butyl ester (256.30) A solution of mg, 1.0 mmol) in tetrahydrofuran (4.0 mL) was added at a solution of sodium hydride (&gt; 55 wt%, dispersed in mobile paraffin (purchased from Kanto Chemical Co., Ltd.) (43.60 mg, 1.0 mmol) at 〇 °C. Ethyl 5-(bromomethyl)pyrazine-2-carboxylate (245.0711^, 1.〇111111〇1, synthesized by the method described in W020 050 1 8 557), and heated under reflux for 1 hour. After the reaction was completed, a saturated aqueous solution of sodium chloride and water were added, and ethyl acetate was evaporated. The obtained residue was subjected to silica gel column chromatography [manufactured by Zhaoguang Scientific Co., Ltd.

Purification of the title compound (200.96 mg, yield 48%) of white solid - 372 - 201211053 am.丨H-NMR (300MHz, CDC13) 3: 1.44- 1.54 (4H, m), 1.46 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 1.62- 1.72 (3H, m), 1.9 1 -1.96(2H,m), 3.28- 3.32(2H,m), 3.40(2H,s),3.82-3.8 6(2H,m),4.52(2H,q,J = 7.1

Hz), 4.69 (2H, s), 8.72 (lH, s), 9, 26 (lH, s). LC/MS [Condition 1]: Hold time 3.89 minutes; ^4442.8^ + -:1+ (ESI positive ion mode), m/z 418.8 [M-Hr (ESI negative ion mode) [Chem. 7 6 6] 1

Reference Example 444-2 5-{[8-(t-Butoxycarbonyl)-2-oxooxy-1-oxo-3,8-diazospiro[4.5]decane-3-φyl]methyl} Production of pyrazine-2-carboxylic acid in place of 3-{[(lr,4〇-4-(methoxycarbonyl)cyclohexyl]methyl}-2-oxanthoxy-1-oxo-3,8-diazo Spiro[4.5]decane-8-carboxylic acid tert-butyl ester, using 3-{[5-(ethoxycarbonyl)pyrazin-2-yl]methyl}-2- side obtained in Reference Example 444-1 The same reaction as in Reference Example 2-3 was carried out to give the title compound (yield: 24 g, m.p. Yield 79%) of a white powder. 1H-NMR (CDCl3) 5: 1.47 (9H, s) s 1.70 (2H, dddJJ = 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), -737- 201211053 3.78-3.94 (2H, m), 4.72 (2H, s), 6.11 (lH, br s), 8.72 ( lH, s), 9.34 〇H, s). LC/MS [Condition 1]: Hold time 3.52 minutes; m/z 392_9 [M + H] +, 3 3 6.8 [M-isobutene + H] + (ESI positive ion mode), m/z 390.9 [MH ]_ (ESI negative ion mode) [Chem. 7 6 7]

Reference Example 4 4 4 - 3 3-({5-[4-(4-^Benzyl)-piperidin-1-ortyl] indole 嗓-2·yl]methyl}_2-side oxygen-1 -Production of (3r)4{8-(t-butoxycarbonyl)-2- Side-oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarboxylic acid, 5-{[8-(t-butoxy) obtained using Reference Example 444_2 Carboxyl)-2-oxo-oxo-oxa-3,8-diazospirin [4.5] 癸院-3 -yl]methyl}卩比晓-2 -residual acid' simultaneously replaces tetrahydrofurfurylamine, The title compound (54 mg, yield 62%) was obtained from the title compound (yield: 62%). 1H-NMR (CDC13) 6: 1.46 (9H, s), 1.61-1.74 (2H, m), 1.76- 1.98 (6H, m), 3.14 (lH, dt, J = 2.4s12 .3Hz),3.22-3.3 8(3H,m)53.42(2H ,s),3.47-3.6 1 (1 H,m),3.7 1-3.92(2H,br m),4.04-4.1 4(2H,m ), 4.63 201211053 (2H, s), 4.69 (1 H, d, J = l 3.5 Hz), 7.17 (2H, t, J = 8.6 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz), 8.55 (lH, d, J = 1.5 Hz), 8.89 (lH, d, J = 1.5 Hz) LC/MS [Condition 1]: Hold time 4.17 minutes; m/z 580.1 [M-H]·, 626.0 [M + HCO〇r (ESI negative ion mode)

【化7 6 8】

Reference Example 444-4 3-({5-[4-(4-Fluorobenzoyl)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-1-oxo-3,8-weight Manufacture of nitrogen snail [4.5] decane-2-one

3-({5-[4_(4-fluorobenzylidinyl)piperidin-1-carbonyl]pyrazin-2-yl]methyl}-2-oxan-1-one obtained in Reference Example 444-3 Oxy-3,8-diazospiro[4.5] brothel-8-decanoic acid butyl vinegar (54 mg, 0.093 mmol) dissolved in methanol (2 mL) 'Add 10% by mass of hydrogen chloride in methanol at room temperature (0.2 3 m L), and the mixture was stirred for 1 hour at 4 ° C. After the reaction was completed, the reaction mixture was concentrated and evaporated to dryness. The organic layer was concentrated to dryness crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssss Hz), 1.79-2.13 (6H, m), 2.8 4 (2H, dt, J = 12.9, 5.0 Hz), 3.07 (2H, ddd, J = 12.6, 9.6, 3.3 Hz), 3.08-3.20 (lH, m )s3.32(lH,ddd,J=14.5,9.9,5.0Hz), 3.42( -739- 201211053 2H,s),3 · 56( lH,tt,J = 9.9,4.6Hz), 4.06-4· 14(1 H,m), 4.63(2H,s) ,4.66-4.74(lH,m),7.17(2H,t,J = 8.6Hz), 7.99(2H,dd,J = 8.9,5.6 Hz), 8.56 ( lH,d,J = i.3Hz), 8.89 ( lH,d,J=1.3Hz) LC/MS [Condition 1]: Hold time 1.56 minutes; m/z48 1 · 7[Μ + Η]+ ( ESI positive ion mode), m/z 479.9 [M-H]-, 525.9 [M + HCOO]. (ESI negative ion mode) [Chem. 7 6 9]

F Example 444 3-({5-[4-(4-Fluorobenzylidyl)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-8-[4-(trifluoromethyl) Substituting (11&quot;, 4〇-4-[(2- Side Oxygen) for the manufacture of benzyl]-1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 444) 1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide hydrochloride, reference 3-({5-[4-(4-Fluorobenzylidinyl)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-1-oxo-3,8- obtained in Example 444-4 Diazospiro[4.5]decane-2-one, while substituting 3-(bromomethyl)pyridine hydrobromide, using 1-(bromomethyl)-4-(trifluoromethyl)benzene (purchased The reaction was carried out in the same manner as in Example 4 to give the title compound ( 7.6 mg (yield 24%) as a pale red powder. 'Η-ΝΜΚίΟϋΟ^ίδ:! .73-2.1 l(8H,m), 2.41-2.68(4H,br m),3.14 -740- 201211053 (lH,dt,J = 3.0,12.8Hz),3.3 2(lH,tt,J = 4.9,8.9Hz), 3.41(2H,s), 3.48-3.64(lH,m),3.57(2H,s),4.09(lH,d,J=12.8Hz),4.63(2H,s),4.69 (lH,d,J=l 3.9Hz),7.17( 2H, t, J = 8.8 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz), 7.99 (2H, dd, J = 8.8, 5.4 Hz), 8.5 5 (lH, d, J = 1.0 Hz), 8.88 (lH, d, J = l · 〇Ηζ).

LC/MS [Condition 1]: Hold time 3.32 minutes; m/z 63 9.8 [M + H]+ (ESI positive ion mode), m/z 637.9 [MH]-, 683.9 [M + HCOO]' (ESI negative ion Mode) 【化7 7 0】 1

Example 445 Φ 3,5--fluoro-4-{[3-({5-[4-(4-fluorobenzylidene)piperidinyl]pyrazine-2-yl}methyl)-2- Production of oxo-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 445) in place of 3-{[(lr,4r)-4- (4-Benzyl hydrazinopiperidine- phenylcarbonyl)cyclohexyl]methyl}-1-oxo-3,8-diazospiro[4.5] oxazol-2-one hydrochloride, using reference example 444-4 3-({5-[4-(4-Fluorobenzoguanidino)piperidine-indole-carbonyl]pyrazine-2-yl}methyl)·1-oxo-3,8-diazospiro[ 4.5] decane-2-one, while substituting 6_(trifluoromethyl)nicotinic aldehyde 'except 3,5-difluoro-4-formylbenzonitrile (purchased) The same reaction as in Example 3 8 4 gave a white powder of titled Compound - 741 - 201211053 (14 mg, yield 56%). • H-NMRiCDCbie: 1.70-2.1 l(8H,m), 2.53-2.71(4H,br m), 3.13( lH,td,J=12.3,3.3Hz),3.24-3.35(lH,m)53.37 (2H, s), 3.55 (lH, tt, J = 9.2, 4.6 Hz), 3.74 (2H, s), 4.09 (lH, d, J = 14.5 Hz), 4.61 (2H, s), 4.69 (lH, d5J = 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 (lH, d, J = 1.3 Hz), 8.88 (lH, d, J = 1 · 3 Ηζ). LC/MS [Condition 1]: Hold time 3.10 minutes; m/z 632.8 [M + H] + (ESI positive ion mode), m/z 630.9 [MH]·, 676.9 [M + HCOO] — (ESI Negative ion mode) [Chem. 7 7 1]

Example 446 3-({5-[4-(4-Cyanophenylamino)piperidin-1-carbonyl]pyrazine-2-yl}methyl)-2-oxan-1-oxo-3 Preparation of 8-(diazaspiro)[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 446) substituted (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride, used The same reaction as in Reference Example 444-3 was carried out, except that 4-(piperidin-4-ylamino)benzonitrile 2 hydrochloride obtained from Example 441-2, and triethylamine afforded the title compound (7). 6 mg, yield 44%) of a colorless amorphous material. Further, 3-[(5-aminomethylpyridylpyrazin-2-yl)methyl]-2-oxo-l-D- __742- 201211053 3,8-diazo snail was obtained as a by-product [ 4.5] A white powder of decane-8-carboxylic acid tert-butyl ester (43 mg, yield 37%). 3-({5-[4-(4-cyanophenylamino)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-2-sideoxy-1-oxo-3,8- Data for diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (Compound No. 446)

1H-NMR (CDCl3) 5: 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(lH,d,J=13.9Hz), 2.21(lH,d,J=ll.lHz), 3.12(lH,dt,J=2.5,12.6Hz), 3.29(3H, t,J = 11.3Hz) , 3.43 (2H, s), 3.56-3.72 (2H, m), 3.83 (2H, d, J = 12.7 Hz), 4.05 (lH, d, J = 13.1 Hz), 4.26 (lH, d, J = 7.8) Hz), 4.63 (2H, s), 4.65 (lH, d, J = ll.lHz), 6.58 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 8.55 (lH , d, J = 1.6 Hz), 8.89 (lH, d, J = 1.6 Hz). LC/MS [Condition 1]: Hold time 4.05 min; m/z 575.9 [M + H]+, 475.7 [M-isobutene + H]+, 4 3 1 . 9 [ Μ - isobutene - C Ο 2 + Η ] + (ESI positive ion mode), m/z5 73.9 [MH]·, 619.9 [M + HCOO]_ (ESI negative ion mode)

3-[(5-Aminomethylpyridazin-2-yl)methyl]-2-oxo-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl The data of the ester (by-product) 1H-NMR (CDCl3) 5: 1.46 (9H, s) 51.62- 1.74 (2H, m) J1.92 (2H, d, J = 12.3 Hz), 3.30 (2H, t, J =11.5 Hz), 3.42 (2H, br s), 3 . 8 3 (2 Η , d, J = 1 3 .1 Hz), 4.67 (2H, s), 5.72 (1 H, br s), 7.6 0 (1 H, brs), 8.58 (lH, s), 9.34 (lH, s). LC/MS [Condition 1]: Hold time 3.41 minutes; m/z 335.9 [M-isobutene + H] + (ESI positive ion mode), m/z 390.1 [MH]- (ESI negative ion mode) -743 - 201211053 【化7 7 2】

Reference Example 4 4 7 4-(l-{5-[(2-Sideoxy-1·oxa-3,8-diazospiro[4.5]decan-3-yl)methyl]pyrazine-2-carbonyl Preparation of <piperidin-4-ylamino)benzonitrile The 3-({5-[4-(4-cyanophenylamino)piperidin-1-carbonyl]pyrazine obtained in Example 446 - 2-Benzyl}methyl)-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (7511^, 0.131«111〇1) dissolved in Methanol (21111 〇 ' was added to a 10% by mass hydrogen chloride methanol solution (〇.32 mL) at room temperature, and mixed at 40 ° C for 1 hour. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was evaporated. Chloroform (20 mL) and aq. EtOAc (EtOAc (EtOAc) ) 5: 1.48-1.79 (4H, m), 1.92 (2H, dt, J = 13.5, 3.6 Hz), 2.10 (lH, d, J = 13.9 Hz), 2.2 1 (lH, d, J = 13.1 Hz) , 2.84 (2H, dt, J = 13.1, 4.5 Hz), 2.99-3.19 (3H, m), 3.29 (lH, dt, J = 2.9, 12.9 Hz), 3.42 (2H, s), 3.56-3.72 (lH , m), 4.05 (lH, d, J = 12.3 Hz), 4.19 (1 H, d, J = 7.8 Hz), 4.63-4.72 (1 H, m), 4.63 (2H, s), 6.5 8 (2H ,d,J = 9. 0 Hz), 7.43 (2H, d, J = 9.0 Hz), 8.5 5 (lH, d, J = 1.6 Hz), 8.89 (lH, d, J = 1.6 Hz) -744- 201211053 LC/MS [conditions 1]: Hold time ι_〇4 minutes; m/z47 5.8 [M + H]+ (ESI positive ion mode), m/z473.9 [MH]-, 52 0.0[M + HCO〇r (ESI negative ion mode )

[化7 7 3]

Example 447 4-{[3-({5-[4-(4-Cyanophenylamino))piperidine-1-carbonyl]pyrazine-2-yl}methyl)-2-oxo-oxy-1 Manufacture of -oxa-3, 8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluoro-benzonitrile (Compound No. 447)

Substituting 3-({5-[4-(4-fluorobenzhydryl)piperidine-1-carbonyl]pyrazine-2-yl}methyl)-1-oxo-3,8-diazosole [4.5 ] decane-2-one, 4-(1-{5-[(2-oxo-oxo-oxa-3,8-diazaspiro[4.5]decan-3-yl) obtained in Reference Example 447 The title compound (14 mg, yield 45%) was obtained as colorless crystals, m. m. Things. 1H-NMR (CDCl3) 5: 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 (lH, m ), 2.22 (lH, d, J = 11.5 Hz), 2.51-2.72 (4H, br m), 3.12 (lH, td, J = 12.5, 2.9 Hz), 3.29 (lH, td, J = 1 2.952.9 Hz) ), 3.37(2H, s), 3.5 6-3.7 1(1 H,m), 3.74(2H, s), 4.04( lH,d,J=13.5Hz), 4.19(lH,d,J = 7.4Hz ))4.61(2H,s),4.65(lHsd, -745- 201211053

J = 12.3 Hz), 6.58 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 6.1 Hz), 7.43 (2 H, d, J = 9.0 Hz), 8.53 (1 H, d, J = 1.5 Hz), 8.88 (1 H, d, J = 1.5 Hz). LC/MS [Condition 1]: Hold time 3.00 min; m/z 626.9 [M + H]+ (ESI positive ion mode), m/z 624.7 [MH]·, 671_0 [M + HCO〇r (ESI Negative ion mode) [Chem. 7 7 4]

Example 4 4 8 4-{[3-({(11:,41:)-4-[4-(4-cyanophenylamino)piperidin-1-carbonyl]cyclohexyl}methyl)- Preparation of 2-sided oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 448) Substitution 6-( Piperidine-4-oxy)nicotinonitrile hydrochloride was substantially carried out in the same manner as in Example 402 except that 4-(piperidin-4-ylamino)benzonitrile dihydrochloride obtained in Reference Example 441-2 was used. The title compound (3 3 mg, yield 78%) was obtained as white powder. W-NMR pOOMHz, CDCl3) 8: 1.03 (2H, q, J = 13.1 Hz), 1.24-1.67 (5H, br m), 1.66-1.84 (6H, br m), 1. 8 3 - 2.0 1 ( 2 H , brm), 2.01 - 2.23 (2H, br m), 2.45 (lH, t, J = l 1.9 Hz), 2.52-2.73 (4H, br m), 2.83 (

lH, t, J = l 1.7 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 (lH, br m) , 3.7 5 (2 H, s), 3 . 8 3 - 3.9 7 ( 1 H, brm), 4.07 (lH, d, J = 7.4 Hz), 4.4 6-4.6 0 (lH, br m), 6.55 ( 2H, d, J = 8.6 Hz), 7.22 (-746-201211053 2H, d, J = 6.1 Hz), 7.42 (2H, d, J = 9.0 Hz).

LC/MS [Condition 1]: Hold time 3.20 min; m/z 631.1 [M + H] + (ESI positive ion mode), m/z 629.2 [MH; T, 675.2 [M + HCOO]- (ESI Negative ion mode)

[化7 7 5]

Example 449 4-[2-(3-{[(1):, 41:)-4-(4-Benzylmercaptopiperidine-1-carbonyl)cyclohexyl]methyl}-2-oxo- Manufacture of 1-oxo-3,8-diazospiro[4.5]decane-8-yl)ethyl]benzonitrile (compound number 9)

Substituting 1_(bromomethyl)-2,4-bis(trifluoromethyl)benzene, substantially the same as Example 25 5 except that the 4-cyanophenethyl methanesulfonate obtained in Reference Example 397-1 was used. The reaction was carried out to give the title compound (3.5 mg, yield: 7.0%). 1H-NMR (CDCl3) 5: 1.06 (2H) q) J = 13.1 Hz), 1.49-1.7 1 (4H, m)) 1.71-1.87 (7H, m), 1.87-2.02 (4H, m), 2.47 (lH, tt, J=l 1.9, 3.3

Hz), 2.53-2.7 3(6H,m), 2.74-2.90(3H,m), 3.11(2H,d,J = 7.4Hz), 3.2 1(lH,br t,J=12.3Hz), 3.26( 2H, s), 3.52 (lH, tt, J = 10.6, 3.7 Hz), 3.98 (lH, br d, J = 1 3 . 5 H z), 4.6 0 (1 H , brd, J = 1 3 . 5 H z), 7.3 1 (2 H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.57 (2H, d &gt; J = 7.8 Hz), 7.59 (l -747 - 201211053 H , t, J = 7.4 Hz), 7.94 (2H, d, J = 7.4 Hz). LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 5 97.0 [M + H]+ (ESI positive ion mode), m/z 641.2 [M + HCOO]- (ESI negative ion mode) [Chem. 7 7 6]

Reference Example 450-1 Preparation of 1H-Imidazole-1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl) Difluoro-2-methylpropan-2-ol ( (1.3 g, 10 mmol) was dissolved in chloroform (10 mL), and 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 the reaction was completed, 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 (MgSO4) (lH, br 8), 7.3 7 (^^1 s), 8.09 (lH, br s). LC/MS [Condition 1]: Hold time 3.46 min; m/z 222.9 [M + H]+ (ESI positive ion mode) [Chem. 7 7 7]

-748- 201211053 Reference Example 4 5 0 - 2 3 -Methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy)carbonyl]-1Η-imidazole- 3-Key Manufacture of iodide

The 1H-imidazole-bucarboxylic acid (ΐ, ι,; ι_trifluoro-2-methylpropan-2-yl) (l.lg, 4.8 mmol) obtained in Reference Example 450-1 was dissolved in acetonitrile (i. After adding methylene iodide (1.2 mL, 19 mmol) at room temperature, the mixture was stirred at room temperature for 3 days. After the completion of the reaction, the title compound (1.2 g, yield yield) was obtained as a yellow oil. 【化7 7 8】

Example 4 5 0

3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidin-1 ·carbonyl)cyclohexyl]methyl b 2_sideoxy-1-oxo-3,8-diazo snail [4.5 Manufacture of decane-8-carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl (Compound No. 450) substituted 1_(bromomethyl)-2,4-bis(trifluoromethyl) Benzene, using 3-methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy)carbonyl]-1H-imidazole-3- obtained in Reference Example 450-2 A white powder of the title compound (32 mg, quantitative) was obtained in the same manner as in Example 255. 1H-NMR (CDCl3) 6: l. 6 (2H, q, J = 11.9 Hz), 1.47-1.87 (llH, m), -749-201211053 1.93 (4H, br d, J = 13.9 Hz), 2.48 (lH, tt, J=ii.9, 3.3 Hz), 2.82 (lH, br t, J = 12.3 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.l3-3.43 (3H, br m ), 3.28 (2H, s), 3.52 (lH, tt, J = 10.6, 3.3 Hz), 3.7 5-4. 〇 5 (3H, br m) , 4.60 ( 1 H, brd, J = 1 3 · 9 H z),7 · 4 9 (2 H,t,J = 7.8 H z), 7.5 9 (1 H,t,J = 7 · 4 H z ), 7.9 5 (2 H,d,J = 8 · 2 H z). LC/MS [Condition 1]: Hold time 4.43 minutes; m/z 62i, 9 [M + H]+ (ESI positive ion mode), m/z 666.1 [M + HCO〇]_ (ESI negative ion mode) 7 7 9] φ

Example 451 4-[(lr,4r)-4-({2-Sideoxy-8·[4-(trifluoromethyl)benzyl]_1-oxo _3,8_ heavy

Azaspiro[4.5]decane-3-yl}methyl)cyclohexyl carbonyl]piperazine-1-carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl (compound number 451) Manufactured by substituting methyl chloroformate for the use of 3-methyl-1-[(indolyl-1,1-trifluoro-2-methylpropenyloxy)-yl]-imidazole obtained from Reference Example 450·2 A white powder of the title compound (28 mg, yield 52%) was obtained. ^-NMRiCDCb)^:! .〇4(2H,q,J=l 15Hz),1.50-1.69(3H,m), 1.70(6H,s),1.72-1.85(6H,m),1.94(2H, d, J=13_lHz), 2.41 (lH, t, J=l 1.5Hz), 2.49-2.65(4H, br m), 3.1 l(2H,d,J = 7.4Hz), 3.25 (2H, s), 3.3 6-3.53(6H,br m),3.54-3.65(2H,m),3.57(2H,s),7.44 8 -750- 201211053 (2H,d,J = 7.8Hz),7.57(2H,d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.38 minutes; m/z 677.1 [M + H]+ (ESI positive ion mode), m/z 721.0 [M + HCO〇r (ESI negative ion mode) 8 0]

Reference Example 4 5 2 -1 1H-Imidazole-1-carboxylic acid (2-cyanopropan-2-yl) was produced by substituting 1,1,1-trifluoro-2-methylpropan-2-ol, using 2 The same reaction as in Reference Example 450-1 was carried out to give a white powder of the title compound (2.0 g, quantitative). 1H-NMR (CDCl3) 6: 1.96 (6H, s), 7.08 (lH, br s), 7.4 1 (1 H, br s) 5 8. 12 (lH'br s) 〇

LC/MS [Condition 1] ESI positive ion mode Hold time 1_18 minutes; m/zl79.9[M + H]+ (【化 7 8 1】 ΙΘ

Reference Example 4 Production of 5 2 - 2 1-[(2-cyanopropan-2-yloxy)carbonyl]-3-methyl-1Η-imidazole-3-yl iodide -751 - 201211053 Substituted 1H-imidazole- 1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl), 1-indole-imidazole-1-carboxylic acid (2-cyanopropane-2-) obtained using Reference Example 452-1 In the same manner as in Reference Example 450·2, the title compound (2. lg, quantitative) was obtained as a yellow oil. LC/MS [Condition 1]: Hold time 〇·5 1 minute; m/zl94.1 M + (ESI positive ion mode) [Chem. 7 8 2]

Example 4 5 2 3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxan-1-oxo-3,8 - Preparation of diazospiro[4.5]decane-8-carboxylic acid 2-cyanopropan-2-yl (Compound No. 452) Substituting 1-(bromomethyl)-2,4-bis(trifluoromethyl) Benzene was substantially the same as the Example except that 1-[(2-cyanopropan-2-oxy)carbonyl]-3-methyl-1H-imidazole-3-yl iodide obtained in Reference Example 452-2 was used. The title compound (28 mg, yield 60%) was obtained as white powder. 1H-NMR (CDCl3) 6: 1.06 (2H, q, J = 11.9 Hz), 1.4 7-2.00 (1 3H, m), 1.78 (6H, s) 52.48 (lH, tt, J=ll.9, 3.3 Hz), 2.82 (lH, 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 (lH, ttsJ = 10.6) , 3.7 Hz), 3.83 (lH, d, J = 10.6 Hz), 3.92-4.10 (2H, m), 4.60 (lH, d, J = 13.1 Hz), 7.49 (2H, t, J = 7.0 Hz), 7.59 (lH,t,J = 7.0Hz -752- 201211053 ), 7.94 (2H,d,J = 7,0Hz). LC/MS [Condition 1]: Hold time 4.13 min; m/z 579.0 [M + H] + (ESI positive ion mode), m/z 612.9 [M + Cl]·, 623.1 [M + HCOO]- (ESI negative ion mode)

Hi

F Example 4 5 3 4-[(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-weight Manufacture of azaspiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carboxylic acid 2-cyanopropan-2-yl (compound No. 45 3)

Substituting methyl chloroformate', except using 1-[(2-cyanopropan-2-oxy)carbonyl]-3-methyl-1H-imidazole-3-yl iodide obtained in Reference Example 452_2, substantially Example 1 The same reaction as 4' gave the title compound (19 mg, yield 39%) as white powder. 1H-NMR (CDCl3) 5: 1. 5 (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 (lH, t, J = l 1.5 Hz), 2.49-2.6 1 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.35-3.66 (8 H , m), 3.5 7 (2H, s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time 3.18 minutes; m/z 634. 〇[M + H]+ (ESI positive ion mode), m/z 668.2 [M + Cl]', 678.0 [M + HCO 〇r (ESI negative ion mode) -753- 201211053 [Chem. 7 8 4] CN °^Ρ Reference example 454-1 1Η-Imidazole-1-carboxylic acid (2,2,2-trifluoroethyl) production substitution 1 1,1,3-trifluoro-2-methylpropan-2-ol, the same reaction as in Reference Example 450-1 was carried out, except for using 2,2,2-trifluoroethanol (available) to give the title compound (2.2 g, quantitative) of a colorless oil. 1H-NMR (CDCl3) 6: 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]: Hold time 1.67 minutes; m/zl94.8 [M + H]+ (ESI positive ion mode) [Chem. 7 8 5] 0

Reference Example 4 Preparation of 5 4 - 2 3-methyl-l-[(2,2,2-trifluoroethoxy)carbonyl]-1H-imidazole-3-iron iodide Substituted 1H-imidazole-1-carboxylate Acid (1,1,1-trifluoro-2-methylpropan-2-yl), using 1H-imidazole-1-carboxylic acid (2,2,2-trifluoroethyl) obtained in Reference Example 454-1. The reaction was carried out in the same manner as in Reference Example 450-2 to give the title compound: 754-201211053 (2.2 g, quantitative) as a yellow oil. 1 H-NMR (CD3 OD) 5: 4.00 (3 H, s), 4.64 (1H, q, J = 7.4 Hz), 4.8 0-5.02 (1 H, m), 7.56-7.59 (1 H, m) , 7.61-7.64 (1 H, m) , 8.96 (1 H, s). LC/MS [Condition 1]: Hold time 0.5 1 minute; m/z 208.9 M + (ESI positive ion mode) [Chem. 7 8 6]

Example 4 5 4 4-[(11*,4〇-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]]oxan-3,8-diazo Manufacture of spiro[4·5]decane-3-yl}methyl)cyclohexanecarbonyl]piperazine-1-carboxylic acid 2,2,2-trifluoroethyl (Compound No. 454)

Substituting methyl chloroformate, using 3-methyl-1-[(2,2,2-trifluoroethoxy)carbonyl]-1H-imidazole-3-carbide iodide obtained in Reference Example 454-2, The title compound (27 mg, yield: 84%) was obtained as pale yellow powder. IH-NMR (CDCl3) 5: 1.05 (2H5q5J = 11.7 Hz), 1.44 - 1.87 (9H, m), 1.88-1.99 (2H, m), 2.43 (lH, t, J = 11.7 Hz), 2.50-2.65 ( 4H,br m), 3.1 l(2H,d,J = 7.3 Hz), 3.26(2H,s), 3.45-3.69(8H,m),3.58(2H,s ),4.5 1(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] + -755 - 201211053 (ESI positive ion mode), m/z 68 3.1 [M + Cl]-, 693·1 [ Μ + Η(:00]·( ESI negative ion mode) 【化7 8 7】

Example 455 3-{[(lr,4r)-4-(4-Benzylhydrazinopiperidin-1-carbonyl)cyclohexyl]methyl}-2-oxan-1-oxo-3,8-weight Manufacture of nitrogen snail [4.5] decane-8-carboxylic acid 2,2,2-trifluoroethyl (compound number 45 5)

Substituting 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene, 3-methyl-l-[(2,2,2-trifluoroethoxy) obtained using Reference Example 454-2 In the same manner as in Example 25 5 except for the carbonyl]-1H-imidazole-3-yl iodide, the title compound (25 mg, yield: 53%) of white powder, 1H-NMR (CDCl3) 6: 1.06(2H,q,J=12.3Hz), 1.47-2.00(4H,m), 2.48(lH,tt,J=11.7,3.1Hz),2.82(lH,t,J=11.7Hz),3.12(2H , d, J = 7.2 Hz), 3.21 (lH, t, J = 13.5 Hz), 3.28 (2H, s), 3.35 (2H, q, J = 11.9 Hz), 3.52 (lH, 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 (lH, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.4 Hz) » LC/MS [Condition 1]: Hold time 4.23 minutes; m/z 593.8 [M + H]+ (ESI positive ion mode), m/z 628.0 [M + Cir, 63 7.9[M + HCOO]_( -756- 1 201211053 ESI Negative Ion Mode) [Chem. 7 8 8]

Example 4 5 6 Φ ' 6-[1-((11*,41*)-4-{[8-(4-Cyano-2,6-difluorobenzyl)-2- oxo-1 Manufacture of 3-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}cyclohexanecarbonyl)azetidin-3-oxy]nicotinonitrile (Compound No. 456) Substitution 6 -(piperidin-4-oxy)nicotinonitrile hydrochloride, substantially the same as Example 402 except that 6-(azetidin-3-oxy)nicotinonitrile obtained in Reference Example 381-2 was used. The title compound (I6 mg, yield 33%) was obtained as white powder.

1H-NMR (CDC13) 5: 0.91-1.10 (2H, m), 1.41-1.85 (9H, m), 1.91 (2H, br, J = 12.7 Hz), 2.12 (lH, tt, J = 11.9) , 3.3 Hz), 2.52-2.7 1 (4H, m), 3.07 (2H, d, J = 7.8 Hz), 3.2 1 (2H, s), 3.75 (2H, s), 4.05 (lH, dd, J = 1 1.1, 4.1 Hz), 4.14 (1 H, dd, J = 9.8, 4.1 Hz), 4.40 (1 H, dd, J = l 1.1, 7.0 Hz), 4.56 (lH, dd, J = 9.8, 7.0 Hz) ), 5.42 (lH, tt, J = 7.0, 4.1 Hz), 6.90 (lH, d, J = 8.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.85 (lH, dd, J = 8.6, 2.5 Hz), 8.45 (lH, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 2.98 minutes; m/z 604.9 [M + H]+ (ESI positive ion mode), m/z 649.1 [M + HCOO]- (ESI negative ion mode) -757- 201211053 【化7 8 9】

Reference Example 4 Production of 5 7 -1 5-[(trifluoromethyl)pyridin-2-yl]methanol 5-(Trifluoromethyl)methylpyridinaldehyde obtained in Reference Example 89 (〇.24 g, 1.4 mmol) The solution was dissolved in chloroform (6.0 mL), and sodium triacetoxyborohydride (〇.51 g, 2.4 mmol) was added at room temperature, and the mixture was stirred and stirred at room temperature for 7.0 minutes. After the reaction was completed, water (1 mL) and aqueous sodium hydrogen sulfate (20 mL) and chloroform (60 mL) were evaporated. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography [塡 剂: HI-FLASH (registered trademark) COLUMNsilicagel 40 pm, developed solvent: The title compound (0.24 g, yield 100%) was obtained. 1H-NMR (CDC13) 5: 3.48 ( lH, br s), 4.86 (2H, s), 7.44 (lH, d, J = 8.3 Hz), 7.94 (1 H, d, J = 8_3 Hz), 8.85 (1) H, s). LC/MS [Condition 1]: Hold time 2.03 minutes: m/zl77.9[M + H]+ (ESI positive ion mode) [Chem. 7 9 Ο]

Reference Example 4 5 7 - 2 -758- 201211053 Preparation of 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}isoindan-1,3-dione 6-(hydroxyl Methyl)nicotinic acid ethyl group was subjected to the same reaction as in Reference Example 431-1 except that 5-[(trifluoromethyl)pyridine-2-yl]methanol obtained in Reference Example 457-1 was used. The title compound (0.31 g, yield 73%) was obtained as white powder.

1H-NMR (CDCl3) 5: 5.08 (2H, s), 7.42 (1H, d, J = 8.2 Hz), 7.67-8.00 (5H, m), 8.77 (lH, s). LC/MS [Condition 1]: Hold time 4.13 minutes; m/z3 06.8 [M + H]+ (ESI positive ion mode) [Chem. 7 9 1] Refer to Reference Example 4 5 7 - 3 [5-(Trifluoromethyl) Preparation of 5-(pyridin-2-yl)methylamine Substituted 5-[(1,3-dioxaisoindan-2-yl)methyl]pyrazine-2-carboxylic acid ethyl, using Reference Example 457 The same as the 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}isoindan-1,3-dione obtained in -2, substantially the same as in Reference Example 43 3 -2 Reaction gave the title compound (0.10 g,yiel. 1H-NMR (CDCl3) 6: 4.07 (2H, s) 57.45 (1H, d, J = 8.2 Hz), 7.89 (1H, dd, J = 8.2, 1.8 Hz), 8.83 (lH, br s). LC/MS [Condition 1]: Hold time 〇_51 minutes; m/zl77.0[M + H]+ ( -759- 201211053 ESI positive ion mode) [Chem. 7 9 2]

Example 457 (lr, 4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-chew_3,8-diazospiro[4.5]癸Manufacture of -3-yl]methyl}-1^-{[5-(trifluoromethyl) ruthenium ratio]]]~_2~yl]methyl}cyclohexanecarbamamine (Compound No. 457) 6-(piperidin-4-oxy)nicotinonitrile hydrochloride was substantially the same as Example 402 except that [5-(trifluoromethyl)pyridin-2-yl]methylamine obtained in Reference Example 457_3 was used. The title compound (1 l mg, yield 23%) was obtained as white powder. 1H-NMR (CDCl3) 6: 1.04 (2H, dq, J = 2.9, 13.1 Hz), 1.4l-1.85 (7H, m), 1.86-2.04 (4H, m), 2.17 (1 H, tt, J = l 1.9, 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 (lH, br t, J = 4.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.39 (lH, d, J = 8.2 Hz), 7.90 (lH, d, J = 8.2) Hz), 8.8 1(lH,s)» LC/MS [Condition 1]: Hold time 3.02 minutes; m/z 605.6 [M + H]+ (ESI positive ion mode), m/z 650.2 [M + HCO〇r (ESI negative ion mode) -760- 201211053 [Chem. 7 9 3 ]

Example 4 5 8 (11*,4〇-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo Manufacture of spiro[4.5]decane-3-yl]methyl}-N-[(6-fluoropyridin-3-yl)methyl]cyclo Φ hexanecarbamamine) (Compound No. 458) Substituted 6-( Piperidine-4-oxy)nicotinonitrile hydrochloride was obtained by substantially the same reaction as in Example 4〇2 except using (6-fluoropyridin-3-yl)methylamine obtained in Reference Example 443-3. The title compound (15 mg, yield 34%) was obtained as white powder.

'H-NMR (CDCl3) 5: 0.99 (2H, dq, J = 3.3, 12.6 Hz), 1.40-1.63 (3H, m), 1.64 - 1.83 (4H, m), 1.9 1 (4H, d, J = 12.7 Hz), 2.07 (lH, 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), 4.4 1 (2H, d, J = 5.7 Hz), 6.14 (lH, t, J = 5.9 Hz), 6.88 (lH, dd, J = 8.2, 2.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.73 (lH, td, J = 8.1, 2. 6 Hz), 8.09 (1 H, s). LC/MS [Condition 1]: Hold time 2.45 minutes; m/z 5 5 5.9 [M + H]+ (ESI positive ion mode), m/z 5 54.1 [M-Hr, m/z 600.1 [M + HCOO] -( ESI Negative Ion Mode) -761 - 201211053 [Chem. 7 9 4]

Example 459 4-[6-({2-Sialoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3- Preparation of ethyl}methyl)nicotinyl]piperazine-1-carboxylate (Compound No. 459) Substituted tetrahydrofurfurylamine, using ethyl piperazine-1-carboxylate (purchased), The title compound (18 mg, yield 78%) was obtained as pale brown crystals. 1 H-NMR (CDC13) 6 : 1.27 (3 H, t, J = 6.7 Hz), 1.71-1.8 9 (2H, m), 1.97 (2H, d, J = 13.5 Hz), 2.46-2.62 (4H, Br m),3.3 5(2H,s),3.3 8-3.6 1( 6H,br m),3.57(2H,s),3.62-3.8 8 (2H,br m), 4.1 7 (2 H , q, J = 7.2 Hz), 4.5 7 (2H, s), 7.38 (lH, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.5 7 (2H, d, J = 8.2 Hz) , 7.76 (lH, dd, J = 7.8, 2.0 Hz), 8.61 (lH, d, J = 2.0 Hz) 0 LC/MS [Cond. 1]: Hold time 2.88 min; m/z 590.0 [M + H] + (ESI positive ion mode), m/z 634.2 [M + HCO〇r (ESI negative ion mode) [Chem. 7 9 5]

-762- 201211053 Example 460 l-[6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-i-oxo-3,8-diazo snail [4.5]癸Manufacture of -3--3-methyl}sodium oxime] 峨U ding-4_nitrile (Compound No. 460)

The title compound (25 mg, quantitative) of pale orange amorphous material was obtained after the same reaction as in Example U1, except for the THF. 1H-NMR (CDCl3) 6: 1.64-2.03 (8H, m), 2.45-2.63 (4H, br m), 2.92-3.02 (lH, m), 3.36 (2H, s), 3.39-4.02 (4H, m ), 3.57 (3H, s), 4.58 (2 H, s), 7.37 (lH, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8) Hz), 7.74 (lH, dd, J = 8.2, 2.0 Hz), 8.59 (lH, d, J = 1.6 Hz). LC/MS [Condition 1]: Hold time 1.90 minutes; m/z 541 ·9 [Μ + Η]+ (ESI positive ion mode), m/z 540.0 [MH]·, 586.1 [M + HCO〇T (ESI Negative ion mode)

Example 4 6 1 4-[6-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane- Manufacture of 3-methyl}methyl)nicotinamide]piperidine-1-carboxylate (Compound-763-201211053 No. 461) Substituted tetrahydrofurfurylamine using 4-aminopiperidine-1-carboxylate A white powder of the title compound (26 mg, quantitative) was obtained. 1H-NMR (CDCl3) 5: 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), 3.3 3 (2H, s), 3.56 (2H, s), 3.99-4.24 (5 H, m), 4.58 (2H, s), 6.29 (lH, d, J = 7.8 Hz), 7.36 (lH, d, J = 7.8 Hz), 7.43 (2H, dsJ = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) ), 8.09 (lH, dd, J = 8.2, 2.0 Hz), 8.9 1 (1 H, d, J = 2.0 Hz).

LC/MS [Condition 1]: Hold time 2.96 minutes; m/z 604_0 [M + H]+ (ESI positive ion mode), m/z 602.1 [MH]·, 648.1 [M + HCOO]- (ESI negative ion mode )

Example 462 N-(furan-2-ylmethyl)-6-((2-oxo-8-(4-trifluoromethyl)benzyl]-1-oxo-3,8-diazo Preparation of spiro[4.5]decane-3-yl}methyl)nicotinium amide (Compound No. 462) Substituted tetrahydrofurfurylamine, using furan-2-ylmethylamine (purchased), substantially The title compound - 764 - 201211053 (23 mg, quantitative) was obtained as a white powder. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (2H,d,J = 12.7Hz), 2.40-2.62(4H,br m),3.3 2(2H,s),3.56(2H,s),4.58(2H,s),4.66(2H,d,J = 5.3 Hz), 6.32 (lH, d, J = 3.3 Hz), 6.36 (lH, dd, J = 3.3, 2.0 Hz), 6.42-6.53 (lH, m), 7.3 7 (lH, d, J = 8.2) Hz), 7.39 (lH, 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 (lH, dd, J = 8.2) , 2.0 Hz), 8.93 (lH, d, J = 2.0 Hz).

LC/MS [Condition 1]: Hold time 2.82 min; m/z 52 8.9 [M + H]+ (ESI positive ion mode), m/z 527.0 [M-H; T (ESI negative ion mode) [Chem. 7 9 8]

Example 463 3-{[5-(4,4-Difluoropiperidin-1-carbonyl)pyridine-2-yl]methyl b- 8-[4-(trifluoromethyl)benzyl]-[Chew -3,8-diazo snail [4·5] brothel _2 ketone (Compound No. 463) was produced by substituting tetrahydrofurfurylamine using 4,4-difluoropiperidine hydrochloride (purchased) The title compound (26 mg, quantitative) was obtained as a pale yellow sm. 1H-NMR (CDCl3) 5: 1.80 (2H, td, J = l3-856-7 Hz^1 - 84 &quot; 2-23 (4H&gt; br m), 1.98 (2H, d, J = 13.8 Hz), 2.44- 2.64(4H,m), 3.36(2H,s),3.43-3.98 -765- 201211053 (4H,m),3.57(2H,s),4.58(2H,s),7.38(lH,d,J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (lH, dd, J = 8.2, 2.0 Hz), 8_61 (lH, d, J = 2_0Hz) ).

LC/MS [Condition 1]: Hold time 2.92 minutes; m/z 552.9 [M + H]+ (ESI positive ion mode), m/Z 551.1 [MH]-, 597.0 [M + HCOO]- (ESI Negative ion mode) [Chem. 7 9 9]

Example 464 6-{1-[6-({2-Sialoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4_5]decane Manufacture of -3-yl}methyl)nicotinyl]azetidin-3-oxy}nicotinonitrile (Compound No. 464) Substituted tetrahydrofurfurylamine, 6-b obtained using Reference Example 381-2 1H-NMR (CDCl3) 6 of the pale orange amorphous substance of the title compound (17 mg, 69%) was obtained from the title compound (17 mg, 69%). 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), 3.3 4 (2 H, s), 3.5 6 (2H, s) , 4.2 3-4.3 9( 2H,br m),4.58(2H,s),4.6 1- 4.79(2H,br m),5.49(lH,tt,J = 7.0,2.5Hz),6.92(lH , d, J = 9.0 Hz), 7.3 7 (lH, d, J = 8.2 Hz), 7.43 (2H, d, J = 8, 2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.86 (lH ,dd,J = 9.0,2.5Hz),7.98 -766- 201211053 (lH,dd,J = 8.2,2.0Hz), 8.44 (lH,d,J = 2.5Hz), 8.80 (lH,d,J = 2.0 Hz )°

LC/MS [Condition 1]: Hold 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 4 6 5 5 —( {2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazo snail [4.5]

Manufacture of decyl-3-yl}}methyl)pyrazine-2-carboxamide (Compound No. 465) 3 - [(5-Aminomethylpyridazin-2-yl) obtained in Example 4 4 6 Methyl 2- 2-oxo-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester (43 mg, O.llmmol) dissolved in methanol (2. 〇mL) A 10% hydrogen chloride·methanol solution (〇_28 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 day. After the end of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The obtained white solid was dissolved in N,N-dimethylformamide (i. 〇mL), and triethylamine (0.03 7 mL, 〇.26 mmol) and 4-(trifluoromethyl)benzene were added at room temperature. Methyl bromide (29 mg, 0.11 mmol) was stirred and mixed at room temperature for 1 day. After the completion of the reaction, ethyl acetate and water were added, and the organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained reaction residue was purified by silica gel column chromatography [lubricant: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> %) of white powder. 1H-NMR (CDCl3) 6: 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 ( 1 H, br s), 7.43 (2H, d, J = 8.2 Hz), 7.52 - 7.64 ( 1 H, br m ), 7.57 (2H,d,J = 8.2Hz), 8.58 (lH,d,J=1.3Hz), 9.34 (lH,d,J=1.3Hz) o

LC/MS [Condition 1]: Hold time 0.80 min; m/z 449.9 [M + H] + (ESI positive ion mode), m/z 448.0 [MH]_, 493.7 [M + HCOO]' (ESI Negative ion mode) [化8 0 1]

Reference Example 466 3-[4-(4-Benzylhydrazinopiperidinyl-indole-carbonyl)benzyl]-indole-oxo-3,8-diazospiro[4.5]decane-2-one hydrochloride Manufactured by substituting 2-side oxygen_3_[((lr,4r)_4_{[(tetrahydrofuran-2-yl)methyl]aminemethanoyl}cyclohexyl)methyl]oxo-3,8-diazospiro [ 4.5] decane-8-carboxylic acid tert-butyl ester 'Used 3-[4-(4-Benzyl hydrazinopiperidine-1 fluorenyl)benzyl]-2-oxan obtained from Example 1 58 The same reaction as in Example 3 was carried out in the same manner as in Example 3 to give the title compound (1.lg, quantitative). Colorless amorphous. -768- 201211053 !Η-ΝΜΚ(300ΜΗζ ' CDC13)5:1.70-2.14(6H,m), 2.25(2H,t,J = 9.8Hz),2.92-4.02(1 0H,m),4.44(2H, s), 4.67 (lH, br s ) , 7.3 0 ( 2 H , d, J = 7.4 Hz), 7.3 6-7.54 (4H, m), 7.59 (lH, t, J = 7.4 Hz), 7.94 (2H , d, J = 7.0 Hz), 9.70 (l H, s). LC/MS [Condition 1]: Hold time 3.16 min; m/z 461.9 [M + H] + (ESI positive ion mode) [Chem. 8 0 2]

Example 466 4-({3-[4-(4-Benzylmercaptopiperidin-1-carbonyl)benzyl]-2-oxo-1-oxo-3, 8-diaza-spiro[ 4.5] decane-8-yl}methyl)-3,5-difluorobenzonitrile (combination φ material number 466) was produced by substituting (lr, 4r)-4-[(2- side oxy-1- oxole) -3,8-diazospiro[4.5]decane-3-yl)methyl]-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamide hydrochloride, obtained using Reference 466 3-[4-(4-Benzylmercaptopiperidin-1-carbonyl)benzyl]-1-oxo-3,8-diaza-spiro[4.5]decane-2-one hydrochloride And simultaneously replacing 3,5·bis(trifluoromethyl)benzaldehyde, using 3,5-difluoro-4-methylindenyl benzoyl nitrile (purchased), substantially in the same manner as in Example 2 3 5 The reaction was carried out to give the title compound (21.4 mg, yield 70%) as white powder. 1H-NMR (CDC13) 5: 1.54-2.03 (8H, m), 2.44-2.70 (4H, br m), 3.03-3.26 -769- 201211053 (2H, m), 3.10 (2H, s), 3.49-3.6 1(lH,m),3.73(2H,s), 3.76-3.97( lH,br m),4.43(2H,s),4.50-4.82(lH,br m), 7.2 1 (2 H, 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 (lH, t, J = 7.4) Hz), 7.95 (2H, d, J = 7.4 Hz). LC/MS [Condition 1]: Hold time 3.30 minutes; m/z 613.0 [M + H]+ (ESI positive ion mode), m/z 647.0 [M + Cl]·, 65 7·1 [Μ + Η(:00]·( ESI negative ion mode) 【化8 0 3 ]

Reference Example 4 6 7 -1 (11*,4〇-4-({8-[2-methoxy-4-(trifluoromethyl)benzyl]]-2-oxo-1-oxo-3 , 8-diazospiro[4.5]decane-3-yl]}methyl) Cyclohexanecarboxylic acid methyl, substituted 3,5-difluoro-4-carboxamidobenzonitrile, 2-A The same reaction as in Reference Example 398.1 was carried out except for the oxy-4-(trifluoromethyl)benzaldehyde (purchased) to give the title compound (yield: 6 8 g, yield: 84%) of white. Powder 〇1H-NMR (CDCl3) 5: 1.02 (2H5dq, J = 3.3, 12.7 Hz), 1.4 1 (2H, dq, J:=: 3.3,1 3.1 Hz), 1.50-2.09 (9H, m), 2.25 (lH, tt, J = 12.3, 3.3 Hz), 2.48-2.76 (4H, br m), 3.09 (2H, d, J = 7 · 4 Hz), 3 · 26 (2 Η, s), 3.60 (2H, s ), 3.66 (3H, s), 3.86 (3H, s), 7.05 (lH, br s), 7.20 (lH, d, J = 7.8 Hz), 7.46 (-770-201211053 1 H, d, J = 7.8 Hz) 〇LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 499.0 [M + H]+ (ESI positive ion mode) [Chem. 8 0 4]

Reference Example 4 6 7 - 2 (1]:, 41') -4-({8-[2-methoxy-4-(dimethylmethyl)-methyl]-2-oxo-oxo-1 Preparation of -3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (lr,4r)-4-({8-[2) obtained in Reference Example 467-1 -Methoxy-4-(trifluoromethyl)benzyl]-2-oxo-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexane Methyl carboxylate (〇.65 g, 1.3 mmol) was dissolved in 1,4-dioxane, and a 1.0 M aqueous sodium hydroxide solution (1.9 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. The precipitated solid was filtered to give the title compound (0.59 g, yield: 94%) as white powder. LC/MS [Condition 1]: Hold time 2.82 minutes; m/z 484.8 [M + H]+ (ESI positive ion mode), m/z 4 83.0 [M-Hr (ESI negative ion mode) -771 - 201211053 8 0 5]

Example 4 6 7 4-{l-[(lr,4r)-4-({8-[2-methoxy-4-(trifluoromethyl)benzyl]-2-oxan-1- Manufacture of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarbonyl]azetidin-3-yloxy}benzonitrile (Compound No. 467) Lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl }Methyl)cyclohexanecarboxylic acid, using (lr,4r)-4-({8-[2-methoxy-4-(trifluoromethyl)benzyl]] obtained from Reference Example 467-2 2-sided oxy-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, substituted tetrahydrofurfurylamine, obtained using Reference Example 3 83-2 The title compound (3 3 mg, yield 84%) was obtained as white solid, m. m. . 1H-NMR (300MHz, CDCl3) 6: 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 (lH, 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)s3.86(3H,s)54.05(lH,dd,J=10.9,4.3Hz), 4.20(1 H,dd, J = 9.2,3 ·3Η z), 4.39(1 H,dd,J =l 0.9, 6.6 Hz), 4.55 (1 H, dd, J = 9.6, 6.9 Hz), 4.99 (lH, tt, J = 6.3, 3.3 Hz), 6.81 (2H, d, J = 8.6)

Hz), 7.06 (lH, s), 7.20 (lH, d, J = 7.9 Hz), 7.47 (lH, d, J = 7.9 Hz), 7.62 -772 - 201211053 (2H, d, J = 8.3 Hz).

LC/MS [Condition 1]: Hold 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 (11&quot;,4〇-4-({8-[2-methoxy-4-(difluoromethyl)benzyl)-2-oxo-1-oxo-3,8-weight Preparation of alkalose [4.5]decane-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexanecarbamamine (Compound No. 468) Substituted (lr, 4r)-4 -({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexane For the alkanoic acid, (lr, 4r)-4-({8-[2-methoxy-4-(trifluoromethyl)benzyl]-2-oxo-oxyl obtained using Reference Example Φ 467-2 The same reaction as in Example 10 was carried out except for 1-oxo-3,8-diazaspiro[4.5]nonane-3-yl}methyl)cyclohexanecarboxylic acid to give the title compound (31 mg). , yield 89%) of pale yellow solid. 1 H-NMR (300MHz, CDCl3) 5: 1.02 (2H, qd, J = l 1.5, 2.9 Hz), 1.48 (2H, qd, J = 13.5, 3.3 Hz) , 1.58-1.67 (lH, m), 1.72-2.03 (12H, m), 2.04 (lH, tt, J = 11.5, 4.1 Hz), 2.54-2.67 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.11 (lH, ddd5J = 13.9, 7.0, 4.5 Hz), 3.25 (2H, s), 3.58 (lH, ddd, J = 13.5, 6.5, 3.3 Hz), 3.60 (2H, s), 3.75 ( lH, dt, J = 8.2, 7.0 Hz), -773 - 201211053 3.85 (lH, dt, J = 8.2, 6.1 Hz), 3.87 (3H, s), 3.94 (lH, qd, J = 7. 0, 2.9 Hz), 5.79 (1 Η, t, J = 5.7 Hz), 7.06 (lH, s), 7.20 (lH, d, J = 8.2 Hz), 7.47 (lH, d, J = 7.4 Hz) LC/MS [Condition 1]: Hold time 2.90 minutes; m/z 567.9 [M + H]+ (ESI positive ion mode), m/z 612.2 [M + HCOO]- (ESI negative ion mode) 8 0 7]

Example 469 8-[2-Methoxy-4-(trifluoromethyl)benzyl]-3-({(lr,4r)-4-[4-(porphyrin-4-yl)piperazine) Manufacture of 1-l-carbonyl]cyclohexyl}methyl)-l-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 469)

Substituted (lr,4〇-4-({2-o-oxo-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 -yl}methyl)cyclohexanecarboxylic acid, using (lr,4r)-4-({8-[2-methoxy-4-(trifluoromethyl)benzyl) obtained in Reference Example 467-2 ]-2-oxo-1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl)cyclohexanecarboxylic acid, substituted tetrahydrofurfurylamine, using Reference Example 27 The title compound (22 mg, yield 51%) was obtained as a pale yellow solid. 1H-NMR (300MHz, CDCl3) 6: 1.08 (2H, q, J = 11.5 Hz), 1.61 (2H, q, J = 13.5 Hz), 1.611-1.70 (lH, m), 1.74-1.90 (6H,m),l.91-2.01(2H -774- 201211053,m),2.52 (lH,tt,J=12.3,3.7Hz),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 (lH, d , J = 4.9 Hz), 7.06 (1 H, s), 7.20 (lH, d, J = 7.4 Hz), 7.47 (lH, d, J = 7.8 Hz), 7.52 (lH, ddd, J = 8.2, 7.0) , 1.2 Hz), 7.69 (lH, ddd, J = 8.2, 6.5, 1.6 Hz), 8.03 (lH, d, J = 8.6 Hz), 8.08 (1 H, d J = 8.2Hz), 8.77 (lH, d, J = 4.9Hz).

LC/MS [Condition 1]: retention time 2.07 minutes; m/z 679.9 [M + H]+ (ESI positive ion mode), m/z 724.3 [M + HCO〇r (ESI negative ion mode) 0 8]

Reference Example 4 7 0 -1 (lr,4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1-φ oxa-3 , the production of 8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid methyl substituted 3,5-difluoro-4-methylindenylbenzonitrile, using 6-(three The same reaction as in Reference Example 3 98-1 was carried out to give the title compound (1. g, yield: 87%) as white powder. 'H-NMR (CDCl3) 5: 1. 〇 2 (2H, dq, J = 3.3, 12.9 Hz), 1.41 (2H5dq, J = 3.3, 13.1 Ηζ), 1.5 1-1.66 (lH, m), l. 68-1.86(4H,m), 1.88-2.08( 4H,m), 2.25(lH,tt,J=12.3,3.6Hz)J2.49-2.65(4H,br m),3.09( 2H,d,J = 7.4 Hz), 3.26 (2H, s), 3.6 1 (2H, s), 3.66 (3H, s), 7.65 (lH, d, J = 7.8 Hz), 7.83 (lH, d, J = 7.8 Hz) , 8.68 (lH, br s). -775- 201211053 LC/MS [Condition 1]: Hold time 2.75 minutes; m/Z 469..7[M + H]+ (ESI positive ion mode), m/z 467.8 [MH]·, m/z 503. 7[M + Cl]·, 5 13.8[M + HCO〇r (ESI negative ion mode) [Chemical 8 0 9]

Reference Example 4 7 0 - 2 (lr, 4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1-carbo-3, Production of 8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid substituted 3-{[(lr,4〇-4-(methoxycarbonyl)cyclohexyl]methyl} 2-tert-oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester, using (lr, 4r)-4-[() obtained in Reference Example 470-1 2-sided oxygen-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1-oxo-3,8-diazospiro[4.5]decane-3-yl)methyl The same reaction as in Reference Example 2-3 was carried out to give the title compound (0.5 lg, yield: 100%) as white powder. 1H-NMR (CDCl3) 6: 1.04 (2H) , dq, J = 3.7, 12.3 Hz), 1.42 (2H, dq, J = 3.3, 13·0Ηζ), 1.51-1.67 (lH, m), 1.80 (4H, dd, J=13.9, 9·0Ηζ), 1.94 (2H, d, J = 13.0 Hz), 2.06 (2H, d, J = 13.0 Hz), 2.28 (lH, tt, J = 12.3, 3.7 Hz), 2.50-2.67 (4H, br m), 3.10 ( 2H,d,J = 7.4Hz), 3.27(2H, s), 3.62(2H,s), 7.64( lH,d,J = 8.2Hz), 7.83(1 H,d,J = 8.2Hz), 8.67 ( lH, s) LC/MS [Condition 1]: Hold time 0.94 minutes; m/z 456.0 [M + H]+ ( -776- 201211053 ESI positive ion mode ), M / z454.1 [M-H] - (ESI negative ion mode) of [810]

Example 4 7 0

3-{[(lr,4r)-4-(4,4-difluoropiperidin-1-carbonyl)cyclohexyl]methyl}-8-{[6-(trifluoromethyl)pyridin-3-yl Substitution of methyl}-1-oxo-3,8-diazospiro[4.5]decane-2-one (compound number 470) for substitution (lr, 4〇-4-({2- sideoxy-8-) [4-(Trifluoromethyl)benzyl]-oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, obtained using Reference Example 470-2 (lr,4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridine-3-yl]methyl}-1-oxo-3,8-diazospiro[ 4.5] decyl-3-yl)methyl]cyclohexanecarboxylic acid, substituted tetrahydrofurfurylamine, substantially the same as Example 1 except that 4,4-difluoropiperidine hydrochloride and triethylamine were used. The title compound (33 mg, yield 90%) was obtained as a white solid. </RTI> <RTIgt; </RTI> NMR (300 MHz, CDCl3) 6: 1.06 (2H, q &gt; J = 11.4 Hz), 1.56 (2H, q, J = 12.9 Hz), 1.60 - 1.67 ( 1 H, m), l-79 (6H, d, J = l 2.2 Hz), 1.95 (6H, d, J = 12.9 Hz), 2.46 (lH, tt, J = 11.9) , 3_3Hz), 2.48-2.67(4H,m), 3_ll(2H,d,J = 7.3Hz), 3.27(2H,s),3.59(2H,brt,J = 7.3Hz),3.6 1( 2H,s ), 3.72 (2H, brt, J = 5.6 Hz), 7.65 (lH, d, J = 7.9 Hz), 7.84 (lH, d J = 6.9 Hz), 8.68 (lH, s) -777- 201211053 LC/MS [Condition 1]: Hold time 2.94 minutes; m/z 558.9 [M + H]+ (ESI positive ion mode), m/ Z603.1[M + HCOO]-(ESI negative ion mode) [Chem. 8 1 1]

Example 471 3-({(11:,4〇-4-[4-(Trifluoromethyl)piperidin-1-carbonyl]cyclohexyl}methyl)-8-{[6-(trifluoromethyl) Manufacture of pyridin-3-yl]methyl}-1-oxo-3,8-diazospiro[4-5]nonan-2-one (Compound No. 471) (lr, 4〇-4-({2 -Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, (lr, 4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridine-3-yl]methyl}-1-oxo-3 obtained using Reference Example 470-2 , 8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid, substituted tetrahydrofurfurylamine, using 4-(trifluoromethyl)piperidine hydrochloride and triethylamine The title compound (36 mg, yield 94%) was obtained as white solid. ), 1.3 7 -1.67 (5H,m), 1.72- 1.86(6H,m),1.87-2.02(4H,m),2.15-2.3 5(lH,m ),2.38-2.53(2H,m),2.54 -2.64(4H,m), 3.02(1 H,t,J=l 3 ·2Ηζ), 3.11(2H,d,J = 7.3Hz), 3.27(2H,s),3.62(2H,s),3 -99 (lH, d, J = 11.6 Hz), 4.76 (lH, d, J = 12.6 Hz), 7.65 (lH,d,J = 7.9 Hz), 7.84 (lH,d,J = -778- 201211053 7.6 Hz), 8.68 (lH, s) LC/MS [condition 1]: hold time 3.16 min; m/z 5 90.9 [M + H]+ (ESI positive ion mode), m/z 635.2 [M + HCO〇r (ESI negative ion mode) [Chem. 8 1 2]

Example 4 7 2 4-(l-{(lr,4〇-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1- Manufacture of oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarbonyl}piperidin-4-ylamino)benzonitrile (Compound No. 472) (lr, 4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decan-3-yl }methyl)cyclohexanecarboxylic acid, using (lr,4r)-4-[(2-oxo-8-{[6-(trifluoromethyl)pyridine-3-) obtained from Reference Example 470-2 Methyl}- oxa-3,8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid, substituted tetrahydrofurfurylamine, obtained using Reference Example 441-2 The title compound (3 Omg, yield 71%) was obtained from the title compound (3Omg, yield: 71%), mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid. 'H-NMRCSOOMHz^DClsjail.OSClH^^^l 1.3Hz), 1.37(2H,q, J=11.9Hz), 1.47- 1.67(3H,m),1.7 1-1.86(6H,m), 1.94(2H,d,J = 13.1Hz), 2.10(2H,brt,J-13.1Hz), 2.46(lH,tt,J=l 1.9,3.3Hz),2.5 2 -779- 201211053 -2.65(4H, m), 2.83 (lH, t, J = 11.5 Hz), 3.11 (2H, d, J = 7.4 Hz), 3. 19 (lH, t, J = 11.9 Hz), 3.27 (2H, s), 3.50-3.64 (lH, m), 3.61 (2H, S), 3.90 (lH, d, J = l4.3 Hz), 4.09 ( lH,d,J = 7.4 Hz), 4.54 (lH, d, J = 13.5 Hz), 6.5 6 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.65 (lH) , d, J = 7.8 Hz), 7.84 (lH, d, J = 8.2 Hz), 8.68 (lH, s). LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 639.0 [M + H]+ (ESI positive ion mode), m/z 683.2 [M + HCOO]- (ESI negative ion mode) 1 3]

Example 473 1-{(11&quot;,4〇-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1-carbo-3, Preparation of 8-diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarbonyl}piperidine-4-carbonitrile (Compound No. 473) Substituted (lr, 4r)-4-({2- side Oxy-8-[4-(trifluoromethyl)benzyl]-oxazo-3,8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, using reference example (lr,4r)-4-[(2-Sideoxy-8-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1-oxo-3,8- obtained from 470-2 The diazospiro[4.5]decane-3-yl)methyl]cyclohexanecarboxylic acid or a substituted tetrahydrofurfurylamine was substantially reacted in the same manner as in Example 10 except that 4-cyanopiperidine was used. The title compound (3 5 mg, yield 96%)yield of pale yellow solid. - 780 - 201211053 IH-NMR (300 MHz, CDCl3) 5: 1.05 (2H, q, J = 11.5 Hz), 1.55 (2H, q, J = 1 1.9 Hz), 1.57- 1.67 ( 1 H, m), 1.70-2.00 (1 2H, m), 2.43 (1 H, tt, J = U.9, 3.3 Hz), 2.49-2.66 (4H, m) , 2.90 (lH, dtt, J = 7.4, 4.1, 4.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.3 8-3.87 (4H, m), 3.62 (2H, s) 57.65 (lH, d, J = 7.8 Hz), 7.84 (lH, d, J = 7.4 Hz), 8.68 (lH, s) o LC/MS [condition 1]: hold time 2.12 Minutes; m/z5 47.8 [M + H]+ (ESI positive ion mode), m/z 592.1 [M + HCOO] — (ESI negative ion mode) [Chem. 8 1 4]. 0 fi^^N Person. Example 474-1

4-[(2-Sideoxy-1-oxo-3,9-diazospiro[5.5]undec-3-yl)methyl]benzoic acid methyl ester was produced in Reference Example 217-3 [4-(Methoxycarbonyl)benzyl]-2-oxo-oxo-3,9-diazospiro[5.5]undecane-9-carboxylic acid tert-butyl ester (〇.35g, A 4 M hydrogen chloride-dioxane solution (5.0 mL) was added to a methanol solution (0.5 mL) of 0.84 mmol. The reaction mixture was concentrated to dryness under reduced pressure. Chloroform (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (5.OmL) were added and shaken, and the organic layer was separated, and the aqueous layer was extracted three times with chloroform (10 mL). The combined organic layer was dried with EtOAc m. The resulting oil was used directly in the next stage of the reaction without purification. [化8 1 5]

Reference Example 4 7 4 - 2 4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-oxo-oxa-3,9-diazo snail [5.5] Methyl monoalkyl-3-yl]methyl}benzoate was prepared as 4-[(2-oxo-oxo-3,9-diazaspiro[5.5]undecane obtained in Reference Example 474-1. To a solution of methyl 3-methyl)methyl]benzoate (0.30 g) in dichloromethane (2.0 mL), 3,5-difluoro-4-methylmercaptobenzonitrile (by Aldrich) (购.15g, 0.92mmol) and sodium triacetate hydride (purchased from Aldrich) (〇.27g, 1.3mmol) were mixed and mixed for 2 hours. An aqueous solution of sodium hydrogencarbonate (5.0 mL) and ethyl acetate (5.0 mL) were added to the mixture and the mixture was shaken, and the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The title compound was obtained as a yellow solid (0.28 g, yield 71%). 'H-NMRCSOOMHz^DChja: 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, dsJ = 6.1 Hz), -782- 201211053 7.35 (2H, d , J = 7.8 Hz), 8.01 (2H, d, J = 8.2 Hz). LC/MS [Condition 1]: Hold time i.7i minutes; m/z469 8 [M + H]+ (ESI positive ion mode) [Chem. 8 1 6] 0

Reference Example 474-3 4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxa-3,9-diazospiro[5.5]undecane 4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-side oxy-1 - which is obtained from Reference Example 474-2 of -3-yl]methyl}benzoic acid Addition of potassium triacetate to tetrahydrofuran (1.0 mL) of methyl-3,9-diazospiro[5 . 5 ]undec-3-yl]methyl benzoate (82 mg, 0.17 mm 〇l) A stanol alkoxide (purchased from Aldrich) (37 mg, ® 〇. 26 mmol) was mixed for 4 hours. After a 4 M solution of hydrogen chloride-dioxane (0.13 mL) was added to the mixture, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate (5. 1 M Hydrochloric acid (5.0 ml) and ethyl acetate were added to the obtained aqueous layer and the mixture was shaken, and the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (1 mL). The combined organic layer was washed with EtOAc EtOAc EtOAc.

1H-NMR (300MHz, CDCl3) 6: 1.74 - 1.94 (6H, m), 2.68-2.90 (4H - 783 - 201211053, br m), 3.2 1 (2H, t, J = 6.5 Hz), 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]: Hold time 0.70 min; m/z 455.8 [M + H]+ (ESI positive ion mode), m/z 453.9 [M-Hr (ESI negative ion mode) [Chem. 8 1 7 】

Example 4 7 4 4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,9-diazospiro[5.5]undecane Manufacture of -3-yl]methyl}-N-[(tetrahydrofuran-2-yl)methyl]benzamide (Compound No. 474) Substituted 4-({2- Side Oxygen-9-[4-(III Fluoromethyl)benzyl]-1-oxo-3,9-diazospiro[5·5]undec-3-yl}methyl)benzoic acid, using 4-{{ [9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-oxo-oxa-3,9-diazospiro[5.5]undec-3-yl]methyl} The title compound was obtained as a yellow oil (14 mg, yield 47%). 1H-NMR (300MHz, CDCl3) 6: 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 (lH,ddd, J = 13.9, 7.4, 4.5 Hz), 3.72-3.94 (3H, m), 3.75 (2H, s), 4.07 (lH, dqsJ = 3.3, 7.4 Hz), 4.59 (2H, s), 6.54 (1 H, 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). -784- 201211053 LC/MS [Condition 1]: Hold time 0.94 min; m/z 53 8.9 [M + H]+ (ESI positive ion mode), m/z 536.9 [M-H]- (ESI negative ion mode)

φ Example 475 6-[1-(4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,9-diazospiro[ Preparation of 5.5]undecano-3-yl]methyl}benzhydryl)azetidin-3-oxy]nicotinonitrile (Compound No. 47 5 ) Substituted tetrahydrofurfurylamine, Reference Example 381 was used. The title compound was obtained as a colorless oil (14 mg, yield 70%). ) °

1H-NMR (300MHz, CDC13) 5: 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), 4.5 1-4.73 (2H, br m), 4.58 (2H, s), 5.42-5.52 ( 1 H,m), 6.9 l(lH,d,J = 8.6Hz), 7.22 (2H,d,J = 6.5Hz), 7.33(2H,d,J = 7_8Hz), 7.62(2H,d,J = 8.2 Hz), 7.85 (lH, dd, J = 8.6, 2.5 Hz), 8.44 (1 H, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 2.86 min; m/z 612.9 [M + H] + (ESI positive ion mode), m/z 657.0 [M + HCOO] - (ESI negative ion mode) -785- 201211053 【化8 1 9】 Ο

Example 476

4-f(3-丨4-[4-(3-gas basic oxy) 峨 steep-1-exyl] methyl side oxo-1-oxa-3,9-diazo snail [5·5] Preparation of eleven-indolyl-9-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 476) Substituting tetrahydrofurfurylamine '3-(piperidine-) synthesized using Reference Example 281-2 The title compound was obtained as a colorless oil (18 mg, yield: 86%).

1H-NMR (300MHz, CDCl3) 5: 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(lH,br m), 3.5 5-4.02(3H,br m),3.74(2H,s),4.52-4.67(1 Η,m), 4.58(2H,s ),7.12-7.18(2H, m), 7.22 (2H, d, J = 5.6 Hz), 7.26 (lH, d, J = 7.4 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.39 (lH, t, J = 7.4 Hz) , 7.39 (2H, d, J = 8.2 Hz) LC/MS [Condition I] ·• Hold time 3.18 min; m/z 640.0 [M + H]+ (ESI positive ion mode), m/z 684.0 [ M + HCOO]-(ESI negative ion mode) -786- 201211053 【化8 2 0】

Example 477 4-{[9-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,9-diazaspiro[5.5]undecane-3 -Methyl}-methyl--(furan-2-ylmethyl)benzamide (Chemical φ, material number 477) was produced in place of tetrahydrofurfurylamine, using mercaptoamine (purchased by Tokyo Chemical Industry Co., Ltd.) The title compound was obtained as a colorless oil (22 mg, yield: 92%). 1H-NMR (300MHz, CDC13) 5: 1.57- 1.87 (6H, m), 2.56-2.68 (4H, m), 3.16 (2H, t, J = 6.5 Hz), 3.73 (2H, s), 4.5 8 ( 2H, s), 4.63 (2H, d, J = 5_7Hz), 6.30 (lH, d, J = 3.0Hz), 6.32-6.36(1 H, m) , 6.57 (1 H, t, J = 5.3Hz) , 7.2 1(2H,d,J = 6.1Hz), 7.33(2H,d,J = 8.6Hz), 7.3 8(lH,d, φ J=1 ·2Ηζ), 7.76(2H,d,J = 8.6 Hz). LC/MS [Condition 1]: Hold time l_69 min; m/z 5 3 4.9 [M + H]+ (ESI positive ion mode), m/z 533.0 [MH; T (ESI negative ion mode) [Chem. 8 2 1 〕

-787- 201211053 Reference Example 4 7 8 -1 3-({5-[4-(4-Cyanophenoxy)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-2- side Manufacture of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester

Substituting (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride, using the 4-(piperidin-4-oxy)benzonitrile hydrochloride obtained in Reference Example 264-2, The title compound (46 mg, yield: 53%) ofyel. LC/MS [Condition 1]: retention time 4.13 minutes; m/z 520.7 [M-isobutene + H]+, 476.8 [M-isobutene-C02 + H] + (ESI positive ion mode), m/z 575.0 [ MH]_, 621.0[M + HCOO]_(ESI negative ion mode) [Chemical 8 2 2] HC1

Reference Example 478·2 4-(1-{5-[(2-Sideoxy-1 -oxa-3,8-diazospiro[4.5]decan-3-yl)methyl]pyrazine-2-carbonyl Manufacture of piperidine-4-oxy)benzonitrile hydrochloride in place of 3-({5-[4-(4-fluorobenzhydryl)piperidine-oxime-carbonyl]pyrazine-2-yl} Methyl)-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-8-carboxylic acid tert-butyl ester, using 3-({5-[] obtained in Reference Example 478-1 4-(4-cyanophenoxy)piperidine-1-cyclocarbonylpyrazin-2-yl}methyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane The title compound (45 mg, quantitative) of a yellow oil was obtained after the reaction of -78-201211053. LC/MS [Condition 1]: Hold time 1.54 minutes; m/z 476.8 [M + H]+ (ESI positive ion mode), m/z 474.9 [MH]- (ESI negative ion mode) [Chem. 8 2 3 】

Example 478 4-{1-[5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane Manufacture of -3-yl}methyl)pyrazine-2-carbonyl]piperidin-4-yl}benzonitrile (Compound No. 478)

4 - (1 - { 5 - [(2-oxo-oxo-1 -oxan-3,8-diazosuccinyl][4.5]decan-3-yl)methyl]pyrene obtained in Reference Example 4 7 8 -2 Pyrazin-2-carbonyl}piperidin-4-yloxy)benzonitrile hydrochloride (20 mg, 0.040 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (purchased) (l 〇_20 mg, 0.040 mmol) was dissolved in N,N-dimethylformamide. Triethylamine (13 μl, 0-090 mmol) was added and stirred vigorously at room temperature for 3 hours. After the 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 concentrated to dryness. The obtained residue was purified by silica gel column chromatography [塡 剂 : M M M 60 60 60 60 60 60 60 60 M M M 60 60 60 60 60 60 60 60 60 60 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 4- 4- 4- 4- 4- 1-[5-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3-yl}- Base) -789- 201211053 Pyrazine-2-carbonyl]piperidin-4-yloxy}benzonitrile (6.6 mg, yield 26%) as a colorless liquid. 'H-NMRCSOOMHz ' CDC13) 6: 1 . 83-2.1 6(6H,m), 2. 1 9-2.48(2H, brm), 2.78 -3.00(2H,m), 3.01-3.25(2H,br m ), 3.48 (2H, s), 3.63 ( lH, ddd, J = 13.5, 6.5, 4.9 Hz), 3.74 - 4.09 (5H, m) 54.63 (2H, s), 4.73 (lH, tt, J = 5.3, 2.9 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.56-7.7 1 (6H, m), 8.53 (lH, d, J = 1.6 Hz), 8.88 (lH, d, J = 1.6 Hz) » LC/MS [Condition 1]: Hold time 3.32 minutes: m/z 634.8 [M + H]+ (ESI positive ion mode), m/z 632.9 [M-Hr (ESI negative ion mode) [Chem. 8 2 4 】

Example 479 4-{[3-({5-[4-(4-Cyanophenoxy)piperidin-1-carbonyl]pyrazin-2-yl}methyl)-2-oxan-1- The production of oxa-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 479) was obtained in Reference Example 478-2 4-( 1-{5-[(2-Sideoxy.-1-oxo-3,8-diazospiro[4.5]癸院-3-yl)methyl]indolebi-2-ylyl}piperidine- 4-Oxo)benzonitrile hydrochloride (15 mg, 0.030 mmol) was added to a sodium hydrogencarbonate aqueous solution, and then extracted three times with chloroform. After the combined organic layer was concentrated under reduced pressure, 3,5-difluoro-4-carbamidobenzonitrile (5.8 mg 'O. 〇 4 〇 mmol) was added to the obtained residue, followed by dissolution. In dichloromethane. Add to the reaction mixture -790- 201211053

Sodium triacetate borohydride (9.5 mg, 〇.〇 50 mmol) was vigorously stirred at room temperature for 1 Torr. After the completion of the reaction, water was added, and extraction was carried out twice with chloroform. The combined organic layers were concentrated under reduced pressure. The residue thus obtained was purified by ruthenium column chromatography [mixing agent: yttrium 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, and concentrated to dryness under reduced pressure to give 4-{[3-({5-[4-(4-cyanophenoxy))- 1-Orchiyl] 嚷-2-yl}methyl)-2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5- Difluorobenzonitrile (14 mg, yield 75%) of a colorless liquid. 'H-NMR (300MHz &gt; CDCl3) 5: 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 (lH, ddd, J = 13.1, 5.7, 4.5 Hz), 3.76 (2H, s), 3.82 (lH, ddd, J = 13.1, 8.2, 3.7 Hz), 3.88 (lH, ddd, J = 13.1, 8.2 , 3.7 Hz), 3.99 (lH, ddd, J = 13.1, 6.5, 4.9 Hz), 4.62 (2H, s), 4.73 (lH, 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 (lH, d, J = 1.6 Hz), 8.90 (lH, d, J = l. 6Hz). LC/MS [Condition 1]: Hold time 3.11 minutes; m/z 627.8 [M + H]+ (ESI positive ion mode), m/z 625.9 [MH]_ (ESI negative ion mode) [Chem. 8 2 5 】

Example 4 8 0 791 - 201211053 3,5-Difluoro-4-{[3-({5-[4-(6-fluorobenzo[(1]isoxazol-3-yl)piperidine-1) -carbonyl]pyridine-2-yl}methyl)_ 2 -oxooxy-1 -oxa-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 480) Preparation of (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride using 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (purchased The title compound (24 mg, yield: 83%) was obtained as a colorless amorphous material. (1H-NMR (CDC13) 6: 1,76 (2H, dt, J = 13.5, 7.4 Hz), l .96 (2H, br d , J = 13.1 Hz), 1.97-2.37 (4H, br m), 2.4 8-2.7 5 (4H, br m), 3.03-3.43 (2H, br m), 3.32 (2H, s), 3.40 (lH, tt, J=ll.l, 3.7 Hz), 3.74 (2H, s), 3.75 - 4.03 (1 H, br m), 4.5 6 - 4.8 6 ( 1 H ,brm), 4.5 7 (2 H, s), 7.1 0 ( lH,dt,J = 2.5,8.8 Hz), 7.22 (2H,d,J = 5.7 Hz), 7.28 (lH,dd,J = 8.8, 2.5 Hz), 7.36 (lH, d &gt; J = 8.2 Hz), 7.63 (lH, dd, J = 8.6, 4.9 Hz), 7.78 (lH, dd, J = 8.2, 2.0 Hz), 8.64 (lH, d, J = 2.0 Hz) LC/MS [Condition 1]: Hold time 3.20 minutes; m/z 644.8 [M + H]+ (ESI is away Mode), m / z688.9 [M + HCOO] - (ESI negative ion mode) of [826]

Example 481 1^-(Benzo[(1][1,3]dioxazole-5-ylmethyl)-6-{[8-(4-cyano-2,6-difluorobenzyl) )-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl} smoke test • 792-201211053 The production of indoleamine (Compound No. 481) was replaced (4 - Fluorophenyl)(piperidin-4-yl)methanone hydrochloride was substantially the same as Example 392 except that benzo[dni,3]dioxazol-5-ylmethylamine (purchased) was used. Reaction gave the title compound (2 mg, yield 77%) as a white solid.

1H-NMR (CDCl3) 5: 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), 4.5 5 (2H, s), 5.96 (2H, s), 6.46 (lH, br t, J = 5.0 Hz), 6.78(3H,d,J = 7.8Hz), 6.82(lH,dd,J-7.8,1.6Hz), 6.85(lH,d,J = 1.6Hz), 7.22(2H,d,J = 6.1Hz), 7.34 (lH, d, J = 8.2 Hz), 8.08 (lH, dd, J = 8.2, 2.0 Hz), 8.9 1 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 2_71 minutes; m/z 57 5.8 [M + H]+ (ESI positive ion mode), m/z 5 73.8 [M-H]_ (ESI negative ion mode)

Example 4 8 2 4-{[3-({5-[4-(4-Cyanophenoxy)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2-oxo-oxyl -(-Fluoro- 3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 482) Pyridin-4-yl)methanone hydrochloride, except for 4-(piperidin-4-oxy)benzonitrile hydrochloride obtained in Reference Example 264-2, substantially -793-201211053 was carried out with Example 392 The same reaction gave the title compound (25 mg,yield: 89%) as a white solid. ???H-NMR CCDCl s: 1.74-2.14 (4H, br m), 1.76 (2H, dt, J=l 2.7, 7.8 Hz), 1.96 (2H, br d, J = 12.7 Hz), 2.5 1- 2.72 (4H, m), 3.29-4.03 (4 H, br m), 3.3 1 (2H, s), 3.74 (2H, s) s4.56 (2H, s), 4.65-4.75 (lH, m), 6.97 (2H, d5J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.36 (lH5d, J = 7.8 Hz), 7.60 (2H) , d, J = 8.6 Hz), 7.76 (lH, dd, J = 8.2, 2.0 Hz), 8.6 1 (lH, d, J = 2.0 Hz) » LC/MS [Condition 1]: Hold time 3.08 min; m /z626.8[M + H]+ (ESI positive ion mode), m/z670_9[M + HCOO]_ (ESI negative ion mode) [Chem. 8 2 8]

Example 4 8 3 6-[ 1-(6-{[8-(4-Mercapto-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazo snail [4.5] Manufacture of (cyclofluoro-3-)(piperidin-4-yl) The same reaction as in Example 392 was carried out to give the title compound (24 mg, m.p. Yield 86%) of a white solid. 1H-NMR (CDCl3) 6: 1.71-2.22 (4H, br m), 1.76 (2H, dt, J = 1 3.9, 6.5 - 794 - 201211053

Hz), 1.95 (2H, d, J = 13.5 Hz), 2.49-2.72 (4H, br m), 3.3 0-3.52 (1 Η , br m), 3.31 (2H, s), 3.5 5-3.84 (2H , br m), 3.74 (2H, s), 3.95-4.18 (lH, br m), 4.56 (2H, s), 5.43 (lH, tt, J = 7.4, 3.7 Hz), 6.82 (lH, d, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1 H, d, J = 8.2 Hz), 7.76 (2H, dd, J = 8.2, 2.5 Hz), 7.8 1 (2H, dd , J = 8.6, 2.5 Hz), 8.46 (lH, d, J = 2_5 Hz), 8.62 (lH, d, J = 2.5 Hz).

LC/MS [Condition 1]: Hold time 2.96 minutes; m/z 627.8 [M + H] + (ESI positive ion mode), m/z 671.9 [M + HCO〇r (ESI negative ion mode) 2 9]

Example 4 8 4 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane Preparation of -3-yl]methyl}-N-(4-cyanobenzyl)nicotinamide (Compound No. 484) Substituted (4-fluorophenyl)(piperidin-4-yl)methanone The title compound (23 mg, yield: 92%) was obtained as white crystals. 1H-NMR (CDCl3) 6: 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), 3.3 1 (2H, s), 3.73 (2H, s), 4.55

(2H, s), 4.71 (2H, d, J = 5.7 Hz), 6.86 (lH, br t, J = 5.7 H z), 7.2 2 (2 H - 795 - 201211053 , d, J = 5.7 Hz), 7.35 (1 H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.65 ( 2H, d, J = 8.2 Hz), 8.12 (lH, dd, J = 8.2, 2.0 Hz) , 8.95 (lH, d, J = 2.〇Hz)0 LC/MS [Condition 1]: Hold time 2.53 minutes; m/z5 56.7 [M + H]+ (ESI positive ion mode), m/z 554.8 [MH]-(ESI negative ion mode) [Chemical 8 3 0]

Example 485 3,5-Difluoro-4-{[2-oxo-3-({5-[4-(quinolin-4-yl)piperazine-1-carbonyl]pyridin-2-yl}A Manufacture of (4-fluorophenyl)(piperidine-) by the formation of 1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 48 5 ) The same reaction as in Example 392 was carried out to give the title compound, except for the 4-(4-piperazin-1-yl)quinoline dihydrochloride salt obtained from Reference 278-2. (25 mg, yield 88%) of a cream solid. 'H-NMRCCDChia: 1,77 (2H, dt, J = 13.1, 7.0 Hz), l, 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),3.5 7-3.8 9(2H,br m), 3.7 5 (2 H, s), 3.9 1 - 4.2 7 (2 H, brm), 4.58 (2H, s), 6.87 (lH, d, J = 4.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.39 (lH, d, J = 8.2 Hz), 7.53 (lH, t, J = 7.8 Hz), 7.7 0 (lH, t, J = 7.4 Hz), 7.82 (l H, dd, J = 7.8, 2.0 Hz), 8.02 (lH, d, J = 8.2 Hz), 8.09 (lH, d, J = 8.6 Hz), 8.67 (-796-201211053 lH, d, J = 2.0 Hz), 8.78 (lH, d, J = 4.9 Hz). LC/MS [Condition 1]: Hold time 0.53 min; m/z 63 8.0 [M + H] +, 319.5 [M + 2H] 2 + (ESI positive ion mode), m/z 681.8 [M + HCOO] ( ESI negative ion mode) [Chem. 8 3 1]

Example 486 4-{[3-({5-[4-(2-Chlorophenylamino)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2-oxo-oxy-1- oxole -3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 48 6) was prepared by substituting (4-fluorophenyl) (piperidine) -4-yl)methanone hydrochloride was the same as Example 392 except that N-(2-chlorophenyl)piperidin-4-amine dihydrochloride obtained in Reference Example 286-2 was used. The reaction gave the title compound (29 mg, m. 1H-NMR (CDC13) 6: 1.3 8- 1.72 (2H, br m), 1.78 (2H, dt, J = 1 3.9, 7.4 Hz), 1,98 (2H, br d, J = 1 3.9 H z) , 2.0 3 - 2.3 6 (2 H ,brm), 2.50-2.78 (4H,br m),3.1 1 1-3.34(2H,br m), 3 . 3 3 (2 H, s), 3.5 5 - 3.7 7 (2 H, brm), 3 · 76 (2 Η, s), 4.27 (lH, d, J = 7.8 Hz), 4.47-4.67 (1 H, brm), 4.58 (2H, s), 6.68 (lH) , t, J = 7.4 Hz), 6.70 (lH, d, J = 7.8 Hz), 7.16 (lH, t, J = 7.8 Hz), 7.24 (2H, d, J = 5.7 Hz), 7.29 (lH, d , J-7.4 Hz), 7.3 7 (lH, br d , J = 8.6 Hz), 7.78 (lH, d, J = 7.9 Hz), 8, 63 (lH, br s). -797- 201211053 LC/MS [Condition 1]: Hold time 3.32 minutes; m/z 63 4.8 [M + H]+ (ESI positive ion mode), m/z 679.0 [M + HCOO]- (ESI negative ion mode) [化8 3 2]

Example 4 8 7 4-{[3-({5-[4-(2,4-difluorobenzylidyl)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2- side Manufacture of (4-fluorobenzene) by the production of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 48 7) (Piperidin-4-yl)methanone hydrochloride, substantially in addition to (2,4-difluorophenyl)(piperidin-4-yl)methanone hydrochloride (purchased) The same reaction as Example 3 was afforded the title compound (27 mg, yield: 1 H-NMR (CDC13) 5: 1.64-1.83 (4H, m), 1.83-2.13 (2H, m), 1.95 (2H, br d, J = l 3.1 Hz), 2.42-2.77 (4H, br m), 2.9 5 - 3.3 0 (2 H, brm), 3.3 l(2H, s) , 3.34 - 3.50 (1 H, m), 3.57-3.94 (1 H, br m), 3.74 (2H, s ) , 4.42-4.80 (lH, br m), 4.56 (2H, s), 6.90 (lH, dt, J = 2.5, 10.0 Hz), 7.00 (lH, t, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.34 (lH, d, J = 8.6 Hz), 7.74 (lH, d, J = 8.6 Hz), 7.89 (lH, q, J = 8.2 Hz), 8.59 (lH, br s). LC/MS [Condition 1]: Hold time 3.16 min; m/z 649.8 [M + H]+ (ESI positive ion mode), m/z 693.9 [M + HCO〇r (ESI negative ion mode) -798- 201211053 【化8 3 3】

Example 488

4-{[3-({5-[4-(3-Cyanophenoxy)piperidine-1-carbonyl]pyridine_2-yl}methyl)-2-oxan-1-oxo-3, Preparation of 8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 48 8) Substituted (4-fluorophenyl)(piperidine-4 Methyl ketone hydrochloride was subjected to the same reaction as in Example 3M to give the title compound (m. 2 9 mg, in quantitative yield, of a colorless amorphous material. 1H-NMR (CDCl3) 6: 1.68-2.13 (4H, br m), 1.76 (2H, dt, J = 13.1, 7.4 Hz), 1.95 (2H, br d, J = 1 3.5 H z) , 2.5 0 - 2.7 2 (4 H , brm), 3.31 (2H, s), 3.3 3-3.56 (lH, br m), 3.5 7 - 3.7 8 ( 1 H, brm), 3.7 4 (2 H, s), 3.78 - 3.99(2H,br m),4.56(2H,s),4.59-4.69(lH,m),7.15(lH,d,J = 7.8

Hz), 7.17 (lH, br s), 7.22 (2H, d, J = 6.5 Hz), 7.27 (lH, d, J = 7.8 Hz), 7.36 (lH, d, J = 8.2 Hz), 7.40 (lH) , t, J = 7.8 Hz), 7.76 (lH, dd, J = 8.2, 2.0 Hz), 8.61 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.14 minutes; m/z 626.8 [M + H]+ (ESI positive ion mode), m/z 670.9 [M + HCOO] _ (ESI negative ion mode) -799- 201211053 【化8 3 4】

Example 489 4-{[3-({5-[4-(4-Chlorobenzoguanidino))piperidine-1-carbonyl]pyridin-2-yl}methyl)-2-oxo-oxy-1-one Preparation of -3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 489) Substituted (4-fluorophenyl) (piperidine- The same reaction as in Example 3 92 was carried out except that (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (purchased) was used. The title compound (27 mg, yield 92%) was obtained as colorless. 1H-NMR (CDCl3) 6: 1.72-2.00 (4H, m), 1.76 (2H, dt, J = 12.7, 8.2 Hz), 1.96 (2H, br, J = 1 3.9 Η z), 2.5 1 - 2.7 2 (4 Η , brm), 3.00-3.36 (2H, br m), 3.3 l (2H, s), 3.45-3.5 9 (lH, m), 3.67-3.94 (lH, br m), 3.74 (2H, s), 4.52-4.77 (lH, br m), 4.56 (2H, s), 7.22 (2H, d, J = 5.7 Hz), 7.35 (lH, d, J = 8.2 Hz), 7.47 (2H, d, J = 9.0 Hz), 7.76 (lH, dd, J = 8.2, 2.5 Hz), 7.90 (2H, d, J = 9.0 Hz), 8.61 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.24 minutes; m/z 647.8 [M + H]+ (ESI positive ion mode), m/z 691.8 [M + HCOO]_ (ESI negative ion mode) 3 5]

-800 - 201211053 Example 4 9 0 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2.Sideoxy-1-oxo-3,8-diazo snail [4.5 Manufacture of decyl-3-yl]methyldihydro-(furan-2-ylmethyl)nicotinium amide (Compound No. 490)

Substituting (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride, the same reaction as in Example 392, except using furan-2-ylmethylamine (p.) (18 mg, 76% yield) of white solid. 1H-NMR (CDC13) 5: 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), 6.39-6.5 1 (lH, br m ), 7.22 ( 2H,d,J = 5.7Hz), 7.36(lH,d,J = 8.2Hz), 7.39(lH,br s), 8.09 (lH,dd,J = 8.2,2.0Hz), 8.92(lH,d, J = 2.0Hz). LC/MS [Condition 1]: Hold time 1.30 minutes; m/z 521.7 [M + H]+ (ESI positive ion mode), m/z 519.9 [M-H]- (ESI negative ion mode)

Example 491 4-{[3-({5-[3-(3-Cyanophenoxy)azetidin-1-carbonyl]pyridin-2-yl}methyl)-2-oxo- Manufacture of 1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 491) -801 - 201211053 Substituted (4-Fluorine Phenyl)(piperidin-4-yl)methanone hydrochloride, except for the 3-(azetidin-3-yloxy)benzonitrile hydrochloride obtained in Reference Example 3 90-2, substantially The title compound (16 mg, yield 59%) was obtained as a white solid. </RTI> <RTIgt; </RTI> NMR (CDCl3) 5: 1.75 (2H, dt, J = 13.5, 7.0 Hz), 1.95 (2H) , br d, J =1 3.1Ηζ), 2.5 l-2.73 (4H, br m), 3.3 1 (2 H, s), 3.7 4 (2 H, s), 4.22 - 4.44 (2H, br m), 4.5 6 (2 H, s) s 4.5 9 - 4.7 7 (2 H , brm), 5.0 5 (1 H, 11, J = 6.1, 3.7 Hz), 6.96-7.05 (2H, m), 7.22 (2H, d, J = 6.0 Hz), 7.33 (lH, dt, J = 7.8, l_2 Hz), 7_37 (lH, d, J = 8.2 Hz), 7.42 (lH, t, J = 7_8 Hz), 7.98 (lH, dd, J = 8.2, 2.0 Hz), 8.72 - 8.84 (lH, m). LC/MS [Condition 1]: Hold time 3.00 min; m/z 5 98.8 [M + H]+ (ESI positive ion mode), m/z 642.9 [M + HCO〇r (ESI negative ion mode) [Chem. 8 3 7]

Example 492 3,5-Difluoro-4-({2-Sideoxy-3-[(5-{4-[4-(trifluoromethyl)phenyl)]piperidin-1-carbonyl}pyridine Manufacture of -2-yl)methyl]-1-oxo-3,8-diazospiro[4.5]decane-8-yl}methyl)benzonitrile (Compound No. 492) (4-fluorophenyl) (piperidin-4-yl)methanone hydrochloride, using the N-[4-(trifluoromethyl)phenyl]piperidin-4-amine dihydrochloride obtained in Reference Example 39, 2 The same reaction as in Example 392 was carried out to give a colorless amorphous material of the title compound: 802-201211053 (25 mg, yield: 85%). 1H-NMR (CDC13) 5: 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, Brm), 2.48-2.74 ( 4H, m), 3.00-3.3 6 (2H, br m), 3.30 (2H, s), 3.53 - 3.69 (lH, m), 3.65 - 3.88 (lH, br m), 3.74 (2H, s), 3.91 (lH, 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 (lH, d, J = 8.2 Hz), 7.41 ( 2H, d, J = 8.2 Hz), 7.75 (lH, dd, J = 7.8, 2.0 Hz), 8.60 (lH, br s). LC/MS [Condition 1]: Hold time 3.50 min; m/z 669.0 [M + H]+ (ESI positive ion mode), m/z 712.9 [M + HCO〇r (ESI negative ion mode) 3 8]

Example 493 4-{[3-({5-[4-(3-Cyano-4-fluorophenylamino)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2- side Production of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 493) Substituted (4-fluorophenyl) (piperidin-4-yl)methanone hydrochloride, except for 2-fluoro-5-(piperidin-4-ylamino)benzonitrile dihydrochloride obtained in Reference Example 442-2, The same reaction as in Example 392 was carried out to give the title compound (25 mg, yield 86%) as a pale white amorphous material. -803- 201211053 1H-NMR (CDCl3) 5: 1.27-1.59 (2H, br m), 1.76 (2H, dt, J = 1 3.9, 7.4

Hz), 1.96 (2H, d, J = 13.5 Hz), 2.00-2.3 1 (2H, br m), 2.45-2.78 (4H, br m), 2.96-3.32 (2H, br m), 3.3 1 (2 H, s), 3.4 1 - 3.5 7 (1 H, m), 3 . 5 8 -3.92 (1 H, br m), 3.69 (lH, d, J = 8.2 Hz), 3.74 (2H, s), 4.42-4.8 1 (lH, br m), 4.47-4.75 (3H, m), 4.55 (2H, s), 6.67-6.84 (2H, m), 7.02 (lH, t, J = 9.0 Hz), 7.22 ( 2H, d, J = 6.1 Hz), 7.35 (lH, d, J = 8.2 Hz), 7.75 (l H, dd, J = 8.2, 2.0 Hz), 8.60 (lH, d, J = 1.6 Hz). LC/MS [Condition 1]: Hold time 3.16 minutes: m/z 643.8 [M + H] + (ESI positive ion mode), m/z 688_0 [M + HCOO] _ (ESI negative ion mode) [Chemical 8 3 9 】

Example 494 3,5-Difluoro-4-({2-o-oxo-3-[(5-{4-[4-(trifluoromethyl)phenylsulfonyl]piperidine-1-carbonyl} Manufacture of pyridin-2-yl)methyl]-1-oxo-3,8-diazaspiro[4·5]nonane-8-yl}methyl)benzonitrile (Compound No. 494) Fluorophenyl)(piperidin-4-yl)methanone hydrochloride, other than 4-[4-(trifluoromethyl)phenylsulfonyl]piperidine hydrochloride obtained in Reference Example 3 93-6 The title compound (27 mg, yield 84%) was obtained as a colorless amorphous material. 1H-NMR (CDCl3) 5: 1.66-1.88 (4H, m) 51.96 (2H, d, J = 13.1 Hz), 2.01-2.1 7 (2H, m), 2.44-2.72 (4H, br m ), 2.7 Ο - 3 . 1 6 ( 2 Η , brm), 3.12-3.27 (lH, m), 3.3 1 (2H, s), 3.7 1- 4.09 (lH, br m), 3.74 (2H, s) 201211053 , 4.55 ( 2H, br s), 4.5 8 - 5.0 0 ( 1 Η, brm), 7.2 2 (2 H, d, J = 5.7 H z), 7.3 4 ( lH,d,J = 7.8 Hz), 7.71 (lH, 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 (lH, s). LC/MS [Condition 1]: Hold time 3.26 minutes; m/z 717.9 [M + H]+ (ESI positive ion mode), m/z 761.9 [M + HCO〇r (ESI negative ion mode)

[化8 4 0 ]

Example 495 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]癸院-3- Substituted by the manufacture of methyl}-N-[3,3,3-dioxa-2-(4-phenylphenyl)-2-propanyl]nicotinium amide (Compound No. 495) Fluorophenyl)(piperidin-4-yl)methanone hydrochloride '3-amino-1,1,1-trifluoro-2-(4-fluorophenyl) obtained using Reference Example φ 434-2 The title compound (20 mg, yield 68%) was obtained as a colorless amorphous material. 1H-NMR (CDCl3) 5: 1.67-1.83 (2H, m), 1.93 (2H, br d, J = 13.5 Hz), 2.43 -2.7 1 (4H, br m), 3.30 (2H, s), 3.72 ( 2H, s), 4.05 (lH, dd, J = 15.1, 7.0 Hz), 4.2 1 (lH, dd, J = 15.1, 6.1 Hz), 4.45 (2H, s), 5.88 (lH, s), 7.07 ( lH,t,J = 8.6Hz), 7.14-7.25(3H,m), 7.36(lH,t,J = 5.3Hz), 7.63(2H,dd,J = 8.2,5.7Hz), 7.98(lH,dd , J = 8.2, 2.0 Hz), 8.80 (lH, d, J = 2.0 Hz). -805- 201211053 LC/MS [Condition 1]: Hold time 3.24 minutes; m/z 647.8 [M + H]+ (ESI positive ion mode), m/z 645.9 [M-Hr (ESI negative ion mode) [ 8 4 1]

Reference Example 4 9 6 -1 4-[2-(Trifluoromethyl)porphyrin-4-yl]piperazine-1-carboxylic acid tert-butyl ester was produced in 4-chloro-2-(trifluoromethyl) Adding N to a solution of quinoline (0.20 g, 〇.86 mmol), piperazine _ 1-resin acid butyl vinegar (0.24 g, 1.3 mmol) in N-methyl-2-indole (2 mL) N-Diisopropylethylamine (0.30 mL, 1.7 mmol). After the reaction mixture was stirred at 1200 ° C for 5 hours, ethyl acetate (8 mL) and water (4 mL). The organic layer was washed with water (4 mL EtOAc). %) Amber solid. LC/MS [Condition 2]: Hold time 3.77 minutes; m/z3 82.0 [M + H]+, 326.0 [M-isobutene + H] + (ESI positive ion mode) [Chem. 8 4 2]

Π.Η 2HCI Reference Example 4 9 6 - 2 4-(Piperazin-1-yl)-2-(trifluoromethyl)quinoline dihydrochloride as a substitute for 4((quinolin-4-yl)per Tert-butyl-1-carboxylic acid tert-butyl ester, using the reference -806-201211053 Example 496-1 4-[2-(trifluoromethyl)quinolin-4-yl]piperazine-1-carboxylic acid third The same reaction as in Reference Example 2 78-2 was carried out except for the butyl ester to give the title compound (0.30 g, yield, quantitative) as a milky white solid. 1H-NMR (DMSO-d6) 5: 3.36-3.48 (4H, m), 3.48-3.60 (4H, m), 7.37 (1H, s), 7.73 (1 H,ddd,J = 8.2,7.0,1 · 2Ηζ), 7.88 (1 H, ddd, J = 8.6, 7.0, 1.2 Hz), 8.12 (lH, d, J = 8.6 Hz), 8.17 (lH, d, J = 8.2 Hz), 9.39 (2 H, Br s) ο • [化8 4 3] r\

Example 496

3,5-Difluoro-4-({2-Sideoxy-3-[(5-{4-[2-(trifluoromethyl)quinolin-4-yl]piperazine-1-carbonyl}pyridine- Production of 2-yl)methyl]-1-oxo-3,8-diazospiro[4.5]decane-8-yl}methyl)benzonitrile (Compound No. 496) Substituted (4-fluorophenyl) (piperidin-4-yl)methanone hydrochloride, using the 4-(piperazin-1-yl)-2-(trifluoromethyl)sormine dihydrochloride obtained in Reference Example 496-2, The same reaction as in Example 392 was afforded to give the title compound (27 mg, yield 84%) as colorless. 1H-NMR (CDCl3) 5: 1.79 (2H, dt, J = 13.5, 7.0 Hz), 1.97 (2H, d, J = 1 3 .1 H z), 2.5 1 - 2.7 6 (4 H , brm), 3 . 1 2 - 3.5 7 (2 H, brm), 3.33 (2H, s), 3.63-4.25 (4H, br m), 3.76 (2 H, s), 4.5 8 (2H, s), 7.1 7 ( 1 H, s), 7.2 3 (2H, d, J = 6.1Hz), 7.39 (lH, d, J = 8.2Hz), 7.64 (lH, t, J = 7.4Hz), 7.79 -807 - 201211053 (lH ,t,J = 7.8Hz),7.8 2(lH,dd,J = 7.8,l .6Hz),8.0 5(lH,d,J = 8.6Hz), 8.20(1 H,d,J = 8.6Hz) , 8.67 (lH, d, J = 1.6 Hz). LC/MS [Condition 1]: Hold time 3.36 min; m/z 705.9 [M + H] +, 353.5 [M + 2H] 2 + (ESI positive ion mode), m/z 749.9 [M + HCO〇 r (ESI negative ion mode) [Chem. 8 4 4]

Example 497 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4_5]decane-3- Manufacture of methyl]-N-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxypyridin-3-yl)propyl]nicotinium amide (Compound No. 497)

Substituting (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride, using 3-aminotrifluoro-2-(6-methoxypyridin-3-yl) obtained in Reference Example 437-2 In the same manner as in Example 392, the title compound (17 mg, yield: 57%) was obtained as a colorless amorphous material. 'H-NMR (CDC13) 6: 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), 3.3 1 (2H, s), 3.72 (2H, s), 3.92 (2H, s), 4.05 (1 H, dd, J = 5.1, 7.0 Hz), 4.2 l (lH, dd, J = l 5.1, 5.7 Hz ), 4.46 (2H, s), 6.03 (lH, s), 6.74 (lH, d5J = 9.0 Hz), 7.14-7.25 (3H, m), 7.56 (lH, br, J = 4.9H z), 7.8 6 (1 H, dd, J = 8.6, 2.5 H z ), 8.00 (1H, dd, J = 8.2, 2.0 Hz), 8.37 (lH, s), 8-83 (lH, s). -808- 201211053 LC/MS [Condition 1]: Hold time 3.04 minutes; m/z 660.7 [M + H]+, 330.9 [M + 2H]2 + (ESI positive ion mode), m./z658.9 [M-Hr (ESI Negative Ion Mode) [Chem. 8 4 5]

Example 4 9 8 4-{[3-({5-[4-(4·T-butylbenzylidene)piperidin-1-carbonyl]pyridin-2-yl}methyl)-2 - side Production of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 498) (4-fluorophenyl) (piperidin-4-yl)methanone hydrochloride, using (4-t-butylphenyl)(piperidin-4-yl)methanone hydrochloride obtained in Reference Example 333-2, substantially The same reaction as in Example 3 92 was carried out to give the title compound (30 mg, yield, quantitative) as a colorless amorphous material. 1H-NMR (CDCh) 5: 1.3 5 (9H, s), 1.73-2.15 (4H, br m), 1.76 (2H, dt, J = 1 3 .5, 7.4 Hz), 1.96 (2H, br d, J = 1 3 . 5 Hz), 2.4 9 - 2.7 2 (4 H , brm ), 3.00-3.36 (2H, br m), 3.30 (2H, s), 3.48-3.65 (lH, m), 3.68 -3.92 (lH, br m), 3.74 (2H, s), 4.53 - 4.75 (lH, br m), 4.5 6 (2 H, s), 7.2 2 (2H, d, J = 6.1 Hz), 7.34 ( lH,d,J = 7.8 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.76 (lH, dd, J = 8.2, 2.0 Hz), 7.89 (2H&gt;d, J = 8.4 Hz), 8.61 ( lH,d,J = 2.0Hz) o LC/MS [Condition 1]: Hold time 3.60 minutes; m/z 669.9 [M + H]+, -809- 201211053 33 5.5 [M + 2H]2 + (ESI Positive ion mode), m/z 714.1 [M + HCO〇r (ESI negative ion mode) [Chem. 8 4 6]

Example 499 3,5-Difluoro-4-{[3-({5-[4-(2-methoxyphenylamino)piperidin-1-carbonyl]pyridin-2-yl}methyl) Preparation of 2-oxo-oxo-oxa-3,8-diazospiro[4.5]decane-8-yl]methyl}benzonitrile (Compound No. 499) Substituted (4-fluorophenyl) (piperider) Pyridin-4-yl)methanone hydrochloride was substantially the same as Example 3 except that N-(2-methoxyphenyl)piperidin-4-amine dihydrochloride obtained in Reference Example 292-2 was used. The same reaction of 92 gave the title compound (23 mg,yield: 81%) as colorless amorphous. 1H-NMR (CDC13) 6: 1.37- 1.64 (2H, br m), 1.7 5 (2 Η, dt, J = 13.5, 6.9 Hz), 1.95 (2H, br d, J = 1 3.5 H z), 2.0 1 - 2.2 8 (2 H, brm), 2.54-2.70 (4H, br m), 3.07-3.32 (2H, br m), 3.3 0 (2 H, s), 3.5 1 - 3.6 5 (1 H, brm ), 3.65-3.80 (lH, br m), 3.74 (2H, s), 3.8 5 (3 H, s), 4.1 2-4.2 5 (1 H, br m) , 4.49-4.64 (lH, br m) , 4.5 6(2 H , s) , 6.63 (1 H , dd, J = 1.7, 7.6 Hz), 6.69 (lH, dt, J = 1.7, 7.9 Hz), 6.79 (lH, dd, J = 1.7, 7.9 Hz), 6.86 (lH, dt, J = 1.7, 7.6 Hz), 7.22 (2H, d, J = 6.3 Hz), 7.35 (lH, d, J = 7.9 Hz), 7.75 (lH, dd, J = 7.9) , 2.3 Hz), 8.60 (lH, d, J = 2_0 Hz). LC/MS [Condition 1]: Hold time 2.71 min; m/z 63 0.8 [M + H]+ (-810-201211053 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-oxan-1-oxo-3,8-diazospiro[ Preparation of 4.5-decane-8-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 500) Substituted (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride The title compound (22 mg, yield 82%) was obtained as a pale-white amorphous material. 1H-NMR (CDCl3) 6: 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 ), 2.6 5 - 2.8 5 ( 1 H, brm), 2.87-3.1 l(lH,br m),3 · 2 8 (2 H,s),3 5 6 - 3 · 7 6 (1 H,br m ), 3.74 (2H, s), 4.54 (2 H, s), 4.58-4.78 (1 H, br m), 7.14 (2H, d, J = 7.8 Hz), 7.17- 7.25 (lH, m), 7.22 (2H, d, J = 7.0 Hz), 7.27-7.37 (3H, m), 7.72 (lH, dd, J = 7.8, 2.0 Hz), 8.57 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 3.38 minutes; m/z 5 9 9.9 [M + H]+ (ESI positive ion mode), m/z 644.1 [M + HCOO]_ (ESI negative ion mode) -811 - 201211053 【化8 4 8】

Example 5 0 1 4-{[3-({(lr,4r)-4-[4-(3-Cyanophenoxy)piperidine-bucarbonyl]cyclohexyl}methyl)-2-oxanoxy 1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 501) was produced in Reference Example 398-2. (lr,4r)-4-{[8-(4-cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane -3-yl]methyl}cyclohexanecarboxylic acid (20 mg, 0.045 mmol), 1-hydroxybenzotriazole (2 mg, O. Olmmol) and 3-(piperidin-4-) obtained in Reference Example 281-2 To a solution of oxy)benzonitrile hydrochloride (12 mg, 0.049 mmol) in chloroform (1 mL), triethylamine (25pL, 0.18mmol) and 1-ethyl-3-(3-dimethylaminopropyl) The carbodiimide hydrochloride (13 mg, 0.067 mmol) was allowed to stand at room temperature for 5 days. After adding a solution of citric acid (26 mg) in water (1 mL), the title compound (27 mg, yield 96%) colorless amorphous material. IH-NMR (CDCl3) 5: 1.04 (2Hsq, J = 12.7 Hz), 1.46-1.67 (3H, m), 1.68-2.03 (1 2H, m), 2.39-2.52 (lH, m), 2.52-2.73 (4H, br m), 3.09 ( 2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.37-3.53 (lH, m), 3.54-3.88 (3H, m), 3.75 (2H, s) , 4.51-4.62 (lH, m), 7.10-7.18 (2H, m), 7.19-7.29 (3H, m), 7.39 (lH, t, J = 7.8 Hz). -812- 201211053 LC/MS [Condition 1]: Hold time 3.36 minutes; m/z 631.8 [M + H]+ (ESI positive ion mode), m/z 675.9 [M + HCOO]- (ESI negative ion mode ) 【化8 4 9】

Example 502 4-{[3-({(11:,4〇-4-[4-(3-Cyano-4-fluorophenylamino)piperidin-1-carbonyl]cyclohexyl}methyl) -2 - Preparation of 3-oxo-1-che-3,8-diazospiro[4.5] brothel-8-yl]methyl}-3,5-difluorobenzonitrile (Compound No. 502) (piperidin-4-yloxy)benzonitrile hydrochloride, using the 2-fluoro-5-(piperidin-4-ylamino)benzonitrile dihydrochloride obtained in Reference Example 442-2, The same reaction as in Example 5 0 1 was obtained to give the title compound (mjjjjjjjjjjjjjjjjjjjjjjjjjjj 1.3 2(2H,q,J= 1 1.9Hz), 1.47-1.6 7(3 H,m), 1.6 9-1.8 6(4H,m), 1.92 (2H,br d,J=13.5Hz) , 2.00-2.18(3H,m), 2.46(lH,tt,J=11.6,2.6Hz),2.53-2.72(4H,m ),2.82(lH,t,J=11.6Hz),3.09(2H,d , J = 7.6 Hz), 3.18 (lH, t, J = 12.9 Hz), 3.22 (2H, s), 3.36-3.51 (lH, m), 3.63 (lH, d, J = 8.3 Hz), 3.75 (2H5s) ), 3.89 (lH, br d, J = 1 3.9 H z), 4.5 3 (1 H, brd, J = 13.2 Hz), 6.68-6.80 (2H, m), 7.0 1 (lH, t, J = 8.6) Hz), 7.22 (2H, d, J = 5.9 Hz) LC/MS [Condition 1]: Hold time 3.34 minutes; m/z 648.8 [M + H]+ (ESI positive ion mode ), m/z692.9[M + HCOO]_(ESI negative ion mode) -813- 201211053 【化8 5 0】

Reference Example 5 03 -1 (lr, 4r)-4-({2-Sideoxy-8-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-1- Preparation of chewing-3,8-diazospiro[4-5]nonane-3_yl}methyl)cyclohexanecarboxylic acid methyl substituted 4-(trifluoromethyl)benzyl bromide using 丨-( The same reaction as in Reference Example 6-2 was carried out except for the bromomethyl)-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene. The title compound (yield: 18 g, yield 52) was obtained. %) of white powder. 1H-NMR (CDCl3) 5: 1.01 (2H, dq, J = 3.7s13.1 Hz), 1.4 1 (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 (lH, tt, J = 12.1, 3.5 Hz), 2.5 1- 2.75 (4H, brm), 3.08 (2H, d, J) = 7.4 Hz), 3.23 (2H, s), 3.66 (3H, s), 3.83 (2H, s). LC/MS [Condition 1]: Hold time 3.87 minutes: m/z 540.6 [M + H]+ (ESI positive ion mode), m/z 53 9.0 [MH]_, 584.9 [M + HCO〇r (ESI anion) Mode) 【化8 5 1】

201211053 Reference Example 5 03 -2

(lr,4r)-4-({2-Sideoxy_8·[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-1-oxo-3,8- Preparation of diazospiro[4.5]nonan-3-ylindolemethyl)cyclohexanecarboxylic acid (ir, 4r)-4-({2-side oxygen-8-) obtained in Reference Example 503-1 [2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-1-oxo-3, 8-diazospiro[4.5]decane-3-yl}methyl) ring To a suspension of hexanecarboxylic acid methyl ester (〇.16 g, 0.30 mmol) in 1,4-dioxane (4 mL) was added water (0.30 mL) and 1M aqueous sodium hydroxide (0.33 mL). Stir for 1 day. Thereafter, water (1.〇^^) was added thereto, and further stirred for 5 days. After concentration under reduced pressure, 1,4-dioxane was distilled off from the reaction mixture, and 1 M hydrochloric acid (0.33 mL) was added to the residue. The organic layer was separated with EtOAc (EtOAc) (EtOAcjjjjjjjjjj q, J = 12.6 Hz), 1.42 (2H, q, J = 13.0 Hz), 1.5 1-1.65 (lH, 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 ( 1 H, 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]: Hold time 3.46 min; m/z 526.6 [M + H]+ (ESI positive ion mode), m/z 524 .8[MH] (ESI negative ion mode) [Chem. 8 5 2]

-815- 201211053 Example 503 3-({(11*,4〇-4-[4-(pyrimidin-4-yl)piperazine-1-carbonyl]cyclohexyl}methyl)_8_ [2,3,5 , 6-tetrafluoro-4-(trifluoromethyl)benzyl]_1-oxo-3,8-diazospiro[4.5]decane-2-one (Compound No. 503) was prepared in Reference Example 503- 2 (lr, 4r)-4-({2-Sideoxy-8-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-i-oxo-3 , 8-diazospiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid (20 mg, 〇_〇 38 mmol), 4-(piperazin-1-yl) obtained in Reference Example 287-3 Pyrimidine dihydrochloride (10 mg, 〇. 〇 42 mmol) and 1-hydroxybenzotriazine (2 mg, 0.1 mmol) in chloroform (1 mL) were added triethylamine (26 01^, 〇.191 ^11〇1) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (llmg, 0.057mmol), after standing at room temperature for 2 days, add A solution of citric acid (22 mg) in water (1 mL), EtOAc (EtOAc m. White solid. 1H-NMR (CDCl3) 6: 1.06 (2H, q, J = 12.3 Hz), 1.49-1.69 (3H, m), I. 70-1.8 7(6H,m), 1.93(2H,br d, J= 1 3.5 Hz), 2.4 7 ( 1 Η, brt, J = II. 5Hz), 2.53-2.76(4H,m),3.11(2H,d , J = 7.4Hz), 3.24 (2H, s),

3.55-3.68(4H,br m),3.66-3.80(4H,br m), 3.8 3 (2H, s), 6.5 2 ( 1 H ,d,J = 6.1Hz), 8.26(lH,d,J = 6.1 Hz), 8.63 (lH, s). LC/MS [Condition 1]: Hold time 2.65 min; 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) -816- 201211053 【化8 5 3】

Example 504

4-{[3-({5-[3-(4-Cyanophenoxy)azetidin-1-phenyl]pyrene H-but-2-yl}methyl)-2-oxan -1-Aceto-3,8-diazo snail [4.5] brothel-8-yl]methyl}·3,5·difluorobenzonitrile (compound number 5〇4) Phenyl)(piperidin-4-yl)methanone hydrochloride, substantially in addition to 4-(azetidin-3-yloxy)benzonitrile obtained in Reference Example 3 8 3 -2 The same reaction of Example 2 9 2 gave the title compound (27 mg, yield, yield) as a milky white amorphous material. 1H-NMR (CDCl3) 5: 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), 3.3 1 (2H, s), 3.74 (2H, s), 4.20-4.47 (2H, br m), 4.56 (2H, s), 4.5 9-4.76 (2H, br m), 5.0 8 (1 H, 11, J = 6.5 Lu , 4.1 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.36 (lH, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.6) Hz), 7.98 (lH, dd, J = 8.2, 2.5 Hz), 8.79 (lH, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 2_94 minutes; m/z 598.9 [M + H]+ (ESI positive ion mode), m/z 643.1 [M + HCOO]- (ESI negative ion mode) 5 4]

201211053 Example 505 6-[1-(6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-oxy-1-oxa-3,8-diazospiro[ Preparation of 4·5]decane-3-yl]methyl}nicotinylsulfonyl)azetidin-3-yloxy]nicotinonitrile (Compound No. 5 05) Substituted (4-fluorophenyl) The same reaction as in Example 392 was carried out except that 6-(azetidin-3-oxy)nicotinonitrile obtained in Reference Example 381-2 was used. The title compound (9 mg, yield 3%) was obtained as colorless. 1H-NMR (CDCl3) 5: 1.75 (2H, dt, J = 13.5, 7.4 Hz), 1.95 (2H, br d, J =1 3.5 Hz), 2.47-2.78 (4H, br m), 3.3 1 (2H) , s), 3.74 (2H, s), 4.25 - 4.45 (2H, br m), 4 · 5 6 (2 H, s), 4.5 6 - 4 · 8 6 (2 H, brm), 5 · 4 3 - 5.5 8 ( 1 H,m), 6.92 (lH,d,J = 8.2 Hz), 7.22 (2H,d,J = 6.1 Hz), 7.36 (1 H,d, J = 8 ·2Ηζ),7.8 6 ( lH, dd, J = 8.2, 2.0 Hz), 7.98 ( lH, dd, J = 8.2, 2.0 Hz), 8.44 (1 H, d, J = 2.0 Hz), 8.80 (1 H, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time 2_73 minutes: m/z600_0[M + H]+ (ESI positive ion mode),! !1/2 644.1[]^ + 11(:00]-(Ugly 31 negative ion mode) [Chem. 8 5 5]

Example 506 4-{[3-({5-[4-(4-Cyanophenylamino))piperidine-1-carbonyl]pyridin-2-yl}methyl-818- 201211053 base)-2- side Preparation of oxy-1-oxo-3,8-diazospiro[4.5]decane-8-yl]methyl}_3,5-difluorobenzonitrile (Compound No. 506) Substituted (4-fluorophenyl) (piperidin-4-yl)methanone hydrochloride, substantially the same as Example 392 except using 4-(piperidin-4-ylamino)benzonitrile dihydrochloride obtained in Reference Example 441-2 The title compound (25 mg, yield 89%) was obtained as white solid. 1H-NMR (CDCl3) 5: 1.32-1.62 (2H, br m), 1.76 (2H, dt, J = 1 3.1, 7.4

Hz), 1.95 (2H, br d, J = 1 3 . 1 H z), 2.0 1 - 2.3 2 (2 H, brm), 2.49-2.72 (4H, br m), 2.99-3.3 9 (2H , br m), 3.3 0 (2 H, s), 3.5 4 - 3.6 9 ( 1 H, m) , 3.62-3.94 ( 1 H, br m), 3.7 4 (2 H, s), 4.0 1 - 4.1 6 (1 H, brm), 4.50-4.78 (lH, br m), 4.55 (2H, s), 6.57 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.35 (lH,d,J = 7.8Hz), 7.44(2H,d,J = 8.6Hz), 7.75(lH,dd, J = 7.8,2.0Hz), 8.60( lH,d,J = 2.0Hz)» LC /MS [Condition 1] ··Retention time 3.00 minutes; m/z 626.0 [M + H]+ (ESI positive ion mode), m/z 670.1 [M + HC〇〇]- (ESI negative ion mode)

[化8 5 6]

Example 507 4-[(3-{[5-(4,4-Difluoropiperidin-1-carbonyl)pyridine-2-yl]methyl}-2-oxan-1-oxo-3,8- Manufacture of Diazospiro[4.5]decane-8-yl)methyl]-3,5-difluorobenzonitrile (Compound No. 507) -819 - 201211053 Substituted (4-fluorophenyl) (piperidine-4) Methyl ketone hydrochloride, the title compound (23 mg, yield: 92%) was obtained from m. Milky white amorphous. 1H-NMR (CDCl3) 6: 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 (lH) , d, J = 8.2 Hz), 7.75 (1 H, dd, J = 7.8, 2.0 Hz), 8.6 1 (lH, d, J = 2.0 Hz). LC/MS [Condition 1]: Hold time ΐ·52 min; m/z 545.9 [M + H]+ (ESI positive ion mode), m/z 590.0 [M + HCOO]- (ESI negative ion mode) 8 5 7]

Example 508 4-{[9-(4-Cyano-2,6-difluorobenzyl)_2_sideoxy-i-oxo-3,9-diazospiro[5·5]undecane- Preparation of 3-yl]methyl}-N-[(3-methoxyisoxazol-5-yl)methyl]benzamide (Compound No. 508) Substituting 6-{[8-(4-cyanide) Base-2,6-difluorobenzyl)-2-oxo-oxo-3,8-diazospiro[4.5]decane-3-yl]methyl}nicotinic acid, using Reference Example 474 4-{[9_(4·Cyano-2,6-difluorobenzyl)_2_sideoxy-i_oxo_3,9_diazospiro[5.5]undecane-3_yl ]Methyl}benzoic acid, at the same time, substituted (4-fluorophenyl)(acridin-4-yl)methanone hydrochloride, using -820-201211053 obtained from Reference Example 401-3 (3-methoxy oxalic acid) The title compound (umg, yield 76%) was obtained as a colorless amorphous material. 1H-NMR (CDC13) 5: 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 (lH, s), 6.70 (lH, t, J = 6.1 Hz), 7.21(2H,d,J = 6. lHz), 7.3 6(2H,d,J = 8.2Hz), 7.7 6(2H,d,J = 8.2

LC/MS [Condition 1]: Hold time 1.42 minutes; m/z 565.8 [M + H]+ (ESI positive ion mode), m/z 564.0 [MH]_ (ESI negative ion mode) [Chem. 8 5 8 】

Example 509 ^ 6-{[8-(4-Cyano-2,6-difluorobenzyl)-2-oxo-1-oxo-3,8-diazospiro[4.5]decane-3 -Methyl}-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl} Nicotinamide (Compound No. 509) was produced by substituting (4-fluorophenyl) ( Piperidin-4-yl)methanone hydrochloride was substantially the same as Example 3 92 except that [5-(trifluoromethyl)pyridin-2-yl]methylamine obtained in Reference Example 457-3 was used. After the reaction, the title compound (4·9 mg, yield: 8%) of white powder was obtained. 'H-NMR (CDCl3) 5: 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), 3.3 1 (2H, s), 3.74 (2Η, s), 4.5 9 (2Η, -821 - 201211053 s), 4.85 (2H, d, J = 4_9Hz), 7.22 (2H, d, J = 6.1Hz), 7.40 (lH, d , J = 8.2 Hz), 7.48 (lH, d, J = 8.2 Hz), 7.59 (lH, t, J = 4.9 Hz), 7.96 (lH, dd, J = 8.2, 2.0 Hz), 8.17 (lH, dd , J = 8.2, 2.0 Hz), 8.84 (lH, s), 9.02 (lH, d, J = 2.5 Hz). LC/MS [Condition 1]: Hold time 2.88 minutes; m/z 600.9 [M + H]+ (ESI positive ion mode), m/z 599.0 [MH]_ (ESI negative ion mode) [Chemical 8 5 9 】

Example 5 1 0 (11*,4〇-4-({2-Sideoxy-8-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-1- Manufacture of oxa-3,8-diazospiro[4.5]decane-3-yl}methyl)-N-[(tetrahydrofuran-2-yl)methyl]cyclohexane. Institute of decylamine (Compound No. 510) Substituting (lr,4r)-4-({2-Sideoxy-8-[4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4.5]decane-3 -yl}methyl)cyclohexanecarboxylic acid, using (lr,4r)-4-({2- sideoxy-8-[2,3,5,6-tetrafluoro-4] obtained in Reference Example 503-2 -(Trifluoromethyl)benzyl]-1-oxo-3,8-diazaspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, substantially the same as Example 1 The title compound (27 mg, yield 78%) was obtained as a white solid. 1H-NMR (300 MHz, CDCl3) 6: 1.01 (2H, qd, J = 12.9, 3.3 Hz), 1.3 9-1.64 (4H , m), 1.69-1.83 (4H, m), 1.84 - 2.00 (7H, m), 2.03 (lH, tt, J = 11.9, 3.6 Hz), 2.52-2.74 (4H, m), 3.08 (2H, d , J = 7.3 Hz), 3.11 (-822-201211053 3H, ddd, J = 10.0, 7.6, 4.3 Hz), 3.23 (2H, s), 3.5 8 (lH, ddd, J = 13.5, 6.3, 3.0 Hz) , 3.75 (lH, dt, J = 7.6, 6.9 Hz), 3.79-3.89 (lH, m), 3.83 (2H, s), 3.94 (lH, qd, J = 7.3, 3.0 Hz) ), 5.80 (lH, t, J = 5.3 Hz) LC/MS [Condition 1]: Hold time 3.46 minutes; m/z 610.0 [M + H]+ (ESI positive ion mode), m/z 654.1 [M + HCOO]-(ESI Negative Ion Mode)

[化8 6 0]

FF Example 5 1 1 4-{l-[(lr,4〇-4-({2-Sideoxy-8-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene) Methyl]-1-oxo-3,8-diazospiro[4.5]nonan-3-yl}methyl)cyclohexanecarbonyl]azetidin-3-yloxy}benzonitrile Substitution of Compound No. 51 1) (11&quot;, 4〇-4-({2-Sideo-8-[4-(trifluoromethyl)benzyl]-1-oxo-# 3,8-weight Alkylspiro[4.5]decane-3-yl}methyl)cyclohexanecarboxylic acid, (lr, 4r)-4-({2- sideoxy- 8-[2,3) obtained using Reference Example 502-3 ,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]-1-oxo-3,8-diazospiro[4·5]decane-3-yl}methyl)cyclohexane The carboxylic acid and the substituted tetrahydrofurfurylamine were substantially reacted in the same manner as in Example 10 except that the 4-(azetidin-3-oxy)benzonitrile obtained in Reference Example 3 83-2 was used. The title compound (3 1 mg, yield 81%) was obtained as a white solid. 1H-NMR (300 MHz, CDCl3) S: 1.00 (2H, q, J = 12.6 Hz), 1.52 (2H, q, J = 12.3 Hz), 1.59-1.68 (lH, m), 1.69-1.86 (6H, m), 1.93 (2H, d, J = 14.2 Hz), 2.l2 (lH, tt, J = 12.2, 3.6 Hz), 2.53-2.75 ( 4H,m),3.08( -823- 201211053 2H,d,J = 7.3Hz), 3.22(2H,s),3.83(2H,s),4.05(lH,dd,J= 10.6, 4.0 Hz), 4.20 (lH, dd, J = 9.4, 3.8 Hz), 4.39 (lH, dd, J = 10.7, 6.8 Hz), 4.55 (lH, dd, J = 8.3, 7.3 Hz), 4.99 ( lH, tt, J = 6.3, 3.6 Hz), 6.8 1 (2H, d, J = 8.9 Hz), 7.62 (2H, d, J = 8.3 Hz) LC/MS [Condition 1]: Hold time 3.87 minutes; m/z 683.0 [M + H]+ (ESI positive ion mode), m/z 727_2 [M + HCO〇r (ESI negative ion mode) In the present invention, the compound to be evaluated is selected and selected to confirm the lipid The direct action of the conjugated receptor is preferred. As the evaluation system, for example, an evaluation system using a cell which can stably express an adiponectin receptor, and an evaluation system of a gene-combined animal (so-called knockout mouse, etc.) can be cited. By using these evaluation systems in an appropriate manner, the inventive compound can be efficiently evaluated. Test Example: ACC Phosphorylation of CHO Cell Line in Human AdipoR1 Stable Expression ACC Phosphorylation Energy in a Synthesis Compound of the Compound of the Present Invention, Construction Human AdipoR1 was stably expressed in CHO cell line (CHOR1) and assayed. For the labeling of the activity, a Rigel compound (W02008/083124 Compound 94) which has been reported as a low molecular compound which exhibits an adiponectin receptor agonist-like action is used as an index. (1) Cells and culture Human AdipoR1 diazepam found that the CHO cell line (CHOR1) was stable and expressed human AdipoRl. Moreover, the CHO cells of the parent strain were less responsive to the Rigel compound (Compound 94) than the CHOR1 ratio -824 to 201211053. The above two cells were subcultured in a F-12 medium containing 10% bovine serum using a C02 constant temperature incubator (5% CO 2 , 37 ° C). (2) Determination of ACC phosphorylation energy

The above subcultured cells were suspended in F-12 medium containing 10% bovine serum, and the suspension was transferred to a 96-well plate for tissue culture. This cell suspension was cultured for 1 day in a C02 constant temperature incubator. The Rigel compound (Compound 94) or the other synthetic compound dissolved in dimethyl hydrazine was diluted with a serum-free medium, and then the culture supernatant of the 96-well plate was removed and added, and the mixture was carried out in a C 02 constant temperature incubator. 3 恒温 minutes constant temperature culture. ACC phosphorylation was measured by the following method using time-based fluorescence decomposition (PerkinElmer DELFIA analysis). Namely, the cells were immobilized on a 96-well plate using 4% paraformaldehyde, washed, and blocked with albumin-containing buffer (purchased by φ Sigma), and primary antibody (ACC phosphorylated antibody) (by Cell signalling). The company purchased) 12 to 15 hours of reaction at 4 °C. After washing, a secondary antibody (purchased by PerkinElmer Co., Ltd.) labeled with hydrazine was added, and incubation was carried out for 1 hour at room temperature. After washing with PBST (0.1 wt% of a mixture of Tween 20 in phosphate buffer (pH 7.4)), an enhancer (registered trademark) (purchased by PerkinElmer Co., Ltd.) was added to decompose the fluorescence detector in time. The measurement was carried out (ARVO-HTS manufactured by PerkinElmer Co., Ltd.). As the active concentration of the compound of the synthesis example, the human AdipoR 1 in the Rigel compound (Compound 94) shows the concentration of the compound which gives the acidification rate of C 细胞-825-201211053 ACC as 1 Ο Ο %. (ECR50) divided by the concentration of the compound (EC5Q) imparting a 50% phosphorylation rate to the Rigel compound (Compound 94) as the specific activity 値. The results are as follows. Compound number specific activity値

8 -826- 19491501908708867405 1463155562 994074911203426008 22224435736372417276 4414388404 920353357147534536 ....................5..........5........ .......... 00000004010100014000/^0011001020/^022000010010000000 -827- 201211053 01234567890 456789012345678900000000001 00 00 00 00 00 00 Qv 9 Qv IX 1 X 1 1 1 ΙΑ IX Ti lx 2345678901234567890123 1111111122222222223333 02041622874374888 35 27857906227202184 Ιο .. ...............5··55............................10010011000010100/^ 11/^/^0501111000000001010000843031 8768582310911527329287604020 4742257578376823411404755184 8 -828- 201211053

4567890123456790123456789 3333334444444445555555555 2332009763564926699635497 8747166260842934728111818 0100800001000101200011022

0123456790123456789012345 6666666667777777777888888 1520354254864208420873671 5137474658436308650131586 0001201005038510122000004 -829- 201211053 67890123457890123456789012345678901234567890123456 88889999999990000000000111111111122222222223333333 11111111111112222222222222222222222222222222222222 28 7209331479264288888644382136899240 7 4 53 2920101528155580484323322273928366 7 3 - 5 5 5 5 ο ·· ••• ♦ • '••••• ♦ · _' ··· »··· *··, '····&lt;· _·· ·»♦ 00&gt;0000010000200001000010010100210000&gt;5&gt;3&gt;70061185 0 2 9 0 6 4 8 5 4 2 '383 2 -830 201211053

78901234567890123456789012345678901234567890123456 333444444444455555555556666666666777777777788888882222222222222222222222222222222222222222222222222222222248284284222262422224027546096516077420865795486 68428604242350990620135616472302321205631 ........5.................................. ....... 00001196^/70016010000001000000000200030000000000200 -831 201211053 78901234567890123456789012345678901234567890123456 88899999999990000000000111111111122222222223333333 2222222222222333333333333333333333333333333333333311285047604425282750806605475016453 933008709931 4295020121546271165322632193453479817 928078701713 ............................. ........5............ 0000000000000000010000025010000300010^000271410000 8 832- 201211053 78901234567890123456789012345678901234567890123456 33344444444445555555555666666666677777777778888888 33333333333333333333333333333333333333333333333333123923928602 645494103144429620583801376068888 4415622026124615 522621412086140751759325728420 201 ................5................................ 0231100000000003/\100000000211002002002004000000001 -833 201211053 78901234567890123456789012345678901234567890123456 88899999999990000000000111111111222222222223333333 33333333333334444444444444444444444444444444444444444939939599606889586646130170640 7 9 9 8 795276488957 07210643210347310262193792327649 0 2 5 2 304069514550 ..................... .....5 · · · - 5............ 10000000010100000200024010002055^9116^631122000001 8 -834- 201211053 78901234567890123456789012345678901234567890123456 3334444444444555555555566666666667777777777888888844444444444444444444444444444444444444444444444444444 8 520195982164304560972 730721404806999 566182251965 420301244124391871984 982072939344854 75 '251981341...... ...............5...............5 · · 3......... 001000001330000200002^371321710501007^201001802621 - 835 201211053 7890123456789012345678901 8889999999999000000000011 4444444444444555555555555 53560257979060623175 5 9 6 277 54395974159357437 9 2 2 . . . . . . . . . . . . . . . . . . . . . . . . . Preparation Example 1 A granule containing the following ingredients was produced. Ingredient Compound of formula (I) Lactose 7 0 0 m g Corn starch 274 mg HPC-L 16 mg Meter 1 OOOmg The compound of formula (I) and lactose were passed through a 60-mesh sieve. The jade-836-201211053 rice starch was passed through a sieve of 120 mesh. These were mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution was added to the mixed powder, and the mixture was subjected to refining, granulation (extrusion granulation pore diameter 〇5 to 1 mm), and dried. The resulting dried granules were sieved through a vibrating sieve (1 2/60 sieve) to obtain granules. Formulation Example 2

A capsule filling powder containing the following ingredients is produced. Ingredient Compound of formula (I) 1 Omg Lactose 7 9 mg Corn starch 1 Omg Magnesium stearate 1 mg 1 OOmg The compound of formula (I) and lactose are passed through a 60-mesh sieve. The corn starch was passed through a sieve of 1 20 mesh. These were mixed with magnesium stearate in a V-type mixer. 1 〇 dilution of l〇〇m g塡 was filled in a hard gelatin capsule No. 5 Formulation Example 3 A capsule granule containing the following ingredients was produced. Ingredient Compound of formula (I) 1 5 m g -837 - 201211053 Lactose 9 0 m g Corn starch 4 2 m g HPC-L 3 mg 1500 m The compound of formula (I) and lactose are passed through a 60-mesh sieve. The corn starch was passed through a 120 mesh sieve. These were mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution was added to the mixed powder, which was subjected to refining, granulation, and dried. The resulting dried granules were sieved and sized by a vibrating sieve (12/60 sieve), and 150 mg of hydrazine was filled in a No. 4 hard gelatin capsule. Formulation Example 4 A tablet containing the following ingredients was produced. Ingredient Formula (I) Compound 1 Omg Lactose 90 mg Microcrystalline cellulose 3 Om g Magnesium stearate 5 mg CMC-Na 1 5 mg Calculated 15 0 m Compound of formula (I), lactose, microcrystalline cellulose, CMC- Na (carboxymethylcellulose sodium salt) was passed through a 60 mesh sieve and mixed. Magnesium stearate was added to the powder at -838-201211053 to obtain a mixed powder for preparation. The mixed powder was directly tableted to obtain a 150 mg tablet. Formulation Example 5 An intravenous preparation was produced as follows. Compound represented by formula (1) lOOmg

Saturated fatty acid glyceride lOOOOmL

The solution of the above components is usually administered intravenously to the patient at a rate of 1 mL in 1 minute. [Industrial Applicability] The compound of the present invention exhibits affinity and/or agonist action for adiponectin receptors, and thus can be used as a disease prevention, treatment, and amelioration drug effective for adiponectin receptor activation. It can be used for metabolic syndrome, in particular, metabolic syndrome caused by obesity or diabetes, and medicines for prevention or treatment of arteriosclerosis. The specification, the scope of the claims, and the abstract of the Japanese Patent Application No. 2010-1 08491, filed on May 10, 2010, is hereby incorporated by reference. -839-

Claims (1)

201211053 VII. Scope of application: 1. A spiro compound, a tautomer of the compound, or a salt acceptable for gastric medicine, characterized by formula (1) [In the formula (1), E represents an oxygen atom or a sulfur atom, L1 represents a single bond, a Cu alkyl group, a c: 2 3 extended alkenyl group or a C 2 3 extended block group (the c丨·3 alkyl group, c: 2· 3 alkenyl and CM extended alkynyl are substituted with no cyclopropyl), L2 represents a single bond, Cu alkyl group 'c: 2.3 extended alkenyl or (: 2.3 extended block (the c, _3 alkyl) , ο: 2" alkenyl and C 2 3 alkynyl are unsubstituted or substituted by cyclopropyl), x represents Cm cycloalkyl, Cm cycloalkenyl (the c3.u ring and C3_n) The cycloalkenyl group is unsubstituted or substituted by more than one substituent independently selected from the group consisting of Ci3 alkyl, C2-3 flaming, -OR16 and cyano), 〇6.1() aryl or 5 ~10 member heteroaryl (the c6_1Q aryl group and -840-201211053 5~10 member heteroaryl) is unsubstituted or independently selected from a halogen atom 'nitro, cyano, Ci-3 Cl. 3 is substituted or substituted by one or more substituents independently selected from a halogen atom and -OR16, C2-3, C2.3, /OR16, -〇 C2-3 嫌 base), -〇 (C3.4 ring yard base), -N(R16)c( = 0)0R17, -N(R16)C( = 0)R17, _n(R16)c( = 〇)h , -N(R16)r&quot;, -nh2, -n(r16)s( = o)2r17, -C( = 0)NRi6Rl7, -C( = 0)nh2, -C( = 0)R16 ' -S( = 0)2R17 ' -S( = 0)2NR16R17 φ , β( = 0)2ΝΗ2 is replaced by one or more substituents in groups), Ζ1 represents the formula (ΙΙ-1) to (ΙΙ- 8) [Chemical 2] (11-1) (ΙΙ-2) R3 R1* 0 0 (ΙΙ-3) 0 0 *% person into R3 R4 (H-4) rVV, R3 R4 (II-5) (&quot;-6) (H-7) (||-8) (wherein J is independently represented by an oxygen atom or a sulfur atom, -841 - 201211053 G1 represents a single bond, an oxygen atom or a sulfur atom, R1 and R3 In the above, R1 represents a hydrogen atom, OR11, NR11. 2, Cm alkyl group (the Cl-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group 3), C3-M Cycloalkyl or 4 to 11 membered heterocycloalkyl (the (^.^ ring-yard and 4 to 11-membered heterocyclic group is available with c6_1() aryl or 5 to 10 membered heteroaryl (the C6- The 1Q aryl group and the 5~1 member heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent group A2 and the Cl alkyl group) and the ring is 'condensed' and ^ Ring-based and 4 to 11-membered heterocyclic groups are unsubstituted or substituted by one or more substituents independently selected from the group of substituents eight and C4.6 alkyl groups) 'R3 represents a hydrogen atom Or a C.3 alkyl group, or R1 and R3 are bonded to the nitrogen atom to which they are bonded to represent a 4 to n membered heterocycloalkyl group (the 4 to 11 membered heterocycloalkyl group is unsubstituted or substituted independently) Substituent eight, and one or more substituents in groups of C4_6 alkyl groups are substituted) R2 represents an alkyl group (the Cl-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group As), a cycloalkyl group or a 4 to 11 membered heterocycloalkyl group (the 匚^) A cycloalkyl group and a 4 to 11 membered heterocycloalkyl group may be substituted with a C6-1G aryl group or a 5 to 1 member heteroaryl group (the c6-1Q aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently The condensed ring is substituted with one or more substituents selected from the group consisting of a substituent group A2 and a C44 alkyl group, and the C3.H ring group and the 4~U member heterocycloalkyl group are unsubstituted or independently Any one or more substituents selected from the group consisting of a substituent group A and a C4.6 alkyl group, and R4 and R5 each independently represent a hydrogen atom or a Cl. 3 alkyl group, -842- 201211053 m represents an integer ' of 1 or 2', R6 is independently a hydrogen atom, C. 3 alkyl or cyclopropyl' or two r6 present on the same carbon atom are bonded to the carbon atom to which they are bonded倂 forming C3_6 naphthenic '' represents an integer from 0 to 4, R7 independently represents a Cu alkyl group, and T represents a formula (VI-1) to (VI-3) [Like 3] Human L4, L5, r8 (VI-1) Vgv (VI-2) j2 (VI-3) (wherein L4 represents an alkylene group, and L5 represents a single bond 'oxygen atom, sulfur atom, S ( = 〇), S( = 0)2, c = 0 or C = NOR12, R8 represents C6_1G aryl or 5~10 membered heteroaryl (the c6.1Q aryl group and the 5~10 membered heteroaryl group are unsubstituted) Or substituted by one or more substituents independently selected from the group of substituent groups A2 and C4.i, J2' represents an oxygen atom or a sulfur atom, and G2 represents an oxygen atom, a sulfur atom or NR1 1, R It is not Cu-based (the Cl-hospital group is unsubstituted or substituted by more than one substituent selected independently from the substituent group A*), c6 1() aryl (the -843-201211053 C6_1Q aryl group) a Cm cycloalkyl group which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a substituent group octa 2 and a c4_6 alkyl group (the c3-M cycloalkyl group is a C6_1Q aryl group or 5 to 10 membered heteroaryl groups (the C6_1() aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or one or more substituents independently grouped from the substituent group A2 and C4-6 alkyl groups Substituted) to carry out condensed ring, and the C3.M cycloalkyl group is unsubstituted or independently selected Substituted from one or more substituents of the substituent group a2), or a CL3 alkyl group (the Ci.3 alkyl group may be a c 6 · 1 fluorenyl group or a c 3 - n cycloalkyl group (the c 6 _, Q aryl) And c 3 ·, cycloalkyl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a group of 2 and a C4.6 alkyl group), R1Q represents (^ _9 alkyl (the C alkyl is unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), c6.1{) aryl, 5 to 10 membered heteroaryl (the C6. The 1G aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent group a2 and the c4_6 alkyl group), C3.U cycloalkyl group (the C3) -M cycloalkyl is a C6-10 aryl group or a 5 to 10 membered heteroaryl group (the C6_1Q aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from the group consisting of a group of 2 and C4_6 alkanes Substituting one or more substituents of a group to form a condensed ring, and the cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), or a cumane a base (the C alkyl group is a C3-H cycloalkyl group (the c3_M cycloalkyl group is Any one of the substituents substituted by or substituted by one or more substituents independently selected from the substituent group 2), wherein the substituent group is (:, .3 alkyl (the Ci.3 alkyl group is a substituent group consisting of an unsubstituted or substituted one or more substituents independently selected from the substituent group A3) and a substituent -844-201211053 group As, the substituent group a3 being a C3-u cycloalkyl group, 4 ~11 membered heterocycloalkyl (the (^-^cycloalkyl group and 4 to 11 membered heterocycloalkyl group can be used with C6_1G aryl or 5 to 10 membered heteroaryl (the C6-1Q aryl group and 5 to 10) a heteroaryl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a substituent group A2 and a C44 alkyl group) is subjected to a condensed ring ' and the Cn, a cycloalkyl group and a 4 to 11 member are heterozygous. The cycloalkyl group is unsubstituted or φ is substituted by i or more substituents independently selected from the group of substituent groups A2 and C4_6 alkyl groups), C6-1G aryl group, 5~1 〇 heteroaryl group (this The c6_1Q aryl group and the 5~1 member heteroaryl group are a heterocyclic alkane which may be 4 to n members (the 4~n member heterocyclic ring is unsubstituted or one or more substituents independently selected from the substituent group A2) Substituted) to perform a condensed ring, and the c: 6iq fang And 5 to 10 membered heteroaryl groups are unsubstituted or substituted by one or more substituents independently selected from the group of substituents and C4 6 alkyl groups), _C(= 〇)〇r丨3, _c ( = 〇)nR丨2R13, -C( = 〇)ru, _c( = n〇r12)r13, _s(=:〇)r13 s( = 〇)2r13 〇r13 _SR ' -N(R12)C( = 0)0R13 ' -N(R12)C( = 0)R13 . -N(R12)R13 , halogen atom, cyano group, nitro group, formazan group ' _c(=nor12)h, _n(r12)c(= o) a substituent group consisting of h or a hydroxyl group, the substituent group a2 being a Cl-3 group (the C, -3 alkyl group being unsubstituted or substituted by one or more halogen atoms) and the substituent group A4 In the group of substituents, the substituent group A4 is a halogen atom, a nitro group, a cyano group, -OR14, _sr14, C(-〇)NR R , -C(=0)R15, -C(=N〇R15). R14,·〇( = ΝΟΙ115)Η -845- 201211053 , _S(=0)Rl4, -S(=〇)2R丨4, -N(R15)C(=〇)〇r]4, -N(R丨5) a group of substituents consisting of c(=o)r14 or -n(r15)c(=0)h, Rl1 is independently a hydrogen atom or acl-6 alkyl group, and R12 is independently a hydrogen atom. Or Cl_3 alkyl, R is each independently, indicating a Ci-6 courtyard group (the Cl alkyl group) Unsubstituted or substituted by one or more substituents independently selected from the substituent group A4), C3-ii cycloalkyl, 4 to 11 membered heterocycloalkyl, c6.l()aryl, or 5 to 10 a heteroaryl group (the C3.M cycloalkyl group, 4 to 11 membered heterocycloalkyl group, (6_1 aryl group and 5 to 10 membered heteroaryl group) is unsubstituted or independently selected from the group of substituents VIII and One or more substituents of a C4-6 alkyl group are substituted), R14 represents an alkyl group (the C, .3 alkyl group is unsubstituted or substituted by one or more halogen atoms), and R15 represents a hydrogen atom. Or a d-3 alkyl group (the C3 alkyl group is unsubstituted or substituted by one or more halogen atoms), R16 represents a hydrogen atom or a d-3 alkyl group, and R17 represents a C?3 alkyl group. 2. A spiro compound according to item 1 of the patent application, a tautomer of the compound or a pharmaceutically acceptable salt thereof, wherein (1) - 846 - 201211053 [in the formula (I), E represents an oxygen atom or a sulfur atom, and L represents a single bond, C, _3 alkylene, C2-3 extended alkenyl or C2·3 extended alkynyl group (the c 1 _ 3 stretching base, c 2 3 stretching base and c 2 _ 3 alkynyl is unsubstituted or substituted by cyclopropyl), L 2 represents a single bond, a C 3 alkyl group, a C 2-3 alkyl group or a C 2-3 alkynyl group (the Ci.3 extension The base, c2_3 alkyl and c2_3 alkynyl are unsubstituted or substituted by cyclopropyl), X represents Cn, cycloalkyl, C3.U cycloalkenyl (the C3_u cycloalkyl and ring extension) The alkenyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a CL3 alkyl group, a C2.3 alkenyl group, an -OR 16 group and a cyano group. An extended aryl group or a 5 to 10 member heterodyne a group (the Ce-iQ aryl group and the 5~1 member heteroaryl group are unsubstituted or independently selected from a halogen atom, a nitro group, a cyano group, a C, _3 alkyl group (the C," alkyl group is none Substituted or substituted by one or more substituents independently selected from a halogen atom and a group of -OR16), C2.3 alkenyl, c2_3 alkynyl, -OR16, -0(C2-3 alkenyl), -0 (c3-4 cycloalkyl) '-N(RI6)C( = 〇)〇R17 ' -N(R16)C( = 〇)R17 , -N(R16)C( = 〇)H , -n(r16 )r17, -nh2, -n(r16) s(=0)2r&quot;, -c( = o)nr16r17 -847- 201211053 , -C( = 〇)NH2, -C( = 0)R16 ' -S( = 0)2R17, -s( = o) 2nr16r17, -s(= 0)2nh2 is substituted by more than one substituent), and Z1 represents formula (II-1) to (II-8) (11-1) (II-2) (II-3) R3 R4 R3 R4 (II-4) (II-5) rKg\^y\ ^G/r\ /V, R4 J1 r4 r4 (II-6 (II-7) (II-8) (wherein, J1 each independently represents an oxygen atom or a sulfur atom, G1 represents a single bond, an oxygen atom or a sulfur atom, and in R1 and R3, R1 represents a hydrogen atom, OR11, NRHR12 , C, .9 alkyl (the C alkyl is unsubstituted or substituted by one or more substituents independently selected from the group VIII), C3. η cycloalkyl or 4 to 11 heterocycloalkane The group (the Cm cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are available with C6.1() aryl or 5 to 10 member hetero-848-201211053 aryl (the C^o aryl group and 5 to 10 members) The heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the C3_M cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are unsubstituted or independently Substituted from one or more substituents of the substituent group A, R3 represents a hydrogen atom or C, -3 alkyl group, or Ri and R3 are combined with a nitrogen atom to which they are bonded, and 4 to 11 members are represented. a heterocycloalkyl group (the 4-n-membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from the group of substituents A!), R2 represents a C?9 alkyl group (the C1-9 alkyl group is unsubstituted or substituted by more than one substituent selected independently from the substituent group As), a cycloalkyl group or a 4 to 11 membered heterocycloalkyl group (this ^^cycloalkyl and 4~h member heterocycloalkyl are available as c6-1{) aryl or 5 to 10 membered heteroaryl (the c61c aryl group and the 5 to 1 member heteroaryl group are unsubstituted or The condensed ring is substituted by one or more substituents independently selected from the substituent group A2), and the C 3 -H cycloalkyl group and the 4 to 11 membered heterocyclic compound are unsubstituted or independently selected from the group of substituents And one or more substituents are substituted), R4 and R5 are each independently represent a hydrogen atom or a Ci3 alkyl group), m represents an integer of 1 or 2, and R is independently represented by a hydrogen atom, Ci 3 alkyl Or a cyclopropyl group, or two R6 groups present on the same carbon atom are combined with the carbon atom to which they are bonded to form a C3.6 ring, π is not an integer from 0 to 4, and r7 is independently represented by Cl. 3 alkyl, τ, formula (Vl-ΐ) to (VI_3) -849- 201211053 [Chemical 6] /\L4/L5V /, r1〇(VI-1) (VI-2) J2 (where, L4 The table does not recognize Ci-3, and L5 indicates not a single bond, an oxygen atom or a sulfurogen. Sub, sb (1), s (= 〇 &gt; 2, C = 0 or C = NOR12, R8 represents c6·, fluorenyl or 5 to 10 membered heteroaryl (the Cy. aryl and 5 to 10 members) The aryl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group hexa 2), J2 represents an oxygen atom or a sulfur atom, G2 represents an oxygen atom, a sulfur atom or NR11, and R9 represents an alkyl group (this C, .9 alkyl is unsubstituted or substituted by one or more substituents independently selected from the group of substituents A*), c6_1() aryl (the Cno aryl group is unsubstituted or independently selected from substituents) a group of Δ2 substituted with one or more substituents), a Cm cycloalkyl group (the C3-n cycloalkyl group may be a C6_ ί aryl group or a 5 to 10 membered heteroaryl group (the c6-1Q aryl group and 5 The hydrazine heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the Cn, cycloalkyl group is unsubstituted or independently selected from substituents. Substituting one or more substituents of group A2), or, Ci-3 alkyl (the Cm alkyl group is a C6_IQ aryl group or a C3.n cycloalkyl group (the C6-10 aryl group and the C3.H naphthenic group) The base is unsubstituted or 1-850 independently selected from the substituent group a2 - 201211053 Substituted by more than one substituent)), R is not a ci·9-yard (the ci.9-based group is unsubstituted or consists of one or more substituents independently selected from the substituent group A*) Substituted), c6 iq aryl '5 to 10 membered heteroaryl (the C6.IQ aryl and 5~1 杂 heteroaryl are unsubstituted or substituted by one or more independently selected from the group A, Substituted), c3. u cycloalkyl (the C^m cycloalkyl group is a Cm aryl group or a 5~1 杂 heteroaryl group (the C6-1G aryl group and the 5~10 member heteroaryl group are The condensed ring is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2, and the C3_11 ring-based group is unsubstituted or independently selected from one or more substituent groups 6-2. a substituent substituted by a) or a C,-3 alkyl group (the Ci3 alkyl group may be a Cm cycloalkyl group (the one of which is unsubstituted or independently selected from the group A2 of the substituent group A2) Any one of the substituents () substituted with a substituent), a substituent group AiM alkyl group (the Cu alkyl group being unsubstituted or substituted by one or more substituents selected from the substituent group As) and a substituent Substituent , φ substituent group A3 is a C3-u cycloalkyl group, a 4 to 11 membered heterocycloalkyl group (the (^^cycloalkyl group and the 4 to 1 1 membered heterocycloalkyl group are compatible with C 6 ·! Or a 5 to 1 member heteroaryl group (the C6-IQ aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by more than one substituent selected independently from the substituent group A2), and the ring is condensed, And the ring and 4 to 11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group A2) 'C6.1Q aryl, 5 to 10 membered heteroaryl (The C6_1Q aryl group and the 5~10 member heteroaryl group are available as a 4~n member heterocycloalkane (the 4~u member heterocycloalkane is unsubstituted or independently selected from the substituent group a2 of 1-851 - 201211053 The condensed ring is substituted with one or more substituents, and the C6.1Q aryl group and the 5-membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from the substituent group Δ2) , _(:( = 0)01^3 ' _c( = 〇)nr12r13, _c( = 〇)r13 ' -C( = N0R12)R13 , _S( = 〇)R13 &gt; -S( = 〇)2R13 &gt ; -OR13 ^ -SR13 , -N(R12)C( = 0)0R&quot;, -N(r12)c( = 〇)r13, n(r12)r13, halogen atom, cyano group , nitro, methoxy, - 〇 ( = ν 〇Ι 112) Η, -n (r12) c ( = o) h, or a group of substituents formed by a group, the substituent group 2 is Cl·3 alkane a substituent group in which the alkyl group is unsubstituted or substituted by more than one halogen atom, and a substituent group a4, wherein the substituent group A4 is a halogen atom, a nitro group, a cyano group, -OR14, _SR" , _c( = 〇) 〇rI4 , -c(=o)nr14r15, -C(=〇)r15, _c(=n〇r15)r14, c(=nor15)h -S( = 0)R14 . -S ( = 0) 2R14 ' -N(R15)C( = 〇)〇R14 &gt; -N(R15)C( = 〇)R14 or -n(r15)c(=0)h R11 is independently represented by a hydrogen atom or a hospital group, R12 is independently represented by a hydrogen atom or a 1.3-membered group, and R13 is independently represented by a Cu alkyl group (the alkyl group is unsubstituted or independently selected from the substituent group A4) Substituted by more than one substituent), Cm cycloalkyl, 4 to 11 membered heterocycloalkyl, c6-1G aryl, or 5 to 1 fluorene heteroaryl (the (:^cycloalkyl, 4~u Heterocycloalkyl' c6.10g and 5 to 10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group of substituents), -852- 2012 11053 R14 represents C,-3 alkyl (the alkyl group is unsubstituted or substituted by more than one atom), and R15 represents a hydrogen atom or a mountain alkyl group (the C!-3 alkyl group is unsubstituted). Alternatively, it may be substituted by one or more halogen atoms, and 'R16 represents a hydrogen atom or a Ci-3 alkyl group, and R17 represents a Cu alkyl group. 3. A spiro compound as claimed in claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein X is Cm cycloalkyl or (^^, cycloalkenyl) The cycloalkylene group and the C3_u cycloalkenyl group are unsubstituted or substituted by one or more substituents independently selected from the group consisting of C, -3 alkyl 'C2.3 alkenyl, -ORR16 and cyano. 4. A spiro compound as claimed in claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein X is a C6.l0 aryl group or a 5 to 10 member heterosexual extension. An aryl group (the (:6.1) aryl group and the 5 to 10 member heteroaryl group are unsubstituted or independently selected from a halogen atom, a nitro group, a cyano group, and a Cm φ alkyl group (the G-3 alkyl group is Unsubstituted or substituted by one or more substituents independently selected from a halogen atom and a group of -OR16), C2-3 alkenyl, C2.3 alkynyl, -OR16,-0-(C2.3 alkenyl) , -〇(C3.4 cycloalkyl), -n(r16)c( = o)or17, -n(r16)c(=o)r17, -n(r16)c( = o)h, -n (r16)r17, -nh2, -n(r16)s(=0)2r17, -c(=o)nr16r17, -c(=o)nh2, -c(=o)r16, -S( = 0) 2R17, -S( = 0)2NR16R17, -S( = 0)2NH2 is substituted by more than one substituent of the group). 5. The spiro compound of claim 4, the tautomer of the compound, or its medicinal Accepted salts, wherein l/ is C!·3 -853- 201211053 alkyl, C2.3 alkenyl or c2.3 alkynyl (the Cl_3 alkyl, c2-3 alkenyl and c2_3 alkyne 6. A spirocyclic compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 is not substituted, or substituted by a cyclopropyl group. Formula (II-1) to (Π-g) (In the formula, J1 each independently represents an oxygen atom or a sulfur atom, G1 represents a single bond, an oxygen atom or a sulfur atom, and in R1 and R3, R1 represents a hydrogen atom, OR11, NRUR12, Cu alkyl group (the c, ^1 · 5 The base of the hospital is unsubstituted or substituted by one or more of the substituents selected from the substituent group A3 (QdA 201211053); but m represents i, and when both R6 represent a hydrogen atom, the q 5 alkyl group is Substituted from one or more substituents of the substituent group ^), C6-9 alkyl group (the C6.9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A; ), a cycloalkyl group or a 4 to η membered heterocycloalkyl group (the C^u cycloalkyl group and the 4~u membered heterocycloalkyl group are a C6-10 group or a 5 to 10 membered heteroaryl group) The c6-1()aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by i or more substituted φ groups independently selected from the substituent group VIII)) and the Cm cycloalkyl group and 4~丨丨 heterocycloalkyl is unsubstituted or substituted by more than one substituent selected independently from the substituent group ,, R represents a hydrogen atom or a Cu alkyl group, or !1 and R3 are Combined Atomic 倂 represents a 4 to 11 membered heterocycloalkyl group (the 4 to 11 membered heterocyclic group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A1), and R2 represents C!. 5-alkyl (the C!-5 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A3; but m represents 1, when both R6 represent a hydrogen atom, the Cl .5 alkyl is substituted by one or more substituents independently selected from the group of substituents), c6.9 alkyl (the c6.9 alkyl group is unsubstituted or is independently selected from the group consisting of the substituent group 3) More than one substituent substituted), C3-11 cycloalkyl or 4 to 11 membered heterocycloalkyl (the C3-H cycloalkyl group and the 4~U membered heterocycloalkyl group are compatible with C6..,. a group or a 5 to 10 membered heteroaryl group (the ce-1()aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or substituted by more than one substituent selected independently from the substituent group A2) a ring, and the C3-11 cycloalkyl group and the 4 to 11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from the group -855-201211053-based group A!), R4 and R5 is independently represented by a hydrogen atom or a Cu-based system. 7. A spirocyclic compound according to item 2 or 3 of the patent application, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein L1 represents 0^3 alkylene group, and L2 is a single bond , Z1 represents the formula (ll-ι), (II-4) or (II-7) [Chemical 8] J1 R3 R~\ (11-1) R^G1^Nx\ R4 (II-7) (wherein, R1, R2, R3, R4, J1 and G1 have the same meanings as defined in the second item of the patent application scope). 8. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein L1 represents a C3 alkyl group, L2 is a single bond, and Z1 represents a formula ( II-1), (II-4) or (II-7) 8 -856- 201211053 (wherein R1, R2, R3, R4, J1 and G1 have the same meanings as defined in the sixth aspect of the patent application scope). 9. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 8, wherein E is an oxygen atom and m is 1, η is 0. The spiro compound, the tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein hydrazine is an oxygen atom, m is 2, as claimed in any one of claims 2 to 8. , η is 0. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 10, wherein Τ is a formula (VI-1) Or (VI-2) [Chemical 1 0] Human L4, L5V / 'R1〇(VI-1) (VI-2) (wherein L4 represents Ci-3 alkylene group, L5 represents a single bond, R8 and Any of the meanings of R1Q and those defined in item 2 of the scope of application. -857 _ 201211053 12 - A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, in any one of claims 2 to 5, wherein Z1 represents a formula (11) -1), (II-4) or (11_7) (II-7) (II-7) (II-7) (wherein, in R1 and R3, R1 represents C^6 alkyl group (the C, ·6) The alkyl group is substituted by 4 to 7 members of an oxygen-containing heterocycloalkyl group or -NHC(=0)0(Cb6 alkyl group), R3 is not a hydrogen atom, or R1 represents a Ci-6 yard group (this The base of Ci-6 is composed of C6.1() aryl or 5~1 杂 heteroaryl (the C6.1G aryl group and 5~10 member heteroaryl group are m4~n member heterocycloalkane (the 4 The 11-membered heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the C6^aryl group and the 5-10 membered heteroaryl group are unsubstituted or Substituted by one or more substituents independently selected from the substituent group ^, and the Cl6-based group may be substituted by one or more groups independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Substituted by a group), R3 represents a hydrogen atom, or R1 represents a 4-11 membered nitrogen-containing heterocycloalkyl group. The 4- to 11-membered nitrogen-containing heterocycloalkyl group is composed of a Ci.3 alkyl group (the (^.3 alkyl group is derived from a phenyl group (the phenyl group is unsubstituted or independently selected from -C(=0)0CH3, One or more substitutions of cyano, nitro, -sch3, -〇CF3, -och3, chlorine atom, -cf3 and -ch3 -858 - 201211053 Substituted by a base or substituted by a cyano group) or - (:( = 0)0((:,.6院-substituted), R3 represents a hydrogen atom, or R1 and R3 are combined with them The nitrogen atom of hydrazine represents 4 nitrogen-containing heterocycloalkyl groups (the 4-11 member nitrogen-containing heterocycloalkyl group is substituted by one or more substituents of the substituent group A i ), and R 2 represents Ci .6 yard base (this (: 丨-6 courtyard base is replaced by 4~7 member alkyl or -NHChC^CKCh6 alkyl)), R4 represents a hydrogen atom, J1 represents an oxygen atom, and G1 represents a single bond or oxygen. Any one of the compounds of item 2 to item 12, the tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 represents a formula (II-1). , (II-4) or (II-7) base) ～1 1 member. Selected from the oxygen ring of the oxygen ring [1 2] (丨丨_4) (&quot;-7) (wherein, R1 and R3, an oxygen heterocyclic ring, or R1 represents a C丨-6 alkyl group (the C丨-6 alkyl group is composed of 4 to 7 alkylene) Base or -NH (: ( = 0) 0 ((^.6 alkyl) substituted), R3 represents hydrogen -859 - 201211053 K clothing not 5 to 7 members nitrogen-containing heterocycloalkyl (the 5 to 7 member contains The nitrogen heterocycloalkyl group is derived from c,-3 fluorenyl (the Ci3 alkyl group is derived from phenyl (the phenyl group is unsubstituted or independently selected from -C(=0) 〇ch3, cyano, nitro, _SCH3) , -OCF3, . OCH3, chlorine atom, _cf3 and _Ch3 are substituted by one or more substituents), substituted by)), R3 represents a hydrogen atom, or R1 and R3 are combined with the nitrogen atom to which they are bonded, and represent a 5- to 7-membered nitrogen-containing heterocyclic group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is independently selected from the group of substituents A! Substituted by the above substituent), R2 represents a Cu alkyl group (the Cl.6 alkyl group is substituted by a 4 to 7 membered oxygen-containing heterocyclic compound or -NHC(= 〇)〇(C|.6 alkyl) And R4 represents a hydrogen atom, J1 represents an oxygen atom, and G1 represents a single bond or an oxygen atom. 14. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 12, wherein Z1 represents formula (II-1) or (II-4) [Chem. 1 3] (11-1) 8 •860- 201211053 (where R1 and R3, R1 represents a Cu alkyl group (the Cu alkyl group is composed of a C6-10 aryl group or a 5-10 membered heteroaryl group (the C6-1() aryl group and a 5-10 membered heteroaryl group are compatible with 4 to 7 members) An oxacyclohexane (the 4 to 7 membered oxacyclohexane is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2), and the aryl group and the 5 to 10 member The heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from the substituent group A2, and the Cl-6 alkyl group may also be independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Substituted by more than one substituent of the group), R3 represents a hydrogen atom, or R1 represents a 4-11 member nitrogen-containing heterocycloalkyl group (the 4-11 member nitrogen-containing heterocycloalkyl group is derived from -(:( = 0) 0 ((^-6 alkyl) is substituted), R3 represents a hydrogen atom, or R 1 and R 3 are bonded to the nitrogen atom to which they are bonded to represent a tetrahydroindenyl group (the tetrahydroindenyl group) It is substituted by one or more substituents selected from the group of substituent group 1), wherein R 4 represents a hydrogen atom, and J1 represents an oxygen atom. 1 5. As disclosed in claims 2 to 14 a spiro compound of any one of the items, the interconversion of the compound Isomer, or a pharmaceutically acceptable salt thereof, wherein T represents a formula (νι·1) or (VI-2) [Chem. 1 4] /\. 4-^L\ /\ L R8 , R10 (Vl -1) (VI-2) -861 - 201211053 (wherein, L4 represents Ci.3 alkylene, L5 represents a single bond, and R8 and R1() are independently represented by Cno aryl or 5-10 member nitrogen-containing The aryl group (c6-1()aryl group and the 5-10 membered nitrogen-containing heteroaryl group are unsubstituted or independently selected from a fluorine atom, a Q-3 alkyl group (the Ci.3 alkyl group is composed of one or more fluorine atoms) Any one of the substituted) and one or more substituents in which the cyano group is substituted. 1 6. The spiro ring of any one of items 2 to 15 of the patent application scope a compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein T represents a formula (VI-1) or (VI-2), a human L4/L, and a R8 human R1. VI-1) (VI-2) (wherein, L4 represents a Cm alkyl group, L5 represents a single bond, and R8 and R1() each independently represent a phenyl or pyridyl group (the phenyl and pyridyl groups are unsubstituted or One or more selected from the group consisting of a fluorine atom, a C, -3 alkyl group (the C!_3 alkyl group is substituted by one or more fluorine atoms) and a group of cyano groups Substituting any of them)) 1 7. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable substance thereof, as claimed in any one of claims 2 to 16. Salt, wherein T represents formula (VI-1) or (VI-2) -862- 201211053 [Chem. 1 6] Human L/〆1^ /, R1. (VI-1) (VI-2) (wherein L4 indicates that C1-3 does not extend the base, l5 indicates a single bond, and ana 8 and r_1q are independent representations (the phenyl represents one or two C, -3 alkyl (which is substituted by one or more fluorine atoms) or one cyano group)) 18. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 16, wherein T represents a formula (VI-1) or (VI_2) [Chem. 1 7] Person 丨 4〆^ (VI-1) Person R1. (VI-2) (wherein L4 represents Cu alkyl group, L5 represents a single bond, and R8 and Ri〇 each independently represent a phenyl group (the phenyl group is substituted by one or more fluorine atoms, and the phenyl group is Any one of C?-3 alkyl (the Ci-3-alkyl group is substituted by one or more fluorine atoms) or any of the cyano groups)). 19. A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 13 or 15 to 18, wherein Ζι expression („^*(„-4) -863- 201211053 【化1 8】 (丨1_1) (II-4) (wherein R1 and R3 are R1 and R3 in combination with the nitrogen atom to which they are bonded to represent a 5 to 7 member nitrogen-containing heterocycloalkyl group (the 5 to 7 member contains The nitrogen heterocycloalkyl group is independently selected from the group consisting of phenyl, 5-10 membered heteroaryl (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or independently selected from the group consisting of Cl-3 (the Cu base is none) Substituted or substituted by more than one fluorine atom, substituted with more than one substituent of a group of halogen atoms and cyano groups), -C( = 〇)〇R&quot;' _c( = 〇)Rl3, _〇 Rl3, Nr12r13, a halogen atom and a cyano group are substituted by one or more substituents), R12 represents a hydrogen atom, and Rl3 represents a Cm alkyl group (the Ci_6 alkyl group is unsubstituted or is composed of one or more φ fluorine atoms) Substituted), C61. aryl or 5~1 杂 heteroaryl (the C6 oxime. The aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from the group consisting of Ci3 alkyl (the Cl.3 alkyl group is Any of π Ci.3 (for substitution of one or more fluorine atoms), a halogen atom cyano group, and one or more substituents in which 〇 〇 Rl4 is grouped (the Cu alkyl group is No replacement or more than i The halogen atom is taken—the R represents the hydrogen atom 'J represents an oxygen atom.' 8 -864- 201211053 20. As in the scope of the patent application, items 2 to 12 or 14 to 18 A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 represents a formula (II-1) or (II-4) R1 [化1 9] (11-1) (wherein, in R1 and R3, R1 represents a G.3 alkyl group (the C1-3 alkyl group is derived from a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, pyridyl group, furyl group and isoxazole) The group may be condensed with a 4 to 7 membered oxacycloalkane group, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or independently selected from a halogen atom, a cyano ' ® Ci-3 alkane The substituent (substituted by one or more substituents in which the Cu alkyl group is substituted by one or more fluorine atoms) and the _ CKCi-3 alkyl group is substituted by any one of the substituents: R3 represents a hydrogen atom, or R1 represents a Cl_3 alkyl group (the Cu alkyl group is a phenyl group, a pyridyl group or a furyl group (the phenyl group, the pyridyl group and the furyl group are condensed with a 4 to 7 membered oxacyclohexane), and the phenyl group And the pyridyl group and the furyl group are unsubstituted or substituted by one or more groups selected from the group consisting of a dentate atom, a cyano group and a Cl_3 alkyl group (the C? d alkyl group is substituted by one or more fluorine atoms) Substituted by any one of the substituents, and the Cl 3 alkyl group is one or more substituents independently selected from the group consisting of a trans group, a halogen atom and a cyano group - 865 - 201211 Substituting 053), R3 represents a hydrogen atom, R4 represents a hydrogen atom, and J1 represents an oxygen atom. 21. A spiro compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 represents a formula (II-1) or (II-4) 0] (11-1) (II-4) (wherein R1 and R3 in R1 and R3 are combined with the nitrogen atom to which they are bonded to represent piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl) (The piperidinyl, piperazinyl, homopiperidinyl and homopyrazinyl groups are independently selected from the group consisting of _(:( = 〇)〇1113, -C(=0)R13, -OR&quot;, _NRi2Rl3, a halogen atom and Substituted by one or more substituents of a group of cyano groups, R12 represents a hydrogen atom, and R13 represents a C?-6 group (the Ci-6 group is unsubstituted or substituted by more than one fluorine atom) , phenyl or hydrazine is a steep group (the phenyl and phenyl group are unsubstituted or independently selected from C, -3 alkyl (the 3 alkyl is unsubstituted or substituted by more than one fluorine atom) A halogen atom, a cyano group, and one or more substituents in groups of -0 (C1 3) are substituted by any one of them, and R4 represents a hydrogen atom, and J1 represents an oxygen atom. A spirocyclic compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 is a formula (II-1) or (II-4) [Chem. 2 1] (wherein, in R1 and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded to represent piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl (the piperidinyl, piperazinyl) , homologous piperidinyl and homopyrazolyl are from phenyl, pyridyl, oxadiazolyl, benzimidazolyl, benzisoxazolyl or sialyl (the phenyl, pyridyl, oxadiazolyl) , benzimidazolyl, benzisoxazolyl and quinolyl are unsubstituted φ or are independently selected from Ci.3 alkyl (the Ch3 alkyl is unsubstituted or substituted by more than one fluorine atom), tooth Any one of the substituents substituted by one or more substituents of a group of a cyano group and a cyano group, and R4 represents a hydrogen atom, and 1 is a non-oxygen atom. 2 3 · A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 2 to item 12, item 14, or a pharmaceutically acceptable salt thereof, wherein Z1 represents Formula (II-1) or (II-4) -867- 201211053 [Chem. 2 2] (wherein, in R1 and R3, R1 and R3 are combined with the nitrogen atom to which they are bonded to represent a tetrahydroindenyl group (the tetrahydroindenyl group is unsubstituted or is independently selected from _C(= 〇) 〇Rl3, _ C( = 0)R13' _aR13' The halogen atom and the cyano group are replaced by more than one substituent; R12 represents a hydrogen atom, and R13 represents C, -6 alkyl, phenyl or Pyridyl (the phenyl and pyridyl groups are unsubstituted or independently selected from C, -3 alkyl groups (the cu alkyl group is unsubstituted or substituted by more than one fluorine atom), a halogen atom, a cyano group, and _0 Any one of (Ci3 fluorenyl) substituted by one or more substituents in the group), R4 represents a nitrogen atom, and J1 represents an oxygen atom. 24. The spiro compound of claim 1, the tautomer of the compound or a pharmaceutically acceptable salt thereof, wherein L1 represents Cu alkyl group 'L2 is a single bond, and e is an oxygen atom, m is an integer of 1 or 2, R6 is a hydrogen atom, η is 〇, and τ represents a formula (VI-1) or (VI-2) 868 - 201211053 [Chem. 2 3] Human l4/L, r8 Human R1. (VI-1) (VI-2) (wherein, L4 represents a Cl_3 alkyl group, L5 represents a single bond, and R8 and R1G represent any of the same meanings as defined in the first aspect of the patent application). 25. A spiro compound according to claim 1 or claim 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 represents formula (II-1) or (II- 4) [Chem. 2 4] (IM) (wherein, in R1 and R3, R1 represents an alkyl group which is substituted by any one of a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted by a C4-6 alkyl group), and R3 represents a hydrogen atom, or R1 represents a piperidinyl group (the piperidinyl group is substituted by a C4-6 alkyl group) 'R3 represents a gas atom, or ^3 and r3 are a nitrogen atom bonded to the same, and a piperidinyl group is represented. (The piperidinyl group is substituted by one or more substituents independently selected from the group consisting of _C(=0)R13, -〇R13 and -NR12R13), R12 represents a hydrogen atom, and R13 represents a phenyl group or a pyridyl group. (The phenyl group and the pyridyl group are either unsubstituted -869-201211053 or substituted by a c4-6 alkyl group), R4 represents a hydrogen atom, and J1 represents an oxygen atom. 26. A spirocyclic compound according to claim 1 or claim 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein Z1 represents formula (II-1) or (II-4) ) 【化2 5】 (11-1) (II-4) (wherein, in R1 and R3, R1 represents a Cu alkyl group (the Cu alkyl group is substituted by 4 to 7 members of an oxygen-containing heterocycloalkyl group or -NHCfCOCKCualkyl group)) R3 represents a hydrogen atom, or R1 represents a Ci-6 alkyl group (the C alkyl group is composed of a C6.1() aryl group or a 5-10 membered heteroaryl group (the C6_1Q aryl group and the 5-10 membered heteroaryl group are It can be condensed with 4 to 7 members of an oxacyclohexane, and the C6-1Q aryl group and the 5 to 10 membered heteroaryl group are unsubstituted or independently selected from a halogen atom, a cyano group, and a Cl-3 alkyl group ( The Cl-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), _0 (C alkyl group) and one or more substituents substituted by an alkyl group are substituted by any one of the substituents' and Ci.6 alkyl may be substituted by one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group, and R3 represents a hydrogen atom, or R1 is a 4-11 membered nitrogen-containing heterocycloalkyl group ( The 4_u member nitrogen-containing heterocycloalkyl group is substituted by -C(=0)〇(Cl·6 alkyl group), R3 represents a hydrogen atom, or Ri 201211053 and R3 are a nitrogen atom bonded to them. Represents tetrahydroanthracene 7 member nitrogen-containing heterocycloalkyl (the tetrahydroindenyl group and 5 to 7 members ^ Independently selected from phenyl, 5-10 membered heteroaryl (the phenyl and 5. are unsubstituted or independently selected from Cl-3 alkyl (how the Cl-3 is substituted by more than one fluorine atom) , a halogen atom and one or more substituents are substituted), _C(=0)0R13, 〇R13, -nr12r13, a halogen atom and a group of 1 cyano groups substituted by a cyano group, and R12 represents a hydrogen atom, R13 Indicates that the Cm-based group is unsubstituted or substituted with more than one fluorine atom (the phenyl and pyridyl groups are unsubstituted or independently selected from the Ci-3) group or are substituted by more than one fluorine atom. Wherein the cyano group and the -CMC, -3 alkyl group are more than one in the group), R4 represents a hydrogen atom, and Ji represents an oxygen atom. 27. In the first and second items of the patent application range to! A spiro compound, a tautomer of the compound, ^ a salt acceptable, wherein T represents a formula (VI-1) or (VI-2), a human L4〆1^, a human R1〇 (VI-1) (VI-2) (wherein L4 represents Cl_3 alkylene, L5 represents a single bond, and R represents phenyl or pyridyl (the phenyl and pyridyl are none; φ fluorenyl or 5 ~ 7 azacycloalkyl 10 member heteroaryl awning group is unsubstituted cyano group C (= 0) R &quot; ' - more than alkyl (the Cm), phenyl or pyridyl c 1 - 3 Any of the substituents of the hospital (this generation), halogen, and substituents. i 26 of them or their medicinal and R1 () each independently or by independent -871 - 201211053 selected from fluorine atom, Ci.3 alkane Any one of the group (the Chs alkyl group is substituted by one or more fluorine atoms) and one or more substituents in which the cyano group is grouped)). The spiro compound, the tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein T represents a formula (VI), or a pharmaceutically acceptable salt thereof. -1) or (VI-2) [Chem. 2 7] Person L〆1&quot;5'# person R1. (VI-1) (VI-2) (wherein L4 represents (^-3 alkylene, L5 represents a single bond, and R8 and RIG each independently represent a phenyl group (the phenyl group is substituted by a C4.6 alkyl group) The spiro compound, the tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein R6 is Φ 3 0. The spiro compound described in any one of items 1 to 3, 7 and 9 to 29 of the patent application, the tautomer of the compound, Or a pharmaceutically acceptable salt thereof, wherein X is a cyclohexyl group. 3 1. As claimed in claim 1 or 2, item 4 to item 6, item 8 to item 29 A spiro compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein X 8 -872- 201211053 is a phenyl, pyridyl, pyrazinediyl or thiophenediyl group. Or a thiazolediyl group. 32. An adiponectin receptor activator characterized by containing a spiro compound as an active ingredient as in any one of items 1 to 31 of the patent application, Tautomers of the compounds, or a salt thereof can be those pharmaceutically acceptable. 3 3 - Adiponectin receptor activation is an effective disease prevention, treatment, and amelioration drug, and is characterized by containing an adiponectin receptor activating drug as an active ingredient as in the 32nd paragraph of the patent application. A prophylactic or therapeutic agent for metabolic syndrome and arteriosclerosis, which comprises an adiponectin receptor activator as an active ingredient in the 32nd item of the patent application. 35_ a medicine characterized by containing a spiro compound as an active ingredient, according to any one of claims 1 to 31, a tautomer of the compound, or a pharmaceutically acceptable thereof Salt. -873 - 201211053 IV. Designated representative map: (1) The designated representative circle of this case is: None (2) The symbol of the representative figure is simple: no -3- 201211053 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: -4- 8