MX2007015506A - 1, 2-di(cyclic group)substituted benzene derivative. - Google Patents

Abstract

A compound represented by the general formula (1) or (100), a salt thereof or a hydrate of the compound or salt, which is excellent in cell adhesion-inhibitory effect and cell infiltration-inhibitory effect: (1) (100) wherein R¹⁰ represents a 5- to 10-membered cycloalkyl group which may be substituted by a hydroxyl group or the like, etc.; R³⁰, R³¹ and R³² independently represent a hydrogen atom, etc.; R⁴⁰ represents a C1-10 alkyl group which may be substituted by a hydroxyl group or the like, etc.; n represents an integer of 0, 1 or 2; X¹ represents a group represented by the formula: CH or a nitrogen atom; R²⁰, R²¹, R²² and R²³ independently represent a hydrogen atom, etc.

Description

BENZENE DERIVATIVE 1,2-DI (CYCLIC GROUP) SUBSTITUTED Technical Field The present invention relates to substituted 1, 2-di (cyclic) benzene derivatives which are useful as inhibitors of cell adhesion or as inhibitors of cellular infiltration, as well as to its salts and hydrates of the previous ones. The present invention relates to substituted 1,2-di (cyclic) benzene derivatives which are useful as therapeutic or prophylactic agents for inflammatory diseases and autoimmune diseases, as well as their salts and hydrates thereof. The invention further relates to substituted 1,2-di (cyclic) benzene derivatives which are useful as therapeutic or prophylactic agents for various diseases associated with adhesion and leukocyte infiltration, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis, as well as their salts and hydrates. Prior Art The inflammatory reaction is accompanied by infiltration of leukocytes, typically neutrophils and lymphocytes, into inflammatory sites.

Leukocyte infiltration is defined as the migration of leukocytes such as neutrophils and lymphocytes, outside the vessels and within the surrounding tissues as a consequence of the initiation and activation by cytokines, chemosins, lipids and complement for the interaction, called "coiled" or "binding", with vascular endothelial cells activated by cytokines such as IL-1 or TNFa !, followed by adhesion to vascular endothelial cells. As explained below, the relationship between the adhesion or infiltration of leukocytes and various inflammatory diseases and autoimmune diseases was reported. Such reports have raised the possibility that compounds that have an action inhibiting cell adhesion or an inhibiting action of cellular infiltration can serve as therapeutic or prophylactic agents for such diseases. (1) Therapeutic or prophylactic agents for inflammatory bowel disease (ulcerative colitis, Crohn's disease and the like) (see documents 1, 2 and 3, not patent) (2) Therapeutic or prophylactic agents for irritable bowel syndrome (see , document 4, not patent) (3) Therapeutic or prophylactic agents for rheumatoid arthritis (see document 5, non-patent) (4) Therapeutic or prophylactic agents for psoriasis (see document 6, non-patent) (5) Therapeutic or prophylactic agents for multiple sclerosis (see document 7, non-patent) (6 ) Therapeutic or prophylactic agents for asthma (see document 8, non-patent) (7) Therapeutic or prophylactic agents for atopic dermatitis (see document 9, non-patent) Accordingly, substances that inhibit cell adhesion or Cell infiltration are useful as therapeutic or prophylactic agents for various diseases associated with adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. Also known are compounds that have an anti-inflammatory action based on the inhibition of the adhesion of leukocytes and vascular endothelial cells, or an anti-inflammatory action based on the inhibition of leukocyte infiltration (these will be referred to below as inhibitors). of cell adhesion and cell infiltration inhibitors, respectively), such as the following compound: [Chemical Formula 1] (see Patent document 1). However, the compounds represented by the general formula (1) or the general formula (100) according to the present invention, are characterized by including a partial chemical structure such as piperazine., piperidine or tetrahydropyridine in the ortho position of a benzene ring linked to an aliphatic carbocyclic group such as cyclohexyl, therefore differ in their structures from the aforementioned cell adhesion inhibitors or cell infiltration inhibitors. The known compound comprising a partial chemical structure such as that having piperazine, piperidine or tetrahydropyridine in the ortho position of a benzene ring linked to an aliphatic carbocyclic group such as cyclohexyl, as a chemical structural feature of the compounds represented by the formula general (1) or the - - Generate formula (100) according to the present invention, is the compound represented by the following formula: [Chemical Formula 2] (see Patent document 2) However, the patent application only describes its use as an anti-obesity agent and a treatment for diabetes based on the agonistic activity of the melanocortin receptor of the compound, while neither describing nor suggesting its use. as an anti-inflammatory agent based on the action of inhibiting the adhesion or infiltration of leukocytes. In contrast to the above compound, the compound represented by the following formula is known: [Chemical Formula 3] (see document 10, non-patent, compound number 45). [Patent Document 1] WO 2002/018320 [Patent Document 2] WO 2002/059108 [Non-patent document 1] Inflammatory bowel disease (N, Engl. J. Med. 347: 417-429 (2002)) [Document 2 non-patent] Natalizumab for active Crohn's disease (N, Engl. J. Med., 348: 24-32 (2003)) [Non-patent document 3] Granulocyte absorption therapy in the active period of ulcerative colitis (Japanese Journal of Aphereses 18: 117-131 (1999)) [Non-patent document 4] A role for inflammation in irritable bowel syndrome (Gut., 51: i41-i44 (2002)) [Non-patent document 5 ] Rheumatoid Arthritis (Int. J. Biochem. Cell Biol., 36: 372-378 (2004)) [Non-patent Document 6] Psoriasis (Lancet, 361: 1197-1204 (2003)) [Non-Patent Document 7] ] New and emerging treatment options for multiple sclerosis (Lancet Neurology, 2: 563-566 (2003)) [Non-patent document 8] The role of T lymphocytes in the pathogenesis of asthma (J. Allergy Clin. Immunol., 111: 450-463 (2003)) [Non-patent document 9] The molecular basis of the supply of lymphocytes to the skin (J. Invest. Dermatol., 121: 951-962 (2003)) [Non-patent document 10] Discovery of 2- (4-pyridin-2-ylpiperazin-1-ylmethyl) -lH-benzimidazole (ABT- 724), a dopaminergic agent with a new mode of action for the potential treatment of erectile dysfunction (J. Med. Chem., 47: 3853-3864 (2004)) Description of the Invention Problems to be Resolved by Invention A goal of the present invention is to provide novel compounds having an excellent cell adhesion inhibitory action and cell infiltration inhibitory action, which are useful as therapeutic or prophylactic agents for various inflammatory diseases and autoimmune diseases associated with adhesion and leukocyte infiltration, such as l to inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. Means to solve problems As a result of intensive research, the present inventors have discovered that the substituted 1, 2-di (cyclic) benzene derivatives having a specific chemical structure exhibit excellent cell adhesion inhibitory action and cell infiltration inhibiting action, and are particularly useful as therapeutic and prophylactic agents for various inflammatory diseases and autoimmune diseases associated with the adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, sclerosis multiple, asthma and atopic dermatitis, and the present invention was completed based on this discovery. Specifically, the invention is a compound, according to the following [1] or [2], a salt thereof or a hydrate of the foregoing. [1] A compound represented by the following general formula (1), a salt thereof or a hydrate of the above: [Chemical Formula 4] (D wherein R 10 represents 5- to 10-membered cycloalkyl optionally substituted with a substituent selected from Al Group or 5- to 10-membered cycloalkenyl optionally substituted with a substituent selected from Al Group, R30, R31 and R32 can be the same or different and each represents hydrogen, hydroxyl, halogen, cyano, carboxyl, Cl-6 alkyl, Cl-6 alkoxy or C2-7 alkoxycarbonyl, or two of R30, R31 and R32 are they join together to form oxo (= 0) or methylene (-CH2-) and the other represents hydrogen, hydroxyl, halogen, cyano, carboxyl, Cl-6 alkyl, Cl-6 alkoxy or C2-7 alkoxycarbonyl, R40 represents Cl alkyl -10 optionally substituted with a substituent selected from Group Dl, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from Group El, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected from the El Group, C 2-7 alkenyl optionally substituted with a substituent selected from Group Fl, C2-7 alkynyl optionally substituted with a substituent selected from Group Fl, C2-7 alkylcarbonyl optionally substituted with a substituent selected from Group Gl, mono (C1-6 alkyl) aminocarbonyl, 4 to 8 membered heterocyclic carbonyl, C2 alkoxycarbonyl -7 or alkylsulfonyl Cl-6, n represents an integer of 0, 1 or 2, X1 represents CH or nitrogen, and R20, R21, R22 and R23 can be the same or different, and each represents hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, alkylthio Cl-6, optionally substituted with a substituent selected from Group Fl, C 2-7 alkoxycarbonyl, phenoxy, -S0 3 H, Cl 6 alkyl optionally substituted with a substituent selected from Group W 1, optionally Cl-6 alkyl substituted with a substituent selected from Group Kl, Cl-6 alkoxy optionally substituted with a substituent selected from the Wl Group, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected of the Wl Group, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Group VI, a 5- to 10-membered heteroaryl ring group optionally substituted with a substituent selected from the Wl Group, an aryl ring group of 6 to 10 members optionally substituted with a substituent selected from Group W1, C2-7 alkenyl optionally substituted with a substituent selected from Group W1, C2-7 alkynyl optionally substituted with a substituent selected from Group W1, 3 to 8 membered cycloalkyl optionally substituted with a substituent selected from Group W1, cycloalkenyl 5 to 8 members optionally substituted with a substituent selected from the Wl Group, -NR1XR2X, -C0-Rlx, -C0-NR1XR2X, -NR1X-C0-R2X, -S02-R3X or -0-S02-R3X, wherein R1X and R2X they may be the same or different and each represents hydrogen, Cl-6 alkyl optionally substituted with a substituent selected from Group Ul or a 4- to 8-membered heterocyclic group, and R3X represents Cl-6 alkyl optionally substituted with a substituent selected from the group Fl; or (i) R20 and R21, (ii) R21 and R22 or (iii) R22 and R23 are joined together to form a ring selected from Group Zl, wherein the group Al consists of hydroxyl, halogen, cyano, Cl-alkoxy 6, phenyl optionally substituted with a substituent selected from Cl Group, Cl-6 alkyl, Cl-6 haloalkyl and C 2-7 alkylene wherein C 2-7 alkylene is only permissible in the case where a spiro bond is formed in conjunction with cycloalkyl substituted from 5 to 10 members or with the substituted cycloalkenyl from 5 to 10 members, Cl group consists of cyano, halogen, Cl-6 alkyl and Cl-6 alkoxy, Group Dl consists of hydroxyl, halogen, cyano, Cl-6 alkoxy, Cl-6 alkylthio, Cl-6 alkylsulfonyl, Cl-6 alkylsulfinyl, mono (C 1-6 alkyl) amino, di (C 1-6 alkyl) amino, C 2-7 alkylcarbonylamino, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from Group Hl, C 2-7 alkoxycarbonyl, carboxyl, a heterocyclic group of 4 to 8 members, a 5- to 10-membered heteroaryl ring group, a 6 to 10 membered aryl ring group, C 2-7 alkylcarbonyl, 6 to 10 membered aryl ring carbonyl, aminocarbonyl, mono (Cl-6 alkyl) aminocarbonyl optionally substituted with halogen, mono (3- to 8-membered cycloalkyl) aminocarbonyl, mono (C2 -7-alkoxyalkyl) aminocarbonyl, di (C1-6 alkyl) aminocarbonyl, mono (5- to 10-membered heteroaryl ring) aminocarbonyl, heterocyclic carbonyl from 4 to 8 member optionally substituted with Cl-6 alkyl, and carbonyl d and 5- to 10-membered heteroaryl ring, the El Group consists of halogen, Cl-6 alkoxy, oxo (= 0) and Cl-6 alkyl, Group Fl consists of halogen and Cl-6 alkoxy, Group Gl consists of cycloalkyl of 3 to 8 members, Group Hl consists of hydroxyl, haloalkyl Cl- 6, Cl-6 alkyl, C2-7 alkoxyalkyl, mono (Cl-6 alkyl) aminocarbonyl, di (C 1-6 alkyl) aminocarbonyl, C 2-7 alkoxycarbonyl, carboxyl and C 2-7 cyanoalkyl, Group W 1 consists of halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl, C 2-7 alkoxyalkyl, C 1-6 alkoxy optionally substituted with a substituent selected from the Group TI, phenoxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, -NR6XRX and -C0-NRG R7X wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl , the IT Group consists of Cl-6 alkoxy, carboxyl, C2-7 alkoxycarbonyl and -C0NR4XR5X wherein R4X and R5X may be the same or different and each represents hydrogen or Cl-6 alkyl, Group VI consists of oxo (= 0) and etiienodioxy (-0-CH2CH2-0-) wherein etiienodioxy is permissible only in the case where a spiro bond is formed together with the substituted heterocyclic group of 4 to 8 members, the Kl Group consists of a heterocyclic group of 4 to 8 members, the Ul Group consists of carboxyl, Cl-6 alkoxy, C2-7 alkoxycarbonyl, halogen or, a 6 to 10 membered aryl ring group and -C0-NR8XR9X wherein R8X and R9X may be the same or different and each represents hydrogen or Cl-6 alkyl, and the Zl Group consists of [Chemical Formula 6] wherein R12 represents hydrogen, Cl-6 alkyl or benzyl, with the exception exception of a compound represented by the formula: [Chemical Formula 5] A compound represented by the following general formula (100), a salt thereof or a hydrate of the above: [Chemical Formula 7] (100) where Rxu, RV RV R ", RV Rj ?, RJ ±, RV R4U and n have the same respective definitions as R10, R20, R21, R22, R23, R30, R31, R32, R40 and n in [1] above. Examples of the "5- to 10-membered cycloalkyl" of the "5- to 10-membered cycloalkyl optionally substituted with a substituent selected from the group Al" for R 10, there may be mentioned cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, among which is preferred particularly cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and particularly cyclohexyl The "5- to 10-membered cycloalkenyl" of the "5- to 10-membered cycloalkenyl optionally substituted with a substituent selected from the group Al" for R 10 may have multiple linkages and, as examples, can be mentioned cyclopentenyl (1-cyclopentenyl, 2-cyclopentenyl or 3-cyclopentenyl), cyclohexenyl (1-cyclohexenyl, 2-cyclohexenyl or 3-cyclohexenyl), cycloheptenyl (1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl or 4-cycloheptenyl), cyclooctenyl (1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl or 4-cyclooctenyl, cyclononenyl (1-cyclononenyl, 2-cyclononenyl, 3-cyclononenyl, 4-cyclononenyl or 5-cyclononenyl) or cyclodecenyl (1-cyclodecenyl, 2-cyclodecenyl, 3-cyclodecenyl, 4-cyclodecenyl or 5-cyclodecenyl), among which cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl, cyclohexenyl is most preferred, and the most preferred is 1-cyclohexenyl, examples of the "halogen" for R20, R21, R22 and R23, there may be mentioned fluorine, chlorine, bromine, iodine or the like, among which bromine, fluorine or chlorine is preferred. "Clcyl alkylthio" of "Cl-6 alkylthio optionally substituted with a substituent selected from the group consisting of Group Fl "for R20, R21, R22 and R 23, is a thio group having the above-described "Cl-6 alkyl" linked thereto, and, as examples, straight chain or branched chain groups such as methylthio, ethylthio, propylthio, isopropylthio, carbonylbutylthio, isobutylthio, s-butylthio, t-butylthio, pentthylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4- methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3, 3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 1-ethylbutylthio or 2-ethylbutylthio, among which Cl-4 groups are preferred, and methylthio is particularly preferred. The "C2-7 alkoxycarbonyl" for R20, R21, R22 and R23, is a carbonyl group having the "Cl-6 alkoxy" described below, linked thereto, and as examples straight chain or branched chain groups such as as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3, 3-dimethylbutoxycarbonyl , 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl, among which is preferred methoxycarbonyl or ethoxycarbonyl. As examples of "Cl-6 alkyl" of "Cl-6 alkyl optionally substituted with a substituent selected from Group Wl" for R20, R21, R22 and R23, straight chain or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, t-pentyl, 2-methylbutyl, 1-methylbutyl, 2-methylbutyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3 , 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl , 1, 2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, among which Cl-4 groups are preferred, methyl, ethyl or t-butyl are more preferred; preferred is methyl. As examples of the "Cl-6 alkyl" of "Cl-6 alkyl optionally substituted with a substituent selected from Group K1" for R20, R21, R22 and R23, the same as listed above may be mentioned, among which Cl- groups are preferred. 4, and methyl is particularly preferred. As examples of "Cl-6 alkoxy" of "Cl-6 alkoxy optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, straight chain or branched chain groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2, 2- dimethylbutoxy, 1,1-dimethylbutoxy, 1,2- dimethylbutoxy, 1,3-dimethylbutoxy, or 2,3-dimethylbutoxy, among which methoxy, ethoxy, propoxy, or isopropoxy is preferred, methoxy or ethoxy is more preferred, and most preferred is methoxy. The "heterocyclic group of 4 to 8 members" of the "4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, is a monovalent group obtained by removing a hydrogen from any desired position of a "4- to 8-membered heterocycle" as is described below. The "4- to 8-membered heterocycle" is a non-aromatic ring (either a fully saturated ring or a partially unsaturated ring) having from 4 to 8 atoms forming the ring and containing one or more heteroatoms between the atoms forming the ring, and, as examples may be mentioned an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, an azocan ring, a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiopyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a diazepane ring, a thiazolidine ring, an isoxazolidine ring, an imidazolidine ring, a pyrazolidine ring, a dioxane ring, a 1,3-dioxolane ring, an oxatian ring, a dithian ring, a pyrano ring, a dihydropyran ring , a pyrrolo ring, a dihydropyridine ring, a pyrazoline ring, a ring oxazoline, an imidazoline ring or a thiazoline ring. Preferably the "4- to 8-membered heterocyclic groups" are fully saturated 4- to 8-membered heterocyclic groups eliminating a bound hydrogen constituting the ring are more preferred, piperazin-1-yl, pyrrolidin-1-yl, azetidin are further preferred. -1-yl, thiomorpholin-4-yl, piperidin-1-yl, or morpholin-4-yl, and most preferred is pyrrolidin-1-yl, piperidin-1-yl, or morpholin-4-yl. As examples of the "4- to 8-membered heterocyclic group" of the "4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Group VI" for R20, R21, R22 and R23, there may be mentioned the same before listed among which it prefers the pyrrolidine ring, piperidine ring, thiomorpholin-4-yl or 1,6-dihydropyridin-2-yl, pyrrolidin-1-yl or piperidin-1-yl is more preferred, and piperidin-1-yl is most preferred. The "4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Group VI" for R20, R21, R22 and R23 is not particularly restricted so long as it is the aforementioned "4- to 8-membered heterocyclic group" optionally substituted with a substituent selected from Group VI ", but preferably it is a group represented by the following formula: [Chemical Formula 8] The "5- to 10-membered heteroaryl ring group" of the "5- to 10-membered heteroaryl group optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, is a monovalent group obtained by removing a hydrogen from any desired position of a "5- to 10-membered heteroaryl ring" as described below. The "5- to 10-membered heteroaryl ring" is an aromatic ring having from 5 to 10 atoms forming the ring and containing one or more heteroatoms between the ring-forming atoms (with respect to fused rings, at least one of the rings are aromatic), and, as examples, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole ring, a ring isothiazole, an imidazole ring, a triazole ring, a tetrazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, an oxadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, an indole ring, an isoindol ring, an indazolo ring, a quinoline ring, an isoquinoline ring, a cinoline ring, a quinazoline ring, a quinoxaline ring, a naphthylidene ring, a phthalazine ring, a purine ring, a pteridine ring, a thienofuran ring, an imidazothiazole ring, a benzofuran ring, a benzothiophene ring, a benzoxazole ring, a benzothiazole ring, a benzothiadiazole ring, a benzimidazole ring, an imidazopyridine ring, a pyrrolopyridine ring, a pyrrolopyrimidine ring, a pyridopyrimidine ring, a coumarane ring, a chromene ring, a chroman ring, an isochroman ring, an indoline ring or an isoindoline ring. Preferably, the "5- to 10-membered heteroaryl ring" is a 5- to 6-membered ring, an isoxazole ring, an oxadiazole ring, a tetrazole ring, a pyridine ring, a thiazole ring or a thiophene ring is more preferred, and is more preferably a pyridine ring, a thiazole ring, a thiophene ring, or a tetrazole ring. The "6 to 10 membered aryl ring group" of the "6 to 10 membered aryl ring group optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, is a hydrocarbon ring group aromatic of 6 to 10 carbons (with respect to fused rings, at least one of the rings is aromatic), as examples may be mentioned phenyl, 1-naphthyl, 2-naphthyl, indenyl, indanyl, azulenyl or heptanyl, among which is preferred the phenyl The "C2-7 alkenyl" of "C2-7 alkenyl optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, is a straight chain or branched chain group of 2 to 7 carbons which may contain 1 or 2 double bonds, and, as examples, there may be mentioned ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl , 1-pentenyl, 1-hexenyl, 1,6-hexanedienyl or 1-heptenyl, among which C2-5 groups containing a double bond are preferred, and ethenyl is particularly preferred. The "C2-7 alkynyl" of "C2-7 alkynyl optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, is a straight chain or branched chain group of 2 to 7 carbons which may contain 1 or 2 double bonds, and, as examples, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, 1,6-hexanedynyl or -heptinyl, among which C2-5 groups containing a triple bond are preferred, and ethynyl or 1-propynyl is particularly preferred.

As examples of the "3- to 8-membered cycloalkyl" of the "3- to 8-membered cycloalkyl optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, there may be mentioned the same listed below, among which is preferred cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cyclopropyl, cyclopentyl or cyclohexyl are particularly preferred. The "5- to 8-membered cycloalkenyl" of the "5- to 8-membered cycloalkenyl optionally substituted with a substituent selected from Group W1" for R20, R21, R22 and R23, may have multiple double bonds, and, as examples, may be mentioned cyclopentenyl (1-cyclopentenyl, 2-cyclopentenyl or 3-cyclopentenyl), cyclohexenyl (1-cyclohexenyl, 2-cyclohexenyl or 3-cyclohexenyl), cycloheptenyl (1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl or 4-cycloheptenyl), and cyclooctenyl (1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl or 4-cyclooctenyl), among which cyclopentenyl or cyclohexenyl is more preferred, and 1-cyclopentenyl or 1-cyclohexenyl is particularly preferred. As examples of the "Cl-6 alkyl" of the "Cl-6 alkyl optionally substituted with a substituent selected from the Ul Group" for R1X and R2X, those listed above may be mentioned. As examples of the "heterocyclic group from 4 to 8"members for R1X and R2X may be mentioned the same as listed above, among which the fully saturated 4 to 8 membered heterocyclic groups are preferred, a tetrahydropyran ring group, a morpholine ring group, a piperidine ring group or a pyrrolidine ring group, and tetrahydropyran-4-yl or morpholin-4-yl is most preferred, as examples of "Cl-6 alkyl" of "Cl-6 alkyl optionally substituted with a substituent selected from Group Fl" for R3X there may be mentioned the same as listed above, among which Cl-4 groups are preferred, and methyl or ethyl is particularly preferred. "-NR1XR2X" for R20, R21, R22 and R23, is an amino group (-NH2) having two hydrogens replaced with R1X and RX, when none of R1X and R2X of "-NR1XR2X" for R20, R21, R22 and R23, is a 4- to 8-membered heterocyclic group, then "-NR1XR2X" is preferably methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, (methoxyethyl) amino, di (methoxyethyl) amino or methyl (methoxyethyl) amino. "-C0-Rlx" for R20, R21, R22 and R23, is a carbonyl group having R1X bonded thereto, and morpholin-4-ylcarbonyl, methoxyethylcarbonyl, ethylcarbonyl or acetyl is preferred. "-C0-NR1XR2X" for R20, R21, R22 and R23, is a carbonyl group having - NR1XR2X bonded thereto.

"-NR1X-C0-R2X" for R20, R21, R22 and R23, is an amino group (-NH2) having two hydrogens replaced with a "carbonyl group having R2X bonded thereto" and R1X. "-S02-R3x" for R20, R21, R22 and R23, is a sulfonyl group having R3X bonded thereto. "-0-S02-R3x" for R20, R21, R22 and R23, is a sulfonyloxy group having R3X bonded thereto. As examples of the "halogen" for R30, R31 and R32, there may be mentioned those listed above, among which fluorine or chlorine are preferred. As examples of "Cl-6 alkyl" for R30, R31 and R32, there may be mentioned those listed above, among which Cl-4 groups are preferred, and methyl is particularly preferred. As examples of "Cl-6 alkoxy" for R30, R31 and R32, there may be mentioned those listed above, among which Cl-4 groups are preferred, and methoxy is particularly preferred. The "C2-7 alkoxycarbonyl" for R30, R31 and R32, is a carbonyl group having the aforementioned "C1-C6 alkoxy" bonded thereto, and, as examples, straight chain or branched chain groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3, 3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1, 1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1, 3 - dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl, among which methoxycarbonyl or ethoxycarbonyl is preferred. Two of R30, R31 and R32, "bonded together to form oxo (= 0)" means that two of R30, R31 and R32, are linked to the same carbon atom to form an oxo group. Two of R30, R31 and R32, "bonded together to form methylene (-CH2-)" means that two of R30, R31 and R32, bind to different carbon atoms to form a methylene group. As examples of "Cl-10 alkyl" of "Cl-10 alkyl optionally substituted with a substituent selected from Group D1" for R40, the same examples listed for the "Cl-6 alkyl" above, as well as C7-10 alkyl groups may be mentioned. straight chain or branched chain such as heptyl, 3-methylhexyl, octyl, nonyl or decyl, among which Cl-6 groups are preferred, and methyl, ethyl, propyl, isopropyl, isobutyl, butyl or pentyl are particularly preferred. As examples of "3 to 8 member cycloalkyl" of the "3- to 8-membered cycloalkyl optionally substituted with a substituent selected from the group" for R40 can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, among which cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are preferred and particularly preferred cyclopentyl or cyclohexyl. As examples of the "4- to 8-membered heterocyclic group" of the "4- to 8-membered heterocyclic group optionally substituted with a substituent selected from the group" for R40 may be mentioned the same as listed above, among which a pyrrolidine ring group is preferred. , a piperidine ring group, a tetrahydropyran ring group or a tetrahydropyran ring group. The "C2-7 alkenyl" of "C2-7 alkenyl optionally substituted with a substituent selected from Group Fl" for R40 is a straight-chain or branched-chain alkenyl group of 2 to 7 carbons which may contain 1 or 2 double bonds, and, as examples, there may be mentioned ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, -hexenyl, 1,6-hexanedienyl or 1-heptenyl, among which C2-5 groups are preferred and 2-propenyl or 2-methyl-2-propenyl is particularly preferred.

The "C2-7 alkynyl" of the "C2-7 alkynyl optionally substituted with a substituent selected from Group Fl" for R40 is a straight-chain or branched-chain alkynyl group of 2 to 7 carbons which may contain 1 or 2 triple bonds, and, as examples, there may be mentioned ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, 1-pentynyl, 1-hexinyl, 1,6-hexanediinyl or 1-heptinyl, among others. which C2-5 groups are preferred and 2-butyl or 2-propynyl is particularly preferred. The "C2-7 alkylcarbonyl group" of the "C2-7 alkylcarbonyl group optionally substituted with a substituent selected from Group Gl" for R40 is a carbonyl having the aforementioned "Cl-6 alkyl" linked thereto, and, as examples, straight chain or branched chain groups such as acetyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, neopentylcarbonyl, 1-ethylpropylcarbonyl, hexylcarbonyl, isohexylcarbonyl, 4-methylpentylcarbonyl, 3-methylpentylcarbonyl, 2-methylpentylcarbonyl, 1-methylpentylcarbonyl, 3, 3-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl, 1, 1-dimethylbutylcarbonyl, 1,2-dimethylbutylcarbonyl, 1,3-dimethylbutylcarbonyl, 2,3- dimethylbutylcarbonyl, 1-ethylbutylcarbonyl, or 2-ethylbutylcarbonyl, among which C2-5 groups are preferred, and acetyl or propylcarbonyl is particularly preferred. The "mono / alkyl Cl-6) aminocarbonyl" for R40 is a carbonyl group having "mono (Cl-6 alkyl) amino" bonded thereto, and, as examples, straight chain or branched chain groups such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, s-buti1aminocarbonilo, t-buti1aminocarboni1o, pentylaminocarbonyl, isopentilaminocarbonilo, 2-methylbutylaminocarbonyl, neopentylaminocarbonyl, 1-ethylpropylaminocarbonyl, hexylaminocarbonyl, isohexilaminocarbonilo, 4-metilpentilaminocarbonilo, 3-metilpentilaminocarbonilo, 2-metilpentilaminocarbonilo, 1-methylphenylaminocarbonyl, 3, 3-dimethylbutylaminocarbonyl, 2,2-dimethylbutylaminocarbonyl, 1,1-dimethylbutylaminocarbonyl, 1,2-dimethylbutylaminocarbonyl, 1,3-dimethylbutylaminocarbonyl, 2,3-dimethylbutylaminocarbonyl, 1-ethylbutylaminocarbonyl or 2-ethylbutylaminocarbonyl, among others which are preferred groups C2-5 (number total carbon) and ethylaminocarbonyl is particularly preferred.

The "4- to 8-member heterocyclic carbonyl" for R40 is a carbonyl group that has the "heterocyclic group of 4 to 8 members "aforementioned linked thereto, among which piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl are preferred. Examples of" C2-7 alkoxycarbonyl "for R40 may be mentioned as listed above, among which prefers methoxycarbonyl or ethoxycarbonyl The "alkylsulfonyl Cl-6" for R40 is a sulfonyl group having the aforementioned "Cl-6 alkyl" linked thereto, and, as examples, straight chain or branched chain groups such as metiisulfonilo, etiisulfonilo, propylsulfonyl, isopropylsulfonyl, carbonilbutilsulfonilo, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, isohexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3, 3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulph onyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl or 2-ethylbutylsulfonyl, among which propylsulfonyl is preferred.

Examples of the "halogen" for the Al Group can be mentioned those listed above, among which bromine, fluorine or chlorine are preferred. As examples of the "Alkoxy Cl-6" of the Al Group can be mentioned those listed above, among which the Cl-4 groups are preferred, and methoxy is particularly preferred. As examples of the "Cl-6 alkyl" of the Al Group and of the Group A2 (mentioned below), there may be mentioned those listed above among which the Cl-4 groups are preferred, and methyl, ethyl, n-butyl or t-butyl. The "haloalkyl Cl-6" of Group Al and Group A2 (mentioned below) is found in the above-mentioned "Cl-6 alkyl" having the aforementioned "halogen" bonded thereto, and, as examples, alkyl groups may be mentioned straight chain or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 -dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl, which has fluorine or chlorine bonded thereto, among which is preferred alkyl Cl-4 having from 1 to 3 fluorine or chlorine linked thereto, and trifluoromethyl is particularly preferred. As examples of "C2-7 alkylene", wherein C2-7 alkylene is permissible only in the case where the spiro bond is formed together with the substituted cycloalkyl of 5 to 10 members or the substituted cycloalkenyl of 5 to 10 members of the Group Al and Group A2 (mentioned below), straight chain or branched chain groups such as 1,2-ethylene, trimethylene, propylene, ethylethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene may be mentioned, among which 1,2-ethylene, trimethylene, tetramethylene or pentamethylene are preferred, and 1,2-ethylene, tetramethylene or pentamethylene is particularly preferred. As examples of the "halogen" of the Wl Group, those listed above may be mentioned, among which fluorine or chlorine is preferred. As examples of the "Cl-6 alkyl" of the Wl Group may be mentioned those listed above, among which the Cl-4 groups are preferred, and methyl or ethyl is particularly preferred. The "C2-7 alkoxyalkyl" of the W1 Group is the above-mentioned "Cl-6 alkyl" having the aforementioned "Cl-6 alkoxy" linked thereto of 2 to 7 carbons (total carbon number), and, as examples , there can be mentioned methoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl or propoxyethyl, among which methoxymethyl is preferred. As examples of the "Cl-6 alkoxy" of the "Cl-6 alkoxy optionally substituted with a substituent selected from the Group TI" of the Wl Group, those listed above may be mentioned, among which Cl-4 groups are preferred, and particularly preferred. methoxy, ethoxy, isopropoxy or propoxy. As examples of the "C2-7 alkoxycarbonyl" of the W1 Group, those listed above may be mentioned, among which methoxycarbonyl or ethoxycarbonyl is preferred. As examples of the "C2-7 alkylcarbonyl" of the W1 Group, those listed above may be mentioned, among which C2-5 groups are preferred, and acetyl is particularly preferred. As examples of "Cl-6 alkyl" for R6X and R7X, those listed above may be mentioned. As examples of the "halogen" of Cl Group, the same as listed above can be mentioned, among which bromine, fluorine or chlorine are preferred. As examples of the "Cl-6 alkyl" of Cl Group, those listed above may be mentioned, among which Cl-4 groups are preferred, and methyl is particularly preferred. As examples of the "Cl-6 alkoxy" of Cl Group, there may be mentioned the same as listed above, among which Cl-4 groups are preferred, and methoxy or ethoxy is particularly preferred. As examples of the "halogen" of Group D1 and Group D2 (mentioned below), those listed above may be mentioned, among which fluorine or chlorine is preferred. As examples of the "Cl-6 alkoxy" of Group D1 and Group D2 (mentioned below), those listed above may be mentioned, among which Cl-4 groups are preferred, and methoxy or ethoxy is particularly preferred. The "alkylthio Cl-6" of Group Dl is a thio group having the above-mentioned "Cl-6 alkyl" linked thereto, and, as examples, straight chain or branched chain groups such as methylthio, ethylthio, propylthio, isopropylthio, carbonylbutylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3, 3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 1-ethylbutylthio or 2-ethylbutylthio, among which are preferred Cl-4 groups, and methylthio or ethylthio is particularly preferred. As examples of the "alkylsulfonyl Cl-6" of the Group D1, the same as listed above can be mentioned, among which Cl-4 groups are preferred, and methylisulfonyl or ethylsulfonyl is particularly preferred. The "Cl-6 alkylsulfinyl" of Group Dl is a sulfinyl group having the above-mentioned "Cl-6 alkyl" linked thereto, and, as examples, straight chain or branched chain groups such as methylisulfinyl, ethylsulfinyl, propylsulfinyl can be mentioned. , isopropylsulfinyl, carbonylbutylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, isohexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, , 3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl or 2-ethylbutylsulfinyl, among which Cl groups are preferred -4, and methylisulfinyl or ethylsulfinyl is particularly preferred. As examples of the "mono (Cl-6 alkyl) amino" group of Dl, straight chain or branched chain groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s- butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3, 3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, -ethylbutylamino or 2-ethylbutylamino, among which methylamino or ethylamino is preferred, and methylamino is particularly preferred. The "Di (alkyl Cl-6) amino" of Group Dl may be either symmetrical or asymmetric, and, as examples, straight chain or branched chain groups such as dimethylamino, methylethylamino, diethylamino, methylpropylamino, ethylpropylamino, dipropylamino, may be mentioned. , diisopropylamino, dibutylamino, diisobutylamino, di (s-butyl) amino, di (t-butyl) amino, methylpentylamino, dipentylamino, diisopentylamino, di (2-methylbutyl) amino, di (neopentyl) amino, di (1-ethylpropyl) amino , dihexylamino, methyl isohexylamino, diisohexylamino, di (4-methylpentyl) amino, di (3-methylpentyl) amino, di (2-methylpentyl) amino, di (1-methylpentyl) amino, di (3, 3-dimethylbutyl) amino, di (2,2-dimethylbutyl) amino, di (1,1-dimethylbutyl) amino), di (1,2-dimethylbutyl) amino, di (1,3-dimethylbutyl) amino, di (2,3-dimethylbutyl) amino, di (1-ethylbutyl) amino or di (2-ethylbutyl) amino, among which dimethylamino is preferred, - methylethylamino or diethylamino, and dimethylamino is particularly preferred. The "C2-7 alkoxycarbonylamino" of Group Dl is an amino group having the "C2-7 alkylcarbonyl" bonded thereto above, and as examples can be mentioned groups straight chain or branched chain such as acetylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, pentylcarbonylamino, isopenti1carbonilamino, 2-methylbutylcarbonylamino, neopentilcarbonilamino, 1-ethylpropylcarbonylamino, hexylcarbonylamino, isohexilcarbonilamino, 4-methylpentylcarbonylamino, 3-methylpentylcarbonylamino, 2-methylpentylcarbonylamino, 1-methylpentylcarbonylamino, 3, 3-dimethylbutylcarbonylamino, 2,2-dimethylbutylcarbonylamino, 1, 1-dimethylbutylcarbonylamino, 1, 2 -dimetilbutilcarbonilamino, 1, 3 -dimetilbutilcarbonilamino, 2, 3-dimethylbutylcarbonylamino, 1-ethylbutylcarbonylamino or 2-ethylbutylcarbonylamino, among which are preferred amino groups having C2-5 alkylcarbonyl linked thereto, and acetylamino or ethylcarbonylamino is particularly preferred. As examples of the "3 to 8 membered cycloalkyl" of optionally substituted 3 to 8 membered cycloalkyl with a substituent selected from Hl Group "of Dl Group and" cycloalkyl of 3 to 8 members "of Group D2 (below mentioned) may be mentioned the same listed above, among which is preferred cyclopropyl, cyclobutyl, cyclopentyl or ciciohexilo, is preferred cyclopropyl or cyclobutyl, and more preferred is cyclopropyl. examples of "C2-7 alkoxycarbonyl" of Dl group may be mentioned the same listed above, among which preferred methoxycarbonyl or ethoxycarbonyl. examples of the "heterocyclic group of 4 to 8 members "of Group D1 and Group D2 (mentioned below) may be mentioned those listed above, among which a tetrahydropyran ring group or a tetrahydrofuran ring group is preferred, and tetrahydropyran-4-yl is particularly preferred. 5 to 10-membered heteroaryl ring group "of Group D1, there may be mentioned the same as listed above, among which is Furanyl, thienyl, pyridyl, pyrazyl, pyrimidinyl or pyridazinyl, and thienyl or pyridyl is particularly preferred. The "6 to 10 membered aryl ring group" of the Dl Group is an aromatic hydrocarbon ring group of 6 to 10 carbons (with respect to fused rings, at least one of the rings is aromatic), and, as examples, may mention may be made of phenyl, 1-naphthyl, 2-naphthyl, indenyl, indanyl, azulenyl, or heptalenyl, among which phenyl, 1-naphthyl or 2-naphthyl are preferred, and phenyl is particularly preferred. As examples of the "C2-7 alkylcarbonyl" of the Group D1 and Group D2 (mentioned below) may be mentioned those listed above, among which C2-5 groups are preferred, and acetyl or ethylcarbonyl is particularly preferred. The "6 to 10 membered aryl ring carbonyl group" of Group D1 is a carbonyl group having the abovementioned "6 to 10 membered aryl ring group" bonded thereto, and, as examples, benzoyl, -naftoilo, 2-naphthoyl, indenilcarbonilo, indanilcarbonilo, azulenilcarbonilo or heptaenilcarbonilo, among which benzoyl, 1-naphthoyl or 2-naphthoyl is preferred, and benzoyl is particularly preferred. As examples of "mono (Cl-6 alkyl) aminocarbonyl" of "mono (Cl-6 alkyl) aminocarbonyl optionally substituted with halogen" of Group Dl and the "mono (Cl-6 alkyl) aminocarbonyl" of Group D2 (mentioned below) , there may be mentioned the same as listed above, among which C2-5 groups (total carbon number) are preferred, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl or butylaminocarbonyl, and methylaminocarbonyl is most preferred, ethylaminocarbonyl, propylaminocarbonyl or isopropylaminocarbonyl. As examples of the "mono (3- to 8-membered cycloalkyl) aminocarbonyl" of Group D1, there may be mentioned cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl or cyclooctylaminocarbonyl, among which cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl or cyclohexylaminocarbonyl is preferred, and is particularly preferred cyclopropylaminocarbonyl. The "mono (C2-7 alkoxyalkyl) aminocarbonyl" of Group D1 is an aminocarbonyl group having "C2-7 alkoxyalkyl" bonded thereto, wherein the "C2-7 alkoxyalkyl" is the aforementioned "Cl-6 alkyl" which it has the abovementioned "Cl-6 alkoxy" linked thereto, of 2 to 7 carbons (total carbon number). As examples of "mono (C2-7 alkoxyalkyl) aminocarbonyl" there may be mentioned methoxymethylaminocarbonyl, methoxyethylaminocarbonyl, ethoxyethylaminocarbonyl, methoxypropyl aminocarbonyl or propoxyethylaminocarbonyl, among which methoxyethylaminocarbonyl is preferred. The "di (C1-6 alkyl) aminocarbonyl" of Group D1 and Group D2 (mentioned below) is a carbonyl group which has the di (C1-6 alkyl) amino linked thereto, and as preferred examples there may be mentioned straight chain or branched chain groups such as dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl, dipropylaminocarbonyl, diisopropylaminocarbonyl, diisobutylaminocarbonyl, di (s) -butyl) aminocarbonyl, di (t-butyl) aminocarbonyl, methylpentylaminocarbonyl, dipentylaminocarbonyl, diisopentylaminocarbonyl, di (2-methylbutyl) aminocarbonyl, di (neopentyl) aminocarbonyl, di (1-ethylpropyl) aminocarbonyl, dihexylaminocarbonyl, methyl isohexylaminocarbonyl, diisohexylaminocarbonyl, di (4-methylcarbonyl) -methylpentyl) aminocarbonyl, di (3-methylpentyl) aminocarbonyl, di (2-methylpentyl) aminocarbonyl, di (1-methylpentyl) aminocarbonyl, di (3,3-dimethylolbutyl) aminocarbonyl, di (2,2-dimethylbutyl) aminocarbonyl, (1,1-dimethylbutyl) aminocarbonyl,, di (1,2-dimethylbutyl) aminocarbonyl, di (1,3-dimethylbutyl) aminocarbonyl) or, di (2,3-dimethylbutyl) aminocarbonyl, di (1-ethylbutyl) aminocarbonyl or di (2-ethylbutyl) aminocarbonyl, among which dimethylaminocarbonyl, methylethylaminocarbonyl or diethylaminocarbonyl is preferred and dimethylaminocarbonyl is particularly preferred.

- The "mono (5- to 10-membered heteroaryl ring) aminocarbonyl" of Group D1 is an aminocarbonyl (carbamoyl) group having one hydrogen replaced with the "5- to 10-membered heteroaryl ring" mentioned above, and as examples of the "heteroaryl ring" from 5 to 10 members "may be mentioned a pyridine ring, a thiophene ring, a furan ring, a pyrrolo ring, an oxazolo ring, an isoxazolo ring, a thiazolo ring, a thiadiazolo ring, an isothiazole ring, an imidazole ring, a ring triazolo, a tetrazolo ring, a pyrazolo ring, a furazano ring, a thiadiazole ring, an oxadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, an indole ring, an isoindol ring, an indazolo ring, an quinoline ring, an isoquinoline ring, a cinoline ring, a quinazoline ring, a quinoxaline ring, a naphthylidine ring, a phthalazine ring, a purine ring, a pteridine ring, a thienofuran ring, an imidazothia ring zol, a benzofuran ring, a benzothiophene ring, a benzoxazole ring, a benzothiazole ring, a benzothiadiazole ring, a benzimidazole ring, an imidazopyridine ring, a pyrrolopyridine ring, a pyrrolopyrimidine ring, a pyridopyrimidine ring, a coumarane ring, a chromene ring, a chroman ring, an isochroman ring, an indoline ring or an isoindoline ring. The mono group (5-heteroaryl ring 10 members) preferred aminocarbonyl is pyridin-2-ylaminocarbonyl. As examples of the "4- to 8-membered heterocyclic carbonyl" of the "4- to 8-membered heterocyclic carbonyl optionally substituted with Cl-6 alkyl" of Group D1 and of the "4- to 8-membered heterocyclic carbonyl" of Group D2 (mentioned below) there may be mentioned those listed above, among which pyrrolidin-1-ylcarbonyl, azepan-1-ylcarbonyl, azocan-1-ylcarbonyl, piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl, and pyrrolidin-1 is particularly preferred. ilcarbonyl, piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl. The "5- to 10-membered heteroaryl ring carbonyl" of Group D1 is a carbonyl group having the above-mentioned "5- to 10-membered heteroaryl ring group" linked thereto. The "5-membered heteroaryl ring group" of group D2 (mentioned below) is a group in which the number of atoms constituting the ring is 5 in the "5- to 10-membered heteroaryl ring group" of the D1 Group, and as examples may be mentioned thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, pyrazolyl, furazanyl or oxadiazolyl, among which thienyl or furyl is preferred. As examples of the "halogen" of the El Group, they can mention the same as listed above, among which bromine, fluorine or chlorine is preferred. As examples of the "Cl-6 alkoxy" of the El Group, there may be mentioned those listed above, among which the Cl-4 groups are preferred, and methoxy is particularly preferred. As examples of the "Cl-6 alkyl" of the El Group, there may be mentioned those listed above, among which the Cl-4 groups are preferred, and methyl is particularly preferred. As examples of the "halogen" of Group Fl, those listed above may be mentioned, among which fluorine or chlorine is preferred. As examples of the "Cl-6 alkoxy" of Group Fl, those listed above may be mentioned, among which Cl-4 groups are preferred, and methoxy is particularly preferred. As examples of the "3- to 8-membered cycloalkyl" of the Gl Group, there may be mentioned those listed above, among which cyclohexyl or cyclopropyl is particularly preferred. As examples of the "haloalkyl Cl-6" of the Hl Group, those listed above may be mentioned, among which chloromethyl or fluoromethyl is particularly preferred.

As examples of the "Cl-6 alkyl" of the Hl Group, those listed above may be mentioned, among which the Cl-4 groups are preferred, and methyl is particularly preferred. As examples of the "C2-7 alkoxyalkyl" of the Group Hl, the same as listed above may be mentioned, among which methoxymethyl is preferred. As examples of the "mono (Cl-6 alkyl) aminocarbonyl" of Group H1, there may be mentioned the same as listed above, among which methylaminocarbonyl is preferred. As examples of the "di (C1-6 alkyl) aminocarbonyl" of Group H1, there may be mentioned those listed above, among which dimethylaminocarbonyl or diethylaminocarbonyl is preferred, and dimethylaminocarbonyl is particularly preferred. As examples of the "C2-7 alkoxycarbonyl" of Group H1, there may be mentioned those listed above, among which methoxycarbonyl or ethoxycarbonyl is preferred. The "cyanoalkyl 0.2 - 1" of the Hl Group is the "alkyl Cl-6"mentioned above having a cyano group bonded thereto, and as examples straight chain or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl, having cyano groups bonded thereto, among which is preferred Cl-4 alkyl having a linked cyano group thereto, and cyanomethyl is particularly preferred. As examples of the "Cl-6 alkoxy" of the IT Group, those listed above may be mentioned. As examples of the "C2-7 alkoxycarbonyl" of the IT Group, the same as listed above can be mentioned. As examples of "Cl-6 alkyl" for R4X and R5X, those listed above may be mentioned. As examples of the "heterocyclyl group 4 to 8" members "of the Kl Group, there may be mentioned the same listed above, among which a ring-ring group of piperidine, a tetrahydropyran ring group or a morpholine ring group is preferred. , and tetrahydropyran-4-yl or morpholin-4-yl is particularly preferred. As examples of "Cl-6 alkoxy" of the Ul Group may be mentioned the same as listed above.

As examples of the "C2-7 alkoxycarbonyl" of the Ul Group, those listed above may be mentioned. As examples of the "halogen" of the Ul Group, those listed above may be mentioned. As examples of the "6 to 10 membered aryl ring group" of the Ul Group, those listed above may be mentioned. As examples of "Cl-6 alkyl" for R8X and R9X, the same ones listed above can be mentioned. As examples of "Cl-6 alkyl" for R12, there may be mentioned those listed above, among which Cl-4 groups are preferred, and methyl is particularly preferred. The term "optionally substituted with a substituent" as used herein has the same meaning as "optionally substituted with substituents 1-6 of 1 or 2 or more types in any desired combination in the substitutable positions", provided that the number and the type of substituent is not particularly restricted. Several of the structural formulas for the compounds throughout the present specification represent only an isomeric form for convenience, but the invention encompasses any and all geometric isomers as well as optical isomers based on asymmetric carbons, stereoisomers and tautomers, and mixtures from those isomers which are involved by the structures of the compounds, without being limited to any of the structural formulas, and may be in the form of one of the isomers or a mixture thereof. The compounds of the invention, accordingly, include all those having asymmetric carbons in the molecule and existing in optically active or racemic form. Some of the compounds may exist in polymorphic crystalline forms, and the compounds may be in a crystalline form or a mixture of different crystalline forms. The invention also encompasses anhydrides and hydrates of the compounds of the invention and their salts. Metabolites of the compounds of the general formulas (1) and (100) of the invention, produced by the decomposition of the compounds in vivo, are also encompassed within the scope of the invention. Additionally, the invention further encompasses compounds that are metabolized in vivo by oxidation, reduction, hydrolysis, conjugation or the like, to produce the compounds of the general formulas (1) and (100) of the invention (i.e., "prodrugs"). The term "salt" as used herein, is not particularly restricted as long as a salt is formed with a compound of the invention, and the salt is pharmacologically acceptable, and as examples may be mentioned inorganic acid salts, acid salts organic, salts of inorganic base, salts of organic base, and acidic or basic amino acid salts. As preferred examples of inorganic acid salts may be mentioned hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and as preferred examples of salts of organic acids may be mentioned acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate , ethanesulfonate, benzenesulfonate and p-toluenesulfonate. As preferred examples of salts of inorganic base may be mentioned alkali metal salts (sodium salts and potassium salts, etc.), alkaline earth metal salts (calcium and magnesium salts, etc.), aluminum salts and salts of ammonium, and as preferred examples of organic base salts may be mentioned diethylamine salts, diethanolamine salts, meglumine salts and salts of NN '-dibenzylethylenediamine. As preferred examples of acidic amino acid salts may be mentioned .aspartate and gultamato, and as preferred examples of basic amino acid salts may be mentioned arginine salts, lysine salts and ornithine salts. As preferred aspects of the compound of [1] or [2] above, its salt or the hydrate of the foregoing, compounds may be mentioned in accordance with the following [2- 2] and [3] - [23], as well as their salts and the hydrates of the above. The compound according to [1] or [2], its salt or the hydrate of the above, with the exception of the compounds wherein R20, R21, R22 and R23 are all hydrogen. The compound according to [1] or [2], its salt or the hydrate of the above, wherein R 10 is 5- to 10-membered cycloalkyl optionally substituted with a substituent of Group A2, or optionally substituted 5 to 10 membered cycloalkenyl with a substituent of Group A2, wherein Group A2 consists of hydroxyl, phenyl, Cl-6 alkyl, haloalkyl Cl-6 and C 2-7 alkylene, wherein C 2-7 alkylene is permissible only in the case where a Spiro bond together with the substituted cycloalkyl of 5 to 10 members or the substituted cycloalkenyl of 5 to 10 members. The compound according to [1] or [2], its salt or the hydrate of the above, wherein R 10 is 5- to 10-membered cycloalkyl optionally substituted with hydroxyl, phenyl, Cl-6 alkyl, haloalkyl Cl-6, , 2-ethylene, trimethylene, tetramethylene or pentamethylene, or 5- to 10-membered cycloalkenyl optionally substituted with hydroxyl, phenyl, Cl-6 alkyl, Cl-6 haloalkyl, 1,2-ethylene, trimethylene, tetramethylene or pentamethylene where 1, 2-ethylene, trimethylene, tetramethylene or pentamethylene is permissible only in the case in which a spiro junction is formed together with the 5 to 10 membered cycloalkyl or 5 to 10 membered cycloalkenyl. The compound according to [1] or [2], its salt or the hydrate of the above, wherein R 10 is cyclohexyl, 4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-diethylcyclohexyl, 3, 3, 5, 5-tetramethylcyclohexyl, 3,5-dimethylcyclohexyl, 4-phenylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-n-butylcyclohexyl, cyclopentyl, 3, 3,4, 4-tetramethylcyclopentyl, cycloheptyl, cyclooctyl, or a group represented by the following formula : [Chemical Formula 9] where s is an integer of 0, 1, 2 or 3. The compound according to either of [1] a [5], its salt or the hydrate of the above, wherein R30, R31 and R32 can be the same or different and each represents hydrogen or C1-6 alkyl, or R30 and R31 are linked together to form oxo (= 0) and R32 is hydrogen or Cl-6 alkyl. The compound according to any of [1] to [5], its salt or the hydrate of the previous ones, where R30, R31 and R32 can be the same or different and each represents hydrogen or methyl or R and R are linked together to form oxo (= 0) and R32 is hydrogen or methyl. The compound according to any of [1] to [5], its salt or the hydrate of the foregoing, wherein R30, R31 and R32 are all hydrogen. The compound according to any of [1] to [8], its salt or the hydrate of the foregoing, wherein R40 is Cl-6 alkyl optionally substituted with a substituent selected from Group Dl, optionally substituted 3 to 8 membered cycloalkyl with a substituent selected from El group, C2-7 alkenyl, C2-7 alkynyl or alkylcarbonyl C2-7 where Group Dl and Group El have the same respective definitions as Group Dl and Group El in [1] • The compound according to any of [1] a [8], its salt or the hydrate of the above, wherein R40 is Cl-6 alkyl optionally substituted with a substituent selected from Group D2, wherein Group D2 consists of hydroxyl, halogen, cyano, Cl-6 alkoxy, alkylthio Cl-6, 3- to 8-membered cycloalkyl, a 4- to 8-membered heterocyclic group, mono (Cl-6-alkyl) aminocarbonyl, di (Cl-6-alkyl) aminocarbonyl, alkylcarbonyl 0.1-1, a heteroaryl-5-ring group members, 4 to 8 membered heterocyclic carbonyl and phenyl.

The compound according to any of [1] to [8], its salt or the hydrate of the above, wherein R40 is n-propyl, n-butyl, n-pentyl, isobutyl, ethylcarbonylmethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl or tetrahydropyran-4-ylmethyl. The compound according to any of [1] to [11], its salt or the hydrate of the above, wherein n is an integer of 1. The compound according to any of [1] and [3] to [12] ], its salt or the hydrate of the previous ones, where X1 is nitrogen. The compound according to any of [1] to [13], its salt or the hydrate of the foregoing, wherein (i) R20 and R21, (ii) R21 and R22 or (iii) R22 and R23 are linked together to form a ring selected from Group Zl wherein the Group Zl has the same definition as the Zl Group in [1]. The compound according to any of [1] to [13], its salt or the hydrate of the foregoing, wherein (i) R21 and R22 or (ii) R22 and R23 are linked together to form a ring selected from the group Z2, where the Z2 Group consists of [Chemical Formula 10] wherein R1Z represents hydrogen, Cl-6 alkyl or benzyl, and the carbon atom indicated by "*" is the carbon atom in the benzene ring to which R22 is attached. The compound according to any of [1] to [13], its salt or the hydrate of the foregoing, wherein (i) R21 and R22 or (ii) R22 and R23 are linked together to form a ring selected from the group Z3, where the Z3 Group consists of [Chemical Formula 11] wherein the carbon atom indicated by "*" is the carbon atom in the benzene ring to which R2 is attached. The compound according to any of [14] to [16], its salt or the hydrate of the above, wherein R20 and R23 are hydrogen. The compound according to any of [1] to [13], its salt or the hydrate of the above, wherein at least one of R20, R21, R22 and R23 is carboxyl, Cl-6 alkylthio optionally substituted with a substituent selected from Group Fl, alkoxycarbonyl 02-1, phenoxy, -S03H, Cl-6 alkyl substituted with a substituent selected from Group W2, Cl-6 alkyl substituted with a substituent selected from Group Kl, Cl-6 alkoxy substituted with a substituent selected from Group W2, a heterocyclic group from 4 to 8 members substituted with a substituent selected from Group W3, a 4- to 8-membered heterocyclic group substituted with a substituent selected from Group VI, a 5- to 10-membered heteroaryl ring group substituted with a substituent selected from Group W3, an aryl ring group of from 6 to 10 members optionally substituted with a substituent selected from the Wl Group, C2-7 alkenyl optionally substituted with a substituent selected from the Wl Group, C2-7 alkynyl optionally substituted with a substituent selected from the Wl Group, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from Group Wl, 5 to 8 membered cycloalkenyl optionally substituted with a substituent selected from the Wl Group, -NR10XR2X, -C0-Rllx, -CO-NRlxR2X, -NR1X-C0-R2X, -S02-R3X or -0-S02-R3X , R1X and R2X can be the same or different and each represents hydrogen, Cl-6 alkyl optionally substituted with a substituent selected from the Ul Group or a 4- to 8-membered heterocyclic group, R 3X represents Cl-6 alkyl optionally substituted with a substituent selected from Group Fl, R10X is Cl-6 alkyl substituted with a substituent selected from the Ul Group or a 4- to 8-membered heterocyclic group, and R11X is hydrogen, C1-6alkyl. substituted with a substituent selected from the Ul Group, or a group 4 to 8 membered heterocyclic, wherein Group W2 consists of hydroxyl, cyano, Cl-6 alkyl, C2-7 alkoxyalkyl, Cl-6 alkoxy optionally substituted with a substituent selected from the TI group, phenoxy, C2-7 alkoxycarbonyl, alkylcarbonyl C2-7, -NR6XR7X and -C0-NRdXR7x wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl, Group W3 consists of hydroxyl, carboxyl, C2-7 alkoxyalkyl, Cl-alkoxy 6 substituted with a substituent selected from Group TI, phenoxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, -NRSXR7X and -CO-NR6XR7X wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl , and Grupo Fl, Grupo Gl, Grupo Hl, Grupo Wl, Grupo TI, Grupo VI, Grupo Kl, and Grupo Ul, have the same respective definitions as Grupo Fl, Grupo Gl, Grupo Hl, Grupo Wl, Grupo TI, Grupo VI, Grupo Kl, and Grupo Ul in [1]. The compound according to any of [1] to [13], its salt or the hydrate of the above, wherein at least one of R20, R21, R22 and R23 represents phenyl optionally substituted with a substituent selected from Group P, alkenyl C2-7 optionally substituted with a substituent selected from Group P, C2-7 alkynyl optionally substituted with a substituent selected from Group P, carbonyl, alkylsulfonyloxy Cl-6 optionally having 1 to 3 fluorine, alkylthio Cl-6, alkoxycarbonyl C2-7, alkoxy-Cl-6-alkoxy Cl-6, alkoxyalkyl C2-7, morpholin-4-yl-alkyl Cl-6, pyrrolidin-1-yl optionally substituted with a substituent selected from Group Q, piperidin-1-yl optionally substituted with a substituent selected from Group Q, a group represented by the following formula: [Chemical Formula 12] -NR80R81, -CO-R82, -C0-NR83R84, or -NR85-CO-R86, wherein R80 represents hydrogen, Cl-6 alkyl, C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R81 represents C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R82 represents C2-7 alkoxyalkyl or morpholin-4-yl, R83 and R84 may be the same or different and each represents hydrogen, Cl-6 alkyl, tetrahydropyran-4-yl or C2-7 alkoxyalkyl, R85 represents hydrogen or Cl-6 alkyl, and R86 represents Cl-6 alkyl, wherein Group P consists of carboxyl, C 2-7 alkoxycarbonyl, C 2-7 alkoxyalkyl, C 1-6 alkoxy and cyano, and Group Q consists of carboxyl, C 2-7 alkoxycarbonyl, C 1-6 alkoxy-C 1-6 alkoxy, carboxyl -alkoxy Cl-6, C2-7 alkoxyalkyl, and hydroxyl. The compound according to any of [1] to [13], its salt or the hydrate of the above, wherein one of R20, R21, R22 and R23 represents phenyl, C2-7 alkoxycarbonyl, C1-6 alkoxy-alkoxy Cl -6, C2-7 alkoxyalkyl, morpholin-4-yl-Cl-6 alkyl, pyrrolidin-1-yl optionally having a substituent selected from Group R, piperidin-1-yl optionally having a substituent selected from Group R, group represented by the following formula: [Chemical Formula 13] -NR90R91, -CO-R92, or -CO-NR93R94, wherein R90 represents hydrogen, Cl-6 alkyl, C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R91 represents C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R92 represents C2-7 alkoxyalkyl, and R93 and R94 may be the same or different and each represents hydrogen or Cl-6 alkyl, wherein Group R consists of Cl-6-alkoxy Cl-6 and C2-7 alkoxyalkyl. The compound according to any of [18] a [20], its salt or the hydrate of the previous ones, where R20 is hydrogen. The compound according to any of [18] to [20], its salt or the hydrate of the above, wherein two of R20, R21, R22 and R23 are hydrogen, and one of the other two is hydrogen or Cl-alkoxy 6 The compound according to any of [18] to [20], its salt or the hydrate of the above, wherein three of R20, R21, R22 and R23 are hydrogen. The "Cl-6 alkyl" of Group W2, the "alkylcarbonyl" C2-7"of Group W2 and Group W3," C2-7 alkoxycarbonyl "of Group W3, Group P and Group Q and" C2-7 alkoxyalkyl "of Group W2, Group W3, Group P, Group Q and Group R have all the same definitions as in Group W1. "Cl-6 alkoxy" of "Cl-6 alkoxy optionally substituted with a substituent selected from Group TI" of Group W2, "Cl-6 alkoxy" of " Cl-6 alkoxy optionally substituted with a substituent selected from Group TI "of Group W3," Cl-6 alkoxy "of Group P," Cl-6 alkoxy "of" Cl-6-alkoxy Cl-6 alkoxy "and "carboxyl-alkoxy Cl-6" of Group Q and the "Cl-6 alkoxy" of "Cl-6-alkoxy Cl-6 alkoxy" of Group R, have the same definitions as "Cl-6 alkoxy" of "Cl-6 alkoxy optionally substituted with a selected substituent of the IT Group "in the Wl Group. As examples of "Cl-6 alkyl" of "Cl-6 alkyl optionally substituted with a substituent selected from Group Ul", for R10X, the same as listed above may be mentioned. As examples of the "4- to 8-membered heterocyclic group" for R10X, those listed above may be mentioned. As examples of the "Cl-6 alkyl" of the "Cl-6 alkyl optionally substituted with a substituent selected from the Ul Group" for R11X, those listed above may be mentioned. As examples of the "4- to 8-membered heterocyclic group" for R11X, the same as listed above may be mentioned. As examples of "Cl-6 alkyl" for R80, the same as listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R80, the same as listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R81, the same as listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R82, the same as listed above may be mentioned. As examples of "Cl-6 alkyl" for R83 and R84, the same as listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R83 and R84, those listed above may be mentioned. As examples of "Cl-6 alkyl" for R85, the same as listed above may be mentioned. As examples of "Cl-6 alkyl" for R8d, those listed above may be mentioned. As examples of "Cl-6 alkyl" for R90, the same as listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R90, the same ones listed above can be mentioned. As examples of "C2-7 alkoxyalkyl" for R91, those listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R92, those listed above may be mentioned. As examples of "C2-7 alkoxyalkyl" for R93 and R94, those listed above may be mentioned. As preferred examples of the compounds of the invention, the following may be mentioned: 1- [2- (4,4-dimethylcyclohexyl) -5-methoxyphenyl] -4-pentylpiperazine, l-butyl-4- [2- (4-t -butylcyclohex-l-enyl) -4- (4-methoxypiperidin-1-yl) phenyl] piperazine, l-butyl-4- [2- (3,3,5,5,5-tetramethylcydohexyl) phenyl] piperazine, l-cyclopropylmethyl-4- [2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine, 2- . { 4- [2- (4-t-Butylcylhexyl) phenyl] piperazin-1-yl} -N-ethylacetamide, cis-4- (4-t-butylcyclohexyl) -3- (4-butylpiperazin-1-yl) benzonitrile, trans-4- (4-t-butylcyclohexyl) -3- (4-butylpiperazin-1) -yl) benzonitrile, l-butyl-4- (2-cyclohexylphenyl) piperazine, l-butyl-4- [2- (4-t-butylcyclohexyl) phenyl] piperazine, 1-. { 4- [2- (4,4-dimethylcyclohexyl) phenyl] piperazin-1-yl} butan-2-one, 4- [3- (4-t-butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] morpholine, 1- [2- (4-t-butylcyclohexyl) phenyl] -4- (2-methoxyethyl) piperazine, 1- [2- (4-t-butylcyclohex-l-enyl) -4- (4-methoxypiperidin-1-yl) phenyl] -4-cyclopropylmethylpiperazine, 1- (tetrahydropyran-4-ylmethyl) -4- [2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] piperazine, 4- [4- (4-propylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohex- 1-enyl) ) phenyl] morpholine, l-. { 4- [2- (4, 4-diethylcyclohex-l-enyl) -4-morpholin-4-ylphenyl] piperazin-1-yl} butan-2-one, 1-propyl -4- [2- (3,3,5, 5-tetramethylcyclohexyl) phenyl] piperazine, l-butyl-4- [4- (4-methoxy-piperidin-1-yl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine, l-butyl-4- [2- (3, 5- dimethylcyclohexyl) phenyl] piperazine, 1- [2- (4,4-diethylcyclohexyl) phenyl] -4- (tetrahydropyran-4-ylmethyl) piperazine, 4- [4- (4-butylpiperazin-1-yl) -3- ( 3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] morpholine, 4- [4- (4-butylpiperazin-1-yl) -3- (3, 3,5,5-tetramethylcyclohexyl) phenyl] morpholine, 1- [4- (4-ethoxypiperidin-1-yl) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine, cis-4- [4- (4-butylpiperazin-1-yl) ) -3- (4,4-dimethylcyclohexyl) phenyl] -2,6-dimethylmorpholine, 4-. { 4- (4-pentylpiperazin-1-yl) -3-spiro [2,5] oct-6-ylphenyl} morpholine, 1- [3-fluoro-2- (3,3,5, 5-tetramethylcyclohex-l-enyl) phenyl] -4-propylpiperazine, l-cyclopropylmethyl-4- [2- (3,3,5, 5 -tetramethylcyclohexyl) phenyl] -1,2,3,6-tetrahydropyridine, l-butyl-4-. { 2- (3,3,4, 4-tetramethylcyclopentyl) phenyl} piperazine, l-butyl-4- [2- (4,4-dimethylcyclohexyl) -4- (4-ethoxypiperidin-1-yl) phenyl] piperazine, l-butyl-4- [2, (3,3,5, 5-tetramethylcyclohex-l-enyl) phenyl] piperazine, l-cyclopropylmethyl-4- [2- (3,3,5, 5-tetramethylcyclohex-1- enyl) phenyl] piperazine, 1-. { 4- [2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] piperazin-1-yl} butan-2-one, 1- (2-methoxyethyl) -4- [2- (3,3,5,5-tetramethylcyclohex-l-enyl) phenyl] piperazine, 1-. { 4- [2- (3,3,5, 5-tetramethylcyclohexyl) phenyl] piperazin-1-yl} butan-2-one, 1- (2-methoxyethyl) -4- [2- (3, 3,5, 5-tetramethylcyclohexyl) phenyl] piperazine, 4- [4- (4-butylpiperazin-1-yl) -5 - (4,4-diethylcyclohexyl) -2-methoxyphenyl] -morpholine, l-butyl-4- (2-spiro [4, 5] dec-8-phenyl) piperazine, 1- [2- (4,4-dimethylcyclohex) -l-enyl) phenyl] -4-isobutylpiperazine, l-cyclopropylmethyl-4- [2- (4,4-diethylcydohexyl) -4- (4-methoxypiperidin-1-yl) phenyl] piperazine, 4- [3- ( 4, 4-dimethylcyclohexyl) -4- (4-isobutylpiperazin-1-yl) phenyl] morpholine,. { 4- [2- (3,3,5, 5-tetramethylcyclohexyl) phenyl] piperazin-1-yl} acetonitrile, 1- (2-ethoxyethyl) -4 - [2 - (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine, (R) -l-butyl-4- [2- (4,4-diethylcyclohexyl) -4- (3-methoxypyrrolidin-1-yl) phenyl] piperazine, 1- [4-methyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine, 1- [4-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] -4- (tetrahydropyran-4-ylmethyl) piperazine, l-butyl-4- [2- (3,3,5, 5-tetramethylcyclohexyl) phenyl] piperidine, 1-isobutyl-4- [2- (3,3,4,4-tetramethylcyclopent-l-enyl) phenyl] piperazine, and 1- [2- (4-cyclopropylmethylpiperazin-1-yl ) phenyl] -3,3,5,5-tetramethylcyclohexanol. The compounds according to [1] to [23] above, or their salts or the hydrates of the foregoing, exhibit excellent cell adhesion inhibitory action or cell infiltration inhibiting action, and can be used as medicaments. More specifically, they can be used as therapeutic or prophylactic agents for inflammatory diseases and autoimmune diseases and particularly, for various diseases associated with the adhesion and infiltration of leukocytes, such as inflammatory bowel disease (especially ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. In other words, the invention also provides the following [24] to [29]. [24] A medicament comprising the compound according to any of [1] to [23] its salt or the hydrate of the above. [25] A cell adhesion or cell infiltration inhibitor comprising the compound according to any of [1] to [23], its salt or the hydrate of the above. [26] A therapeutic or prophylactic agent for an inflammatory disease or an autoimmune disease, comprising the compound according to any of [1] to [23], its salt or the hydrate of the foregoing. [27] A therapeutic or prophylactic agent for an inflammatory bowel disease, irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma or atopic dermatitis, comprising the compound according to any of [1] to [23], its salt or the hydrate of the previous ones. [28] A therapeutic or prophylactic agent for an inflammatory bowel disease comprising the compound according to any of [1] to [23], its salt or the hydrate of the foregoing. [29] A therapeutic or prophylactic agent for ulcerative colitis or Crohn's disease, comprising the compound according to any of [1] to [23], its salt or the hydrate of the foregoing. Effect of the Invention The compounds of the invention have excellent inhibitory action of cell adhesion or inhibitory action of cellular infiltration, and therefore, are useful as therapeutic and prophylactic agents for inflammatory diseases and autoimmune diseases, particularly as therapeutic or prophylactic agents for various diseases associated with adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis) or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. BEST MODE FOR CARRYING OUT THE INVENTION (General Methods of Production) The compounds (1) and (100) of the invention can be produced by the methods described above. However, it should be understood that the production methods for the compounds of the invention are not limited to those described below. The compound (1) of the invention can be produced by the following Method A, Method B, Method C, Method D, Method E, Method N, Method P or Method V. The compound (IA) of the invention (the compound (1) ) wherein X1 is nitrogen) can be produced by the following Method F, Method G, Method H, Method K, Method M, Method Q or Method R. The compound (IB) of the invention (the compound (1) wherein X1 is CH) and the compound (100) of the invention can be produced by the following Method A, Method B, Method C, Method D, Method E, Method K or Method M, Method S, Method T or Method U. Each of these methods will now be explained in detail. (Method A) [Chemical Formula 14] Method A is a method for producing the compound (1) of the invention by reacting the compound (2) with an alkylating agent (3), carbonylating agent (3) or sulfonylating agent (3) in an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, and optionally removing any protecting group in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (200) of a similar way. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1 and n have the same definitions as above, R10a, R20a, R21a, R22a, R23a, R30a, R31a, R32a, and R40a, X1 they have the same definitions as the corresponding groups R10, R20, R21, R22, R23, R30, R31, R32, and R40, X1 or are the corresponding groups R10, R20, R21, R22, R23, R30, R31, R32, and R40, with the respective substituents on the protected groups, and W1 represents a removal group which is chloro, bromo or iodo, alkylsulfonyloxy such as methanesulfonyloxy or ethanesulfonyloxy, haloalkanesulfonyloxy such as trifluoromethanesulfonyloxy or nonafluorobutanesulphonyloxy or arylsulfonyloxy such as benzenesulfonyloxy or p-toluenesulfonyloxy, which is preferred chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, nonafluorobutanesulfonyloxy or trifluoromethanesulfonyloxy.

(Alkylation) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N- may be mentioned. methylpyrrolidone, nitriles such as acetonitrile and isobutyronitrile, aromatic hydrocarbons such as toluene, benzene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether or sulfoxides such as dimethyl sulfoxide, as well as mixtures of these solvents , among which dimethylformamide, acetonitrile, toluene or tetrahydrofuran are preferred. There are no particular restrictions on the base used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, organic bases such as triethylamine and pyridine or inorganic bases such as potassium carbonate, sodium carbonate, can be mentioned, potassium hydrogencarbonate, sodium hydrogencarbonate and cesium carbonate, among which potassium carbonate or triethylamine is preferred. Sodium or potassium iodide is used as an additive to accelerate the reaction if necessary.

The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -30 ° C and 180 ° C, and is preferably between 0 ° C and 120 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 100 hours, and is preferably from 0.5 to 24 hours. (Carbonylation or sulfonylation) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2- dichloroethane and carbon tetrachloride, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, organic bases such as pyridine, or water , as well as mixtures of these solvents, among which dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, pyridine, water and mixtures thereof are preferred. There are no particular restrictions on the base used as long as it can produce the target compound and which does not produce any non-separable by-product, and specifically, organic bases such as triethylamine and pyridine or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogencarbonate, cesium carbonate and sodium hydroxide can be mentioned, among which is preferred potassium carbonate or triethylamine. 4-dimethylaminopyridine is used as an additive to accelerate the reaction, if necessary. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -70 ° C and 120 ° C, and is preferably between -70 ° C and 60 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 48 hours, and is preferably from 0.5 to 12 hours. The compounds (1) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R 10 of the resulting compound (1) or (100) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to hydrogenation to produce the compound (1) of the invention or the compound (IB) of the invention (the compound ( 1) in which X1 is CH), where R10 es1 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it may be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) wherein X 1 in CH). The hydrogenation can be carried out as follows. Specifically, the hydrogenation reaction can be carried out using a metal catalyst in an inert solvent, under a hydrogen atmosphere or in the presence of a hydrogen donating reagent, in the presence or absence of an acid. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, water, alcohols such as methanol and ethanol, ethers such as diethyl ether, diisopropyl ether, may be mentioned. , tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate, amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, aliphatic hydrocarbons such as hexane , heptane, ligroin and petroleum ether or organic acids such as acetic acid, or mixtures of these solvents, between which is preferred methanol, ethanol, ethyl acetate, tetrahydrofuran, a mixed solvent of methanol and tetrahydrofuran, or a mixed solvent of ethanol and tetrahydrofuran. There are no particular restrictions on the metal catalyst used so long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, heterogeneous rare metal catalysts such as palladium, palladium hydroxide, platinum, platinum oxide can be mentioned. , rhodium, ruthenium and nickel (preferably supported in a carrier such as activated carbon, alumina, silica or zeolite) and homogeneous metal complex catalysts such as chlorotris (triphenylphosphine) rhodium (I) (Wiikinson's complex), among which prefer heterogeneous rare metal catalysts (especially activated carbon with 10% palladium or platinum oxide, optionally moistened with water). The number of equivalents of the metal catalyst used (including the vehicle) will differ depending on the starting materials, the solvent and the reactants, but will commonly be a ratio of 0.05 to 10 and preferably 0.05 to 3, in terms of the ratio in weight with respect to the starting material. There are no particular restrictions on acid used as long as it can produce the objective compound and which does not produce any non-separable by-product, and specifically, organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid and trifluoroacetic acid, or inorganic acids such as hydrochloric acid and hydrobromic acid can be mentioned. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -10 ° C and 80 ° C, and is preferably between 0 ° C and 50 ° C. The hydrogen reaction pressure will also differ depending on the starting materials, the solvent and the reactants, but will commonly be between 1 and 100 atmospheres, and preferably between 1 and 5 atmospheres. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 200 hours, and is preferably from 0.5 to 100 hours. When the resulting compound is to be converted to an acid salt, this can be achieved by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method B) [Chemical Formula 15] Method B is a method to produce the compound (1) of the invention, by reacting the compound (2) with an acid anhydride (4) in an inert solvent, in the presence or absence of a base, and optionally, removing any protecting group in the resulting compound, or a method for producing the compound (100) of the invention, by reacting the compound (200) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. Also, R0b is a group consisting of carbonyl or sulfonyl, which is suitable to obtain R40 and can form an acid anhydride. The substituents in R40b can also be protected. This method can also be carried out in a manner similar to the carbonylation or sulfonylation step of Method A above. The compounds (1) and (100) of the invention can be isolated or purified from the reaction mixture obtained above, by the method described below. When the R 10 of the resulting compound (1) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above to produce the compound (1) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the substituent correspondent . When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it may be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) in which X 1 is CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method C) - [Chemical Formula 16] Method C is a method to produce the compound (1) of the invention, by reacting the compound (2) with an aldehyde (5) or ketone (5) in an inert solvent, in the presence of a reducing agent, in the presence or absence of an acid, in the presence or absence of an additive, and optionally removing any protective group in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (200) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. Also, A1 and A2 are suitable groups to obtain R40. The substituents on A1 or A2 can also be protected. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl can be mentioned. ether, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride, nitriles such as acetonitrile and isobutyronitrile, aromatic hydrocarbons such as toluene, benzene and chlorobenzene or alcohols such as methanol and ethanol, among which ethers are preferred (particularly . tetrahydrofuran) and halogenated hydrocarbons (particularly dichloroethane). There are no particular restrictions on the reducing agent used so long as it can produce the target compound and produce no non-separable by-product, and specifically, boron reduction agents such as sodium triacetoxyborohydride, sodium cyanoborohydride and borane-pyridine can be mentioned. , and metal-hydrogen catalyst gas, among which sodium triacetoxyborohydride is preferred. There are no particular restrictions on the acid used as long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, organic acids such as acetic acid and trifluoroacetic acid or Lewis acids such as titanium tetraisopropoxide and zinc chloride, among which organic acids (particularly acetic acid) are preferred. There are no particular restrictions on the use of an additive as long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, molecular sieve or magnesium sulfate can be mentioned, among which Molecular Sieve 4A is preferred. The reaction temperature will differ depending on start materials, solvent and reagents, but will commonly be between -70 ° C and 120 ° C, and is preferably between 0 ° C and 50 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.1 to 200 hours, and is preferably from 0.1 to 24 hours. As supplementary literature that can be used as a reference for carrying out this method, mention may be made, without limitation, of Ahmed F., Abdel-Magid et al., J. Org. Chem., (1996), 61, 3849. The compounds (1) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described above. When the R 10 of the resulting compound (1) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above to produce the compound (1) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it can be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) in which X1 is CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method D) [Chemical Formula 17] Method D is a method to produce the compound (1) of the invention, by reacting the compound (2) with a conjugated carbonyl compound (6) by the Michael addition reaction in an inert solvent, and optionally removing the protecting groups of the resulting compound, or a method of producing the compound (100) of the invention by reacting the compound (200) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. Also, Z1, Z2, Z3 and Z4 are suitable groups to obtain R40. The substituents on Z1, Z2, Z3 and Z4 can also be protected. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, alcohols such as methanol and ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol and glycerin, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether , amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, and N-methylpyrrolidone and aromatic hydrocarbons such as benzene, toluene and xylene, among which halogenated hydrocarbons (particularly chloroform) or ethers (particularly tetrahydrofuran) are preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -30 ° C and 150 ° C, and is preferably between 0 ° C and 120 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 48 hours, and is preferably from 0.5 to 24 hours. The compounds (1) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described above. When the R 10 of the resulting compound (1) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above to produce the compound (1) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it can be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) in which X1 is CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method E) [Chemical Formula 18] (2) (100) Method E is a method to produce the compound (1) of the invention by reacting the compound (2) with an isocyanate compound (7) or a substituted aminocarbonylchloride compound (7) in an inert solvent, in the presence or absence of a base, and optionally removing the protecting groups in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (200) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. Also, A3, A4 and A5 are suitable groups to obtain R40. The substituents in A3, A4, and A5 can also be protected. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride may be mentioned. , aromatic hydrocarbons such as benzene, toluene and chlorobenzene, and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether, among which dichloromethane or tetrahydrofuran is preferred. There are no particular restrictions on the base used as long as it can produce the target compound and - which does not produce any non-separable by-product, and specifically, organic bases such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaminyl, N, N-diethylaniline, 1,5-diazabicyclo [4.4.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), among which triethylamine or pyridine is preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -70 ° C and 100 ° C. The reaction time will differ depending on the starting materials, the solvent, the reagents and the reaction temperature, but will usually be from 1 to 24 hours. The compounds (1) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described above. When the R10 of the resulting compound (1) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above to produce the compound (1) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it may be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) in which X 1 is CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method F) [Chemical Formula 19] (1A) The method F is a method for producing the compound (IA) of the invention (the compound (1) in which X1 is nitrogen) by reacting the compound (8) with the compound (9) (amination or amidation) in an inert solvent in the presence of palladium (0) catalyst or copper catalyst, in the presence or absence of a base, in the presence or absence of an additive, under or not under a gas atmosphere inert and optionally, removing the protecting groups in the resulting compound. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a, have the same definitions as above. Also, Wla, represents chlorine, bromine, or iodine, or a trifluoromethanesulfonyloxy group. (Reaction in the presence of palladium (0) catalyst) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, amides such as dimethylformamide can be mentioned, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, aromatic hydrocarbons such as toluene, benzene, xylene and mesitylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol , isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol, nitriles such as acetonitrile and isobutyronitrile or mixtures of these solvents, among which dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane or dimethoxyethane. There are no particular restrictions in the palladium (0) catalyst used as long as it can produce the objective compound and which does not produce any non-separable by-product, and specifically, tetrakis (triphenylphosphine) palladium, tris (dibenzyldenoacetone) dipalladium, bis (dibenzylideneacetone) palladium, bis (tri) -t-butylphosphine) palladium and palladium black or palladium (0) catalysts produced in the reaction system by combining the palladium complexes which may be the palladium (0) precursors mentioned below and various ligands mentioned below. There are no particular restrictions on the various palladium (0) complexes that can be used as palladium (0) precursors, provided that they can produce the target compound without producing any non-separable by-product, and specifically, palladium acetate [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium, dichlorobis (tri-o-tolylphosphine) palladium, dichlorobis (tris-cyclohexylphosphine) palladium, and the like. There are no particular restrictions on the ligands used, as long as they can produce the objective compound without producing any non-separable by-product, and specifically, 2,2'-bis (diphenylphosphino) -1,1-biphenyl (BINAP), can be mentioned, , 9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos), tri-t-butylphosphine, tri (4-methylphenyl) phosphine, tri-2-furylphosphine, 2- (di-t-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, 1, 1'-bis (diphenylphosphino) ferrocene, di-t-butylphosphonium tetrafluoroborate and 1,3-bis (2,4,6-trimethylphenyl) imidazol-2-ylidene. There are no particular restrictions on the base used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, inorganic bases such as t-butoxide, potassium t-butoxide, tripotassium phosphate, phosphate trisodium, cesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium hydrogen carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, cesium acetate, potassium fluoride, cesium fluoride, sodium hydroxide and potassium hydroxide, or organic bases such as triethylamine, 1,8-bis (dimethylamino) naphthalene, 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.9] undec-7- eno (DBU). There are no particular restrictions on the additive used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, lithium fluoride, sodium fluoride, lithium chloride, sodium chloride, Lithium bromide, sodium bromide, 1,4,7,10,13,16-hexaoxacyclooctadecane (18 -Crown-6), 1,4, 7, 10, 13-pentaoxaciclopentadecane (15-Crown-5), fluoride tetrabutylammonium and tetrabutylammonium bromide. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 150 ° C, and is preferably between 20 ° C and 110 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.1 to 100 hours, and is preferably from 0.5 to 48 hours. When the reaction is carried out in an inert gas atmosphere, the inert gas is not particularly restricted, as long as it does not inhibit the reaction of this step, and can specifically be argon or nitrogen gas. As supplementary literature used as a reference for carrying out this method, mention may be made without limitation to: D. Prim et al., Tetrahedron (2002), 58, 2041; and L. Buchwaid et al., J. Organomet. Chem. (1999), 576, 125. (Reaction in the presence of copper catalyst) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, there may be mentioned amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene and nitrobenzene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve, or mixtures of these solvents, among which isopropanol, N-methylpyrrolidone, toluene and dimethylformamide are preferred. There are no particular restrictions on the copper catalyst used as long as it can produce the target compound and produce no non-separable by-product, and specifically, copper (powder), copper (I) chloride, copper (II) chloride can be mentioned. , copper (I) iodide, copper (I) oxide, copper (II) oxide, copper (II) acetate, copper (II) sulfate pentahydrate, copper (II) acetylacetonate, copper thiocyanate (I) ) and the like, among which copper (powder), copper iodide (I) and copper chloride (I) are preferred. There are no particular restrictions on the ligand used so long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, ethylene glycol, diethylene glycol, cresol, 2,6-dimethylphenol, 1-naphthol, 2-naphthol, ethylenediamine, N, N'-dimethylethylenediamine and diisopropylamine, among which ethylene glycol and ethylene diamine are preferred. There are no particular restrictions on the base used as long as it can produce the target compound and produce no non-separable by-product, and specifically, inorganic bases such as sodium t-butoxide, potassium t-butoxide, tripotassium phosphate, phosphate can be mentioned. trisodium, cesium carbonate, potassium carbonate, sodium carbonate and sodium hydride, or organic bases such as bis (trimethylsilyl) amide potassium, among which potassium carbonate and tripotassium phosphate are preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 250 ° C, and is preferably between 80 ° C and 150 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.1 to 100 hours, and is preferably from 0.5 to 48 hours. When the reaction is carried out in an inert gas atmosphere, the inert gas is not particularly restricted, as long as it does not inhibit the reaction of this stage, and specifically it can be argon gas or nitrogen. As supplemental literature used as a reference for carrying out this method, mention may be made without limitation to: L. Buchwaid et al., J. Org. Lett. (2002), 4, 581. The compound (IA) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (IA) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above, to produce the compound (IA) of the invention wherein R10 is cycloalkyl of 5 to 10. member optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method G) - [Chemical Formula 20] (1A) Method G is a method for producing the compound (IA) of the invention (the compound (1) in which X1 is nitrogen), by reacting the compound (8) with the compound (10) in an inert solvent , in the presence of a copper catalyst, in the presence of a base, in the presence or absence of oxygen and optionally, removing the groups protectors in the resulting compound. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10a, R20a, R21a, R22a, R23a, R30a, R31a, R3a, and R40a have the same definitions as above. Mla is a group represented by the formula -B (0H) 2. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, there may be mentioned amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, hydrocarbons halogenated such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride, aromatic hydrocarbons such as toluene, benzene and xylene, or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, or mixtures of these solvents, among which halogenated hydrocarbons (particularly dichloromethane) are preferred. There are no particular restrictions on the copper catalyst used as long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, copper (II) acetate, copper (I) acetate, copper trifluoromethanesulfonate ( II) and copper (II) isobutyrate, among which copper (II) acetate is preferred.

There are no particular restrictions on the base used as long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, organic bases such as triethylamine, pyridine, 2,6-lutidine, N-methylmorpholine and 1 can be mentioned, 8-diazabicyclo [5.4.0] undec-7-ene, among which triethylamine or pyridine is preferred. There are no particular restrictions on the additive used to accelerate the reaction as long as it can produce the objective compound and produce no non-separable by-product, and specifically, molecular sieve, pyridine-N-oxide, and 2,2,6 can be mentioned, 6-tetramethylpiperidinooxi, among which molecular sieve (particularly 4A) is preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 80 ° C, and is preferably between 10 ° C and 50 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 1 to 100 hours, and is preferably from 24 to 48 hours. The compound (IA) of the invention can be isolated or purified from the reaction mixture obtained in the manner described above by the following method.

When the R10 of the resulting compound (IA) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above, to produce the compound (IA) of the invention wherein R10 is cycloalkyl of 5 to 10. member optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method H) [Chemical Formula 21] (1A) Method H is a method to produce the compound (IA) of the invention (the compound (1) in which X1 is nitrogen), by reacting the compound (11) with the compound (12) in an inert solvent or in the absence of a solvent, under or not under an atmosphere of inert gas, in the presence or absence of a base, in the presence or absence of an additive and optionally, removing the protecting groups in the resulting compound. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40 n W1 R10a p2 ° to R21a 22a R23a R30a P31a P32a v R40a have the same definitions as above. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve, aromatic hydrocarbons such as benzene, chlorobenzene, 1,2-dichlorobenzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether and amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, among which butanol, 1,2-dichlorobenzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide or hexamethylphosphoric triamide are preferred. When no solvent is used, the reaction can be carried out using a microwave reactor or with alumina or silica gel as the carrier. When the reaction is carried out under a Inert gas atmosphere, there are no particular restrictions on the inert gas, as long as it does not inhibit the reaction of this stage, and specifically argon or nitrogen gas can be mentioned. There are no particular restrictions on the base used as long as it can produce the objective compound and produce no non-separable by-product, and specifically, organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, DBU and DABCO, or bases can be mentioned. inorganic materials such as potassium carbonate, sodium carbonate, and sodium hydrogencarbonate. There are no particular restrictions on the additive used to accelerate the reaction as long as it can produce the objective compound and produce no non-separable by-product, and specifically, alkali metal iodides such as sodium iodide and potassium iodide can be mentioned. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 270 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be 0.5 to 100 hours.

The compound (IA) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (IA) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above, to produce the compound (IA) of the invention wherein R10 is cycloalkyl of 5 to 10. member optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method K) [Chemical Formula 22] (100) Method K is a method to produce the compound (IA) of the invention (the compound (1) in which X1 is nitrogen), by reacting the compound (13) with a boron metal reagent (14) or a tin metal reagent (14) (Suzuki reaction) or Stille reaction) in an inert solvent in the presence of a palladium (0) catalyst, under or not under an inert gas atmosphere, in the presence or absence of a base, in the presence or absence of an additive and optionally, removing the groups protectants in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (190) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, Wla, R20a, R21a, R22a, R23a, R30a, R31a, R32a, and R40a have the same definitions as above. R10b optionally represents optionally substituted 5 to 10 membered cycloalkenyl, wherein the substituent has the same definition as the substituent of the optionally substituted "5- to 10-membered cycloalkenyl" for R10, with the proviso that this substituent may be protected. Also, Mlb represents B (OE10c) 2 or Sn (E10b) 3, wherein E10c represents Cl-6 alkyl or both of E10c are linked together to form C2-3 alkylene optionally substituted with methyl, and E10b represents Cl- alkyl. 6 This method will differ depending on the nature of Mlb.

- (Suzuki coupling reaction) This method is a method for producing the compound (IA) of the invention (the compound (1) in which X1 is nitrogen), by reacting the compound (13) with the compound (14) in a inert solvent in the presence of a palladium (0) catalyst, in the presence of a base, in the presence or absence of an additive, under or not under an inert gas atmosphere and optionally, removing the protecting groups in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (190) in a similar manner. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, there may be mentioned amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, hydrocarbons aromatics such as toluene, benzene, xylene and mesitylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t -butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve, nitriles such as acetonitrile and isobutyronitrile, sulfoxides such as dimethyl sulfoxide and sulfolane or water, or mixtures of these solvents, among which dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane or water or mixtures of these solvents are preferred. There are no particular restrictions on the palladium (0) catalyst used as long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, tetrakis (triphenylphosphine) palladium, tris (dibenzyldenoacetone) dipalladium, bis (dibenzylideneacetone) can be mentioned. ) palladium, bis (tri-t-butylphosphine) palladium and palladium black and the like, or palladium (0) catalysts produced in the reaction system by combining the palladium complexes that can be the palladium precursors (0) ) mentioned below and various ligands mentioned below. There are no particular restrictions on the various palladium (0) complexes that can be used as palladium (0) precursors, as long as they can produce the target compound without producing any non-separable by-product, and specifically, palladium acetate [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium, dichlorobis (tri-o-tolylphosphine) palladium, dichlorobis (tris-cyclohexylphosphine) palladium, and the like. There are no particular restrictions on ligands used, so long as they can produce the objective compound without producing any non-separable by-product, and specifically, triphenylphosphine, tri-t-butylphosphine, tri (4-methylphenyl) phosphine, 2- (di-t-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, tricyclohexylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, and di-t-butylphosphonium tetrafluoroborate. There are no particular restrictions on the base used so long as it can produce the objective compound and produce no non-separable by-product, and specifically, inorganic bases such as tripotassium phosphate, trisodium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium acetate, barium hydroxide, potassium hydroxide, potassium fluoride and cesium fluoride, metal alkoxides such as sodium ethoxide and sodium-t-butoxide , alkali metal acetate such as sodium acetate or potassium acetate or organic bases such as triethylamine. There are no particular restrictions on the additive used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, mention may be made of lithium chloride, sodium chloride, lithium bromide, sodium bromide, and bromide. tetrabutylammonium. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 150 ° C, and is preferably between 20 ° C and 120 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 100 hours, and is preferably from 0.5 to 48 hours. When the reaction is carried out in an inert gas atmosphere, the inert gas is not particularly restricted, as long as it does not inhibit the reaction of this step, and can specifically be argon or nitrogen gas. As supplementary literature used as a reference for carrying out this method, mention may be made without restriction to: S. P. Stanforth, Tetrahedron (1998), 54, 263; and N. Miyamura, A. Suzuki, Chem. Rev. (1995), 95, 2457. (Stille coupling reaction) This method is a method for producing the compound (IA) of the invention (the compound (1) in the which X1 is nitrogen), by reacting the compound (13) with the compound (14) in an inert solvent in the presence of a palladium (0) catalyst, in the presence or absence of an additive, under or not under a gas atmosphere inert and optionally, removing the protective groups in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (190) in a similar manner. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, there may be mentioned amides such as, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and N-methylpyrrolidone, aromatic hydrocarbons such as toluene, benzene, xylene and mesitylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, or mixtures of these solvents, among which are preferred dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane, and dimethoxyethane. There are no particular restrictions on the palladium (0) catalyst used as long as it can produce the target compound and that it does not produce any non-separable by-product, and specifically, tetrakis (triphenylphosphine) palladium, tris (dibenzyldenoacetone) dipalladium, bis (dibenzylideneacetone) can be mentioned. ) palladium, bis (tri-t-butylphosphine) palladium and palladium black and the like, or palladium (0) catalysts produced in the reaction system by combining the palladium complexes which may be the palladium (0) precursors mentioned below and various ligands mentioned below. There are no particular restrictions on the various palladium (0) complexes that can be used as palladium (0) precursors, provided that they can produce the target compound without producing any non-separable by-product, and specifically, palladium acetate [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium, dichlorobis (tri-o-tolylphosphine) palladium, dichlorobis (acetonitrile) palladium and dichlorobis (tris-cyclohexylphosphine) palladium. There are no particular restrictions on the ligands used, so long as they can produce the objective compound without producing any non-separable by-product, and specifically, triphenylphosphine, tri-t-butylphosphine, tri (4-methylphenyl) phosphine, 2- (di- t-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, tricyclohexylphosphine, tri-2-furylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, di-t-butylphosphonium tetrafluoroborate and triphenylarsine. There are no particular restrictions on the additive used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, cesium fluoride, potassium fluoride, lithium chloride, lithium bromide, Sodium bromide, tetrabutylammonium fluoride, copper iodide, copper oxide and zinc chloride. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 150 ° C, and is preferably between 20 ° C and 110 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.1 to 100 hours, and is preferably from 0.5 to 48 hours. When the reaction is carried out in an inert gas atmosphere, the inert gas is not particularly restricted, as long as it does not inhibit the reaction of this step, and can specifically be argon or nitrogen gas. As supplementary literature used as a reference for carrying out this method, mention may be made without restriction to: S. P. Stanforth, Tetrahedron (1998), 54, 263; and J. Stille, Angew. Chem. Int. Ed. Engl. (1986), 25, 508. The compounds (IA) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (IA) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above to produce the compound (IA) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it may be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) wherein X 1 in CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method M) [Chemical Formula 23] (100) Method M is a method to produce the compound (IA) of the invention (the compound (1) in which X1 is nitrogen), by reacting the compound (16) with a boron metal reagent (15) or a tin metal reagent (15) (Suzuki reaction) or Stille reaction) in an inert solvent in the presence of a palladium catalyst (0), low or no under an inert gas atmosphere, in the presence or absence of a base, in the presence or absence of an additive and optionally, removing the protecting groups in the resulting compound, or a method for producing the compound (100) of the invention by reacting the compound (180) in a similar manner. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, Wla, R20a, R21a, R2a, R23a, R30a, R31a, R32a, and R40a have the same definitions as above. R10b also has the same previous definition. M1 represents B (OE10a) 2 or Sn (E10b) 3, wherein E10a represents hydrogen, Cl-6 alkyl or both of E10 are linked together to form C2-3 alkylene optionally substituted with methyl, and E10b represents Cl- alkyl 6 This method can be carried out in a manner similar to Method K above. The compounds (IA) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below.

When the R10 of the resulting compound (IA) or (100) is optionally substituted 5- to 10-membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above to produce the compound (IA) of the invention or the compound (IB) of the invention (the compound (1) in which X1 is CH), wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the R 10 of the resulting compound (100) is optionally substituted 5 to 10 membered cycloalkyl, it may be subjected to hydrogenation to produce the compound (IB) of the invention (the compound (1) wherein X 1 in CH). When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method N) [Chemical Formula 24] (17) (1) Method N is a method to produce the compound (1) of the invention, by reacting the compound (17) with a halogenation reagent in an inert solvent in the presence or absence of an additive, in the presence or absence of an inert gas, to produce a halogenated compound in the benzene ring to which R10a is linked (Step N-1-1), and optionally, removing the protecting groups in the resulting compound. Alternatively, Step Nl-1 can be followed by a reaction of the halogenated compound with a compound that can introduce a desired substituent or a reactive derivative thereof in the presence of a transition metal catalyst, in an inert solvent, in the presence or absence of an additive, in the presence or absence of an inert gas (Step Nl -2) and optionally removing any protective group in the resulting compound, to produce the compound (1) of the invention. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R, n, X, R, R, R, R, and R have the same definitions as above. Also, at least one of R20b, R21b, R22b and R23b is hydrogen, and the remaining groups each have the same definition as the corresponding group of R20a, -r-j 2 l3 t-j 22 ci -p 233 (Step N-1 - 1) This is a halogenation step. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether, ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloromethane and tetrachloride of carbon, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, and organic acids such as acetic acid, among which alcohols are preferred (particularly methanol). There are no particular restrictions on the halogenation agent used as long as it can produce the target compound and produce no non-separable by-product, and specifically, chlorine (Cl 2), bromine (Br 2), iodine (I 2), N-chlorosuccinimide, bromosuccinimide, N-iodosuccinimide, iodine monochloride and thionyl chloride, among which chlorine, bromine and iodine are preferred. Alkali metal acetate such as sodium acetate and potassium acetate, among which sodium acetate is preferred, are mentioned as additives that may be used. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but it will commonly be between -20 ° C and 100 ° C, and is preferably between 20 ° C and 50 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.25 to 48 hours, and is preferably from 12 to 24 hours. The compound (1) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (1) is optionally substituted 5- to 10-membered cycloalkenyl, the hydrogenation described for Method A above can be carried out by selecting the reaction conditions in order to avoid reduction of the introduced halogen, to produce the compound (1) of the invention, wherein R 10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Step N-1-2) In this step, the halogenated compound obtained in Step N-1 is converted into a compound having the desired substituent in the presence of a transition metal catalyst, and the protecting groups are optionally removed in the resulting compound by the method described below, to produce the compound (1) of the invention. The aryl halide compound obtained in Step N-1-1 can then be subjected to a cross-coupling reaction with a compound which can introduce a desired substituent or a reactive derivative thereof, in the presence of a transition metal such as palladium, copper, nickel, zinc or zirconium, or a catalyst produced by combining any of these metals with a ligand. The type of reaction of the bond formation can be a carbon-carbon bond formation, a carbon-nitrogen bond formation or a carbon-oxygen bond formation. Method F and Method K are examples of these reactions. As supplementary literature used as a reference for carrying out this step, there may be mentioned, without limitation: John F. Hartwig, Angew. Chem. Int. ED., (1998), 37, 2046; Steven P. Nolan et al., Org. Lett. (2001), 3, 10, 1511; Stephen L. Buchwaid and Gregory C. Fu, et al., Org. Lett. (2000), 2, 12, 1729; Stephen P. Stanforth, Tetrahedron (1998), 54, 263; Karen, E. et al., J.C.S., (2001), 123, 10770; Stephen L. Buchwaid et al., J.A. C.S. (1999), 121, 4369; D.M. Tschaen and R. Desmond et al., Synth. Comm. (1994), 24, 6, 887; John F. Hartwig, et al., J.A. C.S. (2001), 123, 8410; Gregory C. Fu. Et al., Org. Lett. (2001), 3, 26, 4295; and Damien Prim, et al., Tetrahedron (2002) 58, 2041. For example, the introduction of morpholine as a substituent in a carbon-nitrogen bond formation reaction can be carried out in the following manner. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as dioxane, dimethoxyethane can be mentioned. and tetrahydrofuran, and amides such as dimethylformamide, among which xylene is preferred. There are no particular restrictions on the additive used as long as it can produce the objective compound and that it does not produce any non-separable by-product, and it can be an appropriate combination of palladium catalysts such as palladium (II) acetate, bases such as t-butoxide of potassium, sodium t-butoxide and cesium carbonate, and phosphines such as 2,2'-bis (diphenylphosphino) -1,1-biphenyl and tri-butylphosphonium tetrafluoroborate, among the which a combination of palladium (II) acetate is preferred, sodium t-butoxide and tri-t-butylphosphonium tetrafluoroborate. The reaction temperature will differ depending on the starting materials, the solvent and the reactants, but will commonly be between 50 ° C and 200 ° C, and is preferably between 70 ° C and 150 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.5 to 72 hours, and is preferably from 2 to 24 hours. The compound (1) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (1) is optionally substituted 5- to 10-membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above, to produce the compound (1) of the invention, wherein R10 is cycloalkyl of 5 to 10 members optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate.

(Method P) [Chemical Formula 25] (18) (1) Method P is a method for producing the compound (1) of the invention, by reacting the compound (18) with a trifluoromethanesulfonylating agent in an inert solvent to produce a compound in which the phenolic hydroxyl has been trifluoromethanesulfonylated ( Stage Pl-1) and optionally, removing the protecting groups in the resulting compound. Alternatively, Step Pl-1 can be followed by the reaction with a compound that can introduce a desired substituent into the phenyltriflate compound, or a reactive derivative thereof (Step Pl-2), and optionally removing the protecting groups in the resulting compound to produce the compound (1) of the invention. This method can be carried out when a phenolic hydroxyl group is present in the benzene ring to which R10a is attached. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, tR-) 40, "n, X vl, pR10a, R r> > 30a, tR- > 31a, rR > 3 a, "y- pR40a < t-i ^ e "" ne "_n l ia-, s-. "M, i-:" s "m, a--" s previous definitions. Also, at least one of R20c, R21c, R2c and R23c is a phenolic hydroxyl group, and the remaining groups each have the same definition as the corresponding group of R20a, R21a, R22a and R23a. (Step P-1) This step can be carried out in a manner similar to the sulfonylation described for Method A or Method B above. The trifluoromethanesulfonylation can be replaced by nonafluorobutanesulfonylation or toluenesulfonylation. The compound (1) of the invention can be isolated or purified from the reaction mixture obtained previously by the method described below. When the R10 of the resulting compound (1) is optionally substituted 5- to 10-membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above, to produce the compound (1) of the invention, wherein R10 is cycloalkyl of 5 to 10 members optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Step P-1-2) This is a step to convert the trifluoromethanesulfonyloxy group of the compound obtained in Step P-1 to a desired substituent. This step can be carried out in a manner similar to Method N-l-2 above. As supplementary literature used as a reference to carry out this method, it can be mentioned, without limitation, Kurt Ritter, Synthesis, (1993), 735. The compound (1) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (1) is optionally substituted 5 to 10 membered cycloalkenyl, can be subjected to the hydrogenation described for Method A above, to produce the compound (1) of the invention, wherein R 10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method Q) [Chemical Formula 26] (19) (1A) Method Q is a method to produce the compound (IA) of the invention (the compound (1) wherein X1 is nitrogen) by reacting the compound (19) with the compound (20) in an inert solvent, in the presence of a reducing agent, in the presence or absence of an acid, in the presence of an additive, and optionally, removing the protective groups in the resulting compound. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, W1, R10a, R20a, R21a, R22a, R23a and R40a have the same definitions as above. Also E1, E2 and E3 are suitable groups to obtain the desired group of the formula: [Chemical Formula 27] The substituents on E1, E2 and E3 can optionally be protected. This method can be carried out in a manner similar to Method C above. The compound (IA) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R10 of the resulting compound (1A) is optionally substituted 5- to 10-membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above, to produce the compound (IA) of the invention, wherein R10 is cycloalkyl of 5 to 10 members optionally substituted with the corresponding substituent. When the resulting compound is going to become an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method R) [Chemical Formula 28] (twenty-one) (1A) The R Method is a method to produce the compound (IA) of the invention (the compound (1) wherein X1 is nitrogen) by reacting the compound (21) with a base in an inert solvent, and optionally, removing the protecting groups in the resulting compound. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, tR-, 0, "n, tW.tl, tR-) 10a,, R-, 20a, DR21a, tR-, 22a , DR23a "y_ n40a, t_i • e __ne__n ila _" s "same" previous definitions. Also E4, E5 and E6 are suitable groups to obtain the desired group of the formula: [Chemical Formula 29] The substituents on E4, E5 and E6 can optionally be protected. This method can be carried out in a manner similar to Method A above. The compound (IA) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R 10 of the resulting compound (IA) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above, to produce the compound (IA) of the invention, wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method S) [Chemical Formula 30] (1B) Method S is a method for producing the compound (IB) of the invention (the compound (1) wherein X1 is CH) by reacting the compound (22) with the compound (9) in an inert solvent, and optionally, removing the protecting groups in the compound (Method S-1), or a method for producing the compound (100) of the invention by reacting the compound (22) with the compound (9) in the same manner and optionally, removing the protecting groups in the resulting compound (Method S-2) and, if necessary, further driving it to a compound (IB) of the invention by hydrogenation (Method S-3). In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, Wla, Mlb, R10a, R20a, R21a, R22a, R23a, R30a, R31a, R32a and R40a have the same definitions as above . This method can be carried out in a manner similar to a combination of Method K above and the hydrogenation reaction in Method A above. The compounds (IB) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the resulting compound is to be converted to an acid salt, this can be achieved by a conventional method. The production step of the salt and the hydrogenation step after the reaction between the compound (22) and the compound (9), can be carried out in a different order, as appropriate. (Method T) [Chemical Formula 31] (24) (25) Method T is a method to produce the compound (IB) of the invention (the compound (1) in which X1 is CH), by reacting the compound (24) with the compound (25) in an inert solvent, in the presence of a palladium (0) catalyst, and after hydrogenating the product and, optionally, removing the protecting groups in the resulting compound, (Method Tl), or a method for producing the compound (100) of the invention, by reacting the compound (24) with the compound (25) in the same similar manner and, optionally, removing the protecting groups in the resulting compound, (Method T-2), and, if necessary, conducting it to the compound (IB) of the invention by hydrogenation (Method T-3). In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, Wla, M1, R10b, R20a, R21a, R22a, R23a, R30a, R31a, R3a, and 40a have the same previous definitions. This method can be carried out in a manner similar to Method K above, and the hydrogenation reaction in Method A above. The compounds (IB) and (100) of the invention can be isolated or purified from the reaction mixture obtained above, by the method described below. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step after the reaction between the compound (24) and the compound (25), can be carried out in a different order, as appropriate. (Method U) [Chemical Formula 32] (26) U-1-1 (27) (100) The U Method is a method to produce the compound (IB) of the invention (the compound (1) in which X1 is CH), by reacting the compound (26) with the compound (27) (ie, a lithium reagent or a Grignard reagent) in an inert solvent to produce an adduct (170) (Step Ul-1), and then reducing the hydroxyl in the benzyl position of the resulting adduct (170) (Step Ul-2) ) and in addition, optionally, removing the protecting groups, or a method for producing the compound (100) of the invention by reacting in the same manner to produce an adduct (170) (Step Ul-1), then dehydrating the hydroxyl of the adduct (170) in the presence of or in the absence of an acid (Step Ul-3), and, optionally, removing the protecting groups. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, n, R10b, R20a, R21a, R22a, R23a, R30a, R31a, R32a, and 40a have the same definitions as above. M2 is a lithium or magnesium halide. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl can be mentioned. ether, among which tetrahydrofuran is preferred. The reaction temperature will differ depending on start materials, solvent and reagents, but will commonly be between -80 ° C and 30 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.25 to 6 hours. (Step U-1-2) This step can be carried out by reduction in a manner similar to the hydrogenation method described for Method A above, or by reduction using a trialkylsilyl hydride described below, although there is no limitation to these methods. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, in the case of the reduction reaction using trialkylsilyl hydride, halogenated hydrocarbons such as such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride (particularly dichloromethane). There are no particular restrictions on the reducing agents used so long as they can produce the objective compound and that they do not produce any non-separable by-product, and specifically, trialkylsilyl hydrides such as a halide of - triethylsilyl and triisopropylsilyl hydride, among which triethylsilyl hydride is preferred. There are no particular restrictions on the additive used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, halo-substituted acetic acids such as trifluoroacetic acid, and Lewis acids such as boron trifluoride can be mentioned. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -70 ° C and 50 ° C. The reaction time will differ depending on the starting materials, the solvent, the reagents and the reaction temperature, but will commonly be 0.5 to 48 hours. (Step Ul-3) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethyloxyethane can be mentioned. and diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride, water and the mixed solvent thereof. Among which tetrahydrofuran is preferred, toluene, dichloromethane, chloroform or water. This stage can be carried out without solvent. There are no particular restrictions on the acid additive used so long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, halo-substituted acetic acids such as trifluoroacetic acid, Lewis acids such as boron trifluoride, can be mentioned, organic sulfonic acids such as toluenesulfonic acid and camphor sulfonic acid, and inorganic acids such as hydrochloric acid and hydrogen bromide. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -80 ° C and 180 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.25 to 24 hours. The compounds (IB) and (100) of the invention can be isolated or purified from the reaction mixture obtained above by the method described below. When the R 10 of the resulting compound (IB) is optionally substituted 5 to 10 membered cycloalkenyl, it can be subjected to the hydrogenation described for Method A above to produce the compound (IB) of the invention, in wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. (Method V) [Chemical Formula 33] Method V is a method for producing the compound (1) of the invention by reacting the compound (53) with the compound (150) (ie, a lithium reagent or a Grignard reagent) in an inert solvent to produce an adduct (140) (Step Vl-1), and then, if necessary, reducing or dehydrating the hydroxyl in the position benzyl of the resulting adduct (140) (Step Vl-2) and, optionally, removing the protecting groups, or a method to produce the compound (2) by reacting in the same manner to produce an adduct (140) (Step Vl- 1), then, if necessary, reducing or dehydrating the hydroxyl in the benzyl position of the adduct (149) (Step Vl-3) and, additionally, removing the protecting groups. In this scheme, R10, R20, R21, R22, R23, R30, R31, R32, R40, X1, n, R10a, R20a, R21a, R22a, R3a, R30a, R31a and R32a have the same definitions as above. M2 is a lithium or magnesium halide. R200 is a substituent in Group Al, or a substituent in Group A that is protected. U is an integer of 0, 1, 2, 3, 4 or 5. K is an integer of 0, 1, 2, 3, 4, or 5. PR40a has the same definition as the previous R40a, or represents a protective group for amino (preferably, t-butoxycarbonyl or benzyl). This method can be carried out in a manner similar to Method U above, and the hydrogenation reaction in Method A above. The compounds (1) and (2) of the invention can be isolated or purified from the reaction mixture obtained previously by the method described below. When the R 10 of the resulting compound (1) is optionally substituted 5 to 10 membered cycloalkenyl, it may be subjected to the hydrogenation described for Method A above to produce the compound (1) of the invention, wherein R 10 is cycloalkyl of 5 to 10. member optionally substituted with the corresponding substituent. When the resulting compound is to be converted to an acid salt, this can be carried out by a conventional method. The production step of the salt and the hydrogenation step described above can be carried out in a different order, as appropriate. The removal of the protecting group (s) will differ depending on their type, and can be carried out in the following manner according to the protocols commonly known in the field of organic synthetic chemistry such as the described protocol. , for example, in: TW Greene, (Protective Groups in Organic Synthesis), John Wiley & Sons; or J.F.W. McOmis, (Protective Groups in Organic Chemistry), Plenum Press. When the amino protecting group is an optionally substituted silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, it will commonly be removed by treatment with an anion-generating compound of - fluoride such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride. The inert solvent used is not particularly restricted as long as it does not inhibit the reaction, and, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether are preferred. There are no particular restrictions on the reaction temperature and the reaction time, but normally the reaction temperature will be between 0 ° C and 50 ° C, and the reaction time will be between 10 and 18 hours. When the amino protecting group is an optionally substituted aliphatic acyl group, an optionally substituted aromatic acyl group, an optionally substituted alkoxycarboxyl group or a substituted methylene group forming a Schiff base, it can be removed by treatment with an acid or base in the presence of a aqueous solvent. The acid used for this reaction is not particularly restricted, as long as it is an acid ordinarily used for removal of the amino protecting group, and, for example, it can be an inorganic acid such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid , phosphoric acid or acid nitric, or an organic acid such as trifluoroacetic acid and trifluoromethanesulfonic acid, among which hydrochloric acid or trifluoroacetic acid is preferred. The base used for this reaction is not particularly restricted, as long as it is a base ordinarily used for removal of the amino protecting group, but alkali metal carbonic acid salts such as lithium carbonate, sodium carbonate and sodium carbonate are preferably used. potassium; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; and mixtures of ammonia such as ammonia water and concentrated ammonia-methanol. The solvent used for the reaction may be, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methyl cellosolve.; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; Water; or a mixture of water and any of the aforementioned solvents, among which alcohols (more preferably ethanol) are preferred. The reaction temperature and the reaction time will differ depending on the starting compounds, of the solvent and the acid or base used, and are not particularly restricted, but in order to inhibit by-products, the reaction temperature will commonly be between 0 ° C and 150 ° C and the reaction time will commonly be from 1 to 10 hours. When the amino protecting group is an optionally substituted aralkyl group or an optionally substituted aralkoxycarbonyl group, a method of contacting a reducing agent in an inert solvent (preferably catalytic reduction at an ordinary temperature in the presence of a catalyst) is generally preferred. a method for removal by oxidation. The inert solvent used for removal by catalytic reduction is not particularly restricted as long as it is inert to the reaction, and, for example, it may be an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbon such as toluene, benzene or xylene; an ester such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, or methyl cellosolve; an organic acid such as acetic acid; Water; or a mixture of these solvents with water, among which alcohols, ethers, organic acids and water (more preferably alcohols and organic acids) are preferred. The catalyst used for the removal by catalytic reduction is preferably palladium-carbon, Raney nickel, platinum oxide, black-platinum, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate. There are no particular restrictions on pressure, but ordinarily it will be from 1 to 10 atmospheres. The reaction temperature and the reaction time will differ depending on the starting materials, the catalyst and the inert solvent, but, commonly, the temperature will be between 0 ° C and 100 ° C and the reaction time will be between 5 minutes and 72 hours. The inert solvent used for removal by oxidation is not particularly restricted, as long as it does not participate in the reaction, but organic solvents containing water are preferred. Such organic solvents include, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfates such as dimethisulfoxide and sulfolane, among which are preferred halogenated hydrocarbons, ethers or sulfoxides (more preferably halogenated hydrocarbons and sulfoxides). The oxidizing agent used for this reaction is not particularly restricted, so long as it is an oxidizing agent used for the removal of the amino protecting group, but is preferably potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) or 2, 3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The reaction temperature and the reaction time will differ depending on the starting materials, the oxidizing agent and the solvent, but, commonly, the temperature will be between 0 ° C and 150 ° C and the reaction time will be between 10 ° C and 150 ° C. minutes and 24 hours. When the amino protecting group is an optionally substituted aralkyl group, the protecting group can be removed using an acid or a base. The acid used for this reaction is not particularly restricted, as long as it is an acid used for the removal of the optionally substituted aralkyl group as the amino protecting group, and, for example, it can be a Bronsted acid, eg, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, acid sulfonic camphor, trifluoroacetic acid or trifluoromethanesulfonic acid; and Lewis acid such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; or an ion exchange acidic resin, among which are preferred inorganic acids and organic acids (more preferably hydrochloric acid, acetic acid and trifluoroacetic acid.The base used for the reaction is not particularly restricted as long as it is a base ordinarily used for the removal of the optionally substituted aralkyl group as the amino protecting group, but is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, a metal alkoxide such as lithium methoxide, sodium methoxide, sodium or potassium ethoxide-t-butoxide, or a mixture of ammonia such as aqueous ammonia or concentrated ammonia-methanol.The inert solvent used for the first stage of the reaction is not particularly restricted as long as it is inert to the reaction, and, as examples, aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether may be mentioned; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; Water; and mixtures of the aforementioned solvents, among which ethers, alcohols and water (more preferably, dioxane, tetrahydrofuran, ethanol or water) are preferred. The reaction temperature will differ depending on the starting materials, and the acid and solvent used, but will commonly be between -20 ° C and the boiling temperature (preferably between 0 ° C and 100 ° C). The reaction time will differ depending on the starting compounds, the acid and the inert solvent used and the reaction temperature, but will commonly be between 15 minutes and 48 hours (preferably between 30 minutes and 20 hours). When the amino protecting group is an optionally substituted alkenyloxycarbonyl group, removal will commonly be achieved by treatment with an acid or a base, under the same conditions of the withdrawal reaction when the amino protecting group is an optionally substituted aliphatic acyl group, an optionally substituted aromatic acyl group, an optionally substituted alkoxycarbonyl group or a substituted methylene group forming a Schiff base. In the case of an alkyloxycarbonyl group, it is particularly convenient to employ a removal method using palladium and triphenylphosphine or nickel-tetracarbonyl, since the removal can be carried out with few side reactions. When the amino protecting group is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted sulfonyl group, withdrawal can commonly be achieved by treatment with an acid or a base under the same conditions of the withdrawal reaction when the group of amino protection is an aliphatic acyl group, an acyl group aliphatic, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group that forms a Schiff base. When the hydroxyl protecting group is, for example, an optionally substituted silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, it will commonly be removed by treatment with a fluoride anion-generating compound such as fluoride. tetrabutylammonium, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride, or with an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphor sulfonic acid or trifluoromethanesulfonic acid. For removal with fluoride anion, an organic acid such as formic acid, acetic acid or propionic acid can be added to accelerate the reaction. The inert solvent used for the reaction is not particularly restricted as long as it is inert to the reaction, but is preferably an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, a nitrile such as acetonitrile or isobutyronitrile; an organic acid such as acetic acid; Water; or a mixture of these solvents. The reaction temperature and the reaction time will differ depending on the starting compounds, the catalyst and the inert solvent used, but ordinarily, the reaction temperature will be between 0 ° C and 100 ° C (preferably between 10 ° C and 50 ° C), and the reaction time will be from 1 to 24 hours. When the hydroxyl protecting group is an optionally substituted aralkyl group or an optionally substituted aralkoxycarbonyl group, a method of contact with a reducing agent in an inert solvent (preferably catalytic reduction at an ordinary temperature in the presence of a catalyst) is generally preferred. or a method for removal using an oxidizing agent. The inert solvent used for removal by catalytic reduction is not particularly restricted as long as it does not participate in the reaction, and, as examples, aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether may be mentioned; aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and triamide hexamethylphosphoric; aliphatic acids such as formic acid and acetic acid; Water; and mixtures of these solvents, among which alcohols are preferred (more preferably methanol and ethanol). There are no particular restrictions on the catalyst used for the removal by catalytic reduction as long as it is commonly used for removal of the hydroxyl protection group by catalytic reduction, and, as examples, palladium-carbon, black palladium, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate, among which palladium-carbon is preferred. There are no particular restrictions on pressure, but it will commonly be 1 to 10 atmospheres. The reaction temperature and the reaction time will differ depending on the starting compounds, the catalyst and the inert solvent, but, commonly, the reaction temperature will be between 0 ° C and 100 ° C (preferably between 20 ° C and 70 ° C). ° C), and the reaction time will be between 5 minutes and 48 hours (preferably between 1 hour and 24 hours). The inert solvent used for removal by oxidation is not particularly restricted as long as it does not participate in the reaction, but is preferably a solvent containing water, and ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; and sulfoxides such as dimethisulfoxide. The oxidizing agent used for this reaction is not particularly restricted while it is an oxidizing agent used for removal of the hydroxyl protection group, but is preferably potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) or 2.3 -dichloro-5, 6-dicyano-p-benzoquinone (DDQ). The reaction temperature and the reaction time will differ depending on the starting compounds, the oxidation agent and the inert solvent, but commonly, the reaction temperature will be between 0 ° C and 150 ° C and the reaction time will be between 10 minutes and 24 hours. The removal can also be achieved by reaction with an alkali metal such as lithium metal or sodium metal in liquid ammonia or an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, alcohol isoamyl, diethylene glycol, glycerin, octanol, cyclohexanol, or methyl cellosolve, at a temperature between -78 ° C and 0 ° C.

The removal can also be accomplished using sodium aluminum chloride iodide or an alkylsilyl iodide such as trimethylsilyl iodide in an inert solvent. The inert solvent used in this reaction is not particularly restricted as long as it does not participate in the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; a nitrile such as acetonitrile or a mixture of these solvents. The reaction temperature and the reaction time will differ depending on the starting compounds and the inert solvent, but, commonly, the reaction temperature will be between 0 ° C and 50 ° C and the reaction time will be between 5 minutes and 72 hours. When the hydroxyl protecting group is an aliphatic acyl group, an aromatic acyl group or an optionally substituted alkoxycarbonyl group, it can be removed by treatment with a base in an inert solvent. There are no particular restrictions on the base used for this reaction, as long as it is a commonly used basis for the removal of the hydroxyl protection group, and, for example, it may be a salt of carbonic acid of alkali metal such as lithium carbonate, carbonate sodium and potassium carbonate; an alkali hydrogencarbonate such as lithium hydrogencarbonate, - sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxide such as lithium methoxide, sodium methoxide, sodium or potassium ethoxide-t-butoxide; or a mixture of ammonia such as aqueous ammonia or concentrated ammonia-methanol, among which alkali metal hydroxides, metal alkoxides and ammonia mixtures (more preferably alkali metal hydroxides and metal alkoxides) are preferred. The inert solvent used for this reaction is not particularly restricted as long as it is ordinarily used for the hydrolysis reaction, but is preferably an ether such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, or methyl cellosolve; Water; or a mixture of these solvents. The reaction temperature and the reaction time will differ depending on the starting compounds and the base and the inert solvent used, but, in order to inhibit the side products, the reaction temperature will commonly be between -20 ° C and 150 ° C and the reaction time will commonly be from 1 to 10 hours.

When the hydroxyl protecting group is optionally substituted alkoxymethyl, optionally substituted alkylthiomethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or optionally substituted ethyl such as 1-ethoxyethyl, it will commonly be removed by treatment with an acid in an inert solvent. There are no particular restrictions on the acid used for this reaction, as long as it is an acid used for removal of the hydroxyl protection group, but commonly compounds commonly used as Bronsted acids or Lewis acids can be mentioned, and Bronsted acids including chloride are preferred. of hydrogen; inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid; or Lewis acids such as boron trifluoride, although strong acid cation exchange resins such as DOWEX 50W may also be used. There are no particular restrictions on the inert solvent used for this reaction as long as it is inert to the reaction, and, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether may be mentioned; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diidopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; Water; and mixtures of these solvents, among which ethers and alcohols (more preferably tetrahydrofuran and methanol) are preferred. The reaction temperature and the reaction time will differ depending on the starting compound and the acid and the inert solvent used, but ordinarily, the reaction temperature will be between -10 ° C and 200 ° C (preferably between 0 ° C and 150 ° C), and the reaction time will be between 5 minutes and 48 hours (preferably between 30 minutes and 10 hours). When the hydroxyl protecting group is an optionally substituted alkenyloxycarbonyl group or an optionally substituted sulfonyl group, removal can commonly be achieved by treatment with a base, under the same conditions as the withdrawal reaction when the hydroxyl protection group is the optionally substituted aliphatic acyl group, the optionally substituted aromatic acyl group or the above-mentioned optionally substituted alkoxycarbonyl group. In the case of an allyloxycarbonyl group, it is particularly convenient to employ a removal method using palladium or triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate, since removal can be carried out with few side reactions . When the carboxyl protecting group is a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or an optionally substituted silyl group, or when the compound has been converted to an ortho ester for protection purposes, a method of withdrawal by treatment with an acid or a base, or by using an enzyme. There are no particular restrictions on the acid used for this reaction as long as it is used for the removal of the carboxyl protection group, and, for example, it can be hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid. There are no particular restrictions on the basis used for this reaction as long as it is used for the removal of the carboxyl protecting group, and, for example, it can be an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; or concentrated ammonia-methanol solution, among which sodium hydroxide is preferred. Isomerization can occur with hydrolysis using a base. There are no particular restrictions on the enzyme used for the reaction as long as it is an enzyme used for removal of the carboxyl protection group, and, for example, it can be a lipase or an esterase. The solvent used for this reaction may be, for example, water, an alcohol such as methanol, ethanol or n-propanol; an ether such as tetrahydrofuran or dioxane; or a mixture of any of these solvents with water, among which an alcohol (more preferably methanol) is preferred. The reaction temperature and the reaction time will differ depending on the starting compounds, the solvent and the reagents used and are not particularly restricted, but in order to inhibit the side products, the reaction temperature will commonly be between 0 ° C and 220 ° C, and the reaction time will commonly be between 30 minutes and 10 hours. When the carboxyl protection group is a group optionally substituted aralkyl or a lower halogen alkyl group will be commonly removed by reduction in a solvent. The reduction method is preferably a method by chemical reduction with zinc-acetic acid when the carboxyl protection group is a lower alkyl group of halogen, and when it is an optionally substituted aralkyl group, the method can be one of catalytic reduction using a catalyst such as palladium-carbon or platinum, or a chemical reduction method using an alkali metal sulfide such as potassium sulfide or sodium sulfide. The solvent used is not particularly restricted as long as it does not participate in the reaction, but there are preferred alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane; aliphatic acids such as acetic acid; and mixtures of these solvents with water. The reaction temperature and the reaction time will differ depending on the starting compounds, the solvent and the reduction method, but commonly, the reaction temperature will be between 0 ° C and about room temperature and the reaction time will be found between 5 minutes and 12 hours. If the carbonyl group has been protected by conversion into a cyclic or acyclic ketal formed using, for example, an alcohol such as methanol, isopropanol or diethylene glycol or a thiol such as methanethiol, ethanethiol or propanedithiol, an acid can be used for reconversion to a carbonyl group. The acid used for this reaction is not particularly restricted as long as it is an acid ordinarily used for reconversion to a carbonyl group from a cyclic or acyclic ketal formed for the purpose of protecting the carbonyl group, and, for example, may be a Bronsted acid, eg, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphor acid sulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; a Lewis acid such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; or an ion exchange acidic resin, among which are preferred inorganic acids and organic acids (more preferably hydrochloric acid and p-toluenesulfonic acid). There are no particular restrictions on the inert solvent used for the first stage of the reaction as long as it is inert to the reaction, and as examples may be mentioned aliphatic hydrocarbons such such as hexane, heptane, ligroin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; Water; and mixtures of these solvents, among which ethers, alcohols and water (more preferably, acetone, tetrahydrofuran, and water) are preferred. The reaction temperature will differ depending on the starting materials, and the acid and solvent used, but will commonly be between -20 ° C and the boiling temperature (preferably between 0 ° C and 100 ° C). The reaction time will differ depending on the starting compounds, the acid and the inert solvent used and the reaction temperature, but will commonly be between 5 minutes and 48 hours (preferably between 10 minutes). minutes and 24 hours). In the case of a cyclic or acyclic ketal shaped using a thiol, it is particularly convenient to employ a removal method using a substance such as Raney nickel or silver nitrate. In the case of conversion to a cyclic ketal using, for example, formalin or acetone as protection of a diol, an acid can be used for the conversion to the diol. The acid used for this reaction is not particularly restricted so long as it is an acid ordinarily used for reconversion to a diol from a cyclic or acyclic ketal formed for the purpose of protecting the diol, and, for example, it may be a Bronsted acid, eg, an inorganic acid such as such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphor sulphonic acid , trifluoroacetic acid or trifluoromethanesulfonic acid; and Lewis acid such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; or an ion exchange acidic resin, among which are preferred inorganic acids and organic acids (more preferably acid hydrochloric acid, acetic acid and trifluoroacetic acid. There are no particular restrictions on the inert solvent used for the first stage of the reaction as long as it is inert to the reaction, and, as examples, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol and cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; Water; and mixtures of these solvents, among which ethers, alcohols and water (more preferably, acetone, tetrahydrofuran, and water) are preferred. The reaction temperature will differ depending on the starting compounds, and the acid and solvent used, but will commonly be between -20 ° C and the boiling temperature (preferably between 0 ° C and 100 ° C). The reaction time will differ depending on the starting compounds, the acid and the inert solvent used and the reaction temperature, but will commonly be between 5 minutes and 48 hours (preferably between 10 minutes and 24 hours). The removal of the protecting groups for amino, hydroxyl, carbonyl or carboxyl groups, or a diol, can be carried out in an appropriate order. After completing the reactions of each of the methods and steps described above, the objective compound of each step can be recovered from the reaction mixture according to conventional procedures. For example, when the entire reaction mixture is a liquid, it may be returned to room temperature, if necessary, or cooled in ice, then allowed to neutralize an acid, an alkali, an oxidizing agent or a reducing agent, if necessary, and then water and an organic solvent such as ethyl acetate can be added which is non-miscible with water and which does not react with the target compound, and the layer containing the target compound is separated. Then, a non-miscible solvent can be added to the resulting layer, which does not react with the target compound, and the layer containing the objective compound can be washed and separated. If the layer is a layer organic, can be dried using a desiccant such as anhydrous magnesium sulfate or anhydrous sodium sulfate, the solvent can be distilled to recover the target compound. If the layer is an aqueous layer, it can be electrically desalted and then lyophilized to recover the target compound. When the entire reaction mixture is a liquid, in some cases, substances other than the target compound (eg, solvents, reagents, etc.) can simply be distilled at atmospheric pressure or under reduced pressure to recover the target compound. When the target compound is only precipitated as a solid, or when the entire reaction mixture is a liquid and the target compound is only precipitated as a solid during the recovery process, the target compound can first be filtered by a filtration method and the The filtered objective compound is washed with a suitable organic or inorganic solvent and dried to allow treatment of the mother liquor in the same manner as when the entire reaction mixture is a liquid, in order to recover the target compound. When only the reagent or catalyst is present in solid form, or when the entire reaction mixture is a liquid and the reagent or catalyst only precipitates as a solid during the recovery process, With the target compound dissolved in the solution, the reagent or catalyst can first be filtered by a filtration method and the filtered reagent or catalyst washed with a suitable organic or inorganic solvent, and then combine the washing liquids obtained as the mother liquor and treat the mixture obtained in the same manner as when the entire reaction mixture is a liquid, in order to recover the target compound. Particularly, when substances other than the target compound in the reaction mixture do not inhibit the reaction of the subsequent step, the reaction mixture can be used directly for the subsequent step without isolation of the target compound. The purity of the objective compound recovered by the method described above can be improved by appropriately employing a recrystallization method, a chromatography method or a distillation method. When the recovered target compound is a solid, it will commonly be possible to improve the purity of the target compound by recrystallization. For recrystallization, a single solvent that does not react with the target compound can be used. Specifically, the target compound is first dissolved in the single or multiple solvents that do not react with it, either at room temperature or with heating. The solution The resulting product is either cooled in ice or allowed to stand at room temperature until crystallization of the target compound from the solution. When the recovered target compound is a liquid or a solid, the purity of the target compound can be improved by any of several chromatography methods. In most cases, a weak acid silica gel such as Silica Gel 60 (340-400 mesh) may be used by Merck Co. or BW-300 (300 mesh) by Fuji Silysia Chemical Ltd. When the target compound is basic and the absorption is too strong in the aforementioned silica gels, Propylamine Coating Silica Gel can be used (200-300 mesh) by Fuji Silysia Chemical Ltd., or similar.

When the target compound is bipolar or must be eluted with a polar solvent such as methanol, NAM-200H or NAM-300H can be used by Nam Research Co. These silica gels can be used for the elution of the target compound with a single solvent or multiple solvents. which do not react with the objective compound, followed by distillation of the solvent, to produce the objective compound with improved purity. When the recovered target compound is a liquid, its purity can be improved by a distillation method. For distillation, the target compound is subjected to reduced pressure at room temperature or with heat to distill the target compound.

Representative examples of the production methods for the compounds (1) and (100) according to the present invention have been described above, but the starting compounds and the reagents used for the production of the compounds of the invention can also be forming salts or solvates (hydrates, etc.), which will differ depending on the starting materials and solvents used, and are not particularly restricted as long as they do not inhibit the reaction. The solvents used will also differ depending on the starting materials and reagents, but, of course, they are not particularly restricted as long as they dissolve the starting materials to a certain degree and do not inhibit the reaction. When the compound (1) or (100) of the invention is obtained in the free form, a conventional process for converting it into a salt or hydrate which can form the compound (1) or (100) can be carried out. When the compound (1) or (100) of the invention is obtained as a salt of the compound (1) or (100), or a hydrate of the compound (1) or (100), this can be converted into the free form of the compound (1) or (100) according to a conventional procedure. Also, the various isomers obtained for the compound (1) or (100) according to the invention (for example, geometric isomers, optical isomers based on asymmetric carbons, rotational isomers, stereoisomers and tautomers, etc.) can be purified and isolated using ordinary separation means such as recrystallization, diastereomer salt methods, enzyme fractionation methods, and various chromatographies (e.g., thin layer chromatography, column chromatography, gas chromatography and the like). The starting compounds for Method A, Method B, Method C, Method D, Method E, Method F, Method G, Method H, Method K, Method M, Method N, Method P, Method Q, Method R, Method S , Method T, Method U and Method V described above, can be commercially available compounds or can be easily produced from commercially available compounds by methods well known in the art. They can also be produced by the following methods. (Production method for compound (2A)) (Method 1-1) [Chemical Formula 34] (2A) This method is a method for producing a compound (2A) (the compound (2) in which X1 is nitrogen) by reacting the compound (28) with the compound (9) (amination or amidation) in an inert solvent, in the presence of a palladium (0) catalyst or a copper catalyst, in presence or absence of a base, in the presence or absence of an additive, under or not under an atmosphere of inert gas and then removing the protection group Pro1. t E-? n is it-e scheme, n, pWl, tR-? lOa, tR-, 20a, tR-? 21a, tR- > 22a, tR- > 23a, R30a, R31a, and R32a have the same definitions as above. Also Pro1 is an amino protecting group, and, for example, may be an optionally substituted silyl group such as trimethylsilyl, triethylsilyl or t-butyldiphenylsilyl, an optionally substituted aliphatic acyl group such as formyl or acetyl, an optionally substituted aromatic acyl group such as benzoyl, an optionally substituted alkoxycarbonyl group such as ethoxycarbonyl or t-butoxycarbonyl, a substituted methylene group forming a Schiff base, an optionally substituted aralkyl group such as benzyl, 4-methoxybenzyl or 4-nitrobenzyl, an optionally substituted aralkoxycarbonyl group such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, an optionally substituted alkenyloxycarbonyl group such as vinyloxycarbonyl or allyloxycarbonyl, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted sulfonyl group, preferably a lower alkoxycarbonyl group as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or isobutoxycarbonyl, a lower alkoxycarbonyl group substituted with halogen or silyl tri lower alkyl such as 2,2,2-trichloroethoxycarbonyl or 2-trimethylsilylethoxycarbonyl, an alkenyloxycarbonyl group such as vinyloxycarbonyl or allyloxycarbonyl, an optionally substituted aralkyloxycarbonyl group such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, or an optionally substituted aralkyl group such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl or 4-nitrobenzyl, and, more preferably, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, ethoxycarbonyl, -butoxycarbonyl or benzyloxycarbonyl. The method can be carried out in a manner similar to Method F above. (Production method for compound (2A)) (Method 1-2) [Chemical Formula 35] (29) (12) 1-2 (2A) This method is a method for producing the compound (2A) (the compound (2) in which X1 is nitrogen) by reacting the compound (29) with the compound (12) in an inert solvent or without solvent, under or not under an inert gas atmosphere, in the presence or absence of a base, in the presence or absence of an additive, to produce the compound (2A), and subsequently removing the protection group Pro1.

- In this scheme, n, Wla, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. HPro1 is hydrogen or has the same definition as Pro1 above. This method can be carried out in a manner similar to Method H above. (Production method for compound (2C)) (Method 1-3) [Chemical Formula 36] (30) (2C) This method is a method for producing the compound (2C) (the compound (2) in which R10a is R10b) by reacting the compound (30) with the compound (14) in an inert solvent, in the presence of a Palladium catalyst (0), under or not under an inert gas atmosphere, in the presence or absence of a base, in the presence or absence of a additive, and subsequently removing the protection group Pro1. In this scheme, X1, n, Wla, Mlb, Pro1, R10b, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method K described above. (Production method for compound (2C)) (Method 1-4) [Chemical Formula 37] (31) (2C) This method is a method for producing the compound (2C) (the compound (2) in which R10a is R10b) by reacting the compound (31) with the compound (16) in an inert solvent, in the presence of a palladium catalyst (0), under or not under an inert gas atmosphere, in the presence or absence of a base, in the presence or absence of an additive, and subsequently removing the protection group Pro1. In this scheme, X1, n, Wla, M1, Pro1, R10b, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method K described above. (Production method for compound (2A)) (Method 1-5) [Chemical Formula 38] (2A) This method is a method for producing the compound (2A) (the compound (2) in which X1 is nitrogen) by reacting the compound (19) with the compound (33) in an inert solvent, in the presence of a reducing agent. , in the presence or absence of an acid, in the presence or in absence of an additive, to produce the compound (2A) and subsequently removing the protection group Pro1 by the method described above. In this scheme, n, W1, E1, E2, E3, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. Also, HProla is hydrogen or a group represented by Prola below. The Prola group is an optionally substituted aralkyl group such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl or 4-nitrobenzyl, and is preferably benzyl. This method can be carried out in a manner similar to Method C described above. (Production method for compound (2A)) (Method 1-6) [Chemical Formula 39] (3. 4) (2A) This method is a method for producing the compound (2A) (the compound (2) in which X1 is nitrogen) by reacting a base with the compound (34) in an inert solvent, and subsequently removing the protecting group Pro1 by the method described above. In this scheme, n, W1, Pro1, E4, E5, E6, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method A described above. (Production method for compounds (2B) and (200)) (Method 1-7) [Chemical Formula 40] (2B) This method is a method to produce the compound (2B) (the compound (2) in which X1 is CH) by reacting the compound (35) with the compound (9) in an inert solvent, in the presence of a palladium (0) catalyst, by subjecting it to a hydrogenation reaction and subsequently removing the protection group Pro1 (Method 1-7-1), or a method for producing the compound (200) by reacting the compound (35) with the compound (9) in the same manner, then removing the group from Pro1 protection (Method 1-7-2). In this scheme, n, Wla, M1, Pro1, R10a, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method K described above and the hydrogenation reaction in Method A above. (Production method for compounds (2B) and (200C)) (Method 1-8) [Chemical Formula 41] (2B) This method is a method for producing the compound (2B) (the compound (2) in which X1 is CH) by reacting the compound (36) with the compound (25) in an inert solvent, in the presence of a palladium catalyst (0), subjecting it to hydrogenation reaction and subsequently removing the protection group Pro1 (Method 1-8-1), or a method to produce the compound (200C) (the compound (200) in which R10a is R10b) by reacting the compound (36) with the compound (25) in the same manner, then removing the protection group Pro1 (Method 1-8-2). In this scheme, n, Wla, M1, Pro1, R10a, R10, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method K described above and the hydrogenation reaction in Method A above. (Production method for compounds (2B) and (200C)) (Method 1-9) [Chemical Formula 42] (200C) This method is a method to produce the compound (2B) (the compound (2) in which X1 is CH) by reacting the compound (37) with the compound (27) (i.e., a lithium reagent or a Grignard reagent) in an inert solvent, in the presence of an inert gas to produce an adduct (160) (Step 1-9-2), and removing the protection group Pro1, or a method for producing the compound (200C) (the compound (200) in which R10a is R10b) by reacting in the same manner for producing an adduct (160) (Step 1-9-1), then dehydrating hydroxyl in the benzyl position of the adduct (160) resulting in the presence or absence of acid (Stage 1-9-3), and subsequently removing the protection group Pro1. In this scheme, n, M2, Pro1, R10a, R10b, R20a, R21a, R22a, R23a, R30a, R31a, and R32a have the same definitions as above. This method can be carried out in a manner similar to Method U described above. (Production method for compound (19)) (Method 2) [Chemical Formula 43] (12) (38) 2-2 (19) (39) This method is a method for producing the compound (19) by reacting an N-alkylating agent with the compound (12) in an inert solvent to produce the compound (38) (Step 2-1) and subsequently reacting an N-alkylating agent or an N-carbonylating agent with the compound (38) to produce the compound (39) (Step 2-2), and reacting an oxidizing agent with the compound (39) in presence or absence of an additive (Stage 2-3). In this scheme, W1, E1, E2, E3, R10a, R20a, R21a, R22a and R23a, have the same definitions as above. Also E7 it is a suitable group to obtain the desired group of the formula E (C0) E1-. Step 2-1 and Step 2-2 can be carried out in a manner similar to Method A described above. (Step 2-3) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2 may be mentioned. -dichloroethane and carbon tetrachloride, and nitriles such as acetonitrile, and isobutyronitrile, among which halogenated hydrocarbons (particularly dichloromethane) are preferred. There are no particular restrictions on the oxidation agent used as long as it can produce the target compound and does not produce any non-separable by-product, and specifically, chromic acids such as pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC), reagent can be mentioned. Dess-Martin (Dess D.B., Martin J.C., J. Am. Chem. Soc. , (1991), 113, 7277), or catalytic amounts of dimethyl sulfoxide oxidation agents such as tetrapropylamino perruthenate (VII) (TPAP, Law S.V. et al., Synthesis (1994), 639) and dimethylsulfoxide-oxalyl chloride (oxidizing agent Swern; - Swern et al., Synthesis (1981), 165), in the presence of N-methylmorpholine-N-oxide (NMO) as an auxiliary oxidizing agent, among which dimethylsulfoxide-oxalyl chloride (oxidizing agent Swern) is preferred. There are no particular restrictions on the additive used so long as it can produce the objective compound and does not produce any non-separable by-product, and specifically, mention may be made of celite and molecular sieve, among which molecular sieve is preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -80 ° C and 60 ° C, and is preferably between -80 ° C and 40 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 0.1 to 100 hours, and is preferably from 1 to 12 hours. The compound (38), (39) or (19) can be isolated or purified from the reaction mixtures obtained above, by the methods described above. (Production method for compounds (21) and (34)) (Method 3) [Chemical Formula 44] -OH -OH PR '40a. / 3-1 40a / PR '-NH \ E / (40) (41) W1 This method is a method for producing the compound (21) or (34) by reacting an N-alkylating agent or an N-carbonylating agent with the compound (40) in an inert solvent to produce the compound (41) (Step 3-1) and subsequently oxidizing the compound (41) to produce the compound (42) (Step 3-2), and reacting the compound (42) with the compound (12) (Step 3-3). In this scheme, W1, E4, E5, E6, R10a, R20a, R21a, R22a and R3a, have the same definitions as above. Also E8 is a suitable group to obtain the desired group of the formula E (CO) E5-. PR40a has the same definition as R40a above, or is an amino protecting group (preferably t-butoxycarbonyl or benzyl).

Step 3-1 in this method can be carried out in a manner similar to Method A above, Step 3-2 can be carried out in a manner similar to Method 2 above (Step 2-3) and Step 3-3 it can be carried out in a manner similar to Method C above. (Production method for compounds (24A), (36A), (22), (35), (24B) and 36B)) (Method 4) [Chemical Formula 45] (24B) (36B) (22) (35) This method is a method for introducing a trifluoromethanesulfonyl group into the compound (43) in an inert solvent under an inert gas atmosphere to produce the compound (24A) or (36A) (Step 4-1), and then reacting the compound (24A) or (36A) with a reagent from boron metal or a tin metal reagent in the presence of a palladium catalyst (o) to produce the compound (22) or (35) (Step 4-2), and react the compound (22) or (35) with a halogenation reagent in the presence or absence of a base, to produce the compound (24B) or (36B) (Step 4-3). The compound (43) can also be reacted directly with a halogenating agent to produce the compound (24B) or (36B) (Step 4-4). In this scheme, n, R30a, R31a, R32a, and PR40a have the same definitions as above. Hal also represents chlorine, bromine or iodine. Mlb is a group of formula B (OE10c) 2 or Sn (E10b) 3 (wherein E10c represents Cl-6 alkyl or both of E10c are linked together to form C2-3 alkylene optionally substituted with methyl, and E10b represents Cl-6 alkyl). Tf is trifluoromethanesulfonyl. (Step 4-1) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, tetrahydrofuran and dioxane may be mentioned, which tetrahydrofuran is preferred. This step is preferably carried out under a dry atmosphere of inert gas. The inert gas is preferably argon or nitrogen. There are no particular restrictions on the base used as long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically, alkali metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and lithium diisopropylamide, among which lithium bis (trimethylsilyl) amide or lithium diisopropylamide is preferred. There are no particular restrictions on the trifluoromethanesulfonylation reagent used as long as it can produce the objective compound and does not produce any non-separable by-product, but is preferably N-phenyl bis (trifluoromethanesulfonimide). The reaction temperature for enolation will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -100 and 20 ° C, and is preferably between -80 and -30 ° C. The reaction temperature for conversion to an outlet group will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -100 and 50 ° C, and is preferably between -80 and 30 ° C. The reaction time for enolation will differ depending on the starting materials, the solvent, the reagents and the reaction temperature, but will usually be from 0.1 to 5 hours, and is preferably from 0.1 to 3 hours. The reaction time for the conversion to an exit group will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 0.1 to 24 hours, and is preferably from 0.5 to 12 hours. In addition to the method described above, compound (44) can be produced by reacting a ketone compound (43) with trifluoromethanesulfonic anhydride in an inert solvent such as dichloromethane, in the presence of an organic base such as 2,6-di-t-butyl- 4-methylpyridine, as described in David Crich et al., Synthesis (2001), 2, 323, for example. (Step 4-2) (Production method for compounds (22) and (35) as boronate derivatives) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide and sulfolane, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and aromatic hydrocarbons such as benzene, toluene and xylene, among which dimethylsulfoxide and dioxane are preferred. There are no particular restrictions on the metal catalyst used so long as it can produce the target compound and produce no non-separable by-product and specifically bivalent palladium compounds such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) can be ioned. ), and 0-valent palladium compounds such as tetrakis (triphenylphosphine) palladium, among which [1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium is preferred (II). As bases that may be used, potassium phenoxide, triethylamine, potassium phosphate, potassium carbonate and potassium acetate may be ioned, among which potassium acetate is preferred. The catalyst used can be triphenylarsine. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 50 ° C and 80 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 1 to 6 hours, and is preferably from 2 to 3 hours.

(Production method for compounds (22) and (35) as tin derivatives) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, there may be ioned amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, among which ethers (particularly tetrahydrofuran) are preferred. There are no particular restrictions on the metal catalyst used as long as it can produce the objective compound and produce no non-separable by-product and specifically can be ioned 0-valent palladium compounds such as tetrakis (triphenylphosphine) palladium (0) and tris (dibenzylideneacetone) dipaladium (0). As tin reagents that may be used, there may be ioned hexamethylditin (IV), hexabutyldithin (IV) and hexaphenylditin (IV), among which hexamethylditin (IV) is preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but it will commonly be between -70 ° C and 80 ° C and is found preferably between 50 ° C and 80 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 1 to 8 hours, and is preferably from 2 to 4 hours. As a suppleary literature that can be used as a reference for carrying out this method, one can ion Kurt Ritter et al., Synthesis 1993; 735-762. (Stage 4-3) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2 can be mentioned. Dichloroethane and carbon tetrachloride and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, among which dichloromethane, carbon tetrachloride, diethyl ether and tetrahydrofuran are preferred. There are no particular restrictions on the halogenation reagent used as long as it can produce the objective compound and does not produce any non-separable by-product and specifically chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and copper chloride can be mentioned , among which prefers chlorine, bromine and iodine. As bases that may be used, sodium hydroxide, pyridine and sodium methoxide may be mentioned. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -78 ° C and 25 ° C and is preferably between 0 ° C and 25 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 1 to 24 hours, and is preferably from 1 to 6 hours. (Stage 4-4) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2 may be mentioned. -dichloroethane and carbon tetrachloride and aromatic hydrocarbons such as benzene, toluene and xylene, among which chloroform, dichloromethane and carbon tetrachloride are preferred. There are no particular restrictions on the halogenation agent used as long as it can produce the objective compound and does not produce any non-separable by-product and specifically agents of halogenation such as chlorine, oxalic chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, bromine, oxalic bromide, thionyl bromide, phosphorus bromide, 2, 2, 2-tribromo-l, 3, 2-benzodioxafosfol , iodine or phosphorus triiodide, among which phosphorus trichloride, phosphorus tribromide, 2, 2, 2-tribromo-l, 3, 2-benzodioxafosfol and phosphorus triiodide are preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 70 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 1 to 24 hours. (Production method for compounds (25), (27) and (9a)) (Method 5) [Chemical Formula 46] (45) (9A) 5-2 (25) (27) In this method, the compound (45) is reacted with the compound (14) in an inert solvent in the presence of a palladium (0) catalyst to produce the compound (9A) (Step 5-1), and then the compound (9A) is reacted with a lithiation agent or a Grignard reagent producing agent to produce the compound (27) (Step 5-2) and the compound (27) is reacted with a boron metal reagent or a tin metal reagent to produce the compound (25) (Step 5-3).

In this scheme, M1, M1, M2, R10b, R20a, R21a, R22a and R23a have the same definitions as above. Hal1 is chlorine or bromine, and Hal2 is iodine when Hal1 is bromine, and bromine or iodine when Hal1 is chlorine. Step 5-1 of this method can be carried out in a manner similar to Method K above. (Stage 5-2) This stage will differ depending on the nature of M2. (Production stage of the Grignard reagent) In this step, the compound (9A) is reacted directly with magnesium metal in an inert solvent (direct method) or a magnesium-halogen exchange reaction is carried out between the compound (9A) and another Grignard reagent (indirect method) to produce the compound (27) (i.e., Grignard reagent). (1) Direct method There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane may be mentioned. , dimethoxyethane and diethylene glycol dimethyl ether and phosphoric amides such as hexamethylphosphoric triamide, among which ethers are preferred (particularly diethyl ether and tetrahydrofuran). The reaction method can be conducted according to a common procedure, and specifically, magnesium metal is suspended in the solvent under an atmosphere of an inert gas such as nitrogen or argon., in the presence or absence of a catalytic amount of iodine or dibromoethane as the activating agent, and the compound (9A) is slowly added to the reaction system. Upon completion of the reaction, the compound (27) is produced in the supernatant, and is commonly used for the next step without isolation. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -20 ° C and 150 ° C and is preferably between 0 ° C and 100 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 1 to 10 hours. (2) Indirect method The solvent used, the reaction temperature and the reaction time are the same as for the direct method. The reaction method can be carried out according to a common procedure, but the compound (27) (i.e., an organic magnesium compound) can also be produced by reacting the halogen compound (9A) with isopropylmagnesium bromide or the like, under an atmosphere of an inert gas such as nitrogen or argon. The resulting compound (27) is commonly used for the next step without isolation. (Lithiation step) In this step, the lithium-halogen exchange reaction is carried out between the halogen compound (9A) and another alkyllithium reagent in an inert solvent, under an atmosphere of an inert gas such as nitrogen or argon to produce an aryl lithium reagent (27). There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl can be mentioned. ether and phosphoric amides such as hexamethylphosphoric triamide, among which ethers are preferred (particularly diethyl ether and tetrahydrofuran). There are no particular restrictions on the alkyllithium reagent used so long as it can produce the objective compound and does not produce any non-separable by-product, and specifically, alkyl-lithium compounds such as n-2 can be mentioned. butyllithium, sec-butyllithium and t-butyllithium, among which n-butyllithium is preferred. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -100 ° C and 0 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will commonly be from 10 minutes to 2 hours. The resulting compound (27) is commonly used for the next step without isolation. (Stage 5-3) This stage will differ depending on the nature of M1. (Step for the production of a boronic acid reagent) In this step, the lithium agent or Grignard reagent (27) produced in Step 5-2, is reacted with a borate reagent mentioned below, to produce a compound ( 25) of the boronic acid reagent. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether and phosphoric amides such as hexamethylphosphoric triamide, among which ethers are preferred (particularly diethyl ether and tetrahydrofuran). There are no particular restrictions on the borate reagent used as long as it can produce the objective compound and produce no non-separable byproduct, and specifically, trialkylborates such as trisopropylborate and trimethyl borate, among which triisopropylborate is preferred. The obtained trialkylborate can be easily hydrolyzed in water or in aqueous ammonium chloride to produce a compound (25) of boronic acid reagent. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -80 ° C and 50 ° C and is preferably between -80 ° C and 30 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 1 to 10 hours, and is preferably between 2 and 6 hours. (Step for the production of a tin reagent) In this step, the lithium agent O reactant Grignard (27) produced in Step 5-2, is reacted with a halogenated trialkyltin reagent mentioned below, to produce a compound (25) of the tin reagent. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this stage, and specifically, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether and phosphoric amides such as hexamethylphosphoric triamide, among which ethers (particularly diethyl ether and tetrahydrofuran) are preferred. There are no particular restrictions on the halogenated trialkyltin reagent used so long as it can produce the objective compound and produce no non-separable by-product, and specifically, halogenated trialkyltin compounds such as tributyltin chloride and trimethyltin chloride, among which tributyltin is preferred. chloride. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -80 ° C and 50 ° C and is preferably between -80 ° C and 30 ° C. The reaction time will differ depending on the starting materials, the solvent, the reagents and the reaction temperature, but will commonly be from 1 to 10 hours, and is preferably between 1 and 6 hours. (Production method for compound (9B)) (Method 6) [Chemical Formula 47] (46) (47) (9B) (48) In this step, the compound (46) is reacted with the compound (14) in an inert solvent in the presence of a palladium (0) catalyst, to produce the compound (47) (Step 6-1), and then the compound (47) is reacted with a de-alkylating agent or de-aralkylating agent to produce the compound (48) (Step 6-2), and a trifluoromethanesulfonyl group is introduced into the phenolic hydroxyl group of the compound (48) to produce the compound (9B) (Step 6-3). In this scheme Tf, Mlb, Hal, R10a, R10b, R20a, R21a, R22a and R23a have the same definitions as above. Also R100 represents Cl-6 alkyl or optionally substituted aralkyl, and is preferably methyl or benzyl. Step 6-1 of this method can be carried out in a manner similar to Method K above. (Step 6-2) There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, alcohols such as methanol and isopropanol, ethers such as diethyl, may be mentioned. ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, organic acids such as carbon disulfide, acetic acid and hydrogen bromide in acetic acid solution, organic bases such as quinoline and pyridine, and water. These may be selected as appropriate for the de-alkylating agent or the de-aralkylating agent used. There are no particular restrictions on the de-alkylating agent or the de-aralkylating agent used as long as it can produce the objective compound and does not produce any non-separable by-product, and specifically, Lewis acids such as boron tribromide, boron trichloride, boron triiodide, and aluminum chloride, Bronsted acids such as hydrobromic acid, acid can be mentioned hydrochloric and hydrogen bromide in acetic acid solution, metal salts such as lithium iodide, and halogenated silanes such as trimethylsilane iodide. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -80 ° C and 250 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 0.1 to 100 hours. When R100 is an optionally substituted aralkyl group, the de-aralkylation step can be carried out according to the hydrogenation method described for Method A above. The conditions can be selected as appropriate for the starting materials, in order to allow selective deprotection. As supplementary literature that can be used as a reference to carry out this method, you can mention: M. Vivekananda Bhatt, Surendra U. Kulkarni et al., "Cleavage of Ethers" Synthesis (1983), 249; T.W. Greene, (Protective Groups in Organic Synthesis), John Wiley & Sons; and J.F.W., McOmis, (Protective Groups in Organic Chemistry), Plenum Press. Step 6-3 can be carried out in a manner similar to Method A or Method B above. (Production method for compound (25A)) (Method 7) [Chemical Formula 48] In this method, the compound (9C) is reacted with a boron metal reagent or a tin metal reagent in an inert solvent in the presence of a palladium (0) catalyst to produce the compound (25A). In this scheme, Mlb, Hal, R10a, R20a, R21a, R22a and R23a have the same definitions as above. This method can be carried out in a manner similar to Step 4-2 of Method 4.

(Production method for compound (13A)) (Method 8) [Chemical Formula 49] (13A) In this method, the compound (49) is reacted with the compound (8) (amination or amidation) in an inert solvent in the presence of a palladium (0) catalyst or a copper catalyst, in the presence or absence of a base, in the presence or absence of an additive, under or not under an inert gas atmosphere, to produce the compound (50) (Step 8-1) and subsequently the compound (50) is reacted with an agent of alkylation or a de-aralkylating agent to produce the compound (51) (Step 8-2), and a trifluoromethanesulfonyl group is introduced into the phenolic hydroxyl of the compound (51) to produce the compound (13A) (Step 8-3) . In this scheme, Tf, n, R20a, R21a, R22a, R23a R30, R31a, R32a, R0a and R100 have the same definitions as above. MWla also has the same definition as Mla or Wla above. Step 8-1 of this method can be carried out in a manner similar to Method F or Method G described above, Step 8-2 can be carried out in a manner similar to Step 6-2 described above, and Step 8-3 can be carried out in a manner similar to Method A or Method B described above. (Production method for compounds (15) and (13B)) (Method 9) [Chemical Formula 50] (13B) 9-2 (15) In this method, the compound (77) is made reacting with the compound (8) in an inert solvent in the presence of a palladium (0) catalyst or a copper catalyst, in the presence or in the absence of a base, in the presence or absence of an additive, under or not under a inert gas atmosphere, to produce the compound (13B) (Step 9-1) and subsequently the compound (13B) is reacted with a metal reagent to produce the compound (15) (Step 9-2). In this scheme, n, M1, R20a, R21a, R2a, R23a R30a, R31a, R32a, and R40a have the same definitions as above. Hal4 is chlorine or bromine, and Hal3 is iodine when Hal4 is bromine, and bromine or iodine when Hal4 is chlorine. Step 9-1 of this method can be carried out in a manner similar to Method F above, and Step 9-2 can be carried out in a manner similar to Step 5-3 or Method 7 above. (Production method for compounds (16A), (14) and (16B)) (Method 10) [Chemical Formula 51] (53) (16A) R 110UbD _-, OTf R10 -Hal (16B) (14) R10b-M1b In this method, an exit group is introduced into the compound (53), in an inert solvent, under or not under an inert gas atmosphere, to produce the compound (16A) (Step 10-1), and subsequently the compound ( 16A) is reacted with a boron metal reagent or a tin metal reagent in the presence of a palladium (0) catalyst to produce the compound (14) (Step 10-2) and the compound (14) is reacted with a halogenation reagent to produce the compound (16B) (Step 10-3).

- Alternatively, the compound (53) is reacted directly with a halogenating agent to produce the compound (16B) (Step 10.4). In this scheme, Tf ,, R10b, Mlb and Hal have the same definitions above. Also, R200 is a substituent in the Al Group, or a substituent in the Al Group that is protected. U is an integer of 0, 1, 2, 3, 4 or 5. K is an integer of 0, 1, 2, 3, 4 or 5. Stage 10-1 of this method can be carried out in a similar way to Method 4-1 above, Step 10-2 can be carried out in a manner similar to Step 4-2 above, and Step 10-3 can be carried out in a manner similar to Step 4-3 above. Step 10-4 can be carried out in a manner similar to the above Step 4-4, (Production method for compound (12)) (Method 11) [Chemical Formula 52] (12) In this step, the compound (54) is reactivated with a nitrating agent to produce the compound (55) (Step 11-1), and subsequently a metal or metal salt is used in the presence of an acid for the reduction of compound (55) to produce compound (12) (Step 11-2). In this scheme, R10a, R20, R21a, R22a and R23a, have the same definitions as above. (Stage 11-1) There are no particular restrictions on the solvent used as long as it dissolves the compound of start to a certain degree and do not inhibit the reaction of this step, and specifically, may be mentioned, a mixture of sulfuric acid and nitric acid or a mixture of acetic acid and nitric acid, where the nitric acid solvent reacts as a nitrating agent . The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between -20 ° C and 150 ° C and is preferably between 0 ° C and 80 ° C. The reaction time will differ depending on the starting materials, the solvent, the reactants and the reaction temperature, but will usually be from 0.5 to 48 hours, and is preferably between 1 and 12 hours. There are no particular restrictions on the solvent used as long as it dissolves the starting compound to a certain degree and does not inhibit the reaction of this step, and specifically, alcohols such as methanol and ethanol, amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide can be mentioned. , organic acids such as acetic acid, water, and mixtures of these solvents, among which is preferred a mixed solvent of ethanol and water, a mixed solvent of ethanol dimethylformamide and water or acetic acid. There are no particular restrictions on metal or metal salt used as long as it can produce the objective compound and which does not produce any non-separable by-product, and specifically metals such as iron powder, tin powder and zinc powder, and metal salts such as tin chloride ( II), among which a metal (particularly iron powder) is preferred. There are no particular restrictions on the acid used as long as it can produce the objective compound and that it does not produce any non-separable by-product, and specifically organic acids such as acetic acid, and inorganic acids such as hydrochloric acid and ammonium chloride, can be mentioned among the which is preferred ammonium chloride. The equivalents of the metal or metal salt used will differ depending on the starting materials, the solvents and the reactants, but will commonly be a ratio of 2-15 and preferably 3-6, in terms of the molar ratio with respect to the material of start. The reaction temperature will differ depending on the starting materials, the solvent and the reagents, but will commonly be between 0 ° C and 150 ° C and is preferably between 0 ° C and 100 ° C. The reaction time will differ depending on the starting materials, the solvent, the reagents and the reaction temperature, but will commonly be from 0.5 to 48 hours, and is preferably between 1 and 12 hours. The compound (55) or (12) can be isolated or purified from the reaction mixture obtained above, by the method described above. (Production method for compound (55A)) (Method 12) [Chemical Formula 53] (56) (55A) (57) In this method the compound (56) is reacted with the above compound (16) to produce the compound (55A) (Method 12-1), or the compound (57) is reacted with the above compound (14) to produce the compound (55A) (Method 12-2) in an inert solvent, in the presence of a catalyst of palladium (0), low or no under an atmosphere of inert gas, in the presence or absence of a base in the presence or absence of an additive. In this scheme, Wla, M1, Mlb, R10b, R20, R21a, R22a and R3a, have the same definitions as above. Method 12-1 of this method can be carried out in a manner similar to Method K above, and Method 12-2 can be carried out in a manner similar to Method K described above. The starting compounds or intermediates for each of the steps in the general production methods described above to obtain the compound (1) or (100) can be purchased as commercial products or can be obtained as starting compounds or intermediates having several substituents introduced in the positions R20 to R23 of commercially available compounds by well known methods (conversion of substituent, introduction of substituent, introduction of the protection group, deprotection, etc.) which are ordinarily carried out by those skilled in the art. By using such starting compounds or intermediates with various substituents introduced into the positions R20 to R23 for the general production methods described above, it is possible to produce the compound (1) or (100) having several substituents R20 to R23 introduced therein. When the compound of the present invention is to be used as a medicament, it will normally be mixed with additives suitable for use as a formulation. However, it does not exclude the use of the compound of the invention by itself as a medicament. Such additives may include excipients, binders, lubricants, disintegrators, coloring agents, flavor correctors, emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, buffering agents, antiseptics, antioxidants, stabilizers, absorption accelerators and the like. , which are commonly used in pharmaceuticals, and can be added in appropriate combinations as desired. As examples of such excipients may be mentioned lactose, soft white sugar, glucose, corn starch, mannitol, sorbitol, starch, alpha starch, dextrin, crystalline cellulose, mild silicic anhydride, aluminum silicate, calcium silicate, magnesium aluminometasilicate, hydrogen phosphate of calcium and the like. As examples of linkers can be mentioned polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium, polyvinylpyrrolidone, macrogol and the like. As examples of lubricants, there may be mentioned magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silica, and the like. As examples of disintegrants there may be mentioned crystalline cellulose, agar, gelatin, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, substituted lower hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl starch, sodium starch of carboxymethyl and the like. As coloring agents, those approved for addition to pharmaceuticals, such as sesquioxide, yellow iron sesquioxide, carmine, caramel, b-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake and the like can be mentioned. As flavor correctors, mention may be made of cocoa powder, menthol, aromatic powders, peppermint oil, borneol, cinnamon powder stalk, and the like. As emulsifiers or surfactants can mention may be made of stearyl triethanolamine, lauryl sodium sulfate, lauryl aminopropionic acid, lecithin, glycerin monostearate, sucrose fatty acid esters, fatty acid esters of glycerin and the like. As solution aids, polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, nicotinamide and the like can be mentioned. As suspending agents there may be mentioned the surfactants referred to above, as well as hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like. As isotonizing agents there may be mentioned glucose, sodium chloride, mannitol, sorbitol and the like. Buffering agents which may be mentioned are buffer solutions of phosphate, acetate, carbonate, citrate and the like. As antiseptics there may be mentioned methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. As antioxidants, sulfite, ascorbic acid, α-tocopherol, and the like may be mentioned. As stabilizers, those can be mentioned commonly used in pharmaceuticals. As absorption accelerators, those commonly used in pharmaceuticals can also be mentioned. The formulation can be found in oral form such as tablets, powders, granules, capsules, syrups, pills or inhalants, a form of external application such as suppositories, ointments, eye ointment, tape, eye drops, nose drops, ear drops, ointment or lotion or an injection. An oral formulation will be formulated using an appropriate combination of additives among those mentioned above. Its surface can also be coated if necessary. An external application will be formulated using an appropriate combination of additives among those mentioned above, and particularly excipients, binders, flavor correctors, emulsifiers, surfactants, dissolving aids, suspending agents, isotonizing agents, antiseptics, antioxidants, stabilizers, and accelerators. of absorption. An injection will be formulated using an appropriate combination of additives among those mentioned above, and particularly emulsifiers, surfactants, dissolution aids, suspending agents, isotonizing agents, buffering agents, antiseptics, antioxidants, stabilizers and absorption accelerators. When the compound of the invention is to be used as a drug, its dose will differ depending on the symptoms and age of the patient, but will commonly be from 0.15 to 5000 mg (preferably 0.5 to 1500 mg) in the case of an oral formulation, from 0.5 to 1500 mg (preferably from 1.5 to 500 mg) in the case of an external application, and from 0.3 to 5000 mg (preferably from 1 to 500 mg) in the case of one injection, per day, administered at one time or divided into 2 to 6 times. For an oral formulation or injection, this represents the dose actually administered, while for external application, this represents the dose actually absorbed. EXAMPLES Compounds (1) and (100) according to the invention can be produced, for example, by the process described in the following examples. It should be understood, however, that these examples serve merely as an illustration and are not intended to restrict the compounds of the invention under any circumstances. Also, unless otherwise specified, the silica gel mentioned throughout the examples is Silica Gel 60 by Merck & Co., or BW300 by Fuji Silysia Chemical Ltd., and the NH silica gel is silica gel Chromatorex-NH coated with propylamine by Fuji Silysia Chemical Ltd. Also in the TLC analysis, unless otherwise specified, the silica gel is Silica Gel 60 by Merck & Co., and the NH is NH silica gel coated with propylamine by Fuji Silysia Chemical Ltd. (Production Example IA) Trifluoromethanesulfonic acid 4, 4-dimethylcyclohex-lenyl ester [Chemical Formula 54] A mixture of lithium bis (trimethylsilyl) amide (IM of solution in tetrahydrofuran, 172 ml, 172 mol) and anhydrous tetrahydrofuran (400 ml) was stirred, and then cooled to below -70 ° C in a dry ice bath. acetone under a nitrogen atmosphere. A solution of 4,4-dimethylcyclohexanone (18 g, 143 mol) in anhydrous tetrahydrofuran (100 ml) was added dropwise to the solution over 30 minutes. After stirring for 2 hours and 10 minutes under the same conditions, N-phenyl bis (trifluoromethanesulfonamide) (54 g, 150 mol) was added to the reaction mixture, and the stirring was continued for 16 hours while heating slowly to room temperature. .

- - Aqueous saturated ammonium was added to the reaction mixture to quench the reaction. Hexane and water were added to the mixture and the organic layer and the aqueous layer were separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The aqueous layer was re-extracted with hexane and treated in the same manner as the organic layer. The two organic layers were combined, the desiccant was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 26.8 g of the title compound as a light yellow oil. XH-NMR (400 MHz, CDCl 3) d: 0.97 (s, 6H), 1.54 (t, J = 6.4 Hz, 2H), 1.96-1.98 (m, 2H), 2.31-2.36 (m, 2H), 5.66- 5.69 (m, ÍH). (Production Example IB) 1- (4,4-dimethylcyclohex-l-enyl) -2-nitrobenzene [Chemical Formula 55] To a solution of 2-nitrophenylboronic acid (14.2 g, 85.19 mol) in toluene (250 ml) ethanol (125 ml), trifluoromethanesulfonic acid 4, 4-dimethylcyclohex-l-enyl ester (20 g, 77.44 mol) prepared in Example (la), tetrakis (triphenylphosphine) palladium (0) (4.5 g, 3.87 mol) and 2N of aqueous sodium carbonate (128 ml, 256 mol). The mixture was stirred at an external temperature of 100 ° C for 1 hour and 45 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, it was passed through celite and the insoluble matter was filtered. Ethyl acetate and water were added to the resulting filtrate and the filtrate was extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 16.3 g of the title compound as a brown oil. XH-NMR (400 MHz, CDCl 3) d: 1.00 (s, 6H), 1.51 (t, J = 6.4 Hz, 2H), 1.92-1.94 (m, 2H), 2.24-2.29 (m, 2H), 5.55- 5.57 (m, HH), 7.27 (dd, J = 7.6, 1.6 Hz, ÍH), 7.34 (ddd, J = 7.6, 7.6, 1.6 Hz, HH), 7.50 (ddd, J = 7.6, 7.6, 1.6 Hz, ÍH), 7.77 (dd, J = 7.6, 1.6 Hz, ÍH). (Production Example IC) 2- (4,4-dimethylcyclohexyl) phenylamine [Chemical Formula 56] A mixture of 1- (4,4-dimethylcyclohex-l-enyl) -2-nitrobenzene (16.3 g, 70.5 mol), 10% palladium on carbon (1 g, wet) and ethyl acetate (100 ml) was stirred for 14 hours and 30 minutes under an atmosphere of hydrogen at atmospheric pressure and at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. A mixture of the resulting residue, 10% palladium on carbon (3 g, wet) and ethyl alcohol (200 ml) was stirred for 30 hours and 30 minutes under an atmosphere of hydrogen at atmospheric pressure and at room temperature. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 11.79 g of the title compound as a light yellow solid. ^? - NMR (400 MHz, CDC13) d: 0.97 (s, 3H), 0.99 (s, 3H), 1.36 (td, J = 13.2, 4.0 Hz, 2H), 1.47-1.73 (m, 6H), 2.38 (tt, J = 11.6, 3.6 Hz, ÍH), 3.63 (brs, 2H), 6.68 (dd, J = 7.6, 1.6 Hz, ÍH), 6.77 (ddd, J = 7.6, 7.6, 1.6 Hz, ÍH), 7.01 (ddd, J = 7.6, 7.6, 1.6 Hz, ÍH), 7.14 (dd, J = 7.6, 1.6 Hz, ÍH). (Production Example ID) 2- [2- (4,4-dimethylcyclohexyl) phenyl] piperazine - [Chemical Formula 57] To a solution of 2- (4,4-dimethylcyclohexyl) phenylamine (11-79 g, 57.98 mol) in 1,2-dichlorobenzene (30 ml) was added bis (2-chloroethyl) amine hydrochloride (12.42 g, 69.58 mol) , and the mixture was stirred at an external temperature of 200 ° C for 2 hours and 30 minutes under a nitrogen atmosphere. During the reaction, nitrogen was passed through the reactor several times to remove the hydrogen chloride gas. After air-drying the reaction mixture at room temperature, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added and the mixture was extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 12.15 g of the title compound as a brown oil. XH-NMR (400 MHz, CDC13) d: 0.97 (s, 3H), 1.01 (s, 3H), 1.34 (td, J = 12.48, 4.4 Hz, 2H), 1.48-1.68 (m, 6H), 2.82-2.84 (m, 4H), 2.95- 3.03 (m, 5H), 7.05-7.27 (m, 4H). The NH of NH could not be identified. (Production Example ÍE) 4- [2- (4,4-Dimethylcyclohexyl) phenyl] piperazine-1-carboxylic acid [4-methyl] 4- [4-dimethylcyclohexyl] phenyl] -carboxylic acid [Chemical Formula 58] A mixture of l- [2- (4,4-dimethylcyclohexyl) phenyl] piperazine (11 g, 40.4 mol), triethylamine (6.2 ml, 44.4 mol), 4-dimethylaminopyridine (247 mg, 2.02 mol) and dichloromethane (180 ml ) was stirred at an external temperature of 0 ° C under a nitrogen atmosphere. A mixture of di-t-butyl dicarbonate (9.7 g, 44.4 mol) and dichloromethane (20 ml) was added thereto. After stirring for 2 hours and 50 minutes under the same conditions, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with dichloromethane. The collected organic layer was washed with brine and then dried over sodium sulfate - - anhydrous. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 14.89 g of the title compound as a light yellow oil. XH-NMR (400 MHz, CDCl3) d: 0.96 (s, 3H), 1.01 (s, 3H), 1.31 (td, J = 12.8, 4.4 Hz, 2H), 1.49 (s, 9H), 1.49-1.69 ( m, 6H), 2.81 (brs, 4H), 2.95-3.02 (m, ÍH), 3.57 (brs, 4H), 7.06 (dd, J = 7.6, 1.6 Hz, ÍH), 7.10 (ddd, J = 7.6, 7.6, 1.6 Hz, ÍH), 7.16 (ddd, J = 7.6, 7.6, 2.0 Hz, ÍH), 7.28 (dd, J = 7.6, 2.0 Hz, ÍH). (Production Example 1F) 4- [4-Bromo-2- (4,4-dimethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 59] A mixture of 4- [2- (4,4-dimethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (8 g, 21.5 mol), sodium acetate (17.6 g, 215 mol) and methanol (300 g) ml) was stirred at an external temperature of room temperature under a nitrogen atmosphere. Bromine (1.1 ml, 21.5 mol) was added dropwise thereto for 20 minutes, and the mixture was stirred for 17 hours under the same conditions. Sodium acetate (8.8 g, 107.5 mol) was added thereto and then bromine (0.4 ml, 7.8 mol) was added dropwise and the mixture was stirred for 1 hour under the same conditions. A saturated aqueous solution of sodium sulfite was added to the reaction mixture and the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 7.97 g of the title compound as a light yellow solid. ^ -NMR (400 MHz, CDCl3) d: 0.96 (s, 3H), 1.01 (s, 3H), 1.24-1.34 (m, 2H), 1.41-1.64 (m, 6H), 1.49 (s, 9H), 2.77 (brs, 4H), 2.89-2.97 (m, ÍH), 3.55 (brs, 4H), 6.92 (d, J = 8.4 Hz, ÍH), 7.25 (dd, J = 8.4, 2.4 Hz, ÍH), 7.35 (d, J = 2.4 Hz, ÍH). (Production Example 2A) Trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enyl ester [Chemical Formula 60] A solution of 3, 3, 5, 5-tetramethylcyclohexanone (12-8 g, 82.98 mol) in anhydrous tetrahydrofuran (300 ml) was cooled to below -70 ° C in a dry ice-acetone bath under a nitrogen atmosphere . Lithium bis (trimethylsilyl) amide was gradually added dropwise to the stirred solution.

(IM of solution in tetrahydrofuran, 100 ml, 100 mol) for 15 minutes. After stirring for 40 minutes under the same conditions, a solution of N-phenyl bis (trifluoromethanesulfonimide) (32.51 g, 91 mol) in anhydrous tetrahydrofuran (150 ml) was added to the reaction mixture and stirring continued for 13 hours and 30 minutes with slow heating at room temperature. Ethyl acetate and brine were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 23.65 g of the title compound as a colorless oil. ^ -NMR (400 MHz, CDCl3) d: 1.04 (s, 6H), 1.09 (s, 6H), 1.35 (s, 2H), 2.08 (s, 2H), 5. 51 (s, ÍH). (Production Example 2B) 4,4,5, 5-tetramethyl-2- (3,3,5,5-tetramethylcyclohex-1-enyl) - [1,3,2] dioxaborolane [Chemical Formula 61] To a solution of trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-l-enyl ester (45.94 g, 0.16 mol) in dioxane (500 ml) was added bis (pinacolato) diboro (44.9 g, 0.177 mol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane (4 g, 4.9 mol) and potassium acetate (47.3 g, 0.482 mol), and the mixture was stirred at an external temperature of 80 ° C for 16 hours. hours and 30 minutes. Ethyl acetate, water and brine were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 39.7 g of the title compound as a light yellow solid. XH-NMR (400 MHz, CDC13) d: 0.94 (s, 6H), 1.01 (s, 6H), 1.27 (s, 12H), 1.31 (s, 2H), 1.84 (d, J = 1.6 Hz, 2H), 6.26 (t, J = 1.6 Hz , ÍH). (Production Example 2C) 4- (2-Hydroxyphenyl) piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 62] A suspension of 2- (1-piperazino) phenol (3.56 g, 20 mol) in acetonitrile (15 ml) was stirred at room temperature. A solution of di-t-butyl dicarbonate (4.8 g) was added thereto., 22 mol) in acetonitrile (15 ml). After stirring for 1 hour, the insoluble material was filtered and the filtrate was concentrated. Hexane was added to the residue prior to sonication. The resulting solid was filtered and dried under reduced pressure to give a crude product of the title compound (5.35 g) as a light brown solid. XH-NMR (400 MHz, CDCl 3) d: 1.49 (s, 9H), 2.82 (t, J = 4.8 Hz, 4H), 3.59 (t, J = 4.8 Hz, 4H), 6.87 (td, J = 7.6, 1.2 Hz, HH), 6.96 (dd, J = 8.0, 1.2 Hz, HH), 7.07-7.14 (m, 2H).

The OH of OH could not be identified. (Production Example 2D) 4- (2-Trifluoromethanesulfonyloxyphenyl) piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 63] A mixture of 4- (2-hydroxyphenyl) piperazine-l-carboxylic acid t-butyl ester (4.61 g, 16.56 mol), triethylamine (11.5 ml, 82.5 mol) and dichloromethane (100 ml) was cooled in an ice bath under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (4 ml, 23.78 mol) was added dropwise over 40 minutes with stirring of the mixture. After stirring for 17 minutes under the same conditions, saturated aqueous ammonium chloride, ethyl acetate and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The collected organic layer was washed twice with saturated aqueous ammonium chloride, washed once with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under pressure - - reduced. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 5.54 g of the title compound as a light yellow solid. XH-NMR (400 MHz, CDCl3) d: 1.48 (s, 9H), 2.95 (t, J = 4.8 Hz, 4H), 3.62 (t, J = 4.8 Hz, 4H), 7.10-7.16 (m, 2H) , 7.18 (dd, J = 8.0, 1.6 Hz, ÍH), 7.33 (ddd, J = 7.2, 7.2, 1.6 Hz, ÍH). (Production Example 2E) 4- [2- (3,3,5,5-Tetramethylcyclohex-1-enyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester [Chemical Formula 64] A mixture of 4- (2-trifluoromethanesulfonyloxyphenyl) piperazine-1-carboxylic acid t-butyl ester (6.16 g, 15 mol), 4, 4, 5, 5-tetramethyl-2 - (3, 3, 5, 5- tetramethylcyclohex-1-enyl) - [1, 3, 3] dioxaborlane (4.6 g, 17.41 mol), tripotassium phosphate (3.2 g, 15 mol), 1,2-dimethoxyethane (60 ml) and water (3 ml) was stirred at room temperature under a nitrogen atmosphere. Tetrakis (triphenylphosphine) palladium (0) (1.74 g, 1.5 mol) was added to the mixture. The mixture was then stirred at an external temperature of 85 ° C for 2 hours and 20 minutes. Ethyl acetate and water were added to the reaction mixture and then this was passed through celite and filtered. The organic extract of the filtrate was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 5.78 g of the title compound as a light yellow oil. XH-NMR (400 MHz, CDCl 3) d: 1.02 (s, 6H), 1.07 (s, 6H), 1.40 (s, 2H), 1.48 (s, 9H), 2.16 (d, J = 1.6 Hz, 2H) , 2.91 (t, J = 5.2 Hz, 4H), 3.51 (t, J = 5.2 Hz, 4H), 5.50 (t, J = 1.6 Hz, ÍH), 6.97 (dd, J = 8.0, 1.2 Hz, ÍH) , 7.01 (ddd, J = 8.0, 8.0, 1.2 Hz, ÍH), 7.09 (dd, J = 8.0, 1.6 Hz, ÍH), 7.20 (ddd, J = 8.0, 8.0, 1.6 Hz, ÍH). (Production Example 3A) 4, 4 -diethylcyclohexanone [Chemical Formula 65] A mixture of 4,4-diethyl-2-cyclohexanone (1 g, 6.57 mol) (Reference: Michael E. Flaugh, Thomas A. Crowell, and Diane S. Farlow, J. Org. Chem., 1980, 45, 5399), 10% palladium on carbon (60 mg, wet) and ethyl acetate (15 ml) are stirred for 26 hours under an atmosphere of hydrogen at atmospheric pressure and at room temperature. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure to give a crude product of the title compound (720 mg) as a brown oil. ^ -NMR (400 MHz, CDCl3) d: 0.85 (t, J = 7.6 Hz, 6H), 1.43 (q, J = 7.6 Hz, 4H), 1.65 (dd, J = 7.2, 7.2 Hz, 4H), 2.31 (dd, J = 7.2, 7.2 Hz, 4H). (Production Example 3B) Trifluoromethanesulfonic acid 4,4-diethylcyclohex-1-enyl ester [Chemical Formula 66] of 4,4-diethylcyclohexanone (720 mg, 4.67 mol) in anhydrous tetrahydrofuran (20 ml) was cooled to below -70 ° C in a dry ice-acetone bath under a nitrogen atmosphere, and then stirred. Lithium bis (trimethylsilyl) amide (IV of solution in tetrahydrofuran, 5.6 ml, 5.6 mol) was added gradually to this solution. After stirring for 60 minutes under the same conditions, N-phenyl bis (trifluoromethanesulfonamide) (1.75 g, 4.9 mol) was added to the reaction mixture and stirring continued for 27 hours with slow heating room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture. Ethyl acetate and brine were then added to the reaction mixture and the organic layer was separated. After washing the organic layer with dilute hydrochloric acid and aqueous saturated sodium hydrogenate in that order, it was dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 710 mg of the title compound as a yellow oil. XH-NMR (400 MHz, CDCl 3) d: 0.80 (t, J = 7.6 Hz, 6H), 1.21-1.40 (m, 4H), 1.55 (t, J = 6.6 Hz, 2H), 1.95 (dt, J = 4.0, 2.8 Hz, 2H), 2.25-2.30 (m, 2H), 5.63-5.66 (m, ÍH). (Production Example 3C) 2- (4,4-diethylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane [Chemical Formula 67] KaXuna trifluoromethanesulfonic acid solution 4,4-diethylcyclohex-l-enyl ester (5.11 g, 17.8 mol) in dioxane (60 ml) was added bis (pinacolato) diboro (5.2 g, 20.5 mol), complex of [1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane (580 mg, 0.71 mol) and potassium acetate (5.3 g, 53.5 mol) and the mixture was stirred at an external temperature of 90 ° C During 4 hours. The reaction mixture was cooled in air to room temperature, and the insoluble material was filtered. Ethyl acetate and water were added to the resulting filtrate and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4.16 g of the title compound as white crystals. XH-NMR (400 MHz, CDCl 3) d: 0.76 (t, J = 7.6 Hz, 6H), 1.13-1.37 (m, 18H), 1.84-1.86 (m, 2H), 2.05-2.10 (m, 2H), 6.48-6.50 (m, ÍH). (Production Example 3D) 1- (4, 4-diethylcyclohex-l-enyl) -4-methoxy-2-nitrobenzene [Chemical Formula 68] - A mixture of 4-bromo-3-nitroanisole (2 g, 8.62 mol), 2- (4,4-diethylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1, 3, 2] dioxaborlane (2.7 g, 10.3 mol), tripotassium phosphate (2.7 g, 13.0 mol) and 1,2-dimethoxyethane (20 ml) was stirred at room temperature under a nitrogen atmosphere, and then tetrakis (triphenylphosphine) palladium (0) (0.5 g, 0.43 mol) was added. The mixture was then stirred at an external temperature of 80 ° C for 26 hours. After cooling the reaction mixture, brine was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2.4 g of the title compound as a light yellow oil. ^ -NMR (400 MHz, CDC13) d: 0.82 (t, J = 7.2 Hz, 6H), 1.22-1.54 (m, 6H), 1.87-1.94 (m, 2H), 2.14-2.20 (m, 2H), 3.84 (s, 3H), 5.48-5.54 (m, HH), 7.04 (dd, J = 8.4, 2.8 Hz, HH), 7.16 (d, J = 8.4 Hz, HH), 7.29 (d, J = 2.8 Hz , ÍH). (Production Example 3E) 2- (4,4-diethylcyclohex-l-enyl) -5-methoxyphenylamine [Chemical Formula 69] To a solution of 1- (4,4-diethylcyclohex-l-enyl) -4-methoxy-2-nitrobenzene (2.4 g, 8.3 mol) in ethanol (20 ml) was added aqueous solution (5 ml) of ammonium chloride (2.2 g, 41 mol) and iron powder (1.2 g, 20.7 mol), and the mixture was stirred at an external temperature of 90 ° C for 1 hour. The reaction mixture was passed through celite for filtration, and then brine was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered and the filtrate was concentrated under reduced pressure to give 2.6 g of the title compound as a yellow oil. ^ -NR (400 MHz, CDC13) d: 0.82 (t, J = 7.2 Hz, 6H), 1.21-1.56 (m, 6H), 1.92-1.96 (m, 2H), 2.16-2.22 (m, 2H), 3.75 (s, 3H), 5.61-5.65 (m, ÍH), 6.24 (d, J = 2.8 Hz, ÍH), 6.29 (d, J = 8.4, 2.8 Hz, ÍH), 6.87 (d, J = 8.4 Hz , ÍH). The 2H of NH2 could not be identified. (Production Example 3F) 1- [2- (4, 4-diethylcyclohex-l-enyl) -5-methoxyphenyl] piperazine [Chemical Formula 70] A solution of 2- (4,4-diethylcyclohex-l-enyl) -5-methoxyphenylamine (2.6 g, 10 mol) and bis (2-chloroethyl) amine hydrochloride (2.2 g, 12 mol) in 1,2-dichlorobenzene (10 ml) was stirred at an external temperature of 210 ° C. Nitrogen gas was blown into the reactor several times during the reaction to remove excess hydrogen chloride gas in the reactor. After one hour, the reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 1.4 g of the title compound as a yellow oil. XH-NMR (400 MHz, CDC13) d: 0.82 (t, J = 7.2 Hz, 6H), 1.22-1.52 (m, 6H), 1.90-1.96 (m, 2H), 2.38-2.46 (m, 2H), 2.78-3.04 (m, 8H), 3.79 (s, 3H), 5.61-5.66 (m, ÍH), 6.50 (dd, J = 8.4, 2.8 Hz, ÍH), 6.52 (d, J = 2. 8 Hz, ÍH), 6.99 (d, J = 8.4 Hz, ÍH). The NH of NH could not be identified. MS m / e (ESI) 329 (MH +). (Production Example 4A) 4-methoxypiperidine hydrochloride [Chemical Formula 71] 4-Hydroxypiperidine-1-carboxylic acid t-butyl ester (25.5 g, 127 mol) was added to a mixed solution of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (40 ml). The solution was cooled to 0 ° C in an ice bath with stirring. Sodium hydride was added (60% dispersion in oil, 7.6 g, 190 mol) for 3 minutes. The reaction mixture was warmed to room temperature, stirred for 70 minutes and cooled again to 0 ° C. a solution of methyl iodide (9.5 ml, 152 mol) in anhydrous tetrahydrofuran (20 ml) dimethylformamide (5 ml) was gradually added to the reaction mixture for 20 minutes. The ice bath was removed, and the reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction, water and diethyl ether were added to the reaction mixture and the organic layer was separated.

The organic layer was washed three times with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 ml) was added to the residue, and the mixture was cooled to 0 ° C and stirred. A 4N solution of hydrogen chloride in ethyl acetate (100 ml) was then added gradually over 10 minutes and then the temperature rose slowly to room temperature. After stirring for 13 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane. An excess of ethyl acetate was then added and the precipitated solid was filtered and dried under reduced pressure to give 17.0 g of the title compound as colorless crystals. XH-NMR (400 MHz, CDCl 3) d: 1.95-2.02 (m, 2H), 2.05-2.15 (m, 2H), 3.14-3.30 (m, 4H), 3.32 (s, 3H), 3.52-3.57 (m , ÍH). The NH of the NH could not be identified. (Production Example 4B) 5- (4-methoxy-piperidin-1-yl) -2-nitrophenol [Chemical Formula 72] A mixture of 4-methoxypiperidine hydrochloride (9.10 g, 60.01 mol), 5-fluoro-2-nitrophenol (6.91 g, 43.98 mol) and dimethylformamide (12 ml) was stirred under a nitrogen atmosphere. Triethylamine (15.24 ml, 109.95 mol) was added to the reaction mixture and the mixture was stirred at an external temperature of 80 ° C for 3 hours and 30 minutes. After the reaction, saturated aqueous ammonium chloride and a mixed ethyl acetate-diethyl ether solvent were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers obtained were combined and dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 37.36 g of the title compound as orange crystals. ^ -NMR (400 MHz, CDC13) d: 1.60-1.68 (m, 2H), 1.83-1.90 (m, 2H), 3.26 (ddd, J = 13.2, 8.0, 3.6 Hz, 2H), 3.32 (s, 3H ), 3.42-3.47 (m, ÍH), 3.62 (ddd, - J = 13.2, 7.6, 3.6 Hz, 2H), 6.24 (d, J = 2.8 Hz, ÍH), 6.36 (dd, J = 10.0, 2.8 Hz, ÍH), 7.87 (d, J = 10.0 Hz, ÍH). The OH of OH could not be identified. (Production Example 4C) Trifluoromethanesulfonic acid 5- (4-methoxy-piperidin-1-yl) -2-nitrophenyl ester [Chemical Formula 73] a mixture of 5- (4-methoxy-piperidin-1-yl) -2-nitrophenol (2.35 g, 8.16 mol), triethylamine (5.7 ml, 40.9 mol) and dichloromethane (50 ml) was stirred while cooling in a water bath The mixture was then cooled and then trifluoromethanesulfonic anhydride (2 ml, 12.24 mol) was gradually added dropwise over 15 minutes, and the mixture was stirred for 10 minutes under the same conditions. Aqueous saturated ammonium chloride was added to the reaction mixture, and then ethyl acetate and water were added and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography of silica gel (ethyl acetate / hexane) to give 3.276 g of the title compound as an orange solid. XH-NMR (400 MHz, CDC13) d: 1.66-1.74 (m, 2H), 1.84-1.92 (m, 2H), 3.27 (ddd, J = 13.2, 7.6, 3.6 Hz, 2H), 3.23 (s, 3H ), 3.47 (m, ÍH), 3.58 (ddd, J = 12, 8.0, 3.6 Hz, 2H), 6.54 (d, J = 2.8 Hz, ÍH), 6.72 (dd, J = 9.6, 2.8 Hz, ÍH) , 8.07 (d, J = 9.6 Hz, ÍH). (Production Example 4D) Trifluoromethanesulfonic acid 4-t-butylcyclohex-l-enyl ester [Chemical Formula 74] A solution of diisopropylamine (22 ml, 0.157 mol) in anhydrous tetrahydrofuran (500 ml) was cooled to below -70 ° C in a dry ice-acetone bath under a nitrogen atmosphere. Drip n-butyllithium was added slowly (1.56 M solution in hexane, 100 mL, 0.156 mol) to the stirred solution for 15 minutes. The reaction mixture was then heated to -10 ° C and then cooled to below -70 ° C again. After stirring for 10 minutes, a solution of 4-t-butylcyclohexanone (20.05 g, 0.13 mol) in anhydrous tetrahydrofuran (100 ml) was gradually added dropwise to the reaction mixture for 15 minutes. - minutes After stirring for 30 minutes, a solution of N-phenyl bis (trifluoromethanesulfonimide) (51.09 g, 0.143 mol) in anhydrous tetrahydrofuran (200 ml) was gradually added dropwise to the reaction mixture for 15 minutes and the mixture was stirred for 30 minutes. The dry ice bath was then exchanged with an ice bath, and stirring was continued for 30 minutes and then for another 30 minutes at room temperature. Ethyl acetate and brine were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 33.1 g of the title compound as a light yellow oil in racemic form at the t-butyl position. ^ -NMR (400 MHz, CDC13) d: 0.90 (s, 9H), 1.24-1.44 (m, 2H), 1.90-2.00 (m, 2H), 2.16-2.25 (m, ÍH), 2.32-2.46 (m , 2H), 5.72-5.76 (m, ÍH). (Production Example 4E) 2- (4-t-butylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane [Chemical Formula 75] To the trifluoromethanesulfonic acid 4-t-butylcyclohex-1-enyl ester (55.0 g, 192.1 mol) was added bis (pinacolato) diboro (56.1 g, 220.9 mol), complex of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane (4.88 g, 5.98 mol), potassium acetate (56.6 g, 576.3 mol), and dioxane (400 ml) and the mixture was stirred at an external temperature of 80 ° C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature air, ethyl acetate and water were added to the reaction mixture and the organic layer was separated. The obtained organic layer was washed again with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 38.97 g of the title compound as a pale yellow solid in racemic form at the t-butyl position. XH-NMR (400 MHz, CDC13) d: 0.85 (s, 9H), 1.00-1.43 (m, 14H), 1.78-1.90 (m, 2H), 1.98-2.17 (m, 2H), 2.24-2.32 (m, ÍH), 6.59 ( dd, J = 2.0 Hz, ÍH). (Production Example 5) 4- [2- (3,3,5,5-Tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 76] A mixture of 4- [2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (3.87 g, 9.71 mol), 10% palladium on carbon (2.3 g, wet), methanol (25 ml) and tetrahydrofuran (25 ml) was stirred for 22 hours and 30 minutes under an atmosphere of hydrogen at atmospheric pressure and at room temperature. After filtering the reaction mixture, the filtrate was concentrated. Ethyl acetate was added to the residue, the mixture was filtered again and the filtrate was concentrated under reduced pressure to give a crude product of the title compound (3.83 g) as a light yellow oil. ^ -NMR (400 MHz, CDCl3) d: 0.92 (S, 6H), 1.12 (s, 6H), 1.12-1.47 (m, 6H), 1.49 (s, 9H), 2.83 (brs, 4H), 3.59 ( tt, J = 12.4, 2.8 Hz, ÍH), 7.07 (td, J = 7.6, 1.2 Hz, ÍH), 7.10 (dd, J = 7.6, 1.2 Hz, ÍH), 7.16 (td, J = 7.6, 2.0 Hz , ÍH), 7.24 (dd, J = 7.6, 2.0 Hz, ÍH). The 4H of the piperazine ring could not be identified. MS m / e (ESI) 401 (MH +). (Production Example 6A) 4-methoxy-2-nitro-l- (3,3,5,5-tetramethylcyclohex-l-enyl) benzene [Chemical Formula 77] 4, 4, 5, 5-tetramethyl-2- (3,3,5,5-tetramethylcyclohex-1-enyl) - [1, 3, 2] dioxaborlane (2.7 g, 10.3 mol) was used instead of 2- (4,4-diethylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1, 3, 2] dioxaborlane for the reaction in a similar manner to the 3D Production Example, and treated in a similar manner for give 2.5 g of the title compound as a yellow oil. (Production Example 6B) 5-methoxy-2- (3,3,5,5-tetramethylcyclohex-l-enyl) phenylamine [Chemical Formula 78] 4-Methoxy-2-nitro-l- (3, 3, 3, 5, 5-tetramethylcyclohex-1-enyl) benzene (2.5 g, 8.6 mol) was reacted and treated in a manner similar to Production Example 3E to give 2.2 g of the title compound as a yellow oil. (Production Example 6C) - 1- [5-methoxy -2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] piperazine [Chemical Formula 79] 5-Methoxy-2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenylamine (2.2 g, 8.6 mol) was reacted and treated in a manner similar to Production Example 3F to give 2.0 g of the title compound. title as a yellow solid. (Production Example 7A) 4- [2- (4,4-Diethylcyclohex-l-enyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 80] 4- (2-Trifluoromethanesulfonyloxyphenyl) piperazine-1-carboxylic acid t-butyl ester (4.71 g, 11.5 mol) was used as starting material. We used 2 (4,4-diethylcyclohex-l-enyl) -4,4,5,5-te ramethyl [1,3,2] dioxaborolane (3.7 g, 14.0 mol) instead of 4,4,5,5-tetramethyl-2- (3,3,5,5-tetramethylcyclohex-l-enyl) [1,3,2] dioxaborlane for the reaction of similarly to Production Example 2E and treated similarly, to give 3.94 g of the title compound as a brown oil. (Production Example 7B) 4- [2- (4,4-Diethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 81] 4- [2- (4,4-Diethylcyclohex-1-enyl) phenyl) piperazine-1-carboxylic acid t-butyl ester (3.96 g, 9.93 mol) was used as the starting material. Methanol was used as solvent in place of a mixed solvent of tetrahydrofuran-methanol for the reaction in a manner similar to Production Example 5 and treated in a similar manner. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3.79 g of the title compound as a yellow oil. (Production Example 7C) 4- [4-bromo-2- (4-4) 4- t-butyl ester diethylcyclohexyl) phenyl] piperazine-1-carboxylic acid [Chemical Formula 82] 4- [2- (4,4-Diethylcyclohex-1-enyl) phenyl) piperazine-1-carboxylic acid t-butyl ester (3.79 g, 9.46 mol) was used as starting material. This was reacted and treated in a manner similar to Production Example 1F to give 2.75 g of the title compound as a white solid. (Production Example 8A) 1- [4-bromo-2- (4,4-dimethylcyclohexyl) phenyl] piperazine [Chemical Formula 83] A mixture of 4- [4-bromo-2- (4,4-dimethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (1.5 g, 3. 32 mol), trifluoroacetic acid (3 ml, 38.7 mol) and dichloromethane (6 ml) was stirred for 2 hours and 30 minutes at room temperature. room temperature. Aqueous saturated sodium carbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to give 1.21 g of a crude product of the title compound as a brown oil. (Production Example 8B) 1- [4-Bromo-2- (4,4-dimethylcyclohexyl) phenyl] -4-butylpiperazine [Chemical Formula 84] To a mixture of the crude product of 1- [4-bromo-2- (4,4-dimethylcyclohexyl) phenyl] piperazine (1.21 g), butyraldehyde (0.35 ml, 3.98 mol), acetic acid (0.1 ml, 3.32 mol) and tetrahydrofuran (8 ml) was added sodium triacetoxyborohydride (1.1 g, 4.98 mol), followed by stirring for 2 hours and 10 minutes at room temperature. Saturated sodium hydrogencarbonate was added Aqueous to the reaction mixture and extraction was carried out with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 901 mg of the title compound as a yellow oil. XH-NMR (400 MHz, CDCl 3) d: 0.94 (t, J = 7.2 Hz, 3H), 0.97 (s, 3H), 1.01 (s, 3H), 1.24-1.60 (m, 12H), 2.38-2.44 ( m, 2H), 2.59 (brs, 4H), 2.82-2.97 (m, 5H), 6.97 (d, J = 8.8 Hz, ÍH), 7.24 (dd, J = 8.8, 2.4 Hz, ÍH), 7.33 (d , J = 2.4 Hz, ÍH). (Production Example 9A) 3-piperazin-1-yl-4- (3,3,5,5-tetramethylcyclohexyl) phenol [Chemical Formula 85] 1- [5-Met? Xi-2- (3, 3, 3, 5, 5-tetramethylcyclohex-1-enyl) phenyl] piperazine was used as starting material for N-butyloxycarbonylation and hydrogenation by conventional methods. A mixture of acid t-butyl ester 4- [5-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid (3.41 g, 7.92 mol) obtained by the reaction, acetic acid (18 ml, 314 mol) and acid Hydrobromic acid 48% (36 ml, 318 mol) was stirred for 8 hours and 20 minutes at an external temperature of 130 ° C. The reaction mixture was cooled in an ice water bath and stirred, and then added thereto by dripping 5N aqueous sodium hydroxide to adjust the pH of the mixture to 8-9. The produced solid was filtered to give 2.98 g of a crude product of the title compound as a light red solid. ^? - NMR (400 MHz, CDC13) d: 0.94 (s, 6H), 1.54 (s, 6H), 1.17-1.40 (m, 6H), 3.05 (t, J = 4.8 Hz, 4H), 3.42 (tt) , J = 12.8, 2.8 Hz, ÍH), 6.55-6.61 (m, 2H), 7.05 (d, J = 8.0 Hz, ÍH). The 4H of the piperazine ring and the 2H of NH or OH could not be identified. (Production Example 10A) 4-methoxy-1-nitro-2- (3,3,5,5-tetramethylethylhex-1-enyl) benzene [Chemical Formula 86] To a solution of 3-iodo-4-nitroanisole (4.21 g, 15.1 mol) in 1,2-dimethoxyethane (50 ml) was added 4,4,5,5-tetramethyl-2- (3,3,5, 5). -tetramethylcyclohex-l-enyl) [1, 3, 2] dioxaborlane (4.78 g, 18.1 mol), tripotassium phosphate (4.81 g, 22.7 mol) and water (3 ml). Then tetrakis (triphenylphosphine) palladium (0) (870 mg, 0.755 mol) was added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then stirred further for 13 hours at an external temperature of 70 ° C. To the reaction mixture was added tetrakis (triphenylphosphine) palladium (0) (870 mg, 0.755 mol) and water (3 ml), followed by stirring for 26 hours at an external temperature of 100 ° C. The reaction mixture was cooled and then ethyl acetate was added and the mixture was filtered through celite.The filtrate was concentrated to a residue, which was subjected to extraction with ethyl acetate, and the organic layer was washed with brine.The organic layer was dried over sulphate of anhydrous magnesium and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 1.5 g of the title compound as a yellow solid. XH-NMR (400 MHz, CDCl 3) d: 1.05 (s, 6H), 1.07 (s, 6H), 1.41 (s, 2H), 1.99 (d, J = 1.6 Hz, 2H), 3.88 (s, 3H) , 5.35 (m, ÍH), 6.68 (d, J = 2.4 Hz, ÍH), 6.81 (dd, J = 9.2, 2.4 Hz, ÍH), 7.91 (d, J = 9.2 Hz, ÍH). (Production Example 10B) 4-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenylamine [Chemical Formula 87] A mixture of 4-methoxy-1-nitro-2- (3, 3, 3, 5, 5-tetramethylcyclohex-1-enyl) benzene (1.0 g, 3.46 mol), 10% palladium on carbon (500 mg, wet), methanol (8 ml) and tetrahydrofuran (2 ml) was stirred overnight at room temperature and at atmospheric pressure under a hydrogen atmosphere. The mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated. A crude product of the title compound was obtained as a brown oil. The crude product was used without purification for the next reaction.

(Production Example 10C) 1- [4-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine [Chemical Formula 88] A mixture of the crude product of 4-methoxy-2- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenylamine, bis (2-chloroethyl) amine hydrochloride (770 mg, 4.33 mol) and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an external temperature of 220 ° C. During the reaction, the excess hydrogen chloride gas in the reactor was removed several times with nitrogen gas. Bis (2-chloroethyl) amine hydrochloride (180 mg, 1.01 mol) was also added and the mixture was stirred for 1 hour under the same conditions. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added and extraction was carried out with chloroform. The aqueous layer was extracted again with chloroform, and the organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 660 mg of the composed of the title as a brown solid. ^ -NMR (400 MHz, CDCl3) d: 0.92 (s, 6H), 1.12 (s, 6H), 1.15-1.34 (m, 4H), 1.42-1.45 (m, 2H), 2.78-2.81 (m, 4H ), 2.99-3.02 (m, 4H), 3.63 (tt, J = 13, 2.8 Hz, ÍH), 3.78 (s, 3H), 6.69 (dd, J = 8.8, 2.8 Hz, ÍH), 6.77 (d, J = 2.8 Hz, HH), 7.07 (d, J = 8.8 Hz, HH). (Example 1) 1- [2- (4,4-Diethylcyclohexyl) -4- (4-methoxymethylpiperidin-1-yl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 89] (la) 4-methoxymethylpiperidine hydrochloride [Chemical Formula 90] After adding a mixed solvent of anhydrous tetrahydrofuran (6.2 ml) and dimethylformamide (2.5 ml) to sodium hydride (60% dispersion in oil, 83.6 mg, 2.09 mol), the mixture was cooled to 0 ° C in a water bath. low ice a nitrogen atmosphere and stirred for 20 minutes. Then 4-hydroxymethylpiperidine-1-carboxylic acid t-butyl ester (300 mg, 1.39 mol) was added to the reaction mixture. The reaction mixture was warmed to room temperature, stirred for 65 minutes, and then cooled again to 0 ° C. Ethyl iodide (0.13 ml, 2.09 mol) was then added to the reaction mixture. Then, the reaction mixture was warmed to room temperature and stirred for 20 hours and 25 minutes. After the reaction, ice and diethyl ether were added to the reaction mixture, then sodium chloride, and extraction was carried out with diethyl ether. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure to give a crude product of 4-methoxymethylpiperidine-1-carboxylic acid t-butyl ester. Ethyl acetate (2 ml) was added to the crude product and the mixture was cooled to 0 ° C and stirred. Then, a 4N solution of hydrogen chloride in ethyl acetate (10.4 ml, 41.7 mol) was added gradually and the mixture was warmed to room temperature. After stirring the reaction mixture for 4 hours, it was concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane. An excess of ethyl acetate was added additionally, and the precipitated solid was filtered and dried under reduced pressure to give 206 mg of the title compound as colorless crystals. XH-NMR (400 MHz, CDCl 3) d: 1.61-1.76 (m, 2H), 1.80-2.02 (m, 3H), 2.79-2.97 (m, 2H), 3. 26 (d, J = 6.0 Hz, 2H), 3.33 (s, 3H), 3.42-3.60 (m, 2H). The NH of NH could not be identified. (Ib) 1- [4-bromo-2- (4,4-diethylcyclohexyl) phenyl] piperazine [Chemical Formula 91] 4- [4-Bromo-2- (4,4-diethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (221 mg, 0.461 mol) produced in Production Example 7C was dissolved in a mixed solvent of dichloromethane (3 ml) water (0.3 ml). To the reaction mixture was added dropwise a 4N solution of hydrogen chloride in ethyl acetate (0.710 ml, 9.22 mol), followed by stirring for 5 hours and 30 minutes under the same conditions. After the reaction, aqueous potassium carbonate was added to the reaction mixture to produce the basic reaction mixture. The reaction mixture was extracted three times with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 153 mg of the title compound as a yellow oil. -NMR (400 MHz, CDC13) d: 0.79 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 7.6 Hz, 3H), 1.14-1.28 (m, 4H), 1.45-1.65 (m, 8H) ), 2.78-2.80 (m, 4H), 2.83-3.03 (m, 5H), 6.96 (d, J = 8.4 Hz, ÍH), 7.25 (dd, J = 8.4, 2.4 Hz, ÍH), 7.33 (d, J = 2.4 Hz, ÍH). The NH of NH could not be identified. (lc) 1- [4-bromo-2- (4,4-diethylcyclohexyl) phenyl] -4-propylpiperazine [Chemical Formula 92] To a solution of 1- [4-bromo-2- (4,4-diethylcyclohexyl) phenyl] piperazine (153 mg, 0.403 mol) in tetrahydrofuran (5 ml) was added propionaldehyde (0.038 ml, 0.524 mol), sodium triacetoxyborohydride. (111 mg, 0.524 mol) and acetic acid (0.0438 ml, 0.766 mol), followed by stirring at room temperature for 13 hours. After the reaction, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was carried out three times with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 155 mg of the title compound as a white oil. ^? - NMR (400 MHz, CDC13) d: 0.79 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.6 Hz, 3H), 1.13- 1.28 (m, 4H), 1.43-1.64 (m, 10H), 2.35-2.40 (m, 2H), 2.59 (brs, 4H), 2.84-2.94 (m, 5H), 6.96 (d, J = 8.4 Hz, ÍH), 7.22 (dd, J = 8.4, 2.4 Hz, ÍH), 7.31 (d, J = 2.4 Hz, ÍH). (Id) 1- [2- (4,4-Diethylcyclohexyl) -4- (4-methoxymethylpiperidin-1-yl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 93] A mixture of 1- [4-bromo-2- (4,4-diethylcyclohexyl) phenyl] -4-propylpiperazine (155 mg, 0.368 mol), 4-methoxymethylpiperidine hydrochloride (73.2 mg, 0.442 mol), t-butoxide sodium (184 mg, 1.91 mol), palladium (II) acetate (16.5 mg, 0.0736 mol), tri-t-butylphosphonium tetrafluoroborate (64.1 mg, 0.221 mol) and xylene (4 ml) was stirred at an external temperature of 100 ° C for 19 hours and 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 43 mg of l- [2- (4,4-diethylcyclohexyl) -4- (4-methoxymethylpiperidin-1-yl) phenyl] -4-propylpiperazine as an orange solid. ^? - NMR (400 MHz, CDC13) d: 0.79 (t, J = 8.0 Hz, 3H), 0.81 (t, J = 8.0 Hz, 3H), 0.93 (t, J = 7.6 Hz, 3H), 1.14- 1.88 (m, 19H), 2.35-2.39 (m, 2H), 2.57 (brs, 4H), 2.65 (ddd, J = 12.0, 12.0, 2.4 Hz, 2H), 2.82-2.88 (m, 4H), 2.90- 2.98 (m, ÍH), 3.27 (d, J = 6.8 Hz, 2H), 3.26 (s, 3H), 3.56-3.62 (m, 2H), 6.73 (dd, J = 8.4, 2.8 Hz, ÍH), 6.84 (d, J = 2.8 Hz, HH), 7.06 (d, J = 8.4 Hz, HH). This compound was dissolved in dichloromethane (1 ml), and a 4N solution of hydrogen chloride in ethyl acetate (0.0458 ml, 0.183 mol) was added. The solution is concentrated, diethyl ether was added to the resulting residue and the resulting precipitate was triturated by sonication. After filtering, drying was carried out under reduced pressure to give 47 mg of the title compound as a light brown solid. MS / m / e (ESI) 470 (MH +). (Example 2) [4- (4-Butylpiperazin-1-yl) -3- (4,4-dimethylcyclohexyl) phenyl] bis (2-methoxyethyl) amine hydrochloride [Chemical Formula 94] A mixture of 1- [4-bromo-2- (, 4-dimethylcyclohexyl) phenyl] -4-butylpiperazine (50 mg, 0.123 mol) produced in Production Example 8B, bis (2-methoxyethyl) amine (25 mg, 0.185 mol), sodium t-butoxide (30 mg, 0.308 mol), palladium (II) acetate (3 mg, 0.0123 mol), tri-t-butylphosphonium tetrafluoroborate (11 mg, 0.0369 mol) and xylene (1 ml) it was stirred at an external temperature of 100 ° C for 1 hour. The reaction mixture was purified by silica gel column chromatography NH (ethyl acetate / hexane) to give 34 mg of [4- (4-butylpiperazin-1-yl) -3- (4,4-dimethylcyclohexyl) phenyl] bis (2-methoxyethyl) amine as a light yellow oil. XH-NMR (400 MHz, CDC13) d: 0.94 (t, J = 7.2 Hz, 3H), 0.97 (s, 3H), 1.00 (s, 3H), 1.30-1.70 (m, 12H), 2.38-2.42 ( m, 2H), 2.58 (brs, 4H), 2.34-2.38 (m, 2H), 2.84 (brs, 4H), 2.90-3.00 (m, ÍH), 3.36 (s, 6H), 3.50-3.60 (m, 8H), 6.52 (dd, J = 8.8, 3.2 Hz, ÍH), 6.63 (d, J = 3.2 Hz, ÍH), 7.05 (d, J = 8.8 Hz, ÍH). This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated under reduced pressure. Hexane was added to the residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 33 mg of the title compound as a light yellow solid. MS m / e (ESI) 460 (MH +). (Example 3) 1- Hydrochloride. { 4- [4- (4-Butylpiperazin-1-yl) -3- (4,4-dimethylcyclohexyl) phenyl] piperazin-1-yl) ethanone [Chemical Formula 95] A mixture of 1- [4-bromo-2- (4,4-dimethylcyclohexyl) phenyl] -4-butylpiperazine (50 mg, 0.123 mol) produced in Production Example 8B, 1-acetylpiperazine (24 mg, 0.185 mol ), sodium t-butoxide (30 mg, 0.308 mol), palladium (II) acetate (3 mg, 0.0123 mol), tri-t-butylphosphonium tetrafluoroborate (11 mg, 0.0369 mol) and xylene (1 ml) was stirred at an external temperature of 100 ° C for 1 hour. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 32 mg of 1-. { 4- [4- (4-Butylpiperazin-1-yl) -3- (4,4-dimethylcydohexyl) phenyl] piperazin-1-yl} ethanone as colorless crystals. XH-NMR (400 MHz, CDCl 3) d: 0.94 (t, J = 7.6 Hz, 3H), 0.97 (s, 3H), 1.02 (s, 3H), 1.28-1.65 (m, 12H), 2.14 (s, 3H), 2.38-2.43 (m, 2H), 2.59 (brs, 4H), 2.78-2.91 (m, ÍH), 2.92-3.01 (m, ÍH), 3.09 (t, J = 5.2 Hz, 2H), 3.12 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.77 (t, J = 5.2 Hz, 2H), 6.72 (dd, J = 8.4, 2.8 Hz, ÍH), 6.85 (d, J = 2.8 Hz, HH), 7.08 (d, J = 8.4 Hz, HH).

This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate was added. The precipitated solid was filtered to give 31 mg of the title compound as a colorless solid. MS m / e (ESI) 455 (MH +). (Example 4) [4- (4-t-Butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] -methyl- (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 96] (4a) l-butyl-4- (2-methoxy-5-nitrophenyl) piperazine [Chemical Formula 97] To a solution of 1- (2-methoxy-5-nitrophenyl) piperazine (3.08 g, 13 mol) and butyraldehyde (1.4 ml, 15.73 mol) in tetrahydrofuran (40 ml) was added sodium triacetoxyborohydride (3.3 g, 15.57 mol) and acetic acid (0.75 ml, 13.09 mol) in that order, followed by stirring at room temperature. After stirring for 30 minutes, ethyl acetate, aqueous saturated sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 3.88 g of the title compound as a yellow oil. XH-NMR (400 MHz, CDC13) d: 0.94 (t, J = 7.2 Hz, 3H), 1.30-1.42 (m, 2H), 1.48-1.56 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.66 (brs , 4H), 3.15 (brs, 4H), 3.97 (s, 3H), 6.87 (d, J = 9.2 Hz, ÍH), 7.78 (d, J = 2.3 Hz, ÍH), 7.93 (dd, J = 9.2, 2.4 Hz, ÍH). (4b) 2- (4-Butylpiperazin-1-yl) -4-nitrophenol [Chemical Formula 98] A mixture of l-butyl-4- (2-methoxy-5-nitrophenyl) piperazine (3.61 g, 12.3 mol) and 48% hydrobromic acid (50 ml) was heated to reflux. After 134 hours and 30 minutes, the reaction mixture was poured into ice water and made alkaline with 5N aqueous sodium hydroxide. Then, saturated aqueous ammonium chloride was added to the mixed solution to make it weakly acidic and the extraction was carried out with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure to give 2.58 g of a crude product of the title compound as a reddish brown oil. This was used without purification for the next reaction. (4c) Trifluoromethanesulfonic acid 2- (4-butylpiperazin-1-yl) -4-nitrophenyl ester [Chemical Formula 99] A mixture of a crude product of 2- (4-butylpiperazin-1-yl) -4-nitrophenol (2.58 g), triethylamine (6.5 - ml, 46.64 mol) and anhydrous dichloromethane (50 ml) was cooled under a nitrogen atmosphere in an ice-methanol bath. Trifluoromethanesulfonic anhydride (2.3 ml, 13.67 mol) was gradually added to the solution for 15 minutes. After stirring for 20 minutes, ethyl acetate, saturated aqueous ammonium chloride and water were added to the reaction mixture, and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 3.01 g of the title compound as a yellow oil. XH-NMR (400 MHz, CDC13) d: 0.94 (t, J = 7.2 Hz, 3H), 1.30-1.42 (m, 2H), 1.46-1.56 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.66 (brs, 4H), 3.14 (t, J = 4.8 Hz, 4H), 7.32 (d, J = 8.8 Hz, ÍH), 7.94 (dd, J = 8.8, 2.8 Hz, ÍH), 7.98 ( d, J = 2.8 Hz, ÍH). (4d) l-butyl-4- [2- (4-t-butylcyclohex-l-enyl) -5-nitrophenyl] piperazine [Chemical Formula 100] A mixture of 2- (4-t-butylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1,2,2] dioxaborolane (2.9 g, 10.98 mol) produced in Production Example 4E, trifluoromethanesulfonic acid 2- (4-butylpiperazin-1-yl) -4-nitrophenyl ester (3 g, 7.29 mol), tripotassium phosphate (1.55 g, 7.30 mol), 1,2-dimethoxyethane (40 ml) and water (2 ml) ) was stirred at room temperature under a nitrogen atmosphere. Tetrakis (triphenylphosphine) palladium (0) (840 mg, 0.73 mol) was added to the mixture. Then, the mixture was stirred at an external temperature of 85 ° C for 3 hours. Ethyl acetate was added to the reaction mixture, which was then filtered. Water was added to the filtrate and extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 2.88 g of the title compound as a reddish yellow oil in the form racemic in the t-butyl position. ^ -NMR (400 MHz, CDC13) d: 0.93 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H), 1.22-1.40 (, 4H), 1.48-1.56 (m, 2H), 1.92-2.02 (m, 2H), 2.20-2.42 (m, 4H), 2.52-2.68 (m, 5H), 3.02-3.16 (m, 4H), 5.88 (t, J = 2.8 Hz, ÍH), 7.18 (dd, J = 8.4 Hz, HH), 7.75 (d, J = 2.4 Hz, HH), 7.78 (dd, J = 8.4, 2.4 Hz, HH). (4e) 4 - (4-t-Butylcyclohex-l -enyl) -3- (4-butylpiperazin-1-yl) phenylamine [Chemical Formula 101] To a solution of l-butyl-4- [2- (4-t-butylcyclohex-1-enyl) -5-nitrophenyl] piperazine (1.2 g, 3 mol) in ethanol (18 ml) was added an aqueous solution (6 g). ml) of ammonium chloride (54 mg, 1 mol) and iron powder (590 mg, 10.56 mol), followed by stirring at an external temperature of 90 ° C for 3 hours. The reaction mixture was filtered, the insoluble material was washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The resulting residue is purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 1.04 g of the title compound as light brown crystals in racemic form at the t-butyl position. XH-NMR (400 MHz, CDC13) d: 0.91 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H), 1.15-1.40 (m, 4H), 1.46-1.55 (m, 2H), 1.86- 1.97 (m, 2H), 2.11-2.40 (m, 4H), 2.53 (brs, 4H), 2.66-2.75 (m, ÍH), 2.96 (brs, 2H), 3.07 (brs, 2H), 3.57 (brs, 2H), 5.68 (t, J = 2.8 Hz, ÍH), 6.26-6.32 (m, 2H), 6.86 (d, J = 8.4 Hz, ÍH). (4f) [4- (4-t-Butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine [Chemical Formula 102] To a mixture of 4- (4-t-butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenylamine (80 mg, 0.216 mol), tetrahydropyran-4-one (0.022 ml, 0.238 mol) , acetic acid (13 mg, 0.216 mol) and 1,2-dichloromethane (1 ml) was added sodium triacetoxyborohydride (69 mg, 0.325 mol), followed by stirring at room temperature for 15 hours and 30 minutes. minutes Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 98 mg of the title compound as yellow crystals in racemic form at the t-butyl position. XH-NMR (400 MHz, CDC13) d: 0.91 (s, 9H), 0.94 (t, J = 7.6 Hz, 3H), 1.15-1.60 (m, 10H), 1. 87-1.98 (m, 2H), 1.98-2.05 (m, ÍH), 2.11-2.43 (m, 4H), 2.54 (brs, 4H), 2.66-2.76 (m, ÍH), 2.96 (brs, 2H), 3.07 (brs, 2H), 3.40-3.50 (m, ÍH), 3.51 (ddd, J = 11.6, 11.6, 2.0 Hz, 2H), 3.90 (ddd, J = 11.6, 3.2, 3.2 Hz, 2H), 5.66- 5.70 (m, J = 2.4 Hz, ÍH), 6.15-6.25 (m, 2H), 6.89 (d, J = 7.2 Hz, ÍH). (4g) [4- (4-t-Butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] methyl (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 103] To a mixture of [4- (4-t-butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine (15 mg, 0.0331 mol), formaldehyde 36% (3.2 mg, 0.0397 mol), acetic acid (2.9 mg, 0.0331 mol) and 1,2-dichloroethane (1 ml) were added sodium triacetoxyborohydride (11 mg, 0.0497 mol) followed by stirring at room temperature for 15 hours and 40 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The separated organic layer was washed with water and then filtered through celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give [4- (4-t-butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] methyl (tetrahydropyran-4-yl) amine in racemic form at the t-butyl position. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated under reduced pressure. HE added diethyl ether to the residue, and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 15.3 mg of the title compound as a light yellow solid. MS m / e 468 (MH +). (Example 5) [3 - (4-t-Butylcyclohexyl-enyl) -2 - (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 104] (5a) 4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 105] A mixture of 1,2-dichloro-3-nitrobenzene (2 g, 10.4 mol), piperazine-1-carboxylic acid t-butyl ester (2.91 g, 15.6 mol), potassium carbonate (2.16 g, 15.6 mol) and dimethylformamide (10 ml) was stirred at an external temperature of 120 ° C for 10 hours and 30 minutes. Water was added to the reaction mixture and extraction was carried out with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2.97 g of the title compound as a yellow oil. XH-NMR (400 MHz, CDC13) d: 1.48 (s, 9H), 3.06 (brs, 4H), 7.14 (dd, J = 8.0, 8.0 Hz, ÍH), 7.52 (dd, J = 8.0, 1.6 Hz, ÍH), 7.56 (dd) , J = 8.0, 1.6 Hz, ÍH). The 4H of the piperazine ring could not be identified. (5b) 4- [2- (4-t-Butylcyclohex-l-enyl) -6-nitrophenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 106] A mixture of 4- (2-chloro-6-nitrophenyl) piperazine-l-carboxylic acid t-butyl ester (370 mg, 1.08 mol), 2- (4-t-butylcyclohex-l-enyl) -4, 4,5, 5-tetramethyl- [1, 3, 2] dioxaborlane produced in Production Example 4E (428 mg, 1.62 mol), palladium (II) acetate (12 mg, 0.054 mol), 2- (dicyclohexylphosphine) biphenyl (76 mg, 0.216 mol), tripotassium phosphate (459 mg, 2.16 mol), xylene (4 ml) and water (0.3 ml) was stirred at an external temperature of 120 ° C during 13 hours under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture, which was filtered through celite. The filtrate was then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 275 mg of the title compound as yellow crystals in racemic form at the t-butyl position. ^ -NMR (400 MHz, CDCl3) d: 0.98 (s, 9H), 1.26-1.42 (m, 2H), 1.48 (s, 9H), 1.87-2.01 (m, 2H), 2.14-2.37 (m, ÍH) ), 2.39-2.43 (m, 2H), 3.00 (s, 4H), 3.45 (s, 4H), 5.62-5.69 (m, ÍH), 7.11 (dd, J = 8.0, 7.6 Hz, ÍH), 7.21 ( dd, J = 7.6, 2.0 Hz, ÍH), 7.42 (dd, J = 8.0, 2.0 Hz, ÍH). (5c) 1- [2 - (4-t-butylcyclohex-l-enyl) -6-nitrofenyl] piperazine [Chemical Formula 107] A mixture of 4- [2- (4-t-butylcyclohex-1-enyl) -6-nitrophenyl] piperazine-1-carboxylic acid t-butyl ester (275 mg, 0.62 mol), trifluoroacetic acid (4 ml, 51.6 mol) and dichloromethane (4 ml) was stirred at room temperature for 1 hour and 30 minutes. Aqueous saturated sodium carbonate was added to the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer collected was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure to give 225 mg of a crude product of the title compound. (5d) l-butyl-4- [2- (4-t-butylcyclohex-l-enyl) -6-nitrophenyl] piperazine - [Chemical Formula 108] To a mixture of a crude product of l- [2- (4-t-butylcyclohex-1-enyl) -6-nitrophenyl] piperazine (225 mg), butyraldehyde (0.061 ml, 0.682 mol), acetic acid (37 mg, 0.620 mol) and tetrahydrofuran (2 ml) was added sodium triacetoxyborohydride (25 mg, 0.120 mol) followed by stirring at room temperature for 50 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 226 mg of the title compound as a yellow oil in racemic form at the t-butyl position. XH-NMR (400 MHz, CDCl 3) d: 0.89-0.96 (m, 12H), 1.24-1.33 (m, 6H), 1.88-2.00 (, 2H), 2.15-2.26 (m, ÍH), 2.31-2.39 ( m, 4H), 2.42-2.50 (m, 4H), 3. 01-3.16 (m, 4H), 5.61-5.67 (m, ÍH), 7.03 (dd, J = 8.0, 7.6 Hz, ÍH), 7.17 (dd, J = 7.6, 1.6 Hz, ÍH), 7.38 (dd, J = 8.0, 1.6 Hz, ÍH). (5e) 3- (4-t-butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamine [Chemical Formula 109] A mixture of l-butyl-4- [2- (4-t-butylcyclohex-l-enyl) -6-nitrophenyl] piperazine (226 mg, 0.566 mol), 10% palladium on carbon (30 mg, wet) and methanol (3 ml) was stirred at ordinary temperature and atmospheric pressure for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite.

The filtrate was concentrated under reduced pressure to give 204 mg of a crude product of the title compound as a red oil. ^ -NMR (400 MHz, CDCl3) d: 0.91 (s, 9H), 0.94 (t, J = 7.6 Hz, 3H), 1.28-1.42 (m, 4H), 1. 46-1.58 (m, 2H), 1.85-2.00 (m, 2H), 2.08-2.44 (m, 7H), 2.78-3.00 (m, 4H), 3.10-3.24 (m, 2H), 4.07 (brs, 2H) ), 5.50- 5. 57 (m, ÍH), 6.42 (dd, J = 7.6, 1.6, Hz, ÍH), 6.63 (dd, J = 8.0, 1.6 Hz, ÍH), 6.87 (dd, J = 8.0, 7.6 Hz, ÍH). (5f) [3- (4-t-Butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 110] To a mixture of 3- (4-t-butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamine (56 mg, 0.152 mol), tetrahydropyran-4-one (0.015 ml, 0.167 mol) , acetic acid (9 mg, 0.152 mol) and 1,2-dichloroethane (1 ml) was added sodium triacetoxyborohydride (48 mg, 0.228 mol) followed by stirring at room temperature for 19 hours and 20 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography NH (ethyl acetate / hexane) to give 43 mg of [3- (4-t-butylcyclohex-1-enyl) -2- (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine in the form racemic in the t-butyl position. The compound was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The mixture was concentrated under reduced pressure to give 45 mg of the title compound as a colorless solid. MS m / e (ESI) 454 (MH +). (Example 6) 6- (4-t-Butylcyclohexyl) -7- (4-butylpiperazin-1-yl) -4-methyl-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 111] (6a) 6-chloro-7-nitro-4H-benzo [1,4] oxa zin-3 -one [Chemical Formula 112] A mixture of 6-chloro-4H-benzo [1,4] oxazin-3-one (5 - g, 27.2 mol) and concentrated sulfuric acid (60 ml) was cooled in an ice bath and stirred. Potassium nitrate (2.89 g, 28.6 mol) was added gradually to the mixture for 20 minutes followed by further stirring for 10 minutes. The reaction mixture was poured into ice water, and the precipitated solid was filtered. A small amount of acetone was added to the resulting solid and after trituration by sonication, it was filtered. The resulting solid was dried under reduced pressure to give 4.92 g of the title compound as yellow crystals. X H-NMR (400 MHz, CDCl 3) d: 4.71 (s, 2H), 7.08 (s, ÍH), 7.77 (s, ÍH), 11.28 (s, ÍH). (6b) 6-chloro-4-methyl-7-nitro-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 113] A mixture of 6-chloro-7-nitro-4H-benzo [1,4] oxazin-3-one (1 g, 4.37 mol) potassium carbonate (1.21 g, 8.74 mol) and dimethylformamide (10 ml) was stirred at room temperature.

Methyl iodide (0.33 ml, 5.25 mol) was added to the mixture, and the mixture was stirred at room temperature for 4 hours and 30 minutes. Water was added to the reaction mixture and the solid - The precipitate was filtered to give 905 mg of the title compound as light yellow crystals. XH-NMR (400 MHz, CDC13) d: 3.40 (S, 3H), 4.71 (s, 2H), 7.06 (s, ÍH), 7.65 (s, ÍH). (6c) 6- (4-t-butylcyclohex-l-enyl) -4-methyl-7-nitro-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 114] To a solution of 6-chloro-4-methyl-7-nitro-4H-benzo [1,4] oxazin-3-one (905 mg, 3.73 mol) in 1,2-dimethoxyethane (20 ml) was added - (4-t-butylcyclohex-1-enyl) -4,4,5,5-tetramethyl- [1, 3, 2] dioxaborlane (1.48 g, 5.60 mol) produced in Production Example 4E, tetrakis (triphenylphosphine) palladium (0) (216 mg, 0.187 mol) and tripotassium phosphate (1.58 g, 7.46 mol) followed by stirring at an external temperature of 85 ° C for 7 hours under a nitrogen atmosphere. Brine and ethyl acetate were added to the reaction mixture, which was filtered through celite. The filtrate was then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 1.02 g of the title compound as yellow crystals in racemic form at the t-butyl position. XH-NMR (400 MHz, CDCl3) d: 0.91 (s, 9H), 1.32-1.46 (m, 2H), 1.86-1.99 (m, 2H), 2.14-2.24 (m, 2H), 2.25-2.40 (m , ÍH), 3.40 (s, 3H), 4.68 (s, 2H), 5.58-5.66 (m, ÍH), 6.77 (s, ÍH), 7.57 (s, ÍH). (6d) 7-amino-6- (4-t-butylcyclohexyl) -4-methyl-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 115] A mixture of 6 - (4-t-butylcyclohexyl-l-ethyl) -4-methyl-7-nitro-4H-benzo [1,4] oxazin-3-one (300 mg, 0.871 mol), 10% palladium in carbon (300 mg, wet), tetrahydrofuran (3 ml) and methanol (3 ml) was stirred at ordinary temperature and atmospheric pressure for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was - concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 260 mg of the title compound as a colorless solid as a mixture of diastereomers at the t-butylcyclohexyl position. ^ -NMR (400 MHz, CDCl3) d: 0.87 (s, 9H x 0.6), 0.88 (s, 9H x 0.4), 1.09-2.10 (m, 9H), 2.34-2.48 (m, IH x 0.4), 2.92 (brs, HH x 0.6), 3.32 (s, 3H x 0.4), 3.33 (s, 3H x 0.6), 4.53 (s, 2H x 0.4), 4.55 (s, 2H x 0.6), 6.30-6.40 (m, ÍH), 6.68 (s ÍH x 0.4), 6.96 (s, ÍH x 0.6). (6e) 6- (4-t-Butylcyclohexyl) -4-methyl-7-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one [Chemical Formula 116] To a solution of 7-amino-6- (4-t-butylcyclohexyl) -4-methyl-4H-benzo [1,4] oxazin-3-one (260 mg, 0.822 mol) in 1,2-dichlorobenzene (2.6 ml) was added bis (2-chloroethyl) amine hydrochloride (183 mg, 1.03 mol), followed by stirring at an external temperature of 200 ° C for 3 hours under a nitrogen atmosphere. During the reaction gas was passed - nitrogen through the reactor several times to remove the hydrogen chloride gas. After cooling the reaction mixture to room temperature, IN aqueous sodium hydroxide was added and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 183 mg of the title compound as an orange solid as a mixture of diastereomers in the t-butylcyclohexyl position. XH-NMR (400 MHz, CDC13) d: 0.895 (s 9H x 0.6), 0.902 (s, 9H x 0.4), 1.09-1.96 (m, 9H), 2.72-3.06 (m 8H + ÍH x 0.4), 3.35 (brs, ÍH), 3.38-3.46 (s HH x 0.6), 4.58 (s 2H x 0.4), 4.59 (s, 2H x 0.6), 6.76 (s HH x 0.4), 6.78 (s HH x 0.4), 6.80 (s, ÍH x 0.6), 7.06 (s, ÍH x 0.6). (6f) 6- (4-t-Butylcyclohexyl) -7- (4-butylpiperazin-1-yl) -4-methyl-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 117] To a mixture of 6- (4-t-butylcyclohexyl) -4-methyl-7-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one (100 mg, 0.259 mol), butyraldehyde (0.035) ml, 0.389 mol), acetic acid (0.015 mg, 0.259 mol) and tetrahydrofuran (2 ml) was added sodium triacetoxyborohydride (82 mg, 0.389 mol) followed by stirring at room temperature for 1 hour. To the reaction mixture was added IN aqueous sodium hydroxide, and then the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 101 mg of the title compound as colorless crystals as a mixture of diastereomers in the t-butylcyclohexyl position. XH-NMR (400 MHz, CDCl 3) d: 0.89 (s 9H x 0.6), 0.90 (s, 9H x 0.4), 0.94 (t, J = 7.6 Hz, 3H x 0.6), 0.95 (t, J = 7.6 Hz , 3H x 0.4), 1.08-1.96 (m, 13H), 2.30-2.94 (m, 10H), 2.98 (tt, J = 12.0, 3.6 Hz, ÍH x 0.4), 3. 34 (s, 3H), 3.36-3.44 (m, ÍH x 0.6), 4.57 (s 2H x 0.4), 4.58 (s, 2H x 0.6), 6.75-6.78 (m, 2H x 0.4), 6.81 (s, ÍH x 0.6), 7.04 (s, ÍH x 0.6). MS m / e (ESI) 442 (MH +). (Example 7) 6- (4-t-Butylcyclohexyl) -7- (4-butylpiperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride [Chemical Formula] 118] To a mixture of 6- (4-t-butylcyclohexyl) -7- (4-butylpiperazin-1-yl) -4-methyl-4H-benzo [1, 4] oxazin-3 -one (71 mg, 0.161 mol), aluminum chloride (47 mg, 0.354 mol) and tetrahydrofuran (3 ml) was added lithium aluminum hydride (7 mg, 0.177 mol) followed by stirring at room temperature environment for 3 hours and 10 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture which was filtered through celite. The resulting filtrate was then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue is purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 73 mg of 6- (4-t-butylcyclohexyl) -7- (4-butylpiperazin-1-yl) -4-methyl-3, 4 -dihydro-2H-benzo [1,4] oxazine as a colorless oil as a mixture of diastereomers in the t-butylcyclohexyl position. ^ -NMR (400 MHz, CDC13) d: 0.89 (s 9H x 0.6), 0.90 (s, 9H x 0.4), 0.93 (t, J = 7.6 Hz, 3H x 0.6), 0.94 (t, J = 7.6 Hz , 3H x 0.4), 1.07-1.94 (m, 13H), 2.30-2.84 (m, 10H), 2.85 (s, 3H x 0.4), 2.86 (s, 3H x 0.6), 2.96 (tt, J = 12.0, 2.8 Hz, HH x 0.4), 3.18-3.23 (m, 2H), 3.36-3.43 (, HH x 0.6), 4.24-4.30 (s, 2H), 6.51 (s, HH x 0.4), 6.61 (s, ÍH x 0.4), 6.65 (s, ÍH x 0.6), 6.79 (s, ÍH x 0.6). This compound was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The mixture was concentrated under reduced pressure. Hexane was added to the residue, and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 75 mg of the title compound as colorless crystals, as a mixture of diastereomers in the t-butylcyclohexyl position. MS m / e (ESI) 428 (MH +). (Example 8) - - Hydrochloride of 6- (4-t-butylcyclohex-l-enyl) -4-methyl-7- (4-propylpiperazin-1-yl) -3,4-dihydro-2H-benzo [1,4] oxazine [Chemical Formula] 119] (8a) 7-amino-6- (4-t-butylcyclohex-l-enyl) -4-methyl-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 120] A mixture of 6- (4-t-butylcyclohex-l-enyl) -4-methyl-7-nitro-4H-benzo [1,4] oxazin-3-one (1.14 g, 3.30 mol), iron powder ( 553 mg, 9.91 mol), ammonium chloride (707 mg, 13.2 mol), ethanol (15 ml), water (5 ml) and dimethylformamide (3 ml) was stirred at an external temperature of 90 ° C for 7 hours and 30 minutes. minutes under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture which was filtered through celite. The filtrate is then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 940 mg of the title compound as a yellow oil, in racemic form at the t-butyl position. XH-NMR (400 MHz, CDC13) d: 0.92 (s, 9H), 1.28-1.46 (m, 2H), 1.88-2.03 (m, 2H), 2.15-2.36 (m, 3H), 3.30 (s, 3H) ), 4.54 (s, 2H), 5.70-5.80 (m, ÍH), 6.34 (s, ÍH), 6.57 (s, ÍH). The 2H of NH2 could not be identified. (8b) 6- (4-t-Butyl-cyclohex-l-enyl) -4-methyl-7-piperazin-1-1-4H-benzo [1,4] oxazin-3 -one [Chemical Formula 121] To a solution of 7-amino-6- (4-t-butylcyclohex-l-enyl) -4-methyl-4H-benzo [1,4] oxazin-3-one (940 mg, 2.99 mol) in 1,2-dichlorobenzene (3 ml) was added bis (2-chloroethyl) amine hydrochloride (694 mg, 3.89 mol), followed by stirring at an external temperature of 220 ° C for 2 hours and 30 minutes under a nitrogen atmosphere. During the reaction, nitrogen gas was passed through the reactor several times to remove the hydrogen chloride gas. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added and the extraction was carried out with ethyl acetate. The organic layer collected was dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 604 mg of the title compound as light yellow crystals in racemic form at the t-butyl position. XH-NMR (400 MHz, CDCl 3) d: 0.92 (s, 9H), 1.20-1.41 (m, 2H), 1.86-2.01 (m, 2H), 2.15-2.27 (m, ÍH), 2.31-2.44 (m , ÍH), 2.65-2.75 (m, ÍH), 2.79-3.06 (m, 8H), 3.34 (s, 3H), 4.59 (s, 2H), 5.65-5.80 (m, ÍH), 6.61 (s, ÍH) ), 6.70 (s, ÍH). (8c) 6- (4-t-Butylcyclohexyl-enyl) -4-methyl-7-piperazin-1-yl-3,4-dihydro-2H-benzo [1,4] oxazine [Chemical Formula 122] To a mixture of 6- (4-t-butylcyclohex-l-enyl) -4-methyl-7-piperazin-1-yl-4H-benzo [1,4] oxazin-3-one (604 mg, 1.57 mol) , aluminum chloride (840 mg, 6.30 mol) and tetrahydrofuran (20 ml) were added lithium aluminum hydride (120 mg, 3.15 mol) followed by stirring at room temperature for 17 hours and 30 minutes. Diethyl ether, water and 5N aqueous sodium hydroxide were added to the reaction mixture, which was filtered through celite. The resulting filtrate was then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 283 mg of the title compound as colorless crystals in racemic form at the t-butyl position. ^ -NMR (400 MHz, CDCl3) d: 0.91 (s, 9H), 1.18-1.40 (m, 2H), 1.86-1.98 (m, 2H), 2.13- 2. 23 (m, ÍH), 2.31-2.47 (m, ÍH), 2.66-3.00 (m, 12H), 3.15-3.25 (m, 2H), 4.25-4.35 (m, 2H), 5.65-5.70 (m, ÍH) ), 6.46 (s, ÍH), 6.48 (s, ÍH). (8d) 6- (4-t-Butylcyclohex-l-enyl) -4-methyl-7- (4-propylpiperazin-1-yl) -3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride [Chemical Formula 123] To a mixture of 6- (4-t-butylcyclohex-l-enyl) -4-methyl-7-piperazin-1-yl-3,4-dihydro-2H-benzo [1,4] oxazine (10 mg, 0.0284) mol), propionaldehyde (5 mg, 0.0852 mol) and tetrahydrofuran (1 ml) was added sodium triacetoxyborohydride (30 mg, 0.142 mol) followed by stirring at room temperature for 18 hours and 30 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and then filtered through celite. The solvent was removed by blowing nitrogen gas into the filtrate. The resulting residue was purified by column chromatography of - NH silica gel (ethyl acetate / hexane) to give 6- (4-t-butylcyclohex-1-enyl) -4-methyl-7- (4-propylpiperazin-1-yl) -3,4-dihydro-2H- benzo [1,4] oxazine in racemic form at the t-butyl position. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was removed by blowing nitrogen gas thereto. Hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 2.4 mg of the title compound as a colorless solid in racemic form at the t-butyl position. MS m / e (ESI) 412 (MH +). (Example 9) 5- (4-t-Butylcyclohex-l-enyl) -6- (4-butylpiperazin-1-yl) -2-methylbenzthiazolo dihydrochloride [Chemical Formula 124] (9A) 5-chloro-2-methyl-6-nitro-benzothiazolo [Chemical Formula 125] A mixture of 5-chloro-2-methylbenzothiazole (2.5 g, 13. 61 mol) and concentrated sulfuric acid (50 ml) was cooled in an ice bath and stirred. Potassium nitrate (1.38 g, 13.61 mol) was added gradually to the mixture and the mixture was allowed to warm to room temperature and stirred for 5 hours and 30 minutes. The reaction mixture was cooled in an ice bath, 5N aqueous sodium hydroxide was added thereto and the reaction mixture was adjusted to a pH of 7. The mixture was then extracted with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene) to give 1.67 g of the title compound as light yellow crystals. ^ -NMR (400 MHz, DMSO-d6) d: 2.88 (s, 2H), 8.32 (s, ÍH), 8.96 (s, ÍH). (9b) 5- (4-t-butylcyclohex-l-enyl) -2-methyl-6-nitro-benzothiazol [Chemical Formula 126] To a mixture of 5-chloro-2-methyl-6-nitroi-benzothiazole (1 g, 4.37 mol), 1,2-dimethoxyethane (30 ml) and water (5 ml) were added 2- (4-t-butylcyclohex-l-enyl) -4,4,5,5-tetramethyl- [1, 3, 2] dioxaborlane (1.73 g, 6.56 mol) produced in Production Example 4E, tetrakis (triphenylphosphine) palladium (0) (253 mg, 0.219 mol) and tripotassium phosphate (1.86 g, 8.74 mol), followed by stirring at an external temperature of 80 ° C for 14 hours and 45 minutes under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was carried out with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 634 mg of the title compound as purple crystals in racemic form at the t-butyl position. ^ -NMR (400 MHz, CDC13) d: 0.92 (s, 9H), 1.32-1.52 (m, 2H), 1.86-2.46 (m, 6H), 2.89 (s, 3H), 5.68-5.72 (m, ÍH), 7.79 (s, ÍH), 8.34 (s, ÍH). (9c) 5- (4-t-Butylcyclohex-l-enyl) -2-methyl-benzothiazol-6-ylamine [Chemical Formula 127] A mixture of 5- (4-t-butylcyclohex-l-enyl) -2-methyl-6-nitro-benzxothiazole (634 mg, 2.34 mol), 10% palladium on carbon (200 mg, wet) and methanol (30 mg). ml) was stirred at ordinary temperature and atmospheric pressure for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added 10% palladium on carbon (200 mg, wet) and methanol (30 ml) followed by stirring at ordinary temperature and atmospheric pressure for 8 hours and 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give 542 mg of a crude product of the title compound as a colorless solid in racemic form in the t-butyl position. (9d) 5- (4-t-Butylcyclohex-l-enyl) -2-methyl-6-piperazin-1-ylbenzothiazolo [Chemical Formula 128] To a solution of a crude product of 5- (4-t-butylcyclohex-1-enyl) -2-methyl-benzothiazol-6-ylamine (542 mg) in 1,2-dichlorobenzene (5 ml) was added bis hydrochloride. (2-chloroethyl) amine (386 mg, 2.16 mol) followed by stirring at an external temperature of 200 ° C for 2 hours and 30 minutes under a nitrogen atmosphere. During the reaction, nitrogen gas was passed through the reactor several times to remove the hydrogen chloride gas. After cooling the reaction mixture to room temperature, saturated sodium hydrogencarbonate and ethyl acetate were added. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer collected was washed with water and brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography of silica gel column NH (ethyl acetate / hexane) to give 188 mg of the title compound as brown crystals in racemic form at the t-butyl position. -NMR (400 MHz, CDCl3) d: 0.93 (s, 9H), 1.26-1.45 (m, 2H), 1.88-2.03 (m, 2H), 2.18-2.29 (m, ÍH), 2.39-2.53 (m, ÍH), 2.64-2.75 (m, ÍH), 2.78 (s, 3H), 2.88-3.08 (m, 8H), 5.79-5.85 (m, ÍH), 7.34 (s, ÍH), 7.63 (s, ÍH) . (9e) 5- (4-t-Butylcyclohex-l-enyl) -6- (4-buty-piperazin-1-yl) -2-methylbenzthiazolo dihydrochloride [Chemical Formula 129] To a mixture of 5- (4-t-butylcyclohex-l-enyl) -2-methyl-6-piperazin-1-ylbenzothiazole (20 mg, 0.0666 mol), butyraldehyde (5.2 mg, 0.0732 mol), acetic acid (4 mg, 0.0666 mol) and tetrahydrofuran (1 ml) was added sodium triacetoxyborohydride (21 mg, 0.100 mol) followed by stirring at room temperature for 2 hours. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out - out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 20 mg of 5- (4-t-butylcyclohex-l-enyl) -6- (4-butylpiperazin-1-yl) -2-methylbenzothiazolo as a colorless oil in racemic form in the t-butyl position. XH-NMR (400 MHz, CDCl 3) d: 0.94 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H), 1.18-1.60 (m, 6H), 1.88-2.03 (m, 2H), 2.16- 2.29 (m, ÍH), 2.32-2.76 (m, 8H), 2.78 (s, 3H), 2.90-3.20 (m, 4H), 5.80-5.85 (m, ÍH), 7.34 (s, ÍH), 7.62 ( Yes H) . This compound was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. This was concentrated under reduced pressure. Hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 23 mg of the title compound as colorless crystals in racemic form at the t-butyl position. MS m / e (ESI) 426 (MH +). (Example 10) l-Butyl-4- [5- (2-methoxyethoxy) -2- hydrochloride - (3, 3, 5, 5-tetramethylcyclohexyl) phenyl] piperazine [Chemical Formula 130] (10a) 3-piperazin-1-yl-4- (3,3,5,5-tetramethylcyclohexyl) phenol [Chemical Formula 131] The 1- [5-methoxy-2- (3,3,5,5-tetramethylcyclohex-l-enyl) phenyl] piperazine produced in Production Example 6C was used as the starting material for the Nt-butyloxycarbonylation and the reaction of hydrogenation by conventional methods. A mixture of 4- [5-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (3.41 g, 7.92 mol) obtained in the reaction, acetic acid (18 ml, 314 mol) and 48% hydrobromic acid (36 ml, 318 mol) was stirred at an external temperature of - 130 ° C for 8 hours and 20 minutes. The reaction mixture was cooled in an ice water bath and stirred, and then 5N of aqueous sodium hydroxide was added thereto to adjust the reaction mixture to a pH of 8-9. The produced solid was filtered to give 2.98 g of a crude product as a light red solid. hl-NMR (400 MHz, CD3OD) d: 0.94 (s, 6H), 1.54 (s, 6H), 1.17-1.40 (m, 6H), 3.05 (t, J = 4.8 Hz, 4H), 3.42 (tt, J = 12.8, 2.8 Hz, ÍH), 6.55-6.61 (m, 2H), 7.05 (d, J = 8.0 Hz, ÍH). The 4H of the piperazine ring and the 2H of the NH and OH could not be identified. (10b) 4- [5-Hydroxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 132] A mixture of the crude product of 3-piperazin-1-yl-4- (3,3,5,5-tetramethylcyclohexyl) phenol (2.98 g) produced in Production Example 9A and a mixed solvent (100 ml) of chloroform-methanol was stirred at an external temperature of 0 ° C. A solution of di-t-butyl dicarbonate (1.81 g, 8.32 mol) in chloroform was added dropwise to the mixture. After stirring the reaction mixture for 2 hours and 30 minutes, the reaction mixture was concentrated under reduced pressure. Aqueous saturated sodium carbonate and ethyl acetate were added to the resulting residue and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 2.95 g of the title compound as a light red solid. ^ -NMR (400 MHz, CDC13) d: 0.91 (s, 6H), 1.10 (s, 6H), 1.11-1.43 (m, 6H), 1.49 (s, 9H), 2.80 (brs, 4H), 3.43 ( tt, J = 12.4, 2.8 Hz, HH), 3.52 (brs, 4H), 6.55-6.57 (m, 2H), 7.06 (dd, J = 7.2, 1.6 Hz HH). The OH of OH could not be identified. (10c) 4- [5- (2-Methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 133] A mixture of 4- [5-hydroxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.480 mol), dimethylformamide (2 ml) and Sodium hydride (60% dispersion in oil, 28.8 mg, 0.720 mol) was stirred at room temperature for 20 minutes under a nitrogen atmosphere. Then, 2-bromoethyl methyl ether (0.052 ml, 0.528 mol) was added dropwise to the mixture, followed by stirring for 2 hours and 40 minutes. Water was added to the reaction mixture and extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 232 mg of the title compound as a colorless oil. XH-NMR (400 MHz, CDC13) d: 0.91 (s, 6H), 1.10 (s, 6H), 1.11-1.45 (m, 6H), 1.49 (s, 9H), 2.79 (brs, 4H), 3.38-3.49 (m, 4H), 3.55 (brs, 4H), 3.73 (d, J = 4.8 2H), 4.08 (d, J = 4.8 2H), 6.64 (dd, J = 8.4, 2.4 Hz, HH), 6.66 (d, J = 2.4 Hz, HH), 7.11 (d, J = 8.4 Hz, HH). (10d) 1- [5- (2-methoxyethoxy) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] piperazine [Chemical Formula 134] A mixture of 4- [5- (2-methoxyethoxy) -2 - (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (232 mg, 0.489 mol), trifluoroacetic acid (1 ml, 12.9 mol) and dichloromethane (2 ml) was stirred at room temperature for 1 hour. Aqueous saturated sodium carbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography NH (ethyl acetate / heptane) to give 158 mg of the title compound as a colorless solid. ^ -NMR (400 MHz, CDC13) d: 0.91 (s, 6H), 1.11 (s, 6H), 1.13-1.46 (m, 6H), 2.82 (brs, 4H), 2.94-3.06 (m, 4H), 3.37-3.51 (m, 4H), 3.74 (d, J = 4.8 2H), 4.09 (d, J = 4.8 2H), 6.63 (dd, J = 8.4, 2.4 Hz, ÍH), 6.71 (d, J = 2.4 Hz, ÍH), 7.11 (d, J = 8.4 Hz, ÍH). The NH of the piperazine ring could not be identified. (lOe) l-Butyl-4- [5- (2-methoxyethoxy) -2- (3,3,5,5-tetramethylethylhexyl) phenyl] piperazine hydrochloride [Chemical Formula 135] To a mixture of 1- [5- (2-methoxyethoxy) -2- (3,3, 5, 5-tetramethylcyclohexyl) phenyl] piperazine (15 mg, 0.0400 mol), butyraldehyde (0.0107 ml, 0.120 mol) and tetrahydrofuran ( 1 ml) was added sodium triacetoxyborohydride (25 mg, 0.120 mol) followed by stirring at room temperature for 1 hour. Saturated sodium hydrogencarbonate was added Aqueous to the reaction mixture and extraction was carried out with ethyl acetate. The solvent was removed by blowing nitrogen gas into the collected organic layer. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give l-butyl-4- [5- (2-methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine as a colorless solid. XH-NMR (400 MHz, CDCl 3) d: 0.91 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.11 (s, 6H), 1.12-1.57 (m, 10H), 2.34-2.42 ( m, 2H), 2.58 (brs, 4H), 2.90 (t, J = 4.4 Hz, 4H), 3.36-3.47 (m, 4H), 3.70-3.76 (m, 2H), 4.04-4.11 (m, 2H) , 6.61 (dd, J = 8.4, 2.4 Hz, ÍH), 6.71 (d, J = 2.4 Hz, ÍH), 7.09 (d, J = 8.4 Hz, ÍH). This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride was added. The solvent was removed by blowing nitrogen gas to this. Heptane was added to the resulting residue and the resulting precipitate was dried to give 17.7 mg of the title compound as a colorless solid. MS m / e (ESI) 431 (MH +). (Example 11) (S) -l-Butyl-4- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine hydrochloride [Chemical Formula 136] (lia) (S) -4- [2- (4,4-Diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine-1-carboxylic acid tert-butyl ester [Chemical Formula 137] The 4- [4-bromo-2- (4,4-diethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (500 mg, 1.0 mol) produced in Production Example 7C was dissolved in toluene (10 mg). ml). To the mixture was added (S) -2- (methoxymethyl) pyrrolidine (170 mg, 1.5 mol), sodium t-butoxide (240 mg, 2.5 mol), tri-t-butylphosphonium tetrafluoroborate (180 mg, 0.625 mol) and palladium (II) acetate (56 mg, 0.25 mol) followed by stirring at an external temperature of 80 ° C for 15 hours and 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble material was filtered through celite and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 240 mg of the title compound as a black oil. XH-NMR (400 MHz, CDC13) TLC Rf = 0.28 (hexane / AcOEt = 5/1, UV 254 nm) (llb) (S) -1- [2- (4,4-diethylcyclohexyl) -4- (2 -methoxymethylpyrrolidin-1-yl) phenyl] piperazine [Chemical Formula 138] A mixture of (S) -4- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine-1-carboxylic acid t-butyl ester (240 mg, 0.467 mol) ), trifluoroacetic acid (1 ml, 13.0 mol) and dichloromethane (2 ml) was stirred at 0 ° C for 4 hours. The reaction mixture was made basic by the addition of potassium carbonate while cooling on ice, and then dichloromethane and water were added and extraction was carried out with dichloromethane. The collected organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 145 mg of the title compound as a black oil. TLC (NH) Rf = 0-0.30 (design) (hexane / AcOEt = 2/1, UV 254 nm) (11c) Hydrochloride of (S) -l-butyl-4- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine [Chemical Formula 139] To a solution of (S) -1- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine (20 mg, 0.048 mol) in tetrahydrofuran (1 ml) was added butyraldehyde (5.2 mg, 0.073 mol), sodium triacetoxyborohydride (20 mg, 0.097 mol) and acetic acid (2.9 mg, 0.048 mol) in that order followed by stirring at room temperature for 30 min. - - minutes Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture and the extraction was carried out with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give (S) -l-butyl-4- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1) -yl) phenyl] piperazine. XH-NMR (400 MHz, CDCl 3) d: 0.76-0.96 (m, 8H), 1.15-1.72 (m, 17H), 1.91-2.04 (m, 4H), 2.37-2.41 (m, 2H), 2.57 (br , 4H), 2.84 (br, 4H), 2.97 (tt, J = 12, 3.6 Hz, ÍH), 3.06-3.12 (m, ÍH), 3.18 (t, J = 9.2 Hz, ÍH), 3.39 (s, 3H), 3.41-3.45 (m, ÍH), 3.51 (dd, J = 9.2, 3.2 Hz, ÍH), 3.83 (td, J = 8.0, 3.2 Hz, ÍH), 6.46 (dd, J = 8.8, 2.8 Hz , HH), 6.52 (d, J = 2.8 Hz, HH), 7.08 (d, J = 8.8 Hz, HH). The compound thus obtained was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated, hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 22.3 mg of the title compound as a white solid. MS m / e (ESI) 470 (MH +). (Example 12) 1- [4- (2-Methoxyethoxy) -2- (3, 3, 5, 5- Hydrochloride tetramethylcyclohexyl) phenyl] -4-propylpiperazine [Chemical Formula 140] (12a) 4-piperazin-1-yl -3- (3,3,5,5-tetramethylcyclohexyl) phenol [Chemical Formula 141] A mixture of 1- [4-methoxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine (450 mg, 1.36 mol) produced in Production Example 10C, 48% hydrobromic acid (4 ml. ) and acetic acid (2 ml) was stirred at an external temperature of 130 ° C for 7 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was then cooled in an ice water bath and stirred. The reaction mixture was adjusted to a pH of 8-9 by the addition of 5N aqueous sodium hydroxide. The precipitated solid was filtered and washed with water and then a mixed solvent of methanol, ethyl was added to the solid acetate and dichloromethane. The insoluble material was filtered and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue for solidification, followed by trituration by sonication. The resulting solid was filtered, washed with heptane and diethyl ether and subjected to flow drying to give 460 mg of the title compound as a light red solid. The product thus obtained was used for the next reaction without further purification. (12b) 4- [4-hydroxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 142] To a solution of 4-piperazin-1-yl-3- (3,3,5,5-tetramethylcyclohexyl) phenol (460 ml, 1.45 mol) in dimethylformamide (5 ml) was added potassium carbonate (188 mg, 1.36 mol). ) and 4-dimethylaminopyridine (20 mg, 0.164 mol) followed by stirring. Di-t-butyl dicarbonate was added (300 mg, 1.85 mol) was added to the mixture in an ice bath, while the solidification of the solution was prevented. After stirring the reaction mixture to - room temperature for 19 hours and 30 minutes, water was added to the reaction mixture and extraction was carried out with ethyl acetate. The organic layer collected was washed with water and brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 340 mg of the title compound as a colorless solid. XH-NMR (400 MHz, CDC13) d: 0.86-1.56 (m, 6H), 0.91 (s, 6H), 1.10 (s, 6H), 1.49 (s, 9H), 2.75 (br, 4H), 3.05 ( br, 2H), 3.58 (t, J = 12.0 Hz, ÍH), 4.03 (br, 2H), 5.64 (brs, ÍH), 6.62 (d, J = 8.4 Hz, ÍH), 6.71 (s, ÍH), 6.94 (d, J = 8.4 Hz, ÍH). (12c) 4- [4- (2-Methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester [Chemical Formula 143] To a solution of 4- [4-hydroxy-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (290 mg, 0.696 mol) in dimethylformamide (3 ml) HE added sodium hydride (60% dispersion in oil, 100 mg, 2.5 mol) while stirring at room temperature. After the bubbling ceased, 2-bromoethylmethyl ether (0.15 ml, 1.48 mol) was further added to the reaction mixture. The mixture was stirred at room temperature for 1 hour and 10 minutes and then water was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. A crude product of the title compound (340 mg) was obtained. The crude product was used for the next reaction without purification. (12d) 1- [4- (2-methoxyethoxy) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] piperazine [Chemical Formula 144] A solution of 4- [4- (2-methoxyethoxy) -2- (3, 3, 5, 5) t-butyl ester - tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid (400 mg, 0.82 mol) in dichloromethane (4 ml) was stirred while cooling in an ice bath, followed by the gradual addition of trifluoroacetic acid (2 ml) by dripping for 10 minutes . The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was made basic by the addition of aqueous saturated sodium hydrogencarbonate while it was cooled in ice water, and the extraction was carried out with ethyl acetate. The organic layer collected was washed with water and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 296 mg of the title compound as a light yellow solid. (12e) 1- [4- (2-Methoxyethoxy) -2- (3,3, 5, 5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 145] or HCl To a solution of 1- [4- (2-methoxyethoxy) -2- (3,3, 5, 5-tetramethylcyclohexyl) phenyl] piperazine (10 mg, 0.027 mol) in tetrahydrofuran (1 ml) was added propionaldehyde (2.3 mg , 0.040 mol), sodium triacetoxyborohydride (11 mg, 0.053 mol) and acetic acid (1.6 mg, 0.027 mol) in that order, followed by stirring for 30 minutes at room temperature. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture, the extraction was carried out with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give l- [4- (2-methoxyethoxy) -2- (3, 3,5, 5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine. XH-NMR (400 MHz, CD30D) d: 0.96 (s, 6H), 1.06 (t, J = 7.2 Hz, 3H), 1.18 (s, 6H), 1.18-1.43 (m, 7H), 1.77-1.87 ( m, 2H), 3.10-3.22 (m, 8H), 3.42 (s, 3H), 3.57 (tt, J = 12, 2.8 Hz, ÍH), 3.67 (m, ÍH), 3.72-3.74 (m, 2H) , 4.07-4.09 (m, 2H), 6.77 (dd, J = 8.8, 3.2 Hz, ÍH), 6.83 (d, J = 3.2 Hz, ÍH), 7.14 (d, J = 8.8 Hz, ÍH). The compound thus obtained was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated, hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 6.3 - mg of the title compound as a white solid. MS m / e (ESI) 417 (MH +). (Example 13) l-Butyl-4- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 146] (13a) 5-bromo-6-nitrobenzo [1,3] dioxol [Chemical Formula 147] A solution of 4-bromo-l, 2-methylenedioxybenzene (3 g, 14.9 mol) in acetic acid (60 ml) was cooled to 10 ° C and then concentrated nitric acid (20 ml) was added gradually to the mixture while stirring . The reaction mixture was allowed to warm to room temperature and stirring continued for 15 minutes at room temperature. The reaction mixture was cooled to 0 ° C and then ice water was added while stirring.

Diethyl ether and water were added to the reaction mixture and the organic layer was collected. The organic layer was washed with saturated sodium hydrogencarbonate, water and potassium carbonate, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. A crude product of the title compound (3.35 g) was obtained as a light yellow solid. -NMR (400 MHz, CDCl 3) d: 6.15 (s, 2H), 7.12 (s, ÍH), 7.45 (s, ÍH). (13b) 5-nitro-6- (3,3,5,5-tetramethylethylehex-1-enyl) benzo [1,3] dioxol [Chemical Formula 148] To a solution of 5-bromo-6-nitrobenzo [1, 3] dioxol (1.5 g, 6.1 mol) in 1,2-dimethoxyethane (30 ml) was added the 4,4,5,5-tetramethyl-2- (3,3,5,5-tetramethylcyclohex-1-enyl) - [1, 3, 2] dioxaborlane (1.93 g, 7.3 mol) produced in the Production Example 2B, tripotassium phosphate (1.94 g, 9.14 mol) and water (1.5 ml). Tetrakis (triphenylphosphine) palladium (352 mg, - 0. 305 mol) was added to the mixture under a nitrogen atmosphere, followed by stirring at an external temperature of 80 ° C for 4 hours. Then tetrakis (triphenylphosphine) palladium (0) (350 mg, 0.305 mol) and water (1.5 ml) were added to the reaction mixture, stirring continued for 2 hours and 55 minutes. Then tetrakis (triphenylphosphine) palladium (250 mg, 0.305 mol), water (2 ml) and tripotassium phosphate (820 mg, 3.9 mol) were added to the reaction mixture, followed by raising the temperature to an external temperature of 100 °. C and agitation for 2 hours and 30 minutes. The reaction mixture was then stirred at an external temperature of 80 ° C for 18 hours and 30 minutes. Ethyl acetate was added to the reaction mixture which was filtered through celite. The filtrate was then concentrated, the extraction was carried out with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, after which the desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 1.35 g of the title compound as a yellow solid. ^? - NMR (400 MHz, CDC13) d: 1.04 (s, 12H), 1.39 (s, 2H), 1.97 (d, J = 1.6 Hz, 2H), 5.300-5.304 (m, ÍH), 6.08 (s) , 2H), 6.63 (s, ÍH), 7.35 (s, - - ÍH). (13c) 6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-ylamine [Chemical Formula 149] A mixture of 5-nitro-6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxole (900 mg, 2.97 mol), 10% palladium on carbon (450 mg, wet ), methanol (8 ml) and tetrahydrofuran (6 ml) was stirred at ordinary temperature and atmospheric pressure overnight under a hydrogen atmosphere. The mixture was filtered through celite to remove the catalyst and the filtrate was concentrated. A crude product of the title compound (834 mg) was obtained as a yellow oil. (13d) 1- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine [Chemical Formula 150] A solution of 6- (3,3,5,5-tetramethylcyclohex-l-enyl) benzo [1,3] dioxol-5-alamine (834 mg, 3.05 mol) and bis (2-chloroethyl) amine hydrochloride (680 mg, 3.81 mol) in 1,2-dichlorobenzene (10 ml) was stirred at an external temperature of 220 ° C for 7 hours and 35 minutes. The excess hydrogen chloride gas in the reactor was stirred several times by nitrogen gas. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added and extraction was carried out with chloroform. The aqueous layer was re-extracted with chloroform and the organic layers were combined and washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 280 mg of the title compound as a brown oil. X H-NMR (400 MHz, CDCl 3) d: 1.01 (s, 6 H), 1.05 (s, 6 H), 1.37 (s, 2 H), 2.13 (s, 2 H), 2. 81 (br, 4H), 2.93 (br, 4H), 5.37 (s, ÍH), 5.89 (s, 2H), 6.58 (s, ÍH), 6.65 (s, ÍH). (13e) L-Butyl-4- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 151] To a solution of 1- [6- (3, 3, 5, 5-tetramethylcyclohex-1-enyl) benzo [1, 3] dioxol-5-yl] piperazine (30 mg, 0.088 mol) in tetrahydrofuran (1 ml) Butyric aldehyde (9.5 mg, 0.13 mol), sodium triacetoxyborohydride (37 mg, 0.18 mol) and acetic acid (5.3 mg, 0.088 mol) were added in that order, followed by stirring at room temperature for 15 minutes. Aqueous saturated sodium hydrogencarbonate was added to the reaction mixture, and then the extraction was carried out with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give l-butyl-4- [6- (3, 3, 3, 5, 5-tetramethylcyclohex-1-enyl) benzo [1, 3] dioxol-5-yl] piperazine. XH-NMR (400 MHz, CDCl 3) d: 0.86-0.95 (m, 3H), 1.02 (s, 6H), 1.05 (s, 6H), 1.26-1.37 (m, 4H), 1.43-1.53 (m, 2H), 2.13 (s, 2H), 2.33-2.37 (m, 2H), 2.52 (br, 4H), 2.89 (br, 4H), 5.38 (s, ÍH), 5.89 (s, 2H), 6.59 (s, ÍH), 6.67 (s, ÍH) . The compound thus obtained was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated, hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 33 mg of the title compound as a white solid. MS m / e (ESI) 399 (MH +). (Example 14) l-Butyl-4- [6- (3,3,5,5-tetramethylcyclohexyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 152] A mixture of l-butyl-4- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride (16 mg, 0.037 mol), 10% palladium on carbon (94 mg, wet), methanol (10 ml) and tetrahydrofuran (5 ml) were - stirred at room temperature for 9 hours and 20 minutes under an atmosphere of hydrogen at 3 atmospheric pressures. The mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated. Hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 10 mg of the title compound as a white solid. MS m / e (ESI) 401 (MH +). (Example 15) l-Butyl-4- [7- (3,3,5,5-tetramethylcyoohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine hydrochloride [Chemical Formula 153] (15a) 6-bromo-7-nitro -2,3-dihydrobenzo [1,4] dioxin [Chemical Formula 154] - A solution of 3,4-ethylenedioxybromobenzole (785 mg, 3.54 mol) in acetic acid (30 ml) was cooled to 10 ° C and then concentrated nitric acid (10 ml) was gradually added to the reaction mixture while stirring. The reaction mixture was further stirred for 60 minutes at room temperature. Then, the reaction mixture was cooled to 0 ° C and ice water was added while stirring. Diethyl ether and water were added to the reaction mixture and the organic layer was collected. The organic layer was washed with potassium carbonate and IN aqueous sodium hydroxide and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. A crude product of the title compound (870 mg) was obtained as a white solid. XH-NMR (400 MHz, CDC13) d: 4.29-4.35 (m, 4H), 7.21 (s, ÍH), 7.59 (s, ÍH). (15b) 6-nitro-7- (3,3,5,5-tetramethylcyclohex-1-enyl) -2,3-dihydrobenzo [1,4] dioxin [Chemical Formula 155] - To a solution of 6-bromo-7-nitro-2,3-dihydrobenzo [1,4] dioxin (870 mg, 3.35 mol) in 1,2-dimethoxyethane (20 ml) was added 4, 4, 5, 5 -tetramethyl-2- (3,3,5,5-tetramethylcyclohex-1-enyl) - [1,3,2] dioxaborolane (1.06 g, 4.02 mol) produced in Production Example 2B, tripotassium phosphate (1.07 g, 5.03 mol) and water (1 ml). To the mixture was added tetrakis (triphenylphosphine) palladium (0) (194 mg, 0.168 mol) under a nitrogen atmosphere followed by stirring at an external temperature of 80 ° C for 2 hours and 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (220 mg, 0.20 mol) was added to the reaction mixture followed by stirring at an external temperature of 90 ° C for 4 hours and 30 minutes. To the reaction mixture was added additionally an aqueous solution (1.5 ml) of tetrakis (triphenylphosphine) palladium (0) (195 mg, 0.168 mol) and tripotassium phosphate (1 g, 5.0 mol) followed by stirring at an external temperature of 75 ° C for 10 hours and 30 minutes. After the addition of ethyl acetate, the reaction mixture was filtered through celite. The filtrate was concentrated and then the extraction was carried out with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 986 mg of the title compound as a light yellow solid. -NMR (400 MHz, CDCl3) d: 1.03 (s, 6H), 1.05 (s, 6H), 1.39 (s, 2H), 1.95 (d, J = 1.6 Hz, 2H), 4.28-4.34 (m, 4H), 5.30 (t, J = 1.6 Hz, ÍH), 6.69 (s, ÍH), 7.48 (s, ÍH). (15c) 7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-ylamine [Chemical Formula 156] A mixture of 6-nitro-7- (3,3,5,5-tetramethylcyclohex-1-enyl) -2,3-dihydrobenzo [1,4] dioxin (986 mg, 3.11 mol), 10% palladium on carbon (1 g, wet), methanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 6 hours and 30 minutes under an atmosphere of hydrogen at 3 atmospheric pressures. The mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated. A crude product of the title compound (880 mg) was obtained as a light yellow oil. The product thus obtained was used without further purification for the next reaction. (15d) l- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine [Chemical Formula 157] A solution of 7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-alamine (880 mg, 3.04 mol) and bis (2-chloroethyl) amine hydrochloride ( 678 mg, 3.8 mol) in 1,2-dichlorobenzene (10 ml) was stirred at an external temperature of 220 ° C for 6 hours and 20 minutes. The excess hydrogen chloride gas in the reactor was stirred several times by nitrogen gas. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added and extraction was carried out with chloroform. The aqueous layer was re-extracted with chloroform, and the organic layers were combined and washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography of silica gel column NH (ethyl acetate / heptane) to give 511 mg of the title compound as a white solid. -NMR (400 MHz, CDC13) d: 0.99 (s, 6H), 1.11 (s, 6H), 1.13-1.18 (m, 2H), 1.24-1.32 (m, 2H), 1.39-1.43 (m, 2H) , 2.77 (br, 4H), 2.99 (dd, J = 4.8, 4.4 Hz, 4H), 3.45 (tt, J = 13, 2.8 Hz, ÍH), 4.22 (s, 4H), 6.65 (s, ÍH), 6.70 (s, ÍH). (15e) l -butyl -4 - [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine hydrochloride [Chemical Formula 158] solution of 1- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine (10 mg, 0.028 mol) in tetrahydrofuran (1 ml) is added butyraldehyde (3.0 mg, 0.042 mol), sodium triacetoxyborohydride (12 mg, 0.056 mol) and acetic acid (2 mg, 0.028 mol) in that order, followed by stirring at room temperature for 30 minutes. Saturated sodium hydrogencarbonate was added The aqueous mixture was added to the reaction mixture and then the extraction was carried out with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give l-butyl-4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1 , 4] dioxin-6-yl] piperazine as a white solid. ^ -NMR (400 MHz, CDCl3) d: 0.91 (s, 6H), 0.93 (t, J = 7.2 Hz, 3H), 1.10 (s, 6H), 1.25-1.55 (m, 9H), 1.70 (br, ÍH), 2.35-2.40 (m, 2H), 2.56 (br, 4H), 2.85 (t, J = 4.6 Hz, 4H), 3.47 (tt, J = 13, 2.8 Hz, ÍH), 4.21 (s, 4H ), 6.67 (s, ÍH), 6.70 (s, ÍH). The compound thus obtained was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated, hexane was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 12.6 mg of the title compound as a white solid. MS m / e (ESI) 415 (MH +). (Example 16) 4- (4-Propylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester hydrochloride [Chemical Formula 159] (16a) 4- (2-Bromo-4-methoxycarbonylphenyl) piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 160] A mixture of 3-bromo-4-fluorobenzoic acid methyl ester (5.1 g, 21.9 mol), piperazine-1-carboxylic acid t-butyl ester (5.3 g, 28.5 mol), potassium carbonate (6.05 g, 43.8 mol) ) and dimethyl sulfoxide (80 ml) was stirred at an external temperature of 130 ° C. After stirring the reaction mixture for 5 hours and 30 minutes, ethyl acetate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed twice with water, washed once with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3.12 g of the title compound as a light yellow oil. XH-NMR (400 MHz, CDCl 3) d: 1.49 (s, 9H), 3.07 (t, J = 4.8 Hz, 4H), 3.62 (t, J = 4.8 Hz, 4H), 3.90 (s, 3H), 7.01 (d, J = 8.4 Hz, HH), 7.94 (dd, J = 8.4, 2.0 Hz, HH), 8.24 (d, J = 2.0 Hz, HH). (16b) 4- [4-methoxycarbonyl-2- (3,3,5,5-tetramethylcyclohex-1-enyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester [Chemical Formula 161] A mixture of 4- (2-bromo-4-methoxycarbonylphenyl) piperazine-l-carboxylic acid t-butyl ester (3.12 g, 7.81 mol), 4, 4, 5, 5-tetramethyl-2- (3, 3) , 5, 5-tetramethylcyclohex-l-enyl) [1, 3, 2] dioxaborlane (3.1 g, 11.73 mol) produced in Production Example 2B, tripotassium phosphate (3.3 g, 15.55 mol) and 1,2-dimethoxyethane ( 30 ml) was stirred at room temperature under a nitrogen atmosphere. Tetrakis (triphenylphosphine) palladium (0) (905 mg, 0.783 mol) was added to the mixture. Then, the reaction mixture was stirred at an external temperature of 85 ° C for 18 hours and 10 minutes.

Ethyl acetate and water were added to the reaction mixture, which was then filtered through celite. The organic layer obtained from the filtrate was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 3.11 g of the title compound as a yellow oil. ^ -NMR (400 MHz, CDC13) d: 1.02 (s, 6H), 1.09 (s, 6H), 1.40 (s, 2H), 1.48 (s, 9H), 2.13 (d, J = 1.2 Hz, 2H) , 3.01 (t, J = 4.8 Hz, 4H), 3.53 (t, J = 4.8 Hz, 4H), 3.89 (s, 3H), 5.60 (s, ÍH), 6.94 (d, J = 8.4 Hz, ÍH) , 7.73 (d, J = 2.0 Hz, ÍH), 7.86 (dd, J = 8.4, 2.0 Hz, ÍH). (16c) 4- [4-methoxycarbonyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 162] A mixture of 4- [4-methoxycarbonyl-2- (3,3,5,5-tetramethylcyclohex-l-enyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (800 mg, 1.75 mol), palladium al 10% carbon (400 mg, wet), methanol (10 ml) and tetrahydrofuran (10 ml) was stirred at ordinary temperature and atmospheric pressure for 40 hours under a hydrogen atmosphere. The reaction mixture was filtered and then the filtrate was concentrated. Ethyl acetate was added to the residue and after filtration, the filtrate was concentrated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 740 mg of the title compound as colorless crystals. XH-NMR (400 MHz, CDC13) d: 0.94 (s, 6H), 1.10 (s, 6H), 1.15-1.46 (m, 6H), 1.49 (s, 9H), 2.87 (t, J = 4.8 Hz, 4H), 3.48 (tt, J = 12.4, 3.2 Hz, ÍH), 3.58 (brs, 4H), 3.89 (s, 3H), 7.04 (d, J = 8.4 Hz, ÍH), 7.82 (dd, J = 8.4 , 2.4 Hz, ÍH), 7.90 (d, J = 2.4 Hz, ÍH). (16d) 4-piperazin-l-3 - (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester [Chemical Formula 163] A mixture of 4- [4-methoxycarbonyl] -2- (3, 3, 5, 5- t-butyl ester - tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid (738 mg, 1.61 mol), trifluoroacetic acid (2 ml, 25.96 mol) and dichloromethane (10 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water and saturated aqueous sodium hydrogencarbonate was added to make the mixture basic. Then, ethyl acetate, tetrahydrofuran and water were added to the mixture and the organic layer was collected. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The desiccant was filtered and the filtrate was concentrated under reduced pressure to give 538 mg of a crude product of the title compound as a yellow solid. ^ -NMR (400 MHz, CDCl3) d: 0.94 (s, 6H), 1.12 (s, 6H), 1.16-1.46 (m, 6H), 2.98 (t, J = 4.8 Hz, 4H), 3.13 (t, J = 4.8 Hz, 4H), 3.46 (tt, J = 12.4, 3.2 Hz, ÍH), 3.90 (s, 3H), 7.08 (d, J = 8.4 Hz, ÍH), 7.83 (dd, J = 8.4, 2.4 Hz, ÍH), 7.90 (d, J = 2.4 Hz, ÍH). (16e) 4- (4-PropiIpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester hydrochloride [Chemical Formula 164] To a mixture of 4-piperazin-1-yl-3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester (178 mg, 0.496 mol), propionaldehyde (0.07 ml, 0.97 mol) and tetrahydrofuran (7 ml) was added sodium triacetoxyborohydride (260 mg, 1227 mol) and acetic acid (0.03 ml, 0.524 mol) in that order at room temperature. After stirring the reaction mixture for 1 hour, ethyl acetate, aqueous saturated sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 168 mg of methyl 4- (4-propylpiperazin-1-yl) -3- (3, 3, 5, 5-tetramethylcyclohexyl) benzoic acid as a white solid. XH-NMR (400 MHz, CDC13) d: 0.92 (t, J = 8.0 Hz, 3H), 0.92 (s, 6H), 1.11 (s, 6H), 1.17- - - 1. 46 (m, 6H), 1.51-1.63 (m, 2H), 2.39 (t, J = 8.0 Hz, 2H), 2.63 (brs, 4H), 2.98 (t, J = 4.8 Hz, 4H), 3.45 (tt) , J = 12.4, 2.8 Hz, ÍH), 3.88 (s, 3H), 7.06 (d, J = 8.4 Hz, ÍH), 7.80 (dd, J = 8.4, 2.0 Hz, ÍH), 7.87 (d, J = 2.0 Hz, ÍH). This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated, diethyl ether and hexane were added to the resulting residue. The resulting precipitate was filtered and dried with a vacuum pump to give 124 mg of the title compound as colorless crystals. MS / m / e (ESI) 355 (MH +). (Example 17) 4- [4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzyl] morpholine dihydrochloride [Chemical Formula 165] (17a) 4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester [Chemical Formula 166] To a mixture of 4-piperazin-1-yl-3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester (180 mg, 0.502 mol), butyraldehyde (0.09 ml, 1.01 mol) and tetrahydrofuran (7) ml) was added sodium triacetoxyborohydride (265 mg, 1.25 mol) and acetic acid (0.03 ml, 0.524 mol) in that order at room temperature. After stirring the reaction mixture for 1 hour, ethyl acetate, aqueous saturated sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 190 mg of the title compound as colorless crystals. ^ -NMR (400 MHz, CDCl3) d: 0.94 (t, J = 8.0 Hz, 3H), 0.94 (s, 6H), 1.11 (s, 6H), 1.16-1.57 (m, 10H), 2.37-2.43 ( m, 2H), 2.61 (brs, 4H), 2.96 (t, J = 4.8 Hz, 4H), 3.45 (tt, J = 12.4, 3.2 Hz, ÍH), 3.88 (s, 3H), 7. 06 (d, J = 8.4 Hz, ÍH), 7.80 (dd, J = 8.4, 2.4 Hz, ÍH), 7.87 (d, J = 2.4 Hz, ÍH). (17b) 4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid [Chemical Formula 167] A mixture of 4- (4-butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester (158 mg, 0.381 mol), IN of aqueous sodium hydroxide (0.8 ml) and methanol (3 ml) was heated to reflux for 6 hours and 40 minutes. Aqueous saturated ammonium chloride, ethyl acetate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure to give 145 mg of a crude product of the title compound as colorless crystals. XH-NMR (400 MHz, CDCl 3) d: 0.89 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.09 (s, 6H), 1.09- 1-42 (m, 8H), 1.56-1.66 (m, 2H), 2.51-2.60 (m, 2H), 2.80 (brs, 4H), 3.01 (brs, 4H), 3.40 (tt, J = 12.0, 3.2 Hz, HH), 7.01 (d, J = 8.0 Hz, HH), 7.80 (d, J = 8.4, 2.0 Hz, HH), 7.91 (d, J = 2.0 Hz, HH). (17c) [4- (4-Butylpiperazin-1-yl) -3- (3, 3,5,5-tetramethylcyclohexyl) phenyl] morpholin-4-ylmethanone [Chemical Formula 168] To a mixture of 4- (4-butylpiperazin-1-yl) -3- (3, 3, 3, 5, 5-tetramethylcyclohexyl) benzoic acid (131 mg, 0.327 mol) and dimethylformamide (7 ml) was added monohydrate from 1- hydroxybenzothiazole (137 mg, 1.01 mol), morpholine (0.059 ml, 0.677 mol), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (194 mg, 1.01 mol) and triethylamine (0.159 ml, 1.14 mol) in that order at room temperature. After the reaction mixture was stirred for 67 hours and 45 minutes, ethyl acetate, aqueous saturated sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The layer The collected organic was washed twice with water, washed once with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 132 mg of the title compound as a colorless oil. ^ -NMR (400 MHz, CDCl3) d: 0.92 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.11 (s, 6H), 1.15-1.56 (m, 10H), 2.36-2.43 ( m, 2H), 2.60 (brs, 4H), 2.93 (t, J = 4.8 Hz, 4H), 3.51 (tt, J = 12.4, 2.8 Hz, ÍH), 3.69 (brs, 8H), 7.07 (d, J = 8.0 Hz, HH), 7.17 (dd, J = 8.0, 2.0 Hz, HH), 7.26 (d, J = 2.0 Hz, HH). (17d) 4- [4-butylpiperazin-1-yl] -3- (3, 3,5,5-tetramethylcyclohexyl) benzyl] morpholine, and [4- (4-butylpiperazin-1-yl) -3- (3 , 3,5,5-tetramethylcyclohexyl) phenyl] methanol [Chemical Formula 169] Lithium aluminum hydride (31 mg, 0. 817 mol) in anhydrous tetrahydrofuran (5 ml). A solution of [4- (4-butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] morpholin-4-ylmethanone (97 mg, 0.206 mol) in tetrahydrofuran was added to the suspension. anhydrous (5 ml) at room temperature. Then, the reaction mixture was stirred under a nitrogen atmosphere while heating to reflux for 4 hours and 40 minutes, and then lithium aluminum hydride (31 mg, 0.817 mol) was added and the mixture was further stirred for 4 hours while it was heated to reflux. Sodium fluoride (600 mg) was added to the reaction mixture and gradually water (0.24 ml) was added while blowing nitrogen gas. After stirring the reaction mixture for 50 minutes, the insoluble material was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 23 mg of 4- [4- (4-butylpiperazin-1-yl) -3- (3,3,5,5- tetramethylcyclohexyl) benzyl] morpholine as a colorless oil and 53 mg of 4- [4- (4-butylpiperazin-1-yl) -3- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenyl] methanol as colorless crystals. 4- [4- (4-Butylpiperazin-1-yl) -3- (3, 3,5, 5-tetramethylcyclohexyl) benzyl] morpholine: XH-NMR (400 MHz, CDCl 3) d: 0.93 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.09 (s, 6H), 1.13- - 1. 57 (m, 10H), 2.35-2.46 (m, 6H), 2.59 (brs, 4H), 2.91 (t, J = 4.8 Hz, 4H), 3.44 (s, 2H), 3.51 (tt, J = 12.4, 3.2 Hz, HH), 3.71 (tt, J = 4.8 Hz, 4H), 7.06 (d, J = 8.0 Hz, HH), 7.07-7.12 (m, 2H). 4- [4- (4-Butylpiperazin-1-yl) -3- (3, 3,5,5-tetramethylcyclohexyl) phenyl] methanol: ^ -NMR (400 MHz, CDC13) d: 0.93 (S, 6H), 0.95 (t, J = 7.2 Hz, 3H), 1.12 (s, 6H), 1.12-1.57 (m, 10H), 2.35-2.43 (m, 2H), 2.60 (brs, 4H), 2.90 (t, J = 4.8 Hz, 4H), 3.56 (tt, J = 12.8, 3.2 Hz, ÍH), 4.63 (s, 2H), 7.10 (d, J = 8.0 Hz, ÍH), 7.15 (dd, J = 8.0, 1.6 Hz, ÍH), 7.23 (d, J = 1.6 Hz, ÍH). (17e) 4- [4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzyl] morpholine dihydrochloride [Chemical Formula 170] After dissolving 4- [4- (4-butylpiperazin-1-yl) -3- (3, 3, 3, 5, 5-tetramethylcyclohexyl) benzyl] morpholine (23 mg, 0.05 mol) in dichloromethane (2 ml), added to it a 4N solution of hydrogen chloride in ethyl acetate (0.04 ml). The mixture was concentrated by blowing nitrogen gas and then diethyl ether was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 31 mg of the title compound as a colorless solid. MS m / e (ESI) 442 (MH +). Example 18) l-Butyl-4- [4-methoxymethyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 171] Sodium hydride (60% dispersion in oil, 8 mg, 0.2 mol) was suspended in dimethylformamide (1 ml) followed by stirring at room temperature under a nitrogen atmosphere. A solution of 4- [4- (4-butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] methanol (51 mg, 0.1332 mol) in dimethylformamide was added to the suspension. ml). The reaction mixture was stirred for 20 minutes and then the reaction mixture was cooled in ice water and iodomethane (0.013 ml, 0.2 mol) was added. Then, the reaction mixture was stirred at room temperature for 3 hours.

- The reaction mixture was cooled in ice water and then water was added. Then, ethyl acetate was added and the extraction was carried out with ethyl acetate. The organic layer collected was washed twice with water, washed once with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 30 mg of l-butyl-4- [4-methoxymethyl-2- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenyl ] Piperazine as a colorless oil. ^? - NMR (400 MHz, CDC13) d: 0.92 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.12 (s, 6H), 1.12-1.57 (m, 10H), 2.35-2.42 (m, 2H), 2.60 (brs, 4H), 2.91 (t, J = 4.8 Hz, 4H), 3.37 (s, 3H), 3.55 (tt, J = 12.4, 2.8 Hz, ÍH), 4.38 (s, 2H), 7.08 (brs, 2H), 7.17 (brs, ÍH). This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated by blowing nitrogen gas and then diethyl ether was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 33 mg of the title compound as a light brown solid. MS m / e 401 (MH +). (Example 19) - 1- [4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] -3-methoxypropan-1-one hydrochloride [Chemical Formula 172] (19a) 4- [4-bromo-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 173] A mixture of 4- [2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (2.93 g, 7.31 mol) produced in Production Example 5, sodium acetate (6 g, 73.14 mol) and methanol (50 ml) was stirred at room temperature under a nitrogen atmosphere. Bromine (0.37 ml, 7.22 mol) was then added to the mixture. After stirring the reaction mixture for 20 minutes, saturated aqueous sodium thiosulfate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 2.67 g of the title compound as colorless crystals. XH-NMR (400 MHz, CDC13) d: 0.93 (s, 6H), 1-10 (s, 6H), 1.12-1.45 (m, 6H), 1.49 (s, 9H), 2.79 (brs, 4H), 3.48 (br, 4H), 3.54 (tt, J = 12.4, 2.8 Hz, ÍH), 6.93 (d, J = 8.4 Hz, ÍH), 7.25 (dd, J = 8.4, 2.4 Hz, ÍH), 7.32 (d , J = 2.4 Hz, ÍH). (19b) 4- [4- (3-Methoxyprop-1-ynyl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester [Chemical Formula 174] To a mixture of 4- [4-bromo-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (150 mg, 0.313 mol), methylpropargyl ether (0.08) ml, 0.947 mol), copper iodide (I) (5 mg, 0.026 mol) and triethylamine (3 ml) was added dichlorobis (triphenylphosphine) palladium (II) (11 mg, 0.016 mol) followed by stirring at an external temperature of 80 ° C under a nitrogen atmosphere. After stirring the reaction mixture for 2 hours and 30 minutes, methylpropargyl ether (0.12 ml) was further added., 1.42 mol) and dichlorobis (triphenylphosphine) palladium (II) (15 mg, 0.021 mol) followed by stirring for 2 hours and 30 minutes under the same conditions. Ethyl acetate and water were added to the reaction mixture, which was then filtered. To the filtrate was added 5% aqueous potassium hydrogen sulfate and the extraction was carried out with ethyl acetate. The organic layer collected was washed with 5% aqueous potassium hydrogensulfate, saturated aqueous sodium hydrogencarbonate and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / heptane) to give 106 mg of the title compound as a yellowish brown solid. ^ -NMR (400 MHz, CDCl3) d: 0.93 (s, 6H), 1.10 (s, 6H), 1.12-1.45 (m, 6H), 1.49 (s, 9H), 2.82 (brs, 4H), 3.45 ( s, 3H), 3.49 (tt, J = 12.8, 2.8 Hz, ÍH), 3.56 (br, 4H), 4.31 (s, 2H), 6.97 (d, J = 8.4 Hz, ÍH), 7.24 (dd, J = 8.4, 1.6 Hz, ÍH), 7.34 (d, J = 1.6 Hz, ÍH). (19c) 1- [4- (3-methoxyprop-1-ynyl) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] piperazine, and 3-methoxy-1- [4-piperazin-1-yl] -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] propan-1-one [Chemical Formula 175] A mixture of 4- [4- (3-methoxyprop-1-ynyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine-1-carboxylic acid t-butyl ester (104 mg, 0.222 mol) , trifluoroacetic acid (0.5 ml, 3.89 mol) and dichloromethane (1 ml) was stirred at room temperature for 3 hours and 30 minutes.The reaction mixture was cooled in ice water and made basic with the addition of 5N of sodium hydroxide. After that, ethyl acetate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate.The collected organic layer was washed with water and brine and then dried over anhydrous sodium sulfate.

The desiccant was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / heptane) to give 26 mg of 1- [4- (3-methoxyprop-1-ynyl) -2- (3, 3, 5, 5 -tetramethylcyclohexyl) phenyl] piperazine as a light brown oil and 31 mg of 3-methoxy-l- [4-piperazin-1-yl-3- (3,3,5,5-tetramethylcyclohexyl) phenyl] propan-1-one as a light yellow oil. 1- [4- (3-methoxyprop-1-ynyl) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] piperazine: ^ -NR (400 MHz, CDCl 3) d: 0.92 (s, 6H), 1.11 (s, 6H), 1.12-1.46 (m, 6H), 2.48 (t, J = 4.8 Hz, 4H), 3.03 (t, J = 4.8 Hz, 4H), 3.45 (s, 3H), 3.50 (tt) , J = 12.8, 2.8 Hz, ÍH), 4.31 (s, 2H), 7.00 (d, J = 8.0 Hz, ÍH), 7.24 (dd, J = 8.0, 2.0 Hz, ÍH), 7.32 (d, J = 2.0 Hz, ÍH). 3-methoxy -1- [4-piperazin-1-yl-3- (3,3,5,5-tetramethylcyclohexyl) phenyl] propan-1-one: ^ -NMR (400 MHz, CDCl 3) d: 0.94 (s) , 6H), 1.12 (s, 6H), 1.14-1.45 (m, 6H), 2.91 (t, J = 4.8 Hz, 4H), 3.05 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 6.8 Hz, 2H), 3.39 (s, 3H), 3.47 (tt, J = 12.8, 3.2 Hz, ÍH), 3.82 (t, J = 6.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, ÍH) , 7.76 (dd, J = 8.4, 2.0 Hz, ÍH), 7.87 (d, J = 2.0 Hz, ÍH). (19d) 1- [4- (4-Butylpiperazin-1-yl) -3- hydrochloride (3,3,5,5-tetramethyl-cyclohexyl) phenyl] -3-methoxypropan-l-one [Chemical Formula 176] To a mixture of 3-methoxy-l- [4-piperazin-1-yl-3- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenyl] propan-1-one (10 mg, 0.026 mol) and tetrahydrofuran (2 ml) was added sodium triacetoxyborohydride (14 mg, 0.066 mol) and acetic acid (0.002 ml, 0.035 mol) in that order, at room temperature. After stirring the reaction mixture for 1 hour, ethyl acetate, aqueous saturated sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was concentrated by blowing nitrogen. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give 1- [4- (4-butylpiperazin-1-yl) -3- (3, 3,5,5-tetramethylcyclohexyl) phenyl] -3-methoxypropan-l-one. XH-NMR (400 MHz, CDCl 3) d: 0.93 (S, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.11 (s, 6H), 1.15-1.56 (m, 10H), 2.36-2.44 ( m, 2H), 2.62 (brs, 4H), 2.98 (t, J = 4. 8 Hz, 4H), 3.22 (t, J = 6.8 Hz, 2H), 3.39 (s, 3H), 3.44 (t, J = 12.8, 3.2 Hz, ÍH), 3.82 (t, J = 6.8 Hz, 2H) , 7.08 (d, J = 8.4 Hz, ÍH), 7.75 (dd, J = 8.4, 2.0 Hz, ÍH), 7.86 (d, J = 2.0 Hz, ÍH). This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated by blowing nitrogen gas and then diethyl ether was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 9 mg of the title compound as a white solid. MS / m / e (ESI) 443 (MH +). (Example 20) l-Butyl-4- [4- (3-methoxyprop-1-ynyl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 177] To a mixture of 1- [4- (3-methoxyprop-1-ynyl) -2- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenyl] piperazine (8.7 mg, 0.024 mol), butyraldehyde (0.005 ml, 0.056 mol ) and tetrahydrofuran (2 ml) was added sodium triacetoxyborohydride (13 mg, 0.061) mol) and acetic acid (0.002 ml, 0.035 mol) in that order, at room temperature. After stirring for 1 hour, ethyl acetate, saturated aqueous sodium hydrogencarbonate and water were added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer collected was concentrated by blowing nitrogen. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give l-butyl-4- [4- (3-methoxyprop-1-ynyl) -2- (3, 3, 5, 5-tetramethylcyclohexyl) phenyl] piperazine. XH-NMR (400 MHz, CDC13) d: 0.92 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.11 (s, 6H), 1.13-1.56 (m, 10H), 2.36-2.43 ( m, 2H), 2.60 (brs, 4H), 2.92 (t, J = 4.8 Hz, 4H), 3.45 (s, 3H), 3.44 (tt, J = 12.4, 3.2 Hz, ÍH), 4.31 (s, 2H ), 7.01 (d, J = 8.4 Hz, ÍH), 7.23 (dd, J = 8.4, 2.0 Hz, ÍH), 7.32 (d, J = 2.0 Hz, ÍH). This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated by blowing nitrogen gas and then diethyl ether was added to the resulting residue and the resulting precipitate was triturated by sonication. After removing the supernatant, the precipitate was dried to give 8 mg of the title compound as a white solid. MS / m / e (ESI) 425 (MH +). The following compounds were produced by the general production methods described above, the methods described in the production examples and the examples or combinations of these methods with well-known methods. (Example 21) Hydrochloride of. { 3- (4-t-Butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl} -methyl- (tetrahydropyran-4-yl) amine [Chemical Formula 178] MS m / e (ESI) 468 (MH +). (Example 22) Hydrochloride of. { 3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl} -methyl- (tetrahydropyran-4-yl) amine [Chemical Formula 179] MS m / e (ESI) 470 (MH +). (Example 23) l-Cyclopropylmethyl-4- hydrochloride. { 2- (4,4- diethylcyclohexyl) -4- (4-methoxymethylpiperidin-1-yl) phenyl} piperazine [Chemical Formula 180] MS m / e (ESI) 482 (MH +) (Example 24) L- acid. { 3- (4-t-Butylcyclohexyl) -4- (4-but ipiperazin-1-yl) phenyl} piperidin-4-ioxiacético [Chemical Formula 181] MS m / e (ESI) 514 (MH +). (Example 25) l-Butyl-4- hydrochloride. { 4- (4-methoxymethylpiperidin-1-yl) -2- (3,3,5,5-tetramethylcyclohexyl) phenylpiperazine [Chemical Formula 182] - MS m / e (ESI) 484 (MH +). (Example 26) l-Butyl-4- [2- (4-t-butylcyclohexyl) 5- (2-methoxyethoxy) phenylpiperidine hydrochloride [Chemical Formula 183] MS m / e (ESI) 431 (MH +). (Example 27) [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] methyl (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 184] S m / e (ESI) 470 (MH +). (Example 28) 6- (4-t-Butylcyclohexyl) -4-methyl-7- (4-propylpiperazin-1-yl) -3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride [Chemical Formula] 185] MS m / e (ESI) 414 (MH +). (Example 29) 6- (4-t-Butylcyclohex-l-enyl) -7- (4-cyclopropylmethylpiperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzohydrochloride [1, 4] oxazine [Chemical Formula 186] MS m / e (ESI) 424 (MH +). (Example 30) 6- (4-t-Butylcyclohex-l-enyl) -4-methyl-7- [4- (tetrahydropyran-4-ylmethyl) piperazin-1-yl) -3,4-dihydro-2H hydrochloride -benzo [1,4] oxazine [Chemical Formula 187] MS m / e (ESI) 468 (MH +). (Example 31) [3 - (4-t-Butylcyclohexyl) -2 - (4-butylpiperazin-1-yl) phenyl] (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 188] MS m / e (ESI) 456 (MH +). (Example 32) 6- (4-t-Butylcyclohexyl) -7- (4-isobutyl-piperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride [Chemical Formula] 189] MS m / e (ESI) 428 (MH +). (Example 33) 6- (4-t-Butylcyclohexyl) -7- (4-cyclopropylmethylpiperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride [Chemical Formula 190] MS m / e (ESI) 426 (MH +). (Example 34) 6- (4-t-Butylcyclohexyl) -4-methyl-7- [4- (tetrahydropyran-4-ylmethyl) piperazin-1-yl] -3,4-dihydro-2H-benzohydrochloride [1] , 4] oxazine [Chemical Formula 191] MS m / e (ESI) 470 (MH +). (Example 35) 6- (4-t-Butylcyclohexyl) -4-methyl-7- [4- (3-methylbutyl) piperazin-1-yl] -3,4-dihydro-2H-benzohydrochloride [1, 4] ] oxazine - [Chemical Formula 192] MS m / e (ESI) 442 (MH +). (Example 36) 4-Benzyl-6- (4-t-butylcyclohex-l-enyl) -7- (4-butylpiperazin-1-yl) -4H-benzo [1,4] oxazin-3 -one hydrochloride Chemical Formula 193] MS m / e (ESI) 516 (MH +). (Example 37) 6- (4-t-Butylcyclohex-l-enyl) -7- (4-butylpiperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzohydrochloride [1,4] oxazine [Chemical Formula 194] MS m / e (ESI) 426 (MH +). (Example 38) 6- (4-t-Butylcyclohex-l-enyl) -4-methyl-7- (4-pentylpiperazin-1-yl) -3,4-dihydro-2H-benzohydrochloride [1,4] oxazine [Chemical Formula 195] MS m / e (ESI) 440 (MH +). (Example 39) 6- (4-t-Butylcyclohex-l-enyl) -7- (4-isobutyl-piperazin-1-yl) -4-methyl-3,4-dihydro-2H-benzohydrochloride [1,4] oxazine [Chemical Formula 196] MS m / e (ESI) 426 (MH +). (Example 40) 6- (4-t-Butylcyclohex-l-enyl) -4-methyl-7- [4- (3-methylbutyl) piperazin-1-yl] -3,4-dihydro-2H-benzohydrochloride [1,4] oxazine [Chemical Formula 197] MS m / e (ESI) 440 (MH +). (Example 41) (2-Methoxyethyl) methyl [3, (4-propylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenyl] amine hydrochloride [Chemical Formula 198] MS m / e (ESI) 430 (MH +). (Example 42) [3- (4-Cyclopropylmethylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenyl] (2-methoxyethyl) methylamine hydrochloride [Chemical Formula 199] MS m / e (ESI) 442 (MH +). (Example 43) 1- [5- (2-Methoxyethoxy) -2- (3, 3, 3, 5, 5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 200] S m / e (ESI) 417 (MH +). (Example 44) (S) -1- [2- (4,4-Diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 201] MS m / e (ESI) 456 (MH +). (Example 45) (S) -l-Cyclopropylmethyl-4- [2- (4,4-diethylcyclohexyl) -4- (2-methoxymethylpyrrolidin-1-yl) phenyl] piperazine hydrochloride [Chemical Formula 202] - S m / e (ESI) 468 (MH +). (Example 46) l-Butyl-4- [4- (2-methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 203] S m / e (ESI) 431 (MH +). (Example 47) l-Isobutyl-4- [4- (2-methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 204] MS m / e (ESI) 431 (MH +). (Example 48) 1- [4- (2-methoxyethoxy) -2- (3, 3,5,5-tetramethylcyclohexyl) phenyl] -4- (tetrahydropyran-4-ylmethyl) piperazine hydrochloride [Chemical Formula 205] MS m / e (ESI) 473 (MH +). (Example 49) 1-Propyl-4- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 206] MS m / e (ESI) 385 (MH +). (Example 50) l-Cyclopropylmethyl-4- [6- (3,3,5,5-tetramethylcyclohex-1-enyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 207] MS m / e (ESI) 397 (MH +) (Example 51) L-propyl-4- [6- (3,3,5,5-tetramethylcyclohexyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 208] MS m / e (ESI) 387 (MH +). (Example 52) 1-Propyl-4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl) piperazine hydrochloride [Chemical Formula 209] MS m / e (ESI) 401 (MH +). (Example 53) l-Pentyl-4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine hydrochloride [Chemical Formula 210] MS (Example 54) l-Cyclopropylmethyl-4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine hydrochloride [Chemical Formula 211] MS m / e (ESI) 413 (MH +). (Example 55) 1- (Tetrahydropyran-4-ylmethyl) -4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl] piperazine hydrochloride [Chemical Formula 212] MS m / e (ESI) 457 (MH +). (Example 56) l-Cyclopropylmethyl-4- [6- (3,3,5,5-tetramethylcyclohexyl) benzo [1,3] dioxol-5-yl] piperazine hydrochloride [Chemical Formula 213] MS m / e (ESI) 399 (MH +). (Example 57) 4- (4-Cyclopropylmethylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester hydrochloride [Chemical Formula 214] S m / e (ESI) 413 (MH +). (Example 58) 3-Methoxy-l- [4- (4-propylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] propan-1-ane hydrochloride [Chemical Formula 215 ] MS m / e (ESI) 429 (MH +). (Example 59) 4- [4- (4-propylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzyl] morpholine dihydrochloride [Chemical Formula 216] MS m / e (ESI) 442 (MH +). (Example 60) 4- [4- (4-Cyclopropylmethylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzyl] morpholine dihydrochloride [Chemical Formula 217] MS m / e (ESI) 454 (MH +). (Example 61) 1- [4-methoxymethyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 218] MS m / e (ESI) 387 (MH +). (Example 62) l-Cyclopropylmethyl-4- [4-methoxymethyl-2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 219] MS m / e (ESI) 399 (MH +). (Example 63) 4- (4-Butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) benzoic acid methyl ester hydrochloride [Chemical Formula 220] MS m / e (ESI) 415 (MH +). (Example 64) 1- [4- (3-Methoxyprop-1-ynyl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] -4-propylpiperazine hydrochloride [Chemical Formula 221] MS m / e (ESI) 411 (MH +). (Example 65) l-Cyclopropylmethyl-4- [4- (3-methoxyprop-1-ynyl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 222] MS m / e (ESI) 423 (MH +). (Example 66) 4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) benzoic acid methyl ester hydrochloride [Chemical Formula 223] MS m / e (ESI) 415 (MH +). (Example 67) 4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) benzoic acid [Chemical Formula 224] MS m / e (ESI) 401 (MH +). (Example 68) 1- [5- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) -2-methoxyphenyl] piperazin-4-ol hydrochloride [Chemical Formula 225] MS m / e (ESI) 486 (MH +). (Example 69) 3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) benzoic acid ethyl ester hydrochloride [Chemical Formula 226] MS m / e (ESI) 429 (MH +). (Example 70) 4- (4-t-Butylcylhexyl) -2- (4-butylpiperazin-1-yl) -N-isopropylbenzamide hydrochloride [Chemical Formula 227] MS m / e (ESI) 442 (MH +). (Example 71) 3- (4-t-Butylcyclohex-1-enyl) -4- (4-butylpiperazin-1-yl) benzoic acid ethyl ester hydrochloride [Chemical Formula 228] MS m / e (ESI) 427 (MH +). (Example 72) 3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) benzoic acid ethyl ester hydrochloride [Chemical Formula 229] MS m / e (ESI) 429 (MH +). (Example 73) l-Butyl-4- [2- (4-butylcyclohexyl) naphthalen-1-yl] piperazine hydrochloride [Chemical Formula 230] MS m / e (ESI) 407 (MH +). (Example 74) l-butyl-4- [3- (4-t-butylcyclohex-l-enyl) naphthalen-2-yl] piperazine [Chemical Formula 231] MS m / e (ESI) 405 (MH +). (Example 75) l-butyl-4- [3- (4-t-butylcyclohexyl) naphthalen-2-yl] piperazine [Chemical Formula 232] MS m / e (ESI) 407 (MH +). (Example 76) 3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) -N-ethylbenzamide hydrochloride [Chemical Formula 233] MS m / e (ESI) 428 (MH +). (Example 77) 3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) -N, N-dimethylbenzamide hydrochloride [Chemical Formula 234] MS m / e (ESI) 428 (MH +). (Example 78) [3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) phenyl] morpholin-4-ylmethanone hydrochloride [Chemical Formula 235] MS m / e (ESI) 470 (MH +). (Example 79) 3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) benzamide hydrochloride [Chemical Formula 236] MS m / e (ESI) 400 (MH +) (Example 80) 3- (4-t-Butylcyclohexyl) -2- (4-butylpiperazin-1-yl) -N- (tetrahydropyran-4-yl) benzamide hydrochloride [Chemical Formula 237] MS m / e (ESI) 484 (MH +). (Example 81) 2- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] -N-ethylacetamide hydrochloride [Chemical Formula 238] MS m / e (ESI) 442 (MH +). (Example 82) 4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) benzamide hydrochloride [Chemical Formula 239] MS m / e (ESI) 400 (MH +). (Example 83) 4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) -N, N-dimethylbenzamide hydrochloride [Chemical Formula 240] MS m / e (ESI) 428 (MH +). (Example 84) 4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) -N- (2-methoxyethyl) benzamide hydrochloride [Chemical Formula 241] MS m / e (ESI) 458 (MH +). (Example 85) [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] morpholin-4-ylmethanone hydrochloride [Chemical Formula 242] MS m / e (ESI) 470 (MH +). (Example 86) N- [3- (4-t-Butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] acetamide hydrochloride [Chemical Formula 243] MS m (Example 87) Hydrochloride [3- (4-t-butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] - (tetrahydropyran-4-yl) amine [Chemical Formula 244] MS m / e (ESI) 454 (MH +). (Example 88) 2- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenoxy] -N-ethylacetamide hydrochloride [Chemical Formula 245] - MS m / e (ESI) 458 (MH +). (Example 89) 2- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenoxy] -N, N-dimethylacetamide hydrochloride [Chemical Formula 246] MS m / e (ESI) 458 (MH +). (Example 90) [3 - (4-t-Butylcyclohex-1-enyl) -2 - (4-butylpiperazin-1-yl) phenylamino] acetic acid methyl ester hydrochloride [Chemical Formula 247] MS m / e (ESI) 442 (MH +). (Example 91) 2- [3- (4-t-Butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamino] -N-ethylacetamide hydrochloride [Chemical Formula 248] S m / e (ESI) 455 (MH +). (Example 92) 2- [3- (4-t-Butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamino] -N, N-dimethylacetamide hydrochloride [Chemical Formula 249] S m / e (ESI) 455 (MH +). (Example 93) 1- [3- (4-t-Butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-2-one hydrochloride [Chemical Formula 250] - MS m / e (ESI) 452 (MH +). (Example 94) 1- [3- (4-t-Butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidine-2,6-dione hydrochloride [Chemical Formula 251] MS m / e (ESI) 466 (MH +). (Example 95) 3- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] propionamide hydrochloride [Chemical Formula 252] MS m / e (ESI) 428 (MH +). (Example 96) 3- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] -N-ethylpropionamide hydrochloride [Chemical Formula 253] MS m / e (ESI) 456 (MH +). (Example 97) 3- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] -N, Ndiethylpropionamide Hydrochloride [Chemical Formula 254] MS m / e (ESI) 484 (MH +). (Example 98) [2- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenoxy] ethyl] diethylamine dihydrochloride [Chemical Formula 255] MS m / e (ESI) 472 (MH +). (Example 99) 8- [5- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) -2-methoxyphenyl] -1,4-dioxa-8-aza-spiro [4] hydrochloride 5] Dean [Chemical Formula 256] MS m / e (ESI) 528 (MH +). (Example 100) 1- [5- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) -2-methoxyphenyl] piperidin-4-one hydrochloride [Chemical Formula 257] MS m / e (ESI) 484 (MH +). (Example 101) [l- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-4-yloxy] acetic acid ethyl ester hydrochloride [Chemical Formula 258] MS m / e (ESI) 542 (MH +). (Example 102) 5- (4-t-Butylcyclohexyl) -6- (4-butylpiperazin-1-yl) -2-methylbenzoxazole hydrochloride [Chemical Formula 259] MS m / e (ESI) 412 (MH +). (Example 103) [4- (4-t-Butylcyclohex-l-enyl) -3- (4-butylpiperazin-1-yl) phenyl] - (tetrahydropyran-4-yl) amine hydrochloride [Chemical Formula 260] MS m / e (ESI) 454 (MH +). (Example 104) 2- [- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-4-yloxy] -N, N-dimethylacetamide hydrochloride [Chemical Formula 261 ] S m / e (ESI) 541 (MH +). (Example 105) [3- (4-propylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenoxy] acetonitrile hydrochloride [Chemical Formula 262] S m / e (ESI) 398 (MH +). (Example 106) [3- (4-Butylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenoxy] acetonitrile hydrochloride [Chemical Formula 263] MS m / e (ESI) 412 (MH +). (Example 107) Methanesulfonic acid hydrochloride 3- (4-butylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenyl ester [Chemical Formula 264] MS m / e (ESI) 451 (MH +). (Example 108) Trifluoromethanesulfonic acid 3- (4-cyclopropylmethylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenyl ester [Chemical Formula 265] MS m / e (ESI) 503 (MH +). (Example 109) 1- [4- (4-Cyclopropylmethylpiperazin-1-yl) -3- (3, 3, 3, 5-tetramethylcyclohexyl) phenyl] -3-methoxypropan-1-one hydrochloride [Chemical Formula 266] MS m / e (ESI) 441 (MH +). (Example 110) Morphine-4-carboxylic acid hydrochloride [4- (4-butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] amide [Chemical Formula 267] MS m / e (ESI) 485 (MH +). (Example 111) Morpholine-4-carboxylic acid hydrochloride [4- (4-butylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] methylamide [Chemical Formula 268] - MS m / e (ESI) 499 (MH +). (Example 112) l-Isobutyl-4- [7- (3,3,5,5-tetramethylcyclohexyl) -2,3-dihydrobenzo [1,4] dioxin-6-yl) piperazine hydrochloride [Chemical Formula 269] MS m / e (ESI) 415 (MH +). (Example 113) l-Cyclopropylmethyl-4- [3'-methoxy-4- (3,3,5,5,5-tetramethylcyclohexyl) biphenyl-3-yl] piperazine hydrochloride [Chemical Formula 270] S m / e (ESI) 461 (MH +). (Example 114) 3 '- (4-Cyclopropylmethylpiperazin-1-yl) -4, - (3,3,5,5-tetramethylcyclohexyl) biphenyl-3-carbonitrile hydrochloride [Chemical Formula 271] MS m / e (ESI) 456 (MH +). (Example 115) l-Cyclopropylmethyl-4- [5- (2-methoxyethoxy) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 272] MS m / e (ESI) 429 (MH +). (Example 116) l-Butyl-4- [- (4-butylcyclohexyl) -5- hydrochloride (2-Fexethoxy) phenyl] piperazine [Chemical Formula 273] S m / e (ESI) 493 (MH +). (Example 117) l-Butyl-4- [2- (4-t-butylcyclohexyl) hydrochloride) 5- [2- (2-methoxyethoxy) ethoxy] phenyl] piperazine [Chemical Formula 274] MS m / e (ESI) 475 (MH +). (Example 118) 2- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] propan-2-yl hydrochloride [Chemical Formula 275] MS m / e (ESI) 415 (MH +). (Example 119) [1- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-4-yl] dimethylamine dihydrochloride [Chemical Formula 276] MS m / e (ESI) 483 (MH +). (Example 120) 4- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] thiomorpholine-1-oxide hydrochloride [Chemical Formula 277] MS m / e (ESI) 474 (MH +). (Example 121) Hydrochloride 4- [3- (4-t-butylcyclohexyl) -4- (4- butylpiperazin-1-yl) phenyl] thiomorpholine-1,1-dioxide [Chemical Formula 278] MS m / e (ESI) 490 (MH +). (Example 122) 4- [5- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) -2-methoxyphenyl] thiomorpholine-1,1-dioxide hydrochloride [Chemical Formula 279] MS m / e (ESI) 520 (MH +). (Example 123) 6- [4- (4-Cyclopropylmethylpiperazin-1-yl) -3- (3,3,5,5-tetramethylcyclohexyl) phenyl] -lH-pyridin-2-one hydrochloride [Chemical Formula 280] MS m / e (ESI) 488 (MH +). (Example 124) Hydrochloride 1- [2,4-bis (3,3,5,5-tetramethylcyclohexyl) phenyl] -4-butylpiperazine [Chemical Formula 281] MS m / e (ESI) 495 (MH +). (Example 125) 1-Propyl-4- [4- (3,3,5,5-tetramethylcyclohex-1-enyl) -2- (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 282] S m / e (ESI) 479 (MH +) (Example 126) l-Butyl-4- [2- (4-t-butylcyclohexyl) -methanesulfonylphenyl] piperazine hydrochloride [Chemical Formula 283] S m / e (ESI) 435 (MH +). (Example 127) Benzyl- [3- (4-t-butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] methylamine hydrochloride [Chemical Formula 284] S m / e (ESI) 476 (MH +). (Example 128) 2- [3- (4-t-Butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamino] acetamide hydrochloride [Chemical Formula 285] MS m / e (ESI) 427 (MH +). (Example 129) [3- (4-t-Butylcyclohex-l-enyl) -2- (4-butylpiperazin-1-yl) phenylamino] acetic acid [Chemical Formula 286] MS m / e (ESI) 428 (MH +). (Example 130) l-Butyl-4- [2- (4-t-butylcyclohexyl) hydrochloride 4-. { 4- (2-methoxyethoxy) piperidin-1-yl) phenyl] piperazine [Chemical Formula 287] S m / e (ESI) 514 (MH +). (Example 131) [3- (4-Cyclopropylmethylpiperazin-1-yl) -4- (3,3,5,5-tetramethylcyclohexyl) phenoxy] acetonitrile hydrochloride [Chemical Formula 288] MS m / e (ESI) 410 (MH +). (Example 132) 1- [3- (4-t-Butylcyclohex-l-enyl) -4 (4-butylpiperazin-1-yl) phenyl] pyrrolidine-2, 5-dione hydrochloride [Chemical Formula 289] - S m / e (ESI) 452 (MH +) (Example 133) l-Cyclopropylmethyl-4- [5-phenoxy-2 (3,3,5,5-tetramethylcyclohexyl) phenyl] piperazine hydrochloride [Chemical Formula 290] MS m / e (ESI) 447 (MH +) (Example 134) 8- (3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] -1. 4 hydrochloride. -dioxa-8-aza-spiro [4,5] decane [Chemical Formula 291] MS m / e (ESI) 498 (MH +). (Example 135) 1- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-4-one [Chemical Formula 292] - MS m / e (ESI) 454 (MH +). (Example 136) 1- [3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl] piperidin-4-yl hydrochloride [Chemical Formula 293] MS m / e (ESI) 456 (MH +). (Example 137) I- ethyl ester hydrochloride. { 3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl} piperidine-4-carboxylic acid [Chemical Formula 294] MS m / e (ESI) 512 (MH +). (Example 138) Acid l-. { 3- (4-t-Butylcyclohexyl) -4- (4-butylpiperazin-1-yl) phenyl} piperidine-4-carboxylic acid [Chemical Formula 295] MS m / e (ESI) 484 (MH +). (Example 139) [3- (4-Butylpiperazin-1-yl) -4- (3,3,5,5-tetramethylethylhexyl) phenyl] (2-methoxyethyl) methylamine hydrochloride [Chemical Formula 296] - Free form of the title compound: ^ -NR (400 MHz, CDCl 3) d: 0.91 (s, 6H), 0.94 (t, J = 7.2 Hz, 3H), 1.10 (s, 6H), 1.12-1.5 (m, 10H), 2.34-2.43 (m, 2H), 2.59 (brs, 4H), 2.93 (t, J = 4.0 Hz, 4H), 3.35 (s, 3H), 3.36-3.48 (m, 3H), 3.50-3.56 (m, 2H), 6.45 (dd, J = 8.4, 2.8 Hz, ÍH), 6.52 (d, J = 2.8 Hz, ÍH), 7.04 (d, J = 8.4 Hz, ÍH). The title compound, i.e., forms hydrochloride: MS m / e (ESI) 444 (MH +). (Example 140) 1- [3- (4-t-Butylcyclohex-l-enyl) -4- (4-butylpiperazin-1-yl) phenyl] pyrrolidin-2-one hydrochloride [Chemical Formula 297] MS m / e (ESI) 438 (MH +). (Example 141) l-Butyl-4- [1- (4-t-butylcyclohex-l-enyl) naphthalen-2-yl] piperazine hydrochloride [Chemical Formula 298] S m / e (ESI) 405 (MH +). (Example 142) l-Butyl-4- [2- (4-t-butylcyclohexyl) 4-methylsulfanylphenyl] piperazine hydrochloride [Chemical Formula 299] MS m / e (ESI) 403 (MH +). (Example 143) l-Butyl-4- [4- (4-t-butyl cyclohexyl) bifenyl-3-yl] piperazine hydrochloride [Chemical Formula 300] MS m / e (ESI) 433 (MH +). (Example 144) 1- [3 '-methoxy-4- (3,3,5,5-tetramethylcyclohexyl) biphenyl-3-yl] -4-propylpiperazine hydrochloride [Chemical Formula 301] MS m / e (ESI) 449 (MH +). (Example 145) 3 '- (4-Propylpiperazin-1-yl) -4' (3,3,5,5-tetramethylcyclohexyl) biphenyl-3-carbonitrile hydrochloride [Chemical Formula 302] MS m / e (ESI) 444 (MH +). (Example 146) Ethyl ester hydrochloride of 3- [4- (4-t- butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] acrylic [Chemical Formula 303] MS m / e (ESI) 455 (MH +). (Example 147) 3- [4- (4-t-Butylcyclohexyl) -3- (4-butylpiperazin-1-yl) phenyl] acrylic acid [Chemical Formula 304] MS m / e (ESI) 427 (MH +). (Test Example 1: Evaluation of compounds in Jurkat cell adhesion system) (Immobilization of human fibronectin in 96-well plate) Human fibronectin (Becton Dickinson Biosciences) was diluted with phosphate-buffered saline (hereinafter abbreviated as PBS; ) up to 0.1-0.01 ug / ml, and the diluted solution was added to a 96-well plate (Becton Dickinson) at 50 ul / well, and allowed to stand overnight 4 ° C. The next day, the supernatant was removed from the plate, and then PBS containing 1% bovine serum albumin (abbreviated as BSA, Sigma) was added thereto at 100 ul / well and the incubation was carried out at 37 ° C during 2 hours in a C02 incubator (Hirasawa). (Adhesion analysis) The supernatant was removed from each plate and the Jurkat cells suspended in RPMI-1640 (Sigma) containing 1 mg / ml BSA were added at 80 ul / well for 2.5 x 10 5 cells / well. The compound diluted to different concentrations with RPMI 1640 containing 1 mg / ml of BSA was immediately added to 10 ul (well, and then 100 nM of phorbol myristate acetate (hereinafter abbreviated as PMA; Sigma) in RPMI 1640 containing 1 mg was added. / ml of BSA at 10 ul / well and the plate was incubated in a C02 incubator at 37 ° C for 45-60 minutes The supernatant was removed from the plate and each well was washed several times with 100 ul / well of RPMI 1640, after which 50 mM citrate buffer (pH 5.0) containing 3.75 mM p-nitrophenol-N-acetyl-bD-glucosaminide (Sigma) and 0.25% Triton X-100 (Sigma) at 60 ul / well, and the mixture was placed in a C02 incubator and incubated at 37 ° C for 45 minutes.After incubation, 50 mM buffer was added of glycine (pH 10.4) containing 5 mM EDTA at 90 ul / well, and the absorbance at 405 nm was measured with an EL 340 Automated Microplate Reader (BIO-TEK) to determine the count of adhered cells. The concentration of each compound that inhibited the increase in the number of adhered cells by PMA stimulation by 50% is shown as the IC50 (uM) in the table below. [Table 1] (Test Example 2: Evaluation of compounds in the neutrophil adhesion system in human peripheral blood) (Preparation of neutrophils in human peripheral blood) To a plastic centrifuge tube containing 100 units of sodium heparin (Shimizu Pharmaceutical) was added 25 ml of fresh blood taken from a sample of a healthy human. After adding and mixing with it 8 ml of physiological saline (Otsuka Pharmaceutical) containing 6% dextran (Nacalai), the mixture was allowed to stand at room temperature for 45 minutes for erythrocyte sedimentation. The resulting supernatant was transferred to another plastic centrifuge tube and combined with an equivalent volume of phosphate buffered saline (hereinafter abbreviated as PBS, Sigma), and then centrifuged at 1600 rpm for 7 minutes at room temperature. The fraction of hematocytes obtained was suspended in 4 ml of PBS, and the suspension was superimposed on 4 ml of Ficoll -Paque ™ PLUS (Amersham Biosciences). The resulting bilayer liquid was centrifuged at 2000 rpm for 30 minutes at room temperature, after which the supernatant was removed and the precipitate was suspended in 10 ml of PBS and centrifuged at 1200 rpm for 7 minutes, and the supernatant was removed. The resulting precipitate was suspended in 0.5 ml of PBS again, and then 10 ml of distilled water (Otsuka Pharmaceutical) was added, immediately 0.5 ml of an aqueous solution containing 3 M NaCl was added to restore isotonicity, the mixture was centrifuged at 1200 rpm for 7 minutes, and the precipitate obtained was suspended in PBS containing 1 mg / ml of bovine serum albumin (hereinafter abbreviated as BSA).; Sigma) again, and it was stored on ice until used for the experiment. (Fluorescent labeling of neutrophils in human peripheral blood) The obtained neutrophils were suspended in PBS containing 1 mg / ml of BSA at 2 x 10 7 cells / ml. BCECF-AM (Dojin) was added to a final concentration of 5 uM, and the mixture was incubated at 37 ° C for 45 minutes. It was then rinsed twice with PBS containing 1 mg / ml of BSA by centrifugation, resuspended in PBS containing 1 mg / ml of BSA at 5 x 10 7 cells / ml, and stored on ice until use. (Preparation of immobilized plate of HUVEC) Human umbilical vein endothelial cells (hereinafter abbreviated as HUVEC) were suspended in medium MCDB131 (Chlorella Industries) containing 10% fetal calf serum and 30 ug / ml growth supplement endothelial cells (Becton Dickinson Bioscience). The suspension was added at 7.5 x 103 cells / well to a 96-well plate (Iwaki) immobilized with type I collagen, and cultured for 3 days in a C02 incubator (Hirasawa). Upon confirming the confluence of the cells, the supernatant was discarded, the plate was rinsed twice with PBS, and then PBS containing 0.1% glutaraldehyde (Kanto Kagaku) was added at 100 ul (well and the HUVECs were immobilized for 5 minutes. The supernatant was discarded and the plate was washed twice with PBS, and then PBS was added to 100 ul / well and the mixture was stored at 4 ° C until use. (Adhesion analysis) To 6.5 ml of RPMI 1640 medium ( Sigma) containing 1 mg / ml of BSA, 0.5 ml of a suspension of neutrophils labeled with BCECF-AM at 5 x 107 / ml stored on ice was added, which were mixed, and the mixture was added at 80 ul / well to a plate immobilized with HUVEC To this plate 10 ul / well of a solution of the compound diluted at different concentrations with RPMI 1640 containing 1 mg / ml of BSA, and 10 ul / well of 100 nM of phorbol myristate acetate (in forward abbreviated as PMA; Sigma) in RPMI 1640 containing 1 mg / ml of BSA, and the mixture was incubated in a C02 incubator at 37 ° C for 45 minutes. The supernatant was removed from the plate, which was then washed several times with RPMI 1640 at 100 ul / well, and then added to the same PBS containing 0.1% NP-40 (Calbiochem) at 100 ul / well and the fluorescent intensity was measured with a multi-labeled ARVOmSX counter (Wallac) to determine the number of adhered cells. The concentration of each compound that inhibited the increase in the number of adhered cells by PMA stimulation by 50% is shown as the IC50 (uM) in the table below. [Table 2] (Test Example 3: Evaluation of compounds in the model of neutrophil infiltration in colon neutrophils induced with oxazolone) (Sensitization with oxazolone) Male Balb / c mice from five to six weeks of age (Charles River Japan) were shaved in the abdomen to an approximate area of 2 square cm. A solution of 100% ethanol containing 3% of 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (hereinafter referred to as "oxazolone" Sigma) was applied at 150 ul on the abdomen of each mouse. (Preparation of oxazolone-containing emulsion) Distilled water (Otsuka Pharmaceutical) was added in a volume equivalent to 100% peanut oil (Kanto Kagaku) containing 1% oxazolone, and the components were mixed vigorously with a glass syringe (Top Co .) to prepare an emulsion containing 0.5% oxazolone. (induction with oxazolone) Mice were fasted on the third day after sensitization with oxazolone, and challenged with 100 ul of the emulsion containing 0.5% oxazolone prepared in the above-described manner intrathecally at a site of approximately 3 cm. from the anus under ether anesthesia on the fourth day.

- (Neutrophil analysis by colon infiltration) Each compound was suspended or dissolved in an aqueous solution containing 0.5% methyl cellulose (Wako) and orally administered at 30 mg / kg, 30 minutes prior to intrathecal challenge of oxazolone emulsion. Four hours after the intrathecal oxazolone challenge, the mice were sacrificed by cervical dislocation, and the colons were excised, dissected in the longitudinal direction, washed with physiological saline and transferred to ice-cooled plastic centrifuge tubes. After adding 1 ml of 50 mM of potassium phosphate buffer (hereinafter abbreviated as KPB) (pH 6.0) to the tube, and of homogenizing the tissues with PHYSCOTRON (Microtec Nition Co., Ltd.), 2 ml of 50 ml. mM of KPB (pH 6.0) and the mixture was centrifuged at 3000 rpm, 4 ° C for 10 minutes and the supernatant was removed. To the resulting precipitate was added 1 ml of 50 mM KPB (pH 6. 0) containing 0.5% hexadecyltrimethyl ammonium bromide (Sigma), and frozen-thawed 3 to 5 times using liquid nitrogen and hot water, centrifuged at 3000 rpm, at 4 ° C for 10 minutes to produce a supernatant. The activity of the myeloperoxidase enzyme in the supernatant was analyzed in the following manner. Specifically, to 10 ul of the obtained supernatant was added 200 ml of 50 mM KPB (pH 6.0) containing o- 0.017% dianisidine (Sigma) and 0.0005% hydrogen peroxide (Wako), was incubated at 37 ° C and the change in absorbance at 450 nm was measured continuously (the rate of change in absorbency per minute (mO.D / min.)) for 1 minute using an EL 340 Automated Microplate Reader (BIO-TEK) in kinetic mode. The inhibitory rate of myeloperoxidase enzyme activity (%) in each of. the groups to which the compound was administered, relative to the control group of oxazolone (the group challenged intrathecally with oxazolone emulsion / compound-free) is shown in the following table. [Table 3] (Test Example 4: Evaluation of compounds in DSS-induced colitis model) Male Balb / c mice 6 to 7 weeks of age (Charles River Japan) were fed freely with a solution of 1-3% dextran sulfate sodium (hereinafter abbreviated as DSS; ICN) in purified water (Otsuka Pharmaceutical) during 5-7 days to induce colitis. The index of disease activity (abbreviated hereinafter referred to as ICD) measured on the basis of fecal hardness, stool blood content and change in body weight, number of neutrophils infiltrated in the colon and length of colon, are used as indexes to evaluate the compounds. Each compound was suspended or dissolved in an aqueous solution containing 0.5% methyl cellulose (Wako) and orally administered at 30 mg / kg once a day for 5-7 successive days. INDUSTRIAL APPLICABILITY The compounds of the invention have an excellent cell adhesion inhibitory action or cell infiltration inhibitory action and accordingly, they can serve as useful pharmaceuticals as therapeutic or prophylactic agents for various inflammatory diseases and autoimmune diseases associated with adhesion and infiltration. of leukocytes, such as intestinal inflammatory diseases (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis.

Claims (29)

1. A compound represented by the following general formula (1), a salt thereof or a hydrate of the foregoing: [Chemical Formula 1] (D wherein R 10 represents 5- to 10-membered cycloalkyl optionally substituted with a substituent selected from Al Group or 5- to 10-membered cycloalkenyl optionally substituted with a substituent selected from Group Al, R30, R31 and R32 can be the same or different and each represents hydrogen, hydroxyl, halogen, cyano, carboxyl, Cl-6 alkyl, Cl-6 alkoxy or C2-7 alkoxycarbonyl, or two of R30, R31 and R32 join together to form oxo (= 0) or methylene (-CH2-) and the other represents hydrogen, hydroxyl, halogen, cyano, carboxyl, Cl-6 alkyl, alkoxy Cl-6 or C2-7 alkoxycarbonyl, R40 represents Cl-10 alkyl optionally substituted with a substituent selected from Group Dl, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from the El Group, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected from the El Group, C 2-7 alkenyl optionally substituted with a substituent selected from Group Fl, C 2-7 alkynyl optionally substituted with a substituent selected from Group Fl, C 2-7 alkylcarbonyl optionally substituted with a substituent selected from Group Gl, mono (C 1-6 alkyl) aminocarbonyl, heterocyclic carbonyl from 4 to 8 members, C 2-7 alkoxycarbonyl or Cl 6 alkylsulfonyl, n represents an integer of 0, 1 or 2, X 1 represents CH or nitrogen, and R 20, R 21, R 22 and R 23 may be the same or different, and each represents hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, alkylthio Cl-6, optionally substituted with a substituent selected from Group Fl, C 2-7 alkoxycarbonyl, phenoxy, -S0 3 H, Cl-6 alkyl optionally substituted with a substituent selected from the Wl Group, Cl-6 alkyl optionally substituted with a substituent selected from Group Kl, Cl-6 alkoxy optionally substituted with a substituent selected from the Wl Group, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Wl group, a 4- to 8-membered heterocyclic group optionally substituted with a substituent selected from Group VI, a 5- to 10-membered heteroaryl ring group optionally substituted with a substituent selected from the Wl Group, an aryl ring group from 6 to 10 member optionally substituted with a substituent selected from the Wl Group, C2-7 alkenyl optionally substituted with a substituent selected from the Wl Group, C2-7 alkynyl optionally substituted with a substituent selected from the Wl Group, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from the Wl Group, 5- to 8-membered cycloalkenyl optionally substituted with a substituent selected from the group W1, -NR1XR2X, -CO-R1, -C0-NR1XR2X, -NR1X-C0-R2X, -S02-R3X or -0-S02 -R3X, wherein R1X and R2X may be the same or different and each represents hydrogen, Cl-6 alkyl optionally substituted with a substituent selected from the Ul Group or a group 4 to 8 membered tetracyclic, and R3X represents Cl-6 alkyl optionally substituted with a substituent selected from Group Fl; or (i) R20 and R21, (ii) R21 and R22 or (iii) R22 and R23 are joined together to form a ring selected from Group Zl, wherein the group Al consists of hydroxyl, halogen, cyano, Cl-alkoxy 6, optionally substituted phenyl with a substituent selected from Cl Group, Cl-6 alkyl, Cl-6 haloalkyl and C 2-7 alkylene wherein C 2-7 alkylene is only permissible in the case where a spiro bond is formed together with the substituted cycloalkyl of 5 to 10. members or with the substituted cycloalkenyl of 5 to 10 members, the Cl group consists of cyano, halogen, alkyl Cl-6 and alkoxy Cl-6, Group Dl consists of hydroxyl, halogen, cyano, alkoxy Cl-6, alkylthio Cl- 6, alkylsulfonyl Cl-6, alkylsulfinyl Cl-6, mono (C 1-6 alkyl) amino, di (C 1-6 alkyl) amino, C 2-7 alkylcarbonylamino, 3 to 8 membered cycloalkyl optionally substituted with a substituent selected from Group Hl, C2-7 alkoxycarbonyl, carboxyl, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl ring group, a 6 to 10 membered aryl ring group, C2-7 alkylcarbonyl, 6-aryl ring carbonyl 10 members, aminocarbonyl, mono (C 1-6 alkyl) aminocarbonyl optionally substituted with halogen, mono (3- to 8-membered cycloalkyl) aminocarbonyl, mono (C 2-7 alkoxyalkyl) aminocarbonyl, di (C 1-6 alkyl) aminocarbonyl, mono (ring) 5-10 membered heteroaryl) aminocarbonyl, 4- to 8-membered heterocyclic carbonyl optionally substituted with Cl-6 alkyl, and 5-10 membered heteroaryl ring carbonyl, - Group El consists of halogen, Cl-6 alkoxy, oxo (= 0) and Cl-6 alkyl, Group Fl consists of halogen and Cl-6 alkoxy, Group Gl consists of cycloalkyl of 3 to 8 members, Group Hl consists of hydroxyl, haloalkyl Cl-6, alkyl Cl-6, alkoxyalkyl C 2-7, mono (C 1-6 alkyl) aminocarbonyl, di (C 1-6 alkyl) aminocarbonyl, C 2-7 alkoxycarbonyl, carboxyl and C 2-7 cyanoalkyl, Group W1 consists of halogen, hydroxyl, cyano, carboxyl, Cl-6 alkyl, C2-7 alkoxyalkyl, Cl-6 alkoxy optionally substituted with a substituent selected from the TI group, phenoxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, -NR6XR7X and -CO-NR6xR7X wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl, the TI group consists of Cl-6 alkoxy, carboxyl, C2-7 alkoxycarbonyl and -CONR4XR5X wherein RX and R5X can be the same or different and each represents hydrogen or Cl-6 alkyl, Group VI consists of oxo (= 0) and etiienodioxy (-0-CH2CH2-0-) in where etiienodioxy is permissible only in the case where a spiro bond is formed together with the substituted heterocyclic group of 4 to 8 members, the Kl Group consists of a heterocyclic group of 4 to 8 members, - the group Ul consists of carboxyl, alkoxy Cl-6, alkoxycarbonyl C2-7, halogen, a group of aryl ring of 6 to 10 members and -C0-NR8XR9X wherein R8X and R9X can be the same or different and each represents hydrogen or Cl-6 alkyl, and the Zl Group consists of [Chemical Formula 3] wherein R 1 Z represents hydrogen, Cl 6 alkyl or benzyl, with the exception exception of a compound represented by the formula: [Chemical Formula 2]

2. A compound represented by the following general formula (100), a salt thereof or a hydrate of the foregoing: [Chemical Formula 4] (100) wherein R10, R20, R21, R22, R23, R30, R31, R32, R40 and n have the same respective definitions as R10, R20, R21, R22, R23, R30, R31, R32, R40 and n in the claim The compound according to claims 1 or 2, the salt thereof or the hydrate of the foregoing, wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with a substituent of Group A2, or cycloalkenyl of 5 to 10 members optionally substituted with a substituent of Group A2, wherein Group A2 consists of hydroxyl, phenyl, Cl-6 alkyl, Cl-6 haloalkyl and C 2-7 alkylene, wherein C 2-7 alkylene is permissible only in the case where a spiro bond is formed together with the substituted cycloalkyl. from 5 to 10 members or substituted cycloalkenyl from 5 to 10 members. 4. The compound according to claim 1 or 2, its salt or the hydrate of the foregoing, wherein R10 is 5- to 10-membered cycloalkyl optionally substituted with hydroxyl, phenyl, Cl-6 alkyl, haloalkyl Cl-6, , 2-ethylene, trimethylene, tetramethylene or pentamethylene, or 5- to 10-membered cycloalkenyl optionally substituted by hydroxyl, phenyl, Cl-6 alkyl, haloalkyl Cl-6, 1,2-ethylene, trimethylene, tetramethylene or pentamethylene where 1, 2-ethylene, trimethylene, tetramethylene or pentamethylene is permissible only in the case where a spiro bond is formed together with 5- to 10-membered cycloalkyl or 5- to 10-membered cycloalkenyl. The compound according to claims 1 or 2, its salt or the hydrate of the foregoing, wherein R 10 is cyclohexyl, 4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-diethylcyclohexyl, 3,3, 5,5-tetramethylcyclohexyl, 3,5-dimethylcyclohexyl, 4-phenylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-n- butylcyclohexyl, cyclopentyl, 3,3,4,4-tetramethylcyclopentyl, cycloheptyl, cyclooctyl, or a group represented by the following formula: [Chemical Formula 5] wherein s is an integer of 0, 1, 2 or

3. The compound according to claims 1 to 5, its salt or the hydrate of the foregoing, wherein R30, R31 and R32 may be the same or different and each represents hydrogen or Cl-6 alkyl, or R30 and R31 are linked together to form oxo (= 0) and R32 is hydrogen or Cl-6 alkyl. The compound according to claims 1 to 5, its salt or the hydrate of the above, wherein R30, R31 and R32 can be the same or different and each represents hydrogen or methyl or R30 and R31 are linked together to form oxo (= 0) and R32 is hydrogen or methyl. 8. The compound according to claims 1 to 5, its salt or the hydrate of the foregoing, wherein R30, R31 and R32 are all hydrogen. The compound according to claims 1 to 8, its salt or the hydrate of the foregoing, wherein R40 is Cl-6 alkyl optionally substituted with a substituent selected from Group Dl, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from the El group, C2-7 alkenyl, C2-7 alkynyl or C2-7 alkylcarbonyl wherein the D1 Group and the El Group have the same respective definitions as the D1 Group and the El Group in claim 1. 10. The compound according to claims 1 to 8, its salt or the hydrate of the foregoing, wherein R40 is Cl-6 alkyl optionally substituted with a substituent selected from Group D2, wherein Group D2 consists of hydroxyl, halogen, cyano, Cl-6 alkoxy, 3- to 8-membered cycloalkyl, a 4- to 8-membered heterocyclic group, mono (Cl-6-alkyl) aminocarbonyl, di (Cl-6-alkyl) aminocarbonyl, C2-7-alkylcarbonyl, a group of 5-membered heteroaryl ring, 4 to 8 membered heterocyclic carbonyl and phenyl. 11. The compound according to claims 1 to 8, its salt or the hydrate of the foregoing, wherein R40 is n-propyl, n-butyl, n-pentyl, isobutyl, ethylcarbonylmethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl or tetrahydropyran- 4-methylmethyl. 12. The compound according to claims 1 to 11, its salt or the hydrate of the foregoing, wherein n is an integer of 1. The compound according to claims 1 and 3 to 12, its salt or the hydrate of the previous ones, where X1 is nitrogen. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein (i) R20 and R21, (ii) R21 and R22 or (iii) R22 and R23 are bonded together to form a ring selected from Group Zl wherein Group Zl has the same definition as Group Zl in claim 1. 15. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein (i) ) R21 and R22 or (ii) R22 and R23 are linked each other to form a ring selected from Group Z2, where Group Z2 consists of [Chemical Formula 6] wherein R1z represents hydrogen, C1-6 alkyl or benzyl, and the carbon atom indicated by "*" is the carbon atom in the benzene ring to which R2 is attached. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein (i) R21 and R22 or (ii) R22 and R23 are linked together to form a ring selected from Group Z3, where the Z3 Group consists of [Chemical Formula 7] wherein the carbon atom indicated by "*" is the carbon atom in the benzene ring to which R22 is attached. 17. The compound according to claims 14 to 16, its salt or the hydrate of the foregoing, wherein R20 and R23 are hydrogen. 18. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein at least one of R20, R21, R22 and R23 is carboxyl, Cl-6 alkylthio optionally substituted with a substituent selected from the group. Fl, C2-7 alkoxycarbonyl, phenoxy, -S03H, Cl-6 alkyl substituted with a substituent selected from Group W2, Cl-6 alkyl substituted with a substituent selected from Group Kl, Cl-6 alkoxy substituted with a substituent selected from Group W2, a 4- to 8-membered heterocyclic group substituted with a substituent selected from Group W3, a 4- to 8-membered heterocyclic group substituted with a substituent selected from Group VI, a 5- to 10-membered heteroaryl ring group substituted with a substituent selected from Group W3, a 6- to 10-membered aryl ring group optionally substituted with a substituent selected from the Wl Group, C2-7 alkenyl optionally substituted with a selected substituent of the Wl Group, C2-7 alkynyl optionally substituted with a substituent selected from Group Wl, 3- to 8-membered cycloalkyl optionally substituted with a substituent selected from Group Wl, 5- to 8-membered cycloalkenyl optionally substituted with a substituent selected from the Wl Group, NR10XR2X, -C0-R11X, -CO-NRlxR2X, -NRlx-CO-R2x, -S02-R3x or -0-S02-R3X, R1X and R2X can be the same or different and each represents hydrogen, Cl-6 alkyl optionally substituted with a substituent selected from Group Ul or a 4- to 8-membered heterocyclic group, R3X represents Cl-6 alkyl optionally substituted with a substituent selected from Group Fl, R10X is Cl-6 alkyl substituted with a substituent selected from the group Ul or a heterocyclic group of 4 to 8 members, and Rllx is hydrogen, Cl-6 alkyl substituted with a substituent selected from Group Ul, or a 4- to 8-membered heterocyclic group, wherein Group W2 consists of hydroxyl, cyano, Cl-6 alkyl, C2-7 alkoxyalkyl , Cl-6 alkoxy optionally substituted with a substituent selected from the TI group, phenoxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, -NRSXR7X and -C0-NR6XR7X wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl, Group W3 consists of hydroxyl, carboxyl, C2-7 alkoxyalkyl, Cl-6 alkoxy substituted with a substituent selected from the TI group, phenoxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, -NR6XR7X and -CO -NR6XR7X wherein R6X and R7X may be the same or different and each represents hydrogen or Cl-6 alkyl, and the Fl Group, Gl Group, Hl Group, Wl Group, Group TI, Group VI, Group Kl, and Group Ul, have the same respective definitions as Group Fl, Group Gl, Group Hl, Group Wl, Group IT, Group VI, Group Kl, and Group Ul in claim 1. 19. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein one of R20, R21, R22 and R23 represent phenyl optionally substituted with a substituent selected from Group P, C2-7 alkenyl optionally substituted with a substituent selected from Group P, C2-7 alkynyl optionally substituted with a substituent selected from Group P, carbonyl, alkylsulfonyloxy Cl-6 optionally having 1 to 3 fluorine, alkylthio Cl-6, alkoxycarbonyl C2-7, alkoxy-Cl-6-alkoxy Cl-6, alkoxyalkylC2-7, morpholin-4-yl-alkyl Cl-6, pyrrolidin-1-yl optionally substituted with a selected substituent of Group Q, piperidin-1-yl optionally substituted with a substituent selected from Group Q, a group represented by the following formula: [Chemical Formula 8] -NR80R81, -C0-R, 8"2 -C0-NR83R84, or -NR85-C0-R86, wherein R, 8B0U represents hydrogen, Cl-6 alkyl, C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R, 81 represents C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R82 represents C2-7 alkoxyalkyl or morpholin-4-yl, R83 and R84 may be the same or different and each represents hydrogen, Cl-6 alkyl, tetrahydropyran-4-yl or C2-7 alkoxyalkyl, R85 represents hydrogen or Cl alkyl -6, and R8S represents Cl-6 alkyl, wherein Group P consists of carboxyl, C2-7 alkoxycarbonyl, C2-7 alkoxyalkyl, Cl6 alkoxy and cyano, and Group Q consists of carboxyl, alkoxycarbonyl C2-7, Cl-6-alkoxy Cl-6 alkoxy, carboxyl-C 1-6 alkoxy, C 2-7 alkoxyalkyl, and hydroxyl. The compound according to claims 1 to 13, its salt or the hydrate of the foregoing, wherein one of R20, R21, R22 and R23 represents phenyl, C2-7 alkoxycarbonyl, C1-6 alkoxy-C1-6 alkoxy , C2-7 alkoxyalkyl, morpholin-4-yl-Cl-6 alkyl, pyrrolidin-1-yl optionally having a substituent selected from Group R, piperidin-1-yl optionally having a substituent selected from Group R, a group depicted by the following formula: [Chemical Formula 9] -NR90R91, -CO-R92, or -CO-NR93R94, wherein R90 represents hydrogen, Cl-6 alkyl, C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R91 represents C2-7 alkoxyalkyl or tetrahydropyran-4-yl, R92 represents C2-7 alkoxyalkyl, and R93 and R94 may be the same or different and each represents hydrogen or Cl-6 alkyl, wherein Group R consists of Cl-6-alkoxy alkoxy Cl-6 and C2-7 alkoxyalkyl. 21. The compound according to claims 18 to 20, its salt or the hydrate of the previous ones, where R20 is hydrogen. 22. The compound according to claims 18 to 20, its salt or the hydrate of the foregoing, wherein two of R20, R21, R22 and R23 are hydrogen, and one of the other two is hydrogen or Cl-6 alkoxy. 23. The compound according to claims 18 to 20, its salt or the hydrate of the foregoing, wherein three of R20, R21, R22 and R23 are hydrogen. 2

4. A medicament comprising the compound according to claims 1 or 2, its salt or the hydrate of the foregoing. 2

5. An inhibitor of cell adhesion or cell infiltration comprising the compound according to claims 1 or 2, its salt or the hydrate of the above. 2

6. A therapeutic or prophylactic agent for an inflammatory disease or an autoimmune disease, comprising the compound according to claims 1 or 2, its salt or the hydrate of the foregoing. 2

7. A therapeutic or prophylactic agent for an inflammatory bowel disease, irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma or atopic dermatitis, comprising the compound according to claims 1 or 2, its salt or the hydrate of the previous ones. 2

8. A therapeutic or prophylactic agent for an inflammatory bowel disease, comprising the compound according to claims 1 or 2, its salt or the hydrate of the foregoing. 2

9. A therapeutic or prophylactic agent for ulcerative colitis or Crohn's disease, comprising the compound according to claims 1 or 2, its salt or the hydrate of the foregoing.