TW201107306A - Substituted piperidine compounds - Google Patents

Abstract

The invention provides a substituted piperidine compound useful as a therapeutic agent for hypertension and the like. The invention provides a compound having the general formula (I) [in formula, R1: H, optionally substituted alkyl, phenyl, saturated cyclic hydrocarbon group, heterocyclic group etc.; R2: H, alkyl; R3, R4: H, alkyl; A: phenyl, pyridyl; R5, R6, R7: H, optionally substituted alkyl, optionally substituted hydroxy, optionally substituted mercapto, optionally substituted amino, substituted carbonyl, substituted sulfonyl, CN, NO2, halo geno and the like].

Description

201107306 VI. Description of the Invention: [Technical Field] The present invention relates to an excellent renin inhibitory activity, and is useful as a medicine [especially for the treatment or prevention of hypertension (preferably treatment). a novel substituted piperidine compound or a pharmacologically acceptable salt thereof; a renin inhibitor containing a substituted piperidine compound or a pharmacologically acceptable salt thereof; #containing a substituted piperidine compound or A pharmaceutical composition whose pharmacologically acceptable salt is an active ingredient' is preferably a pharmaceutical composition for the treatment or prevention of hypertension; a use of a substituted piperidine compound or a pharmacologically acceptable salt thereof Manufacture of a pharmaceutical composition for the treatment or prophylaxis of a disease, preferably a disease as described above; a method for the treatment or prophylaxis of a disease, preferably a disease as described above, by administering an effective amount of a substituted piperidine A compound or a pharmacologically acceptable salt thereof can be administered to a warm-blooded animal (especially a human): and a substituted piperidine compound or a pharmacologically acceptable salt thereof . [Prior Art] Local blood pressure is the most common symptom of blood pressure of 140 mmHg or more, or minimum blood pressure of 90 mmHg or more, and is defined in the guidelines of WHO/ISH. Once the state of hypertension continues, cerebral hemorrhage, cerebral infarction, large aneurysm, nephrosclerosis, myocardial infarction, or heart failure can occur, leading to death. These diseases are suppressed by the administration of therapeutic drugs for hypertension, such as the large-mode clinical trial [S] 201107306, and now, generally, through the administration of hypertensive therapeutic drugs, exercise, and improvement in eating and drinking, etc. Efforts to actively lower blood pressure have been implemented, but further control of blood pressure is still expected. As one of the main mechanisms of hypertension, activation of the renin-angiotensin system (hereinafter also referred to as R-A system) can be exemplified. The R-A system is a representative pressure-up system of a living body in which the amount of circulating blood is increased or the blood vessel smooth muscle is contracted to increase blood pressure by accumulating sodium (salt) in the body. The RA system means that angiotensinogen (Igiotensin I) becomes angiotensin I via renin, and angiotensin I becomes angiotensin via angiotensin-converting enzyme (hereinafter, also referred to as ACE). II. Angiotensin II acts on angiotensin type 1 receptor (hereinafter also referred to as AT 1 ), causing vasoconstriction, cell proliferation, or collagen production, which causes hypertension, and then causes organ dysfunction. Now, an ACE inhibitor (hereinafter, also referred to as ACEI) which inhibits the production of angiotensin II, and an angiotensin receptor antagonist (hereinafter, also referred to as ARB) which inhibits stimulation of AT1 are known as hypertension. Therapeutic agents are used, and these agents have significant blood pressure lowering effects and organ protection. Renin is an aspartic acid protease that converts angiotensinogen to angiotensin I, and is a rate-determining enzyme of the R-A system. Therefore, the renin inhibitor is considered to efficiently inhibit the R-A system, and is expected to have the same blood pressure lowering effect as ACEI and ARB (Circulation, 2005, Vol. 111, p. 1012-1018). A piperidine compound having a substituent at the 3rd and 5th positions having renin inhibitory activity is known (for example, refer to Patent Documents 1 to 25 or Non-Patent Document 1). Further, a compound having a structure of a piperidone moiety having renin inhibitory activity is known. 201107306 (for example, refer to Patent Documents 26 to 29 or Non-Patent Document 1). However, the structure of the substituent of the compound of the present invention at the 3rd and 5th positions of the piperidine ring and the structure of the piperidone moiety at a specific position of the piperidine ring are greatly different from those of the above-mentioned known compound. . [Prior Art Document] [Patent Document 1] [Patent Document 1] International Publication No. 1 997/0093 1 Booklet [Patent Document 2] International Publication No. 2000/064873 Booklet [Patent Document 3] International Publication No. 2 0 04/0 8 9 903 booklet [Patent Document 4] International Publication No. 2005/06 1457 Booklet [Patent Document 5] International Publication No. 2006/005741 Booklet [Patent Document 6] International Publication No. 2006/094763 Booklet [Patent Document 7] International Publication No. 2006/1 03273 Booklet [Patent Document 8] International Publication No. 2006/1 03275 Booklet [Patent Document 9] International Publication No. 2〇〇6/1 03277 Booklet [Patent Document 1 国际] International Publication No. 2006/1 1 7183 Booklet [Patent Document 11] International Publication No. 2007/006534 Booklet [Patent Document 12] International Publication No. 2007/0 82907 Booklet [Patent Document 13] [International Publication No. 2007/077005] [Patent Document 14] International Publication No. 2008/01 7685 Booklet [Patent Document 15] International Publication No. 2008/040764 Booklet [Patent Document 16] International Publication No. 2 8/07445 nickname booklet [Patent Document 17] International Publication No. 2008/093 737 booklet [Patent Document 18] International Publication No. 2008/ 1 3 6457 Booklet [Special [19] International Publication No. 2008/1 53 1 3 5 Booklet 201107306 [Patent Document 20] International Shutter [Patent Document 2 1] International Publication [Patent Document 22] International Publication [Patent Document 23] International Publication [Patent Literature 24] International Publication [Patent Document 25] International Publication [Patent Document 26] International Publication [Patent Document 27] International Publication [Patent Document 28] International Publication [Patent Document 29] International Publication No. 2009/000811 Booklet No. 2009 /005002 Booklet 2009/01 42 1 Booklet No. 2009/05 1 1 1 Booklet No. 2009/07 1 Booklet No. 2009/072649 Booklet 2004/0899 1 No. 5 Book No. 2006/128659, Booklet No. 2007/034445, Booklet No. 2007/1 48774 [Non-Patent Document] [Non-Patent Document 1] Expert Opinion on Therapeutic Patents, 2008, Vol. 18, p. 581 In the present invention, in order to develop an excellent therapeutic drug for hypertension, the inventors of the present invention conducted a study on a novel substituted piperidine compound, and found a substituted pipe having a specific structure. a pyridine compound or a pharmacologically acceptable salt thereof, which inhibits renin , solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability 'tissue transition, bioavailability (hereinafter also referred to as BA), in vitro activity, in vivo activity' efficacy Fast performance, sustained drug efficacy, physical stability, drug interactions, safety (eg, cardiotoxicity or hepatotoxicity), etc. have excellent properties and are useful as medicines (especially for the treatment of local blood pressure or Medicine for prevention (preferably for treatment)]. The present invention has been completed based on the knowledge of 201107306 and above. Means for Solving the Problems The present invention provides a novel renin-removing activity which has excellent renin inhibitory activity and is useful as a medicine for medicine, in particular, for the treatment or prevention of blood pressure, preferably for treatment. a compound or a pharmacologically acceptable salt thereof; a renin inhibitor containing a substituted piperidine compound or a pharmacologically acceptable salt thereof; containing a substituted piperidine compound or a pharmacologically acceptable salt thereof as effective The pharmaceutical composition of the component, preferably hypertension, 'acute or chronic heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, sciatic disorder, stroke, kidney disease (eg, spheroid nephritis, IgA nephropathy, hypertension) Kidney syndrome), diabetic syndrome (eg, kidney disease, neurological disorder, omental disease, glaucoma), vascular restenosis after angiogenesis, aldosteroneemia, or atherosclerosis A pharmaceutical composition for treating or preventing, or for reducing an event or mortality based on cardiovascular disease or coronary heart disease, more preferably hypertension, chronic heart failure, or diabetes A pharmaceutical composition for the treatment or prevention of renal nephropathy, preferably a pharmaceutical composition for the treatment or prevention of hypertension; a pharmaceutical composition for the treatment or prevention of a disease (preferably the above disease) Use of a substituted piperidine compound or a pharmacologically acceptable salt thereof; by administering an effective amount of a substituted piperidine compound or a pharmacologically acceptable salt thereof to a warm-blooded animal, especially a human, A method for the treatment or prevention of a disease, preferably a disease as described above; and a method for producing a substituted piperidine compound or a pharmacologically acceptable salt thereof IS! 201107306. The present invention provides the following from one aspect. (1) A compound of the formula (I) or a pharmacologically acceptable salt thereof,

[In the formula, R represents a chlorine atom, Ci-C!. Affiliation, phenyl-(C!-C丨〇alkyl)-based (C3-C!. saturated cyclic hydrocarbon KCi-Cioalkyl) group, (4 to 8 membered heterocyclic group MC^-Cu) a group, a phenyl group, a dihydrogenated benzyl group, a C3-C1() saturated cyclic hydrocarbon group or a 4 to 8 membered heterocyclic group, each group in Ri may be independently selected from 1 to 4 groups of the substituent group α Substituted, two such substituents bonded to the same carbon atom may form a C3-C8 cycloalkyl group together with the carbon atom: r2 represents a hydrogen atom or a C^-Ce alkyl group; R3 represents a hydrogen atom or a CmG alkyl group; R4 represents a hydrogen atom or a C^-C:6 alkyl group, R3 and R4 may be formed together with the carbon atom to which they are bonded (: 3-(:8-cycloalkyl; A represents a phenyl or pyridyl group, and R5, R6 and R7 are independently a hydrogen atom or a group selected from the substituent group α; a substituent group α represents a Cl-ce alkyl group, a halogen Ck6 alkyl 'cycloalkyl group, a hydroxyl group, a Cl-c6 alkoxy group, (C3-C8 cycloalkyl group) ) _(CiC6 alkoxy) group 'tooth c, -c6 alkoxy, fluorenyl, Ci_c6 alkylthio' Ci_c6 alkyl 201107306 sulfinyl, C,-C6 alkylsulfonyl, aminoalkyl Amino, bis(C^Ce alkyl)amino (the alkyl is the same or different), formazanyl, ((^-(:6 alkyl) Carbonylamino, carbenyl, alkyl)carbonyl, carboxy, (C^-Ce alkoxy)carbonyl, aminemethanyl, (C^CUalkylamino)carbonyl, di(C alkyl)amino a carbonyl group (the alkyl group is the same or different), an aminosulfonyl group, ((^-(:6 alkylamino))sulfonyl group, a di(C alkyl)aminosulfonyl group (the alkyl group is (2) A compound of the formula (1) or a pharmacologically acceptable salt thereof, wherein R1 is C丨-C, alkyl 'phenyl-(Cl_C丨.alkyl) group, (C3_c丨. saturated cyclic hydrocarbon)-(〇丨-(:decyl)yl, (4 to 8 member heterocycle) a group of -(C丨-C1()alkyl) or C3-C1Q saturated cyclic hydrocarbon, each group of R1 may be substituted with 1 to 4 groups independently selected from the group of substituents α1, bonded to the same carbon atom Two of the substituents may be formed together with the carbon atom (: 3-(:8-cycloalkyl; the substituent group αΐ is composed of Cl-C6 alkyl, c3-c8 cycloalkyl, Cl_C6 alkoxy, di ( a group of Ci_C6 alkyl)amino groups (the alkyl groups are the same or different), a halogen group, and a pendant oxy group; (3) The compound of (1) or a pharmacologically acceptable salt thereof, wherein R is Ci-C!, alkyl group, phenyl group (Ci_Ci()) group or (4 to 8 membered heterocyclic group) Each group in the alkyl) group 'R1 may be substituted with 1 to 4 groups independently selected from the group of substituents'. The substituent group α2 is composed of a C1-C8 alkyl group, a C3_C8 ring-based group, a Ci-C6 alkoxy group and a halogen. (4) The compound of any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein R2 is a hydrogen atom; (5) at (1) to (4) Or a pharmacologically acceptable salt of the compound of the present invention, wherein the compound or the pharmacologically acceptable salt thereof is a compound of the formula (1) to (4) or a pharmacological amount thereof. The compound of any one of (1) to (6) or a pharmacologically acceptable salt thereof, wherein R4 is a C1-C6 alkyl group; The compound of any one of (1) to (6), or a pharmacologically acceptable salt thereof, wherein R4 is a methyl group; (9) The compound according to any one of (1) to (8) Or a pharmacologically acceptable salt thereof, wherein A is a phenyl group; (10) The compound according to any one of (1), wherein R5, r6 and R7 are independently selected from a hydrogen atom, a Cl_c6 alkyl group and a halogen group; (11) at (1), or a pharmacologically acceptable salt thereof The compound of any one of (9) or a pharmacologically acceptable salt thereof, wherein r5, r6 and R7 are independently selected from the group consisting of a hydrogen atom, a methyl group, a fluorine group and a chlorine group. Further, the present invention provides the following from one aspect. (12) A pharmaceutical composition comprising the compound according to any one of (11) to (11) or a pharmacologically acceptable salt thereof as an active ingredient; (1 3) the pharmaceutical composition according to (1) It is used for the treatment or prevention of a disease which can be treated or prevented by inhibiting renin; (14) The pharmaceutical composition according to (12), which is for use in hypertension, acute or chronic heart failure, heart hypertrophy Myocardial infarction, cardiomyopathy, angina, stroke, kidney disease 'diabetic complication, vascular restenosis after angiogenesis' aldosteronism or atherosclerosis treatment or prevention; (1 5 ) (1) The pharmaceutical composition described in the treatment or prevention of hypertension, chronic heart failure or diabetic nephropathy; (16) The pharmaceutical composition according to (12), which is for use in hypertension The compound of any one of (1) to (11), or a pharmacologically acceptable salt thereof, for use in the treatment or prevention of a disease; (18) The compound of (17) or a pharmacologically acceptable salt thereof, wherein the disease is high blood (19) A method for treating or preventing a disease by administering a pharmacologically effective amount of the compound according to any one of (1) to (Π) or a pharmacologically acceptable salt thereof to warm blood (2) The method according to (19), wherein the disease is a disease which can be treated or prevented by inhibiting renin; (21) The method according to (19), wherein the disease is hypertension; (22) The method of any one of (19) to (21), wherein the warm-blooded animal is a human. In the general formula (I) of the present invention, each group has the following meanings. The "C丨-C丨〇alkyl group" and the "C丨-C丨〇alkyl group" of each group are a linear or branched alkyl group having 1 to 10 carbon atoms, and for example, may be as follows The group '1-heptyl, 1-octyl, 1-indenyl or 1-indenyl represented by C^-Ce® alkyl is preferably C2-C8 alkyl. "Phenyl-(CmCmalkyl)" is the above-mentioned (^-(:^alkyl group, preferably phenyl-(Ci-C6)). The "C3-C1G saturated cyclic hydrocarbon" is a monocyclic, bicyclic or tricyclic saturated cyclic hydrocarbon having 3 to 10 carbon atoms. The monocyclic C 3 -C i 〇 saturated cyclic hydrocarbon is a c3-c1G cycloalkyl group, for example, Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl, preferably C3-C8 cycloalkyl, more preferably c3-c6 naphthenic Bicyclic or tricyclic C3-C1Q full ts] -12- 201107306 and cyclic hydrocarbons, such as 'may be bicyclo [2, 2, 1] heptyl (norbornyl)' bicyclo [311] g (norpinyl) 'bicyclo[3,2,1]octyl, bicyclo[hj]decyl, bicyclo[3,3,1]decyl, decahydronaphthyl or adamantyl. "( The C3-C1G saturated cyclic hydrocarbon alkyl group) is the above-mentioned C1-C10-based group substituted by the above-mentioned c3_Cl0 saturated cyclic hydrocarbon, preferably (c3-c8 ring-based alkyl group) or adamantyl-alkyl group. The "4 to 8 membered heterocyclic group" is a 4 to 8 member having 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. a heterocyclic ring comprising 4 to 8 membered saturated heterocyclic groups and 5 to 6 membered aromatic heterocyclic groups. 4 to 8 membered saturated heterocyclic group, for example, tetrahydroindenyl, pyrrolidinyl, imidazolidinyl , pyrazolidine, oxazolidinyl, thiazolidinyl, piperidinyl, piperidinyl, hexahydropyrimidinyl, whufinyl, thiofamidyl, hexahydroazepinyl, a piperazine or a fluprosyl group, preferably a 5- to 7-membered saturated heterocyclic group. A 5- to 6-membered aromatic heterocyclic group, for example, may be a pyridyl group, a furyl group, a thienyl group, a pyrazolyl group, Imidazolyl, carbazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, piperidyl, pyridyl, phosphonium, pyrimidinyl or pyridin "(4 to 8 membered heterocyclic group)-(C丨-C丨〇alkyl)" is the above CpCu alkyl group substituted by the above 4- to 8-membered heterocyclic group, preferably (5 to 7 members saturated) a heterocyclic alkyl group or a (5 to 6 membered aromatic heterocyclic group)-(C,-C6 alkyl group). The "C3-C8 cycloalkyl group" is a cyclic alkyl group having 3 to 8 carbon atoms. For example, it may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexane. a group, a cycloheptyl group or a cyclooctyl group, preferably a C3-C6 cycloalkyl group, "Ci-Ce alkyl group" and a "C^Cfi alkyl group" of each group are straight chains having 1 to 6 carbon atoms. Or branched alkyl, for example, methyl, ethyl, l-[s] • 13- 201107306 propyl, 2-propyl, i-butyl, 2-butyl, 2-methyl-1-propyl , 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl '3-methyl-1-butyl, 2-methyl-dibutyl' 2-methyl-2- Butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 1-hexyl '2-hexyl, 3·hexyl' 2-methyl-oxime-pentyl' 3· Methyl-indole-pentyl '2-ethyl-1-butyl' 2,2-dimethyl-1-butyl or 2,3-dimethyl-1-butyl, preferably C^- Cs alkyl. The "haloalkyl group" is the above alkyl group substituted with 1 to 7 of the following halogen groups, and may, for example, be a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group or a trifluoromethyl group. Trichloromethyl, 2-fluoroethyl, 2-bromoethyl, 2-chloroethyl '2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, three Chloroethyl 'pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 5-fluoropentyl or 6-fluorohexyl 6 alkoxy" is one of the above d-Ce Alkyl-substituted hydroxy (-OH)' can be, for example, methoxy 'ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl -1-propoxy, 2-methyl-2-propoxy ' 1-pentyl, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl Benzyl-2-butoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy' 2 methyl-1-pentyloxy, 3-methyl-1.pentyloxy, 2 Ethyl-1-butoxy, 2,2-dimethyl-1-butoxy or 2,3-dimethyl-1-butoxy. "(C3-C8 cycloalkylalkoxy)" is the above alkoxy group substituted by the above C3-C8 cycloalkyl group, and may, for example, be a cyclopropylmethoxy group, a cyclopropylethoxy group, or a cyclopropyl group. Propoxy, cyclopropylbutoxy, cyclopropylpentyloxy, cyclopropylhexyloxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy Cyclohexylmethoxy, cyclohexylethoxy, cycloheptylmethoxy or cyclooctylmethoxy. -14· 201107306 "_Cr-C6 alkoxy group" is the above C^-C:6 alkoxy group substituted by the same or different 1 to 7 of the following halogen groups, for example, may be a fluoromethoxy group, Difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-chloroethoxy , 2-iodoethoxy, 2,2-di-Ethyloxy, 2,2,2-trifluoroethoxy, trichloroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3 - chloropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy or 6-fluorohexyloxy. "C^-C: 6 alkylthio" is an alkyl group (-S Η ) substituted by i of the above Cl-C6 alkyl groups, and for example, may be a methylthio group or an ethylthio group; _propylthio, 2 _propylthio, 1-butylthio, 2-butylthio, 2-methyl-1-propylthio, 2-methyl-2-propylthio, 1-pentylthio , 2-pentylthio, 3-pentylthio, 2-methyl-2-butylthio, 3-methyl-2-butylthio, 1-hexylthio, 2-hexylthio, 3-hexyl Sulfur, 2-methyl-1-pentylthio, 3-methyl-1-pentylthio, 2-ethyl-1-butylthio, 2,2-dimethylbutylthio or 2,3 - dimethyl-1-butylthio. "CmC6 alkylsulfinyl" is one of the above (^-(^alkyl substituted sulfinyl (-SO-)', for example, may be methylsulfinyl, ethylsulfinyl , 1-propylsulfinyl '2-propylsulfinyl, 1-butylsulfinyl, 2-butylsulfinyl, 2-methyl-1-propylsulfinyl , 2-methyl-2-propylsulfinyl, 1-pentylsulfinyl, 2-pentylsulfinyl, 3-pentylsulfinyl, 2-methyl-2-butyl Isosulfonyl, 3-methyl-2-butylsulfinyl, 1-hexylsulfinyl, 2-hexylsulfinyl, 3-hexylsulfinyl, 2-methyl-1 - amylsulfinyl, 3-methyl-1-pentylsulfinyl, 2-ethyl-1-butylsulfinyl, 2,2-dimethyl-1-butylsulfin Mercapto or 2,3-dimethyl-1-butylsulfinyl. [S] "C^-Ce alkylsulfonyl" is a -15- 201107306 sulfonate substituted by one of the above CrG alkyl groups. Base (-S〇2-) 'for example, may be methanesulfonyl', sulfonate, phenylene sulfonyl, 2-propanyl sulfonyl, ΐ·丁院, _ 醯, 2_丁院醯 醯 '2-methyl-1-propanesulfonyl, 2-methyl-2-propanesulfonyl, 丨pentanesulfonate , 2_Wenyuan expansion base, 3 - Wuyuan expansion base, 2 - methyl 2_ Dingyuan mineral base, 3-methyl-2-butanesulfonyl, 1 · hexanesulfonyl, 2_ already integrated 醯 base, 3_ 己院扩醯, 2-methyl-1·pentanesulfonyl, 3-methyl-indolylsulfonyl, 2-ethyl-1-butane Sulfhydryl, 2,2-dimethyl-1-butanesulfonyl or 2,3 dimethyl-1-butanesulfonyl. "Ci-C6 alkylamino" is one of the above Cl_c6 The alkyl-substituted amine group may, for example, be a methylamino group, an ethylamino group, a fluorenyl-propylamino group, a 2-propylamino group, a 1-butylamino group, a 2-butylamino group, 2 -methyl-1-propylamino '2-methyl-2-propylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, b-hexylamino, 2 a hexylamino group or a 3-hexylamino group. A "di(Ci-C6 alkyl)amino group" is an amine group which is substituted by the same or two different Ci-Ce alkyl groups, for example, 'may be dimethyl Amino group, methyl ethylamino group, methylpropylamino group [for example, N-methyl-N-(l-propyl)amino group, etc.], methylbutylamino group [for example, Ν-(1) · butyl)-N-methylamino group, etc., methyl amylamino group, methylhexylamino group, Ethylamino, ethylpropylamino [for example, N-ethyl-N-(l-propyl)amino, etc.], ethylbutylamino, dipropylamino, propylbutylamine Base, dibutylamino, dipentylamino or dihexylamino.

[SI "(Ci-C^alkyl)carbonylamino group" is an amine group substituted with one of the following (C^C6 alkyl)carbonyl groups, and may, for example, be a methylcarbonylamino group or an ethylcarbonylamino group, 1-propylcarbonylamino, 2-propylcarbonylamino, 1-butylcarbonylamino, 2-butylcarbonyl.amino, 2-methyl-1-propylcarbonylamino, 2-methyl -2-propylcarbonylamino, 1-pentylcarbonylamino '2-pentylcarbonylamino, 3-pentylcarbonylamino'-16-201107306 2-methyl-2-butylcarbonylamino, 3-methyl-2-butylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino '3-hexylcarbonylamino, 2-methyl-1-pentylcarbonylamino' 3- 1-ylpentylcarbonylamino, 2-ethyl-1-butylcarbonylamino, 2,2-dimethyl-1-butylcarbonylamino or 2,3-dimethyl-1. Alkylcarbonyl group. "(Ci-Ce alkyl)carbonyl" is one of the above (^-(6 alkyl-substituted carbonyl (-CO-), for example, may be methylcarbonyl (ethyl), ethylcarbonyl, 1 -propylcarbonyl, 2·propylcarbonyl, 1-butylcarbonyl, 2-butylcarbonyl, 2-methyl^-1-propylcarbonyl, 2-methyl-2-propylcarbonyl, 1-pentyl Carbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 2-methyl-2-butylcarbonyl, 3-methyl-2-butylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, 3-hexylcarbonyl , 2-methyl-1-pentylcarbonyl, 3-methyl-1-pentylcarbonyl, 2-ethyl-1-butylcarbonyl ' 2,2-dimethyl-1-butylcarbonyl or 2, 3-dimethyl-1-butylcarbonyl. Alkoxy)carbonyl" is a carbonyl (-CO-) substituted with one of the above C^-Ce alkoxy groups, for example, may be methoxycarbonyl 'ethoxylated Carbocarbonyl, 1_0 propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-1-propoxycarbonyl, 2-methyl-2- Propoxycarbonyl, pentyloxycarbonyl '2-pentyloxycarbonyl, 3-pentyloxycarbonyl, 2-methyl-2-butoxycarbonyl, 3-methyl-2-butoxycarbonyl, 1- Hexyloxycarbonyl, 2-hexyloxycarbonyl, 3- Hexyloxycarbonyl, 2-methyl-1-pentyloxycarbonyl, 3-methyl-1-pentyloxycarbonyl, 2-ethyl-1-butoxycarbonyl '2,2-dimethyl-1 - Butoxycarbonyl or 2,3-dimethyl-1-butoxycarbonyl. "(C^-CUalkylamino)carbonyl" is a carbonyl group substituted with one of the above alkylamino groups (-CO- , for example, may be methylaminocarbonyl, ethylaminocarbonyl '1-propylaminocarbonyl, 2-propylaminocarbonyl, 1-butylaminocarbonyl, -17-201107306 2-butyl Aminocarbonyl, 2-methyl-1-propylaminocarbonyl, 2-methyl-2-propylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, 3-pentyl Aminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl or 3-hexylaminocarbonyl. "Dialkyl"aminocarbonyl" is one of the above two ((^-(:6 alkyl)) The amino-substituted carbonyl group (-CO-) may, for example, be dimethylaminocarbonyl, methylethylaminocarbonyl or methylpropylaminocarbonyl [for example, N-methyl-N-(l-) Propyl)aminocarbonyl, etc.], methylbutylaminocarbonyl [for example, N-(l-butyl)-N-methylaminocarbonyl, etc.], methylpentylaminocarbonyl, methylhexyl Carbocarbonyl, ® diethylaminocarbonyl, ethylpropylaminocarbonyl [for example, N-ethyl-N-(l-propyl)aminocarbonyl, etc.], ethylbutylaminocarbonyl, dipropyl An aminocarbonylcarbonyl group, a propylbutylaminocarbonyl group, a dibutylaminocarbonyl group, a dipentylaminocarbonyl group or a dihexylaminocarbonyl group. The alkylamino)sulfonyl group is one of the above CrQ alkyl groups. The amine-substituted sulfonyl group (-so2.), for example, may be (methylamino)sulfonyl, (ethylamino)sulfonyl, (1-propylamino)sulfonyl, ( 2-propylamino)sulfonyl, (1-butylamino)sulfonyl, (2-butylamino)sulfonyl, (2-methyl-1-propyl^amino)sulfonate Mercapto '(2-methyl-2-propylamino)sulfonyl, (1-pentylamino)sulfonyl '(2-pentylamino)sulfonyl, (3-pentylamine) A sulfonyl group, a (1-hexylamino)sulfonyl group, a (2-hexylamino)sulfonyl group or a (3-hexylamino)sulfonyl group. The "bis(Ci-C^alkyl)aminosulfonyl group" is a sulfonyl group (-S02_) substituted with one of the above-mentioned di(CVC6 alkyl)amino groups, for example, may be (dimethylamino) Sulfonyl, (methylethylamino)sulfonyl, (methylpropylamino)sulfonyl [eg '[N-methyl-N-(l-propyl)amino)sulfonyl Et-], (methylbutylamino)sulfonyl [for example, [N-(l-butyl)-N-methylamino]sulfonyl, etc.], (methylpent-18- 201107306 amine) Sulfhydryl, (methylhexylamino)sulfonyl, (diethylamino)sulfonyl, (ethylpropylamino)sulfonyl [eg, [N-ethyl-N-] (l-propyl)amino]sulfonyl, etc.], (ethylbutylamino)sulfonyl, (dipropylamino)sulfonyl, (propylbutylamino)sulfonyl' (Dibutylamino)sulfonyl, (dipentylamino)sulfonyl or (dihexylamino)sulfonyl. The "halogen group" may be a fluorine 'chlorine' bromine or an iodine group. The compound of the present invention having the general formula (I) comprises a compound having the following formulas (la) to ([d), preferably having a stereo configuration of (3S, 5R) on the piperidine ring having the formula (la) Compound.

201107306

,a

\n/ lb lc

And d is a compound of the invention having the general formula (I), and the compound shown in the examples is preferred. The compound of the present invention having the general formula (I) can form an acid addition salt, and such acid addition salts are included in the present invention. Such acid addition salts, such as ' Θ are hydrochloride, hydrogen bromide 'sulfate, nitrate, phosphate, acetic acid _ -20- 201107306 oxalate, malonate 'fubutene Acid salt, maleate 'L-malic acid, D-malic acid, L-tartaric acid, D-tartaric acid, decanoate, trifluoroacetate, methanesulfonate, besylate, p-toluene Sulfonate, 2,4-dimethylbenzenesulfonate '2,4,6-trimethylbenzenesulfonate, 4-ethylbenzenesulfonate or naphthalenesulfonate. The compound of the invention having the general formula (I) can form an acid addition salt with an acid of any ratio - its individual acid addition salts (for example, 1 acid salt, 2 acid salt, 1 / 2 acid salt) or Mixtures of the like are included in the present invention. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each of them or a mixture thereof is included in the present invention. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof has at least one asymmetric center, a carbon-carbon double bond, a formazan group, an axis asymmetry, etc., and may have optical isomerism. (including enantiomers and diastereomers), geometric isomers, tautomers and rotamers, such isomers and mixtures thereof such as in formula (I) A single type of record. The present invention encompasses such isomers and mixtures of such ratios (including exosomes). The compound of the present invention having a general formula (I) or a pharmacologically acceptable salt thereof can form an isotope compound in which one or more atoms constituting the same are substituted with an isotope atom at a non-natural ratio. The isotope atom may be radioactive or non-radioactive, for example, 氘(2 Η ; D ), 氚 (3 Η ; T ), carbon-1 4 (1 4 C ), iodine-1 2 5 (1251 ), and the like. The compound which is identified by a radioisotope atom can be used as a therapeutic or prophylactic agent for a disease, a reagent for research (for example, an assay reagent), a diagnostic drug (for example, an imaging diagnostic drug), and the like. The invention encompasses radioactive or non-radioactive isotopic compounds. -21 - 201107306 In the present invention, hypertension includes a commonly known form of hypertension, for example, essential hypertension, renal hypertension, endocrine hypertension, neuropathy, or Primary or secondary pulmonary hypertension. The compound of the present invention having the general formula (I) can be produced according to the following A method (A method A-1 and method A-2) or method B.

[S] -22· 201107306

C02H A-1 Step 〇Y°Y° A-2 Step Me02c

C02H (1) A_3 step, N I Boc Μθ〇2〇

(4) R3R4CHCHO (5) (3) Μθ〇2〇

Step A-5

Me〇2〇

A-6 steps

\Ρ) Me02C

(7) (6) Step A-7 Μβ〇2〇

Me02C

CHO (9) (10) A_9 steps

Me02C

R5

2) ϋ s -23 201107306 A law one 2

R5 Me02C

(12)

A-11 step R5 ho2c

R5 A_12 step r1r2nh2 (15)

(16) R5 A-13 steps

Me02C

-24 (I) 201107306 Method B

(17)

B-2. Steps

(18) R5 B-3 steps

Boc (19) r1r2nh (15)

R5 B-4 steps

H -25- 1 2 In the structural formula of the compound of the above A method or b method, i 201107306 is a reaction of each step of the following A method or B method, and the compound which becomes a starting material has an amine group, a hydroxyl group, In the case where a carboxyl group or the like is inhibited from reacting with a target, the removal of the protecting group into the group and the removal of the introduced protecting group can be suitably carried out as necessary. Such a protecting group is not particularly limited as long as it is a commonly used protecting group, and may be, for example, TW Greene, PG Wuts, Greene, s Protective Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc. The protective groups described. The reaction for introducing and removing these protecting groups can be carried out by the method described in the above literature or by the method according to Φ. The solvent to be used in the reaction of each step of the following A method or B method is not particularly limited as long as it does not inhibit the reaction and dissolves a part of the starting material. For example, it is selected from the following solvent groups. The solvent group is an aliphatic hydrocarbon such as hexane, pentane, petroleum ether or cyclohexane; an aromatic hydrocarbon such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride and dichloro Halogenated hydrocarbons such as ethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane 'diethylene glycol dimethyl ether, and the like Ethers; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone: esters such as ethyl acetate, propyl acetate, butyl acetate; acetonitrile, propionitrile Nitriles such as nitrile and isobutyronitrile: carboxylic acids such as acetic acid and propionic acid; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl Alcohols such as 1-propanol '2-methyl-2-propanol: formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, a guanamine such as hexamethylphosphorus triamide; a hydrazine such as dimethyl hydrazine, cyclazone; water; and a mixture of these. The acid to be used in the reaction of each step of the following A method or B method is not particularly limited as long as it does not inhibit the reaction, and is selected from the group consisting of the following acid groups. The acid group is salt-26- 201107306 Acidic acid such as acid, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, organic acid such as acetic acid, propionic acid, trifluoroacetic acid or pentafluoropropionic acid. And methane acid extension, trifluoromethanesulfonic acid 'p-toluenesulfonic acid, camphorsulfonic acid and other organic sulfonic acid. The base to be used in the reaction of each step of the following A method or B method is not particularly limited as long as it does not inhibit the reaction, and is selected from the group of the following groups. The alkali group is an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate sodium hydrogencarbonate or potassium hydrogencarbonate; lithium hydroxide, I sodium hydroxide An alkali metal hydroxide such as potassium hydroxide: an alkaline earth metal hydroxide such as calcium hydroxide or barium hydroxide; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; Alkali metal amide such as sodium decylamine or potassium decylamine; alkali metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; lithium diisopropyl hydrazine Lithium alkyl decylamine such as amine; decylamine such as bis(trimethyldecyl)amine lithium, bis(trimethyldecyl)amino sodium; η-butyllithium, secondary butyl Alkyl lithium such as lithium or t-butyl lithium: methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride 'Ionic magnesium alkyl bromide, alkyl magnesium halide such as isobutyl magnesium; and triethylamine, tributylamine, diisopropylethylamine, Ν-methyl Piperidine, Ν-methylmorpholine, Ν-ethyl phlomatolin, pyridine, picoline, 4-(anthracene, fluorenyl-dimethylamino)pyridine, 4-pyrrolopyridine, 2,6- Bis(t-butyl)_4-methylpyridine, quinoline, >1,;^-dimethylaniline, >1,1<[_diethylaniline' 1,5-diguanidine bicyclo[4 ,3,0]壬-5-ene (DBN), :1,4-dibicyclo[2,2,2]octane (DABCO), 1,8-dioxinbicyclo[5,4,0] It is made up of an organic amine such as -7-dilute (DBU). The reaction temperature varies depending on the solvent, -27-201107306 starting materials, reagents, and the like, and the reaction time varies depending on the solvent reaction temperature and the like. In the reaction of each step of the following method A or method B, the usual method of separating the steps from the reaction mixture may be, for example, '(in view of the need to add water to the insoluble matter of the catalyst or the like, and not to Water-mixed solvent (such as ethyl ester) to extract the target compound, (iii) water-dried magnesium sulfate and the like desiccant to dry, (iv) distillate and dissolve the target compound, if necessary, according to the usual method (for example, re-column column Further purification can be carried out by chromatography, etc. Further, each step can be directly used in the next reaction without purification. In each step, recrystallization or use of optical activity by using (R)- or (S)-phenylethylamine The column structure of the column. The following describes the reverse of each step of the A method or the B method. The method A is for the production of the compound of the formula (I) (Step A-1) The step A-1 is dehydration. The agent-treating compound (1 (1) can be produced according to the method described in Tetrahedoron Lett., 2003, W0200 7/07 7005, etc. The dehydrating agent to be used is not limited as long as it is a user of a dicarboxylic acid, and is preferably not limited. An acid anhydride, an acid haloalkylcarbodiimide is more preferably an acid anhydride, and is most preferably The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic 'starting material, a reagent, after the reaction, depending on the hydrazine. The target compound, '(ii) in the reaction mixture 二氯甲烷' dichloromethane, an organic layer of acetic acid, using an anhydrous agent Obtained. The obtained crystal 'reprecipitate or the gelatinous compound of the target compound is also optically active, such as amine, which can separate the optically different I. The method of the compound. Volume 44, p. 1 61 1. Anhydride The reaction product, phosphorus halide or hydrazine acetic anhydride. Group hydrocarbons, halogenated hydrocarbons f S] -28- 201107306 or ethers. Step A-1 is preferably carried out without solvent. The reaction temperature is preferably -78. To 15 (TC, more preferably 60 to 1 Torr. (: The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 24 hours. (A-2 step) A-2 step is not The step of reacting the compound (2) with methanol in the presence of a symmetrical catalyst. This step can also be carried out according to the method described in Tetrahedoron Lett., 2003, Vol. 44, p. 1611, WO2007/0 77005, etc. Symmetrical catalysts are preferably those described in Chemical Review, 2007, Vol. 107, p. 5683. Symmetrical organometallic catalysts or asymmetric organic catalysts or asymmetric organic catalysts described in Angew. Chem. Int. Ed., 2008, Vol. 47, p. 7 8 72, more preferably (DHQ) 2AQN or Angew·Chem Chem. Int. Ed., 2008, Vol. 47, p. 7872, Asymmetric Organic Catalyst I. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether or a mixture thereof, more preferably an ether, more preferably diethyl ether β or tetrahydrofuran. The reaction temperature is preferably -78 to 100 ° C, more preferably -40 ° C to 30 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 48 hours. The compound (3) of the racemate can be produced by carrying out the step A-2 in the absence of an asymmetric catalyst. The compound (I) of the racemate can be produced by carrying out the A-3 step to the A-13 step using the compound (3) of the racemate. (Step A-3) [S1 -29-201107306 A-3 step is (A-3 a step): the step of treating the compound (3) with an azide reagent, followed by an alcohol compound or water; and (A- Step 3b): A step of removing the alkoxycarbonyl group in the compound obtained in the step A-3a. The A-3 step can be carried out according to a method well known in the art of organic synthetic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc, p. 867-869) ° ^ (A - 3 a step The azide reagent used, for example, may be a combination of a halogenating agent such as chlorinated grass mash, sulfinium chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or sodium azide. Or diphenylphosphonium azide (DPPA), preferably DPPA. The alcohol compound to be used is preferably a third butanol, an allyl alcohol, a benzyl alcohol, 2,2,2-trichloroethanol or 2-trimethyldecylethanol, more preferably an allyl alcohol or a benzyl alcohol. The solvent to be used is preferably an aliphatic hydrocarbon 'aromatic hydrocarbon, a halogenated hydrocarbon φ, an ether or a mixture thereof, more preferably an aromatic hydrocarbon, and most preferably toluene. The reaction temperature is preferably from -7 8 to 150 ° C, more preferably from 0 to 1 1 〇 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 24 hours. (A - 3 b step) The reagent, solvent, and reaction temperature used in the step A-3b vary depending on the lower alcohol used in the step A_3a. The A-3b step, as a method of removing an alkoxycarbonyl group bonded to an amine group, can be carried out according to a method well known in the field of organic synthetic chemistry (for example, T. W. Greene, P. G. M. Wuts, Greene, s [S] -30- 201107306

Protecive Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.) (Step A-4) The A-4 step is a step of reacting the compound (4) with the compound (5). The compound (5) may be a known or self-known compound which can be easily produced. The reagent to be used is not particularly limited as long as it is a reaction of an amine and an aldehyde. For example, it may be p-toluenesulfonic acid, D-camphorsulfonic acid, p-toluenesulfonic acid pyridyl salt, acetic acid 'trifluorocarbon. An acid catalyst such as acetic acid, titanium tetraisopropoxide, a strong acid-free exchange resin, or a dehydrating agent such as anhydrous magnesium sulfate or molecular sieve is preferably anhydrous magnesium sulfate. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether or a mixture thereof, more preferably a halogenated hydrocarbon, more preferably carbon tetrachloride or dichloromethane. The reaction temperature is preferably -78 to 150 ° C, more preferably 〇 to 80 ° C. The reaction time is preferably from 5 minutes to 24 hours, more preferably from 15 minutes to 2 hours. ▼ (Step A-5) The step A-5 is a step of treating compound (6) with a halogenating reagent. The halogenating agent to be used may, for example, be a chlorinating agent such as chlorine, sulfonium chloride, tert-butyl hypochlorite or N-chlorosuccinimide; bromine, N-bromosuccinimide, N, A brominating reagent such as N'-dibromo-3,3-dimethylhydantoin; an iodinating reagent such as iodine, preferably a chlorinating reagent, most preferably N-chlorosuccinimide. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether or a mixture thereof, more preferably a halogenated hydrocarbon, more preferably tetrachloro [S} -31 - 201107306 carbon Or dichloromethane. The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 40 °C. The reaction time is preferably from 5 minutes to 24 hours, more preferably from 15 minutes to 4 hours. (Step A-6) The step A-6 is that the compound (7) has the formula YOH [wherein, Y is a lower alkyl group; a lower alkenyl group; or a lower alkyl group, a lower alkoxy group or a halogen group (benzene) The step of treating the compound of the benzyl-lower alkyl group]. The ® compound having the formula YOH is known or can be easily produced from known compounds. The compound of the formula YOH used is preferably methanol, ethanol, allyl alcohol or benzyl alcohol, most preferably methanol. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon or an ether. The step A-6 is preferably carried out without a solvent. The reaction temperature is preferably from 0 to 150 ° C, more preferably from 10 to 80 ° C. The reaction time is preferably from 30 minutes to 96 hours, more preferably from 2 to 48 hours. ^ (Step A-7) Step A-7 is the step of (A-7a): removing the third butoxycarbonyl group in the compound (8); and (Step A7b): the step A-7a a step of reacting a compound with ruthenium chloride-nitrobenzenesulfonate in the presence of a base (A-7a step) A-7a as a method for removing a third butoxycarbonyl group bonded to an amine group 'can be carried out according to methods well known in the field of organic synthetic chemistry (eg, T. m -32- 201107306 W· Greene, ρ·G·Μ· Wuts, Greene's Protecive Groups in

Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.). The reagent to be used is selected from the above acid groups, preferably hydrochloric acid, sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, and most preferably trifluoroacetic acid. The solvent used is preferably a halogenated hydrocarbon, most preferably dichloromethane. The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 40 ° C. ^ The reaction time is preferably from 2 minutes to 24 hours, more preferably from 5 minutes to 4 hours. (A-7b step) The base to be used is preferably an alkali metal hydrogencarbonate, an alkali metal hydroxide, an alkali metal alkoxide or an organic amine, more preferably an alkali metal hydrogencarbonate, and most preferably sodium hydrogencarbonate. The solvent to be used is preferably a mixture of an ether and water, and is preferably a mixture of 1,4-dioxane and water. The reaction temperature is preferably -78 to 15 (TC, more preferably -30 to 40 ° C. The reaction time is preferably 5 minutes to 96 hours, more preferably 5 minutes to 2 hours. (A-8 step) A Step -8 is a step of converting the acetal group in the compound (9) to a formyl group. The reagent, solvent, and reaction temperature used vary depending on the compound of the formula YOH used in the step A-6. Step A-8 As a method for converting an acetal group to a formyl group, it can be carried out according to a method well known in the field of organic synthetic chemistry [S1 - 33 - 201107306 (for example, W. Greene, PGM Wuts, Greene's Protecive Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.) (Step A-9) Step A-9 is a step of reacting compound (10) with compound (11) in the presence of a reducing reagent. Step A-9 can be According to well-known methods in the field of organic synthetic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons,

Inc, p·8 3 5 - 8 46 ). The reducing agent to be used is not particularly limited as long as it is a user in the reductive amination reaction, for example, a borane-tetrahydrofuran complex, a borane-dimethyl sulfide complex, and a borane-dimethylamine. a boron hydride compound such as a complex compound, a borane-pyridine complex, sodium borohydride, sodium cyanoborohydride, cyanohydride boron tetra-n-butylammonium or sodium triethoxyborohydride; An aluminum hydride compound such as lithium aluminum hydride, aluminum hydride or diisobutylaluminum hydride; or hydrogen, preferably a boron hydride compound, most preferably sodium triethoxyborohydride. In the step of -9, preferably, an acid such as hydrochloric acid, formic acid 'acetic acid, trifluoroacetic acid or the like (preferably acetic acid) is used in combination with the above reducing agent. The solvent used is preferably an aromatic hydrocarbon or a tooth. The hydrocarbon or mixture of such 'preferably toluene, dichloromethane or a mixture of these. The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 110. (: The reaction time is preferably from 5 minutes to 24 hours, more preferably from 15 minutes to 24 hours. (A-10 step) A-step is a compound (12) and a halomethyl halide m in the presence of a base. 34- 201107306 Step of the compound reaction. The haloacetyl halide used is preferably chloroacetamidine chloride, bromoacetamyl chloride or bromoethene bromide, which is preferably bromoethene bromide. The base used is preferably an alkali metal. A hydrogencarbonate, an alkali metal hydroxide, a metal alkoxide or an organic amine, more preferably an organic amine, most preferably a triethylamine. The solvent to be used is preferably an aromatic hydrocarbon or a halogenated hydrocarbon, most The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 40. The reaction time is preferably from 5 minutes to 24 hours, more preferably from 30 minutes to 6 hours. (Step A-11) The step A-11 is a step of hydrolyzing the compound (13) in the presence of a base. The step A-11 can also be carried out according to a method well known in the art of organic synthetic chemistry (reaction containing hydrolysis) (for example, ' Comprehensive Organic

Transformations, Second Edition, 1 999, John Wiley & Sons,

Inc, p. 1959-1968) ° The base used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, a metal hydroxide or an alkaline earth metal hydroxide, more preferably an alkali metal hydroxide, preferably It is sodium hydroxide. The solvent to be used is preferably a mixture of an alcohol and water or a mixture of an alcohol, an ether and water, and is more preferably a mixture of methanol and water or a mixture of methanol, tetrahydrofurfuran D and water. The reaction temperature is preferably -78 to 150 ° C. More preferably 〇 to 80 〇 c ^ The reaction time is preferably 5 minutes to 24 hours, more preferably 3 minutes to 4 hours [S] -35 - 201107306 (A Step -12) The step A-12 is a step of reacting the compound (14) with the compound (15) in the presence of a condensation reagent and a base. The compound (15) may be known or easily produced by a known compound. The A-12 step can be carried out according to methods well known in the art of organic synthetic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, I nc, p. 1 9 4 1 - 1 9 4 9 ) ° The condensation reagent used is preferably dicyclohexylcarbodiimide (DCC), φ N-(3-diethylaminopropyl)_N'-ethylcarbodiimide (WSC), diphenylphosphonium. Azide (DPPA), diethyl cyanophosphate (DEPC), 0-(benzotriazol-1-yl)-1^ small,]^',>^'-tetramethylurea Fluorophosphate (1^1'11)' 0-(7-indole benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), More preferably HBTU or HATU. In the step A-12, an additive such as 1-hydroxybenzotriazole (HOBt) or 2-hydroxysuccinimide may be used in combination with the above reducing agent. The base to be used is preferably an organic amine, more preferably triethylamine or N,N-diiso-propylethylamine. The solvent to be used is preferably an amide, and most preferably N,N-dimethylformamide. The reaction temperature is preferably from -7 8 to 150 ° C, more preferably from 0 to 40 ° C. The reaction time is preferably from 5 minutes to 48 hours, more preferably from 30 minutes to 12 hours. (Step A-13) The step A-13 is a step of removing the fluorenyl-nitrobenzenesulfonyl group in the compound (16) in the presence of a base. The reagent to be used may, for example, be methylamine, dimethylamine, ethylamine, [S1 -36-201107306 diethylamine, η-propylamine, n-butylamine, pyrrole, piperidine'? Primary or secondary amines such as porphyrin, piperene, hydrazine-methylpiped, hydrazine, ν, hydrazine-dimethylhydrazine; or methane thiol, ethane thiol, η-propane thiol, η- Mercaptans such as butanethiol, η-dodecanethiol, thiophenol, and thioglycolic acid are preferably mercaptans, and most preferably thiophenols. The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydroxide, an alkali metal hydride, an alkali metal decylamine, an alkali metal alkoxide, a lithium alkyl decylamine, a decyl decylamine, The alkyl lithium or organic amine, more preferably an alkali metal ^ carbonate, is preferably a carbonic acid planer. The solvent to be used is preferably a nitrile or a guanamine, more preferably acetonitrile or ν, ν-dimethylformamide. The reaction temperature is preferably -78 to 150 ° C, more preferably 〇 to 40»c. The reaction time is preferably from 5 minutes to 48 hours, more preferably from 15 minutes to i 2 hours. (Method B) The method B is a method for producing a compound having the formula (I). • (Step B-1) Step B-1 is (B-la step): the step of removing the compound obtained in the step A-10 (the fluorene-nitrobenzenesulfonyl group in the step; and (B-lb step) The step of reacting the compound obtained in the Β-la step with di-tertiary-butyl-dicarbonate in the presence of a base. (B-la step) The B-la step can be carried out in the same manner as the step A-13. (B -1 b step) [S3 -37- 201107306 The base used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydroxide 'alkali metal hydride, an alkali metal guanamine, an alkali metal The alkoxide or organic amine, more preferably an alkali metal hydrogencarbonate, is preferably sodium hydrogencarbonate. The solvent used is preferably a mixture of an ester and water, preferably a mixture of ethyl acetate and water. Preferably, it is -78 to 150 ° C, more preferably 0 to 601. The reaction time is preferably 5 minutes to 48 hours, more preferably 15 minutes to 4 hours. ® Amine group used in the B-lb step The protecting group is not limited to the third butoxycarbonyl group as long as it is well known in the field of organic synthetic chemistry (for example, TW Greene, PGM Wuts, Greene) 9s Protecive Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.). The amine protecting group used may, for example, be indenyl, ethyl fluorenyl, chloroethyl, trimethyl Anthracenyl group such as fluorenyl or benzamidine; methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl '2,2,2-trichloroethoxycarbonyl, 2-(trimethyldecyl) Alkoxycarbonyl group of ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl; methoxymethyl '2-(trimethyldecyl)ethoxymethyl, benzyloxy Substituted alkyl group such as trimethylacetoxymethyl, allyl, benzyl, diphenylmethyl or triphenylmethyl; methanesulfonyl, benzenesulfonyl, P-toluene A sulfonyl group such as a fluorenyl group, a fluorenyl-nitrobenzene-expandable group, an anthracene or a p-dinitrobenzenesulfonyl group is preferably a third butoxycarbonyl group. (B-2 step) B-2 The step is a step of hydrolyzing the compound (17) in the presence of a base. The step B-2 can be carried out in the same manner as in the step A-11. (Step B-3) [S] -38 - 201107306 The step B-3 is Compounding in the presence of a condensation reagent and a base (18) A step of reacting with the compound (15). The compound (15) is known or can be easily produced from a known compound. The step B-3 can be carried out in the same manner as in the step A-12. (Step B-4) B- The fourth step is a step of removing the third-butoxycarbonyl group in the compound (19). The step B-4 can be carried out in the same manner as in the step A-7 a. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof, which can be administered as a medicine, can be administered as it is (or as it is) or can be suitably pharmacologically acceptable. The excipient 'diluent or the like is mixed and administered as a preparation for tablets, capsules, granules, powders or syrups, orally, or as a preparation for injection or suppository, etc., preferably by oral administration (preferably orally). These preparations are produced by a known method using an additive such as an excipient, a binder, a disintegrant, a lubricant, an emulsifier, a stabilizer, a flavoring agent, a diluent, a solvent for injection, or the like. The excipient, for example, may be an organic excipient or an inorganic excipient. Organic excipients, for example, may be sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol; corn starch, potato starch, (X-starch, dextrin, carboxymethyl starch, etc.) Starch derivatives; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose 'carboxymethyl cellulose calcium, internal cross-linked carboxymethyl cellulose sodium, etc. Cellulose derivative; gum arabic; dextrose; or pululan vinegar (pul lul an), etc. Inorganic excipients, for example, may be light anhydrous citric acid, -39- 201107306 synthetic aluminum citrate a citrate derivative such as calcium citrate; a phosphate such as calcium phosphate; or a sulfate such as calcium sulphate. The binding agent, for example, may be the above-mentioned excipient; gelatin; polyvinylpyrrolidone Or polyethylene glycol. A disintegrating agent, for example, may be the above excipient; a chemically modified starch or a cellulose derivative such as croscarmellose sodium or sodium carboxymethyl starch; or Bipolyvinyl pyrrolidone. Lubricants, for example, Is talc; stearic acid; stearic acid metal salt such as calcium stearate or magnesium stearate; colloidal vermiculite; waxes such as beeswax and cetyl wax; boric acid; diol; D, L-amine Acid; carboxylic acid such as fumaric acid or adipic acid; sodium carboxylate such as sodium benzoate; sulfate such as sodium sulfate; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate a salt; a phthalic acid such as anhydrous citric acid or citric acid hydrate; or a starch derivative in the above-mentioned excipient. The emulsifier, for example, may be a colloidal substance such as bentonite or veegum. Clay; anionic surfactant such as sodium lauryl sulfate or calcium stearate; ionic surfactant such as benzalkonium chloride; or polyoxyethylene alkyl ether or polyoxyethylene sorbitan fatty acid ester a nonionic surfactant such as a sucrose fatty acid ester. The stabilizer may, for example, be a paraben such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; chlorobutanol or benzyl Alcohols such as alcohol and phenylethyl alcohol; benzalkonium chloride; benzene such as phenol or cresol Sodium thiomethic acid (thimerosal); dehydroacetic acid; or sorbic acid. A flavoring bromineing agent, for example, may be a commonly used sweetener, sour or m-flavor. -40- 201107306 Thinner, for example, It may be water, ethanol, propylene glycol, ethoxylated isostearyl alcohol or polyoxyethylene sorbitan fatty acid ester. The solvent for injection may be, for example, water, ethanol or glycerin. The active ingredient of the present invention has a general formula. The amount of the compound of (I) or the pharmacologically acceptable salt thereof varies depending on the symptoms, age, etc. of the patient, and in the case of oral administration, the lower limit per one time is 0.02 mg/kg (preferably 〇) .lmg/kg), the upper limit is l〇〇mg/kg (preferably l〇mg/kg), and the ratio of non-oral administration is 0.002 mg/kg per one time (preferably O.Olmg) /kg), Φ upper limit is iOmg/kgC is preferably lmg/kg), for adults, 1 to 6 times per 1曰, visual symptoms are administered. EFFECTS OF THE INVENTION The compound of the general formula (I) or a pharmacologically acceptable salt thereof of the present invention has renin inhibiting activity, solubility 'cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue Migration, bioavailability, in vitro activity, in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physical stability, drug interaction, safety (eg, cardiotoxicity or hepatotoxicity), etc. It has excellent properties and is useful as a medicine [especially for the treatment or prevention of hypertension (preferably for treatment)]. [Embodiment] The present invention will be described in more detail with reference to Examples, Test Examples, and Preparation Examples. However, the scope of the present invention is not limited thereto. In the following examples, the compound names recorded indicate the compounds obtained in the examples, and the chemical formulas described indicate the chemical structures of the corresponding free compounds. For example, the compound obtained in Example 1 is (3S,5R)-5-[4-(2-chlorobenzyl)-2,2-dimethyl-41 - 201107306--5-piperidone-1- The group]-N-[(1R)-1-ethyl-3-methylbutyl]piperidine-3-carboxyindoleamine fumarate, the chemical structural formula described in Example 1 is (3S, 5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)-1-ethyl-3-methyl Chemical structure of butyl] piperidine-3-carboxamide. In the following Reference Examples, the compound name and the chemical structural formula are shown to indicate the compound obtained in the reference example. [Examples] (Example 1) (3S, 5R) -5-[4-(2-Chlorophenyl) -2,2-dimethyl-5-piperidone-i-yl]-N-[(III)-1-ethyl-3-methylbutyl]piperazol-3-carboxamide antibutene Diacid salt

(la) 1-tertiary butyl 3-methyl(3S,5R) _5· Μ(benzyloxy)carbonyl]amine-methyl hydrazino}piperidine-, 3 -11 residual acid hydrazine obtained in Reference Example 1 (3R,5S) -1·(tertiary butoxycarbonyl)_5-(methoxycarbonyl)piperidin-3-indole 19.35g (67.35mmo1) in toluene (33 ml) solution Add 12.65 ml (8 0.8 2 mmol) of diethylamine and 20.38 g (74.08 mmol) of diphenylphosphonium azide (DPPA) at a temperature of 1.5 TC for 1.5 hours. After standing for 15 minutes, A solution of 10.92 g (101.02 mm 〇1) of toluene-42-201107306 (10 ml) of benzyl alcohol was added to the reaction mixture, and the mixture was stirred at 90 ° C for 3.5 hours. After cooling to room temperature, water was added to the reaction mixture to give ethyl acetate. The organic layer was washed with saturated aqueous sodium sulfate and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by column chromatography (solvent solvent: η-hexane / ethyl acetate = 4 / 1) The residue was purified to give the title compound: 25.50 g (yield: 96%). Colorless liquid. 'H NMR spectrum (CDC13, 400 MHz), δ: 7.37-7.26 (m, 5H), 5.11 (br s, 3H) , 4.06-4.03 (m, 2H), 3.70-3.63 (m, 5H), 3.09-3.05 (m, 1H), 2.60 (br s, 1H), 2.31-2.27 (m, 1H), 1.6 卜 1.56 (m, 1H), 1.45 (s, 9H). (lb) 1-3-4 1-3-tert-butyl 3-methyl (3S, 5R) obtained from the 3-methyl (3S,5R)-5-aminopiperidine-1,3-dihydroxy vinegar example (la) 5-{[(benzyloxy)carbonyl]amine-carbenylpiperidine-1,3-dicarboxylate 25.50g (64-97mmol) with 10% palladium on carbon (containing 50% water) 2.50g of methanol (100ml) The mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After replacing the hydrogen in the reaction vessel φ with nitrogen, the palladium catalyst was filtered, and the filtrate was concentrated under reduced pressure to purify the column by column chromatography (dissolving solvent: dichloro The residue was purified to give the title compound: 15.98 g (yield: 95%). Colorless liquid. H NMR spectrum (CDC13, 500 MHz) ' δ : 4.34-4.16 (m, 2H), 3.70 (s, 3H), 2.77-2.50 (m5 3H), 2.30-2.25 (m, 2H), 1.46 (s, 9H), 1.35-1.28 (m, 1H), 1.15 (br s, 2H). (lc) 1-tertiary butyl 3-methyl(3S,5R)-5-[(2,2-dimethoxy-1,1-dimethylethyl)amino]piperidine-1, 3-Dicarboxylate [S] -43 - 201107306 1-Tributyl butyl 3-methyl(3S,5R)-5-aminopiperidine-1,3 -di obtained in Example (lb) A solution of 15.98 g (61.86 mmol) of a carboxylic acid ester and a solution of isobutylaldehyde (4.46 ml (61.86 mmol) in methylene chloride (12 ml) was added, and then, about 8 g of anhydrous magnesium sulfate, and stirred at room temperature for 3 hours. The insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. To the obtained reaction mixture, carbon tetrachloride (240 ml) was added and dissolved, and 8.26 g (61.86 mmol) of N-chlorosuccinimide was added thereto, and the mixture was stirred at room temperature for 16 hours. The insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. Methanol (1 20 ml) was added to the reaction mixture thus obtained, dissolved, and stirred at 60 ° C for 23 hr. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and purified mjjjjjjjjjjjjjjj 88%). Colorless liquid. NMR spectrum (CDC13, 500MHz), δ: 4.33-4.06 (m, 2H), 3.90 (s, 1H), 3.68 (s, 3H), 3.53 (s, 6H), 2.66-2.54 (m, 3H), ^ 2.28 (br s, 1H), 2.15 (br d, 1H, J = 12.7 Hz), 1.46 (s, 9H), 1.35 (q, 1H, J = 12.2 Hz), l.〇6(s,6H). (Id)methyl(3S,5R)-5-[(2,2-dimethoxy-l,l-dimethylethyl)amino]nitrophenyl)sulfonyl]piperidine-3 -carboxylic acid ester 1-1,3-tert-butyl 3-methyl(3S,5R)-5-[(2,2-dimethoxy-1,1-dimethylethyl) obtained in Example (lc) To 17.89 g (54.48 mmol) of the amino]piperidine-dicarboxylate, 272 ml (1.09 mol) of a 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) 14.48 g (65.3 7 mmol) of benzenesulfonate was stirred at the same temperature for 10 minutes, then 4.57 g (54.50 mmol) of sodium hydrogencarbonate was added, and the mixture was stirred at the same temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silicagel eluted (Yield: 70%). Colorless solid. iHNMR spectrum (CDC13, 500MHz), δ: 8.01-8.00 (m, 1H), 7.72-7.62 (m, 3H), 4.02 (br d, 1H, J = 8.3 Hz), 3.90 (s, 1H), 3.89- 3.8 5 (m, 1H), 3.69 (s, 3H), 3.53 (s, 3H), 3.52 (s, 3H), 2.90- 2.8 3 (m, 1H), 2.79-2.69 (m, 2H), 2.32- 2.28 (m, 1H), 2.22 (br d, 1 H, J = 1 3.2 Hz), 1.3 0- 1 .23 (m, 1 Η), 1.06 (s, 6H) » (le) methyl (3S, 5R) -5-[(l,l-dimethyl-2-oxoethyl)amino]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate Methyl (3S,5R)-5-[(2,2-dimethoxy-1,1-dimethylethyl)amino]-l-[(2-) obtained in Example (Id) To a solution of 17.71 g (38.54 mmol) of methylene chloride (60 ml), nitrophenyl)sulfonyl]piperidine-3-carboxylate, 60 ml of concentrated hydrochloric acid, and stirred at 40 ° C for 4 hours. The reaction mixture was neutralized with aq. The organic layer was washed with brine and dried over anhydrous sodium sulfate. On the other hand, the water layer was subjected to reverse layer sand rubber column chromatography (reverse layer sand rubber: Cosmosil 75C18 - PREP' water/acetonitrile = 1/0 to 0/1 manufactured by Nacalai Tesque Co., Ltd.) to remove the inorganic substance, and the crude product was obtained (3S, 5R ) -5-[( 1,1-dimethyl-2-oxoethyl)amine m -45- 201107306 yl]-l-[(2-nitrophenyl)sulfonyl]piperidine- 3-carboxylic acid. Adding the reaction mixture obtained from the organic layer to the crude (3S, 5R) -5 obtained from the aqueous layer in a mixture of methanol (4 〇 ml) and sulfinium chloride 1 1 〇 ml (1 51 mm 〇 1 ) -[( 1,1-Dimethyl-2-oxoethyl)amino]-1-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid in methanol (10 0ml The solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjj g (yield: 86%). Colorless solid. iH NMR spectrum (CDC13, 500MHz), δ: 9.44 (s, 1 Η), 8.01- 7.99 (m, 1H), 7.74-7.69 (m, 2H), 7.66-7.63 (m, 1H), 4.01- 3.98 ( m, 1H), 3.8 3 -3.80 (m, 1 H ), 3.6 9 (s, 3 H), 2.79-2.64 (m, 3H), 2.38 (dd, 1H, J = 12.7 Hz, 10.7 Hz), 2.28 (br d, 1H, J = 12.7 Hz), 1.32 (q, 1H, J = 12.2 Hz), 1.24 (s, • 3H), 1 · 1 8 (s, 3H). S1 (If)methyl(3S,5R) -5-({ 2-[(2-chlorophenyl)amino]-1,1-dimethylethyl}amino)-l-[( 2- Methyl(3S,5R)-5-[(l,l-dimethyl-2-oxo) obtained in the example (le) of nitrophenyl)sulfonyl]piperidine-3-carboxylate Base ethyl)amino]_i_[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate 17.1〇g (41.36mmol) with 2-chloroaniline 7.87g (61.7mmol) of toluene ( To 40 ml of the solution, 8 to 67 g (144 mmol) of acetic acid was added, and the mixture was heated under reflux to be stirred for 4 hours while removing the generated water. After cooling, to the reaction mixture, sodium triethoxyborohydride 17.50 g -46 - 201107306 (82.6 mm 〇 1 ) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 4/1 to 7/3) to give the title compound (16.00 g). 74%). Colorless liquid. iNMR spectrum (CDC13, 500 MHz), δ: 7.74 (d5 1H J = 8 3

Hz), 7.64-7.58 (m, 2H), 7.52-7.48 (m, 1H), 7.25-7.23 (m 1H) 7.17-7.14 (m, 1H), 6.65-6.62 (m, 2H), 4.85 (br s ,1H) 4 〇7 (br d,1H,J = 9.3 Hz), 3.75-3.71 (m,1H), 3.69 (s,3H) 2 9? (d,1H, J = 11.7 Hz), 2.94 (d , 1H, J = 11_7 Hz), 2.8l_2 69 (m 3H), 2.34 (dd, 1 H, J = 12.5 Hz, 10.5 Hz), 2.21 (br H 1u T _ u , 1 xi , J — 12.5 Hz) , 1.32 (q, 1H, J = 12.2 Hz), 1.22 (s, 3H), ! 21 (s 3H).

(lg)methyl(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-indolone-1-yl]-l-[(2-nitro Phenyl)anthracenyl] oxime-but-3-yl-acid n methyl (3S,5R)-5-({2·[(2-chlorophenyl)amino]-] obtained in Example (If) 1,1-Dimethylethyl}amino)sulfonyl]piperidine-3-carboxylate 16.00 g (3 0.5 mmol) with triethylamine 24 8 g (245.1 mmol) in dichloromethane (320 ml) A solution of 24.4 g (120.9 mmol) of dibromide (80 ml) of ethidium bromide was added to the solution under ice cooling for 2.5 hours, stirred at room temperature for 45 minutes, and then stirred at 40 ° C for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified (yield solvent: η-hexane/ethyl acetate-47-201107306 ester=7/3~0/1) to give the title compound 13 50 g (yield: 79%). Colorless liquid. 4 NMR spectrum (CDC13, 500MHz), δ: 8.03-8.01 (m, 1H), 7.76-7.70 (m, 2H), 7.67-7.6 5 (m, 1H), 7.48-7.46 (m, 1H), 7.33- 7.23 (m, 3H), 4.03 (br d, 1H, J = 11.2 Hz), 3.87-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.22 (m, 5H), 2.76-2.68 (m , 3H), 2.24-2.17 (m, 1H), 1.73 - 1.66 (m, 1H), 1.41-1.35 (m, 6H). Φ ( lh)(3S,5R) -5-[4-(2-chlorophenyl)-2,2-dimethyl-5-0 oleic acid-1-yl]-l-[ ( 2 -nitrate Methyl (3S,5R)-5-[4-(2-chlorophenyl)-2,2 obtained in Example (lg) - dimethyl-5-piperidone-1-yl]-i-[(2-nitrophenyl)sulfonyl] 峨B-but-3-carboxylic acid 195 mg (〇.35 mmol) of methanol (4 ml In a solution, 2.0 ml (2.0 mmol) of a 1N aqueous sodium hydroxide solution was added and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, 1N hydrochloric acid was added to make acid (pH 2-3). The mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated brine. After filtration, the solvent was evaporated to dryness crystals crystal crystal crystal crystal Colorless solid. WNMR spectrum (CDC13, 500MHz), δ: 8.02-8.01 (m, 1H), 7.75-7.70 (m, 2H), 7.67-7.65 (m, 1H), 7.48 (dd, 1H, J = 7.3 Hz, 1.5 Hz ), 7.3 6-7.22 (m, 3H), 4.01-3.94 (m, 1H), 3.87-3.80 (m, 1H), 3.72 (brd, 1H, J = 17.6 Hz), 3.63 (br d, 1H, J = 17.6 Hz), 3.48-3.41 (m, 1H), 3.29-3.2 3 (m, 2H), 2.77-2.70 (m, 3H), 2.26-2.20 (m, 1H), 1.71-1.58 (m, 1H) , 1.41-1.35 (m, 6H). m -48 · 201107306 (11)(38,511)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[ ( 1R) 1-(3-nitro-3-methylbutyl)-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxamide obtained in Example (lh) (3S, 5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-l-[(2-nitrophenyl)sulfonyl]per 200 mg (0.36 mmol) of pyridine-3-carboxylic acid, 66 mg (0.44 mmol) of (3R)-5-methylhexane-3-amine hydrochloride obtained in Reference Example 2, and 140 mg of diisopropylethylamine ( 1.08 mmol) of N,N-dimethylformamide (3 ml) in a solution of 'φ at room temperature, adding 0-(benzotriazol-1-yl)-oxime, oxime, Ν', Ν'-four Methyl urea hexafluorophosphate (HBTU) 207 mg (0.55 mmol) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel elution elution elution elution elution elution Rate: 89%). Colorless solid.

NMR spectrum (CDC13, 500MHz), δ: 7.97-7.96 (m, 1H), 7.75-7.70 (m, 2H), 7.68-7.63 (m, 1H), 7.46 (br d, 1H, J = 7.8 Hz), 7.32-7.22 (m, 3H), 5.27 (br d, 1H, J = 9.3 Hz), 3.96-3.87 (m, 3H), 3.75-3.47 (m, 2H), 3.3 7-2.99 (m, 3H), 2.81-2.71 (m, 1H), 2.65-2.50 (m, 1H), 1.98-1.88 (m, 2H), 1.61-1.47 (m, 4H), 1_4 卜 1.29 (m, 7H), 0.92-0.83 (m , 9H). (lj)(3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[(1R) -1- Ethyl-3-methylbutyl]piperidine-3-carboxamide anti-butyl [S1 -49- 201107306 enedic acid salt (3S,5R) ·5-[4- obtained in Example (li) (2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-1^-[(11〇-1-ethyl-3-methylbutyl]-1- [(2-Nitrophenyl)sulfonyl]piperidine-3-carboxamide 205mg (0.31mmol) and thiophenol 48μ1 (0·47πιιηο1) in acetonitrile (6ml), at room temperature, add carbonic acid The mixture was stirred for 3 hours at room temperature. Water was added to the reaction mixture for dilution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to chromatography on a NH(H) column chromatography (solvent solvent: ethyl acetate/methanol = 0/1 to 4/1) and a column chromatography (solvent solvent: dichloromethane/methanol) =7/3) Purification to obtain (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]->}- [(111)-1-Ethyl-3-methylbutyl]piperidine-3-carboxamide 126 mg (yield: 86%). (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-heart [(11〇-1-ethyl-) To a solution of 126 mg (0.27 mmol) of 3-methylbutyl]piperidine-3-carboxamide in methanol (1 ml), add 31 mg (0.27 mmol) of fumaric acid, and stir at room temperature for 5 minutes. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane (yield: hexanes, EtOAc) ), δ : 7.85 (brd, 1H, J = 9.8 Hz), 7.53 (dd, 1H, J = 7.3 Hz, 1.5 Hz), 7.42-7.36 (m, 2H), 7.33-7.31 (m, 1H), 6.70 (s, 2H), 3.87-3.83 (m, 1H), 3.67-3.44 (m, 4H), 3.3 8-3.23 (m, 3H), 3.11-3.05 (m, 1H), 2.99 (t,1H, J = 12.5 Hz), 2.85-2.79 (m,1H), 2.13-2.06 (m,[s] •50- 201107306 1H), 2.00-1 .91 (m, 1 H), 1.65 - 1.5 0 (m, 2H ), 1.41-1.25 (m, 9H), 0.94-0.8 8 (m, 9H). Mass spectrum (FAB+), m/z: 463 ((M + H)+). (Example 2) (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-(l-isobutyl) Cyclopentyl)piperidine-3-carboxamide fumarate

( In the same manner as in the examples (1 i ) and (1 j ), (3S,5R)-5-[4-(2-chlorophenyl)-2,2-di which was obtained using the example (1 h ). Methyl-5-piperidone-l-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid and 1-isobutylcyclopentane obtained in Reference Example 3 Alkyl-1-amine hydrochloride gave the title compound 77 mg (3 step: Colorless solid. NMR spectrum (CD3OD, 500MHz)' δ : 7.72 (br s, 1H), 7.53 (dd, 1H, J = 7.3 Hz, 2.0 Hz), 7.42-7.3 6 (m, 2H), 7.3 3 -7.30 (m, 1H), 6.70 (s, 2H), 3.67-3.44 (m, 4H), 3.3 7-3.23 (m, 3H), 3.08 -3.03 (m, 1H), 2.94 (t, 1H, J = 12.5 Hz), 2.8 5 -2.78 (m, 1H), 2.09-2.04 (m, 3H), 1.96-1.8 8 (m, 1 H), 1.77- 1.53 (m, 9H), 1.40- 1.36 (m, 6H), 0_94 (d, 6H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 489 ((M + H)+). (Example 3) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-[s] -51 - 201107306 base]- N-(3,3,3-trifluoro-1,1-dimethylpropyl)piperidine-3-carboxamide fumarate

In the same manner as in the examples (1 i ) and (1 j ), (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl group obtained in the example (1 h) was used. 5--5-piperidone-1-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid and 4,4,4-trifluoroethylene obtained in Reference Example 4 2-methylbutane-2-amine hydrochloride gave the title compound 133 mg (yield: Colorless solid. !H NMR spectrum (CD3OD, 500MHz)' δ : 7.98 (br s,1H), 7.53 (dd, 1H, J = 7.3 Hz, 2.0 Hz), 7.42-7.3 6 (m, 2H), 7.3 3 -7.3 0 (m, 1H), 6.70 (s, 2H), 3.67-3.45 (m, 4H), 3.3 6-3.22 (m, 3H), 3.08-3.03 (m, 1H), 2.93 (t, 1H, J = 12.5 Hz), 2.87-2.72 (m, 3H), 2.12-2.05 (m, 1H), 1.94-1.8 5 (m, 1H), 1.43 (br s, 6H), 1.41-1.36 (m, 6H). Mass spectrum (FAB+), m/z: 489 ((M + H)+). (Example 4) N2-({(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3 -yl}carbonyl)-N,N-dimethyl-L-leucine decyl fumarate [S1 -52- 201107306

(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl group obtained in Example (1 h) was used in the same manner as in Examples (1 i ) and (lj). -5-piperidone-l-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid and hydrazine, hydrazine-dimethyl-L obtained in Reference Example 5 - leucine guanamine hydrochloride to give the title compound Φ 4 1 mg (3 step total yield: 49%). Colorless solid. iH NMR spectrum (CD3OD, 400MHz), δ: 7.55-7.52 (m, 1H), 7.43 -7.3 6 (m, 2H), 7.33-7.31 (m, lH), 6.75 (s, 2H), 4.87-4.83 ( m,lH), 3.70-3.45 (m,4H), 3.40-3.22 (m,3H), 3.15-3.07 (m,4H), 3.00-2.84 (m,5H), 2.18-2.10 2.00-1.91 (m, lH), 1.72-1.58 (m, 2H), 1.51-1.38 (m, 7H), 1.10-0.97 (m, 6H). Mass spectrum (FAB+), m/z: 506 ((M + H)+). (Example 5) (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)- 1-(ethoxymethyl)-3-methylbutyl]piperidine-3-carboxamide fumarate

-53- 201107306 (5a) 1-tertiary butyl 3-methyl(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone- Methyl(35,5 ft)-5-[4-(2-chlorophenyl)-2,2- obtained in Example (18), 1-yl]piperidine-1,3-dicarboxylate Dimethyl-5-piperidin-1-yl]-1-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate 13.50 g (23.9 mmol) and thiophenol 3.64 ml ( 35.7 mmol) of acetonitrile (400 ml) was added to a solution of 9.31 g (28.6 mm 〇1) under ice cooling, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: methylene chloride/methanol = 1/0 to 7/3) to obtain methyl (3S,5R) -5-[ 4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3-carboxylate 9.1 g (yield: quantitative). Methyl (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-l-yl]piperidine-3-carboxylate obtained here Adding a di-tertiary butyl group to a mixture of ethyl acetate 9·lg (23·9mm0l) and sodium bicarbonate 6.20g (73.8mmol) of ethyl acetate (200 mm 1 ) and water (200 m 1 ) Dicarbonate 6.00 g (27.5 mmol) was stirred at room temperature for 30 minutes. The reaction mixture was extracted with EtOAc. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3 to 1/9) and oxime column chromatography (dissolving solvent: η - The residue was purified to give the title compound (yield: 68%). Colorless solid. 4 NMR spectrum (CDC13, 500MHz), δ: 7.47 (dd, 1H, J = 7.3 Hz, 1.5 Hz), 7.34-7.22 (m, 3H), 4.29 (br s, 1H), 4.12 (br s, -54 - 201107306 1H), 3.74-3.52 (m, 5H), 3.3 6-3.29 (m, 2H), 3.02-2.98 (m, 1H), 2.68-2.56 (m, 3H), 2.14 (br s, 1H), 1.84-1.73 (m, 1H), 1.48 (s, 9H), 1.44-1 .3 1 (m,6H) » (5b)(3S,5R) -1-(tertiary butoxycarbonyl)_5_[4 -(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3-carboxylic acid 1-tributyl 3 obtained in Example (5a) -methyl(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-1,3-dicarboxylic acid A mixture of 7.80 g (1. 6 mmol) of THF (150 ml) and water (75 ml) was added, and, under ice cooling, 1.37 g (32.6 mmol) of lithium hydroxide.1 hydrate was added and stirred at the same temperature for 2 hours. To the reaction mixture, 1 N hydrochloric acid was added to make acidity (ρ Η 2·3), which was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (yield: quantitative). Colorless solid. 4 NMR spectrum (CDC13, 500MHz), δ: 7.47 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.34-7.25 (m, 3H), 4.30 (br s, 1H), 4.12 (br s, 1H) , 3.76 (br d, 1H, J = 17.6 Hz), 3.66 (br d, 1 H, J = 17.6 Hz), 3.3 8-3.29 (m, 2H), 3.03-2.99 (m, 1H), 2.69-2.56 (m, 3H), 2.22-2.1 5 (m, 1H), 1.81-1.69 (m, 1H), 1.47 (s, 9H), 1.43-1.32 (m, 6H). (5c) tert-butyl (3R,5S)-3-[4-(2-chlorophenyl)-2,2·dimethyl-5-piperidone-1-yl]-5-{ [( 1R) -1-(ethoxymethyl)-3-methylbutyl]aminemethanyl}piperidine-1-carboxylate (3S,5R) -1- obtained in Example (5b) (tertiary butoxy-yl)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]峨 steep_3_[s] -55 - 201107306 148 mg (0.3 2 mmol) of carboxylic acid, (2R)-1-ethoxy-4-methylpentan-2-amine 9 2 m g (0.63 mmol) and diisopropylethyl group obtained in Reference Example 6. Amine 166 μΐ (0.95 mmol) in a solution of hydrazine-dimethylformamide (3 ml), under ice cooling, add 〇-(benzotriazol-1-yl)·Ν, Ν, Ν', N' - Tetramethyluronium hexafluorophosphate (HBTU) 180 mg (0.48 mmol), stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/1 to 0/1) and hexane column chromatography (dissolving solvent: The residue was purified to give the title compound 137 mg (yield: 73%). Colorless solid. 'H NMR spectrum (CDC13, 500MHz), δ: 7.48-7.46 (m, 1H), 7.3 3 -7.22 (m, 3H), 5.64 (br d, 1H, J = 4.9 Hz), 4.22-4.10 (m, 2H), 3.77-3.70 (m, 1H), 3.62-3.31 (m, 8H), 2.98 (br s, 1H), 2.74-2.68 (m, 2H), 2.34 (br s, 1H), 1.99-1.91 ( m, 2H), 1.58 (br s, 1H), 1.48 (s, 9H), 1.46-1.31 (m, 8H), 1.20 (t, 3H, J = ® 6.8 Hz), 0.93-0.91 (m, 6H) ° (5d) ( 3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[(1R) -1 -(ethoxymethyl)-3-methylbutyl]piperidine-3-carbamidamine fumarate in the third butyl (3S,5R)-3 obtained in Example (5c) -[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-5-{[(11〇-1-(ethoxymethyl)-3 To a solution of 135 mg (0.23 mmol) of methylene chloride (0.7 ml) in methylene butyl]amine-carbamoyl}piperidine-1-carboxylate, 0.35 ml (4.5 mm 〇l) of trifluoroacetic acid, room temperature After stirring for 15 minutes, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Press down The solvent was removed, and the residue was purified by NH.sub.p. column chromatography (solvent solvent: dichloromethane/methanol=20/1~7/3) to give (3S,5R)' - 5-[4-(2-chlorophenyl) -2,2-dimethyl-5-piperidone-1-yl]-^[-[(11〇-1-(ethoxymethyl)-3.methylbutyl]piperidine-3 - Methionine 94 mg (yield: 84%). (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidinone obtained here -1-yl]-N-[(1R)-1-(ethoxymethyl)-3-methylbutyl]piperidine-3-carboxamide 94mg (0.19mmol) in methanol (1ml) 2,2 m g of fumaric acid (0.19 mm 〇1) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The title compound was obtained (yield: 84%). Colorless solid. WNMR spectrum (CD3OD, 400MHz), δ: 7.54 - 7.52 (m, lH), 7.43-7.32 (m, 3H), 6.69 (s, 2H), 4.12-4.08 (m, lH), 3.69-2.94 (m, 13H), 2.84-2.78 (m,lH), 2.16-2.10 (m,lH), 1.98-1.89 (m,lH), 1.67- 1.58 (m,lH), 1.54- 1.32 (m,8H), 1.17 ( t, 3H, J = 7.0 Hz), 0.95-0.90 (m, 6H). Mass spectrum (FAB+), m/z: 493 ((M + H)+). (Example 6) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[l-(4 ,4-difluorocyclohexyl)-1-methylethyl]piperidine-3-carboxamide anti-butenediate m -57- 201107306

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl) obtained in the same manner as in the examples (5c) and (5d). -2,2-dimethyl-5-piperidin-1-yl]piperidine-3-carboxylic acid and 2-(4,4-difluorocyclohexyl)propane-2- obtained in Reference Example 7 Amine, the title compound was obtained (yield: 3:3). Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 7.62 (br s, 1H), 7.53 (dd, 1H, J = 7.8 Hz, 2.0 Hz), 7.42-7.3 6 (m, 2H), 7.3 3 -7.3 0 (m , 1H), 6.69 (s, 2H), 3.70-3.44 (m, 4H), 3.38-3.21 (m, 3H), 3.07-3.02 (m, 1H), 2.92 (t, 1H, J = 12.5 Hz), 2.81-2.75 (m, 1H), 2.22-2.05 (m, 4H), 1.95-1.87 (m, 1H), 1.77-1.65 (m, 4H), 1.4 1 -1.29 (m, 1 4H). Mass Spectrum (FAB+) > m/z: 525 ((M + H)+). (Example 7) (3S,5R) -5-[4·(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]_N-[1-methyl- 1-(tetrahydro-2H-piperazin-4-yl)ethyl]piperidine-3-carbamide amine fumarate

-58-201107306 In the same manner as in the examples (1 i ) and (lj), (3S,5R)-5-[4-(2-chlorophenyl)-2,2 obtained in the example (1 h) was used. -Dimethyl-5-piperidone-1-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid and 2-(tetrahydrogen) obtained in Reference Example 8. -2H-Pylan-4-yl)propan-2-amine gave the title compound 67 mg (yield: 30%). Colorless solid.

1H NMR spectrum (CD3OD, 400MHz), δ: 7.58 (br s,lH), 7.54-7.52 (m,lH), 7.43-7.3 5 (m,2H), 7.3 3 -7.3 0 (m,lH), 6.70 (s, 2H), 4.00-3.97 (m, 2H), 3.70-3.2 1 (m, 9H), 3.07-3.01 (m, 1 H), 2.92 (t, 1 H, J = 12.1 Hz), 2.8 3 -2.77 (m,lH), 2.3 1-2.28 (m, 1 H), 2.12-2.05 (m, 1 H), 1.95 - 1.86 (m, 1 H), 1.5 6- 1.5 2 (m, 2H), 1.46- 1.2 8 (m, 15H). Mass spectrum (FAB+), m/z: 491 ((M + H)+). (Example 8) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl]-N-(l-methyl -l-phenylethyl)piperidine-3-carboxamide fumarate

(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl- obtained by the example (1 h) was used in the same manner as in the examples (Π) and (U). 5-piperidone-1-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylic acid and 2-phenylpropan-2-amine gave the title compound Total yield of steps: 57%). Colorless solid. -59- 201107306 HNMR spectrum (CD3OD, 500MHz)' δ : 8.36 (br s,1H), 7.53 (br d, 1H, J = 7.3 Hz), 7.42-7.36 (m, 4H), 7.3 3 -7.28 (m , 3H), 7.18 (br t, 1H, J = 7.3 Hz), 6.71 (s, 2H), 3.66-3.45 (m, 4H), 3.40-3.22 (m, 3H), 3.06-3.0 0 (m, 1H ), 2.9 3 -2.8 3 (m, 2H), 2.20-2.14 (m, 1H), 1.9 3 - 1.84 (m, 1H), 1.66- 1.65 (m, 6H), 1.44- 1 .3 8 (m, 6H). Mass spectrum (FAB + ), m/z: 483 ( (M + H) +). (Example 9)

(3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl]-N-(l-phenylcyclopentyl)per Pyridin-3-carbamide amine fumarate

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl) obtained in the same manner as in the examples (5c) and (5d). -2,2-dimethyl-5-piperidone-1 -yl]piperidine-3-carboxylic acid and 1-phenylcyclopentan-1-amine hydrochloride obtained in Reference Example 9 were obtained. The title compound was 97 mg (3 step total yield: 48%). Colorless solid. mH NMR spectrum (CD3OD, 500MHz), δ: 8.36 (br s, 1H), 7.53 (br d, 1H, J = 7.3 Hz), 7.42-7.3 6 (m, 4H), 7.3 3 -7.27 (m, 3H), 7.18 (br t, 1H, J = 7.3 Hz), 6.72 (s, 2H), 3.67-3.45 (m, 4H), 3.40-3.21 (m, 3H), 3.07-3.01 (m, 1H), 2.8 9-2.8 5 (m, 2H), 2.36-2.31 (m, 2H), 2.16-2.05 (m, 3H), 1.90-1.81 (m, 5H), -60- 201107306 1.43 - 1.37 (m,6H) . Mass Spectrum (FAB+), m/z: 509 ((M + H) + ) » (Example 1 〇) (3S,5R) -5-[4-(2-chlorophenyl)-2,2-dimethyl 5--5-piperidone-1-yl]-N-[(1R)-1-phenylpropyl]piperidine-3-carboxamide anti-butenediate

(1〇&) Tert-butyl butyl (311,53)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-5- {[(1R)-1-phenylpropyl]amine-carbamoyl}piperidine·1-carboxylate (3S,5R)-1-(tris-butoxycarbonyl) obtained in Example (5b) _5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3-dicarboxylic acid 3 5 7 mg (0.77 mmol), ( 1R 207 mg (1.53 mmol) of -1-phenylpropan-1-amine and 0.40 ml (2.30 mmol) of diisopropylethylamine, in a solution of hydrazine-dimethylformamide (4 ml), under ice cooling, Ο-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) 435 mg (1.55 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by column chromatography (solvent solvent: η - hexane/ethyl acetate = 1/1 to 0 Π) and the reverse layer was subjected to high-speed liquid chromatography (solvent solvent: acetonitrile / 0.1% aqueous ammonium acetate = 7/3). :55%). Colorless solid. -61 - 201107306 4 NMR spectrum (CDC13, 500MHz), δ: 7.46 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.3 7-7.22 (m, 8H), 5.80 (br s, 1H), 4.88 ( Br q, 1H, J = 7.5 Hz), 4.26-4.00 (m, 2H), 3.74-3.50 (m, 2H), 3.34-3.29 (m, 2H), 2.95 (br s, 1H), 2.78-2.70 ( m, 2H), 2.34 (br s, 1H), 1.93 - 1.78 (m, 4H), 1.48 (s, 9H), 1.3 9- 1.27 (m, 6H), 0.89 (t, 3H, J = 7.6 Hz) . (101)) (33,511)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)-1-benzene 3-propyl butyl (3R,5S)-3-[4-(2-chlorobenzene) obtained in the example (1 〇a ) of propyl propyl] piperidine 3-carbamide amine -2,2-dimethyl-5-piperidin-1-yl]-5-{[(11〇-1-phenylpropyl)aminemethanyl}piperidine-1-carboxylate To a solution of 3 62 mg (0.62 mmol) of dichloromethane (2 mL), EtOAc (1. The mixture was neutralized, extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was chromatographed on NH? /methanol = 20/1~7/3) Purification to obtain (35,511)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]- N-[(1R)-1-phenylpropyl)piperidine-3-carboxamide 213 mg (yield: 71%). (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-:^-[(111) To a solution of 213 mg (0.44 mmol) of methanol in MeOH (2 ml), EtOAc (EtOAc) The reaction mixture was concentrated under reduced pressure, and the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'HNMR spectrum (CD3OD, 500MHz), δ: 7.53-7.51 (m, 1H), 7.41-7.21 (m, 8H), 6.70 (s, 2H), 4.73 (br t, 1H, J = 7.3 Hz), 3.63 -3.42 (m, 4H), 3.3 9-3.20 (m, 3H), 3.06-3.01 (m, 1H), 2.96 (br t, 1H, J = 12.2 Hz), 2.90-2.8 5 (m, 1H), 2.08-2.02 (m, 1H), 1.8 9- 1.77 (m, 3H), 1.3 9-1.3 5 (m, 6H), 0.92 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB+), m/z: 48 3 ((M + H)+). • (Example 1 1 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl^N-[(lR) -2-cyclopropyl-l-phenylethyl]piperidine-3-carboxamide antibutene

(11&) Tert-butyl butyl (311,53)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-5- {[ (1R)-2-cyclopropyl-1-phenylethyl]aminemethanyl}piperidine-1-carboxylate [S] (3S,5R) -1- obtained in Example (5b) (tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl]piperidine-3-dicarboxylic acid 200 mg ( 0.43 mmol), (lR)-2-cyclopropyl-1-phenylethane-1-amine hydrochloride obtained in Reference Example 169 mg (0.86 mmol) and diisopropylethylamine 221 nig (1.72 mmol) In a solution of N,N-dimethylformamide (5 ml), under ice cooling, force into 〇-(benzotriazol-1-yl)-N,N,N',N'--63- 201107306 Tetramethylurea hexafluorophosphate (HBTU) 24 4m g (〇.65 mmol), stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3 to 0/1) and oxime column chromatography (dissolving solvent: η_) The residue was purified to give the title compound 150 mg (yield: 57%). Colorless solid. *Η NMR spectrum (CDC13, 500MHz), δ: 7.45 (dd; 1H5 J = 7.8 Hz, 1.5 Hz), 7.36-7.22 (m, 8H), 5.94 (br s, 1H), 5.08-5.04 (m, 1H) ), 4.26-4.00 (m, 2H), 3.73 -3.50 (m, 2H), 3.34-3.29 (in, 2H), 2.95 (br s, 1 H), 2 · 7 6 - 2.6 9 (m, 2 H ), 2 · 3 5 (br s, 1 H), 1.93-1.60 (m, 4H), 1.48- 1.27 (m, 15H), 0.59-0.5 5 (m, 1H), 0.48-0.38 (m, 2H) , 0.16-0.11 (m, 1H), 0.05-0.01 (m, 1H). (llb)(3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)-2- Cyclopropyl-1-phenylethyl]piperidine-3-carboxamide sulfonate fumarate obtained in Example (11a) as a tertiary butyl (3R, 5S) -3-[4-( 2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-5-{[(11〇-2-cyclopropyl-1-phenylethyl)aminecarboxamide To a solution of 150 ml (0.25 mmol) of methylene chloride (2 ml), add trifluoroacetic acid (1.2 ml (15-6 mmol)) and stirred at room temperature for 15 min. The sodium hydrogencarbonate aqueous solution was neutralized, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Solvent solvent: dichloromethane/methanol = 1/0 to 7/3 S] -64 - 201107306 Purified to obtain (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl ··5·piperidone-1-yl]-indole-[(1R) _2_cyclopropyl-1_phenylethyl]piperidine _3·carboxamide 108 mg (yield: 86%). (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5·piperidone-i-yl]_n-[(1) R)_2-cyclopropyl-1·phenylethyl]piperidine-3-carboxamide i〇8mg (0.21mmol) in methanol (1ml) solution, adding 24.7mg (0.21mmol) of fumaric acid The mixture was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (EtOAc). NMR spectroscopy (CD3OD, 500MHz)' δ: 7.53-7.5! (m,1H)' 7.41-7.23 (m,8H),6_71 (s,2H),4.94 (br t,1H,J = 7 6 Hz ), 3.63-3.20 (m, 7H), 3.08-3.03 (m, 1H), 2.98 (brt, 1H, J = 12.5)

Hz), 2.91-2.86 (m, 1H), 2.10-2.03 (m, 1H), 1.90- 1.81 (m, 1H), 1.74- 1.65 (m, 2H), 1.3 9- 1.3 5 (m, 6H), 0.69-0.61 (m, 1H), 0.49-0.3 6 (m, 2H), 0.17-0.13 (m, 1H), 0.05-0.01 (m, 1H)°

Mass spectrum (FAB+), m/z: 509 ((M + H)+). (Example 1 2 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[(lR) -3·methyl-l-phenylbutyl]piperidine-3-carboxamide anti-butyrate

-65- 201107306 (12a) Tert-butyl (3R,5S)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5_piperidin-1-yl]-5 - { [ ( 1R) -3_methyl-1-phenylbutyl]aminomethane}piperidin-1 _ citric acid vinegar (3S,5R) -1- obtained in Example (5b) Tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone oxime-yl]piperidine-3_dihydroic acid 15 〇mg (〇32mm 〇1), 3 mg of 3-methyl-1-phenylbutan-1-amine hydrochloride obtained in Reference Example n, 128 mg (0.64 mmol) of diisopropylethylamine, and 66 mg (1.29 mm 〇l) of diisopropylethylamine. N-dimethylformamide (4ml) in solution under ice cooling, adding 〇_(benzotriazol-fluorenyl-)-N,n,N,,N'-tetramethyluronium hexafluorophosphate (HBTU) I 83 mg (0.48 mmol), stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystalssssssssssssssss %). Colorless solid. NMR spectrum (CDC13, 500MHz), δ: 7.45 (br d, 1H, J = 7,8 Hz), 7.3 5-7.23 (m, 8H), 5.92 (br s, 1H), 4.99-4.96 (m, 1H ), 4.20-3.96 (m, 2H), 3.67-3.48 (m, 2H), 3.31-3.25 (m, 2H), 2.93-2.66 (m, 3H), 2.34 (br s, 1H), 1.88- 1.26 ( m, 20H), 0.94-0.90 (m, 6H). (12b ) ( 3S,5R ) -5-[4-( 2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]·Ν-[ ( 1R) -3- Methyl-1-phenylbutyl]azepine-3-cartoamine fumarate in the third butyl (3R,5S)-3-[4-() obtained in Example (12a) 2--66- 201107306 Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]_5-indole[(1R)-3-methyl-1-phenylbutyl]amine To a solution of 146 mg (p. 24 mmol) of methylene chloride (m.p. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated to dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjj (2-Chlorophenyl)-2,2-dimethyl-5· φ piperidone-1-yl]-indole·((1R)-3-methyl-1-phenylbutyl]piperidine- 3-Methylamine 77 mg (yield: 63%). (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)- To a solution of 77 mg (0.15 mmol) of methanol (1 ml) of 3-methyl-1-phenylbutyl]piperidine-3-carboxamide, 17.5 mg (〇.15 mmol) of fumaric acid at room temperature Stir for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated. ^ Colorless solid. iHNMR spectrum (CD3OD, 500MHz), δ: 7.52-7.22 (m, 9H), 6.70 (s, 2H), 4.94 (br dd, 1H, J = 9.3 Hz, 5.4 Hz), 3.63-3.22 (m, 7H) , (5, 1H) 0.91 (m, 6H). Mass spectrum (FAB+), m/z: 511 ((M + H)+). (Example 1 3 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l·-67- 201107306 base]-N- [( 1R) -1-(2-fluorophenyl)propyl]piperidine-3-carboxamide fumarate

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2-chlorobenzene) obtained in the same manner as in the examples (5c) and (5d). (2)2-dimethyl-5-piperidone-1-yl]piperidine-3-dicarboxylic acid and (1R)-1-(2-fluorophenyl) obtained in Reference Example 12 Propane-1-amine hydrochloride gave the title compound 126 mg (yield: Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 7.52 (br d, 1H, J = 7.8 Hz), 7.41-7.26 (m, 5H), 7.16 (dt, 1H, J = 7.3 Hz, 1.0 Hz), 7.08 (ddd , 1H, J = 10.7 Hz, 8.3 Hz, 1.0 Hz), 6.71 (s, 2H), 5.01 (br t, 1H, J = 7.6 Hz), 3.63 -3.43 (m, 4H), 3.3 9-3.22 (m , • 3H), 3.07- 3.02 (m, 1H), 2.99-2.8 9 (m, 2H), 2.11-2.04 (m, 1H), 1.89- 1.79 (m, 3H), 1.40- 1.36 (m, 6H) , 0.93 (t, 3H, J = 7.3

Hz). Mass spectrum (FAB+), m/z: 501 ((M + H)+). (Example 1 4 ) (3S,5R) -5-[4-(2-Chlorophenyl)·2,2-dimethyl-5-piperidone-l-yl]-N-[(lR) -l-(3-fluorophenyl)propyl]piperidine-3-carboxamide fumarate

[SI -68- 201107306

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl) obtained in the same manner as in the examples (5c) and (5d). -2,2-dimethyl-5-piperidone-1-yl]piperidine-3-dicarboxylic acid and (1R)-1-(3-fluorophenyl)propane obtained in Reference Example 13 1-amine hydrochloride gave the title compound 120 mg (yield: 3). Colorless solid. 1H NMR spectrum (CD3OD, 500MHz), δ: 7.52-7.51 (m, 1H), 7.40-7.27 (m, 4H), 7.12 (br d, 1H, J = 7.8 Hz), 7.06-7.04 (m, 1H), 7.00-6.96 (m, 1H), 6.70 (s, 2H), 4.74 (br t, 1H, J = 7.3 Hz), 3.64-3.42 (m, 4H), 3.3 9 -3.22 (m, 3H), 3.07- 2.89 (m, 3H), 2.10-2.02 (m, 1H), 1.8 9- 1.78 (m, 3H), 1.3 9-1.3 6 (m, 6H), 0.93 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB+), m/z: 501 ((M + H)+). (Example 1 5 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl^N-[(lR)- L-(4-Fluorophenyl)propyl]piperidine-3-carbamide amine fumarate

-69-201107306 (3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2) obtained in the same manner as in the examples (5c) and (5d). -Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3-dicarboxylic acid and (1R)-1-(4-fluorobenzene obtained in Reference Example 14 Propyl-1-amine hydrochloride, the title compound was obtained (yield: 3). Colorless solid. !HNMR spectrum (CD3OD, 400MHz), δ: 7.53-7.51 (m, 1H), 7.3 8 -7.2 8 (m, 5H), 7.09-7.04 (m, 2H), 6.70 (s, 2H), 4.73 (br t, 1H, J = 7.4 Hz), 3.64-3.22 (m, 7H), 3.0 7-2.8 6 (m, 3H), 2.08-2.00 (m, 1H), 1.8 9- 1.77 (m, 3H), 1.3 8 - 1.3 6 (m, 6H), 0.91 (t, 3H, J = 7.4 Hz). Mass spectrum (FAB+) > m/z: 501 ((M + H)+). (Example 1 6 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N - [ ( 1 R ) - 1 -pyridine-2-ylpropyl]piperidine-3-formamide amine fumaric acid

(163) Tert-butyl butyl (311,55)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-5- { [ ( 1R)-1-pyridin-2-ylpropyl]aminemethanyl}piperidine-1-carboxylate (3S,5R)-1-(tris-butoxycarbonyl) obtained in Example (5b) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-3-70-201107306 Dicarboxylic acid 250mg (0.54mmol) , (1R)-1-pyridin-2-ylpropan-1-amine 2 hydrochloride obtained in Reference Example 224 mg (1.07×nmol) and diisopropylethylamine 3 70 μl (2·14ιηιηο1) N, N-dimethylformamide (5ml) solution, under ice cooling, add 〇-(benzotriazol-1-yl)-oxime, hydrazine, Ν', Ν'-tetramethylurea hexafluorophosphate (HBTU) 305 mg (0.80 mmol), stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1 /1 to 0/1) and oxime gel column chromatography (dissolving solvent: η -hexane/ethyl acetate = 3 /1~1 /1~0/1) The residue was purified to afford the title compound 23 3 mg (yield: 74%). Colorless solid. H NMR spectrum (CDC13, 500MHz), δ: 8.55 (br d, 1H, J = 4.4 Hz), 7.68-7.65 (m, 1H), 7.46 (br d, 1H, J = 7.8 Hz), 7.32-7.19 ( m, 4H), 6.90 (br d, 1H, J = 7.8 Hz), 5.01-4.97 (m, 1H), 4.27-4.00 (m, 2H), 3.73-3.51 (m, 2H), 3.30 (br s, 2H), 2.99 (br s, 1H), 2.75 (br t, 2H, J = 12.0 Hz), 2.45 (br s, 1H), 1.95-1.77 (m, 4H), 1.49 (br s, 9H), 1.40 -1.29 (m, 6H), 0.81 (t, 3H, J = 7.3 Hz). (161〇(38,51〇-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-bu)]-N-[ ( 1R ) -1 -pyridine 2-Benzylpropyl]piperidine-3-carboxamide sulfonate fumarate obtained in Example (16a) as a tertiary butyl (3R,5S)-3-[4-(2-chlorobenzene) -2,2-dimethyl-5-piperidin-1-yl]-5-{[(1R)-pyridin-2-ylpropyl]aminemethanyl}piperidine-1-carboxylate Acid ester 223mg (0.38mmol) of two [S] -71- 201107306 methyl chloride m 8 8 o acid ethyl fluoride trisin plus medium solution \ly lim mm stirred at room temperature for 30 minutes. Add the mixture to the reaction mixture under ice cooling The sodium hydrogencarbonate aqueous solution was neutralized, extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Solvent: dichloromethane/methanol = 20/1~7/3) Purified to obtain (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-pipe trap Ketone-1-yl]-N-[(1R)-1-pyridin-2-ylpropyl]piperidine-3-carboxamide 85 mg (yield: 46%). (3S, 5R obtained here) -5·[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[(1R)-1-pyridine 2, propyl propyl] piperidine-3-carboxamide 0.3 mg (0.18 mmol) in methanol (1 ml), 20.3 mg (0.18 mmol) of fumaric acid was added, and stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (br d5 1H, J = 4.4 Hz), 7.80 (br t, 1H, J = 7.6 Hz), 7.53-7.51 (m, 1H), 7.41- 7.35 (m, 3H), 7.31-7.29 (m, 2H) , 6.71 (s, 2H), 4.85-4.82 (m, 1H), 3.65-3.45 (m, 4H), 3.41-3.21 (m, 3H), 3.0 8 -3.03 (m, 1H), 3.00-2.89 (m , 2H), 2.19-2.13 (m, 1H), 1.94-1.78 (m, 3H), 1.42- 1.3 7 (m, 6H), 0.93 (t, 3H, J = 7.3 Hz) Helium Mass Spectrometry (FAB+), m /z: 484((M + H)+). (Example 1 7 ) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-72-201107306 base]-N- [(1R)-3-methyl-1-pyridin-2-ylbutyl]piperidine-3-carboxamide anti-butenediate

(17a) Tert-butyl (3R,5S)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-5-{ [( 1R) -3-methyl-1-pyridin-2-ylbutyl]aminemethanyl}piperidine-1-carboxylate

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidyl obtained in Example (5b) 30 mg (0.643 mmol) of olean-1-yl-piperidine-3-dicarboxylic acid, (1R)-3-methyl-1-pyridin-2-ylbutan-1-amine obtained in Reference Example 16. 2 HCl solution of 305mg ( 1.29mmol) and diisopropylethylamine 447μ1 (2·57ιηπιο1) in N,N-dimethylformamide (6ml), add 〇-(benzotriene) under ice cooling Zyridin-1-yl)_N,N,n',N'-tetramethylpentidyl hexahydroortholine (HBTU) 366 mg (0,96 mmol), stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/1 to 0/1) and oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound 267 mg (yield: 67%). Colorless solid. 4 NMR spectrum (CDC13, 500MHz), δ: 8.55 (br d, 1H, J = 4.4 Hz), 7.45 (br t, 1H, J = 7.3 Hz), 7.46-7.45 (m, 1H), 201107306 7.32-7.18 (m, 5H), 6.60 (br d, 1H, J = 7.8 Hz), 5.12 (br q, 1H, J - 7.8 Hz), 4.26-4.00 (m,. 2H), 3.71-3.50 (m, 2H) , 3.29 (br s, 2H), 2.97 (br s, 1H), 2.78-2.70 (m, 2H), 2.40 (br s, 1H), 1.90 (br s, 2H), 1.70- 1.27 (m, 18H) , 0.95-0.93 (m, 6H). (1715)(38,511)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[( 1R) -3 -methyl 1-pyridin-2-ylbutyl]piperidine-3-carbamide amine fumarate

Tert-butyl (3R,5S)-3-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl obtained in Example (17a) -5-{[(111)-3-methyl-1-pyridin-2-ylbutyl]aminemethanyl}piperidine-1-carboxylate 267 mg (0.44 mmol) in dichloromethane (2 ml) Trifluoroacetic acid 1. 〇ml (1.lmmol) was added, and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjj (2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl]-N-[(lR)-3-methyl-l-pyridin-2-ylbutyl]peri Pyridin-3-carbamide 17 9 mg (yield: 80%). (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]->^-[(111) a solution of 179 mg (1.8 ml) in methanol (1.8 ml) with 3-methyl-1-pyridin-2-ylbutyl]piperidine-3-carbamide. Add fumaric acid 4〇.5ing (〇.35minol), stir at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated. Colorless solid. -74- 201107306 】H NMR spectrum (CD3OD, 500MHz), δ: 8.51 (br d,1H, J =4.9 Hz), 7.79 (br t, 1H, J = 7.6 Hz), 7.52-7.51 (m, 1H) , 7.41-7.35 (m, 3H), 7.31-7.28 (m, 2H), 6.70 (s, 2H), 5.03 (dd, 1H, J = 9.3 Hz, 5.9 Hz), 3.64-3.44 (m, 4H), 3.3 9-3.22 (m, 3H), 3.06-3.01 (m, 1H), 2.98-2.89 (m, 2H), 2.17-2.11 (m, 1H), 1.87- 1.78 (m, 1H), 1.76- 1.5 8 (m, 3H), 1.41-1.36 (m, 6H), 0.98 (d, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 6.3 Hz). Mass spectrum (FAB+), m/z: 5 12 ((M + H) + ).

(Example 1 8 ) (3S,5R) -5_[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-l-yl]-N-[(lR)- L-(5-Fluoro D ratio steep-2-yl)-3_methylbutyl]anthracene II _3·Protonamine fumarate

H Λ

I i. H

(18a) tert-butyl (3R, 5S) 3·[4-(2-chlorophenyl)-2,2·di(5-gas 11 to 11-but-2-yl)-3-methyl-5 -piperidone-1-yl]-5- { [(1R)methylbutyl]aminemethanyl}piperidine-1-carboxylic acid cool 'piperidone-1 -yl]piperidine-3 - (3S,5M-丨-(tris-butoxycarbonyl)-5-[4-(2-chlorophenyl)-2,2-dimethyl 7 obtained in Example (5b) ( 1 R ) -1 -amine 2 hydrochloride 3 2 8 mg decanoic acid 300 mg (0.64 mmol), reference example 5-fluoropyridyl)_3_methylbutanin-u 2.57 mmol) of N,N- added 〇-( Benzotriazole [S] (1.29mmol) and diisopropylethylamine 447 Η 1 dimethylformamide (6ml) solution in 'ice-cold-75- 201107306 -1-base)-:^,&gt ;1,;^',&gt;^'-Tetramethylurea hexafluorophosphate (1^1'1;) 36611^ (0.96mraol), stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/1 to 0/1) and NH </ RTI> column chromatography (dissolving solvent: η- The residue was purified to give the title compound 246 mg (yield: 60%). Colorless solid. NMR spectrum (CDC13, 500 MHz), δ: 8 · 4 1 (br d, 1 Η, J = 2.9 Hz), 7.47-7.45 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.22 (m , 4H), 6.41 (br d, 1H, J = 8.3 Hz), 5.12 (br q, 1H, J = 8.3 Hz), 4.26-4.00 (m, 2H), 3.71-3.50 (m, 2H), 3.29 ( Br s, 2H), 2.97 (br s, 1H), 2.75-2.69 (m, 2H), 2.39 (br s, 1H), 1.92- 1.86 (m, 2H), 1.69-1.27 (m,18H),0.95 -0.92 (m, 6H). (181&gt;)(35,511)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-:^[(111)-1-( 5-fluoropyridin-2-yl)-3-methylbutyl]piperidine-3-carboxamide anti-butenediate The tertiary butyl (3R,5S) obtained in Example (18a) 3-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-5-{[(111)-1-(5-fluoropyridine-2- a solution of trimethylacetate (1.8 ml) in a solution of 24 mg (〇.39 mmol) of dichloroacetic acid (1.8 ml) was added to a solution of trimethylacetate (1.8 ml). 11.7 mmol), stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluting with EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: -5-[4-(2-Chlorophenyl)-2,2-monomethyl-5-anthracepin-1-yl]-&gt;1-[(111)-1-(5-gas [1 -din-2-yl)-3-methylbutyl]piperidine-3-carboxamide 190 mg (yield: 91%). (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidone-1-yl]-N-[(1R)- 1-( 5-fluoropyridin-2-yl)-3-methylbutyl]piperidine-3-carboxamide 190 mg (0.36 mmol) in methanol (1.8 m 〇 solution, added fumarate 41.5 mg) (0.36 mm 〇1), stirring at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride. :86%)» colorless solid. 1H NMR spectrum (CD3OD, 500MHz), δ: 8.41 (brd, 1H, J = 2.0 Hz), 7.58-7.50 (m, 2H), 7.42-7.3 5 (m, 3H) , 7.33-7.30 (m, 1H), 6.71 (s, 2H), 5.05 (dd, 1H, J = 9.3 Hz, 6.4 Hz), 3.64-3.44 (m, 4H), 3.39-3.21 (m, 3H), 3.04 (br t, 1H, J = 11.7 Hz), 2.99-2.89 (m, 2H), 2.15-2.09 (m, 1H), 1.86- 1.78 (m, 1H), 1.76-1.64 (m, 2 H), 1.6 1 -1 . 5 5 (m, 1H), 1.40- 1.3 6 (m, 6H), • 0.97 (d, 3H, J = 6.8 Hz), 0.94 (d, 3H, J = 6.3 Hz). FAB+), m/2: 530 ((M + H)+) (Example 1 9 ) (3S,5R) -5-[4-(2-chlorophenyl)-2,2-dimethyl- 5-piperidone-l -yl]-N-[(lR)-l-pyridin-3-ylpropyl]piperidine-3-carboxamide fumarate m -77- 201107306

Η

In the same manner as in the examples (5c) and (5d), (3S,5R)-1-(tris-butoxycarbonyl)-5-[4--2,2-dimethyl-5- obtained by the use was used. Piperidone-1-yl]piperidine-3-dicarboxylic acid and (1R)-1-pyridin-3-ylpropan-1-amine 2 hydrochloride, obtained 125 mg (3 steps total) Yield: 41%). Colorless solid. 'HNMR spectrum (CD3OD, 400MHz)' δ : 8.51 (br (dd, 1H, J = 4.7 Hz, 1.6 Hz), 7.81-7.79 (m, 1H),, 1H), 7.45-7.2 7 (m, 4H) , 6.71 ( s , 2 H ), 4 · 7 9 (t, 1 H 3.64-3.22 (m, 7H), 3.08-2.91 (m, 3H), 2.16-2. 1.91-1.80 (m, 3H), 1.3 9- 1.3 6 (m, 6H), 0.96 (t,

Hz). Mass spectrum (FAB+) &gt; m/z: 484 ((M + H)+). (Example 20) (3S,5R) -5-[4-(2-Chlorophenyl)-2,2-dimethyl-yl]-N-[(1R)-3-methyl-1-pyridine -3-ylbutyl]piperidine-3. enedic acid salt (5b) (2-chlorophenyl) bolus case 18 obtained the title compound s, 1H), 8.45 7.53-7.51 (m, ,J = 7.6 Hz), 02 (m, 1 Η), 3Η, J = 7.2 5 - piperidone-1 - • formazan

[S] -78-

201107306 The obtained (3S,5R)-1-(tertiary butoxycarbonyl)-2,2-dimethyl-5-piperidin-1 was obtained in the same manner as in the examples (5C) and (5d). (1R)-3-methyl-1-pyridin-3-ylbutan-1-amine compound 121 mg (3 step total yield: 36%). Colorless solid. 1H NMR spectrum (CD3OD, 500MHz), δ:8· (br d, 1H, J = 5.1 Hz), 7.82-7.79 (m, 1H), 7.45-7.26 (m, 4H), 6.72 (s, 2H), 4.99 (dd, Hz), 3.63 -3.22 (m, 7H), 3.09-2.8 5 (m, 3H), 1.8 7- 1.75 (m, 2H), 1.64- 1.57 (m, 2H), 1 0.99 (d, 3H, J = 6.3 Hz), 0.94 (d, 3H, J = mass spectrum (FAB+), m/z: 512 ((M + H)+). (Example 2 1 ) (3S, 5R) -5-[ 4-(2-Chlorophenyl)-2,2-diyl]-N-[ ( 1R ) -1- ( 5-fluoropyridin-3-yl)-3-carbamidamine fumarate Example 5 (5b) 5-[4-(2-chlorophenyl) and the hydrochloride salt obtained in Reference Example 19 gave the title 5 1 (br s, 1 Η), 8.45 7.53-7.5 1 (m, 1 Η), 1Η; J = 9.4 Εζ, 5.5 2.10-2.01 (in, 1Η), .3 9- 1.3 6 (m, 6Η), 6_3 Hz). Methyl-5-pipecolone-1 · butyl butyl] piperidine-3-

( In the same manner as in the examples (5 c ) and (5 d ), the obtained (3S,5R)-1-(tertiary butoxycarbonyl)-2,2-dimethyl-5-piperidone was obtained. (1R)-1-(5-fluoropyridin-3-yl)-3-methylbutan b obtained from -1-yl]piperidin-3-dicarboxylic acid, Example 5(5b) 5-[4- (2-Chlorophenyl) and the amine-1 -amine 2 hydrochloride obtained in Reference Example 20, [?] -79 - 201107306 The title compound 137 mg (yield of 3 steps: 34%) was obtained. Colorless solid.

H NMR spectrum (CD3OD, 400MHz), δ: 8.39-8.37 (m, 2H), 7.62-7.59 (m, 1H)} 7.51 (br d, 1H, J = 7.8 Hz), 7.41-7.35 (m, 2H) , 7.3 1-7.27 (m, 1H), 6.70 (s, 2H), 5.02 (dd, 1H, J = 9.5 Hz, 5.6 Hz), 3.64-3.42 (m, 4H), 3.39-3.21 (m, 3H) , 3.06-3.00 (m, 1H), 2.98-2.86 (m, 2H), 2.09-2.01 (m, 1H), 1.88-1.76 (m, 2H), 1.67- 1.5 8 (m, 2H), 1.3 9- 1.3 6 (m, 6H), 0.99 (d, 3H, J = 6.4 Hz), 0.96 (d, 3H, J = 6.4 Hz). Mass spectrum (FAB+), m/z: 530 ((M + H)+). (Example 22) (3S,5R)-5-[4-(2-Chlorophenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R)- 1-pyridin-4-ylpropyl]piperidine-3-carboxamide fumaric acid

(3S,5R)-Bu (tertiary butoxycarbonyl)-5-[4-(2-chlorophenyl) obtained in the same manner as in the examples (5c) and (5d). -2,2-dimethyl-5-piperidin-1-yl]piperidine-3-dicarboxylic acid and (1R)-1-pyridin-4-ylpropan-1-amine obtained in Reference Example 21 2 Hydrochloride gave the title compound 1 4 7 mg (yield of 3 steps: 43%). Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 8.50-8.48 (m, 2H), -80- 201107306 7.53-7.51 (m, 1H), 7.41-7.35 (m, 4H), 7.32-7.28 (m, 1H), 6.71 (s, 2H), 4.76 (br t, 1H, J = 7.3 Hz), 3.67-3.24 (m, 7H), 3.08-2.93 (m, 3H), 2.18-2.08 (m, 1H), 1.91-1.79 (m, 3H), 1.41-1.37 (m, 6H), 0.97 (t, 3H, J = 7.3 Hz) 〇 mass spectrum (FAB+) &gt; m/z: 484 ((M + H)+). (Example. 23) (3S,5R)-5-[2,2-Dimethyl-4·(2-methylphenyl)-5-piperidone- l-yl]-N-[(1R )-1-(ethoxymethyl)-3-methylbutyl]piperidine-3-carboxamide•amine fumarate

(23a)methyl(3S,5R)-5-({l,l-dimethyl-2-[(2-methylphenyl)amino]ethylphosphonium)-l-[ ( 2- Methyl (3S,5R)-5-[(l,l-dimethyl-2-side oxygen) obtained in the example (le) of nitrophenyl)sulfonyl]piperidine-3-carboxylate 2-ethyl)amino]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate 2.50 g (6.1 mmol) and 2-methylaniline oxime.97 g (9.1 mmol) Into a toluene (60 ml) solution, i.27 g (21.1 mmol) was added, and the mixture was heated under reflux, and the resulting water was removed while stirring for 2.5 hours. After cooling, 2.56 g (12.1 mmol) of sodium triethoxyborohydride was added to the reaction mixture under ice cooling, followed by stirring at room temperature for 18 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated. After filtration, the residue was purified under reduced pressure to dryness elution elution elution elution elution elution elution elution elution OOg (yield: 98%). Colorless solid. NMR spectrum (CDC13, 500 MHz), δ: 7.67 (dd, 1H, J = 8.3 Hz, 1.0 Hz), 7.64-7.58 (m, 2H), 7.48-7.45 (m, 1H), 7.16-7.13 (m, 1H) ), 7.05 (br d, 1H, J = 7.3 Hz), 6.68-6.65 (m, 1H), 6.58 (br d, 1H, J = 8.3 Hz), 4.0 8 -4.05 (m, 1H), 3.73 -3.69 (m, 4H), 2.96 (d, 1H, J = 11.7 Hz), 2.91 (d, 1H, j = 11&gt;7 Hz), 2.81-2.70 (m, 3H), 2.32 (dd, 1H, J = 12.2 Hz, 10.7 Hz), 2.21-2.17 (m, 1H), 2.12 (s, 3H), 1.31 (q, 1H, J = i2.〇Hz), 1.22 (s,3H), 1.2 1 (s, 3H) . (23b)methyl(3S,5R)-5-[2,2-methyl-4-(2-methylphenyl)-5-piperidone-1-yl]-l-[ (2- Methyl (3S,5R) _5_({ u-dimethyl-2-[(2-methyl) obtained in Example (23a), nitrophenyl)sulfonyl]piperidine-3-hydroxyacetic acid Phenyl)amino]ethyl}amino)-1_[(:2-nitrophenyl)anthracene]piperam-3-indole vinegar 3.00g (6.0mmol) and triethylamine 4.81g ( In a solution of 47.5 mmol) of dichloromethane (60 ml), a solution of 4.79 g (23.8 mmol) of bromoacetic acid bromide (i5 ml) was added for 1 hour under ice cooling, followed by stirring at room temperature for 20 minutes. Stir at 40 ° C for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel elution elution elution elution 84%). Colorless solid. iHNMR spectrum (CDC13,500ΜΗζ), δ: 8.03-8.01 (m,1H), [S] -82- 201107306 7.76-7.71 (m, 2H), 7.67-7.65 (m, 1H), 7.27-7.21 (m, 3H), 7.13-7.06 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.81 (m, 1H), 3.72 (s, 3H), 3.68-3.15 (m, 5H), 2.79-2.66 ( m, 3H), 2.24-2.18 (m, 4H), 1.75- 1.66 (m, 1H), 1.3 7- 1.34 (m, 6H). (23c) 1-tertiary butyl 3-methyl(3S,5R)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl Piperidine-1,3-dicarboxylate methyl (3S,5R)-5-[2,2-dimethyl-4-(2-methylphenyl) obtained in Example (23b) -5-piperidone-1-yl]-l-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate 2.73 g (5.0 mmol) and thiophenol 0.77 ml (7.5 mmol) In a solution of acetonitrile (100 ml), 1.96 g (6.0 mmol) of carbonic acid was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with water and extracted with dichloromethane, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: methylene chloride/methanol=I/O~7/3) to obtain methyl (3S,5R) -5-[ 2,2-Dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]piperidine-3-dicarboxylate 1.8 g (yield: quantitative). Methyl (3S,5R)-5-[2,2-dimethyl-4.(2-methylphenyl)-5-piperidone-1-yl]piperidin-3- obtained herein To a mixture of 1,8 g (5.0 mmol) of dicarboxylic acid ester and 1.25 g (14.9 mmol) of sodium hydrogencarbonate in ethyl acetate (50 ml) and water (50 ml) 4_8mtnol), stir at room temperature for 15 minutes. The reaction mixture was extracted with EtOAc. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystalssssssssssssssssssssss :79%)» [S] Colorless solid. -83- 201107306 NMR spectrum (CDC13, 500MHz), δ: 7.27-7.21 (m, 3H), 7.12-7.08 (m, 1H), 4.30 (br s, 1H), 4.08 (br s, 1H), 3.72- 3.52 (m, 5H), 3.3 9-3.3 5 (m, 1H), 3.21 (br d, 1H, J = 11.2 Hz), 3.01-2.97 (m, 1H), 2.70-2.54 (m, 3H), 2.24 -2.23 (m, 3H), 2.12 (br d, 1H, J = 12.7 Hz), 1.8 3 - 1.74 (m, 1 H), 1.48 (s, 9H), 1 .3 6- 1.3 2 (m, 6H ). (23d)(3S,5R)-1-(tertiary butoxycarbonyl)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidone-1- 1-tert-butyl 3-methyl(3S,5R)-5-[2,2-dimethyl-4-(2-) obtained from the compound (23c). Methylphenyl)-5-piperidone-1-yl]piperidine-1,3-dicarboxylate 1.82 g (4.0 mmol) in tetrahydrofuran (36 ml) and water (18 ml) 5小时。 Lithium hydroxide. 1 hydrate 3 3 3mg (7.9mmol), stirred at the same temperature for 3.5 hours. To the reaction mixture, 1 N hydrochloric acid was added to make acidity (pH 2-3), and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give title compound (yield: quantitative).

Colorless solid. H NMR spectrum (CDC13, 500MHz), δ: 7.2 8 -7.23 (m, 3H), 7.12-7.08 (m, 1H), 4.30 (br s, 1H), 4.05 (br s, 1H), 3.79-3.63 ( m, 2H), 3.44-3.18 (m, 2H), 3.00 (br s, 1H), 2.73 -2.54 (m, 3H), 2.24-2.17 (m, 4H), 1.79- 1.70 (m, 1H), 1.47 (s, 9H), 1. 3 6- 1 .3 3 (m, 6H). (23e) tert-butyl (3R,5S)-3-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]-5-{[ (lR) -1-(ethoxymethyl)-3-methylbutyl]aminemethanyl}piperidine-1-carboxylate-84- 201107306 (3S, obtained in Example (23d), 5R) -1-(tertiary butoxycarbonyl)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidinyl]piperidine-3 -residic acid 300 mg (0.67 mmol), (2R)-1-ethoxy-4-methylpentan-2-amine obtained in Reference Example 195 mg (1.35 mmol) and diisopropylethylamine 352 μl (2·02ιηιηο1) After Ν-dimethylformamide (6.5 ml) solution, under ice cooling, add 〇-(benzotriazol-1-yl)-oxime, hydrazine, Ν', Ν'-tetramethylurea A solution of hexafluorophosphate (HBTU) 306 mg (0.81 mmol) in hydrazine-dimethylformamide (1.0 ml) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by column chromatography (solvent solvent: η-hexane/ethyl acetate / 1/1 to 0/1) and NH oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound 236 mg (yield: 61%). Colorless solid. H NMR spectrum (CDC13,500 ΜΗζ), δ: 7.27-7.21 (m, 3H), 7.12-7.08 (m, 1H), 5.64 (br s, 1H), 4.23 -4.03 (ms 2H), 3.7 5 -3.68 ( m, 1H), 3.5 9-3.3 5 (m, 7H), 3.22-3.18 (m, 1H), 2.98 (br s, 1H), 2.7 8 -2.68 (m, 2H), 2.34 (br s, 1H) , 2.24-2.22 (m, 3H), 2.01-1.95 (m, 2H), 1.62- 1.54 (m, 1H), 1.48 (s, 9H), 1.46-1-31 (m, 8H), 1.21-1.18 ( m, 3H), 0.93 (s, 3H), 0.92 (s, 3H). (23f) (3S,5R) -5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]-N-[(1R) -1 -(Ethoxymethyl)-3-methylbutyl]piperidine-3-carbamide amine fumarate in the third butyl (3R,5S) ·3 obtained in Example (23e) -[2,2-[$] -85- 201107306 dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-5-{[(11〇-1· ( Ethoxymethyl)-3-methylbutyl]amine-mercaptopiperidin-1-carboxylate 23 5 mg (0.45 mmol) in dichloromethane (1.37 ml), trifluoroacetic acid 0.68 6 m 1 (8.91 mm 〇1) was stirred at room temperature for 20 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic layer was washed with saturated brine and then evaporated. Drying with sodium. After filtration &gt; The solvent was evaporated under reduced pressure, and the residue was purified by NHH chromatography column chromatography (solvent solvent: dichloromethane/methanol = 20/1 to 7/3) to obtain (3S,5R) -5 -[2,2-Di®methyl-4-(2-methylphenyl)-5-piperidone-buki]-N-[(1R)·1-(ethoxymethyl)-3 -methylbutyl]piperidine-3-carboxamide 154 mg (yield: 73%) ((3S,5R) -5-[2, 2-Dimethyl-4-(2-methylphenyl)-5_piperidin-1-yl]-N-[(lR)-1-(ethoxymethyl)-3-methylbutyl a solution of 154 mg (0.33 mmol) of methanolic acid (3 ml) was added to a solution of 38 mg (0.33 mmol) of re-butanol diacid. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. After the residue was dissolved in an appropriate amount of methylene chloride, an excess of ether was added, and the solid was crystallized to give the title compound (1,54 mg (yield: 8%). Colorless solid. 1HNMR spectrum (CD3OD, 400 MHz), δ: 7.31-7.25 (m) ,3H), 7.15- 7.09 (m, 1 Η), 6.69 (s, 2 Η), 4.1 4 - 4 _ 0 8 (m, 1H), 3.69-2.94 (m, 1 3 H), 2.8 1 - 2 · 7 5 (m, 1 H), 2 · 2 2 (s, 3 H), 2.15- 2.11 (m, 1H), 1.98- 1.89 (m, 1H), 1.66- 1.60 (m, 1H), 1.42- 1.31 (m,8H), 1.17 (t,3H,J = 7-0 Hz), 0.95-0.90 (m, 6H) Mass Spectrum (FAB+), m/z: 473 ((M + H)+). -86-201107306 (Example 24) (33,51〇-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidone-1_yl]-N-[ (1R)-1-phenylpropyl]indole D--3-carbamidine-butyrate

(24&amp;) Tert-butyl butyl (311,53)-3-[2,2-dimethyl-4-(2-methylphenyl)-5-warchone-1-yl 1-5- { [(1R)-1,Phenylpropyl]aminomethanyl}piperidine-1 -carboxylate (3S,5R)-1-(tertiary butoxycarbonyl) obtained in Example (23d) -5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]piperidine-3-carboxylic acid 20 mg (0.45 mmol), (lR) -Phenylpropane q•amine i21mg (0-90mmol) and diisopropylethylamine I74mg ( 1.35mmol) in N,N-dimethylformamide (5ml), under ice cooling, add 〇_(benzene And tridecyl-1-yl)-&gt;^,:^,;^',&gt;1'-tetramethylurea key hexafluorophosphate (1^1'1;) 25611^ (0.68mmol), Stir at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure and purified by EtOAc EtOAc EtOAc EtOAc EtOAc Ethyl acetate = 7/3 - 1 / 1 / 〇 / 1) The residue was purified to give the title compound 232 mg (yield: 92%). Colorless solid. NMR spectrum (CDC13,500 ΜΗζ), δ: 7.3 5-7.20 (m, 8H), 7.11-7.05 (m, 1H), 6.24 (br s, 1H), 4.87 (br q, 1H, J = 7.7 Hz), [s] -87- 201107306 4.26-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.35 (br d, 1H, J = 11.2 Hz), 3.20-2.70 (m, 4H), 2.38 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.89- 1.77 (m, 4H), 1.48 (s, 9H), 1.34- 1.2 7 (m, 6H), 0.88 (t , 3H, J = 7.3 Hz) « (24b)(3S,5R) -5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl] -N-[(1R)-1-phenylpropyl]piperidine-3-carboxamide sulfonate fumarate obtained in Example (24a) as a tertiary butyl (3R, 5S) -3- [2,2-Methyl-4-(2-methylphenyl)-5-indol-1-yl]-5- { [(1R) -1_phenylpropyl]aminecarbenyl} To a solution of 232 mg (0.41 mmol) of methylene chloride (2 ml), m.p. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated to dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-Dimethyl-4-(2-methylphenyl)^-5-piperidin-1-yl]-N-[(1R)-1-phenylpropyl]piperidine-3-carboxamidine Amine 125 mg (yield: 66%). (3S,5R)-5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-N-[(1R) To a solution of 125 mg (0.27 mmol) of methanol (1.5 ml) in -1-phenylpropyl]piperazin-3-methylamine, add 31.4 mg of fumaric acid (〇.2 7 mm〇l)' at room temperature. Stir for 5 minutes. The reaction mixture was concentrated under reduced pressure. After the residue was dissolved in methylene chloride (yield: ethyl ether), ethyl ether (yield: EtOAc) 201107306 4 NMR spectrum (CD3OD, 500 MHz), δ: 7.3 5 -7.24 (m, 8H), 7.12-7.07 (m, 1H), 6.72 (s, 2H), 4.73 (br t, 1H, J = 7.3 Hz ), 3.66-3.46 (m, 4H), 3.40-3.20 (m, 3H), 3.06-2.85 (m, 3H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.07-2.04 (m , 1H), 1.89-1.79 (m, 3H), 1.3 6-1.3 5 (m, 6H), 0.93 - 0.90 (m, 3H). Mass spectrum (FAB+), m/z: 463 ((M + H)+). (Embodiment 25)

(3S,5R) -N-[(1R)-2-cyclopropyl-1-phenylethyl]-5_[2,2-dimethyl-4-(2-methylphenyl)-5- Piperidin-1-yl]piperidine-3-carboxamide fumarate

(25〇 tertiary butyl (3S,5R)-3-{[(lR) -2-cyclopropyl-1-phenylethyl]aminecarbamyl} -5-[2,2-dimethyl 4-(2-methylphenyl)_5_piperidin-1-yl]piperidine-1-carboxylate (3S,5R) -1- (tertiary butoxy) obtained in Example (23d) Benzylcarbonyl)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]piperidine-3-decanoic acid 300 mg (0.67 mmol), reference Example 10 (ir) -2·cyclopropyl-1-phenylethin-1-amine hydrochloride 266 mg ( 1.35 mmol) and diisopropylethylamine 348 mg ( 2.70 mmol) of N,N - in dimethylformamide (7ml) solution, under ice cooling, Π-(benzotriazol-1-yl)-ν, ν, ν', ν'-tetramethyluranyl iron hexafluorophosphate Salt (HBTU) 307 mg (0.81 mmol), stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. -89-201107306 The organic layer was washed with saturated brine. Drying. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (solvent solvent: n-hexane/ethyl acetate = 7/3 to 〇/1) and toluene column chromatography (dissolving solvent: Η-hexane / ethyl acetate = 7/3~1/1~0/1) The residue was purified to give the title compound (yield: 70%) (yield: 70%). NMR NMR (CDC13, 500 MHz), δ: 7.36-7.20 (m, 8H), 7.11-7.05 (m, 1H), 6.03 (br) s, 1H), 5.06 (br q, 1H, J = 7.3 Hz), • 4.26-4.00 (m, 2H), 3.71-3.50 (m, 2H), 3.3 6-3.33 (m, 1H), 3.18 (br t, 1H, J = 11.0 Hz), 2.95-2.69 (m, 3H), 2.36 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.91-1.61 (m, 4H ), 1.48 (s, 9H), 1.34- 1.28 (m, 6H), 0.5 9-0.5 5 (m, 1H), 0.48-0.3 8 (m, 2H), 0.16-0.12 (m, 1H), 0.06- 0.02 (m,1H) (25b)(3S,5R)-N-[( 1R) -2-cyclopropyl-1-phenylethyl]-5-[2,2-dimethyl-4- (2-methylphenyl)-5-piperidone-1-yl]piperidine-3-carboxamide anti-butenediate • In the example (25 三 obtained tri-butyl (3S, 5R)-3-{ [(1R) • 2-cyclopropyl-1-phenylethyl]amine-mercaptopurine-5-[2,2-dimethyl-4-(2-methylphenyl) a solution of 278 mg (0.47 mmol) in dichloromethane (2 ml), EtOAc (1. Stir for 25 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated to dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -2-cyclopropyl-1-phenylethyl [S1 -90- 201107306 yl]-5-[2,2-methyl-4-(2-methylphenyl)-5-piperidone- I_group] Piper steep _3_ 151 mg of formic acid amine (yield: 65%). (3S,5R)-N-[(1R)-2-cyclopropyl-1-phenylethyl]-5-[2,2-dimethyl-4-(2-methyl) obtained here To a solution of 151 mg (0.31 mmol) of fumaric acid, a solution of phenyl)_5·piperidin-1-yl]pipetam-3-caramel 151 mg (〇.31 mmol) in methanol (1.5 ml), room Stir for 5 minutes at warm. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride.

Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 7.34-7.22 (m, 8H), 7-12-7.07 (m, 1H), 6.70 (s, 2H), 4.94 (br t, 1H, J = 7.6 Hz), 3.63-3.19 (m, 7H), 3.07-3.02 (m, 1H), 2.97 (br t, 1H, J = 12.5 Hz), 2.94-2.86 (m, 1H), 2.19 (s, 1.5H), 2.16 ( s, 1.5H), 2.07-2.04 (m, 1H), 1.90- 1.81 (m, 1H), 1.74- 1.64 (m, 2H), 1-36- 1.3 5 (m, 6H), 0.68-0.63 (m , 1H), 0.49-0.3 6 (m, 2H), 017-0.13 (m, 1H), 0.05-0.01 (m, 1H)» Mass Spectrum (FAB+), m/z: 489 ((M + H)+) . (Example 2 6 ) (3S,5R)-5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-l-yl]-N-[(ir ) -3_methyl_:i_phenylbutyl]piperidine_3_carbamidamine fumarate

-91- 201107306 (26a) Tert-butyl (3R,5S)-3-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]- 5-{[(1R)-3-methyl-1-phenylbutyl]aminemethanyl}piperidine-1-carboxylate (3S,5R) -1- obtained in Example (23d) (tertiary butoxycarbonyl)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]piperidine-3-decanoic acid 200 mg ( 0.45 mmol), (1R)-3-methyl-1-phenylbutan-1-amine hydrochloride 179 mg (0.90 mm 〇l) and diisopropylethylamine 232 mg (1.80) obtained in Reference Example 11. M, N-dimethylformamide (5ml) • In solution, add 〇·(benzotriazol-1-yl)-oxime, oxime, Ν', Ν'-tetramethyl group under ice cooling Urea- key hexafluorophosphate (HBTU) 256 mg (0.68 mmol) was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3 to 0/1) and oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound 183 mg (yield: 69%).

NMR spectrum (CDC13, 500MHz), δ: 7.35-7.20 (m, 8H), 7.10-7.05 (m, 1H), 5.90-5.60 (m, 1H), 5.04 (br q, 1H, J = 7.8 Hz), 4.20-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.36-3.3 3 (m, 1H), 3.17 (br t, 1H, J = 11.7 Hz), 2.94-2.69 (m, 3H), 2.3 7-2.30 (m, 1H), 2.23-2.20 (m, 3H), 1.88- 1.26 (m, 20H), 0.95-0.92 (m, 6H). (26b ) ( 3S,5R ) -5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-N-[(1R) -3 -Methyl-1-phenylbutyl]piperidine-3-carboxamide m-92- 201107306 Fumarate The tertiary butyl (3R,5S)-3 obtained in Example (26a) -[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]-5-{[(lR)-3-methyl-1-phenyl To a solution of 183 mg (0.36 mmol) of methylene chloride (2 ml), m.p. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen sulfate, and the mixture was evaporated. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH column chromatography (solvent solvent: dichloromethane/methanol = 1/0 to 7/3) to obtain (3S,5R) -5-[2 ,2-dimethyl- 4·(2-methylphenyl)-5-piperidone-1-yl]-N-[(1R)-3-methyl-1-phenylbutyl]piperidine -3 - formamide 9 1 mg (yield: 52%). (3S,5R)-5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-N-[(1R) obtained here To a solution of 9-mg (0.19 mmol) of methanol (iml) in -3-methyl-1-phenylbutyl]piperidine-3-carboxamide, 21.7 mg of fumaric acid ((K19mm〇l), After stirring at room temperature for 5 minutes, the reaction mixture was concentrated under reduced pressure. After the residue was dissolved in methylene chloride, an excess amount of ether was added, and the solid was collected by filtration to give the title compound 91 mg (yield: 82%). NMR spectroscopy (CD3OD, 500MHz), δ: 7.34-7.23 (m,8H), 7.12-7.06 (m, 1H), 6.70 (s, 2H), 4.94 (br dd, 1H, J = 9.3 Hz, 5.9 Hz), 3.62-3.45 (m, 4H), 3.39-3.19 (m, 3H), 3.04 (brt, 1H, J = 12.0 Hz), 2.96 (t, 1H, J = 12.5 Hz), 2.91-2.83 (m , 1H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.05 -2.02 (m, 1H), 1.87-1.69 (m, 2H), 1.62- 1.55 (m, 2H), 1.36 (br s, 6H), 0.97 (d, 3H, J = -93- 201107306 6.3 Hz), 0.94 (d, 3H, J = 5.9 Hz) ° Mass spectrum (FAB+), m/z: 491 ((m + h)+ (Example 27) (3S,5R)-5-[2,2-Dimethyl_4_(2-methylphenyl)-5-piperidone-1-yl]-N-[(1R) -1- ( 5 -fluoropyridin-2-yl)-3*methylbutyl]piperidine-3-carboxamide fumarate

(27a) Tert-butyl (3R,5S)-3-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]-5·{ [ (1R)-1-(5-fluoropyridin-2-yl)-3-methylbutyl]amine-carbamoyl}piperidine-1-carboxylic acid vinegar obtained in Example (23 ( (3S, 5R) )-1-(tertiary butoxycarbonyl)-5-[2,2-dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]piperidine-3 250 mg (0.56 mmol) of citric acid, (1R)-1-(5-fluoropyridin-2-yl)-3-methylbutan-1-amine 2 hydrochloride obtained in Reference Example 287 mg (1.12 mmol) And diisopropylethylamine 289mg ( 2.24mmol) in hydrazine, hydrazine-dimethylformamide (5ml) solution, under ice cooling, add Ο-(benzotriazol-1-yl)-oxime, Ν , Ν', Ν'-tetramethylurea hexafluorophosphate (HBTU) 2 55mg (0.67mmol), stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, extracted with ethyl acetate, organic layer After washing with saturated brine, it was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3~0/1 And NH 矽 rubber column chromatography (dissolved solvent: η-hexane / ethyl acetate = 7/3~1/1~0/ 1) The residue was purified to give the title compound 228 mg (yield: 67%) as a colorless solid. NMR spectrum (CDC13, 500 MHz), δ: 8.40 (br s, 1H), 7.39-7.35 (m, 1H), 7.26-7.21 (m, 4H), 7.11-7.05 (m, 1H), 6.49-6.48 (m, 1H), 5.13 (br q, 1H, J = 7.7 Hz), 4.26-4.00 (m, 2H ), 3.71-3.49 (m, 2H), 3.35 (br d, 1H, J = 11.7 Hz), 3.19-3.16 (m, 1H), 2.96-2.69 (m, 3H), 2.40 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.89 (br s, 2H), 1.69- 1.28 (m, 18H),

0.95-0.92 (m, 6H). (27b) (3S,5R) -5-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidin-1-yl]-N-[ ( 1R) -1 -( 5-Fluoropyridin-2-yl)-3-methylbutyl]piperidine _3.carbamamine fumarate in the third butyl group obtained in Example (27a) (3R, 5S) -3-[2,2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-5- { [(1R)-1-(5-fluoropyridine) To a solution of 228 mg (0.37 mmol) of dichloromethane (2 ml) in -2-yl)-3-methylbutyl]amine-carbamoyl}piperidine-1-carboxylate, 1.2 ml (15. Methyl), stirred at room temperature for 15 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-Dimethyl-4-(2-methylphenyl)-5-piperidone-1-yl]-:^-[(11〇-1-(5·fluoropyridin-2-yl)-3 -Methylbutyl]piperidine-3-carboxamide 177 mg (yield · · 93 %). (38,511)-5-[2,2-dimethyl-4-(2-A) Phenyl)-5-piperidin-1-yl]-:^-[(111)-1-(5-fluoropyridin-2-yl)-3-methyl-95- 201107306 To a solution of 177 mg (0.35 mmol) of methanol (1.5 ml), 40.3 mg (0.35 mmol) of fumaric acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure to dissolve residue. After an appropriate amount of dichloromethane, an excess of ether was added, and the solid was crystallized to give the title compound (yield: 79%).

4 NMR spectrum (CD3OD, 500MHz), δ: 8.41 (br s, 1H), 7.59-7.54 (m, 1H), 7.41-7.38 (m, 1H), 7.30-7.24 (m, 3H), 7.12-7.09 ( m,lH), 6.70 (s,2H), 5.06-5.03 (m,lH), 3.64-3.46 (m, 4H), 3.41-3.19 (m, 3H), 3.04 (t, 1H, J = 12.2 Hz) , 2.98-2.87 (m, 2H), 2.19 (s, 1.5H), 2.17 (s, 1.5H), 2.13-2.09 (m, 1H), 1.86- 1.57 (m, 4H), 1.3 8- 1.36 (m , 6H), 0.98-0.93 (m, 6H). Mass spectrum (FAB+), m/z: 510 ((M + H)+). (Example 2 8 ) (3S,5R)-N-[(lR)-l-(ethoxymethyl)_3.methylbutyl]-5·[4·(5-fluoro-2-methyl Phenyl)-2,2-dimethyl-5-indole ketone-1-yl]piperidine-3-carbamide amine fumarate

Η (28a)methyl(3S,5R)-5-({2·[(5-fluoro-2.methylphenyl)amino]-1,1-dimethylethyl}amino)-1 -[(2-nitrophenyl)sulfonyl]piperidine-3-carboxylate ε] -96- 201107306 The methyl group (3S,5R) -5-[(l) obtained in the example (le) , l-dimethyl-2-oxo-ethyl)amino]-i-[(2-nitrophenyl)sulfonyl]piperidine-3-indole vinegar 2.5 g (6.1 mmol) To a solution of 1.13 g (9.0 mmol) of 5-fluoro-2-methylaniline in toluene (60 ml), i.27 g (21.1 mmol) of acetic acid was added, and the mixture was heated under reflux, and the mixture was stirred for 2.5 hours while removing water. After cooling, 2.56 g (12.1 mmol) of sodium triethoxyborohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified mjjjjjjjjjjjjjjjjj 98%). Colorless solid. NMR spectrum (CDC13, 500 MHz), δ: 7.75 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.66-7.59 (m, 2H), 7.51 (dt, 1H, J = 7.8 Hz, 1.5 Hz), 6.95 (br t, 1H, J = 7.3 Hz), 6.32 (dt, 1H, J = 8.3 Hz, 2.4 Hz), 6.23 (dd, 1H, J = 11.2 Hz, 2.4 Hz), 4.26 (br s, 1H), Φ 4.07-4.05 (m, 1H), 3.69-3.64 (m, 4H), 2.89-2.84 (m, 2H), 2.80-2.70 (m, 3H), 2.3 6-2.32 (m, 1H), 2.21-2.17 (m, 1H), 2.07 (s, 3H), 1.31 (q, 1H, J = 12.0 Hz), 1.22 (s, 3H), 1.20 (s, 3H). (28b)methyl(3S,5R)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]-l- [(2-Nitrophenyl)sulfonyl]piperidine-3-carboxylate Methyl(3S,5R)-5-({2-[(5-fluoro-) obtained in Example (28a) 2-methylphenyl)amino]·1,1-dimethylethyl}amino)-l-[(2-nitro-97-

201107306 base phenyl) sulfonyl] piperidine-3-carboxylate 3.10g (5.9mm 〇l) and triamine 4.79g (47.4mmol) in dichloromethane (60ml), hail spent 2 hours A solution of 4.77 g (23.7 mmol) of bromoacetic acid in dichloro (15 ml) was stirred at room temperature for 15 minutes and then stirred at 40 ° C. After cooling, water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was evaporated to silica gel elution elution elution elution elution . Colorless solid. 4 NMR spectrum (CDC13, 500MHz), δ: 8.03-8.02 (m, 7.76-7.71 (m, 2H), 7.67-7.65 (m, 1H), 7.27-7.20 (m, 6.95 (dq, 1H, J = 8.3) Hz, 2.4 Hz), 6.87-6.81 (m, 4.05-3.99 (m, 1H), 3.8 7-3.8 0 (m, 1H), 3.72 (s, 3.68-3.14 (m, 5H), 2.80-2.66 (m , 3H), 2.32-2.17 (m, 1.74-1.66 (m, 1H), 1.3 7-1.3 4 (m, 6H). (28c) 1-tertiary butyl 3-methyl (3S,5R) _5_[ 4_(5_Fluoro-based group)-2,2 - _•methyl-5---------------------------------------------------- Base (3S,5r) _5_[4_(-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]_[·[(2·nitro 3)岐D Ding-3 - vinegar vinegar 2.81g (5.0mm 〇l) running sulfuric acid q (7.5mmol) in acetonitrile (100ml), under ice cooling, add 1.96g (6.0mmol) of carbon' stirring at room temperature 2 Hour. The water in the reaction mixture is diluted with dichloromethane. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent is evaporated under reduced pressure. , after, :η - compound 1Η), 1Η), 1Η), 3Η), 4Η), 2-methyl 5-fluoropentyl) 77ml After the acid slurry was added, the column [S ] -98- 201107306 was chromatographed (dissolved solvent: dichloromethane/methanol = 1/0 to 7/3) to purify the residue to obtain methyl (3S, 5R) -5-[ 4-(5-Fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]piperidine-3-carboxylate 1.9 g (yield: quantitative). Methyl (3S,5r) _5_[4_(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidin-3- obtained herein Adding di-tertiary butyl dicarbonate to a mixture of 1.9 g (5.0 mmol) of a carboxylate and 1.25 g (14.9 mmol) of sodium hydrogencarbonate in water (50 ml). Methyl), stirred at room temperature for 15 minutes. The reaction mixture was extracted with EtOAc. After filtration, the solvent was evaporated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjj Yield: 72%). Colorless liquid. WNMR spectrum (CDC13, 500 MHz)' δ : 7.21 (dd, 1H, J = 8.3 Hz, 6.8 Hz), 6.97-6.93 (m, 1H), 6.86-6.83 (m, 1H), 4.29 (br s, 1H ), 4.09 (br s, 1H), 3.71-3.51 (m, 5H), 3.3 7-3.3 3 (m, 1H), 3.19 (br d, 1H, J = 11.7 Hz), 3.01-2.97 (m, 1H) ), 2.69-2.53 (m, • 3H), 2.18-2.10 (m, 4H), 1.81-1.74 (m, 1H), 1.48 (s, 9H), 1.3 6-1.3 2 (m, 6H). (28d ) ( 3S,5R ) -1-(tertiary butoxycarbonyl)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piper trap Keto-1·yl]piperidine-3-carboxylic acid 1-tributyl butyl 3-methyl(3S,5R)-5-[4-(5-gas-2-) obtained in Example (28c) Methyl-based)-2,2-Methyl-5-indol-1-yl]indole-1,3-dicarboxylate 1.72 g (3.6 mmol) in tetrahydrofuran (36 ml) and water (18 ml) To the mixture, 302 mg (7.2 mmol) of lithium hydroxide·1 hydrate was added under ice cooling, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, -99-201107306 IN hydrochloric acid was added to make acidity (pH 2-3), extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give title compound (yield: quantitative). Colorless solid. H NMR spectrum (CDC13, 500 MHz), δ: 7.22 (dd, 1H, J = 8.3 Hz, 6.3 Hz), 6.98-6.94 (m, 1H), 6.87-6.83 (m, 1H), 4.29 (br s, 1H) , 4.09 (br s, 1H), 3.78-3.61 (m, 2H), 3.42-3.18 (m, 2H), 3.01 (br s, 1H), 2.74-2.54 (m, 3H), 2.32-2.16 (m, 4H), • 1 · 78-1.71 (m, 1H), 1.47 (s, 9H), 1.36- 1.34 (m, 6H). (28e) tert-butyl (3S,5R)-3-{[(lR) -1-(ethoxymethyl)-3-methylbutyl]aminecarbamyl} _5-[4_( 5_ Fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone·ι_yl]piperidine-1-carboxylate (3S,5R) obtained in Example (28d) -1-(tertiary butoxycarbonyl)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine 358 mg (0.77 mmol) of 3-carboxylic acid, (2R)-1-ethoxy-4-methylpentan-2-amine obtained in Reference Example 6 22 mg (1.54 mmol) and diisopropyl # B In a solution of N,N-dimethylformamide (6 ml) of 405 μl (2·32ιηηιο1), 〇-(benzotriazol-1-yl)-N,N,N',N was added under ice cooling. A solution of '-tetramethylurea hexafluorophosphate (HBTU) 351 mg (0.93 mmol) N,N-dimethylformamide (1 ml) was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by EtOAc EtOAc EtOAc EtOAc EtOAc The residue was purified to give the title compound (yield: 59%). -100- 201107306 Colorless solid. WNMR spectrum (CDC13, 400MHz), δ: 7.23-7.19 (m, 1H) 6.97-6.92 (m, 1H), 6.87-6.82 (m, 1H), 5.64 (br s, 1H) 4.22-4.05 (m, 2H) ), 3.75-3.68 (m, 1H), 3.59-3.34 (m, 7H) 3.20-3.14 (m, 1H), 2.98 (br s, 1H), 2.74-2.68 (m, 2H), 2.34 (br s, 1H), 2.19-2.17 (m, 3H), 1.94 (br s, 2H), 1.64-1.54 (m 1H), 1.48 (s, 9H), 1.45-1.31 (m, 8H), 1.20 (t, 3H, J = 6.8 Hz) 0.93 (s, 3H), 0.92 (s, 3H). • (28f)(3S,5R) -N-[(1R) -1-(ethoxymethyl)_3_methylbutyl]-5-[4-( 5-per-2-methylphenyl) -2,2-Dimethyl-5-fluorenone. 1-yl] piperidine-3-carbamidamine fumarate. The tertiary butyl group obtained in Example (28e) (3S, 5R) -3·{ [( 1R) -1-(ethoxymethyl)-3-methylbutyl]aminecarboxylidene} -5-[4-(5-fluoro-2-methylphenyl)- To a solution of 2,2-methyl-5-piperidone-1-yl]piperazin-1-residual acid vinegar 268 mg (0.45 mmol) in dichloromethane (1.4 ml) ), stir at room temperature for 20 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by ethylamine chromatography (solvent solvent: methylene chloride/methanol=20/1~7/3) to obtain (3S,5R)-N-[ (1R) -1·(ethoxymethyl)-3-methylbutyl]-5-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piper trap Ketone-1-yl]piperidine-3.carboxamide 184 mg (yield: 83%). (3S,5R)-N-[(1R) -1-(ethoxymethyl)-3-methylbutyl]-5-[4-(5-fluoro-2-methyl) obtained here Phenyl)-2,2-dimethyl-5-piperidin-1-yl]piperidine-3-carboxamide 184 mg (0.38 mmol) in methanol (4 ml), [sl -101 - 201107306 43.5 mg (0.38 mmol) of fumaric acid was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. Colorless solid. hNMR spectrum (CD3OD, 500MHz), δ: 7.31-7.29 (m, 1H), 7.04-7.01 (m, lH), 6.96-6.91 (m, lH), 6.69 (s, 2H), 4.13-4.08 (m, 1H), 3.68-3.16 (m, 11H), 3.08-2.94 (m, 2H), 2.82-2.77 (m, Lu 1H), 2.17-2.10 (m, 4H), 1.96-1.89 (m, 1H), 1.67 -1.59 (m, 1H), 1.44- 1.32 (m, 8H), 1.17 (t, 3H, J = 7.0 Hz), 0.95-0.90 (m, 6H). Mass spectrum (FAB+), m/z: 491 ((M + H)+). (Example 29) (38,51〇-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-N- [(1R)-1-phenylpropyl]piperidine-3-carboxamide anti-butyrate

(29a) tert-butyl (3R,5S)-3-[4-(5-fluoro.2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]- 5-{[(111)-1-phenylpropyl]aminomethionyl}piperidine-1-carboxylate (3S,5R) ·1·(three-stage butoxide) obtained in Example (28d) 5-(4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl][$.] -102- 201107306 峨D--3-residual acid 200 mg (〇.43 mmol), (1R)-ΐ·Phenylpropanol-amine 117 mg (0.86 mmol) and diisopropylethylamine 167 mg (1.29 mmol) of N,N - in dimethylformamide (5 ml) solution, under ice cooling, 〇_(benzotriazin-1-yl)-&gt;1,&gt;1,1^',&gt;1'-tetramethyl Urea hexafluorophosphate (1|61 [1_1) 19.6 mg (0.52 mmol) was disturbed for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3 to 0/1) and NH oxime column chromatography (dissolved solvent: η - hexane / ethyl acetate = 7 / 3 / 〇 / 1) The residue was purified to give the title compound 23 6m (yield: 94%). Colorless solid. HNMR spectrum (CDC13, 500MHz), δ: 7.34-7.18 (m, 6H), 6.95-6.91 (m, 1H), 6.85-6.81 (m, 1H), 6.29-5.95 (m, 1H), 4.87 (br q, 1H, J = 7.8 Hz), 4.21 (br s, 1H), 4.01 (br s, 1H), 3.70-3.48 (m, 2H), 3.33 (br d, 1H, J = 10.7 Hz), 3.18- 2.69 (m, 4H), 2.34 (br s, 1H), 2.18 (s, 1.5H), 2.15 (s, 1.5H), 1.89-1.61 • (m, 3H), 1.5 8- 1.45 (m, 10H) , 1.33- 1.27 (m, 6H), 0.90-0.87 (m, 3H). (29b)(3S,5R)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[ ( 1R) -1-phenylpropyl] piperidine _3_carbamidamine fumarate in the third butyl (3R, 5S) -3-[4- (obtained in Example (29a)) 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]-5-{[(11〇-1-phenylpropyl)aminecarboxamide To a solution of 23 6 mg (〇.41 mmol) in dichloromethane (2 ml), trifluoroacetic acid K2mi (156 mm 〇1), (5) -103 - 201107306 was stirred at room temperature for 15 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by NH(R) rubber column chromatography (solvent solvent: dichloromethane/methanol = 1/0 to 7/3) afforded (3S,5R) -5-[4-(5-fluoro-2-methylphenyl) -2,2-Dimethyl-5-piperidin-1-yl]-N-[(1R)-1-phenylpropyl]piperidine-3-carboxamide 160 mg (yield: 82%) (3S,5R)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-^ obtained here [-[ (111)-1-• Phenylpropyl]piperidine-3-carboxamide 160 mg (0.33 mmol) in methanol (1.5 ml), adding 38.7 mg (0.33 mmol) of fumaric acid at room temperature After stirring for 5 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was evaporated, mjjjjjjjjjjjjjj , 500MHz), δ: 7.34-7.23 (m,6H), 7.04-7.00 (m, 1H), 6.94-6.91 (m, 1H), 6.72 (s, 2H), 4.73 (br ® t, 1H, J = 7.6 Hz), 3.63 -3.46 (m, 4H), 3.40-3.19 (m, 3H), 3.05 (br t, 1H, J = 12.2 Hz), 2.98 (t, 1H, J = 12.2 Hz), 2.92-2.87 (m, 1H), 2.15-2.12 (m, 3H), 2.07-2.02 (m, 1 H), 1.8 8 - 1.77 (m, 3H), 1.36 (br s, 6H), 0.91 (br t, 3H, J = 7.3 Hz). Mass spectrum (FAB+), m/z: 481 ((M + H)+). (Example 3 0 ) (3S,5R) -N-[(1R)-2-cyclopropyl-1-phenylethyl]-5-[4-(5-fluoro-2-methylphenyl) -2,2-dimethyl-5-piperidin-1-yl]piperidine-3-carboxamide fumarate-104- 201107306

(3〇a) tert-butyl (3s,5R) -3_{[(1r) -2_cyclopropylj-phenylethyl]aminecarakilide 丨5-[4-( 5-fluoro-2 -methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidine-indole-carboxylate

(3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl obtained in Example (28d) (5R) -2-cyclopropyl-1-phenyl group obtained by reference example 10 Ethyl-hydrazine amine hydrochloride 255 mg (1.29 mmol) and diisopropylethylamine 334 mg (2.59 mmol) in N,N-dimethylformamide (6 ml) solution 〇-(benzotriazole·1-yl)-N,N,N',N,-tetramethylurea hexafluorophosphate (HBTU) 294 mg (0.77 mmol), stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η·hexane/ethyl acetate = 7/3 to 0/1) and oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound (yield: 58%). Colorless solid. NMR spectrum (CDC13, 500MHz), δ: 7.34-7.18 (m, 6H), 6.95-6.92 (m, 1H), 6.85-6.81 (m, 1H), 5.89 (br s, 1H), 5.08-5.04 (m , 1H), 4.26-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.33 (br d, 1H, J = 11.7 Hz), 3.16 (br t, 1H, J = 10.0 Hz), [S ] -105- 201107306 2.95 -2.69 (m, 3H), 2.35 (br s, 1H), 2.18 (s, 1.5H), 2.15 (s, 1.5H), 1.90-1.61 (m, 4H), 1.48 (s , 9H), 1.3 4- 1.28 (m, 6H), 0.60-0.55 (m, 1H), 0.47-0.40 (m, 2H), 0.16-0.11 (m, 1H), 0.06-0.02 (m, 1H). (3 01〇(33,5 ft)-&gt;1-[(11〇-2-cyclopropyl-1-phenylethyl]_5-[4_(5-fluoro-2-methylphenyl)· Tris-butyl (3S, 5R) obtained in Example (30a), 2,2·dimethyl-5-piperidin-1-yl]piperidine-3-carboxamide sulfonate -3-{[(lR) • -2-cyclopropyl-1-phenylethyl]aminecarboxylidene} -5-[4-( 5-fluoro-2-methylphenyl) '2,2 --Methyl-5-indol-1-yl] sputum-1-indole vinegar 230 mg (0.38 mmol) in dichloromethane (2 ml), then added trifluoroacetic acid i. 2 ml (15.6 mmol) The mixture was stirred for 15 minutes at room temperature. The reaction mixture was combined with EtOAc EtOAc. The solvent was distilled off, and the residue was purified by NH column chromatography (solvent solvent: methylene chloride / methanol = 1 / 0 to 7/3) to obtain (3S,5R) -N-[(1R) -2 - Cyclopropanyl@yl-1-phenylethyl]-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidin Pyridyl-3-carbamide 13 4 mg (yield: .72%). (3S,5R)-N-[(1R)-2-cyclopropyl-1-phenylethyl group obtained here. ]-5-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]piperidine-3-carboxamide 134 mg (〇. To a solution of 27 mmol) in methanol (1.5 ml), 30.7 mg (0.27 mmol) of fumaric acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The ether was collected by filtration to give the title compound (yield: 77%) (yield: 77%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR spectroscopy (CD3OD, 500 MHz), δ: 7.34-7.24 (m, 6H), 7.04- 7.00 (m, 1H), 6.95-6.92 (m, 1H), 6.71 (s, 2H), 4.94 (br t, 1H, J = 7.6 Hz), 3.63-3.47 (m, 4H), 3.41-3.19 (m , 3H), 3.04 (br t, 1H, J = 12.2 Hz), 2.97 (t, IH, J = 12.5 Hz), 2.92-2.86 (m, 1H), 2.15-2.12 (m, 3H), 2.06-2.0 (m, 1H), 1.90-1.81 (m, 1H), 1.74- 1.64 (m, 2H), 1.36 (br s, 6H), 0.6 8 -0.63 (m, 1H), 0.49-0.3 6 (m, 2H ), 0.17-0.12 (m, 1H), 0.05-0.01 (m, 1H). Mass spectrum (FAB+), m/z: 507 ((M + H)+).

(Example 3 1 ) (3S,5R) -5-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]-N -[(1R)-3-methyl-1-phenylbutyl]piperidine-3-carboxamide fumarate

(31a) Tert-butyl (3R,5S)-3-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]- 5-{[(111)-3-methyl-1-phenylbutyl]aminemethanyl}piperidine-1-carboxylate (3S,5R) -1- obtained in Example (28d) (tertiary butoxycarbonyl)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]piperidin-3- 200 mg (0.43 mmol) of carboxylic acid, (1R)-3-methyl-1-phenylbutane-1-amine hydrochloride obtained in Reference Example 11 (172 mg (0.86 mmol)) and diisopropylethylamine 167 mg ( 1.29 mmol) of N,N-dimethylformamide (5 ml) solution, under ice cooling, add 〇-(benzotriazol-1-yl)-n,n,n',n'-[s ;1 -107- 201107306 Tetramethylurea hexafluorophosphate (HBTU) 196 mg (〇.52 mmol), stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 7/3 to 0/1) and oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound i 88 mg (yield: 71%). Colorless solid. _ NMR spectroscopy (CDC13,500 ΜΗζ), δ: 7.34-7.18 (m, 6H). 6.95-6.91 (m, 1H), 6.85-6.81 (m, 1H), 5.89 (brs, 1H), 5.04 (br q, 1H, J = 7.8 Hz), 4.20-4.00 (m, 2H), 3.70-3.48 (m, 2H) 3.33 (br d, 1H, J = 11.7 Hz), 3.16 (br t,1H,J = 10.0 hz) , 2.93-2.69 (m, 3H), 2.3 7-2.32 (m, 1H), 2.18-2.15 (m, 3H) 1.87-1.26 (m, 20H), 0.95-0.92 (m, 6H) » (31b) ( 3S,5R) -5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethylphenyl-5-piperidone-1-yl]-N-[(1R)- 3-methyl-1-phenylbutyl]piperidine _3_methantamine fumarate in the example (31 〇 obtained tertiary butyl (3R, 5S) -3_[4- ( 5-_Fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]-5-{[(111)_3_methyl-1-phenylbutyl]amine A To a solution of hydrazino-piperidin-l-carboxylate i88 mg (0.31 mmol) in dichloromethane (2 ml), trifluoroacetic acid (15.6 mm )l) was then stirred at room temperature for 15 min. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Solvent, residue was purified by NH(R) rubber column chromatography (dissolving solvent: methylene chloride [S] -108 · 201107306 / methanol = 1/0 to 7/3) to obtain (3S, 5R) -5-[4- (5-Fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-N-[(1R) -3_methyl-丨-phenylbutyl Piperidine-3-carbamide 132 mg (yield: 84%). (38,511)-5-[4-(5-fluoro1-2-methylphenyl)-2,2- Dimethyl-5-piperidone-1-yl]-N-[(1R)-3-methyl-1-phenylbutyl] nitrobutylidene 3-carbamide i32 mg (0.26 mmol) of methanol (1.5 ml) solution, add 3 〇.lmg ((K26mmol)), and stir at room temperature for 5 minutes. Concentrate the reaction mixture under reduced pressure, dissolve the residue in an appropriate amount of dichloromethane, and add excess ether. The solid was isolated by filtration to give the title compound (yield: 76%) (yield: 76%). mp NMR (CD3OD, 500 MHz), δ: 7.34-7.24 (m, 6H), 7.04-7.00 (m, 1 Η), 6.94-6.91 (m, 1 Η), 6.7 1 (s, 2H), 4.95-4.93 (m, 1H), 3.62-3.46 (m, 4H), 3.38-3.19 (m, 3H), 3.03 ( Br t, 1H, J - 12.0 Hz), 2.96 (t, 1H, J = 12.2 Hz), 2.91-2.86 (m, 1H), 2.15-2.12 (m, 3H), 2.03- 1.99 (m, 1H), 1.8 6- 1.78 (m, 1H), 1.7 5 - 1.69 (m, 1H), 1.61-1.54 (m, 2H), • 1.35 (br s,6H), 0.97-0.9 3 (m, 6H). Mass spectrum (FAB + ), m/z: 509 ((M + H) +). (Example 3 2 ) (3S,5R) -5-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-&gt ;^-[(11〇-1-(5-fluoropyridin-2-yl)-3-methylbutyl]piperidine-3-carboxamide anti-butenediate m -109 201107306

F (32a) tert-butyl (3R,5S) -3-[4-(5-fluoro-2-methylphenyl)-2,2-methyl-5-piperidone-1-yl] -5- { [ ( 1R) · ΐ _ ( 5-fluoroindole · 2 · yl) - 3 - methyl butyl] amine carbhydryl} piperidine - hydrazine - residue obtained in Example (28d) (3S,5R)-1-(tertiary butoxycarbonyl)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone 1-1-yl] piperidine-3-carboxylic acid 301 mg (0.65 mmol), (ir)-1-(5-fluoroindole-deep-2-yl)-3-methylbutylate obtained in Reference Example 17 1-amine 2 hydrochloride 332 mg (1.30 mmol) and -isopropylethylamine 453 μl (2·60ιηιηο1) in N,N-dimethylformamide (6.5 ml), under ice cooling, add hydrazine - (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) 2 96 mg (0.7 8 mm 〇l), stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/1 to 0/1) and oxime column chromatography (dissolving solvent: η- The residue was purified to give the title compound (yield: EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: ), 7.3 9-7.3 5 (m, 1H), 7.26-7.18 (m, 2H), 6.96-6.91 (m, 1H), 6.85-6.80 (m, 1H), 6.46 (br d,1H,J = 8.2 Hz), 5.13 (br q, 1H, J = 7.8 Hz), 4.29-4.00 (m, 2H), 3.70-3.48 (m, 2H), 3.35 (br d, [S] -110- 201107306 1H, J = 10.5 Hz), 3.18-3.14 (m, 1H), 2.96-2.69 (m, 3H), 2.39 (br s, 1H), 2.18 (s, 1.5H), 2.14 (s, 1.5H), 1.88 (br s , 2H), 1.70-1.28 (m, 18H), 0.95 -0.92 (m, 6H) (32b) (3S,5R) -5-[4-( 5-fluoro-2-methylphenyl)-2 ,2-Dimethyl-5-piperidin-1-yl]-N-[( ir)-丨·( 5-fluoropyridin-2-yl)-3-methylbutyl]piperidin-3- The third butyl (3R,5S)-3-[4-(5-cyclo-2.methylphenyl)-2,2- obtained from the carbamide-fumarate salt of Example (32a) —methyl-5-piperidone-1-yl] -5-{ [( 1R) -1-® (5-fluoropyridin-2-yl)-3-methylbutyl]amine-carbamoyl}piperidine-i-carboxylate 247 mg (0.39 mmol) In a solution of chloromethane (1.2 ml), 0.25 μl (7.8 mmol) of trifluoroacetic acid was added and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a NH(s) gel column (solvent solvent: dichloromethane/methanol = 2 0/1 to 7) /3) Purification to obtain (33,51〇-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidin-1-yl]-1 ^-[(]11)-1-((5-fluoropyridin-2-yl)-3-methylbutyl]piperidine-3-carboxamide 165 mg (yield: 80%). (3S,5R)-5-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-piperidone-1-yl]-&gt; 1-[(111)-1-(5-fluoropyridin-2-yl)-3-methylbutyl]piperidine-3-carboxamide 165 mg (0.31 mmol) in methanol (3 ml) 36 mg (0-31 mmol) of butyric acid was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. Colorless solid. -111- 201107306 H NMR spectrum (CD3〇D, 4〇〇MHz), δ : 8.41 (br s,1H), 7.59-7.52 (m,1H), 7.43 -7.3 8 (m, 1H), 7.31-7.28 (m,1H), 7.04-7.00 (m, 1H), 6.96-6.93 (m, 1H), 6.69 (s, 2H), 5.04 (br dd, 1H, J = 8.4 Hz, 6.5 Hz), 3.64-3.18 (m, 7H), 3.02 (br t, 1H, J = 12.1 Hz), 2.98-2.90 (m, 2H), 2.16-2.07 (m, 4H), 1.89- 1.56 (m, 4H), 1.3 7- 1.3 5 (m, 6H), 0.97 (d, 3H, J = 6.7 Hz), 0.94 (d, 3H, J = 6.7 Hz). Mass spectrum (FAB+), m/z: 528 ((M + H)+). (Reference Example 1) _ (3 R, 5S) -1-(tertiary butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid

(la) 1-tertiary butyl 3,5-dimethylpiperidine-1,3,5-tricarboxylate in methanol (500 ml), added with thionyl chloride 32 ml (441 mmol) &gt; Next, 25.47 g (152 mmol) of pyridine-3,5-dicarboxylic acid was added, and the mixture was stirred under reflux for 6 hours. The reaction mixture was evaporated under reduced pressure to give crude crystals crystals. The obtained mixture of the obtained dimethyl dimethyl sulphate _3,5·diacetate hydrochloride and oxidized platinum (IV) 〇.64 g of acetic acid (2 〇〇 ml) was used in a chlorine atmosphere. Spoiled for 5 days at room temperature. After replacing the hydrogen in the reaction vessel with nitrogen, the platinum catalyst was filtered. The filtrate was concentrated under reduced pressure to azeotrope with toluene and methanol. Dichloromethane (300 ml) was added to the residue to dissolve, and under ice cooling, triethylamine 3 2 · 〇m 1 -112-201107306 (23 0 mmol) and di-tertiary butyl dicarbonate 3 6 · 0 1 were added. g (1 6 5 mm ο 1 ), stirred at room temperature for 3 hours. After completion of the reaction, the insoluble material was filtered off and washed with hexane and ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the insoluble material was filtered again. The filtrate was concentrated under reduced pressure. EtOAc m.jjjjjjjj White solid. NMR spectrum (CDC13, 400 MHz), δ: 4.58-4.10 (1.4H, m), 3.70 (6H, s), 3.84-3.3 5 ( 1 H, m), 2.88-2.56 (2H, m), 2.55- 2.34 (2H, m), 2.20-1.93 (0.6H, m), 1.76- 1.56 (1 H, m), 1.46 and 1.45 (total 9H,each s) o (lb) 1-(tertiary butoxycarbonyl) Piperidine-3,5-dicarboxylic acid 1-1,4-tert-butyl 3,5-dimethylpiperidine-1,3,5-tricarboxylate obtained in Reference Example (la) 45.0 g (149 mmol) To a solution of methanol (600 ml) and water (150 ml), 60.3 g (436 mmol) of potassium carbonate was added, and the mixture was stirred under reflux for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. &lt;EMI ID=9.1&gt; The obtained solid was washed with water and diisopropyl ether and dried to give the title compound 30.0 g (yield: 74%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), δ: 4.32 (2Η, br d, J = 9.8 Hz), 2.80-2.64 (br, 2H), 2.49-2.40 (m, 3H), 1.68-1.60 (m, 1 Η), 1.47 (s, 9H). (lc) (3R,5S)-1-(tertiary butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid [S] -113- 201107306 obtained by reference example (lb) The 1-(tris-butoxycarbonyl)piperidine-3,5-dicarboxylic acid 22.398 (81.9111111〇1) was dissolved in acetic anhydride (2001111) and stirred at 1001 for 10 hours. After cooling at room temperature, the reaction mixture was evaporated under reduced pressure to give crude tris-butyl 2,4-di- oxy-3-oxa-7-indole bicyclo[3,3,1] decane. -7-carboxylate 21.13 g. The crude tertiary butyl 2,4-di-oxy-3-oxa-7-indolebicyclo[3,3,1]nonane-7-carboxylate thus obtained was obtained as a solution of 21.13 g of tetrahydrofuran (82). In a solution of 0 ml), under cooling at -20 ° C, add N-[(9S) -6'-methoxy deoxycinchonine (cinchonane)-9-yl]-3,5-•bis(trifluoroa) Benzene guanamine (Angew. Chem. Int. Ed., 2008, Vol. 47, Asymmetric Organic Catalyst 1 described in ρ. 7872) 7.45 g ( 12.4 mm 〇l) and methanol 33.5 ml ( 827 mmol) Stir at the same temperature for 20 hours. 1N Hydrochloric acid (300 ml) was added to the reaction mixture to make it acidic. After returning to room temperature, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel column chromatography (solvent: · 3 5 g (2 steps total yield: 8 1 %). ^(3R,5S)-1-(tertiary butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid obtained for analysis using an optically active HPLC column [ChiralPakAD-H ( 0.46 cm x 25 cm), manufactured by DAICEL, solvent: η-hexane/ethanol = 95/5, flow rate: 0.5 ml/min)] determines the optical purity. The retention time of the intended (3R,5S) body was 29.6 minutes, the retention time of the corresponding isomer (33,511) was 33.3 minutes, and the optical purity was 96%66. (3 R,5S) -1-(tertiary butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid obtained by forming (R)-phenethylamine in ethanol The salt can be recrystallized from ethanol by the obtained (R)-phenethylamine salt to obtain (3R,5S)-1 (tris-butoxycarbonyl) having a purity of 99% or more. · 5. (Methoxycarbonyl) piperidine-3 -carboxylic acid. Colorless solid. H NMR spectrum (CDC1 3,500 MHz), δ: 4 37 ... s, 2 Η), 3 71 (s, 3 Η), 2.72 (br s, 2 Η), 2.5 5 - 2.45 (m, 3H), 172 (q, 1Η,] = 12.7 Hz), 1.47 (s, 9H). (Reference example 2)

(3R)-5-Methylhexyl-3-amine hydrochloride HCI (2a) tert-butyl [(IS)-3-methylvinylbutyl]carbamate in secondary butyl [ (1S) -1-(hydroxymethyl)·3-methylbutyl]carbamic acid vinegar 1.50 g (6.9 mmol) and triethylamine 2 8 8 ml (2〇7mm〇i) of dimethyl sulfoxide (In a solution of 15 m ', add sulfur trioxide, and a solution of 3.3 〇g (20.7 mm 〇1) of dimethyl hydrazine (ISnU) in a cold solution, and stir at the same temperature for 1 。 minutes. After injecting into ice water and extracting it with diethyl ether for 3 times, the organic layer was washed with 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain hydrazine. The crude butyl [(IS)-1-methylenyl 3-methylbutyl]carbamate is preserved. The tertiary butyl [(IS) - h-methyl thiol group obtained here] To a solution of 3-methylbutyl]carbamate in toluene (Uml), 5.70 g (20.7 mmol) of methylenetriphenylphosphine was added under ice cooling, followed by stirring at room temperature - night. Add water, extract with ethyl acetate, and then organic layer with saturated brine m -115- 2011 After washing with 07,304, it was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (solvent solvent: hexane-hexane/ethyl acetate = 9/1 to 4/1). Purification, the title compound was obtained (yield::::::::::::::::::::::::::::::::::::::::::::::::::::::: 1H, J = 17.6 Hz), 5.06 (br d, 1H, J = l〇·3 Hz)&gt; 4.38 (br s,1H), 4.14 (br s,1H),1.72-1.64 (m,1H), 1.44 (br s, 9H), 1.3 6- 1.30 (m, 2H), 0.93-0.91 (m, 6H) (2b) (3R) -5-methylhexane-3-amine hydrochloride will be referred to (2a) obtained tertiary butyl [(IS) -3-methyl-1 - vinylbutyl] carbazate 〇. 86g (4.0mm 〇l) and 10% palladium carbon (including 50% Water) 430 mg of a mixture of methanol (30 ml) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After replacing the hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered. The filtrate was concentrated under reduced pressure. Crude tertiary butyl [(1R)-1-ethyl-3-methylbutyl]carbamate. The crude tertiary butyl [(1R)-1-ethyl-) obtained herein. 3-methylbutyl]amine Carboxylate of dichloromethane (10ml) was added trifluoroacetic acid 5ml (65mm〇l) 'was stirred at room temperature for 10 minutes. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane, the organic layer was washed with 1 N aqueous sodium hydroxide and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and 2 ml (8 mmol) of 4N hydrochloric acid-di-diamine solution was added to the residue, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the solid was crystallised, washed with ethyl acetate, and dried to give the title compound (yield: m Colorless solid. -116- 201107306 NMR spectrum (CDC13, 500MHz), δ: 8.34 (br s, 3H), 3.22-3.16 (m, 1H), 1.92-1.84 (m, 1H), 1.80- 1.64 (m, 3H), 1.50 - 1.44 (m, 1H), 1.08 (t, 3H, J = 7.8 Hz), 0.95-0.93 (m, 6H). (Reference Example 3) 1-Isobutylcyclopentan-1-amine hydrochloride

To a solution of 5.8 ml (41.3 mmol) of diisopropylamine in tetrahydrofuran (40 ml), n-butyllithium η-hexane solution (1.6 mol/l) 26.4 ml was added under ice for 15 minutes under ice cooling. (42.2 mmol) was stirred at the same temperature for 15 minutes to prepare a lithium diisopropyl decylamine (LDA) solution. The LDA solution was cooled in a dry ice-acetone bath, and 5.30 g (37.4 mmol) of ethyl cyclopentanecarboxylate was added over 5 minutes, and stirred at the same temperature for 40 minutes. Next, 7.60 g (41.3 mmol) of iodine isobutane and 8 m of hexamethylenephosphonate (HMPA) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give EtOAc (EtOAc, m. The crude ethyl 1-isobutylcyclopentane-1-carboxylate obtained by the previous reaction was added to a mixture of 18.60 g (166 mmol) of butyl succinimide and 0.74 ml (41 mmol) of water in tetrahydrofuran (150 ml). A solution of 4.11 g (20.8 mmol) of tetrahydrofuran (50 ml) was stirred at room temperature for 4 hr. To the reaction mixture, 1N hydrochloric acid was added to make acidity, and ethyl acetate was evaporated. The organic layer was washed with brine (S1 • 117 - 201107306) and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to give a crude 1-isobutylcyclopentane-1-carboxylic acid (4.1 g). A solution of 4.0 g (20.2 mmol) of crude 1-isobutylcyclopentane-1-carboxylic acid (86%) obtained in this reaction and 3.4 ml (24.4 mmol) of toluene (45 ml) of triethylamine. 7.10 g (25.8 mmol) of diphenylphosphonium hydride (DPPA) was added, and the mixture was stirred at room temperature for 30 minutes, followed by stirring at 90 ° C for 1 hour. To the reaction mixture, 4.8 ml (44 mmol) of benzyl alcohol was added at 90 ° C, and stirred at 90 ° C for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with EtOAc. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/0 to 4/1) to give benzyl (1-isobutyl) Cyclopentyl)carbamate 4.5 g (3 steps overall yield: 71%). A mixture of 4.5 g (16.3 mmol) of benzyl (1-isobutylcyclopentyl)carbamate obtained herein with 1.5% methanol (60 ml) of 20% palladium hydroxide-carbon (containing 50% water) The mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After replacing the hydrogen in the reaction vessel with nitrogen, the palladium catalyst is filtered. To the filtrate, 8.2 ml (32.4 mmol) of 4N salt acid and dioxane was added, and the solvent was evaporated. Ethyl acetate was added to the residue, and the solid was crystallised, washed with ethyl acetate, and dried to give the title compound 1.50 g (yield: 52%). Colorless solid. H NMR spectrum (CD3OD, 500 MHz), δ: 1.86-1.75 (m, 9H), 1.66 (d, 2H, J = 5_9 Hz), 1.02 (d, 6H, J = 6.8 Hz). (Reference Example 4) 4,4,4-Trifluoro-2-methylbutan-2-amine hydrochloride [S] -118- 201107306

F F

Nh2 hci in a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate 5.0 (^(25_4111111〇1) in ethanol (25 ml)-water (25 ml), 2N aqueous potassium hydroxide solution 50 ml (100 mmol), and the mixture was stirred at 60 ° C for 4 days. The reaction mixture was poured into 1 N hydrochloric acid to give acid, and ethyl acetate was evaporated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to give crude 4,4,4-trifluoro-2,2-dimethylbutyric acid (5) (yield: crude 4,4,4-trifluorobenzene obtained in this reaction. -2,2-Dimethylbutyric acid (86% content) 5.00 g (25_4 mmol) and triethylamine 4.2 ml (30.2 mmol) in toluene (60 ml), added diphenylphosphonium azide (DPPA) 8.90 g (32.3 mmol), stirred at room temperature for 30 minutes, and then stirred at 90 ° C for 1.5 hours. To the reaction mixture, 6.0 ml (5 5 mmol) of benzyl alcohol was added at 90 ° C, and stirred at 90 ° C. 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried and evaporated. Chromatography Solvent: η-hexane/ethyl acetate = 1/0 to 4/1) Purification of the residue ' Obtained benzyl (3,3,3-trifluoro-1,1-dimethylpropyl) carbamic acid 6.40 g of ester (2 step total yield: 92%). Benzyl (3,3,3-trifluoro-1,1-dimethylpropyl) carbamic acid acetate obtained here 6.40 g (23_2 mmol) Mixture with 20% carbonic acid carbon (containing 50% water) 2.00g of methanol (80ml), stir under hydrogen atmosphere for 3 hours at room temperature, β replace the hydrogen in the reaction vessel with nitrogen, and then filter the catalyst. Add the 4 Ν hydrochloric acid-二曙院 12ml (48mmol)' to remove the solvent. Add m-119- 201107306 to the residue. After the water layer is washed with diethyl acid, add 1 N sodium hydroxide solution as alkali. After extracting with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, 4N hydrochloric acid-dioxane 6 ml (24 mmol) was added to the filtrate, and the solid was separated by filtration. Ethyl ether was washed and dried to give the title compound (1.10 g (yield: 51%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; d, 1H, J = 11.2 Hz), 1.50 (s 6H). (Reference Example 5) N, N- dimethyl-acyl -L- leucine hydrochloride

〇丫人NH2 HCI human in N-tertiary butoxycarbonyl-L-leucine 1 hydrate 600mg ^ (2.41mmol) in dichloromethane (8ml), under ice cooling, add 1-hydroxybenzotriene Azole 1 hydrate 369 mg (2.41 mm 〇l), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) hydrochloride 509 mg (2.66 mmol) and dimethylamine A solution of tetrahydrofuran (2.0 mol/l) 2.60 ml (5.20 mmol) was stirred at room temperature for 2.5 hours. To the reaction mixture, 0.5N hydrochloric acid was added, and the mixture was evaporated to dichloromethane. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: methylene chloride / methanol = 100/1 to 50/1) to obtain N2-(tris-butoxycarbonyl) ] -120- 201107306 base) - N,N-dimethyl-L-leucine guanamine 538 mg (yield: 87%). a solution of 538 mg (2.08 mmol) of N2-(tertiary butoxycarbonyl)-N,N-dimethyl-L-leucineamide obtained in 1,4-dioxane (3.0 ml). After adding 4 ml of a 4N hydrochloric acid-dioxane solution (12 mmol), the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give the title compound (yield: 95%). Colorless solid. iNMR spectroscopy (DMSO-d6, 500MHz), δ: 8.44-8.02 (m, 3H), 4.34-4.22 (m, 1H), 3.01 (s, 3H), 2.88 (s, 3H), 1.84- 1.68 (m, 1H), 1.64-1.42 (m, 2H), 0.92 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H). (Reference Example 6) (2R)-1-Ethoxy-4·methylpentane-2-amine

(6a) (2R)-2-(dibenzylamino)-4-methylpentan-1-ol in (R)-leucinol 5g (42.67mmol) and pre-bromide 11.16ml ( To a solution of 93.87 mmol of ethanol (200 ml), 14.74 g (106.7 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjj ). Colorless liquid. 4 NMR spectrum (CDC13, 400 MHz), δ: 7.33.7.21 (m, 10H), 201107306 3.81 (d, 2H, J = 13.3 Hz), 3.48 (dd, 1H, J = 10.6 Hz, 5.1 Hz), 3.42 ( d, 1H, J = 10.6 Hz), 3.37 (d, 2H, J = 13.3 Hz), 3.19 (br s, 1H), 2.84 (ddt, 1H, J = 9.8 Hz, 5.1 Hz, 2.4 Hz), 1.55- 1.46 (m, 2H), 1.20-1.11 (m, 1H), 0.92 (d, 3H, J = 6.3 Hz), 0.86 (d, 3H, J = 6.3 Hz). (6b) (2R)-N,N-Dibenzyl-1-ethoxy-4-methylpentane-2.amine (2R)-2-(dibenzyl) obtained in Reference Example (6a) Amino)-4-methylpentan-1-ol 2.00 g (6.72 mmol) and a solution of 7 ml (8.74 mmol) in tetrahydrofuran (30 ml): at room temperature &gt; Sodium hydride (60% content) 349 mg (8.74 mmol) was added in a minute and stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel column chromatography (yield: hexanes: 81%). Colorless liquid. # WNMR spectroscopy (CDC13, 400MHz), S: 7.37 (brd, 4H, J = 7.4 Hz), 7.30-7.26 (m, 6H), 7.22-7.17 (m, 4H)} 3.75 (d, 2H J =13.7 Hz ), 3.66-3.61 (m, 3H), 3.45 (q, 2H, J = 7.0 Hz) 3 38 (dd, 1H, J = 9.8 Hz, 5.1 Hz), 2.89-2.83 (m, 1H), 1.84- 1.74 (m 1H), 1.46 (ddd, 1H, J = 13.7 Hz, 8.2 Hz, 5.4 Hz), 2.22 (t 3H J = 7.0 Hz), 1.10 (ddd, 1H, J = 13.7 Hz, 8.2 Hz, 5.4 Hz) , 0.82 (d, 3H, J = 6.3 Hz), 0.59 (d, 3H, J = 6.3 Hz). (6c) (2R) -1·ethoxy-4-methylpentan-2-amine (2R)-N,N-dibenzyl-κethoxy[S) obtained in Reference Example (6b) -122- 201107306 -4-methylpentane-2-amine 1.78g (5.47mmol) and 20% palladium hydroxide carbon (containing 50% water) 3 60mg methanol (25ml) mixture, under 1MPa hydrogen atmosphere, Stir at room temperature for 6 hours. After replacing the hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered. The filtrate was concentrated under reduced pressure to give title compound (yield: 98%). Colorless liquid.

4 NMR spectrum (CDC13, 500 ΜΗζ), δ: 3.55-3.45 (m, 2H), 3.39 (dd, 1H, J = 9.0 Hz, 3.7 Hz), 3.12 (t, 1H, J = 8.6 Hz), 3.05 -3.00 (m, 1H), 1.7 7- 1.69 (m, 1H), 1.22-1.13 (m, 5H), 0.93 (d, 3H, J = 6.8 Hz), 0.90 (d, 3H, J = 6.8 Hz). (Reference Example 7) 2-(4,4-Difluorocyclohexyl)propan-2-amine

(7a) benzyl [1-methyl-1·(4-oxocyclohexyl)ethyl]carbamate in diisopropylamine 3.66 ml (26.3 mmol) in tetrahydrofuran (50 ml) Under ice-cooling, add η-butyllithium η-hexane solution (1.6 mol/l) to 16.5 ml (26.3 mmol) in 15 minutes, and stir at the same temperature for 10 minutes to prepare lithium diisopropyl decylamine. (LDA) solution. The LDA solution was cooled in a dry ice-acetone bath to add a solution of 5 g (21.9 mmol) of ethyl (丨,4-dioxaspiro[4,5]indole-8-yl)acetate in tetrahydrofuran (50 ml). After stirring at the same temperature for 1 hour, iodomethane i.WmiUGJ mmol) was added and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was again cooled in a dry ice-acetone bath, and 201107306 was added to a solution of 3.66 ml (26.3 mmol) of n-butyllithium in n-hexane (1.6 mol/l) 16.5 ml (26.3 mmol). The LD A solution prepared in tetrahydrofuran (50 ml) was stirred at the same temperature for 1 hour, then 1.63 ml (26.3 mmol) of methyl iodide was added and stirred at room temperature for 1 hour. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, and ethyl acetate was evaporated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/0 to 7/3) to obtain ethyl 2- (1, 4) - Dioxaspiro[4,5]dec-8-yl)-2-methyl-propionate 3_84 g (yield: 68%). Ethyl 2-(1,4-dioxaspiro[4,5]fluoren-8-yl)-2-methylpropanoate obtained in this reaction 3.84 g (15.0 mmol) of tetrahydrofuran (15 ml) - A solution of 8.4 g (149.8 mmol) of potassium hydroxide in water (15 ml) was added to a solution of methanol (15 ml), and the mixture was stirred under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was concentrated, and 5N hydrochloric acid was added to the mixture, and the mixture was applied to dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give crude 2-(1,4-dioxaspiro[4,5]indole-8-yl)-2-methylpropanoic acid. The crude 2-(1,4-dioxa*[4,5]fluoren-8-yl)-2-methylpropanoic acid obtained in this reaction and 2.7 ml (19.5 mmol) of toluene of triethylamine ( To the solution, 4.53 g (16.5 mmol) of diphenylphosphonium azide (DP PA) was added, stirred at room temperature for 30 minutes, and then stirred at 901 for 2.5 hours. To the reaction mixture, 3.1 ml (30 mmol) of a prenethanol was added at 90 ° C, and the mixture was stirred at 90 ° C for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent-124-201107306: η-hexane/ethyl acetate = 1/0 to 1/1) to obtain a benzyl group [ 1-(1,4-Dioxaspiro[4,5]dec-8-yl)-1·methylethyl]carbamate with benzyl [1-methyl-1-(4_ side) A mixture of oxycyclohexyl)ethyl]carbamate. Benzyl [1-( 1,4-dioxaspiro[4,5]indole-8-yl)-1-methylethyl]carbamate obtained by this reaction and benzyl [1- A solution of a mixture of methyl-1-(4-oxocyclohexyl)ethyl]carbamate in 80% aqueous acetic acid (100 ml) was stirred at room temperature for 16 hours and then at 60 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3 steps total yield: 3 1 %). 4 NMR spectrum (CD3OD, 500MHz), δ: 7.38-7.31 (m, 5H), 5.06 (br s, 2H), 4.69 (br s, 1H), 2.56-2.32 (m, 5H), 2.06-2.04 (m , 2H), 1.51-1.42 (m, 2H), 1.30 (s, 6H). (7b) 2-(4,4·Difluorocyclohexyl)propan-2-amine benzyl [1-methyl-1-(4-o-oxycyclohexyl)ethyl group obtained in Reference Example (7a) A solution of 730 mg (2.52 mmol) of urethane in dichloromethane (25 ml) was added to a solution of sulfur triethylamine trifluoride (D AST ) 0.67 ml (5Ommol) under ice cooling. Stir for 6 hours. The mixture was extracted with a saturated aqueous solution of sodium hydrogencarbonate and aqueous sodium thiosulphate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1 / 〇~4/1) to obtain benzyl [丨-(4, 4_Difluorocyclohexyl)-1_methylethyl]carbamic acid-125- 201107306 Ester 444 mg (yield: 57%). 232 mg (0.75 mmol) of benzyl [1-(4,4-difluorocyclohexyl)-1-methylethyl]carbamate obtained in this reaction, methylene chloride (4 ml) Next, 127 μl (0.89 mmol) of dimethyl iodide was added and stirred at the same temperature for 30 minutes. To the reaction mixture, trimethyl decane iodide (1 〇〇. 70 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate and aq. The aqueous layer was made basic with a 5N aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystal crystal crystal crystal crystal NMR spectrum (CD3OD, 500MHz), δ: 2.18-2.10 (m, 2H), 1.89-1.84 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.21 (m, 3H), 1.08 (s, 6H). (Reference Example 8) ^ 2·(tetrahydro-2H-piperidin-4-yl)propan-2-amine

To a solution of 500 mg (2.90 mmol) of 2-methyl-2-(tetrahydro-2H-piperidin-4-yl)propanoic acid and triethylamine hydrazine - 45 ml (3.2 mmol) in toluene (14 ml) Phenylphosphonium azide (DPPA) 〇.68 ml (0.68 mmol), stirred at room temperature for 30 minutes, then stirred at 90 ° C for 30 minutes. The reaction mixture was stirred at 9 °C (6 ml (5.8 mmol) of benzyl alcohol) and then stirred at 90 ° C for 12 hours. After cooling, water was added to the reaction mixture -126-201107306 and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give crude benzyl [[sup]]-methyl-1-(tetrahydro-2H-pyran-4- ))ethyl]carbamate 597 mg. The crude benzyl [1-methyl-1-(tetrahydro-2H-piperidin-4-yl)ethyl]carbamate 59 thus obtained A mixture of 7 m g (2.1 mmol) and 20% palladium hydroxide-carbon (containing 50% water) in 60 mg of methanol (1 〇ml) was stirred at room temperature for 13 hours under a hydrogen atmosphere. The hydrogen in the reaction vessel was replaced by After nitrogen, the palladium catalyst was filtered, and the filtrate was concentrated to give the title compound (yield: 67%) (yield: 67%). NMR spectrum (CD3OD, 500 MHz), δ: 4.05-4.02 (m, 2H), 3.3 8 -3.3 4 (m, 2H), 1.65- 1.5 5 (m, 3H), 1.41-1.35 (m, 2H), 1.07 (s, 6H) (Reference Example 9) 1-Benzene Cyclopentane-1-amine hydrochloride

S] a solution of 5.0 g (26.3 mmol) of 1-phenylcyclopentane-1-carboxylic acid and 3.8 ml (27. 3 mmol) of toluene (50 ml) of triethylamine, and added diphenylphosphonium azide ( DPPA) 7.90 g (28.7 mmol), stirred at room temperature for 30 minutes, then stirred at 90 ° C for 1 hour. To the reaction mixture, 5.4 ml (50 mmol) of benzyl alcohol was added at 90 ° C, and the mixture was stirred at 90 ° C for 5 hours. After cooling, water was added to the reaction mixture, and the mixture was evaporated. After filtration, the solvent was distilled off under reduced pressure, and purified by chromatography on silica gel column (solvent solvent: η-hexane/ethyl acetate = 1/0 to 4/1) -127 - 201107306 The residue was purified to give benzyl ( -Phenylcyclopentyl)carbamate 7.8 〇g (yield: quantitative). The obtained benzyl (1-phenylcyclopentyl) carbamate 7.8 g (26.3 m mol) and 20% palladium hydroxide-carbon (containing 50% water) 3.00 g of methanol (20 0 ml) The mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After replacing the hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered. To the filtrate, 1 3 ml (52 mmol) of 4N hydrochloric acid-dioxane was added, and the solvent was evaporated. Ethyl acetate was added to the residue, and the precipitated solid was filtered, washed with ethyl acetate, and dried to yield 4.30 g (yield: 83%). Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 7.55-7.53 (m, 2H), 7.48-7.44 (m, 2H), 7.41-7.38 (m, 1H), 2.36-2.24 (m, 4H), 2.02- 1.86 ( m, 4H) » (Reference Example 1 0 ) (1R)-2-Cyclopropyl-1-phenylethane-1-amine hydrochloride

(10a) 2-cyclopropyl-1-phenylethanone in a mixture of ethyl-ethyl-n-hexyl solution (l. 〇mol/l) 46ml (46mmol) and dichloroethane (90ml), ice-cold Next, 16.20 g (92.6 mmol) of chloroiodomethane was added over 1.5 hours, followed by dilution with dichloroethane (60 ml) and stirred at the same temperature for 1 hour. To the reaction mixture, 3.37 g (22.7 mmol) of 1-phenyl-3-buten-1-ol was added thereto, and the mixture was stirred at the same temperature for 2 - 128 - 201107306 hours, and then stirred at room temperature for 12 hours. After the mixture was diluted with water and extracted with dichloromethane, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/0 to 7/3) to obtain 2-cyclopropyl-1- Phenylethanol 2.50 g (yield: 68%). (2,1,1-Triethoxymethoxy)-1 was added to a solution of 2.50 g (15. 1-Dihydro-1,2-phenyliodonium-3 (11〇-ketone (〇633-1^1^11 oxidizing reagent) 9.818 ® ( 23.1 mmol), stirred at room temperature for 4 hours. In the reaction mixture, After adding a saturated aqueous solution of sodium hydrogencarbonate and a 1% aqueous solution of sodium thiosulfate, and extracting with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified to give the title compound 2.45 g (yield: 99%) as a colorless liquid. φ 'H NMR NMR </ br> </ br> Spectrum (CDC13, 500MHz), δ: 7.9 6 - 7.9 4 (m, 2 Η), 7.57-7.54 (m, 1H), 7.48-7.45 (m, 2H), 2.89 (d, 2H, J = 6.8 Hz) , 1.21-1.13 (m, 1H), 0.62-0.58 (m, 2H), 0.21-0.18 (m, 2H). (10b) N-[( IE) -2-cyclopropyl-1-phenylene 2-methylpropylpropane-2-sulfinamide 2.14 g (15.4 mmol) and (S)-(- 2-cyclopropyl-phenyl phenyl ethyl ketone obtained in Reference Example (l〇a) ) - Level 3 To a solution of butane sulfinamide 1.64 g (13_5 mm 〇l) in tetrahydrofuran (30 ml), toluene tetraethyl orthotitanate 5.59 g [S] -129 - 201107306 (24.5 tnmol) was added, and the mixture was stirred at 70 ° C for 8 hours. After cooling to room temperature, saturated brine (30 ml) was added to the reaction mixture, and the insoluble material was filtered using celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine to give anhydrous sulfuric acid. After drying, the residue was evaporated to dryness crystals crystals crystals eluted Yield: 68%). Colorless liquid.

NMR spectrum (CDC13, 500MHz), δ: 7.89-7.87 (m, 2H), 7.50-7.42 (m, 3H), 3.25-3.15 (m, 2H), 1.33 (s, 9H), 1.02-0.94 (m, 1H), 0.52-0.43 (m, 2H), 0.37 (br s, 2H). (10c) N-[(lR)-2-cyclopropyl-1-phenylethyl]-2-methylpropane-2- 2-sulfinamide obtained in Reference Example (1 〇b) ( 1 E ) -2-cyclopropyl-1-phenylethylidene]-2-methylpropane-2-sulfinamide 2.43 g (9.23 mmol) in tetrahydrofuran (20 ml), ice cold, A solution of L-Selectride in tetrahydrofuran (1. 〇mol/l) 27 ml (27 mmol) was added over 5 min and stirred at the same temperature for 10 min. After the reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, and then purified to silica gel column (solvent solvent: s-hexane/ethyl acetate = 1 / 〇~3/2). L. 〇〇g (yield: 41%). Colorless liquid. NMR spectrum (CDC13, 5 〇〇 MHz), δ: 7.37-7.25 (m, 5H), 4.52 (dt, 1H, J = 7.0 Hz, 2.2 Hz), 3.76 (br s, 1H), 1.95-1.90 (m , 1H), 1.46 (dt, 1H, J = 13.7 Hz, 7.8 Hz), 1.20 (s, 9H), 0.65 -0.5 7 (m, 1H), 0.54-0.48 (m, 1H), 0.45-0.40 (m , 1H), 0.16-0.11 (m,1H), 0.05-0.01 (m,iH)e -130- 201107306 (10d)(lR)-2-cyclopropyl-1-phenylethane-1-amine salt N-[(1R)-2-cyclopropyl-1-phenylethyl]-2-methylpropane-2-sulfinamide obtained in Reference Example (l〇c) 1.00 g (3.77) A solution of 4% hydrochloric acid in dioxane (2? ml (8.0 mm)) was added to a solution of EtOAc (m. To the reaction mixture, diethyl ether was added, and the solid was crystallized to give the title compound (yield: 94%). Colorless solid.

4 NMR spectrum (CD3OD, 500MHz), δ: 7.49-7.40 (m, 5H), 4.34 (dd, 1H, J = 8.0 Hz, 6.4 Hz), 2.00- 1.95 (m, 1H), 1.77-1.71 (m, 1H)S 0.6 3 -0.5 5 (m, 1H), 0.5 4-0.49 (m, 1H), 0.47-0.41 (m,1H), 0.21-0.16 (m, 1H), 0.08-0.03 (m,1H) . (Reference Example) (1R)-3-Methyl-1-phenylbutan-1-amine hydrochloride

(113) 2-Methyl-1^-[(1£)-3-methyl-1-phenylbutylene]propane-2-sulfinamide in 3-methyl-1-phenylbutanone 3.00 g (18.5 mmol) and (S)-(-)-tertiary butanesulfinamide 2.00 g (16.5 mmol) in tetrahydrofuran (36 ml) were added to tetraethyl orthotitanate 6.82 g (29.9 mmol) Stir at 70-C for 5 · 5 hours. After cooling to room temperature, a saturated aqueous solution of water (35 ml) was added to the mixture, and the residue was filtered, and ethyl acetate was evaporated. The organic layer was washed with saturated m-131 - 201107306 brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystalsssssssssssssss 47%). Colorless liquid. H NMR spectrum (CDC13, 500 ΜΗζ), δ: 7.82-7·80 (ιη, 2Η), 7.48-7.40 (m, 3H), 3.35-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.10- 2.02 (m, 1H), 1.32 (s, 9H), 0.98-0.96 (m, 6H). (lib) 2-methyl-N-[(1R)-3-methyl-1-phenylbutyl]propane-2-sulfinamide 2-methyl-N obtained in Reference Example (11a) -[( 1E) -3-methyl-1-phenylbutylene] propylidene-2 - stimulating amine 2.31g (8.70mmol) in tetrahydrofuran (20ml), added to L- Selectride in tetrahydrofuran solution (1.0 x n〇l/l) 26 ml (26 mmol), and stirred at the same temperature for 1 hour. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc. . Colorless liquid. 'H NMR spectrum (CDC13, 500 MHz), δ: 7.34 - 7.25 (m, 5H), 4.47- 4.43 (m, 1H), 3.33 (br s, 1H), 1.72- 1.63 (m, 2H), 1.48 - 1.40 (m, 1H), 1.16 (s, 9H), 0.94 (d, 3H, J = 6.4 Hz), 0'89 (d, 3H, J = 6.4 Hz) » (lie) ( 1R) -3 - Methyl-1-phenylbutan-1-amine hydrochloride 2-methyl-N-[(1R)-3-methyl-1-phenylbutylpropane obtained in Reference Example (lib) To a solution of -2-sulfinamide 1.93 g ( 7.22 mmol) in methanol (3.6 ml), 3.6 ml ( 14.4 mmol) of 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred at room-132-201107306 for 40 minutes. To the reaction mixture, diethyl ether was added, and the solid was crystallized to give the title compound 1.30 g (yield: 90%). Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 7.49-7.41 (m, 5H), 4.31 (dd, 1H, J = 10.0 Hz, 5.6 Hz), 1.93 (ddd, 1H, J = 15.6 Hz, 10.3 Hz, 5.4 Hz ), 1.81-1.75 (m, 1H), 1.44- 1.36 (m, 1H), 0.96 (d, 3H, J = 6.8 Hz), 0,92 (d, 3H, J = 6.8 Hz). (Reference example 1 2 )

(1R)-1-(2-fluorophenyl)propan-1-amine hydrochloride

Nh2 hci Similarly to the reference example π, 2-fluoropropiophenone was used to obtain the title compound 1 · 10 g (3 step total yield: 4 4 %). Colorless solid. *H NMR spectrum (CD3OD, 400MHz), δ: 7.51-7.45 (m, 2H), 7.3 3 - 7.29 (m, 1H), 7.25-7.21 (m, 1H), 4.47 (dd, 1H, J = 9.3 Hz , 5.9 Hz), 2.12-1.94 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz). (Reference Example 1 3 ) (1R)-1-(3-Fluorophenyl)propane-1-amine hydrochloride

NH2 HCI 1.20 g (3 steps total yield: 48%) colorless solid. [S] -133- 201107306 'HNMR spectrum (CD3OD, 500MHz), δ: 7.52-7.47 (m,1H), 7.27-7.16 (m, 3H), 4.21 (dd, 1H, J = 9.3 Hz, 5.9 Hz) , 2.08 - 1.90 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz). (Reference Example 1 4 ) (1R)-1-(4-Fluorophenyl)propane-1-amine hydrochloride

In the same manner as in Reference Example 1, 1-fluoropropiophenone was used to obtain 1.23 g of the title compound (yield of three steps: 49%). Colorless solid. *H NMR spectrum (CD3OD, 400MHz), δ: 7.50-7.44 (m, 2H), 7.23-7.18 (m, 2H), 4.19 (dd, 1H, J = 9.2 Hz, 5.7 Hz), 2.09-1.8 8 ( m, 2H), 0.89 (t, 3H, J = 7.4 Hz). (Reference Example 1 5 ) (1 R ) -1 -pyridine·2-ylpropane-1 -amine 2 hydrochloride

NH2 2HCI The title compound 4.35 g (3 step total yield: 48%) was obtained by using 1-pyridin-2-ylpropan-1-one. Colorless solid. iHNMR spectrum (CD3OD, 400MHz), δ: 8.83-8.82 (m, 1H), 8.3 6- 8.3 2 (m, 1H), 7.90 (br d, 1H, J = 7.8 Hz), 7.82-7.79 (m, 1H ), 4.57 (t, 1H, J = 7.2 Hz), 2.19-2.03 (m, 2H), 0.97 (t, 3H, [S] -134- 201107306 J = 7.4 Hz). (Reference Example 1 6 ) (1R)-3-methyl-1-pyridin-2-ylbutan-1-amine 2 hydrochloride Λ

2HCI

In the same manner as Reference Example 11, 3-methyl-1-pyridin-2-ylbutane-1-one was used to give the title compound 1. 7. 3 g (3 Steps. Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 8.81-8.79 (m, 1H), 8.28 (dt, 1H, J = 7.8 Hz, 1.5 Hz), 7.86 (br d, 1H, J = 7.8 Hz), 7.75 (ddd , J = 7.8, 5.4, 1 Hz), 4.66 (t, 1H, J = 7.3 Hz), 1.99- 1.8 7 (m, 2H), 1.57- 1.49 (m, 1H), 1.02 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 6.8 Hz). (Reference Example 1 7 ) (1R) -1-( 5 -pyridin-2-yl)-3-methylbutan-1-amine 2 hydrochloride

(17a) 1-(5-Fluoropyridin-2-yl)-3-methylbutan-1-one in a 2-cyano-5-gas ratio to give 3.07 g (25.1 mmol) of tetrahydrofuran (50 ml) In the solution, under cooling with a dry ice-acetone bath, a solution of isobutylmagnesium bromide in tetrahydrofuran (1. 〇mol/l) 32 ml (32 mmol) was added over 20 minutes, stirred at the same temperature for 1 min, at room temperature. Stir for 1.5 hours. In the reaction mixture -135- 201107306, under ice cooling, 2N hydrochloric acid was added. Next, a saturated aqueous sodium hydrogencarbonate solution was added to make a pH of 7 to 8 and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel elution elution elution elution 55%). Colorless liquid. 'HNMR spectrum (CDC13, 500MHz), δ: 8.49 (d, 1H, J = 2.9 Hz), 8.10 (dd, 1H, J = 8.8 Hz, 4.4 Hz), 7.50 (dt, 1H, J = 8.3 Hz, 2.9 Hz), 3.06 (d, 2H, J = 7.3 Hz), 2.34-2.26 (m, 1H), 0.99 (d, 6H, J = 6_8 Hz). (17b) N-[( IE) -1-( 5-fluoropyridin-2-yl)-3-methylbutylene]-2-methylpropane-2-sulfinamide in Reference Example (l7a) 1-(5-fluoropyridin-2-yl)-3-methylbutan-1-one ketone obtained 2.50 g (13.8 mmol) and (S)-tertiary sulfonium sulfinamide 1.67 g (13.8 mmol) To a solution of tetrahydrofuran (65 ml), 6.29 g (27.6 mm 〇l) of tetraethyl orthotitanate was added, and the mixture was stirred at 70 ° C for 17 hours. After cooling to room temperature, a saturated aqueous solution of sodium chloride (35 ml) was added, and the residue was filtered, and ethyl acetate was evaporated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel elution elution elution elution elution %). Colorless liquid. NMR spectrum (CDC13, 500MHz), δ: 8.47 (d, 1 H, J = 2.9 Hz), 8.11 (br s, 1 H), 7.47-7.43 (m, 1H), 3.45 -3.42 (m, 1H), 3.3 0 -3.2 6 (m,1H), 2.18-2.10 (m, 1H), 1.32 (s,9H), m -136- 201107306 0.96-0.95 (m,6H). (17c) N-[(1E)-l-(5-fluoropyridin-2-ylmethylpropane-2-sulfinamide) N-[(1E)yl)-3 obtained in Reference Example (17b) -Methylbutylene]-2-methylpropane-2-C9.63 mmol) in tetrahydrofuran (36 ml) was added to a solution of L-Selectride (1.Omol/1) 11 ml (llmmol) in 5 min. Temperature loss φ A saturated aqueous solution of ammonium chloride was added to the mixture, and ethyl acetate was added thereto, and the organic layer was washed with brine and dried. After filtration, the solvent was evaporated under reduced pressure, and the residue (yield: &lt;RTIgt;&lt;/RTI&gt;&gt; Colorless liquid. NMR spectroscopy (CDC13, 400 ΜΗζ), δ :: Hz), 7.36 (dt, 1H, J = 8.6 Hz, 2.7 Hz),, 丨• 4.55 (dt, 1H, J = 7.4 Hz, 5.5 Hz), 3.73 (br 1.84- 1.72 (m, 2H), 1.54- 1.44 (m, 1H), 1.1 3H, J = 6.7 Hz), 0.91 (d, 3H, J = 6.7 Hz) (17d) ( 1R) -1- ( 5- Fluoropyridin-2-yl)-hydrochloride N-[(1R)-yl)-3-methylbutyl]-2-methylpropan-2-pyrenesulfonate obtained in Reference Example (17c) A solution of the amine in methanol (20 ml) was stirred at room temperature for 2 hr. In the reaction: )-3-methylbutyl]-2-yl-(5-fluoropyridine-2-sulfinamide 2.74g J, dry ice-acetone bath in tetrahydrofuran solution I mixed for 30 minutes. After the water was digested, it was subjected to column chromatography on anhydrous sodium sulfate (solvent purification to obtain titled 8.4 3 (d, 1 H, J = 2_7 7.29-7.26 (m, 1H), d, 1H, J = 5.5 Hz), 5 (s, 9H), 0.95 (d, o 3-methylbutan-1-amine 2 -1- (5 - gas chlorhexidine-2-2.10g (7.33mmol) dioxane solution 20ml The mixture was added with diethyl ether (S1 - 137 - 201107306), and the solid was crystallized to give the title compound 1.92 g (yield: quantitative). Colorless solid. *11 NMR spectrum (CD3OD, 500 MHz), δ: 8.56 (d, 1H, J = 2.9 Hz), 7.67 (dt, 1H, J = 8.6 Hz, 2.9 Hz), 7.53 (dd, 1H, J = 8.8 Hz, 4.4 Hz), 4.51-4.48 (m, 1H), 1.86 (ddd , 1H, J = 13.7 Hz, 8.3 Hz, 6.4 Hz), 1.76 (ddd, 1H, J = 13.7 Hz, 7.8 Hz, 6.4 Hz), 1.51-1.43 (m, 1H), 1.00 (d, 3H, J = 6.4 Hz), 0.94 (d, 3H, J = 6_4 Hz) φ (Reference Example 1 8 ) (1R )-1-pyridin-3-ylpropan-1-amine 2 hydrochloride if^V^NH2 2HCI , In the same manner as in Reference Example 1, 1, pyridin-3-yl group was used. Propane-1 ketone, 1.51 g of the title compound.

NMR spectrum (CD3OD, 500MHz), δ: 9.11 (d, 1H, J = 2.0 Hz), 8.99- 8.98 (m, 1H), 8.82 (dt, 1H, J = 8.3 Hz, 1.7 Hz), 8.24 (dd, 1H, J = 8.3 Hz, 5.9 Hz), 4.62 (dd, 1H, J = 8.6 Hz, 6.6 Hz), 2.24 - 2.07 (m, 2H), 0.99 (t, 3H, J = 7.6 Hz). (Reference Example 1 9 ) (1 R ) - 3 -Methyl-1 -pyridin-3-butane-1 -amine 2 hydrochloride [S] -138- 201107306

In the same manner as Reference Example 11, 3-methyl-1-pyridin-3-ylbutane-1·one was used to give the title compound 2.20 g (yield: 38%). Colorless solid.

HNMR spectrum (CD3OD, 500MHz), δ: 9.16-9.15 (m, 1H), 8.99-8.98 (m, 1H), 8.87-8.84 (m, 1H), 8.24 (dd, 1H, J = 8.3 Hz, 5.9 Hz), 4.76 (dd, 1H, J = 8.8 Hz, 6.8 Hz), 2.07- 1.96 (m, 2H), 1.54- 1.46 (m, 1H), 1.01 (d, 3H, J = 6.8 Hz), 0.99 ( d, 3H, J = 6.8 Hz). (Reference Example 20) (1R)-1-(5-fluoropyridin-3-yl)-3-methylbutan-1-amine 2 hydrochloride

(20a) 1-(5-fluoropyridin-3-yl)-3-methylbutan-1-one in 2,6-dichloro-5-fluoro-sulphuric acid chloride 1 6.6 g (68 mmol) and hydrazine, To a solution of 9.94 g (102 mmol) of methylene chloride ( 340 ml), m.p. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: π-hexane/ethyl acetate = 1/1 to 0/1) to obtain 2,6-dichloro-5. -Fluoro-N-methoxy[S]-139- 201107306 Base-N-methylnicotinate decylamine 17.3 g (yield: 99%). 17.3 g (68.3 mmol) of 2,6-dichloro-5-fluoro-N-methoxy-N-methylnicotinamide obtained in the reaction and 2.0 g of 10% palladium carbon (50% aqueous) To a mixture of ethanol (200 ml), 21.53 g (341.5 mmol) of ammonium formate and 8 ml (212 mmol) of formic acid were added, and the mixture was stirred at 65 ° C for 7 hours. The reaction mixture was returned to room temperature and the palladium catalyst was filtered. Ethyl acetate was added to the filtrate for dilution, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: η-hexane/ethyl acetate® = 1/1 to 0/1) to obtain 5-fluoro-indole- Oxy-indole-methylnicotinate decylamine 7.20 g (yield: 57%). The solution of 5-fluoro-N-methoxy-N-methylnicotinate decylamine obtained in the reaction was cooled in a dry ice-acetone bath with a solution of 3.50 g (19.0 mmol) of tetrahydrofuran (50 ml). A solution of tetrabutylammonium bromide in tetrahydrofuran (1.0 mol/l) in 24 ml (24 mmol) was added over 20 minutes, and the mixture was stirred at room temperature for 10 minutes and then stirred at room temperature for 1.5 hours. The reaction mixture was cooled to -20 ° C, and a solution of isobutylmagnesium bromide in tetrahydrofuran (1. 〇mol/l) 21 ml (2 lmmol) was added over 20 minutes, followed by stirring at room temperature for 1 hour. To the reaction mixture, a saturated aqueous solution of ammonium chloride and an appropriate amount of water were added, and ethyl acetate was evaporated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjj :9% ). Colorless liquid.

SI 1H NMR spectrum (CDC13, 500 MHz), δ: 8.98 (t, 1H, J = 2.0 Hz), 8.65 (d, 1H, J = 2.9 Hz), 7.91 (ddd, 1H, J = 8.8 Hz, 2.9 Hz, 2.0 Hz), 2.86 (d, 2H, J = 6.8 Hz), 2.36-2.28 (m, 1H), 1.02 -140- 201107306 (d, 6H, J = 6.8 Hz). (20b) (1R)-1-(5-fluoropyridin-3-yl)-3-methylbutan-1-amine 2 hydrochloride was obtained in the same manner as in Reference Example 1 1 using Reference Example (20a). 1-(5-Fluoropyridin-3-yl)-3-methylbutan-1-one gave the title compound 242 mg (yield: 3). Colorless solid. NMR spectrum (CD3OD, 500MHz), δ: 8.18 (d, 1H, J = 2.0 • Hz), 8.67 (br s, 1H), 8.03 (dt, 1H, J = 8.8 Hz, 2.0 Hz), 4.58 (dd, 1H, J = 9.3 Hz, 6.4 Hz), 2.00 - 1.94 (m, 1H), 1.91-1.86 (m, 1H), 1.49-1.41 (m, 1H), 0.99 (d, 3H, J = 6.4 Hz), 0.97 (d, 3H, J = 6.8 Hz). (Reference example 2 1)

(1R)-1-pyridin-4-ylpropan-1-amine 2 hydrochloride NH2 2HCI The title compound 3.46 g (3. Total yield of steps: .66%). Colorless solid. 1H NMR spectrum (CD3OD, 500MHz), δ: 9.00-8.99 (m, 2H), 8.20-8.19 (m, 2H), 4.64 (t, 1H, J = 7.3 Hz), 2.18-2.00 (m, 2H), 1.00 (t, 3H, J = 7.3 Hz). (Test Example 1) Renin activity inhibition test m - 141 - 201107306 The ratio of angiotensin I production after the addition of human renin and synthetic renin matrix reaction at 37 °C was measured as renin activity. Human renin was transiently expressed in 293 T cells, and its culture supernatant was used as an enzyme source. After the prepared culture supernatant is activated by trypsin to activate human renin, the test compound is dissolved in a solution of a solvent (for example, DMSO or the like), or 2 μM of the solvent is added to a final concentration of 1% by weight. Furthermore, a buffer containing a synthetic renin matrix (NUsp-Arg-Val-Tyr-Ile-His-pro-Phe-His-Leu-Val-Ile-His-Thr-Glu-COOH) (ImM EDTA, 100 mM Tris-HCl, pH 7.4, at 37. 〇 cultivating i hours. The resulting angiotensin I concentration was measured using a radioimmunoassay [Renin. RIA B E A D S (registered trademark), YAM AS A soy sauce] according to the attached document. The renin inhibitory activity was evaluated by IC5G値 at a concentration of 50% of each test compound which inhibited the production of angiotensin I. The results are shown in Table 1.

[S] -142- 201107306

[Table 1] Example Compound No. IC5〇(nM) 1 2.8 2 1.2 3 5.6 4 6.8 5 1.3 6 2.0 7 3.6 8 6.5 9 2.0 10 2.1 11 1.8 12 2.1 13 3.3 14 1.8 15 2.4 16 7.6 Example Compound No. IC5 〇( nM ) 17 1.4 18 1.0 19 6.4 20 2.1 2 1 1.7 22 11.7 23 0.7 24 3.3 25 1.1 26 1.5 27 1.6 28 0.7 29 3.4 30 0.9 3 1 1.4 32 1.3 The compound of the present invention exhibits excellent renin inhibitory activity, It is used as a medicine for the treatment or prevention of hypertension or the like. (Test Example 2) Plasma renin activity (PRA) inhibition test was performed to measure the amount of angiotensin I produced per unit time by plasma measurement at 37 ° C and endogenous angiotensinogen and endogenous renin. Renin activity. [S] -143- 201107306 In a reserve of crabmeal plasma or human plasma, a test compound or a solvent (for example, DMSO, etc.) is added, and according to an attached file, a buffer is added and incubated at 37 ° C for 1 hour. The concentration of angiotensin I produced per unit hour was measured by radioimmunoassay (see Test Example 1). Plasma renin inhibitory activity was evaluated by IC5Q値 at a concentration of 50% of each test compound which inhibited PRA. The compound of the present invention exhibits excellent plasma renin inhibitory activity and is useful as a medicine for the treatment or prevention of hypertension or the like. (Test Example 3) In vitro plasma renin activity (pr a ) in the crab-eating sputum 0 Inhibition test The oral administration of the test compound was carried out intramuscularly 2 days before the intramuscular injection of Furosemide (5 mg/kg). With the crabmeat, the renin-angiotensin system is hyperthyroidized. On the day of the test, plasma samples were taken in tubes containing EDT A · 2Na before, after 1, 2, 4, 8 and 24 hours of administration of the test compound. The test compound was suspended in 1% methylcellulose and forcedly administered orally. The obtained plasma was cultured at 37 ° C, and the angiotensin I concentration present in each reaction solution was measured by radioimmunoassay (refer to Test Example 1). I The angiotensin I concentration per unit time was calculated by subtracting the angiotensin I concentration in the reaction solution cultured at 4 °C from the angiotensin I concentration in the reaction solution cultured at 37 °C. The PRA inhibitory activity of the test compound was evaluated by the inhibition rate of PRA after each administration time with respect to the P R A before the administration of the test compound. The compound of the present invention exhibits an excellent PR A inhibitory activity and a decrease in the concentration of angiotensin I in plasma, and is useful as a medicine for the treatment or prevention of hypertension or the like. (Test Example 4) Blood pressure lowering test in crab-eating crabs -144 - 201107306 The embedding operation of the crabmeal was performed by a telemetry transmitter, and an animal having a stable blood pressure waveform was used for one week after the operation. Three days before the oral administration of the test compound, a loze (5 mg/kg) was administered to the muscle of the crab, and the renin-angiotensin system was hyperthyroidized. On the day of the test, the test compound was administered from 1 hour before the administration to 25 hours, and the data was obtained using an instant analysis system (HEM 3.5, NotoCORD SYSTEMS, USA), and the blood pressure signal was continuously measured by a telemetry method. After analyzing the blood pressure and the heart rate, the blood pressure waveform obtained within 30 seconds is averaged every 5 minutes, and then the 12 levels of the ® are calculated as 1 hour data. The test compound was suspended in 1% methylcellulose for forced oral administration. The decrease in blood pressure of the test compound was evaluated by the difference between the mean blood pressure before administration of the test compound and the mean blood pressure after each administration hour. The compound of the present invention exhibits an excellent blood pressure lowering action and is useful as a medicine for the treatment or prevention of hypertension or the like. (Test Example 5) Effect of electrocardiogram on rats The intraperitoneal administration of thiobarbiturate (Inactin) (100 mg/kg) was administered to the rats for anesthesia, and the test compound was administered to the right femoral vein. With the catheter used. The electrocardiogram was measured via the II induction, and the test compound was continuously administered intravenously at a certain rate (1 mg/kg/min). The electrocardiogram was recorded on the thermally sensitive recording paper before the administration of the test compound and at the start of the administration 1 minute after 1 to 30 minutes. The test compound is intravenously administered by dissolving in a physiological saline solution or a physiological saline solution containing a solvent (e.g., DMSO or the like). The effect of the test compound on the electrocardiogram was evaluated with respect to the electrocardiogram before administration of the test compound, and the change in electrocardiogram after each administration time. The change in the electrocardiogram can be evaluated, for example, by the height, width, spacing, etc. of the waveform (especially the degree of decrease of the S wave). Changes in the electrocardiogram, -145- 201107306 Depending on the degree of change, for example, it can be classified as large, medium, small or absent. A compound having a small change in electrocardiogram is preferred. A compound having no change in electrocardiogram is preferred. The compound of the present invention exhibits little or no change in electrocardiogram and has excellent properties as a medicine. (Test Example 6) Drug dynamic test The drug dynamic test can be carried out according to a method well known in the field of pharmacokinetics. The test compound is dissolved in a 1% methylcellulose aqueous solution, and the obtained solution is used in an appropriate range for the animals used in the general drug dynamic test (for example, mice, rats, marmosets, crabs, etc.). (eg, 3 mg/kg to 100 mg/kg) administered orally. Further, the test compound is dissolved in physiological saline, and the resulting solution is used in an appropriate range of the animal (for example, mouse, rat, apes, crab mites, etc.) used in the general drug dynamic test (for example, 1 From mg/kg to 10 mg/kg), it is administered intravenously (for example, tail vein, temporal cutaneous vein, saphenous vein, etc.). After a certain period of time after administration (for example, 0.08, 0.25, 〇·5, 1, 2, 4, 6, 8, or 24 hours), the appropriate blood collection site (for example, jugular vein, orbital venous plexus, temporal cutaneous vein, etc.) Take blood. The obtained blood was centrifuged to prepare a plasma sample, and the concentration of the test compound contained in the plasma sample was measured by quantitative analysis using a liquid chromatography mass spectrometer (LC/MS/MS). The drug dynamics of the test compounds were evaluated by the highest plasma concentration of the test compound (Cm ax ), the area under test compound concentration-time curve (AUC), systemic clearance (CL), and absolute bioavailability. Cm ax represents the highest concentration of the test compound in plasma measured after oral administration. The AUC is calculated from the time point when the test compound is administered to the time when the blood is finally taken, and is calculated by the trapezoidal formula of -146-201107306. The CL system was calculated using the drug dynamic analysis software WinNonlin (registered trademark). The absolute biomass utilization rate was calculated by the following formula. [(AUC/administration amount after oral administration) / (AUC/administration amount after intravenous administration)] The compound of the present invention shows excellent drug dynamics (Cmax, AUC, CL or absolute bioavailability) ), it is used as medicine (especially for the treatment or prevention of hypertension). (Formulation Example 1) Tablets ^ The compound of the example (10 mg), colloidal cerium oxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg), and lactose were used. (98.8 mg), a tablet was prepared according to the usual method. The resulting lozenge can be applied as necessary. (Formulation Example 2) Hard capsules A compound (10 mg), lactose (150 mg), cellulose (50 mg), and magnesium stearate (6 mg) were added in a powder form in a standard distillate hard gelatin capsule to make a hard. Capsules, washed and dried. ^ (Formulation Example 3) Soft capsule A mixture of a digestive oil such as soybean oil, olive oil, and a compound of the example is injected into gelatin in an amount of 10 mg of the active ingredient to prepare a soft capsule, and washed. After drying. INDUSTRIAL APPLICABILITY The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof is capable of renin-inhibiting activity, solubility 'cell membrane permeability, oral absorption, blood concentration' metabolic stability Sexuality, tissue migration, bioavailability, in vitro activity, in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physiology ^ Ii -147- 201107306 Stability, drug interaction, safety (eg, It has excellent properties such as cardiotoxicity or hepatotoxicity, and is useful as a medicine (especially for the treatment or prevention of hypertension (preferably for treatment)]. [Simple description of the diagram] 〇 [Description of main component symbols] 〇 V * N\

m -148 -

Claims (1)

201107306 VII. Patent application scope: 1. A compound having the general formula (1) or a pharmacologically acceptable salt thereof R5 Wherein R represents a hydrogen atom, a ci-c1Q alkyl group, a phenylalkyl group, a (C3_Cl. saturated cyclic hydrocarbon. alkyl) group, (4 to 8 membered heterocyclic group)-(Cl-ClG alkane) a phenyl group, a dihydroindanyl group, a C3_Ci 〇 saturated cyclic hydrocarbon group or a 4 to 8 membered heterocyclic group, and each group in R1 may be independently substituted with hydrazine to 4 groups selected from the group of substituents 'Two substituents bonded to the same carbon atom may form a c3_C8 cycloalkyl group with the carbon atom; R2 represents a hydrogen atom or an alkyl group; R3 represents a hydrogen atom or a Ci-Cs alkyl group; 0 R4 represents a hydrogen atom Or a Ci-C6 building group, R3 and R4 may form a c3-c8 cycloalkyl group together with the carbon atoms to which they are bonded; A represents a phenyl or a π π group, and R5'R6 and R7 independently represent a ruthenium atom or a substituent selected from The group of the group α; the group of substituents α represents a group of ϋ6, a fluorene 6 group, a C3-C8 cycloalkyl group, a hydroxyl group, a fluorenyl group, a (C3-C8 cycloalkyl group)-(Cl_c6 alkoxy group) )-halogen Ci_C6 alkoxy, thiol 'CMC6 sulfonylthio group, C--C6-based sulfhydryl group, Ci-C6-based sulfonyl group, amine group, Ci-C6 alkylamino group, two ( Ci-Ce alkyl)amino group (the alkyl group is the same or phase -149-2) 01107306 iso), carbenylamino, (C^-Ce alkyl)carbonylamino, carbenyl, (Cj-Ce alkyl)carbonyl 'carboxy, (Κ6 alkoxy)carbonyl, amine carbaryl' (C^-C: 6 alkylamino)carbonyl, bis(Cl_C6 alkyl)aminocarbonyl (the alkyl group is the same or different), aminosulfonyl, (Ci-Ce alkylamino) sulfonate a group consisting of a mercapto group, a di(CrC6 alkyl)aminosulfonyl group (the alkyl group is the same or different), a cyano group, a nitro group, a halogen group, and a pendant oxy group. 2_ The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein R 1 is C丨-CH)alkyl, phenyl-(c丨-C丨〇alkyl) group, ® (c3- Ci〇 saturated cyclic hydrocarbon HCi-C, alkyl), (4 to 8 membered heterocyclic)-(Ci-Ci〇alkyl) group or Cs-C丨〇 saturated cyclic hydrocarbon group, each of R1 The substituent may be substituted with 1 to 4 groups independently selected from the substituent group αΐ. 2 such substituents bonded to the same carbon atom may form a C3-C8 ring-forming group with the carbon atom; the substituent group αΐ is Ci -C6, a C3-C8 cycloalkyl group, a Ci-C:6 alkoxy group, a di(Ci-Ce alkyl)amino group (the alkyl group is the same or different), a halogen group and a pendant oxy group Group of. 3. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R is a Ci-Ci oxime, a benzyl-(Ct-Cio) group or a (4 to 8 membered heterocyclic group) The alkyl group, each group in R1 may be substituted with 1 to 4 groups independently selected from the substituent group α2, and the substituent group α2 is a C^-Ce alkyl group, a c3_c8 cycloalkyl group, a Cl_c6 alkoxy group, and The compound of any one of claims 1 to 3, wherein R2 is a hydrogen atom, or a pharmacologically acceptable salt thereof. 5. The compound of any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, wherein 113 is a Crq alkyl group. The compound or a pharmacologically acceptable salt thereof, wherein R3 is a methyl group, is a compound according to any one of claims 1 to 4. 7. A compound or a pharmacologically acceptable salt of any one of claims 1 to 6 wherein 114 is an alkyl group. The compound of any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, wherein R4 is a methyl group. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein A is a phenyl group. The compound of any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, wherein R5, R6 and R7 are independently selected from the group consisting of a hydrogen atom, a Ci-q alkyl group and a halogen group. 11. The compound of any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, wherein R5, R6 and R7 are independently selected from the group consisting of a hydrogen atom, a methyl group, a fluorine group and a chlorine group. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient. 13. The pharmaceutical composition of claim 12, which is for use in the treatment or prevention of a disease treatable or preventable by inhibiting renin. 14. The pharmaceutical composition of claim 12, which is used in the treatment of hypertension, acute or chronic heart failure 'cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, stroke' kidney Treatment or prevention of disease, diabetic complication, vascular restenosis after angiogenesis, aldosteronism or atherosclerosis. 15. The pharmaceutical composition of claim 12, which is used for the treatment or prevention of hypercalcemia, chronic heart failure or diabetic nephropathy. 16. The pharmaceutical composition of claim 12, which is for the treatment or prevention of hypertensive disease. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 11 which is for use in the treatment or prevention of a disease. 1 8 A compound according to claim 17 or a pharmacologically acceptable salt thereof, wherein the disease is hypertension. A method of treating or preventing a disease by administering a pharmacologically effective amount of a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof to a warm-blooded animal. 20. The method of claim 19, wherein the disease is a disease treatable or preventable by inhibiting renin. 21. The method of claim 19, wherein the disease is hypertension. The method of any one of claims 19 to 21, wherein the warm-blooded animal is a human. [S] -152 201107306 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: 〇 y» \\ 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: m