TW201124388A - Substituted oxopiperazine compounds - Google Patents

Abstract

The present invention provides a substituted oxopiperazine compound useful as a therapeutic medicine of hypertension and the like. The present invention provides a compound having the general formula (I) and the like, [wherein, R1 represents optionally substituted adamantly; R2 represents H, alkyl; R3 represents H, substituted carbonyl; R4 represents H, alkyl; R5 represents H, alkyl; R6, R7, and R8 represent H, optionally substituted alkyl, optionally substituted hydroxyl, halo, and the like].

Description

201124388 VI. Description of the Invention: [Technical Field] The present invention relates to having excellent renin inhibitory activity and for use as a medicine (especially for the treatment or prevention of hypertension, preferably for treatment) a novel substituted sideoxypiperane compound or a pharmacologically acceptable salt thereof; a renin inhibitor containing a substituted sideoxypiperane compound or a pharmacologically acceptable salt thereof as an active ingredient; a pharmaceutical composition comprising a sideoxypiperane compound or a pharmacologically acceptable salt thereof as an active ingredient, preferably a pharmaceutical composition for the treatment or prevention of hypertension; for use in treating or preventing a disease (preferably the above disease) a method of substituting a pendant oxypiperidin compound or a pharmacologically acceptable salt thereof; administering a pharmacologically effective amount of a substituted side oxypiperidine compound or a pharmacologically acceptable salt thereof to a warm-blooded animal ( a method for treating or preventing (preferably treating) a disease, preferably the above-mentioned disease, especially a human; and a substituted pendant oxypiperane compound or its pharmacology The salts may be acceptable manufacturing method. [Prior Art] Hypertension is defined as a symptom in which the maximum blood pressure is 140 mmHg or more, or the minimum blood pressure is 90 mmHg or more in the WHO/ISH guidelines. Once the state of the blood pressure syndrome continues, it can cause cerebral hemorrhage, cerebral infarction, aorta 201124388 tumor, nephrosclerosis, myocardial infarction, or heart failure, which eventually leads to death. In the case of the treatment of the disease, the blood pressure is being actively promoted. Efforts to reduce, but still hope for more adequate blood pressure control. 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-increasing system for living organisms that increase the amount of circulating blood or contract the vascular smooth muscle by accumulating sodium (salt) in the body. The RA system converts angiotensinogen to angiotensin I via renin, and angiotensin I is converted to 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, and hypertension, which in turn causes an obstruction of the sputum. Now, an ACE inhibitor (hereinafter referred to as "ACEI") which inhibits the production of angiotensin 11 and an angiotensin receptor antagonist 剤 (hereinafter also referred to as ARB) which inhibits stimulation of AT1 are known to be used as hypertension. Therapeutic drugs' These agents have significant blood pressure lowering effects and sputum protection. The renin system converts angiotensinogen (origiotensinogen) into an aspartic acid protease of angiotensin I, which is a rate-determining enzyme of the R-A system. Therefore, renin inhibitors are thought to efficiently inhibit the R_A system and have an excellent blood pressure lowering effect (Circulation, 2005, Vol. 111 201124388, p. 1012-1018). A compound having a renin inhibitory activity and having a pendant oxy-peptidic structure is known (for example, refer to Patent Documents 1 to 4 or Non-Patent Documents 1 to 5). A compound having renin inhibitory activity and having an adamantyl group is known (for example, refer to Patent Document 5). Further, a compound having renin inhibitory activity is known (for example, refer to Patent Document 6 or 7). [PRIOR ART DOCUMENT] [Patent Document 1] [Patent Document 1] International Publication No. 2004/08991 Booklet No. 5 [Patent Document 2] International Publication No. 2006/〗 28659 Booklet [Patent Document 3] International Publication No. 2007/034445 Booklet [Patent Document 4] International Publication No. 2 007/1 487.74 Booklet [Patent Document 5] International Publication No. 2〇〇7/〇7〇201 Booklet [Patent Document 6] International Publication No. 2007 /1 48775 booklet [Patent Document 7] US Patent No. 5 559 1 1 1 [Non-Patent Document] [Non-Patent Document 1] Expert Opinion on Therapeutic Patents, 2008, Vol. 18, p. 58 1 - 602 [Non-Patent Document 2] Bioorg. Med. Chem., 2005, Vol. 13 , p. 2657-2664 [Non-Patent Document 3] Bioorg. Med. Chem. Lett., 2005, Vol. 15, p .2371-2374 [Non-Patent Document 4] Bioorg.Med.Chem.Lett., 2005, No. 201124388 1 5 Volume, p_47 1 3 -47 1 6 , 2006, the first development, the salt with specific structure tolerance , oral absorption, blood utilization (in vitro) activity, drug-effect interaction, and excellent sexual therapy or prevention (Complete the invention. For use as a medicine for medical use] [Non-Patent Document 5] Bioorg. Med. Chem. Lett. 16 Volume, p, 2500-2504 [Summary of the Invention] [Invented] The present inventors have found a substituted pendant oxypiperazine compound or a pharmacologically renin-inhibiting activity and solubility thereof for the purpose of novelly replacing a oxypiperazine compound with a therapeutic agent for hypertension. , cell membrane permeability, medium concentration, metabolic stability, tissue migration, bioavailability (hereinafter also referred to as BA), in vitro, in vivo activity (inviv 〇), in vitro (e X viv (expression speed) , the efficacy of drug efficacy, physical stability, drug safety (for example, cardiotoxicity or hepatotoxicity), etc., and is used as a medicine for medicine (especially, treatment of hypertension is a treatment)] Based on the above knowledge [means for solving the problem] The present invention provides an excellent renin inhibitory activity, and a drug (especially a treatment or prevention of hypertension (preferably a novel substituted side oxygen oxydez) Well compound Or a pharmacological salt thereof; a renin inhibitor containing a substituted pendant oxypiperidine compound or a pharmacologically acceptable 201124388 salt thereof as an active ingredient; and a substituted pendant oxypiped compound or a pharmacologically acceptable salt thereof The pharmaceutical composition as an active ingredient is preferably hypertension (including essential hypertension and renal hypertension), pulmonary hypertension, heart failure (including acute heart failure, chronic heart failure) And congestive heart failure), cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, stroke, cognitive impairment, kidney disease (including spheroid nephritis, IgA nephropathy, hypertensive nephropathy and diabetic kidney Symptoms, diabetic dysentery (including diabetic nephropathy, neurological disorders, and omental disease), glaucoma, vascular restenosis after angiogenesis, aldosteronism, or treatment or prevention of atherosclerosis, Prevention of diabetes mellitus, protection of sputum (including kidney protection, heart protection), or occurrence of death based on cardiovascular disease or coronary heart disease A pharmaceutical composition for reducing the rate of death, preferably a medical composition for the treatment or prevention of hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy, preferably for hypertension a pharmaceutical composition for therapeutic or prophylactic use; a substituted pendant oxypiperidin compound or a pharmacologically acceptable salt thereof for use in a method for treating or preventing a disease, preferably the above-mentioned disease; The pharmacologically effective amount of the pendant oxypipeplin compound or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal (especially a human) for treating or preventing (preferably treating) the disease (preferably the above-mentioned disease) And a method of producing a substituted pendant oxypiperane compound or a pharmacologically acceptable salt thereof; The present invention provides the following (1) to (5 2 ) via an aspect. (1) a compound having the following formula (I) or a pharmacologically acceptable salt thereof,

[wherein R 1 represents an adamantyl group or a substituted adamantyl group (the substituents are independently selected from the group consisting of 1 to 3 substituents); R 2 represents a hydrogen atom or a Ci-Ce alkyl group; Represents a hydrogen atom, a (q-C6 alkyl)carbonyl group, a (Cl-C6 alkoxy) group, or a substituted (Ci_c6 alkoxy)carbonyl group; R4 represents a hydrogen atom or (^-(:6 alkyl) R5 represents a hydrogen atom or a Cl-c6 alkyl group; R6, R7, and R8 independently represent a hydrogen atom, a Cl_c6 alkyl group, a halogen Cl-c6 group, a C3-C8 cycloalkyl group, a hydroxyl group, a Cl_c6 alkoxy group, a halogen group; C^-Ce alkoxy, or a halogen group; the substituent group α represents a Cl-C6 alkyl group, a halogen CrCe alkyl group, a hydroxyl group, a Cl-Ce & oxy '(Ci-Ce alkyl)carbonyloxy group, (C丨-C6 alkoxy)carbonyloxy 'aminoalkyloxy, (Ci_c6 alkylamino)carbonyloxy, bis(Ci_C6 201124388 alkyl)aminocarbonyloxy (the alkyl group is the same or Different), amine 'C>-C6 alkylamino group, di(c,-c6 alkyl)amino group (the alkyl group is the same or different), formazanyl group, (C^-Ce alkane) Carboxyamino group, (C^-Ce alkoxy)carbonylamino group, amine group A carbonylamino group, ((^-(^alkylamino)carbonylamino), bis(CrG alkyl)aminocarbonylamino group (the alkyl group is the same or different), an amine carbenyl group, (C^- a Cealkylamino)carbonyl group, a di(Ci-Ce alkyl)aminocarbonyl group (the alkyl group is the same or different), and a group of a halogen group]. (2) A compound according to (1) or a pharmacological thereof a permissible salt which is a compound having the following formula (1-1) or a pharmacologically acceptable salt thereof,

Wherein R 1 represents an adamantyl group or a substituted adamantyl group (the substituent represents independently selected from 1 to 3 groups of the substituent group α, R 2 represents a hydrogen atom or a Crq alkyl group; R 3 represents a hydrogen atom, (C丨-C6 alkyl)carbonyl, (C丨-C6 alkoxy)carbonyl, or substituted (C!C6 alkoxy)carbonyl; R4 represents a hydrogen atom or a Crq alkyl group; R5 represents a hydrogen atom or C^ -Ce alkyl; R6, R7, and R8 independently represent a hydrogen atom, a Cl_C6 alkyl group, a halogen Ci_c<alkyl group, a C3-C8 cycloalkyl group, a hydroxyl group, a Cl-c6 alkoxy group, a haloalkoxy-10. 201124388 . a group or a halogen group; the substituent group α represents a Ci-Ce alkyl group, a halogen Ci-Ce group, a hydroxyl group, a q-C6 alkoxy group, a (C|-C6 alkyl)carbonyloxy group, (Ci_c6 alkoxylate) Carboxyoxy, aminocarbonyloxy, (Ci-Ce alkylamino)carbonyloxy, bis(Ci-Ce alkyl)aminocarbonyloxy (the alkyl is the same or different), amine Base, Cl-C6 alkylamino group, bis(C^-Ce alkyl)amino group (the alkyl group is the same or different), decylamino group, alkyl)carbonylamino group, (Cl-C6 alkane) Oxy)carbonylamino, aminocarbonylamino, alkylamino A carbonylamino group, a bis(Cl_C6 alkyl)aminocarbonylamino group (the alkyl group being the same or different), an amine carbenyl group, a (Ci-C6 alkylamino)carbonyl 'dialkyl)aminocarbonyl group ( The alkyl groups are the same or different) and the group of halogen groups. (3) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein R is a Wolverine-2 -yl or substituted Wolverine-2 -yl group (the substituent represents a group selected from the group of substituents αΐ) The substituent group αΐ represents a thiol group, a Ci-C2 oxy group, a (Ci-Ca) carbonyloxy group, a (Cl_c2 alkoxy)carbonyloxy group, an amine carbaryl group, (Ci_C2 A group consisting of an amino)carbonyl group and a dialkyl)aminocarbonyl group (the alkyl group being the same or different). (4) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein R1 is a substituted adamantane-2-yl group (the substituent represents a group selected from the group of substituents α2), a substituent group Α2 represents a group consisting of a hydroxyl group, a methoxy group, and an amine carbenyl group. (5) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein -11- 201124388 R1 is trans-5 - via the fund syllidyl-2-yl, cis-5-hydroxyadamantan-2 Base, trans-5-methoxyadamant-2-yl, cis-5-methoxyadamantane-2-yl, trans-5-aminecarboxamide, alkane-2-yl, or Formula-5_Aminoguanidine fundane-2-yl. (6) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-hydroxyadamantan-2-yl. (7) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-methoxyadamantan-2-yl. (8) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-aminocarboxamantane-2-yl. (9) A compound according to any one of (2) to (8) or a pharmacologically acceptable salt thereof, wherein & 2 is a C, -C3 alkyl group. (10) A compound according to any one of (2) to (8), wherein R2 is a methyl group, an ethyl group or a 2-propyl group, or a pharmacologically acceptable salt thereof. (11) A compound according to any one of (2) to (8), wherein R2 is an ethyl group, or a pharmacologically acceptable salt thereof. (12) A compound according to any one of (2) to (8), wherein R2 is a 2-propyl group, or a pharmacologically acceptable salt thereof. (13) A compound according to any one of (2) to (12), wherein R3 is a hydrogen atom, or a pharmacologically acceptable salt thereof. (14) A compound or a pharmacologically acceptable salt according to any one of (2) to (13), wherein R4 and R5 are a methyl group. (15) A compound according to any one of (2) to (I4), or a pharmacologically acceptable salt of -12 to 201124388, wherein R6, R7 and R8 are each independently a hydrogen atom, a CrQ • a hospital base, a halogen C1- C4 yard base, gas base, or chlorine base. The compound of any one of (2) to (1), wherein R6, R7 and R8 are each independently a hydrogen atom, a C^-C^ alkyl group, or a fluoro group, or a pharmacologically acceptable salt thereof. Or chlorine base. (17) A compound of any one of (2) to (14) or a pharmacologically acceptable salt thereof, which has a group of formula (II):

It is the following group: 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-di Fluorophenyl' or 2-chloro-5-fluorophenyl. (1) The compound of any one of (2) to (1), or a pharmacologically acceptable salt thereof, having a group of the formula (Π):

It is a 2-chlorophenyl group. (1) The compound of any one of (2) to (1), or a pharmacologically acceptable salt thereof, having the group of formula (II):

:S -13- 201124388

The compound of any one of (2) to (14), or a pharmacologically acceptable salt thereof, having the formula (Π) :

R° is 2-chloro-5-fluorophenyl. (21) A compound of (2) or a pharmacologically acceptable salt thereof, wherein: R1 is trans-5-hydroxyadamantan-2-yl, R2 is methyl, ethyl or 2-propyl, and R3 is A hydrogen atom, R4 and R5 are a methyl group, having the group of formula (II):

R7 (II is 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluoro Or a pharmacologically acceptable salt thereof, wherein: -14- 201124388 R1 is trans-5-methoxyadamantane -2-yl, R2 is methyl, ethyl or 2-propyl, R3 is a hydrogen atom, R4 and R5 are a methyl group, having the group of formula (II):

Is 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, Or 2-chloro-5-fluorophenyl. (23) A compound according to (2) or a pharmacologically acceptable salt thereof, wherein: R1 is trans-5-amine-formamidine, adamant-2-yl, and R2 is methyl, ethyl or 2-propyl , R3 is a hydrogen i atom, and R4 and R5 are a methyl group having a formula (Π):

R7 (II is 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluoro A phenyl group or a 2-chloro-5-fluorophenyl group. The compound according to (2) or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds: -15- 201124388 (2S ,4S,5S) - 5-Amino- 6-[4-(2-Chlorophenyl)-2,2-dimethyl-5-oxooxypiped-l-yl]-4-hydroxy-N -(5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine, (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2 ,2-dimethyl-5-oxopiperidin-1-yl]-4-hydroxy-2-isopropyl-N-(5-methoxyadamantan-2-yl)hexane decylamine, (2S,4S,5S) -5-Amino- 6-[2,2-dimethyl-4-(2-methylphenyl)-5-o-indolyl-1-yl]-4经-N- (5 - Funded Pharmacy-2-yl)-2_isopropyl propyl decylamine, (2S,4S,5S)-5-amino-6-[2,2-dimethyl 4-(2-methylphenyl)-5-oxopiperidin-1-yl]-4-hydroxy-2-isopropyl-N-(5-methoxyadamantan-2-yl) Hexane amide, (23.43.53) -5-amino-6-[4-(2-ethylphenyl)-2,2-dimethyl-5-oxoxypiped-1-yl] -4-hydroxyl -N-(5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine, (23.43.53) -5-amino-6-[4-(2,3-difluorophenyl) -2,2-Dimethyl-5-oxopiperidin-1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-isopropylhexanide , (23.43.53) -5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxoxypiped-1-yl]-4 -hydroxy-N-(5-hydroxyadamantan-2-yl)-2-isopropylhexylamine, (2S,4S,5S)-5-amino-6-[4-(2-chloro- 5-fluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-16-201124388 - 2-isopropylhexylamine, (2S,4S,5S)-5-amino-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5 -Sideoxypiped-1-yl]-4-hydroxy-indole-(5-hydroxyadamantan-2-yl)-2-isopropylhexylamine, (2R, 4S, 5S) - 5- Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiped-l-yl]-2-ethyl-4-hydroxy-N-(5 -hydroxyadamantan-2-yl) hexane decylamine, (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5- Oleoxypiped-1-yl]-2-ethyl-4-hydroxy-N- (5-methoxyadamantane-2- Hexane amide, (211,43,53)-5-amino-6-[4-(2,3-difluorophenyl)-2,2-dimethyl-5-side oxy thiophene -1-yl]-2-ethyl-4-hydroxy-N-(5-hydroxyadamantan-2-yl)hexane decylamine, (211,43,53)-5-amino-6-[4 -(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypiped-1 -yl]-2-ethyl-4-hydroxy-N-(5-hydroxyadamantane -2-yl) hexane decylamine, (2R, 4S, 5S ) -5-amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5- Oxyloxyindol-1-yl]-2-ethyl-4-carbyl-N-(5-hydroxydanta-2-yl)hexane decylamine, (2R,4S,5S)-5- Amino-2-ethyl-6-[4-( 5-fluoro-2-methylphenyl)-2,2-methyl-5-oxirane-1-yl]-4 Base - N-(5 - via GF-German-2-yl) hexane decylamine, (2R, 4S, 5S) - 5-amino-6-[4-(2-chlorophenyl)-2,2 -Dimethyl-5--17- 201124388 Side Oxygen Piper-1-yl]_4_Hydroxy·Ν_ (5-Hydroxyadamantane-2-yl)_2 Methylhexanoic acid amine, (2S, 4S, 5S) -5-Amino-N-(5-aminoformamidine alkane-2_yl)-6-[4-(2-chloro-5-fluorophenyl)_2,2_dimethyl_5 _Side oxypiped _ mercapto]·4· hydroxy-2-isopropyl hexane decylamine, (2S ,4S,5S ) -5-Amino-indole-(5-aminoformamidine alkane-2·yl)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5 -Sideoxypiperidin-1_yl]_4_hydroxy-2-isopropylhexane decylamine, and (2R,4S,5S)-5-amino-N-(5-amine formazan alkane _2 "yl"-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxypipeplin-1_yl]-2-ethyl-4-hydroxyhexane Guanamine. (25) (2S,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxypiped as described in (2) 1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-isopropylhexanide or a pharmacologically acceptable salt thereof. (26) (2S,4S,5S)-5-Amino-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side as described in (2) Oxypiperrel-1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-isopropylhexanide or a pharmacologically acceptable salt thereof (27) (2) (2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiperidin-1-yl ]-2-Ethyl-4-hydroxy-N-(5-hydroxyadamantan-2-yl)hexaneguanamine or a pharmacologically acceptable salt thereof. (28) (2R, 4S, 5S) -5-amino-6-[4-(2- -18- 201124388 chlorophenyl)-2,2-dimethyl_5_ side as described in (2) Oxypiperrel-1-yl]-2-ethyl-4-hydroxy-N-(5-methoxyadamantan-2-yl)hexanedecylamine or a pharmacologically acceptable salt thereof. (29) (2R,4S,5S)-5-Amino-6-[4-(2-chloro-5-fluorophenyl)_2,2-dimethyl-5-side oxygen as described in (2) Kepipi-1-yl]-2-ethyl-4-hydroxy-N-(5-hydroxyadamantane-2-yl) hexane decylamine or a pharmacologically acceptable salt thereof. (30) (2R, 4S, 5S)-5-amino-2-ethyl-6-[4-(5-fluoro-2-methylphenyl)-2,2·2 as described in (2) Methyl-5-sideoxypiperidin-i-yl]·4_hydroxy-indole-(5-hydroxyadamantan-2-yl)hexanedecylamine or a pharmacologically acceptable salt thereof. (31) (2S,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxypene as described in (2) -1-yl]-4.hydroxy-indole-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumaric acid

Bej 〇(32) (2S,4S,5S)-5-Amino- 6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl- as described in (2) 5-Phenyloxypipen-1-yl]-4-hydroxy-indole-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate. (33) (2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxypiped well as described in (2) 1-yl]-2-ethyl-4-hydroxy-indole-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate. (34) (2R,4S,5S)-5-Amino- 6-[4-(2- •19- 201124388 chlorophenyl)-2,2-dimethyl-5-side as described in (2) Oxypiperazine-1-yl]-2-ethyl-4-hydroxy-N-(trans-5-methoxyadamantan-2-yl)hexane decylamine fumarate. (35) (2R, 4S, 5S) -5-amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-side as described in (2) Oxypiperidine-1-yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate. (36) (2R,4S,5S)-5-Amino-2-ethyl-6-[4-(5-fluoro-2-methylphenyl)-2,2-di as described in (2) Methyl-5-oxopiperidin-1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate. (37) A pharmaceutical composition comprising the compound according to any one of (1) to (36) or a pharmacologically acceptable salt thereof as an active ingredient. (3) The pharmaceutical composition according to (3), which is for treating or preventing hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, Stroke, cognitive impairment, renal disease, diabetic complication, glaucoma, vascular restenosis after angiogenesis, aldosteronism, or atherosclerosis. (3) The pharmaceutical composition according to (3), which is for use in the treatment or prevention of hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. (40) A pharmaceutical composition according to (37), which is for use in the treatment or prevention of hypertension. (4 1) The pharmaceutical composition according to (3), which is for use in the treatment or -20-201124388 for preventing a disease which can be treated or prevented by inhibiting renin. (42) A renin inhibitor comprising the compound according to any one of (i) to (3) or a pharmacologically acceptable salt thereof as an active ingredient. (43) A compound according to any one of (1) to (3), or a pharmacologically acceptable salt thereof, which is used for treating or preventing a disease. (44) The compound according to (43) or a pharmacologically acceptable salt thereof, wherein the disease is hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, Stroke, cognitive impairment, renal disease, diabetic complication, glaucoma, vascular restenosis after angiogenesis, aldosteronism, or atherosclerosis. (45) A compound according to (43) or a pharmacologically acceptable salt thereof, wherein the disease is hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. (46) A compound according to (43) or a pharmacologically acceptable salt thereof, wherein the disease is hypertension. (4 7) A method for treating or preventing a disease, which comprises administering a pharmacologically effective amount of the compound according to any one of (1) to (36) or a pharmacologically acceptable salt thereof Blood animals. (48) The method according to (47), wherein the disease is hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, stroke, cognitive impairment, kidney disease , Diabetes-21 - 201124388 Combined sputum, glaucoma, vascular restenosis after angiogenesis, aldosteronism, or atherosclerosis. (49) The method according to (47), wherein the disease is hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. (50) The method according to (47), wherein the disease is hypertension. (5) The method according to (47), wherein the disease is a disease treatable or preventable by inhibiting renin. (52) The method of any one of (47) to (51), wherein the warm-blooded animal is a human. With respect to the general formula (I) of the present invention, each group has the following meaning. Hereinafter, the compound of the formula (I) is also referred to as the compound (I), and the compounds of other symbols are also represented. The "CrG alkyl group" and the "Cl-C6 alkyl group" of each group are a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, 1-propyl, 2- Propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 3- Methyl-1·butyl, 2-methyl-1·butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-propyl, l- Hexyl, 2-hexyl, 3-hexyl, 2-methyl·l-pentyl, 3-methyl-bupentyl, 2-ethyl-l-butyl, 2,2-dimethyl-l-butyl Base, or 2,3-dimethyl-1-butyl. The "C,-C6 alkyl group" in R2 is preferably a Ci-C* alkyl group, more preferably a C^-Cs alkyl group, still more preferably a methyl group, an ethyl group or a 2-propyl group, and most preferably Ethyl or 2-propyl. The "CrCe alkyl group" in R4, R5, and the substituent group α is preferably a Κ4 alkyl group, more preferably an alkyl group, and most preferably a methyl group. R6, -22- 201124388 "CrCe alkyl group" in R7 and R8 is preferably a Ci-C* alkyl group, more preferably a G-C2 alkyl group. The "(Ci-C6 compound) group" may be a carbonyl group (-CO-) substituted with one of the above Ci-C: 6 groups, for example, methylcarbonyl (ethinyl), ethyl group , 1-propylcarbonyl, 2-propylcarbonyl, 1-butylcarbonyl, 2-butylcarbonyl, 2-methyl-1-propylcarbonyl, 2-methyl-2-propylcarbonyl, 1-pentyl Carbocarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 2-methyl-2-butylcarbonyl, 3-methyl-2-butylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, 3-hexylcarbonyl , 2-methyl-i-pentylcarbonyl, 3-methyl-1-pentylcarbonyl, 2-ethyl-1-butylcarbonyl, 2,2-dimethyl-1-butylcarbonyl, or 2, 3-dimethyl-1-butylcarbonyl. The "(Ci-Ce alkoxy)carbonyl" group may be a carbonyl group (-CO-) substituted with one of the following Cl-C6 alkoxy groups, for example, methoxycarbonyl group, ethoxycarbonyl group, 1-propyl group. Oxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxyindolyl, 2-methyl-1-propoxycarbonyl, 2-methyl-2-propoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, 2-methyl-2-butoxycarbonyl, 3-methyl-2-butoxycarbonyl, 1-hexyloxy Carbonyl, 2-hexyloxy[3-hexyloxycarbonyl, 2-methyl-1-pentyloxycarbonyl, 3-methyl-1-pentyloxy, 2-ethyl-1-butene Oxycarbonyl, 2,2-dimethyl-1-butoxyindenyl, or 2,3-dimethyl-1-butoxycarbonyl. ^Substituted (Ci-C6-homoyloxy)-based group is a group substituted by the above (Ci-C6-oxyl) fluorenyl group, for example: (5-methyl-2-sidedoxy-1,3) -Dioxo 11 pentyl-4-yl)methyloxycarbonyl, 1-ethenyloxyethyloxycarbonyl' or 丨[[cyclohexyloxy)carbonyloxy]ethyloxycarbonyl . -23- 201124388 "Halo-C-Cealkyl" is the above (^-0:6 alkyl group which may be substituted by 1 to 7 of the following halogen groups, for example, fluoromethyl group, difluoromethyl group, two Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-iodoethyl, 2,2-difluoro Base, 2,2,2-trifluoroethyl, trichloroethyl, pentylfluoroethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 5-fluoropentyl, or 6- The fluorohexyl group is preferably a halogen Ct-C alkyl group, more preferably a halogen C, a -C2 group (the halogen group is one to five groups selected from the group consisting of fluorine and chlorine), and is preferably a trifluoro group. Methyl. "C3-C8 cycloalkyl" is a cyclic alkyl group having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloc-cycloheptyl, Or a cyclooctyl group, preferably a C3-C6 cycloalkyl group, more preferably a (:3-(:4 cycloalkyl group). The "C^-Ce alkoxy group" is substituted by one of the above d-Ce alkyl groups. The hydroxy group (-OH) may be, for example, methoxy, ethoxy, i-propoxy, propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy Base, 2-methyl-2-propoxy, 1-pentyloxy , 2_pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexyloxy, octahexyloxy, 3-hexyloxy Base, 2-methyl-1-pentyloxy, 3-methyl-1-pentyloxy, 2-ethyl-1-butoxy, 2,2-dimethyl-1-butoxy, or 2 3-dimethyl-1-butoxy group, preferably (:1_(:4 alkoxy group) is more preferably Ci-Cz alkoxy group, most preferably methoxy group. "Halo C^-Ce alkane The above-mentioned Ci-C6 alkoxy group substituted by 1 to 7 of the following halogen groups may be, for example, a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group or a dibromomethoxy group. ,Trifluoromethoxy, trichloromethoxy, 2_fluoroethoxy, 2-bromoethoxy '2-chloroethoxy, 2-iodoethoxy, 2,2_ - -24- 201124388 Fluorine B Oxy, 2,2,2·trifluoroethoxy, trichloroethoxy, pentylfluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 5- Fluoropentyloxy or 6-fluorohexyloxy, preferably a halogenic Ci-CU alkoxy group, more preferably a haloalkoxy group (the halogen group is 1 to 5 groups selected from the group consisting of fluorine and chlorine) The "halogen group" may be a fluorine group, a chlorine group, a bromine group, or an iodine group, preferably a fluorine group or The group is preferably a chloro group. The "(CrC^alkyl)carbonyloxy group" may be a hydroxy group (-OH) substituted with one of the above (CrCe alkyl)carbonyl groups, for example, a methylcarbonyloxy group (B) Mercaptooxy), ethylcarbonyloxy, 1-propylcarbonyloxy, 2-propylcarbonyloxy, 1-butylcarbonyloxy, 2-butylcarbonyloxy, 2-methyl-1 -propylcarbonyloxy, 2-methyl-2-propylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, 2-methyl-2 -butylcarbonyloxy, 3-methyl-2-butylcarbonyloxy, 1-hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 2-methyl-1-pentyl Carbonyloxy, 3-methyl-1-pentylcarbonyloxy, 2-ethyl·1·butylcarbonyloxy, 2,2-dimethyl-1-butylcarbonyloxy, or 2,3 a dimethyl-1-butylcarbonyloxy group, preferably a (C^-C^alkyl)carbonyloxy group, more preferably a (Ci-Cz alkyl)carbonyloxy group, most preferably a methylcarbonyloxy group base. The alkoxy)carbonyloxy group may be a hydroxy group (-OH) substituted with one of the above alkoxy)carbonyl groups, for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, or a 1-propoxy group. Carbonyloxy, 2-propoxycarbonyloxy, 1-butoxycarbonyloxy, 2-butoxycarbonyloxy, 2-methyl-1-propoxycarbonyloxy, 2-methyl- 2-propoxycarbonyloxy, 1-pentyloxycarbonyl-25· 201124388 oxy, 2-pentyloxycarbonyloxy, 3-pentyloxycarbonyloxy, 2-methyl-2-butoxy Carbocarbonyloxy, 3-methyl-2-butoxycarbonyloxy, 1-hexyloxycarbonyloxy, 2-hexyloxycarbonyloxy, 3-hexyloxycarbonyloxy, 2-methyl -1-pentyloxycarbonyloxy, 3-methyl-1-pentyloxycarbonyloxy, 2-ethyl-1-butoxycarbonyloxy, 2,2-dimethyl-1-butoxy a carbonyloxy group, or a 2,3-dimethyl-1-butoxycarbonyloxy group, preferably an alkoxy)carbonyloxy group, more preferably a (CPC2 alkoxy)carbonyloxy group, most preferably Methoxycarbonyloxy. The "(Crb alkylamino)carbonyloxy group" is a carbonyloxy group (-COO-) whose carbon atom is substituted with one of the following Ci-Ce alkylamino groups, for example: methylaminocarbonyloxyl , ethylaminocarbonyloxy, 1-propylaminocarbonyloxy, 2-propylaminocarbonyloxy, butylbutylcarbonyloxy, 2-butylaminocarbonyloxy, 2-methyl 1-propylaminocarbonyloxy, 2-methyl-2-propylaminocarbonyloxy, 1-pentylaminocarbonyloxy, 2-pentylaminocarbonyloxy, 3-pentyl Alkylaminocarbonyloxy, 1-hexylaminocarbonyloxy, 2-hexylaminocarbonyloxy, or 3-hexylaminocarbonyloxy, preferably (C^-CUalkylamino)carbonyloxy More preferably, it is a (CrC^-homo-amino)carbonyloxy group. The "di(Ci-Ce alkyl)aminocarbonyloxy group" is a carbonyloxy group (-COO-) whose carbon atom is substituted with one of the following two (Ci-Ce alkyl) amine groups, for example: Dimethylaminocarbonyloxy, methylethylaminocarbonyloxy, methylpropylaminocarbonyloxy [for example, N-methyl-N-(l-propyl)aminocarbonyloxy, etc. ], methylbutylaminocarbonyloxy [for example, N-(l-butyl)-N-methylaminocarbonyloxy, etc.], methylpentylaminocarbonyloxy, methylhexylamino Carbonyloxy, diethylaminocarbonyloxy, ethylpropylaminocarbonyloxy-26- 201124388 [for example, N-ethyl-N-(1-propyl)aminocarbonyloxy, etc.] Ethylbutylaminocarbonyloxy, dipropylaminocarbonyloxy, propylbutylaminocarbonyloxy, dibutylaminocarbonyloxy, dipentylaminocarbonyloxy, or dihexyl The aminocarbonyloxy group is preferably a di(Ci-Q alkyl)aminocarbonyloxy group, more preferably a di(C^-C^alkyl)aminocarbonyloxy group. The "Ci-Q-alkylamino group" may be an amine group (_nh2) substituted with one of the above C^-Ce alkyl groups, for example, a methylamino group, an ethylamino group, a 1-propylamino group, 2-propylamino, 1-butylamino, 2-butylamino, 2-methyl-1-propylamino, 2-methyl-2-propylamino, 1-pentylamino , 2-pentylamino, 3-pentylamino, 1-hexylamino, 2-hexylamino, or 3-hexylamino, preferably C^-C^alkylamino, more preferably Ci-G alkylamino group. The "bis(C^-Ce alkyl)amino group" may be an amine group (·N Η 2 ) substituted by the same or two different C 1 -C 6 alkyl groups, for example, a dimethylamino group. , methyl ethylamino, methylpropylamino [for example, fluorenyl-methyl-N-(l-propyl)amino, etc.], methylbutylamino [for example, N-(l-butyl) Base)-Ν-methylamino group, etc.], methyl amylamino group, methylhexylamino group, diethylamino group, ethylpropylamino group [eg, Ν-ethyl-N-(l - Propyl)amino, etc.], ethylbutylamino, dipropylamino, propylbutylamino 'dibutylamino, dipentylamino, or dihexylamino' are preferably two The (Ci-C*alkyl)amino group is more preferably a di(Ci-C2 alkyl)amino group. The "(C^-C^alkyl)carbonylamino group" may be an amine group (-NH2) substituted with one of the above (Cl_C6 alkyl)carbonyl groups, for example, a methylcarbonylamino group (acetamidoamine group) ), ethylcarbonylamino, 1-propylcarbonylamino, 2-propylcarbonyl-27- 201124388 Amino, 1-butylcarbonylamino, 2-butylcarbonylamino, 2-methyl-1 -propylcarbonylamino, 2-methyl-2-propylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, 2-methyl-2 -butylcarbonylamino, 3-methyl-2-butylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino, 3-hexylcarbonylamino, 2-methyl-1-pentyl Carbonylamino, 3-methyl-1-pentylcarbonylamino, 2-ethyl-1-butylcarbonylamino, 2,2-dimethyl-1-butylcarbonylamino, or 2,3 a dimethyl-1-butylcarbonylamino group, preferably a (C^-CU alkyl)carbonylamino group, more preferably an alkyl)carbonylamino group. The "(C^-Ce alkoxy)carbonylamino group" may be an amine group (-NH2) substituted with one of the above alkoxy)carbonyl groups, for example, a methoxycarbonylamino group or an ethoxycarbonylamine group. , 1-propoxycarbonylamino, 2-propoxycarbonylamino, 1-butoxycarbonylamino, 2-butoxycarbonylamino, 2-methyl-1-propoxycarbonylamine Base, 2-methyl-2-propoxycarbonylamino, pentyloxycarbonylamino, 2-pentyloxycarbonylamino, 3-pentyloxycarbonylamino, 2-methyl-2-butyl Oxycarbonylamino, 3-methyl-2-butoxycarbonylamino, 1-hexyloxycarbonylamino, 2-hexyloxycarbonylamino, 3-hexyloxycarbonylamino, 2-methyl 1-yloxycarbonylamino group, 3-methyl-1-pentyloxycarbonylamino group, 2-ethyl-1-butoxycarbonylamino group, 2,2-dimethyl-1-butene An oxycarbonylamino group or a 2,3-dimethyl-1-butoxycarbonylamino group, preferably a (CrC^alkoxy)carbonylamino group, more preferably a (Ci-Cz alkoxy)carbonyl group Amine. The "(Ci-Q-alkylamino)carbonylamino group" is a carbonylamino group (-conh2-) whose carbon atom is substituted with one of the above-mentioned CrQ alkylamino groups, for example: methylaminocarbonylamino group Ethylaminocarbonylcarbonyl, 1-propylaminocarbonyl-28- 201124388 Amino, 2-propylaminocarbonylamino, 1-butylaminocarbonylamino, 2-butylaminocarbonyl Amino, 2-methyl-1-propylaminocarbonylamino, 2-methyl-2-propylaminocarbonylamino, 1-pentylaminocarbonylamino, 2-pentylaminocarbonyl Amino, 3-pentylaminocarbonylamino, 1-hexylaminocarbonylamino, 2-hexylaminocarbonylamino, or 3-hexylaminocarbonylamino, preferably (CrQ alkylamino) A carbonylamino group, more preferably a (Ci-Q alkylamino)carbonylamino group. The "di(CrCe alkyl)aminocarbonylamino group" is a carbonylamino group (-CONH2-) whose carbon atom is substituted with one of the above-mentioned bis(indenyl)alkyl groups, for example, a dimethylamino group. A carbonylamino group, a methylethylaminocarbonylamino group, a methylpropylaminocarbonylamino group [for example, N-methyl-N-(l-propyl)aminocarbonylamino group, etc.], methyl butyl Aminocarbonylcarbonylamino group [e.g., N-(l-butyl)-N-methylaminocarbonylamino group, etc.], methyl amylaminocarbonylamino group, methylhexylaminocarbonylamino group, Ethylaminocarbonylamino group, ethylpropylaminocarbonylamino group [for example, N-ethyl-N-(l-propyl)aminocarbonylamino group, etc.], ethylbutylaminocarbonylamino group , dipropylaminocarbonylamino, propylbutylaminocarbonylamino, dibutylaminocarbonylamino, dipentylaminocarbonylamino, or dihexylaminocarbonylamino, preferably The bis(CrQ alkyl)aminocarbonylamino group is more preferably a di(C^-Cz alkyl)aminocarbonylamino group. "(<^-(:6alkylamino)carbonyl"" may be a carbonyl group (-CO-) substituted with one of the above alkylamino groups, for example, methylaminocarbonyl, ethylaminocarbonyl , 1-propylaminocarbonyl, 2-propylaminocarbonyl, 1-butylaminocarbonyl, 2-butylaminocarbonyl, 2-methyl-1-propylaminocarbonyl, 2-methyl -2-propylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, -29- 201124388 3-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl Or a 3-hexylaminocarbonyl group, preferably a (CrQ alkylamino)carbonyl group, more preferably an alkylamino group)carbonyl group. The bis(Ci-Ce alkyl)aminocarbonyl group may be a carbonyl group (-CO-) substituted with one of the above-mentioned di(C丨-C6 alkyl)amino groups, for example, a dimethylaminocarbonyl group, Methyl ethylaminocarbonyl, methylpropylaminocarbonyl [for example, N-methyl-N-(l-propyl)aminocarbonyl, etc.], methylbutylaminocarbonyl [for example, N-( L-butyl)-N-methylaminocarbonyl, etc.], methyl amylaminocarbonyl, methylhexylaminocarbonyl, diethylaminocarbonyl, ethylpropylaminocarbonyl [eg, N- Ethyl-N-(l-propyl)aminocarbonyl, etc.], ethylbutylaminocarbonyl, dipropylaminocarbonyl, propylbutylaminocarbonyl, dibutylaminocarbonyl, dipentyl The aminocarbonyl group or the dihexylaminocarbonyl group is preferably a di(Ci-Q alkyl)aminocarbonyl group, more preferably a di(CmCzalkyl)aminocarbonyl group. "Adamantyl" may be adamantyl-1-yl [the following formula (Ilia)], or adamant-2-yl [the following formula (Illb)]

(INb) (Ilia) is best adamantane-2-yl. The substituent of the "substituted adamantyl group" is preferably a hydroxyl group, a C?-C6 alkoxy group, a (C1-C6-group) fluorenyloxy group, a (Ci-Ce alkoxy) or an oxo group, an amine. Mercapto, ((^-Ce alkylamino)carbonyl, or di(CrCe alkyl)aminocarbonyl (the alkyl is the same or different), more preferably hydroxyl, <^-(:2 alkane Oxyl, -30- 201124388 (Ci-C2 alkyl)carbonyloxy, (Cl_c2 alkoxy)carbonyloxy, aminemethionyl '(C,-C2 alkylamino)carbonyl, or di(C^ -G alkyl)aminocarbonyl (the alkyl group being the same or different), more preferably a hydroxyl group, a methoxy group, or an amine carbenyl group, most preferably a hydroxyl group. Substituted adamantane-1 - group The substituent may be substituted at the respective positions of 2 to 10, preferably 3 or 5, most preferably 3. The substituted adamantyl-1-yl substituent may be substituted in the cis or trans configuration. The substituted adamantyl-2-yl substituent may be substituted at the respective positions of the 1 and 3 to 10 positions, preferably at the 1, 3 or 5 position, and most preferably at the 5-position. The substituted adamantane-2 - the substituent may be substituted in a cis or trans configuration, preferably in a trans configuration The hydroxy-substituted adamantane-1 _ group is preferably a 3-hydroxyadamantan-1 -yl group [the following formula (IIU)]. The hydroxy-substituted adamantane-2-yl group is preferably trans- 5- Hydroxyadamantan-2-yl [the following formula (Illd)] or cis-5-hydroxyadamantan-2' group [the following formula (Ille)], preferably trans-5-hydroxyadamantane-2 The methoxy-substituted adamantane-2-yl group is preferably trans-5-methoxyadamantan-2-yl [the following formula (Illf)] or cis-5-methoxy gold Alk-2-yl [the following formula (Illg)], most preferably trans-5-methoxyadamantan-2-yl. The adamantyl-2-yl substituted by the amine mercapto group is preferably trans -5-Aminoguanidine fundane-2, a group [the following formula (Illh)] or a cis-5-amine formamidine fundane-2-yl [the following formula (ΙΙΠ)], the best is the opposite Formula-5-Amine formazan fundane-2-yl. -31- 201124388

OH

ΟΗ(llle)

(lllh)

The name of the compound nomenclature according to adamantane is three [3 .3 · 1.1 · 3'7] decane. The substitution position number of the group having the formula (II) is as shown in the following (II) rrn ring. R6

-32- 201124388

Preferred are 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorobenzene Or a 2-chloro-5-fluorophenyl group, more preferably 2-chlorophenyl, 5-fluoro-2-methylphenyl or 2-chloro-5-fluorophenyl. In the case where the compound (I), R3 is (Ci-Cs alkyl)carbonyl, (CrCe alkoxy)carbonyl, or substituted ((2,-(:6 alkoxy)carbonyl), the compound (I) is When administered to a mammalian living body, it is preferred that R3 can be liberated from a group having the formula -NH-R3 to form an amine group (-NH2) via metabolism (for example, hydrolysis). In the compound (I), R1 When the substituent of the adamantyl group is a Ci-Ce alkoxy group, when the compound (I) is administered into a living body of a mammal, the Ci-Cs alkyl group can be detached from the Ci-Cs alkoxy group via metabolism. A hydroxyl group is formed. When the substituent of the adamantyl group of the compound (I) 'R1 is a (Ci-Ce alkyl) ortho-oxy group or a (C^-C:6 alkoxy)carbonyloxy group, the compound is cast. When in vivo with a mammal, via (eg, hydrolysis), (C, _C6 -33- 201124388 alkyl)carbonyl or (ί^-(:6 alkoxy)carbonyl may be independently (CrG alkyl) It is preferred that the carbonyloxy group or the (C^-Ce alkoxy)carbonyloxy group is detached to form a hydroxyl group. The compound of the formula (I) of the present invention has a compound of the formula (1-1). good,

[wherein, R1, R2, R3, R4, R5, R6, R7, and R8 have the same meanings as in the formula]. The compound of the formula (I) of the present invention is preferably a compound of the examples. When the compound of the formula (I) of the present invention can form an acid addition salt, such acid addition salts are included in the present invention. Such acid addition salts, for example, hydrochloride, hydrogen bromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate, cis. Oleate salt, L-malic acid, D-malic acid, L-tartaric acid 'D-tartaric acid, decanoate, trifluoroacetate, methanesulfonate, ethanesulfonate, besylate, P -tosylate, 2,4-dimethylbenzenesulfonate, 2,4,6-trimethylbenzenesulfonate, 4-ethylbenzenesulfonate, or naphthalenesulfonate, preferably Fumarate (especially, a fumarate), ethanesulfonate, besylate, or p-toluenesulfonate-34- 201124388 salt 'best is fumarate (especially, a fumarate). The compound of the formula (I) of the present invention can form an acid and acid addition salt in any ratio, and the respective acid addition salts (for example, 1 acid salt, 2 acid salt, 1/2 acid salt), or Mixtures of these are included in the present invention. The compound of the present invention having a formula (I) or a pharmacologically acceptable salt thereof can form an anhydrate, a hydrate or a solvate, and various or a mixture thereof is included in the present invention. The compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention has at least one asymmetric center, a carbon-carbon double bond, an asymmetric axis, etc., and may contain optical isomers (including Enantiomers and diastereomers), geometric isomers, and rotamer isomers, such isomers and mixtures thereof are described in a single formula of formula (I). A mixture of such isomers and such proportions (including racemates) is included. The compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof can form an isotope compound in which one or more of the atoms constituting the above are substituted with an isotope atom at a non-natural ratio. The isotope atom may be radioactive or non-radioactive, for example, heavy hydrogen (2 Η ; D ), 氚 (3 η ; T ), carbon-14 (14 c ), iodine - 1 2 5 (12 5 1 ), and the like. The radioactive or non-radioactive isotope compound can be used as a medicine for the treatment or prevention of a disease, a reagent for research (for example, an reagent for analysis), a diagnostic drug (for example, an imaging diagnostic drug), and the like. The present invention encompasses radioactive or non-radioactive isotopic compounds. In the present invention, hypertension includes hypertensive diseases of a generally known state, for example, essential hypertension, renal hypertension, endocrine hypertension, 35-201124388, neuropathy, or Primary or secondary pulmonary hypertension. The compounds of the present invention having the general formulae (I) and (1-1) can be subjected to the following A methods (A method-1, A method-2, and method A-3), method B, method C, method D, Or manufactured by E method (E method-1 and E method-2). -36- 201124388 A law one 1 OH (1) A - 1 project

A - 2 Engineering R2CHCOXa (2) (3) A — 3 Engineering (4) R2

Me ^OBn /OBn A-4 project _^R2/

Xb A - 5 project

••',f N3

-37- 201124388 A law one 2

A —1 1 Project R1NH2 (14) R6

-38- 201124388 A law one 3 R4

A — 1 2 Engineering R3aXc R1.

H (15) 201124388 Method B

(16) 巳一 2 Engineering R6

-40- 201124388 c法

C-1 Engineering R6

(18) R6

(19) C-2 Project

XdCH2COXd (20) R6

C-3 Project (21)

-41 - 201124388 D method

(26) R2

-42- 201124388 E-A-1

(30) E - 3 Engineering R6

-43- (31) 201124388 E Law 1 2 E-4 Project -► E - 5 Engineering R1NH2 (14) E - 6 Project

(32)

(la) -44- 201124388 The structural formulae of the compounds of the above methods A to E, R1, R2, R4, R5, R6' R7' and R8 represent the same meaning as in the formula, and represent the definition in R3 (C^ C: 6 alkyl)carbonyl, (CrC6 alkoxy)carbonyl, or substituted alkoxy)carbonyl, Ra represents Cl_C6 alkyl, X, xb, and oxime (1 independently represents chloro, bromo, or Iodine group, Xe represents a chloro group, a bromo group, an iodo group, or a methanesulfonyloxy group, Bn represents a benzyl group, Boc represents a secondary butoxy group, Ms represents a sulfonyl group, and Ns represents a sulfonium group. a compound which is a starting material in the reaction of each of the following A to E processes, and a compound having an amine group, a hydroxyl group carboxyl group or the like which inhibits a desired reaction, and may be suitably used as necessary These groups are introduced into the protecting group and the introduced protecting group. The protecting group is not particularly limited as long as it is a commonly used protecting group, for example, TW Greene, PG Wuts, Greene's Protective Groups In Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc. The reaction for introducing and removing such a protecting group can be carried out by the method described in the above-mentioned literature or by the method according to the above method. The solvent used in the reaction of each of the following A methods from the E method will start as long as the reaction is not inhibited. A part of the raw material is dissolved, which is not particularly limited. For example, it is selected from the group consisting of the following: The solvent group is composed of the following: aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; , aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl Ether, -45- 201124388 ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, ring Ketones such as ketone; esters such as ethyl acetate, propyl acetate, butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; carboxylic acids such as acetic acid and propionic acid Acids; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol '2-butanol, 2-methyl-1-propanol, 2-methyl-2- Alcohols such as alcohol; formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric acid, 1,3-dimethyl Indoleamines such as dimethyl-3,4,5,6-tetrahydro-211(111)-pyrimidinone (〇1^?1;): fluorenes such as dimethyl hydrazine and cyclobutyl hydrazine The water used in the reaction of each of the following E processes 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 composed of hydrochloric acid, hydrogen bromide acid, hydrogen iodide acid, phosphoric acid, sulfuric acid, inorganic acid such as nitric acid, acetic acid, propionic acid, trifluoroacetic acid, organic acid such as pentofluoropropionic acid, and methane. An organic sulfonic acid such as sulfonic acid, trifluoromethanesulfonic acid, P-toluenesulfonic acid or camphorsulfonic acid. The test used in the reaction of each of the following A to E methods 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 composed of lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonate such as carbonic acid planing; alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; lithium hydroxide and hydrogen An alkali metal hydroxide such as sodium oxide or potassium hydroxide; an alkaline earth metal hydroxide such as barium hydroxide or barium arsenide; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; - 201124388 Alkali metal amides such as lithium decylamine, sodium decylamine, potassium decylamine; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium butoxide or potassium t-butoxide; Lithium alkyl decylamine such as lithium diisopropyl decylamine; decyl decylamine such as lithium bistrimethyl decyl decylamine or sodium bistrimethyl decyl decylamine; η-butyllithium, Alkyl lithium such as butyl lithium or tertiary butyl lithium; methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, chlorinated a propyl group, a brominated isopropyl group, an alkyl magnesium halide such as isobutyl magnesium; and a triethylamine, a tributylamine, a diisopropyl group Amine, Ν-methyl piperidine, Ν-methylmorpholine, Ν-ethyl phlomatolin, pyridine, picoline, 4-(anthracene, fluorenyl-dimethylamino)pyridine, 4-pyrrole Pyridylpyridine, 2,6-di(tributyl)-4-methylpyridine, quinoline, hydrazine, hydrazine-dimethylaniline, anthracene, fluorene-diethylaniline, 1,5-dioxinbicyclo [4,3,0]non-5-ene (DBN), 1,4-dioxabicyclo[2,2,2]octane (DABCO), 1,8-di-bicyclo[5,4,0] Organic amine such as eleven-7-ene (DBU). The reaction temperature varies depending on the solvent, the starting materials, the reagents, and the like, and the reaction time varies depending on the solvent, the starting materials, the reagents, the reaction temperature, and the like. In the reaction of each of the following A to E processes, after the reaction is completed, the target compound of each project is isolated from the reaction mixture by a usual method. The objective compound can be obtained, for example, by (i) filtering out insoluble matter of a catalyst or the like as necessary, and (ii) adding water and a solvent which does not mix with water in the reaction mixture (for example, dichloromethane). The ethyl acetate and the like are extracted to obtain the objective compound, (iii) the organic layer is washed with water, and a drying agent such as anhydrous magnesium sulfate is used to dry -47 to 201124388, and (iv) the solvent is distilled off. The obtained target compound can be used in the next reaction by a usual method (for example, recrystallization, reprecipitation, or ruthenium column layer: further, the compound of interest for each project may not be used for the next reaction. For each of the E-processes, optical isomers can be separated by separate recrystallization of an optically active amine such as (R) 1 *-phenethylamine or separation of a useful column. Reaction to each of the E-processes (A method) The A method is a method for producing the compound (I) and the compound (1-1) (la) or (lb). (A-1 project) A-1 The engineering system allows the compound (1) to react with a compound in the presence of a base. The compound (1) can be produced according to the method described in Tetrahedron Lett., Vol. 28, p. 6497. Compound (2 known or can be known from known compounds) It is preferably obtained. The base used is preferably an alkali metal hydrogencarbonate, an alkali metal hydroxide alkali metal hydride, an alkali metal decylamine, an alkali metal alkoxide, a lithium amine, a decyl decylamine, an alkyl lithium, an alkyl halide. a combination of magnesium, an organic amine, more preferably an alkyl magnesium halide, organic Or such a group is preferably ethylmagnesium bromide, triethylamine, 4-(anthracene, dimethylamino) or a combination thereof. The solvent used is preferably an aliphatic hydrocarbon. Aromatic hydrocarbons, required, jin, etc., while direct K (S) optically active compounds. (2), 1989) are compounds, alkyl hydrazines or the like, the most mouth-to-mouth, halogenated hydrocarbons -48- 201124388 Classes, ethers, or vinegars, more preferably ethers or halogenated hydrocarbons, most preferably dichlorocarbyl or tetrahydrofuran. The reaction temperature is preferably -78 to 150 °C, more preferably -30 to 40 °C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 15 minutes to 48 hours. (A-2 Project) The A-2 project is a project in which the compound (3) obtained by the A-1 project is treated with a hydrazine alkylating agent and a base. The ruthenium alkylating agent to be used may be, for example, chlorotrimethane such as chlorotrimethyl decane, chlorotriethyl decane or tertiary dimethyl dimethyl chlorodecane, or trimethyl decyl trifluoromethanesulfonic acid. a decyl trifluoromethanesulfonate such as ester, triethyl decyl trifluoromethanesulfonate or tert-butyl dimethyl decyl trifluoromethanesulfonate, preferably chlorodecane, most Preferably it is chlorotrimethyl decane. The base to be used is preferably a lithium alkyl decylamine, a decyl decylamine or an alkyl lithium, more preferably a lithium alkyl decylamine, and most preferably lithium diisopropyl decylamine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether, more preferably an ether, and most preferably tetrahydrofuran. The reaction temperature is preferably -78 to 100 ° C, more preferably -78 to 40 ° C. The reaction time is preferably from 30 minutes to 96 hours, more preferably from 1 to 24 hours. (A-3 Project) The A-3 project consists of the following works: (A - 3 a project) · The project of reacting the compound (4) obtained by the A-2 project with the _-49-201124388 reagent; (A - 3 b project): A project in which a compound obtained by the A-3a process is reacted with dimethylamine in the presence of a base. (A-3a project) The halogenating agent used may be, for example, thionyl chloride; phosphorus trichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or halogenated phosphorus pentabromide. Phosphorus; chlorinated grass mash; combination of halogenated carbons such as carbon tetrachloride, carbon tetrabromide, hexachloroethane and triphenylphosphine; and N-chlorosuccinimide, N-bromosinium The N-halo succinimide, such as an amine, is preferably sulfinium chloride or chlorinated mash, and is preferably chlorinated mash. The combination of the above halogenating agent and hydrazine, hydrazine-dimethylformamide is more preferable. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, or a nitrile, more preferably an aromatic hydrocarbon or a halogenated hydrocarbon, and most preferably dichloromethane. The work can also be carried out in the absence of a solvent. The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 80 ° C. The reaction time is preferably from 30 minutes to 96 hours, more preferably from 60 minutes to 6 hours. (A-3b engineering) The base to be used is preferably an alkali metal hydrogencarbonate, an alkali metal hydroxide, an alkali metal hydride, an alkali metal decylamine, an alkali metal alkoxide, a lithium alkyl decylamine or a decyl decyl amide. An alkyl lithium or an organic amine, more preferably an organic amine, most preferably a dimethylamine. In the present process, it is preferred to use an alcohol solution or an aqueous solution of dimethylamine, more preferably an aqueous solution of dimethylamine. -50- 201124388 The solvent used is the same as the A-3a project. The reaction temperature is preferably -78 to 150 °C, more preferably -30 to 40 °C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 5 minutes to 24 hours. The compound (4) in the A-3 process can also be reacted with dimethylamine in the presence of a condensing agent. The condensing agent to be used is not particularly limited as long as it is used for the amide amination reaction, and can be described in RC Larock, Comprehensive Organic Transformations. Second E diti ο n, 1989, J ohn W i 1 ey &; condensing agent of Sons, Inc., etc. The condensing agent to be used may be, for example, (i) a combination of a phosphate such as diethylphosphonium cyanide and a base selected from the above-mentioned base group; (ii) 1,3-dicyclohexylcarbodiimide a carbodiimide such as an amine, a 1,3-diisopropylcarbodiimide or a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC); the above carbonization a combination of a diimine and a base selected from the above base; a combination of the above carbodiimide with an N-hydroxy compound such as N-hydroxysuccinimide; or (iii) N,N'-carbonyl Imidazoles such as imidazole (CDI). (A-4 Project) The A-4 project is a process in which the compound (5) obtained in the A-3 project is treated with a halogenating reagent (the halogenating reagent has a halogen group represented by Xb). The halogenating reagent used may be a halogen such as chlorine, bromine or iodine; N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-51-201124388 N-halothenamine such as -5,5-dimethylhydantoin; α-haloketone such as 5,5-dibromo-methane acid, preferably N-halofluorene The amine is preferably bismuth-bromosuccinimide. In the present process, the halogenating agent is preferably a bromination reagent. In the present project, an additive may be suitably used in combination with the above halogenating agent as needed. The additive used is preferably acetic acid or sodium dihydrogen phosphate, and most preferably acetic acid. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile 'melamine, water, or a mixture thereof, and more preferably a mixture of an ether and water. Most preferred is a mixture of tetrahydrofuran and water. The reaction temperature is preferably -78 to 150 °C, more preferably -30 to 401. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 24 hours. (A-5 project) The A-5 project is a process in which the compound (6) obtained by the A_4 project is treated with a guanidine reagent. The amide amide reagent used may be, for example, a metal azide such as lithium azide or sodium azide; ammonium azide such as tetra-n-butylammonium azide; or trimethyl A mercaptoalkylamine such as a decyl decylamine is preferably a metal azide, most preferably sodium azide. In this project, an additive may be suitably used in combination with the above-described amide amination reagent as necessary. The additive to be used is preferably interphase between tetra-n-butyl bromide, octyltriethyl chloride, Aliquat 336 (registered trademark), 15-crown-5-ether, 18-crown-6-ether. Move the catalyst. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon - 52 - 201124388, an ether, an ester, a nitrile, a guanamine, an anthraquinone, water, or a mixture thereof. Preferably, it is a mixture of guanamines, anthraquinones, or aromatic hydrocarbons with water, preferably 1,3 -dimethyl-3,4,5,6-tetrahydro-2H(1H)-pyrimidinone ( DMPU). The reaction temperature is preferably from 0 to 150 ° C, more preferably from 20 to 100 ° C, most preferably from 40 to 60 ° C. The reaction time is preferably from 5 minutes to 7 days, more preferably from 30 minutes to 96 hours. (A-6 Project) The A-6 Engineering Department is the project to restore the compound (7) obtained from the A-5 project. This project is preferably carried out by catalytic reduction. The catalytic reduction process is carried out in the presence of a catalyst and in a hydrogen atmosphere. The catalyst to be used may be, for example, palladium such as palladium-carbon, palladium rhodium, palladium hydroxide, palladium-barium sulfate; platinum platinum, platinum or the like; bismuth-aluminum hydride, ruthenium chloride- An anthracene such as triphenylphosphine; or a nickel such as Raney nickel, preferably palladium, most preferably palladium-carbon. The hydrogen pressure in the catalytic reduction method is preferably from 1 to 10 atmospheres, more preferably 1 atmosphere. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile 'alcohol, a guanamine, water, or a mixture thereof, more preferably an ether or Alcohols, preferably ethanol. For this project, acid may be used as necessary. The acid used may be, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, or p-toluenesulfonic acid, and most preferably -53-201124388 is hydrochloric acid. In the case of using acid in this project, the compound of the purpose of this project can obtain a salt corresponding to the acid used. The reaction temperature is preferably from -20 to 200 ° C, more preferably from 0 to 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 15 minutes to 24 hours. (A-7 Project) The A-7 project is a project in which the compound (8) obtained in the A_6 project is reacted with hydrazine-nitrobenzenesulfonium chloride in the presence of a base. 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 organic amine, and most preferably a triethylamine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, an alcohol, a guanamine, water, or a mixture thereof, and more preferably an ether and A mixture of water, preferably a mixture of tetrahydrofuran and water. The reaction temperature is preferably -78 to 150 °C, more preferably -30 to 40. (: The reaction time is preferably from 5 minutes to 96 hours, more preferably from 5 minutes to 24 hours. (A-8 project) A-8 engineering is a compound obtained by treating a _ 7 with a dehydrating condensing agent (9) The dehydrating condensing agent to be used is preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, dimethyl decyl azodicarboxylate or diisopropyl azodicarboxylate-54. - 201124388 Azodicarboxylic acid compound such as pyridine amine, combined with phosphines such as triphenylphosphine and diphenylphosphine polystyrene carrier, preferably diethyl azodicarboxylate and three A combination of phenylphosphine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile or a guanamine, more preferably an aromatic hydrocarbon or an ether. Preferably, the reaction temperature of tetrahydrofuran 6 is preferably -78 to 150 ° C, more preferably 0 to 60 ° C. The reaction time is preferably from 1 minute to 24 hours, more preferably from 1 minute to 1 hour. 9 Engineering) The A-9 engineering is a project for reacting a compound (丨〇) with a compound (丨丨). The compound (11) can be produced according to the following C method. The solvent used is preferably a fat. An aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester 'nitrile, or a decylamine, more preferably an aromatic hydrocarbon or an ether, and most preferably toluene. The reaction temperature is preferably 0. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 15 minutes to 24 hours. (A-10 project) The A-10 project is composed of the following: (Α-lOa project): a process in which a compound (12) obtained by a-9 engineering is treated with a deprotecting reagent in the presence of a base; and (Α-lOb engineering): A_10a is present in the presence of a base The engineering obtained the reaction of the compound of -55- 201124388 with the di-tertiary butyl-dicarbonate. (A -10 a engineering) The deprotecting reagent used may be, for example, methylamine or dimethylamine. , ethylamine, diethylamine, η-propylamine, η-butylamine, pyrrole, piperidine, morphine, pipe trap, Ν-methyl piperazine, hydrazine, hydrazine, hydrazine-dimethyl a primary or secondary amine such as hydrazine; or a thiol such as methyl mercaptan, ethanethiol, η-propyl mercaptan, η-butyl mercaptan, thiophenol or thioglycolic acid, preferably mercaptan Class, the best is sulphur. The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, an alkali metal decylamine, an alkali metal alkoxide, a lithium alkyl decylamine, a decyl decylamine, an alkyl lithium, or an organic The amine, more preferably an alkali metal carbonate, is preferably a carbonic acid planer. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, a guanamine or the like. The mixture is more preferably a nitrile or a guanamine, and is preferably ruthenium or dimethylformamide. In the present process, an organic amine can also be used as a solvent. The reaction temperature is preferably -78 to 200 ° C. More preferably, it is up to 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 15 minutes to 24 hours. (Α-lOb engineering) The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, a metal alkoxide or an organic amine, more preferably an alkali metal hydrogencarbonate or an organic amine. Most preferred is sodium bicarbonate. -56- 201124388 The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a vinegar, a nitrile, a guanamine, water, or a mixture thereof, more preferably a halogenated hydrocarbon, and A mixture of an ester and water, preferably a mixture of ethyl acetate and water. Organic amines can also be used as solvents in this project. The reaction temperature is preferably -78 to 150C, more preferably 〇 to 100 °C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 48 hours. The above examples exemplify the use of a tertiary butoxycarbonyl group, but the protecting group which can be used in the Ob·1 Ob project is not limited to a tertiary butoxycarbonyl group, and is used as a protecting group for an alkalamine group, and can be used in the field of general organic synthetic chemistry. a well-known protecting group (eg 'TW Greene, PG Wuts, Protective Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons,

Inc.). Suitable protecting groups can be, for example, mercapto, ethenyl, chloroethyl, trimethylethenyl, benzinyl, fluorenyl; methoxycarbonyl, ethoxycarbonyl, tertiary Alkoxycarbonyl group such as butoxycarbonyl or benzyloxycarbonyl; methoxymethyl, 2-(trimethyldecyl)ethoxymethyl, benzyloxymethyl, allyl, benzyl Substituted alkyl group; methanesulfonyl, benzenesulfonyl, ρ·toluenesulfonyl, fluorenyl-nitrophenylsulfonyl, o,p-dinitrobenzenesulfonyl Most preferred is a tertiary butoxycarbonyl group. (A-1 1 Project) The A-11 project consists of the following: (A-lla project): a project in which a compound (13) obtained by the A-10 project is reacted with a compound (14) in the presence of a reagent; And -57- 201124388 (A-lib Engineering): Engineering for removing the tertiary butoxycarbonyl group of the compound obtained by the A-lla process in the presence of an acid. The compound (1 4 ) can be easily obtained by a known or self-known compound. The A-lla project can also be carried out according to methods well known in the art of general organic synthetic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc., p. 1973-1976) 〇 (A-1 1 a engineering) The reagents used may be, for example, sodium cyanide, potassium cyanide, cyano compounds such as tetra-n-butylammonium cyanide; organoaluminum compounds such as trimethylaluminum; a halogenated organomagnesium compound such as magnesium, ethylmagnesium iodide, ethylmagnesium bromide or isopropylmagnesium chloride; an organic acid such as acetic acid; or an organic amphoteric compound such as 2-hydroxypyrrole Good for organic amphoteric compounds, the best is 2-path base shame. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a guanamine or a mixture thereof. The solvent used in this work is more preferably an organic amine 'optimally triethylamine. The reaction may also be carried out using an excess of the compound (14) in the absence of a solvent. The reaction temperature is preferably -78 to 200 ° C, more preferably 0 to 150 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 24 hours. (A - 1 1 b engineering) The acid used may preferably be hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methyl-58-201124388 alkanesulfonic acid, trifluoromethanesulfonic acid, or P-toluenesulfonic acid, more preferably Hydrochloric acid (especially -1,4-dioxane hydrochloride) or trifluoroacetic acid is preferred as trifluoroacetic acid. The solvent to be used is preferably an aliphatic hydrocarbon, a halogenated hydrocarbon, an ester, an alcohol, or a decylamine, more preferably a halogenated hydrocarbon, and most preferably dichloromethane. The reaction temperature is preferably -78 to 150 ° C, more preferably -30 to 80 ° C, still more preferably 0 to 50 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 5 minutes to 12 hours. In the A-1 Ob project, where a protecting group other than a tertiary butoxycarbonyl group is used as a protecting group for the amine group, the removal of such protecting groups in the A-llb engineering can be based on the well-known in the field of general organic synthetic chemistry. The method is carried out (for example, TW Greene, PG Wuts, Protective Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.). (A - 1 2 Project) A- 1 2 Engineering is a project in which a compound (la) obtained by A-1i engineering is reacted with a compound (15) in the presence of a base. The compound (15) can be easily obtained by a known or self-known compound. This work can also be carried out according to methods well known in the art of general organic synthetic chemistry (for example, Comprehensive Ο rg an ic T ra η sformati ο ns, S ec ο nd E diti ο η, 1999, John Wiley & Sons, Inc.) The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, or an organic amine. The solvent to be used is preferably an aromatic hydrocarbon, a halogenated hydrocarbon or an ester. -59- 201124388 The reaction temperature is preferably from -20 to 150 °C. The reaction time is preferably from 5 minutes to 48 hours. In the method A, a compound (la) or a (lb) racemate can be produced by using the racemate of the compound (1) as a starting material. (Method B) The B method is a method for producing a compound (la) contained in the compound (I) and the compound (ι). (B-1 project) The B-1 project is a process in which a compound (12) obtained by the A-9 project is reacted with a compound (14) in the presence of a reagent. The B-1 project can be carried out in the same way as the A-lla project. (B-2 Project) The B-2 project is a process in which the compound (16) obtained by the B-1 project is treated with a deprotecting reagent in the presence of a base. The B-2 project can be carried out in the same way as the Α-lOa project. (Method C) The C method is a method of producing the compound (11) used in the A-9 project. (C-1 Project) The C-1 project is a process in which a compound (17) is reacted with a compound (18) in the presence of a reducing agent. The compounds (17) and (18) are known or readily obtained from known compounds. The work can also be carried out according to methods well known in the art of general organic synthesis chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, -60-201124388).

Inc., ρ·835-846) ° The reducing agent used may be, for example, a decane-tetrahydrofuran complex, a borane-dimethyl sulfide complex, a borane-dimethylamine complex, Borane compound such as borane-pyridine complex; boron hydride compound such as sodium borohydride, sodium cyanoborohydride, cyanoborohydride tetra-n-butylammonium or sodium triethoxy borohydride An aluminum hydride compound such as lithium aluminum hydride, aluminum hydride or diisobutylaluminum hydride; or hydrogen, preferably a boron hydride compound, most preferably sodium cyanoborohydride or sodium triethoxy borohydride. In the present process, it is preferred to combine the above reducing agent with an acid such as hydrochloric acid, formic acid, acetic acid or trifluoroacetic acid (preferably acetic acid). The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, an alcohol, a guanamine or water, more preferably a halogenated hydrocarbon or an alcohol, most preferably Good is dichloromethane or methanol. The reaction temperature is preferably from -78 to 150 ° C, more preferably from 0 to 1 Torr. Hey. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 30 minutes to 48 hours. (C-2 Project) The C-2 project is a process in which a compound (1 9 ) obtained by a C-1 project is reacted with a compound (20) in the presence of a base. The compound (2 〇 ) is known or can be easily obtained from a known compound. The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, a metal hydride, an alkali metal alkoxide or an organic amine, more preferably a metal hydrogencarbonate, most preferably sodium hydrogencarbonate. -61 - 201124388 The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, a guanamine, water, or a mixture thereof, preferably an ester and water. The mixture, or guanamine, is preferably a mixture of ethyl acetate and water, or N,N-dimethylacetamide. Organic amines can also be used as solvents in this project. The reaction temperature is preferably -78 to 150 ° C, more preferably 0 to 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 1 minute to 24 hours. (C-3 Project) The C-3 Engineering Department works on the alkali treatment of the compound (21) obtained in the C-2 project. The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, an alkali metal decylamine, an alkali metal alkoxide, a lithium alkyl decylamine, a decyl decylamine, or an organic amine, more preferably It is preferably an alkali metal carbonate or an alkali metal alkoxide, preferably a carbonic acid planer or a potassium-tertiary butoxide. The reaction temperature is preferably -78 to 200 °C, more preferably -78 to 80. (:, more preferably -78 to 20 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 5 minutes to 24 hours 'more preferably from 5 minutes to 6 hours. (C-4 Engineering) The C-4 project is a process for removing the tertiary butoxycarbonyl group of the compound (22) obtained in the c-3 project in the presence of an acid. The C-4 project can be carried out in the same manner as in the A-llb process. -62- 201124388 (D method) Method D is a method for producing compound (7) used in A-6 project. (D-1 project) D-1 project is to make compound (23) and compound in the presence of a base. (24) Engineering of the reaction. The compound (23) and the compound (24) are known or can be easily obtained from a known compound. The base to be used is preferably a lithium alkyl decylamine, a decyl decylamine, an alkyl lithium, or The organic amine, more preferably a decyl decylamine, is preferably sodium bistrimethyl decyl decylamine. In this project, an additive may be used as necessary. When lithium alkyl decylamine or decyl decylamine is used as a base The additive used may be, for example, guanamine phosphate such as hexamethylphosphoniumamine (HMPA); or 1,3-dimethyl-3,4,5,6-tetrahydro-2 a cyclic urea such as 11(11-pyrimidinone (0\^1;). In the case of using an organic amine as a base, an additive such as dibutylborate triflate or titanium chloride is used. The Lewis acid used in (IV). The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon or an ether, more preferably an ether, and most preferably tetrahydrofuran. -78 to 6 (TC, more preferably -40 to - 20 ° C. The reaction time is preferably 5 minutes to 96 hours, more preferably 15 minutes to 24 hours. (D-2 Engineering) D-2 Engineering is The hydrolysis of the compound (25) obtained in the D-1 project in the presence of a base. -63- 201124388 The alkali metal carbonate, the alkali metal bicarbonate, the alkali metal hydroxide, the alkaline earth metal hydrogen used. The combination of an oxide, an alkali metal hydroxide and hydrogen peroxide water, or a combination of an alkaline earth metal hydroxide and hydrogen peroxide water is preferably a combination of an alkali metal hydroxide and hydrogen peroxide water, preferably A combination of lithium hydroxide and hydrogen peroxide water. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, an ether or an alcohol. Water, or a mixture of these, more preferably a mixture of ether and water, preferably a mixture of tetrahydrofuran and water. The reaction temperature is preferably -78 to 100 ° C, more preferably -30 to 4 CTC. Preferably, it is from 30 minutes to 96 hours, more preferably from 60 minutes to 24 hours. The compound obtained in the D-2 project (26) or other engineering obtained compounds is via dehydroabietylamine or the like. The respective optically active amines are recrystallized and purified to separate undesired isomers. (D-3 Project) The D-3 Engineering Department is a project in which the compound (26) obtained in the D-2 project is asymmetrically acidified and simultaneously cyclized. Asymmetric acidification in the D-3 process can also be carried out by methods well known in the art of organic synthetic chemistry (for example, Acc. Chem. Res., 2004, Vol. 37, p. 488). A method of using a combination of an optically active ketone compound produced by D engineering from a D-fructose and an oxidizing agent such as a potassium persulfate preparation (Oxone (registered trademark)) is preferred. The oxidizing agent used, for example, Oxone or hydrogen peroxide water, preferably -64-201124388

Oxone. These oxidizing agents can be used in combination with an additive such as tetra-diethyl hydrogen sulfate. A combination of Oxone and tetra-n-butylammonium hydrogen sulfate is preferred. The solvent to be used is preferably an ether, a nitrile, water, or a mixture thereof, more preferably a mixture of dimethoxymethane, acetonitrile, and water. The reaction temperature is preferably from 〇 to 20 °C. The reaction time is preferably from 4 to 12 hours. (D-4 Project) The D-4 project is a project in which the compound (27) obtained in the D-3 project is reacted with methanesulfonyl chloride in the presence of a base. The base to be used is preferably an alkali metal hydride, a lithium alkyl decylamine, a decyl decylamine or an organic amine, more preferably an organic amine, most preferably a triethylamine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile or a guanamine, more preferably a halogenated hydrocarbon, and most preferably a dichlorocarbyl. The reaction temperature is preferably from -7 8 to 150 ° C, more preferably from -3 0 to 40 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 10 minutes to 24 hours. (D-5 Project) The D-5 project works on the compound (28) obtained by treating the D-4 project with an azide reagent. The D-5 project can be carried out in the same way as the A-5 project. (E method) -65- 201124388 The E method is another method for producing the compound (la) contained in the compound (I) and the compound (1-1). (E-1 Project) The E-1 project is a process in which the compound (13) obtained in the A-10 project is selectively hydrolyzed in the lactone site in the presence of a base. The E-1 project can also be carried out according to methods well known in the art of general organic synthetic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc. > p · 1 9 5 9 - 1 9 6 7) ° The base used is an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably an alkali metal hydroxide, most preferably sodium hydroxide. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, an ether, an alcohol, water, or a mixture thereof, and more preferably a mixture of an ether and an alcohol and water, preferably tetrahydrofuran and methanol. a mixture of water. The reaction temperature is preferably -78 to 100 °C, more preferably -30 to 40 °C. The reaction time is preferably from 30 minutes to 96 hours, more preferably from 60 minutes to 24 hours. (E-2 Project) The E-2 project is a project in which the compound (29) obtained by the E-1 project is methylated in the presence of a reagent. The E-2 project can also be carried out in a well-known manner in the field of general organic synthetic chemistry (for example, Comprehensive Organic Transformations» Second Edition, 1999, John Wiley & Sons, Inc., p. 1 9 3 2 - 1 94 1 ) ° -66- 201124388 The methyl esterification reagent used is preferably diazomethane and trimethylsulfonyl diazobenzene. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, methanol, or a mixture thereof, and is preferably a mixture of toluene and methanol. The reaction temperature is preferably -78 to 100 °C, more preferably -30 to 40 °C. The reaction time is preferably from 1 minute to 24 hours, more preferably from 5 minutes to 2 hours. In the above, an example in which a methyl ester group is used is not limited to a protecting group methyl ester group which can be used in the E-2 project, and a protective group known in the field of general organic synthetic chemistry as a protecting group for a carboxylic acid can be used ( For example, TW Greene, PG Wuts, Protective Groups in Organic Synthesis Fourth Edition, 2007, John Wiley & Sons, Inc.). A suitable protecting group may be, for example, an ester group such as a methyl ester group, an ethyl group, a benzyl group or a p-methoxybenzyl group, and most preferably a methyl ester group. (E-3 project) The E-3 engineering system dimethylacetalizes the compound (30) obtained in the E-2 project in the presence of a dimethyl acetalization reagent and an acid catalyst. engineering. The E-3 project can also be carried out according to methods well known in the art of general organic synthetic chemistry (for example, TW Greene, PG Wuts, Protective Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc., p. 306- 318). The dimethyl acetalization reagent to be used is preferably acetone, 2,2-dimethyl-67-201124388 oxypropane, and 2-methoxypropane, more preferably 2,2-dimethoxypropane. The acidic catalyst used is preferably an organic acid, an organic acid, an organic sulfonic acid, and an organic alkali salt of an organic sulfonic acid, more preferably an organic alkali salt of an organic sulfonic acid, preferably a P-toluene acid-expanding solution. salt. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, a guanamine or a mixture thereof, and is preferably N,N-dimethylformamide. The reaction temperature is preferably from -30 to 12 (TC, more preferably from 0 to 80 ° C. The reaction time is preferably from 5 minutes to 96 hours, more preferably from 60 minutes to 12 hours. The above shows the use of dimethyl condensate An example of an aldehyde group, but the protecting group used in the E-3 process is not limited to a dimethyl acetal group, and a protecting group generally known in the field of synthetic chemistry can be used as a simultaneous protection of an adjacent hydroxy group and an amine mercapto group. Base (for example, TW Greene, PG Wuts, Protective Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.). Preferred protecting groups can be, for example, ethylene acetal, ASIM Amyl acetal, benzylidene acetal, P-methoxybenzylidene acetal, dimethyl acetal, diethyl acetal, cyclopentyl acetal The acetal group such as a cyclohexyl acetal group is preferably a dimethyl acetal group. (E-4 Engineering) The E-4 engineering is obtained by the E-3 project in the presence of a base. Compound (31), which selectively hydrolyzes the lactone moiety and converts it to the corresponding carboxylic acid body - 68-201124388. The E-4 project can also be based on general organic synthesis. A well-known method in the field of chemistry is carried out (for example, C 〇mprehen sive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc., p. 1959-1967). The base used is an alkali metal carbonate or an alkali metal. A bicarbonate, an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably an alkali metal hydroxide, most preferably sodium aroxide. The solvent to be used is preferably an aliphatic hydrocarbon or an aromatic hydrocarbon. An ether, an alcohol, water, or a mixture thereof, more preferably a mixture of an ether and an alcohol and water, preferably a mixture of tetrahydrofuran and methanol and water. The reaction temperature is preferably from -30 to 100 ° C. More preferably, the temperature is from 70 to C. The reaction time is preferably from 30 minutes to 96 hours, more preferably from 2 hours to 48 hours. (E-5 Engineering) E-5 Engineering is used to make the E-4 project in the presence of a reagent. The obtained compound (32) is reacted with the compound (14). The E-5 project can also be carried out according to a method well known in the art of general organic synthetic chemistry (for example, Comprehensive Organic Transformations > Second Edition, 199 99, John Wiley & Sons, Inc., P.1941-1949) ° The condensation reagent used, preferably 〇-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU) . The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, an ether, an alcohol, a guanamine, water, or the like - 69- 201124388 More preferably, it is an amine, preferably N,N-dimethylformamide: the reaction temperature is preferably -78 to 100 ° C, more preferably -30 to a reaction time of preferably 1 〇 minutes to 96 Hours, preferably 4 hours. (E-6 Project) The E-6 project is based on the acid. The E-5 project can obtain the (3) tertiary butoxycarbonyl group and the dimethyl acetal group to remove the E-6 project. Well-known in the field of organic synthetic chemistry (for example, TW Greene, PG Wuts, Protective

Organic Synthesis. Fourth Edition, 2007, John V Sons, Inc.) The acid used is preferably an inorganic acid, an organic acid, and an organically determined inorganic acid, most preferably hydrochloric acid. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a ketone 'ether, an alcohol, water, or a mixture thereof, and an alcohol. The reaction temperature is preferably from -7 to 10 ° C, more preferably from 0 to the reaction time, preferably from 5 minutes to 96 hours, more preferably 4 hours. The compound of the present invention having a compound of the formula (I) or a pharmacologically acceptable salt thereof can be used as a medicine, and can be administered as it is, or can be used as a suitable pharmaceutically acceptable lozenge, granule or powder. Or a syrup preparation, etc., orally, .40〇C. 30 minutes to the compound: the project. The method into Groups in /i 1 ey & citric acid, better [, halogenated hydrocarbon best for A 6 5. 〇 30 minutes to two allowable original form) Capsules, or as a preparation of -70-201124388 injections, suppositories, or patches, etc., not administered orally (preferably orally) . These preparations use additives such as excipients, binders, breakers, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, oleaginous bases, water-soluble bases, and the like. It is manufactured in a well-known manner. The excipient can be, for example, an organic excipient or an inorganic excipient. The organic excipient may be a sugar derivative such as lactose, white sugar, glucose, mannitol or sorbitol; starch derived from corn starch, potato starch, starch, dextrin, carboxymethyl starch or the like. a crystalline cellulose, a low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose such as internal cross-linked carboxymethylcellulose sodium Derivatives; gum arabic; dextran; or pullulan (Pullulan) and the like. Inorganic excipients, for example, light anhydrous citric acid, synthetic citrate derivatives such as calcium citrate or calcium citrate; phosphates such as calcium phosphate; or sulfates such as calcium sulfate. The binding agent may be, for example, the above-mentioned excipient; gelatin; polyvinylpyrrolidone; or polyethylene glycol. The breaker may be, for example, the above-mentioned excipient: chemically modified starch or cellulose derivative such as croscarmellose sodium or sodium carboxymethyl starch; or crosslinked polyvinylpyrrolidine ketone. The lubricant may be, for example, talc; stearic acid; calcium stearate, metal stearate such as magnesium stearate; colloidal vermiculite; beeswax, cetyl wax, and the like - 71 - 201124388 : boric acid; diol; D, L-leucine; carboxylic acid such as fumaric acid or adipic acid; sodium carboxylic acid salt such as sodium benzoate; sulfate such as sodium sulfate; a lauryl sulfate such as sodium sulfate or a lauryl sulfate; a tannic acid such as anhydrous citric acid or citric acid hydrate; or a starch derivative in the above-mentioned excipient. An emulsifier, for example, a colloidal clay such as bentonite or colloidal veegum; an anionic surfactant such as sodium lauryl sulfate or calcium stearate; Cationic surfactant: A nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, or sucrose fatty acid ester. Stabilizers such as, for example, parabens such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; ammonium benzyl chloride a phenol such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid. The flavoring agent can be, for example, a commonly used sweetener, sour, or flavor. The diluent may be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters. The solvent for the injection may be, for example, water, ethanol, or glycerin. The oleaginous base can be 'for example: cocoa butter, lauric fat, coconut oil, palm kernel oil, eucalyptus oil, mobile paraffin, white petrolatum, refined lanolin, glyceryl monostearate, polyoxyethylene hardened castor oil, sorbitol Anhydride fatty acid ester, sucrose fatty acid ester, stearyl alcohol, or cetyl alcohol. -72- 201124388 The water soluble base can be, for example, glycerin, polyethylene glycol, ethanol or pure water. The amount of the active ingredient of the present invention having a compound of the formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, etc. of the patient, and the case where it is administered orally is '0.02 mg/per lower limit per one time. Kg (preferably 〇.lmg/kg), upper limit of 100 mg/kg (preferably 1 〇mg/kg), non-oral administration, 0.002 mg/kg per lower limit (preferably 〇) 〇lmg/kg), upper limit i〇mg/kg (preferably 1mg/kg)' Relative to adults, the symptoms can be administered 1 to 6 times per day. Advantageous Effects of Invention The compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention has renin inhibitory activity, solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability, and tissue migration. Bioavailability, in vitro activity, in vivo activity, ex vivo activity, speed of efficacy, persistence of drug efficacy, physical stability, drug interaction, safety ( For example, cardiotoxicity or hepatotoxicity, etc. have excellent properties, and are useful as medicines (especially for the treatment or prevention of hypertension, preferably for treatment). [Embodiment] The present invention will be described in more detail below with reference to examples, test examples, and formulation examples. However, the scope of the invention is not limited thereto. In the following examples, the compound names shown in the examples are shown in the formula -73-201124388 obtained in the examples. The chemical structure formula described above shows the chemical structure of the corresponding free compound. For example, the compound obtained in Example 1 is (2 s, 4 S, 5 S ) - 5 -amino-6-[4·(2-chlorophenyl)-2,2-dimethyl_5_ side Oxypiperazine _ 丨-yl]_4_ thiol-hydrazine-(trans-5-hydroxyadamantan-2-yl)-2-isopropyl hexane decylamine fumarate' in Example 1 The chemical formula shown shows (28,48,53)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiped-1- Chemical structure of -4-hydroxy-indole-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine. The fumarate salt in the compound name of the examples means a fumarate as long as it is not particularly limited. EXAMPLES (Example 1) (2S, 4S, 5S) -5·Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiperidin-l -yl]-4-hydroxy-N-(trans-5-hydroxyadamantane-2-yl)-2-isopropylhexane decylamine fumarate

(la) Tert-butyl butyl {(13,23,43)-1-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiperidin-1-yl] Methyl 2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]-5-methylhexyl}amine formate obtained in Reference Example 1 Butyl butyl { ( IS ) -2-[4-( 2- -74- 201124388 chlorophenyl)-2,2-dimethyl-5-sideoxypoxy-p-isopropyl-5-side A solution of triethylamine (10 ml) of oxytetrahydrofuran-2-yl]ethyl (2.0 mmol) c GF--1-ol 1.00 g (6.0 mmol) and (0.6 0 mm ο 1 ) ' at 1 1 0 Stir at °C for 2 hours. The material was reduced and stirred at 1 20 ° C for an additional 13 hours. After cooling the reaction mixture with dichloromethane, the organic layer was dried over anhydrous sodium sulfate sulfate. After filtration, it was purified by column chromatography under reduced pressure (yield solvent: ethyl acetate / ethyl acetate ethyl acetate and diisopropyl ether), and the solids of the solids of 8.3 g (yield: 62%). iH NMR spectrum (CDC13, 400MHz), δ: 7.34-7.21 (m, 3H), 5.99 (br s, 1H), 4.08 -4.06 (m, 1H), 3.8 8 - 3.8 6 (m, 1H), 17.6 Hz), 3.48-3.21 (m, 4H), 2.80-2.65 (m, 4H), 1.9 5 - 1.46 (m, 22H), 1.26-1.22 (m, 6 H). (lb ) ( 2S,4S,5S ) -5-Amino-6·[4·(methyl-5-oxopiperidin-1-yl)-4-hydroxy-N-(-2-yl) -2-isopropylhexylamine fumaric acid obtained in Example (la) = {(lS, 2S, 4S)-l-{[4-(2-chlorophenyl)-2, 2-二^ 1 '[( 2S,4S ) -4- }carbamate 1. 〇2 g Yin' added trans-4-amine 2-hydroxypyridine 57mg After concentration and concentration reaction mixture, add water, sodium The aqueous solution is washed, and the solvent is added by means of a rubber hose = 1/0 to 6/1) to obtain the title compound 7.49-7.46 (m, 1H), 5.0 8 (br s, 1H), 3.67 (br d, 1 H, J = (m, 2H), 2.14-2.06 (m, 6H), 0.98-0.94 2-chlorophenyl)-2,2-di-trans-5-hydroxyadamantane salt -5-Sideoxypiperane-75- 201124388-1-yl]methyl}-2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]-5- Methylhexyl}carbamate 8 3 8 mg (1 - 24 mmol) in dichloromethane (8.6 ml) was stirred at room temperature under stirring at room temperature, 2.87 ml (3 7.3 mmol), and stirred at the same temperature for 1 hour. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was evaporated to methylene chloride/methanol (1 0/1), the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjj (23,43,53)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl] 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine (93% content) 45111^(0.73111111〇1) in methanol (71111) solution 84 mg (0.73 mmo > l) of fumaric acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. dichloromethane (mjjjjjjjjjjj Colorless solid. 4 NMR spectrum (CD3〇D, 500MHz) « δ : 7.7 8 (brs, 1 Η), 7.54 (br d, 1H, J = 7.8 Hz), 7.43 - 7.3 2 (m, 3H), 6.69 (s, 2H ), 3.97 (br s, 1H), 3.6 5 -3.47 (m, 3H), 3.3 6- 3.26 (m, 2H), 3.21-3.12 (m, 1H), 2.96-2.91 (m, 0.6H), 2.79 -2.70 (m,

〇.8H), 2.5 5 -2.5 2 (m, 0.6 H), 2.45 (br s, 1H), 2.11 (br s, 2H), 2.06 (br s, 1H), 1.9 8- 1.70 (m, 11H) , 1.50- 1.48 (m, 2H), 1.31-1.26 (m, 6H), 1.00 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J -76- 201124388 =6.4 Η z ) 〇. (FAB+), m/z: 575 ((M + H)+). (Example 2) (2S, 4S, 5S) - 5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiperidin-; 4-hydroxy-2-isopropyl-N-(trans-5-methoxyadamantan-2-yl)hexane decylamine fumarate

In the same manner as in Example 1, the tertiary butyl {(13)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxygen obtained in Reference Example 1 was used. Zipidin-1-yl]-l-[(2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}amine formate and trans-5-methoxy Fundane-2-amine, title compound 5 08 mg (2 engineering total yield: 50%). Colorless solid. iH NMR spectrum (CD3OD, 5 00MHz) > δ : 7.7 9- 7.7 7 (m, 1 Η), 7.5 5 -7.5 3 (m, 1Η), 7.44- 7.3 2 (m, 3H), 6.69 (s, 2H), 3.96 (br s, 1 H), 3.6 5 - 3.4 8 (m, 3 H), 3.36-3.12 (m, 6H), 2.95-2.91 (m, 0.6H), 2.7 9 -2.6 9 (m , 0.8H), 2.5 5 -2.5 2 (m, 0.6 H), 2.46-2.43 (m, 1H), 2.15 (br s, 2H), 2.10 (br s, 1H), 1.99 - 1.70 (m, 11H) , 1.5 2 - 1.49 (m, 2H), 1.31-1.26 (m, 6H), -77- 201124388 1.01 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 589 ((M + H)+). (Example 3) (2S, 4S, 5S) -5-Amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-sideoxypene-1 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate

In the same manner as in Example 1, the tertiary butyl {(IS)-2-[2,2-dimethyl-4-(2-methylphenyl)-5- side obtained in Reference Example 12 was used. Oxypiperidine-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and trans-4-amine Fundane-1-one, the title compound was obtained 380 mg (yield: 56%). Colorless solid. 1 H NMR spectrum (CD3OD, 500MHz) > δ : 7 · 7 9 - 7.7 6 (m, 1H), 7.31-7.26 (m, 3H), 7.17-7.11 (m, 1H), 6.69 (s, 2H) , 3.97 (br s, 1H), 3.6 9-3.47 (m, 3H), 3.37-3.14 (m, 3H), 2.94-2.89 (m, 0.6H), 2.82-2.7 8 (m, 0.4H), 2.68 -2.64 (m, 0.4H), 2.5 4-2.5 0 (m, 0.6 H), 2.47-2.43 (m, 1H), 2.24-2.23 (m, 3H), 2.12 (br s, 2H), 2.06 (br s, 1H), 1.98-1.71 (m, -78- 201124388 11H), 1.51-1.48 (m, 2H), 1.28-1.25 (m, 6H), 1.00 (d, 3H, J = 6.8 Hz), 0.98 ( d, 3H, J == 6.4 Hz). Mass spectrum (FAB+), m/z: 555 ((M + H)+). (Example 4) (2S, 4S, 5S) -5-Amino- 6-[2,2-dimethyl-4-(2-methylphenyl)-5-sideoxypiped-1- 4-hydroxy-2-isopropyl-N-(trans-5-methoxyadamantan-2-yl)hexane decylamine fumarate

In the same manner as in Example 1, the tertiary butyl {(IS)-2-[2,2-dimethyl-4-(2-methylphenyl)-5- side obtained in Reference Example 12 was used. Oxypiperidine-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and trans-5-A Oxyadamantan-2-amine, to give the title compound 59.5 mg (yield: yield: 64%). Colorless solid. 1H NMR spectrum (CD3OD, 5 00MHz) > δ : 7.8 0 (brd , 1 Η , J = 6.8 Hz), 7.32-7.25 (m, :3H), 7.18-7.11 (m, 1H), 6.68 (s, 2H ), 3.96 (br s, 1 H), 3.6 9 - 3.47 (m, 3H), 3.37-3.14 (m, 6H), 2.94-2.89 (m, 0.6H), 2.8 2-2.7 8 (m, 0.4H) ), 2.66 (dd, 0.4H, J = 13.7 Hz, 4.4 Hz), 2.52 (dd, 0.6H, J = 13.7 Hz, 4.4 Hz), -79- 201124388 2.48-2.43 (m, 1H), 2.24-2.23 (m, 3H), 2.16-2.15 (m, 2H), 2.06 (br s, 1H), 2.01-1.70 (m, 1 1 H), 1.52- 1.49 (m, 2H), 1.2 8 - 1.2 5 (m , 6H), 1.0 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 569 ((M + H)+). (Example 5) (23,43,53)-5-Amino-6-[4-(2-ethylphenyl)-2,2-dimethyl-5-sideoxypiped-1- 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate

In the same manner as in Example 1, the tertiary butyl {(13)-2-[4-(2-ethylphenyl)-2,2-dimethyl-5- side obtained in Reference Example 13 was used. Oxypiperidine-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and trans-4-amine Fund-cycloalkan-1-ol, the title compound 3 5 3 mg (2 engineering total yield: 46%) was obtained. Colorless solid. 'H NMR spectrum (CD3OD, 500MHz), δ: 7.79 (br d,1H, J = 7.3 Hz), 7.3 8 - 7.26 (m, 3H), 7.16-7.10 (m, 1H), 6.69 (s, 2H) , 3.97 (br s, 1H), 3.6 8 - 3.46 (m, 3H), 3.37-3.14 (m, 3H), -80- 201124388 2.9 5 -2.9 0 (m, 0.6H), 2.79 (dd, 0.4H , J = 13.7 Hz, 10.7 Hz), 2.67 (dd, 0.4H, J = 13.7 Hz, 4.6 Hz), 2.62-2.43 (m, 3.6H), 2.12-2.06 (m, 3 H), 1.9 8 - 1.70 (m, 1 1 H), 1.51-1.48 (m, 2H), 1.28-1.20 (m, 9H), 1.01-0.97 (m, 6 H). Mass spectrum (FAB+), m/z: 569 ((M + H)+). (Example 6) (23,43,53.)-5-Amino-6-[4-(2,3-difluorophenyl)-2,2-dimethyl-5-side gas-based pulse -1-yl]-4-trans-yl-N-(trans-5---------------------------------------------

In the same manner as in Example 1, the tertiary butyl {(13)-2-[4-(2,3-difluorophenyl)-2,2-dimethyl-5 obtained in Reference Example 14 was used. -Side oxypiped-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and trans-4 - Amine alkano-n-l-ol, the title compound was obtained (yield: 5 2 %). Colorless solid. 'HNMR spectrum (CD3OD, 5 00MHz) > δ : 7.7 9 (brd , 1 Η , J = 7.3 Hz), 7.3 3 - 7.22 (m, 2H), 7.16-7.13 (m, 1 H), 6.68 (s , 2H), 3.97 (br s, 1 H), 3.69 (d, 1 H, J = 11.7 Hz), 3.64 (d, 1 H, J = 17.6 Hz), 3.5 0-3.46 (m, 1H), 3.3 7-3.3 0 (m, 2H), 3.18 (dt, -81 - 201124388 1H, J = 10.7 Hz, 4.9 Hz), 2.87 (dd, 1H, J = 13.7 Hz, 11.2 Hz), 2.57 (dd, 1H, J = 13.7 Hz, 3.9 Hz), 2.48 -2.43 (m, 1H), 2.11 (br s, 2H), 2.06 (br s, 1 H), 1.97 (br d, 1H, J = 13.2 Hz), 1.91 ( Br d, 1H, J = 13.2 Hz), 1.86-1.70 (m, 9H), 1.51-1,48 (m, 2H), 1.26 (s, 6H), 1.00 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 577 ((M + H)+). (Example 7) (23,43,53)-5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypiperane- 1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate

(7a) (23,43,53)-6-[4-(2,6-Difluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-4- Hydroxy-N-[(trans-5-hydroxyadamantan-2-yl)-2-isopropyl- 5-{[(2-nitrophenyl)sulfonyl]amino} hexane decylamine Example (1 a ) Similarly, the heart {(13)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5- obtained in Reference Example 15 was used. Oleoxypiperidin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]-82- 201124388 Ethyl}-2-nitrobenzene Sulfonamide and trans-4-amine fundane-1-ol, the title compound 6 0 9 mg (yield: 53%) was obtained. Yellow solid. 'HNMR spectrum (CDC13, 4 〇〇 MHz), 5: 8.14 (dd, lH, J = 7.4 Hz, 2.0 Hz), 7.88 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 7.7 9-7.70 (m , 2H), 7.3 2- 7.2 5 (m, 1H), 7.00-6.9 3 (m, 2H), 6.01 (t, 2H, J = 8.0 Hz), 4.78 (br s, 1H), 4.06-4.04 (m , 1H), 3.94 (br d, 1H, J = 9.8 Hz), 3.44-3.40 (m, 1H), 3.22-3.12 (m 3H), 3.06 (d, 1 H, J = 11.3 Hz), 2.74 (dd , 1 H, J = 13.7 Hz, 8.4 Hz), 2.55 (dd, 1H, J = 13.7 Hz, 5.5 Hz), 2.13-2.05 (m, 3H), 1.92- 1.50(m, 14H), 1.13 (s, 3H), 1.07 (s, 3H), 0.9 6-0.93 (m, 6H). (713)(23,43,53)-5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypeptin-1- 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexyl decylamine fumarate obtained in Example (7a) ( 2S,4S,5S)-6-[4-(2,6-:fluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-4-hydroxy-N- [(trans-5-Hydroxyadamantan-2-yl)-2-isopropyl-5-{{(2-nitrophenyl)sulfonyl]amino} hexane decylamine 609 mg (0.80 mmol) And a solution of thiophenol (content: 95%) in 163 μl (1.60 mmol) in acetonitrile (8 ml) was added to a solvent (3, 3 mg (0.96 mmol) of carbonic acid under ice-cooling, and then stirred at room temperature for 15 hours. Water was added to the reaction mixture, extracted with dichloromethane, and the organic layer dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified from methylene chloride (??? (2S,4S,5S)-5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxoxypiped-1-yl -4-hydroxy-N·(trans- 5---------------------------------------------------------------------------------------------- The diacid 72 mg (0.62 mmol) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc m. WNMR spectrum (CD3OD, 500MHz) > δ : 7.7 8 (brd, 1 Η , J = 7.3 Hz), 7.47-7.41 (m, 1H), 7.13-7.10 (m, 2H), 6.69 (s, 2H), 3.97 (br s, 1H), 3.71-3.65 (m, 2H), 3.5 0-3.48 (m, 1H), 3.35-3.31 (m, 2H), 3.20-3.16 (m, 1H), 2.88 (dd, 1H , J = 13.4 Hz, 11.0 Hz), 2.58 (dd, 1H, J = 13.2 Hz, 4.4 Hz), 2.47-2.42 (m, 1H), 2.11 (br s, 2H), 2.06 (br s, 1H), 1.97 (br d, 1H, J = 12.7 Hz), 1.9 1 (br d, 1H, J = 12.7 Hz), 1.85-1.70 (m, 9H), 1.51-1.48 (m, 2H), 1.26 (s, 6H ), 1.00 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 577 ((M + H)+). (Example 8) (2S, 4S, 5S) -5-Amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxy oxygen trap -Buki]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate-84 - 201124388

(8a) Tert-butyl butyl {(18,23,48)-1-{[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiperane-丨_基]methyl b 2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]·5-methylhexyl}amine formate in Reference Example 16 The obtained tertiary butyl {( is) -2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiped-1_yl]-b [(2S,4S)-4-isopropan-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate i.〇5g (2.0mmol) of triethylamine (i〇ml) solution The trans-4_amine fundane-1-ol 1.00 g (6.0 mmol) and 2-hydroxypyridine 57 mg (0.60 mm〇l) were added and stirred at ii ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and stirred at 1 1 ° C for further 1 hour. After cooling the reaction mixture, water was added, and the mixture was evaporated. After filtration, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent: ethyl acetate/methanol=W0~6/1), ethyl acetate and diisopropyl ether were added, and solids were collected by filtration. The title compound 7 80 mg (yield: 56%) was obtained. Colorless solid. hNMR spectrum (CDC13, 400MHz), δ: 7.45-7.42 (m, 1H), 7.05-6.96 (m, 2H), 5.90 (br d, 1H, J = 8.6 Hz), 5.04 (br s, -85- 201124388 1H), 4.08-4.06 (m, 1H), 3.8 8-3.8 6 (m, 1H), 3.68-3.61 (m, 1H), 3.48-3.22 (m, 4H), 2.75-2.63 (m, 2H), 2.15-2.06 (m, 4H), 1.97-1-46 (m, 22H), 1.23 (br s, 6H), 0.98-0.95 (m, 6H) » (8b)( 2S,4S,5S)-5- Amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5.oxoxypiped-1-yl]_4.hydroxy-N-(trans- 3-hydroxyadamantane-2-yl)-2-isopropylhexane amide amine fumarate The tertiary butyl {(lS, 2S, 4S)-l obtained in the example (8a) -{[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiped-1-yl]methyl}-2-hydroxy-4-[(anti A solution of 776 mg (1.12 mmol) in methylene chloride (7.8 ml) was added to a solution of the formula: 5-hydroxyadamantan-2-yl)amine-carbamoyl]-5-methylhexyl}carbamate. Acetic acid 2.59 ml (3 3.6 m mol ) and stirred at the same temperature for 1.5 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjj (2S,4S,5S)-5-Amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiperazine-1- 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexylamine (93% content) 57〇11^(0.9〇111111〇1) To the methanol (91111) solution, 4 mg of fumaric acid (0.90 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. dichloromethane (1 ml) was added to the residue, and diethyl ether (10 ml) was added, and the solid was collected by filtration to give the title compound - 86 - 201124388 Compound 6 Ο 5 mg (yield · 8 2 % ). Colorless solid. iHNMR spectrum (CD3OD, 5 00MHz) - δ: 7.78 (br d, 1 Η, J = 7.3 Hz), 7.5 8 - 7.5 5 (m, 1H), 7.21-7.18 (m, 2H), 6.69 (s, 2H ), 3.97 (br s, 1H), 3.65- 3.46 (m, 3H), 3.38-3.13 (m, 3H), 2.96-2.91 (m, 0.6H), 2.7 8 -2.70 (m, 0.8H), 2.55 -2.51 (m, 0.6 H), 2.47-2.43 (m, 1H), 2.11(br s, 2H), 2.06 (br s, 1H), 1.9 8 - 1.7 0 (m, 11H), 1.51-1.48 (m , 2H), 1.31-1.26 (m, 6H), 1.01 - 0.97 (m, 6H). Mass Spectrum (FAB+), m/z: 5 9 3 ((M + H) + ), 5 9 5 ((M + 2 + H) (Example 9) (2S, 4S, 5S) -5-Amino- 6-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-4-hydroxy-N-(trans-5 -hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate

(9〇 tertiary butyl {(lS, 2S, 4S)-l-{[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side oxy oxychloride trap -1-yl]methyl-2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]-5-methylhexyl}carbamate-87- 201124388 The tertiary butyl { ( IS ) -2-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side oxypiped well obtained in Reference Example 1) 1-yl]-1-[(2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}carbamate l.Olg (2.0 mmol) triethyl To a solution of the amine (10 ml), 1.00 g (6.0 mmol) of trans-4-amine adamantane-1 alcohol and hexahydroxyl group 57 mg (0.60 mmol) were added, and the mixture was stirred at 110 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and stirred at 1 1 ° C for further 1 hour. After cooling the reaction mixture, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent: ethyl acetate/methanol = 1/0 to 6/1), ethyl acetate and diisopropyl ether were added and filtered. The solid was isolated to give the title compound (yield: 52%). Colorless solid. 4 NMR spectrum (CDC13, 400MHz), δ: 7.23-7.20 (m, 1H), 6.9 8 -6.9 3 (m, 1H), 6.8 3 -6.79 (m, 1H), 5.90 (br d, 1H, J = 7.4 Hz), 5.05 (br s, 1H), 4.08 -4.06 (m, 1H), 3.8 9- 3.8 6 (m, 1H), 3.68-3.61 (m, 1H), 3.48-3.16 (m, 4H), 2.76-2.66 (m, 2H), 2.17-2.09 (m, 7H), 1.97- 1.46 (m, 22H), 1.23 (br s, 6H), 0.9 8 -0.9 5 (m, 6H). , (9b)(2S,4S,5S)-5-Amino- 6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side oxy thiophene 1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine fumarate in Example (9a) Obtained tertiary butyl-88 - 201124388

UlS,2S,4S)-l-{[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]methyl b 2 -Hydroxy._4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]-methylhexyl}carbamate 697^^ (1.04°11110丨) in dichloromethane (7.2ml) In the solution, 2_4 〇ml (31.2 mm·l) of trifluoroacetic acid was added at room temperature, and stirred at the same temperature for 1.5 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with dichloromethane/methanol (1 〇 /1), the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjj (2S,4S,5S) _5-Amino-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-sideoxypiped-1- 4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropylhexane decylamine (93% content) 451 mg (0.82 mmol) in methanol (8 ml) , add anti-butanic acid! 5mg (0.82mmol), stir in the room for 5 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc md. ). Colorless solid. iHNMR spectrum (CD3OD, 500MHz), δ: 7.79 (brd, lH, J = 7.8 Hz), 7.3 3 -7.3 0 (m, IH), 7.06-6.93 (m, 2H), 6.69 (s, 2H), 3.97 (br s, 1H), 3.68 -3.46 (m, 3H), 3.38-3.15 (m, 3H), 2.95-2.90 (m, 0.6H), 2.81-2.76 (m, 0.4H), 2.68-2.65 (m , 0-4H), 2.52-2.44 (m, 1.6H), 2.20 (br s, 3H), 2.12(br s, 2H), 2.06 (br s, 1H), 1.99-1.71 (m, 11H), 1.51 -1.48 (m, 2H), -89- 201124388 1.27- 1.25 (m, 6H), 1.01-0.97 (m, 6H). Mass spectrum (FAB+), m/z: 573 ((M + H)+). (Example 1 〇) (2R, 4S, 5S) - 5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperane-l- 2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2)yl hexane decylamine fumarate

(l〇a) Tert-butyl butyl {(lS,2S,4R)-l-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypipedyl]A A 2-tert-butyl group obtained in Reference Example 1 8 (i-hydroxy-4-[(trans-5-5-hydroxy]-2-yl)-aminomethyl]hexyl}-amino carboxylic acid vinegar S ) -2 - [ 4 - ( 2 -Chlorophenyl)-2,2-dimethyl-5-o-oxypiperazin-1-yl]-1-[(28,411)-4-ethyl-5 -Sideoxytetrahydrofuran-2-yl]ethyl}amine formate 529 mg (1.07 mmol), trans-4-aminedantakan-1-ol 538 mg (3.22 mmol) and 2-hydroxypyridine 39 mg (0.32 mmol) Triethylamine (4 ml) was added to the mixture and stirred at 90 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and stirred at &lt After cooling the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (Yield·· 7 2 %). Yellow solid. NMR spectrum (CDC13, 400MHz), δ: 7.48-7.46 (m, 1H) 7.34-7.21 (m, 3H), 6.09 (br s, 1H), 5.04 (br s, 1H), 4.07-4.05 (m, 1H) ), 3.88 (br s, 1H), 3.66 (br d, 1H, J = lg.i Hz), 3.48-3.22 (m, 4H), 2.7 7 -2.6 3 (m, 2H), 2.36 (br s, 1H), 2.14-2.10 (m, 3H), 1.89- 1.42 (m, 23H), 1.26- 1.22 (m, 6H), 0.94 (t, 3H, J = 7.3 Hz). (10b) ( 2R,4S,5S) -:5-Amino- 6-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiped-1-yl]- 3-Ethyl-4-hydroxy-N-(trans-5-hydroxydanta-2-yl)hexane decylamine fumarate obtained in Example (10a) {(13,23,411)-1-{[4-(2-Chlorophenyl)-2,2-dimethyl-5-oxaoxypiperidin-1-yl]methyl}-2-hydroxy-4 -[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]hexyl}carbamate 512 mg (0.77 mm 〇l) in dichloromethane (3.6 ml), add three at room temperature 1.8 nil (23.2 mmol) of fluoroacetic acid was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with dichloromethane and chloroform / isopropyl alcohol = 3/1, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to chromatography on silica gel column (solvent solvent: methylene chloride/methanol = 50/1 to 7/3) and NH? Methanol = 1/0 to 5/1) Purification. (2R,4S,5S) -5-Amino-6-[4-(2-chlorophenyl)-2,2--91 - 201124388 dimethyl-5-sideoxypiperazine-1- Benzyl-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine 272 mg (0.48 mmol) in methanol (5 ml) Acid 5 6 mg (0.48 mmol) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. dichloromethane was evaporated. Colorless solid.

iNMR spectrum (CD3OD, 500MHz), δ: 7.84 (d, 1H, J = 7.3 Hz), 7.5 5 -7.54 (m, 1H), 7.43 -7.3 2 (m, 3H), 6.68 (s, ·* 2H) , 3.97 (br s, 1H), 3.65-3.26 (m, 5H), 3.22-3.12 (m, 1H), 2.96-2.91 (m, 0.6H), 2.79-2.63 (m, 1.8H), 2.53 (dd , 0.6 H, J = 13.7 Hz, 3.9 Hz), 2.12 (br s, 2H), 2.06 (br s, 1H), 1.9 8 - 1.8 2 (m, 5H), 1.77- 1.74 (m, 4H), 1.69 - 1.47 (m, 5H), 1.3 Bu 1.26 (m, 6H), 0.95 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB+), m/z: 561 ((M + H)+). (Example 1 1 ) (2R, 4S, 5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperane-l- 2-ethyl-4-hydroxy-N-(trans-5-methoxyadamantan-2-yl)hexane decylamine fumarate

-92-201124388 In the same manner as in Example 1, the tertiary butyl group obtained in Reference Example 18 was used. {(IS) -2-[4-(2-chlorophenyl)-2,2-methyl group -5-Phenoxy-indol-1-yl]-l-[( 2S,4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl} carbamic acid ester and trans- 5-methoxyadamantan-2-amine, the title compound was obtained (yield: 68%). Colorless solid. 4 NMR spectrum (CD3OD, 5 00MHz) > δ : 7.87- 7.8 3 (m, 1H), 7.54 (br d, 1H, J = 7.3 Hz), 7.43-7.32 (m, 3H), 6.68 (s, 2H ), 3.96 (br s, 1H), 3.65- 3.52 (m, 3H), 3.36-3.13 (m, 6H), 2.96-2.91 (m, 0.6H), 2.7 9-2.6 3 (m, 1.8H), 2.55-2.51 (m, 0.6 H), 2.15 (br s, 2H), 2.11 (br s, 1H), 1.99- 1.79 (m, 9H), 1.68-1.49 (m, 5H), 1.31-1.2 6 (m , 6H), 0.95 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB+) > m/z: 575 ((M + H)+). (Example 1 2 ) (211,43,53)-5-Amino-6-[4-(2,3-difluorophenyl)-2,2-dimethyl-5-sideoxypiped trap -1-yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate

-93-201124388 In the same manner as in Example 1, the tertiary butyl {(15)-2-[4-(2,3-difluorophenyl)-2,2-di which was obtained in Reference Example 19 was used. Methyl-5-sideoxypiped-1-yl]-l-[(2S,4R)-4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and anti The title compound, 3, 7 mg (2 engineering total yield: 41%) was obtained. Colorless solid.

1H NMR spectrum (CD3OD, 500MHz), δ: 7.8 3 (d, 1 Η, J = 7.3 Hz), 7.3 3 - 7.3 2 (m, 2H), 7.16-7.13 (m, 1H), 6.69 (s, 2H ), 3.97 (br s, 1H), 3.69 (d, 1 H, J = 1 1.7 Hz), 3.64 (d, 1H, J = 17.6 Hz), 3.54-3.5 0 (m, 1H), 3.37 (d, 1H, J = 11.7 Hz), 3.31(d, 1H, J = 17.6 Hz), 3.19-3.15 (ra, 1H), 2.87 (dd, 1H, J = 13.7 Hz, 10.7 Hz), 2.67-2.62 (m, 1H), 2.57 (dd, 1H, J = 13.7 Hz, 4.4 Hz), 2.11 (br s, 2H), 2.07 (br s, 1 H), 1.98-1.82 (m, 5H), 1.77- 1.75 (m, 4H), 1.69- 1.49 (m, 5H), 1.25 (s, 6H), 0.95 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB + ), m/z: 563 ((M + H) +). (Example 1 3 ) (2R, 4S, 5S) -5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypene -1-yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate-94- 201124388

In the same manner as in Example 1, the tertiary butyl {(13)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5- obtained in Reference Example 20 was used. Oleoxypiped-1-yl]-l-[(2S,4R)-4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and trans-4-amine Fundane-1-alcohol, the title compound 3 2 8 mg (2 engineering total yield: 57%) was obtained. Colorless solid.

HNMR spectrum (CD3OD, 500MHz), δ: 7.83 (d, 1H, J = 7.3 Hz), 7.47-7.41 (m, 1H), 7.11 (br d, 2H, J = 8.6 Hz), 6.69 (s, 2H ), 3.97 (br s, 1H), 3.71-3.65 (m, 2H), 3.54-3.51 (m, 1 H), 3.35-3.31 (m, 2H), 3.19-3.15 (m, 1H), 2.87 (dd , 1H, J = 13.7 Hz, 10.7 Hz), 2.6 6 - 2.56 (m, 2H), 2.11 (br s, 2H), 2.07 (br s, 1 H), 1.9 7- 1.8 2 (m, 5H), 1.7 7 - 1.7 5 (m, 4H), 1.6 8 - 1.48 (m, 5H), 1.26 (s, 6H), 0.95 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB + ), m/z: 563 ((M + H) +). (Example 1 4 ) (2R, 4S, 5S) -5-Amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypipe Well-1-yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate-95- 201124388 ci

(14a) Tert-butyl butyl {(lS, 2S, 4R)-l-{[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiperazine- 3-meryl]methyl}-2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]hexyl}amine formate in the third order obtained in Reference Example 21. Butyl { ( 1S ) _2-[4-( 2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypeptin-1-yl]-l-[( 2S, 4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate 2.22g (4.33mmol), trans-4-aminedantapan-1-ol 2.17g (13.0 Triethylamine (6 ml) was added to a mixture of <RTI ID=0.0>> The reaction mixture was concentrated under reduced pressure and stirred at &lt After cooling the reaction mixture, water was added, and the mixture was combined with ethyl acetate-methanol. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj ). Colorless solid. 4 NMR spectrum (CDC13, 500MHz), δ: 7.45-7.42 (m, 1H), 7.05-7.01 (m, 1H), 6.99-6.97 (m, 1H), 6.10 (br s, 1H), 5.06 (br s , 1H), 4.06-4.05 (m, 1H), 3.88 (br s, 1H), 3.64 (br d, •96- 201124388 1H, J = 17.1 Hz), 3.46-3.22 (m, 4H), 2.74-2.63 (m, 2H), 2.40-2.3 4 (m, 1H), 2.13 (br s, 2H), 2.09 (br s, 1H), 1.89- 1.46 (m, 23H), 1-23 (br s, 6H) , 0.93 (t, 3H, J = 7.3 Hz). (14b ) ( 2R,4S,5S ) -5-Amino-6-[4-(2-chloro-5-fluorophenyl)-2,2·dimethyl-5-sideoxypiped-1 -yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate obtained in Example ("a) Tert-butyl butyl {(13,23,411)-1-{[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxoxypiped-1-yl]- a solution of 1.85 g of hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)amine carbamoyl]hexyl}carbamate in 1.85 g (2.72 mmol) in dichloromethane (12 ml) Add trifluoroacetic acid. 4.20ml (54.5mmol) at room temperature and stir for 1 hour at the same temperature. Add saturated aqueous sodium hydrogencarbonate solution to the reaction mixture, extract with dichloromethane / methanol (10/1), organic layer The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to chromatography on a gel column (solvent solvent: dichloromethane / methanol = 20/1 to 6/1) And dichloromethane / methanol / triethylamine = 20 / 5 / 1) and NH 矽 rubber column chromatography (dissolving solvent: dichloromethane / methanol = 1 / 0 ~ 6 / 1) purification. ,4S,5S) -5 -amino group ·6-[4-(2 -chloro-5-fluorophenyl) -2,2-dimethyl-5-sideoxypiped-.1-yl]-2-ethyl-4-hydroxy-indole-(trans-5- Add 176mg (1.5 1 mmol ) of fumaric acid to room temperature in a solution of hexamine (9 3 %) 8 7 7 mg (1.51 mmol) in methanol (15 ml) After stirring for 5 minutes, the reaction mixture was concentrated under reduced pressure -97-201124388, 5% aqueous acetonitrile (30 ml) was added to the residue, and the mixture was stirred at 7 (TC) for 2 hr. After cooling, the solid was filtered to give the title compound. (yield: 5 4 %). Colorless solid. iH NMR spectrum (CD3OD, 5 00 MHz) > δ: 7.80 (m, 1H), 7.5 8 - 7.5 5 (m, 1H), 7.21-7.18 (m, 2H ), 6.69 (s, 2H), 3.97 (br s, 1H), 3.64-3.12 (m, 6H), 2.95-2.91 (m, 0.6H), 2.75-2.61 (m, 1.8H), 2.53-2.51 ( m, 0.6 H), 2.11 (br s, 2H), 2.07 (br s, 1H), 1.9 7 - 1.82 (m, 5H), 1.7 7- 1.7 5 (m, 4H), 1.6 8 - 1.4 8 (m , 5H), 1.3 0- 1.26 (m, 6H), 0.96 (t, 3H, J = 7.3 Hz). Mass spectrum (FAB + ), m/z: 579 ((M + H) +). (Example 1 5 ) (2R, 4S, 5S) -5-Amino-2-ethyl-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl- 5-oxopiperidin-1 -yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate

(15a) Tert-butyl butyl {(lS, 2S, 4R)-l-{[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side oxy oxychloride trap 1-yl]methyl}-2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)aminemethanyl]hexyl}amine formate obtained in Reference Example 22 Butyl butyl { ( IS )-1-[( 2S,4R) -98- 201124388 -4 -ethyl-5 - pendant oxytetraoxan-2-yl]-2-[4_( 5 - gas - 2-methylphenyl)-2,2-dimethyl-5-oxopiperidin-1-yl]ethyl}amine formate 58811^ (1.20 mmol), trans-4-amine fund To a mixture of 600 mg (3.59 mm 〇l) of 2-hydric alcohol and 2-34 mg (0.36 mmol) of hydrazide ratio, triethylamine (5 ml) was added and stirred at 11 CTC for 2 hours. The reaction mixture was concentrated under reduced pressure and stirred at <RTI ID=0.0></RTI> <RTIgt; After the reaction mixture was cooled, water was added, and ethyl acetate was evaporated. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjj 0 % ). Colorless solid. NMR spectrum (CDC13, 400MHz), δ: 7.23-7.20 (m, 1H), 6.9 8 -6.9 3 (m, 1H), 6.83-6.81 (m, 1H), 6.06 (br s, 1H), 5.04 (br d, 1H, J = 8.2 Hz), 4.07-4.05 (m, 1H), 3.90-3.8 5 (m, 1H), 3.66-3.60 (m, 1H), 3.46-3.3 9 (m, 2.5H), 3.3 2-3.2 5 (m, 1H), 3.17 (d, 0.5H, J = 11.7 Hz), 2.77-2.59 (m, 2H), 2.40-2.33 (m, 1H), 2.17-2.09 (m, 6H), 1.8 9-1.8 6 (m, 2H), 1.7 7 - 1.42 (m, 21H), 1.22 (br s, 6H), 0.94 (br t, 3H, J = 7.0 Hz). (15b) (2R,4S,5S) -5-Amino-2-ethyl-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side Oxypiperin-1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine fumarate obtained in Example (15a) Tert-butyl butyl {(lS,2S,4R)-l-{[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side-99- 201124388 oxypipe Tr--1-yl]methyl}-2-hydroxy-4-[(trans-5-hydroxyadamantan-2-yl)amine-carbamoyl]hexyl}carbamate 707 mg (1.07 mmol) of dichloro To a solution of methane (7.4 ml), 2.48 ml (3 2.2 mmol) of trifluoroacetic acid was added at room temperature and stirred at the same temperature for one hour. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added, 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: methylene chloride/methanol = 1/0 to 6/1) to obtain β (2r, 4S, 5S) -5 -amino-2-ethyl-6-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-oxoxypiperane-l-yl]-4- Hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine (93% content) 334 mg (0.55 mmol) in methanol (6 ml) was added with fumaric acid 64 mg (O.55 mm) 〇l), stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. dichloromethane was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless solid. 1 H NMR spectrum (CD3OD, 500MHz) &gt; δ : 7.80 (m, 1H), 7.3 3 -7.3 0 (m, 1H), 7.06-7.02 (m, 1H), 6.98-6.93 (m, 1H), 6.69 (s, 2H), 3.97 (br s, 1H), 3.67-3.13 (m, 6H), 2.94-2.90 (m, 0.6H), 2.8 0 -2.7 5 (m, 0.4H), 2.69-2.62 (m , 1.4H), 2.50 (dd, 0.6 H, J = 13.4 Hz, 4.2 Hz), 2.20 (br s, 3H), 2.11 (br s, 2H), 2.07 (br s, 1H), 1.97- 1.82 (m , 5H), 1.78- 1.75 (m, 4H), 1.6 8- 1.49 (m, 5H), 1.27- 1.25 (m, 6H), 0.96 (t, 3H, J = 7.3 Hz). -100- 201124388 Mass spectrum (FAB + ), m/z : ((M + H)+): 559 ((M + H)+). (Example 1 6 ) (2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2·dimethyl-5_ oxoxypiped-1-yl ]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-methylhexane decylamine fumarate

(16a) (2R,4S,5S)-6-[4-(2-Chlorophenyl)-2,2-dimethyl_5_ oxoxypiped-1-yl]-4-hydroxy-indole· [(trans-5-Hydroxyadamantan-2-yl)-2-methyl-5-anthracene [(2-nitrophenyl)sulfonyl]amino} hexane decylamine was used in Reference Example 23. Obtained N-{(1S) -2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]_1_[(23,41〇- a solution of 4-methyl-5. oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 337 mg (0.59 mmol) in triethylamine (3 ml) with trans-4-amine Fundaneol-1-ol 300mg (1.79minol) and 2-hydroxypyridine 1 7mg (0 · 1 8mm ο 1 ), stirred at 95 ° C for 8 hours. After cooling the reaction mixture, add water 'to ethyl acetate After the extraction, the organic layer was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by column chromatography (solvent solvent: ethyl acetate / methanol = 50/1~10/1 ~4/1), the title compound was obtained 353 mg (yield: 82%). -101 - 201124388 yellow solid. 4 NMR spectrum (CDC13, 400 MHz), δ: 8.17-8.15 (m,1H), 7.91-7.89 ( m, 1H), 7.8 0- 7.72 (m, 2H), 7.45 (br d, 1H, J = 8.2 Hz), 7.3 5 - 7.26 (m, 2H), 7.20-7.17 (m, 1H), 6.30 (br s, 0.6H), 6.06 (br d, 1H, J = 7.8 Hz), 5.94 (br s, 0.4H), 4.66 (br s, 1H), 4.05-4.00 (m, 2H), 3.49-2.5 0 (m, 8H), 2.14 (br s, 3H), 1.8 9- 1.46 (m, 12H) , 1.20-1.11 (m, 9H). (16b) (2R,4S,5S) -5-Amino- 6-[4_(2-chlorophenyl)-2,2-dimethyl-5-side oxygen Kepipi-1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-methylhexane decylamine fumarate in Example (16a) (211,43,53)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-4-hydroxy- obtained in N-[(trans- 5-hydroxyadamantan-2-yl)-2-methyl- 5-{[(2-nitrophenyl)sulfonyl]amino}hexylamine 353 mg (0.48 mmol) And thiopurine (content: 95%) 98μ1 (0.96mmol) of N,N-dimethylformamide (5ml) solution, under nitrogen atmosphere, add 188mg (0.58mmol) of carbonic acid under ice cooling, and then in the room Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent solvent: methylene chloride/methanol = 50/1 to 5/1 to 7/3). (2R,4S,5S)-5-Amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperidin-1-yl]-4- Addition of fumaric acid to a solution of hydroxy-indole-(trans-5-hydroxyadamantan-2-yl)-2-methylhexaneamine 186 mg (0.34!«111〇1) in methanol (3.51111) 4〇1118 -102- 201124388 (0.34 mmol), stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless solid. iHNMR spectrum (CD3OD, 400MHz) - δ: 7.8 2 (brd , 1 Η , J = 7.4 Hz), 7.5 6 -7.5 4 (m, 1H), 7.44-7.3 2 (m, 3H), 6.71 (s, 2H ), 3.93 (br s, 1H), 3.66-3.13 (m, 6H), 2.9 8 -2.7 2 (m, 2.4H), 2.53 (dd, 0.6H, J = 13.3 Hz, 4.3 Hz), 2.10 ( Br s, 3H), 1.9 7 - 1.73 (m, 9H), 1.60- 1.48 (m, 3H), 1.31-1.26 (m, 6H), 1.20 (d, 3H, J = 7.0 Hz). Mass spectrum (FAB+), m/z: 547 ((M + H)+). (Example 1 7 ) (2S, 4S, 5S ) -5-Amino-N-(trans-5-aminecarboxyxan-2-yl)-6-[4-(2-chloro-5) -gas phenyl)-2,2-methyl-methyl-5-o-oxoin-1-yl]-4-hydroxy-2-isopropylhexane decylamine fumarate

(17a) Tert-butyl butyl (4S, 5S) -4-{ [4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiped-1-yl ]methyl}-5-[(23)-2-(methoxycarbonyl)-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidin-3-carboxylate -103- 201124388 Tertiary butyl { ( IS ) -2-[4-( 2-chloro-5-fluorophenyl)-2,2-dimethyl-5-side oxygen obtained in Reference Example 16. Benzyl-1-yl]-l-[(2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}aminecarboxylate 2.0 g (3.8 mmol) of tetrahydrofuran 7.6 ml (7.6 mmol) of a 1N aqueous sodium hydroxide solution was added to a mixed solvent solution of (38 ml) and methanol (19 ml), and the mixture was stirred at room temperature for 2 hours. After adding 3.8 ml (7.6 mmol) of 2N hydrochloric acid, the mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give crude (2S,4S,5S)-5-[(tris-butoxycarbonyl)amino]-6-[4-(2-chloro-5-fluorophenyl) -2,2-Dimethyl-5-oxopiperidin-1-yl]-2,3,5,6-tetradeoxy-2-isopropylhexanecarboxylic acid. The resulting crude (2S,4S,5S)-5-[(tris-butoxycarbonyl)amino]-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl a mixed solvent solution of toluene (30 ml) and methanol (10 ml) of 5-5-oxopiperidin-1-yl]-2,3,5,6-tetradeoxy-2-isopropylhexanecarboxylic acid 5.7 ml (11. 4 mmol) of trimethyldecyl diazomethane (2 mol/l hexane solution) was added at 〇 °c, and stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure to give (2S,4S,5S) -5-[(tris-butoxycarbonyl)amino]-6-[4-(2-chloro-5-fluorophenyl)- 2,2-Dimethyl-5-oxopiperidin-1-yl]-2,3,5,6-tetradeoxy-2-isopropylhexanecarboxylic acid methyl. The resulting crude (2S,4S,5S)-5-[(tertiary butoxycarbonyl)amino]-6-[4-(2-chloro-5.fluorophenyl)-2,2-dimethyl -5-Sideoxypiperidin-1-yl]-2,3,5,6-tetradeoxy-2-isopropylhexyl acid methyl n,N-dimethylformamide (19ml 4.7 ml (38.0 mmol) of 2,2-dimethoxypropane and 1.91 g (7.6 mmol) of p-toluenesulfonic acid pyridinium were added to the solution, and stirred at -104-201124388 70 ° C for 2 hours. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (solvent solvent: hexane/ethyl acetate = 5/1 to 1/1) to give the title compound: 8 0%) ° Colorless solid 4 NMR spectrum (CDC13, 400MHz) - δ 7.45-7.41 (m, 1H), 7.06-7.00 (m, 2H), 3.9 9-3.9 6 (m, 1H), 3.69 - 1.3 8 (m, 29H), 1.25-1.21 (m, 6H), 0.96-0.9 4 (m, 6H). (171&gt;)(23)-2_{[(43,53)-3-〇-butoxycarbonyl)-4-{[4·(2-chloro-5-fluorophenyl)-2,2-di Methyl-5-oxopiperidin-1-yl]methyl}-2,2-dimethyl-1,3-Dfoxazin-5-yl]methyl}-3-methylbutyric acid Tert-butyl (4 S , 5 S ) - 4 - { [ 4 -(2-chloro-5-fluorophenyl)-2,2-dimethyl-5 obtained in Example (17a) -Side oxypiperidin-1-yl]methyl}-5-[(2S)-2-(methoxycarbonyl)-3-methylbutyl]-2,2-dimethyl-l,3 - a solution of 1.81 g (3.0 mmol) of oxazolidine-3-carboxylate in tetrahydrofuran (12 ml) and methanol (6 ml), a solution of 1 N aqueous sodium hydroxide (3.0 ml, 3.0 mmol) Stir at 65t for 2 days. After cooling to room temperature, the solvent was distilled off under reduced pressure. 4.5 ml (9.0 mmol) of 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystal crystal crystal crystal Colorless solid-105- 201124388 4 NMR spectrum (CDC13, 400MHz), δ 7.43-7.40 (m,lH), 7.11-7.00 (m, 2H)S 4.10-4.01 (m, 1H), 3.69- 1.4 3 (m, 26H), 1.26-1.18 (m, 6H), 0.9 8 - 0.9 5 (m, 6H). (17c) Tert-butyl (4S,5S) -5-{(2S)-2-[(trans-5-aminocarboxamido-2-yl)aminemethanyl]-3-methyl Butyl} -4- {[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiperazine-buyl]methyl} -2,2-di Methyl-1,3-oxazolidine-3-carboxylate (2S)-2-{[(4S,5S)-3-(t-butoxycarbonyl)· obtained in Example (17b) 4-{[4-(2-Chloro-5-fluorophenyl)-2,2-dimethyl-5-oxooxypiped-l-yl]methyl}-2,2-dimethyl-l , 3-oxazolidin-5-yl]methyl}-3-methylbutyric acid 519 mg (0.89 mmol), trans-4-amine fundane-1-carbamide obtained in Reference Example 207 mg (1.07 mmol), diisopropylethylamine oxime. 32 ml (1.78 mmol) in N,N-dimethylformamide (4 ml), 0-(benzotriazole-1) -Based - Ν, Ν, Ν', N'-tetramethylurea hexafluorophosphate (HBTU) 506 mg (1.3 3 mmol), stirred at the same temperature for 1 hour. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjj NMR spectrum (CDC13,400ΜΗζ)', δ: 8.02 (s,1 Η), 7.44-7.40 (m, 1H), 7.13-7.11 (m, 1H), 7.04-6.99 (m, 1H), 5.96 (br s , (H, 1H) , 2.63 (br s, 2H), 2.08- 1.47 (m, 26H), 1.22 (br s, 6H), 0.98 -0.94 (m, 6H). (17d) (23,43,53)-5-Amino 4_(trans _5-amine-formamidine, adamant-2-yl)-6-[4-(2-chloro-5-fluorophenyl) -2,2-dimethyl-5-oxooxypiped-1-yl]-4-hydroxy-2-isopropylhexanylamine fumarate in Example (17c) The obtained tertiary butyl (4 S,5 S ) - 5 -{ ( 2 S ) -2-[(trans-5-aminoformamidinedane-2-yl)aminemethanyl]_3_ Methylbutyl}-4-{[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]methyl} ·2, 2-Dimethyl-1,3-Pf哗--3-residual acid vinegar 606mg (0 _ 8 0 mm ο 1 ), adding hydrochloric acid-methanol reagent (hydrochloric acid content 5-10%) (30 ml) '45 Stir at °C for 2 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc:EtOAc Amino-N-(trans-5-aminemethanyl adamant-2-yl)-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5- Side oxypiped-1-yl]- 4-hydroxy-2-isopropylhexanide 373 mg. (2S,4S,5S) -5-Amino-indole-(trans-5-aminoformamidine alkane-2-yl)-6·[4·(2-chloro-5-fluorophenyl) ) 2,2_2-Methyl-5-oxooxypiped-1-yl]·4-hydroxy-2-isopropylhexylamine 3 7 3 mg (0-60 mmol) in methanol (6 ml) 69-8 mg (0.60 mmol) of fumaric acid was added and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure to EtOAc (EtOAc) (EtOAc (EtOAc) : 6 4%). Colorless solid. H NMR spectrum (CD3OD, 400MHz), δ: 7.76 (br d, 1H, J = 7.4 Hz), 7.5 9- 7.5 5 (m, 1H), 7.22-7.17 (m, 2H), 6.69 (s, 2H) , 4.01 (br s, 1H), 3.65-3.12 (m, 6H), 2.98 -2.92 (m, 0.6H), 2.74 (br s, 0.8H), 2.54-2.44 (m, 1.6H), 2.07-1.81 (m, 13H), 1.77-1.70 (m, 1H), 1.62-1.59 (m, 2H), 1.31-1.27 (m, 6H), 1 .02-0.98 (m, 6H). Mass spectrum (FAB+), m/z: 620 ((M + H)+. (Example 18) (2S,4S,5S) -5-Amino-N-(trans-5-amine formazan fund Alkan-2-yl)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxoxypiperane-l-yl]-4-hydroxy-2-isopropyl Hexane amide amine fumarate

In the same manner as in Example 17, the tertiary butyl {(IS)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5- side obtained in Reference Example 1 was used. Oxypiperidine-1-yl]-bu [(2S,4S)-4-isoprop-5-yloxytetrahydrofuran-2-yl]-108- 201124388 Ethyl}carbamate and Reference Example 24 The trans-4-amine fundane-1-carboxamide obtained in the title compound obtained 318 mg (yield: y. Colorless solid. 'HNMR spectrum (CD3OD, 400MHz) &gt; δ : 7.76 (br d, 1 Η, J = 7.0 Hz), 7.5 6-7.5 3 (m, 1H), 7.45 - 7.3 2 (m, 3H), 6.70 (s , 2H), 4.01 (br s, 1H), 3.66-3.14 (m, 6H), 2.9 8 -2.92 (m, 0.6H), 2.81-2.69 (br s, 0.8H), 2.56-2.44 (m, 1 6H), 2.07- 1.8 0 (m, 13H), 1.77-1.71 (m, 1H), 1.62- 1.5 9 (m, 2H), 1.31-1.27 (m, 6H), 1.01 (d: 3H, J = 6.7 Hz), 0.99 (d, 3H, J = 6.7 Hz). Mass Spectrum (ESI+), m/z: 602 ((M + H)+). (Example 1 9 ) (2R, 4S, 5S) -5-Amino-N-(trans-5-aminecarboxyxantane-2-yl)-6-[4-(2-chlorobenyl) -2,2 -monomethyl-5-oxooxyindole-1-yl]-2_ethyl-4-hydroxyhexane decylamine fumarate

In the same manner as in Example 17, the tributyl sulfonium (IS)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5- side obtained in Reference Example 18 was used. Oxypiperone-109- 201124388 cultivum-1-yl]-1-[(2S,4R)-4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate and reference example 24 The trans-4-amine fundane-1-carboxamide obtained in the title compound was obtained 763 mg (yield: 6%). 1H NMR spectrum (CD3OD, 400MHz) &gt; 5:7.91 (br d, 1H, J = 7.4 Hz), 7.56-7.5 3 (m, 1H), 7.44-7.3 2 (m, 3H), 6.69 (s, 2H) , 4.01 (br s, 1H), 3.67-3.51 (m, 3H), 3.37-3.12 (m, 3H), 2.9 8 -2.9 2 (m, 0.6H), 2.81-2.63 (m, 1.8H), 2.55 -2.51 (m, 0.6H), 2.07-1.85 (m, 12H), 1.70-1.51 (m, 5H), 1.31-1.27 (m, 6H), 0.97 (t, 3H, J = 7.4 Hz). Mass spectrum (FAB + ), m/z: 568 ((M + H)+). (Reference Example 1) (3S, 5S) -3 -isopropyl- 5-{(2S)-i_[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran- 2(3H)-ketone

(la) { ( 4S,5S ) -5-[(benzyloxy)methyl]_22 dimethyldioxolan-4-yl hydrazine

201124388 Content) 7.71 g (193 mmol) was added in several portions over 45 minutes and stirred at the same temperature for 1 hour. 23.8 ml (200 mmol) of benzyl bromide was added to the reaction mixture over 30 minutes, and stirred at the same temperature for 3 hours. To the reaction mixture was added 2.2 ml of acetic acid (38 mm 〇1), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. After filtration, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (solvent solvent: hexane-ethyl acetate = 2/1 to 1/1) to give the title compound 35.27 g (yield: 73%). Yellow liquid. NMR spectrum (CDC13, 400MHz), δ: 7.38-7.28 (m, 5H), 4.59 (s, 2H), 4.0 8 -4.0 3 (m, 1H), 3.97-3.93 (m, 1H), 3.77 (dt, 1H, J = 11.7 Hz, 4.3 Hz), 3.71-3.65 (m, 2H), 3.56 (dd, 1H, J = 9.8 Hz, 5.9 Hz), 2.17 (dd, 1H, J = 8.2 Hz, 4.7 Hz), 1.42 (s, 3H), 1.41 (s, 3H). (lb) {(43,53)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methylmethanesulfonic acid Ester (4S,5S )-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolane-4 obtained in Reference Example (la) a solution of methylene chloride (19. A solution of dichloromethane (9 〇 ml) was stirred at the same temperature for 20 minutes. To the reaction mixture was added hydrazine. 76 ml (42 mmol) and then stirred at room-111-201124388 for 15 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc m. After filtration, the solvent was evaporated to dryness crystall </ br> </ br> J = 11.2 Hz, 5.4 Hz), 4.15-4.11 (m, 1H), 4.07-4.03 (m, 1H), 3.69 (dd, 1H, J = 9.8 Hz, 4.9 Hz), 3.58 (dd, 1H, J = 9.8 Hz, 5.4 Hz), 3.02 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H). (lc) ( 4S,5S) -4-[(benzyloxy)methyl]-5-(iodomethyl)-2,2-dimethyl-1,3-dioxolane Reference Example Crude {( 4 S,5 S ) · 5 -[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolane obtained in (1 b ) A solution of 46.19 g (140 mmol) of 4-yl}methylmethanesulfonate and 62.87 g (419 mmol) of sodium iodide (420 ml) was stirred at 80 ° C for 22 hours. After the reaction mixture was cooled, the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated After filtration, the solvent was evaporated under reduced pressure to give the title compound m. Yellow liquid. h NMR spectrum (CDC13, 400MHz), δ: 7.38-7.27 (m, 5H), 4.59 (s, 2H), 3.99-3.95 (m, 1H), 3.9-3.84 (m, 1H), 3.67 (dd, - 112- 201124388 1 H, J = 10.2 Hz, 5 . 1 Hz), 3.64 (dd, 1 H, J = 10.2 3.35 (dd, 1H, J = 10.6 Hz, 5.1 Hz), 3.28 (dd, 1H 5.1 Hz) , 1.47 (s, 3H), 1_42 (s, 3H) (ld) (2R) -1-(benzyloxy)but-3-en-2-ol, crude obtained in Reference Example (1 C ) (4 S , 5 -oxy)methyl]-5-(iodomethyl)-2,2-dimethyl-1,3-di 4 9.2 0 g (136 mmol) and zinc sulphate 26.66 g (408 mmol) The mixture was stirred at 80 ° C for 3 hours. After cooling the reaction mixture, the zinc powder was filtered using a diatomaceous earth product (Celite 545), and the filtrate was concentrated under reduced pressure and diluted with 1N hydrochloric acid to give an organic layer of acetic acid. The aqueous sodium sulfite solution and the saturated sodium salt were dried over anhydrous magnesium sulfate. After filtered, the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 17.1 Hz, 10.3 Hz, 5.4 Hz),

J = 17.1 Hz, 1.5 Hz), 5.20 (dt, 1H, J = 10.3 4.58 (s, 2H), 4.3 8-4.3 3 (m, 1H), 3.55 (dd, 1H 3.4 Hz), 3.38 (dd, 1H , J = 9.8 Hz, 7.8 Hz), 2.4 3.4 Hz). (le) ( 1R) -1-[(benzyloxy)methyl]propan-2-ene-butyrate (2 R ) -1 -(benzyl) obtained in Reference Example (1 d )

Hz, 5.1 Hz), , J = 10.6 Hz, S) -4-[(benzyloxycyclopentane: alcohol (420ml), unreacted and washed with ethanol. After ester extraction, wash with ί water to Obtained crude ^.29 (m, 5H), 5.37 (dt, 1H, Hz, 1.5 Hz), , J = 9.8 Hz, 1 (d, 1H, J = 1-yl 3-methyloxy)- 3--113- 201124388 Dilut-2-ol 24.29g (136mmol), triethylamine 28.5ml (205mmol) and N,N-dimethylaminopyridine 1.65g (13.6mmol) of dichloromethane (2 5 0 ml) solution, 19.9 ml (163 mmol) of dichloromethane (20 ml) of isobutyric acid chloride was added to the solution under ice cooling for 10 minutes, and stirred at room temperature for 4 hours. Water (0.75 ml (42 mm 〇l)) was added to the reaction mixture, and then The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated, evaporated, evaporated, evaporated, evaporated After filtration, the solvent was evaporated under reduced pressure and purified mjjjjjjjjjjjjjjjjjjj %). Yellow liquid. 4 NMR spectrum (CDC13, 400 MHz), δ: 7.36-7.27 (m, 5H), 5.84 (ddd, 1H, J = 17.2 Hz, 10.6 Hz, 5.9 Hz), 5.54-5.49 (1H, m), 5.33 (dt, 1H, J = 17.2 Hz, 1.2 Hz), 5.24 (dt, 1H, J = 10.6 Hz, 1.2 Hz), 4.58 (d, 1H, J = 12.5 Hz), 4.54 (d, 1H, J = 12.5

Hz), 3.58 (dd, 1H, J = ll, 〇Hz, 5.9 Hz), 3.56 (dd, 1H, J = 11.0 Hz, 4.7 Hz), 2.23 (d, 2H, J = 6.6 Hz), 2.17-2.07 (m, 1H), 0.96 (d, 6H, J = 6.6 Hz). Mass spectrum (FAB+), m/z: 263 ((M + H)+). (lf)(2S,4E) -6-(benzyloxy)_2-isopropylhexan-4 acid in tetraisopropylfuran (265 ml) solution of isopropylamine in 23 ml (1, 63 mmol), under nitrogen and ice cold To the solution of η-butyllithium-114-201124388 η-hexane (1.57 mol/l), 94 ml (148 mmol) was added over 45 minutes, and stirred at the same temperature for 20 minutes to prepare a solution of lithium diisopropyl decylamine in tetrahydrofuran. In this solution, (1R)-1-[(benzyloxy)methyl]propan-2-ene-1- obtained in Reference Example (le) cooled by a dry ice-acetone bath was added over 40 minutes. A solution of 34.95 g (l33 mmol) of tetrahydrofuran (70 ml) was stirred at the same temperature for 20 minutes. Next, 39 ml of trimethyl decane chloride (3 〇 7 mmol) was added to the reaction mixture over 20 minutes, stirred at the same temperature for 20 minutes, and then stirred at room temperature for 3 hours. After cooling in an ice bath, 27 ml (667 mmol) of methanol was added to the reaction mixture, and the mixture was added at an internal temperature of not more than 20 ° C, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc EtOAc EtOAc. The aqueous layer was combined with ethyl acetate (78 mL) to give acid. After filtration, the solvent was evaporated to dryness crystall After the obtained (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid is converted into the corresponding methyl ester body by treatment with trimethylsulfonyldiazomethane in methanol, An optically active HPLC column for analysis [ChiralCel OD-H (0.46 cm x 25 cm)' manufactured by Daicel Co., Ltd., solvent: η-hexane / 2-propanol = 90/10, flow rate: 〇.5 ml/min)] purity. The retention time of the intended 2S body was 14.7 minutes, the corresponding isomer 2R body retention time was 16.2 minutes, and the optical purity was 91% ee. Yellow liquid. -115- 201124388 Optical rotation, [a] D = -9.9° (c = 1.07, CHCl3). NMR spectrum (CDC13' 400 MHz), δ: 7.38-7.27 (m, 5H), 5.72-5.62 (m, 2H), 4.47 (s, 2H), 3.99-3.91 (m, 2H), 2.40-2.20 (m, 3H), 1.96-1.8 8 (m, 1H), 0.98 (d, 3H, J = 6.6 Hz), 0.97 (d, 3H, J = 6.6 Hz). (lg) (2S, 4E) -6-(benzyloxy)-2-isopropyl hydrazine, hydrazine-dimethylhex-4-enylamine obtained in Reference Example (If) (2S, 4E) -6-(Benzyloxy)-2-isopropylhex-4-enoic acid 19.02 g (72.5 mmol) in dichloromethane (180 ml). 87mmol) and 0.11ml (1.4mmol) of N,N-dimethylformamide, stirred at the same temperature for 1 hour to prepare (2S,4E)-6-(benzyloxy)-2-isopropyl a solution of 4-enoic acid in dichloromethane. The solution of the above acid chloride in methylene chloride was added to a solution of a mixture of tetrahydrofuran (1,80 ml) and a solution of the third butanol in a solution of a mixture of 50 ml of a dimethylamine solution (76 ml, 725 mmol) in ice-cooled over 1 hour. 20 minutes. The reaction mixture was concentrated to a volume of EtOAc (EtOAc) (EtOAc). After filtration, the solvent was evaporated. Yellow liquid. NMR spectrum (CDCh, 500 MHz), 6: 7.40-7.27 (m, 5H), 5.86-5.60 (m, 2H), 4.47 (s, 2H), 3.97-3.91 (m, 2H), 3.01 (s, 3H) , 2.95 (s, 3H), 2.51-2.47 (m, 1H), 2.43 -2.3 8 (m, 1H), -116- 201124388 2.29-2.2 5 (m, 1H), 1.94- 1.8 7 (m, 1H) , 0.95 (d, 3H, J = 6.9 Hz), 0.90 (d, 3H, J = 6.9 Hz). (lh) (3S,5S)-5·[(1R)·2-(Benzyloxy)-l-bromoethyl]-3-isopropyldihydrofuran-2(3H)-one in Reference Example ( (2S,4E)-6-(benzyloxy)-2-isopropyl-N,N-dimethylhex-4-enenamine obtained in lg) 21.20 g (72.5 mmol) and acetic acid 8.3 ml (145 mmol) of a mixed solvent solution of tetrahydrofuran (290 ml) and water (145 ml) was added with N-bromosuccinimide 2 5.8 1 g (145 mm 〇1) under ice cooling, and stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture (1 mL) and 1M aqueous sodium sulfate solution (10 mL), and then stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness (MgSO4). After filtration, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent: hexane-ethyl acetate = 6/1 to 5 /1) to give the title compound 2 2.7 3 g (3) Total project yield: 50%). Colorless liquid. NMR spectrum (CDC13, 500MHz), δ: 7.38-7.30 (m, 5H), 4.75-4.71 (m, 1H), 4.61 (d, 1H, J = 12.2 Hz), 4.56 (d, 1H, J = 12.2 Hz ), 4.22 (q, 1H, J = 5.9 Hz), 3.8 4 (dd, 1H, J = 10.7 Hz, 5.4 Hz), 3.78 (dd, 1H, J = 10.7 Hz, 6.4 Hz), 2.67-2.63 (m , 1H), 2.27-2.22 (m, 1H), 2.20-2.11 (m, 2H), 1.02 (d, 3H, J = 6.8 Hz), 0.94 (d, 3H, J = 6.8 Hz) ° (li) ( 3S,5S) -5-[(lS)-1-azido- 2-(benzyloxy)ethyl-117- 201124388-yl]-3-isopropyldihydrofuran-2(3H)-one (3S,5S)-5-[(lR)-2-(Benzyloxy)-1-bromoethyl]-3-isopropyldihydrofuran-2(3H)- obtained in (lh) a solution of 22.33 g (65.4 mmol) of ketone 1,3 -dimethyl-3,4,5,6-tetrahydro-2 fluorene (1 Η)-pyrimidinone (DMPU) (130 ml) at room temperature Sodium nitride 5.10 g (7 8.5 mmol) was stirred at 40 ° C for 3 days. After cooling the reaction mixture, it was poured into ice water and extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (solvent solvent: hexane-hexane/ethyl acetate = 6 /1) to give the title compound 1 0.19 g (yield: 5 1 %). Colorless liquid. NMR spectrum (CDC13, 500MHz), δ: 7.38-7.29 (m, 5H), 4.61-4.53 (m, 3H), 3.7 9-3.73 (m, 2H), 3.66-3.63 (m, 1H), 2.7 5 - 2.7 0 (m, 1H), 2.20-2.10 (m, 3H), 1.02 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.8 Hz). (lj) N- {( IS) -2-hydroxy-1·[ ( 2S,4S) -4_isopropyl- 5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonate The amine (3S,5S ) -5-[(IS)-1-azido-2-(benzyloxy)ethyl]-3-isopropyldihydrofuran obtained in Reference Example (li) 2 (3H)-ketone 10.12g (33.5mm〇l), 4N hydrochloric acid-dioxane solution 16.7ml (66.8mm〇l) and 10% palladium carbon (50% aqueous) 3.5 7g of ethanol (170ml) suspension, 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 reaction mixture was diluted with ethanol 1 70 ml, and the palladium carbon was filtered and washed with -118-201124388 ethanol. The solvent was distilled off from the filtrate under reduced pressure to give crude (3S,5S)-5-[(IS)--amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2 (3H) ) - ketone hydrochloride 8.50 g. (3S,5S)-5-[(lS)-1-amino-2-(yl)ethyl]-3-isopropyldihydrofuran-2 (31〇- obtained in the above reaction) To a mixed solvent solution of ketohydrochloride 8.50 g (33_5 mmol) in tetrahydrofuran (170 ml) and water (17 ml), and then, at room temperature, were added 14 ml of triethylamine (10 mmol) and 〇-nitrobenzenesulfonyl chloride 11.12 g ( 50.1mm〇1), stirring at the same temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent: ethyl acetate), then diisopropyl ether 1 10 m 1 and 11 ml of ethyl acetate were added and filtered. The title compound was obtained as a solid (yield: (yield: 70%). N-{(1S) -2 -hydroxy-1-[(2S,4S) -4 -isopropyl- 5- Oxyloxytetrahydrofuran-2-yl]ethylindole-2-nitrobenzenesulfonamide is an optically active HPLC column for analysis [ChiralPak AD-H (0.46 cm x 25 cm), manufactured by Daicel Co., Ltd., solvent: n - Alkane/ethanol = 30/70, flow rate: 1.0 ml / min)] determines the optical purity. The retention time of the [(IS) , (2S, 4S)] body was 5.7 minutes, and the corresponding isomer [(11〇, (211,411)]) had a retention time of 9.0 minutes and an optical purity of 90% ee. Colorless solid. Optical rotation, [a] D = +26.9 ° (c = 1.00, MeOH). -119 - 201124388 4 NMR spectrum (CDC13, 500 MHz), δ: 8.15-8.11 (m, 1H), 7.92-7.8 8 (m, 1H), 7.77-7.74 (m, 2H), 5.85 (br d, 1H, J - 8.3 Hz), 4.64-4.61 (m, 1H), 3.71-3.62 (m, 3H), 2.69 (ddd , 1H, J = 10.3 Hz, 6.8 Hz, 5.4 Hz), 2.41 (ddd, 1H, J = 13.7 Hz, 10.7 Hz, 5.4 Hz), 2.20-2.10 (m, 2H), 1.99 (t, 1H, J = 5.4 H z),1 . 0 0 (d,3 H,J = 6.8 H z ),0 · 9 3 (d,3 H,J = 6 · 8 H z) Mass Spectrometry (FAB+), m/z: 373((m + H)+) (lk )(3S,5S) -3 -isopropyl- 5-{(2S) -l-[(2-nitrophenyl)sulfonyl]aziridine N-{( lS)-2-hydroxy-1-[(2S,4S)-4-isopropyl group obtained in the reference example (lj) of 2-yl}dihydrofuran-2(3H)-one -5-Phenoxytetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 4_00g (10.7mmol) and triphenylphosphine 3.38g (12.9mmol) in tetrahydrofuran (100ml), Icy 5.9 ml (12.9 mmol) of a solution of diethyl azodicarboxylate in toluene (40%) was added over 10 minutes, and the mixture was stirred at the same temperature for 1 〇min. The reaction mixture was concentrated under reduced pressure and purified by a gel column chromatography. Purification (solvent: toluene/acetone = 5/1) to give the title compound 3.40 g (yield: 89%). colourless liquid. 1HNMR spectrum (CDC13, 400 MHz), δ: 8.14 (dd, 1H, J = 7.4 Hz, 1.5 Hz), 7.83-7.73 (m, 3H), 4.74-4.70 (m, 1H), 3.2 6-3.2 3 (m, 1H), 2.83 (d, 1H, J = 7.0 Hz), 2.78 (dt , 1H, J = 9.8 Hz, 4.7 Hz), 2.65 (d, 1H, J = 4.7 Hz), 2.41-2.35 (m, 1H), 2.29 (dt, 1H, J = 12.9 Hz, 9.4 Hz), 2.18- 2.10 (m, 1H), -120- 201124388 1.00 (d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 7.0 Hz) = mass spectrum (FAB+), m/z: 355 ((M + H ))). (Reference Example 2) (3R,5S)-3-Ethyl-5'-{(2S)-l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran -2(3H)-ketone

0 (2a)(4S)-4-benzyl-3-butylidene-1,3-oxazolidine-2·one in (4S)-4-benzyl-1,3-oxazolidin-2-one 25.0 In a solution of g (141 mmol) in tetrahydrofuran (600 ml), 90 ml (144 mmol) of η-butyllithium η-hexane (1.60 mol/l) was added over 10 minutes under nitrogen atmosphere and stirred at the same temperature. minute. Next, 16_5 ml (156 mmol) of η-butyric acid chloride was added over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 3 hours. 90 ml of a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. After filtration, the solvent was evaporated to dryness crystal crystal crystal crystal crystal NMR spectrum (CDC 13, 400 ΜΗζ), δ: 7.37-7.19 (m, 5H), 4.71-4.64 (m, 1H), 4.23-4.14 (m, 2H), 3.30 (dd, 1H, J = -121 - 201124388 13.3 Hz, 3.5 Hz), 3.01-2.83 (m, 2H), 2.77 (dd, 1H, J = 13.3 Hz, 9.4 Hz), 1.79 - 1 .6 8 (m, 2H), 1.01 (t, 3H, J = 7.4 Hz). (2b)({[(2E)-4-Bromobut-2-en-1-yl]oxy}methyl)benzene in trans-1,4-dibromo-2-butene 20.0g (94.7mmol In a solution of dichloromethane (80 ml), benzyl alcohol 10 ( (8 〇 3 mmol), tetrabutylammonium hydrogen sulfate 3.16 g (58.5 mmol) and sodium hydroxide 8.63 g (840 mmol) were added at room temperature. The solution of water (45.6 ml) was stirred for 2 days. The reaction mixture was diluted with water (300 ml). After the filtration, the solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjli Yellow liquid. 4 NMR spectrum (CDC13, 400 MHz), δ: 7.40-7.25 (m, 5H), 6.03 - 5.94 (m, 1H), 5.9 3 - 5.84 (m, 1H), 4.52 (s, 2H), 4.05 (dd , 1H, J = 5.4Hz, 1.0 Hz), 3.97 (dd, 1H, J = 7.4. 0.8 Hz) - (2c)(4S)-4-benzyl-3-[ ( 2R,4E ) -6-( (4S)-4-benzyl-3-butanyl-1,3 obtained from benzyloxy)·2-ethylhex-4-enyl] oxazolidin-2-one in Reference Example (2a) - oxazolidin-2-one 35.3 g (141 mmol) in tetrahydrofuran (330 ml), added sodium bis(trimethylsilyl) guanamine η over 45 minutes under nitrogen atmosphere at -78 °C - 164 ml (169 mmol) of a solution of hexane (l. 〇 3 mol/l) was stirred at the same temperature for 30 minutes. Next, in this solution, ({[( 2E )-4-bromobut-2-en-1-122- 201124388 yl)oxy}methyl) obtained in Reference Example (2b) was added over 30 minutes. A solution of 35.6 g (148 mmol) of benzene in tetrahydrofuran (80 ml) was stirred at the same temperature for 30 minutes, then warmed to -4 (TC, and then stirred for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated The solvent was evaporated, and the residue was purified (jjjjjjjjjjjjjjjjjjj NMR spectrum (CDC13, 500MHz), δ: 7.33-7.20 (m,8H), 7.16 (d, 2H, J = 6.8 Hz), 5.75 (dt, 1H, J = 15.1 Hz, 6.8 Hz), 5.68 (dt , 1H, J = 15.1 Hz, 5.4 Hz), 4.71-4.65 (m, 1H), 4.48 (s, 2H), 4.18 (m, 2H), 3.97 (d, 2H, J = 5.4 Hz), 3.88-3.82 (m, 1H), 3.29 (dd, 1H, J = 13.2 Hz, 3.4 Hz), 2.64 (dd, 1H , J = 13.2 Hz 10.3 Hz), 2.5 2 -2.4 5 (m, 1H), 2.3 7-2.3 0 (m, 1H), 1.81-1.70 (m, 1H), 1.62 - 1.5 2 (m, 1H), 0.92 (t, 3H, J - 7.3 Hz) (2d ) ( 2R,4E ) -6-(benzyloxy)-2-ethylhex-4-enoic acid obtained in Reference Example (2c) ( 4S) -4 -benzyl-3-([2R,4E)-6-(benzyloxy)-2-ethylhex-4-enyl] oxazolidin-2-one 23.4g (57.5mmol) In a mixed solvent solution of tetrahydrofuran (800 ml) and water (260 ml), after cooling in an ice bath, add 35.0 ml of 30% hydrogen peroxide water and 4.83 g (115 mmol) of lithium hydroxide monohydrate. Stir at the same temperature for 1 hour - After the temperature was adjusted to room temperature, the mixture was stirred for further 12 hours. The reaction mixture was concentrated under reduced pressure, and the mixture was diluted with EtOAc EtOAc (EtOAc) It was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude title compound (1. Colorless liquid. 4 NMR spectrum (CDC13, 400MHz), δ: 7.37-7.27 (m, 5H), 5.7 3 -5.62 (m, 2H), 4.49 (s, 2H), 4.03-3.91 (m, 2H), 2.45-2.34 ( m, 2H), 2.33-2.21 (m, 1H), 1.7 3 - 1.5 2 (m, 2H), 0.95 (t, 3H, J = 7_4 Hz). (2e)(3R,5S)-5-[(lR)-2-(Benzyloxy)-1-hydroxyethyl]-3-ethyldihydrofuran-2(3H)-one in Reference Example (2d (2R,4E)-6-(Benzyloxy)-2-ethylhex-4-enoic acid 8.30g (33_5mmol) of acetonitrile (167ml) and dimethoxymethane (3 3 3 ml) In a mixed solvent, 335 ml of sodium tetraborate buffer solution (0.05 M) dissolved in 二. 4 mM aqueous solution of disodium edetate (0.05 M), tetrabutylammonium hydrogen sulfate 〇 503 g ( 1.48 mmol) and 1,2,4,5-di-0-isopropylidene-cold-0-erythro-2,3-hexanedione-2,6-pyranose 8.63 g (33.4 mm〇l), stirring 1 Minutes. After cooling the reaction mixture in an ice bath, 28.4 g (46.1 mmol) of Oxone (registered trademark) was dissolved in a solution of 4 mM aqueous solution of disodium edetate-124-201124388 (168 ml). A solution of 26.7 g (193 mmol) of potassium carbonate in water (168 ml). After stirring at the same temperature for 1 hour, it was diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjjjj Yield: 70%). Colorless liquid. H NMR spectrum (CDC13, 400 MHz), δ: 7.40-7.29 (m, 5H), 4.58 (d, 1H, J = 11.9 Hz), 4.54 (d, 1H, J = 11.9 Hz), 4.46 (ddd, 1H, J = 8.2 Hz, 6.3 Hz, 4.3 Hz), 3.90-3.8 3 (m, 1H), 3.64 (dd, 1H, J = 9.8 Hz, 3.9 Hz), 3.56 (dd, 1H, J = 9.8, 6.3 Hz) , 2.6 5 -2.5 6 (m, 1H), 2.51-2.43 (m, 1H), 2.41 (d, 1H, J = 5.1 Hz), 2.01-1.93 (m, 1H), 1.92 - 1.8 0 (m, 1H ), 1.58-1.46 (m, 1H), 1.01 (t, 3H, J = 7.4 Hz). (2f) ( 1R) -2-(Benzyloxy)_]·[ ( 2S,4R) -4 -ethyl·5-sided oxytetrahydrofuran-2-yl]ethyl sulfonate (3R,5S) _5_[(ir) _2_(benzyloxy)-1-alkylethyl]-3-ethyldihydrofuran-2( 3H)-one 25.0 obtained in Reference Example (2e) g (94.7 mmol) in dichloromethane (6 〇〇mi) solution, after cooling in an ice bath, add 28.7 g (284 mm 〇l) of triethylamine and 15.9 g (l39 mmol) of chloromethane sulfonate at the same temperature. Stir for 3 hours. Water (50 ml) was added to the reaction mixture, and the organic layer was washed with water and saturated brine. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted elution elution elution elution elution elution elution elution elution elution g (yield: 96%). Colorless liquid. NMR spectrum (CDC13, 400MHz), δ: 7.43-7.28 («1,5H), 4.86-4.81 (m, 1H), 4.65 (ddd, 1H, J = 8.2 Hz, 5.1 Hz, 4.5 Hz), 4.56 (s , 2H), 3.77 (dd, 1H, J = 11.0 Hz, 5.9 Hz), 3.74 (dd, 1H, J = 11.0 Hz, 5.5 Hz), 3.04 (s, 3H), 2.66-2.57 (m, 1H), 2.53 - 2.45 (m, 1H), 2.07- 1.98 (m, 1H), 1.91-1.79 (m, 1H), 1.60- 1.48 (m, 1H), 1.01 (t, 3H, J = 7.4 Hz). (2g) (3R,5S)-5-[(IS)-1-azido-2-(benzyloxy)ethyl]-3-ethyldihydrofuran-2(3H)-one in Reference Example (1R)-2-(Benzyloxy)-1-[(2S,4R)-4-isoethyl-5-oxo-tetrahydrofuran-2-yl]ethylmethanesulfonate obtained in (2f) 29.5 g (86.3 mmol) of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (300 ml), azide at room temperature Sodium 7.91 g (122 mmol) was added and the mixture was stirred at 60 ° C for 2 days. After cooling the reaction mixture, it was poured into ice water and extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. . After filtration, the solvent was evaporated under reduced pressure, and the residue was purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless liquid. H NMR spectrum (CDC13, 400 MHz), δ: 7.40-7.29 (m, 5H), 4.62-4.5 5 (m, 3H), 3.8 0-3.7 3 (m, 2H), 3.66 (ddd, 1H, J = -126- 201124388 7.0 Hz, 5.5 Hz, 3.1 Hz), 2.77-2.67 (m, 1H), 2.3 6-2.27 (m, 1H), 2.0 8 - 1.9 9 (m, 1H), 1.92 - 1.8 0 (m , 1H), 1.5 7- 1.43 (m, 1H), 1.00 (t, 3H, J = 7.4 Hz). (2h) N-{( IS) -l-[ ( 2S,4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]-2-hydroxyethyl}-2-nitrophenylsulfonate The amine (3 R,5 S ) - 5 - [ ( 1 S ) -1 -azido-2-(benzyloxy)ethyl]-3-ethyl 2 obtained in Reference Example (2 g ) Hydrogen furan-2(3H)-one 23.5g (81.3mmol), 4N hydrochloric acid-two hospital solution 40_0ml (160mmol) and 10% palladium carbon (50% aqueous) 5.21g ethanol (400ml) suspension, under hydrogen atmosphere Stir at room temperature for 12 hours. After replacing the hydrogen in the reaction vessel with nitrogen, the reaction mixture was diluted with ethanol 300 ml, and the palladium carbon was filtered and washed with ethanol. The solvent was distilled off from the filtrate under reduced pressure to give crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2(3H)- Ketone hydrochloride. (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2(3H)-one hydrochloride obtained in the above reaction a mixed solvent solution of tetrahydrofuran (3 50 m 1 ) and water (3 5 · 0 m 1 ), adding 25.6 g (253 mmol) of triethylamine and 28.6 g of cerium chloride-nitrobenzene at 〇 °C (129 mmol) 'Stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (solvent solvent: ethyl acetate), and then a mixture of diisopropyl ether (20 ml) and ethyl acetate (m. The title compound 17. Og (2 Engineering - 127 - 201124388 Total Yield: 5 9 %). Colorless solid. Optical rotation, [a] D2351c = +34.4 〇 (c = 1.00, MeOH). 4 NMR spectrum (CDC13, 500MHz), δ: 8.15-8.11 (m, 1H), 7.93 -7.8 8 (m, 1H), 7.78-7.7 3 (m, 2H), 5.85 (br d, 1H, J = 7.8 Hz), 4.67 (ddd, 1H, J = 8.3 Hz, 5.4 Hz, 2.9 Hz), 3.73-3.61 (m, 3H), 2.73-2.65 (m, 1H), 2.54 (ddd, 1H, J = 13.2 Hz, 9.8 Hz, 5.4 Hz), 2.08 (ddd, 1H, J = 13.2 Hz, 8.3 Hz, 6.8 Hz), 1.92- 1.87 (m, 1H), 1.87- 1.77 (m, 1H), 1.59-1.49 (m, 1H) ), 1.00 (t, 3H, J = 7.4 Hz). (2i) (3R,5S)-3-ethyl- 5-{(2S)-l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2 ( 3H)-ketone N-{(IS)-l-[(2S,4R)-4-ethyl-5-oxooxytetrahydrofuran-2-yl]-2-hydroxyl group obtained in Reference Example (2h) Ethyl}-2-nitrobenzene allysine 1. 〇 5g ( 2.93mmol) and triphenylphosphine 923mg ( 3.52mmol) in tetrahydrofuran (30ml), azodicarboxylate was added over 5 minutes under ice cooling. A solution of 1.20 ml (3.52 mmol) of diethyl ether in toluene (40%) was stirred at the same temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjj Colorless liquid. 'H NMR spectrum (CDC13, 400 MHz), δ: 8.14 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 7.83-7.72 (m, 3H), 4.75 (dt, 1H, J = 9.0 Hz, -128- 201124388 2.7 Hz), 3.2 6-3.2 3 (m, 1H), 2.84 (d, 1H, J = 7.4 Hz), 2.81-2.72 (m, 1H), 2.65 (d, 1H, J = 4.7 Hz), 2.57 -2.51 (m, 1H), 2.18 (dt, 1H, J = 12.9 Hz, 9.0 Hz), 1.91-1.80 (m, 1H), 1.5 3 - 1.42 (m,1H), 0_98 (t,3H, J = 7.4 Hz). Mass spectrum (FAB+), m/z: 340 ((M + H)+). (Reference Example 3) (3R,5S)-3-methyl-5-{(2S)-l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran- 2 ( 3H)-ketone

(3a)(4S)-4-benzyl-3-([2R,4E)-6-(benzyloxy)-2-methylhex-4-enyl]-1,3-oxazolidine- 2-ketone in (4S)-4-benzyl-3-propenyl-1,3-oxazolidin-2-one 32.9g (Mlmmol) in tetrahydrofuran (330ml), nitrogen atmosphere and - 78 ° C Next, 164 ml (169 mmol) of a solution of sodium bis(trimethyldecyl)decylamine in hexane (1.03 mol/l) was added over 45 minutes, and the mixture was stirred at the same temperature for 30 minutes. Next, in this solution, (5[(2E)-4-bromobut-2-en-1-yl]oxy}methyl)benzene (35.5 g) obtained in Reference Example (2b) was added over 30 minutes ( A solution of 148 mmol) in tetrahydrofuran (80 ml) was stirred at the same temperature for 30 minutes, then warmed to -40 ° C and then stirred for 4 hours. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction mixture and stirred at room temperature for 1 hour. 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 mjjjjjjjjjjjjjjjjj 69%). Colorless liquid. NMR spectrum (CDC13, 400 MHz), δ: 7.40-7.14 (m, 10H), 5.75 (dt, 1H, J = 15.6 Hz, 6.3 Hz), 5.69 (dt, 1H, J = 15.6 Hz, 5.4 Hz), 4.71 -4.63 (m, 1H), 4.49 (s, 2H), 4.22-4.11 (m, 2H), 3.98 (d, 2H, J = 5.5 Hz), 3.92-3.81 (m, 1H), 3.28 (dd, 1H , J = 13.3 Hz, 3.1 Hz), 2.67 (dd, 1H, J = 13.3 Hz, 10.2 Hz), 2.5 8-2.49 (m, 1H), 2.30-2.21 (m, 1H) 1.19 (d, 3H, J = 6.7 Hz). (3b) (2R, 4E) -6-(benzyloxy)-2-methylhex-4-enoic acid (4S)-4-benzyl-3--(() obtained in Reference Example (3a) 2R,4E)-6-(benzyloxy)-2-methylhex-4-enenyl]-1,3-oxazolidin-2-one 18.7 g (47.5 mmol) in tetrahydrofuran (700 ml) In a mixed solvent solution of water (230 ml), after cooling in an ice bath, 30.0 ml of 30% hydrogen peroxide water and 4.15 g (95.3 mmol) of lithium hydroxide monohydrate were added. After stirring at the same temperature for 30 minutes, the temperature was raised to room temperature and stirred for 6 hours. After cooling in an ice bath, 1.5 ml of an aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with water (500 ml), and washed with ethyl acetate, and then, 30 g of sodium dihydrogen phosphate was added to the aqueous layer to make it acidic, and the organic layer was washed with saturated brine. Dry with -130- 201124388 anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness crystall Colorless liquid. 4 NMR spectrum (CDC13, 400MHz), δ: 7.40-7.25 (m, 5H), 5.73 -5.6 2 (m, 2H), 4.49 (s, 2H), 4.03 - 3.93 (m, 2H), 2.61-2.51 ( m, 1H), 2.5 0-2.40 (m, 1H), 2.28-2.17 (m, 1H), 1. 19 (d, 3H, J = 7.0 Hz). (3c)(3R,5S)-5-[(lR)-2-(Benzyloxy)-1-hydroxyethyl]-3-methyldihydrofuran-2(3H)-one in Reference Example (3b (2R,4E)-6-(benzyloxy)-2-methylhex-4-isoacid 10.1 g (43.2 mmol) of acetonitrile (167 ml) and dimethoxymethane (333 ml) In a mixed solvent, 400 ml of a sodium tetraborate buffer solution (0.05 M) dissolved in 0.4 mM aqueous solution of disodium ethylenediaminetetraacetate, tetrabutylammonium hydrogen sulfate, 648 g (1.91 mmol) and I, 2 were added at room temperature. , 4,5- _•-〇-isopropylidene-0-oxime-erythro-2,3-hexamethylene-2,6-batchanose II. lg (43.0 mmol), stirred for 10 minutes. After cooling the reaction mixture in an ice bath, 36.7 g (59.6 mmol) of Oxone (registered trademark) was dissolved in a solution of 0.4 mM aqueous solution of disodium edetate (200 ml) and potassium carbonate (34.3 g (247 mmol)) over 8 hours. The water (200 ml) solution was dripped. After stirring at the same temperature for 1 hour, it was diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjj (2 total project yield: 72%). Colorless liquid. 'H NMR spectrum (CDC13, 400MHz), δ: 7.42-7.29 (m, 5H), 4.59 (d, 1H, J = 11.7 Hz), 4.55 (d, 1H, J = 11.7 Hz), 4.48 (ddd, 1H , J = 8.2 Hz, 6.3 Hz, 3.9 Hz), 3.91-3.84 (m, 1H), 3.64 (dd, 1H, J = 9.8 Hz, 3.9 Hz), 3.56 (dd, 1H, J = 9.8, 6.3 Hz) , 2.81-2.69 (m, 1H), 2.53 (ddd, 1H, J = 13.2 Hz, 9.4 Hz, 3.9 Hz), 2.47 (d, 1H, J = 5.1 Hz), 1.93 (dt, 1H, J = 13.2 Hz , 8.2 Hz), 1.28 (t, 3H, J = 7.0 Hz)-(3d)( 1R) -2-benzyloxy- l-[( 2S,4R) -4-methyl-5-oxo-tetrahydrofuran (3R,5S)-5-[(lR)-2-(benzyloxy)-1-hydroxyethyl]-3 obtained in Reference Example (3c) a solution of methyl dihydrofuran-2(3H)-one 7.80 g (31.2 mmol) in dichloromethane (200 ml). After cooling in ice bath, triethylamine 9.45 g (93.6 mmol) and methanesulfonate 5.36 g (47.0 mmol) of chlorine was stirred at the same temperature for 3 hours. After the mixture was extracted with methylene chloride (5 ml), the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjj 97%). Colorless liquid. NMR spectrum (CDC13, 400MHz), δ: 7.41-7.28 (m, 5H), 4.8 7-4.80 (m, 1H), 4.69-4.63 (m, 1H), 4.56 (s, 2H), -132- 201124388 3.80 -3.71 (m, 2H), 3.05 (s, 3H), 2.82-2.70 (m, 1H), 2.58 (ddd, 1H, J = 13.3 Hz, 9.4 Hz, 3-9 Hz), 1.99 (dt, 1H J = 13.3 Hz, 8.2 Hz), 1.29 (d, 3H, J = 7.4 Hz). (3e)(3R,5S)-5-[(iS)-1-azido-2-(benzyloxy)ethyl]-3-methyldihydrofuran-2(3H)-one in Reference Example (lR)-2-Benzyloxy- l-[( 2S,4R) _4_methyl_5_sideoxytetrahydrofuran-2-yl]ethyl methanesulfonate 9.90g (3d) To a solution of 30.1 mmol) of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (100 ml), 2.93 g of sodium azide was added at room temperature ( 45.1 mm 〇 l ), stirring at 60 ° C 3 曰. After the reaction mixture was cooled, it was poured into ice water and extracted with diethyl ether. The organic layer was washed with water and saturated brine. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjj 1 % ). Colorless liquid. H NMR spectrum (CDC13, 500MHz), δ: 7.40-7.29 (m, 5H), 4.62-4.54 (m, 3H), 3.78 -3.72 (m, 2H), 3.69-3.64 (m, 1H), 2.91-2.82 (m, 1H), 2.38 (ddd, 1H, J = 13.2 Hz, 9.8 Hz, 3.9

Hz), 2.00 (dt, 1H, J = 13.2 Hz, 8.3 Hz), 1.27 (d, 3H, J = 7.3 Hz). (3f) N- {( IS) -2 -hydroxy-i-[ ( 2S,4R) -4 -methyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonate The amine will be (3 R,5 S ) _ 5 _ [( 1 s ) -1 · -133- 201124388 azido-2-(benzyloxy)ethyl]-3 obtained in Reference Example (3 e ) -methyldihydrofuran-2(3H)-one 7.56g (27.5mmol), 4N hydrochloric acid-dioxane solution 15.0ml (60.0mmol) and 10% palladium on carbon (50% aqueous) l_88g of ethanol (150ml) suspension The solution was stirred at room temperature for 6 hours under a hydrogen atmosphere. After replacing the hydrogen in the reaction vessel with nitrogen, the reaction mixture was diluted with 100 ml of ethanol, and the palladium carbon was filtered and washed with ethanol. The solvent was distilled off from the filtrate under reduced pressure to give (3,,,,,,,,,,,, Ketone hydrochloride. (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2(3H)-one hydrochloride obtained in the above reaction a mixed solvent solution of tetrahydrofuran (120 ml) and water (12.0 ml), adding 8.66 g (85.7 mm 〇l) of triethylamine and 9.67 g (41.3 mmol) of 0-nitrobenzenesulfonium chloride at 〇 °C. Stir at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (solvent solvent: ethyl acetate), then diisopropyl ether (1 ml) and ethyl acetate (20 ml). The title compound 5.2 7 g (2 engineering total yield: 56%) was obtained. The resulting N-{(1S)-2-hydroxy-1 -[(2S,4R)-4-methyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide The optical purity was determined by an optically active HPLC column [ChiralPak AD-H (0.46 cm x 25 cm), manufactured by Daicel Co., Ltd., elution solvent: ethanol, flow rate: 〇_8 ml/min). The retention time of the [(IS),(2S,4R)] body is 4.9-134-201124388, and the corresponding isomer [[1R), (2R,4S)] retention time is 6· In minutes, the optical purity is 99% ee or more. Colorless solid. Optical rotation '[a ] d 2 3 8 1 = + 5 6 · 0. ( c = 1 · 0 0, M e Ο Η). NMR spectrum (CDC13, 500 MHz), δ: 8.16-8.09 (m, 1 Η), 7.94-7.8 7 (m, 1H), 7.79-7.71 (m, 2H), 5.89 (brd, 1H, J = 6.8 Hz) , 4.72-4.64 (m, 1H), 3.74-3.5 8 (m, 3H), 2.92-2.81 (m, 1H), 2.63 (ddd, 1H, J = 13.2 Hz, 9.8 Hz, 4.9 Hz), 2.03 (dt , 1H, J = 13.7 Hz, 8.3 Hz), 2.01-1.96 (m, 1H), 1.28 (d, 3H, J = 7.3 Hz). Mass spectrum (FAB+), m/z: 345 ((M + H)+). (3g) (3R,5S)-3-methyl-5-{(2S)-l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2 3H)-ketone N-丨(IS)-2-hydroxy-l-[( 2S,4R ) -4_methyl-5_sideoxytetrahydrofuran·2-yl] obtained in Reference Example (3f) Ethyl}-2-nitrobenzenesulfonamide 1.00 g (2.90 mmol) and triphenylphosphine ruthenium. 91 g (3.48 mmol) in tetrahydrofuran (30 ml), azodicarboxylate was added over 5 minutes under ice cooling. A solution of diethylbenzene in toluene (40%) (1.6 ml, 3.48 mmol) was stirred at the same temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless liquid. NMR spectrum (CDC13, 400 MHz), δ: 8.14 (dd, 1 Η , J = -135- 201124388 7.4 Hz, 1.5 Hz), 7.8 3 -7.7 3 (m, 3H), 4.76 (dt, 1H, J = 8.8 Hz, 2.0 Hz), 3.26-3.23 (m, 1H), 2.9 7-2.8 8 (m, 1H), 2.83 (d, 1H, J = 7.0 Hz), 2.65-2.60 (m, 2H), 2.18-2.10 (m, 1H), 1.26 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB+), m/z: 327 ((M + H)+). (Reference Example 4) 1-(2-Chlorophenyl)-5,5-dimethylpiperidin-2-one

(4a) Tert-butyl (2-hydroxy-1,1-dimethylethyl)amine formate in 2-amino-2-methyl-1-propanol 98.05g (1.10mol) and triethyl A solution of 154 ml of a solution of methylene chloride (50 ml) was added to a solution of di-tert-butyl butyl dicarbonate (230.4 ml (1.0 mmol) at room temperature over 20 minutes, and stirred at room temperature. 2.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated to dryness crystalljjjjjjjjj Colorless solid. , NMR spectroscopy (CDC13, 400MHz), δ: 4.64 (br s, 1H), 4.01 (br s, 1H), 3.59 (d, 2H, J = 6.3 Hz), 1.43 (s, 9H), 1.25 (s, 6H) -136- 201124388 (4b) Tert-butyl (1,1-dimethyl-2-oxoethyl)amine formate, the tertiary butyl group obtained in Reference Example (4a) a mixture of 56.78 g (300 mmol) of dichloromethane (5 〇〇ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 2 5 m 1 ) in a mixture of -hydroxymethylethyl)carbamate, tetramethylmethyl under ice cooling Piper steep N-oxide 0.94 g (6.0 mmol) and potassium bromide 3.57 g (30 mmol) were stirred at the same temperature for 30 minutes. To the reaction mixture was added 5% aqueous sodium chlorite (5,4 ml, (3, 60 mmol)) over 1-5 hrs, and the mixture was stirred at the same temperature for 20 minutes. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was returned to room temperature. After extracted with methylene chloride, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and y-hexanes was added to the residue, and the solid was collected to give the title compound 42.3 2 g (yield: 79%). Colorless solid. NMR spectrum (CDC 13, 400 MHz), δ: 9.43 (s, 1H), 4.97 (br s, 1 Η), 1.44 (s, 9 Η), 1.33 (s, 6 Η). (4c) Tert-butyl butyl {2-[2-(chlorophenyl)amino]-1,1-dimethylethyl}amine formate, the tertiary butyl group obtained in Reference Example (4b) (1,1-Dimethyl-2-oxoethyl)aminecarboxylate 3.00 g (16.0 mmol), 2-chloroaniline 2.04 g (16.0 mmol) and ruthenium acetate. 92 ml (16.0 mmol) of dichloro In a solution (160 ml), 4.07 g (19.3 mmol) of sodium triethoxy hydride hydride was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The saturated aqueous sodium hydrogencarbonate solution -137 - 201124388 was added to the mixture and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the title compound was obtained (yield:yield: 73%). Colorless solid. iHNMR spectrum (CDC13, 400 MHz), δ: 7.23 (dd, II 8.2 Hz, 1.6 Hz), 7.12-7.07 (m, 1 H), 6.72 (dd, 1H, J = 8 1.6 Hz), 6.61-6.57 (m, 1H), 4.59 (br s, 1H), 4.55 (br s, 3·38 (d, 2H, J = 5.9 Hz), 1.43 (s, 9H), 1.36 (s, 6H). (4d) Tertiary butyl {2-[(bromoethenyl)(2-chlorophenyl)-1,1-dimethylethylguanidinate in the third order obtained in Reference Example (4c) a solution of 3.09 g ( ll. 7 mmol) of dimethyl [2-[chloro-5amino]-1,1-dimethylethyl}carbamate in dimethylacetamide (5 8 ml) Next, 1.52 ml (17.5 mmol) of bromine bromide was added, and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous solution of sodium hydrogen was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh : 7.51-7.47 (m, 7.38-7.29 (m, 2H), 4.63 (br s, 1H), 4.16 (d, 1H, J = 14. 3.99 (br d, 1 H, J = 14.1 Hz), 3.69 ( Br d,1H, J = 11.7 Saturated disolvate = i, J = .2 Hz, 1H), ) amine itch) Ν, Ν - acetonitrile carbonate, obtained 2 Η), 1 Hz), Hz), -138- 201124388 3.53 (d, 1H, J = 11.7 Hz), 1.35 (br s, 3H), 1.34 (br s, 3H), 1. 18 (s, 9H). (4e) Tributyl 4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperidin-1carboxylate obtained in Reference Example (4d) Butyl butyl {2-[(bromoethenyl)(2.chlorophenyl)amino]-l,l-dimethylethylguanidinate 468g (ll_2mmol) in tetrahydrofuran (ll 〇ml) A solution of potassium tert-butoxide 1.87 g (16. 7 nmol) in tetrahydrofuran (110 ml) was added over 30 minutes under nitrogen atmosphere and cooled with a dry ice-acetone bath, and stirred at the same temperature for 10 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was evaporated to dryness. After filtration, the solvent was evaporated under reduced pressure and purified mjjjjjjjjjjjjjjjjjj 1 %). Colorless solid. NMR spectrum (CDC13, 400 MHz)' δ: 7.50-7.47 (m, 1H), 7.36-7.27 (m, 3H), 4.41 (br s, 1H), 4.09 (br s, 1H), 3.86 (br s, 1H ), 3.28 (br s, 1H), 1.56 (br s, 6H), 1.50 (s, 9H). (4f) tert-butyl 4-(2-chlorophenyl)-2 obtained in Reference Example (4e), (2-chlorophenyl)-5,5-dimethylpiperidin-2-one, a solution of 2-dimethyl-5-oxo-piperidine-l-carboxylate 3.0 7 ru (9_1111111 〇 1) in dichloromethane (Mml), EtOAc (EtOAc) 'Stir at the same temperature for 3 minutes. The reaction mixture was concentrated under reduced pressure. 139····················· After filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless solid. iH NMR spectrum (CDC13, 400MHz), δ: 7.49-7.46 (m, 1H), 7.3 5-7.24 (m, 3H), 3.76 (d, 1H, J = 18.0 Hz), 3.69 (d, 1H, J = 1 8.0 Hz), 3.47 (d, 1H, J = 11.3 Hz), 3.77 (d, 1H, J = 11.3 Hz), 1.39 (s, 3H), 1.32 (s, 3H). Mass spectrum (FAB+), m/z: 239 ((M + H)+). (Reference Example 5) 5,5-Dimethyl-1-(2-methylphenyl)piperidin-2-one

In the same manner as in Reference Examples (4c) to (4f), the tertiary butyl (1,1-dimethyl-2-oxoethyl)carbamate obtained in Reference Example (4b) and 2 were used. Methylaniline gave the title compound 〇.23 g (4 engineering total yield: 48%). Yellow solid 4 NMR spectrum (CDC13, 400MHz), δ: 7.31-7.21 (m, 3H), 7.12-7.10 (m, 1H), 3.75 (d, 1H, J = 18.0 Hz), 3.69 (d, 1H, J =18.0 Hz), 3.46 (d, 1 H, J = 12.1 Hz), 3.32 (d, 1H, J = 12.1 -140- 201124388

Hz), 2_25 (s, 3H), 1.35 (br s, 3H), 1.33 (br s, 3H). Mass spectrum (FAB+), m/z: 219 ((M + H)+). (Reference Example 6) l-(2-Ethylphenyl)-5,5-dimethylpiperidin-2-one

In the same manner as in Reference Examples (4c) to (4f), the tertiary butyl (1, bisdimethyl-2-oxoethyl) carbinate obtained in Reference Example (4b) and 2- were used. Ethyl aniline gave the title compound 3.43 g (4 engineering total yield: 42%). Colorless solid. NMR spectrum (CDC13, 500MHz), δ: 7.33-7.24 (m, 3H), 7.10 (d, 1H, J = 7.8 Hz), 3.75 (d, 1H, J = 18.1 Hz), 3.69 (d, 1 H, J = 18.1 Hz), 3.44 (d, 1 H, J = 12.1 Hz), 3.33 (d, 1 H, J = 12.1 Hz), 2.66 -2.5 3 (m, 2H), 1.36 (s, 3H), 1.33 (s, 3H), 1.24 (t, 3H, J = 7.6 Hz). Mass spectrum (FAB+), m/z: 233 ((M + H)+). (Reference Example 7) 1-(2,3-difluorophenyl)-5,5-dimethylpiperidin-2-one

-141 - 201124388 Similarly to Reference Examples (4c) to (4f), the tertiary butyl (1,1-dimethyl-2-oxoethyl)amine A obtained in Reference Example (4b) was used. The acid salt and 2,3-difluoroaniline obtained the title compound 〇.24 g (4 engineering total yield: 38%). Colorless solid. 4 NMR spectrum (CDC13, 400MHz), δ: 7.19-7.07 (m, 2H), 7.06-7.00 (m, 1H), 3.73 (s, 2H), 3.47 (s, 2H), 1.33 (s, 6H) 〇 Mass Spectrum (EI+), m/z: 240 (M+). (Reference Example 8) 1-(2,6-Difluorophenyl)-5,5-dimethylpiperidin-2-one

(8a) Tributyl butyl {2-[(2,6-difluorophenyl)amino]-l,l-dimethylethyl}amine formate obtained in Reference Example (4b) 15.0 g (80.0 mmol) of butyl (dimethyl-2-oxoethyl)carbamate, 5.16 g (40.0 mmol) of 2,6-difluoroaniline and 2.09 ml (40.0 mmol) of acetic acid In a solution of methyl chloride (400 ml), 17.0 g (80.Ommol) of sodium triethoxy hydride hydride was added under ice cooling, and the mixture was stirred at room temperature for 19 hr. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjj g (yield: 31%). Colorless solid. 4 NMR spectrum (CDC13' 400 MHz), δ: 6.81-6.77 (m, 2H), 6.67-6.60 (m, 1H), 4.56 (br s, 1H), 3.82 (br s, 1H), 3.47 (br d, 2H, J = 6.7 Hz), 1.43 (s, 9H), 1.32 (s, 6H). (8b) Tert-butyl butyl {2-[(bromoethenyl)(2,6-difluorophenyl)amino]-1,1-dimethylethyl decyl carbamate in Reference Example (8a 3.36 g (12.2 mmol) of N-tert-butyl {2-[(2,6-difluorophenyl)amino]-1,1-dimethylethyl}carbamate obtained in the above, To a solution of N-dimethylacetamide (6 1 m 1 ), 1.17 ml ( 13.4 mmol) of bromide bromide was added under ice cooling, and stirred at the same temperature for 5 minutes. After the mixture was extracted with diethyl ether, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After passing through the solvent, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent··················· of). Colorless solid. WNMR spectrum (CDC13, 500MHz), δ: 7.37-7.32 (m, 1H), 7.02 (br t, 1H, J = 8.3 Hz), 4.43 (br s, 1H), 4.09 (br s, 2H), 3.70 ( s, 2H), 1.31 (br s, 6H), 1,16 (br s, 9H). (8c) Tert-butyl 4-(2,6-difluorophenyl)-2,2-dimethyl- 5-epoxypiperane-1 -carboxylate in Reference Example (8b) The obtained tertiary butyl {2-[(bromoethyl)(2,6-difluorophenyl)amino]-1,1-dimethylethyl}carbamate 5.14 LV-143- 201124388 (12.2 mmol) of tetrahydrofuran (120 ml) in a solution of (12.2 mmol) in tetrahydrofuran (12 ml) under a nitrogen atmosphere and cooled with a dry ice-acetone bath over 30 minutes. The solution was added and stirred at the same temperature for 30 minutes. To the reaction mixture, ruthenium acetate and 33 ml (6.1 mmol) were added, and after returning to room temperature, the solvent was evaporated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium sulfate. Sodium is dry. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj . Colorless solid. NMR spectrum (CDC13, 500MHz), δ: 7.32-7.26 (m,1H), 7.00 (t, 2H, J = 8.3 Hz), 4.26 (s, 2H), 3.57 (s, 2H), 1.54 (br s, 6H), 1 · 50 (s, 9H). (8d) 1-(2,6-difluorophenyl)-5,5-dimethylpipedino-2-one as the tertiary butyl 4-( 2,6- obtained in Reference Example (8c) To a solution of 1.80 g (5.47 mmol) of difluorophenyl)-2,2-dimethyl-5-oxoxypiperane-1-carboxylate in dichloromethane (8.4 ml) 4.2 ml (54.7 mmol) of acetic acid was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjlilililililililililililililili Colorless solid. -144- 201124388 NMR spectrum (CDC13, 400MHz), δ: 7.30-7.26 (m, 2H), 6.98 (t, 1H, J = 8.0 Hz), 3.73 (br s, 2H), 3.46 (br s, 2H) , 1.34 (br s, 6H). Mass spectrum (FAB+), m/z: 241 ((M + H)+). (Reference Example 9) 1-(2-Chloro-5-fluorophenyl)-5,5-dimethylpiped-2-one

(9a) Tributyl butyl {2-[(2-chloro-5-fluorophenyl)amino]-1,1-dimethylethyl}carbamate obtained in Reference Example (4b) Tert-butyl (1,1-dimethyl-2-oxoethyl)amine formate 6.0 g (32.0 mmol), 2-chloro-5-fluoroaniline 4.6 g (32.0 mmol) and acetic acid 1.8 ml A solution of (32.0 mmol) in dichloromethane (320 ml), EtOAc (EtOAc) To the reaction mixture, saturated aqueous sodium hydrogencarbonate solution was added, 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 (jjjjjjjjjjjjj Colorless solid. NMR spectrum (CDC13, 400MHz), δ: 7.16-7.13 (m, 1H), 6.48-6.3 7 (m, 1H), 6.31-6.26 (m, 1H), 4.78 (br s, 1H), 4.52 -145- 201124388 (br s, 1H), 3.35 (br d, 2H, J = 5.9 Hz), 1.43 (s, 9H), 1.35 (s, 6H). (9b) Tert-butyl butyl {2-[(2-bromoethenyl)-(2-chloro-5-fluorophenyl)amino]-1,1-dimethylethyl}amine formate The tertiary butyl {2-[(2-chloro-5-fluorophenyl)amino]-1,1-dimethylethyl}amine formate obtained in Reference Example (9a) 5.3 g ( 16.8 After a solution of dimethyl hydrazine (170 ml), 2.2 ml ( 25.2 mmol) of ethidium bromide was added and the mixture was stirred at the same temperature for 15 minutes. After the mixture was extracted with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. EtOAc was evaporated. Colorless solid.

4 NMR spectrum (CDC13, 500MHz), δ ·· 7.4 5 (br d,1 Η, J =9.0 Hz, 5.6 Hz), 7.29-7.26 (m,1H), 7.08-7.04 (m,1H), 4.51 ( Br s, 1H), 4.15 (br d, 1H, J = 13.7 Hz), 3.99 (br d, 1H, J = 13.7 Hz), 3.69 (d, 1H, J = 11.2 Hz), 3.53 (d, 1H, j = 112 Hz), 1.34 (s, 3H), 1.32 (s, 3H), 1.21 (s, 9H). (9c) Tert-butyl 4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5_sideoxypiperidine-1-carboxylate obtained in Reference Example (9b) Tertiary butyl {2-[(2-bromoethenyl)-(2-chloro-5-fluorophenyl)amino]-1,1-dimethylethyl}amine carboxylic acid vinegar 5.8 g ( 13.3 In a solution of mmol) in tetrahydrofuran (130 ml), nitrogen-ring-146-201124388 and cooled in a dry ice-acetone bath, and a solution of 2.2 g (19.9 mmol) of tetrabutylbutanolate in tetrahydrofuran (130 ml) was added over 30 minutes. Stir at temperature for 1 〇 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was evaporated to dryness. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjj . Colorless solid. 1H NMR spectrum (CDC13, 500MHz), δ: 7.44 (dd, lH, J = 8.8 Hz, 5.4 Hz), 7.07-7.01 (m, 2H), 4.25 (br s, 2H), 3.54 (br s, 2H), 1.55 (br s, 6H), 1_50 (s, 9H). (9d) 1-(2-chloro-5-fluorophenyl)-5,5-dimethylpipedin-2-one obtained as the tertiary butyl 4-(2-chloro group) obtained in Reference Example (9c) -5-fluorophenyl)-2,2-dimethyl-5-oxoxypiperane-1-carboxylate 1.80 g ( 5.47 mmol) in dichloromethane (8.4 ml), added at room temperature Trifluoroacetic acid 4.2 ml (5 4.7 m mo 1 ) was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. After the filtration, the solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjjj Colorless solid. iHNMR spectrum (CDC13, 400MHz), δ: 7.24-7.25 (m, 2H), 7.12-7.08 (m, 1H), 3.71 (br s, 2H), 3.45 (br s, 2H), 1.32 (br -147- 201124388 s, 6H). Mass spectrum (FAB+), m/z: 257 ((M + H)+). (Reference Example 1 〇) 1-(5·Fluoro-2-methylphenyl)_5,5-dimethylpiped-2-one

(l〇a) tertiary butyl {2_[(5-fluoro-2-methylphenyl)amino]n dimethylethyl}amine formate in the third order obtained in Reference Example (4b) Butyl (dimethyl-2. oxoethyl)carbamate 5.08 g (27-1 mmol), 5-fluoro-2-methylphenyl female 5 g (27.1 mmol) and acetic acid 155^1 ( 27.1 mmoI) In a solution of dimethyl chloride (270 ml), 6.9 g (32.5 mmol) of sodium triethoxy hydride hydride was added under ice cooling, and stirred at room temperature for μ hours. 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 (jjjjjjjlili Colorless solid. NMR spectrum (CDC13, 400MHz), δ: 6.96-6.92 (m, 1H), 6.31-6.27 (m, 2H), 4.57 (br s, 2H), 3.25 (d, 2H, J = 5.5 Hz), 2.11 ( s, 3H), 1.43 (s, 9H), 1.39 (s, 6H). (l〇b) Tert-butyl butyl {2-[(bromoethenyl)(5-fluoro-2-methyl-148 - 201124388 phenyl)amino]-1,1-dimethylethyl}amine The tert-butyl {2_[(5-fluoro-2-methylphenyl)amino]-1,1-dimethylethyl}carbamate obtained in the reference example (10a) 5.68 g (19.1 mmol) of a solution of hydrazine-dimethylacetamide (95 ml), and 1.67 ml (19.1 mmol) of bromide bromide, and the mixture was stirred at the same temperature for 10 minutes under ice cooling. After the reaction mixture was added with saturated aqueous sodium hydrogen sulfate, and ethyl acetate was evaporated. After filtration, the solvent was evaporated under reduced pressure. EtOAc was evaporated. Colorless solid. H NMR spectrum (CDC13, 400 MHz), δ: 7.23 (dd, 1H, J = 8.2 Hz, 6.3 Hz), 7.11 (dd, 1H, J = 9.0 Hz, 2.7 Hz), 7.00 (dt, 1 H, J = 8.2 Hz, 2.7 Hz), 4.54 (br s, 1 H), 4.2 1 (d, 1 H, J = 13.7 Hz), 3.80 (br d, 1H, J = 13.7 Hz), 3.59 (br d, 1H, J = 11.0 Hz), 3.52 (d, 1H, J = 11.0 Hz), 2.2 1 (s, 3H), 1.35 (br s, 3H), 1 .3 1 (br s, 3H), 1 .20 (s , 9H) 〇(10c) tert-butyl 4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-sideoxypiped-1-carboxylate in reference example Tertiary butyl {2-[(bromoethenyl)(5-fluoro-2-methylphenyl)amino]-1,1-dimethylethyl}amine obtained in (l〇b) To a solution of 7.13 g (17.0 mmol) of formic acid ester in tetrahydrofuran (170 ml), a solution of 2.87 g (25-6 mmol) of potassium tetrabutoxide in tetrahydrofuran (170 ml) was added over 20 minutes under nitrogen atmosphere and with a dry ice-acetone bath. , Yutong-149- 201124388 Temperature mixing 〇 〇 minutes. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was evaporated to dryness. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjj . Colorless solid. NMR spectrum (CDC13 '400 MHz), δ: 7.23 (dd, 1H, J = 8.2 Hz, 6.3 Hz), 6.96 (dt, 1H, J = 8.2 Hz, 2.7 Hz), 6.88 (dd, 1H, J = 9.0 Hz) , 2.7 Hz), 4.28 (br s, 1H), 4.18 (br s, 1H), 3.64 (br s, 1H), 3.43 (br s, 1H), 2.21 (s, 3H), 1.56 (br s, 6H ), 1.50 (s, 9H). (lOd) 1-(5-fluoro-2-methylphenyl)-5,5-dimethylpiperid-2-one obtained in the reference example (l〇c) as a tertiary butyl 4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-sideoxypiperidine-1-carboxylate 4.5 g (13.4 mmol) in dichloromethane (20 ml) 10 ml of trifluoroacetic acid (134 mm 〇l) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjj Colorless solid. H NMR spectrum (CDC13, 400 MHz), δ: 7.22 (dd, 1H, J = -150 - 201124388 8.4 Hz, 6.5 Hz), 6.95 (dt, 1H, J = 8.4 Hz, 2.7 Hz), 6.84 (dd 1H, J = 9.0 Hz, 2.7 Hz), 3.74 (d, 1H, J = 18.〇Hz), 3.68 V u : 1H, J = 18.0 Hz), 3.43 (d, 1H, J = 11.7 Hz), 3.30 (d , iH j =11.7 Hz), 2.20 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H). Mass spectrum (FAB+) ' m/z : 23 7 ((M + H) + ). (Reference Example 11) Tert-butyl butyl {( IS) -2-[4-(2-chlorophenyl)-2,2-dimethyl-5_ oxaoxypiperidin-1-yl]-1·[ ( 2S,4S) _4_isopropyl-5_sideoxytetrachloropyran-2-yl]ethyl}amine formate

(11a) N-{(1S) -2-[4-(2-Chlorophenyl)_2,2-dimethyl_5· oxaoxypiperidin-1-yl]-l-[ ( 2S, 4S -4-isopropyl-terminated oxytetraazin-2-yl]ethyl}nitrobenzene-propionic acid amine (3S,5S)-3-isopropyl_5_{ obtained in Reference Example 1 (2S)-l-[(2-Nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2(^)-one 192 mg (0.5 4 mm〇l) and Reference Example 4 A solution of 181 mg (0.76 mmol) of toluene (7 ml) of (2-(2-phenylphenyl)-5,5-dimethylpiperidin-2-one) was obtained and stirred at 1100 ° C for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (solvent solvent: methylene chloride/acetic acid-151-201124388 ethyl ester = 5/1) to give the title compound 299 mg (yield: 93%) ). Colorless solid. *H NMR spectrum (CDC13, 400MHz), δ: 8.18-8.16 (m,1H), 7.93 (br s, 1H), 7.83 -7.76 (m, 2H), 7.46 (dd, 1H, J = 7.8 Hz, 2.0 Hz), 7.3 6-7.27 (m, 2H), 7.22-7.11 (m, 1H), 5.93 (br s, 0.5H), 5.53 (br s, 0.5H), 4.88-4.84 (m, 1H), 3.62 (br s, 1H), 3.30-3.10 (m, 3H), 2.92-2.69 (m, 2.5H), 2.56 (br s, 1H), 2.44 (ddd, 1 H, J = 13.7 Hz, 10.6 Hz, 5.9 Hz), 2.27-2.14 (m, 2.5H), 1.17 (br s, 3H), , 1.08 (br s, 3H), 1.04 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H, J = 6.6 Hz). (Ub) tert-butyl butyl {(IS) -2-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperane·1_yl]-l-[ ( 2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}amine formate N-{(1S)-2-[4] obtained in Reference Example (11a) -(2-chlorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-1-[(23,43)-4-isopropyl-5-sideoxy Tetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 299mg (0.50mmol) and sulphur (content: 95%) 0.11ml (1.00mmol) of N,N-dimethylformamide (5 ml) In a solution, 197 mg (0.61 mmol) of carbonic acid was added at room temperature under nitrogen, and the mixture was stirred at the same temperature for 1 hour. Saturated brine was added to the reaction mixture, and the mixture was extracted with dichloromethane. After filtration, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (solvent solvent: methylene chloride / methanol = 2 0/1 to 1 0/1). 4-{(2S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxo-tetrahydro-152- 201124388 furan-2-yl]ethyl} 1 To a solution of 2-(2-chlorophenyl)-5,5-dimethylpipedino-2-one in dichloromethane (5 ml), triethylamine 0.21 ml (1.51 mmol) and di-tert-butyl butyl The carbonate was 132 mg (0.61 mmol) and stirred at room temperature for 15 hours. Saturated brine was added to the reaction mixture, and the mixture was evaporated. After filtration, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (solvent solvent: methylene chloride / ethyl acetate = 2/1) to give the title compound 205 mg (2 ). Colorless solid. 1H NMR spectrum (CDC13, 400MHz), δ: 7.47 (dd, lH, J = 7.8 Hz, 2.0 Hz), 7.34-7.20 (m, 3H), 4.86-4.78 (m, 1H), 4.47-4.42 (m, 1H) ), 3.87-3.81 (m, 1H), 3.5 8-3.24 (m, 4H), 2.79 -2.3 2 (m, 0.5H), 2.62-2.57 (m, 2H), 2.44-2.39 (m, 0.5H) , 2.3 1 -2.24(111, 1 H), 2.21-2.11 (m, 2H), 1-45 (s, 9H), 1.26- 1.22 (m, 6H), 1.03 (d, 3H, J = 7.0 Hz) , 0.97 (d, 3H, J = 6 · 6 Hz). (Reference Example 1 2) Tert-butyl butyl {(lS)-2-[2,2-dimethyl-4-(2-methylphenyl)-5_ oxoxypiped-1-yl]-l -[ ( 2S,4S ) -4-isopropyl_5_sideoxytetrahydrofuran-2-yl]ethyl decyl carboxylate 153 201124388

In the same manner as in Reference Example 11, 1-3-isopropyl-5-{(2S)-l-[(2-nitrophenyl)sulfonyl-3-yl}dihydrofuran-2 obtained in Reference Example 1 was used. (3H)-ketone and the benzyl-1-(2-methylphenyl)piperidin-2-one obtained in Reference Example 5 were obtained to give titled (3 engineering total yield: 80%). Colorless solid. iH NMR spectrum (CDC13, 400 MHz), δ: 7.28-5 7.13-7.06 (m, 1H), 4.84-4.7 8 (m, 1H), 4.45-4 3.8 8 - 3.8 2 (m, 1H), 3.56-3.17 (m, 4H), 2.75-2 2.32-2.11 (m, 6H), 1.46- 1.45 (m, 9H), 1.22 1 .04-0.96 (m, 6H). (Reference Example 1 3 ) Tert-butyl butyl {(lS)-2-[4-(2-ethylphenyl)-2: pendant oxypiperidin-1-yl]-l-[ ( 2S, 4S) (3S,5S ) S ] 卩丫 D D 2 · 5 -5- dimethyl compound 27.69 g ' .22 (m, 3H), .42 (m, 1H), .42 (m, 3H), (brs, 6H), ,2-dimethyl-5-decyloxytetrahydrofur-154- 201124388

In the same manner as in Reference Example 1, (3 S , 5 S )-3-isopropyl-5-{( 2S ) -l-[(2-nitrophenyl)sulfonate obtained in Reference Example 1 was used. Aziridine-2-yl}dihydrofuran-2(3H)-one and 1-(2-ethylphenyl)-5,5-dimethylpiped-2 obtained in Reference Example 6 The ketone gave the title compound 2.54 g (3 engineering total yield: 93%). Colorless solid. NMR spectrum (CDC13, 400 MHz), δ: 7.33-7.22 (m, 3H), 7.11-7.05 (m, 1H), 4.8 4-4.7 8 (m, 1H), 4.46-4.42 (m, 1H), 3.8 8 -3.8 2 (m, 1H), 3.56-3.18 (m, 4H), 2.75-2.41 (m, 5H), 2.32-2.11 (m, 3H), 1.46- 1.45 (m, 9H), 1.2 5 - 1.2 0 (m, 9H), 1.04-0.96 (m, 6H). (Reference Example 1 4) Tert-butyl butyl {(13)-2-[4-(2,3-difluorophenyl)-2,2-dimethyl-5-sideoxypeptin-1-yl ]-l-[ ( 2S,4S ) -4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine-formate-155- 201124388

In the same manner as in Reference Example 11, (3 S,5S)-3-isopropyl-5-{(2S)-l-[(2-nitrophenyl)sulfonyl] obtained in Reference Example 1 was used. Aziridine-2-yl}dihydrofuran-2(3H)-one and 1-(2,3-difluorophenyl)-5,5-dimethylpiperazine obtained in Reference Example 7 - 2-ketone, the title compound was obtained (yield: 673 mg (yield: 67%). iH NMR spectrum (CDC13, 400MHz), δ: 7.18-7.08 (m, 2H), 7.04-7.00 (m, 1H), 4.81 (br t, 1H, J = 7.4 Hz), 4.47 (br d, 1H, J = 9.4 Hz), 3.87-3.81 (m, 1H), 3.56 (d, 1H, J = 17.6 Hz), 3.50 (d, 1H, J = 17.6 Hz), 3.46 (d, 1H, J = 11.7 Hz), 3.33 (d, 1 H, J = 11.7 Hz), 2.72-2.66 (m, 1H), 2.62-2.57 (m, 1 H), 2.48 (dd, 1H, J = 12.7 Hz, 6.5 Hz), 2.31-2.11 (m, 3H), 1.45 (s, 9H), 1.21 (s, 6H), 1.03 (d, 3H, J = 7.0 Hz), 0.97 (d, 3H, J = 7.0 Hz). (Reference Example 1 5 ) N-{(1S) -2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypiped-1-yl]- L-[( 2S,4S)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide-156- 201124388

As in the reference example (1 1 a ), the reference 3 (3S,5S)-3-isopropyl-5-{(2S) -1-[(2-ί 吖 啶 -2- -2- 基 yl) dihydrogen was used. Furan-2(3Η)-one and reference 1-(2,6-difluorophenyl)-5,5-dimethylpiped-2 - compound 3.51 g (yield: quantitative). NMR spectrum (CDC13, 400MHz), δ: 7.94-7.91 (m, 1H), 7.81-7.74 (m, 2H), 7.00-6.94 (m, 2H), 5.72 (d, 1H, J = 7.8 1 H), 3.6 8 -3.62 (m, 1 H), 3.15 (d, 1 H, J = 1H, J = 11.7 Hz), 3.05 (d, 1H, J = 11.7 =1 7.6 Hz), 2.8 0 -2.74 (m, 1 H), 2.6 1-2.48 (m, 2H), 1.11 (s, 3H), 1.04 (d, 3H, J = 7. 0.97 (d, 3H, J = 7.0 Hz) (Reference Example 1 6) Level 3 Butyl { ( IS ) -2-[4-( 2-chloro-5-yl_5_sideoxypiperazin-1-yl]-l-[( 2S,4S ) _4_hydrofuran-2-yl] Ethyl}carbamate; oximeyl phenyl)sulfonyl group obtained in Example 1 The ketone obtained in Test Example 8 was obtained to give the title of 8.17-8.15 (m, 1 Η), 7.3 3 - 7.2 5 (m, 1 Η), Hz), 4.77-4.73 (m, :17.6 Hz), 3.11 (d, Hz), 2.97 (d, 1H, J (m, 3H), 2.26-2.15 0 Hz), 1.03 (s, 3H), fluorophenyl)-2,2-dimethylisopropyl-5-sideoxytetra-157- 201124388 Ci

(16a) &amp;{(13)-2-[4-(2-Chloro-5-fluorophenyl)-2,2-dimethyl-5-sideoxypiped-1-yl]-l- [(2S,4S)-4-Isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide The (3S,5S) obtained in Reference Example 1 3-isopropyl-5-{(2S)-l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2(3H)-one 1.15 g (3.25 Mol) toluene (32 ml) of 1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperidin-2-one 8 8 91^(3.9111111〇1) obtained in Reference Example 9. The solution was stirred at 110 ° C for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (solvent solvent: toluene/acetone = 10/1) to give the title compound 1.77 g (yield: 91%). Colorless solid. 'H NMR spectrum (CDC13, 500 MHz), δ: 8.18-8.16 (m, 1H), 7.94 (br s, 1H), 7.83-7.77 (m, 2H), 7.42 (dd, 1H, J = 8.8 Hz, 5.4 Hz), 7.0 5 -6.8 9 (m, 2H), 5.92 (br s, 0.6H), 5.57 (br s, 0.4H), 4.8 6-4.8 3 (m, 1H), 3.62 (br s, 1H) , 3.30-3.10 (m, 3H), 2.8 8 - 2.40 (m, 4.4H), 2.27-2.15 (m, 2.6H), 1.17 (br s, 3H), , 1.08 (br s, 3H), 1.03 ( d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 6.6 Hz). -158- 201124388 (16b) Tert-butyl butyl {( IS) -2-[4-( 2 -chloro-5-fluorophenyl) -2,2-dimethyl-5-sideoxypiped-1 -Based -1_[(25,43)-4-isopropyl-5-oxooxytetrahydrofuran-2-yl]ethyl}amine formate N-{( obtained in Reference Example (16a) IS) -2-[4-(2-Chloro-5-fluorophenyl)-2,2-dimethyl-5-oxooxypiperidin-1-yl]_i_[(2S,4S)-4- Isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-2 nitrobenzenesulfonamide 1.70 g ( 2.85 mm 〇l) and thiophenol (content: 95%) 0-87 ml ( 8.54 mmol) A solution of N,N-dimethylformamide (15 ml) was added at room temperature under a nitrogen atmosphere at rt (1.42 mmol) and stirred at the same temperature for one hour. Saturated brine was added to the reaction mixture, extracted with dichloromethane and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4-{(2S) -2·amino-2-([2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-1-(2-chloro) To a solution of -5-fluorophenyl)-5,5-dimethylpiperidin-2-one in dichloromethane (24 ml), triethylamine 〇.99 ml (7.11 mmol) and di-tertiary butyl were added. Dicarbonate 620 mg ( 2.84 mmol) was stirred at room temperature for 15 hours. Saturated brine was added to the reaction mixture, which was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjj :7 0 % ). Colorless solid. 1H NMR spectrum (CDC13, 400MHz), δ: 7.43 (dd, 1H, J = -159- 201124388 8.8 Hz, 5.3 Hz), 7.05-6.99 (m, 2H), 4.82 (br s, 1H), 4.44 (br s , 1H), 3.87-3.81 (m, 1H), 3.5 9-2.3 9 (m, 7H), 2.31-2.11 (m, 3H), 1.45 (br s, 9H), 1.25 (br s, 6H), 1.03 (br d, 3H, J = 6.7 Hz), 0.97 (br d, 3H, J = 7.0 Hz). (Reference Example 1 7) Tert-butyl butyl {(13)-2-[4-(5-fluoro-2-methylphenyl)-2,2-dimethyl-5-pentaoxypiperidin-1 -yl]-1 - [( 2 S , 4 S ) - 4 -isopropyl-5 · pendant oxytetrahydrofuran-2-yl]ethyl}carbamate

(17a) N- {( IS) -2-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-side oxypoxy-1 -yl]-1 - [( 2 S , 4 S ) - 4 -isopropyl-5 -oxytetrahydrofuran 2 -yl]ethyl} -2 -nitrobenzenesulfonylamine (3S, obtained in Reference Example 1) 5S) -3 -Isopropyl-5-{(2S) -l-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2(3H)-one 863mg ( 2.43 mmol) and 1-(5-fluoro-2-methylphenyl)-5,5-dimethylpiperidin-2-one obtained in Reference Example 10 805 mg (3.40 mmol) of toluene (30 ml) The solution was stirred at 110 ° C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 99%). Colorless solid. 4 NMR spectrum (CDC13, 400MHz), δ ·· 8.18-8.16 (m,1H), 7.9 8 - 7.9 0 (m, 1H), 7.8 5 -7.7 8 (m, 2H), 7.20 (dd, 1H, J = 8.2 Hz, 6.7 Hz), 6.96 (dt, 1H, J = 8.2 Hz, 2.7 Hz), 6.8 2- 6.67 (m, 1H), 5.89 (br d, 0.6H, J = 6.7 Hz), 5.60 (br d, 0.4H, J = 7.0 Hz), 4.8 8 -4.79 (m, 1H), 3.6 8 -3.5 8 (m, 1H), 3.3 7 - 3.2 7 (m, 1H), 3.16-2.17 (m, 9H ), 2.11 (s, 3H), 1.16-0.93 (m, 12H). (17b) Tert-butyl butyl {(lS)-2-[4-(5-fluoro-2-methylphenyl)-2,2-methyl-5-oxirane-1-yl 1-[( 2S,4S) -4-isopropyl- 5· oxo-tetrahydrofuran-2-yl]ethyl}amine formate N-{(IS) - obtained in Reference Example (17a) 2-[4-( 5-Fluoro-2-methylphenyl)-2,2-dimethyl-5-sideoxypiperidin-1-yl]-1-[(23,45) -4- Isopropyl-5-oxo-tetrahydrofuran-2-yl]ethyl}_2·nitrobenzenesulfonamide 1.44g ( 2.43mmol) and thiophenol (content: 95%) 0.52ml ( 4.87mmol) of acetonitrile ( In a solution of 25 ml), 953 mg (2.92 mmol) of carbonic acid was added at room temperature under a nitrogen atmosphere, and stirred at the same temperature for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with dichloromethane. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent solvent: methylene chloride / methanol = 20/1~1 〇 /1). The resulting 4_{(2S)-2-isoamino-2-[(2S,4S)-4-iso-5-yloxytetrahydrofuran-2-yl]ethyl}-1-(5- a mixture of ethyl acetate (11 ml) of fluoro-2-methyl-methyl)-5,5-methyl oxime-2-one and water (11 ml), sodium hydrogencarbonate-161 - 201124388 211 mg (2.51) Methyl acetate 549 mg (2.5 1 mmol) of di-tertiary butyl dicarbonate was stirred at room temperature for 4 hours. Saturated brine was added to the reaction mixture, which was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjj :9 3 % ). Colorless solid. 1H NMR spectrum (CDC13, 500MHz), δ: 7.21 (dd, lH, J = 8.3 Hz, 6.4 Hz), 6.95 (dt, 1H, J = 8.3 Hz, 2.4 Hz), 6.86-6.80 (m, 1H), 4.8 3 -4.7 6 (m, 1H), 4.47-4.44 (m, 1H), 3.87-3.82 (m, 1H), 3.55-3.16 (m, 4H), 2.75-2.41 (m, 3H), 2.30-2.11 ( m,0H),1 .45 (br s, 9H), 1 .2 2 (brs,6 H),1.03 (br d, 3H, J =6.8 Hz),〇·98·〇·96 (m,3H ). (Reference Example 1 8) Tert-butyl butyl { ( IS ) -2-[4-( 2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperidinyl] ( 2S, 4r) -4_ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl decyl carbamate

(l8a) N-{( IS) -2-[4-(2-Chlorophenyl)-2,2-dimethyl-5--162- 201124388 oxopiperidin-1-yl]-l- [( 2S,4R)-4-Ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide The (3 R,5 S ) obtained in Reference Example 2 - 3 -ethyl-5 - { ( 2 S ) -1 -[( 2 -nitrophenyl)sulfonyl]aziridine-2 -yl}dihydrofuran-2( 3 Η ) -ketone 916 mg ( 2.69 mmol) and a solution of 1-(2-chlorophenyl)-5,5-dimethylpiperane-2 -indole 771 mg (3.23 mmol) in toluene (27 ml) obtained in Reference Example 4 at 1 1 〇 Stir at °C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjj 6%) ° Colorless solid. 'HNMR spectrum (CDC13, 400 MHz), S: 8.17 (brd, lH, J = 7.8 Hz), 7.93 (br s, 1 H), 7.79 (br s, 2H), 7.45 (br d, 1 H, J = 8.2 Hz), 7.3 3 -7.2 6 (m, 2H), 7.19-7.10 (m, 1H), 5.90 (br s, 0.5H), 5.51 (br s, 0.5H), 4.89 (br s, 1 H) , 3.63 (br s, 1 H), 3.30-3.10 (m, 3H), 2.91-2.45 (m, 4.5H), 2.15 (br s, 1.5H), 1.92- 1.82 (m, 1 H), 1.64- 1.51 (m, 1H), 1.17 (br s, 3H), 1.07 (br s, 3H), 1.04 (br t, 3H, J = 7.4 Hz). (18b) Tert-butyl butyl {( IS) -2-[4-(2-chlorophenyl)-2,2-dimethyl-5-sideoxypiperidin-1-yl]-l-[ ( 2S,4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate N-{(IS)-2-[4- obtained in Reference Example (18a) (2-Chlorophenyl)-2,2-dimethyl-5-o-oxypiperazin-1-yl]-1-[(23,411)-4-B-163- 201124388 ke-5-sideoxy Tetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 1.49g (2.57mmol) and thiopurine (content: 95%) 0.52ml (5.14mmol) of N,N-dimethylformamide In a (13 ml) solution, 1.00 g (3.08 mmol) of cesium carbonate was added at room temperature under a nitrogen atmosphere, and stirred at the same temperature for 1.5 hours. Saturated brine 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 mjjjjjjjjjj 4-{(2S)-2-Amino- 2-[(2S,4R)-4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}-1-(2-chlorophenyl) -5,5-Dimethylpiperidin-2-one in ethyl acetate (12 ml) · water (12 ml), sodium bicarbonate 23 5 mg (2.80 mmol) and di-tert-butyldicarbonate The ester was 610 mg (2.80 mmol) and stirred at room temperature for 2.5 hours. Saturated brine was added to the reaction mixture, and the mixture was evaporated. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by mhhhhhhhhhhhhhhhhhhhhhhhhh Total yield: 88%). Colorless solid. NMR spectrum (CDC13, 400 MHz) &gt; 5: 7.47 (br d, 1 H, J = 7.4 Hz), 7.34-7.20 (m, 3H), 4.91-4.83 (m, 1H), 4.46-4.40 (m, 1H) ), 3.88-3.81 (m, 1H), 3.5 8 -3.24 (m, 4H), 2.80-2.3 6(m, 4H), 2.08-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.62 - 1.50 (m, 1 Η), 1.45 (s, 9H), 1.26 (br s, 3H), 1.22 (br s, 3H) 1.03 (br t, 3H, J = 7.4 Hz). -164- 201124388 (Reference Example 1 9) Tert-butyl butyl {(13)-2-[4-(2,3-difluorophenyl)-2,2-dimethyl-5-sideoxypene -1-yl]-l-[( 2S,4R) -4_ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate

In the same manner as in Reference Example 1, the (3 R,5 S )-3-ethyl-5-{( 2S) -1-[(2-nitrophenyl)sulfonyl group obtained in Reference Example 2 was used. Aziridine-2-yl}dihydrofuran-2(3Η)-one and 1-(2,3-difluorophenyl)-5,5-dimethylpiperazine obtained in Reference Example 7 - 2-ketone, the title compound 2.50 g (3 engineering total yield _· 8 6 %) was obtained. Colorless solid. iH NMR spectrum (CDC13,500 ΜΗζ), δ: 7.17-7.09 (m, 2H), 7.05-7.01 (m, 1H), 4.87 (br t, 1H, J = 6.6 Hz), 4.45 (br d, 1H, J = 9.8 Hz), 3.8 7 - 3.8 2 (m, 1H), 3.56 (d, 1H, J = 17.6 Hz), 3.50 (d, 1H, J = 17.6 Hz), 3.46 (d, 1H, J = 11.2 Hz ), 3.33 (d, 1 H, J = 11.2 Hz), 2.71-2.67 (m, 1 H), 2.6 2 -2.5 6 (m, 1 H), 2.48 (dd, 1 H, J = 12.5 Hz, 6.1 Hz), 2.42 -2.3 6 (m, 1 H), 2.08-2.02 (m, 1 Η), 1.90- 1 .8 2 (m, 1 H), 1.61-1.52 (m, 1H), 1.45 ( s, 9H),1 .22 (s, 3 H), 1.2 1 (s, 3 H), 1.03 (t, 3H, J = 7.6 -165- 201124388

Hz). (Reference Example 20) Tert-butyl butyl {(13)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-sideoxypeptin-1-yl ]-l-[ ( 2S,4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate

In the same manner as in Reference Example 1, the (3 R,5 S )-3-ethyl-5-{( 2S) -1-[(2-nitrophenyl)sulfonyl group obtained in Reference Example 2 was used. Aziridine-2-yl}dihydrofuran-2(3H)-one and 1-(2,6-difluorophenyl)-5,5-dimethylpiperazine obtained in Reference Example 8 - The 2-ketone was obtained as the title compound 1.88 (3. Colorless solid. 1^1\]\411 spectrum (€〇(:13,500]^1^), 5:7.3 Bu 7.26(111,111), 6.98 (br t, 2H, J = 8.3 Hz), 4.88 (br t , 1H, J = 6.8 Hz), 4.44 (br d, 1H, J = 9.3 Hz), 3.8 7 -3.8 2 (m, 1H), 3.57 (d, 1H, J = 17.6 Hz), 3.51 (d, 1H , J = 17.6 Hz), 3.44 (d, 1H, J = 11.2 Hz), 3.3 1 (d, 1H, J = 11.2 Hz), 2.71-2.67 (m, 1H), 2.62-2.56 (m, 1H), 2.49 (dd, 1H, J = 12.7 Hz, 6.4 Hz), 2.42-2.3 6 (m, 1H), 2.09-2.03 (m, 1H), 1.90- 1.82 (m, 1H), 1.61-1.52 (m, - 166 - 201124388 1H), 1.45 (s, 9H), 1.22 (s, 6H), 1.03 (t, (Reference Example 2 1) Tertiary butyl { ( IS ) -2-[4- ( 2-chloro-5 -yl-5-sideoxypiped-1-yl]-l-[(2S,4R)-4-furan-2-yl]ethyl}amine formate

Base-5-side oxypiped-1 -yl]-1 - [( 2 S,4 R )-4-furan-2-yl]ethyl} 2-nitrobenzenesulfonamide Reference Example 2 (3R,5S)-l-[(2-Nitrophenyl)sulfonyl]aziridine-2-yl-one 11.63g (34.18 mol) obtained in the same manner as the fluorophenyl group in Reference Example 9) A solution of -5,5-dimethylpipedino-2-one 10.53 g (80 ml) was stirred at 110 ° C for 30 minutes. The residue was purified by EtOAc EtOAc EtOAc EtOAc. NMR spectrum (CDC 13, 500 MHz), δ; 3 Η, J = 7.3 Hz). Fluorophenyl)-2,2-dimethylethyl-5-sideoxytetrahydrofluorophenyl)-2,2-dimethylethyl-5-sideoxytetrahydro-3-ethyl-5- { ( 2S) }Dihydrofuran-2 ( 3 Η ) 1-(2-chloro-5-(4.0 mmol) toluene obtained after cooling, the reaction mixture: /ethyl acetate = 1 / 1 ~ ether - ethyl acetate ( 5/1 ) .3 g (yield: 99%). :8.18-8.16 (m, 1 Η), -167- 201124388 7.94 (br s, 1H), 7.8 3 -7.78 (m, 2H), 7.42 (dd, 1H, J = 8.8 Hz, 5.4 Hz), 7.05-7.01 (m, 1H), 6.94-6.8 7 (m, 1H), 5.87 (br s, 0.6H), 5.54 (br s, 0.4H) , 4.89 (br s, 1H), 3.62 (br s, 1H), 3.30-3.10 (m, 3H), 2.92-2.5 3 (m, 4.5H), 2.14 (br s, 1.5H), 1.91-1.82 ( m, 1H), 1.63-1.56 (m, 1H), 1.17 (br s, 3H), 1.08 (br s, 3H), 1.03 (t, 3H, J = 7.6 Hz) (21b) Tert-butyl hydrazine (IS) -2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-1-[(23,411)-4 -ethyl-5-oxo-tetrahydrofuran-2-yl]ethyl}amine formate N-{( IS) -2-[4-( 2-chloro- 5 ) obtained in Reference Example (21a) -fluorophenyl)-2,2-dimethyl-5-oxooxypiped-1-yl]-1-[(2S,4R)-4-isopropyl-5-oxo-tetrahydrofuran 20.13g (33.72mmol) and thiopurine (content: 95%) 5.2ml (51.0mmol) in acetonitrile (170ml), under a nitrogen atmosphere, with methylene-2-sulfonamide After adding 13.20 g (40.5 mmol) of carbonic acid at room temperature, the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane and washed with a saturated aqueous salt. Drying over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-Amino-2-[(2S,4R)-4-ethyl-5-oxooxytetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5, To a mixed solution of 5-dimethylpiperidin-2-one ethyl acetate (170 ml) and water (170 ml), sodium hydrogencarbonate 3.40 g (40.5 mmol) and di-tert-butyl butyl carbonate 8.85 g were added. (40.6 mmol), stirred at room temperature for 15 hours. -168 - 201124388 The reaction mixture was extracted with EtOAc. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjj Yield: 85%). Colorless solid. iH NMR spectrum (CDC13, 500MHz), δ: 7.45-7.42 (m, 1H), 7.05-6.96 (m, 2H), 4.87 (br s, 1H), 4.56 (br s, 1H), 3.8 5 - 3.8 4 (m, 1H), 3.5 7-2.3 6 (m, 8H), 2.08 -2.02 (m, 1H), 1.90- 1. 8 2 (m, 1H), 1.61-1.52 (m, 1H), 1.46 (br s, 9H), 1.24 (br s, 6H), 1.03 (t, 3H, J = 7.3 Hz). (Reference Example 22) Tert-butyl butyl {( IS ) -l-[( 2S,4R) -4-ethyl-5-oxooxytetrahydrofuran-2-yl]-2-[4-( 5-fluoro- 2-methylphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}amine formate

(22a) N-{( IS) -1-[(2S,4R)-4-Ethyl-5-yloxytetrahydrofuran-2-yl]-2-[4-(5-fluoro-2-methyl Phenyl)-2,2-dimethyl-5-oxopiperidin-1-yl]ethylindole-2-nitrobenzenesulfonamide The (3R,5S) obtained in Reference Example 2 3-ethyl-5-{(2S)-169- 201124388 -1-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}dihydrofuran-2(3^〇-ketone 2.50 g ( 7.35 mmol) of 1-(5-fluoro-2-methylphenyl)-5,5-dimethylpipedino-2-one obtained in Reference Example 10. 1.91 g ( 8.08 mmol) of toluene (50 ml) solution, stirred at ll 〇 ° C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chrome column chromatography (solvent solvent: η-hexane/ethyl acetate = 1/1~0) /1), the title compound 3.72 g (yield: 8 8 %) was obtained as a yellow solid. 4 NMR spectrum (CDC13, 400 MHz), δ: 8.19-8.15 (m,1H), 7.9 8 -7.90 (m, 1H) ), 7.8 3 -7.7 8 (m, 2H), 7.22-7.18 (m, 1H), 6.96 (dt, 1H, J = 8.2 Hz, 2.7 Hz), 6.8 2-6.66 (m, 1H), 5.85 (br d, 0.6H, J = 6.7 Hz), 5.57 (br d, 0.4H, J = 8.2 Hz), 4.93 -4.8 3 (m, 1H), 3.69-3.59 (m, 1H), 3.3 7-2.47 (m , 7.6H), 2.21-2.11 (m , 4.4H), 1.90- 1.82 (m, 1H), 1.62- 1.54 (m, 1H), 1 · 1 7-1.00 (m, 9H) ° (22b) tertiary butyl { ( IS ) -1·[ ( 2S,4R) -4-ethyl-5-oxo-tetrahydrofuran-2-yl]-2-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl·5 ·N-{(1S) -1-[(2S,4R) -4 -ethyl-5 obtained in the reference example (22a) of the pendant oxypiped-1-yl]ethyl}amine formate -Sideoxytetraazapyran-2-yl]-2-[4-(5-aero-2-methylphenyl)-2,2-dimethyl-5-sideoxypiped-1- 3.ethyl 2-ethylbenzenesulfonamide 3.72g ( 6.45mmol) and thioindigo (content: 95%) 0.99ml (9.7mmol) in acetonitrile (32ml), under nitrogen, at room temperature Carbonate-170-201124388 2.52g (7.73 mmol) was added and stirred at the same temperature for 15 hours. The mixture was poured under reduced pressure, and water was evaporated. After filtration, the solvent was evaporated, and the residue was purified by methylene chloride column chromatography (solvent solvent: hexane/methanol = 50/1 to 10/1). The resulting 4-{( 2S)-2-amino-2-[(-4-ethyl-5-oxo-tetrahydrofuran-2-yl]ethylfluoro-2-yl)-5,5-dimethyl Addition of ethyl hydrazide-2-one to ethyl acetate (30 ml) and water, 1.49 g (17.7 mmol) of sodium hydrogencarbonate: 1.93 g (8.84 mm 〇l) of butyl dicarbonate at room temperature After stirring 3, the reaction mixture was extracted with EtOAc. After filtration, the solvent was evaporated under reduced pressure and purified m.jjjjjjjjjjjjj 4 NMR spectrum (CDC13, 400MHz), δ: 7.22 (dd, 8.2 Hz, 6.3 Hz), 6.96 (dt, 1H, J = 8.2 Hz, 2.7 Hz), 6. (m, lH), 4.89-4.82 ( m,lH),4.46-4.42 (m,lH),3. (m, 1H), 3.56-3.15 (m, 4H), 2.7 7 -2.3 6 (m, 4H), 2.1 1.2H), 2.18 (br s, 1.8H), 2.08-2.01 (m, 1H), 1.92-1 1H), 1.62-1.51 (m, 1H), 1.45 (br s, 9H), 1.22 (br 1.03 (br t, 3H, J = 7.2 Hz) 〇 (Reference Example 2 3 ) &gt; 1-{(13)-2-[4-(2-Chlorophenyl)-2,2-dimethyl-5-side concentrated back under saturated decompression Dichloromethane 2S, 4R) • Methylbenzene (30ml) and two to three hours. Wash, slag warp = 3 / 2 ~ 8 6%). 1 H, J = 87- 6.80 88- 3.82 9 (brs, .8 1 (m, s, 6H), oxypiperidin-171- 201124388 well-1-yl]-1-[(2S,4R) -4 -methyl-5-oxo-oxytetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide

(3R,5S)-3-methyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridine-2-yl}2 obtained in Reference Example 3 Hydrofuran-2 (31 〇-ketone 822 mg (2.52 mm 〇l) and 1-(2-chlorophenyl)-5,5-dimethylpiped-2-one obtained in Reference Example 4 722 mg (3.02) A solution of toluene (25 ml) was stirred at 1 1 ° C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by EtOAc EtOAc. /1~2/1), the title compound 1.34g (yield: 94%) was obtained as a colorless solid. NMR spectrum (CDC13, 400MHz), δ: 8.17 (brd, 1 Η , J = 7.0 Hz) , 7.93 (br s, 1 H), 7.79 (br s, 2H), 7.44 (dd, 1H, J = 7.4 Hz, 2.0 Hz), 7.3 5 -7.09 (m, 3H), 5.87 (br s, 0.5H ), 5.53 (br s, 0.5H), 4.90 (br s, 1 H), 3.63 (br s, 1 H), 3.29-3.10 (m, 3H), 2.90-2.56 (m, 4.5H), 2.20- 2.05 (m, 1 . 5H), 1.33 (br d, 3H, J = 7.0 Hz), 1.16 (br s, 3H), 1.07 (br s, 3H) (Reference Example 24) Trans-4-Amine Fund Cyclohexane-1-carbamide-172- 201124388 〇

(24a) Benzyl (trans-5-aminoformamadaxan-2-yl)amine formate in 4-sided oxyadamantane-1-carboxamide 5g (25.9mmol) of 8N ammonia-methanol (1 〇〇ml), 500 mg of 10% palladium carbon (50% aqueous) was added to the solution, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After filtering the diatomaceous earth product, the solvent was distilled off under reduced pressure to obtain a crude trans-4-aminedetane-1-carbamide. To a solution of the obtained crude trans-4-amine fundane-1 -carboxamide in tetrahydrofuran (8 3 m 1 ), water (4 2 m 1 ), sodium hydrogencarbonate 4.3 g (5 1 . 7 mm). ο 1 ) and 5.5 ml (38.8 mmol) of chloroformic acid vinegar were 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 purified by silica gel column chromatography (solvent solvent: ethyl acetate /methanol = 1/0 to 10/1) to give the title compound 5.5 g (yield: 65%) . Colorless solid. 4 NMR spectrum (CDC13, 400 MHz), δ: 7.38-7.32 (m, 5H), 5.57 (br s, 1H), 5.34 (br s, 1H), 5.10 (br s, 2H), 3.81 (br, 1H) , 2.08- 1.76 (m, 12H), 1.60- 1.5 8 (m, 2H). (24b) trans-4-amine, alkane-l-carbamide, benzyl (trans-5-aminocarboxamido-2-yl)aminecarboxylic acid obtained in Reference Example (24a) To a solution of 5.5 g (1.67 mmol) of the ester in methanol (80 ml), 550 mg of 10% palladium on carbon (5% by weight of water) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere at -173 to 201124388. After filtration of the diatomaceous earth product, the solvent was evaporated under reduced pressure to give the title compound 3· 2 g (yield: 9 9 %). 1H NMR spectrum (DMSO-D6, 400 MHz), δ: 6.92 (br s, 1H), 6.65 (br s, 1H), 2.03 - 1.6 6 (m, 12H), 1.3 0 - 1.2 7 (m, 2H). (Test Example 1) Renin activity inhibition test Human renin was transiently expressed in 293 T cells, and the culture supernatant was used as an enzyme source. After the prepared culture supernatant is activated by trypsin to activate human renin, a solution in which the test compound is dissolved in a solvent (for example, 'DMSO or the like) or a solvent is added to a final concentration of 1% by volume is added. Add a buffer containing fluorescently labeled synthetic renin matrix (Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(dabcyl)-Arg) (1 mM EDTA, 1 00 mM Tris-HCl, pH 7.4), incubated at 37 ° C for 90 minutes. After the end of the incubation, the generated angiotensin I concentration was measured by fluorescence (Ex: 340 nm, Em: 4 92 nm). The human renin activity of the test compound 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 1-174-201124388 [Table 1] Example Compound No. IC5〇(nM) 1 1.3 2 0.92 3 0.7 4 0.6 5 1.5 6 2.2 7 1.5 8 1 .9 9 1 .7 10 0.9 11 1 . 12 1 .3 13 1 . 5 14 1.4 15 1 .6 16 1.1 17 1 .2 18 1.5 19 1 .3 The compound of the present invention exhibits excellent inhibition of human renin activity and is used as a treatment or prevention for hypertension or the like. The medicine is useful. -175- 201124388 (Test Example 2) Plasma renin activity (PRA) inhibition test A solution in which a test compound is dissolved in a solvent (for example, DM SO or the like) is added to plasma or human plasma of the assembled Cynomolgus Monkey. Or adding the solvent to the final concentration to be 1% by volume, and adding a buffer according to the attached instruction, incubating at 37 ° C for 1 hour, and adding the reaction solution of the test compound solution as the reaction solution A, adding solvent The reaction liquid was used as the reaction liquid B. Further, a solvent was added in the same manner as above, and the prepared reaction solution was incubated at 4 ° C for 1 hour to obtain a reaction liquid C. In the respective reaction solutions, the concentration of angiotensin I present was measured by radioimmunoassay [Renin Rear Beads (registered trademark), YAM ASA soy sauce]. Plasma renin activity (PRA) was calculated by the following method: self-reaction The angiotensin I concentration in the solution A or B minus the angiotensin I concentration in the reaction solution C as the angiotensin I concentration per unit time. The inhibition of plasma renin activity of the test compound was evaluated by IC50 50 of 50% of the concentration of each test compound which inhibited PRA. The compound of the present invention exhibits excellent inhibition of plasma renin activity and is useful as a medicine for the treatment or prevention of hypertension or the like. (Test Example 3) Ex vivo (ex Vivo) plasma renin activity (PRA) inhibition test in cynomolgus monkeys. Oral administration of test compound 2 days before, furosemide (5 mg/kg) Intramuscular administration of cynomolgus monkeys causes the renin-angiotensin system to advance. On the day of the test, the plasma samples were taken in the tube containing £0. Give the bait after the blood collection. -176- 201124388 The test compound was suspended in 1% methylcellulose and forcedly administered orally. The obtained plasma was incubated at 4 ° C or 37 ° C, and the concentration of angiotensin I present in each reaction solution was measured by radioimmunoassay (refer to Test Example 2). PRA is an angiotensin I concentration in the reaction solution self-cultivated at 37 °C minus the angiotensin I concentration in the reaction solution cultured at 4 °C as the angiotensin I concentration per unit time And calculate. Ex vivo PRA inhibition of the test compound The PRA before administration of the test compound was evaluated by the rate of change of PRA after each administration time. The compound of the present invention exhibits excellent ex vivo PRA inhibition and a decrease in plasma angiotensin I concentration, or ex vivo PRA inhibition and an excellent sustained reduction of plasma angiotensin I concentration. It is used as a medicine for the treatment or prevention of hypertension or the like. (Test Example 4) Blood pressure drop test in cynomolgus monkeys The operation of embedding a telemetry transmitter in a cynomolgus monkey was carried out, and an animal having a stable blood pressure waveform was used for one or more trials after the operation. Three days before the oral administration of the test compound, the cynomolgus monkey diuretic (5 mg/kg) was administered intramuscularly the next day to make the renin-angiotensin system hyperactive. The test was carried out after the hunger in the morning, and the test compound was administered, and the bait was administered 8 hours after the administration. Continuous measurement of blood pressure signals by telemetry from 1 hour before administration to 25 hours after administration of the test compound using Data and effective time anlysis (HEM 3_5, NOTOCORD SYSTEMS &gt; USA) . The analysis of blood pressure and heart rate is based on the blood pressure waveform of -177-201124388 every 30 minutes and the average 値, and then the average of 12 of the 値 is calculated as 1 hour data. The test compound was suspended orally administered to i% methylcellulose forcibly orally. The decrease in blood pressure of the test compound was evaluated by the difference from the mean blood pressure after each administration time of the mean blood pressure before the administration of the test compound. 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) Evaluation of the effect on electrocardiogram in rats. Inoculin (100 mg/kg) was intraperitoneally administered to rats for anesthesia, and the test compound was administered to the right femoral vein. Catheter. The electrocardiogram was measured by Dijon induction, and the test compound was continuously administered intravenously at a certain speed (1 mg/kg/min). Before the administration of the test compound, and 1 minute after the start of the administration, the electrocardiogram was recorded on the thermal-sensitive recording paper [or the ECG data may be transmitted to the Softron ECG Processor (SBP2000, Softron, Japan)] . The test compound is intravenously administered by dissolving it in a physiological saline solution containing a physiological saline solution or a solvent (e.g., DM SO or the like). The effect of the test compound on the electrocardiogram was evaluated by the change in electrocardiogram after each administration time of the electrocardiogram before administration of the test compound. Changes in the ECG can be evaluated by the following ratings, such as the height, width, and spacing of the waveform (especially, the drop in S-wave). The changes in the ECG are classified according to the degree of change, for example, large, medium, small, or none. Small or no compounds are preferred for changes in the electrocardiogram. The compound of the present invention has excellent characteristics as a medicine - 178 - 201124388 at the point of change of the electrocardiogram. (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. The resulting solution is orally administered in an appropriate range (for example, 3 mg/kg to 100 mg/kg) to an animal generally used in a drug dynamic test (eg, 'mouse , rat, marmoset, cynomolgus monkey, etc.). Further, the test compound is dissolved in physiological saline, and the resulting solution is intravenously administered in an appropriate range (for example, 1 mg/kg to 10 mg/kg) (for example, tail vein, temporal cutaneous vein, saphenous vein, etc.) Animals (eg, mice, rats, baboons, cynomolgus monkeys, etc.) used for internal administration and general drug dynamic tests. After a certain period of time after administration (for example, 〇. 0 8, 0.2 5, 0 · 5, 1, 2, 4, 6, 8, or 24 hours), the appropriate blood collection site (for example, jugular vein, orbital venous plexus) , the iliac 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 concentration of test compound concentration (Cmax) in plasma, the area under test compound concentration-time curve (AUC), systemic clearance (CL), and absolute bioavailability. Cmax represents the highest concentration of the test compound in the plasma after oral administration. The AUC is calculated from the trapezoidal formula at the time of administration of the test compound to the time when the blood is finally taken. CL uses drug dynamic analysis software -179- 201124388

Calculated by WinNonlin (registered trademark). The absolute bioavailability is 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) is used as a medicine (especially for the treatment or prevention of hypertension). (Formulation Example 1) A tablet compound (10 mg), colloidal cerium oxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg) and the like were used. Lactose (98.8 mg), a tablet was prepared according to the usual method. The resulting tablet can be coated as needed. (Formulation Example 2) Hard capsule standard dichotomous hard gelatin capsule, compound (10 mg), lactose (150 mg), cellulose (50 mg), and magnesium stearate (6 mg) in the form of powder, Hard capsules are made and 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 examples was poured into gelatin so as to contain 10 mg of the active ingredient to prepare a soft capsule, and washed. After, dry. [Industrial Applicability] The compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention has renin inhibitory activity, solubility, cell membrane permeability, oral absorption, and -180-201124388 blood. Medium concentration, metabolic stability, tissue migration, bioavailability, invitro activity, invivo activity, ex vivo activity, speed of efficacy, persistence of susceptibility, physics The stability, drug interaction, safety (for example, cardiotoxicity or hepatotoxicity), etc., have excellent properties compared with known compounds, and are used as medicines [especially, treatment or prevention of hypertension ( Preferably, the medicine used for the treatment is useful. [Simple description of the diagram] None. [Main component symbol description] None. -181-

Claims (1)

201124388 VII. Patent application scope: 1. A compound having the following formula (I) or a pharmacologically acceptable salt thereof; Wherein R1 represents an adamantyl group or a substituted adamantyl group (the substituent represents one to three groups independently selected from the group of substituents α); R2 represents a hydrogen atom or a CrQ alkyl group; Represents a hydrogen atom, a (Κ6 alkyl)carbonyl group, a (CrCe alkoxy)carbonyl group, or a substituted (Ci-C^alkoxy)carbonyl group; R4 represents a hydrogen atom or a C^-Ce alkyl group; R5 represents a hydrogen atom or an alkyl group; R6, R7, and R8 independently represent a hydrogen atom, a C^-Ce alkyl group, a haloalkyl group, a C3-C8 cycloalkyl group, a hydroxyl group, a Ci-Ce alkoxy group, a halogen oxime, an alkoxy group, Or a dentate group; a substituent group α represents a C^-Ce alkyl group, a halogen C^-Ce alkyl group, a hydroxyl group, a C"C6 alkoxy group, a (Ci-Ce alkyl)carbonyloxy group, (C" C6 alkoxy)carbonyloxy, aminocarbonyloxy, (Ci-Cealkylamino)carbonyloxy, bis(CrCealkyl)aminocarbonyloxy (the alkyl group is the same -182-201124388 or Different), amine group, (^-(^alkylamino group, bis(Ci-Ce alkyl) amine group (the alkyl group is the same or different), formylamino group, ((^-(: 6 alkyl)carbonylamino, (Ci-Ce alkoxy)carbonylamino, Aminocarbonylamino group, (Ci-CU alkylamino)carbonylamino group, bis(Ci-Ce alkyl)aminocarbonylamino group (the alkyl group is the same or different), amine carbenyl, (( ^-(^alkylamino)carbonyl, bis(C^-Cealkyl)aminocarbonyl (the alkyl group is the same or different), and a group consisting of a halogen group. a compound of the formula 1 or a pharmacologically acceptable salt thereof, which is a compound having the following formula (1-1) or a pharmacologically acceptable salt thereof; R2 OH [wherein R 1 represents an adamantyl group or a substituted adamantyl group (the substituent represents one to three groups independently selected from the group of substituents α); R 2 represents a hydrogen atom or an alkyl group; R 3 represents a hydrogen atom, (Ci-C6 alkyl)carbonyl, alkoxy)carbonyl, or substituted (Crh alkoxy)carbonyl; R4 represents a hydrogen atom or a Ci-Ce alkyl; R5 represents a hydrogen atom or a CrCe alkyl group; 201124388 R6' R7, and R8 independently represent a hydrogen atom, a CrCfi alkyl group, a halogen CrCe group, a C3-C8 cycloalkyl group, a hydroxyl group, a Cl_C6 alkoxy group, a halogen Ci-Ce alkoxy group, or a halogen group; α represents an alkyl group, a halogen CrCe alkyl 'hydroxy group, a &lt;^-(:6 alkoxy group, a (Cl_C6 alkyl)carbonyloxy group, a (Cl_c6 alkoxy)carbonyloxy group, an aminocarbonyloxy group, an alkane Amino)carbonyloxy['dialkyl)aminocarbonyloxy (the alkyl group is the same or different), an amine group, an alkylamino group, a di(Ci-Ce alkyl) amine group Is the same or different), a mercaptoamine group, a (Cl_C6 alkyl)carbonylamino group, an alkoxy)carbonylamino group, an aminocarbonylamino group, a (Cl_C6-homoylamino)carbonylamino group 'Bis(CrC^alkyl)aminocarbonylamino (this is the same or different), aminemethanyl, (Cl_C6 alkylamino)carbonyl, di(Ci-C6 alkyl)aminocarbonyl ( The alkyl group is the same or different), and the group consisting of a halogen group]. 3. A compound as claimed in claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is adamantyl-2-yl or substituted adamantane-2-yl (the substituent represents a group selected from the group α) One group), the substituent group αΐ represents a hydroxyl group, a Cl-C2 alkoxy group, a (Cl-C2 alkyl)carbonyloxy group, a (Ci-c:2 alkoxy)carbonyloxy group, an amine methyl group a group consisting of (Ci_C2 compound amino group) carbonyl group and di(CrC: 2 alkyl) aminocarbonyl group (the alkyl group is the same or different). 4. A compound as claimed in claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is a substituted adamantyl-2-yl group (this substituent represents -184 to 201124388 is selected from the group of substituents α2) The substituent group α2 represents a group consisting of a hydroxyl group, a methoxy group, and an amine carbenyl group. 5. The compound of claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-hydroxyadamantan-2-yl, cis-5-hydroxyadamantan-2-yl, counter Formula-5-methoxyadamantane-2-yl, cis-5-methoxyadamantan-2-yl, trans-5-aminecarboxyxan-2-yl, or cis-5 - Aminoguanidine fund, cycloalkan-2-yl. 6_ The compound of claim 2 or a pharmacologically acceptable salt thereof wherein R1 is trans-5-hydroxyadamantane-2-yl. 7. The compound of claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-methoxyadamantan-2-yl" 8 · a compound of claim 2 or A pharmacologically acceptable salt thereof, wherein R1 is trans-5-aminocarboxamide adamant-2-yl. 9. The compound of any one of claims 2 to 8 or a pharmaceutically acceptable salt thereof, wherein. The compound of any one of claims 2 to 8 or a pharmacologically acceptable salt thereof, wherein R2 is methyl, ethyl or 2-propyl. 11. The compound of any one of claims 2 to 8 or a pharmaceutically acceptable salt thereof, wherein R2 is ethyl. 12. The compound of any one of claims 2 to 8 or a pharmaceutically acceptable salt thereof, wherein R2 is 2-propyl. The compound of any one of claims 2 to 12, wherein R3 is a hydrogen atom, or a pharmacologically acceptable salt thereof. The compound of any one of claims 2 to 13 or a pharmacologically acceptable salt thereof, wherein R4 and R5 are a methyl group. The compound or a pharmacologically acceptable salt thereof, wherein each of R6, R7 and R8 is independently a hydrogen atom, a C丨-C4 alkyl group, a halogen C丨- C4 alkyl, fluoro, or chloro. The compound or a pharmacologically acceptable salt thereof, wherein R6, R7 and R8 are independently a hydrogen atom, a Ci-Cs alkyl group, a fluorine group, or a chlorine group, as claimed in any one of claims 2 to 14. . 17. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 14 wherein the base of formula (II): Is the following group: 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-di Fluorophenyl or 2-chloro-5-fluorophenyl. The compound of any one of claims 2 to 14 or a pharmacologically acceptable salt thereof having the group of formula (II): It is a 2-chlorophenyl group. The compound of any one of claims 2 to 14 or a pharmacologically acceptable salt thereof having the formula (II): R6 It is a 5-fluoro-2-methylphenyl group. The compound of any one of claims 2 to 14 or a pharmacologically acceptable salt thereof having the group of formula (II): It is a 2-chloro-5-fluorophenyl group. 21. The compound of claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-hydroxyadamantan-2-yl; R2 is methyl, ethyl or 2-propyl; Is a hydrogen atom; R4 and R5 are a methyl group; have the formula (Π): R7 (Μ -187- 201124388 is the following group: 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorobenzene A compound, or a pharmacologically acceptable salt thereof, wherein R1 is trans-5-, or a pharmaceutically acceptable salt thereof, in the formula 2, 6 or dichloro-5-fluorophenyl. Methoxy adamantane-2-yl; R2 is methyl, ethyl or 2-propyl; R3 is a hydrogen atom; R4 and R5 are methyl; having the formula (Π): R7 (Μ is the following group: 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2, a compound of claim 2 or a pharmacologically acceptable salt thereof, wherein R1 is a trans-5-amine formazan fund. Ranta-2-yl; R2 is methyl, ethyl or 2-propyl; R3 is a hydrogen atom; R4 and R5 are methyl; group having the formula (Π): -188- 201124388 R6 It is the following group: 2-methylphenyl, 2-ethylphenyl, 2-chlorophenyl, 5-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-di Fluorophenyl or 2-chloro-5-gas base. 24. A compound according to claim 2 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: (2S, 4S, 5S) -5-amino-6-[4-( 2-oxophenyl)-2,2-dimethyl-5-sideoxypiperidin-:l-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-iso Propyl hexane decylamine, (2S, 4S, 5S) -5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side oxy-peptin-l -yl]-4-hydroxy-2-isopropyl-N-(5-methoxyadamantan-2-yl)hexane decylamine, (2S,4S,5S)-5-amino- 6- [ 2,2-Dimethyl-4-(2-methylphenyl)-5-oxopiperidin-1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)- 2-isopropylhexylamine, (2S,4S,5S)-5-amino-6-[2,2-dimethyl-4-(2-methylphenyl)-5-sideoxy Piperidin-1-yl]-4-hydroxy-2-isopropyl-N-(5-methoxyadamantan-2-yl)hexane decylamine, (23,43,53)-5-amino group -6-[4-(2-ethylphenyl)-2,2-dimethyl-5-sideoxypiperidin-1-yl]-4-hydroxy-N- (5-hydroxyadamantane-2 -yl)-2-isopropylhexylamine, -189- 201124388 (2S,4S,5S) -5-Amino-6-[4-(2,3-difluorophenyl)-2,2 - two Methyl-5-oxopiperidin-1-yl]_4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-isopropylhexylamine, (23,43,53) -5-Amino-6-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxooxypiped-1 -yl]-4-hydroxy-N - ( 5-hydroxyadamantan-2-yl)-2-isopropylhexylamine, (2S,4S,5S)-5-amino-6-[4-(2-chloro-5-fluorophenyl) -2,2-dimethyl-5-pentaoxypiperidin-1-yl]-4-hydroxy-N-(5-hydroxyadamantane-2-yl)-2-isopropylhexylamine, (2S,4S,5S ) -5-Amino-6-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-oxoxypiped-1-yl ]-4-Hydroxy-N-(5-hydroxyadamantane-2-yl)_2-isopropylhexylamine, (2R,4S,5S) 5-amino-6-[4-( 2- Chlorophenyl)-2,2-dimethyl-5-side gas group 峨哄-l-yl]-2-ethyl-4-yl-N-(5- via fund Hexane amide, (2R, 4S, 5S) - 5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperidin-1-yl ]-2-Ethyl-4-hydroxy-indole (5-methoxyadamantan-2-yl)hexane decylamine, (211,43,53)-5-amino-6-[4-( 2,3-Difluorophenyl)-2,2-dimethyl-5-oxooxypiped-1 -yl]-2 - 4--4-hydroxy-indole-(5-hydroxyadamantan-2-yl)hexane decylamine, (211,43,53)-5-amino-6-[4-(2,6-difluorobenzene -2,2-dimethyl-5-sideoxypiped-1-yl]-2-ethyl-4-hydroxy-indole- (5-hydroxy gold-190- 201124388] Hexane amide, (211,48,55)-5-amino-6-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-side oxetyl Well-1-yl]-2-ethyl-4-hydroxy-N-(5-hydroxyadamantan-2-yl)hexane decylamine, (2R,4S,5S)-5-amino-2-ethyl -6-[4-( 5-fluoro-2-methylphenyl)-2,2-dimethyl-5-oxopiperidin-1 -yl]-4-hydroxy-N-(5- Hydroxydamantane-2-yl) hexane decylamine, (2R, 4S, 5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-side Oxypiperidine-1-yl]-4-hydroxy-N-(5-hydroxyadamantan-2-yl)-2-methyl hexane decylamine, (2S,4S,5S)-5-amino- N-(5-Aminoformamide, adamant-2-yl)-6-[4-(2-chloro-5-carbyl)-2,2-methyl-5-oxime oxime- 1-yl]-4-hydroxy-2-isopropylhexane decylamine, (2S,4S,5S)-5-amino-N-(5-aminoformamidine-cyclohexane-2-yl)-6 -[4-(2-chlorophenyl)-2,2-dimethyl-5- Oxypiperazine-1_yl]-4-hydroxy-2-isopropylhexanylamine, and (2R,4S,5S)-5-amino-N-(5-amineformamidine-fundane_ 2_yl) • 6-[4-(2-Chlorophenyl)-2,2-dimethyl-5-o-oxypiperazin-yl]·2·ethyl-4-hydroxyhexane decylamine 25. A compound according to claim 2 or a pharmacologically acceptable salt thereof, which is (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)22-monomethyl- 5-Hydroxypiperazine-1 -yl]-4-hydroxy·N ·( 5 ·hydroxyadamantan-2-yl)-2-isopropylhexane decylamine. -191- 201124388 26. The compound of claim 2 or a pharmacologically acceptable salt thereof, which is (28,43,53)-5-amino-6-[4-(5-fluoro-2) -Methylphenyl) -2,2-dimethyl-5-oxime oxime-1-yl]_4_diabase _|^_(5- via fund Gangyuan-2-yl)-2 - Isopropyl hexylamine. 27. A compound according to claim 2 or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2, 2. Dimethyl-5-o-oxypiperazin-1-yl]-2-ethyl_4-diabase _!^-(5-pathic fundane-2-yl)hexane decylamine. 28. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2, 2-Dimethyl-5-oxopiperidin-1-yl]-2-ethyl-4-hydroxy-indole-(5-methoxyadamantan-2-yl)hexaneguanamine. 2 9 · A compound of claim 2 or a pharmacologically acceptable salt thereof, which is (2R, 4S, 5S) -5-amino-6-[4-(2-chloro-5-fluorobenzene) -2,2-Dimethyl-5-oxopiperidin-1-yl]-2-ethyl-4-hydroxy-indole-(5-hydroxyadamantan-2-yl)hexane decylamine . 30. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-2-ethyl·6_[4-(5-fluoro-2) -Methylphenyl)-2,2-dimethyl-5-pentaoxypiped-yl]hydroxy-N.(5-hydroxyadamantan-2-yl)hexane decylamine. 31. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2S,4S,5S)-5-amino-6-[4_(2-chlorophenyl)·2,2· Dimethyl-5-oxooxyindole-1-yl]-4-c-yl-indole-(trans-5-yl-yl-192- 201124388 adamantyl-2-yl)-2-isopropyl Alkylamine fumarate. 32. A compound of claim 2, or a pharmacologically acceptable salt thereof, which is (23,4 8,53)-5-amino-6-[4-(5-fluoro-2-methyl) Phenyl) -2,2-dimethyl-5-sideoxypiped-1-yl]-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)-2-isopropyl Hexane amide amine fumarate. 33. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2, 2-Dimethyl-5-oxooxypiped-byl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane decylamine Diacid salt. 34. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2, 2-Dimethyl-5-sideoxypiped-1-yl]-2-ethyl-4-hydroxy-N-(trans-5-methoxyadamantan-2-yl)hexane decylamine Fumarate. 35. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-6-[4-(2-chloro-5-fluorophenyl) -2,2-Dimethyl-5-oxooxypiped-1-yl]-2-ethyl-4-hydroxy-N-(trans-5-hydroxyadamantan-2-yl)hexane Indoleamine fumarate. 36. A compound according to claim 2, or a pharmacologically acceptable salt thereof, which is (2R,4S,5S)-5-amino-2-ethyl-6-[4-(5-fluoro- 2-methylphenyl)-2,2-dimethyl-5-oxopiperidin-1-yl]-4-hydroxy-N_(trans-5-hydroxyadamantan-2-yl)hexane Indoleamine fumarate. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmacologically acceptable salt thereof, is effective from -193 to 201124388. 38. The pharmaceutical composition of claim 37, for use in the treatment or prevention of hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, brain Stroke, cognitive impairment, kidney disease, diabetic complication, glaucoma, vascular restenosis after angiogenesis, aldosteroneemia, or atherosclerosis. 39. The pharmaceutical composition of claim 37, for use in the treatment or prevention of hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. 40. The pharmaceutical composition of claim 37, which is for use in the treatment or prevention of hypertension. 4 1. A pharmaceutical composition according to claim 37, for use in the treatment or prevention of a disease treatable or preventable by inhibiting renin. A renin inhibitor comprising a compound according to any one of claims 1 to 36, or a pharmacologically acceptable salt thereof, as an active ingredient. 43. A compound or a pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 36 is used for the treatment or prevention of a disease. 44. A compound according to claim 43 or a pharmacologically acceptable salt thereof, wherein the disease is hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease , Brain-194- 201124388 Stroke, cognitive impairment, kidney disease, diabetic complication, glaucoma vascular restenosis after angiogenesis, aldosteronism, or atherosclerosis. 45. A compound according to claim 43 or a pharmacologically acceptable salt thereof, wherein the disease is blood pressure, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. 46. A compound according to claim 43 or a pharmacologically acceptable salt thereof, wherein the disease is hypertension. A method for treating or preventing a disease, which is administered to a warm-blooded animal by a pharmacologically effective amount of a compound according to any one of claims 1 to 36 or a pharmacologically acceptable salt thereof. 48. The method of claim 47, wherein the disease is hypertension, pulmonary hypertension, heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, coronary artery disease, stroke, cognitive impairment, kidney Disease, diabetic complication, glaucoma, vascular restenosis after angiogenesis, aldosteronism, or atherosclerosis. 49. The method of claim 47, wherein the disease is hypertension, congestive heart failure, cardiac hypertrophy, coronary artery disease, or diabetic nephropathy. 5. The method of claim 47, wherein the disease is hypertension. 51. The method of claim 47, wherein the disease is a disease treatable or preventable by inhibiting renin. The method of any one of claims 47 to 51, wherein the warm-blooded animal is a human. -195- 201124388 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the component symbols of this representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: OH