WO2011013644A1 - Substituted piperidine compound - Google Patents

Abstract

Disclosed is a substituted piperidine compound useful as a therapeutic agent for high blood pressure, etc. Disclosed is a compound, etc., having a general formula (I) [in the formula, R¹ represents H, an optionally substituted alkyl, phenyl, a saturated cyclic hydrocarbon, heterocyclyl, etc.; R² represents H or an alkyl; R³ and R⁴ represent H or an alkyl; A represents phenyl or pyridyl; R⁵, R⁶, and R⁷ represent H, an optionally substituted alkyl, an optionally substituted hydroxy, an optionally substituted mercapto, an optionally substituted amino, a substituted carbonyl, a substituted sulfonyl, CN, NO2, a halogeno, etc.].

Description

Substituted piperidine compounds

The present invention relates to a novel substituted piperidine compound having excellent renin inhibitory activity and useful as a medicine [particularly, a medicine for treating or preventing (preferably treating) hypertension] or a pharmacologically acceptable compound thereof. salt;
A renin inhibitor comprising a substituted piperidine compound or a pharmacologically acceptable salt thereof;
A pharmaceutical composition comprising a substituted piperidine compound or a pharmacologically acceptable salt thereof as an active ingredient, preferably a pharmaceutical composition for treating or preventing hypertension;
Use of a substituted piperidine compound or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease (preferably the above-mentioned diseases);
A method for the treatment or prevention of a disease (preferably the above-mentioned disease) by administering a pharmaceutically effective amount of a substituted piperidine compound or a pharmacologically acceptable salt thereof to a warm-blooded animal (particularly a human); and ,
The present invention relates to a method for producing a substituted piperidine compound or a pharmacologically acceptable salt thereof.

Hypertension is defined in the WHO / ISH guidelines and symptoms with a maximum blood pressure of 140 mmHg or higher, or a minimum blood pressure of 90 mmHg or higher. If the state of hypertension continues, cerebral hemorrhage, cerebral infarction, aortic aneurysm, nephrosclerosis, myocardial infarction, heart failure, etc. develop and eventually death. The administration of antihypertensive drugs has shown that these diseases can be controlled by large-scale clinical trials.Currently, active administration of antihypertensive drugs, exercise, and improvement of dietary habits have positive effects on blood pressure. Efforts are being made to lower, but more sufficient blood pressure control is desired.

One of the main mechanisms of hypertension is activation of the renin-angiotensin system (hereinafter also referred to as R-A system). The R-A system is a typical boosting system of a living body that increases blood pressure by storing sodium (salt) in the body to increase the circulating blood volume or contracting vascular smooth muscle. In the R-A system, angiotensinogen is converted to angiotensin I by renin, and angiotensin I is converted to angiotensin II by an angiotensin converting enzyme (hereinafter also referred to as ACE). Angiotensin II acts on an angiotensin type 1 receptor (hereinafter also referred to as AT1) to cause vasoconstriction, cell proliferation, or collagen production, and to cause hypertension and subsequently organ damage. Currently, ACE inhibitors that suppress the production of angiotensin II (hereinafter also referred to as ACEI) and angiotensin receptor antagonists that suppress the stimulation of AT1 (hereinafter also referred to as ARB) are used as antihypertensive drugs. These drugs are known to have a significant blood pressure lowering action and organ protection action.

Renin is an aspartic protease that converts angiotensinogen to angiotensin I, and is considered to be a rate-limiting enzyme of the R-A system. Therefore, a renin inhibitor is thought to efficiently inhibit the R-A system and is expected to have a blood pressure lowering effect equivalent to ACEI and ARB (Circulation, 2005, Vol.111, p.1012-1018).

Piperidine compounds having substituents at positions 3 and 5 having renin inhibitory activity are known (see, for example, Patent Documents 1 to 25 or Non-Patent Document 1). In addition, compounds having an oxopiperazine partial structure having renin inhibitory activity are known (see, for example, Patent Documents 26 to 29 or Non-Patent Document 1). However, the compound of the present invention is greatly different from the above-mentioned known compounds in that the structure of the substituents at the 3 and 5 positions of the piperidine ring and the oxopiperazine partial structure at a specific position of the piperidine ring.

International Publication No. 1997/009311 Pamphlet International Publication No. 2000/064873 Pamphlet International Publication No. 2004/089093 Pamphlet International Publication No. 2005/061457 Pamphlet International Publication No. 2006/005741 Pamphlet International Publication No. 2006/094763 Pamphlet International Publication No. 2006/103273 Pamphlet International Publication No. 2006/103275 Pamphlet International Publication No. 2006/103277 Pamphlet International Publication No. 2006/117183 Pamphlet International Publication No. 2007/006534 Pamphlet International Publication No. 2007/082907 Pamphlet International Publication No. 2007/077005 Pamphlet International Publication No. 2008/017685 Pamphlet International Publication No. 2008/040764 Pamphlet International Publication No. 2008/074450 Pamphlet International Publication No. 2008/093737 Pamphlet International Publication No. 2008/136457 Pamphlet International Publication No. 2008/153135 Pamphlet International Publication No. 2009/000811 Pamphlet International Publication No. 2009/005002 Pamphlet International Publication No. 2009/014217 Pamphlet International Publication No. 2009/051112 Pamphlet International Publication No. 2009/071606 Pamphlet International Publication No. 2009/072649 Pamphlet International Publication No. 2004/089915 Pamphlet International Publication No. 2006/128659 Pamphlet International Publication No. 2007/034445 Pamphlet International Publication No. 2007/148774 Pamphlet

The present inventors have studied novel substituted piperidine compounds for the development of excellent antihypertensive drugs, and substituted piperidine compounds having a specific structure or pharmacologically acceptable salts thereof have renin inhibitory activity, dissolution , Cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue migration, bioavailability (hereinafter also referred to as BA), in vitro activity, in vivo activity, rapid onset of drug efficacy, efficacy It has excellent properties in terms of durability, physical stability, drug interaction, safety (for example, cardiotoxicity or hepatotoxicity), etc., and is a drug [especially treatment or prevention of hypertension (preferably treatment). It was found to be useful as a medicine for The present invention has been completed based on the above findings.

The present invention relates to a novel substituted piperidine compound having excellent renin inhibitory activity and useful as a medicine [particularly, a medicine for treating or preventing (preferably treating) hypertension] or a pharmacologically acceptable compound thereof. salt;
A renin inhibitor comprising a substituted piperidine compound or a pharmacologically acceptable salt thereof;
A pharmaceutical composition containing a substituted piperidine compound or a pharmacologically acceptable salt thereof as an active ingredient, preferably hypertension, acute or chronic heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina pectoris, stroke, kidney disease (Eg glomerulonephritis, IgA nephropathy, hypertensive nephropathy), diabetic complications (eg nephropathy, neuropathy, retinopathy, glaucoma), vascular restenosis after angioplasty, aldosteronemia, or A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for reducing the incidence of events or mortality based on cardiovascular or coronary heart disease, more preferably hypertension, chronic heart failure, or A pharmaceutical composition for the treatment or prevention of diabetic nephropathy, most preferably a pharmaceutical composition for the treatment or prevention of hypertension;
Use of a substituted piperidine compound or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease (preferably the above diseases);
A method for the treatment or prevention of a disease (preferably the above-mentioned disease) by administering a pharmaceutically effective amount of a substituted piperidine compound or a pharmacologically acceptable salt thereof to a warm-blooded animal (particularly a human); and ,
A method for producing a substituted piperidine compound or a pharmacologically acceptable salt thereof is provided.

The present invention provides the following from one aspect.
(1) General formula (I)

 

[Wherein R ¹ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a phenyl- (C ₁ -C ₁₀ alkyl) group, (C ₃ -C ₁₀ saturated cyclic hydrocarbon)-(C ₁ -C ₁₀ alkyl) ) Group, (4- to 8-membered heterocyclyl)-(C ₁ -C ₁₀ alkyl) group, phenyl group, indanyl group, C ₃ -C ₁₀ saturated cyclic hydrocarbon group, or 4- to 8-membered heterocyclyl group, each group in the ^1, and together may be substituted with 1 to 4 groups independently selected from substituent group alpha, 2 pieces of the substituents attached to the same carbon atom and the carbon atom May form a C ₃ -C ₈ cycloalkyl group;
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ³ and R ⁴ together with the carbon atom to which they are bonded may form a C ₃ -C ₈ cycloalkyl group. Often;
A represents a phenyl group or a pyridyl group,
R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or a group selected from the substituent group α;
Substituent group α includes C ₁ -C ₆ alkyl group, halogeno C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cyclo group) Alkyl)-(C ₁ -C ₆ alkoxy) group, halogeno C ₁ -C ₆ alkoxy group, mercapto group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group , Amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different), formylamino group, (C ₁ -C ₆ alkyl) carbonylamino group , Formyl group, (C ₁ -C ₆ alkyl) carbonyl group, carboxy group, (C ₁ -C ₆ alkoxy) carbonyl group, carbamoyl group, (C ₁ -C ₆ alkylamino) carbonyl group, di (C ₁ -C ₆ alkyl) aminocarbonyl group (The alkyl groups are the same or different), aminosulfonyl group, (C ₁ -C ₆ alkylamino) sulfonyl group, di (C ₁ -C ₆ alkyl) aminosulfonyl group (the alkyl groups are the same or different), A group consisting of a cyano group, a nitro group, a halogeno group, and an oxo group is shown. ]
Or a pharmacologically acceptable salt thereof,
(2) R ¹ is a C ₁ -C ₁₀ alkyl group, a phenyl- (C ₁ -C ₁₀ alkyl) group, a (C ₃ -C ₁₀ saturated cyclic hydrocarbon)-(C ₁ -C ₁₀ alkyl) group, ( A 4- to 8-membered heterocyclyl)-(C ₁ -C ₁₀ alkyl) group or a C ₃ -C ₁₀ saturated cyclic hydrocarbon group, wherein each group in R ¹ is independently selected from the substituent group α1 May be substituted with 1 to 4 groups, and two such substituents bonded to the same carbon atom may be combined with the carbon atom to form a C ₃ -C ₈ cycloalkyl group; Substituent group α1 is a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₁ -C ₆ alkoxy group, a di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or The compound described in (1), or a pharmacologically acceptable group thereof, which is a group consisting of a halogeno group and an oxo group. ,
(3) R ¹ is a C ₁ -C ₁₀ alkyl group, a phenyl- (C ₁ -C ₁₀ alkyl) group, or a (4- to 8-membered heterocyclyl)-(C ₁ -C ₁₀ alkyl) group; each group of ¹ may be substituted with 1 to 4 groups independently selected from substituent group [alpha] 2, substituent group [alpha] 2 is, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl The compound or a pharmaceutically acceptable salt thereof according to (1), which is a group consisting of an alkyl group, a C ₁ -C ₆ alkoxy group, and a halogeno group;
(4) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (3), wherein R ² is a hydrogen atom,
(5) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (4), wherein R ³ is a C ₁ -C ₆ alkyl group,
(6) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (4), wherein R ³ is a methyl group,
(7) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (6), wherein R ⁴ is a C ₁ -C ₆ alkyl group,
(8) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (6), wherein R ⁴ is a methyl group,
(9) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (8), wherein A is a phenyl group,
(10) Any of (1) to (9), wherein R ⁵ , R ⁶ and R ⁷ are each independently a group selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, and a halogeno group Or a pharmacologically acceptable salt thereof,
(11) Any one of (1) to (9), wherein R ⁵ , R ^6, and R ⁷ are independently selected from a hydrogen atom, a methyl group, a fluoro group, and a chloro group. Or a pharmacologically acceptable salt thereof.

Moreover, this invention provides the following from one side surface.
(12) A pharmaceutical composition comprising the compound described in any one of (1) to (11) or a pharmacologically acceptable salt thereof as an active ingredient,
(13) The pharmaceutical composition described in (12) for treatment or prevention of a disease that can be treated or prevented by inhibiting renin,
(14) Hypertension, acute or chronic heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina, stroke, kidney disease, diabetic complications, vascular restenosis after angioplasty, aldosteronemia, or atheroma A pharmaceutical composition described in (12) for the treatment or prevention of atherosclerosis,
(15) The pharmaceutical composition described in (12) for the treatment or prevention of hypertension, chronic heart failure, or diabetic nephropathy,
(16) The pharmaceutical composition according to (12) for the treatment or prevention of hypertension,
(17) The compound according to any one of (1) to (11) or a pharmacologically acceptable salt thereof for use in a method for treating or preventing a disease,
(18) The compound according to (17), wherein the disease is hypertension, or a pharmacologically acceptable salt thereof,
(19) A method for treating or preventing a disease by administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (11) or a pharmacologically acceptable salt thereof. ,
(20) The method according to (19), wherein the disease is a disease that can be treated or prevented by inhibiting renin.
(21) The method according to (19), wherein the disease is hypertension,
(22) The method according to any one of (19) to (21), wherein the warm-blooded animal is a human.

In the general formula (I) of the present invention, each group has the following meaning.

“C ₁ -C ₁₀ alkyl” and the “C ₁ -C ₁₀ alkyl” portion of each group are straight-chain or branched alkyl having 1 to 10 carbon atoms, such as the following C ₁ — It may be the group shown for C ₆ alkyl, 1-heptyl, 1-octyl, 1-nonyl or 1-decyl, preferably C ₂ -C ₈ alkyl.

“Phenyl- (C ₁ -C ₁₀ alkyl)” is the above C ₁ -C ₁₀ alkyl substituted with phenyl, preferably phenyl- (C ₁ -C ₆ alkyl).

“C ₃ -C ₁₀ saturated cyclic hydrocarbon” is a monocyclic, bicyclic or tricyclic saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Monocyclic C ₃ -C ₁₀ saturated cyclic hydrocarbon is C ₃ -C ₁₀ cycloalkyl, which may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl , Preferably C ₃ -C ₈ cycloalkyl, and more preferably C ₃ -C ₆ cycloalkyl. Bicyclic or tricyclic C ₃ -C ₁₀ saturated cyclic hydrocarbons include, for example, bicyclo [2,2,1] heptyl (norbornyl), bicyclo [3,1,1] heptyl (norpinyl), bicyclo [3 , 2,1] octyl, bicyclo [4,2,1] nonyl, bicyclo [3,3,1] nonyl, decahydronaphthyl, or adamantyl.

“(C ₃ -C ₁₀ saturated cyclic hydrocarbon)-(C ₁ -C ₁₀ alkyl)” is the above C ₁ -C ₁₀ alkyl substituted with the above C ₃ -C ₁₀ saturated cyclic hydrocarbon, Is (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) or adamantyl- (C ₁ -C ₆ alkyl).

The “4- to 8-membered heterocyclyl” is a 4- to 8-membered heterocyclic ring containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Terocyclyl and 5- to 6-membered aromatic heterocyclyl. 4- to 8-membered saturated heterocyclyl is, for example, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, homopiperazinyl, or 5 to 7-membered saturated heterocyclyl is preferred. The 5- to 6-membered aromatic heterocyclyl can be, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. .

“(4 to 8 membered heterocyclyl)-(C ₁ -C ₁₀ alkyl)” is the above C ₁ -C ₁₀ alkyl substituted with the above 4 to 8 membered heterocyclyl, preferably (5 to 7 membered saturated) Heterocyclyl)-(C ₁ -C ₆ alkyl) or (5- to 6-membered aromatic heterocyclyl)-(C ₁ -C ₆ alkyl).

“C ₃ -C ₈ cycloalkyl” is a cyclic alkyl having 3 to 8 carbon atoms, and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably , C ₃ -C ₆ cycloalkyl.

“C ₁ -C ₆ alkyl” and the “C ₁ -C ₆ alkyl” portion of each group are straight or branched alkyl 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-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2- Methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, or 2,3-dimethyl-1-butyl, preferably C ₁ -C ₅ alkyl.

“Halogeno C ₁ -C ₆ alkyl” is the above C ₁ -C ₆ alkyl substituted with 1 to 7 of the following halogeno, such as fluoromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, Trichloromethyl, 2-fluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, trichloroethyl, pentafluoroethyl, 3-fluoropropyl, 3 It can be -chloropropyl, 4-fluorobutyl, 5-fluoropentyl or 6-fluorohexyl.

“C ₁ -C ₆ alkoxy” is hydroxy (—OH) substituted with one of the above C ₁ -C ₆ alkyl, eg, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentyloxy, 3-methyl-1-pentyloxy, 2-ethyl-1-butoxy, 2,2-dimethyl-1- It can be butoxy or 2,3-dimethyl-1-butoxy.

“(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkoxy)” is the above C ₁ -C ₆ alkoxy substituted with the above C ₃ -C ₈ cycloalkyl, such as cyclopropylmethoxy, Cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy, cyclopropylpentyloxy, cyclopropylhexyloxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, cycloheptylmethoxy, or cyclooctyl It can be methoxy.

“Halogeno C ₁ -C ₆ alkoxy” is the above C ₁ -C ₆ alkoxy substituted with the same or different 1 to 7 of the following halogeno, for example, fluoromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trioxy Fluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trichloroethoxy, pentafluoroethoxy, It can be 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, or 6-fluorohexyloxy.

“C ₁ -C ₆ alkylthio” is mercapto (—SH) substituted with one of the above C ₁ -C ₆ alkyl, eg, methylthio, ethylthio, 1-propylthio, 2-propylthio, 1-butylthio, 2-butylthio, 2-methyl-1-propylthio, 2-methyl-2-propylthio, 1-pentylthio, 2-pentylthio, 3-pentylthio, 2-methyl-2-butylthio, 3-methyl-2-butylthio, 1- Hexylthio, 2-hexylthio, 3-hexylthio, 2-methyl-1-pentylthio, 3-methyl-1-pentylthio, 2-ethyl-1-butylthio, 2,2-dimethyl-1-butylthio, or 2,3- It can be dimethyl-1-butylthio.

“C ₁ -C ₆ alkylsulfinyl” is sulfinyl (—SO—) substituted with one of the above C ₁ -C ₆ alkyl, eg, methylsulfinyl, ethylsulfinyl, 1-propylsulfinyl, 2-propyl Sulfinyl, 1-butylsulfinyl, 2-butylsulfinyl, 2-methyl-1-propylsulfinyl, 2-methyl-2-propylsulfinyl, 1-pentylsulfinyl, 2-pentylsulfinyl, 3-pentylsulfinyl, 2-methyl-2 -Butylsulfinyl, 3-methyl-2-butylsulfinyl, 1-hexylsulfinyl, 2-hexylsulfinyl, 3-hexylsulfinyl, 2-methyl-1-pentylsulfinyl, 3-methyl-1-pentylsulfinyl, 2-ethyl- 1-Butylsulfi Nyl, 2,2-dimethyl-1-butylsulfinyl, or 2,3-dimethyl-1-butylsulfinyl.

“C ₁ -C ₆ alkylsulfonyl” is sulfonyl (—SO ₂ —) substituted with one of the above C ₁ -C ₆ alkyl, such as methanesulfonyl, ethanesulfonyl, 1-propanesulfonyl, 2- Propanesulfonyl, 1-butanesulfonyl, 2-butanesulfonyl, 2-methyl-1-propanesulfonyl, 2-methyl-2-propanesulfonyl, 1-pentanesulfonyl, 2-pentanesulfonyl, 3-pentanesulfonyl, 2-methyl- 2-butanesulfonyl, 3-methyl-2-butanesulfonyl, 1-hexanesulfonyl, 2-hexanesulfonyl, 3-hexanesulfonyl, 2-methyl-1-pentanesulfonyl, 3-methyl-1-pentanesulfonyl, 2-ethyl -1-butanesulfonyl, 2,2-dimethyl-1-butanesulfo Le, or may be a 2,3-dimethyl-1-butanesulfonyl.

“C ₁ -C ₆ alkylamino” is amino substituted with one of the above C ₁ -C ₆ alkyl, eg, methylamino, ethylamino, 1-propylamino, 2-propylamino, 1-butyl Amino, 2-butylamino, 2-methyl-1-propylamino, 2-methyl-2-propylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, 1-hexylamino, 2-hexylamino, Alternatively, it can be 3-hexylamino.

“Di (C ₁ -C ₆ alkyl) amino” is an amino substituted with two of the same or different C ₁ -C ₆ alkyl, eg, dimethylamino, methylethylamino, methylpropylamino [eg, N-methyl-N- (1-propyl) amino etc.], methylbutylamino [eg N- (1-butyl) -N-methylamino etc.], methylpentylamino, methylhexylamino, diethylamino, ethylpropylamino [ For example, N-ethyl-N- (1-propyl) amino and the like], ethylbutylamino, dipropylamino, propylbutylamino, dibutylamino, dipentylamino, or dihexylamino.

“(C ₁ -C ₆ alkyl) carbonylamino” is amino substituted with one of the following (C ₁ -C ₆ alkyl) carbonyl, for example, methylcarbonylamino, ethylcarbonylamino, 1-propylcarbonylamino 2-propylcarbonylamino, 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 -Pentylcarbonylamino, - methyl-1-pentyl carbonylamino, 2-ethyl-1-butylcarbonylamino, 2,2-dimethyl-1-butyl carbonylamino, or may be a 2,3-dimethyl-1-butylcarbonylamino.

“(C ₁ -C ₆ alkyl) carbonyl” is carbonyl (—CO—) substituted with one of the above C ₁ -C ₆ alkyl, for example, methylcarbonyl (acetyl), ethylcarbonyl, 1-propyl Carbonyl, 2-propylcarbonyl, 1-butylcarbonyl, 2-butylcarbonyl, 2-methyl-1-propylcarbonyl, 2-methyl-2-propylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 2-methyl-2-butylcarbonyl, 3-methyl-2-butylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, 3-hexylcarbonyl, 2-methyl-1-pentylcarbonyl, 3-methyl-1-pentylcarbonyl 2-ethyl-1-butylcarbonyl, 2,2-dimethyl-1-butyl It can be tilcarbonyl or 2,3-dimethyl-1-butylcarbonyl.

“(C ₁ -C ₆ alkoxy) carbonyl” is carbonyl (—CO—) substituted with one of the above C ₁ -C ₆ alkoxy, for example, methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2 -Propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-1-propoxycarbonyl, 2-methyl-2-propoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, 2-methyl-2-butoxycarbonyl, 3-methyl-2-butoxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl, 2-methyl-1-pentyloxycarbonyl, 3-methyl- 1-pentyloxycarboni , 2-ethyl-1-butoxycarbonyl, 2,2-dimethyl-1-butoxycarbonyl, or it may be a 2,3-dimethyl-1-butoxycarbonyl.

“(C ₁ -C ₆ alkylamino) carbonyl” is carbonyl (—CO—) substituted with one of the above C ₁ -C ₆ alkylamino, for example, methylaminocarbonyl, ethylaminocarbonyl, 1- Propylaminocarbonyl, 2-propylaminocarbonyl, 1-butylaminocarbonyl, 2-butylaminocarbonyl, 2-methyl-1-propylaminocarbonyl, 2-methyl-2-propylaminocarbonyl, 1-pentylaminocarbonyl, 2- It can be pentylaminocarbonyl, 3-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl, or 3-hexylaminocarbonyl.

“Di (C ₁ -C ₆ alkyl) aminocarbonyl” is carbonyl (—CO—) substituted with one of the above di (C ₁ -C ₆ alkyl) amino, for example, dimethylaminocarbonyl, methylethyl Aminocarbonyl, methylpropylaminocarbonyl [eg, N-methyl-N- (1-propyl) aminocarbonyl, etc.], methylbutylaminocarbonyl [eg, N- (1-butyl) -N-methylaminocarbonyl, etc.], methyl Pentylaminocarbonyl, methylhexylaminocarbonyl, diethylaminocarbonyl, ethylpropylaminocarbonyl [eg, N-ethyl-N- (1-propyl) aminocarbonyl, etc.], ethylbutylaminocarbonyl, dipropylaminocarbonyl, propylbutylaminocarbonyl, Dibutylaminocarbonyl, dipen It can be tilaminocarbonyl or dihexylaminocarbonyl.

“(C ₁ -C ₆ alkylamino) sulfonyl” is sulfonyl (—SO ₂ —) substituted with one of the above C ₁ -C ₆ alkylamino, for example, (methylamino) sulfonyl, (ethylamino) ) Sulfonyl, (1-propylamino) sulfonyl, (2-propylamino) sulfonyl, (1-butylamino) sulfonyl, (2-butylamino) sulfonyl, (2-methyl-1-propylamino) sulfonyl, (2- Methyl-2-propylamino) sulfonyl, (1-pentylamino) sulfonyl, (2-pentylamino) sulfonyl, (3-pentylamino) sulfonyl, (1-hexylamino) sulfonyl, (2-hexylamino) sulfonyl, or , (3-hexylamino) sulfonyl.

“Di (C ₁ -C ₆ alkyl) aminosulfonyl” is sulfonyl (—SO ₂ —) substituted with one of the above di (C ₁ -C ₆ alkyl) amino, eg, (dimethylamino) sulfonyl , (Methylethylamino) sulfonyl, (methylpropylamino) sulfonyl [eg, [N-methyl-N- (1-propyl) amino] sulfonyl, etc.], (methylbutylamino) sulfonyl [eg, [N- (1- Butyl) -N-methylamino] sulfonyl and the like], (methylpentylamino) sulfonyl, (methylhexylamino) sulfonyl, (diethylamino) sulfonyl, (ethylpropylamino) sulfonyl [eg, [N-ethyl-N- (1- Propyl) amino] sulfonyl and the like], (ethylbutylamino) sulfonyl, (dipropylamino) sulfonyl, (propylbutylamino) sulfonyl, (dibutylamino) Roh) sulfonyl, (dipentylamino) sulfonyl, or it may be a (dihexylamino) sulfonyl.

“Halogeno” may be fluoro, chloro, bromo, or iodo.

The compound having the general formula (I) of the present invention includes compounds having the following formulas (Ia) to (Id), and a compound having the formula (Ia) in which the configuration on the piperidine ring is (3S, 5R) Is preferred.

Among the compounds having the general formula (I) of the present invention, the compounds shown in the examples are suitable.

化合物 The compound having the general formula (I) of the present invention can form an acid addition salt, and these acid addition salts are included in the present invention. These acid addition salts are, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate, maleate, L-malic acid , D-malic acid, L-tartaric acid, D-tartaric acid, phthalate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, 2,4-dimethylbenzenesulfonate, It can be 2,4,6-trimethylbenzene sulfonate, 4-ethylbenzene sulfonate, or naphthalene sulfonate. The compound having the general formula (I) of the present invention can form an acid addition salt with an arbitrary ratio of acid, and each of its acid addition salts (eg, monoacid salt, diacid salt, ½ acid) Salt) or mixtures thereof are encompassed by the present invention.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each or a mixture thereof is included in the present invention.

When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has at least one asymmetric center, carbon-carbon double bond, amidino group, axial asymmetry, etc., an optical isomer ( (Including enantiomers and diastereomers), geometric isomers, tautomers, and rotamers, and these isomers and mixtures thereof may be represented by a single formula such as formula (I) be written. The present invention includes each of these isomers and mixtures thereof in any proportion (including racemates).

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof forms an isotope compound in which one or more atoms constituting the compound are substituted with isotope atoms in an unnatural ratio. Can do. Isotope atoms can be radioactive or non-radioactive, such as deuterium ( ² H; D), tritium ( ³ H; T), carbon-14 ( ¹⁴ C), iodine-125 ( ¹²⁵ I), and the like. . A compound labeled with a radioactive isotope atom can be used as a therapeutic or prophylactic agent for a disease, a research reagent (eg, an assay reagent), a diagnostic agent (eg, a diagnostic imaging agent), and the like. The present invention includes radioactive or non-radioactive isotope compounds.

In the present invention, hypertension includes a hypertension in a known manner, such as essential hypertension, renal hypertension, endocrine hypertension, neurological hypertension, or primary or secondary hypertension. Including pulmonary hypertension.

The compound having the general formula (I) of the present invention can be produced according to the following Method A (Method A-1 and Method A-2) or Method B.

 

 

 

In the structural formula of the compound of the method A or B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and A have the same significance as in formula (I) , X represents a chloro group, a bromo group, or an iodo group, and Y represents a lower alkyl group; a lower alkenyl group; or a (phenyl-lower alkyl) group optionally substituted with lower alkyl, lower alkoxy, or halogeno. Boc represents tert-butoxycarbonyl, and Ns represents o-nitrobenzenesulfonyl.

In the reaction of each step of the following method A or B, when the compound as a starting material has a group that inhibits the target reaction such as an amino group, a hydroxyl group, a carboxy group, etc. The protecting group may be introduced and the introduced protecting group may be removed. Such a protecting group is not particularly limited as long as it is a commonly used protecting group. For example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis.Fourth Edition, 2007, John Wiley & Sons , Inc., and the like. The reaction for introduction and removal of these protecting groups can be carried out according to the method described in the above literature or a method analogous thereto.

The solvent used in the reaction in each step of the following method A or B is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group, for example. Solvent groups include aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate Esters such as butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; such as acetic acid and propionic acid Rubonic acids; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, dimethylformamide, dimethyl Amides such as acetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.

The acid used in the reaction of each step of the following method A or method B is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. Acid groups include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, organic acids such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, and methane It consists of organic sulfonic acids such as sulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid.

The base used in the reaction of each step of the following method A or method B is not particularly limited as long as it does not inhibit the reaction, and is selected from the following group of bases. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; lithium metal methoxide, sodium methoxide, sodium ethoxide, alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; lithium such as lithium diisopropylamide Silalkylamides such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium; methylmagnesium chloride, methylmagnesium bromide, methyl iodide Magnesium, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide, alkylmagnesium halides such as isobutylmagnesium chloride; and triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine N-ethylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 4-pyrrolidinopyridine, 2, -Di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), It consists of organic amines such as 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU).

In the reaction of each step of the following method A or B, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.

In the reaction of each step of the following method A or B, after completion of the reaction, the target compound of each step is isolated from the reaction mixture according to a conventional method. For example, the target compound can be obtained by (i) filtering out insoluble matters such as a catalyst, if necessary, and (ii) adding water and a solvent immiscible with water (for example, methylene chloride, ethyl acetate) to the reaction mixture. The compound is extracted, (iii) the organic layer is washed with water, dried using a desiccant such as anhydrous magnesium sulfate, and (iv) the solvent is distilled off. The obtained target compound can be further purified by a conventional method (for example, recrystallization, reprecipitation, silica gel column chromatography, etc.) as necessary. In addition, the target compound in each step can be directly used in the next reaction without purification.

In each step, optical isomers can be separated by fractional recrystallization using an optically active amine such as (R)-or (S) -phenethylamine, or by separation using an optically active column.

The reaction of each step of Method A or Method B will be described below.

(Method A)
Method A is a method for producing a compound having the formula (I).
(Process A-1)
Step A-1 is a step of treating compound (1) with a dehydrating agent. Compound (1) can be produced according to the method described in Tetrahedoron Lett., 2003, Vol. 44, p. 1611, WO2007 / 077005 and the like.

The dehydrating agent to be used is not limited as long as it is used for the conversion reaction of dicarboxylic acid to acid anhydride, and preferably acid anhydride, acid halide, phosphorus halide, or alkylcarbodiimides. More preferably, it is an acid anhydride, and most preferably acetic anhydride.

The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, or an ether. Step A-1 is preferably performed without a solvent.

The reaction temperature is preferably −78 to 150 ° C., more preferably 60 to 100 ° C.

The reaction time is preferably 5 minutes to 96 hours, and more preferably 30 minutes to 24 hours.
(Process A-2)
Step A-2 is a step of reacting compound (2) with methanol in the presence of an asymmetric catalyst. This step can also be performed according to a method according to the method described in Tetrahedoron Lett., 2003, Vol. 44, p. 1611, WO2007 / 077005 and the like.

The asymmetric catalyst used is preferably an asymmetric organometallic catalyst or asymmetric organocatalyst described in Chemical Review, 2007, Vol. 107, p.5683, or Angew. Chem. Int. Ed., 2008, 47, p. 7872, more preferably (DHQ) ₂ AQN or Angew. Chem. Int. Ed., 2008, Asymmetric organic catalyst I described in Vol. 47, p.

The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, or a mixture thereof, more preferably an ether, Preference is given to diethyl ether or tetrahydrofuran.

The reaction temperature is preferably −78 to 100 ° C., more preferably −40 to 30 ° C.

The reaction time is preferably 5 minutes to 96 hours, and more preferably 30 minutes to 48 hours.

By performing step A-2 in the absence of an asymmetric catalyst, racemic compound (3) can be produced. Racemic compound (I) can be produced by performing steps A-3 to A-13 using racemic compound (3).
(Process A-3)
Process A-3
(Step A-3a): a step of treating compound (3) with an azidating reagent and then with an alcohol compound or water; and
(Step A-3b): The step comprises removing the alkoxycarbonyl group from the compound obtained in Step A-3a.

Step A-3 can be performed according to a method well known in the field of synthetic organic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc, p.867-869).
(Step A-3a)
The azidation reagent used is, for example, a combination of a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxytrichloride and sodium azide, or diphenylphosphoryl azide (DPPA) DPPA is preferred.

The alcohol compound used is preferably tert-butanol, allyl alcohol, benzyl alcohol, 2,2,2-trichloroethanol or 2-trimethylsilylethanol, more preferably allyl alcohol or benzyl alcohol. is there.

The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether or a mixture thereof, more preferably an aromatic hydrocarbon. And most preferred is toluene.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 110 ° C.

The reaction time is preferably 5 minutes to 96 hours, and more preferably. 30 minutes to 24 hours.
(Step A-3b)
The reagent, solvent, and reaction temperature used in step A-3b differ depending on the lower alcohol used in step A-3a. The step A-3b can be performed according to a method well known in the field of organic synthetic chemistry as a method for removing an alkoxycarbonyl group bonded to an amino group (for example, TW Greene, PGM Wuts, Greene's Protecive Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.).
(Process A-4)
Step A-4 is a step of reacting compound (4) with compound (5). Compound (5) is known or can be easily produced from a known compound.

The reagent used is not limited as long as it is used for the condensation reaction of amine and aldehyde. For example, p-toluenesulfonic acid, D-camphorsulfonic acid, p-toluenesulfonic acid pyridinium salt, acetic acid, trifluoro It can be an acid catalyst such as acetic acid, titanium tetraisopropoxide, a strongly acidic ion exchange resin, or a dehydrating agent such as anhydrous magnesium sulfate or molecular sieves, preferably anhydrous magnesium sulfate.

The solvent used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers or mixtures thereof, more preferably halogenated hydrocarbons. More preferably, carbon tetrachloride or methylene chloride.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 80 ° C.

The reaction time is preferably 5 minutes to 24 hours, and more preferably 15 minutes to 2 hours.
(Process A-5)
Step A-5 is a step of treating compound (6) with a halogenating reagent.

Halogenating reagents used are, for example, chlorinating reagents such as chlorine, sulfuryl chloride, tert-butyl hypochlorite, N-chlorosuccinimide; bromine, N-bromosuccinimide, N, N′-dibromo- Bromination reagent such as 3,3-dimethylhydantoin; may be an iodinating reagent such as iodine, preferably a chlorinating reagent, most preferably N-chlorosuccinimide.

The solvent used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers or mixtures thereof, more preferably halogenated hydrocarbons. More preferably, carbon tetrachloride or methylene chloride.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 40 ° C.

The reaction time is preferably 5 minutes to 24 hours, and more preferably 15 minutes to 4 hours.
(Step A-6)
In step A-6, compound (7) is converted to compound YOH [wherein Y is a lower alkyl group; a lower alkenyl group; or a (phenyl-lower alkyl) group optionally substituted with lower alkyl, lower alkoxy or halogeno]. Is a step of treating with a compound having Compounds having the formula YOH are known or can be readily prepared from known compounds.

The compound having the formula YOH used is preferably methanol, ethanol, allyl alcohol or benzyl alcohol, most preferably methanol.

The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, or an ether. Step A-6 is preferably carried out without a solvent.

The reaction temperature is preferably 0 to 150 ° C, more preferably 10 to 80 ° C.

The reaction time is preferably 30 minutes to 96 hours, more preferably 2 to 48 hours.
(Process A-7)
Process A-7
(Step A-7a): a step of removing the tert-butoxycarbonyl group in compound (8); and
(Step A-7b): The step comprises reacting the compound obtained in Step A-7a with o-nitrobenzenesulfonyl chloride in the presence of a base.
(Step A-7a)
The step A-7a can be performed according to a method well known in the field of synthetic organic chemistry as a method for removing the tert-butoxycarbonyl group bonded to the amino group (for example, TW Greene, PGM Wuts, Greene's Protecive Groups in Organic Synthesis. Fourth Edition, 2007, John Wiley & Sons, Inc.).

The reagent used is selected from the above acid group, preferably hydrochloric acid, sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, or camphorsulfonic acid, most preferably Trifluoroacetic acid.

The solvent used is preferably a halogenated hydrocarbon, and most preferably methylene chloride.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 40 ° C.

The reaction time is preferably 2 minutes to 24 hours, more preferably 5 minutes to 4 hours.
(Step A-7b)
The base used is preferably an alkali metal bicarbonate, an alkali metal hydroxide, an alkali metal alkoxide, or an organic amine, more preferably an alkali metal bicarbonate, most preferably , Sodium bicarbonate.

The solvent used is preferably a mixture of ethers and water, most preferably a mixture of 1,4-dioxane and water.

The reaction temperature is preferably −78 to 150 ° C., and more preferably −30 to 40 ° C.

The reaction time is preferably 5 minutes to 96 hours, more preferably 5 minutes to 2 hours.
(Process A-8)
Step A-8 is a step of converting an acetal group in compound (9) into a formyl group.

The reagent, solvent, and reaction temperature used vary depending on the compound having the formula YOH used in step A-6. Step A-8 can be performed according to a method well known in the field of synthetic organic chemistry as a method for converting an acetal group into a formyl group (for example, TW Greene, PGM Wuts, Greene's Protecive Groups in Organic Synthesis. Fourth Edition, 2007). , John Wiley & Sons, Inc.).
(Step A-9)
Step A-9 is a step of reacting compound (10) with compound (11) in the presence of a reducing reagent. Step A-9 can be performed according to a method well known in the field of synthetic organic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc, p. 835-846).

The reducing reagent used is not limited as long as it is used for the reductive amination reaction. For example, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, borane-dimethylamine complex, borane-pyridine complex, hydrogenation Boron hydride compounds such as sodium borohydride, sodium cyanide borohydride, tetra-n-butylammonium borohydride, sodium triacetoxyborohydride; lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride Such as an aluminum hydride compound; or may be hydrogen, preferably a borohydride compound, and most preferably sodium triacetoxyborohydride. In the step A-9, an acid such as hydrochloric acid, formic acid, acetic acid or trifluoroacetic acid (preferably acetic acid) is preferably used in combination with the reducing reagent.

The solvent used is preferably an aromatic hydrocarbon, a halogenated hydrocarbon, or a mixture thereof, and most preferably toluene, methylene chloride, or a mixture thereof.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 110 ° C.

The reaction time is preferably 5 minutes to 24 hours, and more preferably 15 minutes to 24 hours.
(Step A-10)
Step A-10 is a step of reacting compound (12) with a halogenated acetyl halide in the presence of a base.

The halogenated acetyl halide used is preferably acetyl chloride chloride, acetyl chloride bromide or acetyl bromide bromide, and most preferably acetyl bromide bromide.

The base used is preferably an alkali metal hydrogen carbonate, an alkali metal hydroxide, an alkali metal alkoxide, or an organic amine, more preferably an organic amine, most preferably triethylamine. It is.

The solvent used is preferably an aromatic hydrocarbon or a halogenated hydrocarbon, and most preferably methylene chloride.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 40 ° C.

The reaction time is preferably 5 minutes to 24 hours, and more preferably 30 minutes to 6 hours.
(Process A-11)
Step A-11 is a step of hydrolyzing compound (13) in the presence of a base. Step A-11 can also be performed according to a method well known in the field of synthetic organic chemistry (including reactions other than hydrolysis) (for example, Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc, p. .1959-1968).

The base used is preferably an alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, or alkaline earth metal hydroxide, more preferably an alkali metal hydroxide. And most preferred is sodium hydroxide.

The solvent used is preferably a mixture of alcohols and water, or a mixture of alcohols, ethers and water, more preferably a mixture of methanol and water or methanol, tetrahydrofuran and water. It is a mixture.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 80 ° C.

The reaction time is preferably 5 minutes to 24 hours, and more preferably 30 minutes to 4 hours.
(Process A-12)
Step A-12 is a step of reacting compound (14) with compound (15) in the presence of a condensing reagent and a base. Compound (15) is known or can be easily produced from a known compound. Step A-12 can be performed according to a method well known in the field of synthetic organic chemistry (for example, Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc, p. 1941-1949).

The condensation reagent used is preferably dicyclohexylcarbodiimide (DCC), N- (3-diethylaminopropyl) -N′-ethylcarbodiimide (WSC), diphenylphosphoryl azide (DPPA), diethyl cyanophosphate (DEPC), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), more preferably HBTU or HATU. In the step A-12, additives such as 1-hydroxybenzotriazole (HOBt) and 2-hydroxysuccinimide can be used in combination with the above reducing reagent.

The base used is preferably an organic amine, more preferably triethylamine or N, N-diisopropylethylamine.

The solvent used is preferably an amide, and most preferably N, N-dimethylformamide.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 40 ° C.

The reaction time is preferably 5 minutes to 48 hours, and more preferably 30 minutes to 12 hours.
(Process A-13)
Step A-13 is a step of removing the o-nitrobenzenesulfonyl group in compound (16) in the presence of a base.

Examples of the reagent used include methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, n-butylamine, pyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, hydrazine, and N, N-dimethylhydrazine. Primary or secondary amines; or thiols such as methanethiol, ethanethiol, n-propanethiol, n-butanethiol, n-dodecathiol, thiophenol, thioglycolic acid, preferably thiol Most preferred is thiophenol.

The base used is preferably an alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal hydride, alkali metal amide, alkali metal alkoxide, lithium alkylamide, silylamide, alkyllithium, or An organic amine, more preferably an alkali metal carbonate, and most preferably cesium carbonate.

The solvent used is preferably a nitrile or amide, and more preferably acetonitrile or N, N-dimethylformamide.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 40 ° C.

The reaction time is preferably 5 minutes to 48 hours, and more preferably 15 minutes to 12 hours.

(Method B)
Method B is a method for producing a compound having the formula (I).
(Process B-1)
Process B-1
(Step B-1a): a step of removing the o-nitrobenzenesulfonyl group in the compound (13) obtained in Step A-10; and
(Step B-1b): The step comprises reacting the compound obtained in Step B-1a with di-tert-butyl-dicarbonate in the presence of a base.
(Process B-1a)
The step B-1a can be performed according to the same method as the step A-13.
(Process B-1b)
The base used is preferably an alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal hydride, alkali metal amide, alkali metal alkoxide, or organic amine, and more preferably. Is an alkali metal bicarbonate, most preferably sodium bicarbonate.

The solvent used is preferably a mixture of esters and water, most preferably a mixture of ethyl acetate and water.

The reaction temperature is preferably −78 to 150 ° C., and more preferably 0 to 60 ° C.

The reaction time is preferably 5 minutes to 48 hours, and more preferably 15 minutes to 4 hours.

The amino protecting group used in the step B-1b is not limited to the tert-butoxycarbonyl group as long as it is well known in the field of synthetic organic chemistry (for example, TW Greene, PGM Wuts, Greene's Protecive Groups in Organic Synthesis). Fourth Edition, 2007, John Wiley & Sons, Inc.). Examples of the amino-protecting group used include acyl groups such as formyl group, acetyl group, chloroacetyl group, pivaloyl group and benzoyl group; methoxycarbonyl group, ethoxycarbonyl group, allyloxycarbonyl group, 2,2, Alkoxycarbonyl groups such as 2-trichloroethoxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group; methoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, benzyloxymethyl group Substituted alkyl groups such as pivaloyloxymethyl group, allyl group, benzyl group, diphenylmethyl group, triphenylmethyl group; methanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, o-nitrobenzenesulfonyl group, o , p- It is a sulfonyl group such as nitrobenzene sulfonyl group, and most preferably a tert- butoxycarbonyl group.
(Process B-2)
Step B-2 is a step of hydrolyzing compound (17) in the presence of a base.

Step B-2 can be performed according to the same method as Step A-11.
(Process B-3)
Step B-3 is a step of reacting compound (18) with compound (15) in the presence of a condensing reagent and a base. Compound (15) is known or can be easily produced from a known compound.

Step B-3 can be performed according to the same method as in Step A-12.
(Process B-4)
Step B-4 is a step of removing the tert-butoxycarbonyl group in compound (19).

The step B-4 can be performed according to the same method as the step A-7a.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be administered as it is (as it is) or as an appropriate drug. Physiologically acceptable, mixed with excipients, diluents, etc., orally as a tablet, capsule, granule, powder or syrup preparation, or as an injection or suppository preparation It can be administered parenterally (preferably orally).

These preparations are produced by known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, and the like. .

The excipient may be, for example, an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low substitution Degrees of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; or pullulan. The inorganic excipient can be, for example, light anhydrous silicic acid, synthetic aluminum silicate, a silicate derivative such as calcium silicate; a phosphate such as calcium phosphate; or a sulfate such as calcium sulfate.

The binder can be, for example, the above excipients; gelatin; polyvinyl pyrrolidone; or polyethylene glycol.

The disintegrant can be, for example, the excipients described above; chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch; or cross-linked polyvinyl pyrrolidone.

Lubricants include, for example, talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beeswax and gallows; boric acid; glycol; D, L-leucine; Acids, carboxylic acids such as adipic acid; carboxylic acid sodium salts such as sodium benzoate; sulfates such as sodium sulfate; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride, silicic acid hydrate Or starch derivatives in the above excipients.

The emulsifier may be, for example, a colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate or calcium stearate; a cationic surfactant such as benzalkonium chloride; or a polyoxyethylene alkyl ether And non-ionic surfactants such as polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester.

Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; or sorbic acid.

The flavoring agent can be, for example, a commonly used sweetener, acidulant, or fragrance.

The diluent may be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters.

The solvent for injection can be, for example, water, ethanol, or glycerin.

The dose of the compound having the general formula (I) which is the active ingredient of the present invention or a pharmacologically acceptable salt thereof varies depending on the symptom, age, etc. of the patient. 0.02 mg / kg (preferably 0.1 mg / kg), upper limit 100 mg / kg (preferably 10 mg / kg), and lower limit 0.002 mg / kg per administration for parenteral administration ( Preferably, 0.01 mg / kg) and an upper limit of 10 mg / kg (preferably 1 mg / kg) can be administered to adults 1 to 6 times per day, depending on the symptoms.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has renin inhibitory activity, solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue transferability, and bioavailability. -Has excellent properties in terms of in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained drug efficacy, physical stability, drug interaction, and safety (eg, cardiotoxicity or hepatotoxicity). It is useful as a medicine [particularly, a medicine for the treatment or prevention (preferably treatment) of hypertension].

EXAMPLES Hereinafter, although an Example, a test example, and a formulation example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these. In the following examples, the compound names described indicate the compounds obtained in the examples, and the chemical structural formulas described indicate the chemical structures of the corresponding free compounds. For example, the compound obtained in Example 1 is (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R ) -1-ethyl-3-methylbutyl] piperidine-3-carboxamide fumarate, the chemical structural formula described in Example 1 is (3S, 5R) -5- [4- (2-chlorophenyl) 2 shows the chemical structure of -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-ethyl-3-methylbutyl] piperidine-3-carboxamide.
In the following reference examples, the compound names and chemical structural formulas described indicate the compounds obtained in the reference examples.

Example 1
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-ethyl-3-methylbutyl] piperidine- 3-Carboxamide fumarate

(1a) 1-tert-butyl 3-methyl (3S, 5R) -5-{[(benzyloxy) carbonyl] carbamoyl} piperidine-1,3-dicarboxylate obtained in Reference Example 1 (3R, 5S) A solution of 19.35 g (67.35 mmol) of 1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid in toluene (335 ml) at room temperature at 11.26 ml (80. 82 mmol) and 20.38 g (74.08 mmol) of diphenylphosphoric acid azide (DPPA) were added and stirred at 90 ° C. for 1.5 hours. After cooling for 15 minutes, a toluene (10 ml) solution of 10.92 g (101.02 mmol) of benzyl alcohol was added to the reaction mixture, followed by stirring at 90 ° C. for 3.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1) to give 25.50 g (yield: 96%) of the title compound. )
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37-7.26 (m, 5H), 5.11 (br s, 3H), 4.06-4.03 (m, 2H), 3.70-3.63 (m, 5H), 3.09- 3.05 (m, 1H), 2.60 (br s, 1H), 2.31-2.27 (m, 1H), 1.61-1.56 (m, 1H), 1.45 (s, 9H).
(1b) 1-tert-butyl 3-methyl (3S, 5R) -5-aminopiperidine-1,3-dicarboxylate 1-tert-butyl 3-methyl (3S, 5R) obtained in Example (1a) ) -5-{[(Benzyloxy) carbonyl] carbamoyl} piperidine-1,3-dicarboxylate 25.50 g (64.97 mmol) and 10% palladium carbon (50% water content) 2.50 g of methanol (100 ml) Was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/1) to obtain 15.98 g (yield: 95%) of the title compound.
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 4.34-4.16 (m, 2H), 3.70 (s, 3H), 2.77-2.50 (m, 3H), 2.30-2.25 (m, 2H), 1.46 (s , 9H), 1.35-1.28 (m, 1H), 1.15 (br s, 2H).
(1c) 1-tert-butyl 3-methyl (3S, 5R) -5-[(2,2-dimethoxy-1,1-dimethylethyl) amino] piperidine-1,3-dicarboxylate Example (1b) Of 15.98 g (61.86 mmol) of 1-tert-butyl 3-methyl (3S, 5R) -5-aminopiperidine-1,3-dicarboxylate obtained in the above and 4.46 ml (61.86 mmol) of isobutyraldehyde. About 8 g of anhydrous magnesium sulfate was added to a methylene chloride (120 ml) solution, and the mixture was stirred at room temperature for 3 hours. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Carbon tetrachloride (240 ml) was added to the reaction mixture thus obtained for dissolution, 8.26 g (61.86 mmol) of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 16 hours. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Methanol (120 ml) was added to the reaction mixture thus obtained to dissolve it, and the mixture was stirred at 60 ° C. for 23 hours. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1 to 0/1) to give 17.89 g (yield) of the title compound. Rate: 88%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 4.33-4.06 (m, 2H), 3.90 (s, 1H), 3.68 (s, 3H), 3.53 (s, 6H), 2.66-2.54 (m, 3H ), 2.28 (br s, 1H), 2.15 (br d, 1H, J = 12.7 Hz), 1.46 (s, 9H), 1.35 (q, 1H, J = 12.2 Hz), 1.06 (s, 6H).
(1d) Methyl (3S, 5R) -5-[(2,2-dimethoxy-1,1-dimethylethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylate Examples 1-tert-butyl 3-methyl (3S, 5R) -5-[(2,2-dimethoxy-1,1-dimethylethyl) amino] piperidine-1,3-dicarboxylate obtained in 1c) To 89 g (54.48 mmol), 272 ml (1.09 mol) of 4N hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved by adding dioxane (140 ml) and water (140 ml). Under ice-cooling, sodium bicarbonate 13.72 g (163.4 mmol) and o-nitrobenzenesulfonyl chloride were added. 14.48 g (65.37 mmol) was added, and after stirring at the same temperature for 10 minutes, 4.57 g (54.50 mmol) of sodium hydrogen carbonate was added, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2 to 0/1) to give the title compound 17 0.71 g (yield: 70%) was obtained.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.01-8.00 (m, 1H), 7.72-7.62 (m, 3H), 4.02 (br d, 1H, J = 8.3 Hz), 3.90 (s, 1H) , 3.89-3.85 (m, 1H), 3.69 (s, 3H), 3.53 (s, 3H), 3.52 (s, 3H), 2.90-2.83 (m, 1H), 2.79-2.69 (m, 2H), 2.32 -2.28 (m, 1H), 2.22 (br d, 1H, J = 13.2 Hz), 1.30-1.23 (m, 1H), 1.06 (s, 6H).
(1e) Methyl (3S, 5R) -5-[(1,1-dimethyl-2-oxoethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylate In Example (1d) 17.71 g of methyl (3S, 5R) -5-[(2,2-dimethoxy-1,1-dimethylethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylate obtained 60 ml of concentrated hydrochloric acid was added to a solution of (38.54 mmol) in methylene chloride (60 ml), and the mixture was stirred at 40 ° C. for 4 hours. The reaction mixture was neutralized by adding a 5N aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution under ice cooling, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. On the other hand, the aqueous layer was subjected to reverse-layer silica gel column chromatography (reverse-layer silica gel: Cosmosil 75C _18- PREP, manufactured by Nacalai Tesque, water / acetonitrile = 1/0 to 0/1) to remove the inorganic substance, 3S, 5R) -5-[(1,1-dimethyl-2-oxoethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid was obtained. In a mixture of methanol (40 ml) and thionyl chloride 11.0 ml (151 mmol), the reaction mixture obtained from the organic layer and the crude (3S, 5R) -5-[(1,1-dimethyl) obtained from the aqueous layer. A solution of -2-oxoethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid in methanol (100 ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2 to 0/1) to give the title compound 13 .70 g (yield: 86%) was obtained.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 9.44 (s, 1H), 8.01-7.99 (m, 1H), 7.74-7.69 (m, 2H), 7.66-7.63 (m, 1H), 4.01-3.98 (m, 1H), 3.83-3.80 (m, 1H), 3.69 (s, 3H), 2.79-2.64 (m, 3H), 2.38 (dd, 1H, J = 12.7 Hz, 10.7 Hz), 2.28 (br d , 1H, J = 12.7 Hz), 1.32 (q, 1H, J = 12.2 Hz), 1.24 (s, 3H), 1.18 (s, 3H).
(1f) Methyl (3S, 5R) -5-({2-[(2-chlorophenyl) amino] -1,1-dimethylethyl} amino) -1-[(2-nitrophenyl) sulfonyl] piperidine-3- Carboxylate Methyl (3S, 5R) -5-[(1,1-dimethyl-2-oxoethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine-3- obtained in Example (1e) To a solution of 17.10 g (41.36 mmol) of carboxylate and 7.87 g (61.7 mmol) of 2-chloroaniline in toluene (400 ml) was added 8.67 g (144 mmol) of acetic acid, and the resulting water was heated under reflux. The mixture was stirred for 4 hours while removing. After cooling, 17.50 g (82.6 mmol) of sodium triacetoxyborohydride was added to the reaction mixture under ice cooling, and then stirred at room temperature for 16 hours. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1-7 / 3) to give 16.00 g (yield) of the title compound. Rate: 74%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.74 (d, 1H, J = 8.3 Hz), 7.64-7.58 (m, 2H), 7.52-7.48 (m, 1H), 7.25-7.23 (m, 1H ), 7.17-7.14 (m, 1H), 6.65-6.62 (m, 2H), 4.85 (br s, 1H), 4.07 (br d, 1H, J = 9.3 Hz), 3.75-3.71 (m, 1H), 3.69 (s, 3H), 2.97 (d, 1H, J = 11.7 Hz), 2.94 (d, 1H, J = 11.7 Hz), 2.81-2.69 (m, 3H), 2.34 (dd, 1H, J = 12.5 Hz , 10.5 Hz), 2.21 (br d, 1H, J = 12.5 Hz), 1.32 (q, 1H, J = 12.2 Hz), 1.22 (s, 3H), 1.21 (s, 3H).
(1 g) Methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine- 3-Carboxylate Methyl (3S, 5R) -5-({2-[(2-chlorophenyl) amino] -1,1-dimethylethyl} amino) -1-[(2 -Nitrophenyl) sulfonyl] piperidine-3-carboxylate in a solution of 16.00 g (30.5 mmol) and 24.8 g (245.1 mmol) of triethylamine in methylene chloride (320 ml) under ice cooling with 24. A solution of 4 g (120.9 mmol) of methylene chloride (80 ml) was added over 2.5 hours, stirred at room temperature for 45 minutes, and further at 40 ° C. Stir for 3 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7/3 to 0/1) to give 13.50 g (yield) of the title compound. Rate: 79%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.03-8.01 (m, 1H), 7.76-7.70 (m, 2H), 7.67-7.65 (m, 1H), 7.48-7.46 (m, 1H), 7.33 -7.23 (m, 3H), 4.03 (br d, 1H, J = 11.2 Hz), 3.87-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.22 (m, 5H), 2.76-2.68 ( m, 3H), 2.24-2.17 (m, 1H), 1.73-1.66 (m, 1H), 1.41-1.35 (m, 6H).
(1h) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3 -Carboxylic acid Methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -1-[( To a solution of 2-nitrophenyl) sulfonyl] piperidine-3-carboxylate in 195 mg (0.35 mmol) in methanol (4 ml) under ice cooling was added 2.0 ml (2.0 mmol) of 1N aqueous sodium hydroxide solution, The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was acidified with 1N hydrochloric acid (pH 2-3), extracted with methylene chloride, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 190 mg (yield: quantitative) of the crude title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.02-8.01 (m, 1H), 7.75-7.70 (m, 2H), 7.67-7.65 (m, 1H), 7.48 (dd, 1H, J = 7.3 Hz , 1.5 Hz), 7.36-7.22 (m, 3H), 4.01-3.94 (m, 1H), 3.87-3.80 (m, 1H), 3.72 (br d, 1H, J = 17.6 Hz), 3.63 (br d, 1H, J = 17.6 Hz), 3.48-3.41 (m, 1H), 3.29-3.23 (m, 2H), 2.77-2.70 (m, 3H), 2.26-2.20 (m, 1H), 1.71-1.58 (m, 1H), 1.41-1.35 (m, 6H).
(1i) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-ethyl-3-methylbutyl ] -1-[(2-Nitrophenyl) sulfonyl] piperidine-3-carboxamide (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl obtained in Example (1h) -5-Oxopiperazin-1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid 200 mg (0.36 mmol), (3R) -5-methylhexane obtained in Reference Example 2 A solution of 66 mg (0.44 mmol) of 3-amine hydrochloride and 140 mg (1.08 mmol) of diisopropylethylamine in N, N-dimethylformamide (3 ml) at room temperature ,, O-(benzotriazol-1-yl) -N, N N ', N'- tetramethyluronium hexafluorophosphate (HBTU) 207mg (0.55mmol) was added, and the mixture was stirred for 12 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1 to 0/1) to give 210 mg (yield: 89%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.97-7.96 (m, 1H), 7.75-7.70 (m, 2H), 7.68-7.63 (m, 1H), 7.46 (br d, 1H, J = 7.8 Hz), 7.32-7.22 (m, 3H), 5.27 (br d, 1H, J = 9.3 Hz), 3.96-3.87 (m, 3H), 3.75-3.47 (m, 2H), 3.37-2.99 (m, 3H ), 2.81-2.71 (m, 1H), 2.65-2.50 (m, 1H), 1.98-1.88 (m, 2H), 1.61-1.47 (m, 4H), 1.41-1.29 (m, 7H), 0.92-0.83 (m, 9H).
(1j) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-ethyl-3-methylbutyl ] Piperidine-3-carboxamide fumarate (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl obtained in Example (1i) ] -N-[(1R) -1-ethyl-3-methylbutyl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxamide 205 mg (0.31 mmol) and thiophenol 48 μl (0.47 mmol) Was added at room temperature to 124 mg (0.38 mmol) of cesium carbonate, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, extracted with methylene chloride, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to NH silica gel column chromatography (elution solvent: ethyl acetate / methanol = 0/1 to 4/1) and silica gel column chromatography (elution solvent: methylene chloride / methanol). = 3/3) to give (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R)- 126 mg (yield: 86%) of 1-ethyl-3-methylbutyl] piperidine-3-carboxamide were obtained. The (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-ethyl-3 obtained here To a solution of (methylbutyl) piperidine-3-carboxamide 126 mg (0.27 mmol) in methanol (1 ml) was added 31 mg (0.27 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in an appropriate amount of methylene chloride, an excess amount of diisopropyl ether is added, and the precipitated solid is collected by filtration to obtain 87 mg of the title compound (yield: 55%). It was.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.85 (br d, 1H, J = 9.8 Hz), 7.53 (dd, 1H, J = 7.3 Hz, 1.5 Hz), 7.42-7.36 (m, 2H) , 7.33-7.31 (m, 1H), 6.70 (s, 2H), 3.87-3.83 (m, 1H), 3.67-3.44 (m, 4H), 3.38-3.23 (m, 3H), 3.11-3.05 (m, 1H), 2.99 (t, 1H, J = 12.5 Hz), 2.85-2.79 (m, 1H), 2.13-2.06 (m, 1H), 2.00-1.91 (m, 1H), 1.65-1.50 (m, 2H) , 1.41-1.25 (m, 9H), 0.94-0.88 (m, 9H).
Mass spectrum (FAB ⁺ ), m / z: 463 ((M + H) ⁺ ).

(Example 2)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- (1-isobutylcyclopentyl) piperidine-3-carboxamide fumarate

Similar to Examples (1i) and (1j), (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine-- obtained in Example (1h) Using 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid and 1-isobutylcyclopentan-1-amine hydrochloride obtained in Reference Example 3, 77 mg (3 Total yield of process: 56%) was obtained.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.72 (br s, 1H), 7.53 (dd, 1H, J = 7.3 Hz, 2.0 Hz), 7.42-7.36 (m, 2H), 7.33-7.30 ( m, 1H), 6.70 (s, 2H), 3.67-3.44 (m, 4H), 3.37-3.23 (m, 3H), 3.08-3.03 (m, 1H), 2.94 (t, 1H, J = 12.5 Hz) , 2.85-2.78 (m, 1H), 2.09-2.04 (m, 3H), 1.96-1.88 (m, 1H), 1.77-1.53 (m, 9H), 1.40-1.36 (m, 6H), 0.94 (d, 6H, J = 6.8 Hz).
Mass spectrum (FAB ⁺ ), m / z: 489 ((M + H) ⁺ ).

(Example 3)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- (3,3,3-trifluoro-1,1-dimethyl Propyl) piperidine-3-carboxamide fumarate

Similar to Examples (1i) and (1j), (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine-- obtained in Example (1h) 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid and 4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride obtained in Reference Example 4 were used. Thus, 133 mg of the title compound was obtained (total yield of 3 steps: 53%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.98 (br s, 1H), 7.53 (dd, 1H, J = 7.3 Hz, 2.0 Hz), 7.42-7.36 (m, 2H), 7.33-7.30 ( m, 1H), 6.70 (s, 2H), 3.67-3.45 (m, 4H), 3.36-3.22 (m, 3H), 3.08-3.03 (m, 1H), 2.93 (t, 1H, J = 12.5 Hz) , 2.87-2.72 (m, 3H), 2.12-2.05 (m, 1H), 1.94-1.85 (m, 1H), 1.43 (br s, 6H), 1.41-1.36 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 489 ((M + H) ⁺ ).

Example 4
N ² -({(3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidin-3-yl} carbonyl) -N, N- Dimethyl-L-leucinamide fumarate

Similar to Examples (1i) and (1j), (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine-- obtained in Example (1h) Using 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid and the N, N-dimethyl-L-leucinamide hydrochloride obtained in Reference Example 5, 41 mg of the title compound ( (3 step total yield: 49%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.55-7.52 (m, 1H), 7.43-7.36 (m, 2H), 7.33-7.31 (m, 1H), 6.75 (s, 2H), 4.87- 4.83 (m, 1H), 3.70-3.45 (m, 4H), 3.40-3.22 (m, 3H), 3.15-3.07 (m, 4H), 3.00-2.84 (m, 5H), 2.18-2.10 (m, 1H ), 2.00-1.91 (m, 1H), 1.72-1.58 (m, 2H), 1.51-1.38 (m, 7H), 1.10-0.97 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 506 ((M + H) ⁺ ).

(Example 5)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl ] Piperidine-3-carboxamide fumarate

(5a) 1-tert-butyl 3-methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-1,3-di Carboxylate Methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -1-[(2 -Nitrophenyl) sulfonyl] piperidine-3-carboxylate (13.50 g, 23.9 mmol) and thiophenol (3.64 ml, 35.7 mmol) in a solution of acetonitrile (400 ml) under ice cooling, 9.31 g of cesium carbonate (28.6 mmol) was added, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give methyl (3S, 5R) -5- 9.1 g (yield: quantitative) of [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylate was obtained. Methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylate 9.1 g (23. 9 mmol) and sodium bicarbonate 6.20 g (73.8 mmol) in a mixture of ethyl acetate (200 ml) and water (200 ml) were added di-tert-butyl dicarbonate (6.00 g, 27.5 mmol) at room temperature. And stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 1/9) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 1/0 to 1/1) to obtain 7.80 g (yield: 68%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.47 (dd, 1H, J = 7.3 Hz, 1.5 Hz), 7.34-7.22 (m, 3H), 4.29 (br s, 1H), 4.12 (br s, 1H), 3.74-3.52 (m, 5H), 3.36-3.29 (m, 2H), 3.02-2.98 (m, 1H), 2.68-2.56 (m, 3H), 2.14 (br s, 1H), 1.84-1.73 (m, 1H), 1.48 (s, 9H), 1.44-1.31 (m, 6H).
(5b) (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 1-tert-butyl 3-methyl (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine obtained in Example (5a) To a mixture of 7.80 g (16.3 mmol) of 1,3-dicarboxylate in tetrahydrofuran (150 ml) and water (75 ml), 1.37 g (32.6 mmol) of lithium hydroxide monohydrate was added under ice cooling. ) And stirred at the same temperature for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid (pH 2-3), extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 7.70 g (yield: quantitative) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.47 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.34-7.25 (m, 3H), 4.30 (br s, 1H), 4.12 (br s, 1H), 3.76 (br d, 1H, J = 17.6 Hz), 3.66 (br d, 1H, J = 17.6 Hz), 3.38-3.29 (m, 2H), 3.03-2.99 (m, 1H), 2.69-2.56 (m, 3H), 2.22-2.15 (m, 1H), 1.81-1.69 (m, 1H), 1.47 (s, 9H), 1.43-1.32 (m, 6H).
(5c) tert-Butyl (3R, 5S) -3- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1- ( (Ethoxymethyl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) obtained in Example (5b) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid, 148 mg (0.32 mmol), (2R) -1-ethoxy-4-methylpentane-2 obtained in Reference Example 6 -A solution of 92 mg (0.63 mmol) of amine and 166 μl (0.95 mmol) of diisopropylethylamine in N, N-dimethylformamide (3 ml) Below, 180 mg (0.48 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) was added, and 18 hours at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n Purification by hexane / ethyl acetate = 3/1 to 1/1 to 0/1) gave 137 mg (yield: 73%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.48-7.46 (m, 1H), 7.33-7.22 (m, 3H), 5.64 (br d, 1H, J = 4.9 Hz), 4.22-4.10 (m, 2H), 3.77-3.70 (m, 1H), 3.62-3.31 (m, 8H), 2.98 (br s, 1H), 2.74-2.68 (m, 2H), 2.34 (br s, 1H), 1.99-1.91 ( m, 2H), 1.58 (br s, 1H), 1.48 (s, 9H), 1.46-1.31 (m, 8H), 1.20 (t, 3H, J = 6.8 Hz), 0.93-0.91 (m, 6H).
(5d) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl)- 3-Methylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3S, 5R) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5- obtained in Example (5c) Oxopiperazin-1-yl] -5-{[(1R) -1- (ethoxymethyl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate 135 mg (0.23 mmol) in methylene chloride (0.7 ml) To the mixture, 0.35 ml (4.5 mmol) of trifluoroacetic acid was added and stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl] piperidine-3-carboxamide 94 mg (yield: 84%) was obtained. The obtained (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) ) -3-Methylbutyl] piperidine-3-carboxamide 94 mg (0.19 mmol) in methanol (1 ml) was added with fumaric acid 22 mg (0.19 mmol), and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 97 mg of the title compound (yield: 84%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.54-7.52 (m, 1H), 7.43-7.32 (m, 3H), 6.69 (s, 2H), 4.12-4.08 (m, 1H), 3.69- 2.94 (m, 13H), 2.84-2.78 (m, 1H), 2.16-2.10 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.58 (m, 1H), 1.54-1.32 (m, 8H ), 1.17 (t, 3H, J = 7.0 Hz), 0.95-0.90 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 493 ((M + H) ⁺ ).

(Example 6)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- [1- (4,4-difluorocyclohexyl) -1-methyl Ethyl] piperidine-3-carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid and 2- (4,4-difluorocyclohexyl) propan-2-amine obtained in Reference Example 7 were used to give 106 mg (3 The total process yield was 53%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.62 (br s, 1H), 7.53 (dd, 1H, J = 7.8 Hz, 2.0 Hz), 7.42-7.36 (m, 2H), 7.33-7.30 ( m, 1H), 6.69 (s, 2H), 3.70-3.44 (m, 4H), 3.38-3.21 (m, 3H), 3.07-3.02 (m, 1H), 2.92 (t, 1H, J = 12.5 Hz) , 2.81-2.75 (m, 1H), 2.22-2.05 (m, 4H), 1.95-1.87 (m, 1H), 1.77-1.65 (m, 4H), 1.41-1.29 (m, 14H).
Mass spectrum (FAB ⁺ ), m / z: 525 ((M + H) ⁺ ).

(Example 7)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- [1-methyl-1- (tetrahydro-2H-pyran-4) -Yl) ethyl] piperidine-3-carboxamide fumarate

Similar to Examples (1i) and (1j), (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine-- obtained in Example (1h) Using 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid and 2- (tetrahydro-2H-pyran-4-yl) propan-2-amine obtained in Reference Example 8 This gave 67 mg of the title compound (total yield over 3 steps: 30%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.58 (br s, 1H), 7.54-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.33-7.30 (m, 1H), 6.70 (s, 2H), 4.00-3.97 (m, 2H), 3.70-3.21 (m, 9H), 3.07-3.01 (m, 1H), 2.92 (t, 1H, J = 12.1 Hz), 2.83-2.77 (m , 1H), 2.31-2.28 (m, 1H), 2.12-2.05 (m, 1H), 1.95-1.86 (m, 1H), 1.56-1.52 (m, 2H), 1.46-1.28 (m, 15H).
Mass spectrum (FAB ⁺ ), m / z: 491 ((M + H) ⁺ ).

(Example 8)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- (1-methyl-1-phenylethyl) piperidine-3-carboxy Amide fumarate

Similar to Examples (1i) and (1j), (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine-- obtained in Example (1h) Using 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylic acid and 2-phenylpropan-2-amine, 123 mg of the title compound was obtained (total yield over three steps: 57%). It was.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.36 (br s, 1H), 7.53 (br d, 1H, J = 7.3 Hz), 7.42-7.36 (m, 4H), 7.33-7.28 (m, 3H), 7.18 (br t, 1H, J = 7.3 Hz), 6.71 (s, 2H), 3.66-3.45 (m, 4H), 3.40-3.22 (m, 3H), 3.06-3.00 (m, 1H), 2.93-2.83 (m, 2H), 2.20-2.14 (m, 1H), 1.93-1.84 (m, 1H), 1.66-1.65 (m, 6H), 1.44-1.38 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 483 ((M + H) ⁺ ).

Example 9
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N- (1-phenylcyclopentyl) piperidine-3-carboxamide fumarate

Similar to Examples (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) Using 2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid and 1-phenylcyclopentan-1-amine hydrochloride obtained in Reference Example 9, 97 mg of the title compound (total of 3 steps) Rate: 48%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.36 (br s, 1H), 7.53 (br d, 1H, J = 7.3 Hz), 7.42-7.36 (m, 4H), 7.33-7.27 (m, 3H), 7.18 (br t, 1H, J = 7.3 Hz), 6.72 (s, 2H), 3.67-3.45 (m, 4H), 3.40-3.21 (m, 3H), 3.07-3.01 (m, 1H), 2.89-2.85 (m, 2H), 2.36-2.31 (m, 2H), 2.16-2.05 (m, 3H), 1.90-1.81 (m, 5H), 1.43-1.37 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 509 ((M + H) ⁺ ).

(Example 10)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine-3-carboxy Amido fumarate

(10a) tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1-phenylpropi [Lu] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2,2-dimethyl obtained in Example (5b) -5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid 357 mg (0.77 mmol), (1R) -1-phenylpropan-1-amine 207 mg (1.53 mmol) and diisopropylethylamine 0.40 ml (2. 30 mmol) in N, N-dimethylformamide (4 ml) under ice-cooling, O- (benzotriazol-1-yl ) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HBTU) 435mg (1.15mmol) was added and stirred for 20 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and reverse layer preparative high performance liquid chromatography (elution solvent). : Acetonitrile / 0.1% aqueous ammonium acetate solution = 7/3) to obtain 246 mg (yield: 55%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.46 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.37-7.22 (m, 8H), 5.80 (br s, 1H), 4.88 (br q, 1H, J = 7.5 Hz), 4.26-4.00 (m, 2H), 3.74-3.50 (m, 2H), 3.34-3.29 (m, 2H), 2.95 (br s, 1H), 2.78-2.70 (m, 2H ), 2.34 (br s, 1H), 1.93-1.78 (m, 4H), 1.48 (s, 9H), 1.39-1.27 (m, 6H), 0.89 (t, 3H, J = 7.6 Hz).
(10b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine- 3-Carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl obtained in Example (10a) ] -5-{[(1R) -1-phenylpropyl] carbamoyl} piperidine-1-carboxylate 362 mg (0.62 mmol) in methylene chloride (2 ml) was added 1.0 ml (13.0 mmol) of trifluoroacetic acid. The mixture was further stirred at room temperature for 30 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl) piperidine-3-carboxamide 213 mg (Yield: 71 %). The obtained (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl) To a solution of piperidine-3-carboxamide (213 mg, 0.44 mmol) in methanol (2 ml) was added 51.2 mg (0.44 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 252 mg (yield: 96%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.53-7.51 (m, 1H), 7.41-7.21 (m, 8H), 6.70 (s, 2H), 4.73 (br t, 1H, J = 7.3 Hz ), 3.63-3.42 (m, 4H), 3.39-3.20 (m, 3H), 3.06-3.01 (m, 1H), 2.96 (br t, 1H, J = 12.2 Hz), 2.90-2.85 (m, 1H) , 2.08-2.02 (m, 1H), 1.89-1.77 (m, 3H), 1.39-1.35 (m, 6H), 0.92 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 483 ((M + H) ⁺ ).

(Example 11)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -2-cyclopropyl-1-phenylethyl] Piperidine-3-carboxamide fumarate

(11a) tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -2-cyclo Propyl-1-phenylethyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl)-obtained in Example (5b) 2,2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid 200 mg (0.43 mmol), (1R) -2-cyclopropyl-1-phenylethane-1 obtained in Reference Example 10 -Amine hydrochloride 169 mg (0.86 mmol) and diisopropylethylamine 221 mg (1.72 mmol) N, N-dimethylformamide ( 5 ml) 244 mg (0.65 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) was added to the solution under ice cooling. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 1/1 to 0/1) to obtain 150 mg (yield: 57%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.45 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.36-7.22 (m, 8H), 5.94 (br s, 1H), 5.08-5.04 (m , 1H), 4.26-4.00 (m, 2H), 3.73-3.50 (m, 2H), 3.34-3.29 (m, 2H), 2.95 (br s, 1H), 2.76-2.69 (m, 2H), 2.35 ( br s, 1H), 1.93-1.60 (m, 4H), 1.48-1.27 (m, 15H), 0.59-0.55 (m, 1H), 0.48-0.38 (m, 2H), 0.16-0.11 (m, 1H) , 0.05-0.01 (m, 1H).
(11b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -2-cyclopropyl-1- Phenylethyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxo obtained in Example (11a) Piperazine-1-yl] -5-{[(1R) -2-cyclopropyl-1-phenylethyl] carbamoyl} piperidine-1-carboxylate 150 mg (0.25 mmol) in methylene chloride (2 ml) was added to trifluoro Acetic acid 1.2 ml (15.6 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. -[4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -2-cyclopropyl-1-phenylethyl] piperidine-3-carboxamide 108 mg (Yield: 86%) was obtained. The obtained (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -2-cyclopropyl- To a solution of 1-phenylethyl] piperidine-3-carboxamide 108 mg (0.21 mmol) in methanol (1 ml) was added 24.7 mg (0.21 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, excess ether was added, and the precipitated solid was collected by filtration to obtain 108 mg of the title compound (yield: 81%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.53-7.51 (m, 1H), 7.41-7.23 (m, 8H), 6.71 (s, 2H), 4.94 (br t, 1H, J = 7.6 Hz ), 3.63-3.20 (m, 7H), 3.08-3.03 (m, 1H), 2.98 (br t, 1H, J = 12.5 Hz), 2.91-2.86 (m, 1H), 2.10-2.03 (m, 1H) , 1.90-1.81 (m, 1H), 1.74-1.65 (m, 2H), 1.39-1.35 (m, 6H), 0.69-0.61 (m, 1H), 0.49-0.36 (m, 2H), 0.17-0.13 ( m, 1H), 0.05-0.01 (m, 1H).
Mass spectrum (FAB ⁺ ), m / z: 509 ((M + H) ⁺ ).

(Example 12)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenylbutyl] piperidine -3-Carboxamide fumarate

(12a) tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -3-methyl -1-phenylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2 obtained in Example (5b) , 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid 150 mg (0.32 mmol), (1R) -3-methyl-1-phenylbutan-1-amine obtained in Reference Example 11 To a solution of 128 mg (0.64 mmol) of hydrochloride and 166 mg (1.29 mmol) of diisopropylethylamine in N, N-dimethylformamide (4 ml), Under ice cooling, 183 mg (0.48 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) was added, and at room temperature. Stir for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) to give 146 mg (yield: 74%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.45 (br d, 1H, J = 7.8 Hz), 7.35-7.23 (m, 8H), 5.92 (br s, 1H), 4.99-4.96 (m, 1H ), 4.20-3.96 (m, 2H), 3.67-3.48 (m, 2H), 3.31-3.25 (m, 2H), 2.93-2.66 (m, 3H), 2.34 (br s, 1H), 1.88-1.26 ( m, 20H), 0.94-0.90 (m, 6H).
(12b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenyl [Butyl] piperidine-3-carboxamide fumarate tert-Butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine obtained in Example (12a) 1-yl] -5-{[(1R) -3-methyl-1-phenylbutyl] carbamoyl} piperidine-1-carboxylate in a solution of trifluoroacetic acid 1 in 146 mg (0.24 mmol) in methylene chloride (2 ml). .2 ml (15.6 mmol) was added and stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. 77 mg of [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenylbutyl] piperidine-3-carboxamide ( Yield: 63%). The (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1 obtained here To a solution of (phenylbutyl) piperidine-3-carboxamide 77 mg (0.15 mmol) in methanol (1 ml) was added 17.5 mg (0.15 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 82 mg of the title compound (yield: 87%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.52-7.22 (m, 9H), 6.70 (s, 2H), 4.94 (br dd, 1H, J = 9.3 Hz, 5.4 Hz), 3.63-3.22 ( m, 7H), 3.05-2.88 (m, 3H), 2.06-2.00 (m, 1H), 1.87-1.69 (m, 2H), 1.61-1.54 (m, 2H), 1.38-1.35 (m, 6H), 0.97-0.91 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 511 ((M + H) ⁺ ).

(Example 13)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (2-fluorophenyl) propyl] Piperidine-3-carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid and the (1R) -1- (2-fluorophenyl) propan-1-amine hydrochloride obtained in Reference Example 12 were used. This gave 126 mg of the title compound (total yield over 3 steps: 47%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.52 (br d, 1H, J = 7.8 Hz), 7.41-7.26 (m, 5H), 7.16 (dt, 1H, J = 7.3 Hz, 1.0 Hz) , 7.08 (ddd, 1H, J = 10.7 Hz, 8.3 Hz, 1.0 Hz), 6.71 (s, 2H), 5.01 (br t, 1H, J = 7.6 Hz), 3.63-3.43 (m, 4H), 3.39- 3.22 (m, 3H), 3.07-3.02 (m, 1H), 2.99-2.89 (m, 2H), 2.11-2.04 (m, 1H), 1.89-1.79 (m, 3H), 1.40-1.36 (m, 6H ), 0.93 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 501 ((M + H) ⁺ ).

(Example 14)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (3-fluorophenyl) propyl] Piperidine-3-carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) Using 2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid and (1R) -1- (3-fluorophenyl) propan-1-amine hydrochloride obtained in Reference Example 13, 120 mg (total yield of 3 steps: 45%) of the title compound was obtained.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.52-7.51 (m, 1H), 7.40-7.27 (m, 4H), 7.12 (br d, 1H, J = 7.8 Hz), 7.06-7.04 (m , 1H), 7.00-6.96 (m, 1H), 6.70 (s, 2H), 4.74 (br t, 1H, J = 7.3 Hz), 3.64-3.42 (m, 4H), 3.39-3.22 (m, 3H) , 3.07-2.89 (m, 3H), 2.10-2.02 (m, 1H), 1.89-1.78 (m, 3H), 1.39-1.36 (m, 6H), 0.93 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 501 ((M + H) ⁺ ).

(Example 15)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (4-fluorophenyl) propyl] Piperidine-3-carboxamide fumarate

Similar to Examples (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) Using 2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid and (1R) -1- (4-fluorophenyl) propan-1-amine hydrochloride obtained in Reference Example 14, 115 mg of the title compound was obtained (total yield over 3 steps: 43%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.53-7.51 (m, 1H), 7.38-7.28 (m, 5H), 7.09-7.04 (m, 2H), 6.70 (s, 2H), 4.73 ( br t, 1H, J = 7.4 Hz), 3.64-3.22 (m, 7H), 3.07-2.86 (m, 3H), 2.08-2.00 (m, 1H), 1.89-1.77 (m, 3H), 1.38-1.36 (m, 6H), 0.91 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 501 ((M + H) ⁺ ).

(Example 16)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridin-2-ylpropyl] piperidine -3-Carboxamide fumarate

(16a) tert-Butyl (3R, 5S) -3- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1-pyridine -2-ylpropyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2 obtained in Example (5b) , 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid, 250 mg (0.54 mmol), (1R) -1-pyridin-2-ylpropan-1-amine obtained in Reference Example 15 To a solution of 224 mg (1.07 mmol) of dihydrochloride and 370 μl (2.14 mmol) of diisopropylethylamine in N, N-dimethylformamide (5 ml) Under ice cooling, 305 mg (0.80 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) was added, and at room temperature. Stir for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 3/1 to 1/1 to 0/1) to obtain 233 mg (yield: 74%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.55 (br d, 1H, J = 4.4 Hz), 7.68-7.65 (m, 1H), 7.46 (br d, 1H, J = 7.8 Hz), 7.32- 7.19 (m, 4H), 6.90 (br d, 1H, J = 7.8 Hz), 5.01-4.97 (m, 1H), 4.27-4.00 (m, 2H), 3.73-3.51 (m, 2H), 3.30 (br s, 2H), 2.99 (br s, 1H), 2.75 (br t, 2H, J = 12.0 Hz), 2.45 (br s, 1H), 1.95-1.77 (m, 4H), 1.49 (br s, 9H) , 1.40-1.29 (m, 6H), 0.81 (t, 3H, J = 7.3 Hz).
(16b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridin-2-yl Propyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazine obtained in Example (16a) -1-yl] -5-{[(1R) -1-pyridin-2-ylpropyl] carbamoyl} piperidine-1-carboxylate in a solution of 223 mg (0.38 mmol) in methylene chloride (1.8 ml) Acetic acid 0.88 ml (11.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridin-2-ylpropyl] piperidine-3-carboxamide 85 mg ( Yield: 46%). The (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridine-2 obtained here To a solution of 85 mg (0.18 mmol) of -ylpropyl] piperidine-3-carboxamide in methanol (1 ml) was added 20.3 mg (0.18 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 88 mg (yield: 84%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.52 (br d, 1H, J = 4.4 Hz), 7.80 (br t, 1H, J = 7.6 Hz), 7.53-7.51 (m, 1H), 7.41 -7.35 (m, 3H), 7.31-7.29 (m, 2H), 6.71 (s, 2H), 4.85-4.82 (m, 1H), 3.65-3.45 (m, 4H), 3.41-3.21 (m, 3H) , 3.08-3.03 (m, 1H), 3.00-2.89 (m, 2H), 2.19-2.13 (m, 1H), 1.94-1.78 (m, 3H), 1.42-1.37 (m, 6H), 0.93 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 484 ((M + H) ⁺ ).

(Example 17)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-pyridine-2- Ylbutyl] piperidine-3-carboxamide fumarate

(17a) tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -3-methyl -1-Pyridin-2-ylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) obtained in Example (5b) ) -2,2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid 300 mg (0.643 mmol), (1R) -3-methyl-1-pyridine-2 obtained in Reference Example 16 -Ylbutan-1-amine dihydrochloride 305 mg (1.29 mmol) and diisopropylethylamine 447 μl (2.57 mmol) N, N-dimethylform To an amide (6 ml) solution, 366 mg (0.96 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) under ice-cooling And stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 3/1 to 1/1 to 0/1) to obtain 267 mg (yield: 67%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.55 (br d, 1H, J = 4.4 Hz), 7.45 (br t, 1H, J = 7.3 Hz), 7.46-7.45 (m, 1H), 7.32- 7.18 (m, 5H), 6.60 (br d, 1H, J = 7.8 Hz), 5.12 (br q, 1H, J = 7.8 Hz), 4.26-4.00 (m, 2H), 3.71-3.50 (m, 2H) , 3.29 (br s, 2H), 2.97 (br s, 1H), 2.78-2.70 (m, 2H), 2.40 (br s, 1H), 1.90 (br s, 2H), 1.70-1.27 (m, 18H) , 0.95-0.93 (m, 6H).
(17b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-pyridine -2-ylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2,2-dimethyl-5 obtained in Example (17a) -Oxopiperazin-1-yl] -5-{[(1R) -3-methyl-1-pyridin-2-ylbutyl] carbamoyl} piperidine-1-carboxylate 267 mg (0.44 mmol) in methylene chloride (2 ml) To the solution, 1.0 ml (13.1 mmol) of trifluoroacetic acid was added and stirred at room temperature for 30 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-pyridin-2-ylbutyl] piperidine-3-carboxy 179 mg (yield: 80%) of amide was obtained. The (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1 obtained here -Pyridin-2-ylbutyl] piperidine-3-carboxamide 179 mg (0.35 mmol) in methanol (1.8 ml) was added 40.5 mg (0.35 mmol) of fumaric acid and stirred at room temperature for 5 minutes. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 197 mg (yield: 89%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.51 (br d, 1H, J = 4.9 Hz), 7.79 (br t, 1H, J = 7.6 Hz), 7.52-7.51 (m, 1H), 7.41 -7.35 (m, 3H), 7.31-7.28 (m, 2H), 6.70 (s, 2H), 5.03 (dd, 1H, J = 9.3 Hz, 5.9 Hz), 3.64-3.44 (m, 4H), 3.39- 3.22 (m, 3H), 3.06-3.01 (m, 1H), 2.98-2.89 (m, 2H), 2.17-2.11 (m, 1H), 1.87-1.78 (m, 1H), 1.76-1.58 (m, 3H ), 1.41-1.36 (m, 6H), 0.98 (d, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 6.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 512 ((M + H) ⁺ ).

(Example 18)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridine-2- Yl) -3-methylbutyl] piperidine-3-carboxamide fumarate

(18a) tert-Butyl (3R, 5S) -3- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1- ( 5-Fluoropyridin-2-yl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4 obtained in Example (5b) -(2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid 300 mg (0.64 mmol), (1R) -1- (5 -Fluoropyridin-2-yl) -3-methylbutan-1-amine dihydrochloride 328 mg (1.29 mmol) and diisopropylethylamine 447 μl (2.57 mm) l) in N, N-dimethylformamide (6 ml) under ice-cooling, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate ( HBTU) 366 mg (0.96 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 3/1 to 1/1 to 0/1) to obtain 246 mg (yield: 60%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.41 (br d, 1H, J = 2.9 Hz), 7.47-7.45 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.22 (m, 4H), 6.41 (br d, 1H, J = 8.3 Hz), 5.12 (br q, 1H, J = 8.3 Hz), 4.26-4.00 (m, 2H), 3.71-3.50 (m, 2H), 3.29 (br s, 2H), 2.97 (br s, 1H), 2.75-2.69 (m, 2H), 2.39 (br s, 1H), 1.92-1.86 (m, 2H), 1.69-1.27 (m, 18H), 0.95- 0.92 (m, 6H).
(18b) (3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridine -2-yl) -3-methylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (2-chlorophenyl) -2, obtained in Example (18a) 2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1- (5-fluoropyridin-2-yl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate 246 mg (0 .39 mmol) in methylene chloride (1.8 ml) was added with 0.9 ml (11.7 mmol) of trifluoroacetic acid and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridin-2-yl) -3-methylbutyl] 190 mg (yield: 91%) of piperidine-3-carboxamide was obtained. The (3S, 5R) -5- [4- (2-chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5- To a solution of 190 mg (0.36 mmol) of fluoropyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide in methanol (1.8 ml) was added 41.5 mg (0.36 mmol) of fumaric acid, and the mixture was stirred at room temperature. And stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, excess ether was added, and the precipitated solid was collected by filtration to give 198 mg (yield: 86%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.41 (br d, 1H, J = 2.0 Hz), 7.58-7.50 (m, 2H), 7.42-7.35 (m, 3H), 7.33-7.30 (m , 1H), 6.71 (s, 2H), 5.05 (dd, 1H, J = 9.3 Hz, 6.4 Hz), 3.64-3.44 (m, 4H), 3.39-3.21 (m, 3H), 3.04 (br t, 1H , J = 11.7 Hz), 2.99-2.89 (m, 2H), 2.15-2.09 (m, 1H), 1.86-1.78 (m, 1H), 1.76-1.64 (m, 2H), 1.61-1.55 (m, 1H ), 1.40-1.36 (m, 6H), 0.97 (d, 3H, J = 6.8 Hz), 0.94 (d, 3H, J = 6.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 530 ((M + H) ⁺ ).

(Example 19)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridin-3-ylpropyl] piperidine -3-Carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-Dimethyl-5-oxopiperazin-1-yl] piperidin-3-dicarboxylic acid and (1R) -1-pyridin-3-ylpropan-1-amine dihydrochloride obtained in Reference Example 18 were used. The title compound (125 mg, yield over 3 steps: 41%) was obtained.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 8.51 (br s, 1H), 8.45 (dd, 1H, J = 4.7 Hz, 1.6 Hz), 7.81-7.79 (m, 1H), 7.53-7.51 ( m, 1H), 7.45-7.27 (m, 4H), 6.71 (s, 2H), 4.79 (t, 1H, J = 7.6 Hz), 3.64-3.22 (m, 7H), 3.08-2.91 (m, 3H) , 2.16-2.02 (m, 1H), 1.91-1.80 (m, 3H), 1.39-1.36 (m, 6H), 0.96 (t, 3H, J = 7.2 Hz).
Mass spectrum (FAB ⁺ ), m / z: 484 ((M + H) ⁺ ).

(Example 20)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-pyridine-3- Ylbutyl] piperidine-3-carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid and (1R) -3-methyl-1-pyridin-3-ylbutan-1-amine dihydrochloride obtained in Reference Example 19 Used to obtain 121 mg of the title compound (3 steps total yield: 36%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.51 (br s, 1H), 8.45 (br d, 1H, J = 5.1 Hz), 7.82-7.79 (m, 1H), 7.53-7.51 (m, 1H), 7.45-7.26 (m, 4H), 6.72 (s, 2H), 4.99 (dd, 1H, J = 9.4 Hz, 5.5 Hz), 3.63-3.22 (m, 7H), 3.09-2.85 (m, 3H ), 2.10-2.01 (m, 1H), 1.87-1.75 (m, 2H), 1.64-1.57 (m, 2H), 1.39-1.36 (m, 6H), 0.99 (d, 3H, J = 6.3 Hz), 0.94 (d, 3H, J = 6.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 512 ((M + H) ⁺ ).

(Example 21)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridine-3- Yl) -3-methylbutyl] piperidine-3-carboxamide fumarate

Similar to Examples (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-3-dicarboxylic acid and (1R) -1- (5-fluoropyridin-3-yl) -3-methylbutane-1- obtained in Reference Example 20 Using amine dihydrochloride, 137 mg of the title compound was obtained (total yield over 3 steps: 34%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 8.39-8.37 (m, 2H), 7.62-7.59 (m, 1H), 7.51 (br d, 1H, J = 7.8 Hz), 7.41-7.35 (m , 2H), 7.31-7.27 (m, 1H), 6.70 (s, 2H), 5.02 (dd, 1H, J = 9.5 Hz, 5.6 Hz), 3.64-3.42 (m, 4H), 3.39-3.21 (m, 3H), 3.06-3.00 (m, 1H), 2.98-2.86 (m, 2H), 2.09-2.01 (m, 1H), 1.88-1.76 (m, 2H), 1.67-1.58 (m, 2H), 1.39- 1.36 (m, 6H), 0.99 (d, 3H, J = 6.4 Hz), 0.96 (d, 3H, J = 6.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 530 ((M + H) ⁺ ).

(Example 22)
(3S, 5R) -5- [4- (2-Chlorophenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-pyridin-4-ylpropyl] piperidine -3-Carboxamide fumarate

Similar to Example (5c) and (5d), (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (2-chlorophenyl) -2, obtained in Example (5b) 2-Dimethyl-5-oxopiperazin-1-yl] piperidin-3-dicarboxylic acid and (1R) -1-pyridin-4-ylpropan-1-amine dihydrochloride obtained in Reference Example 21 147 mg of compound (3 steps total yield: 43%) was obtained.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.50-8.48 (m, 2H), 7.53-7.51 (m, 1H), 7.41-7.35 (m, 4H), 7.32-7.28 (m, 1H), 6.71 (s, 2H), 4.76 (br t, 1H, J = 7.3 Hz), 3.67-3.24 (m, 7H), 3.08-2.93 (m, 3H), 2.18-2.08 (m, 1H), 1.91-1.79 (m, 3H), 1.41-1.37 (m, 6H), 0.97 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 484 ((M + H) ⁺ ).

(Example 23)
(3S, 5R) -5- [2,2-Dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) -3- Methylbutyl] piperidine-3-carboxamide fumarate

(23a) Methyl (3S, 5R) -5-({1,1-dimethyl-2-[(2-methylphenyl) amino] ethyl} amino) -1-[(2-nitrophenyl) sulfonyl] piperidine-3 -Carboxylate Methyl (3S, 5R) -5-[(1,1-dimethyl-2-oxo-ethyl) amino] -1-[(2-nitrophenyl) sulfonyl] piperidine obtained in Example (1e) To a toluene (60 ml) solution of 2.50 g (6.1 mmol) of 3-carboxylate and 0.97 g (9.1 mmol) of 2-methylaniline was added 1.27 g (21.1 mmol) of acetic acid, The mixture was stirred for 2.5 hours while removing generated water. After cooling, 2.56 g (12.1 mmol) of sodium triacetoxyborohydride was added to the reaction mixture under ice cooling, and then stirred at room temperature for 18 hours. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1 to 3/7) to give 3.00 g (yield) of the title compound. Rate: 98%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.67 (dd, 1H, J = 8.3 Hz, 1.0 Hz), 7.64-7.58 (m, 2H), 7.48-7.45 (m, 1H), 7.16-7.13 ( m, 1H), 7.05 (br d, 1H, J = 7.3 Hz), 6.68-6.65 (m, 1H), 6.58 (br d, 1H, J = 8.3 Hz), 4.08-4.05 (m, 1H), 3.73 -3.69 (m, 4H), 2.96 (d, 1H, J = 11.7 Hz), 2.91 (d, 1H, J = 11.7 Hz), 2.81-2.70 (m, 3H), 2.32 (dd, 1H, J = 12.2 Hz, 10.7 Hz), 2.21-2.17 (m, 1H), 2.12 (s, 3H), 1.31 (q, 1H, J = 12.0 Hz), 1.22 (s, 3H), 1.21 (s, 3H).
(23b) Methyl (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine -3-Carboxylate Methyl (3S, 5R) -5-({1,1-dimethyl-2-[(2-methylphenyl) amino] ethyl} amino) -1- [obtained in Example (23a) (2-Nitrophenyl) sulfonyl] piperidine-3-carboxylate (3.00 g, 6.0 mmol) and triethylamine (4.81 g, 47.5 mmol) in a methylene chloride (60 ml) solution under ice-cooling and bromoacetyl bromide A solution of 4.79 g (23.8 mmol) in methylene chloride (15 ml) was added over 1 hour, followed by stirring at room temperature for 20 minutes and further at 40 ° C. for 3 hours. Stir for a while. After cooling, water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) to give 2.73 g (yield) of the title compound. Rate: 84%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.03-8.01 (m, 1H), 7.76-7.71 (m, 2H), 7.67-7.65 (m, 1H), 7.27-7.21 (m, 3H), 7.13 -7.06 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.81 (m, 1H), 3.72 (s, 3H), 3.68-3.15 (m, 5H), 2.79-2.66 (m, 3H) , 2.24-2.18 (m, 4H), 1.75-1.66 (m, 1H), 1.37-1.34 (m, 6H).
(23c) 1-tert-butyl 3-methyl (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-1,3- Dicarboxylate Methyl (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -1- [obtained in Example (23b) (2-Nitrophenyl) sulfonyl] piperidine-3-carboxylate 2.73 g (5.0 mmol) and thiophenol 0.77 ml (7.5 mmol) in a solution of acetonitrile (100 ml) under ice cooling with cesium carbonate 1 .96 g (6.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give methyl (3S, 5R) -5- 1.8 g (yield: quantitative) of [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-dicarboxylate was obtained. Methyl (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-dicarboxylate 1.8 g obtained here ( To a mixture of ethyl acetate (50 ml) and 1.25 g (14.9 mmol) of sodium bicarbonate and water (50 ml) was added 1.04 g (4.8 mmol) of di-tert-butyl dicarbonate, Stir for 15 minutes under. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 1/9) to give 1.82 g (yield) of the title compound. Rate: 79%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.27-7.21 (m, 3H), 7.12-7.08 (m, 1H), 4.30 (br s, 1H), 4.08 (br s, 1H), 3.72-3.52 (m, 5H), 3.39-3.35 (m, 1H), 3.21 (br d, 1H, J = 11.2 Hz), 3.01-2.97 (m, 1H), 2.70-2.54 (m, 3H), 2.24-2.23 ( m, 3H), 2.12 (br d, 1H, J = 12.7 Hz), 1.83-1.74 (m, 1H), 1.48 (s, 9H), 1.36-1.32 (m, 6H).
(23d) (3S, 5R) -1- (tert-butoxycarbonyl) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carvone Acid 1-tert-butyl 3-methyl (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl obtained in Example (23c) ] To a mixture of 1.82 g (4.0 mmol) of piperidine-1,3-dicarboxylate in tetrahydrofuran (36 ml) and water (18 ml) was added 333 mg (7.9 mmol) of lithium hydroxide monohydrate under ice-cooling. ) And stirred at the same temperature for 3.5 hours. The reaction mixture was acidified with 1N hydrochloric acid (pH 2-3), extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.78 g (yield: quantitative) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.28-7.23 (m, 3H), 7.12-7.08 (m, 1H), 4.30 (br s, 1H), 4.05 (br s, 1H), 3.79-3.63 (m, 2H), 3.44-3.18 (m, 2H), 3.00 (br s, 1H), 2.73-2.54 (m, 3H), 2.24-2.17 (m, 4H), 1.79-1.70 (m, 1H), 1.47 (s, 9H), 1.36-1.33 (m, 6H).
(23e) tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -5-{[(1R) -1- (Ethoxymethyl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [2,2-dimethyl-] obtained in Example (23d) 4- (2-Methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 300 mg (0.67 mmol), (2R) -1-ethoxy-4-methylpentane obtained in Reference Example 6 -2-amine 195 mg (1.35 mmol) and diisopropylethylamine 352 μl (2.02 mmol) N, N-dimethylformamide (6.5 ml) The solution was mixed with 306 mg (0.81 mmol) of N, N O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) under ice cooling. -A dimethylformamide (1.0 ml) solution was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n Purification by hexane / ethyl acetate = 3/1 to 1/1 to 0/1) gave 236 mg of the title compound (yield: 61%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.27-7.21 (m, 3H), 7.12-7.08 (m, 1H), 5.64 (br s, 1H), 4.23-4.03 (m, 2H), 3.75- 3.68 (m, 1H), 3.59-3.35 (m, 7H), 3.22-3.18 (m, 1H), 2.98 (br s, 1H), 2.78-2.68 (m, 2H), 2.34 (br s, 1H), 2.24-2.22 (m, 3H), 2.01-1.95 (m, 2H), 1.62-1.54 (m, 1H), 1.48 (s, 9H), 1.46-1.31 (m, 8H), 1.21-1.18 (m, 3H ), 0.93 (s, 3H), 0.92 (s, 3H).
(23f) (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) -3-Methylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl)-obtained in Example (23e) 5-oxopiperazin-1-yl] -5-{[(1R) -1- (ethoxymethyl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate 235 mg (0.45 mmol) of methylene chloride (1.37 ml ) 0.686 ml (8.91 mmol) of trifluoroacetic acid was added to the solution, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl] piperidine-3-carboxy 154 mg of amide (yield: 73%) was obtained. The obtained (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (ethoxy Methyl) -3-methylbutyl] piperidine-3-carboxamide 154 mg (0.33 mmol) in methanol (3 ml) was added with fumaric acid 38 mg (0.33 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, excess ether was added, and the precipitated solid was collected by filtration to give 154 mg (yield: 80%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.31-7.25 (m, 3H), 7.15-7.09 (m, 1H), 6.69 (s, 2H), 4.14-4.08 (m, 1H), 3.69- 2.94 (m, 13H), 2.81-2.75 (m, 1H), 2.22 (s, 3H), 2.15-2.11 (m, 1H), 1.98-1.89 (m, 1H), 1.66-1.60 (m, 1H), 1.42-1.31 (m, 8H), 1.17 (t, 3H, J = 7.0 Hz), 0.95-0.90 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 473 ((M + H) ⁺ ).

(Example 24)
(3S, 5R) -5- [2,2-Dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine-3- Carboxamide fumarate

(24a) tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -5-{[(1R) -1- Phenylpropyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [2,2-dimethyl-4- (2-methyl) obtained in Example (23d) (Phenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 200 mg (0.45 mmol), (1R) -1-phenylpropan-1-amine 121 mg (0.90 mmol) and diisopropylethylamine 174 mg (1. 35 mmol) in N, N-dimethylformamide (5 ml) under ice-cooling, O- (benzotriazol-1-yl -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HBTU) 256mg (0.68mmol) was added and stirred for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 1/1 to 0/1) to obtain 232 mg (yield: 92%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.35-7.20 (m, 8H), 7.11-7.05 (m, 1H), 6.24 (br s, 1H), 4.87 (br q, 1H, J = 7.7 Hz ), 4.26-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.35 (br d, 1H, J = 11.2 Hz), 3.20-2.70 (m, 4H), 2.38 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.89-1.77 (m, 4H), 1.48 (s, 9H), 1.34-1.27 (m, 6H), 0.88 (t, 3H, J = 7.3 Hz).
(24b) (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine -3-Carboxamide fumarate salt tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazine-1 obtained in Example (24a) -Yl] -5-{[(1R) -1-phenylpropyl] carbamoyl} piperidine-1-carboxylate in a solution of 232 mg (0.41 mmol) in methylene chloride (2 ml) and 1.2 ml (15.6 mmol) of trifluoroacetic acid ) And stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. 125 [mg of 2- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine-3-carboxamide (yield: 66%). The obtained (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl ] To a solution of piperidine-3-carboxamide 125 mg (0.27 mmol) in methanol (1.5 ml) was added 31.4 mg (0.27 mmol) of fumaric acid and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 128 mg of the title compound (yield: 82%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.35-7.24 (m, 8H), 7.12-7.07 (m, 1H), 6.72 (s, 2H), 4.73 (br t, 1H, J = 7.3 Hz ), 3.66-3.46 (m, 4H), 3.40-3.20 (m, 3H), 3.06-2.85 (m, 3H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.07-2.04 (m , 1H), 1.89-1.79 (m, 3H), 1.36-1.35 (m, 6H), 0.93-0.90 (m, 3H).
Mass spectrum (FAB ⁺ ), m / z: 463 ((M + H) ⁺ ).

(Example 25)
(3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl ] Piperidine-3-carboxamide fumarate

(25a) tert-butyl (3S, 5R) -3-{[(1R) -2-cyclopropyl-1-phenylethyl] carbamoyl} -5- [2,2-dimethyl-4- (2-methylphenyl) -5-Oxopiperazin-1-yl] piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [2,2-dimethyl-4 obtained in Example (23d) -(2-Methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 300 mg (0.67 mmol), (1R) -2-cyclopropyl-1-phenylethane obtained in Reference Example 10 1-amine hydrochloride 266 mg (1.35 mmol) and diisopropylethylamine 348 mg (2.70 mmol) N, N-dimethylformamide ( 7 ml) To the solution was added 307 mg (0.81 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) under ice-cooling. The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 1/1 to 0/1) to obtain 278 mg (yield: 70%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.36-7.20 (m, 8H), 7.11-7.05 (m, 1H), 6.03 (br s, 1H), 5.06 (br q, 1H, J = 7.3 Hz ), 4.26-4.00 (m, 2H), 3.71-3.50 (m, 2H), 3.36-3.33 (m, 1H), 3.18 (br t, 1H, J = 11.0 Hz), 2.95-2.69 (m, 3H) , 2.36 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.91-1.61 (m, 4H), 1.48 (s, 9H), 1.34-1.28 (m, 6H), 0.59-0.55 (m, 1H), 0.48-0.38 (m, 2H), 0.16-0.12 (m, 1H), 0.06-0.02 (m, 1H).
(25b) (3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazine- 1-yl] piperidine-3-carboxamide fumarate tert-butyl (3S, 5R) -3-{[(1R) -2-cyclopropyl-1-phenylethyl] carbamoyl obtained in Example (25a) } -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-1-carboxylate in a solution of 278 mg (0.47 mmol) in methylene chloride (2 ml) 1.2 ml (15.6 mmol) of trifluoroacetic acid was added and stirred at room temperature for 25 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -N -[(1R) -2-cyclopropyl-1-phenylethyl] -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxamide 151 mg (yield: 65%) was obtained. The (3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxo obtained here. Piperazin-1-yl] piperidine-3-carboxamide 151 mg (0.31 mmol) in a methanol (1.5 ml) solution was added with 35.9 mg (0.31 mmol) of fumaric acid and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 160 mg of the title compound (yield: 86%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.34-7.22 (m, 8H), 7.12-7.07 (m, 1H), 6.70 (s, 2H), 4.94 (br t, 1H, J = 7.6 Hz ), 3.63-3.19 (m, 7H), 3.07-3.02 (m, 1H), 2.97 (br t, 1H, J = 12.5 Hz), 2.94-2.86 (m, 1H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.07-2.04 (m, 1H), 1.90-1.81 (m, 1H), 1.74-1.64 (m, 2H), 1.36-1.35 (m, 6H), 0.68-0.63 (m, 1H), 0.49-0.36 (m, 2H), 0.17-0.13 (m, 1H), 0.05-0.01 (m, 1H).
Mass spectrum (FAB ⁺ ), m / z: 489 ((M + H) ⁺ ).

(Example 26)
(3S, 5R) -5- [2,2-Dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenylbutyl] Piperidine-3-carboxamide fumarate

(26a) tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -5-{[(1R) -3- Methyl-1-phenylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [2,2-dimethyl-4-] obtained in Example (23d) (2-Methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 200 mg (0.45 mmol), (1R) -3-methyl-1-phenylbutane-1 obtained in Reference Example 11 -To a solution of 179 mg (0.90 mmol) of amine hydrochloride and 232 mg (1.80 mmol) of diisopropylethylamine in N, N-dimethylformamide (5 ml), Under ice-cooling, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) 256 mg (0.68 mmol) was added, and at room temperature. Stir for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 0/1) to obtain 183 mg (yield: 69%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.35-7.20 (m, 8H), 7.10-7.05 (m, 1H), 5.90-5.60 (m, 1H), 5.04 (br q, 1H, J = 7.8 Hz), 4.20-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.36-3.33 (m, 1H), 3.17 (br t, 1H, J = 11.7 Hz), 2.94-2.69 (m, 3H ), 2.37-2.30 (m, 1H), 2.23-2.20 (m, 3H), 1.88-1.26 (m, 20H), 0.95-0.92 (m, 6H).
(26b) (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1- Phenylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5- obtained in Example (26a) Oxopiperazin-1-yl] -5-{[(1R) -3-methyl-1-phenylbutyl] carbamoyl} piperidine-1-carboxylate in a solution of 183 mg (0.36 mmol) in methylene chloride (2 ml) Acetic acid 1.2 ml (15.6 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. -[2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenylbutyl] piperidine-3-carboxamide 91 mg (Yield: 52%) was obtained. The obtained (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -3-methyl- To a solution of 1-phenylbutyl] piperidine-3-carboxamide 92 mg (0.19 mmol) in methanol (1 ml) was added 21.7 mg (0.19 mmol) of fumaric acid, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 91 mg of the title compound (yield: 82%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.34-7.23 (m, 8H), 7.12-7.06 (m, 1H), 6.70 (s, 2H), 4.94 (br dd, 1H, J = 9.3 Hz , 5.9 Hz), 3.62-3.45 (m, 4H), 3.39-3.19 (m, 3H), 3.04 (br t, 1H, J = 12.0 Hz), 2.96 (t, 1H, J = 12.5 Hz), 2.91- 2.83 (m, 1H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.05-2.02 (m, 1H), 1.87-1.69 (m, 2H), 1.62-1.55 (m, 2H), 1.36 (br s, 6H), 0.97 (d, 3H, J = 6.3 Hz), 0.94 (d, 3H, J = 5.9 Hz).
Mass spectrum (FAB ⁺ ), m / z: 491 ((M + H) ⁺ ).

(Example 27)
(3S, 5R) -5- [2,2-Dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridine-2 -Yl) -3-methylbutyl] piperidine-3-carboxamide fumarate

(27a) tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -5-{[(1R) -1- (5-Fluoropyridin-2-yl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [obtained in Example (23d) 2,2-Dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 250 mg (0.56 mmol), (1R) -1- obtained in Reference Example 17 287 mg (1.12 mmol) (5-fluoropyridin-2-yl) -3-methylbutan-1-amine dihydrochloride and 289 mg (2.24 mm) diisopropylethylamine ol) in an N, N-dimethylformamide (5 ml) solution under ice-cooling, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate ( HBTU) 255 mg (0.67 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 1/1 to 0/1) to obtain 228 mg (yield: 67%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.40 (br s, 1H), 7.39-7.35 (m, 1H), 7.26-7.21 (m, 4H), 7.11-7.05 (m, 1H), 6.49- 6.48 (m, 1H), 5.13 (br q, 1H, J = 7.7 Hz), 4.26-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.35 (br d, 1H, J = 11.7 Hz) , 3.19-3.16 (m, 1H), 2.96-2.69 (m, 3H), 2.40 (br s, 1H), 2.23 (s, 1.5H), 2.20 (s, 1.5H), 1.89 (br s, 2H) , 1.69-1.28 (m, 18H), 0.95-0.92 (m, 6H).
(27b) (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoro Pyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [2,2-dimethyl-4- (3) obtained in Example (27a) 2-methylphenyl) -5-oxopiperazin-1-yl] -5-{[(1R) -1- (5-fluoropyridin-2-yl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate 228 mg To a solution of (0.37 mmol) in methylene chloride (2 ml) was added 1.2 ml (15.6 mmol) of trifluoroacetic acid, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. -[2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridin-2-yl) -3-methylbutyl 177 mg (yield: 93%) of piperidine-3-carboxamide was obtained. The (3S, 5R) -5- [2,2-dimethyl-4- (2-methylphenyl) -5-oxopiperazin-1-yl] -N-[(1R) -1- (5 To a solution of -fluoropyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide 177 mg (0.35 mmol) in methanol (1.5 ml) was added 40.3 mg (0.35 mmol) of fumaric acid at room temperature. For 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, excess ether was added, and the precipitated solid was collected by filtration to give 172 mg (yield: 79%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.41 (br s, 1H), 7.59-7.54 (m, 1H), 7.41-7.38 (m, 1H), 7.30-7.24 (m, 3H), 7.12 -7.09 (m, 1H), 6.70 (s, 2H), 5.06-5.03 (m, 1H), 3.64-3.46 (m, 4H), 3.41-3.19 (m, 3H), 3.04 (t, 1H, J = 12.2 Hz), 2.98-2.87 (m, 2H), 2.19 (s, 1.5H), 2.17 (s, 1.5H), 2.13-2.09 (m, 1H), 1.86-1.57 (m, 4H), 1.38-1.36 (m, 6H), 0.98-0.93 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 510 ((M + H) ⁺ ).

(Example 28)
(3S, 5R) -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxo Piperazin-1-yl] piperidine-3-carboxamide fumarate

(28a) Methyl (3S, 5R) -5-({2-[(5-fluoro-2-methylphenyl) amino] -1,1-dimethylethyl} amino) -1-[(2-nitrophenyl) sulfonyl Piperidine-3-carboxylate Methyl (3S, 5R) -5-[(1,1-dimethyl-2-oxo-ethyl) amino] -1-[(2-nitrophenyl) obtained in Example (1e) ) Sulfonyl] piperidine-3-carboxylate 2.5 g (6.1 mmol) and 5-fluoro-2-methylaniline 1.13 g (9.0 mmol) in a solution of toluene (60 ml) in 1.27 g (21.1 mmol) of acetic acid ) Was added, and the mixture was stirred for 2.5 hours while removing the water produced under heating and reflux. After cooling, 2.56 g (12.1 mmol) of sodium triacetoxyborohydride was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-7 / 3) to give 3.10 g (yield) of the title compound. Rate: 98%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.75 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.66-7.59 (m, 2H), 7.51 (dt, 1H, J = 7.8 Hz, 1.5 Hz) ), 6.95 (br t, 1H, J = 7.3 Hz), 6.32 (dt, 1H, J = 8.3 Hz, 2.4 Hz), 6.23 (dd, 1H, J = 11.2 Hz, 2.4 Hz), 4.26 (br s, 1H), 4.07-4.05 (m, 1H), 3.69-3.64 (m, 4H), 2.89-2.84 (m, 2H), 2.80-2.70 (m, 3H), 2.36-2.32 (m, 1H), 2.21- 2.17 (m, 1H), 2.07 (s, 3H), 1.31 (q, 1H, J = 12.0 Hz), 1.22 (s, 3H), 1.20 (s, 3H).
(28b) Methyl (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -1-[(2-nitrophenyl) ) Sulfonyl] piperidine-3-carboxylate methyl (3S, 5R) -5-({2-[(5-fluoro-2-methylphenyl) amino] -1,1-dimethyl obtained in Example (28a) Ethyl} amino) -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylate 3.10 g (5.9 mmol) and triethylamine 4.79 g (47.4 mmol) in a solution of methylene chloride (60 ml) Under cooling, a solution of 4.77 g (23.7 mmol) of bromoacetyl bromide in methylene chloride (15 ml) was added over 2 hours, and then at room temperature for 15 minutes. The mixture was stirred and further stirred at 40 ° C. for 2 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) to give 2.81 g (yield) of the title compound. Rate: 84%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.03-8.02 (m, 1H), 7.76-7.71 (m, 2H), 7.67-7.65 (m, 1H), 7.27-7.20 (m, 1H), 6.95 (dq, 1H, J = 8.3 Hz, 2.4 Hz), 6.87-6.81 (m, 1H), 4.05-3.99 (m, 1H), 3.87-3.80 (m, 1H), 3.72 (s, 3H), 3.68- 3.14 (m, 5H), 2.80-2.66 (m, 3H), 2.32-2.17 (m, 4H), 1.74-1.66 (m, 1H), 1.37-1.34 (m, 6H).
(28c) 1-tert-butyl 3-methyl (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine- 1,3-Dicarboxylate Methyl (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazine obtained in Example (28b) 1-yl] -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxylate (2.81 g, 5.0 mmol) and thiophenol (0.77 ml, 7.5 mmol) in acetonitrile (100 ml) in ice Under cooling, 1.96 g (6.0 mmol) of cesium carbonate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give methyl (3S, 5R) -5- 1.9 g (yield: quantitative) of [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylate was obtained. Methyl (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylate 1 obtained here 1.9 g (5.0 mmol) and 1.25 g (14.9 mmol) of sodium bicarbonate in a mixture of ethyl acetate (50 ml) and water (50 ml) were added 1.04 g (4.8 mmol) of di-tert-butyl dicarbonate. In addition, the mixture was stirred at room temperature for 15 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 1/9) to give 1.72 g (yield) of the title compound. Rate: 72%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.21 (dd, 1H, J = 8.3 Hz, 6.8 Hz), 6.97-6.93 (m, 1H), 6.86-6.83 (m, 1H), 4.29 (br s , 1H), 4.09 (br s, 1H), 3.71-3.51 (m, 5H), 3.37-3.33 (m, 1H), 3.19 (br d, 1H, J = 11.7 Hz), 3.01-2.97 (m, 1H ), 2.69-2.53 (m, 3H), 2.18-2.10 (m, 4H), 1.81-1.74 (m, 1H), 1.48 (s, 9H), 1.36-1.32 (m, 6H).
(28d) (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine -3-carboxylic acid 1-tert-butyl 3-methyl (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl- obtained in Example (28c) 5-Oxopiperazin-1-yl] piperidine-1,3-dicarboxylate (1.72 g, 3.6 mmol) in tetrahydrofuran (36 ml) and water (18 ml) was mixed with lithium hydroxide. 302 mg (7.2 mmol) of hydrate was added and stirred at the same temperature for 4 hours. The reaction mixture was acidified with 1N hydrochloric acid (pH 2-3), extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.68 g (yield: quantitative) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.22 (dd, 1H, J = 8.3 Hz, 6.3 Hz), 6.98-6.94 (m, 1H), 6.87-6.83 (m, 1H), 4.29 (br s , 1H), 4.09 (br s, 1H), 3.78-3.61 (m, 2H), 3.42-3.18 (m, 2H), 3.01 (br s, 1H), 2.74-2.54 (m, 3H), 2.32-2.16 (m, 4H), 1.78-1.71 (m, 1H), 1.47 (s, 9H), 1.36-1.34 (m, 6H).
(28e) tert-butyl (3S, 5R) -3-{[(1R) -1- (ethoxymethyl) -3-methylbutyl] carbamoyl} -5- [4- (5-fluoro-2-methylphenyl)- 2,2-Dimethyl-5-oxopiperazin-1-yl] piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4-] obtained in Example (28d) (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 358 mg (0.77 mmol), obtained in Reference Example 6 (2R)- 224 mg (1.54 mmol) of 1-ethoxy-4-methylpentan-2-amine and 404 μl (2.32 mmol) of diisopropylethylamine N, N-dimethyl To a formamide (6 ml) solution, 351 mg (0.93 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) under ice-cooling N, N-dimethylformamide (1 ml) solution was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 3/1 to 1/1 to 0/1) to obtain 268 mg (yield: 59%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.23-7.19 (m, 1H), 6.97-6.92 (m, 1H), 6.87-6.82 (m, 1H), 5.64 (br s, 1H), 4.22- 4.05 (m, 2H), 3.75-3.68 (m, 1H), 3.59-3.34 (m, 7H), 3.20-3.14 (m, 1H), 2.98 (br s, 1H), 2.74-2.68 (m, 2H) , 2.34 (br s, 1H), 2.19-2.17 (m, 3H), 1.94 (br s, 2H), 1.64-1.54 (m, 1H), 1.48 (s, 9H), 1.45-1.31 (m, 8H) , 1.20 (t, 3H, J = 6.8 Hz), 0.93 (s, 3H), 0.92 (s, 3H).
(28f) (3S, 5R) -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl- 5-Oxopiperazin-1-yl] piperidine-3-carboxamide fumarate tert-butyl (3S, 5R) -3-{[(1R) -1- (ethoxymethyl) obtained in Example (28e) -3-methylbutyl] carbamoyl} -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-1-carboxylate 268 mg (0.45 mmol) ) In methylene chloride (1.4 ml) was added 699 μl (9.1 mmol) of trifluoroacetic acid and stirred at room temperature for 20 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -N -[(1R) -1- (ethoxymethyl) -3-methylbutyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine 184 mg of -3-carboxamide (yield: 83%) was obtained. The (3S, 5R) -N-[(1R) -1- (ethoxymethyl) -3-methylbutyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2- To a solution of dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxamide 184 mg (0.38 mmol) in methanol (4 ml) was added 43.5 mg (0.38 mmol) of fumaric acid, and at room temperature for 5 minutes. Stir. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 197 mg of the title compound (yield: 87%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.31-7.29 (m, 1H), 7.04-7.01 (m, 1H), 6.96-6.91 (m, 1H), 6.69 (s, 2H), 4.13- 4.08 (m, 1H), 3.68-3.16 (m, 11H), 3.08-2.94 (m, 2H), 2.82-2.77 (m, 1H), 2.17-2.10 (m, 4H), 1.96-1.89 (m, 1H ), 1.67-1.59 (m, 1H), 1.44-1.32 (m, 8H), 1.17 (t, 3H, J = 7.0 Hz), 0.95-0.90 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 491 ((M + H) ⁺ ).

(Example 29)
(3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] Piperidine-3-carboxamide fumarate

(29a) tert-Butyl (3R, 5S) -3- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R ) -1-Phenylpropyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (5-fluoro-2) obtained in Example (28d) -Methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 200 mg (0.43 mmol), (1R) -1-phenylpropan-1-amine 117 mg (0.86 mmol) ) And diisopropylethylamine (167 mg, 1.29 mmol) in a solution of N, N-dimethylformamide (5 ml) under ice-cooling. Benzotriazole-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HBTU) 196mg (0.52mmol) was added, followed by stirring for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n Purification by hexane / ethyl acetate = 7/3 to 0/1) gave 236 mg (yield: 94%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.34-7.18 (m, 6H), 6.95-6.91 (m, 1H), 6.85-6.81 (m, 1H), 6.29-5.95 (m, 1H), 4.87 (br q, 1H, J = 7.8 Hz), 4.21 (br s, 1H), 4.01 (br s, 1H), 3.70-3.48 (m, 2H), 3.33 (br d, 1H, J = 10.7 Hz), 3.18-2.69 (m, 4H), 2.34 (br s, 1H), 2.18 (s, 1.5H), 2.15 (s, 1.5H), 1.89-1.61 (m, 3H), 1.58-1.45 (m, 10H) , 1.33-1.27 (m, 6H), 0.90-0.87 (m, 3H).
(29b) (3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- Phenylpropyl] piperidine-3-carboxamide fumarate salt tert-butyl (3R, 5S) -3- [4- (5-fluoro-2-methylphenyl) -2,2- obtained in Example (29a) Dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1-phenylpropyl] carbamoyl} piperidine-1-carboxylate in a solution of 236 mg (0.41 mmol) in methylene chloride (2 ml) was added to trifluoro Acetic acid 1.2 ml (15.6 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. -[4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1-phenylpropyl] piperidine-3-carboxamide 160 mg (Yield: 82%) was obtained. The obtained (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R)- To a solution of 160 mg (0.33 mmol) of 1-phenylpropyl] piperidine-3-carboxamide in methanol (1.5 ml) was added 38.7 mg (0.33 mmol) of fumaric acid and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, excess ether was added, and the precipitated solid was collected by filtration to give 162 mg (yield: 82%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.34-7.23 (m, 6H), 7.04-7.00 (m, 1H), 6.94-6.91 (m, 1H), 6.72 (s, 2H), 4.73 ( br t, 1H, J = 7.6 Hz), 3.63-3.46 (m, 4H), 3.40-3.19 (m, 3H), 3.05 (br t, 1H, J = 12.2 Hz), 2.98 (t, 1H, J = 12.2 Hz), 2.92-2.87 (m, 1H), 2.15-2.12 (m, 3H), 2.07-2.02 (m, 1H), 1.88-1.77 (m, 3H), 1.36 (br s, 6H), 0.91 ( br t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 481 ((M + H) ⁺ ).

(Example 30)
(3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazine -1-yl] piperidine-3-carboxamide fumarate

(30a) tert-butyl (3S, 5R) -3-{[(1R) -2-cyclopropyl-1-phenylethyl] carbamoyl} -5- [4- (5-fluoro-2-methylphenyl) -2 , 2-Dimethyl-5-oxopiperazin-1-yl] piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (4) obtained in Example (28d) 5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 300 mg (0.65 mmol), (1R) -2 obtained in Reference Example 10 -Cyclopropyl-1-phenylethan-1-amine hydrochloride 255 mg (1.29 mmol) and diisopropylethylamine 334 mg (2.59 mmol) N , N-dimethylformamide (6 ml) solution under ice-cooling, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (294 mg) 0.77 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 0/1) to obtain 230 mg (yield: 58%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.34-7.18 (m, 6H), 6.95-6.92 (m, 1H), 6.85-6.81 (m, 1H), 5.89 (br s, 1H), 5.08- 5.04 (m, 1H), 4.26-4.00 (m, 2H), 3.71-3.49 (m, 2H), 3.33 (br d, 1H, J = 11.7 Hz), 3.16 (br t, 1H, J = 10.0 Hz) , 2.95-2.69 (m, 3H), 2.35 (br s, 1H), 2.18 (s, 1.5H), 2.15 (s, 1.5H), 1.90-1.61 (m, 4H), 1.48 (s, 9H), 1.34-1.28 (m, 6H), 0.60-0.55 (m, 1H), 0.47-0.40 (m, 2H), 0.16-0.11 (m, 1H), 0.06-0.02 (m, 1H).
(30b) (3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5 -Oxopiperazin-1-yl] piperidine-3-carboxamide fumarate tert-Butyl (3S, 5R) -3-{[(1R) -2-cyclopropyl-1- obtained in Example (30a) Phenylethyl] carbamoyl} -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-1-carboxylate (230 mg, 0.38 mmol) To a methylene chloride (2 ml) solution was added 1.2 ml (15.6 mmol) of trifluoroacetic acid, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -N -[(1R) -2-cyclopropyl-1-phenylethyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine- 134 mg (yield: 72%) of 3-carboxamide was obtained. The (3S, 5R) -N-[(1R) -2-cyclopropyl-1-phenylethyl] -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl thus obtained was obtained. To a solution of (5-oxopiperazin-1-yl) piperidine-3-carboxamide 134 mg (0.27 mmol) in methanol (1.5 ml) was added 30.7 mg (0.27 mmol) of fumaric acid, and the mixture was stirred at room temperature. Stir for minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 128 mg of the title compound (yield: 77%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.34-7.24 (m, 6H), 7.04-7.00 (m, 1H), 6.95-6.92 (m, 1H), 6.71 (s, 2H), 4.94 ( br t, 1H, J = 7.6 Hz), 3.63-3.47 (m, 4H), 3.41-3.19 (m, 3H), 3.04 (br t, 1H, J = 12.2 Hz), 2.97 (t, 1H, J = 12.5 Hz), 2.92-2.86 (m, 1H), 2.15-2.12 (m, 3H), 2.06-2.0 (m, 1H), 1.90-1.81 (m, 1H), 1.74-1.64 (m, 2H), 1.36 (br s, 6H), 0.68-0.63 (m, 1H), 0.49-0.36 (m, 2H), 0.17-0.12 (m, 1H), 0.05-0.01 (m, 1H).
Mass spectrum (FAB ⁺ ), m / z: 507 ((M + H) ⁺ ).

(Example 31)
(3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1 -Phenylbutyl] piperidine-3-carboxamide fumarate

(31a) tert-butyl (3R, 5S) -3- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R ) -3-Methyl-1-phenylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) -5- [4- (5) obtained in Example (28d) -Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 200 mg (0.43 mmol), (1R) -3- obtained in Reference Example 11 172 mg (0.86 mmol) of methyl-1-phenylbutan-1-amine hydrochloride and 167 mg (1.29 mmol) of diisopropylethylamine in N, N-dimethylphenol To a solution of lumamide (5 ml) under ice cooling, 196 mg (0.52 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) And stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 7/3 to 0/1) to obtain 188 mg (yield: 71%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.34-7.18 (m, 6H), 6.95-6.91 (m, 1H), 6.85-6.81 (m, 1H), 5.89 (br s, 1H), 5.04 ( br q, 1H, J = 7.8 Hz), 4.20-4.00 (m, 2H), 3.70-3.48 (m, 2H), 3.33 (br d, 1H, J = 11.7 Hz), 3.16 (br t, 1H, J = 10.0 Hz), 2.93-2.69 (m, 3H), 2.37-2.32 (m, 1H), 2.18-2.15 (m, 3H), 1.87-1.26 (m, 20H), 0.95-0.92 (m, 6H).
(31b) (3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3- Methyl-1-phenylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (5-fluoro-2-methylphenyl)-obtained in Example (31a) 2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -3-methyl-1-phenylbutyl] carbamoyl} piperidine-1-carboxylate 188 mg (0.31 mmol) methylene chloride To the (2 ml) solution, 1.2 ml (15.6 mmol) of trifluoroacetic acid was added and stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 1 / 0-7 / 3) to give (3S, 5R) -5. -[4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -3-methyl-1-phenylbutyl] piperidine-3 -132 mg (yield: 84%) of carboxamide was obtained. The obtained (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R)- To a solution of 3-methyl-1-phenylbutyl] piperidine-3-carboxamide 132 mg (0.26 mmol) in methanol (1.5 ml) was added 30.1 mg (0.26 mmol) of fumaric acid, and 5 minutes at room temperature Stir. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 124 mg of the title compound (yield: 76%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.34-7.24 (m, 6H), 7.04-7.00 (m, 1H), 6.94-6.91 (m, 1H), 6.71 (s, 2H), 4.95- 4.93 (m, 1H), 3.62-3.46 (m, 4H), 3.38-3.19 (m, 3H), 3.03 (br t, 1H, J = 12.0 Hz), 2.96 (t, 1H, J = 12.2 Hz), 2.91-2.86 (m, 1H), 2.15-2.12 (m, 3H), 2.03-1.99 (m, 1H), 1.86-1.78 (m, 1H), 1.75-1.69 (m, 1H), 1.61-1.54 (m , 2H), 1.35 (br s, 6H), 0.97-0.93 (m, 6H).
Mass spectrum (FAB ⁺ ), m / z: 509 ((M + H) ⁺ ).

(Example 32)
(3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5- Fluoropyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide fumarate

(32a) tert-Butyl (3R, 5S) -3- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R ) -1- (5-Fluoropyridin-2-yl) -3-methylbutyl] carbamoyl} piperidine-1-carboxylate (3S, 5R) -1- (tert-butoxycarbonyl) obtained in Example (28d) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] piperidine-3-carboxylic acid 301 mg (0.65 mmol), obtained in Reference Example 17 The resulting (1R) -1- (5-fluoropyridin-2-yl) -3-methylbutan-1-amine dihydrochloride 332 mg (1.30 mmol) and diisopropylethyla To a solution of 453 μl of min (2.60 mmol) in N, N-dimethylformamide (6.5 ml) under ice-cooling, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetra 296 mg (0.78 mmol) of methyluronium hexafluorophosphate (HBTU) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) and NH silica gel column chromatography (elution solvent: n -Hexane / ethyl acetate = 3/1 to 1/1 to 0/1) to obtain 247 mg (yield: 61%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 8.41 (br s, 1H), 7.39-7.35 (m, 1H), 7.26-7.18 (m, 2H), 6.96-6.91 (m, 1H), 6.85- 6.80 (m, 1H), 6.46 (br d, 1H, J = 8.2 Hz), 5.13 (br q, 1H, J = 7.8 Hz), 4.29-4.00 (m, 2H), 3.70-3.48 (m, 2H) , 3.35 (br d, 1H, J = 10.5 Hz), 3.18-3.14 (m, 1H), 2.96-2.69 (m, 3H), 2.39 (br s, 1H), 2.18 (s, 1.5H), 2.14 ( s, 1.5H), 1.88 (br s, 2H), 1.70-1.28 (m, 18H), 0.95-0.92 (m, 6H).
(32b) (3S, 5R) -5- [4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-Fluoropyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide fumarate tert-butyl (3R, 5S) -3- [4- (5- Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -5-{[(1R) -1- (5-fluoropyridin-2-yl) -3-methylbutyl] carbamoyl } To a solution of piperidine-1-carboxylate 247 mg (0.39 mmol) in methylene chloride (1.2 ml) was added 606 μl (7.8 mmol) of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. . The reaction mixture was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1-7 / 3) to give (3S, 5R) -5. -[4- (5-Fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R) -1- (5-fluoropyridin-2-yl) 165 mg (yield: 80%) of -3-methylbutyl] piperidine-3-carboxamide was obtained. The obtained (3S, 5R) -5- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-5-oxopiperazin-1-yl] -N-[(1R)- To a solution of 1- (5-fluoropyridin-2-yl) -3-methylbutyl] piperidine-3-carboxamide 165 mg (0.31 mmol) in methanol (3 ml) was added fumaric acid 36 mg (0.31 mmol) at room temperature. For 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in an appropriate amount of methylene chloride, an excess amount of ether was added, and the precipitated solid was collected by filtration to obtain 181 mg (yield: 90%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 8.41 (br s, 1H), 7.59-7.52 (m, 1H), 7.43-7.38 (m, 1H), 7.31-7.28 (m, 1H), 7.04 -7.00 (m, 1H), 6.96-6.93 (m, 1H), 6.69 (s, 2H), 5.04 (br dd, 1H, J = 8.4 Hz, 6.5 Hz), 3.64-3.18 (m, 7H), 3.02 (br t, 1H, J = 12.1 Hz), 2.98-2.90 (m, 2H), 2.16-2.07 (m, 4H), 1.89-1.56 (m, 4H), 1.37-1.35 (m, 6H), 0.97 ( d, 3H, J = 6.7 Hz), 0.94 (d, 3H, J = 6.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 528 ((M + H) ⁺ ).

(Reference Example 1)
(3R, 5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid

(1a) 1-tert-butyl 3,5-dimethylpiperidine-1,3,5-tricarboxylate 32 ml (441 mmol) of thionyl chloride was added to methanol (500 ml) under ice cooling, and then pyridine-3, 25.47 g (152 mmol) of 5-dicarboxylic acid was added, and the mixture was stirred for 6 hours with heating under reflux. The reaction mixture was evaporated under reduced pressure to give crude dimethyl pyridine-3,5-dicarboxylate hydrochloride. A mixture of the crude dimethyl pyridine-3,5-dicarboxylate hydrochloride thus obtained and 0.64 g of platinum (IV) oxide in acetic acid (200 ml) was stirred at room temperature for 5 days in a hydrogen atmosphere. After replacing hydrogen in the reaction vessel with nitrogen, the platinum catalyst was filtered off. The filtrate was concentrated under reduced pressure and azeotroped with toluene and methanol. To this residue was added 300 ml of methylene chloride to dissolve, and 32.0 ml (230 mmol) of triethylamine and 36.01 g (165 mmol) of di-tert-butyl dicarbonate were added under ice cooling, followed by stirring at room temperature for 3 hours. did. After completion of the reaction, the insoluble material was filtered off and washed with hexane and ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the insoluble material was again filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100/1 to 50/1) to give 44.10 g of the title compound (total yield over 3 steps: 90%). )
White solid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 4.58-4.10 (1.4H, m), 3.70 (6H, s), 3.84-3.35 (1H, m), 2.88-2.56 (2H, m), 2.55- 2.34 (2H, m), 2.20-1.93 (0.6H, m), 1.76-1.56 (1H, m), 1.46 and 1.45 (total 9H, each s).
(1b) 1- (tert-Butoxycarbonyl) piperidine-3,5-dicarboxylic acid 1-tert-butyl 3,5-dimethylpiperidine-1,3,5-tricarboxylate 45 obtained in Reference Example (1a) To a solution of 0.0 g (149 mmol) in methanol (600 ml) and water (150 ml) was added 60.3 g (436 mmol) of potassium carbonate, and the mixture was stirred for 12 hours with heating under reflux. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, 3N hydrochloric acid was added to the concentrated mixture to adjust to pH 3, and the precipitated solid was collected by filtration. The obtained solid was washed with water and diisopropyl ether and then dried to obtain 30.0 g (yield: 74%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 4.32 (2H, br d, J = 9.8 Hz), 2.80-2.64 (br, 2H), 2.49-2.40 (m, 3H), 1.68-1.60 (m , 1H), 1.47 (s, 9H).
(1c) (3R, 5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid 1- (tert-butoxycarbonyl) piperidine-3 obtained in Reference Example (1b) , 5-dicarboxylic acid (22.39 g, 81.9 mmol) was dissolved in acetic anhydride (200 ml) and stirred at 100 ° C. for 10 hours. After cooling at room temperature, the reaction mixture was evaporated under reduced pressure to give crude tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo [3,3,1] nonane-7-carboxy. 21.13 g of lato was obtained. The crude tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo [3,3,1] nonane-7-carboxylate obtained here was added to a solution of 21.13 g in tetrahydrofuran (820 ml) at −20 ° C. N-[(9S) -6′-methoxycinconan-9-yl] -3,5-bis (trifluoromethyl) benzenesulfonamide (Angew. Chem. Int. Ed., 2008) In addition, 7.45 g (12.4 mmol) of asymmetric organic catalyst I) described in the year 47, p.7872 and 33.5 ml (827 mmol) of methanol were added and stirred at the same temperature for 20 hours. The reaction mixture was acidified with 1N hydrochloric acid (300 ml), returned to room temperature, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1 to 1/1 to 0/1) to give the title compound 19 .35 g (2 step total yield: 81%) was obtained.

The obtained (3R, 5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid was analyzed using an optically active HPLC column for analysis [ChiralPak AD-H (0.46 cm × 25 cm). , Manufactured by Daicel, elution solvent: n-hexane / ethanol = 95/5, flow rate: 0.5 ml / min)]. The retention time of the target (3R, 5S) isomer is 29.6 minutes, the retention time of the corresponding (3S, 5R) isomer is 33.3 minutes, and the optical purity is 96% ee. there were.

The obtained (3R, 5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid was obtained by forming a salt with (R) -phenethylamine in ethanol. By recrystallizing R) -phenethylamine salt from ethanol, (3R, 5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid having an optical purity of 99% or more was obtained. I was able to get it.
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 4.37 (br s, 2H), 3.71 (s, 3H), 2.72 (br s, 2H), 2.55-2.45 (m, 3H), 1.72 (q, 1H , J = 12.7 Hz), 1.47 (s, 9H).

(Reference Example 2)
(3R) -5-Methylhexane-3-amine hydrochloride

(2a) tert-butyl [(1S) -3-methyl-1-vinylbutyl] carbamate tert-butyl [(1S) -1- (hydroxymethyl) -3-methylbutyl] carbamate 1.50 g (6.9 mmol) and triethylamine To a solution of 2.88 ml (20.7 mmol) of dimethyl sulfoxide (15 ml) was added 3.30 g (20.7 mmol) of a dimethyl sulfoxide (15 ml) solution of sulfur trioxide-pyridine complex under ice-cooling, and the mixture was heated to the same temperature. And stirred for 10 minutes. The reaction mixture was poured into ice water and extracted three times with diethyl ether. The organic layer was washed with 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain crude tert-butyl [(1S) -1-formyl-3-methylbutyl] carbamate. The toluene solution (13 ml) of tert-butyl [(1S) -1-formyl-3-methylbutyl] carbamate obtained here was charged with 5.70 g (20.7 mmol) of methylenetriphenylphosphorane under ice cooling. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1 to 4/1) to give 0.86 g (2 The total process yield was 58%).
Colorless oil.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 5.77-5.70 (m, 1H), 5.15 (br d, 1H, J = 17.6 Hz), 5.06 (br d, 1H, J = 10.3 Hz), 4.38 ( br s, 1H), 4.14 (br s, 1H), 1.72-1.64 (m, 1H), 1.44 (br s, 9H), 1.36-1.30 (m, 2H), 0.93-0.91 (m, 6H).
(2b) (3R) -5-methylhexane-3-amine hydrochloride 0.86 g (4.0 mmol) of tert-butyl [(1S) -3-methyl-1-vinylbutyl] carbamate obtained in Reference Example (2a) ) And 10% palladium carbon (containing 50% water) in 430 mg of methanol (30 ml) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. The filtrate was concentrated under reduced pressure to give crude tert-butyl [(1R) -1-ethyl-3-methylbutyl] carbamate.

To a solution of the crude tert-butyl [(1R) -1-ethyl-3-methylbutyl] carbamate obtained here in methylene chloride (10 ml) was added 5 ml (65 mmol) of trifluoroacetic acid, and the mixture was stirred at room temperature for 10 minutes. . The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, the organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, 2 ml (8 mmol) of 4N hydrochloric acid-dioxane solution was added to the residue, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to obtain 340 mg of the title compound (total yield over two steps: 56%).
Colorless solid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.34 (br s, 3H), 3.22-3.16 (m, 1H), 1.92-1.84 (m, 1H), 1.80-1.64 (m, 3H), 1.50- 1.44 (m, 1H), 1.08 (t, 3H, J = 7.8 Hz), 0.95-0.93 (m, 6H).

(Reference Example 3)
1-isobutylcyclopentan-1-amine hydrochloride

To a solution of 5.8 ml (41.3 mmol) of diisopropylamine in 40 ml of tetrahydrofuran under a nitrogen atmosphere and ice-cooling, 26.4 ml (42.42 ml) of an n-butyllithium n-hexane solution (1.6 mol / l). 2 mmol) was added for 15 minutes and stirred at the same temperature for 15 minutes to prepare a lithium diisopropylamide (LDA) solution. The LDA solution was cooled in a dry ice-acetone bath, 5.30 g (37.4 mmol) of ethyl cyclopentanecarboxylate was added over 5 minutes, and the mixture was stirred at the same temperature for 40 minutes. Next, 7.60 g (41.3 mmol) of isobutyl iodide and 8 ml of hexamethylphosphoric triamide (HMPA) were added, the temperature was raised to room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 6.5 g of crude ethyl 1-isobutylcyclopentane-1-carboxylate.

To a mixture of 18.60 g (166 mmol) of potassium tert-butoxide and 0.74 ml (41 mmol) of water in tetrahydrofuran (150 ml) was added 4.11 g of crude ethyl 1-isobutylcyclopentane-1-carboxylate obtained in the previous reaction ( 20.8 mmol) in tetrahydrofuran (50 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 4.1 g of crude 1-isobutylcyclopentane-1-carboxylic acid.

Crude 1-isobutylcyclopentane-1-carboxylic acid (86% content) 4.0 g (20.2 mmol) obtained in this reaction and triethylamine 3.4 ml (24.4 mmol) in a toluene (45 ml) solution were added to diphenyl. 7.10 g (25.8 mmol) of phosphoric acid azide (DPPA) was added, stirred at room temperature for 30 minutes, and then stirred at 90 ° C. for 1 hour. To the reaction mixture, 4.8 ml (44 mmol) of benzyl alcohol was added at 90 ° C., and the mixture was further stirred at 90 ° C. for 3 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 4/1) to obtain benzyl (1-isobutylcyclopentyl). 4.5 g of carbamate (total yield over 3 steps: 71%) was obtained.

A mixture of 4.5 g (16.3 mmol) of benzyl (1-isobutylcyclopentyl) carbamate obtained above and 1.5 g of 20% palladium hydroxide-carbon (containing 50% water) in methanol (60 ml) was placed under a hydrogen atmosphere at room temperature. For 6 hours. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. To the filtrate, 4N hydrochloric acid-dioxane (8.2 ml, 32.4 mmol) was added, and the solvent was distilled off. Ethyl acetate was added to the residue, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to obtain 1.50 g (yield: 52%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 1.86-1.75 (m, 9H), 1.66 (d, 2H, J = 5.9 Hz), 1.02 (d, 6H, J = 6.8 Hz).

(Reference Example 4)
4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride

To a solution of 5.00 g (25.4 mmol) of ethyl 4,4,4-trifluoro-2,2-dimethylbutyrate in ethanol (25 ml) -water (25 ml) was added 50 ml (100 mmol) of 2N aqueous potassium hydroxide, The mixture was stirred at 60 ° C. for 4 days. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 5.00 g of crude 4,4,4-trifluoro-2,2-dimethylbutyric acid.

Crude 4,4,4-trifluoro-2,2-dimethylbutyric acid (86% content) 5.00 g (25.4 mmol) obtained in this reaction and 4.2 ml (30.2 mmol) of triethylamine (60 ml) ) 8.90 g (32.3 mmol) of diphenyl phosphate azide (DPPA) was added to the solution, and the mixture was stirred at room temperature for 30 minutes and then at 90 ° C. for 1.5 hours. To the reaction mixture, 6.0 ml (55 mmol) of benzyl alcohol was added at 90 ° C., and the mixture was further stirred at 90 ° C. for 3 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 0-4 / 1) to give benzyl (3, 3, 3 -Trifluoro-1,1-dimethylpropyl) carbamate 6.40 g (2 step total yield: 92%) was obtained.

6.40 g (23.2 mmol) of benzyl (3,3,3-trifluoro-1,1-dimethylpropyl) carbamate obtained here and 2.00 g of methanol with 20% palladium hydroxide-carbon (containing 50% water) (80 ml) The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. To the filtrate was added 4N hydrochloric acid-dioxane (12 ml, 48 mmol), and the solvent was distilled off. Water was added to the residue, the aqueous layer was washed with diethyl ether, basified with 1N aqueous sodium hydroxide solution, extracted with diethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. . After filtration, 6N (24 mmol) of 4N hydrochloric acid-dioxane was added to the filtrate, and the precipitated solid was collected by filtration, washed with diethyl ether and dried to obtain 2.10 g (yield: 51%) of the title compound. .
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 2.71 (q, 2H, J = 11.2 Hz), 2.66 (d, 1H, J = 11.2 Hz), 1.50 (s, 6H).

(Reference Example 5)
N, N-dimethyl-L-leucinamide hydrochloride

To a solution of 600 mg (2.41 mmol) of N-tert-butoxycarbonyl-L-leucine monohydrate in methylene chloride (8 ml) was added 369 mg (2.41 mmol) of 1-hydroxybenzotriazole monohydrate under ice cooling. 509 mg (2.66 mmol) of-(3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) hydrochloride and 2.60 ml (5.20 mmol) of dimethylamine in tetrahydrofuran (2.0 mol / l) were added at room temperature. Stir for 2.5 hours. 0.5N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 100/1 to 50/1) to give N ^2- (tert-butoxycarbonyl). There was obtained 538 mg (yield: 87%) of -N, N-dimethyl-L-leucinamide. To a solution of 538 mg (2.08 mmol) of N ^2- (tert-butoxycarbonyl) -N, N-dimethyl-L-leucinamide obtained here in 1,4-dioxane (3.0 ml), 4N hydrochloric acid-dioxane was added. 3.0 ml (12 mmol) of the solution was added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure to obtain 385 mg (yield: 95%) of the title compound.
Colorless solid.
¹ H NMR spectrum (DMSO-d ₆ , 500 MHz), δ: 8.44-8.02 (m, 3H), 4.34-4.22 (m, 1H), 3.01 (s, 3H), 2.88 (s, 3H), 1.84-1.68 (m, 1H), 1.64-1.42 (m, 2H), 0.92 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H).

(Reference Example 6)
(2R) -1-Ethoxy-4-methylpentan-2-amine

(6a) (2R) -2- (Dibenzylamino) -4-methylpentan-1-ol
14.74 g (106.7 mmol) of potassium carbonate was added to a solution of 5 g (42.67 mmol) of (R) -leucinol and 11.16 ml (93.87 mmol) of benzyl bromide in ethanol (200 ml), and the mixture was stirred at room temperature for 4 days. did. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1 to 1/1) to give 10.81 g (yield) of the title compound. Rate: 85%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.33-7.21 (m, 10H), 3.81 (d, 2H, J = 13.3 Hz), 3.48 (dd, 1H, J = 10.6 Hz, 5.1 Hz), 3.42 (d, 1H, J = 10.6 Hz), 3.37 (d, 2H, J = 13.3 Hz), 3.19 (br s, 1H), 2.84 (ddt, 1H, J = 9.8 Hz, 5.1 Hz, 2.4 Hz), 1.55 -1.46 (m, 2H), 1.20-1.11 (m, 1H), 0.92 (d, 3H, J = 6.3 Hz), 0.86 (d, 3H, J = 6.3 Hz).
(6b) (2R) -N, N-dibenzyl-1-ethoxy-4-methylpentan-2-amine (2R) -2- (dibenzylamino) -4-methylpentane obtained in Reference Example (6a) To a solution of -1-ol 2.00 g (6.72 mmol) and ethyl iodide 0.7 ml (8.74 mmol) in tetrahydrofuran (30 ml) at room temperature, sodium hydride (60% content) 349 mg (8.74 mmol) ) Was added for 10 minutes and stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 5/1) to give 1.78 g (yield) of the title compound. Rate: 81%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37 (br d, 4H, J = 7.4 Hz), 7.30-7.26 (m, 6H), 7.22-7.17 (m, 4H), 3.75 (d, 2H, J = 13.7 Hz), 3.66-3.61 (m, 3H), 3.45 (q, 2H, J = 7.0 Hz), 3.38 (dd, 1H, J = 9.8 Hz, 5.1 Hz), 2.89-2.83 (m, 1H) , 1.84-1.74 (m, 1H), 1.46 (ddd, 1H, J = 13.7 Hz, 8.2 Hz, 5.4 Hz), 2.22 (t, 3H, J = 7.0 Hz), 1.10 (ddd, 1H, J = 13.7 Hz , 8.2 Hz, 5.4 Hz), 0.82 (d, 3H, J = 6.3 Hz), 0.59 (d, 3H, J = 6.3 Hz).
(6c) (2R) -1-ethoxy-4-methylpentan-2-amine (2R) -N, N-dibenzyl-1-ethoxy-4-methylpentan-2-amine obtained in Reference Example (6b) A mixture of 1.78 g (5.47 mmol) and 20% palladium hydroxide on carbon (containing 50% water) in 360 mg of methanol (25 ml) was stirred at room temperature for 6 hours under a hydrogen atmosphere of 1 MPa. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 799 mg (yield: 98%) of the title compound.
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 3.55-3.45 (m, 2H), 3.39 (dd, 1H, J = 9.0 Hz, 3.7 Hz), 3.12 (t, 1H, J = 8.6 Hz), 3.05 -3.00 (m, 1H), 1.77-1.69 (m, 1H), 1.22-1.13 (m, 5H), 0.93 (d, 3H, J = 6.8 Hz), 0.90 (d, 3H, J = 6.8 Hz).

(Reference Example 7)
2- (4,4-Difluorocyclohexyl) propan-2-amine

(7a) Benzyl [1-methyl-1- (4-oxocyclohexyl) ethyl] carbamate To a solution of 3.66 ml (26.3 mmol) of diisopropylamine in tetrahydrofuran (50 ml) under a nitrogen atmosphere under ice cooling, n- 16.5 ml (26.3 mmol) of n-hexane solution of butyllithium was added over 15 minutes and stirred for 10 minutes at the same temperature to prepare a lithium diisopropylamide (LDA) solution. . The LDA solution was cooled in a dry ice-acetone bath, and a solution of 5 g (21.9 mmol) of ethyl (1,4-dioxaspiro [4,5] dec-8-yl) acetate in tetrahydrofuran (50 ml) was added at the same temperature. Then, 1.63 ml (26.3 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was cooled again in a dry ice-acetone bath and 3.66 ml (26.3 mmol) of diisopropylamine, 16.5 ml (26.3 mmol) of n-butyllithium in n-hexane (1.6 mol / l) and An LDA solution prepared from tetrahydrofuran (50 ml) was added, and the mixture was stirred at the same temperature for 1 hour. Then, methyl iodide (1.63 ml, 26.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 0-7 / 3) to give ethyl 2- (1,4 -3.84 g (yield: 68%) of dioxaspiro [4,5] dec-8-yl) -2-methylpropanoate was obtained.

Ethyl 2- (1,4-dioxaspiro [4,5] dec-8-yl) -2-methylpropanoate 3.84 g (15.0 mmol) of tetrahydrofuran (15 ml) -methanol (15 ml) obtained by this reaction ) A solution of 8.4 g (149.8 mmol) of potassium hydroxide in water (15 ml) was added to the solution, and the mixture was stirred for 2 days with heating under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To this concentrated mixture, 5N hydrochloric acid was added under ice-cooling, followed by extraction with methylene chloride. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain crude 2- (1,4-dioxaspiro [4,5] dec-8-yl) -2-methylpropionic acid.

Crude 2- (1,4-dioxaspiro [4,5] dec-8-yl) -2-methylpropionic acid and 2.7 ml (19.5 mmol) of triethylamine obtained in this reaction were added to a toluene (75 ml) solution. Then, 4.53 g (16.5 mmol) of diphenylphosphoric acid azide (DPPA) was added, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 90 ° C. for 2.5 hours. To the reaction mixture, 3.1 ml (30 mmol) of benzyl alcohol was added at 90 ° C., and the mixture was further stirred at 90 ° C. for 4 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 1/1) to give benzyl [1- (1, A mixture of 4-dioxaspiro [4,5] dec-8-yl) -1-methylethyl] carbamate and benzyl [1-methyl-1- (4-oxocyclohexyl) ethyl] carbamate was obtained.

Benzyl [1- (1,4-dioxaspiro [4,5] dec-8-yl) -1-methylethyl] carbamate and benzyl [1-methyl-1- (4-oxocyclohexyl) ethyl obtained by this reaction A solution of carbamate in 80% aqueous acetic acid (100 ml) was stirred at room temperature for 16 hours, and further stirred at 60 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 1/1) to give 1.35 g (3 The total process yield was 31%).
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.38-7.31 (m, 5H), 5.06 (br s, 2H), 4.69 (br s, 1H), 2.56-2.32 (m, 5H), 2.06- 2.04 (m, 2H), 1.51-1.42 (m, 2H), 1.30 (s, 6H).
(7b) 2- (4,4-difluorocyclohexyl) propan-2-amine 730 mg (2.52 mmol) of benzyl [1-methyl-1- (4-oxocyclohexyl) ethyl] carbamate obtained in Reference Example (7a) To a methylene chloride (25 ml) solution was added 0.67 ml (5.0 mmol) of sulfur trifluoride diethylamine complex (DAST) under ice cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added under ice cooling, followed by extraction with methylene chloride, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 4/1) to give benzyl [1- (4, There were obtained 444 mg (yield: 57%) of 4-difluorocyclohexyl) -1-methylethyl] carbamate.

Trimethylsilane iodide was added to a solution of 232 mg (0.75 mmol) of benzyl [1- (4,4-difluorocyclohexyl) -1-methylethyl] carbamate obtained in this reaction in methylene chloride (4 ml) under ice cooling. 127 μl (0.89 mmol) was added and stirred at the same temperature for 30 minutes. At the same temperature, 100 μl (0.70 mmol) of trimethylsilane iodide was added to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and 10% aqueous sodium thiosulfate solution, diluted with methylene chloride, and extracted with 2N hydrochloric acid. The aqueous layer was basified with 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 95 mg (yield: 72%) of the crude title compound.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 2.18-2.10 (m, 2H), 1.89-1.84 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.21 (m, 3H), 1.08 (s, 6H).

(Reference Example 8)
2- (Tetrahydro-2H-pyran-4-yl) propan-2-amine

To a toluene (14 ml) solution of 500 mg (2.90 mmol) of 2-methyl-2- (tetrahydro-2H-pyran-4-yl) propionic acid and 0.45 ml (3.2 mmol) of triethylamine was added diphenyl phosphate azide (DPPA). 0.68 ml (0.68 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 90 ° C. for 30 minutes. To the reaction mixture, 0.6 ml (5.8 mmol) of benzyl alcohol was added at 90 ° C., and the mixture was further stirred at 90 ° C. for 12 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 597 mg of crude benzyl [1-methyl-1- (tetrahydro-2H-pyran-4-yl) ethyl] carbamate.

597 mg (2.1 mmol) of crude benzyl [1-methyl-1- (tetrahydro-2H-pyran-4-yl) ethyl] carbamate obtained here and 60 mg of 20% palladium hydroxide-carbon (containing 50% water) methanol The (10 ml) mixture was stirred at room temperature for 13 hours under hydrogen atmosphere. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 208 mg (yield: 67%) of the title compound.
Colorless oil.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 4.05-4.02 (m, 2H), 3.38-3.34 (m, 2H), 1.65-1.55 (m, 3H), 1.41-1.35 (m, 2H), 1.07 (s, 6H).

(Reference Example 9)
1-phenylcyclopentan-1-amine hydrochloride

To a solution of 5.0 g (26.3 mmol) of 1-phenylcyclopentane-1-carboxylic acid and 3.8 ml (27.3 mmol) of triethylamine in toluene (50 ml) was added 7.90 g (28.7 mmol) of diphenyl phosphate azide (DPPA). ) And stirred at room temperature for 30 minutes and then at 90 ° C. for 1 hour. To the reaction mixture, 5.4 ml (50 mmol) of benzyl alcohol was added at 90 ° C., and the mixture was further stirred at 90 ° C. for 5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 4/1) to obtain benzyl (1-phenylcyclopentyl). 7.80 g of carbamate (yield: quantitative) was obtained.

A mixture of 7.80 g (26.3 mmol) of benzyl (1-phenylcyclopentyl) carbamate and 3.00 g of methanol (200 ml) containing 20% palladium hydroxide-carbon (containing 50% water) obtained under the hydrogen atmosphere at room temperature. For 2.5 hours. After replacing hydrogen in the reaction vessel with nitrogen, the palladium catalyst was filtered off. To the filtrate was added 4N hydrochloric acid-dioxane 13 ml (52 mmol), and the solvent was distilled off. Ethyl acetate was added to the residue, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to give 4.30 g (yield: 83%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.55-7.53 (m, 2H), 7.48-7.44 (m, 2H), 7.41-7.38 (m, 1H), 2.36-2.24 (m, 4H), 2.02-1.86 (m, 4H).

(Reference Example 10)
(1R) -2-Cyclopropyl-1-phenylethane-1-amine hydrochloride

(10a) 2-Cyclopropyl-1-phenylethanone n-Hexane solution of diethylzinc (1.0 mol / l) 46 ml (46 mmol) and dichloroethane (90 ml) were mixed with chloroiodomethane 16 under ice cooling. .20 g (92.6 mmol) was added over 1.5 hours, then dichloroethane (60 ml) was added for dilution, and the mixture was stirred at the same temperature for 1 hour. To this reaction mixture, 3.37 g (22.7 mmol) of 1-phenyl-3-buten-1-ol was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours and further stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 0-7 / 3) to give 2-cyclopropyl-1- 2.50 g (yield: 68%) of phenylethanol was obtained.

To a solution of 2.50 g (15.4 mmol) of 2-cyclopropyl-1-phenylethanol obtained here in methylene chloride (150 ml), (1,1,1-triacetoxy) -1,1-dihydro-1, 9.81 g (23.1 mmol) of 2-benziodoxol-3 (1H) -one (Dess-Martin oxidizing reagent) was added, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 0-4 / 1) to give 2.45 g (yield) of the title compound. Rate: 99%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.96-7.94 (m, 2H), 7.57-7.54 (m, 1H), 7.48-7.45 (m, 2H), 2.89 (d, 2H, J = 6.8 Hz ), 1.21-1.13 (m, 1H), 0.62-0.58 (m, 2H), 0.21-0.18 (m, 2H).
(10b) N-[(1E) -2-cyclopropyl-1-phenylethylidene] -2-methylpropane-2-sulfinamide 2-cyclopropyl-1-phenylethanone 2 obtained in Reference Example (10a) To a solution of .46 g (15.4 mmol) and (S)-(−)-tert-butanesulfinamide 1.64 g (13.5 mmol) in tetrahydrofuran (30 ml) was added tetraethyl orthotitanate (5.59 g, 24.5 mmol). In addition, the mixture was stirred at 70 ° C. for 8 hours. After cooling to room temperature, saturated brine (30 ml) was added to the reaction mixture, and the insoluble material was filtered off using Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 0-7 / 3) to give 2.43 g (yield) of the title compound. Rate: 68%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.89-7.87 (m, 2H), 7.50-7.42 (m, 3H), 3.25-3.15 (m, 2H), 1.33 (s, 9H), 1.02-0.94 (m, 1H), 0.52-0.43 (m, 2H), 0.37 (br s, 2H).
(10c) N-[(1R) -2-cyclopropyl-1-phenylethyl] -2-methylpropane-2-sulfinamide N-[(1E) -2-cyclopropyl obtained in Reference Example (10b) 1-Phenylethylidene] -2-methylpropane-2-sulfinamide 2.43 g (9.23 mmol) in tetrahydrofuran (20 ml) was added under ice cooling to a solution of L-selectride in tetrahydrofuran (1.0 mol / mol). l) 27 ml (27 mmol) was added over 5 minutes and stirred at the same temperature for 10 minutes. After returning the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 3/2) to give the title 1.00 g (yield: 41%) of compound was obtained.
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.37-7.25 (m, 5H), 4.52 (dt, 1H, J = 7.0 Hz, 2.2 Hz), 3.76 (br s, 1H), 1.95-1.90 (m , 1H), 1.46 (dt, 1H, J = 13.7 Hz, 7.8 Hz), 1.20 (s, 9H), 0.65-0.57 (m, 1H), 0.54-0.48 (m, 1H), 0.45-0.40 (m, 1H), 0.16-0.11 (m, 1H), 0.05-0.01 (m, 1H).
(10d) (1R) -2-Cyclopropyl-1-phenylethane-1-amine hydrochloride N-[(1R) -2-cyclopropyl-1-phenylethyl] -2 obtained in Reference Example (10c) -To a solution of 1.00 g (3.77 mmol) of methylpropane-2-sulfinamide in methanol (2.0 ml) was added 2.0 ml (8.0 mmol) of 4N hydrochloric acid-dioxane solution and stirred at room temperature for 15 minutes. . Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 0.70 g (yield: 94%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.49-7.40 (m, 5H), 4.34 (dd, 1H, J = 8.0 Hz, 6.4 Hz), 2.00-1.95 (m, 1H), 1.77-1.71 (m, 1H), 0.63-0.55 (m, 1H), 0.54-0.49 (m, 1H), 0.47-0.41 (m, 1H), 0.21-0.16 (m, 1H), 0.08-0.03 (m, 1H) .

(Reference Example 11)
(1R) -3-Methyl-1-phenylbutan-1-amine hydrochloride

(11a) 2-Methyl-N-[(1E) -3-methyl-1-phenylbutylidene] propane-2-sulfinamide 3-methyl-1-phenylbutanone 3.00 g (18.5 mmol) and (S) To a solution of 2.00 g (16.5 mmol) of-(-)-tert-butanesulfinamide in tetrahydrofuran (36 ml) was added 6.82 g (29.9 mmol) of tetraethyl orthotitanate, and the mixture was stirred at 70 ° C for 5.5 hours. did. After cooling to room temperature, saturated brine (35 ml) was added to the reaction mixture, insoluble matter was filtered off, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 0-7 / 3) to give 2.31 g (yield) of the title compound. Rate: 47%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.82-7.80 (m, 2H), 7.48-7.40 (m, 3H), 3.35-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.10 -2.02 (m, 1H), 1.32 (s, 9H), 0.98-0.96 (m, 6H).
(11b) 2-Methyl-N-[(1R) -3-methyl-1-phenylbutyl] propane-2-sulfinamide 2-methyl-N-[(1E) -3 obtained in Reference Example (11a) -Methyl-1-phenylbutylidene] propane-2-sulfinamide in a solution of 2.31 g (8.70 mmol) in tetrahydrofuran (20 ml) was added to a tetrahydrofuran solution of L-selectride (1.0 mol / l under ice-cooling). ) 26 ml (26 mmol) was added over 5 minutes and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/0 to 1/1) to give 1.93 g (yield: 83) of the title compound. %).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.34-7.25 (m, 5H), 4.47-4.43 (m, 1H), 3.33 (br s, 1H), 1.72-1.63 (m, 2H), 1.48- 1.40 (m, 1H), 1.16 (s, 9H), 0.94 (d, 3H, J = 6.4 Hz), 0.89 (d, 3H, J = 6.4 Hz).
(11c) (1R) -3-Methyl-1-phenylbutan-1-amine hydrochloride 2-methyl-N-[(1R) -3-methyl-1-phenylbutyl] obtained in Reference Example (11b) To a solution of 1.93 g (7.22 mmol) of propane-2-sulfinamide in methanol (3.6 ml) was added 3.6 ml (14.4 mmol) of 4N hydrochloric acid-dioxane solution, and the mixture was stirred at room temperature for 40 minutes. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 1.30 g (yield: 90%) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.49-7.41 (m, 5H), 4.31 (dd, 1H, J = 10.0 Hz, 5.6 Hz), 1.93 (ddd, 1H, J = 15.6 Hz, 10.3 Hz, 5.4 Hz), 1.81-1.75 (m, 1H), 1.44-1.36 (m, 1H), 0.96 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.8 Hz).

(Reference Example 12)
(1R) -1- (2-Fluorophenyl) propan-1-amine hydrochloride

Using 2-fluoropropiophenone in the same manner as in Reference Example 11, 1.10 g of the title compound was obtained (total yield over 3 steps: 44%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.51-7.45 (m, 2H), 7.33-7.29 (m, 1H), 7.25-7.21 (m, 1H), 4.47 (dd, 1H, J = 9.3 Hz, 5.9 Hz), 2.12-1.94 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz).

(Reference Example 13)
(1R) -1- (3-Fluorophenyl) propan-1-amine hydrochloride

In the same manner as in Reference Example 11, 1.20 g (total yield over 3 steps: 48%) of the title compound was obtained using 3-fluoropropiophenone.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 7.52-7.47 (m, 1H), 7.27-7.16 (m, 3H), 4.21 (dd, 1H, J = 9.3 Hz, 5.9 Hz), 2.08-1.90 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz).

(Reference Example 14)
(1R) -1- (4-Fluorophenyl) propan-1-amine hydrochloride

Using 4-fluoropropiophenone in the same manner as in Reference Example 11, 1.23 g of the title compound was obtained (total yield over 3 steps: 49%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.50-7.44 (m, 2H), 7.23-7.18 (m, 2H), 4.19 (dd, 1H, J = 9.2 Hz, 5.7 Hz), 2.09-1.88 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz).

(Reference Example 15)
(1R) -1-Pyridin-2-ylpropan-1-amine dihydrochloride

In the same manner as in Reference Example 11, 1.35 g (total yield over 3 steps: 48%) of the title compound was obtained using 1-pyridin-2-ylpropan-1-one.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 8.83-8.82 (m, 1H), 8.36-8.32 (m, 1H), 7.90 (br d, 1H, J = 7.8 Hz), 7.82-7.79 (m , 1H), 4.57 (t, 1H, J = 7.2 Hz), 2.19-2.03 (m, 2H), 0.97 (t, 3H, J = 7.4 Hz).

(Reference Example 16)
(1R) -3-Methyl-1-pyridin-2-ylbutan-1-amine dihydrochloride

In the same manner as in Reference Example 11, using 3-methyl-1-pyridin-2-ylbutan-1-one, 1.73 g of the title compound (total yield over three steps: 55%) was obtained.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.81-8.79 (m, 1H), 8.28 (dt, 1H, J = 7.8 Hz, 1.5 Hz), 7.86 (br d, 1H, J = 7.8 Hz) , 7.75 (ddd, J = 7.8, 5.4, 1 Hz), 4.66 (t, 1H, J = 7.3 Hz), 1.99-1.87 (m, 2H), 1.57-1.49 (m, 1H), 1.02 (d, 3H , J = 6.8 Hz), 0.97 (d, 3H, J = 6.8 Hz).

(Reference Example 17)
(1R) -1- (5-Fluoropyridin-2-yl) -3-methylbutan-1-amine dihydrochloride

(17a) 1- (5-Fluoropyridin-2-yl) -3-methylbutan-1-one To a solution of 3.07 g (25.1 mmol) of 2-cyano-5-fluoropyridine in tetrahydrofuran (50 ml) was added dry ice- Under cooling in an acetone bath, 32 ml (32 mmol) of isobutylmagnesium bromide in tetrahydrofuran (1.0 mol / l) was added over 20 minutes, stirred at the same temperature for 10 minutes, and then at room temperature for 1.5 hours. Stir. 2N hydrochloric acid was added to the reaction mixture under ice cooling. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 7 to 8, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 2/1) to give 2.50 g (yield) of the title compound. Rate: 55%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.49 (d, 1H, J = 2.9 Hz), 8.10 (dd, 1H, J = 8.8 Hz, 4.4 Hz), 7.50 (dt, 1H, J = 8.3 Hz) , 2.9 Hz), 3.06 (d, 2H, J = 7.3 Hz), 2.34-2.26 (m, 1H), 0.99 (d, 6H, J = 6.8 Hz).
(17b) N-[(1E) -1- (5-Fluoropyridin-2-yl) -3-methylbutylidene] -2-methylpropane-2-sulfinamide 1-obtained in Reference Example (17a) Tetrahydrofuran of (5-fluoropyridin-2-yl) -3-methylbutan-1-one 2.50 g (13.8 mmol) and (S)-(−)-tert-butanesulfinamide 1.67 g (13.8 mmol) (65 ml) To the solution was added 6.29 g (27.6 mmol) of tetraethyl orthotitanate, and the mixture was stirred at 70 ° C. for 17 hours. After cooling to room temperature, saturated brine (35 ml) was added to the reaction mixture, insoluble matter was filtered off, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 2/1) to give 2.74 g (yield) of the title compound. Rate: 70%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.47 (d, 1H, J = 2.9 Hz), 8.11 (br s, 1H), 7.47-7.43 (m, 1H), 3.45-3.42 (m, 1H) 3.30-3.26 (m, 1H), 2.18-2.10 (m, 1H), 1.32 (s, 9H), 0.96-0.95 (m, 6H).
(17c) N-[(1R) -1- (5-Fluoropyridin-2-yl) -3-methylbutyl] -2-methylpropane-2-sulfinamide N-[(( 1E) -1- (5-Fluoropyridin-2-yl) -3-methylbutylidene] -2-methylpropane-2-sulfinamide 2.74 g (9.63 mmol) in tetrahydrofuran (36 ml) was added to dry ice. -While cooling in an acetone bath, 11 ml (11 mmol) of a tetrahydrofuran solution (1.0 mol / l) of L-selectride was added over 5 minutes, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and further diluted with water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/0 to 2/1) to give 2.10 g (yield) of the title compound. Rate: 76%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 8.43 (d, 1H, J = 2.7 Hz), 7.36 (dt, 1H, J = 8.6 Hz, 2.7 Hz), 7.29-7.26 (m, 1H), 4.55 (dt, 1H, J = 7.4 Hz, 5.5 Hz), 3.73 (br d, 1H, J = 5.5 Hz), 1.84-1.72 (m, 2H), 1.54-1.44 (m, 1H), 1.15 (s, 9H ), 0.95 (d, 3H, J = 6.7 Hz), 0.91 (d, 3H, J = 6.7 Hz).
(17d) (1R) -1- (5-Fluoropyridin-2-yl) -3-methylbutan-1-amine dihydrochloride N-[(1R) -1- (5 -Fluoropyridin-2-yl) -3-methylbutyl] -2-methylpropane-2-sulfinamide 2.10 g (7.33 mmol) in methanol (20 ml) was added 4N hydrochloric acid-dioxane solution 20 ml (80 mmol). The mixture was further stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 1.92 g (yield: quantitative) of the title compound.
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.56 (d, 1H, J = 2.9 Hz), 7.67 (dt, 1H, J = 8.6 Hz, 2.9 Hz), 7.53 (dd, 1H, J = 8.8 Hz, 4.4 Hz), 4.51-4.48 (m, 1H), 1.86 (ddd, 1H, J = 13.7 Hz, 8.3 Hz, 6.4 Hz), 1.76 (ddd, 1H, J = 13.7 Hz, 7.8 Hz, 6.4 Hz) , 1.51-1.43 (m, 1H), 1.00 (d, 3H, J = 6.4 Hz), 0.94 (d, 3H, J = 6.4 Hz).

(Reference Example 18)
(1R) -1-Pyridin-3-ylpropan-1-amine dihydrochloride

In the same manner as in Reference Example 11, 1-pyridin-3-ylpropan-1-one was used to obtain 1.51 g of the title compound (total yield over 3 steps: 44%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 9.11 (d, 1H, J = 2.0 Hz), 8.99-8.98 (m, 1H), 8.82 (dt, 1H, J = 8.3 Hz, 1.7 Hz), 8.24 (dd, 1H, J = 8.3 Hz, 5.9 Hz), 4.62 (dd, 1H, J = 8.6 Hz, 6.6 Hz), 2.24-2.07 (m, 2H), 0.99 (t, 3H, J = 7.6 Hz) .

(Reference Example 19)
(1R) -3-Methyl-1-pyridin-3-ylbutan-1-amine dihydrochloride

In the same manner as in Reference Example 11, using 2. 3-methyl-1-pyridin-3-ylbutan-1-one, 2.20 g of the title compound was obtained (total yield over 3 steps: 38%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 9.16-9.15 (m, 1H), 8.99-8.98 (m, 1H), 8.87-8.84 (m, 1H), 8.24 (dd, 1H, J = 8.3 Hz, 5.9 Hz), 4.76 (dd, 1H, J = 8.8 Hz, 6.8 Hz), 2.07-1.96 (m, 2H), 1.54-1.46 (m, 1H), 1.01 (d, 3H, J = 6.8 Hz) , 0.99 (d, 3H, J = 6.8 Hz).

(Reference Example 20)
(1R) -1- (5-Fluoropyridin-3-yl) -3-methylbutan-1-amine dihydrochloride

(20a) 1- (5-Fluoropyridin-3-yl) -3-methylbutan-1-one 16.6 g (68 mmol) of 2,6-dichloro-5-fluoronicotinic acid chloride and N, O-dimethylhydroxyamine hydrochloride To a solution of 9.94 g (102 mmol) of the salt in methylene chloride (340 ml) was added 35.6 ml (204 mmol) of diisopropyloethylamine, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) to give 2,6-dichloro-5. 17.3 g (yield: 99%) of -fluoro-N-methoxy-N-methylnicotinamide was obtained.

2,7-dichloro-5-fluoro-N-methoxy-N-methylnicotinamide 17.3 g (68.3 mmol) obtained in this reaction and 10% palladium carbon (containing 50% water) 2.0 g ethanol (200 ml) ) 21.53 g (341.5 mmol) of ammonium formate and 8 ml (212 mmol) of formic acid were added to the mixture and stirred at 65 ° C. for 7 hours. The reaction mixture was returned to room temperature and the palladium catalyst was filtered off. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 0/1) to give 5-fluoro-N-methoxy. 7.20 g of N-methylnicotinamide (yield: 57%) was obtained.

To a solution of 5-fluoro-N-methoxy-N-methylnicotinamide 3.50 g (19.0 mmol) obtained in this reaction in tetrahydrofuran (50 ml) was added isobutylmagnesium bromide under cooling in a dry ice-acetone bath. A tetrahydrofuran solution (1.0 mol / l) of 24 ml (24 mmol) was added over 20 minutes, stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was cooled to −20 ° C., 21 ml (21 mmol) of isobutylmagnesium bromide in tetrahydrofuran (1.0 mol / l) was added over 20 minutes, and then stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and an appropriate amount of water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 0/1) to give 0.32 g (yield) of the title compound. Rate: 9%).
Colorless liquid.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 8.98 (t, 1H, J = 2.0 Hz), 8.65 (d, 1H, J = 2.9 Hz), 7.91 (ddd, 1H, J = 8.8 Hz, 2.9 Hz) , 2.0 Hz), 2.86 (d, 2H, J = 6.8 Hz), 2.36-2.28 (m, 1H), 1.02 (d, 6H, J = 6.8 Hz).
(20b) (1R) -1- (5-Fluoropyridin-3-yl) -3-methylbutan-1-amine dihydrochloride In the same manner as in Reference Example 11, 1- (5 Using -fluoropyridin-3-yl) -3-methylbutan-1-one, 242 mg of the title compound was obtained (total yield over three steps: 36%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 8.18 (d, 1H, J = 2.0 Hz), 8.67 (br s, 1H), 8.03 (dt, 1H, J = 8.8 Hz, 2.0 Hz), 4.58 (dd, 1H, J = 9.3 Hz, 6.4 Hz), 2.00 -1.94 (m, 1H), 1.91-1.86 (m, 1H), 1.49-1.41 (m, 1H), 0.99 (d, 3H, J = 6.4 Hz), 0.97 (d, 3H, J = 6.8 Hz).

(Reference Example 21)
(1R) -1-Pyridin-4-ylpropan-1-amine dihydrochloride

In the same manner as in Reference Example 11, 1.46 g of the title compound was obtained using 1-pyridin-4-ylpropan-1-one (total yield over 3 steps: 66%).
Colorless solid.
¹ H NMR spectrum (CD ₃ OD, 500 MHz), δ: 9.00-8.99 (m, 2H), 8.20-8.19 (m, 2H), 4.64 (t, 1H, J = 7.3 Hz), 2.18-2.00 (m, 2H), 1.00 (t, 3H, J = 7.3 Hz).

Test Example 1 Renin Activity Inhibition Test Renin activity was measured as the ratio of angiotensin I produced after adding human renin and a synthetic renin substrate and reacting at 37 ° C.

Human renin was transiently expressed in 293T cells, and the culture supernatant was used as an enzyme source. After activating human renin by trypsinizing the prepared culture supernatant, a solution of the test compound dissolved in a solvent (for example, DMSO) or 2 μl of the solvent is added to a final concentration of 1% by weight. In addition, a buffer solution (1 mM EDTA, NH ₂ -Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Glu-COOH) containing a synthetic renin substrate 100 mM Tris-HCl, pH 7.4) was added, and the mixture was incubated at 37 ° C. for 1 hour. According to the package insert, the produced angiotensin I concentration was measured using a radioimmunoassay [Renin Riabeads (registered trademark), Yamasa Soy Sauce]. The renin inhibitory activity was evaluated by the IC ₅₀ value, which is the concentration of each test compound that inhibits the production of angiotensin I by 50%.

The results are shown in Table 1.

The compound of the present invention exhibits an excellent renin inhibitory activity and is useful as a medicament for the treatment or prevention of hypertension and the like.

(Test Example 2) Plasma renin activity (PRA) inhibition test Plasma renin activity was measured as the amount of angiotensin I produced per unit time from endogenous angiotensinogen and endogenous renin by incubating plasma at 37 ° C. .

A test compound or a solvent (for example, DMSO and the like) was added to pooled cynomolgus monkey plasma or human plasma, a buffer solution was added according to the package insert, and the mixture was incubated at 37 ° C. for 1 hour. The angiotensin I concentration produced per unit time was measured using a radioimmunoassay (see Test Example 1). Plasma renin inhibitory activity was evaluated by IC ₅₀ value, which is the concentration of each test compound that inhibits PRA by 50%.

The compound of the present invention exhibits excellent plasma renin inhibitory activity and is useful as a medicament for the treatment or prevention of hypertension and the like.

Test Example 3 Ex vivo Plasma Renin Activity (PRA) Inhibition Test in Cynomolgus Monkeys Furosemide (5 mg / kg) was administered intramuscularly to cynomolgus monkeys 2 days before oral administration of the test compound to enhance the renin-angiotensin system. On the day of the test, plasma samples were collected in tubes containing EDTA · 2Na before administration of the test compound, 1, 2, 4, 8 and 24 hours after administration. The test compound was suspended in 1% methylcellulose and orally administered by gavage. The obtained plasma was incubated at 4 ° C. or 37 ° C., and the concentration of angiotensin I present in each reaction solution was measured using a radioimmunoassay (see Test Example 1).

PRA was calculated as the angiotensin I concentration produced per unit time from the value obtained by subtracting the angiotensin I concentration in the reaction solution incubated at 4 ° C. from the angiotensin I concentration in the reaction solution incubated at 37 ° C. The PRA inhibitory activity of the test compound was evaluated by the inhibition rate of PRA after each administration time relative to the PRA before administration of the test compound.

The compound of the present invention exhibits excellent PRA inhibitory activity and plasma angiotensin I concentration lowering action, and is useful as a medicament for the treatment or prevention of hypertension and the like.

(Test Example 4) Blood pressure drop test in cynomolgus monkeys A telemetry transmitter was implanted in a cynomolgus monkey, and animals that had been able to obtain a stable blood pressure waveform after 1 week or more after the operation were used for the test. Furosemide (5 mg / kg) was intramuscularly administered to cynomolgus monkeys 3 days before oral administration of the test compound to enhance the renin-angiotensin system. On the day of the test, from 1 hour before administration of the test compound to 25 hours after administration, the blood pressure signal by the telemetry method was continuously measured using a data acquisition / real time analysis system (HEM 3.5, NOTOCORD SYSTEMS, USA). As the analysis values of blood pressure and heart rate, blood pressure waveforms for 30 seconds were obtained every 5 minutes to obtain an average value, and 12 average values of those values were further calculated as 1 hour data. The test compound was suspended in 1% methylcellulose and orally administered by gavage. The blood pressure drop of the test compound was evaluated by the difference between the average blood pressure before administration of the test compound and the average blood pressure after each administration time.

The compound of the present invention exhibits an excellent blood pressure lowering action and is useful as a medicament for the treatment or prevention of hypertension and the like.

(Test Example 5) Evaluation of influence on electrocardiogram in rats Rats were anesthetized by intraperitoneal administration of inactin (100 mg / kg), and a catheter for test compound administration was placed in the right hip vein. The electrocardiogram was measured by induction II, and the test compound was continuously administered intravenously at a constant rate (1 mg / kg / min). An electrocardiogram was recorded on a thermal recording paper before administration of the test compound and every minute from 1 to 30 minutes after the start of administration. The test compound was intravenously administered after being dissolved in a physiological saline solution or a physiological saline solution containing a solvent (for example, DMSO). The influence of the test compound on the electrocardiogram was evaluated by the change of the electrocardiogram after each administration time with respect to the electrocardiogram before administration of the test compound. Changes in the electrocardiogram can be evaluated in terms of, for example, the height, width, interval, etc. of the waveform (particularly the degree of descending S wave). ECG changes can be categorized according to the degree of change, for example, large, medium, small, or not. Compounds with little or no ECG change are preferred, and compounds with no ECG change are most preferred.

The compound of the present invention is shown to have little or no change in electrocardiogram, and has excellent properties as a medicine.

(Test Example 6) Pharmacokinetic test The pharmacokinetic test can be performed according to a well-known method in the field of pharmacokinetics.

The test compound is dissolved in a 1% aqueous methylcellulose solution, and the resulting solution is generally administered to an animal (eg, mouse, rat, marmoset, cynomolgus monkey, etc.) used for pharmacokinetic studies in an appropriate range (eg, 3 mg / kg to 100 mg / kg). In addition, a test compound is dissolved in physiological saline, and the resulting solution is generally administered to an animal (for example, mouse, rat, marmoset, cynomolgus monkey, etc.) used for a pharmacokinetic test in an appropriate range (for example, 1 mg / kg to 10 mg / kg) was administered into a vein (eg, tail vein, cephalic vein, saphenous vein, etc.). Appropriate blood collection sites (eg, jugular vein, orbital venous plexus, cephalic vein, etc.) after a certain time (eg, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, or 24 hours) from administration More blood was collected. 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 pharmacokinetics of the test compound was evaluated by the maximum plasma test compound concentration (Cmax), the area under the plasma test compound concentration-time curve (AUC), systemic clearance (CL), and absolute bioavailability. Cmax indicates the highest measured plasma test compound concentration after oral administration. AUC was calculated according to the trapezoidal formula from the time when the test compound was administered to the time when blood was last collected. CL was calculated using pharmacokinetic analysis software WinNonlin (registered trademark). The absolute bioavailability is expressed by the following formula [(AUC / dose after oral administration) / (AUC / dose after intravenous administration)]
Calculated by

The compound of the present invention exhibits excellent pharmacokinetics (Cmax, AUC, CL, or absolute bioavailability), and is useful as a medicament (particularly, a medicament for treating or preventing hypertension).

(Formulation Example 1) Tablet Compound of Example (10 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg) and lactose (98.8 mg) is used to produce tablets according to conventional methods. The obtained tablets can be coated as necessary.

(Formulation Example 2) Hard Capsule In a standard bisected hard gelatin capsule, powdered compound of the example (10 mg), lactose (150 mg), cellulose (50 mg), and magnesium stearate (6 mg) is filled to produce hard capsules, washed and dried.

Formulation Example 3 Soft Capsules A mixture of digestible oils such as soybean oil, olive oil, and the compounds of Examples is injected into gelatin so as to contain 10 mg of active ingredients, and soft capsules Are manufactured, washed and dried.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has renin inhibitory activity, solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue transferability, and bioavailability. -Has excellent properties in terms of in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained drug efficacy, physical stability, drug interaction, and safety (eg, cardiotoxicity or hepatotoxicity). It is useful as a medicine [particularly, a medicine for the treatment or prevention (preferably treatment) of hypertension].

Claims (22)

1. Formula (I)
   

   

   
   
   [Wherein R ¹ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a phenyl- (C ₁ -C ₁₀ alkyl) group, (C ₃ -C ₁₀ saturated cyclic hydrocarbon)-(C ₁ -C ₁₀ alkyl) ) Group, (4- to 8-membered heterocyclyl)-(C ₁ -C ₁₀ alkyl) group, phenyl group, indanyl group, C ₃ -C ₁₀ saturated cyclic hydrocarbon group, or 4- to 8-membered heterocyclyl group, each group in the ^1, and together may be substituted with 1 to 4 groups independently selected from substituent group alpha, 2 pieces of the substituents attached to the same carbon atom and the carbon atom May form a C ₃ -C ₈ cycloalkyl group;
   R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
   R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
   R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ³ and R ⁴ together with the carbon atom to which they are bonded may form a C ₃ -C ₈ cycloalkyl group. Often;
   A represents a phenyl group or a pyridyl group,
   R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or a group selected from the substituent group α;
   Substituent group α includes C ₁ -C ₆ alkyl group, halogeno C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cyclo group) Alkyl)-(C ₁ -C ₆ alkoxy) group, halogeno C ₁ -C ₆ alkoxy group, mercapto group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group , Amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different), formylamino group, (C ₁ -C ₆ alkyl) carbonylamino group , Formyl group, (C ₁ -C ₆ alkyl) carbonyl group, carboxy group, (C ₁ -C ₆ alkoxy) carbonyl group, carbamoyl group, (C ₁ -C ₆ alkylamino) carbonyl group, di (C ₁ -C ₆ alkyl) aminocarbonyl group (The alkyl groups are the same or different), aminosulfonyl group, (C ₁ -C ₆ alkylamino) sulfonyl group, di (C ₁ -C ₆ alkyl) aminosulfonyl group (the alkyl groups are the same or different), A group consisting of a cyano group, a nitro group, a halogeno group, and an oxo group is shown. ]
   Or a pharmacologically acceptable salt thereof.
   
2. R ¹ represents a C ₁ -C ₁₀ alkyl group, a phenyl- (C ₁ -C ₁₀ alkyl) group, a (C ₃ -C ₁₀ saturated cyclic hydrocarbon)-(C ₁ -C ₁₀ alkyl) group, (4 to 8 _{1- to 4-} membered heterocyclyl)-(C ₁ -C ₁₀ alkyl) group or a C ₃ -C ₁₀ saturated cyclic hydrocarbon group, wherein each group in R ¹ is independently selected from substituent group α1 Two substituents bonded to the same carbon atom may be combined with the carbon atom to form a C ₃ -C ₈ cycloalkyl group; α1 represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₁ -C ₆ alkoxy group, a di (C ₁ -C ₆ alkyl) amino group (the alkyl groups may be the same or different), The compound or pharmacologically acceptable salt thereof according to claim 1, which is a group consisting of a halogeno group and an oxo group.
   
3. R ¹ is, C ₁ -C ₁₀ alkyl group, phenyl - (C ₁ -C ₁₀ alkyl) group, or (4-8 membered heterocyclyl) - is (C ₁ -C ₁₀ alkyl) group, each of R ¹ The group may be substituted with 1 to 4 groups independently selected from the substituent group α2, and the substituent group α2 includes a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, The compound or pharmacologically acceptable salt thereof according to claim 1, which is a group consisting of a C ₁ -C ₆ alkoxy group and a halogeno group.
   
4. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R ² is a hydrogen atom.
   
5. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R ³ is a C ₁ -C ₆ alkyl group.
   
6. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R ³ is a methyl group.
   
7. R ⁴ is C ₁ -C ₆ alkyl group, a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6.
   
8. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein R ⁴ is a methyl group.
   
9. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 8, wherein A is a phenyl group.
   
10. The compound according to any one of claims 1 to 9, wherein R ⁵ , R ⁶ and R ⁷ are independently a group selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, and a halogeno group. Or a pharmacologically acceptable salt thereof.
    
11. R ⁵ , R ^6, and R ⁷ are each independently a group selected from a hydrogen atom, a methyl group, a fluoro group, and a chloro group, or a compound thereof, Pharmacologically acceptable salt.
    
12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.
    
13. The pharmaceutical composition according to claim 12, for the treatment or prevention of a disease that can be treated or prevented by inhibiting renin.
    
14. Hypertension, acute or chronic heart failure, cardiac hypertrophy, myocardial infarction, cardiomyopathy, angina pectoris, stroke, kidney disease, diabetic complications, vascular restenosis after angioplasty, aldosteronemia, or atherosclerosis A pharmaceutical composition according to claim 12 for the treatment or prevention of symptom.
    
15. The pharmaceutical composition according to claim 12, for the treatment or prevention of hypertension, chronic heart failure, or diabetic nephropathy.
    
16. A pharmaceutical composition according to claim 12 for the treatment or prevention of hypertension.
    
17. The compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof for use in a method for treating or preventing a disease.
    
18. The compound according to claim 17, or a pharmacologically acceptable salt thereof, wherein the disease is hypertension.
    
19. A method for treating or preventing a disease by administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof.
    
20. 20. The method of claim 19, wherein the disease is a disease that can be treated or prevented by inhibiting renin.
    
21. 20. A method according to claim 19, wherein the disease is hypertension.
    
22. The method according to any one of claims 19 to 21, wherein the warm-blooded animal is a human.