KR100522012B1 - Amino acid derivatives - Google Patents

Abstract

The present invention relates to compounds represented by the following formula (I), salts thereof, and N-type calcium channel inhibitors containing them>

Formula I

In the above formula,

R ¹ is optionally substituted alkyl, alkoxy or phenyl, a heterocyclic group, and the like,

A is a single bond, CO or SO ₂ ,

R ² is a hydrogen atom, optionally substituted alkyl, or the like,

D is alkylene and the like,

E is COO, OCO, O, S, SO, SO _{2 and the like} ,

R ³ is an optionally substituted alkyl, carbocyclic group, heterocyclic group,

J is O or NR ¹⁶ , wherein R ¹⁶ is a hydrogen atom or optionally substituted alkyl,

R ⁴ is an optionally substituted alkyl, carbocyclic or heterocyclic group.

Since the compounds of formula (I) inhibit N calcium channels, they are useful as prophylactic and / or therapeutic agents for cerebral infarction, transient cerebral ischemic attack, cerebral spinal cord injury after cardiac surgery, spinal vascular disorders, stress hypertension, neurological disease, epilepsy.

Description

Amino acid derivative {AMINO ACID DERIVATIVES}

The present invention relates to an amino acid derivative represented by the following formula (I), a method for producing the same, and a drug containing the derivative as an active ingredient.

More specifically, the present invention relates to amino acid derivatives represented by the following general formula (I), their nontoxic salts and their hydrates, their preparation methods and N-type calcium channel inhibitors containing them.

(In the formula, all symbols are as described later.)

Calcium ions are known as one of intracellular delivery substances, and it has been suggested that changes in calcium concentration in a cell become a starting point and various physiological functions are expressed. Inflow of calcium ion from the outside is mentioned as a factor which raises intracellular calcium concentration. Corresponding to the inlet of the inflow is the membrane potential dependent calcium channel. Membrane potential dependent calcium channels are opened by polarization of the membrane potential and selectively introduce extracellular calcium ions according to the electrochemical gradient. Membrane potential dependent calcium channels are currently classified into N type, L type, P type, Q type and T type. Although L-type and T-type calcium channels exist in a wide variety of tissues, L-types are known to be particularly present in smooth muscle and cardiomyocytes. On the other hand, N-type and P-type calcium channels exist mainly in the nervous system and are involved in the release of various neurotransmitters. This neurotransmitter is usually stored in the synaptic vesicles of nerve endings, but when the action potentials of nerves reach the nerve endings through the transmission of information, membrane potential-dependent calcium channels are activated and At the end, calcium ions are introduced. As a result, the synaptic vesicles fuse to the synaptic membrane, and the neurotransmitter is released. The released neurotransmitters act on receptors in the synaptic thick film and participate in synaptic transmission. From this, N-type calcium channel inhibitors are thought to be useful for various diseases caused by the massive release of neurotransmitters, for example cerebral infarction ( J. Cereb. Blood Flow Metab., Vol. 17, 421-429, 1997). , Preventive and / or therapeutic drugs for transient cerebral ischemic attack, cerebral spinal cord disorder after cardiac surgery, spinal cord vascular disorder, stress hypertension ( Science, 239 , 57-61, 1988), neurological disease, epilepsy, or pain medication (e.g., acute Pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.) ( Pain, 60 , 83-90, 1995).

As the N-type calcium channel inhibitors, ω-conotoxin GVIA and ω-conotoxin MVIIA isolated from the poison of potato clam (conidae) are known.

However, since these ω-conotoxins are peptide compounds, various problems, such as transfer into a living body, are anticipated, for example. For this reason, these peptides are required to be non-peptidized, in other words low molecular weight, and some low molecular compounds as shown below have been reported.

For example, Japanese Patent Application Laid-Open No. 8-217671 discloses that the glycine derivative represented by the following formula (A) and salts thereof are N-type calcium channel inhibitors.

R ^1A CH (OCOR ^2A ) CH ₂ CONHCH ₂ CO ₂ H

(Wherein R ^1A and R ^2A are the same or different and represent a C _{1 to} C ₁₉ straight or branched alkyl group or C _{2 to} C ₁₉ straight or branched alkenyl group.)

EP805l47 discloses that the compounds represented by the following general formula (B), their salts or esters thereof have calcium channel modulating action (the description of the groups in the formula is necessary.).

(Wherein R ^1B represents alkyl, R ^2B represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, R ^3B represents a hydrogen atom, CN, X ^B is a single bond or SO ₂ , R ^4B , R ^5B , R ^6B , R ^8B , R ^9B and R ^10B each represent a hydrogen atom or alkyl, and A ^B represents CH ₂ or Y ^B CO (wherein Y ^B represents a single bond R ^7B represents a C-α substituent of an amino acid or an ester thereof, and R ^6B and R ^7B are together C _3-5 alkylene or CH ₂ − which may be substituted with a C ₁ -alkyl or hydroxyl group. Z ^B -CH ₂ (wherein Z ^B represents CO, S, SO, SO ₂ ), and R ^7B and R ^8B are C _3-4 alkyl which may be substituted with C _1-4 alkyl or hydroxyl group together. REN, B ^B represents CON (R ^21B ), mB represents 0 to 2, R ^11B represents a hydrogen atom or alkyl, R ^12B represents a hydrogen atom, Alkyl, optionally substituted aryl or optionally substituted heteroaryl, R ^13B represents alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and R ^12B and R ^13B together represent C _3-8 cycloalkyl. )

In addition, Japanese Patent Laid-Open No. 61-200950 discloses that the compound represented by the following general formula (C) or a pharmaceutically acceptable salt thereof is an anticonvulsant.

( ^Wherein R ^C and R ^1C are each unsubstituted or substituted with at least one electron withdrawing group or at least one electron donor group, lower alkyl, aryl lower alkyl or phenyl, R ^2C and R ^3C are each hydrogen, or at least Lower alkyl, aryl lower alkyl or phenyl, substituted or unsubstituted with one electron withdrawing group or with at least one electron donor group, and nC means 1-4)

The inventors of the present invention have made intensive studies to find a compound having an inhibitory action on an N-type calcium channel and found that the compound represented by the formula (I) achieves the object. Most of the compounds represented by the formula (I) are novel compounds.

The present invention relates to an N-type calcium channel inhibitor comprising 1) an amino acid derivative represented by the formula (I), a nontoxic salt thereof, or a hydrate thereof as an active ingredient;

Formula I

[In the meal,

R ¹ is

1) a C _1-15 alkyl group,

2) a C _1-8 alkoxy group,

3) phenyl group,

4) a C _3-8 cycloalkyl group,

5) heterocyclic group,

6) a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group,

7) a C _1-4 alkoxy group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, or

8) A phenyl group, a C _3-8 cycloalkyl group, or a C _2-4 alkenyl group substituted with a heterocyclic group (wherein all phenyl groups, C _3-8 cycloalkyl groups, and heterocyclic groups in the R ¹ group are represented by the following (i Or may be substituted with 1 to 3 groups selected from (xi):

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ⁵ group (wherein R ⁵ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) —NR ⁶ R ⁷ groups (wherein R ⁶ and R ⁷ each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ⁶ and R ⁷ are bonded) May be combined with a nitrogen atom to represent a 5 to 7 membered saturated heterocycle containing another nitrogen atom or one oxygen atom.),

A represents a single bond, a -CO- group or a -SO ₂ -group,

R ² represents a hydrogen atom or a C _1-4 alkyl group which may be substituted with one phenyl group,

D represents a C _1-4 alkylene group or a C _2-4 alkenylene group,

E is

1) -COO-group,

2) -OCO-group,

3) -CONR ⁸ -group (wherein R ⁸ represents a hydrogen atom or a C _1-4 alkyl group),

4) -NR ⁹ CO-group (wherein R ⁹ represents a hydrogen atom or a C _1-4 alkyl group),

5) -O-group,

6) -S-group,

7) -SO- group,

8) -SO ₂ -group,

9) -NR ¹⁰ -group (wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group),

10) -CO-group,

11) -SO ₂ NR ¹¹ -group (wherein R ¹¹ represents a hydrogen atom or a C _1-4 alkyl group), or

12) represents a -NR ¹² SO ₂ -group (wherein R ¹² represents a hydrogen atom or a C _1-4 alkyl group),

R ³ is

1) carbon ring,

2) heterocyclic group, or

3) a C _1-4 alkyl group substituted with a carbon ring group or a hetero ring group, provided that all of the carbon ring groups and heterocyclic groups in the R ³ group are 1 to 3 selected from the following (i) to (xi) May be substituted with a group:

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ¹³ groups (wherein R ¹³ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) -NR ¹⁴ R ¹⁵ groups (wherein R ¹⁴ and R ¹⁵ each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ¹⁴ and R ¹⁵ are bonded to May be combined with a nitrogen atom to represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.),

J represents an -O- group or -NR ¹⁶ -group (wherein R ¹⁶ represents a hydrogen atom or a C _1-4 alkyl group),

R ⁴ is

1) a C _1-8 alkyl group,

2) carbon ring,

3) heterocyclic group,

4) a C _1-8 alkyl group substituted with one to three groups selected from the following (i) to (v);

(i) a carbon ring,

(ii) heterocyclic groups,

(iii) a COOR ¹⁷ group (wherein R ¹⁷ is a C _1-4 alkyl group substituted with a hydrogen atom or one phenyl group (wherein phenyl may be substituted with a C _1-4 alkoxy group),

(iv) SR ¹⁸ group (wherein R ¹⁸ represents a hydrogen atom or a C _1-4 alkyl group),

(v) represents an OR ¹⁹ group (wherein, R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group),

In addition, when J represents a -NR ¹⁶ -group, R ⁴ and R ¹⁶ may be combined with the nitrogen atom to which they are bonded to represent a heterocyclic group, provided that all of the carbocyclic and heterocyclic groups in the R ⁴ group, and The heterocyclic group represented by one of the nitrogen atoms to which R ⁴ and R ¹⁶ are bonded may be substituted with one to three groups selected from the following (i) to (xi):

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ²⁰ group (wherein R ²⁰ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) —NR ²¹ R ²² groups (wherein R ²¹ and R ²² each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ²¹ and R ²² are bonded) It may be combined with a nitrogen atom to represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.)).

2) amino acid derivatives represented by general formula (I), nontoxic salts thereof, or hydrates thereof; And

[In the meal,

R ¹ is

1) a C _1-15 alkyl group,

2) a C _1-8 alkoxy group,

3) phenyl group,

4) a C _3-8 cycloalkyl group,

5) heterocyclic group,

6) a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group,

7) a C _1-4 alkoxy group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, or

8) A phenyl group, a C _3-8 cycloalkyl group, or a C _2-4 alkenyl group substituted with a heterocyclic group (wherein all phenyl groups, C _3-8 cycloalkyl groups, and heterocyclic groups in the R ¹ group are represented by the following (i Or may be substituted with 1 to 3 groups selected from (xi):

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ⁵ group (wherein R ⁵ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) —NR ⁶ R ⁷ groups (wherein R ⁶ and R ⁷ each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ⁶ and R ⁷ are bonded) May be combined with a nitrogen atom to represent a 5 to 7 membered saturated heterocycle containing another nitrogen atom or one oxygen atom.),

A represents a single bond, a -CO- group or a -SO ₂ -group,

R ² represents a hydrogen atom or a C _1-4 alkyl group which may be substituted with one phenyl group,

D represents a C _1-4 alkylene group or a C _2-4 alkenylene group,

E is

1) -COO-group,

2) -OCO-group,

3) -CONR ⁸ -group (wherein R ⁸ represents a hydrogen atom or a C _1-4 alkyl group),

4) -NR ⁹ CO-group (wherein R ⁹ represents a hydrogen atom or a C _1-4 alkyl group),

5) -O-group,

6) -S-group,

7) -SO- group,

8) -SO ₂ -group,

9) -NR ¹⁰ -group (wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group),

10) -CO-group,

11) -SO ₂ NR ¹¹ -group (wherein R ¹¹ represents a hydrogen atom or a C _1-4 alkyl group), or

12) —NR ¹² SO ₂ — group (wherein R ¹² represents a hydrogen atom or a C _1-4 alkyl group),

R ³ is

1) carbon ring,

2) heterocyclic group, or

3) a C _1-4 alkyl group substituted with a carbon ring group or a heterocyclic group, provided that all of the carbon ring groups and heterocyclic groups in the R ³ group are 1 to 3 groups selected from the following groups (i) to (xi): May be substituted:

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ¹³ groups (wherein R ¹³ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) -NR ¹⁴ R ¹⁵ groups (wherein R ¹⁴ and R ¹⁵ each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ¹⁴ and R ¹⁵ are bonded to May be combined with a nitrogen atom to represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.),

J represents an -O- group or -NR ¹⁶ -group (wherein R ¹⁶ represents a hydrogen atom or a C _1-4 alkyl group),

R ⁴ is

1) a C _1-8 alkyl group,

2) carbon ring,

3) heterocyclic group,

4) a C _1-8 alkyl group substituted with one to three groups selected from the following (i) to (v);

(i) a carbon ring,

(ii) heterocyclic groups,

(iii) a COOR ¹⁷ group (wherein R ¹⁷ is a C _1-4 alkyl group substituted with a hydrogen atom or one phenyl group (wherein phenyl may be substituted with a C _1-4 alkoxy group),

(iv) SR ¹⁸ group (wherein R ¹⁸ represents a hydrogen atom or a C _1-4 alkyl group),

(v) represents an OR ¹⁹ group (wherein, R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group),

In addition, when J represents an -NR ¹⁶ -group, R ⁴ and R ¹⁶ may be combined with the nitrogen atom to which they are bonded to represent a heterocyclic group (provided that all of the carbon and heterocyclic groups in the R ⁴ group, and The heterocyclic group represented by one of the nitrogen atoms to which R ⁴ and R ¹⁶ are bonded may be substituted with one to three groups selected from the following (i) to (xi):

(i) a C _1-4 alkyl group,

(ii) a C _1-4 alkoxy group,

(iii) a phenyl group,

(iv) phenoxy,

(v) benzyloxy groups,

(vi) -SR ²⁰ group (wherein R ²⁰ represents a hydrogen atom or a C _1-4 alkyl group),

(vii) a C _2-5 acyl group,

(viii) halogen atoms,

(ix) a C _1-4 alkoxycarbonyl group,

(x) nitro groups,

(xi) —NR ²¹ R ²² groups (wherein R ²¹ and R ²² each represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ²¹ and R ²² are bonded) It may be one with a nitrogen atom, and may represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.)).

However, the compound of following (1)-(37) is excluded.

(1) N- (2-amino-5-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(2) N-phenyl-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(3) N- (2-aminophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(4) N- (4-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(5) N- (adamantan-2-yl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(6) N- (pyridin-4-yl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(7) N- (2-aminophenyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

(8) N- (4-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

(9) N- (3-bromo-4, 5-dihydroisooxazol-5-ylmethyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

(10) N-methyl-N- (2, 6-dimethoxy-4-methylphenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

(11) N- (4-nitrophenyl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide,

(12) N- (quinolin-6-yl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide,

(13) N- (2-aminophenyl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide,

(14) N- (adamantan-2-yl) -3- (3-ethoxycarbonylpyridin-2-ylthio) -2-t-butoxycarbonylaminopropanamide,

(15) N-methyl-N- (2-ethoxyphenyl) -3- (3-methoxycarbonylpyridin-2-yl) -2-t-butoxycarbonylaminopropanamide,

(16) N- (4-methoxycarbonylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(17) N- (3-bromo-4, 5-dihydroisoxazol-5-ylmethyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(18) N- (2-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(19) N- (3-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(20) N- (4-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(21) N-phenyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(22) N- (naphthalen-2-yl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(23) N- (naphthalen-1-yl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(24) N-benzyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(25) N- (4-chlorophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(26) N- (4-bromophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(27) N- (4-nitrophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide,

(28) N- (1, 2, 3, 4-tetrahydronaphthalen-2yl) -3-benzylthio-2- (4-chlorobenzyloxycarbonylamino) propanamide,

(29) N-methyl-N- (2-ethoxyphenyl) -3- (3-methoxycarbonylpyridin-2-ylthio) -2- (3,4-dichlorophenylcarbonylamino) propanamide,

(30) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-nitrobenzyl ester,

(31) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester,

(32) 3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester,

(33) 3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester,

(34) 3- (2-isopropyl-5-methylcyclohexyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester,

(35) N- (benzyloxycarbonylmethyl) -3- (2-isopropyl-5-methylcyclohexyloxycarbonyl) -2-t-butoxycarbonylaminopropanamide,

(36) 3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid benzyl ester, and

(37) N-phenyl-2, 3-bis (benzoylamino) propanamide]

3) Amino acid derivative represented by the formula (I) and a method for producing these nontoxic salts.

Detailed description of the invention

In the present invention, unless otherwise indicated, the isomers include all of them. For example, alkyl, alkoxy, alkylene and alkenylene groups include those which are straight and branched. Double bonds in alkenylene groups include those which are mixtures of E, Z and EZ. Also included are isomers (optical isomers) produced by the presence of asymmetric carbon atoms, such as when branched alkyl, alkoxy, alkylene and alkenylene groups are present.

In the formula (I), the C _1-15 alkyl group represented by R ¹ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl And their isomers.

In the general formula (I), the C _1-8 alkoxy group represented by R ^{1 means} methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group, and isomers thereof.

In the formula I, is C _3~8 cycloalkyl, C _1~4 alkyl group R, C _1~4 alkoxy group and a C _3~8 cycloalkyl group the substituents of C _2~4 alkenyl group of ¹ being represented by R ^1, By cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups are meant.

In formula (I), R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁸ , R ¹⁹ , R ²⁰ , R C _1-4 alkyl group represented by ²¹ or R ²² means methyl, ethyl, propyl, butyl group and isomers thereof.

In formula I, R ¹ a phenyl group, C _3~8 cycloalkyl group and a C _1~4 alkyl group substituents of the heterocyclic group, or R ^3, R ⁴ group carbocyclic group and heterocyclic group in, or R ⁴ and R in ^The C _1-4 alkyl group which is a substituent of the heterocyclic group represented by one with the nitrogen atom to which ¹⁶ is bonded means methyl, ethyl, propyl, butyl group and isomer thereof.

In formula (I), a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group or a heterocyclic group represented by R ¹ is methyl, ethyl, propyl, substituted with a phenyl group, a C _3-8 cycloalkyl group or a heterocyclic group; Butyl group and isomer thereof.

In the general formula (I), the C _1-4 alkyl group which may be substituted with one phenyl group represented by R ² means methyl, ethyl, propyl, butyl group and isomers thereof which may be substituted with one phenyl group.

In formula (I), the C _1-4 alkyl group substituted with one phenyl group represented by R ¹⁷ means a methyl, ethyl, propyl, butyl group and isomer thereof substituted with one phenyl group.

In the general formula (I), the C _1-4 alkyl group substituted with a carbocyclic group or heterocyclic group represented by R ³ means methyl, ethyl, propyl, butyl group and isomers thereof substituted with carbocyclic or heterocyclic groups.

Of formula I, a phenyl group, C _3~8 cycloalkyl group or heterocyclic group substituted by a C _1~4 alkoxy group refers to a phenyl group, C _3~8 cycloalkyl group or a methoxy, ethoxy, propoxy, butoxy substituted with a heterocyclic And their isomers.

In formula I, the R ¹ phenyl group, C _3~8 cycloalkyl group and a C _1~4 alkoxy group substituent of a heterocyclic group, or R ^3, R ⁴ carbocyclic group and heterocyclic group in the group, or R ⁴ of the The C _1-4 alkoxy group which is a substituent of the heterocyclic group which is represented by one with the nitrogen atom which R <^16> couple | bonds means a methoxy, ethoxy, propoxy, butoxy group, and these isomers.

In formula (I), the C _1-4 alkoxy group which is a substituent of the phenyl group of the C _1-4 alkyl group substituted with one phenyl group in the R ¹⁷ group means a methoxy, ethoxy, propoxy, butoxy group and isomer thereof.

In the general formula (I), the C _2-4 alkenyl group substituted with a phenyl group, a cycloalkyl group or a heterocyclic group means an ethenyl, propenyl, butenyl group and isomers thereof.

In formula (I), a C _2-5 acyl group which is a substituent of a phenyl group, a C _3-8 cycloalkyl group and a heterocyclic group in the R ¹ group, or a carbocyclic group and a heterocyclic group in R ³ , R ⁴ , or R ⁴ and The C _2-5 acyl group which is a substituent of the heterocyclic group represented by being one with the nitrogen atom which R <^16> couple | bonds means an acetyl, propionyl, butyryl, valeryl group, and these isomers.

In formula (I), a halogen atom which is a substituent of a phenyl group, a C _3-8 cycloalkyl group and a heterocyclic group in R ¹ group, or a carbocyclic and heterocyclic group in R ³ , R ⁴ group, or R ⁴ and R ¹⁶ are bonded The halogen atom which is a substituent of the heterocyclic group represented by one with the nitrogen atom which is made is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In formula (I), C _1-4 alkoxycarbonyl group represented by R ⁶ , R ⁷ , R ¹⁴ , R ¹⁵ , R ²¹ , R ²² is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group And their isomers.

In formula I, the R ¹ phenyl group, C _3~8 cycloalkyl and the substituent of C _1~4 alkoxycarbonyl group, or R ^3, R ⁴ group carbon ring group and the heterocyclic group in the heterocyclic group, or R ⁴ of the The C _1-4 alkoxycarbonyl group which is a substituent of the heterocyclic group represented by one with the nitrogen atom which R <^16> couple | bonds is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, and these isomers it means.

In the general formula (I), the C _1-4 alkylene group represented by D means a methylene, ethylene, propylene, butylene group and isomers thereof.

In the general formula (I), the C _2-4 alkenylene group represented by D means an ethenylene, propenylene, butenylene group and isomers thereof.

The C _1-8 alkyl group represented by the formula (I), R ⁴ means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.

In the general formula (I), a C _1-8 alkyl group substituted with 1 to 3 groups selected from (i) to (v) represented by R ⁴ is substituted with 1 to 3 groups selected from (i) to (v). Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl groups and isomers thereof.

In the general formula (I), ⁵ to ⁵ may be one with the nitrogen atom to which R ⁶ and R ⁷ , R ¹⁴ and R ¹⁵ , and R ²¹ and R ²² are bonded, and may include another nitrogen atom or one oxygen atom. 7-membered saturated heterocycle means, for example, pyrrolidine, piperidine, piperazine, morpholine, perhydroazepine.

In the general formula (I), the carbon ring group in the groups R ³ and R ^{4 represents a} C _3-10 monocyclic ring, a bicyclic carbon ring and a crosslinked carbon ring. For example, as C _3-10 monocyclic, bicyclic carbon ring and crosslinked carbon ring, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclo Pentadiene, cyclohexadiene, benzene, pentylene, indene, naphthalene, azlene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, indane (dihydroindene), perhydroindene, bicyclopentane, bicyclo Hexane, bicycloheptane (bicyclo [2.1.1] heptane), bicycloheptene (bicyclo [2.1.1] hepta-2-ene), bicyclooctane, bicyclononane, bicyclodecane, Adamantane etc. are mentioned.

In the general formula (I), the heterocyclic group in the groups R ¹ , R ³ and R ⁴ is an unsaturated, partially or fully saturated 5 to 1 containing 1 to 2 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom. A 15-membered monocyclic or bicyclic heterocyclic group is shown. For example, as an unsaturated, partially or fully saturated 5 to 15 membered monocyclic or bicyclic heterocyclic group containing 1 to 2 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom, pyrroline, pyrroli Dean, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazine, Dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydro Oxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydrooxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetraisothiazole, morpholine, thiomorpholine, indolin, tooth Indolin, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthala Gin, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazolin, tetrahydroquinazolin , Perhydroquinazolin, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole , Perhydrobenzoimidazole, dihydrobenzoxazine, dioxane, benzodioxane, quinuclidin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrida , Azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiaine (thiopyran), thiene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine , Oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzoti Offen, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, oxatetrahydrofuran, diazolidinone, thiazoli Dindione etc. are mentioned.

In the general formula (I), the heterocyclic group represented by becoming one with the nitrogen atom to which R ⁴ and R ¹⁶ are bonded includes one nitrogen atom and includes one nitrogen atom, one oxygen atom, and / or one sulfur atom. An unsaturated, partially or fully saturated 5- to 15-membered monocyclic or bicyclic heterocyclic group is further included. For example, a partially or fully saturated 5 to 15-membered monocyclic or bicyclic heterocyclic group which necessarily includes one nitrogen atom and further includes one nitrogen atom, one to two oxygen atoms and / or one sulfur atom , Pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine , Hexahydroazine, tetrahydrooxazole, tetrahydroisoxazole, tetrahydrothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indolin, isoindolin, dihydroindazole, perhydroindazole , Dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthala Gin, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazolin, tetrahydroquinazoline, perhydroquinazolin, Dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole , Pyrrole, imidazole, pyrazole, indole, isoindole, indazole, benzoimidazole and the like.

Preferred as R ¹ are a C _1-8 alkoxy group, a phenyl group, a C _3-8 cycloalkyl group, a heterocyclic group, or a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group or a heterocyclic group, more preferably Heterocyclic group.

Preferred as A is a single bond or a -CO- group, more preferably -CO- group.

Preferred as E are -COO- group, -O- group, -S- group, -SO- group, or -SO ₂ -group, more preferably -S- group.

Preferred examples of the carbon ring group represented by the R ³ group and the substituent group of the C _1-4 alkyl group include C ₃ to C represented by cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane and cyclodecane. ₁₀ cycloalkyl group, more preferably cyclopentane and cyclohexane.

Preferred as J is a -NR ¹⁶ -group (wherein R ¹⁶ represents the same meaning as described above).

Preferred as R ⁴ is a C _1-8 alkyl group substituted with a carbocyclic group, a heterocyclic group, or a carbocyclic group or a heterocyclic group, more preferably a C _1-8 alkyl group substituted with a carbocyclic group.

[salt]

In the present invention, all non-toxic salts are included.

For example, the compounds of the present invention represented by the formula (I) are converted into salts corresponding to known methods. The salt is nontoxic and preferably water soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, Cyclopentylamine, dicyclohexylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine, etc.) Salts may be mentioned.

The compounds of the present invention represented by the formula (I) are converted into the corresponding acid addition salts by known methods. Acid addition salts are nontoxic and preferably water soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, lactate, phosphate, nitrate, or acetates, trifluoroacetates, sulfates, tartarates, oxalates, fumarates, maleates, citrates, and benzoates. And organic acid salts such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, isethionate, glucuronate and gluconate.

In addition, the compound of the present invention represented by the formula (I) or a salt thereof may be converted into a hydrate by a known method.

As a preferable compound among the compound represented by general formula (I), the compound represented by the following general formula (Ia), Ib, Ic, Id, Ie, If, Ig, Ih, these non-toxic salts, or hydrates thereof are mentioned.

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

As a specific compound, the compound shown in Table 1 below, the nontoxic salts thereof, the hydrates thereof, and the compound shown in the Example are mentioned. In addition, the specific compound shown below shall also contain isomers produced | generated by presence of an asymmetric carbon, ie, an R body, an S body, and an RS body. In each of the following tables, Me represents a methyl group, Boc represents a t-butoxycarbonyl group, i-Bu represents an isobutyl group, and Ac represents an acetyl group.

[Method for Producing Compound of the Invention]

delete

(a) Among the compounds represented by the formula (I), E is -COO- group, -OCO- group, -CONR ⁸ -group, -NR ⁹ CO- group, -O- group, -S- group, or -CO- The compound which is a group, ie, the compound of the present invention represented by the following general formula (IA), may be prepared by amidating or esterifying the compound represented by the following general formula (II) with the compound represented by the following general formula (III), or The compound represented by the following general formula (V) and the compound represented by amidation or esterification can be manufactured.

(In formula, R <^1-1> has the same meaning as R <^1> , but the amino group contained in the group represented by R < ^1-1 shall be protected when protection is needed, and R < ^3-1 is the same as R <^3>. The amino group included in the group represented by R ^3-1 is shown to be protected when necessary for protection, and R ^4-1 has the same meaning as R ⁴ but is represented by the group represented by R ^4-1 . The -COOH group, hydroxyl group or amino group included shall be protected when protection is required, and E ¹ is -COO- group, -OCO- group, -CONR ⁸ -group, -NR ⁹ CO- group, -O- Group, -S- group, or -CO- group, and the other symbols represent the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

J ² -R ^4-1

(Wherein, J ² is a heterocyclic group having an —OH group, —NHR ¹⁶ group, or NH group. (This heterocyclic group has the same meaning as the heterocycle represented by becoming one with the nitrogen atom to which R ⁴ and R ¹⁶ are bonded. ) And other symbols have the same meaning as above.)

(Wherein, E ² represents a -COOH group, -NHR ⁹ group or -OH, and other symbols have the same meanings as defined above.)

E ³ -R ^3-1

(Wherein, E ³ represents a group -OH, -NHR ⁸ or -COOH group, the other symbols have the same meanings as defined above.)

The said amidation reaction is well-known, For example, the following method etc. are mentioned.

(1) How to use an acid halide

(2) How to use mixed acid anhydride

(3) Method using condensing agent

In detail, these methods

(1) A method of using an acid halide is, for example, an acid halide (oxalyl chloride, thi chloride) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, ethyl acetate, etc.) or without solvent. Amine and organic solvent in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, N-methylmorpholine, etc.). (Chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.), the reaction is carried out at 0 to 40 ° C.

(2) A method of using a mixed acid anhydride is, for example, tertiary amine (pyridine, triethylamine, carboxylic acid) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without solvent. Acid halides (pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of dimethylaniline, dimethylaminopyridine, N-methylmorpholine and the like at -20 to 40 ° C. The resulting mixed acid anhydride is reacted with an appropriate amine in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0 to 40 ° C.

(3) Condensing agents (1, 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 2-chloro-1-methylpyridine Dinium iodine, 1, 1'-carbonyldiimidazole (CDI) and the like are used by mixing, for example, carboxylic acid and amine, organic solvents (chloroform, methylene chloride, dimethylformamide, diethyl ether, tetra 1-hydroxybenzotriazole (with or without a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) or without using as a solvent, or without solvent. HOBt) is carried out by the reaction at 0 ~ 40 ℃ with or without.

It is preferable that all of these reactions (1), (2) and (3) be performed under anhydrous conditions under an inert gas (argon, nitrogen, etc.) atmosphere.

In addition, the said esterification reaction is well-known, For example, the following method etc. are mentioned.

(1) How to use an acid halide

(2) How to use mixed acid anhydride

(3) Method using condensing agent

In detail, these methods

(1) A method of using an acid halide is, for example, an acid halide (oxalyl chloride, thi chloride) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, ethyl acetate, or the like) or without solvent. And the acid halide obtained by reacting at -20 ° C to reflux temperature with an alcohol and an organic solvent in the presence of tertiary amines (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, N-methylmorpholine, etc.). (Chloroform, methylene chloride, diethyl ether, tetrahydrofuran, and the like).

(2) A method of using a mixed acid anhydride is, for example, tertiary amine (pyridine, triethylamine, or the like) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without solvent. Acid halides (pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of dimethylaniline, dimethylaminopyridine, N-methylmorpholine, etc., at -20 to 40 ° C. The resulting mixed acid anhydride is reacted with the corresponding alcohol in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0-40 占 폚.

(3) Condensing agents (1, 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 2-chloro-1-methylpyridine Dinium iodide, 1, 1'-carbonyldiimidazole (CDI) and the like is used by mixing, for example, carboxylic acid and alcohol, organic solvents (chloroform, methylene chloride, dimethylformamide, diethyl ether, tetra 1-hydroxybenzotriazole (with or without a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) or without using a hydrofuran or the like as a solvent. HOBt) is carried out by the reaction at 0 ~ 40 ℃ with or without.

It is preferable that all of these reactions (1), (2) and (3) be performed under anhydrous conditions under an inert gas (argon, nitrogen, etc.) atmosphere.

In addition, among the compounds represented by the formula (IA), the compound represented by the formula (IA-1), that is, the compound represented by the following formula (IA-1), is prepared by reacting the compound represented by the following formula (VI) with the compound represented by the following formula (VII). You may.

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

XR ^3-1

(Wherein X represents a halogen atom and other symbols have the same meaning as above).

The reaction of the compound represented by the formula (VI) with the compound represented by the formula (VII) is well known, and is carried out by reacting, for example, in an organic solvent (dimethylformamide, acetone, etc.) at 0-40 DEG C in the presence of a base (potassium carbonate, etc.). .

(b) Among the compounds represented by the formula (I), a compound in which E is a -SO- group and a -SO ₂ -group, that is, a compound represented by the following formula (IB) is a compound represented by the formula (IA), wherein E ¹ is a -S- group. It can manufacture by oxidizing a compound.

(Wherein, E ⁴ represents a —SO— group or a —SO ₂ — group, and other symbols have the same meanings as above).

The oxidation reaction is well known, and in the case where the sulfide group is oxidized to a sulfoxide group, for example, one equivalent of an oxidizing agent (hydrogen peroxide, periodioic acid) in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol, etc.) is used. In the presence of sodium, acyl nitrite, sodium perborate, peracid (m-chloroperbenzoic acid, peracetic acid, etc.), the reaction is carried out for several minutes at a temperature of -78 to 0 캜.

In the case of oxidizing the sulfide group with a sulfone group, for example, an excess oxidizing agent (hydrogen peroxide, sodium periodate, potassium permanganate, perborate) in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol, etc.) is used. In the presence of sodium, potassium persulfate, peracid (m-chloroperbenzoic acid, peracetic acid, etc.) and the like at a temperature of -78 to 40 ° C for several hours.

(c) Among the compounds represented by the formula (I), a compound in which E is a -NR ¹⁰ -group, that is, a compound represented by the following formula (IC) can be prepared by reacting the compound represented by the formula (VIII) with the compound represented by the formula (IX). have.

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

NHR ¹⁰ -R ^3-1

(In the formula, all symbols have the same meaning as above.)

The reaction between the compound represented by the formula (VIII) and the compound represented by the formula (IX) is known, and for example, the compound represented by the formula (IV) is reduced in organic solvents (methanol, ethanol, etc.), and a reducing agent (sodium hydride sodium sodium, sodium borohydride). Etc.) or, if necessary, by reacting with a compound represented by the formula (V) at a temperature of 0 to 40 ° C. using a pH adjuster (acetic acid or the like).

(d) Among the compounds represented by the formula (I), a compound in which E is a -SO ₂ NR ¹¹ -group, that is, a compound represented by the following formula ID is prepared by reacting a compound represented by the following formula (X) with a compound represented by the formula (XI). can do.

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

NHR ¹¹ -R ^3-1

(In the formula, all symbols have the same meaning as above.)

The reaction between the compound represented by the formula (X) and the compound represented by the formula (XI) is well known. For example, the compound represented by the formula (X) may be reacted with an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) Triphenylphosphine and the like) and an acid halide (oxalyl chloride, thionyl chloride, sulfuryl chloride, etc.) at -20 ° C to reflux temperature, followed by tertiary amines (pyridine, triethylamine, dimethylaniline, dimethylamino In the presence of pyridine) and a compound represented by the formula (XI) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at a temperature of 0 to 40 ° C.

(e) Among the compounds represented by the formula (I), a compound in which E is a -NR ¹² SO ₂ -group, that is, a compound represented by the following formula (IE) may be prepared by reacting a compound represented by the formula (XII) with a compound represented by the formula (XIII). Can be.

(In the formula, all symbols have the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

X-SO ₂ -R ^3-1

(Wherein X represents a halogen atom and other symbols have the same meaning as above).

The reaction of the compound represented by the formula (XII) with the compound represented by the formula (XIII), for example, the tertiary amine (pyridine) in the organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) , Triethylamine, dimethylaniline, dimethylaminopyridine and the like) can be carried out by reacting with a compound represented by the formula (XIII) at a temperature of 0 to 40 ° C.

(f) Among the compounds represented by the formula (I), a compound in which A is a -CO- group or a -SO ₂ -group, that is, a compound represented by the following formula IF is a compound represented by the following formula (XIV) and a compound represented by the formula (XV). Can be prepared by an amidation reaction or sulfonamide reaction.

(Wherein A ¹ represents a —CO— group or a —SO ₂ — group, and other symbols represent the same meanings as above).

Formula XIV

(In the formula, all symbols have the same meaning as above.)

R ^1-1 -A ²

(Wherein, A ² represents a -COOH group or a -SO ₃ H, the other symbols have the same meanings as defined above.)

Sulfonamide reactions are well known, for example, sulfonic acid is dissolved in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or in the absence of an acid halide (oxalyl chloride, thionyl chloride, phosphorus pentachloride). , Phosphorus trichloride, etc.) and the sulfonyl halide obtained by reacting at -20 ° C to reflux temperature in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) and an inert organic solvent (chloroform , Methylene chloride, diethyl ether, tetrahydrofuran and the like).

In addition, the amidation reaction can be carried out in the same manner as described above.

(g) Among the compounds represented by the formula (I), A represents a single bond, and R ¹ represents a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, that is, with the following formula (IG) The compound represented can be prepared by reacting the compound represented by the formula (XIV) with the formula (XVI).

R ^1-2 represents a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group (substituent for each ring, and when an amino group is present, it is protected if protection is required) And other symbols indicate the same meaning as above.)

(In the formula, all symbols have the same meaning as above.)

R ^1-3 -CHO

_Wherein R ^1-3 represents a C _1-3 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, a heterocyclic group, or a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group (as a substituent for each ring, When amino groups are present, they are protected if protection is required).

This reaction can be carried out in the same manner as the reaction of the compound represented by the formula (VIII) with the compound represented by the formula (IX).

(h) Of the compounds represented by the formula (I), R ¹ represents a C _1-4 alkyl group substituted with a heterocyclic group or a heterocyclic group, and the substituent of the hetero ring is a C _2-5 acyl group or a C _1-4 alkoxycarbonyl group A phosphorus compound, ie, a compound represented by the following formula (IH), can be produced by amidation reaction between the compound represented by the formula (XVII) and the compound represented by the formula (XVIII).

In the formula, R ²³ represents a single bond or a C _1-4 alkylene group, R ²⁴ represents a C _1-4 alkoxycarbonyl group or C _2-5 acyl group, R ²⁵ represents a C _1-4 alkyl group, C _1-4 An alkoxy group, a phenyl group, a phenoxy group, a benzyloxy group, a -SR ⁵ group, a halogen atom, a nitro group or a -NR ⁶ R ⁷ group, n represents 0 to 2, Represents the same meaning as the heterocyclic group in the R ¹ group, but means a heterocyclic group containing at least one nitrogen atom. In addition, when an amino group exists in the substituent represented by R <^25> , when protection is needed, it shall be protected. Other symbols have the same meanings as above.)

(In the formula, all symbols have the same meaning as above.)

R ²⁴ -OH

(Wherein, R ²⁴ represents the same meaning as above).

The amidation reaction can be performed by the same method as the above.

(i) Among the compounds represented by the formula (I), the compound represented by the following formula (II) is represented by the formula (IA), (IA-1), (IB), (IC), (ID), (IE), (IF), (IG) or (IH). The compound to be produced can be produced by a deprotection reaction in alkali hydrolysis, a deprotection reaction under acidic conditions and / or a hydrogenolysis reaction.

(In formula, R <^1-4> , R < ^3-2 , R <^4-2> has the same meaning as R <^1> , R <^3> and R <^4> , respectively, At least 1 group of these contains a -COOH group, a hydroxyl group, or an amino group. The other symbols represent the same meaning as above.)

Alkali hydrolysis reactions are well known, for example, alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (calcium hydroxide, etc.) in organic solvents (methanol, tetrahydrofuran, dioxane, etc.). Or using a carbonate (sodium carbonate, potassium carbonate, or the like) or an aqueous solution thereof, or a mixture thereof.

Deprotection reactions under acidic conditions are well known, for example organic solvents (trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide, etc.) in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisol, etc.) or without solvent. ), Or an inorganic acid (such as hydrochloric acid) or a mixture thereof (such as hydrobromic acid) at a temperature of 0 to 90 ° C.

Hydrogen decomposition reactions are well known, for example, in organic solvents (tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, methanol, ethanol, etc.) under a hydrogen atmosphere, catalysts (palladium carbon, palladium hydroxide, palladium hydroxide, palladium acetate, Palladium Black, Platinum Black, Nickel, Ranickel, etc.), and the reaction is carried out at 0 to 80 DEG C under atmospheric pressure or pressure.

Those skilled in the art can easily understand, but examples of the protecting group for the carboxyl group and the hydroxyl group include t-butyl group and benzyl group, but are not particularly limited as long as they can be easily and selectively detached. For example TW Greene, Protective Groups in Oganic Synthesis, Wiley, New York, 1991 can be used. Although a benzyloxycarbonyl group and t-butoxycarbonyl group are mentioned as a protecting group of an amino group, It will not specifically limit, if it is a group which can be easily and selectively detach | desorbed in addition to it. Moreover, by using these protecting groups separately, the target compound of the present invention can be easily produced.

Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII Although the compound represented by itself can be manufactured by a well-known or well-known well-known method or the method as described in an Example, it is not specifically limited to these.

For example, compounds represented by the formula (X) are described in Liebigs Ann. Chem, 776-783, 1979].

For example, compounds represented by the formula (XII) are described in J. Org. Chem., Vol. 44, No. 10, 1979].

For example, among the compounds represented by the formula (XIV), E is a -O- group, -S- group, -SO- group, -SO ₂ -group, that is, the compound represented by the formula (XIV ') and the compound represented by the formula (XVII) , A compound wherein E is -O- group, -S- group, -SO- group, -SO ₂ -group, that is, the compound represented by the formula (XVII ') can be prepared by the method represented by Scheme 1 and Scheme 2 below. Can be.

In each scheme, E ⁵ represents a -O- group, -S- group, -SO- group, or SO ₂ -group, Boc represents a t-butoxycarbonyl group, and (Boc) ₂ O represents a di-t- group. Butyl dicarbonate, R ²⁶ represents a single bond or a C _1-3 alkylene group, and the other symbols represent the same meaning as above.)

Reaction in the said reaction formula is performed by a well-known method. In the above reaction formula, the compound used as the starting material is known per se or can be easily produced by a known method.

In addition, the other starting material and each reagent in this invention are known per se or can be manufactured by a well-known method.

In each reaction in the present specification, the reaction product is a conventional purification means, such as distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, or the like. It can refine | purify by a method. Purification may be performed for each reaction or may be carried out after the completion of several reactions.

Pharmacological activity of the compound of the present invention

It was demonstrated by the following experiment that the compound of this invention represented by general formula (I) has N type calcium channel inhibitory activity.

N-type calcium channel inhibitory activity:

Cells were induced to differentiate according to the method described in FEBS Letters, 235 , 178-182, 1988 and loaded with fluorescent reagent Fura-2.AM (final concentration 10 μM) at 37 ° C. for 30 minutes, followed by HEPES ( Cell suspension was prepared by substitution with Krebs buffer containing 25 mM). The cell suspension and the solution containing nifedipine and the compound of the present invention or the solution containing no compound of the present invention were incubated for 5 minutes. Subsequently, after adding the potassium chloride solution (final concentration 80 mM) to depolarize the cells, the intensity of the fluorescent wavelength of 500 nm when the UV of the excitation wavelengths 340 nm and 380 nm were alternately irradiated was measured by intracellular calcium measuring apparatus (Nihon Bunko Corporation, CAF110) was used. The inhibitory effect of the compound of the present invention (final concentration 3 μM) on calcium influx into cells was calculated by the following equation from the change in fluorescence intensity ratio (ΔR) at the peak.

Compound (3 μM) Calcium Influx Inhibition Effect (%) of the Present Invention = (1-Average value of ΔR of the group to which the solution containing the compound of the present invention was added / of the group to which the solution containing no compound of the present invention was added Average of ΔR) × 100

The results are shown in Table 41.

Example number Calcium influx inhibitory effect (%) 2 75 2 (29) 75 2 (80) 87 2 (86) 83 6 (22) 79 6 (27) 72 6 (44) 86 6 (68) 73 9 (13) 88

In addition, as described in Pflungers Archives, 391, 85-100, 1981, the compounds of the invention were measured using the patch clamp method, and the compounds of the invention were found to pass through the N-type calcium channel at a concentration of 10 μM. The movement of the barium ions (calcium current) was clearly suppressed. In addition, the cells used for the measurement were cultured according to [ FEBS Letters, 235, 178-182, 1988].

[toxicity]

The toxicity of the compounds of the invention is very low and is considered safe enough for use as a medicament.

[Application to Drugs]

Compounds represented by the formula (I) inhibit N-type calcium channels and thus prevent and / or treat drugs such as cerebral infarction, transient cerebral ischemic attack, cerebral spinal cord injury after cardiac surgery, spinal vascular disorder, stress hypertension, neurological disease, epilepsy, or pain It is useful as a therapeutic drug (eg, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.).

In order to use the compound of the present invention represented by the formula (I), its nontoxic salt, acid addition salt, or hydrate thereof for the above purpose, it is usually administered systemically or topically in the form of oral or parenteral.

Dosages vary depending on age, weight, symptoms, therapeutic effect, method of administration, treatment time, etc., but are usually oral or administered once a day in the range of 1 mg to 1000 mg per adult, once Or parenteral administration (preferably intravenously) once a day, in the range of 1 mg to 100 mg per adult, per dose, or in the range of 1 hour to 24 hours per day Administration is continued intravenously.

Of course, as mentioned above, since a dosage varies with various conditions, an amount smaller than the said dosage may be sufficient, and it may be necessary beyond the range.

When administering the compounds of the present invention, they are used as solid compositions, liquid compositions and other compositions for oral administration, and injections, external preparations, suppositories, and the like for parenteral administration.

Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate silicate do. The composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, dissolution aids such as glutamic acid or aspartic acid according to conventional methods. Tablets or pills may be coated with a film of gastric or enteric substances, such as white sugar, gelatin, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose phthalate, if necessary. You may coat. Also included are capsules of absorbable materials, such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs, and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). In addition to the inert diluent, the composition may contain auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and prescribed by methods known per se. In addition to the inert diluent, the composition may contain a stabilizer such as sodium hydrogen sulfite and a buffer to impart isotonicity, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid. Methods of making sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

Injectables for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, emulsions. Examples of the aqueous solution and suspending agent include distilled water for injection and physiological saline. Examples of the water-insoluble solution and suspending agent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (registered trademark). Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), dissolution aids (eg glutamic acid, aspartic acid). They are sterilized by filtration through a bacterial retention filter, formulation of bactericide or irradiation. They may also be prepared by aseptic solid compositions, for example, dissolved in sterile or sterile distilled water or other solvents prior to use of the lyophilized product.

Other compositions for parenteral administration include external preparations, ointments, coatings, suppositories for rectal administration and pessaries for intravaginal administration, which comprise one or more active substances and which are prescribed by conventional methods.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be described in detail by reference examples and examples, but the present invention is not limited thereto.

The part of the separation by chromatography and the solvent in parentheses indicated in TLC indicate the elution solvent or the developing solvent used, and the ratio indicates the volume ratio.

The solvent in brackets shown in the part of NMR represents the solvent used for the measurement.

Reference Example 1

(2S) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoic acid

(2S) -3-hydroxy-2-t-butoxycarbonylaminopropanoic acid (10.11 g) in dimethylformamide (200 ml, hereinafter referred to as DMF) solution under ice-cooling, sodium hydride (60%, 3.95 g) was added and stirred for 30 minutes at 0 ° C. (Bromomethyl) cyclohexane (9.0 ml) was added dropwise to the reaction mixture solution under ice cooling, tetra-n-butylammonium iodide (910 mg) was added, and the mixture was stirred at room temperature for 23 hours. Furthermore, (bromomethyl) cyclohexane (2.1 ml) was added dropwise to the reaction mixture solution, followed by stirring for 4 hours, (bromomethyl) cyclohexane (2.1 ml) was added dropwise, followed by stirring at room temperature for 25 hours. . After the reaction mixture solution was concentrated, the residue was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3) to give the title compound (2.52 g) having the following chemical data.

TLC: Rf 0.21 (chloroform: methanol = 9: 1);

NMR (CDCl ₃ ): δ 5.59-5.40 (1H, m), 4.46-4.27 (1H, m), 3.89-3.76 (1H, m), 3.64 (1H, dd, J = 9.4, 4.6 Hz), 3.27 ( 2H, d, J = 6.2 Hz), 1.79-0.79 (20H, m).

Reference Example 2

(2R) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanoic acid

To a solution of L-cysteine (133 mg) in ethanol (10 ml) was added 2N aqueous sodium hydroxide solution (1.1 ml) and (bromomethyl) cyclohexane (0.17 ml) and stirred at room temperature for 2.5 hours. 2N aqueous sodium hydroxide solution (0.6 ml) and di-t-butoxycarbonate (0.28 ml) were added to the reaction mixture, followed by stirring for 1 hour. After ethanol was distilled off, 1N hydrochloric acid was added to make acid, and it extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give the title compound (135 mg) with the following chemical data.

TLC: Rf 0.21 (ethyl acetate: acetic acid: water = 9: 1: 1);

NMR (CDCl ₃ ): δ 4.42-4.28 (1H, m), 3.01 (1H, dd, J = 14.2, 5.2 Hz), 2.92 (1H, dd, J = 14.2, 3.4 Hz), 2.45 (2H, d, J = 7.0 Hz), 1.91-0.81 (20H, m).

Example 1

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester

Methylene chloride (2 ml) solution of (3S) -3-benzyloxycarbonyl-3-t-butoxycarbonylaminopropanoic acid (3.22 g), cyclopentanol (1.73 g) and dimethylaminopyridine (127 mg) 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (3.83 g, hereinafter referred to as EDC-HCl) was added thereto, followed by stirring at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction mixture and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give a compound of the present invention (4.19 g) having the following chemical data.

TLC: Rf 0.42 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34 (5H, s), 5.50 (1H, d, J = 8.3 Hz), 5.25-5.11 (3H, m), 4.64-4.56 (1H, m), 2.97 (1H, dd, J = 5.1, 16.9 Hz), 2.77 (1H, dd, J = 4.8, 16.9 Hz), 1.88-1.54 (8H, m), 1.43 (9H, s).

Example 1 (1)-Example 1 (20)

The following compounds of the present invention were obtained by reacting the corresponding carboxylic acid derivative with the corresponding alcohol derivative or amine derivative in the same manner as in Example 1.

Example 1 (1)

(2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.45 (hexane: AcOEt = 4: 1);

7.35 (5H, s), 5.50 (1H, d, J = 7.5 Hz), 5.12 (2H, s), 4.86-4.73 (1H, m), 4.58-4.49 (1H, m), 3.04 (1H, dd, J = 4.5, 16.8 Hz), 2.86 (1H, dd, J = 4.8, 16.8 Hz), 1.86-1.58 (4H, m), 1.55-1.18 (15H, m).

Example 1 (2)

(2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.42 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.35 (5H, s), 5.97 (1H, d, J = 7.8 Hz), 5.22-5.15 (1H, m), 5.12 (2H, s), 4.56-4.47 (1H, m) , 3.02 (1H, dd, J = 4.8, 16.9 Hz), 2.84 (1H, dd, J = 4.8, 16.9 Hz), 1.88-1.49 (8H, m), 1.44 (9H, s).

Example 1 (3)

(2R) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.45 (hexane: ethyl acetate = 4: 1);

7.35 (5H, s), 5.50 (1H, d, J = 7.5 Hz), 5.12 (2H, s), 4.86-4.73 (1H, m), 4.58-4.49 (1H, m), 3.04 (1H, dd, J = 4.5, 16.8 Hz), 2.86 (1H, dd, J = 4.8, 16.8 Hz), 1.86-1.58 (4H, m), 1.55-1.18 (15H, m).

Example 1 (4)

(2R) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.42 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34 (5H, s), 5.51 (1H, d, J = 7.6 Hz), 5.22-5.15 (1H, m), 5.12 (2H, s), 4.57-4.47 (1H, m) , 3.01 (1H, dd, J = 4.8, 16.8 Hz), 2.84 (1H, dd, J = 4.8, 16.8 Hz), 1.86-1.50 (8H, m), 1.44 (9H, s).

Example 1 (5)

(2R) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.30 (hexane: AcOEt = 6: 1);

NMR (CDCl ₃ : δ 7.40-7.30 (5H, m), 5.50 (1H, bd, J = 9.0 Hz), 5.20 (1H, d, J = 12 Hz), 5.18 (1H, d, J = 12 Hz), 5.20 -5.07 (1H, m), 4.65-4.50 (1H, m), 2.93 (1H, dd, J = 18, 5 Hz), 2.78 (1H, dd, J = 18, 5 Hz), 1.80-1.48 (8H, m ), 1.44 (9H, s).

Example 1 (6)

(2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester

TLC: Rf 0.26 (hexane: AcOEt = 5: 1);

NMR (CDCl ₃ ): δ 7.40-7.30 (5H, m), 5.24-5.08 (4H, m), 4.43-4.25 (1H, m), 2.40-1.50 (12H, m), 1.43 (9H, s).

Example 1 (7)

(2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester

TLC: Rf 0.46 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.35 (5H, s), 5.20 (1H, d, J = 12.4 Hz), 5.13 (1H, d, J = 9.2 Hz), 4.79-4.67 (1H, m), 4.41-4.31 (1H, m), 2.44-2.30 (2H, m), 2.24-2.08 (1H, m), 2.04-1.66 (5H, m), 1.61-1.25 (15H, m).

Example 1 (8)

(2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester

TLC: Rf 0.42 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.35 (5H, s), 5.23-5.08 (4H, m), 4.40-4.29 (1H, m), 2.43-2.28 (2H, m), 2.23-2.03 (1H, m), 2.02-1.49 (9H, m), 1.42 (9H, s).

Example 1 (9)

(2S) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.51 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34 (5H, s), 5.18-5.04 (3H, m), 4.85-4.74 (1H, m), 4.37-4.24 (1H, m), 2.59-1.25 (23H, m).

Example 1 (10)

(2S) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

TLC: Rf 0.50 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.36 (5H, s), 5.25-5.11 (4H, m), 4.37-4.15 (1H, m), 2.58-1.34 (21H, m).

Example 1 (11)

(2R) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.51 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.36 (5H, s), 5.13 (2H, s), 5.14-5.04 (1H, m), 4.88-4.73 (1H, m), 4.39-4.22 (1H, m), 2.58- 1.24 (23 H, m).

Example 1 (12)

(2R) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

NMR (CDCl ₃ ): δ 7.35 (5H, s), 5.25-5.03 (4H, m), 4.37-4.13 (1H, m), 2.59-1.37 (21H, m).

Example 1 (13)

(2S) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.29 (hexane: AcOEt = 2: 1);

NMR (CDCl ₃ ): δ 7.43-7.25 (5H, m), 5.81 (1H, bd, J = 9 Hz), 5.50 (1H, bd, J = 9 Hz), 5.21 (1H, d, J = 10 Hz), 5.16 (1H, d, J = 10 Hz), 4.59-4.46 (1H, m), 3.81-3.60 (1H, m), 2.83 (1H, dd, J = 16, 5 Hz), 2.68 (1H, dd, J = 16 , 5 Hz), 1.95-0.94 (10H, m), 1.42 (9H, s).

Example 1 (14)

(2S) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.26 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.43-7.25 (5H, m), 5.90-5.74 (1H, m), 5.73-5.55 (1H, m), 5.21 (1H, d, J = 12 Hz), 5.16 (1H, d , J = 12 Hz), 4.60-4.46 (1H, m), 4.24-4.05 (1H, m), 2.82 (1H, dd, J = 16, 5 Hz), 2.68 (1H, dd, J = 16, 5 Hz), 2.08-1.19 (8H, m), 1.42 (9H, s).

Example 1 (15)

(2S) -4- (pyrrolidin-1-ylcarbonyl) -2-t-butoxycarbonylaminobutanoic acid benzyl ester

TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.40-7.30 (5H, m), 5.60-5.45 (1H, m), 5.21 (1H, d, J = 12 Hz), 5.14 (1H, d, J = 12 Hz), 4.40-4.23 (1H, m), 3.44 (2H, t, J = 7 Hz), 3.27 (2H, t, J = 7 Hz), 2.37-1.65 (8H, m), 1.44 (9H, s).

Example 1 (l6)

(2S) -3-cyclopentyloxycarbonyl-2- (N-t-butoxycarbonyl-N-methylamino) propanoic acid 4-nitrobenzyl ester

TLC: Rf 0.49 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.25-8.18 (2H, m), 7.51 (2H, d, J = 8.8 Hz), 5.30-5.11 (3H, m), 4.82-4.60 (1H, m), 3.17-2.66 ( 5H, m), 1.98-1.33 (17H, m).

Example 1 (17)

(2S) -3-cyclohexyloxycarbonyl-2- (N-t-butoxycarbonyl-N-amino) propanoic acid 4-nitrobenzyl ester

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.28-8.15 (2H, m), 7.51 (2H, d, J = 8.8 Hz), 5.38-5.14 (2H, m), 4.85-4.62 (2H, m), 3.18-3.01 ( 1H, m), 2.98-2.69 (4H, m), 1.94-1.16 (19H, m).

Example 1 (18)

(2S) -3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.59 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.36-7.31 (5H, m), 5.50 (1H, d, J = 8.0 Hz), 5.22 (1H, d, J = 12.4 Hz), 5.14 (1H, d, J = 12.4 Hz ), 5.01-4.86 (1H, m), 4.65-4.56 (1H, m), 2.99 (1H, dd, J = 16.4, 6.0 Hz), 2.78 (1H, dd, J = 16.4, 4.8 Hz), 2.39- 2.21 (2H, m), 2.12-1.50 (4H, m), 1.43 (9H, s).

Example 1 (19)

(2S) -3- (adamantan-2-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.46 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34 (5H, s), 5.54 (1H, d, J = 8.8 Hz), 5.22 (1H, d, J = 12.2 Hz), 5.13 (1H, d, J = 12.2 Hz), 4.93-4.87 (1H, br), 4.66-4.57 (1H, m), 3.04 (1H, dd, J = 4.4, 16.8 Hz), 2.85 (1H, dd, J = 4.6, 16.8 Hz), 2.01-1.65 ( 12H, m), 1.60-1.46 (2H, m), 1.43 (9H, s).

Example 1 (20)

(2S) -3- (adamantan-1-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester

TLC: Rf 0.46 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34 (5H, s), 5.50 (1H, d, J = 8.6 Hz), 5.23 (1H, d, J = 12.4 Hz), 5.13 (1H, d, J = 12.4 Hz), 4.60-4.52 (1H, m), 2.93 (1H, dd, J = 4.6, 16.8 Hz), 2.71 (1H, dd, J = 4.8, 16.8 Hz), 2.19-2.08 (3H, br), 2.02 (6H, d, J = 3.0 Hz), 1.63 (6H, s), 1.44 (9H, s).

Reference Example 3

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid

The compound (4.19 g) prepared in Example 1 was stirred in ethyl acetate (25 g) under argon gas atmosphere, palladium carbon (5%, 500 mg) was added, and stirred at room temperature under hydrogen atmosphere for 13 hours. The reaction mixture solution was filtered through celite. The filtrate was concentrated to give the title compound (2.98 g) with the following chemical data.

TLC: Rf 0.53 (chloroform: methanol = 9: 1);

NMR (CDCl ₃ ): δ 5.54 (1H, d, J = 8.1 Hz), 5.24-5.17 (1H, m), 4.63-4.55 (1H, m), 2.97 (1H, dd, J = 4.8, 17.1 Hz) , 2.79 (1H, doublet of doublets, J = 4.8, 17.1 Hz), 1.87-1.55 (8H, m), 1.45 (9H, s).

Example 2

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

The compound prepared in Reference Example 1 (90 mg), dimethylaminopyridine (6 mg) and 4-methoxybenzylamine (43 mg) were dissolved in methylene chloride, and EDC-HCl (122 mg) was added thereto at room temperature. Stirred for time. The reaction mixture solution was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the compound of the present invention (84 mg) having the following chemical data.

TLC: Rf 0.20 (hexane: AcOEt = 3: 1);

NMR (CDCl ₃ ): δ 7.19 (2H, d, J = 8.2 Hz), 6.85 (2H, d, J = 8.2 Hz), 6.80-6.66 (1H, br), 5.52-5.26 (1H, br), 4.44 (1H, dd, J = 5.2, 15.0 Hz), 4.36 (1H, dd, J = 5.8, 15.0 Hz), 4.30-4.15 (1H, br), 3.89-3.79 (4H, m), 3.44 (1H, dd , J = 7.0, 9.2 Hz), 3.27 (1H, dd, J = 6.1, 9.3 Hz), 3.20 (1H, dd, J = 6.1, 9.3 Hz), 1.94 (5H, m), 1.44 (9H, s) , 1.34-1.04 (4H, m), 0.96-0.74 (2H, m).

Example 2 (1)-Example 2 (119)

Carboxylic acid derivatives obtained by operating the compound prepared in Reference Example 1, Reference Example 2, Reference Example 3, or the compound prepared in Examples 1 (1) to 1 (20) in the same manner as Reference Example 3, or The following compounds of the present invention were obtained by reacting the carboxylic acid derivatives corresponding to these and the corresponding alcohol derivatives or amine derivatives in the same operation as in Example 2.

Example 2 (1)

(2S) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester

TLC: Rf 0.37 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 5.27 (2H, s), 5.12 (1H, d, J = 8.6 Hz), 4.80-4.69 (1H, m), 4.44-4.33 (1H, m), 2.43-2.36 (2H, m), 2.31-1.20 (21H, m).

Example 2 (2)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-fluorobenzyl ester

TLC: Rf 0.36 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.36-7.29 (2H, m), 7.08-6.99 (2H, m), 5.48 (1H, d, J = 12.3 Hz), 5.17 (1H, d, J = 12.4 Hz), 5.09 (1H, d, J = 12.4 Hz), 4.80-4.65 (1H, m), 4.65-4.52 (1H, m), 2.99 (1H, dd, J = 4.5, 16.8 Hz), 2.78 (1H, dd, J = 4.8, 16.8 Hz), 1.87-1.47 (6H, m), 1.43 (9H, s), 1.40-1.20 (4H, m).

Example 2 (3)

(2R) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-fluorobenzyl ester

TLC: Rf 0.46 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.36-7.29 (2H, m), 7.08-6.99 (2H, m), 5.49 (1H, d, J = 8.5 Hz), 5.19 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 4.73-4.57 (2H, m), 2.98 (1H, dd, J = 16.8, 4.8 Hz), 2.78 (1H, dd, J = 16.8, 4.7 Hz), 1.80- 1.24 (19 H, m).

Example 2 (4)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.39 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.52-5.42 (1H, m), 5.15 (1H, d, J = 12.0 Hz ), 5.07 (1H, d, J = 12.0 Hz), 4.75-4.64 (1H, m), 4.62-4.50 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 4.4, 16.8 Hz), 2.76 (1H, doublet of doublets, J = 5.0, 16.8 Hz), 1.90-1.52 (6H, m), 1.43 (9H, s), 1.40-1.22 (4H, m).

Example 2 (5)

(2R) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.31 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 5.48 (1H, d, J = 10.4 Hz), 5.15 (1H, d, J = 12.0 Hz), 5.07 (1H, d, J = 12.0 Hz), 4.73-4.55 (2H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 16.8, 4.8 Hz), 2.77 (1H , dd, J = 16.8, 4.6 Hz), 1.82-1.09 (19H, m).

Example 2 (6)

(2S) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid, 4-nitrobenzyl ester

TLC: Rf 0.17 (ethyl acetate: hexane = 1: 4).

NMR (CDCl ₃ ): δ 8.20 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.35 (5H, s), 5.78 (1H, d, J = 8.8 Hz), 5.33-5.19 (2H, m), 5.13 (2H, s), 4.76-4.67 (2H, m), 3.06 (1H, dd, J = 17.2, 4.4 Hz), 2.83 (1H, dd, J = 17.2, 4.4 Hz), 1.75-1.22 (10H, m).

Example 2 (7)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-nitrophenethyl ester

TLC: Rf 0.44 (hexane: ethyl acetate = 3: 1);

NMR (CDCl ₃ ): δ 8.18 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 5.43 (1H, d, J = 9.6 Hz), 4.78-4.61 (1H, m ), 4.60-4.46 (1H, m), 4.40 (2H, t, J = 6.6 Hz), 3.07 (2H, t, J = 6.6 Hz), 2.94 (1H, dd, J = 4.8, 17.1 Hz), 2.76 (1H, doublet of doublets, J = 4.6, 17.1 Hz), 1.88-1.48 (6H, m), 1.44 (9H, s), 1.41-1.22 (4H, m).

Example 2 (8)

(2S) -N-benzyl-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.37 (hexane: ethyl acetate = 3: 1);

NMR (CDCl ₃ ): δ 7.38-7.21 (5H, m), 6.88-6.72 (1H, br), 5.75-5.58 (1H, m), 4.82-4.68 (1H, m), 4.58-4.38 (3H, m ), 3.02 (1H, dd, J = 4.6, 17.0 Hz), 2.70 (1H, dd, J = 6.4, 17.0 Hz), 1.91-1.47 (6H, m), 1.43 (9H, s), 1.40-1.23 ( 4H, m).

Example 2 (9)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.34 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 5.48 (1H, d, J = 8.8 Hz), 5.18-5.04 (3H, m ), 4.60-4.51 (1H, m), 3.81 (3H, s), 2.96 (1H, dd, J = 4.8, 17.0 Hz), 2.76 (1H, dd, J = 4.8, 16.8 Hz), 1.83-1.54 ( 8H, m), 1.43 (9H, s).

Example 2 (10)

(2S) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.39 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 5.48 (1H, d, J = 8.6 Hz), 5.05 (2H, s), 4.84-4.72 (1H, m), 4.57-4.47 (1H, m), 3.81 (3H, s), 3.02 (1H, dd, J = 4.4, 16.8 Hz), 2.82 (1H, dd, J = 4.8, 16.8 Hz), 1.85-1.60 (4H, m), 1.56-1.27 (15H, m).

Example 2 (11)

(2S) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.18 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 5.48 (1H, d, J = 8.0 Hz), 5.22 (2H, s), 4.86-4.74 (1H, m), 4.60-4.52 (1H, m), 3.07 (1H, dd, J = 4.6, 16.8 Hz), 2.92 (1H, dd, J = 5.0, 16.8 Hz), 1.88-1.58 ( 4H, m), 1.56-1.20 (15H, m).

Example 2 (12)

(2S) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.24 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.47 (1H, d, J = 8.4 Hz), 5.21-5.16 (1H, m ), 5.05 (2H, s), 4.54-4.45 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 4.8, 16.8 Hz), 2.76 (1H, dd, J = 4.6, 16.8 Hz), 1.88-1.51 (8H, m), 1.44 (9H, s).

Example 2 (13)

(2S) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.15 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 5.44 (1H, d, J = 8.4 Hz), 5.22-5.17 (3H, m ), 4.59-4.50 (1H, m), 3.04 (1H, dd, J = 4.8, 16.8 Hz), 2.92 (1H, dd, J = 5.0, 16.8 Hz), 1.94-1.52 (8H, m), 1.44 ( 9H, s).

Example 2 (14)

(2R) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.39 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 5.48 (1H, d, J = 8.6 Hz), 5.05 (2H, s), 4.84-4.72 (1H, m), 4.57-4.47 (1H, m), 3.81 (3H, s), 3.02 (1H, dd, J = 4.4, 16.8 Hz), 2.82 (1H, dd, J = 4.8, 16.8 Hz), 1.85-1.60 (4H, m), 1.56-1.27 (15H, m).

Example 2 (15)

(2R) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.18 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 5.48 (1H, d, J = 8.0 Hz), 5.22 (2H, s), 4.86-4.74 (1H, m), 4.60-4.52 (1H, m), 3.07 (1H, dd, J = 4.6, 16.8 Hz), 2.92 (1H, dd, J = 5.0, 16.8 Hz), 1.88-1.58 ( 4H, m), 1.56-1.20 (15H, m).

Example 2 (16)

(2R) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.24 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.47 (1H, d, J = 8.4 Hz), 5.21-5.16 (1H, m ), 5.05 (2H, s), 4.54-4.45 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 4.8, 16.8 Hz), 2.76 (1H, dd, J = 4.6, 16.8 Hz), 1.88-1.51 (8H, m), 1.44 (9H, s).

Example 2 (17)

(2R) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester

TLC: Rf 0.15 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 5.44 (1H, d, J = 8.4 Hz), 5.22-5.17 (3H, m ), 4.59-4.50 (1H, m), 3.04 (1H, dd, J = 4.8, 16.8 Hz), 2.92 (1H, dd, J = 5.0, 16.8 Hz), 1.94-1.52 (8H, m), 1.44 ( 9H, s).

Example 2 (18)

(2R) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.20 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 9 Hz), 6.88 (2H, d, J = 9 Hz), 5.48 (1H, d, J = 8 Hz), 5.20-5.03 (3H, m), 4.63 -4.48 (1H, m), 3.81 (3H, s), 2.93 (1H, dd, J = 18, 5 Hz), 2.77 (1H, dd, J = 18, 5 Hz), 1.90-1.48 (8H, m), 1.43 (9 H, s).

Example 2 (19)

(2S) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.33 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.22 (2H, d, J = 9 Hz), 6.81 (2H, d, J = 9 Hz), 5.12-4.95 (3H, m), 4.75-4.59 (1H, m), 4.33-4.15 (1H, m), 3.74 (3H, s), 2.40-1.05 (14H, m), 1.35 (9H, s).

Example 2 (20)

(2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.17 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 9 Hz), 6.88 (2H, d, J = 9 Hz), 5.20-5.03 (4H, m), 4.40-4.23 (1H, m), 3.81 (3H , s), 2.40-1.48 (12H, m), 1.42 (9H, s).

Example 2 (21)

(2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester

TLC: Rf 0.16 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 9 Hz), 7.53 (2H, d, J = 9 Hz), 5.27 (2H, s), 5.21-5.05 (2H, m), 4.47-4.28 (1H) m), 2.46-1.49 (12H, m), 1.44 (9H, s).

Example 2 (22)

(2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.33 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.17-5.04 (3H, m), 4.79-4.69 (1H, m), 4.39 -4.25 (1H, m), 3.81 (3H, s), 2.43-2.29 (2H, m), 2.24-2.05 (1H, m), 2.03-1.53 (7H, m), 1.51-1.27 (13H, m) .

Example 2 (23)

(2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester

TLC: Rf 0.26 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 5.29 (2H, s), 5.12 (1H, d, J = 9.0 Hz), 4.81-4.69 (1H, m), 4.45-4.34 (1H, m), 2.48-2.35 (2H, m), 2.30-2.11 (1H, m), 2.07-1.53 (7H, m), 1.51-1.28 (13H , m).

Example 2 (24)

(2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.34 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.19-5.04 (4H, m), 4.37-4.26 (1H, m), 3.81 (3H, s), 2.44-2.27 (2H, m), 2.23-2.04 (1H, m), 2.00-1.57 (9H, m), 1.43 (9H, s).

Example 2 (25)

(2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester

TLC: Rf 0.21 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 8.23 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 5.27 (2H, s), 5.20-5.09 (2H, m), 4.43-4.33 (1H, m), 2.50-2.33 (2H, m), 2.28-2.10 (1H, m), 2.06-1.52 (9H, m), 1.43 (9H, s).

Example 2 (26)

(2S) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.29 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.34-7.20 (2H, m), 6.94-6.81 (2H, m), 5.12-5.00 (1H, m), 5.05 (2H, s), 4.84-4.74 (1H, m), 4.36-4.20 (1H, m), 3.81 (3H, s), 2.47-1.22 (23H, m).

Example 2 (27)

(2S) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.27 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 8.29-8.18 (2H, m), 7.56-7.46 (2H m), 7.52 (2H, d, J = 8.8 Hz), 5.30-5.05 (3H, m), 4.86-4.75 (1H m), 4.37-4.25 (1H, m), 2.64-2.38 (2H, m), 2.33-2.13 (1H, m), 2.06-1.17 (20H, m).

Example 2 (28)

(2S) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

TLC: Rf 0.29 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 11.2 Hz), 6.89 (2H, d, J = 11.2 Hz), 5.24-5.20 (1H, m), 5.13-5.01 (1H, m), 5.05 (2H, s), 4.31-4.21 (1H, m), 3.81 (3H, s), 2.47-1.59 (12H, m), 1.43 (9H, s).

Example 2 (29)

(2S) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

TLC: Rf 0.20 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 8.28-8.18 (2H, m), 7.76-7.46 (2H, m), 5.25-5.06 (2H, m), 5.22 (2H, s), 4.35-4.24 (1H, m), 2.55-2.47 (2H, m), 2.40-1.53 (10H, m), 1.44 (9H, s).

Example 2 (30)

(2R) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.33-7.23 (2H, m), 6.93-6.84 (2H, m), 5.12-5.00 (1H, m), 5.05 (2H, s), 4.84-4.74 (1H, m), 4.36-4.20 (1H, m), 3.81 (3H, s), 2.47-1.22 (23H, m).

Example 2 (31)

(2R) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester

TLC: Rf 0.27 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 8.26-8.18 (2H, m), 7.56-7.46 (2H, m), 5.22 (2H, s), 5.15-5.06 (1H, m), 4.86-4.75 (1H, m), 4.37-4.25 (1 H, m), 2.56-1.20 (23 H, m).

Example 2 (32)

(2R) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

TLC: Rf 0.29 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.33-7.24 (2H, m), 7.28 (2H, d, J = 11.2 Hz), 6.93-6.84 (2H, m), 6.89 (2H, d, J = 11.2 Hz), 5.24 -5.03 (2H, m), 5.05 (2H, s), 4.31-4.21 (1H, m), 3.81 (3H, s), 2.47-1.59 (12H, m), 1.43 (9H, s).

Example 2 (33)

(2R) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 8.25-8.18 (2H, m), 7.55-7.47 (2H, m), 5.25-5.06 (2H, m), 5.22 (2H, s), 4.35-4.24 (1H, m), 2.55-2.47 (2H, m), 2.31-1.53 (10H, m), 1.44 (9H, s).

Example 2 (34)

(2S) -N- (4-methoxybenzyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.18 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 7.18 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 6.85-6.67 (1H, m), 5.80-5.58 (1H, m), 4.83-4.67 (1H, m), 4.60-4.40 (1H, m), 4.43-4.25 (2H, m), 3.79 (3H, s), 2.98 (1H, dd, J = 18, 5 Hz), 2.68 (1H, dd, J = 18, 5 Hz), 1.95-1.60 (5H, m), 1.60-1.10 (5H, m), 1.42 (9H, s).

Example 2 (35)

(2S) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.31 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 9 Hz), 6.87 (2H, d, J = 9 Hz), 5.85-5.70 (1H, m), 5.53-5.35 (1H, m), 5.14 (1H , d, J = 12 Hz), 5.10 (1H, d, J = 12 Hz), 4.55-4.43 (1H, m), 3.80 (3H, s), 3.78-3.58 (1H, m), 2.81 (1H, dd, J = 15, 5 Hz), 2.66 (1H, dd, J = 15, 5 Hz), 1.95-1.48 (5H, m), 1.48-0.94 (5H, m), 1.42 (9H, s).

Example 2 (36)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.19 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 7.25-7.10 (1H, m), 7.17 (2H, d, J = 9 Hz), 6.84 (2H, d, J = 9 Hz), 6.33-6.15 (1H, m), 5.87-5.70 (1H, m), 4.53-4.40 (1H, m), 4.36 (2H, d, J = 6 Hz), 3.79 (3H, s), 3.78-3.58 (1H, m), 2.84 (1H, dd, J = 15, 5 Hz), 2.51 (1H, dd, J = 15, 5 Hz), 1.94-1.50 (5H, m), 1.50-0.97 (5H, m), 1.42 (9H, s).

Example 2 (37)

(2S) -N- (4-methoxybenzyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 7.18 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 6.80-6.70 (1H, m), 5.78-5.62 (1H, m), 5.23-5.08 (1H, m), 4.59-4.23 (3H, m), 3.80 (3H, s), 2.96 (1H, dd, J = 18, 5 Hz), 2.65 (1H, dd, J = 18, 8 Hz), 1.93- 1.48 (8H, m), 1.42 (9H, s).

Example 2 (38)

(2S) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.46 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.28 (2H, d, J = 9 Hz), 6.87 (2H, d, J = 9 Hz), 5.83-5.73 (1H, m), 5.64-5.47 (1H, m), 5.14 (1H , d, J = 12 Hz), 5.09 (1H, d, J = 12 Hz), 4.56-4.40 (1H, m), 4.21-4.04 (1H, m), 3.81 (3H, s), 2.79 (1H, dd, J = 15, 5 Hz), 2.65 (1H, dd, J = 15, 5 Hz), 2.05-1.84 (2H, m), 1.75-1.48 (4H, m), 1.46-1.17 (2H, m), 1.42 (9H , s).

Example 2 (39)

(2S) -N- (4-methoxybenzyl) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.33 (methanol: methylene chloride = 1: 19);

NMR (CDCl ₃ ): δ 7.23-7.10 (1H, m), 7.17 (2H, d, J = 9 Hz), 6.84 (2H, d, J = 9 Hz), 6.32-6.15 (1H, m), 6.00-5.82 (1H, m), 4.51-4.31 (3H, m), 4.20-4.03 (1H, m), 3.79 (3H, s), 2.83 (1H, dd, J = 15, 5 Hz), 2.50 (1H, dd, J = 15, 8 Hz), 2.05-1.80 (2H, m), 1.75-1.46 (4H, m), 1.46-1.23 (2H, m), 1.42 (9H, s).

Example 2 (40)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 2-pyridylmethyl ester

TLC: Rf 0.41 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 8.58 (1H, d, J = 4.6 Hz), 7.74-7.66 (1H, m), 7.37 (1H, d, J = 7.8 Hz), 7.23 (1H, dd, J = 4.6, 7.8 Hz), 5.55 (1H, d, J = 8.8 Hz), 5.31 (2H, s), 5.20-5.12 (1H, m), 4.72-4.62 (1H, m), 3.02 (1H, dd, J = 4.8 , 16.8 Hz), 2.81 (1H, dd, J = 4.8, 16.8 Hz), 1.84-1.56 (8H, m), 1.44 (9H, s).

Example 2 (41)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-t-butylbenzyl ester

TLC: Rf 0.45 (hexane: AcOEt = 6: 1);

NMR (CDCl ₃ ): δ 7.38 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 8.6 Hz), 5.21-5.08 (3H, m ), 4.62-4.53 (1H, m), 2.96 (1H, dd, J = 4.8, 16.8 Hz), 2.77 (1H, dd, J = 4.8, 16.8 Hz), 1.76-1.52 (8H, m), 1.43 ( 9H, s), 1.32 (9H, s).

Example 2 (42)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 2-methoxybenzyl ester

TLC: Rf 0.32 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.34-7.26 (2H, m), 6.95 (1H, d, J = 6.6 Hz), 6.86 (1H, d, J = 8.4 Hz), 5.50 (1H, d, J = 8.8 Hz ), 5.23 (2H, s), 5.18-5.10 (1H, m), 4.65-4.56 (1H, m), 3.83 (3H, s), 2.96 (1H, dd, J = 4.8, 16.8 Hz), 2.87 ( 1H, dd, J = 4.8, 16.8 Hz), 1.84-1.45 (8H, m), 1.44 (9H, s).

Example 2 (43)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 3-methoxybenzyl ester

TLC: Rf 0.32 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.31-7.23 (1H, m), 6.93-6.84 (3H, m), 5.50 (1H, d, J = 8.8 Hz), 5.22-5.08 (3H, m), 4.64-4.54 ( 1H, m), 3.81 (3H, s), 2.97 (1H, dd, J = 4.8, 16.8 Hz), 2.77 (1H, dd, J = 4.8, 16.8 Hz), 1.86-1.50 (8H, m), 1.44 (9H, s).

Example 2 (44)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 3-pyridylmethyl ester

TLC: Rf 0.36 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 8.60-8.57 (2H, m), 7.69 (1H, d, J = 7.6 Hz), 7.33-7.27 (1H, m), 5.50 (1H, d, J = 9.4 Hz), 5.28 -5.10 (3H, m), 4.64-4.54 (1H, m), 2.97 (1H, dd, J = 4.8, 17.0 Hz), 2.77 (1H, dd, J = 4.8, 17.0 Hz), 1.86-1.49 (8H m), 1.43 (9H, s).

Example 2 (45)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-pyridylmethyl ester

TLC: Rf 0.29 (hexane: AcOEt = 1: 1);

NMR (CDCl ₃ ): δ 8.60 (2H, d, J = 6.0 Hz), 7.25 (2H, d, J = 6.0 Hz), 5.54 (1H, d, J = 8.8 Hz), 5.28-5.12 (3H, m ), 4.70-4.61 (1H, m), 3.02 (1H, dd, J = 4.8, 16.8 Hz), 2.80 (1H, dd, J = 4.8, 16.8 Hz), 1.87-1.52 (8H, m), 1.45 ( 9H, s).

Example 2 (46)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-chlorobenzyl ester

TLC: Rf 0.26 (hexane: AcOEt = 6: 1);

NMR (CDCl ₃ ): δ 7.33 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 5.49 (1H, d, J = 8.0 Hz), 5.22-5.06 (3H, m ), 4.63-4.54 (1H, m), 2.96 (1H, dd, J = 4.6, 16.8 Hz), 2.76 (1H, dd, J = 4.6, 16.8 Hz), 1.83-1.53 (8H, m), 1.44 ( 9H, s).

Example 2 (47)

(2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-bromobenzyl ester

TLC: Rf 0.25 (hexane: ethyl acetate = 6: 1);

NMR (CDCl ₃ ): δ 7.48 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 8.4 Hz), 5.20-5.04 (3H, m ), 4.63-4.54 (1H, m), 2.96 (1H, dd, J = 4.6, 17.0 Hz), 2.76 (1H, dd, J = 4.6, 17.0 Hz), 1.83-1.52 (8H, m), 1.43 ( 9H, s).

Example 2 (48)

(2S) -4- (pyrrolidin-1-ylcarbonyl) -2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.33 (methylene chloride: methanol = 19: 1);

NMR (CDCl ₃ ): δ 7.30 (2H, d, J = 9 Hz), 6.87 (2H, d, J = 9 Hz), 5.58-5.40 (1H, m), 5.15 (1H, d, J = 13 Hz), 5.06 (1H, d, J = 13 Hz), 4.38-4.20 (1H, m), 3.81 (3H, s), 3.48-3.38 (2H, m), 3.32-3.20 (2H, m), 2.16-1.78 (8H, m), 1.42 (9H, s).

Example 2 (49)

(2S) -3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.25 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 9 Hz), 6.88 (2H, d, J = 9 Hz), 5.28 (1H, d, J = 8 Hz), 5.14 (1H, d, J = 12 Hz) , 5.09 (1H, d, J = 12 Hz), 4.64-4.52 (1H, m), 4.45 (1H, dd, J = 11, 4 Hz), 4.26 (1H, dd, J = 11, 4 Hz), 3.81 (3H , s), 2.27-2.10 (1H, m), 1.89-1.53 (5H, m), 1.53-1.05 (5H, m), 1.44 (9H, s).

Example 2 (50)

(2S) -3-cyclopentyloxycarbonyl-2- (N-methyl-N-t-butoxycarbonylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.65 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.25 (2H, m), 6.91-6.83 (2H, m), 5.23-5.01 (3H, m), 4.86-4.55 (1H, m), 3.81 (3H, s), 3.03 (1H, dd, J = 16.2, 6.4 Hz), 2.91-2.83 (2H, m), 2.71 (1H, dd, J = 16.2, 7.8 Hz), 1.96-1.52 (8H, m), 1.43-1.38 ( 9H, m).

Example 2 (51)

(2S) -3-cyclohexylcarbonyl-2- (N-methyl-N-t-butoxycarbonylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.75 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.18-5.01 (2H, m), 4.88-4.55 (2H, m), 3.81 (3H, s), 3.05 (1H, dd, J = 16.4, 6.4 Hz), 2.91-2.83 (3H, m), 2.74 (1H, dd, J = 16.4, 8.4 Hz), 1.89-1.16 (19H, m ).

Example 2 (52)

(2R) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TCL: Rf 0.18 (ethyl acetate: hexane = 1: 8);

NMR (CDCl ₃ ): δ 7.32-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H, br.d, J = 8.8 Hz), 5.18 (1H, d, J = 12.0 Hz) , 5.06 (1H, d, J = 12.0 Hz), 4.48-4.34 (1H, m), 3.81-3.76 (4H, m), 3.60 (1H, dd, J = 9.8, 3.2 Hz), 3.19 (1H, dd , J = 9.4, 6.6 Hz), 3.09 (1H, dd, J = 9.4, 6.4 Hz), 1.74-1.13 (19H, m).

Example 2 (53)

(2S) -3-cyclohexyl methoxy-2-t-butoxycarbonylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.18 (ethyl acetate: hexane = 1: 8);

NMR (CDCl ₃ ): δ 7.32-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H, br.d, J = 8.8 Hz), 5.18 (1H, d, J = 12.0 Hz) , 5.06 (1H, d, J = 12.0 Hz), 4.48-4.34 (1H, m), 3.81-3.76 (4H, m), 3.60 (1H, dd, J = 9.8, 3.2 Hz), 3.19 (1H, dd , J = 9.4, 6.6 Hz), 3.09 (1H, dd, J = 9.4, 6.4 Hz), 1.74-1.13 (19H, m).

Example 2 (54)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-methoxyphenethyl ester

TLC: Rf 0.60 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.17-7.09 (2H, m), 6.88-6.80 (2H, m), 5.45 (1H, br.d, J = 8.8 Hz), 4.78-4.65 (1H, m), 4.59- 4.49 (1H, m), 4.40-4.22 (2H, m), 3.79 (3H, s), 2.99-2.85 (3H, m), 2.76 (1H, dd, J = 17.0, 4.6 Hz), 1.86-1.24 ( 19H, m).

Example 2 (55)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 3- (4-methoxyphenyl) propyl ester

TLC: Rf 0.67 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ : δ 7.13-7.05 (2H, m), 6.86-6.79 (2H, m), 5.49 (1H, br.d, J = 8.6 Hz), 4.81-4.70 (1H, m), 4.60-4.51 (1H, m), 4.24-4.04 (2H, m), 3.79 (3H, s), 2.98 (1H, dd, J = 16.6, 4.6 Hz), 2.79 (1H, dd, J = 16.6, 4.8 Hz), 2.62 (2H, t, J = 7.4 Hz), 2.00-1.16 (21H, m).

Example 2 (56)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, furan-2-ylmethyl ester

TLC: Rf 0.63 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.42-7.40 (1H, m), 6.41 (1H, d, J = 3.2 Hz), 6.35 (1H, dd, J = 3.2, 2.0 Hz), 5.46 (1H, d, J = 8.6 Hz), 5.12 (2H, s), 4.81-4.67 (1H, m), 4.62-4.53 (1H, m), 2.96 (1H, dd, J = 16.8, 4.8 Hz), 2.77 (1H, dd, J = 16.8, 5.0 Hz), 1.86-1.16 (19H, m).

Example 2 (57)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid thiophen-2-ylmethyl ester

TLC: Rf 0.62 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.32 (1H, dd, J = 5.0, 1.4 Hz), 7.10-7.08 (1H, m), 6.98 (1H, dd, J = 5.0, 3.2), 5.48 (1H, d, J = 8.4 Hz), 5.37 (1H, d, J = 12.8 Hz), 5.28 (1H, d, J = 12.8 Hz), 4.76-4.66 (1H, m), 4.62-4.53 (1H, m), 2.97 (1H , dd, J = 17.2, 4.8 Hz), 2.78 (1H, dd, J = 17.2, 4.6 Hz), 1.86-1.22 (19H, m).

Example 2 (58)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4- (4-methoxyphenyl) butyl ester

TLC: Rf 0.63 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.12-7.05 (2H, m), 6.86-6.79 (2H, m), 5.47 (1H, d, J = 8.8 Hz), 4.79-4.68 (1H, m), 4.58-4.49 ( 1H, m), 4.18-4.12 (2H, m), 2.96 (1H, dd, J = 17.2, 4.0 Hz), 2.78 (1H, dd, J = 17.2, 4.8 Hz), 2.61-2.54 (2H, m) , 1.89-1.16 (23H, m).

Example 2 (59)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.82 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 5.48 (1H, d, J = 8.4 Hz), 4.88-4.70 (2H, m), 4.56-4.47 (1H, m), 2.97 (1H, dd, J = 16.6, 4.0 Hz) , 2.78 (1H, doublet of doublets, J = 16.6, 4.8 Hz), 1.90-1.18 (29H, m).

Example 2 (60)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid methyl ester

TLC: Rf 0.55 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 5.47 (1H, d, J = 8.0 Hz), 4.82-4.71 (1H, m), 4.62-4.53 (1H, m), 3.76 (3H, s), 2.97 (1H, dd, J = 16.8, 4.6 Hz), 2.78 (1H, dd, J = 16.8, 5.0 Hz), 1.90-1.18 (19H, m).

Example 2 (61)

(2S) -N- (4-methoxyphenyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.51 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.41 (1H, br.s), 7.45-7.37 (2H, m), 6.89-6.81 (2H, m), 5.80 (1H, d, J = 7.0 Hz), 4.84-4.73 ( 1H, m), 4.66-4.57 (1H, m), 3.79 (3H, s), 3.01 (1H, dd, J = 16.8, 4.4 Hz), 2.73 (1H, dd, J = 16.8, 7.0 Hz), 1.86 -1.16 (19 H, m).

Example 2 (62)

(2S) -3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.57 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.24 (2H, m), 6.92-6.85 (2H, m), 5.48 (1H, d, J = 9.0 Hz), 5.15 (1H, d, J = 11.8 Hz), 5.07 (1H, d, J = 11.8 Hz), 5.01-4.86 (1H, m), 4.62-4.52 (1H, m), 3.81 (3H, s), 2.96 (1H, dd, J = 17.2, 5.2 Hz), 2.76 (1H, doublet of doublets, J = 17.2, 4.8 Hz), 2.37-2.22 (2H, m), 2.12-1.43 (13H, m).

Example 2 (63)

(2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid diphenylmethyl ester

TLC: Rf 0.33 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.45-7.18 (10H, m), 6.90 (1H, s), 5.56 (1H, d, J = 8 Hz), 4.75-4.58 (2H, m), 3.03 (1H, dd, J = 18, 5 Hz), 2.83 (1H, dd, J = 18, 5 Hz), 1.80-1.08 (10H, m), 1.43 (9H, s).

Example 2 (64)

(2S) -N-((1S) -2-phenyl-1-benzyloxycarbonylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.53 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.39-7.19 (8H, m), 7.08-7.03 (2H, m), 6.97 (1H, d, J = 8.4 Hz), 5.61 (1H, d, J = 8.4 Hz), 5.14 (1H, d, J = 12.4 Hz), 5.08 (1H, d, J = 12.4 Hz), 4.90-4.69 (2H, m), 4.56-4.42 (1H, m), 3.10 (2H, d, J = 6.0 Hz), 2.93 (1H, dd, J = 17.2, 4.6 Hz), 2.62 (1H, dd, J = 17.2, 6.2 Hz), 1.89-1.18 (19H, m).

Example 2 (65)

(2S) -N-((1S) -1-benzyloxycarbonylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.47 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.41-7.31 (5H, m), 7.09 (1H, d, J = 6.4 Hz), 5.67 (1H, d, J = 7.8 Hz), 5.20 (1H, d, J = 12.0 Hz ), 5.13 (1H, d, J = 12.0 Hz), 4.81-4.46 (3H, m), 2.96 (1H, dd, J = 16.8, 4.4 Hz), 2.64 (1H, dd, J = 16.8, 6.6), 1.92-1.18 (19 H, m).

Example 2 (66)

(2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.33 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 7.40-7.27 (5H, m), 7.23 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 5.56-5.40 (1H, m), 5.07 (4H , s), 4.65-4.50 (1H, m), 3.80 (3H, s), 3.03 (1H, dd, J = 18, 5 Hz), 2.85 (1H, dd, J = 18, 5 Hz), 1.42 (9H, s).

Example 2 (67)

(2S) -3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.36 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.4 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.48 (1H, d, J = 8.4 Hz), 5.15 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 4.94-4.82 (1H, m), 4.61-4.52 (1H, m), 3.81 (3H, s), 2.95 (1H, dd, J = 4.4, 16.8 Hz), 2.76 (1H, dd, J = 4.8, 16.8 Hz), 1.90-1.75 (2H, m), 1.68-1.34 (19H, m).

Example 2 (68)

(2S) -3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.38 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ : δ 7.27 (2H, d, J = 8.4 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.49 (1H, d, J = 8.4 Hz), 5.16 (1H, d, J = 12.0 Hz), 5.07 (1H, d, J = 12.0 Hz), 4.96-4.84 (1H, m), 4.61-4.52 (1H, m), 3.81 (3H, s), 2.94 (1H, dd, J = 4.4 , 16.8 Hz), 2.75 (1H, dd, J = 4.8, 16.8 Hz), 1.75-1.46 (14H, m), 1.43 (9H, s).

Example 2 (69)

(2S) -3- (adamantan-2-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.43 (hexane: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.51 (1H, d, J = 8.4 Hz), 5.16 (1H, d, J = 12.0 Hz), 5.06 (1H, d, J = 12.0 Hz), 4.92-4.87 (1H, br), 4.63-4.54 (1H, m), 3.81 (3H, s), 3.01 (1H, dd, J = 4.6, 16.8 Hz), 2.83 (1H, dd, J = 4.8, 16.8 Hz), 2.01-1.67 (12H, m), 1.58-1.45 (2H, m), 1.43 (9H, s).

Example 2 (70)

(2S) -3- (adamantan-1-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.42 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.49 (1H, d, J = 8.4 Hz), 5.17 (1H, d, J = 11.9 Hz), 5.05 (1H, d, J = 11.9 Hz), 4.57-4.48 (1H, m), 3.80 (3H, s), 2.90 (1H, dd, J = 4.4, 16.8 Hz), 2.69 (1H) , dd, J = 4.8, 16.8 Hz), 2.18-2.07 (3H, br), 2.01 (6H, d, J = 3.0 Hz), 1.63 (6H, t, J = 3.0 Hz), 1.44 (9H, s) .

Example 2 (71)

(2S, 3R) -3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

TLC: Rf 0.35 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.29 (2H, d, J = 9 Hz), 6.88 (2H, d, J = 9 Hz), 5.46-5.30 (1H, m), 5.17 (1H, d, J = 10 Hz), 5.06 (1H, d, J = 13 Hz), 5.04 (1H, d, J = 13 Hz), 4.44 (1H, dd, J = 10, 2 Hz), 3.81 (3H, s), 2.20-2.00 (1H, m), 1.85-1.50 (5H, m), 1.46 (9H, s), 1.40-1.00 (5H, m), 1.25 (3H, d, J = 6 Hz).

Example 2 (72)

(2S) -N-((1S) -1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide

TLC: Rf 0.31 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.39-7.24 (7H, m), 7.03 (1H, d, J = 7.2 Hz), 6.92-6.85 (2H, m), 5.91 (1H, d, J = 7.8 Hz), 5.16 -5.03 (4H, m), 4.82-4.69 (1H, m), 4.64-4.47 (2H, m), 3.81 (3H, s), 2.99 (1H, dd, J = 17.2, 4.0 Hz), 2.65 (1H , dd, J = 17.2, 6.4 Hz), 1.84-1.18 (13H, m).

Example 2 (73)

(2S) -N-((1S) -2-phenyl-1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide

TLC: Rf 0.36 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.38-7.33 (5H, m), 7.25-7.16 (5H, m), 7.05-6.84 (5H, m), 5.87 (1H, d, J = 8.2 Hz), 5.15-4.98 ( 4H, m), 4.86-4.67 (2H, m), 4.59-4.50 (1H, m), 3.82 (3H, s), 3.06 (2H, d, J = 6.0 Hz), 2.94 (1H, dd, J = 17.2, 4.4 Hz), 2.62 (1H, dd, J = 17.2, 6.6 Hz), 1.84-1.18 (10H, m).

Example 2 (74)

(3S) -3-t-butoxycarbonylamino-3- (1, 2, 3, 4-tetrahydroquinolin-1-ylcarbonyl) propanoic acid cyclohexyl ester

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 2);

NMR (DMSO-d ₆ ): δ 7.50-7.05 (5H, m), 4.97 (1H, doublet of doublets, J = 15.4, 7.0 Hz), 4.67-4.52 (1H, m), 3.83-3.50 (2H, m), 2.70-2.38 (4H, m), 1.94-1.80 (2H, m), 1.75-1.18 (19H, m).

Example 2 (75)

(3S) -3-t-butoxycarbonylamino-3- (1, 2, 3, 4-tetrahydroisoquinolin-2-ylcarbonyl) propanoic acid cyclohexyl ester

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.23-7.11 (4H, m), 5.42 (1H, d, J = 9.2 Hz), 5.14-5.03 (1H, m), 4.88-4.58 (3H, m), 4.02-3.71 ( 2H, m), 2.97-2.55 (4H, m), 1.92-1.08 (19H, m).

Example 2 (76)

(2S) -N-methyl-N- (1, 1-dimethyl-2-phenylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.56 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.09 (5H, m), 5.39 (1H, d, J = 9.2 Hz), 4.99-4.88 (1H, m), 4.81-4.71 (1H, m), 3.35 (1H, d, J = 13.2 Hz), 3.00 (1H, d, J = 13.2 Hz), 2.73 (1H, dd, J = 15.4, 6.6 Hz), 2.65 (3H, s), 2.54 (1H, dd, J = 15.4 , 6.6 Hz), 1.93-1.19 (25H, m).

Example 2 (77)

(2S) -6-cyclohexylcarbonylamino-2-t-butoxycarbonylaminohexanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ : δ 7.32-7.25 (2H, m), 6.93-6.85 (2H, m), 5.55-5.44 (1H, m), 5.17-5.03 (3H, m), 4.35-4.21 (1H, m) , 3.81 (3H, s), 3.23-3.14 (2H, m), 2.08-1.96 (1H, m), 1.88-1.18 (25H, m).

Example 2 (78)

(2R) -3- (4-methoxybenzylthio) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester

TLC: Rf 0.70 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.28-7.19 (2H, m), 6.88-6.81 (2H, m), 5.29 (1H, d, J = 7.4 Hz), 4.90-4.77 (1H, m), 4.54-4.44 ( 1H, m), 3.79 (3H, s), 3.70 (2H, s), 2.89 (1H, dd, J = 14.0, 4.4 Hz), 2.79 (1H, dd, J = 14.0, 6.0 Hz), 1.92-1.18 (19H, m).

Example 2 (79)

(2R) -N- (4-methoxybenzyl) -3- (4-methoxybenzylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.26-7.16 (4H, m), 6.89-6.78 (4H, m), 6.53-6.41 (1H, m), 5.26 (1H, d, J = 7.4 Hz), 4.38 (2H, d, J = 5.4 Hz), 4.27-4.18 (1H, m), 3.79 (3H, s), 3.78 (3H, s), 3.68 (2H, s), 2.91 (1H, dd, J = 14.0, 5.4 Hz ), 2.74 (1H, doublet of doublets, J = 14.0, 6.8 Hz), 1.43 (9H, s).

Example 2 (80)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.89-6.84 (2H, m), 6.68-6.60 (1H, m), 5.36 (1H, d, J = 7.0 Hz), 4.39 (2H, d, J = 5.6 Hz), 4.28-4.18 (1H, m), 3.80 (3H, s), 2.98 (1H, dd, J = 14.0, 5.8 Hz), 2.82 (1H, dd, J = 14.0, 7.0 Hz ), 2.46 (1H, dd, J = 12.8, 7.0 Hz), 2.39 (1H, dd, J = 12.8, 6.6 Hz), 1.83-0.82 (20H, m).

Example 2 (81)

(2S) -N- (4-methoxybenzyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.26 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.38-7.12 (7H, m), 6.84-6.77 (2H, m), 6.69-6.61 (1H, m), 5.44-5.34 (1H, m), 4.56 (1H, d, J = 11.4 Hz), 4.47 (1H, d, J = 11.4 Hz), 4.39 (2H, d, J = 5.8 Hz), 4.34-4.24 (1H, m), 3.95 (1H, dd, J = 9.2, 3.8 Hz ), 3.78 (3H, s), 3.59 (1H, doublet of doublets, J = 9.2, 6.6 Hz), 1.43 (9H, s).

Example 2 (82)

(2S) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.18-7.11 (2H, m), 6.72-6.56 (3H, m), 5.46-5.30 (1H, m), 4.41 (1H, dd, J = 14.2, 5.4 Hz), 4.30 ( 1H, dd, J = 14.2, 5.2 Hz, 4.29-4.15 (1H, m), 3.82 (1H, dd, J = 9.2, 3.6 Hz), 3.47 (1H, dd, J = 9.2, 6.8), 3.31- 3.16 (2H, m), 2.93 (6H, s), 1.75-0.74 (20H, m).

Example 2 (83)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.18 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.23-7.16 (2H, m), 6.89-6.82 (2H, m), 6.78-6.68 (1H, m), 5.46-5.28 (1H, m), 4.45 (1H, dd, J = 14.2, 5.4 Hz), 4.35 (1H, dd, J = 14.2, 5.6 Hz), 4.28-4.16 (1H, m), 3.86-3.79 (4H, m), 3.47 (1H, dd, J = 9.2, 7.0 Hz), 3.27 (1H, dd, J = 8.8, 6.4 Hz), 3.20 (1H, dd, J = 8.8, 6.2 Hz), 1.75-0.74 (20H, m).

Example 2 (84)

(2S) -N-methyl-N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.56 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.21-7.13 (2H, m), 6.89-6.80 (2H, m), 5.47-5.38 (1H, m), 5.00-4.70 (2H, m), 4.45 (0.3H, d, J = 16.6 Hz), 4.30 (0.7H, d, J = 14.4 Hz), 3.79 (3H, s), 3.66-3.47 (2H, m), 3.22-3.14 (2H, m), 3.01 (2.1H, s ), 2.89 (0.9H, s), 1.74-0.74 (20H, m).

Example 2 (85)

(2RS) -N- (4-methoxybenzyl) -4-cyclohexylmethoxy-2-t-butoxycarbonylaminobutanamide

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 9 Hz), 6.86 (2H, d, J = 9 Hz), 6.83-6.68 (1H, m), 6.00-5.85 (1H, m), 4.39 (2H , d, J = 6 Hz), 4.37-4.17 (1H, m), 3.80 (3H, s), 3.62-3.43 (2H, m), 3.13 (2H, d, J = 6 Hz), 2.16-1.97 (2H, m), 1.80-1.00 (9H, m), 1.42 (9H, s), 1.00-0.70 (2H, m).

Example 2 (86)

(2S) -N- (4-nitrobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.22-8.14 (2H, m), 7.48-7.41 (2H, m), 7.02-6.94 (1H, m), 5.37 (1H, d, J = 6.4 Hz), 4.64 (1H, dd, J = 13.2, 5.8 Hz), 4.53 (1H, dd, J = 13.2, 6.2 Hz), 4.34-4.22 (1H, m), 3.87 (1H, dd, J = 9.2, 3.6 Hz), 3.52 (1H , dd, J = 9.2, 6.6 Hz), 3.30 (1H, dd, J = 9.2, 6.2 Hz), 3.24 (1H, dd, J = 9.2, 6.0 Hz), 1.77-0.78 (20H, m).

Example 2 (87)

(2S) -N- (4-methoxybenzyl) -3- (2-cyclohexenyloxy) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.26 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 9 Hz), 6.84 (2H, d, J = 9 Hz), 6.84-6.59 (1H, m), 5.90-5.78 (1H, m), 5.74-5.60 (1H, m), 5.52-5.34 (1H, m), 4.41 (2H, d, J = 6 Hz), 4.30-4.15 (1H, m), 4.00-3.83 (2H, m), 3.79 (3H, s) , 3.64-3.48 (1H, m), 2.05-1.90 (2H, m), 1.90-1.35 (4H, m), 1.43 (9H, s).

Example 2 (88)

(2S) -N- (4-methoxybenzyl) -3-cyclohexyloxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 6.85-6.70 (1H, m), 5.50-5.30 (1H, m), 4.41 (2H , d, J = 6 Hz), 4.26-4.14 (1H, m), 3.88 (1H, dd, J = 9,4 Hz), 3.80 (3H, s), 3.50 (1H, dd, J = 9,7 Hz), 3.36-3.20 (1H, m), 1.90-1.05 (10H, m), 1.44 (9H, s).

Example 2 (89)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.43 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.68-6.58 (1H, m), 5.35 (1H, d, J = 7.4 Hz), 4.40 (2H, d, J = 6.0 Hz), 4.28-4.18 (1H, m), 3.80 (3H, s), 2.99 (1H, dd, J = 13.6, 5.6 Hz), 2.82 (1H, dd, J = 13.6, 7.0 Hz ), 2.48 (1H, dd, J = 12.8, 7.0), 2.39 (1H, dd, J = 12.8, 6.6 Hz), 1.86-0.80 (20H, m).

Example 2 (90)

(2R) -N- (4-methoxybenzyl) -3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.36 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.89-6.82 (2H, m), 6.68-6.59 (1H, m), 5.36 (1H, d, J = 7.4 Hz), 4.39 (2H, d, J = 5.6 Hz), 4.29-4.19 (1H, m), 3.80 (3H, s), 3.00 (1H, dd, J = 13.6, 5.4 Hz), 2.84 (1H, dd, J = 13.6, 6.6 Hz ), 2.54 (2H, d, J = 7.4 Hz), 2.10-1.95 (1H, m), 1.91-1.08 (17H, m).

Example 2 (91)

(2S) -N- (4-methoxybenzyl) -3-cyclopentylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.33 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.16 (2H, m), 7.01-6.82 (2H, m), 6.81-6.69 (1H, m), 5.42 (1H, d, J = 5.8 Hz), 4.44 (1H, dd, J = 15.4, 6.0 Hz), 4.37 (1H, dd, J = 15.4, 5.8 Hz), 4.29-4.18 (1H, m), 3.84 (1H, dd, J = 9.2, 3.8 Hz), 3.80 (3H , s), 3.50 (1H, dd, J = 9.2, 7.0 Hz), 3.37 (1H, dd, J = 16.8, 7.4 Hz), 3.28 (1H, dd, J = 16.8, 6.8 Hz), 2.14-1.99 ( 1 H, m), 1.75-0.83 (17 H, m).

Example 2 (92)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylcarbonylamino-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.20 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ + CD ₃ OD): δ 7.22-7.14 (2H, m), 6.87-6.80 (2H, m), 4.40 (1H, d, J = 14.8 Hz), 4.29 (1H, d, J = 14.8 Hz), 4.25-4.20 (1H, m), 3.78 (3H, s), 3.72-3.48 (2H, m), 2.09-1.97 (1H, m), 1.86-1.16 (19H, m).

Example 2 (93)

(2S) -N- (4-methoxybenzyl) -4- (2-cyclohexenyloxy) -2-t-butoxycarbonylaminobutanamide

TLC: Rf 0.19 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.24-7.15 (2H, m), 6.94-6.78 (3H, m), 5.94-5.74 (2H, m), 5.72-5.60 (1H, m), 4.50-4.15 (3H, m ), 3.82-3.52 (3H, m), 3.80 (3H, s), 2.13-1.90 (4H, m), 1.80-1.35 (4H, m), 1.42 (9H, s).

Example 2 (94)

(2S) -N- (4-methoxybenzyl) -4-cyclohexyloxy-2-t-butoxycarbonylaminobutanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.15 (2H, m), 7.00-6.80 (3H, m), 6.03-5.88 (1H, m), 4.52-4.15 (3H, m), 3.80 (3H, s), 3.71-3.42 (2H, m), 3.26-3.08 (1H, m), 2.10-1.95 (2H, m), 1.85-1.05 (10H, m), 1.42 (9H, s).

Example 2 (95)

(2S) -N- (4-methoxybenzyl) -3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.53 (ethyl acetate: chloroform = 15: 100);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.64 (1H, t, J = 6.0 Hz), 5.36 (1H, d, J = 7.2 Hz), 4.39 (2H, d, J = 6.0 Hz), 4.29-4.19 (1H, m), 3.80 (3H, s), 3.00 (1H, dd, J = 14.0, 5.4 Hz), 2.84 (1H, dd, J = 14.0 , 7.0 Hz), 2.54 (2H, d, J = 7.0 Hz), 2.13-1.91 (1H, m), 1.90-1.08 (17H, m).

Example 2 (96)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.21-8.14 (2H, m), 7.48-7.41 (2H, m), 7.03 (1H, t, J = 5.8 Hz), 5.39 (1H, d, J = 6.2 Hz), 4.63 (1H, dd, J = 16.2, 5.8 Hz), 4.53 (1H, dd, J = 16.2, 6.2 Hz), 4.36-4.22 (1H, m), 3.87 (1H, dd, J = 9.0, 3.6 Hz), 3.53 (1H, dd, J = 9.2, 6.6 Hz), 3.30 (1H, dd, J = 9.2, 6.2 Hz), 3.24 (1H, dd, J = 9.2, 6.2 Hz), 1.79-0.76 (20H, m) .

Example 2 (97)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.40 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.19-8.14 (2H, m), 7.48-7.43 (2H, m), 7.12 (1H, t, J = 6.0 Hz), 5.44 (1H, d, J = 7.2 Hz), 4.66 -4.47 (2H, m), 4.36-4.25 (1H, m), 2.98 (1H, dd, J = 13.8, 5.8 Hz), 2.86 (1H, dd, J = 13.8, 6.6 Hz), 2.56-2.33 (2H m), 1.95-0.71 (20H, m).

Example 2 (98)

(2R) -N- (furan-2-ylmethyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.60 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.37-7.34 (1H, m), 6.76-6.71 (1H, m), 6.33 (1H, dd, J = 5.0, 1.8 Hz), 6.26-6.23 (1H, m), 5.35 ( 1H, d, J = 7.2 Hz), 4.51 (1H, dd, J = 15.4, 5.4 Hz), 4.40 (1H, dd, J = 15.4, 5.4 Hz), 4.28-4.18 (1H, m), 2.98 (1H , dd, J = 13.8, 5.4 Hz), 2.81 (1H, dd, J = 13.8, 7.0 Hz), 2.45 (1H, dd, J = 12.6, 7.0 Hz), 2.39 (1H, dd, J = 12.6, 6.6 Hz), 1.88-0.78 (20H, m).

Example 2 (99)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.43 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.20-7.12 (2H, m), 6.73-6.67 (2H, m), 6.55-6.51 (1H, m), 5.35 (1H, d, J = 7.4 Hz), 4.44-4.17 ( 3H, m), 2.98 (1H, dd, J = 13.8, 5.4 Hz), 2.94 (6H, s), 2.82 (1H, dd, J = 13.8, 7.0 Hz), 2.51-2.34 (2H, m), 1.88 -0.79 (20H, m).

Example 2 (100)

(2R) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanoic acid 4-methoxybenzyl ester

TLC: Rf 0.68 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.34-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H, d, J = 8.0 Hz), 5.16 (1H, d, J = 11.6 Hz), 5.08 (1H, d, J = 11.6 Hz), 4.57-4.48 (1H, m), 3.81 (3H, s), 2.93 (2H, d, J = 4.8 Hz), 2.35 (2H, d, J = 7.0 Hz) , 1.85-0.75 (20 H, m).

Example 2 (101)

(2R) -N- (4-methoxycyclohexylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 2 (102).)

TLC: Rf 0.40 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 6.47 (1H, t, J = 6.0 Hz), 5.37 (1H, d, J = 7.4 Hz), 4.22-4.12 (1H, m), 3.46-3.36 (1H, m), 3.29 (3H, s), 3.17-3.09 (2H, m), 2.95 (1H, dd, J = l3.6, 5.6 Hz), 2.78 (1H, dd, J = 13.6, 6.8 Hz), 2.54-2.38 (2H , m), 2.00-0.81 (29H, m).

Example 2 (102)

(2R) -N- (4-methoxycyclohexylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 2 (101).)

TLC: Rf 0.30 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 6.46 (1H, t, J = 5.6 Hz), 5.36 (1H, d, J = 7.0 Hz), 4.22-4.12 (1H, m), 3.34 (3H, s), 3.17-2.91 (4H, m), 2.79 (1H, doublet of doublets, J = 13.8, 7.0 Hz), 2.54-2.38 (2H, m), 2.15-2.01 (2H, m), 1.89-0.82 (27H, m).

Example 2 (103)

(2R) -N- (4-phenoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

NMR (CDCl ₃ ): δ 7.39-7.22 (m, 4H), 7.15-7.06 (m, 1H), 7.03-6.93 (m, 4H), 6.70 (t, J = 5.3 Hz, 1H), 5.35 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.30-4.20 (m, 1H), 2.99 (dd, J = 14.0, 5.6 Hz, 1H), 2.83 (dd, J = 14.0 , 7.0 Hz, 1H), 2.52-2.36 (m, 2H), 1.88-0.79 (m, 20H).

Example 2 (104)

(2R) -N-((1S) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.46 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.25-8.15 (2H, m), 7.54-7.45 (2H, m), 6.84 (1H, d, J = 7 Hz), 5.36 (1H, d, J = 7 Hz), 5.15 (1H , Quintet, J = 7 Hz, 4.21 (1H, td, J = 7, 5 Hz), 2.93 (1H, dd, J = 14, 5 Hz), 2.79 (1H, dd, J = 14, 7 Hz), 2.44 ( 2H, d, J = 7 Hz, 1.88-0.78 (11 H, m), 1.52 (3H, d, J = 7 Hz), 1.46 (9H, s).

Example 2 (105)

(2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.47 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.22-8.15 (2H, m), 7.51-7.44 (2H, m), 6.89 (1H, d, J = 7.8 Hz), 5.32 (1H, d, J = 7.0 Hz), 5.21-5.06 (1H, m), 4.27-4.17 (1H, m), 2.95 (1H, dd, J = 14.0, 5.8 Hz), 2.80 (1H, dd, J = 14.0, 7.0 Hz), 2.44 (1H, dd, J = 12.4, 6.8 Hz), 2.38 (1H, dd, J = 12.4, 6.6 Hz), 1.88-0.80 (23H, m).

Example 2 (106)

(2R) -N-methyl-N- (4-nitrobenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.25-8.16 (2H, m), 7.48-7.41 (2H, m), 5.38-5.25 (1H, m), 4.95-4.60 (3H, m), 3.14 (2.33H, s) , 2.98 (0.67H, s), 2.96-2.66 (2H, m), 2.46 (1.56H, d, J = 6.6 Hz), 2.33 (0.44H, d, J = 6.6 Hz), 1.88-0.81 (20H, m).

Example 2 (107)

(2R) -N- (1- (4-methoxyphenyl) -1-methylethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 5);

NMR (CDCl ₃ ): δ 7.37-7.26 (2H, m), 6.89-6.79 (2H, m), 6.70 (1H, bs), 5.36 (1H, d, J = 8 Hz), 4.11 (1H, td, J = 7, 5 Hz), 3.80 (3H, s), 2.91 (1H, dd, J = l4, 5 Hz), 2.75 (1H, dd, J = 14, 7 Hz), 2.47 (2H, d, J = 7 Hz), 1.90-0.80 (11H, m), 1.70 (3H, s), 1.69 (3H, s), 1.47 (9H, s).

Example 2 (108)

(2R) -N- (1-methyl-1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.34 (ethyl acetate: hexane = 1: 3);

NMR (CDCl ₃ ): δ 8.22-8.12 (2H, m), 7.60-7.49 (2H, m), 6.89 (1H, bs), 5.31 (1H, d, J = 8 Hz), 4.14 (1H, td, J = 7, 5 Hz), 2.90 (1H, dd, J = 14, 5 Hz), 2.75 (1H, dd, J = 14, 7 Hz), 2.47 (2H, d, J = 7 Hz), 1.90-0.80 (11H, m ), 1.71 (3H, s), 1.70 (3H, s), 1.50 (9H, s).

Example 2 (109)

(2S) -N-((1R) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.23-8.16 (2H, m), 7.53-7.46 (2H, m), 6.83 (1H, d, J = 7.4 Hz), 5.36 (1H, d, J = 7.4 Hz), 5.22 -5.08 (1H, m), 4.25-4.16 (1H, m), 2.94 (1H, dd, J = 13.6, 5.6 Hz) 2.78 (1H, dd, J = 13.6, 7.0 Hz), 2.44 (2H, d, J = 6.8 Hz), 1.88-0.80 (23H, m).

Example 2 (110)

(2R) -N-methyl-N- (4-methoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.44 (ethyl acetate: hexane = 1: 2).

Example 2 (111)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (N'-methyl-N '-(t-butoxycarbonyl) amino) propanamide

TLC: Rf 0.71 (hexane: AcOEt = 1: 1).

Example 2 (112)

(2R) -N- (4-benzyloxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.54 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.46-7.15 (m, 7H), 6.98-6.88 (m, 2H), 6.64 (t, J = 6.0 Hz, 1H), 5.35 (d, J = 6.6 Hz, 1H), 5.05 (s, 2H), 4.39 (d, J = 5.4 Hz, 2H), 4.28-4.18 (m, 1H), 2.98 (dd, J = 13.8, 5.8 Hz, 1H), 2.82 (dd, J = 13.8, 7.0 Hz, 1H), 2.42 (d, J = 7.8 Hz, 2H), 1.88-0.76 (m, 20H).

Example 2 (113)

(2R) -N- (3-benzyloxy-4-methoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.33 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.47-7.30 (m, 5H), 6.86-6.84 (m, 3H), 6.60 (t, J = 6.0 Hz, 1H), 5.31 (d, J = 6.8 Hz, 1H), 5.14 (s, 2H), 4.35 (d, J = 6.0 Hz, 2H), 4.26-4.16 (m, 1H), 3.87 (s, 3H), 2.96 (dd, J = 13.6, 5.6 Hz, 1H), 2.80 ( dd, J = 13.6, 6.6 Hz, 1H), 2.50-2.34 (m, 2H), 1.85-1.57 (m, 5H), 1.53-1.35 (m, 10H), 1.33-0.78 (m, 5H).

Example 2 (114)

N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester

TLC: Rf 0.49 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.33-7.25 (m, 2H), 6.95-6.89 (m, 3H), 5.41 (d, J = 8.7 Hz, 1H), 4.86-4.78 (m, 1H), 3.82-3.76 ( m, 4H), 3.26-3.17 (m, 4H), 2.87 (dd, J = 13.5, 7.5 Hz, 1H), 2.76 (dd, J = 13.5, 6.0 Hz, 1H), 2.44 (d, J = 6.9 Hz , 2H), 1.84-0.86 (m, 20H).

Example 2 115

(2R) -N- (2-phenoxypyridin-5-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.56 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.53 (br. S, 1H), 8.20 (d, J = 3.0 Hz, 1H), 8.07 (dd, J = 9.0, 2.8 Hz, 1H), 7.44-7.34 (m, 2H) , 7.22-7.09 (m, 3H), 6.89 (d, J = 9.2 Hz, 1H), 5.47 (d, J = 7.2 Hz, 1H), 4.42-4.32 (m, 1H), 3.04 (dd, J = 13.8 , 6.2 Hz, 1H), 2.88 (dd, J = 13.8, 7.0 Hz, 1H), 2.48 (d, J = 6.6 Hz, 2H), 1.90-0.79 (m, 20H).

Example 2 (116)

(2R) -N- (2-phenoxypyridin-5-ylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.59 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.11-8.07 (m, 1H), 7.66 (dd, J = 8.4, 2.2 Hz, 1H), 7.46-7.35 (m, 2H), 7.25-7.08 (m, 4H), 6.87 ( d, J = 8.4 Hz, 1H, 6.82-6.74 (m, 1H), 5.34 (d, J = 7.2 Hz, 1H), 4.42 (d, J = 6.4 Hz, 2H), 4.29-4.19 (m, 1H ), 2.97 (dd, J = 13.6, 5.6 Hz, 1H), 2.82 (dd, J = 13.6, 6.6 Hz, 1H), 2.42 (d, J = 6.6 Hz, 2H), 1.88-0.78 (m, 20H) .

Example 2 (117)

(2R) -N- (4- (morpholin-4-yl) benzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.41 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.23-7.18 (m, 2H), 6.89-6.84 (m, 2H), 6.60 (t, J = 5.1 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 4.26-4.20 (m, 1H), 3.88-3.84 (m, 4H), 3.16-3.12 (m, 4H), 2.98 (dd, J = 13.8, 5.7 Hz, 1H ), 2.82 (dd, J = 13.8, 6.9 Hz, 1H), 2.45 (dd, J = 12.6, 6.6 Hz, 1H), 2.40 (dd, J = 12.6, 6.9 Hz, 1H), 1.85-0.82 (m, 20H).

Example 2 (118)

(2R) -N- (1-phenylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.42 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.29-7.22 (m, 2H), 6.95-6.92 (m, 2H), 6.88-6.82 (m, 1H), 6.37 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 4.20-4.13 (m, 1H), 4.01-3.88 (m, 1H), 3.63-3.56 (m, 2H), 2.99-2.86 (m, 3H), 2.78 (dd, J = 13.5, 6.9 Hz, 1H), 2.48 (dd, J = 12.6, 6.9 Hz, 1H), 2.45 (dd, J = 12.6, 6.6 Hz, 1H), 2.08-1.98 (m, 2H), 1.87-1.78 (br , 2H), 1.76-1.54 (m, 5H), 1.52-1.38 (m, 10H), 1.31-1.06 (m, 3H), 1.00-0.86 (m, 2H).

Example 2 (119)

(2R) -N- (1-methylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

TLC: Rf 0.41 (chloroform: methanol = 9: 1);

NMR (CDCl ₃ ): δ 6.41 (d, J = 6.9 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 4.19-4.12 (m, 1H), 3.88-3.75 (m, 1H), 2.97 -2.75 (m, 4H), 2.51-2.40 (m, 2H), 2.36 (s, 3H), 2.31-2.21 (m, 2H), 1.99-1.88 (m, 2H), 1.86-1.56 (m, 7H) , 1.53-1.59 (m, 10H), 1.30-0.86 (m, 5H).

Example 3-Example 3 (1)

The following compounds of the present invention were obtained by reacting the compounds prepared in Examples 2 (64) and 2 (65) by the same purpose as in Reference Example 3.

Example 3

(2S) -N-((1S) -1-carboxy-2-phenylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.51 (chloroform: methanol = 9: 1):

NMR (CDCl ₃ ): δ 7.35-7.17 (5H, m), 7.04 (1H, d, J = 7.8 Hz), 6.90-6.10 (1H, br.s), 5.64 (1H, d, J = 8.0 Hz) , 4.86-4.69 (2H, m), 4.61-4.42 (1H, m), 3.18 (1H, dd, J = 13.8, 5.4 Hz), 3.07 (1H, dd, J = 13.8, 6.2 Hz), 2.86 (1H , dd, J = 17.0, 5.0 Hz), 2.64 (1H, dd, J = 17.0, 6.2 Hz), 1.88-1.18 (19H, m).

Example 3 (1)

(2S) -N-((1S) -1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.46 (CHCl 3: MeOH = 9: 1);

NMR (CDCl ₃ ): δ 7.20 (1H, d, J = 6.0 Hz), 6.50-6.00 (1H, br.s), 5.74 (1H, d, J = 8.4 Hz), 4.85-4.69 (1H, m) , 4.66-4.47 (2H, m), 2.93 (1H, dd, J = 17.0, 5.2 Hz), 2.69 (1H, dd, J = 17.0, 6.0 Hz), 1.92-1.20 (22H, m).

Example 4-Example 4 (1)

The following compounds of the present invention were obtained by reacting the compound prepared in Example 3 and Example 3 (1) with an alcohol derivative in the same manner as in Example 2.

Example 4

(2S) -N-((1S) -1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.34 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.24 (2H, m), 7.07 (1H, d, J = 7.0 Hz), 6.92-6.85 (2H, m), 5.66 (1H, d, J = 8.2 Hz), 5.13 (1H, d, J = 12.2 Hz), 5.06 (1H, d, J = 12.2 Hz), 4.84-4.70 (1H, m), 4.62-4.46 (2H, m), 3.81 (3H, s), 2.96 ( 1H, dd, J = 16.8, 4.4 Hz), 2.64 (1H, dd, J = 16.8, 6.4 Hz), 1.92-1.24 (22H, m).

Example 4 (1)

(2S) -N-((1S) -2-phenyl-1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.26-7.19 (5H, m), 7.06-7.01 (2H, m), 6.97 (1H, d, J = 8.0 Hz), 6.91-6.84 (2H, m), 5.61 (1H, d, J = 7.8 Hz), 5.09 (1H, d, J = 12.0 Hz), 5.01 (1H, d, J = 12.0 Hz), 4.86-4.69 (2H, m), 4.56-4.40 (1H, m), 3.82 (3H, s), 3.08 (1H, d, J = 5.8 Hz), 2.93 (1H, dd, J = 17.0, 4.4 Hz), 2.62 (1H, dd, J = 17.0, 6.2 Hz), 1.90-1.18 (19H, m).

Reference Example 4

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-aminopropanamide hydrochloride

4N hydrochloric acid-dioxane solution (12 ml) was added dropwise to the compound (1180 mg) prepared in Example 2 under ice-cooling, and the mixture was raised to room temperature, followed by stirring for 1 hour. The reaction mixture solution was concentrated to give the title compound (920 mg) having the following chemical data.

TLC: Rf 0.78 (chloroform: methanol = 9: 1);

NMR (CD ₃ OD): δ 7.26-7.19 (2H, m), 6.91-6.83 (2H, m), 4.43 (1H, d, J = 14.6 Hz), 4.28 (1H, d, J = 14.6 Hz), 4.03 (1H, doublet of doublets, J = 5.8, 4.0 Hz), 3.83-3.66 (5H, m), 3.35-3.20 (2H, m), 1.75-0.81 (11H, m).

Reference Example 5

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-benzoylaminopropanamide

Benzoyl chloride (0.04 ml) was added dropwise to a methylene chloride (2 ml) solution of the compound (95 mg) and pyridine (0.07 ml) prepared in Reference Example 4, followed by stirring at room temperature for 1 hour. The reaction mixture solution was diluted with methylene chloride, washed sequentially with 1N hydrochloric acid, water, and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a compound of the present invention (90 mg) having the following chemical data.

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.86-7.80 (2H, m), 7.56-7.39 (3H, m), 7.27-7.18 (3H, m), 6.93-6.83 (3H, m), 4.70 (1H, ddd, J = 8.8, 6.4, 4.2 Hz), 4.47 (1H, dd, J = 14.8, 5.6 Hz), 4.39 (1H, dd, J = 14.8, 5.6 Hz), 3.95 (1H, dd, J = 9.0, 4.2 Hz) , 3.80 (3H, s), 3.50 (1H, t, J = 8.4 Hz), 3.36 (1H, dd, J = 9.0, 6.2 Hz), 3.24 (1H, dd, J = 9.0, 6.2 Hz), 1.77- 0.71 (11 H, m).

Examples 6-6 (86)

Example 2, Example 2 (4), Example 2 (9), Example 2 (80), Example 2 (83), Example 2 (100) to Example 2 (119), Example 3 and The following compounds of the present invention were obtained by reacting the compound prepared in Example 3 (1) by the same purpose as in Reference Example 4-Example 5.

In the preparation of the compound of Example 6 (60), (-)-3-t-butoxycarbonylthiazolidine-2-ylcarboxylic acid was used.

In preparing the compound of Example 6 (61), (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was used.

In preparing the compound of Example 6 (63), (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was used.

Example 6

(2S) -3-cyclopentyloxycarbonyl-2-methylcarbonylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.27 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.29-7.23 (2H, m), 6.92-6.84 (2H, m), 6.50 (1H, br.d, J = 7.0 Hz), 5.19-5.05 (3H, m), 4.88- 4.80 (1H, m), 3.81 (3H, s), 2.97 (1H, dd, J = 17.2, 4.4 Hz), 2.78 (1H, dd, J = 17.2, 4.4 Hz), 2.02 (3H, s), 1.92 -1.46 (8H, m).

Example 6 (1)

(2S) -3-cyclopentyloxycarbonyl-2-benzoylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.54 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.82-7.77 (2H, m), 7.56-7.38 (3H, m), 7.32-7.21 (3H, m), 6.91-6.84 (2H, m), 5.18-5.01 (4H, m ), 3.81 (3H, s), 3.08 (1H, dd, J = 17.0, 4.2 Hz), 2.91 (1H, dd, J = 17.0, 4.6 Hz), 1.92-1.49 (8H, m).

Example 6 (2)

(2S) -3-cyclopentyloxycarbonyl-2-pivaloylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.53 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.29-7.23 (2H, m), 6.91-6.85 (2H, m), 6.71 (1H, br.d, J = 8.2 Hz), 5.18-5.04 (3H, m), 4.86- 4.77 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 17.2, 4.4 Hz), 2.77 (1H, dd, J = 17.2, 4.4 Hz), 1.94-1.45 (8H, m) , 1.19 (9H, s).

Example 6 (3)

(2S) -3-cyclopentyloxycarbonyl-2-cinnamoylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.56 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.63 (1H, d, J = 15.6 Hz), 7.53-7.46 (2H, m), 7.40-7.33 (3H, m), 7.32-7.25 (2H, m), 6.92-6.84 ( 2H, m), 6.68 (1H, br.d, J = 8.0 Hz), 6.44 (1H, d, J = 15.6 Hz), 5.22-5.08 (3H, m), 5.03-4.94 (1H, m), 3.80 (3H, s), 3.05 (1H, doublet of doublets, J = 17.4, 4.4 Hz), 2.87 (1H, doubled, J = 17.4, 4.4 Hz), 1.93-1.44 (8H, m).

Example 6 (4)

(2S) -3-cyclopentyloxycarbonyl-2- valerylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.50 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.30-7.23 (2H, m), 6.92-6.84 (2H, m), 6.47 (1H, d, J = 8.3 Hz), 5.16 (1H, d, J = 12.0 Hz), 5.08 (1H, d, J = 12.0 Hz), 4.90-4.81 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 17.0, 4.3 Hz), 2.77 (1H, dd, J = 17.0 , 4.5 Hz), 2.22 (2H, t, J = 7.4 Hz), 1.92-1.46 (10H, m), 1.42-1.24 (2H, m), 0.98 (3H, t, J = 8.0 Hz).

Example 6 (5)

(2S) -3-cyclopentyloxycarbonyl-2- (octylcarbonylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.62 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.30-7.23 (2H, m), 6.91-6.84 (2H, m), 6.46 (1H, d, J = 7.6 Hz), 5.18-5.04 (3H, m), 4.89-4.81 ( 1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 17.2, 4.2 Hz), 2.77 (1H, dd, J = 17.2, 4.4 Hz), 2.21 (2H, t, J = 7.0 Hz ), 1.92-1.46 (8H, m), 1.38-1.15 (12H, m), 0.88 (3H, t, J = 7.2 Hz).

Example 6 (6)

(2S) -3-cyclopentyloxycarbonyl-2-mesylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.54 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.31-7.24 (2H, m), 6.92-6.85 (2H, m), 5.48 (1H, d, J = 9.2 Hz), 5.22-5.05 (3H, m), 4.41-4.32 ( 1H, m), 3.81 (3H, s), 3.00 (1H, dd, J = l7.4, 4.6 Hz), 2.99 (3H, s), 2.80 (1H, dd, J = 17.4, 4.4 Hz), 1.94 -1.46 (8H, m).

Example 6 (7)

(2S) -3-cyclopentyloxycarbonyl-2-phenylsulfonylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.69 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.87-7.82 (2H, m), 7.60-7.41 (3H, m), 7.16-7.10 (2H, m), 6.89-6.81 (2H, m), 5.69 (1H, d, J = 8.3 Hz), 5.13-5.03 (1H, m), 4.94 (3H, s), 4.21-4.12 (1H, m), 3.81 (3H, s), 2.92 (1H, dd, J = 17.0, 4.3 Hz) , 2.77 (1H, doublet of doublets, J = 17.0, 4.8 Hz), 1.93-1.44 (8H, m).

Example 6 (8)

(2S) -3-cyclopentyloxycarbonyl-2- (butylsulfonylamino) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.60 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.22 (2H, m), 6.92-6.83 (2H, m), 5.36 (1H, d, J = 9.0 Hz), 5.21-5.05 (3H, m), 4.39-4.30 ( 1H, m), 3.79 (3H, s), 3.06-2.93 (3H, m), 2.79 (1H, dd, J = 17.2, 4.4 Hz), 1.92-1.24 (12H, m), 0.91 (3H, t, J = 7.2 Hz).

Example 6 (9)

(2S) -3-cyclopentyloxycarbonyl-2- (octylsulfonylamino) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.55 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.31-7.23 (2H, m), 6.92-6.73 (2H, m), 6.88 (2H, d, J = 8.8 Hz), 5.35 (1H, d, J = 10.0 Hz), 5.21 -5.05 (3H, m), 4.39-4.30 (1H, m), 3.81 (3H, s), 3.03-2.93 (3H, m), 2.79 (1H, dd, J = 17.2, 4.4 Hz), 1.87-1.27 (20H, m), 0.89 (3H, t, J = 6.8 Hz).

Example 6 (10)

(2S) -3-cyclopentyloxycarbonyl-2-((E) -styrylsulfonylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.49-7.41 (6H, m), 7.17 (2H, d, J = 8.8 Hz), 6.82-6.71 (3H, m), 5.55 (1H, d, J = 8.6 Hz), 5.15 -5.00 (3H, m), 4.26-4.17 (1H, m), 3.78 (3H, s), 3.01 (1H, dd, J = 17.2, 4.4 Hz), 2.84 (1H, dd, J = 17.2, 4.4 Hz ), 1.89-1.44 (8H, m).

Example 6 (11)

(2S) -3-cyclopentyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.67 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.39-7.23 (7H, m), 6.91-6.82 (2H, m), 5.74 (1H, d, J = 9.2 Hz), 5.17-5.04 (5H, m), 4.67-4.58 ( 1H, m), 3.80 (3H, s), 2.97 (1H, dd, J = 17.0, 4.6 Hz), 2.78 (1H, dd, J = 17.0, 4.8 Hz), 1.88-1.46 (8H, m).

Example 6 (12)

(2S) -3-cyclohexyloxycarbonyl-2-benzoylaminopropanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.83-7.76 (2H, m), 7.52-7.39 (3H, m), 7.32-7.21 (3H, m), 6.91-6.83 (2H, m), 5.21 (1H, d, J = 12.0 Hz), 5.11 (1H, d, J = 12.0 Hz), 5.10-5.02 (1H, m), 4.77-4.64 (1H, m), 3.81 (3H, s), 3.11 (1H, dd, J = 17.0, 4.2 Hz), 2.93 (1H, dd, J = 17.0, 4.6 Hz), 1.84-1.16 (10H, m).

Example 6 (13)

(2S) -3-cyclohexyloxycarbonyl-2- (4-fluorobenzoylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.86-7.76 (2H, m), 7.32-7.06 (5H, m), 6.91-6.84 (2H, m), 5.20 (1H, d, J = 11.8 Hz), 5.11 (1H, d, J = 11.8 Hz), 5.08-4.99 (1H, m), 4.77-4.63 (1H, m), 3.81 (3H, m), 3.10 (1H, dd, J = 17.2, 5.0 Hz), 2.91 (1H , dd, J = 17.2, 5.0 Hz), 1.84-1.13 (10H, m).

Example 6 (14)

(2S) -3-cyclohexyloxycarbonyl-2- (4-methoxybenzoyl) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.32 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.80-7.73 (2H, m), 7.31-7.15 (2H, m), 7.13 (1H, d, J = 7.8 Hz), 6.96-6.85 (4H, m), 5.20 (1H, d, J = 12.0 Hz), 5.13 (1H, d, J = 12.0 Hz), 5.08-5.00 (1H, m), 4.77-4.63 (1H, m), 3.85 (3H, s), 3.81 (3H, s ), 3.09 (1H, dd, J = 17.2, 4.4 Hz), 2.91 (1H, dd, J = 17.2, 4.4 Hz), 1.84-1.09 (10H, m).

Example 6 (15)

(2S) -3-cyclohexyloxycarbonyl-2- (4-phenylbenzoylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.42 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.91-7.84 (2H, m), 7.69-7.58 (4H, m), 7.52-7.25 (6H, m), 6.92-6.85 (2H, m), 5.22 (1H, d, J = 12.0 Hz), 5.11 (1H, d, J = 12.0 Hz), 5.13-5.04 (1H, m), 4.80-4.64 (1H, m), 3.81 (3H, s), 3.12 (1H, dd, J = 17.2, 4.2 Hz), 2.94 (1H, dd, J = 17.2, 4.6 Hz), 1.84-1.14 (10H, m).

Example 6 (16)

(2S) -3-cyclohexyloxycarbonyl-2- (4-nitrobenzoylamino) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.36 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.32-8.26 (2H, m), 7.99-7.92 (2H, m), 7.36 (1H, br.d, J = 7.8 Hz), 7.32-7.25 (2H, m), 6.92- 6.85 (2H, m), 5.22 (1H, d, J = 12.0 Hz), 5.12 (1H, d, J = 12.0 Hz), 5.08-5.00 (1H, m), 4.78-4.63 (1H, m), 3.81 (3H, s), 3.13 (1H, doublet of doublets, J = 17.2, 4.2 Hz), 2.93 (1H, doubled, J = 17.2, 4.4 Hz), 1.84-1.14 (10H, m).

Example 6 (17)

(2S) -3-cyclohexyloxycarbonyl-2- (4-acetylbenzoylamino) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.05-7.98 (2H, m), 7.90-7.85 (2H, m), 7.33-7.25 (3H, m), 6.92-6.84 (2H, m), 5.21 (1H, d, J = 11.8 Hz), 5.12 (1H, d, J = 11.8 Hz), 5.09-5.01 (1H, m), 4.78-4.64 (1H, m), 3.81 (3H, s), 3.12 (1H, dd, J = 17.0, 4.2 Hz), 2.93 (1H, dd, J = 17.0, 4.6 Hz), 2.64 (3H, s), 1.84-1.18 (10H, m).

Example 6 (18)

(2S) -3-cyclohexyloxycarbonyl-2- (4-methylthiobenzoylamino) propanoic acid, 4-methoxybenzyl ester

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.75-7.68 (2H, m), 7.30-7.22 (4H, m), 7.18 (1H, br.d, J = 7.8 Hz), 6.91-6.84 (2H, m), 5.20 ( 1H, d, J = 11.8 Hz), 5.11 (1H, d, J = 11.8 Hz), 5.08-5.00 (1H, m), 4.78-4.62 (1H, m), 3.81 (3H, s), 3.10 (1H , dd, J = 17.2, 4.4 Hz, 2.91 (1H, dd, J = 17.2, 4.6 Hz), 2.51 (3H, s), 1.84-1.12 (10H, m).

Example 6 (19)

(2S) -3-cyclohexyloxycarbonyl-2- (4-dimethylaminobenzoylamino) propanoic acid 4-methoxybenzyl ester

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.74-7.66 (2H, m), 7.32-7.25 (2H, m), 7.04 (1H, br.d, J = 7.4 Hz), 6.91-6.83 (2H, m), 6.69- 6.63 (2H, m), 5.19 (1H, d, J = 12.2 Hz), 5.11 (1H, d, J = 12.2 Hz), 5.10-5.02 (1H, m), 4.78-4.64 (1H, m), 3.81 (3H, s), 3.09 (1H, dd, J = 17.0, 4.4 Hz), 3.02 (6H, s), 2.91 (1H, dd, J = 17.0, 4.6 Hz), 1.84-1.16 (10H, m).

Example 6 (20)

(2S) -N-((1S) -1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide

TLC: Rf 0.48 (chloroform: methanol = 8: 2);

NMR (CDCl ₃ + CD ₃ OD): δ 7.52 (1H, d, J = 6.2 Hz), 7.37-7.28 (5H, m), 6.36 (1H, d, J = 9.2 Hz), 5.15 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 4.79-4.52 (2H, m), 4.42-4.29 (1H, m), 2.87 (1H, dd, J = 16.8, 6.2 Hz), 2.74 (1H, doublet of doublets, J = 16.8, 5.8 Hz), 1.82-1.08 (13H, m).

Example 6 (21)

(2S) -N-((1S) -2-phenyl-1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide dicyclohexylamine salt

TLC: Rf 0.46 (chloroform: methanol = 8: 2);

NMR (CDCl ₃ + CD ₃ OD): δ 7.37-7.28 (5H, m), 7.19-7.12 (5H, m), 5.13 (1H, d, J = 12.0 Hz), 5.01 (1H, d, J = 12.0 Hz), 4.79-4.64 (1H, m), 4.61-4.40 (2H, m), 3.26-2.66 (6H, m), 2.06-1.08 (30H, m).

Example 6 (22)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-phenylsulfonylaminopropanamide

TLC: Rf 0.31 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.91-7.85 (2H, m), 7.66-7.48 (3H, m), 7.16-7.09 (2H, m), 7.00-6.95 (1H, m), 6.88-6.80 (2H, m ), 5.67-5.64 (1H, m), 4.36 (1H, dd, J = 14.6, 5.6 Hz), 4.27 (1H, dd, J = 14.6, 5.4 Hz), 3.82-3.70 (5H, m), 3.29- 3.21 (1H, m), 3.16 (1H, dd, J = 9.0, 6.2 Hz), 3.04 (1H, dd, J = 9.0, 6.6 Hz), 1.72-0.64 (11H, m).

Example 6 (23)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-pivaloylaminopropanamide

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 2):

NMR (CDCl ₃ ): δ 7.23-7.15 (2H, m), 6.89-6.77 (3H, m), 6.67 (1H, d, J = 6.0 Hz), 4.50-4.29 (3H, m), 3.83-3.76 ( 4H, m), 3.43-3.16 (3H, m), 1.72-0.71 (20H, m).

Example 6 (24)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-methoxybenzoylamino) propanamide

TLC: Rf 0.11 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.83-7.75 (2H, m), 7.25-7.17 (2H, m), 7.10 (1H, d, J = 5.8 Hz), 6.97-6.82 (5H, m), 4.68 (1H, ddd, J = 10.0, 5.8, 3.8 Hz), 4.42 (2H, d, J = 5.4 Hz), 3.95 (1H, dd, J = 9.2, 4.0 Hz), 3.86 (3H, s), 3.80 (3H, s ), 3.49 (1H, t, J = 9.2 Hz), 3.36 (1H, dd, J = 9.2, 6.2 Hz), 3.24 (1H, dd, J = 9.2, 6.6 Hz), 1.76-0.74 (11H, m) .

Example 6 (25)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-nitrobenzoylamino) propanamide

TLC: Rf 0.26 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 8.33-8.26 (2H, m), 8.01-7.94 (2H, m), 7.38 (1H, d, J = 5.8 Hz), 7.25-7.18 (2H, m), 6.95-6.83 ( 3H, m), 4.67 (1H, ddd, J = 9.6, 5.8, 4.0 Hz), 4.48 (1H, dd, J = 14.6, 5.8 Hz), 4.38 (1H, dd, J = 14.6, 5.4 Hz), 3.92 (1H, dd, J = 9.2, 4.4 Hz), 3.80 (3H, s), 3.49 (1H, t, J = 9.2 Hz), 3.37 (1H, dd, J = 9.6, 6.2 Hz), 3.24 (1H, dd, J = 9.6, 6.6 Hz), 1.74-0.70 (11H, m).

Example 6 (26)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (l2-methyltridecylcarbonylamino) propanamide

TLC: Rf 0.60 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.23-7.15 (2H, m), 6.89-6.82 (2H, m), 6.81-6.70 (1H, m), 6.41 (1H, d, J = 6.2 Hz), 4.50 (1H, ddd, J = 8.4, 6.6, 4.4 Hz), 4.39 (2H, d, J = 6.2 Hz), 3.86-3.73 (4H, m), 3.39 (1H, t, J = 8.8 Hz), 3.30 (1H, dd , J = 9.4, 6.0 Hz), 3.19 (1H, dd, J = 9.4, 6.2 Hz), 2.22 (1H, t, J = 7.0 Hz), 1.74-0.70 (38H, m).

Example 6 (27)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.22-7.15 (2H, m), 6.89-6.73 (3H, m), 6.43 (1H, d, J = 6.4 Hz), 4.48 (1H, ddd, J = 8.2, 6.4, 4.2 Hz), 4.46-4.29 (2H, m), 3.82-3.73 (4H, m), 3.38 (1H, t, J = 8.4 Hz), 3.31 (1H, dd, J = 9.2, 6.4 Hz), 3.20 (1H , dd, J = 9.2, 6.2 Hz), 2.14 (1H, tt, J = 11.6, 4.0 Hz), 1.94-0.71 (21H, m).

Example 6 (28)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-methoxyphenylsulfonylamino) propanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.83-7.76 (2H, m), 7.16-7.09 (2H, m), 7.05-6.94 (3H, m), 6.88-6.80 (2H, m), 5.55 (1H, d, J = 5.4 Hz), 4.38 (1H, dd, J = 14.6, 5.8 Hz), 4.28 (1H, dd, J = 14.6, 5.6 Hz), 3.88 (3H, s), 3.82-3.67 (5H, m), 3.26 (1H, dd, J = 8.8, 6.4 Hz), 3.17 (1H, dd, J = 9.2, 6.2 Hz), 3.05 (1H, dd, J = 9.2, 6.2 Hz), 1.74-0.79 (11H, m).

Example 6 (29)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylsulfonylaminopropanamide

TLC: Rf 0.24 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.23-7.16 (2H, m), 7.01 (1H, t, J = 4.8 Hz), 6.90-6.82 (2H, m), 5.23 (1H, d, J = 6.6 Hz), 4.40 (2H, d, J = 5.8 Hz), 4.06-3.97 (1H, m), 3.85 (1H, dd, J = 9.2, 4.0 Hz), 3.80 (3H, s), 3.55 (1H, dd, J = 9.2 , 7.2 Hz), 3.28 (1H, dd, J = 9.2, 6.6 Hz), 3.20 (1H, dd, J = 9.2, 6.2 Hz), 2.90 (1H, tt, J = 11.8, 3.2 Hz), 2.28-2.08 (2H, m), 1.93-1.82 (2H, m), 1.76-1.04 (15H, m), 0.94-0.70 (2H, m).

Example 6 (30)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclopentylcarbonylaminopropanamide

TLC: Rf 0.19 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.24-7.05 (3H, m), 6.87-6.80 (2H, m), 6.59 (1H, d, J = 7.0 Hz), 4.62-4.52 (1H, m), 4.39 (1H, dd, J = 15.0, 5.8 Hz), 4.31 (1H, dd, J = 15.0, 5.4 Hz), 3.78 (3H, s), 2.93 (1H, dd, J = 13.4, 5.4 Hz), 2.79 (1H, dd , J = 13.4, 7.4 Hz), 2.66-2.50 (1H, m), 2.45 (2H, d, J = 7.0 Hz), 1.95-0.78 (19H, m).

Example 6 (31)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide

TLC: Rf 0.27 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.24-7.16 (2H, m), 6.89-6.78 (3H, m), 6.46 (1H, d, J = 6.8 Hz), 4.52-4.42 (1H, m), 4.38 (2H, d, J = 5.8 Hz), 3.79 (3H, S), 2.95 (1H, dd, J = 13.6, 5.0 Hz), 2.74 (1H, dd, J = 13.6, 8.0 Hz), 2.47 (2H, d, J = 7.0 Hz), 2.20-2.05 (1 H, m), 1.92-0.82 (21 H, m).

Example 6 (32)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclobutylcarbonylaminopropanamide

TLC: Rf 0.15 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.80-6.72 (1H, br), 6.35 (1H, d, J = 7.0 Hz ), 4.52-4.38 (3H, m), 3.80 (3H, s), 3.09-2.91 (2H, m), 2.73 (1H, dd, J = 8.0, 14.0 Hz), 2.48 (2H, d, J = 6.6 Hz), 2.38-2.07 (4H, m), 2.06-1.32 (8H, m), 1.27-1.08 (3H, m), 1.03-0.89 (2H, m).

Example 6 (33)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cycloheptylcarbonylaminopropanamide

TLC: Rf 0.30 (hexane: AcOEt = 2: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.80-6.74 (1H, br), 6.37 (1H, d, J = 7.0 Hz ), 4.50-4.37 (3H, m), 3.80 (3H, s), 2.95 (1H, dd, J = 5.6, 14.0 Hz), 2.74 (1H, dd, J = 8.0, 14.0 Hz), 2.47 (2H, d, J = 6.6 Hz), 2.35-2.20 (1H, m), 1.95-1.33 (18H, m), 1.30-1.08 (3H, m), 1.03-0.90 (2H, m).

Example 6 (34)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-methoxycyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 6 (35).)

Hypopolar

TLC: Rf 0.46 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.82-6.79 (1H, br), 6.49 (1H, d, J = 7.0 Hz ), 4.51-4.37 (3H, m), 3.80 (3H, s), 3.46-3.39 (1H, m), 3.29 (3H, s), 2.95 (1H, dd, J = 5.6, 14.0 Hz), 2.73 ( 1H, dd, J = 8.0, 14.0 Hz), 2.47 (2H, d, J = 6.6 Hz), 2.28-2.13 (1H, m), 2.00-1.59 (12H, m), 1.51-0.93 (7H, m) .

Example 6 (35)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-methoxycyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 6 (34).)

High Polarity

TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.77 (1H, t, J = 5.8 Hz), 6.48 (1H, d, J = 7.0 Hz), 4.50-4.37 (3H, m), 3.80 (3H, s), 3.35 (3H, s), 3.12 (1H, tt, J = 4.2, 10.6 Hz), 2.94 (1H, dd, J = 5.1, 13.9 Hz), 2.72 (1H, dd, J = 8.1, 13.9 Hz), 2.47 (2H, d, J = 6.6 Hz), 2.17-2.03 (3H, m), 2.00-1.57 (8H, m), 1.51-0.93 (9H, m).

Example 6 (36)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.29 (ethyl acetate: hexane = 2: 3);

NMR (CD ₃ OD): δ 7.23 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 5.23 (1H, bs), 4.56-4.44 (1H, m), 4.44-4.22 ( 2H, m), 4.00-3.84 (1H, m), 3.81-3.63 (1H, m), 3.77 (3H, s), 3.40-2.65 (4H, m), 2.42 (2H, d, J = 7 Hz), 1.91-1.58 (6H, m), 1.58-1.10 (3H, m), 1.45 and 1.40 (9H, s), 1.05-0.80 (2H, m).

Example 6 (37)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-methylpropylcarbonylamino) propanamide

TLC: Rf 0.36 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.26-7.16 (2H, m), 6.91-6.76 (3H, m), 6.43 (1H, d, J = 8 Hz), 4.50 (1H, td, J = 8, 5 Hz), 4.38 (2H, d, J = 6 Hz), 3.80 (3H, s), 2.95 (1H, dd, J = 14, 6 Hz), 2.76 (1H, dd, J = 14, 8 Hz), 2.47 (2H, d, J = 7 Hz), 2.20-1.95 (3H, m), 1.89-1.56 (6H, m), 1.56-1.05 (3H, m), 1.05-0.78 (2H, m), 0.94 (3H, d, J = 7 Hz) , 0.93 (3H, d, J = 7 Hz).

Example 6 (38)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-methylpropyloxycarbonylamino) propanamide

TLC: Rf 0.53 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.26-7.15 (2H, m), 6.92-6.80 (2H, m), 6.75-6.58 (1H, m), 5.58 (1H, d, J = 8 Hz), 4.40 (2H, d , J = 6 Hz), 4.27 (1H, d, J = 8, 5 Hz), 3.85 (2H, d, J = 7 Hz), 3.80 (3H, s), 2.99 (1H, dd, J = 14, 5 Hz), 2.82 (1H, dd, J = 14, 8 Hz), 2.44 (2H, d, J = 7 Hz), 2.02-1.55 (6H, m), 1.55-1.03 (4H, m), 1.03-0.77 (2H, m) , 0.92 (6H, doublet, J = 7 Hz).

Example 6 (39)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (1- (t-butoxycarbonyl) piperidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.17 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.2 Hz), 6.87 (2H, d, J = 8.2 Hz), 6.79-6.73 (1H, br), 6.54 (1H, d, J = 7.2 Hz ), 4.50-4.38 (3H, m), 4.16-4.10 (2H, br), 3.80 (3H, s), 2.93 (1H, dd, J = 4.9, 13.7 Hz), 2.81-2.67 (3H, m), 2.48 (2H, d, J = 7.0 Hz), 2.29 (1H, tt, J = 4.0, 11.8 Hz), 1.83-1.57 (9H, m), 1.46 (9H, s), 1.36-0.84 (6H, m) .

Example 6 (40)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4- (t-butoxycarbonylamino) cyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the t-butoxycarbonylamino group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 6 (41).)

TLC: Rf 0.27 (hexane: AcOEt = 1: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.8 Hz), 6.94-6.82 (3H, m), 6.61 (1H, d, J = 6.8 Hz), 4.71 (1H, d, J = 8.0 Hz ), 4.54-4.44 (1H, m), 4.38 (2H, d, J = 5.4 Hz), 3.79-3.65 (4H, m), 2.92 (1H, dd, J = 5.4, 13.8 Hz), 2.75 (1H, dd, J = 8.0, 13.8 Hz), 2.47 (2H, d, J = 6.6 Hz), 2.30-2.15 (1H, br), 1.92-1.53 (13H, m), 1.44 (9H, s), 1.26-1.08 (4H, m), 1.00-0.83 (2H, m).

Example 6 (41)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4- (t-butoxycarbonylamino) cyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the t-butoxycarbonylamino group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 6 (40).)

TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.20 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.78-6.73 (1H, br), 6.48 (1H, d, J = 6.6 Hz ), 4.49-4.37 (4H, m), 3.80 (3H, s), 3.51-3.30 (1H, br), 2.93 (1H, dd, J = 5.1, 13.9 Hz), 2.72 (1H, dd, J = 8.1 , 13.9 Hz), 2.48 (2H, d, J = 6.6 Hz), 2.14-1.53 (14H, m), 1.44 (9H, s), 1.27-1.07 (4H, m), 1.00-0.83 (2H, m) .

Example 6 (42)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (tetrahydrofuran-2-ylcarbonylamino) propanamide

TLC: Rf 0.27 (hexane: ethyl acetate = 2: 1);

NMR (DMSO-d ₆ ): δ 7.43 (1H, t, J = 10.6 Hz), 7.20 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 6.80-6.71 (1H , br), 4.55-4.31 (4H, m), 4.05-3.83 (2H, m), 3.79 (3H, s), 3.00-2.74 (2H, m), 2.45 (2H, t, J = 6.6 Hz), 2.36-1.62 (9H, m), 1.51-1.07 (4H, m), 1.03-0.90 (2H, m).

Example 6 (43)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide

TLC: Rf 0.31 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.25-7.14 (2H, m), 6.93-6.72 (3H, m), 6.43 (1H, d, J = 6 Hz), 4.49 (1H, ddd, J = 8, 6, 4 Hz) , 4.43-4.28 (2H, m), 3.84-3.73 (1H, m), 3.80 (3H, s), 3.45-3.33 (1H, m), 3.29 (1H, dd, J = 9, 5 Hz), 3.21 ( 1H, dd, J = 9,6 Hz), 2.24-2.06 (1H, m), 1.95-0.70 (21H, m).

Example 6 (44)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

TLC: Rf 0.29 (ethyl acetate: hexane = 2: 3);

NMR (CD ₃ OD): δ 7.27-7.17 (2H, m), 6.90-6.80 (2H, m), 4.67-4.43 (4H, m), 4.32 (1H, d, J = 15 Hz), 4.30 (1H, d, J = 15 Hz), 3.76 (3H, s), 3.42-3.30 (1H, m), 3.12 (1H, dd, J = 12, 5 Hz), 3.00-2.70 (2H, m), 2.41 (2H, d , J = 6 Hz), 1.90-0.78 (11H, m), 1.45 (9H, s).

Example 6 (45)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2S) -1-t-butoxycarbonylpyrrolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.38 (ethyl acetate: chloroform = 1: 4);

NMR (DMSO-d ₆ ): δ 8.03-7.97 (1H, m), 7.57 (1H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 4.45-4.40 (1H, m), 4.21 (2H, d, J = 7.5 Hz), 4.15-4.12 (1H, m), 3.73 (3H, s), 3.40-3.30 (2H, m), 2.85 (1H, dd, J = 15.0, 8.7 Hz), 2.76 (1H, dd, J = 15.0, 6.3 Hz), 2.42 (2H, d, J = 13.0 Hz), 2.11-2.03 (1H, m), 1.88 -1.72 (4H, m), 1.69-1.58 (3H, m), 1.45-1.33 (2H, m), 1.26-1.10 (3H, m), 0.98-0.92 (2H, m).

Example 6 (46)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (thiazol-4-ylcarbonylamino) propanamide

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.77 (1H, d, J = 1.8 Hz), 8.18 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J = 1.8 Hz), 7.25-7.18 (2H, m ), 6.88-6.81 (3H, m), 4.78-4.68 (1H, m), 4.51-4.33 (2H, m), 3.79 (3H, s), 3.16 (1H, dd, J = 14.0, 5.6 Hz), 2.92 (1H, doublet of doublets, J = 14.0, 7.4 Hz), 2.57-2.41 (2H, m), 1.88-0.80 (11H, m).

Example 6 (47)

(2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4- Ylcarbonylamino) propanamide

TLC: Rf 0.67 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.19-8.12 (2H, m), 7.58-7.32 (3H, m), 7.12 (1H, d, J = 8.0 Hz), 5.20-5.06 (1H, m), 4.67-4.46 ( 4H, m), 3.40-3.15 (3H, m), 2.75 (1H, dd, J = 13.6, 5.8 Hz), 2.38-2.14 (2H, m), 1.80-0.64 (23H, m).

Example 6 (48)

(2S) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcar Carbonylamino) propanamide

TLC: Rf 0.61 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.21-8.14 (2H, m), 7.58-7.30 (3H, m), 7.05 (1H, d, J = 7.4 Hz), 5.19-5.05 (1H, m), 4.65-4.47 ( 4H, m), 3.37-3.06 (3H, m), 2.79 (1H, dd, J = 13.8, 6.2 Hz), 2.50 (1H, dd, J = 12.4, 6.6 Hz), 2.40 (1H, dd, J = 12.4, 7.0 Hz), 1.90-0.78 (23H, m).

Example 6 (49)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-t-butoxycarbonylaminothiazol-4-ylcarbonylamino) propanamide

TLC: Rf 0.28 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 8.09 (1H, bs), 7.91 (1H, bd, J = 8 Hz), 7.66 (1H, s), 7.25-7.15 (2H, m), 6.89-6.78 (3H, m), 4.66 (1H, td, J = 8, 6), 4.50-4.28 (2H, m), 3.80 (3H, s), 3.07 (1H, dd, J = 14, 6 Hz), 2.91 (1H, dd, J = 14, 8 Hz), 2.48 (2H, d, J = 7 Hz), 1.90-0.78 (11H, m), 1.56 (9H, s).

Example 6 (50)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

TLC: Rf 0.34 (ethyl acetate: hexane = 2: 3);

NMR (CD ₃ OD): δ 7.27-7.17 (2H, m), 6.90-6.80 (2H, m), 4.66-4.43 (4H, m), 4.40-4.23 (2H, m), 3.78 (3H, s) , 3.43-3.30 (1H, m), 3.16 (1H, dd, J = 12, 6 Hz), 3.08-2.75 (1H, m), 2.78 (1H, dd, J = 14, 7 Hz), 2.41 (2H, d , J = 7 Hz), 1.90-0.80 (11H, m), 1.43 (9H, s).

Example 6 (51)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

TLC: Rf 0.36 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 8.25-8.15 (2H, m), 7.61-7.51 (2H, m), 4.70-4.41 (6H, m), 3.45-3.32 (1H, m), 3.22-3.08 (1H, m), 3.04-2.72 (2H, m), 2.45 (2H, d, J = 7 Hz), 1.91-0.80 (11H, m), 1.45 (9H, s).

Example 6 (52)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 8.23-8.14 (2H, m), 7.61-7.49 (2H, m), 5.22 (1H, bs), 4.62-4.42 (3H, m), 4.00-3.87 (1H, m) , 3.80-3.64 (1H, m), 3.33-2.70 (4H, m), 2.45 (2H, d, J = 7 Hz), 1.91-0.80 (11H, m), 1.45 and 1.40 (9H, s).

Example 6 (53)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.32 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.23-8.16 (2H, m), 7.89 (1H, d, J = 7.4 Hz), 7.49-7.42 (2H, m), 7.20-7.09 (1H, m), 4.61 (1H, dd, J = 15.6, 6.2 Hz), 4.50 (1H, dd, J = 15.6, 5.8 Hz), 4.51-4.40 (1H, m), 4.18 (1H, d, J = 9.8 Hz), 3.89 (1H, dd , J = 9.8, 1.0 Hz), 3.79 (1H, dd, J = 7.4, 2.6 Hz), 3.52 (1H, dd, J = 11.0, 2.6 Hz), 3.13 (1H, dd, J = 11.0, 7.4 Hz) , 2.98-2.80 (2H, m), 2.47 (3H, s), 2.45 (2H, d, J = 7.4 Hz), 1.88-0.80 (11H, m).

Example 6 (54)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

TLC: Rf 0.35 (ethyl acetate: hexane = 2: 3);

NMR (CD ₃ OD): δ 7.20-7.10 (2H, m), 6.77-6.67 (2H, m), 4.67-4.43 (4H, m), 4.29 (1H, d, J = 16 Hz), 4.28 (1H, d, J = 16 Hz), 3.41-3.30 (1H, m), 3.12 (1H, dd, J = 12, 5 Hz), 3.00-2.65 (8H, m), 2.41 (2H, d, J = 7 Hz), 1.88 -0.80 (11 H, m), 1.45 (9 H, s).

Example 6 (55)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.29 (ethyl acetate: hexane = 2: 3);

NMR (CD ₃ OD): δ 7.20-7.10 (2H, m), 6.77-6.67 (2H, m), 5.23 (1H, bs), 4.55-4.43 (1H, m), 4.40-4.16 (2H, m) , 4.00-3.84 (1H, m), 3.79-3.63 (1H, m), 3.30-2.66 (10H, m), 2.42 (2H, d, J = 7 Hz), 1.90-0.80 (11H, m), 1.45 and 1.42 (9 H, s).

Example 6 (56)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (1-t-butoxycarbonylimidazol-4-ylcarbonylamino) propanamide

TLC: Rf 0.48 (methylene chloride: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.17 (2H, d, J = 8.8 Hz), 8.03 (1H, d, J = 1.4 Hz), 7.98 (1H, d, J = 1.4 Hz), 7.85 (1H, d, J = 7.4 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.10 (1H, t, J = 6.2 Hz), 4.78-4.68 (1H, m), 4.57 (2H, d, J = 6.2 Hz), 3.12 (1H, dd, J = 5.8, 13.6 Hz), 2.96 (1H, dd, J = 7.0, 13.6 Hz), 2.50 (2H, d, J = 6.6 Hz), 1.88-1.36 (15H, m), 1.30 -0.90 (5H, m).

Example 6 (57)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -2,2-dimethylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.47 (ethyl acetate: hexane = 2: 1);

NMR (CDCl ₃ ): δ 8.24-8.l7 (2H, m), 7.81 (1H, bd, J = 8 Hz), 7.50-7.42 (2H, m), 7.09 (1H, bt J = 6 Hz), 4.68- 4.45 (3H, m), 4.16 (1H, t, J = 7 Hz), 3.45 (1H, dd, J = 11, 8 Hz), 3.37 (1H, dd, J = 11,7 Hz), 2.97 (1H, dd, J = 14, 5 Hz), 2.82 (1H, dd, J = 14, 8 Hz), 2.62-2.35 (1H, b), 2.49 (2H, d, J = 7 Hz), 1.88-0.78 (11H, m), 1.65 (3H, s), 1.57 (3H, s).

Example 6 (58)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (thiophen-2-ylcarbonylamino) propanamide

TLC: Rf 0.20 (hexane: AcOEt = 2: 1);

NMR (CDCl ₃ ): δ 8.18 (2H, d, J = 8.8 Hz), 7.58-7.52 (2H, m), 7.47 (2H, d, J = 8.8 Hz), 7.31-7.25 (1H, br), 7.11 (1H, dd, J = 3.6, 5.2 Hz), 7.04, (1H, d, J = 6.6 Hz), 4.77-4.49 (3H, m), 3.13 (1H, dd, J = 5.2, 14.0 Hz), 2.87 (1H, doublet of doublets, J = 8.2, 14.0 Hz), 2.54 (2H, d, J = 7.0 Hz), 1.88-1.37 (6H, m), 1.33-0.82 (5H, m).

Example 6 (59)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (5-methyloxazol-2-ylcarbonylamino) propanamide

TLC: Rf 0.48 (methylene chloride: ethyl acetate = 4: 1);

NMR (CDCl ₃ ): δ 8.18 (2H, d, J = 8.8 Hz), 7.81 (1H, d, J = 7.4 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.06 (1H, t, J = 5.4 Hz), 6.88 (1H, d, J = 1.2 Hz), 4.75-4.49 (3H, m), 3.09 (1H, dd, J = 5.8, 13.8 Hz), 2.90 (1H, dd, J = 7.6, 13.8 Hz), 2.59-2.46 (2H, m), 2.41 (3H, d, J = 1.2 Hz), 1.88-1.37 (6H, m), 1.34-0.81 (5H, m).

Example 6 (60)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[a] _D = -40.4 (c 0.1, CHCl ₃ );

TLC: Rf 0.19 (hexane: AcOEt = 2: 1);

NMR (CDCl ₃ ): δ 7.21 (2H, d, J = 8.4 Hz), 7.13-6.85 (2H, br), 6.84 (2H, d, J = 8.4 Hz), 5.24 (1H, s), 4.57-4.46 (1H, m), 4.37 (2H, d, J = 5.6 Hz), 3.90-3.80 (2H, m), 3.79 (3H, s), 3.22-3.03 (2H, m), 2.95 (1H, dt, J = 5.2, 11.0 Hz), 2.81 (1H, dd, J = 7.0, 14.0 Hz), 2.50-2.32 (2H, m), 1.85-1.56 (6H, m), 1.41 (9H, s), 1.30-0.77 ( 5H, m).

Example 6 (61)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[a] _D = + 22.0 (c 0.11, CHCl ₃ );

TLC: Rf 0.19 (hexane: AcOEt = 2: 1);

NMR (CDCl ₃ ): δ 7.43-7.25 (1H, br), 7.21 (2H, d, J = 8.8 Hz), 6.90-6.78 (3H, m), 5.16 (1H, s), 4.61-4.20 (3H, m), 3.94-3.81 (2H, br), 3.79 (3H, s), 3.40-3.02 (2H, br), 2.96 (1H, dt, J = 5.0, 11.0 Hz), 2.76 (1H, dd, J = 7.0, 13.8 Hz), 2.50-2.31 (2H, m), 1.83-1.57 (6H, m), 1.42 (9H, s), 1.29-0.77 (5H, m).

Example 6 (62)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide

TLC: Rf 0.58 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.17-7.13 (2H, m), 6.79-6.69 (3H, m), 6.51 (1H, d, J = 6.6 Hz), 4.50-4.44 (1H, m), 4.34 (2H, d, J = 5.4 Hz), 2.96-2.90 (7H, m), 2.74 (1H, dd, J = 13.5, 8.1 Hz), 2.49 (1H, dd, J = 12.9, 6.9 Hz), 2.44 (1H, dd , J = 12.9, 6.6 Hz), 2.18-2.08 (1H, m), 1.98-0.83 (21H, m).

Example 6 (63)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[α] _D = + 31.11 (c 1.08, CHCl ₃ );

TLC: Rf 0.19 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.21 (2H, d, J = 8.7 Hz), 7.10-6.73 (4H, m), 5.24 (1H, s), 4.57-4.45 (1H, m), 4.38 (2H, d, J = 5.4 Hz), 3.88-3.73 (5H, m), 3.20-3.11 (2H, m), 2.99-2.92 (1H, m), 2.79 (1H, dd, J = 13.8, 7.2 Hz), 2.48-2.35 (2H, m), 1.83-1.58 (5H, m), 1.51-1.37 (10H, m), 1.28-1.05 (3H, m), 0.98-0.83 (2H, m).

Example 6 (64)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

TLC: Rf 0.57 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 7.25-7.18 (2H, m), 6.88-6.81 (2H, m), 4.65-4.45 (4H, m), 4.35 (1H, d, J = 14.6 Hz), 4.26 (1H , d, J = 14.6 Hz), 3.75 (3H, s), 3.35 (1H, dd, J = 12.2, 7.4 Hz), 3.11 (1H, dd, J = 12.2, 4.8 Hz), 2.98-2.72 (2H, m), 2.41 (2H, d, J = 6.6 Hz), 1.88-0.80 (20H, m).

Example 6 (65)

(2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

TLC: Rf 0.61 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 7.25-7.17 (2H, m), 6.88-6.81 (2H, m), 4.64-4.44 (4H, m), 4.32 (2H, br.s), 3.75 (3H, s) , 3.35 (1H, dd, J = 12.2, 7.4 Hz), 3.13 (1H, dd, J = 12.2, 5.4 Hz), 2.97 (1H, br.s), 2.76 (1H, dd, J = 13.6, 8.4 Hz ), 2.40 (2H, d, J = 7.0 Hz), 1.88-0.80 (20H, m).

Example 6 (66)

(2R) -N-methyl-N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino Propanamide

TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.24-7.02 (3H, m), 6.90-6.83 (2H, m), 5.16-5.06 (1H, m), 4.90-4.38 (5H, m), 3.80-3.79 (3H, m ), 3.39-3.16 (2H, m), 3.03-2.69 (5H, m), 2.44-2.23 (2H, m), 1.85-0.76 (20H, m).

Example 6 (67)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -N'-methyl-N '-(3-t-butoxycarbonylthiazolidine-4 -Ylcarbonyl) amino) propanamide

TLC: Rf 0.37 (ethyl acetate: hexane = 1: 2);

NMR (CD ₃ OD): δ 7.23-7.17 (2H, m), 6.86-6.82 (2H, m), 5.18-5.00 (2H, m), 4.70-4.66 (1H, m), 4.49-4.18 (3H, m), 3.76 and 3.75 (3H, s), 3.54-2.68 (7H, m), 2.47-2.43 (2H, m), 1.90-1.60 (5H, m), 1.50-1.05 (4H, m), 1.44 and 1.33 (9 H, m), 1.05-0.87 (2 H, m).

Example 6 (68)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

TLC: Rf 0.58 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.36-7.23 (5H, m), 7.15-7.07 (2H, m), 7.01-6.91 (4H, m), 4.65-4.32 (6H, m), 3.33-3.13 (3H, m ), 2.79 (1H, dd, J = 14.1, 6.3 Hz), 2.45-2.30 (2H, m), 1.83-0.78 (20H, m).

Example 6 (69)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -3-t-butoxycarbonyl-2- (2-methylpropyl) thiazolidine -4-ylcarbonylamino) propanamide

TLC: Rf 0.32 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.40-7.19 (3H, m), 7.14 (1H, d, J = 8 Hz), 6.86-6.80 (2H, m), 5.20-5.07 (1H, m), 4.64 (1H, t , J = 7 Hz), 4.63-4.52 (1H, m), 4.43 (1H, dd, J = 15, 6 Hz), 4.32 (1H, dd, J = 15, 6 Hz), 3.78 (3H, s), 3.36- 3.15 (3H, m), 2.78 (1H, dd, J = 14, 6 Hz), 2.46-2.24 (2H, m), 1.91-1.53 (8H, m), 1.50-1.30 (10H, m), 1.30-1.03 (3H, m), 1.00-0.78 (8H, m).

Example 6 (70)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (pyridin-3-ylcarbonylamino) propanamide

TLC: Rf 0.19 (ethyl acetate: hexane = 3: 1);

NMR (CDCl ₃ ): δ 9.04 (1H, dd, J = 3, 1 Hz), 8.75 (1H, dd, J = 5, 2 Hz), 8.10 (1H, ddd, J = 8, 3, 2 Hz), 7.39 ( 1H, ddd, J = 8, 5, 1 Hz), 7.43-7.36 (1H, m), 7.26-7.19 (2H, m), 6.97-6.90 (1H, m), 6.90-6.83 (2H, m), 4.72 -4.63 (1H, m), 4.43 (1H, dd, J = 15, 6 Hz), 4.42 (1H, dd, J = 15, 6 Hz), 3.79 (3H, s), 3.09 (1H, dd, J = 14 , 5 Hz), 2.84 (1H, dd, J = 14, 8 Hz), 2.54 (1H, dd, J = 12, 7 Hz), 2.52 (2H, dd, J = 12, 7 Hz), 1.86-1.59 (5H, m ), 1.56-1.39 (1H, m), 1.30-1.03 (3H, m), 1.00-0.85 (2H, m).

Example 6 (71)

(2R) -N- (4-benzyloxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.63 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.44-7.18 (8H, m), 7.13 (1H, d, J = 7.8 Hz), 6.93-6.88 (2H, m), 5.04 (2H, s), 4.65-4.21 (6H, m), 3.32-3.12 (3H, m), 2.78 (1H, doublet of doublets, J = 13.8, 6.3 Hz), 2.44-2.30 (2H, m), 1.80-0.78 (20H, m).

Example 6 (72)

(2R) -N- (3-benzyloxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl Amino) propanamide

TLC: Rf 0.46 (hexane: ethyl acetate = 1: 1);

NMR (CD ₃ OD): δ 7.47-7.25 (5H, m), 7.00 (1H, d, J = 1.4 Hz), 6.92-6.83 (2H, m), 5.09 (2H, s), 4.63-4.42 (4H , m), 4.35 (1H, d, J = 14.8 Hz), 4.24 (1H, d, J = 14.8 Hz), 3.81 (3H, s), 3.41-3.30 (1H, m), 3.12 (1H, dd, J = 5.0, 12.2 Hz), 3.00-2.71 (2H, br), 2.40 (2H, d, J = 7.0 Hz), 1.89-1.59 (5H, m), 1.54-1.31 (10H, m), 1.29-1.08 (3H, m), 1.04-0.76 (2H, m).

Example 6 (73)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (pyridin-4-ylcarbonylamino) propanamide

TLC: Rf 0.23 (ethyl acetate: methylene chloride = 1: 1);

NMR (CDCl ₃ ): δ 8.79-8.72 (2H, m), 7.66-7.61 (2H, m), 7.47 (1H, d, J = 6 Hz), 7.26-7.19 (2H, m), 6.96-6.84 (3H , m), 4.69-4.61 (1H, m), 4.43 (1H, dd, J = 15, 6 Hz), 4.42 (1H, dd, J = 15, 6 Hz), 3.80 (3H, s), 3.08 (1H, dd, J = 14, 5 Hz), 2.82 (1H, dd, J = 14, 9 Hz), 2.54 (1H, dd, J = 14, 7 Hz), 2.53 (2H, dd, J = 14, 7 Hz), 1.86- 1.75 (2H, m), 1.75-1.59 (3H, m), 1.55-1.39 (1H, m), 1.30-1.03 (3H, m), 1.03-0.85 (2H, m).

Example 6 (74)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -3-t-butoxycarbonyl-2-phenylthiazolidin-4-ylcar Carbonylamino) propanamide

TLC: Rf 0.26 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.53-7.20 (m, 9H), 6.85-6.79 (m, 2H), 5.99 (bs, 1H), 4.80 (dd, J = 8, 5 Hz, 1H), 4.72-4.60 (b , 1H), 4.44 (dd, J = 15, 6 Hz, 1H), 4.31 (dd, J = 15, 6 Hz, 1H), 3.77 (s, 3H), 3.47 (dd, J = 12, 5 Hz, 1H), 3.36 (dd, J = 12, 8 Hz, 1H), 3.25-3.10 (b, 1H), 2.85-2.73 (m, 1H), 2.38 (dd, J = 12, 6 Hz, 1H), 2.29 (dd, J = 12, 8 Hz, 1H), 1.78-1.56 (m, 5H), 1.47-1.00 (m, 13H), 0.94-0.74 (m, 2H).

Example 6 (75)

(4R) -N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonylthiazolidine-ylcar Voxamide

TLC: Rf 0.57 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.32-7.26 (m, 2H), 7.20-7.05 (br. S, 1H), 6.95-6.89 (m, 2H), 5.14-5.07 (m, 1H), 4.80-4.58 (m , 2H), 4.40 (d, J = 9.3 Hz, 1H), 3.88-3.66 (m, 4H), 3.38 (dd, J = 11.7, 2.7 Hz, 1H), 3.25-3.16 (m, 5H), 2.91 ( dd, J = 13.8, 7.2 Hz, 1H), 2.77 (dd, J = 13.8, 5.7 Hz, 1H), 2.44 (d, J = 6.6 Hz, 2H), 1.86-1.59 (m, 5H), 1.54-1.34 (m, 10H), 1.30-1.04 (m, 3H), 0.99-0.84 (m, 2H).

Example 6 (76)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino) propanamide

TLC: Rf 0.34 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.26-7.18 (m, 2H), 7.06-6.82 (m, 4H), 5.00 (bs, 1H), 4.63-4.52 (m, 1H), 4.50-4.10 (m, 3H), 3.79 (s, 3H), 3.30-3.05 (m, 3H), 2.89-2.57 (m, 3H), 2.53-2.28 (m, 3H), 1.85-1.56 (m, 5H), 1.55-1.35 (m, 10H ), 1.30-1.03 (m, 3H), 1.00-0.81 (m, 2H).

Example 6 (77)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino) propanamide

TLC: Rf 0.27 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.37-7.29 (m, 2H), 7.29-7.22 (m, 2H), 7.14-7.07 (m, 1H), 7.05-6.90 (m, 6H), 5.06-4.93 (m, 1H ), 4.65-4.10 (m, 4H), 3.35-3.00 (m, 3H), 2.91-2.57 (m, 3H), 2.55-2.30 (m, 3H), 1.84-1.56 (m, 5H), 1.56-1.35 (m, 10H), 1.30-1.03 (m, 3H), 1.00-0.83 (m, 2H).

Example 6 (78)

(2R) -N- (2-phenoxypyridin-5-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propane amides

TLC: Rf 0.57 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.93 (br. S, 1H), 8.49 (br. S, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.42-7.35 (m, 2H), 7.24-7.08 ( m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 4.80-4.70 (m, 1H), 4.66 (dd, J = 7.2, 3.9 Hz, 1H), 4.60 (d, J = 9.9 Hz, 1H ), 4.55 (d, J = 9.9 Hz, 1H), 3.41-3.27 (m, 3H), 2.84 (dd, J = 13.8, 5.7 Hz, 1H), 2.48-2.33 (m, 2H), 1.82-1.58 ( m, 5H), 1.54-1.35 (m, 10H), 1.28-1.02 (m, 3H), 0.96-0.78 (m, 2H).

Example 6 (79)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -4-t-butoxycarbonylthiomorpholin-2-ylcarbonylamino) propanamide

TLC: Rf 0.27 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.65-7.30 (b, 1H), 7.24-7.18 (m, 2H), 6.90-6.83 (m, 2H), 6.77-6.67 (b, 1H), 4.51-4.04 (m, 4H ), 3.92-3.46 (m, 3H), 3.80 (s, 3H), 3.40-3.29 (m, 1H), 3.03-2.92 (m, 1H), 2.90-2.67 (m, 2H), 2.60-2.49 (m) , 1H), 2.49-2.42 (m, 2H), 1.94-1.55 (m, 5H), 1.53-1.33 (m, 10H), 1.30-1.04 (m, 3H), 1.00-0.83 (m, 2H).

Example 6 (80)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -3-t-butoxycarbonyl-1, 3-perhydrothiazin-4-ylcar Carbonylamino) propanamide

TLC: Rf 0.38 (ethyl acetate: hexane = 2: 3);

NMR (CDCl ₃ ): δ 7.24-7.17 (m, 2H), 7.04-6.93 and 6.79-6.68 (m, 2H), 6.90-6.82 (m, 2H), 4.86-4.20 (m, 6H), 3.79 (s , 3H), 3.04-2.70 (m, 3H), 2.66-2.37 (m, 4H), 2.07-1.85 (m, 1H), 1.85-1.55 (m, 5H), 1.53-1.33 (m, 10H), 1.30 -1.04 (m, 3 H), 1.00-0.83 (m, 2H).

Example 6 (81)

(2R) -N- (2-phenoxypyridin-5-ylmethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) Propanamide

TLC: Rf 0.56 (ethyl acetate: hexane = 2: 1);

NMR (CDCl ₃ ): δ 8.11 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.4, 2.4 Hz, 1H), 7.50-7.35 (m, 3H), 7.22-7.16 (m, 1H) , 7.14-7.08 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 4.68-4.31 (m, 6H), 3.35-3.20 (m, 3H), 2.78 (dd, J = 13.8, 6.0, 1H), 2.44-2.28 (m, 2H), 1.82-1.60 (m, 5H), 1.51-1.36 (m, 10H), 1.32-1.08 (m, 3H), 0.98-0.80 (m, 2H).

Example 6 (82)

(2R) -N- (4- (morpholin-4-yl) benzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcar Carbonylamino) propanamide

TLC: Rf 0.34 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.20 (d, J = 8.7 Hz, 1H), 7.17-7.12 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.64 (dd, J = 6.6, 4.2 Hz , 1H), 4.58 (br.s, 2H), 4.44 (d, J = 9.3 Hz, 1H), 4.41-4.28 (m, 2H), 3.87-3.84 (m, 4H), 3.31 (dd, J = 12.3 , 3.9, 1H), 3.26 (dd, J = 12.3, 6.6 Hz, 1H), 3.20 (br.s, 1H), 3.19-3.11 (m, 4H), 2.78 (dd, J = 13.5, 6.3 Hz, 1H ), 2.44-2.28 (m, 2H), 1.82-1.60 (m, 5H), 1.5-1.34 (m, 10H), 1.31-1.04 (m, 3H), 0.96-0.80 (m, 2H).

Example 6 (83)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcar Carbonylamino) propanamide

TLC: Rf 0.33 (ethyl acetate: hexane = 1: 2);

NMR (CD ₃ OD): δ 7.37-7.25 (m, 4H), 7.13-7.06 (m, 1H), 6.99-6.89 (m, 4H), 4.94-4.30 (m, 6H), 3.08-2.87 (m, 2H), 2.87-2.76 (m, 1H), 2.68-2.50 (m, 1H), 2.50-2.30 (m, 3H), 2.08-1.76 (m, 3H), 1.76-1.60 (m, 3H), 1.60- 1.35 (m, 10 H), 1.35-1.07 (m, 3 H), 1.03-0.85 (m, 2H).

Example 6 (84)

(2R) -N- (1-phenylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl Amino) propanamide

TLC: Rf 0.46 (hexane: ethyl acetate = 1: 1);

NMR (CD ₃ OD): δ 7.24-7.18 (m, 2H), 6.97 (dd, J = 8.7, 0.9 Hz, 2H), 6.81 (t, J = 7.5 Hz, 1H), 4.65-4.56 (m, 2H ), 4.50-4.45 (m, 2H), 3.86-3.76 (m, 1H), 3.68-3.57 (br, 2H), 3.43-3.32 (br, 1H), 3.16 (dd, J = 12.0, 4.8 Hz, 1H ), 2.94-2.77 (m, 4H), 2.46 (d, J = 6.6 Hz, 2H), 2.00-1.79 (br, 4H), 1.78-1.59 (m, 5H), 1.52-1.38 (m, 10H), 1.33-1.09 (m, 3 H), 1.01-0.89 (m, 2 H).

Example 6 (85)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -2-oxothiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.30 (ethyl acetate: hexane = 2: 1);

NMR (CDCl ₃ ): δ 7.72-7.58 (1H, m), 7.30-7.11 (3H, m), 7.11-6.96 (1H, m), 6.89-6.79 (2H, m), 4.59 (1H, q, J = 7 Hz), 4.45-4.18 (3H, m), 3.78 (3H, s), 3.69 (1H, dd, J = 11, 8 Hz), 3.57 (1H, dd, J = 11, 5 Hz), 2.86 (2H, d, J = 7 Hz), 2.43 (2H, d, J = 7 Hz), 1.86-0.75 (11 H, m).

Example 6 (86)

(2R) -N- (1-methylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl Amino) propanamide

TLC: Rf 0.44 (chloroform: methanol = 9: 1);

NMR (CD ₃ OD): δ 4.65-4.56 (m, 2H), 4.49-4.43 (m, 2H), 3.72-3.62 (m, 1H), 3.42-3.33 (m, 1H), 3.14 (dd, J = 12.0, 4.8 Hz, 1H), 2.93-2.70 (br, 4H), 2.45 (d, J = 6.9 Hz, 2H), 2.30 (s, 3H), 2.26-2.14 (br, 2H), 1.93-1.79 (br , 4H), 1.76-1.37 (m, 15H), 1.33-1.09 (m, 3H), 1.02-0.88 (m, 2H).

Example 7

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide

The methylene chloride (5 ml) solution of the compound (147 mg) prepared in Example 2 (80) was cooled to -78 ° C, and then m-chloroperbenzoic acid (117 mg) was added and stirred for 1 hour 10 minutes. The reaction mixture solution was stirred for 3.5 hours while raising to room temperature. M-chloroperbenzoic acid (10 mg) was added to the reaction mixture and the mixture was stirred for 1 hour. The reaction mixture solution was diluted with chloroform, washed sequentially with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by recrystallization (ethyl acetate) to give the compound (101 mg) of the present invention having the following chemical data.

TLC: Rf 0.25 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.24-7.17 (2H, m), 7.00 (1H, t, J = 5.6 Hz), 6.89-6.82 (2H, m), 5.84 (1H, d, J = 8.2 Hz), 4.66 (1H, dt, J = 8.0, 5.0 Hz), 4.47 (1H, dd, J = 15.0, 5.8 Hz), 4.31 (1H, dd, J = 15.0, 5.6 Hz), 3.79 (3H, s), 3.70 ( 1H, dd, J = 14.6, 5.0 Hz), 3.39 (1H, dd, J = 14.6, 5.2 Hz), 3.09-2.91 (2H, m), 2.16-0.96 (20H, m).

Example 7 (1) -7 (4)

The following compounds of the present invention were obtained by operating the compounds prepared in Example 2 (80), Example 2 (90), Example 2 (95) and Example 6 (31) for the same purpose as in Example 7.

Example 7 (1)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.51 (methanol: chloroform = 1: 19);

NMR (CDCl ₃ ): δ 7.65 (0.33H, br.s), 7.37-7.17 (2.67H, m), 6.89-6.81 (2H, m), 6.39-6.27 (0.67H, m), 5.87 (0.33H , d, J = 5.8 Hz), 4.80-4.60 (1H, m), 4.51-4.28 (2H, m), 3.79 (3H, s), 3.34-3.21 (1H, m), 3.01-2.86 (1H, m ), 2.78-2.66 (1H, m), 2.55-2.45 (1H, m), 2.02-0.92 (20H, m).

Example 7 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.21 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.99 (1H, t, J = 4.8 Hz), 6.90-6.82 (2H, m), 5.84 (1H, d, J = 8.0 Hz), 4.71 -4.62 (1H, m), 4.47 (1H, dd, J = 14.6, 6.2 Hz), 4.32 (1H, dd, J = 14.6, 5.4 Hz), 3.81-3.68 (4H, m), 3.40 (1H, dd , J = 15.0, 5.2 Hz), 3.20 (1H, dd, J = 14.2, 6.8 Hz), 3.11 (1H, dd, J = 14.2, 6.8 Hz), 2.46-2.26 (1H, m), 2.05-1.91 ( 2H, m), 1.75-1.19 (15H, m).

Example 7 (3)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cyclohexylcarbonylaminopropanamide

TLC: Rf 0.18 (chloroform: ethyl acetate = 100: 5);

NMR (CDCl ₃ ): δ 7.26-7.15 (3H, m), 6.93-6.82 (3H, m), 4.84 (1H, td, J = 6.6, 4.4 Hz), 4.44 (1H, dd, J = 14.6, 5.8 Hz), 4.31 (1H, dd, J = 14.6, 5.4 Hz), 3.79 (3H, s), 3.63 (1H, dd, J = 15.0, 4.4 Hz), 3.30 (1H, dd, J = 15.0, 6.2 Hz ), 3.17 (1H, dd, J = 14.2, 6.6 Hz), 3.07 (1H, dd, J = 14.2, 6.2 Hz), 2.24-1.00 (22H, m).

Example 7 (4)

(2S) -N- (4-methoxybenzyl) -3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.22 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.25-7.17 (2H, m), 6.97 (1H, LJ = 5.4 Hz), 6.90-6.82 (2H, m), 5.82 (1H, d, J = 8.4 Hz), 4.71-4.62 (1H, m), 4.48 (1H, dd, J = 14.8, 6.4 Hz), 4.32 (1H, dd, J = 14.8, 5.4 Hz), 3.79-3.68 (4H, m), 3.39 (1H, dd, J = 14.6, 5.0 Hz), 3.21 (1H, dd, J = 14.2, 7.4 Hz), 3.11 (1H, dd, J = 14.2, 7.0 Hz), 2.46-2.30 (1H, m), 2.05-1.91 (2H, m), 1.75-1.17 (15H, m).

Example 8- Example 8 (12)

The following compounds of the present invention were obtained by operating the compounds prepared in Example 7 and Example 7 (1) for the same purpose as in Example 6.

In the preparation of the compound of Example 8 (8), (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was used.

Example 8

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-methoxycyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 8 (1).)

High Polarity

TLC: Rf 0.68 (ethyl acetate);

NMR (CDCl ₃ ): δ 7.30-7.24 (1H, m), 7.22-7.15 (2H, m), 6.97 (1H, d, J = 6.6 Hz), 6.89-6.82 (2H, m), 4.90-4.81 ( 1H, m), 4.42 (1H, dd, J = 14.6, 5.8 Hz), 4.30 (1H, dd, J = 14.6, 5.6 Hz), 3.79 (3H, s), 3.60 (1H, dd, J = 15.0, 4.8 Hz), 3.45-3.26 (5H, m), 3.15 (1H, dd, J = 14.0, 6.2 Hz), 3.05 (1H, dd, J = 14.0, 6.2 Hz), 2.28-1.00 (20H, m).

Example 8 (1)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-methoxycyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 8.)

Hypopolar

TLC: Rf 0.59 (ethyl acetate);

NMR (CDCl ₃ ): δ 7.28-7.14 (3H, m), 6.94 (1H, d, J = 7.0 Hz), 6.89-6.82 (2H, m), 4.91-4.82 (1H, m), 4.42 (1H, dd, J = 14.6, 5.8 Hz), 4.30 (1H, dd, J = 14.6, 5.4 Hz), 3.79 (3H, s), 3.60 (1H, dd, J = 15.0, 4.8 Hz), 3.38-3.24 (4H m), 3.18-2.99 (3H, m), 2.21-1.00 (20H, m).

Example 8 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cyclobutylcarbonylaminopropanamide

TLC: Rf 0.26 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.30-7.15 (3H, m), 6.89-6.78 (3H, m), 4.89-4.80 (1H, m), 4.43 (1H, dd, J = 14.6, 5.8 Hz), 4.31 ( 1H, dd, J = 14.6, 5.6 Hz), 3.79 (3H, s), 3.62 (1H, dd, J = 15.0, 4.2 Hz), 3.31 (1H, dd, J = 15.0, 6.6 Hz), 3.23-2.98 (3H, m), 2.38-1.01 (17H, m).

Example 8 (3)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (tetrahydrofuran-2-ylcarbonylamino) propanamide

TLC: Rf 0.14 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.82-7.77 (1H, m), 7.23-7.05 (3H, m), 6.89-6.82 (2H, m), 4.99-4.90 (0.5H, m), 4.85-4.75 (0.5H m), 4.49-4.27 (3H, m), 4.09-3.79 (5H, m), 3.73-3.33 (2H, m), 3.21-2.94 (2H, m), 2.38-0.98 (15H, m).

Example 8 (4)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cycloheptylcarbonylaminopropanamide

TLC: Rf 0.14 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.26-7.15 (3H, m), 6.89-6.82 (3H, m), 4.88-4.79 (1H, m), 4.44 (1H, dd, J = 14.8, 6.0 Hz), 4.30 ( 1H, dd, J = 14.8, 5.6 Hz), 3.79 (3H, s), 3.61 (1H, dd, J = 15.0, 4.4 Hz), 3.31 (1H, dd, J = 15.0, 6.2 Hz), 3.17 (1H , dd, J = 14.0, 6.2 Hz), 3.06 (1H, dd, J = 14.0, 5.8 Hz), 2.38-1.00 (24H, m).

Example 8 (5)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (tetrahydrofuran-3-ylcarbonylamino) propanamide

TLC: Rf 0.08 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.25-7.15 (3H, m), 7.02 (1H, d, J = 7.0 Hz), 6.90-6.82 (2H, m), 4.88-4.80 (1H, m), 4.43 (1H, dd, J = 14.8, 6.0 Hz), 4.31 (1H, dd, J = 14.8, 5.6 Hz), 4.01-3.73 (7H, m), 3.64-3.54 (1H, m), 3.39-3.27 (1H, m) , 3.21-2.89 (3H, m), 2.20-1.00 (13H, m).

Example 8 (6)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((2RS) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

TLC: Rf 0.32 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 7.23 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 5.20 (s) and 5.16 (bs) (1H), 4.97-4.84 (1H, m ), 4.42-4.23 (2H, m), 4.02-3.85 (1H, m), 3.84-3.60 (2H, m), 3.77 (3H, s), 3.53-3.10 (2H, m), 3.08-2.90 (3H m), 2.20-1.58 (6H, m), 1.44 and 1.40 (9H, s), 1.35-1.00 (5H, m).

Example 8 (7)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

TLC: Rf 0.61 (methylene chloride: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.96 (1H, brs), 7.67 (1H, brs), 7.25-7.22 (2H, m), 6.84-6.82 (2H, m), 5.02-4.91 (1H, m), 4.62- 4.42 (4H, m), 4.30 (1H, dd, J = 14.4, 5.0 Hz), 4.06-3.92 (1H, m), 3.78 (3H, s), 3.34-3.15 (3H, m), 2.93-2.72 ( 2H, m), 2.10-1.59 (6H, m), 1.40 (9H, s), 1.50-0.85 (5H, m).

Example 8 (8)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (3-t-butoxycarbonylthiazolidin-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[a] _D = + 1.23 (c 1.31, CHCl ₃ );

TLC: Rf 0.63 (methylene chloride: ethyl acetate = 2: 1);

NMR (CD ₃ OD): δ 7.23-7.18 (2H, m), 6.86-6.81 (2H, m), 5.16 (1H, br), 4.96-4.84 (1H, m), 4.40-4.23 (2H, m) , 4.00-3.82 (1H, m), 3.80-3.50 (2H, m), 3.75 (3H, s), 3.50-3.10 (2H, m), 3.09-2.95 (1H, m), 3.00 (2H, d, J = 6.2 Hz), 2.17-1.80 (3H, m), 1.80-1.55 (3H, m), 1.39 (9H, s), 1.42-1.00 (5H, m).

Example 8 (9)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((4R) -3-t-butoxycarbonylthiazolidine-ylcarbonylamino) propanamide

TLC: Rf 0.65 (chloroform: methanol = 14: 1);

NMR (CD3OD): δ 7.23-7.18 (2H, m), 6.87-6.83 (2H, m), 4.90-4.75 (1H, m), 4.63-4.45 (3H, m), 4.34-4.32 (2H, m) , 3.76 (3H, s), 3.41-3.05 (4H, m), 2.84-2.59 (2H, m), 2.01-1.60 (6H, m), 1.43 and 1.42 (9H, s), 1.43-1.00 (5H, m).

Example 8 (10)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (1-t-butoxycarbonylpiperidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.25 (ethyl acetate: chloroform = 2: 3);

NMR (CDCl ₃ ): δ 7.28-7.15 (3H, m), 6.97 (1H, d, J = 6.6 Hz), 6.90-6.82 (2H, m), 4.88-4.79 (1H, m), 4.43 (1H, dd, J = 14.2, 5.8 Hz), 4.31 (1H, dd, J = 14.2, 5.4 Hz), 4.22-4.04 (2H, m), 3.79 (3H, s), 3.61 (1H, dd, J = 15.2, 4.8 Hz), 3.30 (1H, dd, J = 15.2, 6.6 Hz), 3.16 (1H, dd, J = 14.4, 6.6 Hz), 3.06 (1H, dd, J = 14.4, 6.2 Hz), 2.79-2.66 ( 2H, m), 2.39-1.00 (25H, m).

Example 8 (11)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-t-butoxycarbonylaminocyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the t-butoxycarbonylamino group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 8 (12).)

TLC: Rf 0.17 (ethyl acetate: chloroform = 3: 7);

NMR (CDCl ₃ ): δ 7.27-7.15 (3H, m), 6.97 (1H, d, J = 7.0 Hz), 6.90-6.82 (2H, m), 4.90-4.81 (1H, m), 4.67 (1H, d, J = 7.6 Hz), 4.43 (1H, dd, J = 14.6, 5.8 Hz), 4.31 (1H, dd, J = 14.6, 6.0 Hz), 3.79-3.57 (5H, m), 3.32 (1H, dd , J = 15.0, 6.2 Hz), 3.17 (1H, dd, J = 14.2, 6.6 Hz), 3.05 (1H, dd, J = 14.2, 6.2 Hz), 2.34-1.00 (29H, m).

Example 8 (12)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-t-butoxycarbonylaminocyclohexylcarbonylamino) propanamide

(The relative arrangement of the cyclohexyl ring in which the t-butoxycarbonylamino group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 8 (11).)

TLC: Rf 0.17 (ethyl acetate: chloroform = 3: 7);

NMR (CDCl ₃ ): δ 7.28-7.14 (3H, m), 6.95 (1H, d, J = 6.6 Hz), 6.89-6.82 (2H, m), 4.88-4.79 (1H, m), 4.47-4.24 ( 3H, m), 3.79 (3H, s), 3.60 (1H, dd, J = 15.0, 4.8 Hz), 3.50-3.25 (2H, m), 3.15 (1H, dd, J = 14.4, 6.4 Hz), 3.05 (1H, doublet of doublets, J = 14.4, 6.2 Hz), 2.18-0.96 (29H, m).

Example 9- Example 9 (16)

Example 6 (36), Example 6 (39), Example 6 (40), Example 6 (41), Example 6 (44), Example 6 (47), Example 6 (50) to Example Prepared in Example 6 (52), Example 6 (54) to Example 6 (56), Example 6 (71), Example 6 (72), Example 6 (84) and Example 8 (6). By operating the compound for the same purpose as in Reference Example 4, the following compound of the present invention was obtained.

Example 9

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.27 (methylene chloride: methanol = 97: 3);

NMR (CD ₃ OD): δ 7.22 (2H, d, J = 9 Hz), 6.85 (2H, d, J = 9 Hz), 5.41 and 5.39 (1H, s), 4.55-4.44 (1H, m), 4.36- 4.26 (2H, m), 3.85-3.70 (1H, m), 3.76 (3H, s), 3.70-3.52 (1H, m), 3.40-3.10 (2H, m), 3.00-2.84 (1H, m), 2.84-2.68 (1H, m), 2.46-2.38 (2H, m), 1.90-1.55 (5H, m), 1.55-1.08 (4H, m), 1.07-0.77 (2H, m).

Example 9 (1)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.25 (methylene chloride: methanol = 97: 3);

NMR (CD ₃ OD): δ 7.22 (2H, d, J = 9 Hz), 6.86 (2H, d, J = 9 Hz), 5.44 (s) and 5.37 (1H, s), 5.03-4.93 (1H, m) , 4.42-4.22 (2H, m), 3.84-3.34 (4H, m), 3.77 (3H, s), 3.34-3.12 (2H, m), 3.05 (2H, d, J = 6 Hz), 2.10-1.83 ( 3H, m), 1.83-1.58 (3H, m), 1.50-1.00 (5H, m).

Example 9 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (piperidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.19 (CHCl 3: MeOH = 9: 1);

NMR (DMSO-d ₆ ): δ 9.06-8.90 (1H, br), 8.74-8.52 (2H, m), 8.19 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.8 Hz) , 6.86 (2H, d, J = 8.8 Hz), 4.48-4.37 (1H, m), 4.21 (2H, d, J = 6.0 Hz), 3.73 (3H, s), 3.33-3.23 (2H, br), 2.96-2.76 (3H, m), 2.59 (1H, dd, J = 8.8, 13.4 Hz), 2.55-2.43 (1H, m), 2.39 (2H, d, J = 7.0 Hz), 1.94-1.52 (9H, m), 1.49-1.03 (4H, m), 0.99-0.77 (2H, m).

Example 9 (3)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-aminocyclohexylcarbonylamino) propanamide hydrochloride

(The relative arrangement of the cyclohexyl ring in which the amino group is substituted is not determined, but is a single product. This compound corresponds to the isomer of the compound of Example 9 (4).)

TLC: Rf 0.16 (CHCl 3: MeOH = 9: 1);

NMR (DMSO-d ₆ ): δ 8.49 (1H, d, J = 6.0 Hz), 8.06-7.85 (4H, m), 7.18 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 4.47-4.36 (1H, m), 4.21 (2H, d, J = 6.0 Hz), 3.73 (3H, s), 3.17-3.04 (1H, br), 2.82 (1H, dd, J = 5.6 , 13.4 Hz), 2.64 (1H, dd, J = 8.6, 13.4 Hz), 2.44-2.31 (3H, m), 1.99-1.49 (12H, m), 1.46-1.03 (5H, m), 0.98-0.76 ( 2H, m).

Example 9 (4)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-aminocyclohexylcarbonylamino) propanamide hydrochloride

(The relative arrangement of the cyclohexyl ring in which the amino group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 9 (3).)

TLC: Rf 0.11 (chloroform: methanol = 9: 1);

NMR (DMSO-d ₆ ): δ 8.53-8.47 (1H, br), 8.05-7.94 (4H, br), 7.17 (2H, d, J = 8.4 Hz), 6.85 (2H, d, J = 8.4 Hz) , 4.45-4.35 (1H, br), 4.19 (2H, br), 3.72 (3H, s), 3.16 (1H, d, J = 5.2 Hz), 3.04-2.88 (1H, br), 2.78 (1H, dd , J = 5.8, 13.2 Hz), 2.59 (1H, dd, J = 8.2, 13.2 Hz), 2.38 (2H, d, J = 6.6 Hz), 2.35-2.08 (2H, br), 1.98-1.55 (8H, m), 1.49-1.02 (7H, m), 0.99-0.77 (2H, m).

Example 9 (5)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.26 (methylene chloride: methanol = 97: 3);

NMR (CD ₃ OD): δ 7.27-7.17 (2H, m), 6.93-6.80 (2H, m), 4.61-4.47 (2H, m), 4.41 (2H, s), 4.33 (1H, d, J = 14 Hz), 4.31 (1H, d, J = 14 Hz), 3.77 (3H, s), 3.55 (1H, dd, J = 12, 7), 3.22 (1H, dd, J = 12, 7 Hz), 2.92 (1H , dd, J = 14, 7 Hz), 2.80 (1H, dd, J = 14, 8 Hz), 2.43 (2H, d, J = 6 Hz), 1.90-0.80 (11H, m).

Example 9 (6)

(2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide Hydrochloride

TLC: Rf 0.74 (methanol: chloroform = 5: 95);

NMR (CD ₃ OD): δ 8.92 (1H, d, J = 7.2 Hz), 8.21-8.14 (2H, m), 7.60-7.54 (2H, m), 5.12-4.98 (1H, m), 4.55 (2H , t, J = 7.0 Hz, 4.44 (1H, d, J = 10.2 Hz), 4.38 (1H, d, J = 10.2 Hz), 3.51 (1H, dd, J = 12.2, 7.4 Hz), 3.12 (1H , dd, J = 12.2, 7.0 Hz), 2.94 (1H, dd, J = 13.6, 6.6 Hz), 2.80 (1H, dd, J = 13.4, 8.2 Hz), 2.50 (2H, d, J = 6.6 Hz) , 1.93-0.85 (14H, m).

Example 9 (7)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.44 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD): δ 7.29-7.18 (2H, m), 6.91-6.81 (2H, m), 4.65-4.51 (2H, m), 4.44 (1H, d, J = 11 Hz), 4.43 (1H, d, J = 11 Hz), 4.32 (2H, m), 3.77 (3H, s), 3.59 (1H, dd, J = 12, 8 Hz), 3.38-3.26 (1H, m), 2.97 (1H, dd, J = 14, 5 Hz), 2.76 (1H, dd, J = 14,9 Hz), 2.42 (2H, d, J = 7 Hz), 1.89-0.80 (11 H, m).

Example 9 (8)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.43 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD): δ 8.25-8.15 (2H, m), 7.62-7.50 (2H, m), 4.63-4.49 (4H, m), 4.43 (1H, d, J = 10 Hz), 4.41 (1H, d, J = 10 Hz), 3.56 (1H, dd, J = 12, 7 Hz), 3.26 (1H, dd, J = 12, 7 Hz), 2.96 (1H, dd, J = 13,7 Hz), 2.85 (1H, dd, J = 13, 8 Hz), 2.46 (2H, d, J = 7 Hz), 1.91-0.80 (11 H, m).

Example 9 (9)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.41 (methylene chloride: methanol = 19: 1);

NMR (DMSO-d ₆ ): δ 9.10-8.93 (2H, m), 8.24-8.14 (2H, m), 7.62-7.52 (2H, m), 5.35 and 5.27 (1H, s), 4.58-4.39 (3H , m), 3.72-3.46 (2H, m), 3.28-3.03 (2H, m), 2.94-2.64 (2H, m), 2.44 (2H, d, J = 7 Hz), 1.94-0.75 (11H, m) .

Example 9 (10)

(2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (imidazol-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.31 (chloroform: methanol = 9: 1);

NMR (DMSO-d ₆ ): δ 9.10-9.01 (3H, m), 8.28 (1H, s), 8.18 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 4.73 -4.61 (1H, m), 4.40 (2H, d, J = 6.0 Hz), 2.98 (1H, dd, J = 6.0, 13.6 Hz), 2.82 (1H, dd, J = 8.4, 13.6 Hz), 2.45 ( 2H, d, J = 7.0 Hz), 1.80-1.30 (6H, m), 1.28-0.78 (5H, m).

Example 9 (11)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide dihydrochloride

TLC: Rf 0.42 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD): δ 7.67-7.60 (2H, m), 7.60-7.50 (2H, m), 4.66-4.37 (6H, m), 3.59 (1H, dd, J = 12, 8 Hz), 3.33- 3.21 (1H, m), 3.28 (6H, s), 2.94 (1H, dd, J = 16, 7 Hz), 2.84 (1H, dd, J = 16, 8 Hz), 2.48 (2H, d, J = 7 Hz) , 1.93-0.83 (11 H, m).

Example 9 (12)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide dihydrochloride

TLC: Rf 0.40 (methylene chloride: methanol = 19 :);

NMR (CD ₃ OD): δ 7.68-7.59 (2H, m), 7.59-7.51 (2H, m), 5.47 and 5.42 (1H, s), 4.59-4.43 (3H, m), 3.92-3.76 (1H, m), 3.72-3.68 (1H, m), 3.39-3.17 (2H, m), 3.29 (6H, m), 3.07-2.73 (2H, m), 2.47 (2H, d, J = 7 Hz), 1.93- 0.83 (11 H, m).

Example 9 (13)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.65 (ethyl acetate);

NMR (CD ₃ OD): δ 8.71 (1H, t, J = 5.7 Hz), 7.36-7.28 (4H, m), 7.09 (1H, t, J = 7.2 Hz), 6.96-6.89 (4H, m), 4.59-4.51 (2H, m), 4.44-4.30 (4H, m), 3.55 (1H, dd, J = 11.7, 7.5 Hz), 3.24 (1H, dd, J = 11.7, 6.9 Hz), 2.93 (1H, dd, J = 13.5, 6.3 Hz), 2.81 (1H, dd, J = 13.5, 7.5 Hz), 2.46 (1H, dd, J = 12.6, 6.9 Hz), 2.42 (1H, dd, J = 12.6, 6.6 Hz ), 1.88-1.79 (2H, m), 1.74-1.61 (3H, m), 1.53-1.36 (1H, m), 1.31-1.08 (3H, m), 1.00-0.88 (2H, m).

Example 9 (14)

(2R) -N- (4-benzyloxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.30 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 8.81 (1H, d, J = 8.1 Hz), 8.63 (1H, t, J = 7.5 Hz), 7.43-7.19 (7H, m), 6.95-6.69 (2H, m), 5.05 (2H, s), 4.60-4.25 (6H, m), 3.56 (1H, dd, J = 12.3, 7.5 Hz), 3.21 (1H, dd, J = 12.3, 7.2 Hz), 2.91 (1H, dd, J = 13.8, 6.6 Hz), 2.78 (1H, dd, J = 13.8, 7.5 Hz), 2.44 (1H, dd, J = 12.6, 6.9 Hz), 2.40 (1H, dd, J = 12.6, 6.6 Hz), 1.86-0.83 (11 H, m).

Example 9 (15)

(2R) -N- (3-benzyloxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride

TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1);

NMR (CD ₃ OD): δ 7.47-7.26 (m, 5H), 7.00 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 1.8 Hz, 1H), 5.08 (s, 2H), 4.60-4.48 (m, 2H), 4.39 (s, 2H), 4.36 (d, J = 14.8 Hz, 1H), 4.23 (d, J = 14.8 Hz, 1H ), 3.82 (s, 3H), 3.56 (dd, J = 12.2, 7.4 Hz, 1H), 3.22 (dd, J = 12.2, 7.0 Hz, 1H), 2.91 (dd, J = 13.8, 6.6 Hz, 1H) , 2.77 (dd, J = 13.8, 7.8 Hz, 1H), 2.42 (d, J = 6.8 Hz, 2H), 1.85-1.56 (m, 5H), 1.54-0.80 (m, 6H).

Example 9 (16)

(2R) -N- (1-phenylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide dihydrochloride

TLC: Rf 0.26 (hexane: ethyl acetate = 1: 1);

NMR (CD ₃ OD): δ 7.80-7.76 (m, 2H), 7.65-7.54 (m, 3H), 4.63 (t, J = 7.2 Hz, 1H), 4.54 (t, J = 7.2 Hz, 1H), 4.45 (d, J = 9.9 Hz, 1H), 4.42 (d, J = 9.9 Hz, 1H), 4.20-4.10 (m, 1H), 3.87-3.70 (br, 4H), 3.61 (dd, J = 12.0, 7.5 Hz, 1H), 3.29 (dd, J = 12.0, 6.9 Hz, 1H), 2.95 (dd, J = 13.2, 6.6 Hz, 1H), 2.83 (dd, J = 13.2, 7.8 Hz, 1H), 2.57- 2.46 (m, 2H), 2.32-2.14 (m, 4H), 1.90-1.81 (br, 2H), 1.77-1.63 (m, 3H), 1.54-1.40 (m, 1H), 1.36-1.10 (m, 3H ), 1.03-0.91 (m, 2H).

Reference Example 5

Bis ((2R) -2- (4-methoxybenzylcarbamoyl) -2-t-butoxycarbonylaminoethyl) disulfide

Bis ((2R) -carboxy-2-t-butoxycarbonylaminoethyl) disulfide (5 g), 4-methoxybenzylamine (3.7 ml) and 1-hydroxybenzotriazole (3.84 g) were methylene chloride (50 ml) -DMF (10 ml) was dissolved in a mixed solvent, and EDC-HCl (5.45 g) was added under ice cooling, followed by stirring for 12 hours. The reaction mixture solution was diluted with chloroform, washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with ether to give the title compound (8.15 g) having the following chemical data.

TLC: Rf 0.16 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): 8.03 (2H, t, J = 6.3 Hz), 7.23-7.15 (4H, m), 6.87-6.80 (4H, m), 5.54 (2H, d, J = 9.6 Hz), 4.94- 4.82 (2H, m), 4.46 (2H, dd, J = 14.6, 6.2 Hz), 4.30 (2H, dd, J = 14.6, 5.8 Hz), 3.78 (6H, s), 3.04-2.82 (4H, m) , 1.26 (18 H, s).

Reference Example 6

(2R) -N- (4-methoxybenzyl) -3-mercapto-2-t-butoxycarbonylaminopropanamide

Compound (315 mg), tributylphosphine (103 mg) and acetic acid (15 drops) prepared in Reference Example 5 were dissolved in a mixed solvent of dioxane (8 ml) -water (2 ml) and stirred at room temperature for 3 days. It was. The reaction mixture solution was concentrated. The residue was purified by silica gel column chromatography- (ethyl acetate: chloroform = 1: 19) to give the title compound (242 mg) having the following chemical data.

TLC: Rf 0.47 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 7.24-7.16 (2H, m), 6.90-6.82 (2H, m), 6.70-6.51 (1H, m), 5.41 (1H, d, J = 7.6 Hz), 4.49-4.29 ( 3H, m), 3.80 (3H, s), 3.14 (1H, ddd, J = 14.0, 7.8, 4.4 Hz), 2.73 (1H, ddd, J = 14.0, 10.2, 5.8 Hz), 1.59-1.50 (1H, m), 1.43 (9H, s).

Example 10

(2R) -N- (4-methoxybenzyl) -3- (tetrahydropyran-2-yl) methylthio-2-t-butoxycarbonylaminopropanamide

Compound (103 mg), 2- (bromomethyl) tetrahydropyran (0.05 ml) and potassium carbonate (168 mg) in DMF (5 ml) solution prepared in Reference Example 6 were degassed and then stirred at room temperature for 15 hours. It was. The reaction mixture solution was concentrated. The residue was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain a compound of the present invention (68 mg) having the following chemical data.

TLC: Rf 0.40 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 7.28-7.20 (2H, m), 7.09-6.95 (1H, m), 6.90-6.82 (2H, m), 5.88-5.78 (1H, m), 4.42-4.38 (2H, m ), 4.32-4.20 (1H, m), 3.96-3.76 (4H, m), 3.52-3.18 (2H, m), 3.13-3.01 (1H, m), 2.84-2.51 (3H, m), 1.88-1.74 (1H, m), 1.65-1.08 (14H, m).

Example 10 (1)-Example 10 (11)

The following compounds of the present invention were obtained by operating the compound prepared in Reference Example 6 for the same purpose as in Example 10.

Example 10 (1)

(2R) -N- (4-methoxybenzyl) -3- (bicyclo [2.1.1] heptan-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.81 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.68-6.58 (1H, m), 5.35 (1H, d, J = 6.6 Hz), 4.40 (2H, d, J = 6.0 Hz), 4.29-4.19 (1H, m), 3.80 (3H, s), 3.05-2.94 (1H, m), 2.90-2.78 (1H, m), 2.65-2.25 (2H, m) , 2.24-0.60 (20H, m).

Example 10 (2)

(2R) -N- (4-methoxybenzyl) -3- (4-methoxycyclohexylmethylthio) -2-t-butoxycarbonylaminopropanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 10 (3).)

Hypopolar

TLC: Rf 0.41 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 7.25-7.17 (2H, m), 6.89-6.82 (2H, m), 6.62 (1H, t, J = 5.4 Hz), 5.34 (1H, d, J = 7.2 Hz), 4.39 (2H, d, J = 5.8 Hz), 4.28-4.18 (1H, m), 3.79 (3H, s), 3.44-3.37 (1H, m), 3.29 (3H, s), 2.99 (1H, dd, J = 14.0, 6.0 Hz), 2.82 (1H, dd, J = 14.0, 7.0 Hz), 2.53-2.37 (2H, m), 1.94-1.80 (2H, m), 1.68-1.20 (16H, m).

Example 10 (3)

(2R) -N- (4-methoxybenzyl) -3- (4-methoxycyclohexylmethylthio) -2-t-butoxycarbonylaminopropanamide

(The relative arrangement of the cyclohexyl ring in which the methoxy group is substituted is not determined, but is a single substance. This compound corresponds to the isomer of the compound of Example 10 (2).)

High Polarity

TLC: Rf 0.38 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 7.25-7.17 (2H, m), 6.89-6.82 (2H, m), 6.62 (1H, t J = 5.0 Hz), 5.34 (1H, d, J = 7.8 Hz), 4.39 ( 2H, d, J = 5.8 Hz), 4.28-4.18 (1H, m), 3.80 (3H, s), 3.34 (3H, s), 3.14-2.93 (2H, m), 2.83 (1H, dd, J = 13.8, 6.6 Hz), 2.47 (1H, dd, J = 12.8, 7.0 Hz), 2.40 (1H, dd, J = 12.8, 6.8 Hz), 2.13-1.98 (2H, m), 1.85-1.81 (2H, m ), 1.54-0.84 (14H, m).

Example 10 (4)

(2R) -N- (4-methoxybenzyl) -3- (1-methylpiperidin-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.45 (methanol: chloroform = 1: 9);

NMR (CDCl ₃ ): δ 7.27-7.13 (2.5H, m), 6.89-6.74 (2.5H, m), 6.05 (0.5H, d, J = 6.8 Hz), 5.69 (0.5H, d, J = 7.0 Hz), 4.49-4.15 (3H, m), 3.80 (3H, s), 3.15-1.18 (25H, m).

Example 10 (5)

(2R) -N- (4-methoxybenzyl) -3- (pyridin-4-ylmethylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.12 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 8.54-8.51 (2H, m), 7.27-7.17 (4H, m), 6.89-6.82 (2H, m), 6.58 (1H, t, J = 5.4 Hz), 5.30 (1H) , d, J = 7.6 Hz), 4.39 (2H, d, J = 5.4 Hz), 4.32-4.22 (1H, m), 3.79 (3H, s), 3.70 (1H, d, J = 13.8 Hz), 3.62 (1H, d, J = 13.8 Hz), 2.89 (1H, dd, J = 14.0, 5.6 Hz), 2.76 (1H, dd, J = 14.0, 6.6 Hz), 1.43 (9H, s).

Example 10 (6)

(2R) -N- (4-methoxybenzyl) -3- (quinolin-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.50 (ethyl acetate: chloroform = 1: 4);

NMR (CDCl ₃ ): δ 8.13 (1H, d, J = 8.4 Hz), 7.94 (1H, d, J = 8.2 Hz), 7.80 (1H, dd, J = 8.0, 1.4 Hz), 7.68-7.43 (3H , m), 7.17-7.10 (2H, m), 7.05-6.90 (1H, m), 6.82-6.74 (2H, m), 6.19 (1H, d, J = 7.8 Hz), 4.51-4.36 (2H, m ), 4.30 (1H, dd, J = 11.4, 5.4 Hz), 4.06 (2H, s), 3.78 (3H, s), 2.96 (1H, dd, J = 14.4, 6.6 Hz), 2.79 (1H, dd, J = 14.4, 5.8 Hz), 1.43 (9H, s).

Example 10 (7)

(2R) -N- (4-methoxybenzyl) -3- (imidazol-4-ylmethylthio) -2-t-butoxycarbonylaminopropanamide

TLC: Rf 0.61 (methanol: chloroform = 1: 9);

NMR (CDCl ₃ ): δ 7.63 (1H, br.s), 7.34 (1H, s), 7.24-7.18 (2H, m), 6.90-6.81 (2H, m), 5.81 (1H, dd, J = 7.6 Hz), 4.46-4.30 (3H, m), 3.82-3.66 (5H, m), 2.96 (1H, d, J = 14.2, 5.4 Hz), 2.78 (1H, dd, J = 14.2, 7.2 Hz), 1.44 (9H, s).

Example 10 (8)

(2R) -N- (4-methoxybenzyl) -3-((1R, 4R, 5R) -bicyclo [2.1.1] hepta-2-en-5-ylmethylthio) -2-t Butoxycarbonylaminopropanamide

TLC: Rf 0.25 (ethyl acetate: chloroform = 1:19);

NMR (CDCl ₃ ): δ 7.27-7.16 (2H, m), 6.92-6.82 (2H, m), 6.67-6.55 (1H, m), 6.17 (1H, dd, J = 6,3 Hz), 5.92 (1H , dd, J = 6,3 Hz), 5.33 (1H, d, J = 7 Hz), 4.39 (2H, d, J = 6 Hz), 4.29-4.16 (1H, m), 3.81 (3H, s), 2.98 ( 1H, dd, J = 14, 6 Hz), 2.91-2.75 (3H, m), 2.38-2.14 (3H, m), 1.98-1.82 (1H, m), 1.55-1.38 (1H, m), 1.45 (9H , s), 1.29-1.21 (1H, m), 0.63-0.52 (1H, m).

Example 10 (9)

(2R) -N- (4-methoxybenzyl) -3-((1S, 4S, 5S) -bicyclo [2.1.1] hepta-2-en-5-ylmethylthio) -2-t Butoxycarbonylaminopropanamide

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.27-7.17 (2H, m), 6.93-6.81 (2H, m), 6.70-6.55 (1H, m), 6.16 (1H, dd, J = 6,3 Hz), 5.94 (1H , dd, J = 6,3 Hz), 5.33 (1H, d, J = 7 Hz), 4.39 (2H, d, J = 6 Hz), 4.29-4.15 (1H, m), 3.81 (3H, s), 2.96 ( 1H, dd, J = 14, 6 Hz), 2.92-2.74 (3H, m), 2.37-2.13 (3H, m), 1.97-1.82 (1H, m), 1.55-1.38 (1H, m), 1.44 (9H , s), 1.29-1.20 (1H, m), 0.63-0.51 (1H, m).

Example 10 (10)

(2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-t-butoxycar Carbonylaminopropanamide

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.27-7.17 (2H, m), 6.93-6.83 (2H, m), 6.71-6.57 (1H, m), 5.35 (1H, d, J = 7 Hz), 4.40 (2H, d , J = 6 Hz), 4.32-4.19 (1H, m), 3.81 (3H, s), 2.99 (1H, dd, J = 14, 6 Hz), 2.86 (1H, dd, J = 14, 7 Hz), 2.58 ( 1H, dd, J = 12, 8 Hz), 2.55 (1H, dd, J = 12, 8 Hz), 2.23-2.13 (2H, m), 2.13-1.88 (1H, m), 1.88-1.70 (1H, m) , 1.64-1.18 (5H, m), 1.45 (9H, s), 1.16-1.01 (1H, m), 0.66 (1H, ddd, J = 12, 5,2 Hz).

Example 10 (11)

(2R) -N- (4-methoxybenzyl) -3-((1R, 2S, 4S) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-t-butoxycar Carbonylaminopropanamide

TLC: Rf 0.23 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.27-7.16 (2H, m), 6.93-6.81 (2H, m), 6.73-6.57 (1H, m), 5.36 (1H, d, J = 7 Hz), 4.40 (2H, d , J = 6 Hz), 4.31-4.18 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J = 14, 6 Hz), 2.87 (1H, dd, J = 14, 7 Hz), 2.58 ( 1H, dd, J = 12, 8 Hz), 2.55 (1H, dd, J = 12, 8 Hz), 2.24-2.13 (2H, m), 2.10-1.88 (1H, m), 1.87-1.69 (1H, m) , 1.60-1.20 (5H, m), 1.43 (9H, s), 1.16-1.01 (1H, m), 0.66 (1H, ddd, J = 12, 5,2 Hz).

Reference Example 7

(2S) -4-hydroxy-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester

(2S) -3-carboxy-2-t-butoxycarbonylaminopropanoic acid, 4-methoxybenzyl ester, dicyclohexylamine salt (1350 mg), tetrahydrofuran of N-methylmorpholine (0.32 ml) (6 ml) To the solution, isobutyl chloroformate (0.35 ml) was added dropwise under ice cooling, followed by stirring for 45 minutes. The reaction mixture solution was filtered through Celite, sodium borohydride (229 mg) was added to the filtrate under ice cooling, and methanol (1.2 ml) was added dropwise over 1 hour. 1N hydrochloric acid was added to the reaction mixture solution, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and brine and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (180 mg) having the following chemical data.

TLC: Rf 0.42 (Methanol: Chloroform = 1: 9);

NMR (CDCl ₃ ): δ 7.30 (2H, d, J = 8.7 Hz), 6.89 (2H, d, J = 8.7 Hz), 5.38 (1H, brd, J = 8.4 Hz), 5.13 (2H, s), 4.55-4.43 (1H, m), 3.82 (3H, s), 3.75-3.55 (2H, m), 3.24-3.05 (1H, m), 2.23-2.06 (1H, m), 1.69-1.56 (1H, m ).

Reference Example 8

(2S) -3-formyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester

The compound (162 mg) and triethylamine (0.40 ml) prepared in Reference Example 7 were dissolved in a mixed solvent of methylene chloride (4 ml) -dimethylsulfoxide (4 ml) and, under ice cooling, a sulfur trioxide pyridine complex (228 mg) was added to raise to room temperature. The reaction mixture solution was diluted with water and extracted with ethyl acetate. The extract was washed sequentially with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The title compound (180 mg) obtained was used in the next reaction without purification.

Example 11

(2S) -4-cyclopentylamino-2-t-butoxycarbonylaminobutanoic acid, 4-methoxybenzyl ester

To a solution of the compound (180 mg), cyclopentylamine (0.10 ml) and acetic acid (0.04 ml) prepared in Reference Example 8, methanol (5 ml), sodium cyanoborohydride (74 mg) was added under ice cooling, followed by ice cooling. Stir under 6.5 hours and at room temperature for 12 hours. The reaction mixture solution was diluted with water, methanol was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the compound (35 mg) of the present invention having the following chemical data.

TLC: Rf 0.17 (methanol: chloroform = 1: 9);

NMR (CD ₃ OD): δ 7.31 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz), 5.17 (1H, d, J = 11.8 Hz), 5.04 (1H, d, J = 11.8 Hz), 4.26-4.14 (1H, m), 3.78 (3H, s), 3.27-3.12 (1H, m), 2.77 (2H, t, J = 6.2 Hz), 2.12-1.49 (10H, m ), 1.42 (9H, s).

Example 12

(2S) -N- (4-methoxybenzyl) -3-cyclohexylsulfonylamino-2-t-butoxycarbonylaminopropanamide

(2S) -N- (4-methoxybenzyl) -3-amino-2-t-butoxycarbonylaminopropanamide (98 mg) in a mixed solvent of pyridine (3 ml) -methylene chloride (5 ml) It dissolved, cyclohexylsulfonyl chloride (166 mg) was added under ice cooling, dimethylaminopyridine (3 mg) was added, and it stirred for 1 hour. The reaction mixture solution was diluted with water and extracted with ethyl acetate. The extract was washed sequentially with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the compound (25 mg) of the present invention having the following chemical data.

TLC: Rf 0.43 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.22-7.14 (2H, m), 7.12-7.00 (1H, m), 6.89-6.81 (2H, m), 5.75 (1H, d, J = 7.2 Hz), 5.34-5.20 ( 1H, m), 4.46-4.21 (3H, m), 3.79 (3H, s), 3.60 (1H, dt, J = 14.0, 4.8 Hz), 3.38 (1H, ddd, J = 14.0, 8.6, 4.2 Hz) , 2.97-2.82 (1 H, m), 2.24-1.08 (19 H, m).

Reference Example 9

(2R) -2-t-butoxycarbonylamino-2- (4-methoxybenzylcarbamoyl) sodium sulphonate

Dicyclohexylcarbodii under ice cooling in a solution of DMF (15 ml) of (2R) -2-t-butoxycarbonylamino-2-carboxyethanesulfonate (893 mg) and p-nitrophenol (470 mg) Mid (823 mg) was added and stirred for 30 minutes. The reaction mixture solution was left at 5 ° C. for 4 days. Acetic acid was added to the reaction mixture solution, and excess dicyclohexylcarbodiimide was treated to perform filtration. The filtrate was concentrated. To the DMF (10 ml) solution of the residue, 4-methoxybenzylamine (0.4 ml) was added under ice cooling, followed by stirring for 2 hours. The reaction mixture solution was concentrated. The residue was diluted with water. After the aqueous layer was washed with ethyl acetate, the solvent in the aqueous layer was distilled off under reduced pressure to obtain a compound of the present invention (610 mg) having the following chemical data.

TLC: Rf 0.33 (methanol: chloroform = 1: 4);

NMR (CD ₃ OD): δ 7.24-7.18 (2H, m), 6.87-6.81 (2H, m), 4.42-4.21 (3H, m), 3.75 (3H, s), 3.22-3.16 (2H, m) , 1.41 (9 H, s).

Example 13

(2R) -N- (4-methoxybenzyl) -3-cyclohexylsulfamoyl-2-t-butoxycarbonylaminopropanamide

Sulfuryl chloride (0.045 ml) was added dropwise to triphenylphosphine (127 mg) methylene chloride (1 ml) solution under ice-cooling, and the mixture was stirred while rising to room temperature. A methylene chloride (2 mL) solution of the compound (100 mg) prepared in Reference Example 9 was added to the reaction mixture solution, and the mixture was stirred at room temperature for 1 hour. A mixture of cyclohexylamine (0.14 ml) and triethylamine (0.17 ml) was added to the reaction mixture solution, and the mixture was stirred for 1 hour. The reaction mixture solution was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed sequentially with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the compound (15 mg) of the present invention having the following chemical data.

TLC: Rf 0.56 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.24-7.15 (2H, m), 6.90-6.81 (3H, m), 5.72 (1H, d, J = 8.4 Hz), 4.75 (1H, d, J = 7.4 Hz), 4.69 -4.60 (1H, m), 4.43 (1H, dd, J = 14.0, 5.4 Hz), 4.33 (1H, dd, J = 14.0, 5.8 Hz), 3.79 (3H, s), 3.60 (1H, dd, J = 15.0, 6.2 Hz), 3.50 (1H, dd, J = 15.0, 4.8 Hz), 3.38-3.19 (1H, m), 2.04-1.08 (19H, m).

Example 13 (1)

(2R) -N- (4-methoxybenzyl) -3- (piperidin-1-ylsulfonyl) -2-t-butoxycarbonylaminopropanamide

The compound of the present invention having the following chemical data was obtained by operating the compound prepared in Reference Example 9 for the same purpose as in Example 13.

TLC: Rf 0.41 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.25-7.17 (2H, m), 6.89-6.82 (3H, m), 5.64 (1H, d, J = 7.4 Hz), 4.61-4.51 (1H, m), 4.45 (1H, dd, J = 15.0, 6.2 Hz), 4.35 (1H, dd, J = 15.0, 5.4 Hz), 3.79 (3H, s), 3.54 (1H, dd, J = 13.2, 5.8 Hz), 3.39 (1H, dd , J = 13.2, 5.4 Hz), 3.26-3.21 (4H, m), 1.75-1.50 (6H, m), 1.44 (9H, s).

Example 14

(2S) -3-cyclohexyloxycarbonyl-2- (N-benzyl-N-t-butoxycarbonylamino) propanoic acid 4-methoxybenzyl ester

To a solution of compound (122 mg) of DMF (3 ml) prepared in Example 2 (4), sodium hydride (60%, 13 mg) was added under ice cooling, followed by stirring at 0 ° C for 30 minutes. Benzyl bromide (37 µl) was added to the reaction mixture and the mixture was stirred at 0 ° C for 3 hours. 1N hydrochloric acid was added to the reaction mixture solution, the mixture was diluted with acid, diluted with water, and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to obtain a compound of the present invention (52 mg) having the following chemical data.

TLC: Rf 0.44 (ethyl acetate: hexane = 1: 4);

NMR (CDCl ₃ ): δ 7.34-7.14 (7H, m), 6.89-6.82 (2H, m), 5.10-4.25 (6H, m), 3.81 (3H, s), 3.25-3.03 (1H, m), 2.72-2.46 (1 H, m), 1.84-1.22 (19 H, m).

Example 15

(2S) -3-cyclohexyloxycarbonyl-2-benzylaminopropanoic acid 4-methoxybenzyl ester

P-toluenesulfonic acid monohydrate (42 mg) was added to an ether (0.5 ml) solution of the compound (115 mg) prepared in Example 14, followed by stirring at room temperature for 19 hours. The reaction mixture solution was washed with ether. The obtained crystals were dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a compound of the present invention (89 mg) having the following chemical data.

TLC: Rf 0.63 (ethyl acetate: hexane = 1: 2);

NMR (CDCl ₃ ): δ 7.34-7.22 (7H, m), 6.93-6.85 (2H, m), 5.11 (2H, s), 4.80-4.66 (1H, m), 3.85 (1H, d, J = 12.8 Hz), 3.81 (3H, s), 3.69 (1H, d, J = 12.8 Hz), 3.68 (1H, dd, J = 6.8, 6.2 Hz), 2.73 (1H, dd, J = 15.8, 6.2 Hz), 2.63 (1H, doublet of doublets, J = 15.8, 6.8 Hz), 1.95 (1H, br.s), 1.84-1.19 (10H, m).

Example 16

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

The ethyl acetate (10 ml) solution of the compound (107 mg) prepared in Example 9 (13) was washed sequentially with saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. , Compound of the present invention (96 mg) having the following chemical data was obtained.

TLC: Rf 0.39 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 7.88 (d, J = 7.5H 41H), 7.37-7.30 (m, 2H), 7.25-7.21 (m, 2H), 7.14-7.08 (m, 1H), 7.02-6.94 (m , 4H), 6.84-6.80 (m, 1H), 4.49-4.36 (m, 3H), 4.26 (d, J = 9.9 Hz, 1H), 4.19-4.15 (m, 1H), 4.05 (d, J = 9.9 Hz, 1H), 3.42 (dd, J = 11.1, 4.2 Hz, 1H), 3.10 (dd, J = 11.1, 7.5 Hz, 1H), 2.93 (dd, J = 13.8, 6.3 Hz, 2H), 2.83 (dd , J = 13.8, 7.2 Hz, m), 2.45 (d, J = 6.6 Hz, 2H), 1.86-1.58 (m, 5H), 1.51-1.36 (m, 1H), 1.29-1.05 (3H, m), 0.98-0.85 (m, 2 H).

Example 16 (1)

(2R) -N- (1-phenylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

By operating the compound prepared in Example 9 (16) for the same purpose as in Example 16, the compound of the present invention having the following chemical data was obtained.

TLC: Rf 0.26 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.86 (d, J = 7.5 Hz, 1H), 7.29-7.23 (m, 2H), 6.95-6.91 (m, 2H), 6.88-6.83 (m, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.37 (dd, J = 14.1, 7.5 Hz, 1H), 4.27 (d, J = 9.9 Hz, 1H), 4.18 (dd, J = 7.8, 4.2 Hz, 1H), 4.05 ( d, J = 9.9 Hz, 1H), 4.00-3.88 (m, 1H), 3.63-3.51 (m, 2H), 3.43 (dd, J = 11.1, 4.2 Hz, 1H), 3.12 (dd, J = 11.1, 7.8 Hz, 1H), 2.95-2.86 (m, 3H), 2.79 (dd, J = 13.8, 7.5 Hz, 1H), 2.48 (d, J = 6.9 Hz, 2H), 2.08-1.98 (m, 2H), 1.84-1.39 (m, 8H), 1.31-1.06 (m, 3H), 1.00-0.87 (m, 2H).

Examples 17-17 (16)

Example 6 (36), Example 6 (44), Example 6 (49), Example 6 (60), Example 6 (61), Example 6 (69), Example 6 (74) to Example The compound of the present invention was obtained by operating the compound prepared in Example 6 (83) and Example 6 (86) for the same purpose as in Example 9-Example 16.

Example 17

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.45 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD): δ 7.27-7.17 (2H, m), 6.92-6.82 (2H, m), 5.01 and 4.98 (1H, s), 4.49 and 4.48 (1H, t, J = 7 Hz), 4.34 ( 1H, d, J = 15 Hz), 4.28 (1H, d, J = 15 Hz), 3.77 (3H, s), 3.48-3.02 (2H, m), 3.00-2.71 (4H, m), 2.41 and 2.39 (2H , d, J = 7 Hz), 1.90-0.78 (11H, m).

Example 17 (1)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.59 (methylene chloride: methanol = 9: 1);

NMR (CDCl ₃ ): δ 7.87 (1H, d, J = 8 Hz), 7.25-7.18 (2H, m), 6.90-6.83 (2H, m), 6.78-6.70 (1H, m), 4.48-4.31 (3H , m), 4.30-4.21 (1H, m), 4.20-4.12 (1H, m), 4.10-4.00 (1H, m), 3.80 (3H, s), 3.41 (1H, dd, J = 11, 4 Hz) , 3.10 (1H, dd, J = 11, 8 Hz), 2.92 (1H, dd, J = 14, 6 Hz), 2.83 (1H, dd, J = 14, 7 Hz), 2.50-2.38 (1H, b), 2.44 (2H, d, J = 7 Hz), 1.85-1.55 (5H, m), 1.50-1.35 (1H, m), 1.31-1.03 (3H, m), 0.98-0.84 (2H, m).

Example 17 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-aminothiazol-4-ylcarbonylamino) propanamide

TLC: Rf 0.30 (methylene chloride: methanol = 19: 1);

(3 drops of CDCl ₃ + CD ₃ OD): δ 7.33 (1H, s), 7.27-7.17 (2H, m), 6.90-6.80 (2H, m), 4.44 (1H, d, J = 6 Hz), 4.41 ( 1H, d, J = 15 Hz, 4.35 (1H, d, J = 15 Hz), 3.80 (3H, s), 3.08-2.84 (2H, m), 2.44 (2H, d, J = 7 Hz), 1.87-0.78 (11 H, m).

Example 17 (3)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[a] _D = -71.7 (c 0.21, CHCL ₃ );

TLC: Rf 0.27 (hexane: ethyl acetate = 1: 2);

NMR (CDCl ₃ ): δ 7.65 (1H, d, J = 7.4 Hz), 7.21 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.80-6.73 (1H, br ), 4.99 (1H, s), 4.50-4.38 (3H, m), 3.80 (3H, s), 3.51-3.40 (1H, m), 3.15-2.94 (3H, m), 2.88-2.75 (2H, m) ), 2.44 (2H, d, J = 7.0 Hz), 1.83-1.30 (6H, m), 1.28-0.78 (5H, m).

Example 17 (4)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[a] _D = + 51.5 (c 0.19, CHC1 ₃ );

TLC: Rf 0.16 (hexane: AcOEt = 1: 2);

NMR (CDCl ₃ ): δ 7.69 (1H, d, J = 7.0 Hz), 7.21 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.81-6.69 (1H, br ), 5.01 (1H, s), 4.51-4.37 (3H, m), 3.80 (3H, s), 3.52-3.39 (1H, m), 3.08-2.91 (3H, m), 2.89-2.73 (2H, m) ), 2.53-2.40 (2H, m), 1.83-1.37 (6H, m), 1.34-0.79 (5H, m).

Example 17 (5)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -2- (2-methylpropyl) thiazolidin-4-ylcarbonylamino) propane amides

TLC: Rf 0.41 (methanol: methylene chloride = 1: 19);

NMR (CD ₃ OD): δ 7.25-7.18 (2H, m), 6.89-6.82 (2H, m), 4.61-4.46 (2H, m), 4.39-4.24 (2H, m), 4.39-4.24 (m) And 3.84 (t, J = 8 Hz) (1H), 3.76 (3H, s), 3.39 (dd, J = 10, 3 Hz) and 3.19 (dd, J = 10, 8 Hz) (1H), 3.09 (dd, J = 10, 8 Hz) and 2.99-2.90 (m) (1H), 2.90-2.76 (2H, m), 2.38 and 2.41 (2H, d, J = 6 Hz), 1.90-1.55 (8H, m), 1.49-1.33 (1H, m), 1.33-1.06 (3H, m), 1.06-0.83 (8H, m).

Example 17 (6)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -2-phenylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.43 (methanol: methylene chloride = 1: 19);

NMR (5 drops of CDCl ₃ + CD ₃ OD): δ 7.57-7.48 (m, 2H), 7.45-7.33 (m, 3H), 7.25-7.18 (m, 2H), 6.90-6.83 (m, 2H), 5.60 And 5.53 (s, 1H), 4.53-4.29 and 3.99-3.90 (m, 4H), 3.79 (s, 3H), 3.43-3.35 (m) and 3.64 (dd, J = 11, 3 Hz) (1H), 3.19 And 3.39 (dd, J = 11, 8 Hz, 1H), 2.73 and 2.92 (d, J = 7 Hz, 2H), 2.40 and 2.43 (d, J = 7 Hz, 2H), 1.85-1.58 (m, 5H), 1.51 -1.34 (m, 1 H), 1.31-1.03 (m, 3H), 1.00-0.80 (m, 2H).

Example 17 (7)

(4R) -N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide

TLC: Rf 0.55 (methanol: chloroform = 1: 19);

NMR (CDCl ₃ ): δ 7.85 (d, J = 8.7 Hz, 1H), 7.32-7.26 (m, 2H), 6.94-6.89 (m, 3H), 5.12-5.04 (m, 1H), 4.27 (d, J = 9.9 Hz, 1H), 4.15 (dd, J = 7.5, 4.2 Hz, 1H), 4.07 (d, J = 9.9 Hz, 1H), 3.89-3.74 (m, 4H), 3.44 (dd, J = 10.8 , 4.2 Hz, 1H), 3.32-3.09 (m, 5H), 2.91 (dd, J = 13.5, 3.9 Hz, 1H), 2.76 (dd, J = 13.5, 6.3 Hz, 1H), 2.54-2.34 (m, 3H), 1.86-1.60 (m, 5H), 1.50-1.35 (m, 1H), 1.30-1.04 (m, 3H), 1.02-0.84 (m, 2H).

Example 17 (8)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -thiomorpholin-3-ylcarbonylamino) propanamide

TLC: Rf 0.31 and 0.27 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD): δ 7.26-7.18 (m, 2H), 6.88-6.83 (m, 2H), 4.54-4.46 (m, 1H), 4.38-4.24 (m, 2H), 3.76 (s, 3H) , 3.60-3.52 (m, 1H), 3.36-3.28 (m, 1H), 3.02-2.60 (m, 6H), 2.44-2.32 (m, 3H), 1.86-1.60 (m, 5H), 1.50-1.34 ( m, 1H), 1.34-1.07 (m, 3H), 1.00-0.83 (m, 2H).

Example 17 (9)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -thiomorpholin-3-ylcarbonylamino) propanamide

TLC: Rf 0.14 and 0.16 (methylene chloride: methanol = 19: 1);

NMR (CDCl ₃ ): δ 7.69 and 7.62 (d, J = 8 Hz, 1H), 7.38-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.15-7.08 (m, 1H), 7.03-6.93 (m, 4H), 6.91-6.77 (m, 1H), 4.54-4.35 (m, 4H), 3.60-3.51 (m, 1H), 3.38-3.23 (m, 1H), 3.10-2.90 (m, 2H) , 2.88-2.76 (m, 2H), 2.75-2.37 (m, 5H), 1.86-1.52 (m, 5H), 1.52-1.35 (m, 1H), 1.30-1.04 (m, 3H), 1.00-0.84 ( m, 2H).

Example 17 (10)

(2R) -N- (2-phenoxypyridin-5-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.18 (methanol: chloroform = 1: 9);

NMR (CDCl ₃ ): δ 8.94-8.82 (m, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.05-8.00 (m, 2H), 7.42-7.35 (m, 2H), 7.21-7.16 ( m, 1H), 7.12-7.07 (m, 2H), 6.86 (d, J = 8.7H 1H), 4.64-4.57 (m, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.29-4.26 ( m, 1H), 4.07 (d, J = 9.9 Hz, 1H), 3.48 (dd, J = 10.8, 3.3 Hz, 1H), 3.14 (dd, J = 10.8, 8.1, 1H), 3.00 (dd, J = 13.8, 7.2 Hz, 1H), 2.92 (dd, J = 13.8, 6.9 Hz, 1H), 2.48 (d, J = 6.6 Hz, 2H), 1.88-1.60 (m, 5H), 1.54-1.39 (m, 1H ), 1.32-1.04 (m, 3H), 1.01-0.84 (m, 2H).

Example 17 (11)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiomorpholin-2-ylcarbonylamino) propanamide

TLC: Rf 0.46 and 0.41 (methylene chloride: methanol = 9: 1);

NMR (CDCl ₃ ): δ 8.92 and 8.62 (d, J = 8 Hz, 1H), 7.25-7.17 (m, 2H), 6.90-6.82 (m, 2H), 4.66-4.52 (m, 1H), 4.48-4.29 (m, 2H), 3.79 (s, 3H), 3.61-3.53 (m, 1H), 3.31-2.81 (m, 7H), 2.55-2.40 (m, 2H), 2.36-2.24 (m, 1H), 1.86 -1.58 (m, 5H), 1.53-1.35 (m, 1H), 1.31-1.04 (m, 3H), 1.00-0.83 (m, 2H).

Example 17 (12)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -1,3-perhydrothiazin-4-ylcarbonylamino) propanamide

TLC: Rf 0.22 and 0.19 (methylene chloride: methanol = 49: 1);

NMR (CDCl ₃ ): δ 7.66-7.56 (m, 1H), 7.24-7.16 (m, 2H), 6.90-6.82 (m, 2H), 6.78-6.65 (m, 1H), 4.52-4.41 (m, 1H) ), 4.41-4.30 (m, 2H), 4.17-4.01 (m, 2H), 3.80 (s, 3H), 3.36-3.28 (m, 1H), 2.99-2.73 (m, 4H), 2.49-2.42 (m) , 2H), 2.31-2.20 (m, 1H), 1.85-1.35 (m, 7H), 1.30-1.03 (m, 3H), 1.00-0.83 (m, 2H).

Example 17 (13)

(2R) -N- (2-phenoxypyridin-5-ylmethyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.41 (methanol: chloroform = 1: 9);

NMR (CDCl ₃ ): δ 8.09 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.43-7.37 (m , 2H), 7.20 (tt, J = 7.2, 1.2 Hz, 1H), 7.14-7.09 (m, 2H), 6.94 (t, J = 6.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H) , 4.43 (dd, J = 13.8, 7.2, 1H), 4.40 (d, J = 6.0H 42H), 4.27 (d, J = 9.9 Hz, 1H), 4.18 (dd, J = 7.8, 4.2 Hz, 1H) , 4.04 (d, J = 9.9 Hz, 1H), 3.42 (dd, J = 11.1, 3.9 Hz, 1H), 3.10 (dd, J = 11.1, 7.8 Hz, 1H), 2.92 (dd, J = 13.8, 6.6 Hz, 1H), 2.82 (dd, J = 13.8, 7.2 Hz, 1H), 2.43 (d, J = 9.3 Hz, 2H), 1.86-1.58 (m, 5H), 1.48-1.35 (m, 1H), 1.30 -1.04 (m, 3H), 0.98-0.82 (m, 2H).

Example 17 (14)

(2R) -N- (4- (morpholin-4-yl) benzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.46 (methanol: chloroform = 1: 9);

NMR (CDCl ₃ ): δ 7.86 (d, J = 7.5 Hz, 1H), 7.21-7.16 (m, 2H), 6.89-6.84 (m, 2H), 6.71 (t, J = 5.1 Hz, 1H), 4.44 (dd, J = 13.8, 6.9 Hz, 1H), 4.40 (dd, J = 14.7, 5.7 Hz, 1H), 4.34 (dd, J = 14.7, 5.4 Hz, 1H), 4.26 (d, J = 9.9 Hz, 1H), 4.14 (dd, J = 7.5, 3.9 Hz, 1H), 4.04 (d, J = 9.9 Hz, 1H), 3.87-3.84 (m, 4H), 3.40 (dd, J = 11.1, 4.2 Hz, 1H ), 3.16-3.12 (m, 4H), 3.09 (dd, J = 11.1, 7.8 Hz, 1H), 2.92 (dd, J = 13.8, 6.3 Hz, 1H), 2.82 (dd, J = 13.8, 7.2 Hz, 1H), 2.43 (d, J = 6.9 Hz, 2H), 1.85-1.58 (m, 5H), 1.51-1.35 (m, 1H), 1.30-1.04 (m, 3H), 0.98-0.82 (m, 2H) .

Example 17 (15)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -1,3-perhydrothiazin-4-ylcarbonylamino) propanamide

TLC: Rf 0.39 and 0.30 (methylene chloride: methanol = 19: 1);

NMR (CDCl ₃ ): δ 7.68-7.56 (m, 1H), 7.38-7.29 (m, 2H), 7.29-7.20 (m, 2H), 7.14-7.07 (m, 1H), 7.05-6.90 (m, 4H ), 6.87-6.82 (m, 1H), 4.54-4.34 (m, 3H), 4.18-4.00 (m, 2H), 3.37-3.29 (m, 1H), 3.00-2.74 (m, 4H), 2.50-2.43 (m, 2H), 2.32-2.20 (m, 1H), 1.86-1.35 (m, 8H), 1.31-1.03 (m, 3H), 1.03-0.83 (m, 2H).

Example 17 (16)

(2R) -N- (1-methylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.24 (chloroform: methanol = 9: 1);

NMR (CD ₃ OD): δ 4.46-4.39 (m, 1H), 4.23-4.09 (m, 3H), 3.75-3.64 (m, 1H), 3.23 (dd, J = 10.2, 4.4 Hz, 1H), 3.03 (dd, J = 10.2, 7.2 Hz, 1H), 2.93-2.70 (m, 4H), 2.43 (d, J = 6.6 Hz, 2H), 2.27 (s, 3H), 2.22-2.06 (m, 2H), 1.94-1.10 (m, 13 H), 1.03-0.82 (m, 2 H).

Example 18

(2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropylcarbonyl) thiazolidine- 4-ylcarbonylamino) propanamide

To a methylene chloride (3 ml) solution of the compound (98 mg) and triethylamine (0.06 ml) prepared in Example 9 (6), isovaleryl chloride (0.025 ml) was added under ice cooling, followed by stirring for 1 hour. . The reaction mixture solution was washed sequentially with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the compound (81 mg) of the present invention having the following chemical data.

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 1);

NMR (CDCl ₃ ): δ 8.16 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.45 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.2 Hz), 5.20-5.06 (1H, m), 4.87 (1H, t, J = 5.6 Hz), 4.66-4.56 (3H, m) 3.33 (2H, d, J = 5.6 Hz), 3.23 (1H, dd, J = 13.8, 4.0 Hz), 2.75 (1H, dd, J = 13.8, 5.8 Hz), 2.34 (2H, d, J = 7.0 Hz), 2.24-2.01 (3H, m), 1.72-0.60 (20H , m).

Example 18 (1)-Example 18 (5)

The following compounds of the present invention were obtained by operating the compounds prepared in Example 16, Example 17, and Example 17 (1) for the same purpose as in Example 18.

Example 18 (1)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-acetylthiazolidin-2-ylcarbonylamino) propanamide

TLC: Rf 0.40 (ethyl acetate);

NMR (CDCl ₃ ): δ 7.46 (1H, t, J = 6.2 Hz), 7.27-7.21 (2H, m), 6.89-6.77 (3H, m), 5.49-5.29 (1H, m), 4.62-4.34 ( 3H, m), 4.06-3.94 (1H, m), 3.88-3.72 (4H, m), 3.64-3.00 (3H, m), 2.85-2.74 (1H, m), 2.49-2.27 (2H, m), 2.18-2.03 (3H, m), 1.85-0.74 (11H, m).

Example 18 (2)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.39 (hexane: AcOEt = 1: 1);

NMR (CDCl ₃ ): δ 7.37-6.93 (m, 11H), 4.73-4.32 (m, 6H), 3.67 (s, 3H), 3.32 (dd, J = 12.0, 3.9 Hz, 1H), 3.28 (dd, J = 12.0, 6.9 Hz, 1H), 3.23-3.01 (br, 1H), 2.82 (dd, J = 13.8, 6.6 Hz, 1H), 2.48-2.34 (m, 2H), 1.82-1.52 (m, 5H) , 1.49-1.04 (m, 4H), 0.96-0.81 (m, 2H).

Example 18 (3)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropoxycarbonyl) thiazolidin-4-ylcarbonylamino) Propanamide

TLC: Rf 0.32 (hexane: AcOEt = 2: 1):

NMR (CDCl ₃ ): δ 7.37-6.92 (m, 11H), 4.73-4.29 (m, 6H), 3.84 (d, J = 6.6 Hz, 2H), 3.32 (dd, J = 12.3, 4.5 Hz, 1H) , 3.29 (dd, J = 12.3, 6.6 Hz, 1H), 3.24-3.17 (br, 1H), 2.81 (dd, J = 13.5, 6.6 Hz, 1H), 2.46-2.32 (m, 2H), 1.99-1.54 (m, 6H), 1.49-1.04 (m, 4H), 0.95-0.86 (m, 8H).

Example 18 (4)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide

TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 7.22 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.72-4.24 (m, 6H ), 3.79 (s, 3H), 3.65 (brs, 3H), 3.31 (dd, J = 12.0, 4.2 Hz, 1H), 3.26 (dd, J = 12.0, 6.9 Hz, 1H), 3.18-3.00 (br, 1H), 2.81 (dd, J = 13.8, 6.6 Hz, 1H), 2.46-2.32 (m, 2H), 1.78-1.60 (m, 5H), 1.48-1.04 (m, 4H), 0.94-0.80 (m, 2H).

Example 18 (5)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropoxycarbonyl) thiazolidin-4-ylcarbonylamino) Propanamide

TLC: Rf 0.17 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.21 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.1H, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.72-4.21 (m, 6H ), 3.78 (s, 5H), 3.31 (dd, J = 12.3, 4.2 Hz, 1H), 3.28 (dd, J = 12.3, 6.6 Hz, 1H), 3.25-3.17 (br, 1H), 2.80 (dd, J = 13.8, 6.6 Hz, 1H), 2.45-2.30 (m, 2H), 1.94-1.62 (m, 6H), 1.47-1.04 (m, 4H), 0.98-0.80 (br, 8H).

Example 19- Example 19 (1)

The compound of the present invention was obtained by operating the compound prepared in Example 2 (99) for the same purpose as in Reference Example 4-Example 5-Example 17.

In the preparation of the compound of Example 19, (-)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was used.

In preparing the compound of Example 19 (1), (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was used.

Example 19

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[α] _D = 77.07 (c 0.99, CHCl ₃ );

TLC: Rf 0.46 (ethyl acetate: hexane = 2: 1);

NMR (CDCl ₃ ): δ 7.68 (1H, d, J = 7.2 Hz), 7.19-7.12 (2H, m), 6.73-6.65 (3H, m), 4.98 (1H, s), 4.49-4.39 (1H, m), 4.34 (2H, d, J = 5.4 Hz), 3.51-3.39 (1H, m), 3.15-2.74 (11H, m), 2.44 (2H, d, J = 6.6 Hz), 1.88-0.77 (11H) , m).

Example 19 (1)

(2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide

(We do not determine absolute arrangement of *, but are single optical isomer.)

[α] _D = + 70.27 (c 1.06, CHCl ₃ );

TLC: Rf 0.41 (ethyl acetate: hexane = 2: 1);

NMR (CDCl ₃ ): δ 7.69 (1H, d, J = 7.4 Hz), 7.19-7.12 (2H, m), 6.73-6.65 (2H, m), 6.60 (1H, d, J = 5.2 Hz), 5.00 (1H, s), 4.49-4.39 (1H, m), 4.34 (2H, d, J = 5.4 Hz), 3.49-3.38 (1H, m), 3.09-2.72 (11H, m), 2.51 (1H, dd , J = 12.4, 6.6 Hz), 2.44 (1H, dd, J = 12.4, 7.0 Hz), 1.88-0.77 (11 H, m).

Example 20

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3-t-butoxycarbonylthiazolidin-ylmethyl) amino) propanamide

N-methylmorpholine (0.18 ml), (4R) -3- in a ethanol (2 ml) suspension of compound (611 mg) obtained by operating the compound prepared in Example 2 (80) for the same purpose as in Reference Example 4. t-butoxycarbonyl-4-formylthiazolidine (355 mg) and sodium cyanoborohydride (206 mg) were added and stirred at room temperature for 3.5 hours. The reaction mixture solution was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1 → 1: 1) to obtain a compound of the present invention (637.5 mg) having the following chemical data.

TLC: Rf 0.30 (ethyl acetate: hexane = 1: 2);

NMR (CD ₃ OD): δ 7.27-7.20 (m, 2H), 6.89-6.83 (m, 2H), 4.54 (d, J = 9 Hz, 1H), 4.37 (d, J = 14 Hz, 1H), 4.33- 4.21 (m, 2H), 4.17 (d, J = 9 Hz, 1H), 3.77 (3H, s), 3.25 (dd, J = 8, 5 Hz), 3.14-3.05 (m, 1H), 2.98-2.80 (m , 2H), 2.77-2.60 (m, 3H), 2.41 (dd, J = 12, 8 Hz, 1H), 2.40 (dd, J = 12,8 Hz, 1H), 1.88-1.60 (m, 5H), 1.55- 1.35 (m, 10 H), 1.35-1.07 (m, 3 H), 1.03-0.85 (2 H, m).

Example 20 (1)-Example 20 (7)

A compound obtained by manipulating the compound prepared in Example 2 (103) for the same purpose as Reference Example 4, or a compound obtained by manipulating the compound prepared in Example 2 (80) as in Reference Example 4 was the same as Example 20 By the operation for the purpose, the following compounds of the present invention were obtained.

Example 20 (1)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3-t-butoxycarbonylthiazolidin-4-ylmethyl) amino) propanamide

TLC: Rf 0.60 (methylene chloride: ethyl acetate = 9: 1);

NMR (CD ₃ OD): δ 7.39-7.28 (m, 4H), 7.14-7.04 (m, 1H), 6.99-6.88 (m, 4H), 4.54 (d, J = 9.0 Hz, 1H), 4.43 (d , J = 14.7 Hz, 1H), 4.37-4.21 (m, 1H), 4.33 (d, J = 14.7 Hz, 1H), 4.15 (d, J = 9.0 Hz, 1H), 3.26 (dd, J = 7.6, 5.4 Hz, 1H), 3.16-2.60 (m, 6H), 2.41 (d, J = 6.6 Hz, 2H), 1.45 (s, 9H), 1.90-0.80 (m, 11H).

Example 20 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl) amino) propanamide

TLC: Rf 0.19 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.64 (t, J = 5.4 Hz, 1H), 7.22-7.18 (m, 3H), 6.95-6.84 (m, 4H), 4.39 (dd, J = 14.4, 6.0 Hz, 1H) , 4.37 (dd, J = 14.4, 6.0 Hz, 1H), 3.93 (s, 2H), 3.80 (s, 3H), 3.30 (dd, J = 9.3, 3.9 Hz, 1H), 3.03 (dd, J = 13.8 , 3.9 Hz, 1H), 2.63 (dd, J = 13.8, 9.3 Hz, 1H), 2.31. (Dd, J = 12.3, 6.9 Hz, 1H), 2.25 (dd, J = 12.3, 6.9 Hz, 1H), 1.83-1.32 (m, 6H), 1.28-1.04 (m, 3H), 0.95-0.80 (m, 2H).

Example 20 (3)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((cyclohexylmethyl) amino) propanamide

TLC: Rf 0.24 (hexane: AcOEt = 4: 1);

NMR (CDCl ₃ ): δ 7.67 (t, J = 5.5 Hz, 1H), 7.23-7.16 (m, 2H), 6.90-6.83 (m, 2H), 4.40 (dd, J = 14.4, 6.2 Hz, 1H) , 4.35 (dd, J = 14.6, 5.8 Hz, 1H), 3.80 (s, 3H), 3.17-3.02 (m, 2H), 2.60-2.24 (m, 5H), 1.87-0.70 (m, 22H).

Example 20 (4)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4RS) -3-t-butoxycarbonyl-1,3-perhydrothiazin-4-yl Methyl) amino) propanamide

TLC: Rf 0.17 (ethyl acetate: hexane = 1: 2);

NMR (CD ₃ OD): δ 7.29-7.20 (m, 2H), 6.91-6.81 (m, 2H), 4.71-4.50 (m, 1H), 4.41-4.22 (m, 4H), 3.77 (s, 3H) , 3.28-3.19 (m, 1H), 3.03-2.75 (m, 3H), 2.71-2.35 (m, 5H), 2.00-1.60 (m, 7H), 1.52-1.34 (m, 10H), 1.33-1.10 ( m, 3H), 1.02-0.84 (m, 2H).

Example 20 (5)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl) amino) propanamide

TLC: Rf 0.41 (hexane: ethyl acetate = 2: 1);

NMR (CD ₃ OD): δ 7.37-7.25 (m, 5H), 7.12-7.05 (m, 1H), 7.00-6.91 (m, 6H), 4.42 (d, J = 14.6 Hz, 1H), 4.34 (d , J = 14.6 Hz, 1H), 3.98 (d, J = 14.1 Hz, 1H), 3.86 (d, J = 14.1 Hz, 1H), 3.33-3.28 (m, 1H), 2.83 (dd, J = 13.4, 6.0 Hz, 1H), 2.68 (dd, J = 13.4, 7.4 Hz, 1H), 2.32 (dd, J = 12.6, 6.9 Hz, 1H), 2.26 (dd, J = 12.6, 6.9 Hz, 1H), 1.84- 1.59 (m, 5H), 1.47-1.06 (m, 4H), 0.99-0.80 (m, 2H).

Example 20 (6)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((cyclohexylmethyl) amino) propanamide

TLC: Rf 0.52 (hexane: ethyl acetate = 2: 1);

NMR (CD ₃ OD): δ 7.38-7.27 (m, 4H), 7.13-7.04 (m, 1H), 6.98-6.89 (m, 4H), 4.45 (d, J = 14.6 Hz, 1H), 4.30 (d , J = 14.6 Hz, 1H), 3.17 (dd, J = 7.4, 6.2 Hz, 1H), 2.83 (dd, J = 13.2, 6.2 Hz, 1H), 2.65 (dd, J = 13.2, 7.4 Hz, 1H) , 2.42-2.23 (m, 4H), 1.90-0.70 (m, 22H).

Example 20 (7)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3- (3-methylbutyryl) thiazolidin-4-ylmethyl) amino) propane amides

TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1);

NMR (DMSO-d ₆ ): δ 8.06-8.00 (br, 1H), 7.20 (d, J = 8.0H 42H), 6.85 (d, J = 8.0 Hz, 2H), 4.76-4.68 (br, 1H), 4.53-4.42 (br, 1H), 4.28-4.18 (m, 3H), 3.74 (s, 3H), 3.24-3.21 (m, 1H), 3.09-2.95 (m, 2H), 2.77-2.60. 4H), 2.45-2.38. (M, 2H), 2.28-2.17 (m, 3H), 2.09-2.00 (m, 1H), 1.79-1.73 (m, 2H), 1.69-1.58 (m, 3H), 1.46 -1.38 (m, 1H), 1.26-1.10 (m, 3H), 0.99-0.91 (m, 8H).

Example 21- Example 2 (2)

The following compounds of the present invention were obtained by operating the compounds prepared in Examples 20 to 20 (1) and 20 (4) for the same purpose as in Example 17.

Example 21

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -thiazolidin-4-ylmethyl) amino) propanamide

TLC: Rf 0.34 (methylene chloride: methanol = 19: 1);

NMR (CDCl ₃ ): δ 7.76-7.66 (m, 1H), 7.23-7.16 (m, 2H), 6.89-6.83 (m, 2H), 4.37 (d, J = 6 Hz, 2H), 4.16 (d, J = 10 Hz, 1H), 4.10 (d, J = 10 Hz, 1H), 3.80 (3H, s), 3.39 (5 wires, J = 7Hz, 1H), 3.19 (dd, J = 10, 3Hz, 1H), 3.08 (dd, J = 14,3 Hz, 1H), 2.96 (dd, J = 10, 7 Hz, 1H), 2.68 (d, J = 7 Hz, 2H), 2.61 (dd, J = 14, 10 Hz, 1H), 2.47 (dd, J = 10, 7 Hz, 1H), 2.42 (dd, J = 13, 7 Hz, 1H), 2.39 (dd, J = 13,7 Hz, 1H), 2.00-1.58 (m, 7H), 1.53-1.36 (m, 1 H), 1.32-1.05 (m, 3 H), 1.02-0.83 (2 H, m).

Example 21 (1)

(2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -thiazolidin-4-ylmethyl) amino) propanamide

TLC: Rf 0.47 (chloroform: methanol = 19: 1);

NMR (CD ₃ OD): δ 7.40-7.29 (m, 4H), 7.15-7.04 (m, 1H), 7.00-6.90 (m, 4H), 4.43 (d, J = 14.6 Hz, 1H), 4.34 (d , J = 14.6 Hz, 1H), 4.13 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 9.2 Hz, 1H), 3.78-3.54 (m, 1H), 3.33-3.23 (m, 1H) 2.99-2.60 (m, 6H), 2.52 (dd, J = 9.8, 7.0 Hz, 1H), 2.41 (d, J = 6.6 Hz, 2H), 1.90-0.80 (m, 11H).

Example 21 (2)

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4RS) -1,3-perhydrothiazin-4-ylmethyl) amino) propanamide

TLC: Rf 0.37 (methylene chloride: methanol = 9: 1);

NMR (CD ₃ OD)): δ 7.28-7.21 (m, 2H), 6.90-6.83 (m, 2H), 4.42-4.25 (m, 2H), 4.08-3.97 (m, 1H), 3.95-3.86 (m , 1H), 3.77 (s, 3H), 3.23-3.13 (m, 1H), 3.01-2.76 (m, 2H), 2.76-2.56 (m, 3H), 2.56-2.32 (m, 4H), 1.87-1.60 (m, 6H), 1.50-1.08 (m, 5H), 1.03-0.84 (m, 2H).

Example 22

(2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-((4R)- 3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide

By operating the compound prepared in Example 10 (10) for the same purpose as in Example 6, the compound of the present invention having the following chemical data was obtained.

TLC: Rf 0.50 (ethyl acetate: hexane = 1: 1);

NMR (CD ₃ OD): δ 7.27-7.15 (2H, m), 6.90-6.79 (2H, m), 4.67-4.43 (4H, m), 4.33 (1H, d, J = 15 Hz), 4.31 (1H, d, J = 15 Hz), 3.76 (3H, s), 3.43-3.25 (1H, m), 3.14 (1H, dd, J = 12, 4 Hz), 3.02-2.70 (2H, m), 2.57 (1H, dd , J = 12, 8 Hz), 2.55 (1H, dd, J = 12, 8 Hz), 2.22-2.10 (2H, m), 2.10-1.69 (2H, m), 1.61-1.03 (6H, m), 1.45 ( 9H, s), 0.68 (1H, ddd, J = 12, 5, 2 Hz).

Example 23

(2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-((4R) thia Zolidin-4-ylcarbonylamino) propanamide hydrochloride

By operating the compound prepared in Example 22 for the same purpose as in Example 9, the compound of the present invention having the following chemical data was obtained.

TLC: Rf 0.51 (methylene chloride: methanol = 19: 1);

NMR (CD ₃ OD)): δ 7.30-7.18 (2H, m), 6.93-6.83 (2H, m), 4.60-4.46 (2H, m), 4.39 (2H, s), 4.36-4.24 (2H, m ), 3.78 (3H, s), 3.50 (1H, dd, J = 12, 7 Hz), 3.24 (1H, dd, J = 12, 7 Hz), 2.94 (1H, dd, J = 13, 6 Hz), 2.82 ( 1H, dd, J = 13, 8 Hz), 2.59 (1H, dd, J = 12, 8 Hz), 2.57 (1H, dd, J = 12, 8 Hz), 2.22-2.11 (2H, m), 2.10-1.89 ( 1H, m), 1.89-1.70 (1H, m), 1.62-1.03 (6H, m), 0.68 (1H, ddd, J = 12, 5, 2 Hz).

[Example]

Formulation Example 1

Each of the following components was mixed by a conventional method and then compressed into tablets to obtain 100 tablets containing 50 mg of the active ingredient in one tablet.

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide 5.0 g

Carboxymethyl cellulose calcium (disintegrant) 0.2 g

Magnesium stearate (lubricant) 0.1 g

Microcrystalline cellulose 4.7 g

Formulation Example 2

After mixing each of the following components by a conventional method, the solution was sterilized by a conventional method, filled in 5 ml of ampoules and lyophilized by a conventional method, and containing 20 mg of active ingredient in 1 ampoule. 100 ampoules were obtained.

(2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide 2.00 g

20 g of mannitol ················· 20 g

500 g of distilled water

Claims (12)

Cerebral infarction, transient cerebral ischemic attack, cerebral spinal cord injury after cardiac surgery, spinal cord vascular disorder, stress hypertension And / or treatment for neurological disorders, epilepsy: Formula I [In the meal, R ¹ is 1) a C _1-15 alkyl group, 2) a C _1-8 alkoxy group, 3) phenyl group, 4) a C _3-8 cycloalkyl group, 5) heterocyclic group, 6) a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, 7) a C _1-4 alkoxy group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, or 8) A phenyl group, a C _3-8 cycloalkyl group, or a C _2-4 alkenyl group substituted with a heterocyclic group, provided that all of the phenyl groups, C _3-8 cycloalkyl groups and heterocyclic groups in the R ¹ group are represented by the following (i) May be substituted with 1 to 3 groups selected from-(xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ⁵ group (wherein R ⁵ represents a hydrogen atom or a C _1-4 alkyl group) (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ⁶ R ⁷ groups (wherein R ⁶ and R ⁷ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ⁶ and R ⁷ are a bond; It may be one with a nitrogen atom, and may represent a 5-7 membered saturated hetero ring containing another nitrogen atom or one oxygen atom.), A represents a single bond, a -CO- group or a -SO ₂ -group, R ² represents a hydrogen atom or a C _1-4 alkyl group which may be substituted with one phenyl group, D represents a C _1-4 alkylene group or a C _2-4 alkenylene group, E is 1) -COO-group, 2) -OCO-group, 3) -CONR ⁸ -group (wherein R ⁸ represents a hydrogen atom or a C _1-4 alkyl group), 4) -NR ⁹ CO-group (wherein R ⁹ represents a hydrogen atom or a C _1-4 alkyl group), 5) -O-group, 6) -S-group, 7) -SO- group, 8) -SO ₂ -group, 9) -NR ¹⁰ -group (wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group), 10) -CO-group, 11) -SO ₂ NR ¹¹ -group (wherein R ¹¹ represents a hydrogen atom or a C _1-4 alkyl group), or 12) represents an -NR ¹² SO ₂ -group (wherein R ¹² represents a hydrogen atom or a C _1-4 alkyl group), R ³ is 1) carbon ring, 2) heterocyclic group, or 3) a C _1-4 alkyl group substituted with a carbon ring group or a hetero ring group, provided that all carbon ring groups and heterocyclic groups in the R ³ group are 1 to 3 selected from the following (i) to (xi) May be substituted with a group: (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ¹³ groups (wherein R ¹³ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ¹⁴ R ¹⁵ groups (wherein, R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ¹⁴ and R ¹⁵ are bonded It may be one with a nitrogen atom, and may represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.), J represents an -O- group or -NR ¹⁶ -group (wherein R ¹⁶ represents a hydrogen atom or a C _1-4 alkyl group), R ⁴ is 1) a C _1-8 alkyl group, 2) carbon ring, 3) heterocyclic group, 4) a C _1-8 alkyl group substituted with one to three groups selected from the following (i) to (v); (i) a carbon ring, (ii) heterocyclic groups, (iii) a COOR ¹⁷ group (wherein R ¹⁷ is a C _1-4 alkyl group substituted with a hydrogen atom or one phenyl group (wherein phenyl may be substituted with a C _1-4 alkoxy group), (iv) SR ¹⁸ group (wherein R ¹⁸ represents a hydrogen atom or a C _1-4 alkyl group), (v) represents an OR ¹⁹ group (wherein, R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group), In addition, when J represents -NR <^16> -, R <^4> and R <^16> may become one with the nitrogen atom to which it is couple | bonded, and may represent a heterocyclic group (However, all the carbon ring and heterocyclic group in R <^4> group, and The heterocyclic group represented by one of the nitrogen atoms to which R ⁴ and R ¹⁶ are bonded may be substituted with one to three groups selected from the following (i) to (xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ²⁰ group (wherein R ²⁰ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ²¹ R ²² groups (wherein R ²¹ and R ²² each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ²¹ and R ²² are bonded) It may be one with a nitrogen atom, and may represent a 5 to 7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.)). delete A therapeutic agent for pain, which is an N-type calcium channel inhibitor containing an amino acid derivative represented by the formula (I), a nontoxic salt thereof, or a hydrate thereof as an active ingredient: Formula I [In the meal, R ¹ is 1) a C _1-15 alkyl group, 2) a C _1-8 alkoxy group, 3) phenyl group, 4) a C _3-8 cycloalkyl group, 5) heterocyclic group, 6) a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, 7) a C _1-4 alkoxy group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, or 8) A phenyl group, a C _3-8 cycloalkyl group, or a C _2-4 alkenyl group substituted with a heterocyclic group, provided that all of the phenyl groups, C _3-8 cycloalkyl groups and heterocyclic groups in the R ¹ group are represented by the following (i) May be substituted with 1 to 3 groups selected from-(xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ⁵ group (wherein R ⁵ represents a hydrogen atom or a C _1-4 alkyl group) (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ⁶ R ⁷ groups (wherein R ⁶ and R ⁷ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ⁶ and R ⁷ are a bond; It may be one with a nitrogen atom, and may represent a 5-7 membered saturated hetero ring containing another nitrogen atom or one oxygen atom.), A represents a single bond, a -CO- group or a -SO ₂ -group, R ² represents a hydrogen atom or a C _1-4 alkyl group which may be substituted with one phenyl group, D represents a C _1-4 alkylene group or a C _2-4 alkenylene group, E is 1) -COO-group, 2) -OCO-group, 3) -CONR ⁸ -group (wherein R ⁸ represents a hydrogen atom or a C _1-4 alkyl group), 4) -NR ⁹ CO-group (wherein R ⁹ represents a hydrogen atom or a C _1-4 alkyl group), 5) -O-group, 6) -S-group, 7) -SO- group, 8) -SO ₂ -group, 9) -NR ¹⁰ -group (wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group), 10) -CO-group, 11) -SO ₂ NR ¹¹ -group (wherein R ¹¹ represents a hydrogen atom or a C _1-4 alkyl group), or 12) represents an -NR ¹² SO ₂ -group (wherein R ¹² represents a hydrogen atom or a C _1-4 alkyl group), R ³ is 1) carbon ring, 2) heterocyclic group, or 3) a C _1-4 alkyl group substituted with a carbon ring group or a hetero ring group, provided that all carbon ring groups and heterocyclic groups in the R ³ group are 1 to 3 selected from the following (i) to (xi) May be substituted with a group: (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ¹³ groups (wherein R ¹³ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ¹⁴ R ¹⁵ groups (wherein, R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ¹⁴ and R ¹⁵ are bonded It may be one with a nitrogen atom, and may represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.), J represents an -O- group or -NR ¹⁶ -group (wherein R ¹⁶ represents a hydrogen atom or a C _1-4 alkyl group), R ⁴ is 1) a C _1-8 alkyl group, 2) carbon ring, 3) heterocyclic group, 4) a C _1-8 alkyl group substituted with one to three groups selected from the following (i) to (v); (i) a carbon ring, (ii) heterocyclic groups, (iii) a COOR ¹⁷ group (wherein R ¹⁷ is a C _1-4 alkyl group substituted with a hydrogen atom or one phenyl group (wherein phenyl may be substituted with a C _1-4 alkoxy group), (iv) SR ¹⁸ group (wherein R ¹⁸ represents a hydrogen atom or a C _1-4 alkyl group), (v) represents an OR ¹⁹ group (wherein, R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group), In addition, when J represents -NR <^16> -, R <^4> and R <^16> may become one with the nitrogen atom to which it is couple | bonded, and may represent a heterocyclic group (However, all the carbon ring and heterocyclic group in R <^4> group, and The heterocyclic group represented by one of the nitrogen atoms to which R ⁴ and R ¹⁶ are bonded may be substituted with one to three groups selected from the following (i) to (xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ²⁰ group (wherein R ²⁰ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ²¹ R ²² groups (wherein R ²¹ and R ²² each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ²¹ and R ²² are bonded) It may be one with a nitrogen atom, and may represent a 5 to 7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.)). Amino acid derivatives represented by the general formula (I), their nontoxic salts, or their hydrates: Formula I [In the meal, R ¹ is 1) a C _1-15 alkyl group, 2) a C _1-8 alkoxy group, 3) phenyl group, 4) a C _3-8 cycloalkyl group, 5) heterocyclic group, 6) a C _1-4 alkyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, 7) a C _1-4 alkoxy group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, or 8) a C _2-4 alkenyl group substituted with a phenyl group, a C _3-8 cycloalkyl group, or a heterocyclic group, provided that all of the phenyl groups, C _3-8 cycloalkyl groups, and heterocyclic groups in the R ¹ group are represented by the following (i) May be substituted with 1 to 3 groups selected from-(xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ⁵ group (wherein R ⁵ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ⁶ R ⁷ groups (wherein R ⁶ and R ⁷ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ⁶ and R ⁷ are a bond; It may be one with a nitrogen atom, and may represent a 5-7 membered saturated heterocyclic ring containing another nitrogen atom or one oxygen atom.), A represents a single bond, a -CO- group or a -SO ₂ -group, R ² represents a hydrogen atom or a C _1-4 alkyl group which may be substituted with one phenyl group, D represents a C _1-4 alkylene group or a C _2-4 alkenylene group, E is 1) -COO-group, 2) -OCO-group, 3) -CONR ⁸ -group (wherein R ⁸ represents a hydrogen atom or a C _1-4 alkyl group), 4) -NR ⁹ CO-group (wherein R ⁹ represents a hydrogen atom or a C _1-4 alkyl group), 5) -O-group, 6) -S-group, 7) -SO- group, 8) -SO ₂ -group, 9) -NR ¹⁰ -group (wherein R ¹⁰ represents a hydrogen atom or a C _1-4 alkyl group), 10) -C0- group, 11) -SO ₂ NR ¹¹ -group (wherein R ¹¹ represents a hydrogen atom or a C _1-4 alkyl group), or 12) represents an -NR ¹² SO ₂ -group (wherein R ¹² represents a hydrogen atom or a C _1-4 alkyl group), R ³ is 1) carbon ring, 2) heterocyclic group, or 3) a C _1-4 alkyl group substituted with a carbon ring group or a hetero ring group, provided that all carbon ring groups and heterocyclic groups in the R ³ group are 1 to 3 selected from the following (i) to (xi) May be substituted with a group: (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ¹³ groups (wherein R ¹³ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ¹⁴ R ¹⁵ groups (wherein, R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ¹⁴ and R ¹⁵ are bonded It may be one with a nitrogen atom, and may represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom.), J represents an -O- group or -NR ¹⁶ -group (wherein R ¹⁶ represents a hydrogen atom or a C _1-4 alkyl group), R ⁴ is 1) a C _1-8 alkyl group, 2) carbon ring, 3) heterocyclic group, 4) a C _1-8 alkyl group substituted with one to three groups selected from the following (i) to (v); (i) a carbon ring, (ii) heterocyclic groups, (iii) a COOR ¹⁷ group (wherein R ¹⁷ is a C _1-4 alkyl group substituted with a hydrogen atom or one phenyl group (wherein phenyl may be substituted with a C _1-4 alkoxy group), (iv) SR ¹⁸ group (wherein R ¹⁸ represents a hydrogen atom or a C _1-4 alkyl group), (v) represents an OR ¹⁹ group (wherein, R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group), In addition, when J represents -NR <^16> -group, R <^4> and R <^16> may become one with the nitrogen atom to which it couple | bonds, and may represent heterocyclic group (However, all the carbon ring and heterocyclic group in R <^4> , And the heterocyclic group represented by one of the nitrogen atoms to which R ⁴ and R ¹⁶ are bonded may be substituted with one to three groups selected from the following (i) to (xi): (i) a C _1-4 alkyl group, (ii) a C _1-4 alkoxy group, (iii) a phenyl group, (iv) phenoxy, (v) benzyloxy groups, (vi) -SR ²⁰ group (wherein R ²⁰ represents a hydrogen atom or a C _1-4 alkyl group), (vii) a C _2-5 acyl group, (viii) halogen atoms, (ix) a C _1-4 alkoxycarbonyl group, (x) nitro groups, (xi) —NR ²¹ R ²² groups (wherein R ²¹ and R ²² each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxycarbonyl group, or R ²¹ and R ²² are bonded) In combination with one nitrogen atom, and may represent a 5-7 membered saturated carbon ring containing another nitrogen atom or one oxygen atom), However, the compound of following (1)-(37) is excluded. (1) N- (2-amino-5-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (2) N-phenyl-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (3) N- (2-aminophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (4) N- (4-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (5) N- (adamantan-2-yl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (6) N- (pyridin-4-yl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (7) N- (2-aminophenyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide, (8) N- (4-nitrophenyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide, (9) N- (3-bromo-4, 5-dihydroisooxazol-5-ylmethyl) -3-benzyloxy-2-t-butoxycarbonylaminobutanamide, (10) N-methyl-N- (2, 6-dimethoxy-4-methylphenyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (11) N- (4-nitrophenyl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide, (12) N- (quinolin-6-yl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide, (13) N- (2-aminophenyl) -3-benzylthio-2-t-butoxycarbonylaminopropanamide, (14) N- (adamantan-2-yl) -3- (3-ethoxycarbonylpyridin-2-ylthio) -2-t-butoxycarbonylaminopropanamide, (15) N-methyl-N- (2-ethoxyphenyl) -3- (3-methoxycarbonylpyridin-2-yl) -2-t-butoxycarbonylaminopropanamide, (16) N- (4-methoxycarbonylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (17) N- (3-bromo-4, 5-dihydroisoxazol-5-ylmethyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (18) N- (2-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (19) N- (3-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (20) N- (4-methylphenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (21) N-phenyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide, (22) N- (naphthalen-2-yl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (23) N- (naphthalen-1-yl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (24) N-benzyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide, (25) N- (4-chlorophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (26) N- (4-bromophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (27) N- (4-nitrophenyl) -3-benzylthio-2-benzyloxycarbonylaminopropanamide, (28) N- (1, 2, 3, 4-tetrahydronaphthalen-2yl) -3-benzylthio-2- (4-chlorobenzyloxycarbonylamino) propanamide, (29) N-methyl-N- (2-ethoxyphenyl) -3- (3-methoxycarbonylpyridin-2-ylthio) -2- (3,4-dichlorophenylcarbonylamino) propanamide, (30) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-nitrobenzyl ester, (31) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (32) 3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (33) 3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (34) 3- (2-isopropyl-5-methylcyclohexyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester, (35) N- (benzyloxycarbonylmethyl) -3- (2-isopropyl-5-methylcyclohexyloxycarbonyl) -2-t-butoxycarbonylaminopropanamide, (36) 3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid benzyl ester, and (37) N-phenyl-2, 3-bis (benzoylamino) propanamide.] The compound of claim 4, wherein E is an —S— group, —SO— group, or —SO ₂ — group. The compound of claim 4, wherein E is an —O— group. The compound of claim 4, wherein E is a -COO- group. The group of claim 4, wherein E is an -OCO- group, a CONR ⁸ -group, -NR ⁹ CO- group, -NR ¹⁰ -group, -CO- group, -SO ₂ NR ¹¹ -group or NR ¹² SO ₂ -group (In each group, R <^8> , R <^9> , R <^10> , R <^11> and R <^12> have the same meaning as the description of Claim 4. The compound of claim 5, wherein the compound is (1) (2R) -3- (4-methoxybenzylthio) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (2) (2R) -N- (4-methoxybenzyl) -3- (4-methoxybenzylthio) -2-t-butoxycarbonylaminopropanamide, (3) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide, (4) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide, (5) (2R) -N- (4-methoxybenzyl) -3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide, (6) (2S) -N- (4-methoxybenzyl) -3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide, (7) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide, (8) (2R) -N- (furan-2-ylmethyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide, (9) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide, (10) (2R) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanoic acid 4-methoxybenzyl ester, (11) (2R) -N- (4-methoxycyclohexylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (12) (2R) -N- (4-methoxycyclohexylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (13) (2R) -N- (4-phenoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (14) (2R) -N-((1S) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (15) (2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (16) (2R) -N-methyl-N- (4-nitrobenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (17) (2R) -N- (1- (4-methoxyphenyl) -1-methylethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (18) (2R) -N- (1-methyl-1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (19) (2S) -N-((1R) -1- (4-nitrophenyl) ethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (20) (2R) -N-methyl-N- (4-methoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (21) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (N'-methyl-N '-(t-butoxycarbonyl) amino) propanamide, (22) (2R) -N- (4-benzyloxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (23) (2R) -N- (3-benzyloxy-4-methoxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (24) N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester, (25) (2R) -N- (2-phenoxypyridin-5-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (26) (2R) -N- (2-phenoxypyridin-ylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (27) (2R) -N- (4- (morpholin-4-yl) benzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (28) (2R) -N- (1-phenylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (29) (2R) -N- (1-methylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (30) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclopentylcarbonylaminopropanamide, (31) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide, (32) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cyclobutylcarbonylaminopropanamide, (33) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-cycloheptylcarbonylaminopropanamide, (34) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-methoxycyclohexylcarbonylamino) propanamide, (35) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) Propanamide, (36) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-methylpropylcarbonylamino) propanamide, (37) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-methylpropyloxycarbonylamino) propanamide, (38) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (l- (t-butoxycarbonyl) piperidin-4-ylcarbonylamino) propanamide , (39) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4- (t-butoxycarbonylamino) cyclohexylcarbonylamino) propanamide, (40) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (tetrahydrofuran-2-ylcarbonylamino) propanamide, (41) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (42) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2S) -1-t-butoxycarbonylpyridin-2-ylcarbonylamino) propanamide , (43) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (thiazol-4-ylcarbonylamino) propanamide, (44) (2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine -4-ylcarbonylamino) propanamide, (45) (2S) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine -4-ylcarbonylamino) propanamide, (46) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-t-butoxycarbonylaminothiazol-4-ylcarbonylamino) propanamide, (47) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (48) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propane amides, (49) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propane amides, (50) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methylthiazolidin-4-ylcarbonylamino) propanamide, (51) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (52) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) Propanamide, (53) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (1-t-butoxycarbonylimidazol-4-ylcarbonylamino) propanamide, (54) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -2, 2-dimethylthiazolidin-4-ylcarbonylamino) propanamide, (55) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (thiophen-2-ylcarbonylamino) propanamide, (56) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (5-methyloxazol-2-ylcarbonylamino) propanamide, (57) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (58) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (59) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide, (60) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (61) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (62) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (63) (2R) -N-methyl-N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-yl Carbonylamino) propanamide, (64) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -N'-methyl-N '-(3-t-butoxycarbonylthiazoli Din-4-ylcarbonyl) amino) propanamide, (65) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (66) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -3-t-butoxycarbonyl-2- (2-methylpropyl) Thiazolidin-4-ylcarbonylamino) propanamide, (67) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (pyridin-3-ylcarbonylamino) propanamide, (68) (2R) -N- (4-benzyloxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) Propanamide, (69) (2R) -N- (3-benzyloxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4- Ylcarbonylamino) propanamide, (70) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (pyridin-4-ylcarbonylamino) propanamide, (71) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -3-t-butoxycarbonyl-2-phenylthiazolidine-4 -Ylcarbonylamino) propanamide, (72) (4R) -N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonylthiazolidine -4-ylcarboxamide, (73) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino) Propanamide, (74) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino) Propanamide, (75) (2R) -N- (2-phenoxypyridin-5-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidin-4-yl Carbonylamino) propanamide, (76) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -4-t-butoxycarbonylthiomorpholin-2-ylcarbonylamino) Propanamide, (77) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -3-t-butoxycarbonyl-1, 3-perhydrothiazine-4 -Ylcarbonylamino) propanamide, (78) (2R) -N- (2-phenoxypyridin-5-ylmethyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4- Ylcarbonylamino) propanamide, (79) (2R) -N- (4- (morpholin-4-yl) benzyl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4 -Ylcarbonylamino) propanamide, (80) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -3-t-butoxycarbonyl-1, 3-perhydrothiazine-4 -Ylcarbonylamino) propanamide, (81) (2R) -N- (l-phenylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4- Ylcarbonylamino) propanamide, (82) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -2-oxothiazolidin-4-ylcarbonylamino) propanamide, (83) (2R) -N- (1-methylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -3-t-butoxycarbonylthiazolidine-4- Ylcarbonylamino) propanamide, (84) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide, (85) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide, (86) (2R) -N- (4-methoxybenzyl) -3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide, (87) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cyclohexylcarbonylaminopropanamide, (88) (2S) -N- (4-methoxybenzyl) -3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide, (89) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-methoxycyclohexylcarbonylamino) propanamide, (90) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-methoxycyclohexylcarbonylamino) propanamide, (91) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cyclohexylmethylsulfonylaminopropanamide, (92) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (tetrahydrofuran-2-ylcarbonylamino) propanamide, (93) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-cycloheptylcarbonylaminopropanamide, (94) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (tetrahydrofuran-3-ylcarbonylamino) propanamide, (95) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino Propanamide, (96) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino Propanamide, (97) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (98) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino Propanamide, (99) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (1-t-butoxycarbonylpiperidin-4-ylcarbonylamino) propanamide, (100) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2- (4-t-butoxycarbonylaminocyclohexylcarbonylamino) propanamide, (101) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylsulfonyl-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide, (102) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (piperidin-4-ylcarbonylamino) propanamide, (103) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (4-aminocyclohexylcarbonylamino) propanamide, (104) (2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) Propanamide, (105) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4S) -thiazolidin-4-ylcarbonylamino) propanamide, (106) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (107) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide, (108) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethylthio-2- (imidazol-4-ylcarbonylamino) propanamide, (109) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (110) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide, (111) (2R) -N- (4-benzyloxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (112) (2R) -N- (3-benzyloxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (113) (2R) -N- (4-methoxybenzyl) -3- (tetrahydropyran-2-yl) methylthio-2-t-butoxycarbonylaminopropanamide, (114) (2R) -N- (4-methoxybenzyl) -3- (bicyclo [2.2.1] heptan-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide, (115) (2R) -N- (4-methoxybenzyl) -3- (4-methoxycyclohexylmethylthio) -2-t-butoxycarbonylaminopropanamide, (116) (2R) -N- (4-methoxybenzyl) -3- (1-methylpiperidin-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide, (117) (2R) -N- (4-methoxybenzyl) -3- (pyridin-4-ylmethylthio) -2-t-butoxycarbonylaminopropanamide, (118) (2R) -N- (4-methoxybenzyl) -3- (quinolin-2-ylmethylthio) -2-t-butoxycarbonylaminopropanamide, (119) (2R) -N- (4-methoxybenzyl) -3- (imidazol-4-ylmethylthio) -2-t-butoxycarbonylaminopropanamide, (120) (2R) -N- (4-methoxybenzyl) -3-((1R, 4R, 5R) -bicyclo [2.1.1] hepta-2-en-5-ylmethylthio)- 2-t-butoxycarbonylaminopropanamide, (121) (2R) -N- (4-methoxybenzyl) -3-((1S, 4S, 5S) -bicyclo [2.1.1] hepta-2-en-5-ylmethylthio)- 2-t-butoxycarbonylaminopropanamide, (122) (2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-t- Butoxycarbonylaminopropanamide, (123) (2R) -N- (4-methoxybenzyl) -3-((1R, 2S, 4S) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-t- Butoxycarbonylaminopropanamide, (124) (2R) -N- (4-methoxybenzyl) -3- (piperidin-1-ylsulfonyl) -2-t-butoxycarbonylaminopropanamide, (125) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (126) (2R) -N- (1-phenylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (127) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiazolidin-2-ylcarbonylamino) propanamide, (128) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (129) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (2-aminothiazol-4-ylcarbonylamino) propanamide, (130) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide, (131) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -2- (2-methylpropyl) thiazolidin-4-ylcarbonyl Amino) propanamide, (132) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS, 4R) -2-phenylthiazolidin-4-ylcarbonylamino) propanamide, (133) (4R) -N-((1R) -2-cyclohexylmethylthio-1- (4-phenylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (134) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -thiomorpholin-3-ylcarbonylamino) propanamide, (135) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((3RS) -thiomorpholin-3-ylcarbonylamino) propanamide, (136) (2R) -N- (2-phenoxypyridin-5-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (137) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -thiomorpholin-2-ylcarbonylamino) propanamide, (138) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -1,3-perhydrothiazin-4-ylcarbonylamino) propanamide, (139) (2R) -N- (2-phenoxypyridin-5-ylmethyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (140) (2R) -N- (4- (morpholin-4-yl) benzyl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide , (141) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4RS) -1,3-perhydrothiazin-4-ylcarbonylamino) propanamide, (142) (2R) -N- (l-methylpiperidin-4-yl) -3-cyclohexylmethylthio-2-((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (143) (2R) -N-((1R) -1- (4-nitrophenyl) ethyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropylcarbonyl) thia Zolidin-4-ylcarbonylamino) propanamide, (144) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((2RS) -3-acetylthiazolidin-2-ylcarbonylamino) propanamide, (145) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide , (146) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropoxycarbonyl) thiazolidin-4-ylcar Carbonylamino) propanamide, (147) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide , (148) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((4R) -3- (2-methylpropoxycarbonyl) thiazolidin-4-ylcar Carbonylamino) propanamide, (149) (2R) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethylthio-2- (thiazolidin-2-ylcarbonylamino) propanamide, (150) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3-t-butoxycarbonylthiazolidin-4-ylmethyl) amino Propanamide, (151) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3-t-butoxycarbonylthiazolidin-4-ylmethyl) amino Propanamide, (152) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl) amino) propanamide, (153) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-((cyclohexylmethyl) amino) propanamide, (154) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4RS) -3-t-butoxycarbonyl-1,3-perhydrothiazine- 4-ylmethyl) amino) propanamide, (155) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl) amino) propanamide, (156) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-((cyclohexylmethyl) amino) propanamide, (157) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -3- (3-methylbutyl) thiazolidin-4-ylmethyl) amino Propanamide, (158) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -thiazolidin-4-ylmethyl) amino) propanamide, (159) (2R) -N- (4-phenoxybenzyl) -3-cyclohexylmethylthio-2-(((4R) -thiazolidin-4-ylmethyl) amino) propanamide, (160) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethylthio-2-(((4RS) -1,3-perhydrothiazin-4-ylmethyl) amino) propanamide , (161) (2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.1.1] heptan-2-ylmethylthio) -2-(( 4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, or (162) (2R) -N- (4-methoxybenzyl) -3-((1S, 2R, 4R) -bicyclo [2.2.1] heptan-2-ylmethylthio) -2-((4R) -Thiazolidin-4-ylcarbonylamino) propanamide, or a nontoxic salt thereof, or a hydrate thereof. The compound of claim 6, wherein the compound is (1) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (2) (2R) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (3) (2S) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (4) (2S) -N- (4-methoxybenzyl) -3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (5) (2S) -N- (4-dimethylaminobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (6) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (7) (2S) -N-methyl-N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (8) (2RS) -N- (4-methoxybenzyl) -4-cyclohexylmethoxy-2-t-butoxycarbonylaminobutanamide, (9) (2S) -N- (4-nitrobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (10) (2S) -N- (4-methoxybenzyl) -3- (2-cyclohexenyloxy) -2-t-butoxycarbonylaminopropanamide, (11) (2S) -N- (4-methoxybenzyl) -3-cyclohexyloxy-2-t-butoxycarbonylaminopropanamide, (12) (2S) -N- (4-methoxybenzyl) -3-cyclopentylmethoxy-2-t-butoxycarbonylaminopropanamide, (13) (2S) -N- (4-methoxybenzyl) -4- (2-cyclohexenyloxy) -2-t-butoxycarbonylaminobutanamide, (14) (2S) -N- (4-methoxybenzyl) -4-cyclohexyloxy-2-t-butoxycarbonylaminobutanamide, (15) (2R) -N- (4-nitrobenzyl) -3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide, (16) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-benzoylaminopropanamide, (17) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-phenylsulfonylaminopropanamide, (18) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-pivaloylaminopropanamide, (19) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-methoxybenzoylamino) propanamide, (20) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-nitrobenzoylamino) propanamide, (21) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (12-methyltridecylcarbonylamino) propanamide, (22) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide, (23) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2- (4-methoxyphenylsulfonylamino) propanamide, (24) (2S) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylsulfonylaminopropanamide, or (25) (2R) -N- (4-methoxybenzyl) -3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide, Or a nontoxic salt thereof, or a hydrate thereof. The compound of claim 7, wherein the compound is (1) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (2) (2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (3) (2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (4) (2R) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (5) (2R) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (6) (2R) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (7) (2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester, (8) (2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester, (9) (2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid benzyl ester, (10) (2S) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (11) (2S) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (12) (2R) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (13) (2R) -4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (14) (2S) -3-cyclopentyloxycarbonyl-2- (N-t-butoxycarbonyl-N-methylamino) propanoic acid, 4-nitrobenzyl ester, (15) (2S) -3-cyclohexyloxycarbonyl-2- (N-t-butoxycarbonyl-N-amino) propanoic acid 4-nitrobenzyl ester, (16) (2S) -3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (17) (2S) -3- (adamantan-2-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester, (18) (2S) -3- (adamantane-1-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid benzyl ester, (19) (2S) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester, (20) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-fluorobenzyl ester, (21) (2R) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-fluorobenzyl ester, (22) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (23) (2R) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (24) (2S) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid, 4-nitrobenzyl ester, (25) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-nitrophenethyl ester, (26) (2S) -N-benzyl-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (27) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (28) (2S) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (29) (2S) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (30) (2S) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (31) (2S) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (32) (2R) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (33) (2R) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (34) (2R) -3- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (35) (2R) -3- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid cyclopentyl ester, (36) (2R) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (37) (2S) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (38) (2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (2) (2S) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester, (40) (2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (41) (2R) -4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester, (42) (2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (43) (2R) -4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid 4-nitrobenzyl ester, (44) (2S) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (45) (2S) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (46) (2S) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (47) (2S) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (48) (2R) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (49) (2R) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclohexyl ester, (50) (2R) -4- (4-methoxybenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (51) (2R) -4- (4-nitrobenzyloxycarbonyl) -2-t-butoxycarbonylaminobutanoic acid cyclopentyl ester, (52) (2S) -N- (4-methoxybenzyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (53) (2S) -N- (4-methoxybenzyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (54) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 2-pyridylmethyl ester, (55) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-t-butylbenzyl ester, (56) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 2-methoxybenzyl ester, (57) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 3-methoxybenzyl ester, (58) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 3-pyridylmethyl ester, (59) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-pyridylmethyl ester, (60) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4-chlorobenzyl ester, (61) (2S) -3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-bromobenzyl ester, (62) (2S) -3-cyclopentyloxycarbonyl-2- (N-methyl-N-t-butoxycarbonylamino) propanoic acid 4-methoxybenzyl ester, (63) (2S) -3-cyclohexyloxycarbonyl-2- (N-methyl-N-t-butoxycarbonylamino) propanoic acid 4-methoxybenzyl ester, (64) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxyphenethyl ester, (65) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 3- (4-methoxyphenyl) propyl ester, (2) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, furan-2-ylmethyl ester, (67) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid thiophen-2-ylmethyl ester, (68) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid, 4- (4-methoxyphenyl) butyl ester, (69) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid cyclohexyl ester, (70) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid methyl ester, (71) (2S) -N- (4-methoxyphenyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (72) (2S) -3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (73) (2S) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid diphenylmethyl ester, (74) (2S) -N-((1S) -2-phenyl-1-benzyloxycarbonylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (75) (2S) -N-((1S) -1-benzyloxycarbonylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (76) (2S) -3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (77) (2S) -3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (78) (2S) -3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (79) (2S) -3- (adamantan-2-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (80) (2S) -3- (adamantane-1-yloxycarbonyl) -2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (81) (2S) -N-((1S) -1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide, (82) (2S) -N-((1S) -2-phenyl-1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropane amides, (83) (3S) -3-t-butoxycarbonylamino-3- (1, 2, 3, 4-tetrahydroquinolin-1-ylcarbonyl) propanoic acid cyclohexyl ester, (84) (3S) -3-t-butoxycarbonylamino-3- (1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl) propanoic acid cyclohexyl ester, (85) (2S) -N-methyl-N- (1, 1-dimethyl-2-phenylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (86) (2S) -N-((1S) -1-carboxy-2-phenylethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (87) (2S) -N-((1S) -1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (88) (2S) -N-((1S) -1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide, (89) (2S) -N-((1S) -2-phenyl-1- (4-methoxybenzyloxycarbonyl) ethyl) -3-cyclohexyloxycarbonyl-2-t-butoxycarbonyl Aminopropanamide, (90) (2S) -3-cyclopentyloxycarbonyl-2-methylcarbonylaminopropanoic acid 4-methoxybenzyl ester, (91) (2S) -3-cyclopentyloxycarbonyl-2-benzoylaminopropanoic acid, 4-methoxybenzyl ester, (92) (2S) -3-cyclopentyloxycarbonyl-2-pivaloylaminopropanoic acid 4-methoxybenzyl ester, (93) (2S) -3-cyclopentyloxycarbonyl-2-cinnamoylaminopropanoic acid 4-methoxybenzyl ester, (94) (2S) -3-cyclopentyloxycarbonyl-2- valerylaminopropanoic acid, 4-methoxybenzyl ester, (95) (2S) -3-cyclopentyloxycarbonyl-2- (octylcarbonylamino) propanoic acid, 4-methoxybenzyl ester, (96) (2S) -3-cyclopentyloxycarbonyl-2-mesylaminopropanoic acid, 4-methoxybenzyl ester, (97) (2S) -3-cyclopentyloxycarbonyl-2-phenylsulfonylaminopropanoic acid, 4-methoxybenzyl ester, (98) (2S) -3-cyclopentyloxycarbonyl-2- (butylsulfonylamino) propanoic acid 4-methoxybenzyl ester, (99) (2S) -3-cyclopentyloxycarbonyl-2- (octylsulfonylamino) propanoic acid 4-methoxybenzyl ester, (100) (2S) -3-cyclopentyloxycarbonyl-2-((E) -styrylsulfonylamino) propanoic acid 4-methoxybenzyl ester, (101) (2S) -3-cyclopentyloxycarbonyl-2-benzyloxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (102) (2S) -3-cyclohexyloxycarbonyl-2-benzoylaminopropanoic acid, 4-methoxybenzyl ester, (103) (2S) -3-cyclohexyloxycarbonyl-2- (4-fluorobenzoylamino) propanoic acid 4-methoxybenzyl ester, (104) (2S) -3-cyclohexyloxycarbonyl-2- (4-methoxybenzoyl) propanoic acid 4-methoxybenzyl ester, (105) (2S) -3-cyclohexyloxycarbonyl-2- (4-phenylbenzoylamino) propanoic acid 4-methoxybenzyl ester, (106) (2S) -3-cyclohexyloxycarbonyl-2- (4-nitrobenzoylamino) propanoic acid 4-methoxybenzyl ester, (107) (2S) -3-cyclohexyloxycarbonyl-2- (4-acetylbenzoylamino) propanoic acid 4-methoxybenzyl ester, (108) (2S) -3-cyclohexyloxycarbonyl-2- (4-methylthiobenzoylamino) propanoic acid 4-methoxybenzyl ester, (109) (2S) -3-cyclohexyloxycarbonyl-2- (4-dimethylaminobenzoylamino) propanoic acid, 4-methoxybenzyl ester, (110) (2S) -N-((1S) -1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide, (111) (2S) -N-((1S) -2-phenyl-1-carboxyethyl) -3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide, (112) (2S) -3-cyclohexyloxycarbonyl-2- (N-benzyl-N-t-butoxycarbonylamino) propanoic acid, 4-methoxybenzyl ester, or (113) (2S) -3-cyclohexyloxycarbonyl-2-benzylaminopropanoic acid 4-methoxybenzyl ester, Or a nontoxic salt thereof, or a hydrate thereof. The compound of claim 8, wherein the compound is (1) (2S) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (2) (2S) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid benzyl ester, (3) (2S) -4- (pyrrolidin-1-ylcarbonyl) -2-t-butoxycarbonylaminobutanoic acid benzyl ester, (4) (2S) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (5) (2S) -N- (4-methoxybenzyl) -3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanamide, (6) (2S) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (7) (2S) -N- (4-methoxybenzyl) -3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanamide, (8) (2S) -4- (pyrrolidin-1-ylcarbonyl) -2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (9) (2S) -3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminopropanoic acid 4-methoxybenzyl ester, (10) (2S, 3R) -3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (11) (2S) -6-cyclohexylcarbonylamino-2-t-butoxycarbonylaminohexanoic acid, 4-methoxybenzyl ester, (12) (2S) -N- (4-methoxybenzyl) -3-cyclohexylcarbonylamino-2-t-butoxycarbonylaminopropanamide, (13) (2S) -4-cyclopentylamino-2-t-butoxycarbonylaminobutanoic acid 4-methoxybenzyl ester, (14) (2S) -N- (4-methoxybenzyl) -3-cyclohexylsulfonylamino-2-t-butoxycarbonylaminopropanamide, or (15) A compound which is (2R) -N- (4-methoxybenzyl) -3-cyclohexylsulfamoyl-2-t-butoxycarbonylaminopropanamide, or a nontoxic salt thereof, or a hydrate thereof.