JP2881688B2 - Sulfonamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sulfonamide derivative useful as a medicine. More specifically, the present invention relates to (1) a compound represented by the general formula (I): Sulfonamide derivatives represented by, non-toxic salts thereof,
Their acid addition salts or their solvates, specifically 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl ) Butanoic acid ester, 4-
(2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2-
(Morpholin-4-yl) ethylaminosulfonyl)-
2-methylphenyl 2R- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid esters, their acid adduct salts, or their solvates, (2) their production methods, and (3) drugs containing them as active ingredients.

[0002]

BACKGROUND OF THE INVENTION Lysosomal hydrolases released from neutrophils play an important role in host defense reactions against tissue damage caused by microorganisms or inflammation. Among the lysosomal enzymes, elastase and cathepsin G belonging to neutral serine proteinase localized in azul granules mainly play a role in connective tissue degradation. In particular, elastase degrades the elastic connective tissue by cutting the elastin cross-linking structure and the hydrophobic site of the protein which directly functions to maintain the elasticity of lung tissue and the like [J. Cell. Biol., 40 , 366 (1969) )].
In addition, elastase selectively degrades not only elastin but also the crosslinked region of collagen fibers [J. Biochem., 8
4 , 559 (1978)] and also play a central role in connective tissue metabolism, such as acting on tissue structural proteins such as proteoglycans [J. Clin. Invest., 57 , 615 (1976)].

[0003] In living organisms, elastase is inactivated by α1-proteinase inhibitor (α1-PI), a common inhibitor of serine enzymes, but when the balance of the enzyme-inhibitor system is disturbed, tissue destruction occurs. Sexual symptoms appear [Schweiz. Hed. Wshr., 114 , 895 (198
Four)].

[0004] Elastin turnover in normal tissues is very slow [Endocrinology, 120 , 92 (1978)], but atherogenic arteries, including emphysema [Am. Rev. Respir. Dis., 110 , 254 (1974)]. Induration [Lab. Invest., 22 , 228 (1970)] or rheumatoid arthritis [in Neutral Proteases of Human
Polymorphonuclear Leukocytes, Urban and Schwarzenb
erg, Baltimore-Hunich (1978) , 390] Various In pathological conditions of observed bulimia elastin degradation, association with elastase and disease has attracted attention [infection, inflammation, immunity and the like, 13, 13 (1983)].

[0005]

2. Description of the Related Art Under such circumstances, research and development of compounds having elastase inhibitory activity have been actively conducted recently. For example, (1) general formula (A)

Embedded image

(Wherein, Y ^A represents a sulfonyl group or a carbonyl group, and (i) R ^1A and R ^2A may be the same or different and each represent a hydrogen atom, a C1-16 alkyl group or a compound represented by the formula

Embedded image (Wherein X ^A represents a single bond, a sulfonyl group, a C1-4 alkylene group or a C1-4 alkylene group which may be substituted with a -COOH group or a benzyloxycarbonyl group,

[0007]

Embedded image Represents a carbocyclic or heterocyclic ring, nA represents an integer of 1 to 5, R ^4A may be the same or different, and represents a hydrogen atom, a C1-8 alkyl group, a C1-14 alkoxy group, a C1 6, an alkylthio group, a hydroxyl group, a halogen atom, a nitro group, a trihalomethyl group, a group represented by the formula -NR ^41A R ^42A , a group represented by the formula -Z ^41A -COOR ^43A , and a group represented by the formula -CONR ^41A R ^42A ,formula

Embedded image (Where

Embedded image Represents an amino acid residue, R ^49A represents a hydroxyl group, a C1-4 alkoxy group, an amino group, and one or two C1-4
Represents an amino group, a carbamoylmethoxy group, etc. substituted with an alkyl group. )) Or

(Ii) R ^1A and R ^2A together with the nitrogen atom to which they are attached, may be a heterocyclic ring containing at least one nitrogen atom substituted with —COOH, or an unsubstituted at least one nitrogen atom. Represents a heterocyclic ring containing nitrogen atoms,
R ^3A represents a hydrogen atom, a hydroxy group, a C1-6 alkyl group, etc., and mA represents an integer of 1 to 4. ) Or non-toxic salts or acid addition salts thereof have elastase inhibitory activity (see JP-A-3-20253).

(2) General formula (B)

Embedded image (Wherein R ^1B and R ^2B are the same or different, and hydrogen, C1
-6 alkyl, C3-6 cycloalkyl, or together, a methylene group, an ethylene group, a polymethylene group-(CH
₂ ) _nB- (nB is an integer of 1 to 6), and R ^3B is hydrogen, halogen, C1-12 haloalkyl, C1-12
Alkyl, alkoxy C1-12, alkenyl of C2-12, cycloalkyl of C3-12, mono- or bicyclic aryl, -Z ^B R ^5B (Z ^B is O, S, S (O) , or SO ₂ And R ^5B is hydrogen, C1-18 alkyl, C3-12 cycloalkyl or phenyl group.), —NR ^6B R ^7B (R ^6B and R ^7B are the same or different, and , C1-12 alkyl, C3
6 cycloalkyl, phenyl, alkoxy of C1~12, -C (O) R ^3B or R ^6B and R ^7B is -C together,
_{(O) CH 2 CH 2 C} (O) -, - C (O) -C 6 H 4 C
(O) - or _{- (CH 2) xB - (} xB is 2,3,4,
5 or 6). ), 1 to 5 substituents selected from the group consisting of morpholino, imidazolyl, piperazino and the like linked to the phenyl ring through a nitrogen atom, and R ^4B represents hydrogen, halogen, nitro, -C
(O) CH ₃ , S (O) _pB R ^9B (pB is 0, 1, or 2, and R ^9B is hydroxy, —ONa, or C1-12 alkyl which may be substituted or substituted. Selected from cycloalkyl which may be
５5 substituents. ) And non-toxic pharmaceutically acceptable salts have elastase inhibitory activity (see JP-A-4-226939).

(3) General formula (C)

Embedded image (Wherein R ^1C and R ^2C are the same or different, and hydrogen, C1
To 6 alkyl groups, C3 to 6 cycloalkyl groups, or together a methylene group, an ethylene group, a polymethylene group-
(CH _{2) nC} - _(nC is an integer from 1 to 6) represents, Ar ^C
Is an optionally substituted phenyl group, and Het ^C represents a heterocyclic ring having one or more nitrogen, sulfur or oxygen atoms in the ring. )
It has been disclosed that the compound represented by the formula (1) has an elastase inhibitory activity (see JP-A-4-283576).

[0011] Among the conventional compounds having an elastase inhibitory activity, few compounds have been reported to exhibit their activity upon oral administration, and most of the compounds cannot be expected to exert their effects upon oral administration. In order to exert the effect of a drug by oral administration, it is essential that the drug has good absorbability from the gastrointestinal tract and that its activity can be maintained up to the site of action. Therefore, it is considered that a compound excellent in stability in the gastrointestinal tract, absorbability, and solubility at the absorption site can sufficiently obtain its effects by oral administration.

[0012]

DISCLOSURE OF THE INVENTION The present inventors have conducted research to find a novel compound having an excellent inhibitory effect on elastase and high safety, and the sulfonamide derivative represented by the general formula (I) The inventors have found that the object has been achieved and completed the present invention. Further, among the compounds of the present invention, a novel compound having good stability, absorbability, and solubility and showing an inhibitory action on elastase by oral administration was also found.

[0013]

Comparison with the prior art The sulfonamide derivative of the compound of the present invention is a novel compound which has never been known before. More specifically, the compound represented by the general formula (A) described in the prior art (1) is a group of compounds having a pivaloyloxy group as an essential component. In contrast, the compound of the present invention is a compound having a D ring having various substituents (R ¹ groups). Therefore, the compound of the present invention has the general formula (A)
It can be said that the compound represented by is completely different in structure.

The general formula (B) described in the prior art (2)
_May represent a compound in which the R ^4B group is S (O) _pB R ^9B . However, the group represented by R ^9B is
Hydroxy, -ONa, or optionally substituted C
1 to 12 alkyl or cycloalkyl which may be substituted, and does not represent an amino group. Also, the compound represented by the general formula (C) described in the prior art (3) may have S (O) _pC R ^9C as a substituent of Ar ^C , but R ^9C is hydroxy, -ONa Or an optionally substituted C1-12 alkyl or an optionally substituted cycloalkyl, and does not represent an amino group. On the other hand, the compound of the present invention is a compound having a sulfonamide having various substituents, and can be said to be completely different from the compounds represented by the general formulas (B) and (C). Furthermore, although the conventional compound has no effect when administered orally, some of the compounds of the present invention are excellent in stability, absorbability, and solubility, and the effect can be obtained by oral administration.

[0015]

DISCLOSURE OF THE INVENTION The present invention relates to (1) a compound represented by the general formula (I)

Embedded image [Wherein, R ¹ represents a C1-8 alkyl group, a C1-8 alkoxy group, a hydroxyl group, a keto group, a nitro group, a halogen atom,
Trihalomethyl group, cyano group, amidino group, -COOR
⁷ groups (wherein R ⁷ represents a hydrogen atom or a C1-8 alkyl group)

Or

Embedded image (In the group, p represents 0 or an integer of 1 to 4, and R ⁸ and R ⁹ are each independently a hydrogen atom, a C 1-4 alkyl group, a C 2-5 acyl group, a —COOR ¹⁰ group (group During,
R ¹⁰ represents a hydrogen atom or a C1~8 alkyl group. ), -. CONR ¹¹ R ¹² group (wherein, R ¹¹ and R ¹² each independently represent a hydrogen atom or a C1~4 alkyl group) or

[0017]

Embedded image (In the group, R ¹³ is a hydrogen atom, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, benzyl, 4-hydroxybenzyl, carboxymethyl, 2-carboxy Ethyl, 3-guanidylpropyl, 4-aminobutyl, 4-imidazolylmethyl, 3-
It represents an indolylmethyl, carbamoylmethyl or 2-carbamoylethyl group, and R ¹⁴ represents a hydrogen atom, or R ¹³ and R ¹⁴ together represent a propylene group. Ie

Embedded image Represents an α-amino acid residue. ) Or

Or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form an aliphatic heterocycle or C 1-4
Represents an aliphatic heterocyclic ring substituted with an alkyl group or a phenyl C1-4 alkyl group. ) Where n is 0
Or represents an integer of 1 to 5,

Embedded image Represents a carbocyclic or heterocyclic ring,

Embedded image R ² and R ³ each independently represent a hydrogen atom, C 1-4
Represents an alkyl group, a C1-4 alkoxy group, a halogen atom, a trihalomethyl group, or a phenyl group; R ² and R ³ together represent a C1-4 alkylidene group;

Embedded image Is, R ² and R ³ together with the carbon atoms to which they are attached represent a cycloalkyl group C3-7,

R ⁴ represents a C1-4 alkyl group or a C1-4 alkoxy group, or two adjacent R ⁴
Together represent a C3-5 alkylene group;
Represents 0 or an integer of 1 to 4,

Embedded image R ⁵ and R ⁶ are each independently 1) a hydrogen atom, 2) a hydroxyl group, 3) a C1-8 alkyl group, 4) a C1-8 alkoxy group, 5) a phenyl C1-4 alkoxy group, 6) an amidino Group) 7) -MR ¹⁶ group (wherein M represents a single bond or a C1-8 alkylene group,

R ¹⁶ is i) -NR ¹⁷ R ¹⁸ group (wherein R ¹⁷ and R ¹⁸ each independently represent a hydrogen atom or a C1-4 alkyl group), ii) -CONR ¹⁹ R ²⁰ A group (wherein, R ¹⁹ and R ²⁰ each independently represent a hydrogen atom or a C1-4 alkyl group),

Embedded image (In the base,

Embedded image Represents a carbocycle, r represents 0 or an integer of 1 to 5,

R ²¹ is a C 1-4 alkyl group, a C 1-4 alkoxy group, a nitro group, an amidino group, a —COOR ²² group (wherein R ²² is a hydrogen atom, a C 1-8 alkyl group, a phenyl group or phenyl represents a C1 -4 alkyl group.), in SO ₃ H groups, -CONR ²³ -E-R ²⁴ group (group, R ²³ represents a hydrogen atom, C1 -4 alkyl group,
E represents a C1-4 alkylene group, and R ²⁴ represents —COO
R ²⁵ group (wherein, R ²⁵ is a hydrogen atom, an alkyl group of C1-8, a phenyl group or a phenyl C1~4 alkyl group.) Represent or tetrazole ring. ), A tetrazole ring or a morpholino ring. Or iv) a heterocyclic ring or a C1-4 alkyl group, C1-4
Alkoxy group, a hydroxyl group, a phenyl C1~4 alkyl group, -COOR ²⁶ group (wherein, R ²⁶ is a hydrogen atom, C1-8
Represents a phenyl group or a phenyl C1-4 alkyl group. ), A heterocyclic ring substituted with 1 to 4 groups selected from hydroxy C1-4 alkyl groups and C2-4 alkoxyalkyl groups. ),

8) One or two OR ²⁷ groups (in the group, R ²⁷
C2-4 is substituted with a hydrogen atom, an alkyl group of C1 -4, alkoxyalkyl group or OR ²⁸ groups C2-4 (in group, R ²⁸ represents a hydrogen atom, an alkoxyalkyl group of C2-4.) Represents an alkyl group. )) Substituted C1-8 alkyl group,

9) -J-COOR ²⁹ group (wherein R ²⁹ represents a hydrogen atom, a C1-8 alkyl group, a phenyl group or a phenyl C1-4 alkyl group, J is a single bond,-(C
H ₂ ) _s −,

Embedded image And s represents an integer of 2 to 6, and R ³⁰ and R ³¹
Independently, i) hydrogen atom, ii) C1-8 alkyl group, iii) -COOR ³² radical (wherein, R ³² is a hydrogen atom, C1-8
Represents a phenyl group or a phenyl C1-4 alkyl group. Iv) a carbocycle, a heterocycle, or a C1-4 alkyl group,
A carbocyclic or heterocyclic ring substituted by a group selected from C1-4 alkoxy, amino, nitro, hydroxyl, halogen, nitrile, guanidino and amidino, or v) hydroxyl, -COOR ³³ Group (wherein R ³³ is a hydrogen atom,
C1-8 alkyl, phenyl or phenyl C1
Represents a -4 alkyl group. ), -NR ³⁴ R ³⁵ groups (in the groups,
R ³⁴ and R ³⁵ represent a hydrogen atom or a C1-4 alkyl group. ), A carbon ring, a heterocyclic ring, or a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a hydroxyl group, a halogen atom, a nitrile group, a guanidino group and an amidino group. C1-8 alkyl group substituted by a group selected from a carbocyclic ring or a heterocyclic ring (provided that one carbon atom of the C1-8 alkyl group may be replaced by one sulfur atom. )

[0024]

Embedded image Represents a heterocyclic ring in which R ⁵ and R ⁶ together with the nitrogen atom to which they are bonded, q represents 0 or an integer of 1 to 4, R ¹⁵ represents 1) a hydroxyl group, 2) a keto group (an oxo group) ), 3) protected keto group (oxo group), 4) C1-4 alkyl group, 5) C1-4 alkoxy group, 6) phenyl group, 7) phenoxy group, 8) phenyl C1-4 alkyl group, 9) a phenyl C1~4 alkoxy group, 10) a nitro group, 11) -COOR ³⁶ radical (wherein, R ³⁶ is a hydrogen atom, C1 to
8 alkyl group, (wherein, independently R ³⁷ and R ³⁸ are each a hydrogen atom or a. Represents an alkyl group of C1~4) -CONR ³⁷ R ³⁸ group C1 -4 alkyl group which is substituted with , -NR ³⁹ R ⁴⁰ group (wherein, R ³⁹ and R ⁴⁰ each independently represent a hydrogen atom or an alkyl group of C1 -4.) C1 -4 alkyl group substituted with,
-OR ⁴¹ group (wherein R ⁴¹ represents an alkyl group of C2-4 OR ⁴² group (wherein, the R ⁴² is substituted with representing.) Alkoxyalkyl group hydrogen atom or C2-4.) Represents a C1-4 alkyl group substituted with a C1-C4 alkyl group or a C1-4 alkyl group substituted with a piperazino ring. 12) —NR ⁴³ R ⁴⁴ group (wherein R ⁴³ and R ⁴⁴ are each independently a hydrogen atom, a C1-4 alkyl group, a C2-4
5 represents an acyl group. ), 13) —CONR ⁴⁵ R ⁴⁶ group (wherein R ⁴⁵ and R ⁴⁶ are each independently a hydrogen atom, a hydroxyl group, a C1-4 alkyl group, a phenyl C1-4 alkyloxy or a hydroxyl group or a —COOR ⁴⁷ group) (In the group, R ⁴⁷ is a hydrogen atom or C
Represents an alkyl group of 1 to 8; C1 substituted with
Represents up to 4 alkyl groups. ), 14) a hydroxyl group, -COOR ⁴⁸ group (wherein, R ⁴⁸ represents a hydrogen atom or a C1~8 alkyl group), -. NR ⁴⁹ R
⁵⁰ groups (in the groups, R ⁴⁹ and R ⁵⁰ each independently represent a hydrogen atom or a C1-4 alkyl group), OSO
5 or 6 containing one or two ₃ H and nitrogen atoms
1-4 substituted with a group selected from membered heterocycles
15) 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, 16) halogen atom, 17) -CHO group, 18) -NR ⁵¹ -COOR ⁵² group (in the group, R ⁵¹ and R ⁵²
Each independently represents a hydrogen atom or a C1-8 alkyl group. ). A non-toxic salt thereof, an acid addition salt thereof and a solvate thereof, (2) a production method thereof, and (3) a drug containing the same as an active ingredient.

In the general formula (I), R ² , R ³ , R ⁴ , R ⁸ , R
^{9, R 11, R 12,} R 15, R 17, R 18, R 19, R 20,
^{R 21, R 23, R 27} , R 34, R 35, R 36, R 37, R 38, R
^{39, R 40, R 43,} R 44, R 45, or represented by ^{R 46, R 49, R 50} , aliphatic heterocyclic, and C1~4 alkyl group as a substituent of carbocyclic ring or heterocyclic ring , Methyl, ethyl, propyl, butyl and isomers thereof.

In the general formula (I), R ¹ , R ⁵ , R ⁶ , R ⁷ , R
^{10, R 22, R 25,} R 26, R 29, R 30, R 31, R 32,
C1~ represented by ^{R 33, R 36, R 47} , R 48, R 51, R 52
The alkyl group 8 is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group or an isomer thereof.

In the general formula (I), C represented by R ²⁷ and R ⁴¹
The 2 to 4 alkyl groups are ethyl, propyl, butyl and isomers thereof. In the formula (I), the alkylene group C3~5 represented by two R ⁴ Adjacent
Trimethylene, tetramethylene, pentamethylene and isomers thereof.

In the general formula (I), the C1-8 alkylene group represented by M includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof. It is. In general formula (I), C1 to E represented by E
The alkylene group 4 is a methylene, ethylene, trimethylene, tetramethylene group or an isomer thereof.

In the general formula (I), the phenyl C1-4 alkyl group or the phenyl C1-4 alkoxy group is a C1-4 alkyl group or a C1-4 alkoxy group substituted by one phenyl group. In the general formula (I), R ²⁹ ,
The phenyl C1-4 alkyl group represented by R ³² , R ³³ or R ¹⁵ or as a substituent of an aliphatic heterocycle or a heterocycle is a methyl, ethyl, propyl or butyl group substituted by one phenyl group. And their isomeric groups.

In the general formula (I), R ⁵ , R ⁶ , R ¹⁵ , R ⁴⁵ ,
The phenyl C1-4 alkoxy group represented by R ⁴⁶ means methoxy, ethoxy,
Propoxy, butoxy and isomers thereof. In the formula (I), the acyl group C2~5 represented by ^{R 8, R 9, R 43} , R 44, acetyl, propionyl, butyryl, valeryl and the isomers thereof.

In the general formula (I), the C2-4 alkoxyalkyl group represented by R ²⁷ , R ²⁸ or R ⁴² or as a substituent of a heterocyclic ring includes a methoxymethyl group, a methoxyethyl group and a methoxypropyl group. Group, ethoxymethyl group, ethoxyethyl group, propyloxymethyl group and isomers thereof. In the general formula (I), the C1-8 alkoxy group represented by R ¹ , R ⁵ and R ⁶ means methoxy, ethoxy,
Propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.

In the general formula (I), R ² , R ³ , R ⁴ , R ¹⁵ ,
A C1-4 alkoxy group represented by R ²¹ or as a substituent on a carbocyclic or heterocyclic ring includes methoxy, ethoxy,
Propoxy, butoxy and their isomeric groups.
In the general formula (I), the halogen atoms represented by R ¹ , R ² , R ³ and R ¹⁵ are fluorine, chlorine, bromine and iodine.

In the general formula (I),

Embedded image May be any α-amino acid residue. Specific examples include glycine, alanine, serine, threonine, cysteine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, arginine, glutamine, lysine, histidine, and proline residues.

In the general formula (I), the C3-7 cycloalkyl group represented by R ² and R ³ together with the carbon atom to which they are bonded is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group It is. In the formula (I), a C1~4 alkylidene group represented together R ² and R ^3, methylidene, ethylidene, propylidene, and butylidene and isomeric groups thereof.

In the general formula (I), m is preferably 0, 1 or 2, and more preferably 0 or 1. In the general formula (I),
R ⁴ is preferably a C 1-4 alkyl group or a C 1-4 alkoxy group, for example, a methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy group. Among them, a methyl group is particularly preferred. When R ⁴ takes one or two substituents, they are attached to one or both of the positions adjacent to the portion of the phenyl ring to which the oxygen atom is attached, and when R ⁴ takes two substituents, Those bonded to the ortho and meta positions of the portion where the ring oxygen atom is bonded, or those bonded together to form a 5-membered ring fused to a phenyl ring when R ⁴ takes two substituents are preferred. Particularly preferred are compounds wherein m is 1 and R ⁴ is a methyl group and is bonded to the ortho-position of the portion where the oxygen atom of the phenyl ring is bonded.

In the general formula (I), one of R ² and R ³ is a hydrogen atom, a methyl, ethyl or methoxy group, the other is a methyl, ethyl, isopropyl, phenyl or trifluoromethyl group, or R ² and R 3 Preferred is ethylidene or a C3-6 cycloalkyl group wherein ³ together with the carbon atom to which they are attached.

In the general formula (I), the ring D is phenyl, naphthyl (preferably 1- or 2-naphthyl), thiophenyl (preferably thiophen-2-yl), cyclohexyl, pyridinyl (preferably pyridine-3). -Yl), thiazoyl (preferably thiazol-4-yl), imidazolinyl (preferably imidazoline-2)
-Yl), benzimidazoyl (preferably benzimidazol-5-yl), 2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzodioxol-5-yl or 1H -1-methyl-2-pyridone-
3-yl is preferred. Phenyl is particularly preferred.

In the general formula (I), n is 0, 1, 2, or 3
Is preferable, and 0 or 1 is more preferable. R ¹ is C1
4 alkyl groups (e.g., methyl group), C1-4 alkoxy groups (e.g., methoxy group), amino group,
An amino group (e.g., a dimethylamino group) substituted with a 1-4 alkyl group, a methyl group substituted with a carbamoyl group, a methyl group (e.g., an acetyl group) substituted with a C2-5 alkanoyl group, a nitro group, Hydroxy group,
Cyano group, carboxy group, trihalomethyl group (for example,
Trifluoromethyl group), an amino group substituted with an amidino group, an alkoxycarbonyl group, a halogen (eg, a chlorine atom), a pyrrolidinyl group, a piperidinyl group, a perhydroazepinyl group, a morpholinyl group or optionally a benzyl group at the 4-position A substituted piperazinyl group is preferred.

Ring D is preferably monosubstituted with phenyl. When ring D is a phenyl group, at least one substituent is preferably in the 4-position. The substituent at the 4-position of the phenyl group is preferably a 5-, 6-, or 7-membered ring containing a nitrogen atom bonded to the phenyl group via a nitrogen atom. Pyrrolidin-1-yl is preferred.

In the general formula (I), in the NR ⁵ R ⁶ group, R
^{When 5} and R ⁶ together with the nitrogen atom to which they are attached do not represent a heterocycle, one of the NR ⁵ R ⁶ groups is a hydrogen atom, methyl, ethyl, propyl, methoxy, benzyl,
Methoxymethoxyethyl and a 1-hydroxyethyl group are preferred, and a hydrogen atom is particularly preferred. The other is phenyl, phenyl substituted by a substituent (for example, 2-((1
-Carboxymethyl) aminocarbonyl) phenyl or 4-nitrophenyl group), a heterocycle (eg, quinuclidine, piperidine, pyridine, imidazole, morpholine, tetrazole ring), C1 substituted by a heterocycle
To 8 (e.g., pyrazin-1-ylethyl, piperidin-1-ylethyl, morpholin-1-ylethyl, pyridin-2-ylethyl, pyrrol-2-yl)
Ylethyl) is preferred, and morpholin-1-ylethyl is particularly preferred.

In the group NR ⁵ R ⁶ , when R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent a heterocycle,
As the ring, pyrrolidine, indole, indoline, perhydroindole, benzimidazole, morpholine,
Piperidine, piperazine, 7-azabicyclo [3.2.
1] Octane, 3-azabicyclo [3.2.2] nonane, tetrahydrooxazole, tetrahydrothiazole, imidazole, hexahydrodiazepine, aziridine, and azetidine are preferable, and piperazine is particularly preferable.

In the group NR ⁵ R ⁶ , when R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent a heterocycle,
As R ¹⁵ , a hydroxyl group, a C1-4 alkyl group substituted with a hydroxyl group (eg, a hydroxymethyl group), a C1-4 alkyl group substituted with a heterocycle (eg, a pyrrolidin-1-ylmethyl), a benzyloxy group, Amino group,
Methoxy group, dimethylamino group, acetylamino group, methyl group, nitro group, halogen atom (eg, fluorine atom), keto group (oxo group), carboxy group, ester group (eg, ethoxycarbonyl group, t-butoxycarbonyl group) , 2-aminoethoxycarbonyl group, 2- (2-
(Hydroxyethoxy) ethoxycarbonyl group, 2- (piperazin-1-yl) ethoxycarbonyl group) and amide group (for example, carboxymethylaminocarbonyl group) are preferable, and carboxy group is particularly preferable. In the NR ⁵ R ⁶ group, when R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent a heterocyclic ring, p is 0, 1 or 2
Is preferable, and 0 or 1 is more preferable.

In the general formula (I), the aliphatic heterocyclic ring represented by R ⁸ and R ⁹ together with the nitrogen atom to which they are bonded is one or two nitrogen atoms or one nitrogen atom.
5 to 1 containing one and one sulfur or oxygen atom
Represents a 5-membered monocyclic or bicyclic saturated heterocycle or a partially saturated heterocycle. For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole , Dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydro Isoquinoline, Jihi Rofutarajin, tetrahydronaphthyl phthalazine, perhydro phthalazine, dihydro naphthyridine, tetrahydronaphthyridine, perhydro naphthyridine, dihydroquinoxaline,
Tetrahydroquinoxaline, perhydroquinoxaline,
Dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole ring And the like.

In the general formula (I),

Embedded image The carbocycle represented by R ³⁰ or R ³¹ represents a 3- to 15-membered monocyclic or polycyclic aromatic or alicyclic hydrocarbon. For example, cyclopentadiene, benzene, pentalene, indene, naphthalene, azulene, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, dihydroindene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydro Examples include naphthalene, bicyclo [2.2.1] heptane, bicyclo [3.2.2] nonane, and adamantane ring. In the case where the carbocycle is divalent, it is assumed that the bond comes from the same carbon atom or from a different carbon atom.

In the general formula (I),

Embedded image The heterocyclic ring represented by R ¹⁶ , R ³⁰ or R ³¹ means 1 to 4 nitrogen atoms, 1 or 2 sulfur atoms, 1 or 2 oxygen atoms, or 1 nitrogen atom and sulfur atom or A 5- to 15-membered monocyclic or bicyclic aromatic heterocycle, saturated heterocycle or partially saturated heterocycle containing one oxygen atom. For example, pyrrole, imidazole,
Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiane (thiopyran), tiepin, oxazole, isoxazole, thiazole, isothiazole, oxazine, oxazepine, thiazine,
Thiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,
Phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, Hexahydroazepine,
Hexahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiane (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole,
Tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran , Dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole,
Dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,
Dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzo Oxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzoxazine, 1,3-dioxaindane,
Examples include 1,4-benzodioxane, quinuclidine, triazole, and tetrazole rings.

In the general formula (I),

Embedded image The heterocyclic ring represented by R ⁵ and R ⁶ together with the nitrogen atom to which they are bonded is represented by the following formula:
Or a 3- to 15-membered monocyclic or bicyclic aromatic heterocyclic ring, saturated heterocyclic ring or partially saturated heterocyclic ring containing one nitrogen atom and one sulfur atom or one oxygen atom. Express. For example, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,
Azepine, diazepine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, hexahydrodiazepine, oxazole, Isoxazole, thiazole, isothiazole,
Oxazine, oxaazepine, thiazine, thiazepine, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroiso Oxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline,
Perhydrindole, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine , Perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,
Tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, 7-azabicyclo [3.2.1] octane, 3- And azabicyclo [3.2.2] nonane ring.

In the general formula (I), the 5- or 6-membered heterocyclic ring having one or two nitrogen atoms represented by R ¹⁵ includes, for example, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, Examples include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine and the like.

In the general formula (I), one or two keto groups (oxo groups) represented by R ¹⁵ may be bonded from the same or different sulfur atoms. General formula (I)
Inside, protected keto group (oxo group) binds

Embedded image Is a ring represented by 1,3-dioxolane

Embedded image Represents a ring forming a spiro ring.

In the present invention, all isomers are included unless otherwise indicated in the specification and the structural formula. For example, the alkyl group, the alkylene group and the alkenylene group include linear and branched ones, and the double bond in the double bond in the alkenylene group is a mixture of E, Z and EZ. Including. It also includes isomers resulting from the presence of asymmetric carbon atoms, such as when branched alkyl, alkylene, and alkenylene groups are present.

The compound represented by formula (I) can be converted into a non-toxic salt or acid addition salt by a known method. Salt is
Non-toxic, water-soluble ones are preferred. 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, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, Arginine, N-methyl-D-glucamine and the like).

The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoate Organic acid salts such as acid, citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.

The compound of the present invention represented by the general formula (I) or a salt thereof may be converted into a solvate by a known method. Preferably, the solvate is non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water, alcoholic solvents (eg, ethanol, etc.).

[0053]

Specific Compounds of the Present Invention The preferred compounds of the present invention include compounds represented by the following general formulas (I-A1), (I-A2) and
Compounds represented by (IB1) and (IB2) are included.

Embedded image (In the formula, all symbols have the same meanings as described above.)

Specific compounds of the present invention include the compounds shown in the following Tables 1 to 46, the compounds of the examples, the non-toxic salts and the acid addition salts thereof. In the table, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents an isopropyl group, and tBu represents a t-butyl group.

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

[0058]

[Table 4]

[0059]

[Table 5]

[0060]

[Table 6]

[0061]

[Table 7]

[0062]

[Table 8]

[0063]

[Table 9]

[0064]

[Table 10]

[0065]

[Table 11]

[0066]

[Table 12]

[0067]

[Table 13]

[0068]

[Table 14]

[0069]

[Table 15]

[0070]

[Table 16]

[0071]

[Table 17]

[0072]

[Table 18]

[0073]

[Table 19]

[0074]

[Table 20]

[0075]

[Table 21]

[0076]

[Table 22]

[0077]

[Table 23]

[0078]

[Table 24]

[0079]

[Table 25]

[0080]

[Table 26]

[0081]

[Table 27]

[0082]

[Table 28]

[0083]

[Table 29]

[0084]

[Table 30]

[0085]

[Table 31]

[0086]

[Table 32]

[0087]

[Table 33]

[0088]

[Table 34]

[0089]

[Table 35]

[0090]

[Table 36]

[0091]

[Table 37]

[0092]

[Table 38]

[0093]

[Table 39]

[0094]

[Table 40]

[0095]

[Table 41]

[0096]

[Table 42]

[0097]

[Table 43]

[0098]

[Table 44]

[0099]

[Table 45]

[0100]

[Table 46]

[0101]

[Table 47]

[0102]

[Table 48]

[0103]

[Table 49]

[0104]

[Table 50]

[0105]

[Table 51]

[0106]

[Table 52]

[0107]

[Table 53]

[0108]

[Production Method of the Compound of the Present Invention] The compound of the present invention represented by the general formula (I) is represented by the general formula (II):

Embedded image (Wherein R ^1a represents a C1-8 alkyl group, a C1-8 alkoxy group, a hydroxyl group, a protected hydroxyl group, a keto group, a nitro group, a halogen atom, a trihalomethyl group, a cyano group,
An amidino group, a -COOR ^7a group (wherein, R ^7a represents a C1-8 alkyl group or a benzyl group) or

[0109]

Embedded image (Wherein p has the same meaning as described above, and R ^8a and R ^9a
Are each independently a hydrogen atom (provided that R ^8a and R ^8a
9a cannot be a hydrogen atom at the same time. ), T-butoxycarbonyl group, benzyloxycarbonyl group, C1
4 alkyl group, an acyl group of C2-5, -COOR ^10a
A group (wherein, R ^10a represents a C1-8 alkyl group or a benzyl group), a —CONR ¹¹ R ¹² group (wherein, R ¹¹ and R ¹² represent the same meaning as described above), or

[0110]

Embedded image Represents a protected α-amino acid residue. ) Or

Or R ^8a and R ^9a are taken together with the nitrogen atom to which they are attached to form an aliphatic heterocycle or C1
Represents an aliphatic heterocyclic ring substituted by an alkyl group of 4 or a phenyl C1-4 alkyl group, and other symbols have the same meanings as described above. ) And a compound of the general formula (I
II):

[0112]

Embedded image (Where

Embedded image R ^5a and R ^6a are each independently protected by 1) a hydrogen atom (provided that R ^8a and R ^9a are not hydrogen atoms at the same time), 2) a hydroxyl group, and 3) a group removable by an acid. Hydroxyl group, 4) t-butoxycarbonyl group, 5) benzyloxycarbonyl group, 6) C1-8 alkyl group, 7) C1-8 alkoxy group, 8) phenyl C1-4 alkoxy group, 9) amidino group, 10 ) -MR ^16a group (wherein M has the same meaning as described above, and R ^16a is i) -NR ^17a R ^18a group (wherein, R ^17a and R ^18a are each independently a hydrogen atom (provided that , R ^17a
And R ^18a are not simultaneously hydrogen atoms. ),
represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a C1-4 alkyl group. ), Ii)-
CONR ¹⁹ R ²⁰ groups (wherein R ¹⁹ and R ²⁰ represent the same meaning as described above),

[0113]

Embedded image (In the group, all symbols have the same meanings as described above.)
Or iv) a heterocyclic ring, or a C1-4 alkyl group,
C1-4 alkoxy group, hydroxyl group, hydroxyl group protected with an acid-removable group, phenyl C1-4 alkyl group, -C
An OOR ²⁶ group (wherein R ²⁶ has the same meaning as described above), a hydroxyalkyl group, a hydroxy C1-4 alkyl group protected with an acid-removable group, and a C2-4
Represents a heterocyclic ring substituted with 1 to 4 groups selected from an alkoxyalkyl group. ),

11) One or two OR ^27a groups (in the group,
R ^27a is a hydrogen atom, a C1-4 alkyl group, a C2-4 alkoxyalkyl group, a t-butyl-dimethylsilyl group, a tetrahydropyranyl group (THP), a benzyl group or an OR ^28a group (in the group, R ^28a is Hydrogen atom, C2-4 alkoxyalkyl group, t-butyl-dimethylsilyl group,
THP represents a benzyl group. C2-4 substituted with
Represents an alkyl group. C1~8 alkyl group substituted with), 12) -Ja-COOR ²⁹ group (wherein, R ²⁹ represents the same meaning as above, Ja is a single _{bond, - (CH 2) s -} ,

Embedded image And s represents the same meaning as described above,

R ^30a and R ^31a are each independently i)
A hydrogen atom, ii) a C1-8 alkyl group, iii) -COOR
³² groups (in which R ³² has the same meaning as described above), iv)
Carbocycle, heterocycle, or C1-4 alkyl group, C1
~ 4 alkoxy groups, protected amino groups, nitro groups,
A carbocyclic or heterocyclic ring substituted by a group selected from a hydroxyl group, a protected hydroxyl group, a halogen atom, a nitrile group, a guanidino group and an amidino group, or v)
Hydroxyl group, protected hydroxyl group, -COOR ³³ group (in the group, R
³³ has the same meaning as described above. ), -NR ^34a R ^35a group (wherein R ^34a and R ^35a are hydrogen atoms (provided that R ^34a
And R ^35a are not simultaneously hydrogen atoms. ),
represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a C1-4 alkyl group. ), Carbocycle, heterocycle, or C1-4 alkyl group, C1-4 alkoxy group, protected amino group, nitro group, hydroxyl group, protected hydroxyl group, halogen atom, nitrile group, guanidino group, and amidino group A C1-8 alkyl group substituted by a group selected from a carbocyclic or heterocyclic ring substituted by a group selected from
May be replaced by a sulfur atom. )

Embedded image Represents a heterocyclic ring wherein R ^5a and R ^6a together with the nitrogen atom to which they are attached, q has the same meaning as described above;

R ^15a represents 1) a hydroxyl group, 2) a hydroxyl group protected by an acid-removable group, 3) a keto group (oxo group), 4) a protected keto group (oxo group), 5) a C1-4 Alkyl group, 6) C1-4 alkoxy group, 7) phenyl group, 8) phenoxy group, 9) phenyl C1-4 alkyl group, 10) phenyl C1-4 alkoxy group, 11) nitro group, 12) -COOR ^36a Group (in the group, R ^36a is a hydrogen atom, C1
8 alkyl group or a -CONR ³⁷ R ³⁸ group, (wherein, R ³⁷ and R ³⁸ represent the same meanings as defined above.)
—NR ^39a R ^40a group (wherein R ^39a and R ^40a are each independently a hydrogen atom (however, R ^34a and R ^35a are not simultaneously hydrogen atoms), a t-butoxycarbonyl group, a benzyl group An oxycarbonyl group, a C1-4 alkyl group), ^-OR41a group (wherein ^R41a is OR
^42a (in group, R ^42a is a hydrogen atom,. An alkoxyalkyl group or a benzyl group C2-4) represents a C2-4 alkyl group substituted with. ) Or C1-4 substituted with a group selected from a protected piperazino ring
Represents an alkyl group. ),

13) —NR ^43a R ^44a group (wherein R ^43a and R ^44a are each independently a hydrogen atom (provided that R
^34a and R ^35a are not hydrogen atoms at the same time. ), T-butoxycarbonyl group, benzyloxycarbonyl group, C1-4 alkyl group or C2-5 acyl group. ), 14) -CONR ^45a R ^46a group (wherein R ^45a and R ^46a
Each independently represents a hydrogen atom, a C1-4 alkyl group, a hydroxyl group, a hydroxyl group protected with an acid-removable group, a phenyl C1-4 alkoxy group, or a hydroxyl group, a protected hydroxyl group, or a -COOR ^47a group ( In the group, R ^47a represents a hydrogen atom, a C1-8 alkyl group or a benzyl group), and represents a C1-4 alkyl group. ),

15) Hydroxyl group, protected hydroxyl group, -CO
An OR ^48a group (wherein, R ^48a represents a hydrogen atom, a C1-8 alkyl group or a benzyl group), a —NR ^49a R ^50a group (R ^49a and R ^50a each independently represent a hydrogen atom (provided that R ^49a and R ^50a are not hydrogen atoms at the same time.), Represents a t-butoxycarbonyl group, a benzyloxycarbonyl group or a C1-4 alkyl group), and 5 contains one or two nitrogen atoms. Or C1 substituted with a group selected from a 6-membered heterocyclic ring
~ 4 alkyl groups,

16) 5 containing one or two nitrogen atoms
Or a 6-membered heterocyclic ring, 17) a halogen atom, 18) a -CHO group protected by an acid-removable group, or 19) a -NR ^51a -COOR ^52a group (wherein R ^51a and R ^52a are each independently Represents a hydrogen atom or a C1-8 alkyl group.), And the other symbols have the same meanings as described above. ) Can be produced by subjecting the compound to an esterification reaction, or a protected group (protected carboxylic acid,
When it has a hydroxyl group, an amino group, an α-amino acid, a piperazino ring or a —CHO group), following the esterification reaction, a deprotection reaction (t-butyl ester hydrolysis reaction, acid treatment for deprotection or / and hydrogenation) Addition reaction, etc.), or
For compounds with C1~4 alkyl group substituted with OSO ₃ H as ^15, the esterification reaction, or was prepared by performing the deprotection reaction if necessary, it is substituted by hydroxyl group as R ¹⁵ C1 It can be produced by subjecting a compound having an alkyl group of from 4 to 4 to a sulfuric acid esterification reaction.

The protected hydroxyl group is, for example, a group which can be removed by an acid (for example, a C2-4 alkoxyalkyl group,
t-butyl-dimethylsilyl group, THP, triphenylmethyl) or a group that can be removed by hydrogenation (eg,
A benzyl group).

The hydroxyl group protected by an acid-removable group is, for example, a C2-4 alkoxyalkyl group, a t-butyl-dimethylsilyl group, THP, or a hydroxyl group protected by triphenylmethyl.

A protected amino group, α-amino acid or piperazino ring is defined as t-butoxycarbonyl (Boc)
Represents an amino group protected with a benzyloxycarbonyl (Cbz) group or the like, an α-amino acid or a piperazino ring.

The --CHO group protected by a group which can be removed with an acid is protected with an acetal (eg, dimethyl acetal, diethyl acetal, etc.) and a ketal (eg, ethylene dioxy ketal, trimethylene dioxy ketal, etc.). Represents a -CHO group.

The above esterification reaction is known, and examples thereof include (1) a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent.

[0125] These methods will be specifically described.
(1) The method using an acid halide is, for example, a method in which a carboxylic acid is reacted with an acid halide (oxalyl chloride, thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent. The reaction is carried out at 20 ° C. to reflux temperature, and the obtained acid halide is reacted with an alcohol and an inert organic solvent (chloroform,
(Methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0 to 40 ° C.

(2) In the method using a mixed acid anhydride, for example, carboxylic acid is converted into an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.).
An acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) in a medium or no solvent. Isobutyl chloroformate, etc.)
The mixture is reacted at 0 to 40 ° C., and the obtained mixed anhydride is reacted with an alcohol in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) in an amount of 0 to 4 ° C.
The reaction is carried out at 0 ° C.

(3) Condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3-
(Dimethylamino) propyl] carbodiimide (ED
C), 2-chloro-1-methylpyridinium iodine, etc.)
The method using, for example, a carboxylic acid and an alcohol,
A tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) may or may not be used in an inert organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether, etc.) or without a solvent. The reaction is carried out at 0 to 40 ° C. These reactions (1), (2) and (3) are desirably performed under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

The hydrolysis of the t-butyl ester group and the acid treatment reaction (elimination of a C2-4 alkoxyalkyl group, a t-butoxycarbonyl group and dimethyl acetal) are known, and examples thereof include an inert organic solvent (methylene chloride, methylene chloride, The reaction is carried out in an organic acid (such as trifluoroacetic acid) or an inorganic acid (such as hydrochloric acid) or a mixture thereof in chloroform, methanol, dioxane, ethyl acetate, anisole or a mixed solvent thereof at a temperature of 0 to 90 ° C.

The hydrogenation reaction is known. For example, an inert solvent [ether (eg, tetrahydrofuran, dioxane,
Dimethoxyethane, diethyl ether, etc., alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.) , Water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof] in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, etc.) and an inorganic acid (Hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or organic acids (acetic acid, p
-Toluenesulfonic acid, oxalic acid, trifluoroacetic acid,
0 to 20 in the presence or absence of formic acid or the like, in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate.
It is performed at a temperature of 0 ° C. When an acid is used, its salt may be used.

The sulfuric acid esterification reaction is known, for example, by reacting a sulfur trioxide pyridine complex at 0 to 40 ° C. in the presence of a base (eg, pyridine).

The general formulas (II) and (I) used as starting materials
The compound represented by II) is obtained by the method shown in the reaction scheme 1.
Alternatively, the compound can be produced by a known method, or is a commercially available compound. For example, it can be produced by the method described herein. Also, for example, 2
-Phenylbutanoic acid is commercially available.

[0132]

Embedded image

In the reaction scheme 1, W represents an alkali metal, Y represents a benzyl group, a benzyloxycarbonyl group, a group removable with an acid (C2-4 alkoxyalkyl group, t
-Butyl-dimethylsilyl group, tetrahydropyran (T
HP), triphenylmethyl, etc.), and other symbols have the same meanings as described above.

[0134]

The compound of the present invention has an inhibitory effect on elastase. The inhibitory effect on elastase is
For example, it was confirmed by a screening system described below in a laboratory.

(1) Inhibitory effect on human granulocyte elastase 0.2 mM HEPS buffer (pH 8.0) (0.5 ml)
2.5 M aqueous sodium chloride solution (0.2 ml), 1% polyethylene glycol 6000 (0.1 ml), distilled water (0.13 ml),
A mixed solution of a test compound in dimethyl sulfoxide (DMSO) (0.01 ml) and 0.8 U / ml human granulocyte elastase (HSE) (0.05 ml) was preincubated at 37 ° C. for 20 minutes. 5 mM MeO-S
uc-Ala-Ala-Pro-Val-pNA (DM
SO solution; 0.01 ml) was added to the above mixed solution,
For 5 minutes. Add 50 to the reaction solution.
After stopping the reaction by adding 0.1% acetic acid (0.1 ml), the released p-nitroanilide (pNA) was measured at an absorbance of 405 nm, and the inhibition rate was determined by the following equation. Inhibition rate (%) = 1 − {(sample value−blank value) / (control value−blank value)} × 100 The results are shown in Table 47.

[0136]

[Table 54]

(2) Elastase inhibitory action in human granulocyte elastase-induced hamsters Male Syrian hamsters (5 animals)
0.5% sodium carboxymethylcellulose or 80% polyethylene glycol 400 or 2% Tw
The test compound suspended in eeen80 was administered orally. 60 minutes after administration, sodium pentobarbital (60 mg /
kg, i. p. ) HSE in the bronchi exfoliated under anesthesia
(10 U / 100 μl / Lung) to induce lung injury. 60 minutes after the induction, the blood was exsanguinated and killed, and the bronchoalveolar vesicles were washed with physiological saline (2.5 ml).
F) was recovered. The recovered BALF (0.5 ml)
The solution was diluted 4-fold with a 10% aqueous solution of sodium carbonate and subjected to ultrasonic treatment for 10 seconds. In addition, with 2% sodium carbonate aqueous solution
A 2.5-fold diluted solution is measured at an absorbance of 414 nm,
The blood volume in BALF was calculated from the calibration curve. The results are shown in Tables 48 and 49.

[0138]

[Table 55]

[0139]

[Table 56] The above experiments confirmed that the compound of the present invention is a compound having an elastase inhibitory action, particularly an elastase inhibitory action by oral administration.

[0140]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low.
It was confirmed that it can be used safely as a pharmaceutical.

[0141]

[Application to Pharmaceuticals] The compounds of the present invention represented by the general formula (I), their non-toxic salts and acid addition salts are compounds having an elastase inhibitory effect, and are used for elastin degradation by elastase in mammals, especially humans, Diseases caused by abnormal degradation of fiber and / or proteoglycan degradation, for example, chronic obstructive pulmonary disease such as emphysema, rheumatoid arthritis, atherosclerosis, adult respiratory distress (ARDS), glomerulonephritis, myocardium It is useful for treating and / or preventing infarction, ulcerative colitis, periodontal disease and the like.

In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt thereof or a solvate thereof for the above-mentioned purpose, the compound is usually used systemically or locally, in an oral or parenteral form. Is administered. The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is usually orally administered once to several times a day, in the range of 1 mg to 1000 mg per adult per dose. Or parenterally (preferably intravenously) once to several times daily, in the range of 0.1 mg to 100 mg per adult per day, or 1 hour to 24 hours daily It is continuously administered intravenously within the range. Of course, as mentioned above,
Since the dose varies depending on various conditions, a dose lower than the above-mentioned dose may be sufficient, or administration outside the range may be necessary. When administering the compound of the present invention, it is used as a solid composition, a liquid composition and other compositions for oral administration, an injection, an external preparation, a suppository and the like for parenteral administration.

Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, mannitol,
It is mixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The composition may contain, in a conventional manner, an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a solubilizing agent such as glutamic acid or aspartic acid. It may be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers, if necessary. . 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). This composition contains, in addition to the inert diluent, humectants, adjuvants such as suspending agents, sweetening agents, flavoring agents,
It may contain fragrances and preservatives.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition contains, in addition to the inert diluent, a stabilizing agent such as sodium bisulfite to render it isotonic and an isotonic agent such as sodium chloride, sodium citrate or citric acid. You may. Methods for producing sprays are described, for example, in U.S. Patent Nos. 2,868,691 and 3,095,3.
No. 55 describes it in detail.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions 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 preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are sterilized or dissolved in sterile distilled water for injection or other solvents before use.

Other compositions for parenteral administration include external solutions, ointments, liniments, suppositories and vagina for rectal administration, which contain one or more active substances and are formulated in a conventional manner. Pessaries for internal administration, etc. are included.

[0147]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses shown in the chromatographic separation and in the TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Further, the parentheses described in the NMR section indicate the measuring solvent.

Reference Example 1 Potassium salt of 3-methyl-4-hydroxybenzenesulfonic acid

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Heat concentrated sulfuric acid (26 ml) to 100 ° C.
Slowly add o-cresol (50 ml) and add 100
Stirred at C for 5 hours. The reaction solution was cooled to room temperature, and an aqueous solution of potassium hydroxide (27.5 g) (35 ml) was slowly added to neutralize the solution. Add methanol (100 ml) to the reaction mixture
, And filtered, to give the title compound (5
6.5 g). TLC: Rf 0.18 (chloroform: methanol: water =
6: 4: 1).

Reference Example 2 3-methyl-4- (benzyloxycarbonyloxy)
Benzenesulfonic acid potassium salt

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The compound (12.2 g) produced in Reference Example 1 was treated with tetrahydrofuran (hereinafter abbreviated as THF) (100).
2N-aqueous sodium hydroxide solution (28 m
l) was added at room temperature, benzyloxycarbonyl chloride (8 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was concentrated, cooled on ice, and filtered to give the title compound (7.3 g) having the following physical data. TLC: Rf 0.51 (chloroform: methanol: water =
6: 4: 1).

Reference Example 3 3-methyl-4- (benzyloxycarbonyloxy)
Benzenesulfonyl chloride

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Dimethylformamide (hereinafter abbreviated as DMF) of the compound (46.1 g) produced in Reference Example 2 (10)
0 ml) The suspension was ice-cooled, thionyl chloride (15 ml) was slowly added, and the mixture was stirred at 5 ° C or lower for 30 minutes. The reaction solution was poured into ice water and filtered to obtain the title compound (39.4 g) having the following physical data. TLC: Rf 0.56 (chloroform: methanol: water =
6: 4: 1).

Reference Example 4 4- (2S-t-butyloxycarbonylpyrrolidine-
1-ylsulfonyl) -2-methylphenol

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L-proline t-butyl ester (1.9
A solution of g) in pyridine (10 ml) was ice-cooled, the compound (3.7 g) produced in Reference Example 3 was added, and the mixture was stirred for 30 minutes.
Ethyl acetate (200 ml) and a 2N aqueous hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. To a solution of the residue (4.9 g) in methanol (200 ml) was added 10% palladium-carbon (500 mg), and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 2 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated to give the title compound (3.4 g) having the following physical data. TLC: Rf 0.35 (hexane: ethyl acetate = 1:
1).

Reference Example 5 2RS- (4-nitrophenyl) butanoic acid

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Concentrated nitric acid (150 ml) was slowly added to a mixed solution of 2-phenylbutyric acid (200 g) in acetic acid (200 ml) and concentrated sulfuric acid (200 ml).
Stirred for 0 minutes. The reaction solution was poured into ice water and filtered. The residue was recrystallized from a mixed solvent of hexane / ethyl acetate to give the title compound (103 g) having the following physical data. TLC: Rf 0.50 (ethyl acetate).

Reference Example 6 2RS- (4-aminophenyl) butanoic acid methyl ester

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D of the compound (15.7 g) produced in Reference Example 5
Potassium carbonate (12 g) was added to the MF (60 ml) solution, methyl iodide (5 ml) was added under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature. A hexane / ethyl acetate (1: 1, 200 ml) mixed solvent and a 1N aqueous hydrochloric acid solution (200 ml) were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. To a solution of the residue in methanol (300 ml) was added 5% palladium-carbon (1.3 g), and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 2 hours. After the reaction solution was filtered through celite, the filtrate was concentrated to give the title compound (14.2 g) having the following physical data. TLC: Rf 0.47 (hexane: ethyl acetate = 1:
1).

Reference Example 7 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid

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Dimethyl sulfoxide (hereinafter abbreviated as DMSO) of the compound (14.2 g) produced in Reference Example 6 (7)
Potassium carbonate (11 g) and 1,4-dibromobutane (9 ml) were added to the solution (5 ml), and the mixture was stirred at 40 ° C for 1 hour. Sodium iodide (11.2 g) was added to the reaction solution, and 40
The mixture was stirred for 3 hours at 60 ° C and 2 hours at 60 ° C. Hexane / ethyl acetate (1: 1, 1 l) and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. A 5N aqueous solution of sodium hydroxide (2 ml) was added to a solution of the residue in methanol (80 ml).
0 ml) and stirred at room temperature for 5 hours. The reaction solution was adjusted to pH 8 by adding hydrochloric acid, and washed with ethyl acetate. The aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from a mixed solvent of hexane / ethyl acetate (3: 1) to give the title compound (9.83 g) having the following physical data. TLC: Rf 0.30 (hexane: ethyl acetate = 1:
1).

Example 1 4- (2S-tert-butyloxycarbonylpyrrolidine-
1-ylsulfonyl) -2-methylphenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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The compound prepared in Reference Example 4 (748m
g), a solution of the compound (537 mg) prepared in Reference Example 7 and dimethylaminopyridine (64 mg) in methylene chloride (20 ml) was added at room temperature to 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (482 m2).
g) was added and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed twice with a 1N aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (1.04 g) having the following physical data. TLC: Rf 0.23 (hexane: ethyl acetate = 5:
1).

Examples 1 (1) to 1 (147) Example 1 was repeated using the corresponding phenol derivative instead of the compound prepared in Reference Example 4 and the corresponding carboxylic acid derivative instead of the compound prepared in Reference Example 7. The compound of the present invention having the following physical data was obtained by the same procedure as in or by conversion to the corresponding salt or acid addition salt by a conventional method.

Example 1 (1) 4- (2S-hydroxymethylpyrrolidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 7.85 (2H, d, J = 9 Hz),
7.28 (2H, d, J = 9Hz), 7.28 (2H, d, J = 9Hz), 6.83 (2H, d, J = 9Hz)
Hz), 3.75 (1H, t, J = 7Hz), 3.60-3.44 (2H, m), 3.40-3.20
(6H, m), 3.11-2.95 (1H, m), 2.21-1.90 (5H, m), 1.90-1.65
(3H, m), 1.55-1.30 (2H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.48 (ethyl acetate: hexane = 1:
1).

Example 1 (2) 4- (2-oxopyrrolidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 8.05 (2H, d, J = 8.8 Hz),
7.61 (2H, d, J = 8.6Hz), 7.47 (2H, d, J = 8.6Hz), 7.19 (2H, d, J = 8.6Hz)
d, J = 8.8Hz), 3.89 (2H, t, J = 7.2Hz), 3.74 (1H, t, J = 7.8H
z), 3.85-3.45 (4H, brs), 2.44 (2H, t, J = 7.8Hz), 2.40-2.
25 (4H, m), 2.35-1.75 (2H, m), 2.20-2.00 (2H, m), 0.99 (3
H, t, J = 7.4Hz), TLC: Rf 0.39 (ethyl acetate: hexane = 1:
1).

Example 1 (3) 4- (pyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.68-7.57 (2H, m), 7.
23 (2H, d, J = 8Hz), 7.06 (1H, d, J = 8Hz), 6.55 (2H, d, J = 8Hz),
3.61 (1H, t, J = 7Hz), 3.35-3.13 (8H, m), 2.30-1.65 (13H,
m), 0.98 (3H, t, J = 7 Hz), TLC: Rf 0.49 (ethyl acetate: hexane = 3:
7).

Example 1 (4) 4- (2S- (pyrrolidin-1-ylmethyl) pyrrolidin-1-ylsulfonyl) -2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.95-7.75 (2H, m), 7.
65 (4H, s), 7.22 (1H, d, J = 8.5Hz), 4.26-3.90 (2H, m), 3.9
9 (1H, t, J = 7.5Hz), 3.90-3.70 (5H, m), 3.50-3.10 (6H, m),
2.40-2.25 (4H, m), 2.40-1.35 (10H, m), 2.07 (3H, s), 1.
00 (3H, t, J = 7.5Hz), TLC: Rf 0.43 (water: methanol: chloroform =
1:10:90).

Example 1 (5) 4- (pyrrolidin-1-ylsulfonyl) phenyl 2
RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.85-7.74 (2H, m), 7.
41-7.24 (5H, m), 7.23-7.10 (2H, m), 3.71 (1H, t, J = 7Hz),
3.30-3.15 (4H, m), 2.39-2.10 (1H, m), 2.03-1.80 (1H, m),
1.80-1.68 (4H, m), 0.99 (3H, t, J = 7Hz), TLC: Rf 0.43 (hexane: ethyl acetate = 2:
1).

Example 1 (6) 4- (Indoline-1-ylsulfonyl) phenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.78 (2H, d, J = 8.8 Hz),
7.62 (1H, d, J = 8.0Hz), 7.50-7.34 (4H, m), 7.24-7.12 (1
H, m), 7.08 (3H, d, J = 8.8Hz), 6.97 (1H, dt, J = 1.0 and 7.2
Hz), 3.90 (2H, d, J = 8.4Hz), 3.68 (1H, t, J = 7.6Hz), 3.70-
3.45 (4H, m), 2.89 (2H, t, J = 8.4Hz), 2.40-2.20 (4H, m),
2.30-2.05 and 2.00-1.75 (each 1H, m), 0.96 (3H, t, J = 7.
2 Hz), TLC: Rf 0.47 (ethyl acetate: hexane = 1:
2).

Example 1 (7) 4- (2- (ethoxycarbonyl) indolin-1-ylsulfonyl) 2-methylphenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.7-7.5 (m, 3H), 7.2-
6.9 (m, 6H), 6.8-6.4 (m, 2H), 4.71 (q, J = 5.2Hz, 1H), 4.23
(q, J = 7.2Hz, 2H), 3.57 (t, J = 7.6Hz, 1H), 3.4-3.0 (m, 6H),
2.4-1.8 (m, 9H), 1.29 (t, J = 7.2Hz, 3H), 1.0-0.9 (m, 3
H), TLC: Rf 0.63 (hexane: ethyl acetate = 2:
1).

Example 1 (8) 4- (2- (ethoxycarbonyl) indoline-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.77 (2H, d, J = 8.5 Hz),
7.53 (1H, d, J = 8.0Hz), 7.24-6.93 (7H, m), 6.52 (2H, d, J =
8.5Hz), 4.71 (1H, dd, J = 10.0,5.5Hz), 4.24 (2H, q, J = 7.0H
z), 3.54 (1H, t, J = 8.0Hz), 3.32-3.22 (4H, m), 3.22 (1H, d
d, J = 10.0,16.0Hz), 3.06 (1H, dd, J = 16.0,5.5Hz), 2.05-
1.90 (4H, m), 2.25-1.70 (2H, m), 1.29 (3H, t, J = 7.0Hz),
0.95 (3H, t, J = 7.5Hz), TLC: Rf 0.57 (hexane: ethyl acetate = 1:
1).

Example 1 (9) 4- (2RS- (N, N-dimethylaminocarbonylmethoxycarbonyl) indolin-1-ylsulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-
1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.7-7.5 (m, 3H), 7.2-
6.9 (m, 6H), 6.54 (d, J = 8.6Hz, 2H), 4.85 (d, J = 14.5Hz, 1
H), 4.82 (dd, J = 1.0,10.8Hz, 1H), 4.70 (d, J = 14.5Hz, 1H),
3.58 (t, J = 7.7Hz, 1H), 3.65-3.50 (m, 1H), 3.45 (dd, J = 1
0.8, 16.1Hz, 1H), 3.4-3.2 (m, 4H), 2.96 (s, 3H), 2.94 (s, 3H)
H), 2.3-1.8 (m, 6H), 1.97 (s, 3H), 0.96 (t, J = 7.4Hz, 3
H), TLC: Rf 0.52 (chloroform: ethyl acetate = 1:
1).

Example 1 (10) 4- (2RS- (N-benzyloxycarbamoyl) indolin-1-ylsulfonyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 9.22 (1H, s), 7.60 (1
H, d, J = 8.0Hz), 7.51 (2H, d, J = 9.0Hz), 7.29 (5H, s), 7.17
-7.00 (8H, m), 6.52 (2H, d, J = 9.0Hz), 4.88 (2H, s), 4.60
(1H, dd, J = 10.0Hz, 1.5Hz), 3.53 (1H, t, J = 7.0Hz), 3.26 (5
H, t-like, J = 6.0Hz), 2.74 (1H, dd, J = 16.0Hz, 10.0Hz), 2.
20-1.77 (2H, m), 2.03-1.98 (4H, m), 0.92 (3H, t, J = 7.0H
z), TLC: Rf 0.44 (hexane: ethyl acetate = 1:
1).

Example 1 (11) 4- (6-nitroindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.10 (dd, J = 2.4,8.8H
z, 1H), 7.96 (s, 1H), 7.7-7.6 (m, 3H), 7.18 (d, J = 8.4Hz, 2
H), 7.05 (d, J = 8.0Hz, 1H), 6.52 (d, J = 8.4Hz, 2H), 4.01
(t, J = 8.6Hz, 2H), 3.58 (t, J = 7.8Hz, 1H), 3.3-3.2 (m, 4H),
3.08 (t, J = 8.6Hz, 2H), 2.3-1.8 (m, 2H), 2.00 (s, 3H), 2.
1-1.9 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), TLC: Rf 0.33 (hexane: ethyl acetate = 3:
1).

Example 1 (12) 4- (6-aminoindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.6-7.4 (m, 3H), 7.20
(d, J = 8.7Hz, 2H), 6.94 (d, J = 8.4Hz, 1H), 6.53 (d, J = 8.7H
z, 2H), 6.6-6.4 (m, 2H), 3.83 (t, J = 8.2Hz, 2H), 3.58 (t, J
= 7.7Hz, 1H), 3.4-3.2 (m, 4H), 2.64 (t, J = 8.2Hz, 2H), 2.3
-1.8 (m, 6H), 1.95 (s, 3H), 0.97 (t, J = 7.4 Hz,
3H), TLC: Rf 0.59 (hexane: ethyl acetate = 1:
1).

Example 1 (13) 4- (7-Nitroindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.38 (d, J = 2.2 Hz, 1H),
7.85 (dd, J = 2.0,8.4Hz, 1H), 7.8-7.6 (m, 2H), 7.2-7.1
(m, 1H), 7.18 (d, J = 8.6Hz, 2H), 7.03 (d, J = 8.2Hz, 1H), 6.
52 (d, J = 8.6Hz, 2H), 3.99 (t, J = 8.6Hz, 2H), 3.58 (t, J = 7.6
Hz, 1H), 3.3-3.2 (m, 4H), 3.05 (t, J = 8.6Hz, 2H), 2.3-1.7
(m, 9H), 0.96 (t, J = 7.4 Hz, 3H), TLC: Rf 0.49 (hexane: ethyl acetate = 1:
1).

Example 1 (14) 4- (7-aminoindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.6-7.5 (m, 2H), 7.15
(d, J = 8.6Hz, 2H), 7.0-6.9 (m, 2H), 6.82 (d, J = 8.0Hz, 1H),
6.52 (d, J = 8.6Hz, 2H), 6.29 (dd, J = 2.0,8.0Hz, 1H), 3.84
(t, J = 8.0Hz, 2H), 3.58 (t, J = 7.6Hz, 1H), 3.4-3.2 (m, 4H),
2.76 (t, J = 7.6Hz, 2H), 2.3-1.8 (m, 9H), 0.97 (t, J = 7.4H
z, 3H), TLC: Rf 0.40 (hexane: ethyl acetate = 2:
1).

Example 1 (15) 4- (benzimidazol-1-ylsulfonyl) -2
-Methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.35 (1H, s), 7.79 (4
H, m), 7.35 (2H, m), 7.17 (2H, d, J = 8.8Hz), 7.08 (1H, d, J =
9.4Hz), 6.52 (2H, d, J = 8.8Hz), 3.57 (1H, t, J = 7.8Hz), 3.
26 (4H, m), 2.10 (1H, m), 2.00 (3H, s), 1.97 (4H, m), 1.88
(1H, m), 0.95 (3H, t, J = 7.4Hz), TLC: Rf 0.49 (hexane: ethyl acetate = 2:
1).

Example 1 (16) 4- (morpholin-4-ylsulfonyl) phenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 7.75 (2H, d, J = 7 Hz),
7.27 (2H, d, J = 7Hz), 7.16 (2H, d, J = 7Hz), 6.52 (2H, d, J = 7Hz)
Hz), 3.67 (1H, t, J = 7Hz), 3.61 (4H, t-like), 3.20 (4H, t-like)
like), 2.83 (4H, t-like), 2.04 (1H, m), 1.94 (4H, t-lik
e), 1.79 (1H, m), 0.88 (3H, t, J = 7 Hz), TLC: Rf 0.54 (hexane: ethyl acetate = 1:
1).

Example 1 (17) 4- (6-aza-7-oxo-bicyclo [3.2.1]
Octane-6-ylsulfonyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.19 (2H, d, J = 9 Hz),
7.38 (2H, d, J = 9Hz), 7.19 (4H, d, J = 9Hz), 4.65-4.55 (1H,
m), 3.68 (1H, t, J = 7Hz), 3.61-3.37 (4H, m), 2.59-2.49 (1
H, m), 2.35-1.46 (12H, m), 1.35-1.10 (2H, m), 0.99 (3H,
t, J = 7Hz), TLC: Rf 0.17 (ethyl acetate: hexane = 1:
3).

Example 1 (18) 4- (4-benzylpiperazin-1-ylsulfonyl)
Phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.83 (2H, d, J = 8.6 Hz),
7.75-7.40 (9H, m), 7.29 (2H, d, J = 8.6Hz), 4.35 (2H, s),
4.00-3.62 (7H, m), 3.60-3.40 (2H, m), 3.30-3.10 (2H, m),
2.98-2.72 (2H, m), 2.38-2.10 (5H, m), 2.04-1.80 (1H, m
m), 0.99 (3H, t, J = 7.4 Hz), TLC: Rf 0.40 (ethyl acetate: hexane = 3:
7).

Example 1 (19) 4- (4- (2-hydroxyethyl) piperidine-1-
Ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.71 (2H, d, J = 9.0 Hz),
7.72 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 9.0Hz), 6.55 (2H,
d, J = 8.7Hz), 3.74 (2H, d, J = 10.2Hz), 3.63 (2H, t, J = 6.0H
z), 3.58 (1H, t, J = 8.0Hz), 3.36-3.22 (4H, m), 2.35-1.78
(8H, m), 1.72 (2H, d, J = 10.0Hz), 1.54-1.20 (5H, m), 0.98
(3H, t, J = 7.4Hz), TLC: Rf 0.52 (chloroform: methanol = 1
9: 1).

Example 1 (20) 4- (2RS-hydroxymethylpiperidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 7.85 (2H, d, J = 9 Hz),
7.27 (2H, d, J = 9Hz), 7.22 (2H, d, J = 9Hz), 6.83 (2H, d, J = 9Hz)
Hz), 3.93-3.80 (1H, m), 3.75 (1H, t, J = 7Hz), 3.69-3.45
(2H, m), 3.45-3.20 (5H, m), 3.06-2.88 (1H, m), 2.21-1.80
(5H, m), 1.80-1.64 (2H, m), 1.55-1.30 (3H, m), 1.30-0.9
9 (2H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.46 (ethyl acetate: hexane = 1:
1).

Example 1 (21) 4- (4- (N, N-dimethylamino) piperidine-1
-Ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.71 (2H, d, J = 8.7 Hz),
7.20 (2H, d, J = 8.8Hz), 7.16 (2H, d, J = 8.7Hz), 6.54 (2H, d
d, J = 8.8Hz), 3.75 (2H, d, J = 13.7Hz), 3.58 (1H, t, J = 7.7H
z), 3.29 (4H, t, J = 6.6Hz), 2.36-1.53 (19H, m), 0.98 (3H,
t, J = 7.4Hz), TLC: Rf 0.25 (hexane: ethyl acetate = 2:
1).

Example 1 (22) 4- (4- (pyrimidin-2-yl) piperazine-1-
Ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8.8 Hz),
7.72 (2H, d, J = 8.7Hz), 7.22-7.12 (4H, m), 6.56-6.47 (3
H, m), 3.93 (4H, t, J = 5.2Hz), 3.57 (1H, t, J = 7.7Hz), 3.31
-3.25 (4H, m), 3.04 (4H, t, J = 5.1Hz), 2.25-1.65 (6H, m),
0.97 (3H, t, J = 7.3Hz), TLC: Rf 0.43 (hexane: ethyl acetate = 1:
1).

Example 1 (23) 4- (1,4-dioxa-8-azaspiro [4.5] decane-8-ylsulfonyl) phenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.72 (2H, d, J = 8.7 Hz),
7.24-7.15 (4H, m), 6.56 (2H, d, J = 8.7Hz), 3.89 (4H, s),
3.59 (1H, t, J = 7.7Hz), 3.29 (4H, t, J = 6.6Hz), 3.14 (4H, t, J
J = 5.7Hz), 2.30-1.61 (10H, m), 0.98 (3H, t, J = 7.4Hz), TLC: Rf 0.48 (hexane: ethyl acetate = 1:
1).

Example 1 (24) 4- (3-Azabicyclo [3.2.2] nonan-3-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.73 (2H, d, J = 8.6 Hz),
7.53 (2H, d, J = 8.6Hz), 7.45 (2H, d, J = 8.6Hz), 7.15 (2H, d, J = 8.6Hz)
d, J = 8.8Hz), 3.72 (1H, t, J = 7.6Hz), 3.75-3.50 (4H, m),
3.22 (4H, d, J = 4.2Hz), 2.40-2.20 (4H, m), 2.40-1.75 (2H,
m), 2.10-2.00 (2H, m), 1.80-1.50 (8H, m), 0.99 (3H, t, J =
7.4 Hz), TLC: Rf 0.57 (ethyl acetate: hexane = 1:
3).

Example 1 (25) 4- (1,3,3-trimethyl-6-azabicyclo [3.2.1] octan-6-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) Phenyl) butanoate / hydrochloride

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NMR (CDCl ₃ ): δ 7.81 (2H, d, J = 8.8 Hz),
7.40 (2H, d, J = 8.4Hz), 7.36-7.18 (2H, brs), 7.15 (2H, d,
J = 8.8Hz), 4.08 (1H, t-like), 3.69 (1H, t, J = 7.8Hz), 3.6
4-3.38 (4H, m), 3.32 (1H, d, J = 9.6Hz), 2.76 (1H, dd, J = 9.6
and 1.4Hz), 2.36-2.08 (5H, m), 2.02-1.76 (2H, m), 1.5
2 (2H, d, J = 14.4Hz), 1.34 (2H, d, J = 12.4Hz), 1.22 (3H, s),
1.16-1.02 (1H, m), 0.99 (3H, t, J = 7.4Hz), 0.94 (3H, s),
0.92 (3H, s), TLC: Rf 0.54 (ethyl acetate: hexane = 1:
3).

Example 1 (26) 4- (2-oxopiperidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 8.03 (2H, d, J = 9.0 Hz),
7.65 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz)
d, J = 9.0Hz), 3.89 (2H, t, J = 5.8Hz), 3.74 (1H, t, J = 7.8H
z), 3.80-3.50 (4H, m), 2.42 (2H, t, J = 6.6Hz), 2.50-2.25
(4H, m), 2.40-1.70 (2H, m), 2.00-1.70 (4H, m), 0.99 (3H,
t, J = 7.4 Hz), TLC: Rf 0.83 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (27) 4- (2-oxo-4S-benzyltetrahydrooxazol-3-ylsulfonyl) phenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.13 (2H, d, J = 8.8 Hz),
7.64 (2H, d, J = 8.8Hz), 7.48 (2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz)
d, J = 8.8Hz), 7.40-7.16 (5H, m), 4.75-4.58 (1H, m), 4.24
-4.05 (2H, m), 3.76 (1H, t, J = 7.6Hz), 3.85-3.50 (4H, br
s), 3.50 (1H, dd, J = 13.2,3.8Hz), 2.83 (1H, dd, J = 13.2,1
0.2Hz), 2.44-2.26 (4H, m), 2.34-2.10 and 2.10-1.76 (e
ach1H, m), 0.99 (3H, t, J = 7.4Hz), TLC: Rf 0.51 (ethyl acetate: hexane = 1:
2).

Example 1 (28) 4- (2-oxo-4S-isopropylperhydrooxazol-3-ylsulfonyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.10 (2H, d, J = 9.0 Hz),
7.63 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz)
d, J = 9.0Hz), 4.43 (1H, dt, J = 8.2,3.0Hz), 4.29 (1H, t, J =
8.8Hz), 4.16 (1H, dd, J = 8.8,3.0Hz), 3.75 (1H, t, J = 7.6H
z), 3.90-3.45 (4H, brs), 2.56-1.76 (7H, m), 0.99 (3H, t,
J = 7.2 Hz), 0.93 (3H, d, J = 6.8 Hz), 0.75 (3H, d, J = 6.8 Hz), TLC: Rf 0.62 (ethyl acetate: hexane = 1:
1).

Example 1 (29) 4- (2-oxo-4S-methyl-5S-phenylperhydrooxazol-3-ylsulfonyl) phenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.13 (2H, d, J = 8.8 Hz),
7.72 (2H, d, J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 7.46-7.34
(3H, m), 7.23 (2H, d, J = 8.8Hz), 7.30-7.20 (2H, m), 5.71
(1H, d, J = 7.2Hz), 4.78 (1H, dq, J = 7.2Hz), 3.77 (1H, t, J =
7.2Hz), 3.90-3.50 (4H, brs), 2.50-2.25 (4H, brs), 2.40
-1.80 (2H, m), 1.00 (3H, t, J = 7.2Hz), 0.97 (3H, d, J = 7.2H
z), TLC: Rf 0.66 (ethyl acetate: hexane = 1:
2).

Example 1 (30) 4- (1RS-oxo-4S-methoxycarbonylperhydrothiazol-3-ylsulfonyl) phenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 9.0 Hz),
7.21 (2H, d, J = 9.0Hz), 7.19 (2H, d, J = 9.0Hz), 6.55 (2H, d
d, J = 9.0Hz), 5.28-5.16 (2H, m), 4.09-4.01 (1H, m), 3.69
-3.44 (5H, m), 3.33-3.26 (4H, m), 3.08-2.97 (1H, m), 2.2
4-1.80 (6H, m), 0.98 (3H, t, J = 7.4 Hz), TLC: Rf 0.50 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 1 (31) 4- (morpholin-4-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.56-7.51 (2H, m), 7.
26-7.21 (2H, m), 7.10 (1H, d, J = 8Hz), 6.55 (2H, d, J = 8Hz),
3.75-3.71 (4H, m), 3.62 (1H, t, J = 8Hz), 3.32-3.26 (4H, m
m), 3.01-2.96 (4H, m), 2.37-1.73 (2H, m), 2.06 (3H, s),
2.04-1.96 (4H, m), 1.00 (3H, t, J = 8Hz), TLC: Rf 0.27 (hexane: ethyl acetate = 3:
1).

Example 1 (32) 4- (Imidazol-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl)
Phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.99 (1H, m), 7.75 (1
H, s), 7.72 (1H, m), 7.27-7.08 (5H, m), 6.54 (2H, d, J = 8.8H
z), 3.60 (1H, t, J = 7.6Hz), 3.28 (4H, m), 2.14 (1H, m), 2.
04 (3H, s), 2.01 (4H, m), 1.91 (1H, m), 0.97 (3H, t, J = 7.4H
z), TLC: Rf 0.36 (hexane: ethyl acetate = 2:
1).

Example 1 (33) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.80-7.56 (6H, m), 7.
18 (1H, d, J = 8.2Hz), 4.00 (1H, t, J = 7.6Hz), 3.90-3.72 (4
H, m), 3.30 (8H, s-like), 2.43-2.15 (5H, m), 2.06 (3H,
s), 2.15-1.84 (1H, m), 1.00 (3H, t, J = 7.2 Hz), TLC: Rf 0.53 (chloroform: methanol: acetic acid = 15: 2: 1).

Example 1 (34) 4- (morpholin-4-ylsulfonyl) phenyl 2
RS- (4-nitrophenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8 Hz),
7.77 (2H, d, J = 8Hz), 7.59 (2H, d, J = 8Hz), 7.20 (2H, d, J = 8H)
z), 3.86 (1H, t, J = 7Hz), 3.80-3.68 (4H, m), 3.06-2.94 (4
H, m), 2.30 (1H, ddq, J = 14Hz, 7Hz, 7Hz), 1.97 (1H, ddq, J = 1
4 Hz, 7 Hz, 7 Hz), 1.03 (3 H, t, J = 7 Hz), TLC: Rf 0.16 (hexane: ethyl acetate = 7:
3).

Example 1 (35) 4- (morpholin-4-ylsulfonyl) phenyl 1
-(4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8 Hz),
7.77 (2H, d, J = 8Hz), 7.56 (2H, d, J = 8Hz), 7.16 (2H, d, J = 8H
z), 3.79-3.66 (4H, m), 3.15-2.91 (6H, m), 2.80-2.60 (2
H, m), 2.39-1.91 (2H, m), TLC: Rf 0.16 (hexane: ethyl acetate = 7:
3).

Example 1 (36) 4- (6-aza-7-oxobicyclo [3.2.1] octan-6-ylsulfonyl) phenyl 2- (4-methoxyphenyl) -2-ethylbutanoate

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NMR (CDCl ₃ ): δ 8.08 (2H, d, J = 8.8 Hz),
7.27 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.8Hz), 6.91 (2H, d, J = 8.8Hz)
d, J = 8.8Hz), 4.59 (1H, brt, J = 4.8Hz), 3.82 (3H, s), 2.53
(1H, brs), 2.32-1.15 (12H, m), 0.84 (6H, t, J = 7.4Hz), TLC: Rf 0.85 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (37) 4- (morpholin-4-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.57-7.52 (2H, m), 7.
30-7.08 (5H, m), 3.75-3.67 (5H, m), 3.01-2.96 (4H, m),
2.36 (3H, s), 2.32-2.13 and 2.03-1.82 (each 1H, m), 2.
02 (3H, s), 1.00 (3H, t, J = 7Hz), TLC: Rf 0.30 (hexane: ethyl acetate = 3:
1).

Example 1 (38) 4- (Imidazol-1-ylsulfonyl) phenyl
2RS-phenylbutanoic acid ester

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NMR (CDCl ₃ ): δ 7.99 (1H, s), 7.97-
7.86 (2H, m), 7.40-7.28 (5H, m), 7.28-7.25 (1H, m), 7.25
-7.15 (2H, m), 7.13-7.05 (1H, m), 3.68 (1H, t, J = 7Hz), 2.
34-2.05 (1H, m), 2.05-1.98 (1H, m), 0.96 (3H, t, J = 7 Hz), TLC: Rf 0.29 (hexane: ethyl acetate = 6:
4).

Example 1 (39) 4- (morpholin-4-ylsulfonyl) phenyl 2
RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.78-7.67 (2H, m), 7.
43-7.24 (5H, m), 7.24-7.15 (2H, m), 3.78-3.65 (5H, m),
3.03-2.93 (4H, m), 2.36-2.11 (1H, m), 2.05-1.80 (1H, m),
0.99 (3H, t, J = 7Hz), TLC: Rf 0.26 (hexane: ethyl acetate = 2:
1).

Example 1 (40) 4- (N-1RS- (ethoxycarbonyl) -2- (morpholin-4-yl) ethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl)
Butanoic acid ester

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NMR (CDCl ₃ ): δ 7.84 (2H, d, J = 8.6 Hz),
7.20 (2H, d, J = 8.6Hz), 7.12 (2H, d, J = 8.6Hz), 6.55 (2H, d
d, J = 8.6Hz), 4.01 (3H, m), 3.57 (5H, m), 3.29 (4H, t, J = 6.
4Hz), 2.63 (2H, m), 2.36 (4H, m), 2.14 (1H, m), 2.01 (4H, m
m), 1.89 (1H, m), 1.17 (3H, t, J = 7.0Hz), 0.97 (3H, t, J = 7.
4 Hz), TLC: Rf 0.34 (hexane: ethyl acetate = 1:
1).

Example 1 (41) 4- (N-1RS- (ethoxycarbonyl) -2- (morpholin-4-yl) ethylsulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8.8 Hz),
7.89 (2H, d, J = 8.6Hz), 7.57 (2H, d, J = 8.8Hz), 7.13 (2H, d, J = 8.8Hz)
d, J = 8.6Hz), 4.03 (2H, q, J = 7.2Hz), 3.96 (1H, t, J = 7.0H
z), 3.84 (1H, t, J = 7.0Hz), 3.58 (4H, m), 2.68 (1H, dd, J = 1
3.1,7.0Hz), 2.61 (1H, dd, J = 13.1,7.0Hz), 2.36 (4H, m),
2.82 (1H, m), 1.95 (1H, dq, J = 13.6,7.2Hz), 1.17 (3H, t, J =
7.2 Hz), 1.02 (3H, t, J = 7.2 Hz), TLC: Rf 0.45 (ethyl acetate).

Example 1 (42) 4- (N-1RS- (ethoxycarbonyl) -2- (morpholin-4-yl) ethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8.8 Hz),
7.86 (2H, d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz), 7.09 (2H, d, J = 8.8Hz)
d, J = 8.8Hz), 4.03 (2H, q, J = 7.2Hz), 3.95 (1H, t, J = 6.2H
z), 3.57 (4H, t, J = 5.2Hz), 3.05 (2H, m), 2.67 (2H, m), 2.
66 (1H, dd, J = 12.6,6.2Hz), 2.60 (1H, dd, J = 12.6,6.2Hz),
2.35 (4H, t, J = 5.2Hz), 2.23 (1H, m), 2.04 (1H, m), 1.17 (3
H, t, J = 7.2Hz), TLC: Rf 0.40 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (43) 4- (N-1RS- (ethoxycarbonyl) -2- (morpholin-4-yl) ethylsulfamoyl) phenyl 2RS-phenyl-2-methoxyacetic acid ester

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NMR (CDCl ₃ ): δ 7.86 (2H, d, J = 8.8 Hz),
7.52 (2H, m), 7.42 (3H, m), 7.12 (2H, d, J = 8.8Hz), 5.00
(1H, s), 4.01 (2H, q, J = 7.0Hz), 3.94 (1H, t, J = 6.6Hz), 3.
57 (4H, t, J = 5.2Hz), 3.49 (3H, s), 2.66 (1H, dd, J = 12.8,6.
6Hz), 2.60 (1H, dd, J = 12.8,6.6Hz), 2.34 (4H, t, J = 5.2H
z), 1.16 (3H, t, J = 7.0Hz), TLC: Rf 0.26 (hexane: ethyl acetate = 1:
1).

Example 1 (44) 4- (N-benzyloxycarbonylsulfamoyl)
Phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.3-8.0 (1H, brs), 8.
00 (2H, d, J = 8.8Hz), 7.56 (2H, d-like), 7.46 (2H, d-like),
7.38-7.22 (5H, m), 7.15 (2H, d, J = 8.8Hz), 5.07 (2H, s),
3.74 (1H, t, J = 7.8Hz), 3.8-3.5 (4H, m), 2.4-2.2 (4H, m),
2.40-2.10 and 2.10-1.80 (each 1H, m), 1.00 (3H, t, J = 7.
2Hz), TLC: Rf 0.50 (acetic acid: ethyl acetate: hexane =
1: 8: 16).

Example 1 (45) 4- (N-1RS-phenyl-2RS-methylbutylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.80-7.57 (2H, m), 7.
57-7.32 (4H, m), 7.12-6.93 (3H, m), 6.93-6.70 (4H, m),
5.38 (1H, m), 4.19-3.99 (1H, m), 3.90-3.30 (5H, m), 2.5
0-2.04 (5H, m), 1.96-1.40 (3H, m), 1.28-0.57 (10H,
m), TLC: Rf 0.24 (ethyl acetate: hexane = 1:
4).

Example 1 (46) 4-Sulfamoylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.88 (2H, d, J = 8.6 Hz),
7.18 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.8Hz), 6.57 (2H, d
d, J = 8.6Hz), 3.61 (1H, t, J = 7.6Hz), 3.34-3.19 (4H, m),
2.26-2.00 and 2.00-1.70 (each 1H, m), 2.07-1.96 (4H,
m), 0.96 (3H, t, J = 7.4 Hz), TLC: Rf 0.22 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (47) 4- (N-2-methoxyethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.83 (2H, d, J = 9.0 Hz),
7.22 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 9.0Hz), 6.56 (2H,
d, J = 8.6Hz), 4.85 (1H, br), 3.59 (1H, t, J = 7.7Hz, CH), 3.
42-3.20 (9H, m), 3.11 (2H, m), 2.28-1.70 (6H, m), 0.98 (3
H, t, J = 7.6Hz), TLC: Rf 0.55 (hexane: ethyl acetate = 2:
3).

Example 1 (48) 4- (N-2-methoxyethyl-N-benzylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.82 (2H, d, J = 6.8 Hz),
7.29 (5H, s), 7.19 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 6.8H
z), 6.56 (2H, d, J = 8.6Hz), 4.40 (2H, s), 3.60 (1H, t, J = 7.
4Hz), 3.2-3.4 (8H, m), 3.10 (3H, s), 1.8-2.3 (6H, m), 0.
99 (3H, t, J = 7.3Hz), TLC: Rf 0.40 (hexane: ethyl acetate = 3:
1).

Example 1 (49) 4- (Nt-butyloxysulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl)
Butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz),
7.24-7.15 (4H, m), 6.56 (2H, d, J = 8.2Hz), 6.44 (1H, s),
3.59 (1H, t, J = 7.2Hz), 3.33-3.26 (4H, m), 2.45-1.80 (6H,
m), 1.21 (9H, s), 0.982 (3H, t, J = 7.2 Hz), TLC: Rf 0.40 (hexane: ethyl acetate: acetic acid =
5: 2: 0.1).

Example 1 (50) 4- (N-4-hydroxybutylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.82 (2H, d, J = 8.7 Hz),
7.22 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.7Hz), 6.56 (2H, d
d, J = 8.6Hz), 5.00 (1H, t, J = 5.2Hz), 3.70-3.48 (3H, m),
3.40-3.12 (4H, m), 3.06-2.86 (2H, m), 2.30-1.76 (6H, m),
1.78-1.62 (1H, br.s), 1.60-1.40 (4H, m), 0.97 (3H, t, J =
7.4 Hz), TLC: Rf 0.48 (ethyl acetate).

Example 1 (51) 4- (N-1RS-hydroxymethyl-2-methylpropylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.85 (2H, d, J = 8.4 Hz),
7.21 (2H, d, J = 8.6Hz), 7.12 (2H, d, J = 8.4Hz), 6.55 (2H, d
d, J = 8.6Hz), 5.06 (1H, d, J = 8.4Hz), 3.58 (1H, t, J = 5.8H
z), 3.56-3.48 (2H, m), 3.36-3.22 (4H, m), 3.10-2.90 (1
H, m), 2.23-1.65 (8H, m), 0.97 (3H, t, J = 7.2Hz), 0.78 (6
H, d, J = 6.8 Hz), TLC: Rf 0.25 (ethyl acetate: hexane = 2:
3).

Example 1 (52) 4- (N-2RS, 3-dihydroxypropylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.80 (2H, d, J = 8.6 Hz),
7.20 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.6Hz), 6.54 (2H,
d, J = 8.8Hz), 5.63 (1H, t, J = 6.3Hz), 3.80-3.64 (1H, m),
3.62-3.41 (3H, m), 3.35-3.20 (4H, m), 3.10-2.80 (3H, m),
2.30-1.70 (7H, m), 0.96 (3H, t, J = 7.4Hz), TLC: Rf 0.28 (ethyl acetate: hexane = 4:
1).

Example 1 (53) 4- (N-benzyloxysulfamoyl) phenyl
2RS- (4- (pyrrolidin-1-yl) phenyl)
Butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 8.8 Hz),
7.32-7.12 (9H, m), 6.93 (1H, s), 6.54 (2H, d, J = 8.8Hz),
4.94 (2H, s), 3.57 (1H, t, J = 7.8Hz), 3.31-3.25 (4H, m),
2.25-1.80 (6H, m), 0.968 (3H, t, J = 7.4Hz), TLC: Rf 0.55 (hexane: ethyl acetate: acetic acid =
5: 2: 0.2).

Example 1 (54) 4- (N- (N ', N'-dimethylamino) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.92 (2H, d, J = 8.7 Hz),
7.23 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 8.7Hz), 6.55 (2H, d
d, J = 8.7Hz), 3.58 (1H, d, J = 7.7Hz), 3.29 (4H, t, J = 6.6H
z), 2.37 (6H, s), 2.25-1.75 (6H, m), 0.98 (3H, t, J = 7.4H
z), TLC: Rf 0.45 (hexane: ethyl acetate = 1:
1).

Example 1 (55) 4- (N- (N'-methylamino) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.82 (2H, d, J = 8.7 Hz),
7.23 (4H, m), 6.56 (2H, d, J = 8.6Hz), 3.60 (1H, m), 3.29
(4H, t, J = 6.6Hz), 2.85 (3H, s), 2.25-1.80 (6H, m), 0.99
(3H, t, J = 7.4Hz), TLC: Rf 0.35 (hexane: ethyl acetate = 1:
1).

Example 1 (56) 4- (N- (carbamoylmethyl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.78 (2H, d, J = 8.7 Hz),
7.20 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.7Hz), 6.54 (2H,
d, J = 8.6Hz), 6.42-6.30 (1H, brs), 6.20-5.96 (2H, m), 3.
58 (1H, t, J = 7.8Hz), 3.50 (2H, s), 3.38-3.18 (4H, m), 2.2
6-1.74 (6H, m), 0.96 (3H, t, J = 7.3Hz), TLC: Rf 0.41 (chloroform: methanol = 9:
1).

Example 1 (57) 4- (Nt-butylsulfamoyl) phenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.89 (2H, d, J = 8.8 Hz),
7.63 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 7.12 (2H, d, J = 8.6Hz)
d, J = 8.8Hz), 4.83 (1H, s), 3.74 (1H, t, J = 7.6Hz), 3.80-
3.50 (4H, m), 2.40-2.25 (4H, m), 2.40-2.10 and 2.05-1.
75 (each 1H, m), 1.22 (9H, s), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.55 (ethyl acetate: hexane = 1:
2).

Example 1 (58) 4- (N-adamantan-1-ylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.89 (2H, d, J = 8.6 Hz),
7.60-7.45 (4H, m), 7.12 (2H, d, J = 8.6Hz), 4.64 (1H, brs,
NH), 3.80-3.55 (5H, m), 2.40-1.48 (21H, m), 0.999 (3H,
t, J = 7.2 Hz), TLC: Rf 0.44 (hexane: ethyl acetate: acetic acid =
5: 2: 0.2).

Example 1 (59) 4-guanidinosulfonyl-2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 7.66-7.53 (2H, m),
7.28 (2H, d, J = 8.0Hz), 7.04 (1H, d, J = 8.0Hz), 7.10-6.50
(6H, m), 3.76 (1H, t, J = 7.5Hz), 3.50-3.20 (4H, m), 2.20-
1.70 (2H, m), 2.10-1.90 (4H, m), 1.93 (3H, s), 0.91 (3H,
t, J = 7.5Hz), TLC: Rf 0.36 (water: methanol: chloroform =
1:10:90).

Example 1 (60) 4- (N-2RS, 3-dihydroxypropylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 7.70-7.60 (2H, m),
7.47 (1H, t, J = 6.0Hz), 7.18 (2H, d, J = 8.5Hz), 7.13 (1H, d,
J = 8.5Hz), 6.55 (2H, d, J = 8.5Hz), 3.70 (1H, t, J = 7.5Hz),
3.55-3.35 (6H, m), 2.94-2.78 (1H, m), 2.66-2.54 (1H, m),
2.25-1.60 (2H, m), 2.05-1.90 (4H, m), 1.96 (3H, s), 0.9
1 (3H, t, J = 7.5Hz), TLC: Rf 0.29 (water: methanol: chloroform =
1:10:90).

Example 1 (61) 4- (N, N-bis (2- (methoxymethoxy) ethyl) sulfamoyl) -2-methylphenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.58 (2H, m), 7.
22 (2H, d, J = 9Hz), 7.03 (1H, d, J = 8Hz), 6.55 (2H, d, J = 9Hz),
4.54 (4H, s), 3.67 (4H, t, J = 6Hz), 3.60 (1H, t, J = 7Hz),
3.43 (4H, t, J = 6Hz), 3.35-3.20 (10H, m), 2.30-1.75 (9H,
m), 0.99 (3H, t, J = 7 Hz), TLC: Rf 0.27 (hexane: ethyl acetate = 2:
1).

Example 1 (62) 4- (N, N-bis (2- (2- (methoxymethoxy)
Ethoxy) ethyl) sulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.68-7.58 (2H, m), 7.
22 (2H, d, J = 9Hz), 7.03 (1H, d, J = 8Hz), 6.55 (2H, d, J = 9Hz),
4.63 (4H, s), 3.70-3.50 (13H, m), 3.45-3.20 (8H, m), 3.
35 (6H, s), 2.30-1.75 (9H, m), 0.99 (3H, t, J = 7Hz), TLC: Rf 0.20 (hexane: ethyl acetate = 1:
1).

Example 1 (63) 4- (N-methyl-N-methoxysulfamoyl) -2
-Methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.68 (1H, s), 7.66 (1
H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.6Hz), 7.11 (1H, d, J = 8.4H
z), 6.55 (2H, d, J = 8.6Hz), 3.78 (3H, s), 3.62 (1H, t, J = 7.
7Hz), 3.28 (4H, t, J = 6.6Hz), 2.76 (3H, s), 2.3-2.1 (1H,
m), 2.06 (3H, s), 2.1-1.9 (4H, m), 2.1-1.8 (1H, m), 0.99
(3H, t, J = 7.3Hz), TLC: Rf 0.36 (hexane: ethyl acetate = 4:
1).

Example 1 (64) 4- (N-benzylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.66-7.62 (2H, m), 7.
29-7.15 (7H, m), 7.05 (1H, d, J = 9.0Hz), 6.55 (2H, d, J = 8.6H
z), 4.65 (1H, t, J = 5.6Hz), 4.11 (2H, d, J = 5.6Hz), 3.62 (1
(H, t, J = 7.8Hz), 3.33-3.26 (4H, m), 2.27-1.82 (6H, m), 2.
00 (3H, s), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.86 (hexane: ethyl acetate = 1:
1).

Example 1 (65) 4- (N-2- (N ', N'-dimethylamino) ethylsulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 8.27 (2H, d, J = 8.5 Hz),
7.93 (2H, d, J = 8.5Hz), 7.68 (2H, d, J = 8.5Hz), 7.28 (2H, d, J = 8.5Hz)
d, J = 8.5Hz), 4.04 (1H, t, J = 7.6Hz), 3.22 (4H, m), 2.93 (6
H, s), 2.28 (1H, m), 1.97 (1H, m), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.39 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (66) 4-guanidinosulfonylphenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 8.8 Hz),
7.85 (2H, d, J = 8.8Hz), 7.57 (2H, d, J = 8.8Hz), 7.04 (2H,
d, J = 8.8Hz), 6.34 (1H, brs), 3.14-2.96 (2H, m), 2.77-2.
59 (2H, m), 2.38-1.90 (2H, m), TLC: Rf 0.56 (acetic acid: methanol: chloroform = 1: 5: 25).

Example 1 (67) 4-guanidinosulfonylphenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 8.27 (2H, d, J = 8.8H)
z), 7.78 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.19 (2H, d, J = 8.8Hz)
(H, d, J = 8.8Hz), 7.0-6.4 (4H, brs), 4.15 (1H, t, J = 7.6Hz),
2.30-2.05 and 2.05-1.75 (each 1H, m), 0.92 (3H, t, J =
7.6 Hz), TLC: Rf 0.09 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (68) 4- (N-2RS, 3-dihydroxypropylsulfamoyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.67-7.61 (2H, m), 7.
27 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8Hz), 7.04 (1H, d, J = 8Hz),
5.54 (1H, br), 3.80-3.46 (3H, m), 3.42 (1H, br), 3.70 (1
H, t, J = 8Hz), 3.11-2.87 (2H, m), 2.83 (1H, br), 2.35 (3H,
s), 2.32-2.11 and 2.03-1.79 (each 1H, m), 1.98 (3H,
s), 0.99 (3H, t, J = 8Hz), TLC: Rf 0.40 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (69) 4- (N-2-methoxyethylsulfamoyl) phenyl 2- (4-methoxyphenyl) -2-ethylbutanoate

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NMR (CDCl ₃ ): δ 7.83 (2H, d, J = 8.8 Hz),
7.27 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 9.2Hz), 6.90 (2H, d
d, J = 8.8Hz), 4.92 (1H, t, J = 6.5Hz), 3.82 (3H, s), 3.38 (2
H, t, J = 5.4Hz), 3.25 (3H, s), 3.11 (2H, t, J = 6.0Hz), 2.28
-2.04 (4H, m), 0.846 (6H, t, J = 7.4Hz), TLC: Rf 0.16 (hexane: ethyl acetate = 2:
1).

Example 1 (70) 4- (N-2- (N ', N'-dimethylamino) ethylsulfamoyl) phenyl 2- (4-methoxyphenyl) -2-ethylbutanoate / acetate

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NMR (CDCl ₃ ): δ 7.85 (2H, d, J = 8.6 Hz),
7.28 (2H, d, J = 8.8Hz), 7.09 (2H, d, J = 8.6Hz), 6.92 (2H, d, J = 8.6Hz)
d, J = 8.8Hz), 3.83 (3H, s), 2.53-2.47 (4H, m), 2.24 (6H,
s), 2.24-2.11 (4H, m), 0.847 (6H, t, J = 7.4Hz), TLC: Rf 0.26 (chloroform: methanol: water =
25: 5: 1).

Example 1 (71) 4- (guanidinosulfonyl) -2-methylphenyl
2RS- (4-methoxyphenyl) butanoic acid ester
Hydrochloride

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NMR (DMSO-d ₆ ): δ 7.62 (1H, s), 7.60
(1H, d, J = 8.0Hz), 7.30 (2H, d, J = 8.5Hz), 6.96 (1H, d, J = 8.0Hz)
Hz), 6.90 (2H, d, J = 8.5Hz), 6.6-6.1 (4H, brs), 3.80 (1H,
t, J = 7.5Hz), 2.3-2.0 and 2.0-1.7 (each 1H, m), 1.65 (3
H, s), 0.98 (3H, t, J = 7.5Hz), TLC: Rf 0.60 (water: methanol: chloroform =
1:10:40).

Example 1 (72) 4- (N, N-diethylsulfamoyl) phenyl 2
RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.83-7.73 (2H, m), 7.
40-7.23 (5H, m), 7.16-7.07 (2H, m), 3.69 (1H, t, J = 7Hz),
3.20 (4H, q, J = 7Hz), 2.35-1.75 (2H, m), 1.11 (6H, t, J = 7H
z), 0.98 (3H, t, J = 7 Hz), TLC: Rf 0.39 (hexane: ethyl acetate = 7:
3).

Example 1 (73) 4- (N-benzylsulfamoyl) phenyl 2RS
-Phenylbutanoic acid ester

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NMR (CDCl ₃ ): δ 7.89-7.79 (2H, m), 7.
42-7.08 (12H, m), 4.61 (1H, t, J = 7Hz), 4.13 (2H, d, J = 7Hz),
3.70 (1H, t, J = 7Hz), 2.36-2.11 (1H, m), 2.05-1.80 (1H,
m), 0.99 (3H, t, J = 7 Hz), TLC: Rf 0.41 (hexane: ethyl acetate = 2:
1).

Example 1 (74) 4- (N-methyl-N-benzylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.86-7.76 (2H, m), 7.
43-7.14 (12H, m), 4.11 (2H, s), 3.73 (1H, t, J = 7Hz), 2.59
(3H, s), 2.38-2.13 (1H, m), 2.06-1.81 (1H, m), 1.01 (3H,
t, J = 7 Hz), TLC: Rf 0.57 (hexane: ethyl acetate = 2:
1).

Example 1 (75) 4- (N-2-phenylethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.81-7.71 (2H, m), 7.
43-7.03 (12H, m), 4.40 (1H, t, J = 7Hz), 3.71 (1H, t, J = 7Hz),
3.21 (2H, q, J = 7Hz), 2.76 (2H, t, J = 7Hz), 2.24 (1H, ddq, J
= 14Hz, 7Hz, 7Hz), 1.93 (1H, ddq, J = 14Hz, 7Hz, 7Hz), 1.00
(3H, t, J = 7Hz), TLC: Rf 0.46 (hexane: ethyl acetate = 3:
2).

Example 1 (76) 4- (N-methyl-N-2-phenylethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.77-7.68 (2H, m), 7.
41-7.08 (12H, m), 3.71 (1H, t, J = 7Hz), 3.33-3.18 (2H, m),
2.92-2.79 (2H, m), 2.73 (3H, s), 2.24 (1H, ddq, J = 14Hz, 7H
z, 7Hz), 1.92 (1H, ddq, J = 14Hz, 7Hz, 7Hz), 0.99 (3H, t, J = 7
Hz), TLC: Rf 0.32 (hexane: ethyl acetate = 3:
2).

Example 1 (77) 4- (N-1RS- (4-methylphenyl) butylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.55 (2H, d, J = 8 Hz),
7.41-7.23 (5H, m), 6.98-6.78 (6H, m), 4.81 (1H, d, J = 7H
z), 4.23 (1H, q, J = 7Hz), 3.68 (1H, t, J = 7Hz), 2.35-2.08
(1H, m), 2.20 (3H, s), 1.91 (1H, ddq, J = 14Hz, 7Hz, 7Hz),
1.79-1.52 (2H, m), 1.38-1.06 (2H, m), 0.99 (3H, t, J = 7Hz),
0.83 (3H, t, J = 7Hz), TLC: Rf 0.15 (hexane: ethyl acetate = 4:
1).

Example 1 (78) 4- (N-2- (pyridin-2-yl) ethylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.79 (1H, d, J = 5.0H)
z), 8.50 (1H, t, J = 7.4Hz), 8.04 (1H, m), 7.90 (2H, m), 7.7
9 (2H, d, J = 8.6Hz), 7.28 (2H, m), 7.21 (2H, d, J = 8.4Hz),
6.90 (2H, m), 3.76 (1H, t, J = 7.0Hz), 3.34 (4H, brs), 3.23
(4H, brs), 2.01 (5H, m), 1.80 (1H, m), 0.91 (3H, t, J = 7.0H
z), TLC: Rf 0.48 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (79) 4- (N-2- (piperidin-1-yl) ethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-
Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.92 (2H, d, J = 8.8 Hz),
7.71 (2H, d, J = 8.8Hz), 7.63 (2H, d, J = 8.8Hz), 7.26 (2H, d, J = 8.8Hz)
d, J = 8.8Hz), 3.95 (1H, t, J = 7.2Hz), 3.81 (4H, m), 3.55
(2H, br.d, J = 12.0Hz), 3.24 (4H, br.s), 2.98 (2H, br.t, J
= 12.0Hz), 2.32 (4H, m), 1.89 (7H, m), 1.55 (1H, m), 0.99
(3H, t, J = 7.2Hz), TLC: Rf 0.39 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (80) 4- (N- (tetrazol-5-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CD ₃ OD): δ 7.89 (2H, d, J = 8.6 Hz),
7.15 (2H, d, J = 8.6Hz), 7.02 (2H, d, J = 8.6Hz), 6.55 (2H,
d, J = 8.6Hz), 3.58 (1H, t, J = 7.8Hz), 3.35-3.15 (4H, m),
2.20-1.95 and 1.95-1.70 (each 1H, m), 2.05-1.95 (4H,
m), 0.93 (3H, t, J = 7.2 Hz), TLC: Rf 0.46 (acetic acid: methanol: chloroform = 1: 5: 25).

Example 1 (81) 4- (N- (morpholin-4-yl) sulfamoyl)
Phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.97 (2H, d, J = 8.6 Hz),
7.61 (2H, d-like), 7.48 (2H, d-like), 7.16 (2H, d, J = 8.6H
z), 5.99 (1H, s), 3.74 (1H, t, J = 7.8Hz), 3.76-3.63 (4H,
m), 3.65-3.54 (4H, m), 2.70-2.58 (4H, m), 2.42-2.29 (4
H, m), 2.37-2.10 and 2.04-1.77 (each 1H, m), 1.00 (3H,
t, J = 7.2Hz), TLC: Rf 0.45 (methanol: chloroform = 1:
20).

Example 1 (82) 4- (N- (pyrrolidin-3-yl) sulfamoyl)
Phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CDCl ₃ ): δ 7.7-7.5 (4H, m), 7.42
(2H, d, J = 8.6Hz), 6.96 and 6.92 (2H, d, J = 8.6Hz), 4.35-
4.13 (1H, m), 3.5-2.9 (10H, m), 2.40-2.25 (4H, m), 2.20-
1.55 (4H, m), 0.94 (3H, t, J = 7.2Hz), TLC: Rf 0.35 (methanol: chloroform = 1:
10).

Example 1 (83) 4- (N- (1-benzylpiperidin-4-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1
-Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.82 (2H, d, J = 9.0 Hz),
7.36-7.08 (5H, m), 7.21 (2H, d, J = 9.0Hz), 7.13 (2H, d, J =
8.8Hz), 6.55 (2H, d, J = 8.8Hz), 4.50 (1H, d, J = 5.7Hz), 3.
58 (1H, t, J = 5.0Hz), 3.43 (2H, s), 3.36-3.21 (4H, m), 3.2
1-3.02 (1H, m), 2.78-2.61 (2H, m), 2.28-1.65 (10H, m),
1.56-1.34 (1H, m), 0.97 (3H, t, J = 7.2Hz), TLC: Rf 0.60 (ethyl acetate: hexane = 9:
1).

Example 1 (84) 4- (N- (pyridin-2-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CDCl ₃ ): δ 8.26 (1H, d, J = 6.0 Hz),
7.96 (2H, d, J = 8.6Hz), 7.83 (1H, t, J = 8.6Hz), 7.72 (2H, d, J = 8.6Hz)
d, J = 8.6Hz), 7.55 (1H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6H
z), 7.12 (2H, d, J = 8.6Hz), 6.95 (1H, t, J = 6.0Hz), 3.74 (1
(H, t, J = 7.6Hz), 3.80-3.60 (4H, m), 2.44-2.24 (4H, m), 2.3
2-2.02 and 2.02-1.72 (each 1H, m), 0.97 (3H, t, J = 7.2H
z), TLC: Rf 0.51 (ethyl acetate: hexane = 2:
1).

Example 1 (85) 4- (N-2- (morpholin-4-yl) ethylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.83 (2H, d, J = 8.9 Hz),
7.21 (2H, d, J = 8.7Hz), 7.13 (2H, d, J = 8.9Hz), 6.55 (2H,
d, J = 8.7Hz), 6.23-5.06 (1H, br.s), 3.64-3.52 (5H, m),
3.36-3.20 (4H, m), 2.98 (2H, t, J = 6.0Hz), 2.38 (2H, t, J =
6.0Hz), 2.30-2.20 (4H, m), 2.20-1.70 (6H, m), 0.97 (3H,
t, J = 7.2Hz), TLC: Rf 0.24 (ethyl acetate: hexane = 7:
3).

Example 1 (86) 4- (N- (pyrazin-2-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester trihydrochloride

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NMR (CDCl ₃ ): δ 8.46 (1H, s), 8.17 (2
H, s), 8.01 (2H, d, J = 8.2Hz), 7.7-7.4 (4H, m), 7.14 (2H,
d, J = 8.2Hz), 3.9-3.5 (5H, m), 2.5-2.2 (4H, m), 2.4-2.1
and 2.1-1.8 (each 1H, m), 0.98 (3H, t, J = 7.2Hz), TLC: Rf 0.18 (hexane: ethyl acetate = 1:
1).

Example 1 (87) 4- (N- (imidazol-2-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.90 (2H, d, J = 8.8 Hz),
7.19 (4H, d, J = 8.8Hz), 6.81 (1H, d, J = 2.0Hz), 6.54 (1H,
d, J = 2.0Hz), 6.54 (2H, d, J = 8.8Hz), 3.57 (1H, t, J = 7.8H
z), 3.28 (4H, t-like), 2.30-2.00 and 2.00-1.70 (each
1H, m), 2.00 (4H, t-like), 0.96 (3H, t, J = 7.4Hz), TLC: Rf 0.67 (methanol: chloroform = 1:
10).

Example 1 (88) 4- (N- (quinuclidin-3RS-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz),
7.21 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.8Hz), 6.55 (2H, d
d, J = 8.8Hz), 3.58 (1H, t, J = 7.6Hz), 3.60-3.47 (1H, m),
3.35-3.20 (4H, m), 3.30-2.80 (6H, m), 2.10-1.95 (4H, m),
2.30-1.40 (7H, m), 0.98 (3H, t, J = 7.2 Hz), TLC: Rf 0.43 (acetic acid: methanol: chloroform = 1: 5: 25).

Example 1 (89) 4- (N- (2,2,6,6-tetramethylpiperidin-4-yl) sulfamoyl) phenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.85 (2H, d, J =
8.8Hz), 7.22 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.8Hz), 6.
57 (2H, d, J = 8.6Hz), 3.59 (1H, t, J = 7.8Hz), 3.60-3.42 (1
H, m), 3.35-3.20 (4H, m), 2.30-1.75 (2H, m), 2.06-1.96
(4H, m), 1.63 (2H, dd, J = 13.2 and 3.8Hz), 1.33-1.08 (2
H, m), 1.19 (12H, s), 0.98 (3H, t, J = 7.3 Hz), TLC: Rf 0.55 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 1 (90) 4- (N- (quinuclidin-3RS-yl) sulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.69 (1H, d, J = 2 Hz),
7.66 (1H, dd, J = 8 and 2Hz), 7.30-7.13 (2H, m), 7.06 (1H,
d, J = 8Hz), 6.55 (2H, d, J = 9Hz), 3.62 (1H, t, J = 8Hz), 3.38
-3.23 (5H, m), 3.23-3.05 (1H, m), 2.90-2.48 (5H, m), 2.3
2-2.08 (1H, m), 2.04 (3H, s), 2.08-1.03 (10H, m), 0.99 (3
H, t, J = 7Hz), TLC: Rf 0.43 (chloroform: methanol: water =
8: 2: 0.2).

Example 1 (91) 4- (N-2- (morpholin-4-yl) ethylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester・ 2
Hydrochloride

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NMR (DMSO-d ₆ ): δ 11.3-11.1 (1H, br
s), 8.18 (1H, brs), 7.75 (1H, s), 7.70 (1H, d, J = 8.0Hz),
7.27 (2H, d, J = 8.6Hz), 7.18 (2H, d, J = 9.2Hz), 4.0-3.7 (5
H, m), 3.4-3.0 (12H, m), 2.2-2.0 (1H, m), 2.1-1.9 (4H, br
s), 2.0-1.7 (1H, m), 1.98 (3H, s), 0.91 (3H, t, J = 7.3Hz), TLC: Rf 0.50 (chloroform: methanol = 9:
1).

Example 1 (92) 4- (N-2- (piperazin-4-yl) ethylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester・ 3
Hydrochloride

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NMR (DMSO-d ₆ ): δ 9.6-9.2 (2H, br),
7.71 (1H, s), 7.67 (1H, d, J = 8.0Hz), 7.18 (2H, d, J = 8.4H
z), 7.14 (1H, d, J = 8.0Hz), 6.53 (2H, d, J = 8.4Hz), 3.69 (1
(H, t, J = 7.3Hz), 3.7-2.6 (16H, br), 2.2-2.0 (1H, m), 2.0-
1.9 (4H, brs), 1.96 (3H, s), 1.9-1.7 (1H, m), 0.90 (3H, t,
J = 7.1 Hz), TLC: Rf 0.46 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 1 (93) 4- (N- (piperidin-4-yl) sulfamoyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 9.1-8.7 (1H, br),
8.00 (1H, d, J = 7.2Hz), 7.71 (1H, s), 7.68 (1H, d, J = 8.4H
z), 7.26 (2H, d, J = 8.4Hz), 7.15 (1H, d, J = 8.4Hz), 6.79 (2H, d, J = 8.4Hz)
H, d, J = 8.4Hz), 3.76 (1H, t, J = 7.8Hz), 3.4-3.2 (4H, brs),
3.2-3.0 (3H, br), 3.0-2.7 (2H, br), 2.2-1.9 (1H, m), 1.
99 (4H, brs), 1.97 (3H, s), 1.9-1.5 (5H, m), 0.91 (3H, t, J
= 7.3 Hz), TLC: Rf 0.46 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 1 (94) 4- (N-2- (morpholin-4-yl) ethylsulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoate hydrochloride

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NMR (CD ₃ OD): δ 8.27 (2H, d, J = 8.6 Hz),
7.92 (2H, d, J = 9.0Hz), 7.67 (2H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz)
d, J = 9.0Hz), 4.03 (1H, t, J = 7.6Hz), 3.90 (2H, m), 3.50 (2
H, m), 3.28 (8H, m), 2.28 (1H, m), 1.99 (1H, m), 1.00 (3H,
t, J = 7.4Hz), TLC: Rf 0.61 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (95) 4- (N-2- (pyridin-2-yl) ethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester hydrochloride

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NMR (CD ₃ OD): δ 8.72 (1H, d, J = 8.0 Hz),
8.53 (1H, t, J = 8.0Hz), 8.28 (2H, d, J = 8.6Hz), 7.96 (1H,
d, J = 8.0Hz), 7.93 (1H, d, J = 8.0Hz), 7.79 (2H, d, J = 8.6H
z), 7.66 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 3.30 (4
H, m), 3.06 (2H, m), 2.72 (2H, m), 2.23 (1H, m), 2.04 (1H,
m), TLC: Rf 0.54 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (96) 4- (N-2- (piperidin-1-yl) ethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester hydrochloride

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NMR (CD ₃ OD): δ 8.28 (2H, d, J = 8.4 Hz),
7.90 (2H, d, J = 8.4Hz), 7.66 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz)
d, J = 8.4Hz), 3.50 (2H, m), 3.30 (4H, m), 3.06 (4H, m), 2.
73 (2H, m), 2.22 (1H, m), 1.99 (1H, m), 1.87 (6H, m), TLC: Rf 0.45 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (97) 4- (N-2- (1-methylpyrrol-2-yl) ethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ ): δ 8.26 (2H, d, J = 9.0 Hz),
7.78 (2H, d, J = 9.0Hz), 7.56 (2H, d, J = 9.0Hz), 7.09 (2H, d, J = 9.0Hz)
d, J = 9.0Hz), 6.52 (1H, dd, J = 2.0,2.4Hz), 6.01 (1H, dd, J =
2.4,2.6Hz), 5.80 (1H, m), 4.64 (1H, t, J = 6.6Hz), 3.42 (3
H, s), 3.16 (2H, q, J = 6.6Hz), 3.05 (2H, m), 2.74 (2H, t, J =
6.6 Hz), 2.66 (2H, m), 2.25 (1H, m), 2.03 (1H, m), TLC: Rf 0.26 (hexane: ethyl acetate = 2:
1).

Example 1 (98) 4- (N- (tetrazol-5-ylmethyl) sulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 8.54 (1H, t, J = 5.8H)
z), 8.28 (2H, d, J = 8.8Hz), 7.85 (2H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz)
H, d, J = 8.8Hz), 7.32 (2H, d, J = 8.8Hz), 4.30 (2H, d, J = 5.8H
z), 4.17 (1H, t, J = 7.6Hz), 2.35-2.05 and 2.03-1.75 (ea
ch 1H, m), 0.92 (3H, t, J = 7.2 Hz), TLC: Rf 0.45 (acetic acid: methanol: chloroform = 1: 5: 25).

Example 1 (99) 4- (N- (tetrazol-5-ylmethyl) sulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CD ₃ OD): δ 8.28 (2H, d, J = 8.8 Hz),
7.85 (2H, d, J = 8.8Hz), 7.67 (2H, d, J = 8.8Hz), 7.19 (2H, d
d, J = 8.8Hz), 4.37 (2H, s), 3.16-2.96 (2H, m), 2.82-2.62
(2H, q-like), 2.37-2.12 and 2.12-1.90 (each 1H, m), TLC: Rf 0.11 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (100) 4- (N- (tetrazol-5-yl) sulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 8.26 (2H, d, J = 8.8H)
z), 7.84 (2H, d, J = 8.8Hz), 7.69 (2H, d, J = 8.8Hz), 7.12 (2
H, d, J = 8.8Hz), 3.08-2.88 (2H, m), 2.74-2.54 (2H, q-lik
e), 2.24-2.04 and 2.04-1.84 (each 1H, m), TLC: Rf 0.29 (acetic acid: methanol: chloroform = 1: 5: 25).

Example 1 (101) 4- (N- (tetrazol-5-yl) sulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 13.88 (1H, brs), 8.
26 (2H, dJ = 8.8Hz), 7.82 (2H, d, J = 8.8Hz), 7.70 (2H, d, J =
8.8Hz), 7.06 (2H, d, J = 8.8Hz), 4.12 (1H, t, J = 7.4Hz), 2.
30-2.00and 2.00-1.70 (each 1H, m), 0.91 (3H, t, J = 7.2H
z), TLC: Rf 0.26 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 1 (102) 4- (N- (quinuclidin-3RS-yl) sulfamoyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70 (1H, d, J = 2 Hz),
7.67 (1H, dd, J = 8 and 2Hz), 7.27 (2H, d, J = 8Hz), 7.18 (2H
H, d, J = 8Hz), 7.06 (1H, d, J = 8Hz), 3.70 (1H, t, J = 8Hz), 3.
38-3.23 (1H, m), 3.23-3.05 (1H, m), 2.90-2.49 (5H, m),
2.36 (3H, s), 2.35-2.11 (1H, m), 2.00 (3H, s), 2.05-1.22
(6H, m), 1.00 (3H, t, J = 7Hz), TLC: Rf 0.40 (chloroform: methanol: water =
8: 2: 0.2).

Example 1 (103) 4- (N-2R-methoxy-3R-hydroxy-4S-
Hydroxy-5R-hydroxyperhydropyran-6R
-Ylmethylsulfamoyl) -2-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ +6 drops of CD ₃ OD): δ 7.6
8-7.63 (m, 2H), 7.22 (d, J = 8.8Hz, 2H), 7.05 (d, J = 8.1Hz, 1
H), 6.55 (d, J = 8.8Hz, 2H), 4.63 (d, J = 3.7Hz, 1H), 3.70-
3.50 (m, 3H), 3.50-3.10 (m, 11H), 2.30-1.80 (m, 9H), 0.9
9 (t, J = 7.4 Hz, 3H), TLC: Rf 0.41 (chloroform: methanol = 8:
1).

Example 1 (104) 4- (N-phenylsulfamoyl) phenyl 2RS
-Phenylbutanoic acid ester

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NMR (CDCl ₃ ): δ 7.73 (2H, dd, J = 2Hz, 8H
z), 7.40-7.16 (7H, m), 7.16-7.00 (5H, m), 6.76 (1H, s),
3.67 (1H, t, J = 7Hz), 2.20 (1H, m), 1.89 (1H, m), 0.96 (3H,
t, J = 7 Hz), TLC: Rf 0.57 (hexane: ethyl acetate = 1:
1).

Example 1 (105) 4- (N-4-nitrophenylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 8.10 and 7.85 (each
2H, dd, J = 2Hz, 8Hz), 7.75 (1H, br.s), 7.35 (5H, m), 7.20
and 7.14 (each 2H, dd, J = 2Hz, J = 8Hz), 3.69 (1H, t, J = 7H
z), 2.20 and 1.90 (each 1 H, m), 0.96 (3 H, t, J = 7 Hz), TLC: Rf 0.59 (hexane: ethyl acetate = 1:
1).

Example 1 (106) 4- (N-phenylsulfamoyl) phenyl 2RS
-(4-aminophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 7.72 (2H, d, J = 8 Hz),
7.42-6.91 (9H, m), 6.80-6.54 (3H, m), 3.56 (1H, t, J = 7H
z), 2.23-1.64 (2H, m), 0.92 (3H, t, J = 7 Hz), TLC: Rf 0.39 (hexane: ethyl acetate = 1:
1).

Example 1 (107) 4- (N- (2- (tetrazol-5-yl) benzene-1-yl) sulfamoyl) phenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.76 (1H, d, J = 7.8 Hz),
7.59 (1H, d, J = 7.8Hz), 7.48 (1H, t-like), 7.35 (2H, d, J =
8.8Hz), 7.26 (1H, t-like), 7.17 (2H, d, J = 8.4Hz), 6.77
(2H, d, J = 8.6Hz), 6.55 (2H, d, J = 8.4Hz), 3.57 (1H, t, J = 7.
2Hz), 3.31-3.24 (4H, t-like), 2.25-1.75 (2H, m), 2.05-
1.95 (4H, m), 0.97 (3H, t, J = 7.2Hz), TLC: Rf 0.33 (acetic acid: methanol: chloroform = 1: 20: 200).

Example 1 (108) 4- (N-4- (morpholin-4-yl) phenylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1)
-Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.83 (2H, d, J = 8.8 Hz),
7.60 (4H, s), 7.55 (2H, d, J = 9.0Hz), 7.29 (2H, d, J = 9.0H
z), 7.16 (2H, d, J = 8.8Hz), 4.05 (4H, t-like), 3.89 (1H,
t, J = 7.4Hz), 3.84-3.68 (4H, m), 3.58 (4H, t-like), 2.35
-2.23 (4H, m), 2.30-2.09 and 2.04-1.78 (each 1H, m),
0.96 (3H, t, J = 7.2Hz), TLC: Rf 0.52 (methanol: chloroform = 1:
20).

Example 1 (109) 2- (N- (4- (2RS- (4- (pyrrolidine-1-)
Yl) phenyl) butyryloxy) -3-methylphenylsulfonyl) amino) sodium phenylsulfonate

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NMR (DMSO-d ₆ ): δ 10.6 (1H, s), 7.81
(1H, d, J = 2Hz), 7.71 (1H, dd, J = 9,2Hz), 7.57 (1H, dd, J = 8,2
Hz), 7.37 (1H, dd, J = 8,1Hz), 7.22 (1H, td, J = 8,1Hz), 7.1
6 (2H, d, J = 9Hz), 7.06 (1H, d, J = 9Hz), 6.97 (1H, td, J = 8,1H
z), 6.57 (2H, d, J = 9Hz), 3.67 (1H, t, J = 7Hz), 3.30-3.15
(4H, m), 2.18-1.90 (5H, m), 1.88 (3H, s), 1.87-1.65 (1H,
m), 0.86 (3H, t, J = 7 Hz), TLC: Rf 0.19 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 1 (110) 4- (N-3,5-dimethoxyphenylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.62-7.55 (2H, m), 7.
18 (2H, d, J = 8.4Hz), 6.98 (1H, d, J = 8.2Hz), 6.69 (1H, s),
6.52 (2H, d, J = 8.4Hz), 6.21-6.16 (3H, m), 3.69 (6H, s),
3.57 (1H, t, J = 7.6Hz), 3.31-3.24 (4H, m), 2.25-1.80 (9H,
m), 0.97 (3H, t, J = 7.4 Hz), TLC: Rf 0.83 (hexane: ethyl acetate = 1:
1).

Example 1 (111) 4- (N-phenylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.56-7.49 (2H, m), 7.
26-6.94 (8H, m), 6.68 (1H, brs), 6.52 (2H, d, J = 8.4Hz),
3.57 (1H, t, J = 7.8Hz), 3.31-3.24 (4H, m), 2.27-1.75 (6H,
m), 1.95 (3H, s), 0.97 (3H, t, J = 7.4 Hz), TLC: Rf 0.83 (hexane: ethyl acetate = 3:
1).

Example 1 (112) 4- (N-2- (N '-(tetrazol-5-ylmethyl) carbamoyl) benzene-1-ylsulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 9.60-9.48 (1H, m),
8.25 (2H, d, J = 8Hz), 7.88-7.63 (5H, m), 7.55-7.45 (2H, m),
7.30-7.09 (3H, m), 4.79-4.65 (2H, m), 4.13 (1H, t, J = 7H
z), 2.31-2.04 (1H, m), 2.04-1.78 (1H, m), 0.88 (3H, t, J =
7 Hz), TLC: Rf 0.28 (acetic acid: methanol: chloroform = 1: 2: 30).

Example 1 (113) 4- (N-2- (N '-(tetrazol-5-ylmethyl) carbamoyl) benzene-1-ylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.60-9.48 (1H, m),
8.33-8.20 (2H, m), 7.85-7.62 (5H, m), 7.55-7.40 (2H, m),
7.30-7.10 (3H, m), 4.78-4.65 (2H, m), 3.06-2.85 (2H, m),
2.75-2.55 (2H, m), 2.26-2.03 (1H, m), 2.03-1.80 (1H,
m), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 1 (114) 4- (N- (4-amidinophenyl) sulfamoyl)
Phenyl 2RS- (4-nitrophenyl) butanoate / acetate

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NMR (DMSO-d ₆ ): δ 9.40-9.10 (2H, m),
8.75-8.55 (2H, m), 8.24 (2H, d, J = 8Hz), 7.78-7.61 (4H, m),
7.44 (2H, d, J = 8Hz), 7.05 (2H, d, J = 8Hz), 6.83 (2H, d, J = 8
Hz), 4.09 (1H, t, J = 7Hz), 2.23-2.00 (1H, m), 1.95-1.65 (4
H, m), 0.88 (3H, t, J = 7 Hz), TLC: Rf 0.52 (acetic acid: methanol: chloroform = 1: 2: 10).

Example 1 (115) 4- (N- (4-amidinophenyl) sulfamoyl)
Phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester / acetate

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NMR (CD ₃ OD): δ 8.26 (2H, d, J = 8 Hz),
7.87 (2H, d, J = 8Hz), 7.63 (4H, d, J = 8Hz), 7.23 (2H, d, J = 8H)
z), 7.12 (2H, d, J = 8Hz), 3.10-2.94 (2H, m), 2.78-2.60 (2
H, m), 2.35-1.95 (5H, m), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 2: 15).

Example 1 (116) 4- (N-2- (tetrazol-5-yl) phenylsulfamoyl) phenyl 1- (4-nitrophenyl)
Cyclobutanecarboxylic acid ester

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NMR (CD ₃ OD): δ 8.22 (2H, d, J = 8.8 Hz),
7.86-7.18 (8H, m), 6.96 (2H, d, J = 8.8Hz), 3.08-2.88 (2
H, m), 2.65 (2H, q-like), 2.28-2.08 (2H, m), 2.08-1.88
(2H, m), TLC: Rf 0.43 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 1 (117) 4- (N-4- (morpholin-4-yl) phenylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester hydrochloride

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NMR (CD ₃ OD): δ 8.25 (2H, d, J = 8.8 Hz),
7.82 (2H, d, J = 8.8Hz), 7.61 (2H, d, J = 8.8Hz), 7.54 (2H, d
d, J = 8.8Hz), 7.28 (2H, d, J = 8.8Hz), 7.12 (2H, d, J = 8.8H
z), 4.08 (4H, t, J = 4.8Hz), 3.57 (4H, t, J = 4.8Hz), 3.02 (2
H, m), 2.70 (2H, m), 2.21 (1H, m), 2.03 (1H, m), TLC: Rf 0.35 (hexane: ethyl acetate = 1:
1).

Example 1 (118) 4- (N-2- (tetrazol-5-yl) phenylsulfamoyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (CD ₃ OD): δ 8.22 (2H, m), 7.93 (1
H, d, J = 7.8Hz), 7.68 (1H, d, J = 7.8Hz), 7.64-7.60 (2H, tl
ike), 7.60-7.56 (2H, m), 7.33 (1H, t, J = 7.8Hz), 7.16 (1H,
t, J = 7.8Hz), 7.00-6.92 (2H, m), 3.92 (1H, t, J = 8.0Hz),
2.30-2.05 and 2.05-1.75 (each 1H, m), 0.93 (3H, t, J = 7.
2 Hz), TLC: Rf 0.27 (acetic acid: methanol: chloroform = 1: 20: 200).

Example 1 (119) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Nt-butyloxycarbonylamino) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.77 (1H, brs), 9.
34 (1H, t-like), 7.82 (1H, d, J = 7Hz), 7.79 (2H, d, J = 8Hz),
7.44 (2H, d, J = 8Hz), 7.28-7.04 (7H, m), 6.78-6.70 (1H,
m), 3.86 (2H, d-like), 3.72 (1H, t, J = 7Hz), 2.11-1.90 a
nd 1.81-1.67 (each 1H, m), 1.47 (9H, s), 0.87 (3H, t, J = 7
Hz), TLC: Rf 0.21 (chloroform: methanol: water =
8: 2: 0.2).

Example 1 (120) 4- (3,5-dimethoxybenzylaminosulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.67-7.62 (2H, m), 7.
22 (2H, d, J = 8.6Hz), 7.05 (1H, d, J = 9.4Hz), 6.54 (2H, d, J =
8.6Hz), 6.32 (3H, s), 4.64 (1H, t, J = 6.0Hz), 4.05 (2H, d,
J = 6.0Hz), 3.72 (6H, s), 3.61 (1H, t, J = 7.6Hz), 3.33-3.2
6 (4H, m), 2.27-1.81 (6H, m), 2.02 (3H, s), 0.99 (3H, t, J =
7.2 Hz), TLC: Rf 0.86 (hexane: ethyl acetate = 1:
1).

Example 1 (121) 4-((4-t-butoxycarbonylaminopiperidin-1-yl) sulfonyl) -2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.55 (1H, s), 7.53 (1
H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.6Hz), 7.08 (1H, d, J = 8.4H
z), 6.55 (2H, d, J = 8.6Hz), 4.40 (1H, brs), 3.7-3.6 (2H, b
r), 3.62 (1H, t, J = 7.7Hz), 3.5-3.2 (1H, br), 3.28 (4H, b
r), 2.6-2.4 (2H, m), 2.3-2.1 (1H, m), 2.04 (3H, s), 2.00
(4H, brs), 2.1-1.8 (1H, m), 1.6-1.4 (4H, m), 1.41 (9H,
s), 0.99 (3H, t, J = 7.3 Hz), TLC: Rf 0.81 (hexane: ethyl acetate = 1:
1).

Example 1 (122) 4- (N-methoxy-N-benzylaminosulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.74 (1H, s), 7.72 (1
H, d, J = 9.0Hz), 7.32 (5H, s), 7.24 (2H, d, J = 8.8Hz), 7.14
(1H, d, J = 9.0Hz), 6.56 (2H, d, J = 8.8Hz), 3.98 (2H, s), 3.
64 (1H, t, J = 7.7Hz), 3.43 (3H, s), 3.29 (4H, brs), 2.3-2.
1 (1H, m), 2.08 (3H, s), 2.00 (4H, brs), 2.1-1.8 (1H, m),
1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.79 (hexane: ethyl acetate = 2:
1).

Example 1 (123) 4- (N-benzyloxy-N-methylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.71 (1H, s), 7.68 (1
H, d, J = 8.2Hz), 7.5-7.2 (9H, brs), 7.09 (1H, d, J = 8.2Hz),
5.00 (2H, s), 3.73 (1H, t, J = 7.5Hz), 3.7-3.4 (4H, m), 2.
65 (3H, s), 2.4-2.1 (5H, m), 2.03 (3H, s), 2.1-1.8 (1H,
m), 0.99 (3H, t, J = 7.2 Hz), TLC: Rf 0.66 (hexane: ethyl acetate = 2:
1).

Example 1 (124) 4- (2- (N, N-dimethylamino) ethylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.69-7.63 (2H, m), 7.
22 (2H, d, J = 8.6Hz), 7.05 (1H, d, J = 8.4Hz), 6.55 (2H, d, J =
8.6Hz), 3.61 (1H, t, J = 8.2Hz), 3.32-3.25 (4H, m), 2.95
(2H, t, J = 5.8Hz), 2.30 (2H, t, J = 5.8Hz), 2.27-1.65 (15H,
m), 0.99 (3H, t, J = 7.2Hz), TLC: Rf 0.72 (chloroform: methanol: water =
8: 2: 0.2).

Example 1 (125) 4- (2- (Piperidin-1-yl) ethylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.7-7.4 (m, 2H), 7.23
(d, J = 8.7Hz, 2H), 7.05 (d, J = 8.4Hz, 1H), 6.56 (d, J = 8.7H
z, 2H), 3.61 (t, J = 7.4Hz, 1H), 3.4-3.2 (m, 4H), 3.1-2.9
(m, 2H), 2.5-2.4 (m, 2H), 2,4-2.3 (m, 4H), 2.3-1.8 (m, 2
H), 2.1-1.9 (m, 4H), 2.03 (s, 3H), 1.6-1.3 (m, 6H), 0.99
(t, J = 7.4 Hz, 3H), TLC: Rf 0.55 (chloroform: methanol = 7:
1).

Example 1 (126) 4- (3- (morpholin-4-yl) propylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2
Hydrochloride

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NMR (CDCl ₃ ): δ 7.8-7.4 (m, 5H), 7.3-
7.0 (m, 3H), 4.3-3.4 (m, 11H), 3.2-2.8 (m, 6H), 2.4-1.8
(m, 11H), 0.99 (t, J = 7.2 Hz, 3H), TLC: Rf 0.56 (chloroform: methanol = 9:
1).

Example 1 (127) 4- (Indoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.66-7.51 (3H, m), 7.
24-6.88 (6H, m), 6.53 (2H, d, J = 8.8Hz), 3.88 (2H, t, J = 8.4H
z), 3.58 (1H, t, J = 7.8Hz), 3.27 (4H, m), 2.89 (2H, t, J = 8.
4Hz), 2.29-1.72 (9H, m), 0.96 (3H, t, J = 7.2Hz), TLC: Rf 0.80 (hexane: ethyl acetate = 1:
1).

Example 1 (128) 4-((2-oxo-4R-isopropylperhydrooxazol-3-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butane Acid ester

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NMR (CDCl ₃ ): δ 7.93 (1H, s), 7.86 (1
H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.4Hz), 7.11 (1H, d, J = 8.6H)
z), 6.55 (2H, d, J = 8.4Hz), 4.43-4.33 (1H, m), 4.26 (1H,
t, J = 8.6Hz), 4.15 (1H, dd, J = 8.6,3.2Hz), 3.61 (1H, t, J =
7.7Hz), 3.40-3.20 (4H, m), 2.55-2.33 (1H, m), 2.33-1.7
0 (9H, m), 0.99 (3H, t, J = 7.4Hz), 0.91 (3H, d, J = 6.9Hz),
0.76 (3H, d, J = 6.9 Hz), TLC: Rf 0.43 (hexane: ethyl acetate = 7:
3).

Example 1 (129) 4- (N-2- (morpholin-4-yl) ethyl-N-
Methoxyaminosulfonyl) -2-methylphenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 7.85-7.65 (2H, m),
7.27 (3H, d, J = 8.0Hz), 6.95-6.70 (2H, brd), 4.05-3.70 (5
H, m), 3.85 (3H, s), 3.50-2.95 (12H, m), 2.30-1.65 (6H,
m), 2.02 (3H, s), 0.92 (3H, t, J = 7.5 Hz), TLC: Rf 0.52 (hexane: ethyl acetate = 2:
1).

Example 1 (130) 4- (5-Nitroindolin-1-ylsulfonyl)-
2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.10 (1H, d, J = 9.0 Hz),
7.95 (1H, s), 7.72-7.56 (3H, m), 7.18 (2H, d, J = 8.0Hz),
7.05 (1H, d, J = 8.0Hz), 6.52 (2H, d, J = 8.0Hz), 4.01 (2H, t,
J = 8.5Hz), 3.58 (1H, t, J = 7.5Hz), 3.35-3.18 (4H, m), 3.0
8 (2H, t, J = 8.5Hz), 2.30-1.70 (6H, m), 2.00 (3H, s), 0.96
(3H, t, J = 7.5Hz), TLC: Rf 0.60 (hexane: ethyl acetate = 2:
1).

Example 1 (131) 4- (morpholin-4-ylaminosulfonyl) -2-
Methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.84-7.70 (2H, m), 7.
64 (4H, s-like), 7.13 (1H, d, J = 8.2Hz), 3.97 (1H, t, J = 7.4H
z), 3.87-3.66 (4H, m), 3.54 (4H, t, J = 4.4Hz), 2.55 (4H, m
t, J = 4.4Hz), 2.43-2.14 (5H, m), 2.14-1.80 (4H, m), 1.00
(3H, t, J = 7.4Hz), TLC: Rf 0.51 (hexane: ethyl acetate = 1:
1).

Example 1 (132) 4- (6-Fluoroindoline-1-ylsulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD: CDCl ₃ = 1: 1): δ 7.75-7.40
(6H, m), 7.29 (1H, dd, J = 10.0 and 2.0Hz), 7.15-7.01 (2
H, m), 6.69 (1H, td, J = 8.6 and 2.0Hz), 3.94 (2H, t, J = 8.4
Hz), 3.87 (1H, t, J = 7.6Hz), 3.79-3.63 (4H, m), 2.89 (2H,
t, J = 8.4Hz), 2.40-2.12 (5H, m), 2.08-1.79 (4H, m), 0.99
(3H, t, J = 7.4Hz), TLC: Rf 0.29 (hexane: ethyl acetate = 3:
1).

Example 1 (133) 4- (5- (N, N-dimethylamino) indoline-1
-Ylsulfonyl) -2-methylphenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.78-7.64 (3H, m), 7.
60 (4H, s-like), 7.52-7.42 (2H, m), 7.11 (1H, d, J = 8.4H
z), 4.01 (2H, t, J = 8.5Hz), 3.93 (1H, t, J = 8.4Hz), 3.87-
3.70 (4H, m), 3.23 (6H, s), 3.06 (2H, t, J = 8.5Hz), 2.40-
2.10 (5H, m), 2.10-1.80 (4H, m), 0.97 (3H, t, J = 7.2Hz), TLC: Rf 0.24 (hexane: ethyl acetate = 3:
1).

Example 1 (134) 4- (4-Methylpiperazin-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.75-7.59 (6H, m), 7.
23 (1H, d, J = 8.2Hz), 4.06-3.84 (3H, m), 3.84-3.68 (4H, m),
3.64-3.49 (2H, m), 3.32-3.11 (2H, m), 2.89 (3H, s), 2.8
4-2.64 (2H, m), 2.44-2.14 (5H, m), 2.13-1.82 (4H, m), 1.
00 (3H, t, J = 7.2Hz), TLC: Rf 0.36 (ethyl acetate).

Example 1 (135) 4- (5-Nitroindoline-1-ylsulfonyl)-
2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.10 (1H, dd, J = 9.0,2.
2Hz), 7.95 (1H, d, J = 2.2Hz), 7.66 (1H, d, J = 9.0HZ), 7.66
(1H, s), 7.63 (1H, d, J = 8.2Hz), 7.18 (2H, d, J = 8.8Hz), 7.
05 (1H, d, J = 8.2Hz), 6.53 (2H, d, J = 8.8Hz), 4.01 (2H, t, J =
8.5Hz), 3.58 (1H, t, J = 7.7Hz), 3.3-3.2 (4H, brs), 3.08 (2
(H, t, J = 8.5Hz), 2.3-2.0 (1H, m), 2.1-1.9 (4H, brs), 2.00
(3H, s), 2.0-1.8 (1H, m), 0.96 (3H, t, J = 7.3Hz), TLC: Rf 0.60 (hexane: ethyl acetate = 2:
1).

Example 1 (136) 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-ethylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2 hydrochloric acid salt

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NMR (CD ₃ OD): δ 7.83-7.58 (6H, m), 7.
18 (1H, d, J = 8.0Hz), 4.12-3.70 (9H, m), 3.53 (2H, d, J = 12.0
Hz), 3.38-3.08 (6H, m), 2.45-1.80 (8H, m), 1.00 (6H, t, J
= 7.5 Hz), TLC: Rf 0.41 (hexane: ethyl acetate = 1:
4).

Example 1 (137) 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-ethylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2HCl salt

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NMR (CD ₃ OD): δ 7.83-7.58 (6H, m), 7.
19 (1H, d, J = 8.0Hz), 4.12-3.70 (9H, m), 3.53 (2H, d, J = 12.0
Hz), 3.40-3.08 (6H, m), 2.50-1.80 (8H, m), 0.99 (6H, t, J
= 7.5 Hz), TLC: Rf 0.41 (hexane: ethyl acetate = 1:
4).

Example 1 (138) 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2HCl salt

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NMR (DMSO-d ₆ ): δ 11.0-10.8 (1H, br
s), 7.75 (1H, s), 7.70 (1H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.4
Hz), 7.18 (1H, d, J = 8.6Hz), 6.64 (2H, d, J = 8.4Hz), 4.0-
3.7 (5H, m), 3.4-3.0 (12H, m), 2.2-2.0 (1H, m), 2.1-1.9
(4H, brs), 2.0-1.7 (1H, m), 1.97 (3H, s), 0.91 (3H, t, J =
7.3 Hz), TLC: Rf 0.50 (chloroform: methanol = 9:
1).

Example 1 (139) 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2 hydrochloric acid salt

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NMR (DMSO-d ₆ ): δ 11.4-11.2 (1H, br
s), 7.76 (1H, s), 7.70 (1H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.4
Hz), 7.18 (1H, d, J = 8.6Hz), 6.87 (2H, d, J = 8.4Hz), 4.0-
3.7 (5H, m), 3.5-3.3 (6H, m), 3.3-3.0 (6H, m), 2.2-2.0 (1
H, m), 2.1-1.9 (4H, brs), 2.0-1.7 (1H, m), 1.98 (3H, s),
0.91 (3H, t, J = 7.2Hz), TLC: Rf 0.50 (chloroform: methanol = 9:
1).

Example 1 (140) 4- (4-Methyl-1,4-perhydrodiazepine-1
-Ylsulfonyl) -2-methylphenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 7.72 (1H, d, J = 2 Hz),
7.66 (1H, dd, J = 2 and 8Hz), 7.25 (2H, d, J = 8Hz), 7.19 (1
(H, d, J = 8Hz), 6.76 (2H, d-like), 3.76 (1H, t, J = 7Hz), 3.7
5-3.01 (12H, m), 2.76 and 2.74 (total 3H, each s), 2.2
1-1.66 (8H, m), 1.99 (3H, s), 0.91 (3H, t, J = 7Hz), TLC: Rf 0.52 (chloroform: methanol: water =
9: 1: 0.1).

Example 1 (141) 4- (2RS-ethoxycarbonylindolin-1-ylsulfonyl) -2-methylphenyl 2S- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.62-7.51 (3H, m), 7.
23-7.15 (3H, m), 7.07-6.95 (3H, m), 6.52 (2H, d, J = 9Hz),
4.75-4.67 (1H, m), 4.24 (2H, q, J = 7Hz), 3.57 (1H, t, J = 7H
z), 3.31-3.24 (4H, m), 3.21-3.00 (2H, m), 2.23-1.75 (2
H, m), 2.04-1.99 (4H, m), 1.96 (3H, s), 1.29 (3H, t, J = 7H
z), 0.96 (3H, t, J = 7 Hz), TLC: Rf 0.29 (hexane: ethyl acetate = 3:
1).

Example 1 (142) 4- (Quinuclidin-3RS-ylaminosulfonyl)
-2-methylphenyl 2S- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.35 (1H, d, J = 7 Hz),
7.74-7.64 (2H, m), 7.26 (2H, d, J = 8Hz), 7.17 (1H, d, J = 8H
z), 6.82-6.70 (2H, br), 3.75 (1H, t, J = 7Hz), 3.61-3.43
(1H, br), 3.40-3.22 (5H, m), 3.18-2.94 (5H, m), 2.90-2.
79 (1H, m), 2.17-1.60 (13H, m), 0.91 (3H, t, J = 7Hz), TLC: Rf 0.35 (chloroform: methanol: water =
8: 2: 0.2).

Example 1 (143) 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2methane Sulfonate

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NMR (CD ₃ OD): δ 7.80-7.70 (2H, m), 7.
67 (4H, s), 7.17 (1H, d, J = 8.0Hz), 4.10-3.70 (9H, m), 3.5
4 (2H, d, J = 12.0Hz), 3.40-3.10 (6H, m), 2.70 (6H, s), 2.4
0-1.80 (6H, m), 2.05 (3H, s), 1.00 (3H, t, J = 7.5Hz), TLC: Rf 0.31 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 1 (144) 4- (3,5-dimethoxyphenylaminosulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester / methanesulfonic acid salt

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NMR (CD ₃ OD): δ 7.70-7.50 (6H, m), 7.
05 (1H, d, J = 8.5Hz), 6.24 (2H, d, J = 2.0Hz), 6.16 (1H, t, J =
2.0Hz), 3.94 (1H, t, J = 7.5Hz), 3.77 (4H, t-like), 3.67
(6H, s), 2.70 (3H, s), 2.40-1.80 (6H, m), 1.96 (3H, s), 0.
98 (3H, t, J = 7.5Hz), TLC: Rf 0.73 (hexane: ethyl acetate = 1:
1).

Example 1 (145) 4- (5-Nitroindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 8.11 (1H, dd, J = 2.0,9.
0Hz), 7.96 (1H, d, J = 2.0Hz), 7.72-7.60 (3H, m), 7.55 (2
H, d, J = 8.0Hz), 7.44 (2H, d, J = 8.0Hz), 7.06 (1H, d, J = 8.0H)
z), 4.03 (2H, t, J = 8.5Hz), 3.75 (1H, t, J = 7.5Hz), 3.85-
3.40 (4H, m), 3.10 (2H, t, J = 8.5Hz), 2.45-2.20 (4H, m),
2.40-1.75 (2H, m), 2.02 (3H, s), 0.98 (3H, t, J = 7.5Hz), TLC: Rf 0.60 (hexane: ethyl acetate = 2:
1).

Example 1 (146) 4- (5-Nitroindoline-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester / methanesulfonate

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NMR (CDCl ₃ ): δ 8.11 (1H, dd, J = 2.5,
9.0Hz), 7.97 (1H, d, J = 2.5Hz), 7.74-7.62 (3H, m), 7.57
(2H, d, J = 8.5Hz), 7.49 (2H, d, J = 8.5Hz), 7.07 (1H, d, J = 8.
0Hz), 4.03 (2H, t, J = 8.5Hz), 3.77 (1H, t, J = 7.5Hz), 4.10
-3.30 (4H, m), 3.11 (2H, t, J = 8.5Hz), 2.85 (3H, s), 2.50-
2.20 (4H, m), 2.40-2.10 and 2.10-1.80 (each 1H, m), 2.
04 (3H, s), 0.99 (3H, t, J = 7.5Hz), TLC: Rf 0.60 (hexane: ethyl acetate = 2:
1).

Example 1 (147) 4- (Indoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.65-7.53 (3H, m), 7.
32 (2H, d, J = 8.4Hz), 7.24-6.90 (6H, m), 3.89 (2H, t, J = 8.5H
z), 3.66 (1H, t, J = 8.2Hz), 3.45 (4H, brs), 2.89 (2H, t, J =
8.5Hz), 2.34-2.04 (5H, m), 1.97 (3H, s), 2.04-1.73 (1H,
m), 0.97 (3H, t, J = 7.2 Hz), TLC: Rf 0.42 (hexane: ethyl acetate = 3:
1).

Example 2 4- (2S-carboxypyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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To a mixed solution of the compound prepared in Example 1 (1.04 g) in methylene chloride (5 ml) and anisole (5 ml) was slowly added trifluoroacetic acid (5 ml) at 0 ° C., followed by stirring at room temperature for 6 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give N- {4- [2
RS- (4- (1-Pyrrolidinyl) phenyl) butyryloxy] -3-methylphenylsulfonyl} -L-proline was obtained. The compound obtained above was converted into its hydrochloride by the following method. N- {4- [2RS- (4- (1-pyrrolidinyl) phenyl) butyryloxy] -3-methylphenylsulfonyl} -L-proline dioxane (5 m
l) 4N-dioxane hydrochloride solution (1m
l) was added and stirred for 5 minutes. The reaction solution was concentrated to give the title compound (1 g) having the following physical data.

NMR (CDCl ₃ ): δ 7.70 (1H, s), 7.67 (1
H, d, J = 8.0Hz), 7.59 (2H, d, J = 8.5Hz), 7.49 (2H, d, J = 8.5H
z), 7.07 (1H, d, J = 8.0Hz), 4.26 (1H, dd, J = 3.5,7.0Hz),
3.78 (1H, t, J = 7.5Hz), 3.75-3.60 (4H, m), 3.52-3.40 (1H,
m), 3.33-3.14 (1H, m), 2.40-2.25 (4H, m), 2.40-1.65 (6
H, m), 2.04 (3H, s), 1.00 (3H, t, J = 7.5Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 40).

Examples 2 (1) to 2 (296) Example 1 was repeated using the corresponding phenol derivative instead of the compound prepared in Reference Example 4 and the corresponding carboxylic acid derivative instead of the compound prepared in Reference Example 7. The compound of the present invention having the following physical data was obtained by the same procedure as in Example 2, or conversion to the corresponding salt or acid addition salt or solvate by a conventional method.

Example 2 (1) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (DMSO-d ₆ ): δ 7.86 (2H, d, J = 8 Hz),
7.24 (4H, d, J = 8Hz), 6.78 (2H, d, J = 8Hz), 4.15-4.05 (1H,
m), 3.73 (1H, t, J = 7Hz), 3.40-3.05 (6H, m), 2.20-1.45 (1
0H, m), 0.89 (3H, t, J = 7 Hz), TLC: Rf 0.26 (acetic acid: methanol: chloroform = 1: 2: 60).

Example 2 (2) 4- (2R-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 7.86 (2H, d, J = 8.8H)
z), 7.25 (4H, d, J = 8.8Hz), 6.78 (2H, d, J = 8.8Hz), 4.16-
4.05 (1H, m), 3.74 (1H, t, J = 7.2Hz), 3.44-3.06 (2H, m),
3.36-3.24 (4H, m), 2.22-1.46 (10H, m), 0.90 (3H, t, J = 7.2
Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (3) 4- (2S-carboxy-4R-hydroxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 7.83 (2H, d, J = 9 Hz),
7.31-7.18 (4H, m), 6.85-6.68 (2H, m), 4.25-4.14 (1H, m),
4.04 (1H, t, J = 7Hz), 3.73 (1H, t, J = 7Hz), 3.50-3.38 (5H,
m), 3.18-3.05 (1H, m), 2.20-1.65 (8H, m), 0.90 (3H, t, J =
7 Hz), TLC: Rf 0.27 (chloroform: methanol: acetic acid = 20: 2: 1).

Example 2 (4) 4- (2S-carboxy-4R-benzyloxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.84 (2H, d, J = 9 Hz),
7.62 (2H, d, J = 9Hz), 7.47 (2H, d, J = 9Hz), 7.34-7.19 (3H,
m), 7.17-7.00 (4H, m), 4.30 (1H, t, J = 8Hz), 4.23 (2H, s),
4.15-4.03 (1H, m), 3.86-3.42 (7H, m), 2.47-2.05 (7H,
m), 2.05-1.74 (1H, m), 0.97 (3H, t, J = 7 Hz), TLC: Rf 0.35 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (5) 4- (2S-carboxy-4S-aminopyrrolidine-1
-Ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.55-8.20 (2H, br
s), 7.89 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.25 (2H, d,
J = 9Hz), 6.73 (2H, d, J = 9Hz), 5.80-4.40 (1H, m), 4.18 (1H
(H, t, J = 7Hz), 3.74 (1H, t, J = 7Hz), 3.64-3.10 (7H, m), 2.6
7-2.40 (1H, m), 2.20-1.65 (7H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.49 (ethyl acetate: acetic acid: water = 6: 2:
1).

Example 2 (6) 4- (2S-carboxy-4R-aminopyrrolidine-1
-Ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.60-8.30 (2H, br
s), 7.88 (2H, d, J = 9Hz), 7.28 (2H, d, J = 9Hz), 7.23 (2H, d,
J = 9Hz), 6.72 (2H, d, J = 9Hz), 5.40-4.20 (1H, m), 4.40 (1
(H, dd, J = 9Hz, 4Hz), 3.90-3.50 (2H, m), 3.50-3.10 (6H, m),
2.33-1.60 (8H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.42 (ethyl acetate: acetic acid: water = 6: 2:
1).

Example 2 (7) 4- (2S- (N-carboxymethylcarbamoyl) pyrrolidin-1-ylsulfonyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.84 (2H, d, J =
8.8Hz), 7.28-7.18 (4H, m), 6.72 (2H, d, J = 8.8Hz), 4.09-
3.85 (3H, m), 3.71-3.53 (2H, m), 3.41-3.31 (4H, m), 3.20
-3.08 (1H, m), 2.26-1.59 (10H, m), 0.99 (3H, t, J = 7.4H
z), TLC: Rf 0.24 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (8) 4- (2S- (2-aminoethoxycarbonyl) pyrrolidin-1-ylsulfonyl) -2-methylphenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.21 (2H, brs), 7.7
5 (1H, s), 7.69 (1H, d, J = 8.2Hz), 7.22 (3H, m), 6.70 (2H,
d, J = 8.8Hz), 4.26 (3H, m), 3.50-3.36 (2H, m), 3.31 (4H, m
m), 3.20 (1H, m), 3.08 (2H, m), 2.12 (1H, m), 2.00 (3H,
s), 1.96 (4H, m), 1.87 (4H, m), 1.66 (1H, m), 0.92 (3H, t,
J = 7.2 Hz), TLC: Rf 0.31 (chloroform: methanol: acetic acid = 12: 1: 1).

Example 2 (9) 4- (2S- (2- (2-hydroxyethoxy) ethoxycarbonyl) pyrrolidin-1-ylsulfonyl) -2
-Methylphenyl 2RS- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.69 (1H, s), 7.67 (2
H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz), 7.07 (1H, d, J = 8.2H
z), 6.56 (2H, d, J = 8.4Hz), 4.29 (3H, m), 3.75-3.58 (7H,
m), 3.50 (1H, m), 3.29 (4H, m), 3.22 (1H, m), 2.16 (1H,
m), 2.04 (3H, s), 2.01 (4H, m), 1.98-1.64 (5H, m), 0.99
(3H, t, J = 7.2Hz), TLC: Rf 0.62 (chloroform: methanol = 9:
1).

Example 2 (10) 4- (2S-hydroxymethylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.58 (2H, m), 7.
22 (2H, d, J = 8.5Hz), 7.09 (1H, d, J = 8.0Hz), 6.55 (2H, d, J =
8.5Hz), 3.80-3.52 (3H, m), 3.62 (1H, t, J = 7.5Hz), 3.52-
3.35 (1H, m), 3.35-3.12 (5H, m), 2.90-2.55 (1H, brs), 2.
35-1.70 (2H, m), 2.05 (3H, s), 2.05-1.95 (4H, m), 1.80-
1.30 (4H, m), 0.99 (3H, t, J = 7.5Hz), TLC: Rf 0.36 (hexane: ethyl acetate = 1:
1).

Example 2 (11) 4- (2S- (2- (piperazin-4-yl) ethyl)
Oxycarbonylpyrrolidin-1-ylsulfonyl)-
2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.82-7.63 (6H, m), 7.
00 (1H, d, J = 8.2Hz), 4.62 (2H, m), 4.41 (1H, m), 4.00 (1H,
t, J = 7.6Hz), 3.81-3.66 (8H, m), 3.57 (1H, m), 3.21 (1H,
m), 2.33 (7H, m), 2.07 (3H, s), 2.03-1.89 (5H, m), 1.69
(1H, m), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.48 (chloroform: methanol: water =
40: 10: 1).

Example 2 (12) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2- (2-methoxyphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 7.89 (2H, d, J = 9 Hz),
7.34-7.16 (4H, m), 7.06-6.95 (2H, m), 4.03 (1H, dd, J = 2a
nd 8Hz), 3.82 (3H, s), 3.36-3.23 and 3.20-3.09 (each
1H, m), 2.23-1.91 (4H, m), 1.87-1.47 (4H, m), 0.72 (6H,
t, J = 7Hz), TLC: Rf 0.19 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (13) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (2-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.69 (1H, s), 7.68 (1
(H, d, J = 9.0Hz), 7.35-7.22 (2H, m), 7.10 (1H, d, J = 9.0Hz),
6.98 (1H, d, J = 7.6Hz), 6.92 (1H, d, J = 7.8Hz), 4.28-4.16
(1H, m), 4.15 (1H, t, J = 7.6Hz), 3.85 (3H, s), 3.60-3.43 (1
H, m), 3.26-3.07 (1H, m), 2.35-1.56 (4H, m), 2.04 (3H,
s), 0.98 (3H, t, J = 7.6Hz), TLC: Rf 0.54 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (14) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 7.74 (1H, s), 7.69 (1
H, d, J = 8.2Hz), 7.33 (2H, d, J = 8.8Hz), 7.17 (1H, d, J = 8.2H
z), 6.95 (2H, d, J = 8.8Hz), 4.11 (1H, m), 4.14 (1H, m), 3.
76 (3H, s), 3.30 (1H, m), 3.17 (1H, m), 2.10 (1H, m), 1.96
(3H, s), 1.82 (4H, m), 1.56 (1H, m), 0.91 (3H, t, J = 7.2H
z), TLC: Rf 0.58 (chloroform: methanol: acetic acid = 12: 1: 1).

Example 2 (15) 4- (2S- (2- (piperazin-1-yl) ethyl)
Oxycarbonylpyrrolidin-1-ylsulfonyl)-
2-methylphenyl 2RS- (4-methoxyphenyl) butanoate dihydrochloride

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NMR (CD ₃ OD): δ 7.77 (1H, s), 7.75 (1
H, d, J = 7.4Hz), 7.32 (2H, d, J = 8.6Hz), 7.16 (1H, d, J = 7.4H
z), 6.93 (2H, d, J = 8.6Hz), 4.62 (2H, brs), 4.5-4.3 (1H, b
r), 3.8-3.4 (12H, br), 3.79 (3H, s), 3.3-3.1 (1H, br),
2.3-1.8 (6H, br), 2.00 (3H, s), 0.98 (3H, t, J = 7.3 Hz), TLC: Rf 0.16 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (16) 4- (2S- (2- (2-hydroxyethoxy) ethoxycarbonyl) pyrrolidin-1-ylsulfonyl) -2
-Methylphenyl 2RS- (4-methoxyphenyl)
Butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70 (1H, s), 7.68 (1
H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.4Hz), 7.01 (1H, d, J = 8.8H)
z), 6.90 (2H, d, J = 8.4Hz), 4.3-4.2 (3H, m), 3.82 (3H, s),
3.8-3.7 (6H, m), 3.7-3.5 (2H, m), 3.3-3.2 (1H, m), 2.4-
2.1 (2H, m), 2.00 (3H, s), 2.1-1.7 (4H, m), 0.99 (3H, t, J =
7.3 Hz), TLC: Rf 0.24 (hexane: ethyl acetate = 1:
2).

Example 2 (17) 4- (2S- (2-aminoethyl) oxycarbonylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 8.40 (2H, brs), 7.73
(1H, s), 7.70 (1H, d, J = 9.2Hz), 7.30 (2H, d, J = 8.6Hz), 7.
08 (1H, d, J = 9.2Hz), 6.89 (2H, d, J = 8.6Hz), 4.6-4.3 (3H, b
r), 3.80 (3H, s), 3.67 (1H, t, J = 7.6Hz), 3.6-3.3 (3H, b
r), 3.2-3.1 (1H, br), 2.4-1.8 (6H, br), 2.00 (3H, s), 0.
98 (3H, t, J = 7.3Hz), TLC: Rf 0.23 (chloroform: methanol = 9:
1).

Example 2 (18) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.69 (1H, s), 7.66 (1
H, d, J = 9.0Hz), 7.25 (2H, d, J = 8.0Hz), 7.15 (2H, d, J = 8.0H
z), 7.05 (1H, d, J = 9.0Hz), 4.20 (1H, m), 3.67 (1H, t, J = 8.
0Hz), 3.60-3.40 (1H, m), 3.20-3.00 (1H, m), 2.34 (3H,
s), 2.30-1.50 (6H, m), 1.96 (3H, s), 0.97 (3H, t, J = 7.5H
z), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (19) 4- (2S-hydroxymethylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.67 (1H, s), 7.65 (1
H, d, J = 8.0Hz), 7.28 (2H, d, J = 8.0Hz), 7.18 (2H, d, J = 8.0H
z), 7.09 (1H, d, J = 8.0Hz), 3.70 (1H, t, J = 7.5Hz), 3.74-
3.54 (3H, m), 3.54-3.38 (1H, m), 3.30-3.14 (1H, m), 2.71
(1H, t-like), 2.36 (3H, s), 2.40-1.80 (2H, m), 2.02 (3H,
s), 1.90-1.60 (3H, m), 1.60-1.40 (1H, m), 1.00 (3H, t, J =
7.5 Hz), TLC: Rf 0.23 (ethyl acetate: hexane = 1:
2).

Example 2 (20) 4- (2S- (2-aminoethyl) oxycarbonylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoic acid ester
Hydrochloride

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NMR (DMSO-d ₆ ): δ 8.22 (3H, brs), 7.7
5 (1H, d, J = 1.8Hz), 7.70 (1H, dd, J = 8.4and 1.8Hz), 7.30
(2H, d, J = 8.0Hz), 7.20 (3H, d, J = 8.0Hz), 4.33-4.15 (1H,
m), 4.26 (2H, t, J = 5.0Hz), 3.85 (1H, t, J = 7.6Hz), 3.49-
3.01 (2H, m), 3.09 (2H, t, J = 5.6Hz), 2.32 (3H, s), 2.25-
1.50 (6H, m), 1.98 (3H, s), 0.92 (3H, t, J = 7.2Hz), TLC: Rf 0.56 (chloroform: methanol: acetic acid = 15: 2: 1).

Example 2 (21) 4- (2S- (2- (piperazin-4-yl) ethyl)
Oxycarbonylpyrrolidin-1-ylsulfonyl)-
2-methylphenyl 2RS- (4-methylphenyl)
Butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.78 (1H, s), 7.75 (1
(H, dd, J = 8.6 and 1.2Hz), 7.29 (2H, d, J = 8.0Hz), 7.24-7.
12 (3H, m), 4.66-4.54 (2H, m), 4.45-4.32 (1H, m), 3.85-
3.60 (11H, m), 3.60-3.38 (1H, m), 3.26-3.15 (1H, m), 2.3
4 (3H, s), 2.30-1.55 (6H, m), 1.99 (3H, s), 0.
98 (3H, t, J = 7.2 Hz), TLC: Rf 0.45 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (22) 4- (2S- (2- (2-hydroxyethoxy) ethyl) oxycarbonylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.70 (1H, s), 7.68 (1
H, dd, J = 7.4 and 2.4Hz), 7.28 (2H, d, J = 8.2Hz), 7.18 (2
H, d, J = 8.2Hz), 7.07 (1H, d, J = 8.8Hz), 4.40-4.20 (3H, m),
3.73-3.37 (8H, m), 3.37-3.16 (1H, m), 2.24-1.63 (6H, m
m), 2.36 (3H, s), 2.02 (3H, s), 1.70 (1H, s), 1.00 (3H, t,
J = 7.2Hz), TLC: Rf 0.28 (ethyl acetate: hexane = 2:
1).

Example 2 (23) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 8.25 (2H, d, J = 8 Hz),
7.90 (2H, d, J = 8Hz), 7.58 (2H, d, J = 8Hz), 7.19 (2H, d, J = 8
Hz), 5.70-4.80 (1H, brs), 4.30 (1H, dd, J = 7Hz, 4Hz), 3.8
5 (1H, t, J = 7Hz), 3.60-3.39 (1H, m), 3.39-3.15 (1H, m),
2.45-1.65 (6H, m), 1.01 (3H, t, J = 7 Hz), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (24) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2R- (4-nitrophenyl) butanoate

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NMR (CDCl ₃ ): δ 8.26 (d, J = 8.8 Hz, 2H),
7.90 (d, J = 8.8Hz, 2H), 7.58 (d, J = 8.8Hz, 2H), 7.20 (d, J =
8.8Hz, 2H), 4.30 (dd, J = 4.0,7.8Hz, 1H), 3.86 (t, J = 7.6H
z, 1H), 3.5-3.4 (m, 1H), 3.4-3.2 (m, 1H), 2.4-1.7 (m, 6H)
1.02 (t, J = 7.3 Hz, 3H), TLC: Rf 0.63 (chloroform: methanol = 6:
1).

Example 2 (25) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2S- (4-nitrophenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.26 (d, J = 8.8 Hz, 2H),
7.90 (d, J = 8.8Hz, 2H), 7.58 (d, J = 8.8Hz, 2H), 7.19 (d, J =
8.8Hz, 2H), 4.31 (dd, J = 4.0,7.2Hz, 1H), 3.86 (t, J = 7.7H
z, 1H), 3.6-3.4 (m, 1H), 3.4-3.2 (m, 1H), 2.4-1.7 (m, 6H),
1.03 (t, J = 7.6 Hz, 3H), TLC: Rf 0.63 (chloroform: methanol = 6:
1).

Example 2 (26) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 8.27 (2H, d, J = 8 Hz),
7.88 (2H, d, J = 8Hz), 7.56 (2H, d, J = 8Hz), 7.16 (2H, d, J = 8
Hz), 6.00-5.10 (1H, brs), 4.29 (1H, dd, J = 7Hz, 4Hz), 3.5
5-3.40 (1H, m), 3.34-3.19 (1H, m), 3.15-2.98 (2H, m), 2.
80-2.60 (2H, m), 2.38-1.66 (6H, m), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (27) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 8.27 (2H, d, J = 8.8H)
z), 7.74 (2H, d, J = 8.8Hz), 7.79-7.66 (2H, m), 7.23 (1H,
d, J = 8.4Hz), 4.20 (1H, t, J = 7.6Hz), 4.12-4.06 (1H, m),
3.40-3.07 (2H, m), 2.35-1.40 (6H, m), 2.00 (3H, s), 0.92
(3H, t, J = 7.2Hz), TLC: Rf 0.19 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (28) 4- (2R-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 13.5-11.6 (1H, br
s), 8.27 (2H, d, J = 8.8Hz), 7.88 (2H, d, J = 8.8Hz), 7.73 (2H
H, d, J = 8.8Hz), 7.32 (2H, d, J = 8.8Hz), 4.16 (1H, t, J = 7.2H
z), 4.16-4.06 (1H, m), 3.5-3.0 (2H, m), 2.35-1.45 (6H,
m), 0.92 (3H, t, J = 7.2 Hz), TLC: Rf 0.43 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (29) 4- (2R-carboxypyrrolidin-1-ylsulfonyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.9-12.6 (1H, br
s), 8.28 (2H, d, J = 8.8Hz), 7.87 (2H, d, J = 8.8Hz), 7.71 (2
H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 4.16-4.04 (1H, m),
3.43-3.10 (2H, m), 3.10-2.90 (2H, m), 2.75-2.55 (2H, q-
like), 2.28-1.46 (6H, m), TLC: Rf 0.46 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (30) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.93-7.83 (2H, m), 7.
50-7.14 (5H, m), 7.23-7.14 (2H, m), 7.14-6.70 (1H, brs),
4.26 (1H, dd, J = 10Hz, 5Hz), 3.71 (1H, t, J = 7Hz), 3.56-3.
43 (1H, m), 3.33-3.17 (1H, m), 2.35-1.65 (6H, m), 0.98 (3
H, t, J = 7Hz), TLC: Rf 0.67 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (31) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.73 (2H, d, J = 8.6 Hz),
7.58 (1H, d, J = 8.2Hz), 7.17 (2H, d, J = 8.6Hz), 7.12-6.94
(5H, m), 6.53 (2H, d, J = 8.8Hz), 4.73 (1H, dd, J = 8.9Hz and
6.8Hz), 3.54 (1H, t, J = 7.8Hz), 3.35-3.21 (4H, m), 3.17
(2H, d, J = 6.8Hz), 2.25-1.70 (2H, m), 2.05-1.94 (4H, m),
0.95 (3H, t, J = 7.2 Hz), TLC: Rf 0.46 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (32) 4- (2-carboxyindol-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (DMSO-d ₆ ): δ 8.08 (2H, d, J = 8.8H)
z), 8.01 (1H, d, J = 8.4Hz), 7.68 (1H, d, J = 8.0Hz), 7.46 (1
H, m), 7.40-7.16 (2H, m), 7.24 (2H, d, J = 8.8Hz), 7.20 (2H
(H, d, J = 8.6Hz), 6.85-6.60 (2H, m), 3.69 (1H, t, J = 7.4Hz),
3.40-3.15 (4H, m), 2.20-1.84 (5H, m), 1.84-1.60 (1H,
m), 0.86 (3H, t, J = 7.4Hz), TLC: Rf 0.20 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (33) 4- (2S-Carboxyindolin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.72 (2H, d, J = 8.6 Hz),
7.57 (1H, d, J = 7.8Hz), 7.17 (2H, d, J = 8.6Hz), 7.28-6.88
(5H, m), 6.53 (2H, d, J = 8.6Hz), 4.72 (1H, dd, J = 5.8Hz and
9.1Hz), 3.54 (1H, t, J = 7.8Hz), 3.35-3.22 (4H, m), 3.22
-3.08 (2H, m), 2.25-1.70 (2H, m), 2.05-1.95 (4H, m), 0.9
5 (3H, t, J = 7.2 Hz), TLC: Rf 0.46 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (34) 4- (2S-carboxyperhydroindol-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.89 (2H, d, J = 8.8 Hz),
7.71 (2H, d, J = 8.6Hz), 7.51 (2H, d, J = 8.6Hz), 7.17 (2H, d
d, J = 8.8Hz), 4.20 (1H, t, J = 8.6Hz), 4.0-3.5 (6H, m), 2.5
-2.2 (4H, m), 2.4-1.0 (13H, m), 0.99 (3H, t, J = 7.4Hz), TLC: Rf 0.60 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (35) 4- (2RS-Carboxyindolin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 7.79 (1H, d-like),
7.67 (1H, dd, J = 2.2 and 8.4Hz), 7.35-6.95 (7H, m), 6.71
-6.67 (2H, m), 4.97 (1H, dd, J = 4.4 and 10.7Hz), 3.71 (1
(H, t, J = 7.6Hz), 3.35-2.96 (6H, m), 2.14-1.68 (2H, m), 2.
00-1.94 (4H, m), 1.91 (3H, s), 0.87 (3H, t, J = 7.2Hz), TLC: Rf 0.45 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (36) 4- (2RS- (N-carboxymethylcarbamoyl)
Indolin-1-ylsulfonyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70 (1H, d, J = 7.8 Hz),
7.58 (2H, d, J = 8.8Hz), 7.28-7.02 (8H, m), 6.66 (2H, d, J =
8.8Hz), 4.64 (1H, dd, J = 10.4,2.8Hz), 4.02 (2H, d, J = 3.0H
z), 3.56 (1H, t, J = 7.6Hz), 3.37-3.05 (5H, m), 2.81 (1H, d
d, J = 16.0,10.4Hz), 2.35-1.74 (6H, m), 0.95 (3H, t, J = 7.6
Hz), TLC: Rf 0.33 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (37) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.72 (2H, d, J = 8 Hz),
7.59 (1H, d, J = 8Hz), 7.27-7.03 (7H, m), 6.54 (2H, d, J = 8H
z), 6.08 (1H, br), 4.77-4.69 (1H, m), 3.55 (1H, t, J = 8H
z), 3.31-3.24 (4H, m), 3.19-3.15 (2H, m), 2.20-1.76 (2
H, m), 2.03-1.96 (4H, m), 0.95 (3H, t, J = 8 Hz), TLC: Rf 0.45 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (38) 4- (2RS-carboxy-3,3-dimethylindoline-1-ylsulfonyl) phenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.83 (2H, d, J = 8.5 Hz),
7.55 (1H, d, J = 8.0Hz), 7.25-6.93 (3H, m), 7.17 (2H, d, J =
8.5Hz), 7.09 (2H, d, J = 8.5Hz), 6.53 (2H, d, J = 8.5Hz), 4.
36 (1H, s), 3.54 (1H, t, J = 8.0Hz), 3.35-3.10 (4H, m), 2.0
5-1.90 (4H, m), 2.25-1.70 (2H, m), 1.31 (3H, s), 1.04 (3
H, s), 0.94 (3H, t, J = 7.5 Hz), TLC: Rf 0.48 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (39) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methoxyphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.7-7.6 (m, 1H), 7.5-
6.9 (m, 8H), 6.5-6.4 (m, 2H), 4.8-4.6 (m, 1H), 3.8-3.5
(m, 4H), 3.4-3.0 (m, 6H), 2.2-1.7 (m, 6H), 1.1-0.9 (m, 3
H), TLC: Rf 0.65 (chloroform: methanol = 3:
1).

Example 2 (40) 4- (2RS- (N-2-carboxyethylcarbamoyl) indoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butane Acid ester

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NMR (CDCl ₃ ): δ 7.8-6.8 (m, 11H), 4.7
-4.5 (m, 1H), 3.8-3.5 (m, 7H), 3.3-3.1 (m, 1H), 3.0-2.8
(m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m, 4H), 2.1-1.8 (m, 5
H), 0.97 (t, J = 7.2 Hz, 3H), TLC: Rf 0.76 (methanol: chloroform = 1:
3).

Example 2 (41) 4- (2RS- (N-2-hydroxyethylcarbamoyl) indoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butane Acid ester

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NMR (CDCl ₃ ): δ 7.72 (1H, d, J = 8.0 Hz),
7.45-6.92 (9H, m), 6.51 (2H, d, J = 8.6Hz), 4.57 (1H, dd, J
= 2.8,10.6Hz), 3.77-3.52 (5H, m), 3.39-3.17 (5H, m), 2.
88 (1H, dd, J = 10.6,16.8Hz), 2.23-1.78 (6H, m), 1.92 (3H,
s), 0.96 (3H, t, J = 7.4 Hz), TLC: Rf 0.43 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (42) 4- (2-carboxy-5,6-dimethoxyindol-1-ylsulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.78-7.62 (3H, m), 7.
35 (1H, s), 7.18 (2H, d, J = 9Hz), 7.00 (1H, d, J = 8Hz), 6.95
(1H, s), 6.52 (2H, d, J = 9Hz), 4.00 (3H, s), 3.91 (3H, s),
3.70-3.10 (1H, brs), 3.57 (1H, t, J = 7Hz), 3.35-3.18 (4H,
m), 2.25-1.75 (9H, m), 0.96 (3H, t, J = 7Hz). TLC: Rf 0.19 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (43) 4- (2RS- (2-aminoethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid Ester dihydrochloride

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NMR (DMSO-d ₆ ): δ 8.30 (2H, brs), 7.7
6 (1H, s), 7.66 (1H, d, J = 8.0Hz), 7.37 (1H, d, J = 8.0Hz),
7.23-7.00 (6H, m), 6.70 (2H, d, J = 8.0Hz), 5.08 (1H, dd, J =
6.2,9.4Hz), 4.37-4.32 (2H, m), 3.69 (1H, t, J = 7.2Hz),
3.35-3.07 (8H, m), 2.14-1.69 (9H, m), 0.89 (3H, t, J = 7.2H
z), TLC: Rf 0.46 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (44) 4- (2-Carboxyndol-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.13 (1H, d, J = 9 Hz),
7.90-7.78 (2H, m), 7.60 (1H, d, J = 9Hz), 7.46 (1H, td, J = 8,1
Hz), 7.39 (1H, s), 7.35-7.25 (1H, m), 7.21 (2H, d, J = 9H
z), 6.75-6.50 (2H, m), 3.59 (1H, t, J = 7Hz), 3.38-3.23 (4
H, m), 3.23-2.90 (1H, brs), 2.25-1.75 (6H, m), 0.96 (3H,
t, J = 7Hz), TLC: Rf 0.20 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (45) 4- (2RS-carboxy-5,6-dimethoxyindolin-1-ylsulfonyl) -2-methylphenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.6-7.4 (m, 2
H), 7.26 (s, 1H), 7.19 (d, J = 8.7Hz, 2H), 6.96 (dd, J = 1.2,
8.4Hz, 1H), 6.58 (s, 1H), 6.54 (d, J = 8.7Hz, 2H), 4.7-4.6
(m, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.58 (t, J = 7.7Hz, 1H),
3.4-3.2 (m, 4H), 3.1-2.9 (m, 2H), 2.3-1.8 (m, 6H), 1.94
(s, 3H), 0.96 (t, J = 7.4 Hz, 3H), TLC: Rf 0.45 (chloroform: methanol = 4:
1).

Example 2 (46) 4- (2-carboxy-5-hydroxyindole-1
-Ylsulfonyl) -2-methylphenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CD ₃ OD): δ 7.85-7.63 (3H, m), 7.
03 (2H, d, J = 8Hz), 6.93 (1H, d, J = 8Hz), 6.87-6.70 (3H, m),
6.53 (2H, d, J = 8Hz), 3.56 (1H, t, J = 7Hz), 3.30-3.10 (4H,
m), 2.20-1.90 (5H, m), 1.90-1.65 (1H, m), 1.84 (3H, s),
0.91 (3H, t, J = 7Hz), TLC: Rf 0.23 (ethyl acetate: hexane: acetic acid = 1
0: 10: 0.5).

Example 2 (47) 4- (2RS- (2- (2-hydroxyethoxy) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) ) Phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.61-7.51 (3H, m), 7.
23-7.10 (3H, m), 7.10-6.95 (3H, m), 6.51 (2H, d, J = 8.0H
z), 4.75 (1H, dd, J = 5.6,10.2Hz), 4.38-4.33 (2H, m), 3.7
5-3.51 (7H, m), 3.30-3.22 (5H, m), 3.09 (1H, dd, J = 5.6,1
6.6Hz), 2.23-1.78 (6H, m), 1.96 (3H, s), 0.96 (3H, t, J =
7.4 Hz), TLC: Rf 0.65 (chloroform: methanol = 1)
5: 1).

Example 2 (48) 4- (2RS-Hydroxymethylindoline-1-ylsulfonyl) -methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 7.60 (1H, s-like),
7.51-7.40 (2H, m), 7.22-6.97 (6H, m), 6.51 (2H, d, J = 8Hz),
4.40-4.24 (1H, m), 3.68-3.37 (3H, m), 3.65 (1H, t, J = 7H
z), 3.23-3.17 (4H, m), 2.87-2.69 (2H, m), 2.19-1.62 (ea
ch 1H, m), 1.99-1.93 (4H, m), 1.86 (3H, s),
0.87 (3H, t, J = 7 Hz), TLC: Rf 0.29 (hexane: ethyl acetate = 2:
1).

Example 2 (49) 4- (2RS-carboxy-5-hydroxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ +3 drops of CD ₃ OD): δ 7.5
-7.4 (m, 3H), 7.2-7.1 (m, 3H), 7.0-6.9 (m, 1H), 6.5-6.4
(m, 3H), 4.7-4.6 (m, 1H), 3.58 (t, J = 7.8Hz, 1H), 3.4-3.2
(m, 4H), 3.1-2.9 (m, 2H), 2.2-1.8 (m, 6H), 1.94 (s, 3H),
0.97 (t, J = 7.2 Hz, 3H), TLC: Rf 0.2 (chloroform: methanol = 6:
1).

Example 2 (50) 4- (2RS- (2- (piperazin-1-yl) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidine-1-) Yl) phenyl) butanoic acid ester trihydrochloride

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NMR (CD ₃ OD): δ 7.72-7.64 (3H, m), 7.
57-7.49 (4H, m), 7.26-7.00 (4H, m), 5.12 (1H, dd, J = 6.0,
8.8Hz), 4.63-4.59 (2H, m), 3.90 (1H, t, J = 8.0Hz), 3.77-
3.59 (14H, m), 3.23-3.20 (2H, m), 2.32-1.83 (6H, m), 1.9
6 (3H, s), 0.97 (3H, t, J = 7.4 Hz), TLC: Rf 0.41 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (51) 4- (2RS- (N-hydroxycarbamoyl) indolin-1-ylsulfonyl) phenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CD ₃ OD): δ 7.75 (2H, d, J = 8.6 Hz),
7.60 (1H, d, J = 8.0Hz), 7.58-7.48 (4H, m), 7.21 (1H, dd, J
= 6.5Hz, 1.5Hz), 7.12 (2H, d, J = 8.6Hz), 7.09-7.01 (2H,
m), 4.68 (1H, dd, J = 9.0Hz, 5.0Hz), 3.87 (1H, t, J = 7.0Hz),
3.77-3.70 (4H, m), 3.03-2.98 (2H, m), 2.28-2.23 (4H, m
m), 2.20-2.13 (0.5H, m), 1.97-1.81 (1.5H, m), 0.90 (3H,
t, J = 7.0 Hz), TLC: Rf 0.49 (hexane: ethyl acetate: acetic acid =
8: 8: 1).

Example 2 (52) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.74 (2H, d, J = 8.8 Hz),
7.58 (1H, d, J = 8.0Hz), 7.29-7.02 (7H, m), 6.87 (2H, d, J =
8.8Hz), 4.90 (1H, brs), 4.73 (1H, dd, J = 9.2,5.8Hz), 3.8
0 (3H, s), 3.60 (1H, t, J = 7.8Hz), 3.20-3.15 (2H, m), 2.23
-2.05 (1H, m), 1.94-1.76 (1H, m), 0.951 (3H, t, J = 7.6H
z), TLC: Rf 0.36 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (53) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 7.82 (1H, d-like),
7.72 (1H, d-like), 7.38 (2H, d, J = 8.6Hz), 7.32 (1H, d, J =
7.8Hz), 7.23-7.10 (3H, m), 7.03-6.96 (3H, m), 4.73 (1H,
dd, J = 5.2 and 9.3Hz), 3.88 (1H, t, J = 7.6Hz), 3.82 (3H,
s), 3.14-3.05 (2H, m), 2.25-2.10and 1.96-1.79 (each 1
H, m), 0.96 (3H, t, J = 7.2Hz), TLC: Rf 0.41 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (54) 4- (2-carboxy-5,6-dimethoxyindol-1-ylsulfonyl) -2-methylphenyl 2RS
-(4-methoxyphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.79-7.64 (3H, m), 7.
36 (1H, s), 7.23 (2H, d, J = 9Hz), 7.01 (1H, d, J = 9Hz), 6.96
(1H, s), 6.88 (2H, d, J = 9Hz), 4.00 (3H, s), 3.91 (3H, s),
3.80 (3H, s), 3.64 (1H, t, J = 7Hz), 2.27-2.03 (1H, m), 2.0
0-1.80 (1H, m), 1.96 (3H, s), 0.96 (3H, t, J = 7Hz), TLC: Rf 0.10 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (55) 4- (2-Carboxyndol-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 8.14 (1H, d, J = 9 Hz),
7.90-7.78 (2H, m), 7.60 (1H, d, J = 9Hz), 7.52-7.40 (1H, m),
7.38 (1H, s), 7.35-7.20 (3H, m), 7.03 (1H, d, J = 9Hz), 6.
87 (2H, d, J = 9Hz), 3.79 (3H, s), 3.64 (1H, t, J = 7Hz), 2.28
-2.05 (1H, m), 2.00-1.79 (1H, m), 1.96 (3H, s), 0.96 (3H,
t, J = 7Hz), TLC: Rf 0.26 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (56) 4- (2-carboxy-5-hydroxyindole-
1-ylsulfonyl) -2-methylphenyl 2RS-
(4-methoxyphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.94 (1H, d, J = 9 Hz),
7.80-7.69 (2H, m), 7.26 (2H, d, J = 9Hz), 7.17 (1H, s), 6.99
(1H, d, J = 9Hz), 6.96 (1H, dd, J = 9,2Hz), 6.87 (2H, d, J = 9H
z), 6.87 (1H, d, J = 2Hz), 3.80-3.40 (1H, brs), 3.79 (3H,
s), 3.64 (1H, t, J = 7Hz), 2.26-2.05 (1H, m), 2.00-1.75 (1
H, m), 1.93 (3H, s), 0.95 (3H, t, J = 7Hz), TLC: Rf 0.16 (ethyl acetate: hexane: acetic acid = 1
0: 10: 0.5).

Example 2 (57) 4- (2RS-Hydroxymethylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 7.61 (1H, s-like),
7.50-7.40 (2H, m), 7.28 (2H, d, J = 8Hz), 7.21-6.96 (4H, m),
6.92 (2H, d, J = 8Hz), 5.02 (1H, t-like), 4.32 (1H, m), 3.
78 (1H, t, J = 7Hz), 3.74 (3H, s), 3.67-3.57 and 3.47-3.3
7 (each 1H, m), 2.83-2.70 (2H, m), 2.10-1.95 and 1.86-
1.65 (each 1H, m), 1.85 (3H, s), 0.88 (3H, t, J = 7Hz), TLC: Rf 0.21 (hexane: ethyl acetate = 2:
1).

Example 2 (58) 4- (2RS- (2-aminoethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 8.25 (3H, brs), 7.7
8-7.65 (2H, m), 7.39-7.00 (5H, m), 7.28 (2H, d, J = 8.8Hz),
6.91 (2H, d, J = 8.8Hz), 5.08 (1H, dd, J = 5.8,10.0Hz), 4.3
4 (2H, t, J = 5.2Hz), 3.83-3.74 (1H, m), 3.74 (3H, s), 3.30
-3.09 (4H, m), 2.17-1.75 (2H, m), 1.90 (3H,
s), 0.89 (3H, t, J = 7.2 Hz), TLC: Rf 0.53 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (59) 4- (2RS- (2- (piperazin-4-yl) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoic acid Ester dihydrochloride

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NMR (CD ₃ OD): δ 7.68-7.63 (2H, m), 7.
51 (1H, d, J = 7.8Hz), 7.27 (2H, d, J = 8.4Hz), 7.22-7.02 (4
H, m), 6.90 (2H, d, J = 8.4Hz), 5.10 (1H, t, J = 7.2Hz), 4.60
(2H, brs), 3.78 (3H, s), 3.75-3.19 (13H, m), 2.23-1.78
(2H, m), 1.89 (3H, s), 0.95 (3H, t, J = 7.4Hz), TLC: Rf 0.16 (chloroform: methanol = 1
0: 1).

Example 2 (60) 4- (2RS- (2- (2-hydroxyethoxy) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.62-7.51 (3H, m), 7.
26 (2H, d, J = 8.4Hz), 7.28-6.96 (4H, m), 6.87 (2H, d, J = 8.4H
z), 4.76 (1H, dd, J = 5.4,10.6Hz), 4.38-4.34 (2H, m), 3.8
0 (3H, s), 3.75-3.55 (7H, m), 3.31-3.04 (2H, m), 2.26-1.
80 (2H, m), 1.93 (3H, s), 0.97 (3H, t, J = 7.4Hz), TLC: Rf 0.11 (hexane: ethyl acetate = 1:
1).

Example 2 (61) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (3-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.75 (2H, d, J = 8.8 Hz),
7.57 (1H, d, J = 7.8Hz), 7.30-6.79 (9H, m), 4.73 (1H, t, J =
8.0Hz), 3.80 (3H, s), 3.62 (1H, t, J = 7.8Hz), 3.20-3.17
(2H, m), 2.28-2.05 (1H, m), 1.99-1.77 (1H, m), 0.96 (3H,
t, J = 7.4 Hz), TLC: Rf 0.66 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (62) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (2-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.75 (2H, d, J = 8.8 Hz),
7.58 (1H, d, J = 8.0Hz), 7.25 (2H, d, J = 8.8Hz), 7.31-6.87
(7H, m), 4.74 (1H, t, J = 8.0Hz), 4.04 (1H, t, J = 7.2Hz), 3.
84 (3H, s), 3.18 (2H, brd, J = 7.2Hz), 2.22-2.05 (1H, m),
1.96-1.74 (1H, m), 0.95 (3H, t, J = 7.6 Hz), TLC: Rf 0.48 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (63) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (2-methoxyphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 13.19 (1H, br), 7.7
9 (1H, d, J = 2.0Hz), 7.68 (1H, dd, J = 2.0and 8.5Hz), 7.36-
6.92 (9H, m), 4.96 (1H, dd, J = 4.2 and 10.9Hz), 4.08 (1H, m
t, J = 7.6Hz), 3.80 (3H, s), 3.39-2.96 (2H, m), 2.19-1.69
(2H, m), 1.95 (3H, s), 0.87 (3H, t, J = 7.2H
z), TLC: Rf 0.39 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (64) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (3,4-dimethoxyphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.76 (2H, d, J = 8.8 Hz),
7.57 (1H, d, J = 8.0Hz), 7.25-7.02 (5H, m), 6.86-6.85 (3
H, m), 4.73 (1H, t, J = 8.0Hz), 3.87 (6H, s), 3.59 (1H, t, J =
7.8Hz), 3.21-3.17 (2H, brd), 2.24-2.05 (1H, m), 1.97-1.
76 (1H, m), 0.97 (3H, t, J = 7.6 Hz), TLC: Rf 0.50 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (65) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (3,4-dimethoxyphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 13.14 (1H, br), 7.8
0 (1H, s), 7.68 (1H, d-like), 7.35-7.11 (4H, m), 7.02-6.
86 (4H, m), 4.97 (1H, dd, J = 4.2 and 10.5Hz), 3.79 (1H, t,
J = 7.4Hz), 3.74 (6H, s), 3.39-2.97 (2H, m), 2.16-1.98a
nd 1.95-1.72 (each 1H, m), 1.91 (3H, s), 0.89 (3H, t, J =
7.2 Hz), TLC: Rf 0.39 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (66) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.74 (2H, d, J = 8.8 Hz),
7.58 (1H, d, J = 8.0Hz), 7.24-7.02 (9H, m), 4.74 (1H, t, J =
8.6Hz), 3.62 (1H, t, J = 7.8Hz), 3.18 (2H, brd), 2.34 (3H,
s), 2.27-2.05 (1H, m), 1.97-1.75 (1H, m), 0.96 (3H, t, J =
7.4 Hz), TLC: Rf 0.43 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (67) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (DMSO-d ₆ ): δ 13.08 (1H, br), 7.7
3 (1H, d, J = 2.0Hz), 7.61 (1H, dd, J = 2.0and 8.6Hz), 7.28-
6.87 (9H, m), 4.90 (1H, dd, J = 4.0 and 10.8Hz), 3.75 (1H, m
t, J = 7.6Hz), 3.32-2.90 (2H, m), 2.22 (3H, s), 2.13-1.91
and 1.86-1.64 (each 1H, m), 1.82 (3H, s), 0.80 (3H, t, J =
7.2 Hz), TLC: Rf 0.43 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (68) 4- (2-carboxy-5,6-dimethoxyindol-1-ylsulfonyl) -2-methylphenyl 2RS
-(4-methylphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.78-7.64 (3H, m), 7.
35 (1H, s), 7.23 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz), 7.00
(1H, d, J = 9Hz), 6.95 (1H, s), 4.00 (3H, s), 3.91 (3H, s),
3.85-3.30 (1H, br), 3.65 (1H, t, J = 7Hz), 2.33 (3H, s), 2.
30-2.10 (1H, m), 2.00-1.80 (1H, m), 1.96 (3
H, s), 0.96 (3H, t, J = 7 Hz), TLC: Rf 0.23 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (69) 4- (2-carboxyindol-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 8.14 (1H, d, J = 9 Hz),
7.90-7.78 (2H, m), 7.60 (1H, d, J = 9Hz), 7.52-7.41 (1H, m),
7.39 (1H, s), 7.35-7.10 (5H, m), 7.03 (1H, d, J = 9Hz), 4.
00-3.60 (1H, br), 3.66 (1H, t, J = 7Hz), 2.33 (3H, s), 2.30
-2.07 (1H, m), 2.00-1.75 (1H, m), 1.97 (3H, s), 0.96 (3H,
t, J = 7Hz), TLC: Rf 0.28 (ethyl acetate: hexane: acetic acid =
5: 10: 0.5).

Example 2 (70) 4- (2-carboxy-5-hydroxyindole-1
-Ylsulfonyl) -2-methylphenyl 2RS-
(4-methylphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.95 (1H, d, J = 9 Hz),
7.81-7.69 (2H, m), 7.22 (2H, d, J = 8Hz), 7.20 (1H, s), 7.15
(2H, d, J = 8Hz), 7.00 (1H, d, J = 8Hz), 6.97 (1H, dd, J = 9,2H
z), 6.89 (1H, d, J = 2Hz), 3.80-3.30 (1H, br), 3.66 (1H, t,
J = 7Hz), 2.33 (3H, s), 2.28-2.10 (1H, m), 2.00-1.80 (1H,
m), 1.94 (3H, s), 0.96 (3H, t, J = 7Hz), TLC: Rf 0.24 (ethyl acetate: hexane: acetic acid = 1
0: 10: 0.5).

Example 2 (71) 4- (2RS- (2-aminoethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate hydrochloride

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NMR (CDCl ₃ + CD ₃ OD): δ 7.8-7.5 (m, 4
H), 7.3-7.0 (m, 7H), 5.0-4.8 (m, 1H), 4.6-4.4 (m, 2H),
3.67 (t, J = 9.2Hz, 1H), 3.4-3.3 (m, 2H), 3.3-3.2 (m, 2H),
2.34 (s, 3H), 2.3-1.8 (m, 2H), 1.95 (s, 3H), 0.97 (t, J = 7.
0 Hz, 3H), TLC: Rf 0.5 (chloroform: methanol = 4:
1).

Example 2 (72) 4- (2RS-Hydroxymethylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 7.61 (1H, s-like),
7.51-7.40 (2H, m), 7.27-6.96 (8H, m), 5.04 (1H, t-like),
4.34 (1H, m), 3.81 (1H, t, J = 7Hz), 3.67-3.57 and 3.48-
3.39 (each 1H, m), 2.83-2.68 (2H, m), 2.29 (3H, s), 2.20
-1.97 and 1.88-1.67 (each 1H, m), 1.86 (3H, s), 0.87 (3
H, t, J = 7Hz), TLC: Rf 0.30 (hexane: ethyl acetate = 2:
1).

Example 2 (73) 4- (2RS- (2- (2-hydroxyethoxy) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoate

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NMR (CDCl ₃ ): δ 7.7-7.5 (m, 3H), 7.3-
6.9 (m, 8H), 4.9-4.7 (m, 1H), 4.4-4.3 (m, 2H), 3.8-3.5
(m, 7H), 3.4-3.0 (m, 2H), 2.34 (s, 3H), 2.4-1.8 (m, 2H),
1.93 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), TLC: Rf 0.25 (hexane: ethyl acetate = 1:
1).

Example 2 (74) 4- (2RS- (2- (Piperazin-4-yl) ethyl) oxycarbonylindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-methylphenyl) butanoic acid Ester and hydrochloride

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NMR (CDCl ₃ ): δ 7.7-7.5 (m, 3H), 7.5-
7.4 (m, 1H), 7.3-6.9 (m, 7H), 5.2-5.0 (m, 1H), 4.7-4.5
(m, 2H), 4.0-3.5 (m, 11H), 3.4-3.0 (m, 2H), 2.30 (s, 3H),
2.4-2.0 (m, 1H), 1.88 (s, 3H), 2.0-1.8 (m, 1H), 0.93 (t,
J = 7.2Hz, 3H), TLC: Rf 0.3 (chloroform: methanol = 2:
1).

Example 2 (75) 4- (2RS-carboxyindoline-1-ylsulfonyl) -2-methylphenyl 2RS- (4-hydroxyphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.7-7.5 (3H, m), 7.3-
7.1 (3H, m), 7.1-6.9 (3H, m), 6.80 (2H, d, J = 8.4Hz), 4.8-
4.7 (1H, m), 3.7-3.3 (1H, m), 3.3-3.1 (2H, m), 2.3-2.0 (1
H, m), 2.0-1.8 (1H, m), 1.91 (3H, s), 0.96 (3H, t, J = 7.4H
z), TLC: Rf 0.42 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (76) 4- (2RS-carboxyindoline-1-ylsulfonyl) phenyl 2RS- (4-aminophenyl) butanoate

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NMR (DMSO-d ₆ ): δ 7.83 (2H, d, J = 8.4H)
z), 7.30 (1H, d, J = 8.2Hz), 7.12 (2H, d, J = 8.4Hz), 6.97 (2
(H, d, J = 8.4Hz), 7.17-6.90 (3H, m), 6.53 (2H, d, J = 8.4Hz),
4.80-4.73 (1H, m), 3.54 (1H, t, J = 7.6Hz), 3.25-2.93 (2
H, m), 2.09-1.90 (1H, m), 1.78-1.60 (1H, m), 0.86 (3H, t,
J = 7.2 Hz), TLC: Rf 0.20 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (77) 4- (4S-carboxyperhydrothiazol-3-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.85 (2H, d, J = 8.8 Hz),
7.21 (2H, d, J = 8.8Hz), 7.17 (2H, d, J = 8.8Hz), 6.57 (2H,
d, J = 8.8Hz), 4.83 (1H, dd, J = 7.0 and 3.4Hz), 4.67 (1H,
d, J = 9.0Hz), 4.40 (1H, d, J = 9.0Hz), 3.59 (1H, t, J = 7.6H
z), 3.40-3.18 (5H, m), 3.01 (1H, dd, J = 11.4 and 7.0Hz),
2.30-2.05 and 2.05-1.75 (each 1H, m), 2.10-1.95 (4H,
m), 0.98 (3H, t, J = 7.6 Hz), TLC: Rf 0.36 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (78) 4- (4-Carboxypiperidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.71 (2H, d, J = 8.8 Hz),
7.21 (2H, d, J = 8.8Hz), 7.17 (2H, d, J = 8.8Hz), 6.55 (2H,
d, J = 8.8Hz), 3.72-3.54 (2H, m), 3.59 (1H, t, J = 7.6Hz),
3.36-3.20 (4H, m), 2.45 (2H, t-like) 2.38-1.70 (7H, m),
2.08-1.94 (4H, m), 0.98 (3H, t, J = 7.4Hz), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (79) 4- (2RS-carboxypiperidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.75 (2H, d, J = 8.8 Hz),
7.21 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 8.8Hz), 6.55 (2H,
d, J = 8.8Hz), 4.8-4.7 (1H, m), 3.8-3.7 (1H, m), 3.58 (1H,
t, J = 7.5Hz), 3.4-3.1 (5H, m), 2.3-1.2 (12H, m), 0.97 (3
H, t, J = 7.4Hz), TLC: Rf 0.48 (acetic acid: methanol: chloroform = 1: 2: 50).

Example 2 (80) 4- (3RS-carboxypiperidin-1-ylsulfonyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.75 (2H, d, J = 8.4 Hz),
7.7-7.3 (4H, m), 7.19 (2H, d, J = 8.4Hz), 4.0-3.4 (8H, m),
2.7-2.5 (2H, m), 2.5-2.1 (5H, m), 2.1-1.3 (5H, m), 1.00
(3H, t, J = 7.4Hz), TLC: Rf 0.32 (acetic acid: methanol: chloroform = 1: 2: 100).

Example 2 (81) 4- (4S-carboxyperhydrothiazol-3-ylsulfonyl) -2-methylphenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.69 (1H, s),
7.66 (1H, d, J = 8.0Hz), 7.21 (2H, d, J = 8.6Hz), 7.07 (1H, d,
J = 8.0Hz), 6.55 (2H, d, J = 8.6Hz), 4.71 (1H, dd, J = 7.2,3.2
Hz), 4.63 (1H, d, J = 9.8Hz), 4.45 (1H, d, J = 9.8Hz), 3.61
(1H, t, J = 7.7Hz), 3.4-3.2 (5H, m), 2.84 (1H, dd, J = 11.2,7.
2Hz), 2.3-2.1 (1H, m), 2.1-1.8 (4H, br), 2.02 (3H, s),
0.98 (3H, d, J = 7.3 Hz), TLC: Rf 0.55 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (82) 4- (2RS-carboxymorpholin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CD ₃ OD): δ 7.65-7.54 (2H, m), 7.
20 (2H, d, J = 8Hz), 7.15 (1H, d, J = 8Hz), 6.58 (2H, d, J = 8Hz),
4.03-3.80 (3H, m), 3.71-3.38 (3H, m), 3.37-3.15 (4H, m
m), 2.50-1.78 (11H, m), 0.97 (3H, t, J = 7 Hz), TLC: Rf 0.25 (methanol: chloroform = 3:
17).

Example 2 (83) 4- (1S-oxo-4S-carboxyperhydrothiazol-3-ylsulfonyl) -2-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD): δ 7.90-7.75 (2H, m), 7.
61 (4H, s), 7.18 (1H, d, J = 8.5Hz), 5.25 (1H, dd, J = 8.5,2.0
Hz), 5.19 (1H, d, J = 12.0Hz), 4.13 (1H, d, J = 12.0Hz), 3.9
8 (1H, t, J = 7.5Hz), 3.85-3.70 (4H, m), 3.41 (1H, dd, J = 14.
5,2.0Hz), 3.03 (1H, dd, J = 14.5,8.5Hz), 2.35-2.20 (4H,
m), 2.40-1.80 (2H, m), 2.04 (3H, s), 1.00 (3H, t, J = 7.5H
z), TLC: Rf 0.18 (chloroform: methanol: acetic acid = 40: 10: 1).

Example 2 (84) 4- (4S-carboxy-1,1-dioxoperhydrothiazol-3-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) Butanoic acid ester / hydrochloride

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NMR (CDCl ₃ ): δ 7.75-7.65 (2H, m), 7.
48 (4H, s), 7.10 (1H, d, J = 8.5Hz), 5.06 (1H, dd, J = 8.5,4.0
Hz), 4.68 (1H, d, J = 11.0Hz), 4.26 (1H, d, J = 11.0Hz), 3.7
8 (1H, t, J = 7.5Hz), 3.70-3.55 (4H, m), 3.55-3.35 (2H, m),
2.40-2.25 (4H, m), 2.40-1.80 (2H, m), 2.07 (3H, s), 1.0
1 (3H, t, J = 7.5Hz), TLC: Rf 0.14 (chloroform: methanol: acetic acid = 40: 10: 1).

Example 2 (85) 4- (4- (2-hydroxyethyl) piperazine-1-
Ylsulfonyl) -2-methylphenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.75-7.47 (6H, m), 7.
23 (1H, d, J = 8.8Hz), 4.03-3.79 (5H, m), 3.79-3.57 (6H, m),
3.40-3.14 (4H, m), 2.77 (2H, t-like, J = 13.8Hz), 2.38-
2.15 (5H, m), 2.06 (3H, s), 2.15-1.84 (1H, m), 1.00 (3H, m
t, J = 7.4Hz), TLC: Rf 0.21 (hexane: ethyl acetate = 1:
1).

Example 2 (86) 4- (4-Carboxymethylpiperazin-1-ylsulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.79-7.53 (6H, m), 7.
24 (1H, d, J = 8.0Hz), 4.14 (2H, s), 4.00 (1H, t, J = 7.8Hz),
3.87-3.70 (4H, m), 3.52 (8H, brs), 2.44-2.15 (5H, m), 2.
07 (3H, s), 2.15-1.82 (1H, m), 1.00 (3H, t, J = 7.2Hz), TLC: Rf 0.63 (chloroform: methanol: acetic acid = 15: 2: 1).

Example 2 (87) 4- (4S-carboxyperhydrothiazol-3-ylsulfonyl) phenyl 2RS- (4-nitrophenyl) butanoate

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NMR (CDCl ₃ ): δ 8.27 (2H, d, J = 8.8 Hz),
7.94 (2H, d, J = 8.8Hz), 7.68 (2H, d, J = 8.8Hz), 7.26 (2H, d
d, J = 8.8Hz), 4.86 (1H, dd, J = 3.6 and 7.4Hz), 4.73 (1H,
d, J = 8.0Hz), 4.41 (1H, d, J = 8.0Hz), 4.03 (1H, t, J = 7.6H
z), 3.17 (1H, dd, J = 11.5 and 3.6Hz), 2.93 (1H, dd, J = 11.
5 and 7.4Hz), 2.40-2.15 and 2.10-1.85 (each 1H, m),
1.00 (3H, t, J = 7.2Hz), TLC: Rf 0.38 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (88) 4- (N-carboxymethyl-N-2-methoxyethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate / trifluoroacetate

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NMR (CD ₃ OD): δ 7.85 (2H, d, J = 8.6 Hz),
7.41 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.6Hz)
d, J = 8.6Hz), 4.10 (2H, s), 3.77 (1H, t, J = 6.0Hz), 3.46 (8
H, m), 3.20 (3H, s), 2.20 (1H, m), 2.15 (4H, m), 1.90 (1H,
m), 0.97 (3H, t, J = 7.0Hz), TLC: Rf 0.32 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (89) 4- (N-1RS, 2-dicarboxyethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate trifluoroacetate

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NMR (CD ₃ OD): δ 7.87 (2H, d, J = 8.6 Hz),
7.36 (2H, br.d, J = 8.6Hz), 7.14 (2H, d, J = 8.6Hz), 7.00 (2
H, br.d, J = 8.6Hz), 4.21 (1H, t, J = 6.0Hz), 3.74 (1H, m),
3.48 (4H, m), 2.72 (2H, d, J = 6.2Hz), 2.18 (1H, m), 2.13 (4
H, m), 1.87 (1H, m), 0.97 (3H, t, J = 7.4Hz), TLC: Rf 0.26 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (90) 4- (N- (1-Carboxycyclopropyl) sulfamoyl) phenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

NMR (CDCl ₃ ): δ 7.81 (2H, d, J = 8.8 Hz),
7.15 (2H, d, J = 8.8Hz), 7.05 (2H, d, J = 8.8Hz), 6.55 (2H,
d, J = 8.8Hz), 5.66 (1H, s), 3.58 (1H, t, J = 7.6Hz), 3.36-
3.18 (4H, t-like), 2.30-2.00 and 2.00-1.75 (each 1H,
m), 2.06-1.96 (4H, m), 1.56-1.35 (4H, m), 0.97 (3H, t, J =
7.4 Hz), TLC: Rf 0.38 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (91) 4- (N-1RS-carboxy-2-phenylethylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (DMSO-d ₆ ): δ 8.38 (1H, d, J = 10H)
z), 7.55 (2H, d, J = 9Hz), 7.30-7.00 (9H, m), 6.76 (2H, d, J
= 9Hz), 3.95-3.79 (1H, m), 3.71 (1H, t, J = 7Hz), 3.40-3.2
0 (4H, m), 2.94 (1H, dd, J = 15Hz, 5Hz), 2.70 (1H, dd, J = 15Hz,
8Hz), 2.20-1.90 (5H, m), 1.90-1.65 (1H, m), 0.90 (3H, t,
J = 7Hz), TLC: Rf 0.19 (ethyl acetate: hexane: acetic acid =
5: 5: 0.1).

Example 2 (92) 4- (N-1S-carboxy-2-methylpropylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1)
-Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 8.05 (1H, d, J = 9 Hz),
7.78 (2H, d, J = 8Hz), 7.25 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8Hz)
Hz), 6.86-6.70 (2H, m), 3.73 (1H, t, J = 7Hz), 3.50 (1H, d
d, J = 9Hz, 6Hz), 3.38-3.20 (4H, m), 2.20-1.68 (7H, m), 0.
88 (3H, t, J = 7Hz), 0.80 (3H, d, J = 7Hz), 0.76 (3H, d, J = 7H
z), TLC: Rf 0.34 (ethyl acetate).

Example 2 (93) 4- (N- (1S-carboxy-2-carboxymethylthioethyl) sulfamoyl) phenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD): δ 7.89 (2H, d, J = 8.8 Hz),
7.63 (2H, d, J = 15.0Hz), 7.62 (2H, d, J = 15.0Hz), 7.18 (2H, d, J = 15.0Hz)
H, d, J = 8.8Hz), 4.08 (1H, dd, J = 5.9,7.5Hz), 3.91 (1H, t, J
= 7.5Hz), 3.82-3.70 (4H, m), 3.19 (2H, s), 3.00 (1H, dd, J
= 5.9,14.0Hz), 2.84 (1H, dd, J = 7.5,14.0Hz), 2.40-2.12
(5H, m), 2.02-1.80 (1H, m), 0.98 (3H, t, J = 7.0Hz), TLC: Rf 0.20 (chloroform: methanol: water =
7: 3: 0.3).

Example 2 (94) 4- (N-1RS-carboxy-1- (thiophene-2)
-Yl) methylsulfamoyl) phenyl 2RS-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 8.88 (1H, d, J = 9.0H)
z), 7.77 (2H, d, J = 8.8Hz), 7.40 (1H, dd, J = 1.2,5.0Hz),
7.24 (2H, d, J = 8.4Hz), 7.14 (2H, d, J = 8.8Hz), 7.00-6.91
(1H, m), 6.88 (1H, dd, J = 3.7,5.0Hz), 6.85-6.72 (2H, m),
5.16 (1H, d, J = 9.0Hz), 3.71 (1H, t, J = 7.2Hz), 3.40-3.20
(4H, m), 2.20-1.90 (5H, m), 1.88-1.70 (1H, m), 0.89 (3H, m
t, J = 7.2Hz), TLC: Rf 0.27 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (95) 4- (N-1RS-carboxy-1- (furan-2-yl) methylsulfamoyl) phenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (DMSO-d ₆ ): δ 8.78 (1H, d, J = 9.0H)
z), 7.75 (2H, d, J = 8.6Hz), 7.46 (1H, m), 7.24 (2H, d, J = 8.2
Hz), 7.12 (2H, d, J = 8.6Hz), 6.90-6.70 (2H, m), 6.31-6.2
4 (1H, m), 6.19 (1H, d, J = 2.8Hz), 5.02 (1H, d, J = 9.0Hz),
3.71 (1H, t, J = 7.6Hz), 3.40-3.20 (4H, m), 2.20-1.86 (5H,
m), 1.86-1.68 (1H, m), 0.89 (3H, t, J = 7.4Hz), TLC: Rf 0.27 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (96) 4- (N-carboxymethyl-N-2-methoxyethylsulfamoyl) -2-methylphenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.64 (1H, d, J = 2.0 Hz),
7.61 (1H, dd, J = 8.0,2.0Hz), 7.21 (2H, d, J = 8.5Hz), 7.04
(1H, d, J = 8.0Hz), 6.55 (2H, d, J = 8.5Hz), 4.08 (2H, s), 3.
61 (1H, t, J = 7.5Hz), 3.55 (2H, t, J = 4.5Hz), 3.40 (2H, t, J =
4.5Hz), 3.35-3.20 (4H, m), 3.29 (3H, s), 2.30-1.70 (2H,
m), 2.05-1.95 (4H, m), 2.01 (3H, s), 0.99 (3H, t, J = 7.5H
z), TLC: Rf 0.47 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (97) 4- (N-propyl-N-carboxymethylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.55 (2H, m), 7.
23 (2H, d, J = 8Hz), 7.01 (1H, d, J = 8Hz), 6.55 (2H, d, J = 8Hz),
4.20-3.80 (1H, br), 3.98 (2H, s), 3.60 (1H, t, J = 7Hz),
3.35-3.07 (6H, m), 2.28-1.75 (9H, m), 1.60-1.38 (2H, m),
0.98 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.23 (chloroform: methanol = 1
9: 1).

Example 2 (98) 4- (N-1S-carboxy-5-aminopentylsulfamoyl) -2-methylphenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.80-7.47 (6H, m), 7.
10 (1H, d, J = 8Hz), 3.95 (1H, t, J = 7Hz), 3.90-3.68 (5H, m),
2.95-2.80 (2H, m), 2.35-2.20 (5H, m), 2.10-1.85 (1H, m),
1.99 (3H, s), 1.85-1.30 (6H, m), 0.98 (3H, t, J = 7Hz), TLC: Rf 0.22 (chloroform: methanol: water =
8: 2: 0.1).

Example 2 (99) 4- (N-carboxymethylsulfamoyl) phenyl 2- (4-methoxyphenyl) -2-ethylbutanoate

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NMR (CDCl ₃ ): δ 7.80 (2H, d, J = 8.8 Hz),
7.25 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.6Hz), 6.90 (2H, d
d, J = 8.8Hz), 3.80 (3H, s), 3.73 (2H, brs), 2.25-2.00 (4
H, m), 0.82 (6H, t, J = 7.4Hz), TLC: Rf 0.10 (hexane: ethyl acetate = 2:
1).

Example 2 (100) 4- (N-2-methoxyethyl-N-carboxymethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ ): δ 8.25 (2H, d, J = 9.0 Hz),
7.82 (2H, d, J = 9.0Hz), 7.55 (2H, d, J = 9.0Hz), 7.11 (2H, d, J = 9.0Hz)
d, J = 9.0Hz), 4.13 (2H, s), 3.53 (2H, t, J = 5.0Hz), 3.41 (2H
(H, t, J = 5.0Hz), 3.27 (3H, s), 3.06 (2H, m), 2.67 (2H, m),
2.26 (1H, m), 2.04 (1H, m), TLC: Rf 0.29 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (101) 4- (N-1RS, 2-dicarboxyethylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CD ₃ OD): δ 8.27 (2H, d, J = 8.8 Hz),
7.87 (2H, d, J = 8.8Hz), 7.65 (2H, d, J = 8.8Hz), 7.15 (2H, d, J = 8.8Hz)
d, J = 8.8Hz), 4.21 (1H, t, J = 5.8Hz), 3.05 (2H, m), 2.71 (4
H, m), 2.25 (1H, m), 2.04 (1H, m), TLC: Rf 0.17 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (102) 4- (N-carboxymethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (DMSO-d ₆ ): δ 8.04 (1H, br.s), 7.
82 (2H, d, J = 8Hz), 7.45-7.25 (5H, m), 7.21 (2H, d, J = 8Hz),
3.86 (1H, t, J = 7Hz), 3.56 (2H, s), 2.10 and 1.85 (each
1H, m), 0.91 (3H, t, J = 7 Hz), TLC: Rf 0.32 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (103) 4- (N-propyl-N-carboxymethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (DMSO-d ₆ ): δ 12.65 (1H, br.s),
8.04 (1H, br.s), 7.84 (2H, d, J = 8Hz), 7.45-7.25 (5H, m),
7.21 (2H, d, J = 8Hz), 3.92 (2H, s), 3.85 (1H, t, J = 7Hz), 3.
10 (2H, t), 2.10 and 1.86 (each 1H, m), 1.44 (2H, m), 0.
92 (3H, t, J = 7 Hz), 0.77 (3H, t, J = 7 Hz), TLC: Rf 0.54 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (104) 4- (N-benzyl-N-carboxymethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.90-7.79 (2H, m), 7.
43-7.08 (12H, m), 6.34 (1H, br), 4.46 (2H, s), 3.90 (2H,
s), 3.70 (1H, t, J = 7Hz), 2.22 (1H, ddq, J = 14Hz, 7Hz, 7Hz),
1.92 (1H, ddq, J = 14 Hz, 7 Hz, 7 Hz), 0.98 (3 H, t, J = 7 Hz), TLC: Rf 0.42 (methylene chloride: methanol = 9:
1).

Example 2 (105) 4- (N-2-phenylethyl-N-carboxymethisulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.77 (2H, d, J = 8 Hz),
7.40-7.04 (12H, m), 5.89 (1H, br), 3.95 (2H, s), 3.69 (1
(H, t, J = 7Hz), 3.53-3.40 (2H, m), 2.91-2.80 (2H, m), 2.21
(1H, ddq, J = 14Hz, 7Hz, 7Hz), 1.90 (1Hddq, J = 14Hz, 7Hz, 7h
z), 0.97 (3H, t, J = 7 Hz), TLC: Rf 0.41 (methylene chloride: methanol = 9:
1).

Example 2 (106) 4- (N-phenyl-N-carboxymethylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.63 (2H, d, J = 8 Hz),
7.45-7.04 (12H, m), 6.20 (1H, br), 4.40 (2H, s), 3.70 (1
H, t, J = 7Hz), 2.23 (1H, ddq, J = 14Hz, 7Hz, 7hz), 1.91 (1H, d
dq, J = 14 Hz, 7 Hz, 7 Hz), 0.99 (3H, t, J = 7 Hz), TLC: Rf 0.41 (methylene chloride: methanol = 9:
1).

Example 2 (107) 4- (N, N-bis (2-hydroxyethyl) sulfamoyl) -2-methyl2RS- (4- (pyrrolidine-1)
-Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD): δ 7.78-7.50 (6H, m), 7.
15 (1H, d, J = 8Hz), 3.96 (1H, t, J = 7Hz), 3.95-3.80 (8H, m),
3.35-3.18 (4H, m), 2.40-2.15 (5H, m), 2.10-1.80 (1H, m),
2.02 (3H, s), 0.99 (3H, t, J = 7 Hz), TLC: Rf 0.23 (hexane: ethyl acetate = 1:
1).

Example 2 (108) 4- (N, N-bis (2- (2-hydroxyethoxy))
Ethyl) sulfamoyl) -2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.55 (2H, m), 7.
23 (2H, d, J = 9Hz), 7.06 (1H, d, J = 8Hz), 6.55 (2H, d, J = 9Hz),
3.75-3.45 (13H, m), 3.43-3.23 (8H, m), 3.05 (2H, brs),
2.30-1.73 (9H, m), 0.98 (3H, t, J = 7Hz), TLC: Rf 0.33 (ethyl acetate).

Example 2 (109) 4- (N- (3RS-carboxy-1,4-benzodioxan-5-yl) sulfamoyl) phenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 9.67 (1H, s), 7.80
(2H, d, J = 9Hz), 7.20 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz),
6.84-6.57 (5H, m), 4.78 (1H, t, J = 3Hz), 4.28 (1H, dd, J = 11
Hz, 3Hz), 4.13-4.00 (1H, m), 3.68 (1H, t, J = 7Hz), 3.35-
3.18 (4H, m), 2.15-1.88 (5H, m), 1.88-1.60 (1H, m), 0.88
(3H, t, J = 7Hz), TLC: Rf 0.18 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (110) 4- (N-2RS-hydroxy-4R-hydroxy-5
R-hydroxy-6R-hydroxymethylperhydropyran-3R-ylsulfamoyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (DMSO-d ₆ +3 drop of CD ₃ OD): δ 7.
80-7.60 (2H, m), 7.20 (2H, d, J = 8.5Hz), 7.05 (1H, d, J = 8.5H
z), 6.60 (2H, d, J = 8.5Hz), 4.78 (1H, d, J = 3.5Hz), 3.70 (1H
(H, t, J = 7.5Hz), 3.65-3.35 (4H, m), 3.30-3.15 (4H, m), 3.
03 (1H, t, J = 9.0Hz), 2.90 (1H, dd, J = 10.5,3.5Hz), 2.20-
1.60 (2H, m), 2.00-1.90 (4H, m), 1.94 (3H, s), 0.91 (3H,
t, J = 7.5Hz), TLC: Rf 0.55 (chloroform: methanol: water =
40: 10: 1).

Example 2 (111) 4- (N-3-carboxyadamantan-1-ylsulfamoyl) phenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.85 (2H, d, J = 8.8 Hz),
7.22 (2H, d, J = 8.8Hz), 7.12 (2H, d, J = 8.8Hz), 6.54 (2H, d
d, J = 8.8Hz), 4.60 (1H, s), 3.59 (1H, t, J = 7.4Hz), 3.40-
3.15 (4H, m), 2.30-1.40 (20H, m), 0.98 (3H, t, J = 7.6Hz), TLC: Rf 0.60 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (112) 4- (N- (1S, 4R, 3R-carboxybicyclo [2.2.1] heptane-2S-yl) sulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) ) Phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.83 (2H, d, J = 8.6 Hz),
7.21 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.6Hz), 6.55 (2H,
d, J = 8.6Hz), 7.6-7.4 (1H, br), 3.58 (1H, t, J = 7.6Hz), 3.
58 (1H, t, J = 8.0Hz), 3.40-3.20 (4H, m), 2.64 (1H, d, J = 8.0Hz)
Hz), 2.42 (1H, s), 2.30-1.70 (4H, m), 2.10-1.90 (4H, m),
1.50-1.30 (2H, m), 1.30-0.90 (3H, m), 0.97 (3H, t, J = 7.3
Hz), TLC: Rf 0.33 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (113) 4- (N-3S-carboxycyclohexane-1R-ylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 7.90-7.70 (3H, m),
7.30-7.10 (4H, m), 6.70 (2H, d, J = 9Hz), 3.71 (1H, t, J = 7H
z), 3.35-3.15 (4H, m), 3.09-2.86 (1H, m), 2.27-1.45 (11
H, m), 1.33-0.95 (4H, m), 0.89 (3H, t, J = 7Hz), TLC: Rf 0.36 (ethyl acetate: hexane: acetic acid =
5: 5: 0.1).

Example 2 (114) 4- (N-2RS-carboxycyclohexane-1RS
-Ylsulfamoyl) phenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.84 (2H, d, J = 8.8 Hz),
7.23-7.08 (4H, m), 6.55 (2H, d, J = 8.6Hz), 5.70 (1H, br
s), 3.59 (1H, t, J = 8.0Hz), 3.45 (1H, brs), 3.32-3.26 (4
H, m), 2.65 (1H, brs), 2.25-1.20 (14H, m), 0.98 (3H, t, J =
7.0 Hz), TLC: Rf 0.22 (hexane: ethyl acetate = 1:
1).

Example 2 (115) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (2H-1,4-benzoxazin-3-one-6yl) butanoate

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NMR (DMSO-d ₆ ): δ 10.73 (1H, s), 7.88
(2H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.6Hz), 6.95 (3H, s), 4.
57 (2H, s), 4.13-4.00 (1H, m), 3.79 (1H, t, J = 7.6Hz), 3.4
0-3.08 (2H, m), 2.20-1.40 (6H, m), 0.91 (3H, t, J = 7.2H
z), TLC: Rf 0.35 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (116) 4- (2R-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (2H-1,4-benzoxazin-3-one-6yl) butanoate

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NMR (DMSO-d ₆ ): δ 13.4-12.2 (1H, br),
10.72 (1H, s), 7.88 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6H
z), 6.95 (3H, s), 4.57 (2H, s), 4.16-4.08 (1H, m), 3.80
(1H, t, J = 7.6Hz), 3.50-3.05 (2H, m), 2.05-1.45 (6H, m),
0.91 (3H, t, J = 7.2 Hz), TLC: Rf 0.36 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (117) 4- (2S-carboxypyrrolidin-1-ylsulfonyl) phenyl 2RS- (2-methylbenzimidazol-5-yl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.90-7.61 (5H, m), 7.
23 (2H, d, J = 9Hz), 4.23-4.17 (1H, m), 4.06 (1H, t, J = 8Hz),
3.51-3.40 (1H, m), 3.31-3.20 (2H, m), 2.87 (3H, s), 2.3
8-2.24 (1H, m), 2.06-1.86 (3H, m), 1.76-1.64 (1H, m), 1.
01 (3H, t, J = 7Hz), TLC: Rf 0.21 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (118) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (naphthalen-1-yl) acetic acid ester

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NMR (DMSO-d ₆ ): δ 12.74 (1H, br), 11.
58 (1H, br), 9.20 (1H, t, J = 5Hz), 8.08-7.70 (6H, m), 7.63
-7.42 (6H, m), 7.29 (2H, d, J = 9Hz), 7.17-7.10 (1H, m), 4.
46 (2H, s), 3.89 (2H, d, J = 6 Hz), TLC: Rf 0.28 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (119) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (naphthalen-2-yl) acetic acid ester

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NMR (DMSO-d ₆ ): δ 12.67 (1H, br), 11.
63 (1H, br), 9.24 (1H, t-like), 7.93-7.71 (7H, m), 7.54-
7.43 (5H, m), 7.36-7.29 (2H, m), 7.18-7.10 (1H, m), 4.15
(2H, s), 3.90 (2H, d, J = 6 Hz), TLC: Rf 0.31 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (120) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-
(1,3-benzodioxol-5-yl) butanoate

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NMR (DMSO-d ₆ ): δ 12.73 (1H, br), 11.
62 (1H, br), 9.22 (1H, t, J = 6Hz), 7.82-7.71 (3H, m), 7.53
-7.42 (2H, m), 7.26-7.10 (3H, m), 6.94-6.79 (3H, m), 6.0
1 (2H, s), 3.89 (2H, d, J = 5Hz), 3.75 (1H, t, J = 8Hz), 2.16-
1.95 and 1.86-1.64 (each 1H, m), 0.86 (3H, t, J = 7Hz), TLC: Rf 0.68 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (121) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (thiophen-2-yl) butanoate

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NMR (DMSO-d ₆ ): δ 9.4-9.2 (1H, br),
7.9-7.7 (3H, m), 7.6-7.4 (3H, m), 7.3-7.0 (5H, m), 4.19
(1H, t, J = 7Hz), 3.90 (2H, d, J = 5Hz), 2.2-2.0 (1H, m), 2.0
-1.8 (1H, m), 0.92 (3H, t, J = 7Hz), TLC: Rf 0.18 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (122) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (1,3
-Benzodioxol-5-yl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 12.62 (1H, br), 11.
66 (1H, br), 9.24 (1H, t-like), 7.82-7.71 (3H, m), 7.52-
7.42 (2H, m), 7.31-7.10 (3H, m), 6.91-6.76 (3H, m), 6.01
(2H, s), 3.89 (2H, d, J = 5Hz), 2.09-1.96 (4H, m), 0.75 (6
H, t, J = 8Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (123) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (thiophen-2-yl) -3-methylbutanoate

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NMR (DMSO-d ₆ ): δ 12.64 (1H, br), 11.
70 (1H, br), 9.24 (1H, t-like), 7.82 (2H, d, J = 8Hz), 7.74
(1H, d, J = 8Hz), 7.54-7.43 (3H, m), 7.26-7.00 (5H, m), 3.
95 (1H, d, J = 7Hz), 3.90 (2H, d, J = 6Hz), 2.36-2.18 (1H, m),
1.07 and 0.83 (each 3H, eachd, J = 7 Hz), TLC: Rf 0.24 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (124) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (cyclohexane-1-yl) butanoate

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NMR (DMSO-d ₆ ): δ 12.72 (1H, br), 11.
64 (1H, br), 9.27 (1H, br), 7.83 (2H, d, J = 10Hz), 7.75 (1H
H, d, J = 10Hz), 7.51 (1H, t, J = 10Hz), 7.48 (1H, t, J = 8Hz),
7.27 (2H, d, J = 12Hz), 7.15 (1H, t, J = 10Hz), 3.90 (2H, d, J =
3Hz), 2.35-2.30 (1H, m), 1.78 (1H, d-like), 1.71-1.55
(7H, m), 1.25-0.98 (5H, m), 0.92 (3H, t, J = 7Hz), TLC: Rf 0.30 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 2 (125) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (pyridin-3-yl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.00 (2H, br), 9.3
6 (1H, br), 8.68-8.46 (2H, br), 7.85-7.78 (4H, m), 7.50-
7.10 (6H, m), 4.04-3.75 (3H, br), 2.27-2.02 and 1.96-
1.74 (each 1H, m), 0.90 (3H, br), TLC: Rf 0.37 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (126) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
H-1,4-benzoxazin-3-one-6yl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.69 (1H, s), 9.53
(1H, t-like), 8.29 (1H, s), 7.83-7.73 (3H, m), 7.49-7.3
9 (2H, m), 7.20-6.91 (6H, m), 4.55 (2H, s), 3.90-3.86 (2
H, d-like), 3.73 (1H, t, J = 7Hz), 2.14-1.98 and 1.80-1.
66 (each 1H, m), 0.88 (3H, t, J = 7Hz), TLC: Rf 0.38 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (127) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-(N-methoxycarbonylamino) thiazole-4-
Yl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.30 (1H, br), 11.
81 (2H, br), 9.24 (1H, t-like), 7.81 (2H, d, J = 7Hz), 7.74
(1H, d, J = 8Hz), 7.51-7.45 (2H, m), 7.25-7.10 (3H, m), 7.
07 (1H, s), 3.90 (1H, t, J = 7Hz), 3.89 (2H, d, J = 4Hz), 3.73
(3H, s), 2.12-1.81 (2H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.28 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (128) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-Methylbenzimidazol-5-yl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.75-7.68 (4H, m), 7.
63-7.57 (3H, m), 7.46-7.37 (1H, m), 7.16-7.07 (3H, m),
4.00 (1H, t, J = 8Hz), 3.94 (2H, s), 2.85 (3H, s), 2.34-2.1
5 and 2.06-1.88 (each 1H, m), 0.97 (3H, t, J = 7Hz), TLC: Rf 0.26 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (129) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (1
H-1-methyl-2-pyridone-3-yl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.59 (1H, br), 11.
65 (1H, br), 9.23 (1H, t-like), 7.82-7.63 (4H, m), 7.49-
7.40 (3H, m), 7.25-7.09 (3H, m), 6.23 (1H, t, J = 7Hz), 3.9
0 (2H, d, J = 6Hz), 3.72 (1H, t, J = 7Hz), 3.45 (3H, s), 2.04-
1.70 (2H, m), 0.88 (3H, t, J = 7Hz), TLC: Rf 0.27 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (130) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-phenylbutanoate

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NMR (CDCl ₃ ): δ 7.67 (3H, m), 7.50-7.
20 (7H, m), 7.08 (1H, t, J = 8Hz), 6.97 (2H, d, J = 8Hz), 6.60
(1H, s), 5.69 (2H, br.s), 4.00 (2H, m), 3.66 (1H, t, J = 7H
z), 2.16 (1H, m), 1.86 (1H, m), 0.94 (3H, t, J = 7Hz), TLC: Rf 0.23 (chloroform: methanol = 5:
1).

Example 2 (131) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2-phenyl-2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 12.63 (1H, br), 11.
67 (1H, br), 9.22 (1H, t-like), 7.82-7.70 (3H, m), 7.51-
7.07 (10H, m), 3.89 (2H, d, J = 6Hz), 2.09 (4H, m), 0.76 (6
H, m), TLC: Rf 0.58 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (132) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-phenylpropanoate

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NMR (DMSO-d ₆ ): δ 12.73 (1H, br), 11.
59 (1H, br), 9.25-9.19 (1H, t-like), 7.82-7.70 (3H, m),
7.50-7.10 (10H, m), 4.10 (1H, q, J = 7Hz), 3.89 (2H, d, J = 5H
z), 1.49 (3H, d, J = 7 Hz), TLC: Rf 0.32 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (133) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2R-phenylbutanoate

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NMR (CDCl ₃ ): δ 10.22 (1H, s), 7.71-
7.65 (3H, m), 7.49-7.26 (6H, m), 7.15-7.10 (2H, m), 6.99
-6.95 (2H, m), 6.49 (1H, br), 6.36 (1H, br), 4.01 (2H, d, J
= 5Hz), 3.65 (1H, t, J = 7Hz), 2.24-2.11 and 1.95-1.81 (ea
ch 1H, m), 0.95 (3H, t, J = 7Hz), TLC: Rf 0.36 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (134) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2S-phenylbutanoate

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NMR (CDCl ₃ ): δ 10.29 (1H, s), 7.70-
7.65 (3H, m), 7.45-7.26 (6H, m), 7.13-7.05 (2H, m), 7.00
-6.96 (2H, m), 6.60 (1H, br), 4.01 (2H, d, J = 5Hz), 3.66 (1
(H, t, J = 8Hz), 2.24-2.10 and 1.95-1.81 (each 1H, m), 0.
95 (3H, t, J = 7Hz), TLC: Rf 0.36 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (135) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2-phenyl-2-methylpropanoate

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NMR (DMSO-d ₆ ): δ 12.67 (1H, br), 11.
65 (1H, br), 9.22 (1H, t-like), 7.82-7.71 (3H, m), 7.52-
7.09 (10H, m), 3.89 (2H, d, J = 6Hz), 1.63 (6H, s), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (136) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1-phenylcyclohexanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.72 (1H, br), 11.
61 (1H, br), 9.24 (1H, t-like), 7.81-7.70 (3H, m), 7.48-
7.25 (7H, m), 7.14-7.10 (3H, m), 3.88 (2H, d, J = 6Hz), 2.5
6-2,41 (2H, m), 1.85-1.23 (8H, m), TLC: Rf 0.48 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (137) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1-phenylcyclopropanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.3-9.1 (1H, brt),
7.8-7.6 (3H, m), 7.5-7.0 (10H, m), 3.88 (2H, d, J = 5Hz),
1.68 (2H, dd, J = 6.4 Hz), 1.39 (2H, dd, J = 6.4 Hz), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (138) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1-phenylcyclopentanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.3-9.1 (1H, brt),
7.8-7.7 (3H, m), 7.5-7.2 (7H, m), 7.2-7.0 (3H, m), 3.87
(2H, d, J = 5Hz), 2.7-2.5 (2H, m), 2.1-1.9 (2H, m), 1.9-1.
6 (4H, m), TLC: Rf 0.21 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (139) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1-phenylcyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.3-9.1 (1H, brt),
7.8-7.6 (3H, m), 7.5-7.2 (7H, m), 7.2-7.1 (3H, m), 3.88
(2H, d, J = 5Hz), 3.0-2.8 (2H, m), 2.6-2.4 (2H, m), 2.1-1.
8 (2H, m), TLC: Rf 0.19 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (140) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2-phenylacetate

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NMR (DMSO-d ₆ ): δ 10.01-9.76 (1H, b
r), 7.82-7.76 (4H, m), 7.41-7.22 (9H, m), 7.03-6.90 (1
H, m), 3.96 (2H, s), 3.86 (2H, m), TLC: Rf 0.66 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (141) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-chloro-2-phenylacetic acid ester

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NMR (DMSO-d ₆ ): δ 9.2-9.1 (1H, brt),
7.82 (2H, d, J = 8Hz), 7.71 (1H, d, J = 8Hz), 7.6-7.4 (7H, m),
7.29 (2H, d, J = 8Hz), 7.2-7.1 (1H, m), 6.26 (1H, s), 3.88
(2H, d, J = 5 Hz), TLC: Rf 0.18 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (142) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-chloro-2-phenylbutanoate

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NMR (DMSO-d ₆ ): δ 9.3-9.2 (1H, br),
7.93 (2H, d, J = 8Hz), 7.72 (1H, d, J = 8Hz), 7.65-7.55 (2H,
m), 7,6-7.4 (5H, m), 7.37 (2H, d, J = 8Hz), 7.2-7.1 (1H,
m), 3.88 (2H, d, J = 5Hz), 2.6-2.4 (2H, m), 0.97 (3H, t, J = 7
Hz), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (143) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2,2-diphenylbutanoate

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NMR (DMSO-d ₆ ): δ 9.51-9.38 (1H, m),
7.86-7.68 (4H, m), 7.51-7.20 (11H, m), 7.19-7.01 (4H, m),
3.84 (2H, d, J = 6Hz), 2.53-2.41 (2H, m), 0.79 (3H, t, d = 7H
z), TLC: Rf 0.44 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (144) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-methyl-2-phenylbutanoate

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NMR (DMSO-d ₆ ): δ 9.3-9.2 (1H, br),
7.88 (2H, d, J = 8Hz), 7.70 (1H, d, J = 8Hz), 7.5-7.1 (10H, m),
3.88 (2H, d, J = 5Hz), 2.2-1.9 (2H, m), 1.57 (3H, s), 0.85
(3H, t, J = 7Hz), TLC: Rf 0.15 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (145) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2R-trifluoromethyl-2-phenyl-2-methoxyacetic acid ester

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NMR (CD ₃ OD): δ 7.81 (2H, d, J = 8.8 Hz),
7.62 (4H, m), 7.48 (4H, m), 7.27 (2H, d, J = 8.8Hz), 7.15
(1H, t, J = 7.6Hz), 3.97 (2H, s), 3.65 (3H, s), TLC: Rf 0.28 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (146) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2S-trifluoromethyl-2-phenyl-2-methoxyacetic acid ester

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NMR (CD ₃ OD): δ 7.81 (2H, d, J = 8.6 Hz),
7.62 (4H, m), 7.47 (4H, m), 7.27 (2H, d, J = 8.6Hz), 7.15
(1H, t, J = 7.6Hz), 3.97 (2H, s), 3.65 (3H, s), TLC: Rf 0.27 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (147) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Methoxyphenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.64 (2H, m), 7.
42 (2H, t, J = 8Hz), 7.27-7.06 (4H, m), 6.97 (2H, d, J = 9Hz),
6.88 (2H, d, J = 9Hz), 6.55 (1H, t-like), 4.82 (2H, br.s),
3.99 (2H, d, J = 5Hz), 3.79 (3H, s), 3.61 (1H, t, J = 8Hz),
2.12 and 1.85 (each 1H, m), 0.94 (3H, t, J = 7Hz), TLC: Rf 0.50 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (148) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Methoxyphenyl) -3-methylbutanoate

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NMR (CDCl ₃ ): δ 10.20 (1H, s), 7.73-
7.64 (3H, m), 7.48-7.39 (2H, m), 7.33-7.22 (2H, m), 7.12
(1H, t, J = 8Hz), 6.98-6.85 (4H, m), 6.46 (1H, t-like), 5.
08 (1H, br), 4.00 (2H, d, J = 4Hz), 3.80 (3H, s), 3.31 (1H,
d, J = 10Hz), 2.46-2.27 (1H, m), 1.12 and 0.76 (each 3H,
each d, J = 7 Hz), TLC: Rf 0.58 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (149) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (4-methoxyphenyl) -2-methylpropanoate

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NMR (DMSO-d ₆ ): δ 12.66 (1H, br), 11.
64 (1H, br), 9.23 (1H, t-like), 7.81-7.70 (3H, m), 7.52-
7.10 (7H, m), 6.92 (2H, d, J = 9Hz), 3.89 (2H, d, J = 6Hz), 3.
74 (3H, s), 1.60 (6H, s), TLC: Rf 0.35 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (150) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Methoxyphenyl) propanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.67 (1H, br), 11.
64 (1H, br), 9.21 (1H, t-like), 7.81-7.70 (3H, m), 7.52-
7.41 (2H, m), 7.30-7.09 (5H, m), 6.91 (2H, d, J = 8Hz), 4.0
0 (1H, q, J = 7Hz), 3.88 (2H, d, J = 5Hz), 3.73 (3H, s), 1.46
(3H, d, J = 7 Hz), TLC: Rf 0.30 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (151) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (4-methoxyphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 12.68 (1H, br), 11.
62 (1H, br), 9.24 (1H, t-like), 7.82-7.71 (3H, m), 7.52-
7.46 (2H, m), 7.30-7.09 (5H, m), 6.93 (2H, d, J = 9Hz), 3.8
9 (2H, d, J = 6Hz), 3.75 (3H, s), 2.10-1.98 (4H, m), 0.75 (6H
H, t, J = 7Hz), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (152) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-methoxyphenyl) cyclohexanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.71 (1H, br), 11.
57 (1H, br), 9.19 (1H, t-like), 7.77-7.66 (3H, m), 7.44-
7.30 (4H, m), 7.13-7.04 (3H, m), 6.89 (2H, d, J = 8Hz), 3.8
5 (2H, d, J = 6Hz), 3.69 (3H, s), 2.47-2.36 (2H, m), 1.77-
1.20 (8H, m), TLC: Rf 0.51 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (153) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-methoxyphenyl) cyclopentanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.69 (1H, br), 11.
66 (1H, br), 9.23 (1H, t-like), 7.80-7.71 (3H, m), 7.51-
7.29 (4H, m), 7.18-7.07 (3H, m), 6.92 (2H, dd, J = 1 and 8H
z), 3.89 (2H, d, J = 5Hz), 3.74 (3H, s), 2.66-2.53 (2H, m),
2.01-1.87 (2H, m), 1.79-1.67 (4H, m), TLC: Rf 0.68 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (154)

4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1
-(4-methoxyphenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.2-9.1 (1H, brt),
7.8-7.7 (3H, m), 7.5-7.4 (2H, m), 7.30 (2H, d, J = 8Hz), 7.
2-7.0 (3H, m), 6.92 (2H, d, J = 8Hz), 3.87 (2H, d, J = 5Hz),
3.74 (3H, s), 2.9-2.7 (2H, m), 2.6-2.4 (2H, br), 2.1-1.7
(2H, br), TLC: Rf 0.21 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (155) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-methoxyphenyl) cyclopropanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.53-9.38 (1H, m),
7.79-7.72 (3H, m), 7.51-7.28 (4H, m), 7.26-7.19 (2H, m),
7.16-7.00 (1H, m), 6.89-6.84 (2H, m), 3.88 (2H, d, J = 6H
z), 3.73 (3H, s), 1.70-1.61 (2H, m), 1.38-1.29 (2H, m), TLC: Rf 0.49 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (156) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (3,4
-Dimethoxyphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 9.52-9.38 (1H, br),
7.83-7.71 (3H, m), 7.53-7.39 (2H, m), 7.19-7.02 (3H, m),
7.00-6.78 (3H, m), 3.89 (2H, d, J = 6Hz), 3.76 (6H, s), 2.
06 (4H, q, J = 7 Hz), 0.78 (6H, t, J = 7 Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (157) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-
(3,4-dimethoxyphenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.45-7.41 (2H,
m), 7.30-7.19 (2H, m), 7.18-7.01 (1H, m), 6.82-6.69 (3
H, m), 6.56-6.52 (3H, m), 3.63 (2H, s), 3.53 (6H, s), 3.2
8 (1H, t, J = 7Hz), 1.98-1.42 (2H, m), 0.63 (3H, t, J = 7Hz), TLC: Rf 0.64 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (158) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (3-methoxyphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 12.71 (1H, br), 11.
65 (1H, br), 9.23 (1H, t-like), 7.83-7.71 (3H, m), 7.53-
7.42 (2H, m), 7.35-7.10 (4H, m), 6,92-6,84 (3H, m), 3.89
(2H, d, J = 6Hz), 3.75 (3H, s), 2.12-2.01 (4H, m), 0.76 (6
H, t, J = 7Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (159) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-Methoxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 11.58 (1H, s), 9.24
-9.18 (1H, m), 7.86-7.64 (3H, m), 7.57-7.44 (2H, m), 7.3
8-7.09 (5H, m), 7.08-6.91 (3H, m), 4.02-3.98 (1H, m), 3.
88 (2H, d, J = 6Hz), 3.77 (3H, s), 2.18-1.842H, m), 0.87 (3
H, t, J = 7 Hz), TLC: Rf 0.41 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (160) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (2-methoxyphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 9.28-9.19 (1H, m),
7.82-7.69 (3H, m), 7.48-7.41 (2H, m), 7.28-7.08 (4H, m),
7.00-6.75 (4H, m), 3.89 (2H, d, J = 6Hz), 3.77 (3H, s), 2.1
8-1.82 (4H, m), 0.86 (6H, t, J = 7 Hz), TLC: Rf 0.39 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (161) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (3
-Methoxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.79 (1H, br), 7.8
5-7.79 (3H, m), 7.33-7.25 (2H, m), 7.17-7.06 (3H, m), 6.
95-6.85 (3H, m), 6.74 (1H, t, J = 7Hz), 3.85 (2H, d-like),
3.80-3.69 (1H, m), 3.75 (3H, s), 2.15-2.01 and 1.91-1.
71 (each 1 H, m), 0.89 (3 H, t, J = 7 Hz), TLC: Rf 0.47 (acetic acid: methanol: chloroform = 1: 2: 40)

Example 2 (162) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (2-methoxyphenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.9-12.5 (1H, br),
11.7-11.4 (1H, br), 9.20 (1H, t-like), 7.78 (2H, d, J = 8.
6Hz), 7.72 (1H, d, J = 7.4Hz), 7.52-7.38 (3H, m), 7.28 (1H
Ht-like), 7.20-7.08 (3H, m), 7.00 (2H, d, J = 7.8Hz), 3.
89 (2H, d, J = 5.6Hz), 3.77 (3H, s), 2.85-2.65 (2H, m), 2.55
-2.35 (2H, m) 2.20-2.00 and 2.00-1.80 (each 1H, m), TLC: Rf 0.30 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (163) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,6-dimethylphenyl 2RS- (4-methoxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.8-9.5 (brs, 1H),
7.8-7.7 (m, 1H), 7.5-7.2 (m, 6H), 7.1-6.8 (m, 4H), 4.0-
3.7 (m, 3H), 3.74 (s, 3H), 2.2-1.7 (m, 8H), 0.90 (t, J = 7.0
Hz, 3H), TLC: Rf 0.30 (hexane: ethyl acetate = 1:
1).

Example 2 (164) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2-isopropylphenyl 2RS- (4-methoxyphenyl) butanoate

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NMR (CDCl ₃ ): δ 10.0-9.9 (m, 1H), 7.8
-7.7 (m, 1H), 7.6-7.2 (m, 6H), 7.2-7.0 (m, 1H), 7.0-6.8
(m, 3H), 6.5-6.3 (m, 1H), 4.0-3.4 (m, 2H), 3.80 (s, 3H),
3.64 (t, J = 7.8Hz, 1H), 2.7-2.5 (m, 1H), 2.3-2.1 (m, 1H),
2.0-1.8 (m, 1H), 0.95 (t, J = 7.6Hz, 3H), 0.83 (dd, J = 2.0,
6.9 Hz, 6H), TLC: Rf 0.49 (chloroform: methanol = 3:
1).

Example 2 (165) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(2-methylpropyloxy) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.25-9.07 (1H, br),
8.02-7.98 (1H, d-like), 7.89-7.80 (2H, d-like), 7.79-
7.65 (2H, m), 7.59-7.38 (3H, m), 7.18-7.09 (1H, m), 7.01
-6.77 (2H, m), 3.97-3.65 (3H, m), 3.80 (3H, s), 3.97-3.6
5 (3H, s), 1.19 (6H, d, J = 7 Hz), TLC: Rf 0.37 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (166) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Isopropyloxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 11.58 (1H, s), 9.22
-9.13 (1H, m), 7.80-7.63 (4H, m), 7.49-7.40 (2H, m), 7.2
5-7.06 (5H, m), 6.88-6.84 (2H, m), 4.63-4.48 (1H, m), 3.
88 (2H, d, J = 6Hz), 3.72 (1H, t, J = 7Hz), 2.18-1.63 (2H, m),
1.26 (6H, d, J = 6 Hz), 0.88 (3H, t, J = 7 Hz), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (167) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Propyloxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.38-9.20 (1H, m),
7.81-7.77 (2H, d-like), 7.77-7.70 (2H, m), 7.49-7.31 (2
H, m), 7.28-7.03 (5H, m), 6.93-6.89 (2H, d-like), 3.94-
3.87 (4H, m), 3.72 (1H, t, J = 6Hz), 2.20-1.98 (1H, m), 1.8
3-1.62 (3H, m), 0.98 (3H, t, J = 7Hz), 0.88 (3H, t, J = 7Hz), TLC: Rf 0.35 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (168) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Methylphenyl) pentanoic acid ester

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NMR (CDCl ₃ ): δ 10.20 (1H, s), 7.68 (1
(H, d, J = 8Hz), 7.65 (2H, d, J = 8Hz), 7.50-7.35 (2H, m), 7.2
5-7.05 (5H, m), 6.95 (2H, d, J = 8Hz), 6.6-6.5 (1H, br), 4.
00 (2H, d, J = 5Hz), 3.72 (1H, t, J = 7Hz), 2.35 (3H, s), 2.2-
2.0 (1H, m), 1.9-1.7 (1H, m), 1.4-1.2 (2H, m), 0.92 (3H,
t, J = 7 Hz), TLC: Rf 0.25 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (169) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-methylphenyl) cyclopentanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.70 (1H, br), 11.
66 (1H, br), 9.23 (1H, t-like), 7.80-7.70 (3H, m), 7.51-
7.41 (2H, m), 7.33-7.29 (2H, m), 7.19-7.09 (5H, m), 3.89
(2H, d, J = 6Hz), 2.65-2.55 (2H, m), 2.29 (3H, s), 2.04-1.
90 (2H, m), 1.79-1.65 (4H, m), TLC: Rf 0.69 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (170) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (3-methylphenyl) cyclopentanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.22-9.18 (1H, m),
7.80-7.68 (3H, m), 7.49-7.41 (2H, m), 7.29-7.10 (7H, m),
3.89 (2H, d, J = 6Hz), 2.70-2.51 (2H, m), 2.32 (3H, s), 2.0
4-1.83 (2H, m), 1.74-1.60 (4H, m), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (171) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-Methylphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.4-9.2 (1H, br),
7.8-7.7 (3H, m), 7.5-7.4 (2H, m), 7.3-7.0 (7H, m), 4.06
(1H, t, J = 7Hz), 3.88 (2H, d, J = 5Hz), 2.37 (3H, s), 2.2-2.
0 (1H, m), 1.9-1.7 (1H, m), 0.87 (3H, t, J = 7 Hz), TLC: Rf 0.16 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (172) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (2-methylphenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 9.5-9.3 (1H, br),
7.9-7.6 (3H, m), 7,6-7.0 (9H, br), 4.0-3.8 (2H, br), 2.2
7 (3H, s), 2.3-1.9 (4H, br), 0.8-0.6 (6H, br), TLC: Rf 0.15 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (173) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Methylphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.61-10.32 (1H,
m), 7.85-7.74 (3H, m), 7.36-7.04 (8H, m), 6.90-6.75 (1
H, m), 3.92-3.83 (2H, m), 3.77 (1H, t, J = 7.6Hz), 2.29 (3
H, s), 2.21-1.96 and 1.89-1.63 (each 1H, m), 0.87 (3H,
t, J = 7.4Hz), TLC: Rf 0.23 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (174) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Nitrophenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 8.24 (2H, d, J = 8
Hz), 7.85-7.55 (6H, m), 7.10 (4H, m), 3.95 (2H, s), 3.87
(1H, t, J = 7Hz), 2.25 and 1.98 (each 1H, m), 0.99 (3H, t,
J = 7 Hz), TLC: Rf 0.33 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (175) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (4-nitrophenyl) -2-methylpropanoate

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NMR (DMSO-d ₆ ): δ 13.50-11.00 (2H, b
r), 9.30-9.16 (1H, m), 8.23 (2H, d, J = 8Hz), 7.88-7.68 (5
H, m), 7.55-7.40 (2H, m), 7.25 (2H, d, J = 8Hz), 7.20-7.09
(1H, m), 3.89 (2H, d, J = 6 Hz), 1.68 (6H, s), TLC: Rf 0.41 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (176) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclopropanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.2-9.1 (1H, brt),
8.18 (2H, d, J = 8Hz), 7.8-7.6 (5H, m), 7.5-7.4 (2H, m), 7.
29 (2H, d, J = 8Hz), 7.2-7.0 (1H, m), 3.90 (2H, d, J = 5Hz),
1.77 (2H, dd, J = 6.4 Hz), 1.48 (2
H, dd, J = 6.4 Hz), TLC: Rf 0.17 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (177) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclopentanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.2-9.1 (1H, brt),
8.22 (2H, d, J = 8Hz), 7.8-7.6 (5H, m), 7.5-7.4 (2H, m), 7.
2-7.1 (3H, m), 3.88 (2H, d, J = 5Hz), 2.8-2.6 (2H, m), 2.2-
1.9 (2H, m), 1.9-1.6 (4H, m), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (178) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (4-nitrophenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 13.40-11.20 (2H, b
r), 9.35-9.15 (1H, m), 8.24 (2H, d, J = 8Hz), 7.82 (2H, d, J
= 8Hz), 7.74 (1H, t, J = 8Hz), 7.67 (2H, d, J = 8Hz), 7.55-7.
40 (2H, m), 7.23 (2H, d, J = 8Hz), 7.19-7.08 (1H, m), 3.89
(2H, d, J = 6 Hz), 2.25-1.98 (4H, m), 0.76 (6H, t, J = 7 Hz), TLC: Rf 0.28 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (179) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.2-9.1 (1H, brt),
8.24 (2H, d, J = 8Hz), 7.8-7.6 (5H, m), 7.5-7.4 (2H, m), 7.
3-7.1 (3H, m), 3.88 (2H, d, J = 5Hz), 3.0-2.8 (2H, br), 2.7
-2.5 (2H, m), 2.2-1.8 (2H, m), TLC: Rf 0.22 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (180) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2-methylphenyl
2RS- (4-nitrophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 13.00-12.40 (1H, b
r), 11.80-11.40 (1H, br), 9.19 (1H, t, J = 5Hz), 8.24 (2H,
d, J = 8Hz), 7.80-7.55 (5H, m), 7.55-7.40 (2H, m), 7.23-
7.06 (2H, m), 4.15 (1H, t, J = 7Hz), 3.88 (2H, d, J = 5Hz), 2.
19 (1H, ddq, J = 14Hz, 7Hz, 7Hz), 2.05-1.75 (4H, m), 0.88 (3
H, t, J = 7Hz), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 2 (181) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2-methylphenyl
1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.80-11.00 (2H, b
r), 9.20 (1H, t, J = 5Hz), 8.24 (2H, d, J = 8Hz), 7.80-7.55
(5H, m), 7.55-7.37 (2H, m), 7.25-7.05 (2H, m), 3.86 (2H, m
d, J = 5Hz), 3.04-2.85 (2H, m), 2.74-2.54 (2H, m), 2.23-
1.78 (5H, m), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (182) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -3-methylphenyl
1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 13.30-12.30 (1H, b
r), 12.00-11.56 (1H, br), 9.34-9.16 (1H, m), 8.26 (2H,
d, J = 8Hz), 7.85-7.65 (4H, m), 7.50-7.35 (2H, m), 7.22 (1
H, d, J = 8Hz), 7.18-7.05 (1H, m), 6.85 (1H, s), 3.97 (2H,
d, J = 5Hz), 3.22-3.03 (2H, m), 2.78-2.58 (2H, m), 2.28 (3
H, s), 2.28-2.08 (1H, m), 2.05-1.80 (1H, m), TLC: Rf 0.43 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (183) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,3-dimethylphenyl 1- (4-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 13.10-12.40 (1H, b
r), 12.00-11.70 (1H, br), 9.35-9.22 (1H, m), 8.27 (2H,
d, J = 8Hz), 7.88-7.73 (3H, m), 7.65 (1H, d, J = 8Hz), 7.51-
7.39 (2H, m), 7.20 (1H, d, J = 8Hz), 7.15-7.06 (1H, m), 4.0
8-3.95 (2H, m), 3.18-2.99 (1H, m), 2.99-2.78 (1H, m), 2.6
6-2.47 (1H, m), 2.33-2.05 (1H, m), 2.18 (3H, s), 2.05-1.
82 (1H, m), 1.35 (3H, s), TLC: Rf 0.43 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (184) 7- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,3-dihydroinden-4-yl 1- (4-nitrophenyl) cyclobutanecarboxylic Acid ester

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NMR (DMSO-d ₆ ): δ 13.10-12.30 (1H, b
r), 12.00-11.46 (1H, br), 9.22 (1H, t, J = 5Hz), 8.25 (2H,
d, J = 8Hz), 7.80-7.60 (4H, m), 7.50-7.34 (2H, m), 7.18-
7.02 (2H, m), 3.90 (2H, d, J = 5Hz), 3.14-2.78 (4H, m), 2.7
4-2.33 (4H, m), 2.20-1.78 (4H, m), TLC: Rf 0.20 (acetic acid: methanol: chloroform = 1: 2: 60).

Example 2 (185) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 11.60 (1H, s), 9.23
(1H, t, J = 6Hz), 7.85-7.70 (3H, m), 7.55-7.40 (2H, m), 7.
27-7.08 (5H, m), 6.80-6.55 (2H, m), 3.88 (2H, d, J = 6Hz),
3.68 (1H, t, J = 7Hz), 3.38-3.19 (4H, m), 2.20-1.86 (5H,
m), 1.86-1.62 (1H, m), 0.86 (3H, t, J = 7 Hz), TLC: Rf 0.44 (chloroform: methanol: acetic acid = 30: 2: 1).

Example 2 (186) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 11.56 (1H, s), 9.23
(1H, t, J = 5Hz), 7.83-7.55 (3H, m), 7.55-7.40 (2H, m), 7.
30-7.05 (4H, m), 6.84-6.60 (2H, m), 3.88 (2H, d, J = 5Hz),
3.70 (1H, t, J = 7Hz), 3.40-3.13 (4H, m), 2.20-1.65 (9H,
m), 0.86 (3H, t, J = 7 Hz), TLC: Rf 0.45 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (187) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -3-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 12.20 (1H, s), 9.28
(1H, t, J = 5Hz), 7.85 (2H, d, J = 8Hz), 7.50-7.35 (2H, m),
7.30-7.18 (3H, m), 7.18-7.03 (1H, m), 6.80 (1H, s), 6.73
(2H, d, J = 8Hz), 4.00 (2H, d, J = 5Hz), 3.93-3.75 (1H, m),
3.38-3.20 (4H, m), 2.28 (3H, s), 2.20-2.00 (1H, m), 2.03
-1.92 (4H, m), 1.92-1.65 (1H, m), 0.88 (3H, t, J = 7Hz), TLC: Rf 0.41 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (188) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,3-dimethylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) Butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 12.09 (1H, s), 9.35
-9.18 (1H, m), 7.92-7.77 (1H, m), 7.77-7.63 (1H, m), 7.4
6-7.38 (2H, m), 7.30-7.17 (3H, m), 7.17-7.03 (1H, m), 6.
86-6.60 (2H, m), 4.02 (2H, d, J = 5Hz), 3.93-3.80 (1H, m),
3.40-3.15 (4H, m), 2.19 (3H, s), 2.05-1.90 (4H, m), 1.90-
1.50 (1H, m), 1.45 (3H, s), 1.30-0.98 (1H, m), 0.88 (3H,
t, J = 7 Hz), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (189) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-
(Pyrrolidin-1-yl) phenyl) cyclobutanecarboxylic acid ester

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NMR (CD ₃ OD): δ 7.75-7.50 (4H, m), 7.
50-7.25 (3H, m), 7.20-6.90 (5H, m), 3.92 (2H, s), 3.46 (4
H, br.s), 2.90 (2H, m), 2.56 (2H, m), 2.25-1.85 (6H, m), TLC: Rf 0.36 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (190) 7- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,3-dihydroinden-4-yl 2RS- (4- (pyrrolidine-1- Yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 11.69 (1H, s), 9.24
(1H, t, J = 5Hz), 7.75 (1H, d, J = 8Hz), 7.69 (1H, d, J = 8Hz),
7.50-7.38 (2H, m), 7.19 (2H, d, J = 8Hz), 7.15-7.04 (1H,
m), 6.98 (1H, d, J = 8Hz), 6.68 (2H, d, J = 8Hz), 3.89 (2H, d,
J = 5Hz), 3.66 (1H, t, J = 5Hz), 3.35-3.15 (4H, m), 3.15-3.
00 (2H, m), 2.55-2.40 (2H, m), 2.18-1.85 (7H, m), 1.85-
1.60 (1H, m), 0.86 (3H, t, J = 7Hz), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (191) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2,6-dimethylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) Butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 11.49 (s, 1H), 9.3-
9.2 (m, 1H), 7.8-7.1 (m, 10H), 6.8-6.6 (m, 1H), 4.0-3.7
(m, 3H), 3.4-3.1 (m, 4H), 2.2-1.7 (m, 12H), 0.89 (t, J = 7.
0Hz, 3H), TLC: Rf 0.60 (chloroform: methanol = 2:
1).

Example 2 (192) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) -2-isopropylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid Ester and hydrochloride

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NMR (CDCl ₃ ): δ 10.04 (s, 1H), 7.8-7.
7 (m, 3H), 7.6-7.5 (m, 7H), 7.2-7.1 (m, 1H), 6.9-6.8 (m, 1
H), 6.4-6.3 (m, 1H), 4.0-3.6 (m, 7H), 2.8-2.7 (m, 1H),
2.4-2.2 (m, 5H), 2.0-1.8 (m, 1H), 0.98 (t, J = 7.0Hz, 3H),
0.91 (d, J = 7.0 Hz, 6H), TLC: Rf 0.61 (chloroform: methanol = 2:
1).

Example 2 (193) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Piperidin-1-yl) phenyl) butanoic acid ester / trifluoroacetate

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NMR (DMSO-d ₆ ): δ 12.60-11.50 (1H, b
r), 9.43-9.23 (1H, br), 7.83-7.68 (3H, m), 7.52-7.35 (2
H, m), 7.30-7.02 (5H, m), 6.88 (2H, d, J = 8Hz), 3.88 (2H,
d, J = 7Hz), 3.66 (1H, t, J = 8Hz), 3.20-3.05 (4H, m), 2.15-
1.91 (1H, m), 1.85-1.43 (7H, m), 0.93 (3H, t, J = 7Hz), TLC: Rf 0.28 (chloroform: methanol: acetic acid = 30: 3: 1).

Example 2 (194) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Perhydroazepin-1-yl) phenyl) butanoic acid ester / trifluoroacetate

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NMR (DMSO-d ₆ ): δ 11.57 (1H, s), 9.19
(1H, t, J = 7Hz), 7.85-7.65 (3H, m), 7.55-7.40 (2H, m), 7.
30-7.05 (5H, m), 6.64 (2H, d, J = 8Hz), 3.88 (2H, d, J = 7Hz),
3.60 (1H, t, J = 8Hz), 3.48-3.28 (4H, m), 2.10-1.93 (1H,
m), 1.88-1.55 (5H, m), 1.55-1.30 (4H, m), 0.86 (3H, t, J =
7 Hz), TLC: Rf 0.35 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (195) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (4-aminophenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 11.58 (1H, br), 9.2
2 (1H, t, J = 5Hz), 7.80-7.70 (3H, m), 7.53-7.42 (2H, m),
7.18-7.14 (3H, m), 6.98 (2H, d, J = 8Hz), 6.56 (2H, d, J = 8H
z), 3.89 (2H, d, J = 6Hz), 2.09-1.88 (4H, m), 0.74 (6H, t, J
= 7 Hz), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (196) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Aminophenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 10.65 (1H, br), 7.8
3-7.76 (3H, m), 7.31-6.96 (6H, m), 6.80-6.73 (1H, m), 6.
53 (2H, d, J = 8.6Hz), 3.86 (2H, d-like), 3.55 (1H, t, J = 7.4
Hz), 2.12-1.90 and 1.83-1.62 (each 1H, m), 0.87 (3H,
t, J = 7.0Hz), TLC: Rf 0.16 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (197) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N, N-dimethylamino) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 11.62 (1H, s), 9.25
(1H, t, J = 6Hz), 7.80 (2H, d, J = 9Hz), 7.76 (1H, d, J = 8Hz),
7.50-7.44 (5H, m), 7.27-7.14 (4H, m), 3.89 (2H, d, J = 6H
z), 3.86 (1H, t, J = 8Hz), 3.04 (6H, s), 2.17-2.03 and 1.
91-1.71 (each 1H, m), 0.88 (3H, t, J = 7 Hz), TLC: Rf 0.48 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (198) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-
(N, N-dimethylamino) phenyl) cyclobutanecarboxylic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 11.62 (1H, s), 9.24
(1H, t-like), 7.79 (2H, d, J = 8.8Hz), 7.74 (1H, d, J = 8.0H
z), 7.81-7.70 (9H, m), 3.89 (2H, d, J = 5.0Hz), 3.02 (6H,
s), 2.93-2.80 (2H, m), 2.59-2.39 (2H, m), 2.09-1.81 (2
H, m), TLC: Rf 0.26 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (199) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N, N-diethylaminomethyl) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 13.00-11.00 (2H, b
r), 9.35-9.18 (1H, m), 7.90-7.71 (3H, m), 7.68-7.56 (2
H, m), 7.56-7.38 (4H, m), 7.30-7.08 (3H, m), 4.24 (2H,
s), 3.99-3.79 (2H, m), 3.71-3.65 (1H, m), 3.10-2.90 (4
H, m), 2.11 (1H, ddq, J = 14Hz, 7Hz, 7Hz), 1.82 (1H, ddq, J = 1
4 Hz, 7 Hz, 7 Hz), 1.23 (6 H, t, J = 7 Hz), 0.88 (3 H, t, J = 7 Hz), TLC: Rf 0.18 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 2 (200) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Hydroxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.90-11.20 (2H, b
r), 9.39 (1H, br), 9.22 (1H, t-like), 7.79 (2H, d, J = 8.8H
z), 7.73 (1H, d, J = 7.8Hz), 7.53-7.42 (2H, m), 7.19-7.12
(5H, m), 6.74 (2H, d, J = 8.6Hz), 3.89 (2H, d, J = 5.6Hz), 3.6
8 (1H, t, J = 7.6Hz), 2.11-1.93 and 1.84-1.62 (each 1H,
m), 0.86 (3H, t, J = 7.2Hz), TLC: Rf 0.12 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (201) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Cyanophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.72-10.41 (1H,
m), 7.88-7.69 (5H, m), 7.59 (2H, d, J = 8.2Hz), 7.29 (2H,
d, J = 8.2Hz), 7.22-7.06 (3H, m), 6.78 (1H, t, J = 8.2Hz),
4.01 (1H, t, J = 7.4Hz), 3.91-3.77 (2H, m), 2.24-2.01 and
1.95-1.70 (each 1H, m), 0.88 (3H, t, J = 7.4Hz), TLC: Rf 0.24 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (202) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Carboxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 11.36 (1H, s), 10.4
5 (1H, s), 9.16 (1H, t-like), 7.90 (2H, d, J = 8Hz), 7.71 (1
(H, d, J = 8Hz), 7.60-7.38 (7H, m), 7.18-7.03 (1H, m), 6.81
(2H, d, J = 8Hz), 3.89 (2H, d, J = 6Hz), 3.40 (1H, t, J = 7Hz),
2.04-1.58 (2H, m), 0.83 (3H, t, J = 7 Hz), TLC: Rf 0.53 (acetic acid: methanol: chloroform = 1: 5: 15).

Example 2 (203) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Trifluoromethylphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.75-10.45 (1H,
m), 7.87-7.56 (7H, m), 7.35-7.07 (4H, m), 6.87-6.72 (1
H, m), 4.02 (1H, t, J = 7.7Hz), 3.93-3.82 (2H, m), 2.25-2.
02 and 1.95-1.71 (each 1H, m), 0.89 (3H, t, J = 7.0Hz), TLC: Rf 0.23 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (204) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Amidinophenyl) butanoate / trifluoroacetate

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NMR (DMSO-d ₆ ): δ 10.42-10.20 (1H,
m), 9.95-9.44 (2H, m), 9.44-8.90 (2H, m), 7.86-7.66 (4
H, m), 7.66-7.30 (4H, m), 7.30-7.04 (3H, m), 6.88-6.75
(1H, m), 4.01 (1H, t, J = 7Hz), 3.90-3.79 (2H, m), 2.26-2.
03 (1H, m), 1.95-1.74 (1H, m), 0.96-0.76 (3H, m), TLC: Rf 0.40 (acetic acid: methanol: chloroform = 1: 2: 10).

Example 2 (205) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Imidazolin-2-yl) phenyl) butanoic acid ester / trifluoroacetate

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NMR (DMSO-d ₆ ): δ 10.60-10.34 (1H,
m), 7.95 (2H, d, J = 8Hz), 7.82-7.71 (3H, m), 7.64 (2H, d, J
= 8Hz), 7.34 (1H, d, J = 8Hz), 7.26-7.00 (4H, m), 6.80 (1H,
t, J = 8Hz), 4.60-3.93 (7H, m), 2.15 (1H, ddq, J = 14Hz, 7Hz,
7 Hz), 1.94-1.71 (1H, m), 0.87 (3H, t, J = 7 Hz), TLC: Rf 0.2 (acetic acid: methanol: chloroform = 1: 2: 10).

Example 2 (206) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-chlorophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 9.3-9.1 (1H, brt),
7.8-7.6 (3H, m), 7.5-7.3 (6H, m), 7.2-7.0 (3H, m), 3.88
(2H, d, J = 5Hz), 3.0-2.8 (2H, m), 2.6-2.4 (2H, m), 2.2-1.
8 (2H, m), TLC: Rf 0.22 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (207) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-Chlorophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.4-9.2 (1H, br),
7.8-7.7 (3H, m), 7.5-7.3 (6H, m), 7.3-7.0 (3H, m), 4.24
(1H, t, J = 7Hz), 3.88 (2H, d, J = 5Hz), 2.2-2.0 (1H, m), 2.0
-1.8 (1H, m), 0.87 (3H, t, J = 7Hz), TLC: Rf 0.16 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (208) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (2-chlorophenyl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 9.5-9.3 (1H, br),
7.82 (2H, d, J = 8Hz), 7.72 (1H, d, J = 8Hz), 7.6-7.3 (6H, m),
7.23 (2H, d, J = 8Hz), 7.09 (1H, t, J = 8Hz), 3.90 (2H, d, J = 5H
z), 2.4-2.1 (2H, m), 2.2-1.9 (2H, m), 0.70 (6H, t, J = 7H
z), TLC: Rf 0.12 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (209) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (2-chlorophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 7.72 (2H, d, J =
8.5Hz), 7.68-7.05 (8H, m), 7.02 (2H, d, J = 8.5Hz), 3.99
(2H, s), 3.01-2.82 (2H, m), 2.75-2.50 (2H, m), 2.41-2.1
5 (1H, m), 2.10-1.80 (1H, m), TLC: Rf 0.30 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (210) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Chlorophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.47-10.18 (1H,
m), 7.86-7.74 (3H, m), 7.51-7.08 (8H, m), 6.93-6.81 (1
H, m), 3.95-3.82 (3H, m), 2.20-1.96 and 1.90-1.66 (eac
h 1H, m), 0.87 (3H, t, J = 7.4Hz), TLC: Rf 0.26 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (211) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (3
-Nitro-4-hydroxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.36 (1H, t-like),
7.90-7.72 (4H, m), 7.58-7.40 (3H, m), 7.24-7.07 (4H, m),
3.90 (2H, d, J = 6Hz), 2.20-1.97 and 1.89-1.69 (each 1H,
m), 0.88 (3H, t, J = 7 Hz), TLC: Rf 0.21 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (212) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (2
-Chloro-5-nitrophenyl) butanoic acid ester

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[0887] _{NMR (DMSO-d 6):} δ 12.10 (2H, br), 9.2
6 (1H, t-like), 8.32 (1H, t, J = 3Hz), 8.20 (1H, dd, J = 3 and
9Hz), 7.85-7.79 (3H, m), 7.73 (1H, d, J = 8Hz), 7.52-7.4
1 (2H, m), 7.27 (2H, d, J = 9Hz), 7.15-7.08 (1H, m), 4.43 (1
(H, t, J = 6Hz), 3.89 (2H, d, J = 6Hz), 2.32-2.18 and 2.09-
1.91 (each 1H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.51 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (213) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (2-chloro-5-nitrophenyl) cyclobutanecarboxylic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 8.32 (1H, d, J =
2.5Hz), 8.14 (1H, dd, J = 2.5,8.5Hz), 7.76 (2H, d, J = 8.5H
z), 7.62 (2H, t, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.43 (1
H, d, J = 8.5Hz), 7.12 (1H, d, J = 8.5Hz), 7.06 (2H, d, J = 8.5H)
z), 3.99 (2H, brs), 3.10-2.90 (2H, m), 2.80-2.59 (2H,
m), 2.52-2.20 (1H, m), 2.15-1.90 (1H, m), TLC: Rf 0.23 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (214) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (3-nitro-4-chlorophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 12.73 (1H, br.s), 1
1.60 (1H, br.s), 9.17 (1H, t, J = 7Hz), 8.04 (1H, s), 7.90-
7.65 (4H, m), 7.55-7.40 (2H, m), 7.35-7.05 (4H, m), 3.90
(2H, d, J = 7Hz), 2.90 (2H, m), 2.60 (2H, m), 2.25-1.80 (2
H, m), TLC: Rf 0.34 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (215) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (3
-Nitro-4-chlorophenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 10.79 (1H, br), 8.1
2 (1H, s), 7.85-7.75 (5H, m), 7.28-7.08 (4H, m), 6.74 (1
H, t-like), 4.08 (1H, t, J = 7.4Hz), 3.84 (2H, d-like), 2.
22-2.04and 1.98-1.76 (each 1H, m), 0.89 (3H, t, J = 7.2H
z), TLC: Rf 0.30 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (216) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-Ureidophenyl) butanoate

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[0895] _{NMR (DMSO-d 6):} δ 10.5 (1H, br), 8.61
(1H, s), 7.81-7.70 (3H, m), 7.41-7.05 (10H, m), 6.80 (1H,
t, J = 7.6Hz), 5.85 (2H, s), 3.84 (2H, s), 3.70 (1H, t, J = 7.
2Hz), 2.30 (2H, s), 2.60-1.95 and 1.90-1.65 (each 1H,
m), 0.88 (3H, t, J = 7.0 Hz), TLC: Rf 0.22 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (217) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 1- (4-ureidophenyl) cyclobutanecarboxylic acid ester

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NMR (DMSO-d ₆ ): δ 10.0 (1H, brs), 8.5
0 (1H, s), 7.67 (4H, d, J = 8.8Hz), 7.32-7.09 (2H, m), 7.30
(2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.8Hz), 6.96 (2H, d, J = 8.
6Hz), 6.76 (1H, t, J = 6.8Hz), 5.74 (2H, s), 3.75-3.73 (2H,
m), 2.80-2.63 (2H, m), 2.53-2.26 (2H, m), 2.23-2.00 (2
H, m), TLC: Rf 0.10 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (218) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N- (2S-aminopropionyl) amino) phenyl) butanoic acid ester hydrochloride

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[0899] _{NMR (DMSO-d 6):} δ 10.92 (1H, s), 9.47
-9.32 (1H, m), 7.85-7.73 (3H, m), 7.66 (2H, d, J = 9Hz), 7.
54-7.42 (2H, m), 7.34 (2H, d, J = 9Hz), 7.27-7.04 (4H, m),
4.16-3.99 (1H, m), 3.89 (2H, d, J = 5Hz), 3.81 (1H, t, J = 6H
z), 2.19-1.98 and 1.88-1.67 (each 1H, m), 1.47 (3H, d,
J = 8Hz), 0.97 (3H, t, J = 8Hz), TLC: Rf 0.11 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (219) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N- (2S-amino-3-methylbutyryl) amino) phenyl) butanoic acid ester hydrochloride

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NMR (DMSO-d ₆ ): δ 10.96-10.85 (1H,
m), 9.45-9.30 (1H, m), 7.85-7.72 (2H, m), 7.66 (2H, d, J =
8.4Hz), 7.54-7.42 (2H, m), 7.34 (2H, d, J = 8.4Hz), 7.27-
7.06 (4H, m), 3.90 (2H, d, J = 6.0Hz), 3.81 (1H, t, J = 7.8H
z), 2.33-1.98 and 1.92-1.66 (each1H, m), 1.01 (6H, d, J
= 7.2Hz), 0.87 (3H, t, J = 7.4Hz), TLC: Rf 0.19 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (220) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N- (pyrrolidin-2S-ylcarbonyl) amino) phenyl) butanoic acid ester hydrochloride

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[0903] _{NMR (DMSO-d 6):} δ 10.62-10.52 (1H,
m), 9.95-9.70 (1H, m), 7.86-7.70 (3H, m), 7.62 (2H, d, J =
(8.8Hz), 7.48-7.27 (4H, m), 7.13 (2H, d, J = 8.8Hz), 7.04-
6.93 (1H, m), 4.34-4.20 (1H, m), 3.95-3.85 (2H, m), 3.81
(1H, t, J = 7.1Hz), 3.33-3.16 (2H, m), 2.45-2.21 (1H, m),
2.21-1.68 (5H, m), 0.77 (3H, t, J = 7.1Hz), TLC: Rf 0.09 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (221) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-
(3,4,5-trimethoxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.71 (1H, br), 11.
69 (1H, br), 9.22 (1H, t-like), 7.80 (2H, d, J = 8Hz), 7.73
(1H, d, J = 8Hz), 7.53-7.41 (2H, m), 7.25-7.09 (3H, m), 6.
63 (2H, s), 3.89 (2H, d, J = 5Hz), 3.77 (6H, s), 3.65 (3H,
s), 3.63 (1H, t, J = 7Hz), 2.19-1.97 and 1.88-1.67 (each
1H, m), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.57 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (222) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS-
(2,4,6-trimethylphenyl) butanoic acid ester

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NMR (CD ₃ OD): δ 7.80-6.80 (12H, m),
4.21 (1H, dd, J = 8.0 and 6.0Hz), 3.93 (2H, s), 2.30-2.20
(each 3H, s), 1.90-1.60 (2H, m), 0.90 (3H, t, J = 7.2Hz), TLC: Rf 0.46 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (223) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (3
-Nitro-4-methoxyphenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.72 (1H, br), 11.
60 (1H, br), 9.18 (1H, t-like), 7.89-7.59 (5H, m), 7.53-
7.46 (2H, m), 7.36 (1H, d, J = 9Hz), 7.24 (2H, d, J = 9Hz), 7.
13 (1H, t, J = 8Hz), 3.95 (1H, t, J = 8Hz), 3.92 (3H, s), 3.89
(2H, d, J = 6Hz), 2.23-2.02 and1.94-1.72 (each 1H, m),
0.88 (3H, t, J = 7Hz), TLC: Rf 0.51 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (224) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (3
-Nitro-4-aminophenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 12.14 (2H, br), 9.3
6 (1H, t-like), 7.95 (1H, d, J = 2.0Hz), 7.79 (2H, d, J = 8.8H
z), 7.76 (1H, d, J = 6.6Hz), 7.51-7.38 (5H, m), 7.21 (2H,
m), 7.15-7.02 (2H, m), 3.89 (2H, d, J = 5.6Hz), 3.80 (1H,
t, J = 7.6Hz), 2.13-1.99 and 1.84-1.69 (each 1H, m), 0.
88 (3H, t, J = 7.6Hz), TLC: Rf 0.18 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (225) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N-acetylamino) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 12.76 (1H, br), 11.
58 (1H, s), 9.94 (1H, s), 9.20 (1H, t, J = 6Hz), 7.81-7.70
(3H, m), 7.58-7.46 (4H, m), 7.29-7.10 (5H, m), 3.89 (2H,
d, J = 6Hz), 3.76 (1H, t, J = 7Hz), 2.14-1.99 and 1.83-1.6
9 (each 1H, m), 2.03 (3H, s), 0.87 (3H, t, J = 7Hz), TLC: Rf 0.20 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (226) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(N-methyl-N-acetylamino) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 11.59 (1H, s), 9.19
(1H, t, J = 5Hz), 7.80 (2H, d, J = 9Hz), 7.73 (1H, d, J = 8Hz),
7.53-7.41 (4H, m), 7.34-7.10 (5H, m), 3.89 (2H, d, J = 6H
z), 3.69 (1H, t, J = 7Hz), 3.16 (3H, s), 2.18-2.01 and 1.
92-1.71 (each 1H, m), 1.78 (3H, s), 0.90 (3H, t, J = 7Hz), TLC: Rf 0.27 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (227) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Morpholin-4-ylmethyl) phenyl) butanoic acid ester / trifluoroacetic acid

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NMR (DMSO-d ₆ ): δ 12.00-11.20 (2H, b
r), 9.28-9.15 (1H, m), 7.88-7.68 (3H, m), 7.56-7.27 (6
H, m), 7.27-7.08 (3H, m), 3.95-3.79 (4H, m), 3.68-3.59
(5H, m), 2.90-2.60 (4H, m), 2.20-1.95 (1H, m), 1.95-1.6
5 (1H, m), 0.95-0.80 (3H, m), TLC: Rf 0.47 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 2 (228) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(4-benzylpiperazin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ + CD ₃ OD): δ 9.21 (1H, d-lik
e), 7.95-7.86 (4H, m), 7.78-7.71 (1H, m), 7.65-7.58 (2
H, m), 7.54-7.46 (6H, m), 7.40-7.32 (2H, m), 7.21-7.10
(2H, m), 3.91 (2H, d, J = 7Hz), 3.50-3.06 (11H, m), 1.68-1.
45 (2H, m), 0.78 (3H, t, J = 7 Hz), TLC: Rf 0.65 (acetic acid: methanol: chloroform = 1: 3: 30).

Example 2 (229) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2RS- (4
-(Pyrrolidin-1-ylmethyl) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 9.65 (1H, brs), 7.7
7 (2H, d, J = 8Hz), 7.73 (1H, d, J = 8Hz), 7.45-7.30 (6H, m),
7.14 (2H, d, J = 8Hz), 6.99 (1H, d, J = 8Hz), 4.03-3.93 (2H,
m), 3.93-3.80 (3H, m), 2.88 (4H, brs), 2.09 (1H, ddq, J = 1
4 Hz, 7 Hz, 7 Hz), 1.88-1.73 (5 H, m), 0.88 (3 H, t, J = 7 Hz), TLC: Rf 0.10 (acetic acid: methanol: chloroform = 1: 2: 20).

Example 2 (230) 4- (N-2- (N'-carboxymethylcarbamoyl) phenylsulfamoyl) phenyl 2- (thiophen-2-yl) -2-ethylbutanoate

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NMR (DMSO-d ₆ ): δ 9.5-9.3 (1H, brs),
7.9-7.7 (3H, m), 7.5-7.4 (3H, m), 7.3-7.0 (5H, m), 3.87
(2H, d, J = 5Hz), 2.3-1.9 (4H, m), 0.82 (6H, t, J = 7Hz), TLC: Rf 0.19 (acetic acid: methanol: chloroform = 1: 2: 40).

Example 2 (231) 4-((1R-oxo-4S-carboxyperhydrothiazol-3-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butane Acid ester

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NMR (DMSO-d ₆ ): δ 7.85-7.70 (2H, m),
7.18 (2H, d, J = 8.5Hz), 7.09 (1H, d, J = 8.5Hz), 6.53 (2H, d, J
J = 8.5Hz), 4.85-4.65 (2H, m), 4.30 (1H, d, J = 12.5Hz), 3.
69 (1H, t, J = 7.5Hz), 3.35-3.05 (6H, m), 2.20-1.60 (2H,
m), 1.99 (3H, s), 2.00-1.85 (4H, m), 0.90 (3H, t, J = 7.5H
z), TLC: Rf 0.36 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (232) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.89-7.69 (2H, m), 7.
54 and 7.41 (each 2H, d, J = 8Hz), 7.15 (1H, d, J = 8Hz), 4.
28-4.16 (1H, m), 3.90 (1H, t, J = 7Hz), 3.69-3.64 (4H, m),
3.51-3.40 and 3.31-3.21 (each 1H, m), 2.28-2.21 (5H,
m), 2.02 (3H, s), 2.01-1.89 (4H, m), 1.80-1.65 (1H, m),
0.99 (3H, t, J = 7Hz), TLC: Rf 0.17 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (233) 4-((2R-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.81-7.68 (2H, m), 7.
56 and 7.45 (each 2H, d, J = 8Hz), 7.15 (1H, d, J = 8Hz), 4.
28-4.16 (1H, m), 3.91 (1H, t, J = 7Hz), 3.71-3.64 (4H, m),
3.50-3.40 and 3.33-3.22 (each 1H, m), 2.31-2.22 (5H,
m), 2.03 (3H, s), 2.02-1.84 (4H, m), 1.80-1.64 (1H, m),
1.00 (3H, t, J = 7Hz), TLC: Rf 0.18 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (234) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.80-7.68 (2H, m), 7.
50 and 7.31 (each 2H, d, J = 8Hz), 7.14 (1H, d, J = 8Hz), 4.
22-4.16 (1H, m), 3.87 (1H, t, J = 7Hz), 3.68-3.56 (4H, m),
3.50-3.42 and 3.35-3.20 (each 1H, m), 2.32-2.18 (5H,
m), 2.02 (3H, s), 2.01-1.83 (4H, m), 1.79-1.65 (1H, m),
0.99 (3H, t, J = 7Hz), TLC: Rf 0.17 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (235) 4-((2R-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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NMR (CD ₃ OD): δ 7.77-7.68 (2H, m), 7.
57 and 7.48 (each 2H, d, J = 8Hz), 7.15 (1H, d, J = 8Hz), 4.
22-4.17 (1H, m), 3.93 (1H, t, J = 7Hz), 3.74-3.66 (4H, m),
3.52-3.42 and 3.35-3.21 (each 1H, m), 2.28-2.22 (5H,
m), 2.02 (3H, s), 2.01-1.87 (4H, m), 1.80-1.64 (1H, m),
0.99 (3H, t, J = 7Hz), TLC: Rf 0.18 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (236) 4-((2S-Aminomethylpyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2
Hydrochloride

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NMR (CD ₃ OD): δ 7.85-7.70 (2H, m), 7.
64 (4H, s), 7.22 (1H, d, J = 8.0Hz), 3.98 (1H, t, J = 8.0Hz),
4.00-3.80 (1H, m), 3.85-3.70 (4H, m), 3.55-3.20 (2H, m),
3.15-2.95 (2H, m), 2.40-1.80 (2H, m), 2.35-2.25 (4H, m
m), 2.06 (3H, s), 2.00-1.40 (4H, m), 1.00 (3H, t, J = 7.5H
z), TLC: Rf 0.29 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (237) 4-((4-Aminopiperidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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[0937] _{NMR (DMSO-d 6):} δ 8.14 (2H, brs), 7.6
3 (1H, s), 7.60 (1H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz),
7.20 (1H, d, J = 8.4Hz), 6.64 (2H, d, J = 8.4Hz), 3.8-3.5 (4
H, br), 3.3-3.2 (5H, br), 3.2-3.0 (1H, br), 2.5-2.3 (2H,
m), 2.2-2.0 (1H, m), 2.0-1.9 (4H, br), 1.98 (3H, s), 1.9
-1.7 (1H, m), 1.7-1.5 (2H, m), 0.90 (3H, t, J = 7.2Hz), TLC: Rf 0.20 (chloroform: methanol = 9:
1).

Example 2 (238) 4-((2S-aminoazetidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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[0939] _{NMR (CD 3 OD): δ} 7.72 (1H, s), 7.71 (1
H, d, J = 8.0Hz), 7.22 (2H, d, J = 8.8Hz), 7.17 (1H, d, J = 8.0H
z), 6.58 (2H, d, J = 8.8Hz), 4.30 (1H, t, J = 8.5Hz), 3.8-3.
6 (3H, m), 3.4-3.2 (4H, m), 2.4-2.1 (3H, m), 2.1-2.0 (4H,
brs), 2.0-1.8 (1H, m), 2.04 (3H, s), 1.00 (3H, t, J = 7.4H
z), TLC: Rf 0.59 (chloroform: methanol: acetic acid = 25: 5: 1).

Example 2 (239) 4-((2RS-carboxypiperidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.65 (1H, s), 7.63 (1
H, d, J = 8.2Hz), 7.21 (2H, d, J = 8.6Hz), 6.99 (1H, d, J = 8.2H
z), 6.53 (2H, d, J = 8.6Hz), 4.7-4.6 (1H, brs), 4.7-4.1 (1
H, br), 3.59 (1H, t, J = 7.7Hz), 3.5-3.2 (6H, brs), 2.3-2.1
(1H, m), 2.1-1.9 (4H, brs), 2.0-1.8 (1H, m), 1.98 (3H,
s), 1.6-1.2 (6H, br), 0.96 (3H, t, J = 7.4Hz), TLC: Rf 0.12 (chloroform: methanol = 9:
1).

Example 2 (240) 4-((2-oxo-5S-carboxypyrrolidine-1
-Yl) sulfonyl) -2-methylphenyl 2R-
(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD): δ 7.96-7.82 (2H, m), 7.
57 (2H, d, J = 8.5Hz), 7.42 (2H, d, J = 8.5Hz), 7.13 (1H, d, J =
8.0Hz), 4.90-4.80 (1H, m), 3.92 (1H, t, J = 7.5Hz), 3.74-
3.60 (4H, m), 2.65-1.80 (10H, m), 2.02 (3H, s), 0.99 (3H,
t, J = 7.5 Hz), TLC: Rf 0.35 (chloroform: methanol: acetic acid = 4: 1: 0.1).

Example 2 (241) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (3- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.70-7.64 (2H, m), 7.
20 (1H, t, J = 7.8Hz), 7.09 (1H, d, J = 7.8Hz), 6.66 (1H, d, J =
7.8Hz), 6.53-6.47 (2H, m), 4.3-4.2 (1H, m), 3.8-3.4 (2
H, m), 3.4-3.2 (5H, m), 2.3-1.7 (13H, m), 1.01 (3H, t, J =
7.4 Hz), TLC: Rf 0.58 (chloroform: methanol: acetic acid = 9: 1: 0.2).

Example 2 (242) 4-((2S-carboxy-4R-methoxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 7.73 (1H, s), 7.66
(1H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.8Hz), 7.15 (1H, d, J = 8.6Hz)
Hz), 6.78 (2H, d, J = 8.8Hz), 5.00 (1H, brs), 4.02 (1H, t, J
= 7Hz), 3.82 (1H, m), 3.76 (1H, t, J = 7Hz), 3.41 (2H, m), 3.
31 (4H, m), 2.83 (3H, s), 2.15 (2H, m), 2.00 (4H, m), 1.98
(3H, s), 1.95 (2H, m), 0.92 (3H, t, J = 7.4Hz), TLC: Rf 0.34 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (243) 4-((2R-carboxy-4R-methoxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2R
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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[0949] _{NMR (DMSO-d 6):} δ 7.77 (1H, d, J = 2.4H
z), 7.70 (1H, dd, J = 8.4Hz, 2.4Hz), 7.26 (2H, d, J = 8.2Hz),
7.16 (1H, d, J = 8.4Hz), 6.75 (2H, d, J = 8.2Hz), 4.80 (1H, b
rs), 4.31 (1H, dd, J = 9.2Hz, 3.2Hz), 3.76 (2H, m), 3.33
(6H, m), 3.12 (3H, s), 2.12 (2H, m), 2.02 (4H, m), 1.98 (3H
H, s), 1.80 (2H, m), 0.91 (3H, t, J = 7.2Hz), TLC: Rf 0.47 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (244) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (2-methyl-4- (pyrrolidin-1-yl) phenyl) butanoate・ Hydrochloride

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NMR (CD ₃ OD): δ 7.76-7.66 (2H, m), 7.
60-7.40 (3H, m), 7.15 (1H, d, J = 8.0Hz), 4.30-4.10 (2H, m),
3.85-3.70 (4H, m), 3.55-3.15 (2H, m), 2.57 (3H, s), 2.4
0-2.15 (5H, m), 2.00 (3H, s), 2.10-1.60 (5H, m), 1.01 (3
H, t, J = 7.5Hz), TLC: Rf 0.33 (chloroform: methanol: acetic acid = 4: 1: 0.1).

Example 2 (245) 4-((2S-carboxy-4R-hydroxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (CD ₃ OD): δ 7.72 (1H, s), 7.70 (1
H, m), 7.20 (2H, d, J = 8.6Hz), 7.09 (1H, d, J = 8.0Hz), 6.58
(2H, d, J = 8.6Hz), 4.32 (1H, m), 4.21 (1H, m), 3.73-3.42
(2H, m), 3.38-3.16 (5H, m), 2,35-1.68 (11H, m), 0.98 (3H,
t, J = 7.0 Hz), TLC: Rf 0.55 (chloroform: methanol: acetic acid = 15: 2: 1).

Example 2 (246) 4- (N-methoxy-N-carboxymethylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CDCl ₃ ): δ 7.66 (1H, s), 7.63 (1
H, d, J = 8.0Hz), 7.22 (2H, d, J = 8.8Hz), 7.08 (1H, d, J = 8.0H)
z), 6.54 (2H, d, J = 8.8Hz), 5.3-4.6 (1H, br), 3.81 (3H,
s), 3.70 (2H, s), 3.69 (1H, t, J = 7.8Hz), 3.3-3.2 (4H, br
s), 2.2-2.0 (1H, m), 2.1-1.9 (4H, brs), 2.01 (3H, s), 2.
0-1.8 (1H, m), 0.97 (3H, t, J = 7.4Hz), TLC: Rf 0.44 (hexane: ethyl acetate = 2:
1).

Example 2 (247) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (2-methoxy-4- (pyrrolidin-1-yl) phenyl) butanoate・ Hydrochloride

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NMR (DMSO-d ₆ ): δ 7.74 (1H, s), 7.68
(1H, d, J = 8.5Hz), 7.24-7.06 (2H, m), 6.50-6.30 (2H, m),
4.18-4.06 (1H, m), 4.00 (1H, t, J = 7.0Hz), 3.83 (3H, s),
3.40-3.05 (6H, m), 2.20-1.45 (10H, m), 2.05 (3H, s), 0.8
9 (3H, t, J = 7.5 Hz), TLC: Rf 0.40 (chloroform: methanol: acetic acid = 4: 1: 0.1).

Example 2 (248) 4-((2S-carboxyaziridin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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[0959] NMR (CDCl ₃ + CD ₃ OD): δ 7.74 (1H, s),
7.70 (1H, d, J = 8.4Hz), 7.20 (2H, d, J = 8.4Hz), 7.08 (1H, d, J
J = 8.4Hz), 6.54 (2H, d, J = 8.4Hz), 3.61 (1H, t, J = 7.5Hz),
3.3-3.2 (4H, brs), 2.6-2.3 (3H, brs), 2.3-2.1 (1H, m),
2.1-1.9 (4H, brs), 2.0-1.8 (1H, m), 1.99 (3H, s), 0.97 (3
H, t, J = 7.4Hz), TLC: Rf 0.28 (chloroform: methanol = 4:
1).

Example 2 (249) 4- (N, N-bis (2-aminoethyl) aminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate ・ 3 Hydrochloride

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NMR (DMSO-d ₆ ): δ 8.25 (4H, m), 7.80
(1H, d, J = 1.0Hz), 7.71 (1H, dd, J = 8.6Hz, 1.0Hz), 7.26 (3
H, m), 6.82 (2H, m), 3.78 (1H, t, J = 7.8Hz), 3.35 (8H, m),
3.04 (4H, m), 2.13 (1H, m), 2.02 (3H, s), 1.98 (4H, m), 1.
85 (1H, m), 0.92 (3H, t, J = 7.2Hz), TLC: Rf 0.31 (chloroform: methanol: water =
6: 4: 1).

Example 2 (250) 4- (N-carboxymethyl-N- (2- (N ′, N ′)
-Dimethylamino) ethyl) aminosulfonyl) -2-
Methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate / trifluoroacetate

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NMR (CDCl ₃ ): δ 7.61-7.55 (2H, m), 7.
21 (2H, d, J = 8.7Hz), 7.07 (1H, d, J = 8.2Hz), 6.54 (2H, d, J =
8.7Hz), 3.80 (2H, s), 3.60 (1H, t, J = 7.8Hz), 3.55-3.10
(8H, m), 2.83 (6H, s), 2.30-1.70 (9H, m), 0.98 (3H, t, J = 7.
4Hz), TLC: Rf 0.43 (chloroform: methanol: water =
8: 2: 0.2).

Example 2 (251) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-ethylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.8-7.6 (m, 2H), 7.36
(d, J = 8.4Hz, 2H), 7.07 (d, J = 8.4Hz, 1H), 7.02 (d, J = 8.4H
z, 2H), 4.3-4.2 (m, 1H), 3.70 (t, J = 7.2Hz, 1H), 3.6-3.4
(m, 5H), 3.3-3.1 (m, 1H), 2.37 (q, J = 7.6Hz, 2H), 2.3-1.6
(m, 10H), 1.03 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), TLC: Rf 0.33 (chloroform: methanol: acetic acid = 50: 2: 1).

Example 2 (252) 4- (N-carboxymethyl-N-benzyloxyaminosulfonyl) -2-methylphenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoate hydrochloride

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[0967] _{NMR (DMSO-d 6):} δ 7.70 (1H, s), 7.68
(1H, d, J = 8.6Hz), 7.32 (5H, s), 7.20 (2H, d, J = 8.2Hz), 7.
16 (1H, d, J = 8.6Hz), 6.52 (2H, d, J = 8.2Hz), 5.25 (2H, s),
3.8-3.4 (2H, m), 3.5-3.4 (2H, brs), 3.3-3.1 (4H, brs),
2.2-2.0 (1H, m), 2.0-1.8 (4H, brs), 1.9-1.7 (1H, m), 1.9
3 (3H, s), 0.89 (3H, t, J = 7.2Hz), TLC: Rf 0.29 (chloroform: methanol = 9:
1).

Example 2 (253) 4- (N- (4-carboxybutyl) aminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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[0969] _{NMR (DMSO-d 6 + 2drops} of D 2 O): δ 7.6
6 (1H, s-like), 7.63 (1H, dd, J = 2 and 8Hz), 7.24 (2H, d, J
= 8Hz), 7.14 (2H, d, J = 8Hz), 6.69 (2H, d, J = 8Hz), 3.74 (1
(H, t, J = 7Hz), 3.31-3.25 (4H, m), 2.71 (2H, t, J = 7Hz), 2.1
8-1.72 (2H, m), 2.15 (2H, t, J = 7Hz), 2.01-1.94 (4H, m),
1.96 (3H, s), 1.53-1.34 (4H, m), 0.91 (3H, t, J = 7Hz), TLC: Rf 0.38 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (254) 4- (N- (1,1-dimethyl-1-carboxymethyl) aminosulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (DMSO-d ₆ ): δ 7.68 (1H, s-like),
7.64 (1H, dd, J = 2 and 8Hz), 7.39 (1H, br), 7.18 (2H, d, J =
8Hz), 7.07 (1H, d, J = 8Hz), 6.53 (2H, d, J = 8Hz), 3.69 (1H,
t, J = 7Hz), 3.24-3.18 (4H, m), 2.20-1.65 (2H, m), 1.98-
1.91 (4H, m), 1.93 (3H, s), 1.18 (6H, s), 0.90 (3H, t, J = 7H
z), TLC: Rf 0.19 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (255) 4- (N-methyl-N-hydroxyaminosulfonyl)
-2-methylphenyl 2RS- (4- (pyrrolidine-1
-Yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 7.71 (1H, s), 7.69 (1
H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.8Hz), 7.13 (1H, d, J = 8.6H)
z), 6.55 (2H, d, J = 8.8Hz), 6.54 (1H, s), 3.63 (1H, t, J = 7.
7Hz), 3.3-3.2 (4H, brs), 2.81 (3H, s), 2.3-2.1 (1H, m),
2.1-1.9 (4H, brs), 2.06 (3H, s), 2.0-1.8 (1H, m), 0.99 (3
H, t, J = 7.3Hz), TLC: Rf 0.43 (hexane: ethyl acetate = 2:
1).

Example 2 (256) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (2-methyl-4-nitrophenyl) butanoate

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NMR (CDCl ₃ ): δ 8.15-8.05 (2H, m), 7.
75-7.65 (2H, m), 7.56 (1H, d, J = 8.0Hz), 7.09 (1H, d, J = 9.0H
z), 4.25 (1H, dd, J = 3.5,7.0Hz), 4.13 (1H, t, J = 7.5Hz),
3.60-3.40 (1H, m), 3.30-3.10 (1H, m), 2.59 (3H, s), 2.45
-1.60 (6H, m), 1.99 (3H, s), 1.02 (3H, t, J = 7.5Hz), TLC: Rf 0.24 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (257) 4- (N-carboxymethylaminosulfonyl) -2-
Methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate

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NMR (CDCl ₃ ): δ 7.70-7.58 (2H, m), 7.
25 (2H, d, J = 8Hz), 7.01 (1H, d, J = 8Hz), 6.65 (2H, d, J = 8Hz),
5.43-5.23 (1H, br), 5.18-4.80 (1H, br), 3.75 (2H, brs),
3.63 (1H, t, J = 7Hz), 3.40-3.20 (4H, m), 2.28-1.80 (9H,
m), 0.98 (3H, t, J = 7 Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (258) 4- (N- (1,1-dimethyl-1-carboxymethyl) -N-propylaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) Phenyl) butanoate

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[0979] _{NMR (DMSO-d 6 +2 drops} of D 2 O): δ 7.
80 (1H, s-like), 7.78 (1H, dd, J = 2 and8Hz), 7.18 (2H, d, J
= 8Hz), 7.11 (1H, d, J = 8Hz), 6.54 (2H, d, J = 8Hz), 3.70 (1H
(H, t, J = 7Hz), 3.25-3.17 (4H, m), 3.12-3.04 (2H, m), 2.20
-1.70 (2H, m), 1.99-1.92 (4H, m), 1.95 (3H, s), 1.57-1.4
2 (2H, m), 1.45 (6H, s), 0.91 (3H, t, J = 7Hz), 0.71 (3H, t, J
= 7Hz), TLC: Rf 0.57 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (259) 4-((2S-carboxy-4S-aminopyrrolidine-
1-yl) sulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.83-7.68 (2H, m), 7.
63 (4H, s-like), 7.22 (1H, d, J = 8.2Hz), 4.21 (1H, dd, J = 9.2
and 3.4Hz), 3.98 (1H, t, J = 7.8Hz), 3.90-3.43 (7H, m),
2.70-1.84 (8H, m), 2.06 (3H, s), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.46 (ethyl acetate: acetic acid: water = 6: 2:
1).

Example 2 (260) 4-((2S-carboxy-4R-aminopyrrolidine-
1-yl) sulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.84-7.68 (2H, m), 7.
63 (4H, s-like), 7.18 (1H, d, J = 8.0Hz), 4.55 (1H, dd, J = 8.4
and 4.2Hz), 4.07-3.90 (2H, m), 3.90-3.63 (5H, m), 3.4
7-3.26 (1H, m), 2.53-1.82 (8H, m), 2.05 (3H, s), 1.00 (3
H, t, J = 7.4Hz), TLC: Rf 0.42 (ethyl acetate: acetic acid: water = 6: 2:
1).

Example 2 (261) 4- (N-carboxymethyl-N- (2- (morpholin-4-yl) ethyl) aminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) ) Phenyl) butanoate hydrochloride

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NMR (CDCl ₃ ): δ 7.66-7.52 (2H, m), 7.
21 (2H, d, J = 8.5Hz), 7.09 (1H, d, J = 8.5Hz), 6.55 (2H, d, J =
8.5Hz), 3.95-3.80 (4H, m), 3.75 (2H, s), 3.61 (1H, t, J =
7.5Hz), 3.45-3.20 (6H, m), 3.10-2.70 (6H, m), 2.30-1.75
(6H, m), 2.04 (3H, s), 0.99 (3H, t, J = 7.5Hz), TLC: Rf 0.24 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (262) 4-((2S-carboxy-4S-acetylaminopyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl)
Butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 8.02 (1H, d, J = 7.8H)
z), 7.74 (1H, d, J = 2.2Hz), 6.69 (1H, dd, J = 8.4Hz, 2.2Hz),
7.17 (2H, d, J = 8.6Hz), 7.17 (1H, d, J = 8.4Hz), 6.54 (2H,
d, J = 8.6Hz), 4.13 (1H, t, J = 7.8Hz), 3.82 (1H, m), 3.70 (1
H, t, J = 7.6Hz), 3.50 (1H, m), 3.22 (4H, m), 3.06 (1H, m),
2.31 (1H, m), 2.07 (1H, m), 1.99 (3H, s), 1.96 (4H, m), 1.
82 (2H, m), 1.75 (3H, s), 0.91 (3H, t, J = 7.4Hz), TLC: Rf 0.18 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (263) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) -2-butenoate

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NMR (CDCl ₃ ): δ 7.80-7.65 (2H, m), 7.
32 (1H, q, J = 7Hz), 7.23 (1H, d, J = 8Hz), 7.13 (2H, d, J = 8Hz),
6.59 (2H, d, J = 8Hz), 4.30-4.20 (1H, m), 4.10-3.60 (1H,
b), 3.60-3.45 (1H, m), 3.40-3.20 (5H, m), 2.30-1.65 (8
H, m), 2.25 (3H, s), 1.88 (3H, d, J = 7Hz), TLC: Rf 0.28 (chloroform: methanol: acetic acid = 4: 2: 0.1).

Example 2 (264) 4-((2S-carboxy-4R-acetylaminopyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl)
Butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 7.78 (1H, d, J = 5 Hz),
7.68 (1H, s), 7.64 (1H, d, J = 8.0Hz), 7.19 (2H, d, J = 8.6H
z), 7.16 (1H, d, J = 8.0Hz), 6.56 (2H, d, J = 8.6Hz), 4.28 (1H
(H, t, J = 7.8Hz), 4.12 (1H, m), 3.75 (1H, m), 3.48 (1H, m),
3.23 (4H, m), 3.06 (1H, m), 2.12 (1H, m), 2.03 (2H, m), 1.
99 (3H, s), 1.96 (4H, m), 1.80 (1H, m), 1.54 (3H, s), 0.91
(3H, t, J = 7.2 Hz), TLC: Rf 0.19 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (265) 4-((2RS-carboxy-5-nitroindoline-
1-yl) sulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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NMR (CDCl ₃ ): δ 8.33 (1H, d, J = 2 Hz),
7.89 (1H, dd, J = 8,2Hz), 7.67 (1H, s), 7.62 (1H, d, J = 8Hz),
7.20 (1H, d, J = 8Hz), 7.18 (2H, d, J = 8Hz), 7.02 (1H, d, J = 8
Hz), 6.55 (2H, d, J = 8Hz), 4.85 (1H, dd, J = 10,5Hz), 4.60
-4.25 (1H, br), 3.59 (1H, t, J = 7Hz), 3.40-3.15 (6H, m),
2.25-1.75 (9H, m), 0.95 (3H, t, J = 7 Hz), TLC: Rf 0.30 (chloroform: methanol: acetic acid = 4: 2: 0.1).

Example 2 (266) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (2-methoxy-4-nitrophenyl) butanoate

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[0995] _{NMR (CDCl 3): δ 7.88} (1H, dd, J = 2.0,
8.5Hz), 7.78 (1H, d, J = 2.0Hz), 7.75-7.65 (2H, m), 7.49
(1H, d, J = 8.5Hz), 7.12 (1H, d, J = 9.0Hz), 4.30-4.15 (2H,
m), 3.98 (3H, s), 3.60-3.40 (1H, m), 3.30-3.10 (1H, m),
2.40-1.60 (6H, m), 2.08 (3H, s), 1.00 (3H, t, J = 7.5Hz), TLC: Rf 0.38 (chloroform: methanol: acetic acid = 4: 2: 0.1).

Example 2 (267) 4-((2S-carboxy-4S-methylaminopyrrolidin-1-yl) sulfonyl) -2-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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[0997] _{NMR (CD 3 OD): δ} 7.77 (1H, s), 7.75 (1
H, d, J = 8.0Hz), 7.37 (2H, d, J = 8.6Hz), 7.19 (1H, d, J = 8.0H
z), 6.98 (2H, d, J = 8.6Hz), 4.18 (1H, m), 3.69 (3H, m), 3.
59 (1H, m), 3.46 (4H, m), 2.72 (3H, s), 2.57 (1H, m), 2.21
(2H, m), 2.13 (4H, m), 2.02 (3H, s), 1.93 (1H, m), 0.98 (3
H, t, J = 7.4Hz), TLC: Rf 0.28 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (268) 4-((2S-carboxy-4S- (N, N-dimethylamino) pyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidine-1- Yl) phenyl) butanoic acid ester dihydrochloride

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[0999] _{NMR (CD 3 OD): δ} 7.81 (1H, s), 7.78 (1
H, d, J = 8.2Hz), 7.62 (4H, s), 7.21 (1H, d, J = 8.2Hz), 4.25
(1H, t, J = 7Hz), 3.98 (1H, t, J = 7Hz), 3.77 (4H, m), 3.65 (3
H, m), 2.90 (6H, s), 2.80 (1H, m), 2.29 (4H, m), 2.24 (2H,
m), 2.06 (3H, s), 1.99 (1H, m), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.42 (chloroform: methanol: water =
6: 4: 1).

Example 2 (269) 4- (N-hydroxyaminosulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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[1001] _{NMR (CDCl 3): δ 7.73} (1H, s), 7.68 (1
(H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.0Hz), 7.2-7.0 (2H, br),
7.04 (1H, d, J = 8.6Hz), 6.63 (2H, d, J = 8.0Hz), 3.63 (1H, t,
J = 7.7Hz), 3.4-3.2 (4H, brs), 2.3-2.1 (1H, m), 2.1-1.9
(4H, brs), 2.00 (3H, s), 2.0-1.8 (1H, m), 0.97 (3H, t, J =
7.3 Hz), TLC: Rf 0.25 (hexane: ethyl acetate = 2:
1).

Example 2 (270) 4-((2S, 6S-dimethylpiperazin-4-yl)
Sulfonyl) -2-methylphenyl 2RS- (4-
(Pyrrolidin-1-yl) phenyl) butanoic acid ester / 2-methanesulfonate

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[1003] _{NMR (CDCl 3): δ 7.76-7.62} (6H, m), 7.
23 (1H, d, J = 8.5Hz), 4.01 (1H, t, J = 7.5Hz), 4.00-3.75 (6
H, m), 3.55-3.30 (2H, m), 2.68 (6H, s), 2.45-1.80 (8H,
m), 2.07 (3H, s), 1.31 (6H, d, J = 6.5Hz), 1.00 (3H, t, J = 7.
5Hz), TLC: Rf 0.66 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (271) 4-((2RS-Methylpiperazin-4-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2 methanesulfone Acid salt

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NMR (CDCl ₃ ): δ 7.76-7.60 (6H, m), 7.
23 (1H, d, J = 8.0Hz), 4.01 (1H, t, J = 7.5Hz), 3.90-3.72 (6
H, m), 3.55-3.35 (2H, m), 3.32-3.13 (1H, m), 2.82-2.62
(1H, m), 2.67 (6H, s), 2.49 (1H, dd, J = 13.0,10.0Hz), 2.40
-1.80 (6H, m), 2.07 (3H, s), 1.32 (3H, d, J = 6.5Hz), 1.00
(3H, t, J = 7.5Hz), TLC: Rf 0.45 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (272) 4-((2S-carboxy-4R- (N, N-dimethylamino) pyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidine-1- Yl) phenyl) butanoic acid ester dihydrochloride

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[1007] _{NMR (DMSO-d 6):} δ 11.38 (1H, m), 7.77
(1H, s), 7.72 (1H, d, J = 8.2Hz), 7.19 (3H, m), 6.63 (2H, d,
J = 8.6Hz), 4.38 (1H, m), 4.01 (1H, m), 3.82 (1H, m), 3.73
(1H, t, J = 7.4Hz), 3.49 (1H, t, J = 8.6Hz), 3.24 (4H, m), 2.
70 (6H, s), 2.36 (2H, m), 2.11 (1H, m), 1.99 (3H, s), 1.97
(4H, m), 1.83 (1H, m), 0.91 (3H, t, J = 7.2Hz), TLC: Rf 0.44 (chloroform: methanol: water =
6: 4: 1).

Example 2 (273) 4-((2S-carboxy-4R-methylaminopyrrolidin-1-yl) sulfonyl) -2-methylphenyl
2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.76 (1H, s), 7.73 (1
H, d, J = 8.0Hz), 7.25 (2H, d, J = 8.4Hz), 7.13 (1H, d, J = 8.0H
z), 6.71 (2H, d, J = 8.4Hz), 4.53 (1H, m), 3.97 (1H, m), 3.
86 (1H, m), 3.70 (1H, t, J = 8Hz), 3.41 (1H, m), 3.35 (4H,
m), 2.70 (3H, s), 2.49 (1H, m), 2.31 (1H, m), 2.17 (1H,
m), 2.06 (4H, m), 2.00 (3H, s), 1.92 (1H, m), 0.98 (3H, t,
J = 7.2Hz), TLC: Rf 0.46 (chloroform: methanol: water =
6: 4: 1).

Example 2 (274) 4- (Piperazin-4-ylsulfonyl) -2-ethylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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NMR (CD ₃ OD): δ 7.75-7.50 (6H, m), 7.
25 (1H, d, J = 9.0Hz), 3.97 (1H, t, J = 7.5Hz), 3.85-3.70 (4
H, m), 3.35-3.15 (8H, m), 2.50-1.80 (8H, m), 1.00 (6H, t,
J = 7.5Hz), TLC: Rf 0.46 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (275) 4- (Piperazin-4-ylsulfonyl) -2-ethylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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[1013] _{NMR (CD 3 OD): δ} 7.75-7.58 (6H, m), 7.
25 (1H, d, J = 9.0Hz), 3.98 (1H, t, J = 7.5Hz), 3.90-3.70 (4
H, m), 3.40-3.20 (8H, m), 2.50-1.80 (8H, m), 1.00 (6H, t,
J = 7.5Hz), TLC: Rf 0.46 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (276) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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[1015] _{NMR (CD 3 OD): δ} 7.71 (6H, m), 7.22 (1
H, d, J = 8.0Hz), 4.00 (1H, t, J = 8Hz), 3.81 (4H, m), 3.31 (8
H, s), 2.33 (4H, m), 2.24 (1H, m), 2.07 (3H, s), 1.98 (1H,
m), 1.01 (3H, t, J = 7.4Hz), TLC: Rf 0.66 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (277) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride

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[1017] _{NMR (CD 3 OD): δ} 7.70 (6H, m), 7.22 (1
H, d, J = 8.0Hz), 4.00 (1H, t, J = 8Hz), 3.81 (4H, m), 3.30 (8
H, s), 2.32 (4H, m), 2.24 (1H, m), 2.06 (3H, s), 1.99 (1H,
m), 1.00 (3H, t, J = 7.4Hz), TLC: Rf 0.66 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (278) 4-((2S-carboxymethylpyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester

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[1019] _{NMR (CDCl 3): δ 7.70-7.58} (2H, m), 7.2
3 (2H, d, J = 8Hz), 7.09 (1H, d, J = 8Hz), 6.55 (2H, d, J = 8Hz),
4.00-3.84 (1H, m), 3.62 (1H, t, J = 7Hz), 3.50-3.35 (1H, m
m), 3.35-3.20 (4H, m), 3.18-3.03 (2H, m), 2.54 (1H, dd, J
= 15,10Hz), 2.30-1.40 (13H, m), 0.98 (3H, t, J = 7Hz), TLC: Rf 0.39 (hexane: ethyl acetate: acetic acid = 5)
0: 50: 1).

Example 2 (279) 4-((2S-carboxy-4-acetylaminopyrrolidin-1-yl) sulfonyl) -2-methylphenyl
2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 8.02 (1H, d, J = 6 Hz),
7.74 (1H, s), 7.69 (1H, d, J = 8.8Hz), 7.24 (2H, d, J = 8.6H
z), 7.18 (1H, d, J = 8.6Hz), 6.69 (1H, d, J = 8.8Hz), 4.15 (1
(H, t, J = 7Hz), 3.75 (2H, m), 3.51 (1H, m), 3.28 (4H, m), 3.
05 (1H, m), 2.33 (1H, m), 2.12 (1H, m), 1.99 (7H, s-like),
1.83 (2H, m), 1.75 (3H, s), 0.91 (3H, t, J = 7.4Hz), TLC: Rf 0.67 (chloroform: methanol: water =
6: 4: 1).

Example 2 (280) 4-((2-Carboxy-5,6-dimethoxyindol-1-yl) sulfonyl) -2-methylphenyl 2
S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / hydrochloride

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NMR (DMSO-d ₆ ): δ 7.87 (1H, d, J = 2.2H)
z), 7.79 (1H, dd, J = 8.6Hz, 2.2Hz), 7.50 (1H, s), 7.25-
7.13 (5H, m), 6.66 (2H, d, J = 8.0Hz), 3.88 (3H, s), 3.78 (3H
H, s), 3.71 (1H, t, J = 7.2Hz), 3.26 (4H, m), 2.08 (1H, m),
1.97 (4H, m), 1.93 (3H, s), 1.78 (1H, m), 0.88 (3H, t, J = 7.
6 Hz), TLC: Rf 0.45 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (281) 4-((2RS-carboxyindolin-1-yl) sulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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[1025] _{NMR (DMSO-d 6):} δ 7.78 (1H, s), 7.67
(1H, dd, J = 2 and 8Hz), 7.35-6.94 (7H, m), 6.80-6.64 (2
H, br), 5.00-4.93 (1H, m), 3.70 (1H, t, J = 7Hz), 3.39-2.9
6 (6H, m), 2.17-1.64 (2H, m), 2.04-1.94 (4H, m), 1.91 (3H,
s), 0.87 (3H, t, J = 7Hz), TLC: Rf 0.30 (chloroform: methanol: water =
4: 1: 0.1).

Example 2 (282) 4-((2RS-Methylpiperazin-4-yl) sulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester · 2 methanesulfone Acid salt

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[1027] _{NMR (CD 3 OD): δ} 7.75-7.60 (6H, m), 7.
23 (1H, d, J = 8.5Hz), 4.00 (1H, t, J = 7.5Hz), 3.90-3.70 (6
H, m), 3.55-3.35 (2H, m), 3.35-3.10 (1H, m), 2.80-2.65
(1H, m), 2.66 (6H, s), 2.47 (1H, t, J = 10.0Hz), 2.06 (3H,
s), 1.31 (3H, d, J = 6.5 Hz), 1.00 (3H, t, J = 7.5 Hz), TLC: Rf 0.45 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (283) 4-((4-Formylpiperazin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester hydrochloride

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NMR (CD ₃ OD): δ 7.96 (1H, s), 7.73-7.
52 (6H, m), 7.19 (1H, d, J = 8.4Hz), 3.97 (1H, t, J = 7.6Hz),
3.88-3.67 (4H, m), 3.67-3.44 (4H, m), 3.12-2.93 (4H, m),
2.43-2.14 (5H, m), 2.12-1.81 (4H, m), 1.00 (3H, t, J = 7.
2 Hz), TLC: Rf 0.38 (hexane: ethyl acetate = 1:
2).

Example 2 (284) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate sodium salt

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NMR (DMSO-d ₆ ): δ 7.78-7.64 (2H, m),
7.18 (2H, d, J = 8.0Hz), 7.08 (1H, d, J = 8.0Hz), 6.53 (2H, d,
J = 8.0Hz), 3.95-3.80 (1H, m), 3.69 (1H, t, J = 7.5Hz), 3.5
0-3.00 (6H, m), 2.20-1.30 (10H, m), 1.96 (3H, s), 0.91 (3
H, t, J = 7.5Hz), TLC: Rf 0.32 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (285) 4-((2S-carboxypyrrolidin-1-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoate / methanesulfonic acid salt

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NMR (CDCl ₃ ): δ 7.65 (4H, d, J = 8.5 Hz),
7.54 (2H, d, J = 8.5Hz), 7.05 (1H, d, J = 8.5Hz), 4.30-4.15
(1H, m), 4.10-3.50 (4H, m), 3.80 (1H, t, J = 7.5Hz), 3.55-
3.35 (1H, m), 3.30-3.10 (1H, m), 2.87 (3H, s), 2.50-1.60
(10H, m), 2.03 (3H, s), 0.99 (3H, t, J = 7.5Hz), TLC: Rf 0.32 (chloroform: methanol: water =
9: 1: 0.1).

Example 2 (286) 4-((Piperazin-4-yl) sulfonyl) -2-methylphenyl 2RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester ・ 2 methanesulfonic acid salt

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[1035] _{NMR (CD 3 OD): δ} 7.75-7.60 (6H, m), 7.
23 (1H, d, J = 8.0Hz), 4.01 (1H, t, J = 7.5Hz), 3.90-3.70 (4
H, m), 3.35-3.20 (8H, m), 2.68 (6H, s), 2.40-1.80 (6H,
m), 2.06 (3H, s), 1.00 (3H, t, J = 7.5 Hz), TLC: Rf 0.14 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (287) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / citrate / ethanol salt

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[1037] _{NMR (CD 3 OD): δ} 7.66 (1H, brs), 7.62
(1H, brd, J = 8.0Hz), 7.20 (2H, d, J = 8.5Hz), 7.18 (1H, d, J =
8.0Hz), 6.58 (2H, d, J = 8.5Hz), 3.67 (1H, t, J = 7.5Hz), 3.
60 (2H, q, J = 7.0Hz), 3.40-3.15 (12H, m), 2.76 (4H, dd, J =
8.0,14.0Hz), 2.30-1.70 (9H, m), 1.17 (3H, t, J = 7.0Hz),
0.97 (3H, t, J = 7.5Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (288) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester succinate

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[1039] _{NMR (CD 3 OD): δ} 7.64 (1H, brs), 7.61
(1H, brd, J = 8.0Hz), 7.19 (2H, d, J = 8.5Hz), 7.17 (1H, d, J =
8.0Hz), 6.57 (2H, d, J = 8.5Hz), 3.64 (1H, t, J = 7.5Hz), 3.
40-3.20 (4H, m), 3.12 (8H, s), 2.51 (4H, s), 2.30-1.76 (9
H, m), 0.97 (3H, t, J = 7.5 Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (289) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / L-malate

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[1041] _{NMR (CD 3 OD): δ} 7.67 (1H, brs), 7.62
(1H, brd, J = 8.0Hz), 7.22 (2H, d, J = 8.5Hz), 7.19 (1H, d, J =
8.0Hz), 6.58 (2H, d, J = 8.5Hz), 4.28 (1H, dd, J = 5.0,7.5H
z), 3.68 (1H, t, J = 7.5Hz), 3.40-3.05 (12H, m), 2.78 (1H,
(dd, J = 5.0,15.0Hz), 2.52 (1H, dd, J = 7.5,15.0Hz), 2.40-
1.72 (9H, m), 0.98 (3H, t, J = 7.5 Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (290) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoate fumarate

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[1043] _{NMR (CD 3 OD): δ} 7.68 (1H, brs), 7.63
(1H, brd, J = 8.0Hz), 7.21 (2H, d, J = 8.5Hz), 7.19 (1H, d, J =
8.0Hz), 6.82 (2H, s), 6.59 (2H, d, J = 8.5Hz), 3.65 (1H, t,
J = 7.5Hz), 3.40-3.10 (12H, m), 2.30-1.70 (9H, m), 0.98
(3H, t, J = 7.5Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (291) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoate oxalate

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[1045] _{NMR (CD 3 OD): δ} 7.68 (1H, s), 7.63 (1
H, brd, J = 8.0Hz), 7.20 (2H, d, J = 8.5Hz), 7.19 (1H, d, J = 8.0Hz)
Hz), 6.60 (2H, d, J = 8.5Hz), 3.66 (1H, t, J = 7.5Hz), 3.45-
3.10 (12H, m), 2.30-1.75 (9H, m), 0.98 (3H, t, J = 7.5Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (292) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / L-lactate

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[1047] _{NMR (CD 3 OD): δ} 7.65 (1H, s), 7.61 (1
H, brd, J = 8.0Hz), 7.20 (2H, d, J = 8.5Hz), 7.17 (1H, d, J = 8.0
Hz), 6.57 (2H, d, J = 8.5Hz), 4.04 (1H, q, J = 7.0Hz), 3.65
(1H, t, J = 7.5Hz), 3.40-3.20 (4H, m), 3.14 (8H, s), 2.15
(3H, s), 2.20-1.75 (6H, m), 1.31 (3H, d, J = 7.0Hz), 0.97
(3H, t, J = 7.5Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (293) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / L-tartrate

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[1049] _{NMR (CD 3 OD): δ} 7.68 (1H, s), 7.64 (1
H, brd, J = 8.0Hz), 7.21 (2H, d, J = 8.5Hz), 7.18 (1H, d, J = 8.0
Hz), 6.59 (2H, d, J = 8.5Hz), 4.43 (2H, s), 3.68 (1H, t, J =
7.5Hz), 3.45-3.10 (12H, m), 2.40-1.78 (9H, m), 0.98 (3H,
t, J = 7.5 Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (294) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester di (p-toluenesulfonic acid) salt

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[1051] _{NMR (CD 3 OD): δ} 7.68 (6H, d, J = 8.0Hz),
7.63 (4H, d, J = 9.0Hz), 7.22 (5H, d, J = 8.0Hz), 3.99 (1H,
t, J = 7.4Hz), 3.83-3.65 (4H, m), 3.30 (8H, m), 2.36 (6H,
s), 2.36-2.20 (5H, m), 2.04 (3H, s), 1.95 (1H, m), 0.99
(3H, t, J = 7.4Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (295) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester / phosphate

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[1053] _{NMR (DMSO-d 6):} δ 8.00-7.40 (3H, m),
7.67 (1H, brs), 7.62 (1H, brd, J = 8.8Hz), 7.25 (1H, d, J = 8.
8Hz), 7.21 (2H, d, J = 8.8Hz), 6.56 (2H, d, J = 8.8Hz), 3.75
(1H, t, J = 7.4Hz), 3.23 (4H, brs), 2.94 (8H, brs), 2.01 (3
H, s), 2.20-1.80 (6H, m), 0.93 (3H, t, J = 7.4Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 2 (296) 4- (Piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoate maleate

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NMR (CD ₃ OD): δ 7.67 (1H, s), 7.62 (1
H, brd, J = 8.0Hz), 7.20 (2H, d, J = 8.5Hz), 7.19 (1H, d, J = 8.0Hz)
Hz), 6.58 (2H, d, J = 8.5Hz), 6.23 (2H, s), 3.65 (1H, t, J =
7.5Hz), 3.40-3.05 (12H, m), 2.30-1.78 (6H, m), 1.98 (3H,
s), 0.97 (3H, t, J = 7.5 Hz), TLC: Rf 0.11 (chloroform: methanol: acetic acid = 40: 2: 1).

Example 3 4- (2S-hydroxysulfonyloxymethylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2
RS- (4-methylphenyl) butanoic acid ester

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The compound (69) produced in Example 2 (19)
(0 mg) in a pyridine (10 ml) solution was added with sulfur trioxide pyridine complex (766 mg) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (chloroform: methanol = 1).
0: 1) to give the title compound (700 mg) having the following physical data. NMR (DMSO-d ₆ ): δ 7.74 (1H, d, J = 2.0 Hz), 7.67 (1H, d
d, J = 8.5,2.0Hz), 7.30 (2H, d, J = 8.5Hz), 7.20 (2H, d, J = 8.
5Hz), 7.18 (1H, d, J = 8.5Hz), 3.94-3.78 (2H, m), 3.76-3.
60 (1H, m), 3.58 (1H, t, J = 7.0Hz), 3.3-3.2 (1H, m), 3.12-
2.94 (1H, m), 2.31 (3H, s), 2.25-2.00 and 1.95-1.70 (ea
ch 1H, m), 1.97 (3H, s), 1.90-1.60 (2H, m), 1.60-1.30 (2
H, m), 0.91 (3H, t, J = 7.5 Hz), TLC: Rf 0.39 (water: methanol: chloroform =
1:10:40).

Example 3 (1) 4- (2S-hydroxysulfonyloxymethylpyrrolidin-1-ylsulfonyl) -2-methylphenyl 2
RS- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester

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The title compound having the following physical data was obtained in the same manner as in Example 3 using the compound prepared in Reference Example 2 (10). NMR (DMSO-d ₆ ): δ 7.74 (1H, s), 7.67 (1H, d, J = 8.5H
z), 7.25-7.10 (3H, m), 6.55 (2H, d, J = 8.0Hz), 3.91 (1H,
d, J = 8.5Hz), 3.80-3.50 (3H, m), 3.40-3.20 (1H, m), 3.35-
3.20 (4H, m), 3.15-2.90 (1H, m), 2.20-1.60 (2H, m), 1.98
(3H, s), 2.05-1.90 (4H, m), 1.90-1.60 (2H, m), 1.60-1.3
0 (2H, m), 0.91 (3H, t, J = 7.5Hz), TLC: Rf 0.38 (water: methanol: chloroform =
1:10:40).

[1060]

[Formulation example]

Formulation Example 1 The following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient. -4- (piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride ... 5.0 g-calcium carboxymethylcellulose (disintegrated) 0.2g-Magnesium stearate (lubricant)-0.1g-Microcrystalline cellulose-4.7g

Formulation Example 2 The following components were mixed by a conventional method, and the solution was sterilized by a conventional method, filled into ampoules in 5 ml portions, lyophilized by a conventional method, and 20 mg per ampoule was prepared.
100 ampoules containing the active ingredient were obtained. 4- (piperazin-4-ylsulfonyl) -2-methylphenyl 2S- (4- (pyrrolidin-1-yl) phenyl) butanoic acid ester dihydrochloride 2.0 g mannitol・ ・ 20 g ・ Distilled water ・ ・ ・ ・ 500ml

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 ACK A61K 31/535 ACK ACL ACL ACV ACV C07D 295/14 C07D 295/14 Z (72) Inventor Kento Fujita Mishima-gun, Osaka 3-1-1 Sakurai, Shimamoto-cho Ono Pharmaceutical Co., Ltd. In Minase Research Institute (72) Inventor Kawa-Itakawa 3-1-1 Sakurai, Shimamotocho, Mishima-gun, Osaka Ono Pharmaceutical Co., Ltd. Within Minase Research Institute (72) Inventor Hiroyuki Ohno 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Ono Pharmaceutical Co., Ltd. Within Minase Research Institute (56) References JP-A-4-283576 (JP, A JP-A-4-226939 (JP, A) JP-A-5-194366 (JP, A) JP-A-3-20253 (JP, A) JP-A-6-179645 (JP, A) JP-A-62-1987 111963 (JP, A) JP-A-63-165357 (JP, A) JP-A-7-173062 (JP, A) JP-B-6-94450 (JP, B2) JP 7-64801 (JP, B2) JP-T 7-502505 (JP, A) Trends in Pharmacological Science (1987), Vol. 8, pages 303-307 Annual Reports in Medical Chemistry (1994), Vol. 29, pages195-204 (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/00-31/80 C07D 295/00-295/22 CAPLUS (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butane Acid esters, their acid addition salts or their solvates. 2. 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butane A pharmaceutical composition comprising, as an active ingredient, a compound selected from an acid ester, an acid addition salt thereof, and a solvate thereof. 3. 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butane An elastase inhibitor containing an acid ester, an acid addition salt thereof, or a solvate thereof as an active ingredient. 4. 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2RS
-(4- (pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2S- (4
-(Pyrrolidin-1-yl) phenyl) butanoic acid ester, 4- (2- (morpholin-4-yl) ethylaminosulfonyl) -2-methylphenyl 2R- (4- (pyrrolidin-1-yl) phenyl) butane An agent for treating and / or preventing a disease caused by an abnormal increase in elastin degradation, collagen fiber degradation and / or proteoglycan degradation by elastase containing an acid ester, an acid addition salt thereof, or a solvate thereof as an active ingredient. . 5. The formula: 2RS- (4- (pyrrolidin-1-yl)
Phenyl) butanoic acid, 2S- (4- (pyrrolidine-1-
Yl) phenyl) butanoic acid or 2R- (4- (pyrroli
Zin-1-yl) phenyl) butanoic acid and the formula: 2. The method for producing a compound according to claim 1, wherein the compound is subjected to an esterification reaction.