JP2003002832A - Inhibitor of activated blood coagulation factor x - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an inhibitor of activated blood coagulation factor X, which contains a benzamidine derivative or its pharmacologically acceptable salt that are effective as a therapeutic or preventing drug for blood coagulation disorders. SOLUTION: This inhibitor of activated blood coagulation factor X contains, as an active ingredient, a benzamidine derivative or its pharmacologically acceptable salt represented by formula (I) [wherein, R<1> is H, a halogen atom, an alkyl group or OH; R<2> is H, a halogen atom or an alkyl group; R<3> is H, an alkyl group which may have substituent, an aralkyl group, an alkanoyl group which may have substituent or an alkylsulfonyl group which may have substituent; R<4> and R<5> are each independently H, a halogen atom, an alkyl group which may have substituent, an alkoxy group, carboxyl group, an alkoxycarbonyl group or a carbamoyl group which may have substituent; and R<6> is a substituted pyrrolidine or a substituted piperidine].

Description

Detailed Description of the Invention TECHNICAL FIELD OF THE INVENTION

The present invention relates to an activated blood coagulation factor X inhibitor comprising a benzamidine derivative or a pharmacologically acceptable salt thereof, which is useful as a therapeutic or prophylactic agent for blood coagulation diseases.

[0002]

2. Description of the Related Art In recent years, with the aging of the population, the number of cardiovascular diseases associated with aging has been increasing. Among them, thrombotic diseases such as cerebral infarction, myocardial infarction, and peripheral circulatory disorder not only lead directly to the cause of death, but also impose many personal and social burdens such as poor patient prognosis and restrictions on life. As a treatment method for these thrombosis, anticoagulant therapy is expected to become more important in the future.

Blood coagulation undergoes a multi-step amplification process of an enzymatic reaction that is activated due to some stimulus, and finally activated thrombin decomposes fibrinogen, which is a soluble plasma protein, into a fibrin. Is generated. Fibrin is an insoluble protein that forms clots. This process is known as the blood coagulation cascade, and there are two pathways, an intrinsic system and an extrinsic system, each of which activates blood coagulation factor X and joins. As described above, the generated activated blood coagulation factor X is an enzyme that occupies an important position in the blood coagulation cascade, and finally 2
Valuate calcium ions, phospholipids and activated blood coagulation V
Complexes with factors etc. to efficiently convert prothrombin to thrombin and accelerate the blood coagulation reaction [eg, Principles of Biochemistry: Marmarian Biochemistry, 7th Edition (1983)]
[EL Smith, A. White et al 'Principles of Bioche
mistry: Mammalian Biochemistry 7th edition 'McGraw
-Hill, Inc. (1983)], etc.].

Currently, warfarin and antithrombin agents are known and used as anticoagulants. However, although warfarin is widely used as an oral antithrombotic drug,
It is a vitamin K antagonist, and it is known that it is difficult to control the anticoagulant ability due to frequent interactions with diet and concomitant drugs [eg, Clinical Pharmacokinetics, Volume 30, Vol. P. 416 (19
1996) [Clin. Pharmacokinet., 30, 416 (1996)]
etc]. In addition, since current antithrombin agents are observed to have a bleeding tendency as a side effect associated with drug efficacy, development of new anticoagulants is desired. Activated blood coagulation factor X is directly involved in the production of thrombin, and its inhibitor is known to exhibit an anticoagulant action, and its potential as a novel anticoagulant has been suggested [eg Drugs , Volume 49, 8
56 (1995) [Drugs, 49,856 (1995)], etc.].

By the way, as a competitive antagonistic activated blood coagulation factor X inhibitor, JP-A-5-208946 (EP 54005) is used.
1), WO 96/16940 (EP 798295) or WO 00/47553,
Aromatic amidine derivatives or amidinonaphthyl derivatives are described. In addition, in WO 98/31661 (EP 976722),
For example, benzamidine derivatives such as N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) ethyl] sulfamoylacetic acid 2 trifluoroacetate are described. There is.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have, for many years, earnestly studied the pharmacological activity of various benzamidine derivatives with the aim of developing compounds having excellent activated blood coagulation factor X inhibitory activity. As a result, the benzamidine derivative having a unique structure has an excellent activated blood coagulation factor X inhibitory action and does not show a trypsin inhibitory action, so that there are no side effects resulting from it, and a preventive agent for blood coagulation diseases. Alternatively, they have found that they are useful as therapeutic agents (particularly therapeutic agents), and have completed the present invention.

The present invention provides an activated blood coagulation factor X inhibitor containing a benzamidine derivative or a pharmacologically acceptable salt thereof, which is useful as a therapeutic or prophylactic agent for blood coagulation diseases.

[0008]

The present invention has the general formula (I)

[0009]

[Chemical 5] There is provided an activated blood coagulation factor X inhibitor, which comprises a benzamidine derivative having: or a pharmacologically acceptable salt thereof.

In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a hydroxyl group, and R ² represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
R ³ is a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ alkyl group substituted with a hydroxyl group, a carboxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group;

[0011]

[Chemical 6] (In the formula, R ⁷ represents a C ₁ -C ₆ alkyl group, and m and n
Are the same or different and each represents an integer of 1 to 6. Group having C); C ₇ -C ₁₅ aralkyl group; C ₁ -C ₆ alkanoyl group; hydroxy C ₂ -C ₆ alkanoyl group; C ₁ -C ₆ alkylsulfonyl group; or (C ₁ -C ₆ alkoxy) carbonyl. C _1- substituted with a radical or a carboxyl group
C ₆ alkylsulfonyl group, wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group. , A carboxyl group, a (C ₁ -C ₆ alkoxy) carbonyl group, a carbamoyl group, a (C ₁ -C ₆ alkyl) carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, and R ⁶ is 1-aceto Imidoylpyrrolidine-3
Represents an -yl group or a 1-acetimidoylpiperidin-4-yl group.

The present invention also provides a therapeutic agent for blood coagulation diseases, which comprises an activated blood coagulation factor X inhibitor consisting of a benzamidine derivative having the general formula (I) or a pharmacologically acceptable salt thereof. Alternatively, a preventive drug is provided.

In the above general formula (I), the "halogen atom" in the definition of R ¹ may be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or chlorine. An atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.

In the above, "C ₁ -C" in the definition of R ¹
“ ₆ alkyl group” means, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s
-Butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-
Methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2,3-
A linear or branched alkyl group having 1 to 6 carbon atoms such as a dimethylbutyl group or a 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or An ethyl group is preferred, and a methyl group is particularly preferred.

In the above, the "halogen atom" in the definition of R ² may have the same meaning as defined in the above R ¹ , and is preferably a fluorine atom or a chlorine atom, particularly preferably Is a fluorine atom.

[0016] In the above-mentioned, in the definition of R ² "C ₁ -
The “C ₆ alkyl group” may have the same meaning as defined for R ¹ above, and is preferably a C ₁ -C ₄ alkyl group,
A methyl group or an ethyl group is more preferable, and a methyl group is particularly preferable.

In the above, R³In the definition of "C₁−
C₆Alkyl group "and" hydroxyl group, carboxyl group
Is (C₁-C₆Alkoxy) carbonyl group substituted C
₁-C₆"C" of "alkyl group"₁-C₆The "alkyl group" part is
For example, the R¹Can have the same meaning as defined in
"C₁-C₆"Alkyl group" is preferably C₁-C_FourAlkyl
And more preferably a methyl group, an ethyl group or an isoprene group.
It is a ropyl group, particularly preferably an isopropyl group.
On the other hand, "a hydroxyl group, a carboxyl group or (C₁-C₆A
Lucoxy) carbonyl group substituted C₁-C₆Alkyl
"C" of "Moto"₁-C ₆The "alkyl group" moiety is preferably C₁−
C_FourAn alkyl group, more preferably a methyl group or ethyl
Group, particularly preferably a methyl group.

In the above, R³In the definition of
Group, carboxyl group or (C₁-C₆Alkoxy)
C substituted with a rubonyl group₁-C₆Substituent of "alkyl group"
And "(C₁-C₆Alkoxy) carbonyl group or
C substituted with a ruboxyl group ₁-C₆Alkylsulfonyl
In the definition of the substituent of "group"₁-C₆Alkoxy)
A "carbonyl group" refers to, for example, a methoxycarbonyl group,
Toxycarbonyl group, propoxycarbonyl group, isop
Ropoxycarbonyl group, butoxycarbonyl group, isobutane
Toxycarbonyl group, s-butoxycarbonyl group, t-
Butoxycarbonyl group, pentyloxycarbonyl group,
Isopentyloxycarbonyl group, 2-methylbutoxy
Carbonyl group, neopentyloxycarbonyl group, 1-
Ethylpropoxycarbonyl group, hexyloxycarbo
Nyl group, 4-methylpentyloxycarbonyl group, 3-
Methylpentyloxycarbonyl group, 2-methylpentyl
Luoxycarbonyl group, 1-methylpentyloxycal
Bonyl group, 3,3-dimethylbutoxycarbonyl group,
2,2-dimethylbutoxycarbonyl group, 1,1-dime
Cylbutoxycarbonyl group, 1,2-dimethylbutoxy
Carbonyl group, 1,3-dimethylbutoxycarbonyl
Group, 2,3-dimethylbutoxycarbonyl group or 2-eth
1 to 6 carbon atoms such as tylbutoxycarbonyl group
A linear or branched alkoxy group of
Group, preferably (C₁-C_FourAlkoxy) carboni
Group, more preferably a methoxycarbonyl group or an ether group.
A toxycarbonyl group, particularly preferably ethoxycarl
It is a bonyl group.

In the above, "a C ₁ -C ₆ alkyl group substituted with a hydroxyl group, a carboxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group" in the definition of R ³ is, for example, a hydroxymethyl group. , 1-hydroxyethyl group, 2
-Hydroxyethyl group, 1-hydroxypropyl group, 2
-Hydroxypropyl group, 3-hydroxypropyl group,
1-hydroxybutyl group, 2-hydroxybutyl group, 3
-Hydroxybutyl group, 4-hydroxybutyl group, 5-
Hydroxypentyl group or 6-hydroxyhexyl group, carboxymethyl group, 1-carboxyethyl group, 2
-Carboxyethyl group, 1-carboxypropyl group, 2
-Carboxypropyl group, 3-carboxypropyl group,
1-carboxybutyl group, 2-carboxybutyl group, 3
-Carboxybutyl group, 4-carboxybutyl group, 5-
Carboxypentyl group or 6-carboxyhexyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group, butoxycarbonylmethyl group, isobutoxycarbonylmethyl group, s-butoxycarbonylmethyl group, t -Butoxycarbonylmethyl group,
Pentyloxycarbonylmethyl group, isopentyloxycarbonylmethyl group, 2-methylbutoxycarbonylmethyl group, neopentyloxycarbonylmethyl group, 1
-Ethylpropoxycarbonylmethyl group, hexyloxycarbonylmethyl group, 4-methylpentyloxycarbonylmethyl group, 3-methylpentyloxycarbonylmethyl group, 2-methylpentyloxycarbonylmethyl group, 1-methylpentyloxycarbonylmethyl group,
3,3-dimethylbutoxycarbonylmethyl group, 2,2
-Dimethylbutoxycarbonylmethyl group, 1,1-dimethylbutoxycarbonylmethyl group, 1,2-dimethylbutoxycarbonylmethyl group, 1,3-dimethylbutoxycarbonylmethyl group, 2,3-dimethylbutoxycarbonylmethyl group, 2-ethyl Butoxycarbonylmethyl group, 1- (methoxycarbonyl) ethyl group, 1- (ethoxycarbonyl) ethyl group, 1- (propoxycarbonyl) ethyl group, 1- (isopropoxycarbonyl) ethyl group, 1- (butoxycarbonyl) ethyl group , 1- (isobutoxycarbonyl) ethyl group, 1- (s-butoxycarbonyl) ethyl group, 1- (t-butoxycarbonyl) ethyl group, 1- (pentyloxycarbonyl) ethyl group, 1- (isopentyloxycarbonyl) ) Ethyl group, 1- (2-methylbutane) Alkoxycarbonyl) ethyl group,
1- (neopentyloxycarbonyl) ethyl group, 1-
(1-Ethylpropoxycarbonyl) ethyl group, 1-
(Hexyloxycarbonyl) ethyl group, 1- (4-methylpentyloxycarbonyl) ethyl group, 1- (3-
Methylpentyloxycarbonyl) ethyl group, 1- (2
-Methylpentyloxycarbonyl) ethyl group, 1-
(1-methylpentyloxycarbonyl) ethyl group, 1
-(3,3-dimethylbutoxycarbonyl) ethyl group,
1- (2,2-dimethylbutoxycarbonyl) ethyl group, 1- (1,1-dimethylbutoxycarbonyl) ethyl group, 1- (1,2-dimethylbutoxycarbonyl) ethyl group, 1- (1,3-dimethyl Butoxycarbonyl)
Ethyl group, 1- (2,3-dimethylbutoxycarbonyl) ethyl group, 1- (2-ethylbutoxycarbonyl)
Ethyl group, 2- (methoxycarbonyl) ethyl group, 2-
(Ethoxycarbonyl) ethyl group, 2- (propoxycarbonyl) ethyl group, 2- (isopropoxycarbonyl) ethyl group, 2- (butoxycarbonyl) ethyl group,
2- (isobutoxycarbonyl) ethyl group, 2- (s-
Butoxycarbonyl) ethyl group, 2- (t-butoxycarbonyl) ethyl group, 2- (pentyloxycarbonyl) ethyl group, 2- (isopentyloxycarbonyl)
Ethyl group, 2- (2-methylbutoxycarbonyl) ethyl group, 2- (neopentyloxycarbonyl) ethyl group, 2- (1-ethylpropoxycarbonyl) ethyl group, 2- (hexyloxycarbonyl) ethyl group, 2-
(4-methylpentyloxycarbonyl) ethyl group, 2
A-(3-methylpentyloxycarbonyl) ethyl group,
2- (2-methylpentyloxycarbonyl) ethyl group, 2- (1-methylpentyloxycarbonyl) ethyl group, 2- (3,3-dimethylbutoxycarbonyl) ethyl group, 2- (2,2-dimethylbutoxycarbonyl) )
Ethyl group, 2- (1,1-dimethylbutoxycarbonyl) ethyl group, 2- (1,2-dimethylbutoxycarbonyl) ethyl group, 2- (1,3-dimethylbutoxycarbonyl) ethyl group, 2- (2,2 3-dimethylbutoxycarbonyl) ethyl group, 2- (2-ethylbutoxycarbonyl) ethyl group, 3- (methoxycarbonyl) propyl group, 3- (ethoxycarbonyl) propyl group, 3- (propoxycarbonyl) propyl group, 3- (Isopropoxycarbonyl) propyl group, 3- (butoxycarbonyl) propyl group, 3- (isobutoxycarbonyl) propyl group, 3- (s-butoxycarbonyl) propyl group,
3- (t-butoxycarbonyl) propyl group, 3- (pentyloxycarbonyl) propyl group, 3- (isopentyloxycarbonyl) propyl group, 3- (hexyloxycarbonyl) propyl group, 4- (methoxycarbonyl) butyl group A 4- (ethoxycarbonyl) butyl group,
4- (propoxycarbonyl) butyl group, 4- (isopropoxycarbonyl) butyl group, 4- (butoxycarbonyl) butyl group, 4- (isobutoxycarbonyl) butyl group, 4- (s-butoxycarbonyl) butyl group, 4 −
(T-butoxycarbonyl) butyl group, 4- (pentyloxycarbonyl) butyl group, 4- (isopentyloxycarbonyl) butyl group, 4- (hexyloxycarbonyl) butyl group, 5- (methoxycarbonyl) pentyl group, 5 -(Ethoxycarbonyl) pentyl group, 5- (propoxycarbonyl) pentyl group, 5- (butoxycarbonyl) pentyl group, 5- (pentyloxycarbonyl) pentyl group, 5- (hexyloxycarbonyl) pentyl group, 6- (methoxy Carbonyl) hexyl group, 6
Hydroxyl group such as-(ethoxycarbonyl) hexyl group, 6- (propoxycarbonyl) hexyl group, 6- (butoxycarbonyl) hexyl group, 6- (pentyloxycarbonyl) hexyl group or 6- (hexyloxycarbonyl) hexyl group A carboxyl group or the (C ₁ -C ₆ alkoxy) carbonyl group is the C ₁ -C ₆
It may be a group bonded to an alkyl group, preferably a hydroxy C ₁ -C ₄ alkyl group, a carboxy C ₁ -C ₄ alkyl group or a (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) group. And more preferably a hydroxy C ₁ -C ₄ alkyl group or a (C ₁ -C ₄ alkoxy) carbonylmethyl group, and even more preferably a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group. Group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group, particularly preferably 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group or ethoxycarbonylmethyl group, most preferably , A carboxymethyl group or an ethoxycarbonylmethyl group.

In the above general formula (II), the “C ₁ -C ₆ alkyl group” in the definition of R ⁷ is, for example, the above R ¹
It may have the same meaning as defined above, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably an ethyl group.

In the above, m is preferably an integer of 1 to 4, and more preferably 1 or 2.

In the above, n is preferably an integer of 1 to 4, and more preferably 1 or 2.

In the above general formula (I), the "C ₇ -C ₁₅ aralkyl group" in the definition of R ³ is, for example, benzyl group, naphthylmethyl group, indenylmethyl group, phenanthrenylmethyl group. Group, anthracenylmethyl group, diphenylmethyl group, phenethyl group, naphthylethyl group, phenylpropyl group, naphthylpropyl group, phenylbutyl group, naphthylbutyl group, phenylpentyl group, naphthylpentyl group or phenylhexyl group, Carbon number 6
1 to 2 of 14 to 14 aromatic hydrocarbon groups may be a group bonded to the above-mentioned “C ₁ -C ₆ alkyl group”, and preferably benzyl group, naphthylmethyl group, diphenylmethyl group or phenethyl group A group, more preferably a benzyl group or a phenethyl group, and particularly preferably a benzyl group.

In the above, "C ₁ ---" in the definition of R ³
“C ₆ alkanoyl group” means, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group,
A linear or branched alkanoyl group having 1 to 6 carbon atoms such as a pivaloyl group, a valeryl group, an isovaleryl group or a hexanoyl group, preferably a C ₁ -C ₄ alkanoyl group, and more preferably Is a formyl group or an acetyl group, particularly preferably an acetyl group.

In the above, "hydroxy C ₂ -C ₆ alkanoyl group" in the definition of R ³ is, for example, hydroxyacetyl group, 2-hydroxypropionyl group, 3-hydroxypropionyl group, 4-hydroxybutyryl group. Base,
A hydroxyl group, such as a 5-hydroxyvaleryl group or a 6-hydroxyhexanoyl group, may be a group bonded to the above-mentioned “C ₁ -C ₆ alkanoyl group”, preferably a hydroxyacetyl group, a 3-hydroxypropionyl group or It is a 4-hydroxybutyryl group, and particularly preferably a hydroxyacetyl group.

In the above, in the definition of R ³ , "C _1-
“C ₆ alkylsulfonyl group” means, for example, methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group,
The “C ₁ -C ₆ alkyl group” is a sulfonyl group such as an isopropanesulfonyl group, a butanesulfonyl group, an isobutanesulfonyl group, a pentanesulfonyl group, an isopentanesulfonyl group, a neopentanesulfonyl group, a hexanesulfonyl group or an isohexanesulfonyl group. It may be a group bonded to a group, preferably a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group or a hexanesulfonyl group, more preferably a methanesulfonyl group, an ethanesulfonyl group. Alternatively, it is a butanesulfonyl group, and particularly preferably an ethanesulfonyl group.

[0027] In the above, in the definition of R ³ "(C ₁
And a “C ₁ -C ₆ alkylsulfonyl group substituted with a —C ₆ alkoxy) carbonyl group or a carboxyl group” is, for example, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group, propoxycarbonylmethanesulfonyl group, isopropoxycarbonylmethanesulfonyl group. Group, butoxycarbonylmethanesulfonyl group, isobutoxycarbonylmethanesulfonyl group, s-
Butoxycarbonylmethanesulfonyl group, t-butoxycarbonylmethanesulfonyl group, pentyloxycarbonylmethanesulfonyl group, isopentyloxycarbonylmethanesulfonyl group, 2-methylbutoxycarbonylmethanesulfonyl group, neopentyloxycarbonylmethanesulfonyl group, 1-ethylpropoxy Carbonylmethanesulfonyl group, hexyloxycarbonylmethanesulfonyl group, 4-methylpentyloxycarbonylmethanesulfonyl group, 3-methylpentyloxycarbonylmethanesulfonyl group, 2-methylpentyloxycarbonylmethanesulfonyl group, 1-methylpentyloxycarbonylmethanesulfonyl group Group, 3,3-dimethylbutoxycarbonylmethanesulfonyl group, 2,2-dimethylbutoxycarbonyl Tansuruhoniru group, 1,1-dimethyl-butoxycarbonyl methanesulfonyl group, 1,2-dimethyl-butoxycarbonyl methanesulfonyl group, 1,3
-Dimethylbutoxycarbonylmethanesulfonyl group,
2,3-dimethylbutoxycarbonylmethanesulfonyl group, 2-ethylbutoxycarbonylmethanesulfonyl group, 1- (methoxycarbonyl) ethanesulfonyl group,
1- (ethoxycarbonyl) ethanesulfonyl group, 1-
(Propoxycarbonyl) ethanesulfonyl group, 1-
(Isopropoxycarbonyl) ethanesulfonyl group, 1
-(Butoxycarbonyl) ethanesulfonyl group, 1-
(Isobutoxycarbonyl) ethanesulfonyl group, 1-
(S-Butoxycarbonyl) ethanesulfonyl group, 1-
(T-butoxycarbonyl) ethanesulfonyl group, 1-
(Pentyloxycarbonyl) ethanesulfonyl group, 1
-(Isopentyloxycarbonyl) ethanesulfonyl group, 1- (2-methylbutoxycarbonyl) ethanesulfonyl group, 1- (neopentyloxycarbonyl) ethanesulfonyl group, 1- (1-ethylpropoxycarbonyl) ethanesulfonyl group, 1 -(Hexyloxycarbonyl) ethanesulfonyl group, 1- (4-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (3-methylpentyloxycarbonyl) ethanesulfonyl group,
1- (2-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (1-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (3,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (2,2-
Dimethylbutoxycarbonyl) ethanesulfonyl group, 1
-(1,1-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (1,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (1,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (2,3 −
Dimethylbutoxycarbonyl) ethanesulfonyl group, 1
-(2-ethylbutoxycarbonyl) ethanesulfonyl group, 2- (methoxycarbonyl) ethanesulfonyl group,
2- (ethoxycarbonyl) ethanesulfonyl group, 2-
(Propoxycarbonyl) ethanesulfonyl group, 2-
(Isopropoxycarbonyl) ethanesulfonyl group, 2
-(Butoxycarbonyl) ethanesulfonyl group, 2-
(Isobutoxycarbonyl) ethanesulfonyl group, 2-
(S-Butoxycarbonyl) ethanesulfonyl group, 2-
(T-butoxycarbonyl) ethanesulfonyl group, 2-
(Pentyloxycarbonyl) ethanesulfonyl group, 2
-(Isopentyloxycarbonyl) ethanesulfonyl group, 2- (2-methylbutoxycarbonyl) ethanesulfonyl group, 2- (neopentyloxycarbonyl) ethanesulfonyl group, 2- (1-ethylpropoxycarbonyl) ethanesulfonyl group, 2 -(Hexyloxycarbonyl) ethanesulfonyl group, 2- (4-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (3-methylpentyloxycarbonyl) ethanesulfonyl group,
2- (2-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (1-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (3,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (2,2-
Dimethylbutoxycarbonyl) ethanesulfonyl group, 2
-(1,1-Dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (1,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (1,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (2,3 −
Dimethylbutoxycarbonyl) ethanesulfonyl group, 2
-(2-ethylbutoxycarbonyl) ethanesulfonyl group, 1- (methoxycarbonyl) propanesulfonyl group, 1- (ethoxycarbonyl) propanesulfonyl group, 1- (propoxycarbonyl) propanesulfonyl group, 1- (butoxycarbonyl) propanesulfonyl group Group, 1- (pentyloxycarbonyl) propanesulfonyl group, 1- (hexyloxycarbonyl) propanesulfonyl group, 2- (methoxycarbonyl) propanesulfonyl group, 2- (ethoxycarbonyl) propanesulfonyl group, 2- (propoxycarbonyl) Propanesulfonyl group, 2- (butoxycarbonyl) propanesulfonyl group, 2- (pentyloxycarbonyl) propanesulfonyl group, 2- (hexyloxycarbonyl) propanesulfonyl group, 3- (meth) Xycarbonyl) propanesulfonyl group, 3- (ethoxycarbonyl) propanesulfonyl group, 3- (propoxycarbonyl) propanesulfonyl group, 3- (isopropoxycarbonyl) propanesulfonyl group, 3- (butoxycarbonyl) propanesulfonyl group, 3- (Isobutoxycarbonyl) propanesulfonyl group, 3- (s-butoxycarbonyl) propanesulfonyl group, 3- (t-butoxycarbonyl) propanesulfonyl group, 3- (pentyloxycarbonyl)
Propanesulfonyl group, 3- (isopentyloxycarbonyl) propanesulfonyl group, 3- (2-methylbutoxycarbonyl) propanesulfonyl group, 3- (neopentyloxycarbonyl) propanesulfonyl group, 3-
(1-ethylpropoxycarbonyl) propanesulfonyl group, 3- (hexyloxycarbonyl) propanesulfonyl group, 3- (4-methylpentyloxycarbonyl) propanesulfonyl group, 3- (3-methylpentyloxycarbonyl) propanesulfonyl group, 3- (2-
Methylpentyloxycarbonyl) propanesulfonyl group, 3- (1-methylpentyloxycarbonyl) propanesulfonyl group, 3- (3,3-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (2,2-dimethylbutoxycarbonyl) propane Sulfonyl group, 3-
(1,1-Dimethylbutoxycarbonyl) propanesulfonyl group, 3- (1,2-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (1,3-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (2,2
3-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (2-ethylbutoxycarbonyl) propanesulfonyl group, 2-methoxycarbonyl-1-methylethanesulfonyl group, 2-ethoxycarbonyl-1-methylethanesulfonyl group, 2-propoxy Carbonyl-1-
Methylethanesulfonyl group, 2-butoxycarbonyl-
1-methylethanesulfonyl group, 1- (methoxycarbonyl) butanesulfonyl group, 1- (ethoxycarbonyl) butanesulfonyl group, 1- (propoxycarbonyl) butanesulfonyl group, 1- (butoxycarbonyl)
Butanesulfonyl group, 1- (pentyloxycarbonyl) butanesulfonyl group, 1- (hexyloxycarbonyl) butanesulfonyl group, 2- (methoxycarbonyl) butanesulfonyl group, 2- (ethoxycarbonyl)
Butanesulfonyl group, 2- (propoxycarbonyl) butanesulfonyl group, 2- (butoxycarbonyl) butanesulfonyl group, 2- (pentyloxycarbonyl) butanesulfonyl group, 2- (hexyloxycarbonyl) butanesulfonyl group, 3- (methoxy Carbonyl) butanesulfonyl group, 3- (ethoxycarbonyl) butanesulfonyl group, 3- (propoxycarbonyl) butanesulfonyl group, 3- (butoxycarbonyl) butanesulfonyl group, 3- (pentyloxycarbonyl) butanesulfonyl group, 3- ( Hexyloxycarbonyl) butanesulfonyl group, 4- (methoxycarbonyl) butanesulfonyl group, 4- (ethoxycarbonyl) butanesulfonyl group,
4- (propoxycarbonyl) butanesulfonyl group, 4
-(Isopropoxycarbonyl) butanesulfonyl group,
4- (butoxycarbonyl) butanesulfonyl group, 4-
(Isobutoxycarbonyl) butanesulfonyl group, 4-
(S-Butoxycarbonyl) butanesulfonyl group, 4-
(T-butoxycarbonyl) butanesulfonyl group, 4-
(Pentyloxycarbonyl) butanesulfonyl group, 4
-(Isopentyloxycarbonyl) butanesulfonyl group, 4- (2-methylbutoxycarbonyl) butanesulfonyl group, 4- (neopentyloxycarbonyl) butanesulfonyl group, 4- (1-ethylpropoxycarbonyl) butanesulfonyl group, 4 -(Hexyloxycarbonyl) butanesulfonyl group, 4- (4-methylpentyloxycarbonyl) butanesulfonyl group, 4- (3-methylpentyloxycarbonyl) butanesulfonyl group,
4- (2-methylpentyloxycarbonyl) butanesulfonyl group, 4- (1-methylpentyloxycarbonyl) butanesulfonyl group, 4- (3,3-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (2,2-
Dimethylbutoxycarbonyl) butanesulfonyl group, 4
-(1,1-Dimethylbutoxycarbonyl) butanesulfonyl group, 4- (1,2-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (1,3-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (2,3 −
Dimethylbutoxycarbonyl) butanesulfonyl group, 4
— (2-Ethylbutoxycarbonyl) butanesulfonyl group, 3-methoxycarbonyl-2-methylpropanesulfonyl group, 3-ethoxycarbonyl-2-methylpropanesulfonyl group, 5- (methoxycarbonyl) pentanesulfonyl group, 5- (ethoxy Carbonyl) pentanesulfonyl group, 5- (propoxycarbonyl) pentanesulfonyl group, 5- (butoxycarbonyl) pentanesulfonyl group, 5- (pentyloxycarbonyl) pentanesulfonyl group, 5- (hexyloxycarbonyl) pentanesulfonyl group, 6- (Methoxycarbonyl) hexanesulfonyl group, 6- (ethoxycarbonyl) hexanesulfonyl group, 6- (propoxycarbonyl) hexanesulfonyl group, 6- (butoxycarbonyl) hexanesulfonyl group, 6- Pentyloxycarbonyl) hexanesulfonyl group, 6- (hexyloxycarbonyl) hexanesulfonyl group, carboxy methanesulfonyl group,
2-carboxyethanesulfonyl group, 3-carboxypropanesulfonyl group, 2-carboxy-1-methylethanesulfonyl group, 4-carboxybutanesulfonyl group,
3-carboxy-2-methylpropanesulfonyl group, 5
One substituent selected from the group consisting of the (C ₁ -C ₆ alkoxy) carbonyl group and the carboxyl group, such as a -carboxypentanesulfonyl group or a 6-carboxyhexanesulfonyl group, is a C ₁ -C ₆ alkyl group. It may be a group bonded to a sulfonyl group, preferably a (C ₁ -C ₄ alkoxy) carbonyl group or a C ₁ -C ₄ alkylsulfonyl group substituted with a carboxyl group, and more preferably (C ₁ -C ₄ alkoxy) substituted with a carbonyl group or a carboxyl group, a methanesulfonyl group or an ethanesulfonyl group, and more preferably more, methoxycarbonyl methanesulfonyl group, an ethoxycarbonyl methanesulfonyl group, carboxy methanesulfonyl group, 2- Methoxycarbonylethanesulfonyl group, 2-ethoxycarbonylethane It is a sulfonyl group or a 2-carboxyethanesulfonyl group, and particularly preferably an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group.

In the above, "halogen atom" in the definition of R ⁴ and R ⁵ may have the same meaning as defined for R ¹ above, and preferably, a fluorine atom, a chlorine atom or It is a bromine atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.

In the above, "C ₁ -C ₆ alkyl group" in the definition of R ⁴ and R ⁵ may have the same meaning as defined for R ¹ above, and preferably C an ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, particularly preferably methyl group.

In the above, "halogeno C ₁ -C ₆ alkyl group" in the definition of R ⁴ and R ⁵ is, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group. , 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 4-fluorobutyl group, 6-fluorohexyl group, chloromethyl group, 2
-Chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, bromomethyl group, 3-bromopropyl group, dibromopentyl group, iodomethyl group or 2-fluoro-
The “C ₁ -C ₆ alkyl group” such as a 1-chloroethyl group may be a group substituted with 1 to 5 of the “halogen atom”, and preferably a group consisting of a fluorine atom and a chlorine atom. C substituted with a halogen atom selected from 1 to 3
_1- C ₄ alkyl group, more preferably, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2
It is a -fluoroethyl group, a 2,2-difluoroethyl group or a 2,2,2-trifluoroethyl group, and particularly preferably a trifluoromethyl group.

In the above, "C ₁ -C ₆ alkoxy group" in the definition of R ⁴ and R ⁵ is, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. , S-butoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentyloxy group, 3- Methylpentyloxy group, 2-methylpentyloxy group, 1-methylpentyloxy group, 3,3-
Dimethylbutoxy group, 2,2-dimethylbutoxy group,
The above-mentioned “C ₁ -C ₆ alkyl group” such as 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group or 2-ethylbutoxy group. Is a group bonded to an oxygen atom, preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group or an ethoxy group, and particularly preferably a methoxy group.

In the above, "(C ₁ -C ₆ alkoxy) carbonyl group" in the definition of R ⁴ and R ⁵ is, for example,
It may have the same meaning as defined for R ³ above, and preferably,
(C ₁ -C ₄ alkoxy) carbonyl group, more preferably methoxycarbonyl group or ethoxycarbonyl group, and particularly preferably ethoxycarbonyl group.

In the above, "(C ₁ -C ₆ alkyl) carbamoyl group" in the definition of R ⁴ and R ⁵ is, for example,
C ₁ such as a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a butylcarbamoyl group, an isobutylcarbamoyl group, a s-butylcarbamoyl group, a t-butylcarbamoyl group, a pentylcarbamoyl group or a hexylcarbamoyl group. A -C ₆ alkyl group may be a group bonded to a carbamoyl group, preferably a C ₁ -C ₄ alkylcarbamoyl group, more preferably a methylcarbamoyl group or an ethylcarbamoyl group, and particularly preferably methylcarbamoyl group. It is a base.

In the above, "di (C ₁ -C ₆ alkyl) carbamoyl group" in the definition of R ⁴ and R ⁵ is, for example, N, N-dimethylcarbamoyl group, N-ethyl-N.
-Methylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group, N, N-diisobutylcarbamoyl group, N,
N-di-s-butylcarbamoyl group, N, N-di-t-
Such as a butylcarbamoyl group, N, N-dipentylcarbamoyl group or N, N-dihexylcarbamoyl group,
Two alkyl groups that are the same or different from the C ₁ -C ₆ alkyl group may be bonded to a carbamoyl group, preferably a di (C ₁ -C ₄ alkyl) carbamoyl group. , More preferably N, N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group or N,
N-diethylcarbamoyl group, particularly preferably N,
It is an N-dimethylcarbamoyl group.

The compound having the general formula (I) which is the activated blood coagulation factor X inhibitor of the present invention can be converted into its corresponding pharmacologically acceptable salt by treating with an acid according to a conventional method. it can. For example, activated blood coagulation X
The factor inhibitor (I) may be in a solvent (for example, ethers, esters or alcohols, preferably ethers or alcohols) with the corresponding acid at room temperature for 1 minute to 30 minutes.
It can be obtained by treating for minutes and collecting the precipitated crystals by filtration or distilling off the solvent under reduced pressure. Such salts include carbonates; hydrofluorides, hydrochlorides, hydrobromides, hydroiodes, nitrates, perchlorates, sulphates or phosphates or other mineral salts; methane. Sulfonates such as sulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates or p-toluenesulfonates; acetates, propionates, butyrates, fumarates, succinates , Citrates, tartrates, oxalates or carboxylates such as maleates or benzoates; or amino acid salts such as glutamate or aspartate.

The compounds of the general formula (I) which are the activated blood coagulation factor X inhibitors of the present invention correspond to each other by treating with a base according to a conventional method such as when R ³ contains a carboxyl group. It can be a pharmaceutically acceptable salt. For example, the activated blood coagulation factor X inhibitor (I) is treated with a corresponding base at room temperature for 1 to 30 minutes in a solvent (which may be, for example, ethers, esters or alcohols, preferably alcohols). Then, the precipitated crystals can be collected by filtration or the solvent can be distilled off under reduced pressure. Examples of such salts include sodium salts, potassium salts, alkali metal salts such as lithium salts, calcium salts, alkaline earth metal salts such as magnesium salts, aluminum salts, iron salts, zinc salts, copper salts,
Metal salts such as nickel salts and cobalt salts; ammonium salts,
t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N '. It may be an organic amine salt such as dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, preferably Is an alkali metal salt (particularly sodium salt or potassium salt).

The compound having the general formula (I) which is an activated blood coagulation factor X inhibitor of the present invention or a pharmacologically acceptable salt thereof has an R-coordination, when it has an asymmetric carbon atom in the molecule. There are stereoisomers that are S-coordinated, each of which is
Alternatively, any of those compounds in any proportion are included in the present invention. Such stereoisomers are prepared, for example, by synthesizing the compound (I) using an optically resolved raw material compound or optically synthesizing the synthesized compound (I) by a conventional optical resolution or separation method. be able to.

The compound of the general formula (I) which is an activated blood coagulation factor X inhibitor of the present invention or a pharmacologically acceptable salt thereof is allowed to stand in the air or recrystallize to give water. In some cases, the compound and salt containing such water may be absorbed and adsorbed with water or become a hydrate.

In the compound of the general formula (I) which is an activated blood coagulation factor X inhibitor of the present invention, a suitable activated blood coagulation factor X inhibitor is, for example, (1) R
¹ is hydrogen atom, fluorine atom, chlorine atom, bromine atom, C ₁ −
An activated blood coagulation factor X inhibitor which is a C ₄ alkyl group or a hydroxyl group,

(2) An activated blood coagulation factor X inhibitor in which R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a hydroxyl group,

(3) An activated blood coagulation factor X inhibitor in which R ¹ is a hydrogen atom, a fluorine atom, a methyl group or a hydroxyl group,

(4) An activated blood coagulation factor X inhibitor in which R ¹ is a hydrogen atom or a hydroxyl group,

(5) An activated blood coagulation factor X inhibitor in which R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a C ₁ -C ₄ alkyl group,

(6) An activated blood coagulation factor X inhibitor in which R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group,

(7) An activated blood coagulation factor X inhibitor, wherein R ² is a hydrogen atom, a fluorine atom or a methyl group,

(8) An activated blood coagulation factor X inhibitor, wherein R ² is a hydrogen atom or a fluorine atom,

(9) An activated blood coagulation factor X inhibitor, wherein R ² is a hydrogen atom,

(10) R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; hydroxy C ₁ -C ₄ alkyl group, carboxy C ₁ -C ₄ alkyl group or (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) group; general formula

[0049]

[Chemical 7] (In the formula, R ⁷ represents a C ₁ -C ₄ alkyl group, and m and n
Are the same or different and each represents an integer of 1 to 4. Group having); benzyl group, naphthylmethyl group, diphenylmethyl group or phenethyl group; C ₁ -C ₄ alkanoyl group; hydroxyacetyl group, 3-hydroxypropionyl group or 4-hydroxybutyryl group; methanesulfonyl group, ethanesulfonyl group Group, propanesulfonyl group,
Butanesulfonyl group, pentane sulfonyl group or hexanesulfonyl group; or, C ₁ substituted with (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group -
An activated blood coagulation factor X inhibitor which is a C ₄ alkylsulfonyl group,

(11) R ³ is hydrogen atom; C ₁ -C ₄ alkyl group; 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group General formula

[0051]

[Chemical 8] (In the formula, R ⁷ represents a methyl group or an ethyl group, and m and n are the same or different and represent 1 or 2.); benzyl group or phenethyl group; formyl group or acetyl group; hydroxyacetyl Group; methanesulfonyl group, ethanesulfonyl group or butanesulfonyl group; or activated blood coagulation factor X which is a methanesulfonyl group or ethanesulfonyl group substituted with a (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group Inhibitor,

(12) R ³ is a hydrogen atom, a methyl group,
Ethyl group, isopropyl group, 2-hydroxyethyl group,
Carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, butoxycarbonylmethyl group, acetyl group, hydroxyacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxy An activated blood coagulation factor X inhibitor which is a carbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group,

(13) R ³ is isopropyl group, 2-
Hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group, carboxymethanesulfonyl group, 2-methoxycarbonylethanesulfonyl group, 2-ethoxy An activated blood coagulation factor X inhibitor which is a carbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group,

(14) An activated blood coagulation factor X inhibitor in which R ³ is an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,

(15) An activated blood coagulation factor X inhibitor in which R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,

(16) R ⁴ and R ⁵ are the same or different and are hydrogen atom, fluorine atom, chlorine atom, bromine atom, C _1-.
C ₄ alkyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group,
2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, carboxyl group,
An activated blood coagulation factor X inhibitor which is a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group,

(17) R^FourBut hydrogen atom, fluorine atom,
A chlorine atom or a trifluoromethyl group, R^FiveBut water
Elemental atom, fluorine atom, chlorine atom, bromine atom, C₁-C_FourAl
Kill group, fluoromethyl group, difluoromethyl group, tri group
Fluoromethyl group, 2-fluoroethyl group, 2,2-di
Fluoroethyl group, 2,2,2-trifluoroethyl
Base, C ₁-C_FourAlkoxy group, carboxyl group, methoxy
Carbonyl group, ethoxycarbonyl group, carbamoyl
Group, methylcarbamoyl group or N, N-dimethylcarba
An activated blood coagulation factor X inhibitor which is a moyl group,

(18) R ⁴ is a hydrogen atom, a fluorine atom or a chlorine atom, and R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group or a methoxy group. An activated blood coagulation factor X inhibitor which is an ethoxy group or a carbamoyl group,

(19) R ⁴ is a hydrogen atom, and R ^4
An activated blood coagulation factor X inhibitor, wherein ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group,

(20) R ⁴ is a hydrogen atom, and R ^4
An activated blood coagulation factor X inhibitor wherein ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group,

(21) An activated blood coagulation factor X inhibitor in which R ⁶ is a 1-acetimidoylpiperidin-4-yl group can be mentioned, and with respect to R ¹ , (1)
From the order in raises the preferred order of (4), with respect to R ^2, raise the suitable ranking in the order of (5) from (9), R ³
(10) to (15) in order of preference, and R ⁴ and R ⁵ (16) to (20)
The preferred rank increases in the order of.

As the activated blood coagulation factor X inhibitor having the general formula (I), (1)-(4),
(5)-(9), (10)-(15), (16)-(2
It is also possible to select 2 to 5 selected from the group consisting of 0) and (21) and to arbitrarily combine them, and preferable examples of the combination include, for example,
(22) R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group or a hydroxyl group, and R 1
² is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or C ₁
A -C ₄ alkyl group, R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; hydroxy C ₁ -C ₄ alkyl group, carboxy C ₁ -C ₄ alkyl or (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) group; general formula

[0063]

[Chemical 9] (In the formula, R ⁷ represents a C ₁ -C ₄ alkyl group, and m and n
Are the same or different and each represents an integer of 1 to 4. Group having); benzyl group, naphthylmethyl group, diphenylmethyl group or phenethyl group; C ₁ -C ₄ alkanoyl group; hydroxyacetyl group, 3-hydroxypropionyl group or 4-hydroxybutyryl group; methanesulfonyl group, ethanesulfonyl group Group, propanesulfonyl group,
Butanesulfonyl group, pentane sulfonyl group or hexanesulfonyl group; or, C ₁ substituted with (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group -
A C ₄ alkylsulfonyl group, wherein R ⁴ and R ⁵ are the same or different and are hydrogen atom, fluorine atom, chlorine atom, bromine atom, C ₁ -C ₄ alkyl group, fluoromethyl group, difluoromethyl group, trifluoro Methyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group,
An activated blood coagulation factor X inhibitor which is a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group,

(23) R ¹ is a hydrogen atom, a fluorine atom,
A chlorine atom, a methyl group, an ethyl group or a hydroxyl group, R ²
Is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, and R ³ is a hydrogen atom; a C ₁ -C ₄ alkyl group;
2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group,
Propoxycarbonylmethyl group or butoxycarbonylmethyl group; general formula

[0065]

[Chemical 10] (In the formula, R⁷Represents a methyl group or an ethyl group, and m and
And n are the same or different and represent 1 or 2. )
Group having; benzyl group or phenethyl group; formyl
Group or acetyl group; hydroxyacetyl group; methane
Sulfonyl group, ethanesulfonyl group or butanesul
Honyl group; or (C₁-C_FourAlkoxy) carbonyl group
Or methanesulphonyl substituted with a carboxyl group
R group or ethanesulfonyl group, R^FourBut hydrogen
Atom, fluorine atom, chlorine atom or trifluoromethyl group
Yes, R^FiveHowever, hydrogen atom, fluorine atom, chlorine atom, bromine source
Child, C₁-C_FourAlkyl group, fluoromethyl group, difluor
Romethyl group, trifluoromethyl group, 2-fluoroethyl
Group, 2,2-difluoroethyl group, 2,2,2-tri
Fluoroethyl group, C ₁-C_FourAlkoxy group, carboxy
Group, methoxycarbonyl group, ethoxycarbonyl group,
Carbamoyl group, methylcarbamoyl group or N, N-di
A methylcarbamoyl group, R⁶But 1-acetimi
Activated blood coagulation that is a doylpiperidin-4-yl group
Factor X inhibitor,

(24) R ¹ is a hydrogen atom, a fluorine atom,
A methyl group or a hydroxyl group, R ² is a hydrogen atom, a fluorine atom or a methyl group, and R ³ is a hydrogen atom, a methyl group,
Ethyl group, isopropyl group, 2-hydroxyethyl group,
Carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, butoxycarbonylmethyl group, acetyl group, hydroxyacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxy A carbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group, and R ⁴ is a hydrogen atom, a fluorine atom or a chlorine atom, R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a carbamoyl group, and R 5
^An activated blood coagulation factor X inhibitor, wherein ⁶ is a 1-acetimidoylpiperidin-4-yl group,

(25) R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom or a fluorine atom, and R ³ is an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group. An ethoxycarbonylmethyl group, an ethanesulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group. R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group, and R ⁶ is 1-acetimidoylpiperidine-4-. An activated blood coagulation factor X inhibitor which is an yl group,

(26) R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom or a fluorine atom, and R ³ is an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group. Or a carboxymethanesulfonyl group, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group, and R ⁶ is a 1-acetimidoylpiperidin-4-yl group. An activated blood coagulation factor X inhibitor which is

(27) R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom or a fluorine atom, R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group, and R ⁴ is A hydrogen atom, R ⁵
Is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group, and R ⁶ is 1-acetimidoylpiperidine-4.
An activated blood coagulation factor X inhibitor which is an -yl group, and in the above, (22) to (27)
The preferred rank increases in the order of.

Examples of the activated blood coagulation factor X inhibitor of the present invention, which comprises the benzamidine derivative having the general formula (I) or a pharmacologically acceptable salt thereof, include those listed in the following table. However, the present invention is not limited to these activated blood coagulation factor X inhibitors.

The abbreviations in the table are as follows. Ac: acetyl group AI: acetimidoyl group 1-AI-Pip (4): 1-acetimidoylpiperidin-4-yl group 1-AI-Pyrd (3): 1-acetimidoylpyrrolidin-3-yl group Bn: benzyl group Bu: Butyl group iBu: Isobutyl group sBu: Secondary butyl group tBu: Tertiary butyl group Byr: Butyryl group Et: ethyl group Hx: Hexyl group Me: Methyl group Np (1): 1-naphthyl group Np (2): 2-naphthyl group Ph: Phenyl group Pn: Pentyl group Pr: propyl group iPr: Isopropyl group Prn: Propionyl group Va: Valeryl group

[0072]

[Table 1]

[0073]

[Chemical 11] Compound R¹    R²  R³               R^Four          R^Five          R⁶ number 1 H H H H H 1-AI-Pyrd (3) 2 H H Me H H 1-AI-Pyrd (3) 3 H H Et H H 1-AI-Pyrd (3) 4 H HiPr H H 1-AI-Pyrd (3) 5 H HiPr 3-Cl H 1-AI-Pyrd (3) 6 H HiPr 3-Me H 1-AI-Pyrd (3) 7 H HiPr 3-CONH₂     H 1-AI-Pyrd (3) 8 H HiPr 3-F 5-F 1-AI-Pyrd (3) 9 H HiPr 3-Cl 5-Cl 1-AI-Pyrd (3) 10 H HiPr 3-Me 5-Me 1-AI-Pyrd (3) 11 H HiPr 3-Cl 5-CONH₂     1-AI-Pyrd (3) 12 H HiPr 2-Me 5-CONH₂     1-AI-Pyrd (3) 13 H HiPr 3-Me 5-CONH₂     1-AI-Pyrd (3) 14 H HiPr 3-CONH₂     5-CONH₂     1-AI-Pyrd (3) 15 6-OH HiPr H H 1-AI-Pyrd (3) 16 6-OH HiPr 3-Cl H 1-AI-Pyrd (3) 17 6-OH HiPr 3-Me H 1-AI-Pyrd (3) 18 6-OH HiPr 3-CONH₂     H 1-AI-Pyrd (3) 19 H H Bu H H 1-AI-Pyrd (3) 20 H H Pn H H 1-AI-Pyrd (3) 21 H H Hx H H 1-AI-Pyrd (3) 22 H H CH₂OH H H 1-AI-Pyrd (3) 23 H H (CH₂)₂OH H H 1-AI-Pyrd (3) 24 6-OH H (CH₂)₂OH H H 1-AI-Pyrd (3) 25 H H (CH₂)₃OH H H 1-AI-Pyrd (3) 26 H H (CH₂)_FourOH H H 1-AI-Pyrd (3) 27 H H (CH₂)_FiveOH H H 1-AI-Pyrd (3) 28 H H (CH₂)₆OH H H 1-AI-Pyrd (3) 29 H H CH₂COOH H H 1-AI-Pyrd (3) 30 H H CH₂COOH 3-Cl H 1-AI-Pyrd (3) 31 H H CH₂COOH 3-Me H 1-AI-Pyrd (3) 32 H H CH₂COOH 3-CONH₂     H 1-AI-Pyrd (3) 33 H H CH₂COOH 3-F 5-F 1-AI-Pyrd (3) 34 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd (3) 35 H H CH₂COOH 3-Me 5-Me 1-AI-Pyrd (3) 36 H H CH₂COOH 3-Cl 5-CONH₂     1-AI-Pyrd (3) 37 H H CH₂COOH 2-Me 5-CONH₂     1-AI-Pyrd (3) 38 H H CH₂COOH 3-Me 5-CONH₂     1-AI-Pyrd (3) 39 H H CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pyrd (3) 40 6-OH H CH₂COOH H H 1-AI-Pyrd (3) 41 6-OH H CH₂COOH 3-Cl H 1-AI-Pyrd (3) 42 6-OH H CH₂COOH 3-Me H 1-AI-Pyrd (3) 43 6-OH H CH₂COOH 3-CONH₂     H 1-AI-Pyrd (3) 44 H H (CH₂)₂COOH H H 1-AI-Pyrd (3) 45 H H (CH₂)₃COOH H H 1-AI-Pyrd (3) 46 H H (CH₂)_FourCOOH H H 1-AI-Pyrd (3) 47 H H (CH₂)_FiveCOOH H H 1-AI-Pyrd (3) 48 H H (CH₂)₆COOH H H 1-AI-Pyrd (3) 49 H H CH₂COOMe H H 1-AI-Pyrd (3) 50 H H CH₂COOEt H H 1-AI-Pyrd (3) 51 H H CH₂COOEt 3-Cl H 1-AI-Pyrd (3) 52 H H CH₂COOEt 3-Me H 1-AI-Pyrd (3) 53 H H CH₂COOEt 3-CONH₂     H 1-AI-Pyrd (3) 54 H H CH₂COOEt 3-F 5-F 1-AI-Pyrd (3) 55 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd (3) 56 H H CH₂COOEt 3-Me 5-Me 1-AI-Pyrd (3) 57 H H CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pyrd (3) 58 H H CH₂COOEt 2-Me 5-CONH₂     1-AI-Pyrd (3) 59 H H CH₂COOEt 3-Me 5-CONH₂     1-AI-Pyrd (3) 60 H H CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pyrd (3) 61 6-OH H CH₂COOEt H H 1-AI-Pyrd (3) 62 6-OH H CH₂COOEt 3-Cl H 1-AI-Pyrd (3) 63 6-OH H CH₂COOEt 3-Me H 1-AI-Pyrd (3) 64 6-OH H CH₂COOEt 3-CONH₂     H 1-AI-Pyrd (3) 65 H H CH₂COOPr H H 1-AI-Pyrd (3) 66 H H CH₂COOBu H H 1-AI-Pyrd (3) 67 H H CH₂COOPn H H 1-AI-Pyrd (3) 68 H H CH₂COOHx H H 1-AI-Pyrd (3) 69 H H (CH₂)₂COOEt H H 1-AI-Pyrd (3) 70 H H (CH₂)₃COOMe H H 1-AI-Pyrd (3) 71 H H (CH₂)_FourCOOPr H H 1-AI-Pyrd (3) 72 H H (CH₂)_FiveCOOBu H H 1-AI-Pyrd (3) 73 H H (CH₂)₆COOHx H H 1-AI-Pyrd (3) 74 H H Bn H H 1-AI-Pyrd (3) 75 H H (CH₂)₂Ph H H 1-AI-Pyrd (3) 76 H H (CH₂)₃Ph H H 1-AI-Pyrd (3) 77 H H (CH₂)_FourPh H H 1-AI-Pyrd (3) 78 H H CHO H H 1-AI-Pyrd (3) 79 H H Ac H H 1-AI-Pyrd (3) 80 H H Prn H H 1-AI-Pyrd (3) 81 H H Va H H 1-AI-Pyrd (3) 82 H H SO₂Me H H 1-AI-Pyrd (3) 83 H H SO₂Et H H 1-AI-Pyrd (3) 84 6-OH H SO₂Et H H 1-AI-Pyrd (3) 85 H H SO₂Pr H H 1-AI-Pyrd (3) 86 H H SO₂Bu H H 1-AI-Pyrd (3) 87 H H SO₂Pn H H 1-AI-Pyrd (3) 88 H H SO₂Hx H H 1-AI-Pyrd (3) 89 H H SO₂CH₂COOMe H H 1-AI-Pyrd (3) 90 H H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 91 H H SO₂CH₂COOEt 3-F H 1-AI-Pyrd (3) 92 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pyrd (3) 93 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pyrd (3) 94 H H SO₂CH₂COOEt 2-Me H 1-AI-Pyrd (3) 95 H H SO₂CH₂COOEt 3-Me H 1-AI-Pyrd (3) 96 H H SO₂CH₂COOEt 3-Et H 1-AI-Pyrd (3) 97 H H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pyrd (3) 98 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pyrd (3) 99 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pyrd (3) 100 H H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pyrd (3) 101 H H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pyrd (3) 102 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pyrd (3) 103 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd (3) 104 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pyrd (3) 105 H H SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pyrd (3) 106 H H SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pyrd (3) 107 H H SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pyrd (3) 108 H H SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pyrd (3) 109 H F SO₂CH₂COOEt H H 1-AI-Pyrd (3) 110 H Cl SO₂CH₂COOEt H H 1-AI-Pyrd (3) 111 H Me SO₂CH₂COOEt H H 1-AI-Pyrd (3) 112 H Et SO₂CH₂COOEt H H 1-AI-Pyrd (3) 113 2-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 114 4-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 115 5-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 116 6-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 117 2-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 118 6-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 119 4-Me H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 120 6-Me H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 121 5-Et H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 122 6-Pr H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 123 2-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 124 4-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 125 5-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 126 6-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3) 127 H H SO₂CH₂COOPr H H 1-AI-Pyrd (3) 128 H H SO₂CH₂COOBu H H 1-AI-Pyrd (3) 129 H H SO₂CH₂COOPn H H 1-AI-Pyrd (3) 130 H H SO₂CH₂COOHx H H 1-AI-Pyrd (3) 131 H H SO₂(CH₂)₂COOMe H H 1-AI-Pyrd (3) 132 H H SO₂(CH₂)₂COOEt H H 1-AI-Pyrd (3) 133 H H SO₂(CH₂)₂COOPr H H 1-AI-Pyrd (3) 134 H H SO₂(CH₂)₂COOBu H H 1-AI-Pyrd (3) 135 H H SO₂(CH₂)₂COOPn H H 1-AI-Pyrd (3) 136 H H SO₂(CH₂)₂COOHx H H 1-AI-Pyrd (3) 137 H H SO₂CH₂COOH H H 1-AI-Pyrd (3) 138 H H SO₂CH₂COOH 3-F H 1-AI-Pyrd (3) 139 H H SO₂CH₂COOH 2-Cl H 1-AI-Pyrd (3) 140 H H SO₂CH₂COOH 3-Cl H 1-AI-Pyrd (3) 141 H H SO₂CH₂COOH 2-Me H 1-AI-Pyrd (3) 142 H H SO₂CH₂COOH 3-Me H 1-AI-Pyrd (3) 143 H H SO₂CH₂COOH 3-Et H 1-AI-Pyrd (3) 144 H H SO₂CH₂COOH 3-CF₃       H 1-AI-Pyrd (3) 145 H H SO₂CH₂COOH 2-OMe H 1-AI-Pyrd (3) 146 H H SO₂CH₂COOH 3-OEt H 1-AI-Pyrd (3) 147 H H SO₂CH₂COOH 2-CONH₂     H 1-AI-Pyrd (3) 148 H H SO₂CH₂COOH 3-CONH₂     H 1-AI-Pyrd (3) 149 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pyrd (3) 150 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd (3) 151 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pyrd (3) 152 H H SO₂CH₂COOH 3-Cl 5-CONH₂     1-AI-Pyrd (3) 153 H H SO₂CH₂COOH 2-Me 5-CONH₂     1-AI-Pyrd (3) 154 H H SO₂CH₂COOH 3-Me 5-CONH₂     1-AI-Pyrd (3) 155 H H SO₂CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pyrd (3) 156 H F SO₂CH₂COOH H H 1-AI-Pyrd (3) 157 H Cl SO₂CH₂COOH H H 1-AI-Pyrd (3) 158 H Me SO₂CH₂COOH H H 1-AI-Pyrd (3) 159 H Et SO₂CH₂COOH H H 1-AI-Pyrd (3) 160 2-F H SO₂CH₂COOH H H 1-AI-Pyrd (3) 161 4-F H SO₂CH₂COOH H H 1-AI-Pyrd (3) 162 5-F H SO₂CH₂COOH H H 1-AI-Pyrd (3) 163 6-F H SO₂CH₂COOH H H 1-AI-Pyrd (3) 164 2-Cl H SO₂CH₂COOH H H 1-AI-Pyrd (3) 165 6-Cl H SO₂CH₂COOH H H 1-AI-Pyrd (3) 166 4-Me H SO₂CH₂COOH H H 1-AI-Pyrd (3) 167 6-Me H SO₂CH₂COOH H H 1-AI-Pyrd (3) 168 5-Et H SO₂CH₂COOH H H 1-AI-Pyrd (3) 169 6-Pr H SO₂CH₂COOH H H 1-AI-Pyrd (3) 170 2-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3) 171 4-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3) 172 5-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3) 173 6-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3) 174 H H SO₂CH₂COOH H H 1-AI-Pyrd (3) 175 H H SO₂CH₂COOH H H 1-AI-Pyrd (3) 176 H H SO₂(CH₂)₂COOH H H 1-AI-Pyrd (3) 177 H H H H H 1-AI-Pip (4) 178 H H H 2-F H 1-AI-Pip (4) 179 H H H 3-F H 1-AI-Pip (4) 180 H H H 2-Cl H 1-AI-Pip (4) 181 H H H 3-Cl H 1-AI-Pip (4) 182 H H H 2-Br H 1-AI-Pip (4) 183 H H H 3-Br H 1-AI-Pip (4) 184 H H H 2-I H 1-AI-Pip (4) 185 H H H 3-I H 1-AI-Pip (4) 186 H H H 2-Me H 1-AI-Pip (4) 187 H H H 3-Me H 1-AI-Pip (4) 188 H H H 2-Et H 1-AI-Pip (4) 189 H H H 3-Et H 1-AI-Pip (4) 190 H H H 2-Pr H 1-AI-Pip (4) 191 H H H 3-Pr H 1-AI-Pip (4) 192 H H H 2-Bu H 1-AI-Pip (4) 193 H H H 3-Bu H 1-AI-Pip (4) 194 H H H 2-Pn H 1-AI-Pip (4) 195 H H H 3-Pn H 1-AI-Pip (4) 196 H H H 2-Hx H 1-AI-Pip (4) 197 H H H 3-Hx H 1-AI-Pip (4) 198 H H H 2-CF₃       H 1-AI-Pip (4) 199 H H H 3-CF₃       H 1-AI-Pip (4) 200 H H H 2-OMe H 1-AI-Pip (4) 201 H H H 3-OMe H 1-AI-Pip (4) 202 H H H 2-OEt H 1-AI-Pip (4) 203 H H H 3-OEt H 1-AI-Pip (4) 204 H H H 2-COOH H 1-AI-Pip (4) 205 H H H 3-COOH H 1-AI-Pip (4) 206 H H H 2-COOMe H 1-AI-Pip (4) 207 H H H 3-COOMe H 1-AI-Pip (4) 208 H H H 2-COOEt H 1-AI-Pip (4) 209 H H H 3-COOEt H 1-AI-Pip (4) 210 H H H 2-COOPr H 1-AI-Pip (4) 211 H H H 3-COOPr H 1-AI-Pip (4) 212 H H H 2-COOBu H 1-AI-Pip (4) 213 H H H 3-COOBu H 1-AI-Pip (4) 214 H H H 2-COOPn H 1-AI-Pip (4) 215 H H H 3-COOPn H 1-AI-Pip (4) 216 H H H 2-COOHx H 1-AI-Pip (4) 217 H H H 3-COOHx H 1-AI-Pip (4) 218 H H H 2-CONH₂     H 1-AI-Pip (4) 219 H H H 3-CONH₂     H 1-AI-Pip (4) 220 H H H 2-CONHMe H 1-AI-Pip (4) 221 H H H 3-CONHMe H 1-AI-Pip (4) 222 H H H 2-CONHEt H 1-AI-Pip (4) 223 H H H 3-CONHEt H 1-AI-Pip (4) 224 H H H 2-CON (Me)₂  H 1-AI-Pip (4) 225 H H H 3-CON (Me)₂  H 1-AI-Pip (4) 226 H H H 2-CON (Me) Et H 1-AI-Pip (4) 227 H H H 3-CON (Me) Et H 1-AI-Pip (4) 228 H H H 2-CON (Et)₂  H 1-AI-Pip (4) 229 H H H 3-CON (Et)₂  H 1-AI-Pip (4) 230 H H H 3-F 5-F 1-AI-Pip (4) 231 H H H 3-Cl 5-Cl 1-AI-Pip (4) 232 H H H 3-Me 5-Me 1-AI-Pip (4) 233 H H H 3-Cl 5-CONH₂     1-AI-Pip (4) 234 H H H 2-Me 5-CONH₂     1-AI-Pip (4) 235 H H H 3-Me 5-CONH₂     1-AI-Pip (4) 236 H H H 3-CONH₂     5-CONH₂     1-AI-Pip (4) 237 H H Me H H 1-AI-Pip (4) 238 H H Me 2-F H 1-AI-Pip (4) 239 H H Me 3-F H 1-AI-Pip (4) 240 H H Me 2-Cl H 1-AI-Pip (4) 241 H H Me 3-Cl H 1-AI-Pip (4) 242 H H Me 2-Br H 1-AI-Pip (4) 243 H H Me 3-Br H 1-AI-Pip (4) 244 H H Me 2-I H 1-AI-Pip (4) 245 H H Me 3-I H 1-AI-Pip (4) 246 H H Me 2-Me H 1-AI-Pip (4) 247 H H Me 3-Me H 1-AI-Pip (4) 248 H H Me 2-Et H 1-AI-Pip (4) 249 H H Me 3-Et H 1-AI-Pip (4) 250 H H Me 2-Pr H 1-AI-Pip (4) 251 H H Me 3-Pr H 1-AI-Pip (4) 252 H H Me 2-Bu H 1-AI-Pip (4) 253 H H Me 3-Bu H 1-AI-Pip (4) 254 H H Me 2-Pn H 1-AI-Pip (4) 255 H H Me 3-Pn H 1-AI-Pip (4) 256 H H Me 2-Hx H 1-AI-Pip (4) 257 H H Me 3-Hx H 1-AI-Pip (4) 258 H H Me 2-CF₃       H 1-AI-Pip (4) 259 H H Me 3-CF₃       H 1-AI-Pip (4) 260 H H Me 2-OMe H 1-AI-Pip (4) 261 H H Me 3-OMe H 1-AI-Pip (4) 262 H H Me 2-OEt H 1-AI-Pip (4) 263 H H Me 3-OEt H 1-AI-Pip (4) 264 H H Me 2-COOH H 1-AI-Pip (4) 265 H H Me 3-COOH H 1-AI-Pip (4) 266 H H Me 2-COOMe H 1-AI-Pip (4) 267 H H Me 3-COOMe H 1-AI-Pip (4) 268 H H Me 2-COOEt H 1-AI-Pip (4) 269 H H Me 3-COOEt H 1-AI-Pip (4) 270 H H Me 2-COOPr H 1-AI-Pip (4) 271 H H Me 3-COOPr H 1-AI-Pip (4) 272 H H Me 2-COOBu H 1-AI-Pip (4) 273 H H Me 3-COOBu H 1-AI-Pip (4) 274 H H Me 2-COOPn H 1-AI-Pip (4) 275 H H Me 3-COOPn H 1-AI-Pip (4) 276 H H Me 2-COOHx H 1-AI-Pip (4) 277 H H Me 3-COOHx H 1-AI-Pip (4) 278 H H Me 2-CONH₂     H 1-AI-Pip (4) 279 H H Me 3-CONH₂     H 1-AI-Pip (4) 280 H H Me 2-CONHMe H 1-AI-Pip (4) 281 H H Me 3-CONHMe H 1-AI-Pip (4) 282 H H Me 2-CONHEt H 1-AI-Pip (4) 283 H H Me 3-CONHEt H 1-AI-Pip (4) 284 H H Me 2-CON (Me)₂  H 1-AI-Pip (4) 285 H H Me 3-CON (Me)₂  H 1-AI-Pip (4) 286 H H Me 2-CON (Me) Et H 1-AI-Pip (4) 287 H H Me 3-CON (Me) Et H 1-AI-Pip (4) 288 H H Me 2-CON (Et)₂  H 1-AI-Pip (4) 289 H H Me 3-CON (Et)₂  H 1-AI-Pip (4) 290 H H Me 3-F 5-F 1-AI-Pip (4) 291 H H Me 3-Cl 5-Cl 1-AI-Pip (4) 292 H H Me 3-Me 5-Me 1-AI-Pip (4) 293 H H Me 3-Cl 5-CONH₂     1-AI-Pip (4) 294 H H Me 2-Me 5-CONH₂     1-AI-Pip (4) 295 H H Me 3-Me 5-CONH₂     1-AI-Pip (4) 296 H H Me 3-CONH₂     5-CONH₂     1-AI-Pip (4) 297 H H Et H H 1-AI-Pip (4) 298 H H Et 2-F H 1-AI-Pip (4) 299 H H Et 3-F H 1-AI-Pip (4) 300 H H Et 2-Cl H 1-AI-Pip (4) 301 H H Et 3-Cl H 1-AI-Pip (4) 302 H H Et 2-Br H 1-AI-Pip (4) 303 H H Et 3-Br H 1-AI-Pip (4) 304 H H Et 2-I H 1-AI-Pip (4) 305 H H Et 3-I H 1-AI-Pip (4) 306 H H Et 2-Me H 1-AI-Pip (4) 307 H H Et 3-Me H 1-AI-Pip (4) 308 H H Et 2-Et H 1-AI-Pip (4) 309 H H Et 3-Et H 1-AI-Pip (4) 310 H H Et 2-Pr H 1-AI-Pip (4) 311 H H Et 3-Pr H 1-AI-Pip (4) 312 H H Et 2-Bu H 1-AI-Pip (4) 313 H H Et 3-Bu H 1-AI-Pip (4) 314 H H Et 2-Pn H 1-AI-Pip (4) 315 H H Et 3-Pn H 1-AI-Pip (4) 316 H H Et 2-Hx H 1-AI-Pip (4) 317 H H Et 3-Hx H 1-AI-Pip (4) 318 H H Et 2-CF₃       H 1-AI-Pip (4) 319 H H Et 3-CF₃       H 1-AI-Pip (4) 320 H H Et 2-OMe H 1-AI-Pip (4) 321 H H Et 3-OMe H 1-AI-Pip (4) 322 H H Et 2-OEt H 1-AI-Pip (4) 323 H H Et 3-OEt H 1-AI-Pip (4) 324 H H Et 2-COOH H 1-AI-Pip (4) 325 H H Et 3-COOH H 1-AI-Pip (4) 326 H H Et 2-COOMe H 1-AI-Pip (4) 327 H H Et 3-COOMe H 1-AI-Pip (4) 328 H H Et 2-COOEt H 1-AI-Pip (4) 329 H H Et 3-COOEt H 1-AI-Pip (4) 330 H H Et 2-COOPr H 1-AI-Pip (4) 331 H H Et 3-COOPr H 1-AI-Pip (4) 332 H H Et 2-COOBu H 1-AI-Pip (4) 333 H H Et 3-COOBu H 1-AI-Pip (4) 334 H H Et 2-COOPn H 1-AI-Pip (4) 335 H H Et 3-COOPn H 1-AI-Pip (4) 336 H H Et 2-COOHx H 1-AI-Pip (4) 337 H H Et 3-COOHx H 1-AI-Pip (4) 338 H H Et 2-CONH₂     H 1-AI-Pip (4) 339 H H Et 3-CONH₂     H 1-AI-Pip (4) 340 H H Et 2-CONHMe H 1-AI-Pip (4) 341 H H Et 3-CONHMe H 1-AI-Pip (4) 342 H H Et 2-CONHEt H 1-AI-Pip (4) 343 H H Et 3-CONHEt H 1-AI-Pip (4) 344 H H Et 2-CON (Me)₂  H 1-AI-Pip (4) 345 H H Et 3-CON (Me)₂  H 1-AI-Pip (4) 346 H H Et 2-CON (Me) Et H 1-AI-Pip (4) 347 H H Et 3-CON (Me) Et H 1-AI-Pip (4) 348 H H Et 2-CON (Et)₂  H 1-AI-Pip (4) 349 H H Et 3-CON (Et)₂  H 1-AI-Pip (4) 350 H H Et 3-F 5-F 1-AI-Pip (4) 351 H H Et 3-Cl 5-Cl 1-AI-Pip (4) 352 H H Et 3-Me 5-Me 1-AI-Pip (4) 353 H H Et 3-Cl 5-CONH₂     1-AI-Pip (4) 354 H H Et 2-Me 5-CONH₂     1-AI-Pip (4) 355 H H Et 3-Me 5-CONH₂     1-AI-Pip (4) 356 H H Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 357 H H Pr H H 1-AI-Pip (4) 358 H HiPr H H 1-AI-Pip (4) 359 H HiPr 2-F H 1-AI-Pip (4) 360 H HiPr 3-F H 1-AI-Pip (4) 361 H HiPr 2-Cl H 1-AI-Pip (4) 362 H HiPr 3-Cl H 1-AI-Pip (4) 363 H HiPr 2-Br H 1-AI-Pip (4) 364 H HiPr 3-Br H 1-AI-Pip (4) 365 H HiPr 2-I H 1-AI-Pip (4) 366 H HiPr 3-I H 1-AI-Pip (4) 367 H HiPr 2-Me H 1-AI-Pip (4) 368 H HiPr 3-Me H 1-AI-Pip (4) 369 H HiPr 2-Et H 1-AI-Pip (4) 370 H HiPr 3-Et H 1-AI-Pip (4) 371 H HiPr 2-Pr H 1-AI-Pip (4) 372 H HiPr 3-Pr H 1-AI-Pip (4) 373 H HiPr 2-Bu H 1-AI-Pip (4) 374 H HiPr 3-Bu H 1-AI-Pip (4) 375 H HiPr 2-Pn H 1-AI-Pip (4) 376 H HiPr 3-Pn H 1-AI-Pip (4) 377 H HiPr 2-Hx H 1-AI-Pip (4) 378 H HiPr 3-Hx H 1-AI-Pip (4) 379 H HiPr 2-CF₃       H 1-AI-Pip (4) 380 H HiPr 3-CF₃       H 1-AI-Pip (4) 381 H HiPr 2-OMe H 1-AI-Pip (4) 382 H HiPr 3-OMe H 1-AI-Pip (4) 383 H HiPr 2-OEt H 1-AI-Pip (4) 384 H HiPr 3-OEt H 1-AI-Pip (4) 385 H HiPr 2-COOH H 1-AI-Pip (4) 386 H HiPr 3-COOH H 1-AI-Pip (4) 387 H HiPr 2-COOMe H 1-AI-Pip (4) 388 H HiPr 3-COOMe H 1-AI-Pip (4) 389 H HiPr 2-COOEt H 1-AI-Pip (4) 390 H HiPr 3-COOEt H 1-AI-Pip (4) 391 H HiPr 2-COOPr H 1-AI-Pip (4) 392 H HiPr 3-COOPr H 1-AI-Pip (4) 393 H HiPr 2-COOBu H 1-AI-Pip (4) 394 H HiPr 3-COOBu H 1-AI-Pip (4) 395 H HiPr 2-COOPn H 1-AI-Pip (4) 396 H HiPr 3-COOPn H 1-AI-Pip (4) 397 H HiPr 2-COOHx H 1-AI-Pip (4) 398 H HiPr 3-COOHx H 1-AI-Pip (4) 399 H HiPr 2-CONH₂     H 1-AI-Pip (4) 400 H HiPr 3-CONH₂     H 1-AI-Pip (4) 401 H HiPr 2-CONHMe H 1-AI-Pip (4) 402 H HiPr 3-CONHMe H 1-AI-Pip (4) 403 H HiPr 2-CONHEt H 1-AI-Pip (4) 404 H HiPr 3-CONHEt H 1-AI-Pip (4) 405 H HiPr 2-CON (Me)₂  H 1-AI-Pip (4) 406 H HiPr 3-CON (Me)₂  H 1-AI-Pip (4) 407 H HiPr 2-CON (Me) Et H 1-AI-Pip (4) 408 H HiPr 3-CON (Me) Et H 1-AI-Pip (4) 409 H HiPr 2-CON (Et)₂  H 1-AI-Pip (4) 410 H HiPr 3-CON (Et)₂  H 1-AI-Pip (4) 411 H HiPr 3-F 5-F 1-AI-Pip (4) 412 H HiPr 3-Cl 5-Cl 1-AI-Pip (4) 413 H HiPr 3-Me 5-Me 1-AI-Pip (4) 414 H HiPr 3-Cl 5-CONH₂     1-AI-Pip (4) 415 H HiPr 2-Me 5-CONH₂     1-AI-Pip (4) 416 H HiPr 3-Me 5-CONH₂     1-AI-Pip (4) 417 H HiPr 3-CONH₂     5-CONH₂     1-AI-Pip (4) 418 6-OH HiPr H H 1-AI-Pip (4) 419 6-OH HiPr 2-F H 1-AI-Pip (4) 420 6-OH HiPr 3-F H 1-AI-Pip (4) 421 6-OH HiPr 2-Cl H 1-AI-Pip (4) 422 6-OH HiPr 3-Cl H 1-AI-Pip (4) 423 6-OH HiPr 2-Br H 1-AI-Pip (4) 424 6-OH HiPr 3-Br H 1-AI-Pip (4) 425 6-OH HiPr 2-I H 1-AI-Pip (4) 426 6-OH HiPr 3-I H 1-AI-Pip (4) 427 6-OH HiPr 2-Me H 1-AI-Pip (4) 428 6-OH HiPr 3-Me H 1-AI-Pip (4) 429 6-OH HiPr 2-Et H 1-AI-Pip (4) 430 6-OH HiPr 3-Et H 1-AI-Pip (4) 431 6-OH HiPr 2-Pr H 1-AI-Pip (4) 432 6-OH HiPr 3-Pr H 1-AI-Pip (4) 433 6-OH HiPr 2-Bu H 1-AI-Pip (4) 434 6-OH HiPr 3-Bu H 1-AI-Pip (4) 435 6-OH HiPr 2-Pn H 1-AI-Pip (4) 436 6-OH HiPr 3-Pn H 1-AI-Pip (4) 437 6-OH HiPr 2-Hx H 1-AI-Pip (4) 438 6-OH HiPr 3-Hx H 1-AI-Pip (4) 439 6-OH HiPr 2-CF₃       H 1-AI-Pip (4) 440 6-OH HiPr 3-CF₃       H 1-AI-Pip (4) 441 6-OH HiPr 2-OMe H 1-AI-Pip (4) 442 6-OH HiPr 3-OMe H 1-AI-Pip (4) 443 6-OH HiPr 2-OEt H 1-AI-Pip (4) 444 6-OH HiPr 3-OEt H 1-AI-Pip (4) 445 6-OH HiPr 2-COOH H 1-AI-Pip (4) 446 6-OH HiPr 3-COOH H 1-AI-Pip (4) 447 6-OH HiPr 2-COOMe H 1-AI-Pip (4) 448 6-OH HiPr 3-COOMe H 1-AI-Pip (4) 449 6-OH HiPr 2-COOEt H 1-AI-Pip (4) 450 6-OH HiPr 3-COOEt H 1-AI-Pip (4) 451 6-OH HiPr 2-COOPr H 1-AI-Pip (4) 452 6-OH HiPr 3-COOPr H 1-AI-Pip (4) 453 6-OH HiPr 2-COOBu H 1-AI-Pip (4) 454 6-OH HiPr 3-COOBu H 1-AI-Pip (4) 455 6-OH HiPr 2-COOPn H 1-AI-Pip (4) 456 6-OH HiPr 3-COOPn H 1-AI-Pip (4) 457 6-OH HiPr 2-COOHx H 1-AI-Pip (4) 458 6-OH HiPr 3-COOHx H 1-AI-Pip (4) 459 6-OH HiPr 2-CONH₂     H 1-AI-Pip (4) 460 6-OH HiPr 3-CONH₂     H 1-AI-Pip (4) 461 6-OH HiPr 2-CONHMe H 1-AI-Pip (4) 462 6-OH HiPr 3-CONHMe H 1-AI-Pip (4) 463 6-OH HiPr 2-CONHEt H 1-AI-Pip (4) 464 6-OH HiPr 3-CONHEt H 1-AI-Pip (4) 465 6-OH HiPr 2-CON (Me)₂  H 1-AI-Pip (4) 466 6-OH HiPr 3-CON (Me)₂  H 1-AI-Pip (4) 467 6-OH HiPr 2-CON (Me) Et H 1-AI-Pip (4) 468 6-OH HiPr 3-CON (Me) Et H 1-AI-Pip (4) 469 6-OH HiPr 2-CON (Et)₂  H 1-AI-Pip (4) 470 6-OH HiPr 3-CON (Et)₂  H 1-AI-Pip (4) 471 H H Bu H H 1-AI-Pip (4) 472 H HiBu H H 1-AI-Pip (4) 473 H HsBu H H 1-AI-Pip (4) 474 H HtBu H H 1-AI-Pip (4) 475 H H Pn H H 1-AI-Pip (4) 476 H H Hx H H 1-AI-Pip (4) 477 H H CH₂OH H H 1-AI-Pip (4) 478 H H (CH₂)₂OH H H 1-AI-Pip (4) 479 H H (CH₂)₂OH 2-F H 1-AI-Pip (4) 480 H H (CH₂)₂OH 3-F H 1-AI-Pip (4) 481 H H (CH₂)₂OH 2-Cl H 1-AI-Pip (4) 482 H H (CH₂)₂OH 3-Cl H 1-AI-Pip (4) 483 H H (CH₂)₂OH 2-Br H 1-AI-Pip (4) 484 H H (CH₂)₂OH 3-Br H 1-AI-Pip (4) 485 H H (CH₂)₂OH 2-I H 1-AI-Pip (4) 486 H H (CH₂)₂OH 3-I H 1-AI-Pip (4) 487 H H (CH₂)₂OH 2-Me H 1-AI-Pip (4) 488 H H (CH₂)₂OH 3-Me H 1-AI-Pip (4) 489 H H (CH₂)₂OH 2-Et H 1-AI-Pip (4) 490 H H (CH₂)₂OH 3-Et H 1-AI-Pip (4) 491 H H (CH₂)₂OH 2-Pr H 1-AI-Pip (4) 492 H H (CH₂)₂OH 3-Pr H 1-AI-Pip (4) 493 H H (CH₂)₂OH 2-Bu H 1-AI-Pip (4) 494 H H (CH₂)₂OH 3-Bu H 1-AI-Pip (4) 495 H H (CH₂)₂OH 2-Pn H 1-AI-Pip (4) 496 H H (CH₂)₂OH 3-Pn H 1-AI-Pip (4) 497 H H (CH₂)₂OH 2-Hx H 1-AI-Pip (4) 498 H H (CH₂)₂OH 3-Hx H 1-AI-Pip (4) 499 H H (CH₂)₂OH 2-CF₃       H 1-AI-Pip (4) 500 H H (CH₂)₂OH 3-CF₃       H 1-AI-Pip (4) 501 H H (CH₂)₂OH 2-OMe H 1-AI-Pip (4) 502 H H (CH₂)₂OH 3-OMe H 1-AI-Pip (4) 503 H H (CH₂)₂OH 2-OEt H 1-AI-Pip (4) 504 H H (CH₂)₂OH 3-OEt H 1-AI-Pip (4) 505 H H (CH₂)₂OH 2-COOH H 1-AI-Pip (4) 506 H H (CH₂)₂OH 3-COOH H 1-AI-Pip (4) 507 H H (CH₂)₂OH 2-COOMe H 1-AI-Pip (4) 508 H H (CH₂)₂OH 3-COOMe H 1-AI-Pip (4) 509 H H (CH₂)₂OH 2-COOEt H 1-AI-Pip (4) 510 H H (CH₂)₂OH 3-COOEt H 1-AI-Pip (4) 511 H H (CH₂)₂OH 2-COOPr H 1-AI-Pip (4) 512 H H (CH₂)₂OH 3-COOPr H 1-AI-Pip (4) 513 H H (CH₂)₂OH 2-COOBu H 1-AI-Pip (4) 514 H H (CH₂)₂OH 3-COOBu H 1-AI-Pip (4) 515 H H (CH₂)₂OH 2-COOPn H 1-AI-Pip (4) 516 H H (CH₂)₂OH 3-COOPn H 1-AI-Pip (4) 517 H H (CH₂)₂OH 2-COOHx H 1-AI-Pip (4) 518 H H (CH₂)₂OH 3-COOHx H 1-AI-Pip (4) 519 H H (CH₂)₂OH 2-CONH₂     H 1-AI-Pip (4) 520 H H (CH₂)₂OH 3-CONH₂     H 1-AI-Pip (4) 521 H H (CH₂)₂OH 2-CONHMe H 1-AI-Pip (4) 522 H H (CH₂)₂OH 3-CONHMe H 1-AI-Pip (4) 523 H H (CH₂)₂OH 2-CONHEt H 1-AI-Pip (4) 524 H H (CH₂)₂OH 3-CONHEt H 1-AI-Pip (4) 525 H H (CH₂)₂OH 2-CON (Me)₂  H 1-AI-Pip (4) 526 H H (CH₂)₂OH 3-CON (Me)₂  H 1-AI-Pip (4) 527 H H (CH₂)₂OH 2-CON (Me) Et H 1-AI-Pip (4) 528 H H (CH₂)₂OH 3-CON (Me) Et H 1-AI-Pip (4) 529 H H (CH₂)₂OH 2-CON (Et)₂  H 1-AI-Pip (4) 530 H H (CH₂)₂OH 3-CON (Et)₂  H 1-AI-Pip (4) 531 H H (CH₂)₂OH 3-F 5-F 1-AI-Pip (4) 532 H H (CH₂)₂OH 3-Cl 5-Cl 1-AI-Pip (4) 533 H H (CH₂)₂OH 3-Me 5-Me 1-AI-Pip (4) 534 H H (CH₂)₂OH 3-Cl 5-CONH₂     1-AI-Pip (4) 535 H H (CH₂)₂OH 2-Me 5-CONH₂     1-AI-Pip (4) 536 H H (CH₂)₂OH 3-Me 5-CONH₂     1-AI-Pip (4) 537 H H (CH₂)₂OH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 538 H H (CH₂)₃OH H H 1-AI-Pip (4) 539 H H (CH₂)_FourOH H H 1-AI-Pip (4) 540 H H (CH₂)_FiveOH H H 1-AI-Pip (4) 541 H H (CH₂)₆OH H H 1-AI-Pip (4) 542 H H CH₂COOH H H 1-AI-Pip (4) 543 H H CH₂COOH 2-F H 1-AI-Pip (4) 544 H H CH₂COOH 3-F H 1-AI-Pip (4) 545 H H CH₂COOH 2-Cl H 1-AI-Pip (4) 546 H H CH₂COOH 3-Cl H 1-AI-Pip (4) 547 H H CH₂COOH 2-Br H 1-AI-Pip (4) 548 H H CH₂COOH 3-Br H 1-AI-Pip (4) 549 H H CH₂COOH 2-I H 1-AI-Pip (4) 550 H H CH₂COOH 3-I H 1-AI-Pip (4) 551 H H CH₂COOH 2-Me H 1-AI-Pip (4) 552 H H CH₂COOH 3-Me H 1-AI-Pip (4) 553 H H CH₂COOH 2-Et H 1-AI-Pip (4) 554 H H CH₂COOH 3-Et H 1-AI-Pip (4) 555 H H CH₂COOH 2-Pr H 1-AI-Pip (4) 556 H H CH₂COOH 3-Pr H 1-AI-Pip (4) 557 H H CH₂COOH 2-Bu H 1-AI-Pip (4) 558 H H CH₂COOH 3-Bu H 1-AI-Pip (4) 559 H H CH₂COOH 2-Pn H 1-AI-Pip (4) 560 H H CH₂COOH 3-Pn H 1-AI-Pip (4) 561 H H CH₂COOH 2-Hx H 1-AI-Pip (4) 562 H H CH₂COOH 3-Hx H 1-AI-Pip (4) 563 H H CH₂COOH 2-CF₃       H 1-AI-Pip (4) 564 H H CH₂COOH 3-CF₃       H 1-AI-Pip (4) 565 H H CH₂COOH 2-OMe H 1-AI-Pip (4) 566 H H CH₂COOH 3-OMe H 1-AI-Pip (4) 567 H H CH₂COOH 2-OEt H 1-AI-Pip (4) 568 H H CH₂COOH 3-OEt H 1-AI-Pip (4) 569 H H CH₂COOH 2-COOH H 1-AI-Pip (4) 570 H H CH₂COOH 3-COOH H 1-AI-Pip (4) 571 H H CH₂COOH 2-COOMe H 1-AI-Pip (4) 572 H H CH₂COOH 3-COOMe H 1-AI-Pip (4) 573 H H CH₂COOH 2-COOEt H 1-AI-Pip (4) 574 H H CH₂COOH 3-COOEt H 1-AI-Pip (4) 575 H H CH₂COOH 2-COOPr H 1-AI-Pip (4) 576 H H CH₂COOH 3-COOPr H 1-AI-Pip (4) 577 H H CH₂COOH 2-COOBu H 1-AI-Pip (4) 578 H H CH₂COOH 3-COOBu H 1-AI-Pip (4) 579 H H CH₂COOH 2-COOPn H 1-AI-Pip (4) 580 H H CH₂COOH 3-COOPn H 1-AI-Pip (4) 581 H H CH₂COOH 2-COOHx H 1-AI-Pip (4) 582 H H CH₂COOH 3-COOHx H 1-AI-Pip (4) 583 H H CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 584 H H CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 585 H H CH₂COOH 2-CONHMe H 1-AI-Pip (4) 586 H H CH₂COOH 3-CONHMe H 1-AI-Pip (4) 587 H H CH₂COOH 2-CONHEt H 1-AI-Pip (4) 588 H H CH₂COOH 3-CONHEt H 1-AI-Pip (4) 589 H H CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 590 H H CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 591 H H CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 592 H H CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 593 H H CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 594 H H CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 595 H H CH₂COOH 3-F 5-F 1-AI-Pip (4) 596 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4) 597 H H CH₂COOH 3-Me 5-Me 1-AI-Pip (4) 598 H H CH₂COOH 3-Cl 5-CONH₂     1-AI-Pip (4) 599 H H CH₂COOH 2-Me 5-CONH₂     1-AI-Pip (4) 600 H H CH₂COOH 3-Me 5-CONH₂     1-AI-Pip (4) 601 H H CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 602 6-OH H CH₂COOH H H 1-AI-Pip (4) 603 6-OH H CH₂COOH 2-F H 1-AI-Pip (4) 604 6-OH H CH₂COOH 3-F H 1-AI-Pip (4) 605 6-OH H CH₂COOH 2-Cl H 1-AI-Pip (4) 606 6-OH H CH₂COOH 3-Cl H 1-AI-Pip (4) 607 6-OH H CH₂COOH 2-Br H 1-AI-Pip (4) 608 6-OH H CH₂COOH 3-Br H 1-AI-Pip (4) 609 6-OH H CH₂COOH 2-I H 1-AI-Pip (4) 610 6-OH H CH₂COOH 3-I H 1-AI-Pip (4) 611 6-OH H CH₂COOH 2-Me H 1-AI-Pip (4) 612 6-OH H CH₂COOH 3-Me H 1-AI-Pip (4) 613 6-OH H CH₂COOH 2-Et H 1-AI-Pip (4) 614 6-OH H CH₂COOH 3-Et H 1-AI-Pip (4) 615 6-OH H CH₂COOH 2-Pr H 1-AI-Pip (4) 616 6-OH H CH₂COOH 3-Pr H 1-AI-Pip (4) 617 6-OH H CH₂COOH 2-Bu H 1-AI-Pip (4) 618 6-OH H CH₂COOH 3-Bu H 1-AI-Pip (4) 619 6-OH H CH₂COOH 2-Pn H 1-AI-Pip (4) 620 6-OH H CH₂COOH 3-Pn H 1-AI-Pip (4) 621 6-OH H CH₂COOH 2-Hx H 1-AI-Pip (4) 622 6-OH H CH₂COOH 3-Hx H 1-AI-Pip (4) 623 6-OH H CH₂COOH 2-CF₃       H 1-AI-Pip (4) 624 6-OH H CH₂COOH 3-CF₃       H 1-AI-Pip (4) 625 6-OH H CH₂COOH 2-OMe H 1-AI-Pip (4) 626 6-OH H CH₂COOH 3-OMe H 1-AI-Pip (4) 627 6-OH H CH₂COOH 2-OEt H 1-AI-Pip (4) 628 6-OH H CH₂COOH 3-OEt H 1-AI-Pip (4) 629 6-OH H CH₂COOH 2-COOH H 1-AI-Pip (4) 630 6-OH H CH₂COOH 3-COOH H 1-AI-Pip (4) 631 6-OH H CH₂COOH 2-COOMe H 1-AI-Pip (4) 632 6-OH H CH₂COOH 3-COOMe H 1-AI-Pip (4) 633 6-OH H CH₂COOH 2-COOEt H 1-AI-Pip (4) 634 6-OH H CH₂COOH 3-COOEt H 1-AI-Pip (4) 635 6-OH H CH₂COOH 2-COOPr H 1-AI-Pip (4) 636 6-OH H CH₂COOH 3-COOPr H 1-AI-Pip (4) 637 6-OH H CH₂COOH 2-COOBu H 1-AI-Pip (4) 638 6-OH H CH₂COOH 3-COOBu H 1-AI-Pip (4) 639 6-OH H CH₂COOH 2-COOPn H 1-AI-Pip (4) 640 6-OH H CH₂COOH 3-COOPn H 1-AI-Pip (4) 641 6-OH H CH₂COOH 2-COOHx H 1-AI-Pip (4) 642 6-OH H CH₂COOH 3-COOHx H 1-AI-Pip (4) 643 6-OH H CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 644 6-OH H CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 645 6-OH H CH₂COOH 2-CONHMe H 1-AI-Pip (4) 646 6-OH H CH₂COOH 3-CONHMe H 1-AI-Pip (4) 647 6-OH H CH₂COOH 2-CONHEt H 1-AI-Pip (4) 648 6-OH H CH₂COOH 3-CONHEt H 1-AI-Pip (4) 649 6-OH H CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 650 6-OH H CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 651 6-OH H CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 652 6-OH H CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 653 6-OH H CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 654 6-OH H CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 655 6-OH H CH₂COOH 3-F 5-F 1-AI-Pip (4) 656 6-OH H CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4) 657 6-OH H CH₂COOH 3-Me 5-Me 1-AI-Pip (4) 658 6-OH H CH₂COOH 3-Cl 5-CONH₂     1-AI-Pip (4) 659 6-OH H CH₂COOH 2-Me 5-CONH₂     1-AI-Pip (4) 660 6-OH H CH₂COOH 3-Me 5-CONH₂     1-AI-Pip (4) 661 6-OH H CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 662 H H (CH₂)₂COOH H H 1-AI-Pip (4) 663 H H (CH₂) 3COOH H H 1-AI-Pip (4) 664 H H (CH₂)_FourCOOH H H 1-AI-Pip (4) 665 H H (CH₂)_FiveCOOH H H 1-AI-Pip (4) 666 H H (CH₂)₆COOH H H 1-AI-Pip (4) 667 H H CH₂COOMe H H 1-AI-Pip (4) 668 H H CH₂COOEt H H 1-AI-Pip (4) 669 H H CH₂COOEt 2-F H 1-AI-Pip (4) 670 H H CH₂COOEt 3-F H 1-AI-Pip (4) 671 H H CH₂COOEt 2-Cl H 1-AI-Pip (4) 672 H H CH₂COOEt 3-Cl H 1-AI-Pip (4) 673 H H CH₂COOEt 2-Br H 1-AI-Pip (4) 674 H H CH₂COOEt 3-Br H 1-AI-Pip (4) 675 H H CH₂COOEt 2-I H 1-AI-Pip (4) 676 H H CH₂COOEt 3-I H 1-AI-Pip (4) 677 H H CH₂COOEt 2-Me H 1-AI-Pip (4) 678 H H CH₂COOEt 3-Me H 1-AI-Pip (4) 679 H H CH₂COOEt 2-Et H 1-AI-Pip (4) 680 H H CH₂COOEt 3-Et H 1-AI-Pip (4) 681 H H CH₂COOEt 2-Pr H 1-AI-Pip (4) 682 H H CH₂COOEt 3-Pr H 1-AI-Pip (4) 683 H H CH₂COOEt 2-Bu H 1-AI-Pip (4) 684 H H CH₂COOEt 3-Bu H 1-AI-Pip (4) 685 H H CH₂COOEt 2-Pn H 1-AI-Pip (4) 686 H H CH₂COOEt 3-Pn H 1-AI-Pip (4) 687 H H CH₂COOEt 2-Hx H 1-AI-Pip (4) 688 H H CH₂COOEt 3-Hx H 1-AI-Pip (4) 689 H H CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 690 H H CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 691 H H CH₂COOEt 2-OMe H 1-AI-Pip (4) 692 H H CH₂COOEt 3-OMe H 1-AI-Pip (4) 693 H H CH₂COOEt 2-OEt H 1-AI-Pip (4) 694 H H CH₂COOEt 3-OEt H 1-AI-Pip (4) 695 H H CH₂COOEt 2-COOH H 1-AI-Pip (4) 696 H H CH₂COOEt 3-COOH H 1-AI-Pip (4) 697 H H CH₂COOEt 2-COOMe H 1-AI-Pip (4) 698 H H CH₂COOEt 3-COOMe H 1-AI-Pip (4) 699 H H CH₂COOEt 2-COOEt H 1-AI-Pip (4) 700 H H CH₂COOEt 3-COOEt H 1-AI-Pip (4) 701 H H CH₂COOEt 2-COOPr H 1-AI-Pip (4) 702 H H CH₂COOEt 3-COOPr H 1-AI-Pip (4) 703 H H CH₂COOEt 2-COOBu H 1-AI-Pip (4) 704 H H CH₂COOEt 3-COOBu H 1-AI-Pip (4) 705 H H CH₂COOEt 2-COOPn H 1-AI-Pip (4) 706 H H CH₂COOEt 3-COOPn H 1-AI-Pip (4) 707 H H CH₂COOEt 2-COOHx H 1-AI-Pip (4) 708 H H CH₂COOEt 3-COOHx H 1-AI-Pip (4) 709 H H CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 710 H H CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 711 H H CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 712 H H CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 713 H H CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 714 H H CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 715 H H CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 716 H H CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 717 H H CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 718 H H CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 719 H H CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 720 H H CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 721 H H CH₂COOEt 3-F 5-F 1-AI-Pip (4) 722 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 723 H H CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 724 H H CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 725 H H CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 726 H H CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 727 H H CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 728 6-OH H CH₂COOEt H H 1-AI-Pip (4) 729 6-OH H CH₂COOEt 2-F H 1-AI-Pip (4) 730 6-OH H CH₂COOEt 3-F H 1-AI-Pip (4) 731 6-OH H CH₂COOEt 2-Cl H 1-AI-Pip (4) 732 6-OH H CH₂COOEt 3-Cl H 1-AI-Pip (4) 733 6-OH H CH₂COOEt 2-Br H 1-AI-Pip (4) 734 6-OH H CH₂COOEt 3-Br H 1-AI-Pip (4) 735 6-OH H CH₂COOEt 2-I H 1-AI-Pip (4) 736 6-OH H CH₂COOEt 3-I H 1-AI-Pip (4) 737 6-OH H CH₂COOEt 2-Me H 1-AI-Pip (4) 738 6-OH H CH₂COOEt 3-Me H 1-AI-Pip (4) 739 6-OH H CH₂COOEt 2-Et H 1-AI-Pip (4) 740 6-OH H CH₂COOEt 3-Et H 1-AI-Pip (4) 741 6-OH H CH₂COOEt 2-Pr H 1-AI-Pip (4) 742 6-OH H CH₂COOEt 3-Pr H 1-AI-Pip (4) 743 6-OH H CH₂COOEt 2-Bu H 1-AI-Pip (4) 744 6-OH H CH₂COOEt 3-Bu H 1-AI-Pip (4) 745 6-OH H CH₂COOEt 2-Pn H 1-AI-Pip (4) 746 6-OH H CH₂COOEt 3-Pn H 1-AI-Pip (4) 747 6-OH H CH₂COOEt 2-Hx H 1-AI-Pip (4) 748 6-OH H CH₂COOEt 3-Hx H 1-AI-Pip (4) 749 6-OH H CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 750 6-OH H CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 751 6-OH H CH₂COOEt 2-OMe H 1-AI-Pip (4) 752 6-OH H CH₂COOEt 3-OMe H 1-AI-Pip (4) 753 6-OH H CH₂COOEt 2-OEt H 1-AI-Pip (4) 754 6-OH H CH₂COOEt 3-OEt H 1-AI-Pip (4) 755 6-OH H CH₂COOEt 2-COOH H 1-AI-Pip (4) 756 6-OH H CH₂COOEt 3-COOH H 1-AI-Pip (4) 757 6-OH H CH₂COOEt 2-COOMe H 1-AI-Pip (4) 758 6-OH H CH₂COOEt 3-COOMe H 1-AI-Pip (4) 759 6-OH H CH₂COOEt 2-COOEt H 1-AI-Pip (4) 760 6-OH H CH₂COOEt 3-COOEt H 1-AI-Pip (4) 761 6-OH H CH₂COOEt 2-COOPr H 1-AI-Pip (4) 762 6-OH H CH₂COOEt 3-COOPr H 1-AI-Pip (4) 763 6-OH H CH₂COOEt 2-COOBu H 1-AI-Pip (4) 764 6-OH H CH₂COOEt 3-COOBu H 1-AI-Pip (4) 765 6-OH H CH₂COOEt 2-COOPn H 1-AI-Pip (4) 766 6-OH H CH₂COOEt 3-COOPn H 1-AI-Pip (4) 767 6-OH H CH₂COOEt 2-COOHx H 1-AI-Pip (4) 768 6-OH H CH₂COOEt 3-COOHx H 1-AI-Pip (4) 769 6-OH H CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 770 6-OH H CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 771 6-OH H CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 772 6-OH H CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 773 6-OH H CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 774 6-OH H CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 775 6-OH H CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 776 6-OH H CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 777 6-OH H CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 778 6-OH H CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 779 6-OH H CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 780 6-OH H CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 781 6-OH H CH₂COOEt 3-F 5-F 1-AI-Pip (4) 782 6-OH H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 783 6-OH H CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 784 6-OH H CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 785 6-OH H CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 786 6-OH H CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 787 6-OH H CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 788 H H CH (CH₃) COOEt H H 1-AI-Pip (4) 789 H H CH (CH₃) COOEt 2-F H 1-AI-Pip (4) 790 H H CH (CH₃) COOEt 3-F H 1-AI-Pip (4) 791 H H CH (CH₃) COOEt 2-Cl H 1-AI-Pip (4) 792 H H CH (CH₃) COOEt 3-Cl H 1-AI-Pip (4) 793 H H CH (CH₃) COOEt 2-Br H 1-AI-Pip (4) 794 H H CH (CH₃) COOEt 3-Br H 1-AI-Pip (4) 795 H H CH (CH₃) COOEt 2-I H 1-AI-Pip (4) 796 H H CH (CH₃) COOEt 3-I H 1-AI-Pip (4) 797 H H CH (CH₃) COOEt 2-Me H 1-AI-Pip (4) 798 H H CH (CH₃) COOEt 3-Me H 1-AI-Pip (4) 799 H H CH (CH₃) COOEt 2-Et H 1-AI-Pip (4) 800 H H CH (CH₃) COOEt 3-Et H 1-AI-Pip (4) 801 H H CH (CH₃) COOEt 2-Pr H 1-AI-Pip (4) 802 H H CH (CH₃) COOEt 3-Pr H 1-AI-Pip (4) 803 H H CH (CH₃) COOEt 2-Bu H 1-AI-Pip (4) 804 H H CH (CH₃) COOEt 3-Bu H 1-AI-Pip (4) 805 H H CH (CH₃) COOEt 2-Pn H 1-AI-Pip (4) 806 H H CH (CH₃) COOEt 3-Pn H 1-AI-Pip (4) 807 H H CH (CH₃) COOEt 2-Hx H 1-AI-Pip (4) 808 H H CH (CH₃) COOEt 3-Hx H 1-AI-Pip (4) 809 H H CH (CH₃) COOEt 2-CF₃       H 1-AI-Pip (4) 810 H H CH (CH₃) COOEt 3-CF₃       H 1-AI-Pip (4) 811 H H CH (CH₃) COOEt 2-OMe H 1-AI-Pip (4) 812 H H CH (CH₃) COOEt 3-OMe H 1-AI-Pip (4) 813 H H CH (CH₃) COOEt 2-OEt H 1-AI-Pip (4) 814 H H CH (CH₃) COOEt 3-OEt H 1-AI-Pip (4) 815 H H CH (CH₃) COOEt 2-COOH H 1-AI-Pip (4) 816 H H CH (CH₃) COOEt 3-COOH H 1-AI-Pip (4) 817 H H CH (CH₃) COOEt 2-COOMe H 1-AI-Pip (4) 818 H H CH (CH₃) COOEt 3-COOMe H 1-AI-Pip (4) 819 H H CH (CH₃) COOEt 2-COOEt H 1-AI-Pip (4) 820 H H CH (CH₃) COOEt 3-COOEt H 1-AI-Pip (4) 821 H H CH (CH₃) COOEt 2-COOPr H 1-AI-Pip (4) 822 H H CH (CH₃) COOEt 3-COOPr H 1-AI-Pip (4) 823 H H CH (CH₃) COOEt 2-COOBu H 1-AI-Pip (4) 824 H H CH (CH₃) COOEt 3-COOBu H 1-AI-Pip (4) 825 H H CH (CH₃) COOEt 2-COOPn H 1-AI-Pip (4) 826 H H CH (CH₃) COOEt 3-COOPn H 1-AI-Pip (4) 827 H H CH (CH₃) COOEt 2-COOHx H 1-AI-Pip (4) 828 H H CH (CH₃) COOEt 3-COOHx H 1-AI-Pip (4) 829 H H CH (CH₃) COOEt 2-CONH₂     H 1-AI-Pip (4) 830 H H CH (CH₃) COOEt 3-CONH₂     H 1-AI-Pip (4) 831 H H CH (CH₃) COOEt 2-CONHMe H 1-AI-Pip (4) 832 H H CH (CH₃) COOEt 3-CONHMe H 1-AI-Pip (4) 833 H H CH (CH₃) COOEt 2-CONHEt H 1-AI-Pip (4) 834 H H CH (CH₃) COOEt 3-CONHEt H 1-AI-Pip (4) 835 H H CH (CH₃) COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 836 H H CH (CH₃) COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 837 H H CH (CH₃) COOEt 2-CON (Me) Et H 1-AI-Pip (4) 838 H H CH (CH₃) COOEt 3-CON (Me) Et H 1-AI-Pip (4) 839 H H CH (CH₃) COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 840 H H CH (CH₃) COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 841 H H CH (CH₃) COOEt 3-F 5-F 1-AI-Pip (4) 842 H H CH (CH₃) COOEt 3-Cl 5-Cl 1-AI-Pip (4) 843 H H CH (CH₃) COOEt 3-Me 5-Me 1-AI-Pip (4) 844 H H CH (CH₃) COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 845 H H CH (CH₃) COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 846 H H CH (CH₃) COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 847 H H CH (CH₃) COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 848 H H (CH₂)₂COOEt H H 1-AI-Pip (4) 849 H H (CH₂)₃COOEt H H 1-AI-Pip (4) 850 H H (CH₂)_FourCOOEt H H 1-AI-Pip (4) 851 H H (CH₂)_FiveCOOEt H H 1-AI-Pip (4) 852 H H (CH₂)₆COOEt H H 1-AI-Pip (4) 853 H H CH₂COCH₂COOMe H H 1-AI-Pip (4) 854 H H CH₂COCH₂COOEt H H 1-AI-Pip (4) 855 H H CH₂COCH₂COOPr H H 1-AI-Pip (4) 856 H H CH₂COCH₂COOBu H H 1-AI-Pip (4) 857 H H CH₂COCH₂COOPn H H 1-AI-Pip (4) 858 H H CH₂COCH₂COOHx H H 1-AI-Pip (4) 859 H H (CH₂)₂COCH₂COOEt H H 1-AI-Pip (4) 860 H H (CH₂)₃COCH₂COOEt H H 1-AI-Pip (4) 861 H H (CH₂)_FourCOCH₂COOEt H H 1-AI-Pip (4) 862 H H (CH₂)_FiveCOCH₂COOEt H H 1-AI-Pip (4) 863 H H (CH₂)₆COCH₂COOEt H H 1-AI-Pip (4) 864 H H Bn H H 1-AI-Pip (4) 865 H H Bn 2-F H 1-AI-Pip (4) 866 H H Bn 3-F H 1-AI-Pip (4) 867 H H Bn 2-Cl H 1-AI-Pip (4) 868 H H Bn 3-Cl H 1-AI-Pip (4) 869 H H Bn 2-Br H 1-AI-Pip (4) 870 H H Bn 3-Br H 1-AI-Pip (4) 871 H H Bn 2-I H 1-AI-Pip (4) 872 H H Bn 3-I H 1-AI-Pip (4) 873 H H Bn 2-Me H 1-AI-Pip (4) 874 H H Bn 3-Me H 1-AI-Pip (4) 875 H H Bn 2-Et H 1-AI-Pip (4) 876 H H Bn 3-Et H 1-AI-Pip (4) 877 H H Bn 2-Pr H 1-AI-Pip (4) 878 H H Bn 3-Pr H 1-AI-Pip (4) 879 H H Bn 2-Bu H 1-AI-Pip (4) 880 H H Bn 3-Bu H 1-AI-Pip (4) 881 H H Bn 2-Pn H 1-AI-Pip (4) 882 H H Bn 3-Pn H 1-AI-Pip (4) 883 H H Bn 2-Hx H 1-AI-Pip (4) 884 H H Bn 3-Hx H 1-AI-Pip (4) 885 H H Bn 2-CF₃       H 1-AI-Pip (4) 886 H H Bn 3-CF₃       H 1-AI-Pip (4) 887 H H Bn 2-OMe H 1-AI-Pip (4) 888 H H Bn 3-OMe H 1-AI-Pip (4) 889 H H Bn 2-OEt H 1-AI-Pip (4) 890 H H Bn 3-OEt H 1-AI-Pip (4) 891 H H Bn 2-COOH H 1-AI-Pip (4) 892 H H Bn 3-COOH H 1-AI-Pip (4) 893 H H Bn 2-COOMe H 1-AI-Pip (4) 894 H H Bn 3-COOMe H 1-AI-Pip (4) 895 H H Bn 2-COOEt H 1-AI-Pip (4) 896 H H Bn 3-COOEt H 1-AI-Pip (4) 897 H H Bn 2-COOPr H 1-AI-Pip (4) 898 H H Bn 3-COOPr H 1-AI-Pip (4) 899 H H Bn 2-COOBu H 1-AI-Pip (4) 900 H H Bn 3-COOBu H 1-AI-Pip (4) 901 H H Bn 2-COOPn H 1-AI-Pip (4) 902 H H Bn 3-COOPn H 1-AI-Pip (4) 903 H H Bn 2-COOHx H 1-AI-Pip (4) 904 H H Bn 3-COOHx H 1-AI-Pip (4) 905 H H Bn 2-CONH₂     H 1-AI-Pip (4) 906 H H Bn 3-CONH₂     H 1-AI-Pip (4) 907 H H Bn 2-CONHMe H 1-AI-Pip (4) 908 H H Bn 3-CONHMe H 1-AI-Pip (4) 909 H H Bn 2-CONHEt H 1-AI-Pip (4) 910 H H Bn 3-CONHEt H 1-AI-Pip (4) 911 H H Bn 2-CON (Me)₂  H 1-AI-Pip (4) 912 H H Bn 3-CON (Me)₂  H 1-AI-Pip (4) 913 H H Bn 2-CON (Me) Et H 1-AI-Pip (4) 914 H H Bn 3-CON (Me) Et H 1-AI-Pip (4) 915 H H Bn 2-CON (Et)₂  H 1-AI-Pip (4) 916 H H Bn 3-CON (Et)₂  H 1-AI-Pip (4) 917 H H Bn 3-F 5-F 1-AI-Pip (4) 918 H H Bn 3-Cl 5-Cl 1-AI-Pip (4) 919 H H Bn 3-Me 5-Me 1-AI-Pip (4) 920 H H Bn 3-Cl 5-CONH₂     1-AI-Pip (4) 921 H H Bn 2-Me 5-CONH₂     1-AI-Pip (4) 922 H H Bn 3-Me 5-CONH₂     1-AI-Pip (4) 923 H H Bn 3-CONH₂     5-CONH₂     1-AI-Pip (4) 924 H H CH₂Np (1) H H 1-AI-Pip (4) 925 6-OH H CH₂Np (1) H H 1-AI-Pip (4) 926 H H CH₂Np (2) H H 1-AI-Pip (4) 927 6-OH H CH₂Np (2) H H 1-AI-Pip (4) 928 H H (CH₂)₂Ph H H 1-AI-Pip (4) 929 6-OH H (CH₂)₂Ph H H 1-AI-Pip (4) 930 H H (CH₂)₂Np (1) H H 1-AI-Pip (4) 931 6-OH H (CH₂)₂Np (1) H H 1-AI-Pip (4) 932 H H (CH₂)₂Np (2) H H 1-AI-Pip (4) 933 6-OH H (CH₂)₂Np (2) H H 1-AI-Pip (4) 934 H H (CH₂)₃Ph H H 1-AI-Pip (4) 935 6-OH H (CH₂)₃Ph H H 1-AI-Pip (4) 936 H H (CH₂)₃Np (1) H H 1-AI-Pip (4) 937 6-OH H (CH₂)₃Np (1) H H 1-AI-Pip (4) 938 H H (CH₂)₃Np (2) H H 1-AI-Pip (4) 939 6-OH H (CH₂)₃Np (2) H H 1-AI-Pip (4) 940 H H (CH₂)_FourPh H H 1-AI-Pip (4) 941 6-OH H (CH₂)_FourPh H H 1-AI-Pip (4) 942 H H (CH₂)_FivePh H H 1-AI-Pip (4) 943 6-OH H (CH₂)_FivePh H H 1-AI-Pip (4) 944 H H (CH₂)₆Ph H H 1-AI-Pip (4) 945 6-OH H (CH₂)₆Ph H H 1-AI-Pip (4) 946 H H CHO H H 1-AI-Pip (4) 947 6-OH H CHO H H 1-AI-Pip (4) 948 H H Ac H H 1-AI-Pip (4) 949 H H Ac 2-F H 1-AI-Pip (4) 950 H H Ac 3-F H 1-AI-Pip (4) 951 H H Ac 2-Cl H 1-AI-Pip (4) 952 H H Ac 3-Cl H 1-AI-Pip (4) 953 H H Ac 2-Br H 1-AI-Pip (4) 954 H H Ac 3-Br H 1-AI-Pip (4) 955 H H Ac 2-I H 1-AI-Pip (4) 956 H H Ac 3-I H 1-AI-Pip (4) 957 H H Ac 2-Me H 1-AI-Pip (4) 958 H H Ac 3-Me H 1-AI-Pip (4) 959 H H Ac 2-Et H 1-AI-Pip (4) 960 H H Ac 3-Et H 1-AI-Pip (4) 961 H H Ac 2-Pr H 1-AI-Pip (4) 962 H H Ac 3-Pr H 1-AI-Pip (4) 963 H H Ac 2-Bu H 1-AI-Pip (4) 964 H H Ac 3-Bu H 1-AI-Pip (4) 965 H H Ac 2-Pn H 1-AI-Pip (4) 966 H H Ac 3-Pn H 1-AI-Pip (4) 967 H H Ac 2-Hx H 1-AI-Pip (4) 968 H H Ac 3-Hx H 1-AI-Pip (4) 969 H H Ac 2-CF₃       H 1-AI-Pip (4) 970 H H Ac 3-CF₃       H 1-AI-Pip (4) 971 H H Ac 2-OMe H 1-AI-Pip (4) 972 H H Ac 3-OMe H 1-AI-Pip (4) 973 H H Ac 2-OEt H 1-AI-Pip (4) 974 H H Ac 3-OEt H 1-AI-Pip (4) 975 H H Ac 2-COOH H 1-AI-Pip (4) 976 H H Ac 3-COOH H 1-AI-Pip (4) 977 H H Ac 2-COOMe H 1-AI-Pip (4) 978 H H Ac 3-COOMe H 1-AI-Pip (4) 979 H H Ac 2-COOEt H 1-AI-Pip (4) 980 H H Ac 3-COOEt H 1-AI-Pip (4) 981 H H Ac 2-COOPr H 1-AI-Pip (4) 982 H H Ac 3-COOPr H 1-AI-Pip (4) 983 H H Ac 2-COOBu H 1-AI-Pip (4) 984 H H Ac 3-COOBu H 1-AI-Pip (4) 985 H H Ac 2-COOPn H 1-AI-Pip (4) 986 H H Ac 3-COOPn H 1-AI-Pip (4) 987 H H Ac 2-COOHx H 1-AI-Pip (4) 988 H H Ac 3-COOHx H 1-AI-Pip (4) 989 H H Ac 2-CONH₂     H 1-AI-Pip (4) 990 H H Ac 3-CONH₂     H 1-AI-Pip (4) 991 H H Ac 2-CONHMe H 1-AI-Pip (4) 992 H H Ac 3-CONHMe H 1-AI-Pip (4) 993 H H Ac 2-CONHEt H 1-AI-Pip (4) 994 H H Ac 3-CONHEt H 1-AI-Pip (4) 995 H H Ac 2-CON (Me)₂  H 1-AI-Pip (4) 996 H H Ac 3-CON (Me)₂  H 1-AI-Pip (4) 997 H H Ac 2-CON (Me) Et H 1-AI-Pip (4) 998 H H Ac 3-CON (Me) Et H 1-AI-Pip (4) 999 H H Ac 2-CON (Et)₂  H 1-AI-Pip (4) 1000 H H Ac 3-CON (Et)₂  H 1-AI-Pip (4) 1001 H H Ac 3-F 5-F 1-AI-Pip (4) 1002 H H Ac 3-Cl 5-Cl 1-AI-Pip (4) 1003 H H Ac 3-Me 5-Me 1-AI-Pip (4) 1004 H H Ac 3-Cl 5-CONH₂     1-AI-Pip (4) 1005 H H Ac 2-Me 5-CONH₂     1-AI-Pip (4) 1006 H H Ac 3-Me 5-CONH₂     1-AI-Pip (4) 1007 H H Ac 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1008 H H Prn H H 1-AI-Pip (4) 1009 6-OH H Prn H H 1-AI-Pip (4) 1010 H H Byr H H 1-AI-Pip (4) 1011 6-OH H Byr H H 1-AI-Pip (4) 1012 H H Va H H 1-AI-Pip (4) 1013 6-OH H Va H H 1-AI-Pip (4) 1014 H H COCH₂OH H H 1-AI-Pip (4) 1015 H H COCH₂OH 2-F H 1-AI-Pip (4) 1016 H H COCH₂OH 3-F H 1-AI-Pip (4) 1017 H H COCH₂OH 2-Cl H 1-AI-Pip (4) 1018 H H COCH₂OH 3-Cl H 1-AI-Pip (4) 1019 H H COCH₂OH 2-Br H 1-AI-Pip (4) 1020 H H COCH₂OH 3-Br H 1-AI-Pip (4) 1021 H H COCH₂OH 2-I H 1-AI-Pip (4) 1022 H H COCH₂OH 3-I H 1-AI-Pip (4) 1023 H H COCH₂OH 2-Me H 1-AI-Pip (4) 1024 H H COCH₂OH 3-Me H 1-AI-Pip (4) 1025 H H COCH₂OH 2-Et H 1-AI-Pip (4) 1026 H H COCH₂OH 3-Et H 1-AI-Pip (4) 1027 H H COCH₂OH 2-Pr H 1-AI-Pip (4) 1028 H H COCH₂OH 3-Pr H 1-AI-Pip (4) 1029 H H COCH₂OH 2-Bu H 1-AI-Pip (4) 1030 H H COCH₂OH 3-Bu H 1-AI-Pip (4) 1031 H H COCH₂OH 2-Pn H 1-AI-Pip (4) 1032 H H COCH₂OH 3-Pn H 1-AI-Pip (4) 1033 H H COCH₂OH 2-Hx H 1-AI-Pip (4) 1034 H H COCH₂OH 3-Hx H 1-AI-Pip (4) 1035 H H COCH₂OH 2-CF₃       H 1-AI-Pip (4) 1036 H H COCH₂OH 3-CF₃       H 1-AI-Pip (4) 1037 H H COCH₂OH 2-OMe H 1-AI-Pip (4) 1038 H H COCH₂OH 3-OMe H 1-AI-Pip (4) 1039 H H COCH₂OH 2-OEt H 1-AI-Pip (4) 1040 H H COCH₂OH 3-OEt H 1-AI-Pip (4) 1041 H H COCH₂OH 2-COOH H 1-AI-Pip (4) 1042 H H COCH₂OH 3-COOH H 1-AI-Pip (4) 1043 H H COCH₂OH 2-COOMe H 1-AI-Pip (4) 1044 H H COCH₂OH 3-COOMe H 1-AI-Pip (4) 1045 H H COCH₂OH 2-COOEt H 1-AI-Pip (4) 1046 H H COCH₂OH 3-COOEt H 1-AI-Pip (4) 1047 H H COCH₂OH 2-COOPr H 1-AI-Pip (4) 1048 H H COCH₂OH 3-COOPr H 1-AI-Pip (4) 1049 H H COCH₂OH 2-COOBu H 1-AI-Pip (4) 1050 H H COCH₂OH 3-COOBu H 1-AI-Pip (4) 1051 H H COCH₂OH 2-COOPn H 1-AI-Pip (4) 1052 H H COCH₂OH 3-COOPn H 1-AI-Pip (4) 1053 H H COCH₂OH 2-COOHx H 1-AI-Pip (4) 1054 H H COCH₂OH 3-COOHx H 1-AI-Pip (4) 1055 H H COCH₂OH 2-CONH₂     H 1-AI-Pip (4) 1056 H H COCH₂OH 3-CONH₂     H 1-AI-Pip (4) 1057 H H COCH₂OH 2-CONHMe H 1-AI-Pip (4) 1058 H H COCH₂OH 3-CONHMe H 1-AI-Pip (4) 1059 H H COCH₂OH 2-CONHEt H 1-AI-Pip (4) 1060 H H COCH₂OH 3-CONHEt H 1-AI-Pip (4) 1061 H H COCH₂OH 2-CON (Me)₂  H 1-AI-Pip (4) 1062 H H COCH₂OH 3-CON (Me)₂  H 1-AI-Pip (4) 1063 H H COCH₂OH 2-CON (Me) Et H 1-AI-Pip (4) 1064 H H COCH₂OH 3-CON (Me) Et H 1-AI-Pip (4) 1065 H H COCH₂OH 2-CON (Et)₂  H 1-AI-Pip (4) 1066 H H COCH₂OH 3-CON (Et)₂  H 1-AI-Pip (4) 1067 H H COCH₂OH 3-F 5-F 1-AI-Pip (4) 1068 H H COCH₂OH 3-Cl 5-Cl 1-AI-Pip (4) 1069 H H COCH₂OH 3-Me 5-Me 1-AI-Pip (4) 1070 H H COCH₂OH 3-Cl 5-CONH₂     1-AI-Pip (4) 1071 H H COCH₂OH 2-Me 5-CONH₂     1-AI-Pip (4) 1072 H H COCH₂OH 3-Me 5-CONH₂     1-AI-Pip (4) 1073 H H COCH₂OH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1074 H H CO (CH₂)₂OH H H 1-AI-Pip (4) 1075 H H CO (CH₂)₃OH H H 1-AI-Pip (4) 1076 H H CO (CH₂)_FourOH H H 1-AI-Pip (4) 1077 H H CO (CH₂)_FiveOH H H 1-AI-Pip (4) 1078 H H SO₂Me H H 1-AI-Pip (4) 1079 6-OH H SO₂Me H H 1-AI-Pip (4) 1080 H H SO₂Et H H 1-AI-Pip (4) 1081 H H SO₂Et 2-F H 1-AI-Pip (4) 1082 H H SO₂Et 3-F H 1-AI-Pip (4) 1083 H H SO₂Et 2-Cl H 1-AI-Pip (4) 1084 H H SO₂Et 3-Cl H 1-AI-Pip (4) 1085 H H SO₂Et 2-Br H 1-AI-Pip (4) 1086 H H SO₂Et 3-Br H 1-AI-Pip (4) 1087 H H SO₂Et 2-I H 1-AI-Pip (4) 1088 H H SO₂Et 3-I H 1-AI-Pip (4) 1089 H H SO₂Et 2-Me H 1-AI-Pip (4) 1090 H H SO₂Et 3-Me H 1-AI-Pip (4) 1091 H H SO₂Et 2-Et H 1-AI-Pip (4) 1092 H H SO₂Et 3-Et H 1-AI-Pip (4) 1093 H H SO₂Et 2-Pr H 1-AI-Pip (4) 1094 H H SO₂Et 3-Pr H 1-AI-Pip (4) 1095 H H SO₂Et 2-Bu H 1-AI-Pip (4) 1096 H H SO₂Et 3-Bu H 1-AI-Pip (4) 1097 H H SO₂Et 2-Pn H 1-AI-Pip (4) 1098 H H SO₂Et 3-Pn H 1-AI-Pip (4) 1099 H H SO₂Et 2-Hx H 1-AI-Pip (4) 1100 H H SO₂Et 3-Hx H 1-AI-Pip (4) 1101 H H SO₂Et 2-CF₃       H 1-AI-Pip (4) 1102 H H SO₂Et 3-CF₃       H 1-AI-Pip (4) 1103 H H SO₂Et 2-OMe H 1-AI-Pip (4) 1104 H H SO₂Et 3-OMe H 1-AI-Pip (4) 1105 H H SO₂Et 2-OEt H 1-AI-Pip (4) 1106 H H SO₂Et 3-OEt H 1-AI-Pip (4) 1107 H H SO₂Et 2-COOH H 1-AI-Pip (4) 1108 H H SO₂Et 3-COOH H 1-AI-Pip (4) 1109 H H SO₂Et 2-COOMe H 1-AI-Pip (4) 1110 H H SO₂Et 3-COOMe H 1-AI-Pip (4) 1111 H H SO₂Et 2-COOEt H 1-AI-Pip (4) 1112 H H SO₂Et 3-COOEt H 1-AI-Pip (4) 1113 H H SO₂Et 2-COOPr H 1-AI-Pip (4) 1114 H H SO₂Et 3-COOPr H 1-AI-Pip (4) 1115 H H SO₂Et 2-COOBu H 1-AI-Pip (4) 1116 H H SO₂Et 3-COOBu H 1-AI-Pip (4) 1117 H H SO₂Et 2-COOPn H 1-AI-Pip (4) 1118 H H SO₂Et 3-COOPn H 1-AI-Pip (4) 1119 H H SO₂Et 2-COOHx H 1-AI-Pip (4) 1120 H H SO₂Et 3-COOHx H 1-AI-Pip (4) 1121 H H SO₂Et 2-CONH₂     H 1-AI-Pip (4) 1122 H H SO₂Et 3-CONH₂     H 1-AI-Pip (4) 1123 H H SO₂Et 2-CONHMe H 1-AI-Pip (4) 1124 H H SO₂Et 3-CONHMe H 1-AI-Pip (4) 1125 H H SO₂Et 2-CONHEt H 1-AI-Pip (4) 1126 H H SO₂Et 3-CONHEt H 1-AI-Pip (4) 1127 H H SO₂Et 3-CONHPr H 1-AI-Pip (4) 1128 H H SO₂Et 3-CONHBu H 1-AI-Pip (4) 1129 H H SO₂Et 3-CONHPn H 1-AI-Pip (4) 1130 H H SO₂Et 3-CONHHx H 1-AI-Pip (4) 1131 H H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4) 1132 H H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4) 1133 H H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4) 1134 H H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4) 1135 H H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4) 1136 H H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4) 1137 H H SO₂Et 3-CON (Pr)₂  H 1-AI-Pip (4) 1138 H H SO₂Et 3-CON (Bu)₂  H 1-AI-Pip (4) 1139 H H SO₂Et 3-CON (Pn)₂  H 1-AI-Pip (4) 1140 H H SO₂Et 3-CON (Hx)₂  H 1-AI-Pip (4) 1141 H H SO₂Et 2-F 3-F 1-AI-Pip (4) 1142 H H SO₂Et 2-F 5-F 1-AI-Pip (4) 1143 H H SO₂Et 2-F 6-F 1-AI-Pip (4) 1144 H H SO₂Et 3-F 5-F 1-AI-Pip (4) 1145 H H SO₂Et 2-Cl 3-Cl 1-AI-Pip (4) 1146 H H SO₂Et 2-Cl 5-Cl 1-AI-Pip (4) 1147 H H SO₂Et 2-Cl 6-Cl 1-AI-Pip (4) 1148 H H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4) 1149 H H SO₂Et 2-Me 3-Me 1-AI-Pip (4) 1150 H H SO₂Et 2-Me 5-Me 1-AI-Pip (4) 1151 H H SO₂Et 2-Me 6-Me 1-AI-Pip (4) 1152 H H SO₂Et 3-Me 5-Me 1-AI-Pip (4) 1153 H H SO₂Et 2-Cl 5-CONH₂     1-AI-Pip (4) 1154 H H SO₂Et 2-Cl 6-CONH₂     1-AI-Pip (4) 1155 H H SO₂Et 3-Cl 5-CONH₂     1-AI-Pip (4) 1156 H H SO₂Et 2-Me 5-CONH₂     1-AI-Pip (4) 1157 H H SO₂Et 3-Me 5-CONH₂     1-AI-Pip (4) 1158 H H SO₂Et 2-CONH₂     5-CONH₂     1-AI-Pip (4) 1159 H H SO₂Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1160 H F SO₂Et H H 1-AI-Pip (4) 1161 H F SO₂Et 2-F H 1-AI-Pip (4) 1162 H F SO₂Et 3-F H 1-AI-Pip (4) 1163 H F SO₂Et 2-Cl H 1-AI-Pip (4) 1164 H F SO₂Et 3-Cl H 1-AI-Pip (4) 1165 H F SO₂Et 2-Br H 1-AI-Pip (4) 1166 H F SO₂Et 3-Br H 1-AI-Pip (4) 1167 H F SO₂Et 2-I H 1-AI-Pip (4) 1168 H F SO₂Et 3-I H 1-AI-Pip (4) 1169 H F SO₂Et 2-Me H 1-AI-Pip (4) 1170 H F SO₂Et 3-Me H 1-AI-Pip (4) 1171 H F SO₂Et 2-Et H 1-AI-Pip (4) 1172 H F SO₂Et 3-Et H 1-AI-Pip (4) 1173 H F SO₂Et 2-Pr H 1-AI-Pip (4) 1174 H F SO₂Et 3-Pr H 1-AI-Pip (4) 1175 H F SO₂Et 2-Bu H 1-AI-Pip (4) 1176 H F SO₂Et 3-Bu H 1-AI-Pip (4) 1177 H F SO₂Et 2-Pn H 1-AI-Pip (4) 1178 H F SO₂Et 3-Pn H 1-AI-Pip (4) 1179 H F SO₂Et 2-Hx H 1-AI-Pip (4) 1180 H F SO₂Et 3-Hx H 1-AI-Pip (4) 1181 H F SO₂Et 2-CF₃       H 1-AI-Pip (4) 1182 H F SO₂Et 3-CF₃       H 1-AI-Pip (4) 1183 H F SO₂Et 2-OMe H 1-AI-Pip (4) 1184 H F SO₂Et 3-OMe H 1-AI-Pip (4) 1185 H F SO₂Et 2-OEt H 1-AI-Pip (4) 1186 H F SO₂Et 3-OEt H 1-AI-Pip (4) 1187 H F SO₂Et 2-COOH H 1-AI-Pip (4) 1188 H F SO₂Et 3-COOH H 1-AI-Pip (4) 1189 H F SO₂Et 2-COOMe H 1-AI-Pip (4) 1190 H F SO₂Et 3-COOMe H 1-AI-Pip (4) 1191 H F SO₂Et 2-COOEt H 1-AI-Pip (4) 1192 H F SO₂Et 3-COOEt H 1-AI-Pip (4) 1193 H F SO₂Et 2-COOPr H 1-AI-Pip (4) 1194 H F SO₂Et 3-COOPr H 1-AI-Pip (4) 1195 H F SO₂Et 2-COOBu H 1-AI-Pip (4) 1196 H F SO₂Et 3-COOBu H 1-AI-Pip (4) 1197 H F SO₂Et 2-COOPn H 1-AI-Pip (4) 1198 H F SO₂Et 3-COOPn H 1-AI-Pip (4) 1199 H F SO₂Et 2-COOHx H 1-AI-Pip (4) 1200 H F SO₂Et 3-COOHx H 1-AI-Pip (4) 1201 H F SO₂Et 2-CONH₂     H 1-AI-Pip (4) 1202 H F SO₂Et 3-CONH₂     H 1-AI-Pip (4) 1203 H F SO₂Et 2-CONHMe H 1-AI-Pip (4) 1204 H F SO₂Et 3-CONHMe H 1-AI-Pip (4) 1205 H F SO₂Et 2-CONHEt H 1-AI-Pip (4) 1206 H F SO₂Et 3-CONHEt H 1-AI-Pip (4) 1207 H F SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4) 1208 H F SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4) 1209 H F SO₂Et 2-CON (Me) Et H 1-AI-Pip (4) 1210 H F SO₂Et 3-CON (Me) Et H 1-AI-Pip (4) 1211 H F SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4) 1212 H F SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4) 1213 H F SO₂Et 3-F 5-F 1-AI-Pip (4) 1214 H F SO₂Et 3-Cl 5-Cl 1-AI-Pip (4) 1215 H F SO₂Et 3-Me 5-Me 1-AI-Pip (4) 1216 H F SO₂Et 3-Cl 5-CONH₂     1-AI-Pip (4) 1217 H F SO₂Et 2-Me 5-CONH₂     1-AI-Pip (4) 1218 H F SO₂Et 3-Me 5-CONH₂     1-AI-Pip (4) 1219 H F SO₂Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1220 H Me SO₂Et H H 1-AI-Pip (4) 1221 H Me SO₂Et 2-F H 1-AI-Pip (4) 1222 H Me SO₂Et 3-F H 1-AI-Pip (4) 1223 H Me SO₂Et 2-Cl H 1-AI-Pip (4) 1224 H Me SO₂Et 3-Cl H 1-AI-Pip (4) 1225 H Me SO₂Et 2-Br H 1-AI-Pip (4) 1226 H Me SO₂Et 3-Br H 1-AI-Pip (4) 1227 H Me SO₂Et 2-I H 1-AI-Pip (4) 1228 H Me SO₂Et 3-I H 1-AI-Pip (4) 1229 H Me SO₂Et 2-Me H 1-AI-Pip (4) 1230 H Me SO₂Et 3-Me H 1-AI-Pip (4) 1231 H Me SO₂Et 2-Et H 1-AI-Pip (4) 1232 H Me SO₂Et 3-Et H 1-AI-Pip (4) 1233 H Me SO₂Et 2-Pr H 1-AI-Pip (4) 1234 H Me SO₂Et 3-Pr H 1-AI-Pip (4) 1235 H Me SO₂Et 2-Bu H 1-AI-Pip (4) 1236 H Me SO₂Et 3-Bu H 1-AI-Pip (4) 1237 H Me SO₂Et 2-Pn H 1-AI-Pip (4) 1238 H Me SO₂Et 3-Pn H 1-AI-Pip (4) 1239 H Me SO₂Et 2-Hx H 1-AI-Pip (4) 1240 H Me SO₂Et 3-Hx H 1-AI-Pip (4) 1241 H Me SO₂Et 2-CF₃       H 1-AI-Pip (4) 1242 H Me SO₂Et 3-CF₃       H 1-AI-Pip (4) 1243 H Me SO₂Et 2-OMe H 1-AI-Pip (4) 1244 H Me SO₂Et 3-OMe H 1-AI-Pip (4) 1245 H Me SO₂Et 2-OEt H 1-AI-Pip (4) 1246 H Me SO₂Et 3-OEt H 1-AI-Pip (4) 1247 H Me SO₂Et 2-COOH H 1-AI-Pip (4) 1248 H Me SO₂Et 3-COOH H 1-AI-Pip (4) 1249 H Me SO₂Et 2-COOMe H 1-AI-Pip (4) 1250 H Me SO₂Et 3-COOMe H 1-AI-Pip (4) 1251 H Me SO₂Et 2-COOEt H 1-AI-Pip (4) 1252 H Me SO₂Et 3-COOEt H 1-AI-Pip (4) 1253 H Me SO₂Et 2-COOPr H 1-AI-Pip (4) 1254 H Me SO₂Et 3-COOPr H 1-AI-Pip (4) 1255 H Me SO₂Et 2-COOBu H 1-AI-Pip (4) 1256 H Me SO₂Et 3-COOBu H 1-AI-Pip (4) 1257 H Me SO₂Et 2-COOPn H 1-AI-Pip (4) 1258 H Me SO₂Et 3-COOPn H 1-AI-Pip (4) 1259 H Me SO₂Et 2-COOHx H 1-AI-Pip (4) 1260 H Me SO₂Et 3-COOHx H 1-AI-Pip (4) 1261 H Me SO₂Et 2-CONH₂     H 1-AI-Pip (4) 1262 H Me SO₂Et 3-CONH₂     H 1-AI-Pip (4) 1263 H Me SO₂Et 2-CONHMe H 1-AI-Pip (4) 1264 H Me SO₂Et 3-CONHMe H 1-AI-Pip (4) 1265 H Me SO₂Et 2-CONHEt H 1-AI-Pip (4) 1266 H Me SO₂Et 3-CONHEt H 1-AI-Pip (4) 1267 H Me SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4) 1268 H Me SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4) 1269 H Me SO₂Et 2-CON (Me) Et H 1-AI-Pip (4) 1270 H Me SO₂Et 3-CON (Me) Et H 1-AI-Pip (4) 1271 H Me SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4) 1272 H Me SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4) 1273 H Me SO₂Et 3-F 5-F 1-AI-Pip (4) 1274 H Me SO₂Et 3-Cl 5-Cl 1-AI-Pip (4) 1275 H Me SO₂Et 3-Me 5-Me 1-AI-Pip (4) 1276 H Me SO₂Et 3-Cl 5-CONH₂     1-AI-Pip (4) 1277 H Me SO₂Et 2-Me 5-CONH₂     1-AI-Pip (4) 1278 H Me SO₂Et 3-Me 5-CONH₂     1-AI-Pip (4) 1279 H Me SO₂Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1280 6-F H SO₂Et H H 1-AI-Pip (4) 1281 6-F H SO₂Et 2-F H 1-AI-Pip (4) 1282 6-F H SO₂Et 3-F H 1-AI-Pip (4) 1283 6-F H SO₂Et 2-Cl H 1-AI-Pip (4) 1284 6-F H SO₂Et 3-Cl H 1-AI-Pip (4) 1285 6-F H SO₂Et 2-Br H 1-AI-Pip (4) 1286 6-F H SO₂Et 3-Br H 1-AI-Pip (4) 1287 6-F H SO₂Et 2-I H 1-AI-Pip (4) 1288 6-F H SO₂Et 3-I H 1-AI-Pip (4) 1289 6-F H SO₂Et 2-Me H 1-AI-Pip (4) 1290 6-F H SO₂Et 3-Me H 1-AI-Pip (4) 1291 6-F H SO₂Et 2-Et H 1-AI-Pip (4) 1292 6-F H SO₂Et 3-Et H 1-AI-Pip (4) 1293 6-F H SO₂Et 2-Pr H 1-AI-Pip (4) 1294 6-F H SO₂Et 3-Pr H 1-AI-Pip (4) 1295 6-F H SO₂Et 2-Bu H 1-AI-Pip (4) 1296 6-F H SO₂Et 3-Bu H 1-AI-Pip (4) 1297 6-F H SO₂Et 2-Pn H 1-AI-Pip (4) 1298 6-F H SO₂Et 3-Pn H 1-AI-Pip (4) 1299 6-F H SO₂Et 2-Hx H 1-AI-Pip (4) 1300 6-F H SO₂Et 3-Hx H 1-AI-Pip (4) 1301 6-F H SO₂Et 2-CF₃       H 1-AI-Pip (4) 1302 6-F H SO₂Et 3-CF₃       H 1-AI-Pip (4) 1303 6-F H SO₂Et 2-OMe H 1-AI-Pip (4) 1304 6-F H SO₂Et 3-OMe H 1-AI-Pip (4) 1305 6-F H SO₂Et 2-OEt H 1-AI-Pip (4) 1306 6-F H SO₂Et 3-OEt H 1-AI-Pip (4) 1307 6-F H SO₂Et 2-COOH H 1-AI-Pip (4) 1308 6-F H SO₂Et 3-COOH H 1-AI-Pip (4) 1309 6-F H SO₂Et 2-COOMe H 1-AI-Pip (4) 1310 6-F H SO₂Et 3-COOMe H 1-AI-Pip (4) 1311 6-F H SO₂Et 2-COOEt H 1-AI-Pip (4) 1312 6-F H SO₂Et 3-COOEt H 1-AI-Pip (4) 1313 6-F H SO₂Et 2-COOPr H 1-AI-Pip (4) 1314 6-F H SO₂Et 3-COOPr H 1-AI-Pip (4) 1315 6-F H SO₂Et 2-COOBu H 1-AI-Pip (4) 1316 6-F H SO₂Et 3-COOBu H 1-AI-Pip (4) 1317 6-F H SO₂Et 2-COOPn H 1-AI-Pip (4) 1318 6-F H SO₂Et 3-COOPn H 1-AI-Pip (4) 1319 6-F H SO₂Et 2-COOHx H 1-AI-Pip (4) 1320 6-F H SO₂Et 3-COOHx H 1-AI-Pip (4) 1321 6-F H SO₂Et 2-CONH₂     H 1-AI-Pip (4) 1322 6-F H SO₂Et 3-CONH₂     H 1-AI-Pip (4) 1323 6-F H SO₂Et 2-CONHMe H 1-AI-Pip (4) 1324 6-F H SO₂Et 3-CONHMe H 1-AI-Pip (4) 1325 6-F H SO₂Et 2-CONHEt H 1-AI-Pip (4) 1326 6-F H SO₂Et 3-CONHEt H 1-AI-Pip (4) 1327 6-F H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4) 1328 6-F H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4) 1329 6-F H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4) 1330 6-F H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4) 1331 6-F H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4) 1332 6-F H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4) 1333 6-F H SO₂Et 3-F 5-F 1-AI-Pip (4) 1334 6-F H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4) 1335 6-F H SO₂Et 3-Me 5-Me 1-AI-Pip (4) 1336 6-F H SO₂Et 3-Cl 5-CONH₂     1-AI-Pip (4) 1337 6-F H SO₂Et 2-Me 5-CONH₂     1-AI-Pip (4) 1338 6-F H SO₂Et 3-Me 5-CONH₂     1-AI-Pip (4) 1339 6-F H SO₂Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1340 6-OH H SO₂Et H H 1-AI-Pip (4) 1341 6-OH H SO₂Et 2-F H 1-AI-Pip (4) 1342 6-OH H SO₂Et 3-F H 1-AI-Pip (4) 1343 6-OH H SO₂Et 2-Cl H 1-AI-Pip (4) 1344 6-OH H SO₂Et 3-Cl H 1-AI-Pip (4) 1345 6-OH H SO₂Et 2-Br H 1-AI-Pip (4) 1346 6-OH H SO₂Et 3-Br H 1-AI-Pip (4) 1347 6-OH H SO₂Et 2-I H 1-AI-Pip (4) 1348 6-OH H SO₂Et 3-I H 1-AI-Pip (4) 1349 6-OH H SO₂Et 2-Me H 1-AI-Pip (4) 1350 6-OH H SO₂Et 3-Me H 1-AI-Pip (4) 1351 6-OH H SO₂Et 2-Et H 1-AI-Pip (4) 1352 6-OH H SO₂Et 3-Et H 1-AI-Pip (4) 1353 6-OH H SO₂Et 2-Pr H 1-AI-Pip (4) 1354 6-OH H SO₂Et 3-Pr H 1-AI-Pip (4) 1355 6-OH H SO₂Et 2-Bu H 1-AI-Pip (4) 1356 6-OH H SO₂Et 3-Bu H 1-AI-Pip (4) 1357 6-OH H SO₂Et 2-Pn H 1-AI-Pip (4) 1358 6-OH H SO₂Et 3-Pn H 1-AI-Pip (4) 1359 6-OH H SO₂Et 2-Hx H 1-AI-Pip (4) 1360 6-OH H SO₂Et 3-Hx H 1-AI-Pip (4) 1361 6-OH H SO₂Et 2-CF₃       H 1-AI-Pip (4) 1362 6-OH H SO₂Et 3-CF₃       H 1-AI-Pip (4) 1363 6-OH H SO₂Et 2-OMe H 1-AI-Pip (4) 1364 6-OH H SO₂Et 3-OMe H 1-AI-Pip (4) 1365 6-OH H SO₂Et 2-OEt H 1-AI-Pip (4) 1366 6-OH H SO₂Et 3-OEt H 1-AI-Pip (4) 1367 6-OH H SO₂Et 2-COOH H 1-AI-Pip (4) 1368 6-OH H SO₂Et 3-COOH H 1-AI-Pip (4) 1369 6-OH H SO₂Et 2-COOMe H 1-AI-Pip (4) 1370 6-OH H SO₂Et 3-COOMe H 1-AI-Pip (4) 1371 6-OH H SO₂Et 2-COOEt H 1-AI-Pip (4) 1372 6-OH H SO₂Et 3-COOEt H 1-AI-Pip (4) 1373 6-OH H SO₂Et 2-COOPr H 1-AI-Pip (4) 1374 6-OH H SO₂Et 3-COOPr H 1-AI-Pip (4) 1375 6-OH H SO₂Et 2-COOBu H 1-AI-Pip (4) 1376 6-OH H SO₂Et 3-COOBu H 1-AI-Pip (4) 1377 6-OH H SO₂Et 2-COOPn H 1-AI-Pip (4) 1378 6-OH H SO₂Et 3-COOPn H 1-AI-Pip (4) 1379 6-OH H SO₂Et 2-COOHx H 1-AI-Pip (4) 1380 6-OH H SO₂Et 3-COOHx H 1-AI-Pip (4) 1381 6-OH H SO₂Et 2-CONH₂     H 1-AI-Pip (4) 1382 6-OH H SO₂Et 3-CONH₂     H 1-AI-Pip (4) 1383 6-OH H SO₂Et 2-CONHMe H 1-AI-Pip (4) 1384 6-OH H SO₂Et 3-CONHMe H 1-AI-Pip (4) 1385 6-OH H SO₂Et 2-CONHEt H 1-AI-Pip (4) 1386 6-OH H SO₂Et 3-CONHEt H 1-AI-Pip (4) 1387 6-OH H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4) 1388 6-OH H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4) 1389 6-OH H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4) 1390 6-OH H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4) 1391 6-OH H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4) 1392 6-OH H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4) 1393 6-OH H SO₂Et 3-F 5-F 1-AI-Pip (4) 1394 6-OH H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4) 1395 6-OH H SO₂Et 3-Me 5-Me 1-AI-Pip (4) 1396 6-OH H SO₂Et 3-Cl 5-CONH₂     1-AI-Pip (4) 1397 6-OH H SO₂Et 2-Me 5-CONH₂     1-AI-Pip (4) 1398 6-OH H SO₂Et 3-Me 5-CONH₂     1-AI-Pip (4) 1399 6-OH H SO₂Et 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1400 H H SO₂Pr H H 1-AI-Pip (4) 1401 H H SO₂ iPr H H 1-AI-Pip (4) 1402 H H SO₂Bu H H 1-AI-Pip (4) 1403 H H SO₂ sBu H H 1-AI-Pip (4) 1404 H H SO₂ iBu H H 1-AI-Pip (4) 1405 H H SO₂ tBu H H 1-AI-Pip (4) 1406 H H SO₂Pn H H 1-AI-Pip (4) 1407 H H SO₂Hx H H 1-AI-Pip (4) 1408 H H SO₂CH₂COOMe H H 1-AI-Pip (4) 1409 6-OH H SO₂CH₂COOMe H H 1-AI-Pip (4) 1410 H H SO₂CH₂COOEt H H 1-AI-Pip (4) 1411 H H SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1412 H H SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1413 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1414 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1415 H H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1416 H H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1417 H H SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1418 H H SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1419 H H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1420 H H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1421 H H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1422 H H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1423 H H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1424 H H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1425 H H SO₂CH₂COOEt 2-iPr H 1-AI-Pip (4) 1426 H H SO₂CH₂COOEt 3-iPr H 1-AI-Pip (4) 1427 H H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1428 H H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1429 H H SO₂CH₂COOEt 2-iBu H 1-AI-Pip (4) 1430 H H SO₂CH₂COOEt 3-iBu H 1-AI-Pip (4) 1431 H H SO₂CH₂COOEt 2-sBu H 1-AI-Pip (4) 1432 H H SO₂CH₂COOEt 3-sBu H 1-AI-Pip (4) 1433 H H SO₂CH₂COOEt 2-tBu H 1-AI-Pip (4) 1434 H H SO₂CH₂COOEt 3-tBu H 1-AI-Pip (4) 1435 H H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1436 H H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1437 H H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1438 H H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1439 H H SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1440 H H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1441 H H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1442 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1443 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1444 H H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1445 H H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1446 H H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1447 H H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1448 H H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1449 H H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1450 H H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1451 H H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1452 H H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1453 H H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1454 H H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1455 H H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1456 H H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1457 H H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1458 H H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1459 H H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1460 H H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1461 H H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1462 H H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1463 H H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1464 H H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1465 H H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1466 H H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1467 H H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1468 H H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1469 H H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1470 H H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1471 H H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip (4) 1472 H H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip (4) 1473 H H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip (4) 1474 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1475 H H SO₂CH₂COOEt 2-Cl 3-Cl 1-AI-Pip (4) 1476 H H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip (4) 1477 H H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip (4) 1478 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1479 H H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip (4) 1480 H H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip (4) 1481 H H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip (4) 1482 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1483 H H SO₂CH₂COOEt 2-Cl 5-CONH₂     1-AI-Pip (4) 1484 H H SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1485 H H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip (4) 1486 H H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip (4) 1487 H H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip (4) 1488 H H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip (4) 1489 H H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip (4) 1490 H H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip (4) 1491 H H SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1492 H H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip (4) 1493 H H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip (4) 1494 H H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip (4) 1495 H H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip (4) 1496 H H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip (4) 1497 H H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip (4) 1498 H H SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1499 H H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip (4) 1500 H H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip (4) 1501 H H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip (4) 1502 H H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip (4) 1503 H H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip (4) 1504 H H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip (4) 1505 H H SO₂CH₂COOEt 2-CONH₂     6-CONH₂     1-AI-Pip (4) 1506 H H SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1507 H H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip (4) 1508 H H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip (4) 1509 H F SO₂CH₂COOEt H H 1-AI-Pip (4) 1510 H F SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1511 H F SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1512 H F SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1513 H F SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1514 H F SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1515 H F SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1516 H F SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1517 H F SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1518 H F SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1519 H F SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1520 H F SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1521 H F SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1522 H F SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1523 H F SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1524 H F SO₂CH₂COOEt 2-iPr H 1-AI-Pip (4) 1525 H F SO₂CH₂COOEt 3-iPr H 1-AI-Pip (4) 1526 H F SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1527 H F SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1528 H F SO₂CH₂COOEt 2-iBu H 1-AI-Pip (4) 1529 H F SO₂CH₂COOEt 3-iBu H 1-AI-Pip (4) 1530 H F SO₂CH₂COOEt 2-sBu H 1-AI-Pip (4) 1531 H F SO₂CH₂COOEt 3-sBu H 1-AI-Pip (4) 1532 H F SO₂CH₂COOEt 2-tBu H 1-AI-Pip (4) 1533 H F SO₂CH₂COOEt 3-tBu H 1-AI-Pip (4) 1534 H F SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1535 H F SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1536 H F SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1537 H F SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1538 H F SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1539 H F SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1540 H F SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1541 H F SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1542 H F SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1543 H F SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1544 H F SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1545 H F SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1546 H F SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1547 H F SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1548 H F SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1549 H F SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1550 H F SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1551 H F SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1552 H F SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1553 H F SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1554 H F SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1555 H F SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1556 H F SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1557 H F SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1558 H F SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1559 H F SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1560 H F SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1561 H F SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1562 H F SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1563 H F SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1564 H F SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1565 H F SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1566 H F SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1567 H F SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1568 H F SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1569 H F SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1570 H F SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1571 H F SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1572 H F SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1573 H F SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1574 H F SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1575 H F SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1576 H F SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1577 H Me SO₂CH₂COOEt H H 1-AI-Pip (4) 1578 H Me SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1579 H Me SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1580 H Me SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1581 H Me SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1582 H Me SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1583 H Me SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1584 H Me SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1585 H Me SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1586 H Me SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1587 H Me SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1588 H Me SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1589 H Me SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1590 H Me SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1591 H Me SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1592 H Me SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1593 H Me SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1594 H Me SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1595 H Me SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1596 H Me SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1597 H Me SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1598 H Me SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1599 H Me SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1600 H Me SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1601 H Me SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1602 H Me SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1603 H Me SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1604 H Me SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1605 H Me SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1606 H Me SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1607 H Me SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1608 H Me SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1609 H Me SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1610 H Me SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1611 H Me SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1612 H Me SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1613 H Me SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1614 H Me SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1615 H Me SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1616 H Me SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1617 H Me SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1618 H Me SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1619 H Me SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1620 H Me SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1621 H Me SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1622 H Me SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1623 H Me SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1624 H Me SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1625 H Me SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1626 H Me SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1627 H Me SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1628 H Me SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1629 H Me SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1630 H Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1631 H Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1632 H Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1633 H Me SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1634 H Me SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1635 H Me SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1636 H Me SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1637 2-F H SO₂CH₂COOEt H H 1-AI-Pip (4) 1638 4-F H SO₂CH₂COOEt H H 1-AI-Pip (4) 1639 4-F H SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1640 4-F H SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1641 4-F H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1642 4-F H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1643 4-F H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1644 4-F H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1645 4-F H SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1646 4-F H SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1647 4-F H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1648 4-F H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1649 4-F H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1650 4-F H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1651 4-F H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1652 4-F H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1653 4-F H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1654 4-F H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1655 4-F H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1656 4-F H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1657 4-F H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1658 4-F H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1659 4-F H SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1660 4-F H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1661 4-F H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1662 4-F H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1663 4-F H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1664 4-F H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1665 4-F H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1666 4-F H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1667 4-F H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1668 4-F H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1669 4-F H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1670 4-F H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1671 4-F H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1672 4-F H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1673 4-F H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1674 4-F H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1675 4-F H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1676 4-F H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1677 4-F H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1678 4-F H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1679 4-F H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1680 4-F H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1681 4-F H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1682 4-F H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1683 4-F H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1684 4-F H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1685 4-F H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1686 4-F H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1687 4-F H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1688 4-F H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1689 4-F H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1690 4-F H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1691 4-F Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1692 4-F Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1693 4-F Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1694 4-F Me SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1695 4-F Me SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1696 4-F Me SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1697 4-F Me SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1698 5-F H SO₂CH₂COOEt H H 1-AI-Pip (4) 1699 6-F H SO₂CH₂COOEt H H 1-AI-Pip (4) 1700 2-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4) 1701 4-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4) 1702 5-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4) 1703 6-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4) 1704 2-Br H SO₂CH₂COOEt H H 1-AI-Pip (4) 1705 4-Br H SO₂CH₂COOEt H H 1-AI-Pip (4) 1706 5-Br H SO₂CH₂COOEt H H 1-AI-Pip (4) 1707 6-Br H SO₂CH₂COOEt H H 1-AI-Pip (4) 1708 2-Me H SO₂CH₂COOEt H H 1-AI-Pip (4) 1709 3-Me H SO₂CH₂COOEt H H 1-AI-Pip (4) 1710 4-Me H SO₂CH₂COOEt H H 1-AI-Pip (4) 1711 5-Me H SO₂CH₂COOEt H H 1-AI-Pip (4) 1712 5-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1713 5-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1714 5-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1715 5-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1716 5-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1717 5-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1718 5-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1719 5-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1720 5-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1721 5-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1722 5-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1723 5-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1724 5-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1725 5-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1726 5-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1727 5-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1728 5-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1729 5-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1730 5-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1731 5-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1732 5-Me H SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1733 5-Me H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1734 5-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1735 5-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1736 5-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1737 5-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1738 5-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1739 5-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1740 5-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1741 5-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1742 5-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1743 5-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1744 5-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1745 5-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1746 5-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1747 5-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1748 5-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1749 5-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1750 5-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1751 5-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1752 5-Me H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1753 5-Me H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1754 5-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1755 5-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1756 5-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1757 5-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1758 5-Me H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1759 5-Me H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1760 5-Me H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1761 5-Me H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1762 5-Me H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1763 5-Me H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1764 5-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1765 5-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1766 5-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1767 5-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1768 5-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1769 5-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1770 5-Me Me SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1771 6-Me H SO₂CH₂COOEt H H 1-AI-Pip (4) 1772 6-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1773 6-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1774 6-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1775 6-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1776 6-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1777 6-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1778 6-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1779 6-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1780 6-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1781 6-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1782 6-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1783 6-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1784 6-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1785 6-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1786 6-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1787 6-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1788 6-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1789 6-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1790 6-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1791 6-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1792 6-Me H SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1793 6-Me H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1794 6-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1795 6-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1796 6-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1797 6-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1798 6-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1799 6-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1800 6-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1801 6-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1802 6-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1803 6-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1804 6-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1805 6-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1806 6-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1807 6-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1808 6-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1809 6-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1810 6-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1811 6-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1812 6-Me H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1813 6-Me H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1814 6-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1815 6-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1816 6-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1817 6-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1818 6-Me H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1819 6-Me H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1820 6-Me H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1821 6-Me H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1822 6-Me H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1823 6-Me H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1824 6-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1825 6-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1826 6-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1827 6-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1828 6-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1829 6-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1830 6-Me Me SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1831 2-Et H SO₂CH₂COOEt H H 1-AI-Pip (4) 1832 4-Et H SO₂CH₂COOEt H H 1-AI-Pip (4) 1833 5-Et H SO₂CH₂COOEt H H 1-AI-Pip (4) 1834 6-Et H SO₂CH₂COOEt H H 1-AI-Pip (4) 1835 2-Pr H SO₂CH₂COOEt H H 1-AI-Pip (4) 1836 4-Bu H SO₂CH₂COOEt H H 1-AI-Pip (4) 1837 5-Pn H SO₂CH₂COOEt H H 1-AI-Pip (4) 1838 6-Hx H SO₂CH₂COOEt H H 1-AI-Pip (4) 1839 6-OH H SO₂CH₂COOEt H H 1-AI-Pip (4) 1840 6-OH H SO₂CH₂COOEt 2-F H 1-AI-Pip (4) 1841 6-OH H SO₂CH₂COOEt 3-F H 1-AI-Pip (4) 1842 6-OH H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4) 1843 6-OH H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4) 1844 6-OH H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4) 1845 6-OH H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4) 1846 6-OH H SO₂CH₂COOEt 2-I H 1-AI-Pip (4) 1847 6-OH H SO₂CH₂COOEt 3-I H 1-AI-Pip (4) 1848 6-OH H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4) 1849 6-OH H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4) 1850 6-OH H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4) 1851 6-OH H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4) 1852 6-OH H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4) 1853 6-OH H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4) 1854 6-OH H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4) 1855 6-OH H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4) 1856 6-OH H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4) 1857 6-OH H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4) 1858 6-OH H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4) 1859 6-OH H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4) 1860 6-OH H SO₂CH₂COOEt 2-CF₃       H 1-AI-Pip (4) 1861 6-OH H SO₂CH₂COOEt 3-CF₃       H 1-AI-Pip (4) 1862 6-OH H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4) 1863 6-OH H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4) 1864 6-OH H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4) 1865 6-OH H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4) 1866 6-OH H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4) 1867 6-OH H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4) 1868 6-OH H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4) 1869 6-OH H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4) 1870 6-OH H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4) 1871 6-OH H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4) 1872 6-OH H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4) 1873 6-OH H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4) 1874 6-OH H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4) 1875 6-OH H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4) 1876 6-OH H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4) 1877 6-OH H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4) 1878 6-OH H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4) 1879 6-OH H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4) 1880 6-OH H SO₂CH₂COOEt 2-CONH₂     H 1-AI-Pip (4) 1881 6-OH H SO₂CH₂COOEt 3-CONH₂     H 1-AI-Pip (4) 1882 6-OH H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4) 1883 6-OH H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4) 1884 6-OH H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4) 1885 6-OH H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4) 1886 6-OH H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4) 1887 6-OH H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4) 1888 6-OH H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4) 1889 6-OH H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4) 1890 6-OH H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4) 1891 6-OH H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4) 1892 6-OH H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip (4) 1893 6-OH H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip (4) 1894 6-OH H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip (4) 1895 6-OH H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4) 1896 6-OH H SO2CH₂COOEt 2-Cl 3-Cl 1-AI-Pip (4) 1897 6-OH H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip (4) 1898 6-OH H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip (4) 1899 6-OH H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4) 1900 6-OH H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip (4) 1901 6-OH H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip (4) 1902 6-OH H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip (4) 1903 6-OH H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4) 1904 6-OH H SO₂CH₂COOEt 2-Cl 5-CONH₂     1-AI-Pip (4) 1905 6-OH H SO₂CH₂COOEt 3-Cl 5-CONH₂     1-AI-Pip (4) 1906 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip (4) 1907 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip (4) 1908 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip (4) 1909 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip (4) 1910 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip (4) 1911 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip (4) 1912 6-OH H SO₂CH₂COOEt 2-Me 5-CONH₂     1-AI-Pip (4) 1913 6-OH H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip (4) 1914 6-OH H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip (4) 1915 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip (4) 1916 6-OH H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip (4) 1917 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip (4) 1918 6-OH H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip (4) 1919 6-OH H SO₂CH₂COOEt 3-Me 5-CONH₂     1-AI-Pip (4) 1920 6-OH H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip (4) 1921 6-OH H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip (4) 1922 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip (4) 1923 6-OH H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip (4) 1924 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip (4) 1925 6-OH H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip (4) 1926 6-OH H SO₂CH₂COOEt 2-CONH₂     6-CONH₂     1-AI-Pip (4) 1927 6-OH H SO₂CH₂COOEt 3-CONH₂     5-CONH₂     1-AI-Pip (4) 1928 6-OH H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip (4) 1929 6-OH H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip (4) 1930 H H SO₂CH₂COOPr H H 1-AI-Pip (4) 1931 H H SO₂CH₂COOBu H H 1-AI-Pip (4) 1932 H H SO₂CH₂COOPn H H 1-AI-Pip (4) 1933 H H SO₂CH₂COOHx H H 1-AI-Pip (4) 1934 H H SO₂(CH₂)₂COOEt H H 1-AI-Pip (4) 1935 H H SO₂(CH₂)₃COOEt H H 1-AI-Pip (4) 1936 H H SO₂(CH₂)_FourCOOEt H H 1-AI-Pip (4) 1937 H H SO₂(CH₂)_FiveCOOEt H H 1-AI-Pip (4) 1938 H H SO₂(CH₂)₆COOEt H H 1-AI-Pip (4) 1939 H H SO₂CH₂COOH H H 1-AI-Pip (4) 1940 H H SO₂CH₂COOH 2-F H 1-AI-Pip (4) 1941 H H SO₂CH₂COOH 3-F H 1-AI-Pip (4) 1942 H H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 1943 H H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 1944 H H SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 1945 H H SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 1946 H H SO₂CH₂COOH 2-I H 1-AI-Pip (4) 1947 H H SO₂CH₂COOH 3-I H 1-AI-Pip (4) 1948 H H SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 1949 H H SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 1950 H H SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 1951 H H SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 1952 H H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 1953 H H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 1954 H H SO₂CH₂COOH 2-iPr H 1-AI-Pip (4) 1955 H H SO₂CH₂COOH 3-iPr H 1-AI-Pip (4) 1956 H H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 1957 H H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 1958 H H SO₂CH₂COOH 2-iBu H 1-AI-Pip (4) 1959 H H SO₂CH₂COOH 3-iBu H 1-AI-Pip (4) 1960 H H SO₂CH₂COOH 2-sBu H 1-AI-Pip (4) 1961 H H SO₂CH₂COOH 3-sBu H 1-AI-Pip (4) 1962 H H SO₂CH₂COOH 2-tBu H 1-AI-Pip (4) 1963 H H SO₂CH₂COOH 3-tBu H 1-AI-Pip (4) 1964 H H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 1965 H H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 1966 H H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 1967 H H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 1968 H H SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 1969 H H SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 1970 H H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 1971 H H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 1972 H H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 1973 H H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 1974 H H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 1975 H H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 1976 H H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 1977 H H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 1978 H H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 1979 H H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 1980 H H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 1981 H H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 1982 H H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 1983 H H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 1984 H H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 1985 H H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 1986 H H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 1987 H H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 1988 H H SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 1989 H H SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 1990 H H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 1991 H H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 1992 H H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 1993 H H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 1994 H H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 1995 H H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 1996 H H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 1997 H H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 1998 H H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 1999 H H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2000 H H SO₂CH₂COOH 2-F 3-F 1-AI-Pip (4) 2001 H H SO₂CH₂COOH 2-F 5-F 1-AI-Pip (4) 2002 H H SO₂CH₂COOH 2-F 6-F 1-AI-Pip (4) 2003 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pip (4) 2004 H H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip (4) 2005 H H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip (4) 2006 H H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip (4) 2007 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4) 2008 H H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip (4) 2009 H H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip (4) 2010 H H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip (4) 2011 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip (4) 2012 H H SO₂CH₂COOH 2-Cl 5-CONH₂     1-AI-Pip (4) 2013 H H SO₂CH₂COOH 3-Cl 5-CONH₂     1-AI-Pip (4) 2014 H H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip (4) 2015 H H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip (4) 2016 H H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip (4) 2017 H H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip (4) 2018 H H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip (4) 2019 H H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip (4) 2020 H H SO₂CH₂COOH 2-Me 5-CONH₂     1-AI-Pip (4) 2021 H H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip (4) 2022 H H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip (4) 2023 H H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip (4) 2024 H H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip (4) 2025 H H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip (4) 2026 H H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip (4) 2027 H H SO₂CH₂COOH 3-Me 5-CONH₂     1-AI-Pip (4) 2028 H H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip (4) 2029 H H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip (4) 2030 H H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip (4) 2031 H H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip (4) 2032 H H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip (4) 2033 H H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip (4) 2034 H H SO₂CH₂COOH 2-CONH₂     6-CONH₂     1-AI-Pip (4) 2035 H H SO₂CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 2036 H H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip (4) 2037 H H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip (4) 2038 H F SO₂CH₂COOH H H 1-AI-Pip (4) 2039 H F SO₂CH₂COOH 2-F H 1-AI-Pip (4) 2040 H F SO₂CH₂COOH 3-F H 1-AI-Pip (4) 2041 H F SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 2042 H F SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 2043 H F SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 2044 H F SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 2045 H F SO₂CH₂COOH 2-I H 1-AI-Pip (4) 2046 H F SO₂CH₂COOH 3-I H 1-AI-Pip (4) 2047 H F SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 2048 H F SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 2049 H F SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 2050 H F SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 2051 H F SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 2052 H F SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 2053 H F SO₂CH₂COOH 2-iPr H 1-AI-Pip (4) 2054 H F SO₂CH₂COOH 3-iPr H 1-AI-Pip (4) 2055 H F SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 2056 H F SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 2057 H F SO₂CH₂COOH 2-iBu H 1-AI-Pip (4) 2058 H F SO₂CH₂COOH 3-iBu H 1-AI-Pip (4) 2059 H F SO₂CH₂COOH 2-sBu H 1-AI-Pip (4) 2060 H F SO₂CH₂COOH 3-sBu H 1-AI-Pip (4) 2061 H F SO₂CH₂COOH 2-tBu H 1-AI-Pip (4) 2062 H F SO₂CH₂COOH 3-tBu H 1-AI-Pip (4) 2063 H F SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 2064 H F SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 2065 H F SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 2066 H F SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 2067 H F SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 2068 H F SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 2069 H F SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 2070 H F SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 2071 H F SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 2072 H F SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 2073 H F SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 2074 H F SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 2075 H F SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 2076 H F SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 2077 H F SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 2078 H F SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 2079 H F SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 2080 H F SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 2081 H F SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 2082 H F SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 2083 H F SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 2084 H F SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 2085 H F SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 2086 H F SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 2087 H F SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 2088 H F SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 2089 H F SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 2090 H F SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 2091 H F SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 2092 H F SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 2093 H F SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 2094 H F SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 2095 H F SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 2096 H F SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 2097 H F SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 2098 H F SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2099 H Me SO₂CH₂COOH H H 1-AI-Pip (4) 2100 H Me SO₂CH₂COOH 2-F H 1-AI-Pip (4) 2101 H Me SO₂CH₂COOH 3-F H 1-AI-Pip (4) 2102 H Me SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 2103 H Me SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 2104 H Me SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 2105 H Me SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 2106 H Me SO₂CH₂COOH 2-I H 1-AI-Pip (4) 2107 H Me SO₂CH₂COOH 3-I H 1-AI-Pip (4) 2108 H Me SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 2109 H Me SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 2110 H Me SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 2111 H Me SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 2112 H Me SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 2113 H Me SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 2114 H Me SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 2115 H Me SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 2116 H Me SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 2117 H Me SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 2118 H Me SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 2119 H Me SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 2120 H Me SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 2121 H Me SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 2122 H Me SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 2123 H Me SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 2124 H Me SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 2125 H Me SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 2126 H Me SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 2127 H Me SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 2128 H Me SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 2129 H Me SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 2130 H Me SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 2131 H Me SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 2132 H Me SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 2133 H Me SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 2134 H Me SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 2135 H Me SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 2136 H Me SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 2137 H Me SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 2138 H Me SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 2139 H Me SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 2140 H Me SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 2141 H Me SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 2142 H Me SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 2143 H Me SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 2144 H Me SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 2145 H Me SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 2146 H Me SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 2147 H Me SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 2148 H Me SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 2149 H Me SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 2150 H Me SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 2151 H Me SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2152 6-F H SO₂CH₂COOH H H 1-AI-Pip (4) 2153 6-F H SO₂CH₂COOH 2-F H 1-AI-Pip (4) 2154 6-F H SO₂CH₂COOH 3-F H 1-AI-Pip (4) 2155 6-F H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 2156 6-F H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 2157 6-F H SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 2158 6-F H SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 2159 6-F H SO₂CH₂COOH 2-I H 1-AI-Pip (4) 2160 6-F H SO₂CH₂COOH 3-I H 1-AI-Pip (4) 2161 6-F H SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 2162 6-F H SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 2163 6-F H SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 2164 6-F H SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 2165 6-F H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 2166 6-F H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 2167 6-F H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 2168 6-F H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 2169 6-F H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 2170 6-F H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 2171 6-F H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 2172 6-F H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 2173 6-F H SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 2174 6-F H SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 2175 6-F H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 2176 6-F H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 2177 6-F H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 2178 6-F H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 2179 6-F H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 2180 6-F H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 2181 6-F H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 2182 6-F H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 2183 6-F H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 2184 6-F H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 2185 6-F H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 2186 6-F H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 2187 6-F H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 2188 6-F H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 2189 6-F H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 2190 6-F H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 2191 6-F H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 2192 6-F H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 2193 6-F H SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 2194 6-F H SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 2195 6-F H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 2196 6-F H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 2197 6-F H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 2198 6-F H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 2199 6-F H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 2200 6-F H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 2201 6-F H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 2202 6-F H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 2203 6-F H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 2204 6-F H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2205 2-Me H SO₂CH₂COOH H H 1-AI-Pip (4) 2206 3-Me H SO₂CH₂COOH H H 1-AI-Pip (4) 2207 4-Me H SO₂CH₂COOH H H 1-AI-Pip (4) 2208 5-Me H SO₂CH₂COOH H H 1-AI-Pip (4) 2209 5-Me H SO₂CH₂COOH 2-F H 1-AI-Pip (4) 2210 5-Me H SO₂CH₂COOH 3-F H 1-AI-Pip (4) 2211 5-Me H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 2212 5-Me H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 2213 5-Me H SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 2214 5-Me H SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 2215 5-Me H SO₂CH₂COOH 2-I H 1-AI-Pip (4) 2216 5-Me H SO₂CH₂COOH 3-I H 1-AI-Pip (4) 2217 5-Me H SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 2218 5-Me H SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 2219 5-Me H SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 2220 5-Me H SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 2221 5-Me H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 2222 5-Me H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 2223 5-Me H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 2224 5-Me H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 2225 5-Me H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 2226 5-Me H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 2227 5-Me H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 2228 5-Me H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 2229 5-Me H SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 2230 5-Me H SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 2231 5-Me H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 2232 5-Me H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 2233 5-Me H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 2234 5-Me H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 2235 5-Me H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 2236 5-Me H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 2237 5-Me H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 2238 5-Me H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 2239 5-Me H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 2240 5-Me H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 2241 5-Me H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 2242 5-Me H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 2243 5-Me H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 2244 5-Me H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 2245 5-Me H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 2246 5-Me H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 2247 5-Me H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 2248 5-Me H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 2249 5-Me H SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 2250 5-Me H SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 2251 5-Me H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 2252 5-Me H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 2253 5-Me H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 2254 5-Me H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 2255 5-Me H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 2256 5-Me H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 2257 5-Me H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 2258 5-Me H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 2259 5-Me H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 2260 5-Me H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2261 6-Me H SO₂CH₂COOH H H 1-AI-Pip (4) 2262 6-OH H SO₂CH₂COOH H H 1-AI-Pip (4) 2263 6-OH H SO₂CH₂COOH 2-F H 1-AI-Pip (4) 2264 6-OH H SO₂CH₂COOH 3-F H 1-AI-Pip (4) 2265 6-OH H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4) 2266 6-OH H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4) 2267 6-OH H SO₂CH₂COOH 2-Br H 1-AI-Pip (4) 2268 6-OH H SO₂CH₂COOH 3-Br H 1-AI-Pip (4) 2269 6-OH H SO₂CH₂COOH 2-I H 1-AI-Pip (4) 2270 6-OH H SO₂CH₂COOH 3-I H 1-AI-Pip (4) 2271 6-OH H SO₂CH₂COOH 2-Me H 1-AI-Pip (4) 2272 6-OH H SO₂CH₂COOH 3-Me H 1-AI-Pip (4) 2273 6-OH H SO₂CH₂COOH 2-Et H 1-AI-Pip (4) 2274 6-OH H SO₂CH₂COOH 3-Et H 1-AI-Pip (4) 2275 6-OH H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4) 2276 6-OH H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4) 2277 6-OH H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4) 2278 6-OH H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4) 2279 6-OH H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4) 2280 6-OH H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4) 2281 6-OH H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4) 2282 6-OH H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4) 2283 6-OH H SO₂CH₂COOH 2-CF₃       H 1-AI-Pip (4) 2284 6-OH H SO₂CH₂COOH 3-CF₃       H 1-AI-Pip (4) 2285 6-OH H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4) 2286 6-OH H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4) 2287 6-OH H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4) 2288 6-OH H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4) 2289 6-OH H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4) 2290 6-OH H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4) 2291 6-OH H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4) 2292 6-OH H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4) 2293 6-OH H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4) 2294 6-OH H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4) 2295 6-OH H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4) 2296 6-OH H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4) 2297 6-OH H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4) 2298 6-OH H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4) 2299 6-OH H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4) 2300 6-OH H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4) 2301 6-OH H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4) 2302 6-OH H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4) 2303 6-OH H SO₂CH₂COOH 2-CONH₂     H 1-AI-Pip (4) 2304 6-OH H SO₂CH₂COOH 3-CONH₂     H 1-AI-Pip (4) 2305 6-OH H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4) 2306 6-OH H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4) 2307 6-OH H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4) 2308 6-OH H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4) 2309 6-OH H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4) 2310 6-OH H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4) 2311 6-OH H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4) 2312 6-OH H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4) 2313 6-OH H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4) 2314 6-OH H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4) 2315 6-OH H SO₂CH₂COOH 2-F 3-F 1-AI-Pip (4) 2316 6-OH H SO₂CH₂COOH 2-F 5-F 1-AI-Pip (4) 2317 6-OH H SO₂CH₂COOH 2-F 6-F 1-AI-Pip (4) 2318 6-OH H SO₂CH₂COOH 3-F 5-F 1-AI-Pip (4) 2319 6-OH H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip (4) 2320 6-OH H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip (4) 2321 6-OH H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip (4) 2322 6-OH H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4) 2323 6-OH H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip (4) 2324 6-OH H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip (4) 2325 6-OH H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip (4) 2326 6-OH H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip (4) 2327 6-OH H SO₂CH₂COOH 2-Cl 5-CONH₂     1-AI-Pip (4) 2328 6-OH H SO₂CH₂COOH 3-Cl 5-CONH₂     1-AI-Pip (4) 2329 6-OH H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip (4) 2330 6-OH H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip (4) 2331 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip (4) 2332 6-OH H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip (4) 2333 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip (4) 2334 6-OH H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip (4) 2335 6-OH H SO₂CH₂COOH 2-Me 5-CONH₂     1-AI-Pip (4) 2336 6-OH H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip (4) 2337 6-OH H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip (4) 2338 6-OH H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip (4) 2339 6-OH H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip (4) 2340 6-OH H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip (4) 2341 6-OH H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip (4) 2342 6-OH H SO₂CH₂COOH 3-Me 5-CONH₂     1-AI-Pip (4) 2343 6-OH H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip (4) 2344 6-OH H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip (4) 2345 6-OH H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip (4) 2346 6-OH H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip (4) 2347 6-OH H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip (4) 2348 6-OH H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip (4) 2349 6-OH H SO₂CH₂COOH 2-CONH₂     6-CONH₂     1-AI-Pip (4) 2350 6-OH H SO₂CH₂COOH 3-CONH₂     5-CONH₂     1-AI-Pip (4) 2351 6-OH H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip (4) 2352 6-OH H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip (4) 2353 H H SO₂(CH₂)₂COOH H H 1-AI-Pip (4) 2354 H H SO₂(CH₂)₃COOH H H 1-AI-Pip (4) 2355 H H SO₂(CH₂)_FourCOOH H H 1-AI-Pip (4) 2356 H H SO₂(CH₂)_FiveCOOH H H 1-AI-Pip (4) 2357 H H SO₂(CH₂)₆COOH H H 1-AI-Pip (4) 2358 H H SO₂CH₂COOMe 2-F H 1-AI-Pip (4) 2359 H H SO₂CH₂COOMe 3-F H 1-AI-Pip (4) 2360 H H SO₂CH₂COOMe 2-Cl H 1-AI-Pip (4) 2361 H H SO₂CH₂COOMe 3-Cl H 1-AI-Pip (4) 2362 H H SO₂CH₂COOMe 2-Br H 1-AI-Pip (4) 2363 H H SO₂CH₂COOMe 3-Br H 1-AI-Pip (4) 2364 H H SO₂CH₂COOMe 2-I H 1-AI-Pip (4) 2365 H H SO₂CH₂COOMe 3-I H 1-AI-Pip (4) 2366 H H SO₂CH₂COOMe 2-Me H 1-AI-Pip (4) 2367 H H SO₂CH₂COOMe 3-Me H 1-AI-Pip (4) 2368 H H SO₂CH₂COOMe 2-Et H 1-AI-Pip (4) 2369 H H SO₂CH₂COOMe 3-Et H 1-AI-Pip (4) 2370 H H SO₂CH₂COOMe 2-Pr H 1-AI-Pip (4) 2371 H H SO₂CH₂COOMe 3-Pr H 1-AI-Pip (4) 2372 H H SO₂CH₂COOMe 2-iPr H 1-AI-Pip (4) 2373 H H SO₂CH₂COOMe 3-iPr H 1-AI-Pip (4) 2374 H H SO₂CH₂COOMe 2-Bu H 1-AI-Pip (4) 2375 H H SO₂CH₂COOMe 3-Bu H 1-AI-Pip (4) 2376 H H SO₂CH₂COOMe 2-iBu H 1-AI-Pip (4) 2377 H H SO₂CH₂COOMe 3-iBu H 1-AI-Pip (4) 2378 H H SO₂CH₂COOMe 2-sBu H 1-AI-Pip (4) 2379 H H SO₂CH₂COOMe 3-sBu H 1-AI-Pip (4) 2380 H H SO₂CH₂COOMe 2-tBu H 1-AI-Pip (4) 2381 H H SO₂CH₂COOMe 3-tBu H 1-AI-Pip (4) 2382 H H SO₂CH₂COOMe 2-Pn H 1-AI-Pip (4) 2383 H H SO₂CH₂COOMe 3-Pn H 1-AI-Pip (4) 2384 H H SO₂CH₂COOMe 2-Hx H 1-AI-Pip (4) 2385 H H SO₂CH₂COOMe 3-Hx H 1-AI-Pip (4) 2386 H H SO₂CH₂COOMe 2-CF₃       H 1-AI-Pip (4) 2387 H H SO₂CH₂COOMe 3-CF₃       H 1-AI-Pip (4) 2388 H H SO₂CH₂COOMe 2-OMe H 1-AI-Pip (4) 2389 H H SO₂CH₂COOMe 3-OMe H 1-AI-Pip (4) 2390 H H SO₂CH₂COOMe 2-OEt H 1-AI-Pip (4) 2391 H H SO₂CH₂COOMe 3-OEt H 1-AI-Pip (4) 2392 H H SO₂CH₂COOMe 2-COOH H 1-AI-Pip (4) 2393 H H SO₂CH₂COOMe 3-COOH H 1-AI-Pip (4) 2394 H H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip (4) 2395 H H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip (4) 2396 H H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip (4) 2397 H H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip (4) 2398 H H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip (4) 2399 H H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip (4) 2400 H H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip (4) 2401 H H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip (4) 2402 H H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip (4) 2403 H H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip (4) 2404 H H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip (4) 2405 H H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip (4) 2406 H H SO₂CH₂COOMe 2-CONH₂     H 1-AI-Pip (4) 2407 H H SO₂CH₂COOMe 3-CONH₂     H 1-AI-Pip (4) 2408 H H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip (4) 2409 H H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip (4) 2410 H H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip (4) 2411 H H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip (4) 2412 H H SO₂CH₂COOMe 2-CON (Me)₂  H 1-AI-Pip (4) 2413 H H SO₂CH₂COOMe 3-CON (Me)₂  H 1-AI-Pip (4) 2414 H H SO₂CH₂COOMe 2-CON (Me) Et H 1-AI-Pip (4) 2415 H H SO₂CH₂COOMe 3-CON (Me) Et H 1-AI-Pip (4) 2416 H H SO₂CH₂COOMe 2-CON (Et)₂  H 1-AI-Pip (4) 2417 H H SO₂CH₂COOMe 3-CON (Et)₂  H 1-AI-Pip (4) 2418 H H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip (4) 2419 H H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip (4) 2420 H H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip (4) 2421 H H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip (4) 2422 H H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip (4) 2423 H H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip (4) 2424 H H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip (4) 2425 H H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip (4) 2426 H H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip (4) 2427 H H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip (4) 2428 H H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip (4) 2429 H H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip (4) 2430 H H SO₂CH₂COOMe 2-Cl 5-CONH₂     1-AI-Pip (4) 2431 H H SO₂CH₂COOMe 3-Cl 5-CONH₂     1-AI-Pip (4) 2432 H H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip (4) 2433 H H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip (4) 2434 H H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip (4) 2435 H H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip (4) 2436 H H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip (4) 2437 H H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip (4) 2438 H H SO₂CH₂COOMe 2-Me 5-CONH₂     1-AI-Pip (4) 2439 H H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip (4) 2440 H H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip (4) 2441 H H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip (4) 2442 H H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip (4) 2443 H H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip (4) 2444 H H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip (4) 2445 H H SO₂CH₂COOMe 3-Me 5-CONH₂     1-AI-Pip (4) 2446 H H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip (4) 2447 H H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip (4) 2448 H H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip (4) 2449 H H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip (4) 2450 H H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip (4) 2451 H H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip (4) 2452 H H SO₂CH₂COOMe 2-CONH₂     6-CONH₂     1-AI-Pip (4) 2453 H H SO₂CH₂COOMe 3-CONH₂     5-CONH₂     1-AI-Pip (4) 2454 H H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip (4) 2455 H H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip (4) 2456 6-OH H SO₂CH₂COOMe 2-F H 1-AI-Pip (4) 2457 6-OH H SO₂CH₂COOMe 3-F H 1-AI-Pip (4) 2458 6-OH H SO₂CH₂COOMe 2-Cl H 1-AI-Pip (4) 2459 6-OH H SO₂CH₂COOMe 3-Cl H 1-AI-Pip (4) 2460 6-OH H SO₂CH₂COOMe 2-Br H 1-AI-Pip (4) 2461 6-OH H SO₂CH₂COOMe 3-Br H 1-AI-Pip (4) 2462 6-OH H SO₂CH₂COOMe 2-I H 1-AI-Pip (4) 2463 6-OH H SO₂CH₂COOMe 3-I H 1-AI-Pip (4) 2464 6-OH H SO₂CH₂COOMe 2-Me H 1-AI-Pip (4) 2465 6-OH H SO₂CH₂COOMe 3-Me H 1-AI-Pip (4) 2466 6-OH H SO₂CH₂COOMe 2-Et H 1-AI-Pip (4) 2467 6-OH H SO₂CH₂COOMe 3-Et H 1-AI-Pip (4) 2468 6-OH H SO₂CH₂COOMe 2-Pr H 1-AI-Pip (4) 2469 6-OH H SO₂CH₂COOMe 3-Pr H 1-AI-Pip (4) 2470 6-OH H SO₂CH₂COOMe 2-iPr H 1-AI-Pip (4) 2471 6-OH H SO₂CH₂COOMe 3-iPr H 1-AI-Pip (4) 2472 6-OH H SO₂CH₂COOMe 2-Bu H 1-AI-Pip (4) 2473 6-OH H SO₂CH₂COOMe 3-Bu H 1-AI-Pip (4) 2474 6-OH H SO₂CH₂COOMe 2-iBu H 1-AI-Pip (4) 2475 6-OH H SO₂CH₂COOMe 3-iBu H 1-AI-Pip (4) 2476 6-OH H SO₂CH₂COOMe 2-sBu H 1-AI-Pip (4) 2477 6-OH H SO₂CH₂COOMe 3-sBu H 1-AI-Pip (4) 2478 6-OH H SO₂CH₂COOMe 2-tBu H 1-AI-Pip (4) 2479 6-OH H SO₂CH₂COOMe 3-tBu H 1-AI-Pip (4) 2480 6-OH H SO₂CH₂COOMe 2-Pn H 1-AI-Pip (4) 2481 6-OH H SO₂CH₂COOMe 3-Pn H 1-AI-Pip (4) 2482 6-OH H SO₂CH₂COOMe 2-Hx H 1-AI-Pip (4) 2483 6-OH H SO₂CH₂COOMe 3-Hx H 1-AI-Pip (4) 2484 6-OH H SO₂CH₂COOMe 2-CF₃       H 1-AI-Pip (4) 2485 6-OH H SO₂CH₂COOMe 3-CF₃       H 1-AI-Pip (4) 2486 6-OH H SO₂CH₂COOMe 2-OMe H 1-AI-Pip (4) 2487 6-OH H SO₂CH₂COOMe 3-OMe H 1-AI-Pip (4) 2488 6-OH H SO₂CH₂COOMe 2-OEt H 1-AI-Pip (4) 2489 6-OH H SO₂CH₂COOMe 3-OEt H 1-AI-Pip (4) 2490 6-OH H SO₂CH₂COOMe 2-COOH H 1-AI-Pip (4) 2491 6-OH H SO₂CH₂COOMe 3-COOH H 1-AI-Pip (4) 2492 6-OH H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip (4) 2493 6-OH H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip (4) 2494 6-OH H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip (4) 2495 6-OH H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip (4) 2496 6-OH H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip (4) 2497 6-OH H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip (4) 2498 6-OH H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip (4) 2499 6-OH H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip (4) 2500 6-OH H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip (4) 2501 6-OH H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip (4) 2502 6-OH H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip (4) 2503 6-OH H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip (4) 2504 6-OH H SO₂CH₂COOMe 2-CONH₂     H 1-AI-Pip (4) 2505 6-OH H SO₂CH₂COOMe 3-CONH₂     H 1-AI-Pip (4) 2506 6-OH H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip (4) 2507 6-OH H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip (4) 2508 6-OH H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip (4) 2509 6-OH H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip (4) 2510 6-OH H SO₂CH₂COOMe 2-CON (Me)₂  H 1-AI-Pip (4) 2511 6-OH H SO₂CH₂COOMe 3-CON (Me)₂  H 1-AI-Pip (4) 2512 6-OH H SO₂CH₂COOMe 2-CON (Me) Et H 1-AI-Pip (4) 2513 6-OH H SO₂CH₂COOMe 3-CON (Me) Et H 1-AI-Pip (4) 2514 6-OH H SO₂CH₂COOMe 2-CON (Et)₂  H 1-AI-Pip (4) 2515 6-OH H SO₂CH₂COOMe 3-CON (Et)₂  H 1-AI-Pip (4) 2516 6-OH H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip (4) 2517 6-OH H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip (4) 2518 6-OH H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip (4) 2519 6-OH H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip (4) 2520 6-OH H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip (4) 2521 6-OH H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip (4) 2522 6-OH H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip (4) 2523 6-OH H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip (4) 2524 6-OH H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip (4) 2525 6-OH H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip (4) 2526 6-OH H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip (4) 2527 6-OH H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip (4) 2528 6-OH H SO₂CH₂COOMe 2-Cl 5-CONH₂     1-AI-Pip (4) 2529 6-OH H SO₂CH₂COOMe 3-Cl 5-CONH₂     1-AI-Pip (4) 2530 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip (4) 2531 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip (4) 2532 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip (4) 2533 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip (4) 2534 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip (4) 2535 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip (4) 2536 6-OH H SO₂CH₂COOMe 2-Me 5-CONH₂     1-AI-Pip (4) 2537 6-OH H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip (4) 2538 6-OH H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip (4) 2539 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip (4) 2540 6-OH H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip (4) 2541 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip (4) 2542 6-OH H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip (4) 2543 6-OH H SO₂CH₂COOMe 3-Me 5-CONH₂     1-AI-Pip (4) 2544 6-OH H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip (4) 2545 6-OH H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip (4) 2546 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip (4) 2547 6-OH H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip (4) 2548 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip (4) 2549 6-OH H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip (4) 2550 6-OH H SO₂CH₂COOMe 2-CONH₂     6-CONH₂     1-AI-Pip (4) 2551 6-OH H SO₂CH₂COOMe 3-CONH₂     5-CONH₂     1-AI-Pip (4) 2552 6-OH H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip (4) 2553 6-OH H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip (4)

The activated blood coagulation factor X inhibitor of the present invention is preferably Exemplified Compound No. 83, 90, 93, 101, 137,
140, 142, 148, 177, 237, 297, 358, 478, 542, 663,
668, 788, 849, 864, 948, 1014, 1080, 1220, 1280, 1
408, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 141
9, 1420, 1422, 1424, 1426, 1434, 1440, 1442, 144
8, 1450, 1460, 1462, 1466, 1474, 1478, 1482, 148
4, 1492, 1498, 1509, 1513, 1539, 1638, 1711, 177
1, 1839, 1843, 1849, 1881, 1939, 1941, 1943, 194
5, 1949, 1951, 1955, 1963, 1969, 1971, 1975, 197
7, 1979, 1989, 1991, 1995, 2003, 2007, 2011, 201
3, 2027, 2038, 2040, 2042, 2044, 2048, 2054, 206
8, 2070, 2076, 2078, 2088, 2094, 2109, 2208, 226
2, 2266, 2272, 2304 or 2353 of activated blood coagulation factor X inhibitors may be mentioned,

More preferably, Exemplified Compound Nos. 90, 137, 1
77, 237, 297, 358, 478, 542, 663, 668, 788, 849, 8
64, 948, 1014, 1080, 1408, 1410, 1412, 1414, 141
6, 1419, 1420, 1426, 1440, 1442, 1450, 1460, 146
2, 1466, 1474, 1478, 1482, 1484, 1492, 1498, 150
9, 1513, 1638, 1711, 1771, 1839, 1843, 1849, 188
1, 1939, 1941, 1943, 1945, 1949, 1951, 1955, 196
9, 1971, 1975, 1979, 1989, 1991, 1995, 2003, 200
7, 2011, 2013, 2027, 2038, 2040, 2042, 2094, 220
8, 2262, 2266, 2272 or 2304 activated blood coagulation factor X inhibitors may be mentioned,

Even more preferably, Exemplified Compound Nos. 668, 8
49, 1014, 1410, 1412, 1414, 1420, 1426, 1440, 144
2, 1450, 1460, 1462, 1466, 1474, 1478, 1482, 148
4, 1498, 1509, 1839, 1843, 1939, 1941, 1943, 194
5, 1949, 1955, 1969, 1971, 1975, 1979, 1989, 199
1, 1995, 2003, 2007, 2011, 2013, 2027 or 2038, activated blood coagulation factor X inhibitors,

Particularly preferably, Exemplified Compound No. 1410: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate, Exemplified compound No. 1414: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate, Exemplified Compound No. 1420: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl). -2-
(E) -Propenyl] sulfamoylethyl acetate, Exemplified Compound No. 1460: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl). -2-
(E) -Propenyl] sulfamoylethyl acetate, Exemplified Compound No. 1939: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid, Exemplified compound number 1941: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylacetic acid, Exemplified Compound No. 1943: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2. −
(E) -Propenyl] sulfamoylacetic acid, Exemplified Compound No. 1949: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl)- 2-
(E) -Propenyl] sulfamoylacetic acid, Exemplified Compound No. 1969: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) )
2- (E) -Propenyl] sulfamoylacetic acid, Exemplified Compound Number 1989: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidino) Phenyl) -2-
(E) -Propenyl] sulfamoylacetic acid, Exemplified Compound No. 2003: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate, Exemplified Compound No. 2007: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) ) -2-
(E) -Propenyl] sulfamoylacetic acid, or exemplified compound No. 2038: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2-fluoro-2-
(E) -propenyl] sulfamoyl acetic acid may be mentioned.

[0078]

BEST MODE FOR CARRYING OUT THE INVENTION The activated blood coagulation factor X inhibitor of the present invention can be easily produced according to the following method.

[0079]

[Chemical 12]

[0080]

[Chemical 13]

[0081]

[Chemical 14]

[0082]

[Chemical 15] In the above, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above, R ³ a represents a hydrogen atom,
R ³ b is a C ₁ -C ₆ alkyl group; C substituted with a protected hydroxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group
₁ -C ₆ alkyl group; general formula

[0083]

[Chemical 16] (Wherein R ⁷ , m and n have the same meanings as described above); C ₇ -C ₁₅ aralkyl group; C ₁ -C ₆
An alkylsulfonyl group; or (C ₁ -C ₆ alkoxy)
A C ₁ -C ₆ alkylsulfonyl group substituted with a carbonyl group, and R ³ c is a C ₁ -C ₆ alkyl group or C ₇ -C ₁₅
An aralkyl group, R ³ d represents an C ₂ -C ₆ alkanoyl group substituted by C ₁ -C ₆ alkanoyl group or a protected hydroxyl group, R ⁸ is, in addition to the amino group is protected R ⁶
And the same meaning, R ⁹ is, C ₁ -C ₅ alkyl group, C ₆ -C
_{A 14} aryl group or a C ₇ -C ₁₄ aralkyl group, R ¹⁰
Represents a C ₁ -C ₆ alkanoyl group; or a C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group, and R ¹¹ represents
A C ₁ -C ₆ alkyl group is shown, R ¹² is a hydroxyl-protecting group, R ¹³ is the same as R ¹ except that the hydroxyl group is protected, and X is a halogen atom.

In the above, in the definition of R ³ b, "C
₁ -C ₆ alkyl group "," (C ₁ -C ₆ alkoxy) carbonyl C ₁ -C ₆ alkyl group substituted with a group "," the general formula

[0085]

[Chemical 17] (Wherein R ⁷ , m and n have the same meanings as described above), “C ₇ -C ₁₅ aralkyl group”,
"C ₁ -C ₆ alkylsulfonyl group", "(C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkylsulfonyl group substituted with a carbonyl group;" in the definition of R ³ c "C ₁ -C ₆ “Alkyl group”, “C ₇ -C ₁₅ aralkyl group”; and “C ₁ -C ₆ alkanoyl group” in the definition of R ³ d is respectively R ³
Has the same meaning as defined in.

[0086] In the above, R ³ b "C ₁ -C ₆ alkyl group substituted with a protected hydroxyl group" in the definition of the other hydroxyl groups are protected, as defined by R ³ Show the same meaning as the thing.

In the above, “C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group” in the definition of R ³ d
Is, in addition to the hydroxyl group is protected, as defined for defined in R ³ "hydroxy C ₂ -C ₆ alkanoyl group".

[0088] In the above, "hydroxyl protecting group" in R ³ b "C ₁ -C ₆ alkyl group substituted with a protected hydroxyl group" in the definition of, in the definition of R ³ d and R ¹⁰ in "hydroxyl protecting group" in "protected C ₂ -C ₆ alkanoyl group substituted by a hydroxyl group", in the definition of R ¹² "hydroxyl-protecting group", the protection of "hydroxyl groups contained in R ¹³ The “group” is not particularly limited as long as it is a group generally used as a protective group for a hydroxyl group, and examples thereof include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group and pivaloyl group. , Valeryl group, isovaleryl group, octanoyl group, nonanoyl group, decanoyl group, 3-methylnonanoyl group, 8-methylnonanoyl group, 3-ethyloctanoyl group, 3,7-dimethyloctanoyl group, u Decanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, 1-methylpentadecanoyl group, 14-methylpentadecanoyl group, 13,13-dimethyltetradecanoyl group, Heptadecanoyl group, 15
-Methylhexadecanoyl group, octadecanoyl group, 1
-Alkanoyls such as methylheptadecanoyl, nonadecanoyl, eicosanoyl or heniicosanoyl; carboxylated alkanoyls such as succinoyl, glutaroyl or adipoyl; chloroacetyl, dichloroacetyl, trichloroacetyl or tri Halogenoalkanoyls such as fluoroacetyl group; alkoxyalkanoyls such as methoxyacetyl group; unsaturated alkanoyls such as (E) -2-methyl-2-butenoyl group; benzoyl group, α-naphthoyl group or β- Arylcarbonyls such as naphthoyl; halogenoarylcarbonyls such as 2-bromobenzoyl or 4-chlorobenzoyl; 2,4,6
Alkylated arylcarbonyls such as trimethylbenzoyl or 4-toluoyl; alkoxylated arylcarbonyls such as 4-anisoyl; like 2-carboxybenzoyl, 3-carboxybenzoyl or 4-carboxybenzoyl Carboxylated arylcarbonyls; Nitrated arylcarbonyls such as 4-nitrobenzoyl group or 2-nitrobenzoyl group; Alkoxycarbonylated arylcarbonyls such as 2- (methoxycarbonyl) benzoyl group; 4-phenylbenzoyl group Arylated arylcarbonyls such as; tetrahydropyran-2-yl group, 3-bromotetrahydropyran-2-yl group, 4-methoxytetrahydropyran-4-yl group, tetrahydrothiopyran-
2-yl group or 4-methoxytetrahydrothiopyran-
Tetrahydropyranyls or tetrahydrothiopyranyls such as 4-yl group; Tetrahydrofuranyls or tetrahydrothiofuranyls such as tetrahydrofuran-2-yl group or tetrahydrothiofuran-2-yl group; Methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group,
Alkoxymethyls such as isopropoxymethyl, butoxymethyl or t-butoxymethyl; alkoxylated alkoxymethyls such as 2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl or bis (2 -Chloroethoxy) methyl group such as halogenoalkoxymethyls; 1-ethoxyethyl group or 1-
Alkoxylated ethyls such as (isopropoxy) ethyl group; halogenated ethyls such as 2,2,2-trichloroethyl group; benzyl group, α-naphthylmethyl group, β
-Naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group or 9-
Aralkyls substituted with 1 to 3 aryl groups such as anthrylmethyl group; 4-methylbenzyl group, 2,
4,6-trimethylbenzyl group, 3,4,5-trimethylbenzyl group, 4-methoxybenzyl group, 4-methoxyphenyldiphenylmethyl group, 2-nitrobenzyl group,
Aralkyls in which the aryl ring is substituted with an alkyl, alkoxy, halogen or cyano group, such as a 4-nitrobenzyl group, a 4-chlorobenzyl group, a 4-bromobenzyl group or a 4-cyanobenzyl group; a methoxycarbonyl group,
Alkoxycarbonyls such as ethoxycarbonyl group, t-butoxycarbonyl group or isobutoxycarbonyl group or halogenated alkoxycarbonyls such as 2,2,2-trichloroethoxycarbonyl group; vinyloxycarbonyl group or allyloxycarbonyl group Or an benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 3,4-dimethoxybenzyloxycarbonyl group, a 2-nitrobenzyloxycarbonyl group or 4-
1 or 2 such as a nitrobenzyloxycarbonyl group
Aralkyloxycarbonyls in which the aryl ring may be substituted with four alkoxy or nitro groups; trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group, methyldiisopropylsilyl group, methyldi-t-butylsilyl Group, a triisopropylsilyl group, a diphenylmethylsilyl group, a diphenylbutylsilyl group, a diphenylisopropylsilyl group or a phenyldiisopropylsilyl group, which may be a "substituted by a protected hydroxyl group" in the definition of R ³ b. “C ₁ -C ₆ alkyl group”, “protecting group for hydroxyl group”, “C ₂ -C ₆ alkanoyl group substituted with protected hydroxyl group” in the definitions of R ³ d and R ¹⁰ The "protecting group" is preferably an alkanoyl group, particularly preferably acetyl group. A group. On the other hand, the “hydroxyl protecting group” in the definition of R ^{12 and} the “hydroxyl protecting group” contained in R ¹³ are preferably alkoxylated alkoxymethyls, and particularly preferably methoxymethyl group.

In the above, the "amino group-protecting group" for R ⁸ is not particularly limited as long as it is a group generally used as an amino group-protecting group. For example, formyl group, C ₁ -C ₆ alkanoyl groups such as acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, triaryl group Fluoroacetyl group, 3-fluoropropionyl group, 4,4-
Dichloro butyryl group, methoxyacetyl group, butoxy acetyl group, ethoxy propionyl group or a propoxy butyrate such as Lil groups, halogen or C ₁ -C C ₁ -C substituted with ₄ alkoxy ₄ alkanoyl group; an acryloyl group, propioloyl group Unsaturated C ₁ -C ₄ alkanoyl groups such as, methacryloyl group, crotonoyl group or isocrotonoyl group; benzoyl group, α-naphthoyl group, β-
Naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro-α-naphthoyl group, 4-toluoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group , 2,
4,6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group, 4-anisoyl group, 4-propoxybenzoyl group, 4-t-butoxybenzoyl group, 6-ethoxy-α-naphthoyl group, 2-ethoxycarbonylbenzoyl group Group, 4-t-butoxycarbonylbenzoyl group, 6-
Methoxycarbonyl-α-naphthoyl group, 4-phenylbenzoyl group, 4-phenyl-α-naphthoyl group, 6-
α-naphthylbenzoyl group, 4-nitrobenzoyl group,
Halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ such as 2-nitrobenzoyl group or 6-nitro-α-naphthoyl group.
Alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₆ -C
C ₆ -C ₁₀ arylcarbonyl group which may be substituted with ₁₀ aryl or nitro; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s -Butoxycarbonyl group, t-butoxycarbonyl group, chloromethoxycarbonyl group, 2,
2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group, 2-
Trimethylsilyl ethoxycarbonyl group, 4-tripropylsilyl butoxy such as carbonyl group or t- butyldimethylsilyl propoxycarbonyl group, a halogen or tri C ₁ -C ₄ optionally substituted with an alkyl silyl C ₁
-C ₄ alkoxycarbonyl group; C ₂ -C ₅ alkenyloxycarbonyl group such as vinyloxycarbonyl group, allyloxycarbonyl group, 1,3-butadienyloxycarbonyl group or 2-pentenyloxycarbonyl group; phthaloyl group Aryldicarbonyl groups such as; benzyl, phenethyl, 3-phenylpropyl, 4
An aralkyl group such as -phenylbutyl group, α-naphthylmethyl group, β-naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group or 9-anthrylmethyl group; or benzyloxycarbonyl Group, (1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β
-C ₇ -C ₁₅ aralkyl optionally substituted with methoxy or nitro, such as naphthylmethyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group. It may be an oxycarbonyl group, preferably a C ₁ -C ₄ alkanoyl group; a trifluoroacetyl group; a methoxyacetyl group; a benzoyl group; an α-naphthoyl group; a β-naphthoyl group; an anisoyl group; a nitrobenzoyl group; C ₁ -C ₄ alkoxycarbonyl group; 2,2
2-trichloroethoxycarbonyl group; triethylsilylmethoxycarbonyl group; 2-trimethylsilylethoxycarbonyl group; vinyloxycarbonyl group; allyloxycarbonyl group; phthaloyl group; benzyl group; benzyloxycarbonyl group; or nitrobenzyloxycarbonyl group, More preferably, formyl group, acetyl group, benzoyl group, 4-anisoyl group, 4-nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, phthaloyl group, benzyl group, benzyl. It is an oxycarbonyl group or a p-nitrobenzyloxycarbonyl group, and particularly preferably a t-butoxycarbonyl group.

In the above, "C _1-in the definition of R ⁹
“C ₅ alkyl group” means, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
a linear or branched alkyl group having 1 to 5 carbon atoms such as s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group or 1-ethylpropyl group. It is preferably a C ₁ -C ₃ alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group.

In the above, in the definition of R ⁹ , "C _6-
The "C ₁₄ aryl group" may be, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group or an anthracenyl group, preferably a phenyl group or a naphthyl group. And more preferably a phenyl group.

In the above, "C _7-in the definition of R ⁹
“C ₁₄ aralkyl group” is, for example, a benzyl group, α-naphthylmethyl group, indenylmethyl group, diphenylmethyl group, 2-phenethyl group, 2-α-naphthylethyl group, 3
-Phenylpropyl group, 3-α-naphthylpropyl group,
Phenylbutyl group, 4-α-naphthylbutyl group or 5-
One or two aromatic hydrocarbon groups having 6 to 14 carbon atoms such as a phenylpentyl group may be a group bonded to a "C ₁ -C ₅ alkyl group", and preferably a benzyl group, α
-Naphthylmethyl group, diphenylmethyl group or 2-phenethyl group, more preferably benzyl group or 2-phenethyl group, and particularly preferably benzyl group.

In the above, "C _{1 in} the definition of R ¹⁰ "
“C ₆ alkanoyl group” is, for example, a straight or branched chain having 1 to 6 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group. It is a branched alkanoyl group, preferably a C ₁ -C ₄ alkanoyl group, and particularly preferably an acetyl group.

[0094] In the above, "C ₂ -C ₆ alkanoyl group" portion of the at "substituted with a protected hydroxy group the C ₂ -C ₆ alkanoyl group" in the definition of R ¹⁰ is the "C ₁ - In the “C ₆ alkanoyl group”, a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, preferably a C ₂ -C ₄ alkanoyl group, and more preferably an acetyl group.

In the above, "C _{1 in} the definition of R ¹¹ "
“C ₆ alkyl group” is, for example, a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-
Ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1
-Methylpentyl group, 3,3-dimethylbutyl group, 2,
2-dimethylbutyl group, 1,1-dimethylbutyl group,
It may be a linear or branched alkyl group having 1 to 6 carbon atoms, such as a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group. , preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, particularly preferably an ethyl group.

In the above, the "halogen atom" in the definition of X is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Method A is a method for producing an activated blood coagulation factor X inhibitor having the general formula (I).

The step A1 is a step for producing a compound having the general formula (V), which comprises reacting the compound having the general formula (III) in the presence of a phosphine compound and an azo compound in an inert solvent. Is achieved by condensing with a compound having

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is, for example, an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane. Or ethers such as diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or ethers, and more preferably halogenated hydrocarbons (dichloromethane. ) Or d Ethers (particularly diethyl ether or tetrahydrofuran). The phosphines used are, for example, tri C ₁ -C ₆ alkylphosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; triphenylphosphine, triindenylphosphine or triindenylphosphine or triindenylphosphine. Tri C ₆ -C ₁₀ arylphosphine such as naphthylphosphine;
Or tri C _6-, which may have C ₁ -C ₄ alkyl as a substituent, such as tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine. It may be a C ₁₀ arylphosphine, preferably triC ₁ -C ₆ alkylphosphines (especially trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or triC ₆ -C ₁₀ arylphosphine (especially triphenylphosphine). , Triindenylphosphine or trinaphthylphosphine), and more preferably tributylphosphine or triphenylphosphine. The azo compounds used are, for example, di-C ₁ -C ₄ alkyl azodicarboxylates such as azodicarbonyldipiperidine or dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate. Get
Preference is given to azodicarbonyldipiperidine, dimethyl azodicarboxylate or diethyl azodicarboxylate.
The reaction temperature will vary depending on the starting compounds, reagents, etc., but is usually −50 ° C. to 100 ° C., and preferably 0 ° C. to 60 °
℃. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours, and preferably 10 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, if an insoluble matter is present, it is filtered off and the solvent is distilled off, or after the reaction is completed, the solvent is distilled off and water is poured into the resulting residue to form water. After extraction by adding an immiscible solvent (eg benzene, ether, ethyl acetate, etc.), the extract is washed with water, the organic layer is dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound. . The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Step A2 is a step of producing an activated blood coagulation factor X inhibitor having the general formula (I),
(A) a reaction for converting a cyano group into an amidino group,
(B) a reaction for removing a protecting group of a protected amino group,
(C) Acetoimidoylation reaction of an amino group, optionally (d) a hydrolysis reaction of an ester, and (e) a reaction of removing a protecting group of a protected hydroxyl group, by appropriately changing the order and combining them. To be done.

The "reaction for converting a cyano group into an amidino group" which is the essential reaction (a) is generally carried out according to a method well known in the art of the present invention. In the absence of solvent (preferably in an inert solvent),
In the presence of an acid, it is reacted with an alcohol to ammonolyse the imino ether compound produced as an intermediate, or (2) the starting compound is reacted with hydroxylamine in an inert solvent in the presence or absence of a base, This can be achieved by hydrogenolysis of an amidoxime compound produced as an intermediate.

The reaction (a) (1) is a reaction consisting of two steps. First, the first step is a reaction of reacting a nitrile group with an alcohol in the presence of an acid to obtain an imino ether compound. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene;
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; methyl acetate or ethyl acetate Esters such as; nitro compounds such as nitromethane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2
-Amides such as pyrrolidinone; sulfoxides such as dimethyl sulfoxide or sulfolane; or mixed solvents of the above organic solvents, preferably aromatic hydrocarbons (especially benzene) or halogenated hydrocarbons ( Dichloromethane is particularly preferable, and halogenated hydrocarbons (especially dichloromethane) are particularly preferable, and the reaction also serves as a solvent in an excess of alcohols (for example, methanol, ethanol, propanol, 2-propanol, Butanol or isobutanol, etc., and preferably methanol or ethanol).
In addition, the reaction is usually carried out in alcohol as long as there is no problem. Examples of the acid used include mineral acids such as hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, Benzenesulfonic acid or p
A sulfonic acid such as toluene sulfonic acid; or a Lewis acid such as boron trifluoride, aluminum chloride, iron (III) chloride, zinc chloride, mercury (II) chloride, preferably a mineral acid or a Lewis acid An acid, particularly preferably hydrogen chloride. The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 10 minutes to 48 hours, and preferably 1 hour to 15 hours. After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method in which the solvent is distilled off), but it can also be used in the next reaction without isolation or purification.

The second step of the reaction (a) (1) is a reaction in which the imino ether compound produced in the first step is subjected to ammonia decomposition. This reaction is usually performed in an inert solvent,
It is carried out in the presence of ammonium ions. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; It may be water; or a mixed solvent of alcohols and water, preferably methanol, ethanol, water, water-containing methanol or water-containing ethanol, and particularly preferably water-containing methanol or water-containing ethanol. The ammonium source of ammonium ions used may be, for example, aqueous ammonia, ammonium chloride, ammonium carbonate or a mixture thereof, preferably ammonium chloride. The pH in the reaction is neutral to weakly basic, and preferably pH 7 to 9 using aqueous ammonia and hydrochloric acid. The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −
The temperature is 10 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 10 minutes to 48 hours, and preferably 1 hour to 15 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.
For example, after the reaction is completed, the solvent is distilled off, or after the reaction is completed, water is added to the reaction solution and a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound. After that, wash the extracted organic layer with water,
After drying with anhydrous magnesium sulfate or the like, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The reaction (a) (2) is a reaction consisting of two steps. First, the first step is a reaction of reacting a nitrile group with hydroxylamine in an inert solvent, if desired, in the presence of a base to obtain an amidoxime compound. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, hexane,
Aliphatic hydrocarbons such as cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane,
Chloroform, carbon tetrachloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane Nitriles such as acetonitrile or isobutyronitrile; Alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N -Methyl-2
Amides such as pyrrolidinone; sulfoxides such as dimethyl sulfoxide or sulfolane; or water, preferably alcohols (especially methanol or ethanol). The source of hydroxylamine used can include aqueous solutions of hydroxylamine, solutions of organic solvents or salts with acids. The base used is not particularly limited as long as it can neutralize a salt of hydroxylamine with an acid (in addition, it is not always necessary when directly using a solution of hydroxylamine). No.), for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal acetates such as sodium acetate; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide. Alkali metal alkoxides;
Alternatively, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N
-Dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane (DA
BCO) or an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates (particularly sodium carbonate) or alkali metal alkoxides. Class (especially potassium t-butoxide). The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually 0 ° C. to 150 ° C.,
It is preferably 50 ° C to 100 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 1 hour to 24 hours, and preferably 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method in which the solvent is distilled off), but it can also be used in the next reaction without particular isolation and purification.

The second step of the reaction (a) (2) is a reaction for hydrogenolysis of the amidooxime compound produced in the first step. Usually, the hydroxyl group is modified with a leaving group prior to hydrogenolysis, but an acetyl group is commonly used for convenience. Acetylation is usually carried out using acetic anhydride in acetic acid, but it can also be carried out in a solvent if necessary. The solvent used for acetylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Aromatics such as benzene, toluene or xylene;
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro such as nitromethane Compounds; or may be nitriles such as acetonitrile or isobutyronitrile, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially tetrahydrofuran). The reaction temperature for acetylation varies depending on the starting compounds, reagents, etc., but is usually 0 ° C. to 150 ° C., and preferably 10 ° C. to 50 ° C. The reaction time for acetylation varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 24 hours, and preferably 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction can be prepared by a conventional method (for example, after completion of the reaction,
It is collected from the reaction mixture according to the method of distilling off the solvent), but it can also be used for the next reaction without isolation or formation.

The hydrogenolysis of the amidooxime compound (deacetoxylation when the hydroxyl group is acetylated) is usually carried out subsequently without changing the reaction solvent. If desired, the solvent is once distilled off, and the resulting residue is again
It can also be dissolved in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; meta Lumpur, ethanol, propanol, alcohols such as 2-propanol, butanol or isobutanol; formamide, N, N- dimethylformamide, N, N- dimethylacetamide or N- methyl-2
-Amides such as pyrrolidinone; sulfoxides such as dimethylsulfoxide or sulfolane; carboxylic acids such as formic acid or acetic acid; water; or may be a mixed solvent of the above solvents, preferably alcohols (especially methanol or Ethanol), acetic acid, or a mixed solvent thereof. The catalyst used in the hydrogenolysis is not particularly limited as long as it is used in a usual catalytic reduction reaction, and for example, palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon. , Raney nickel, rhodium-aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferably palladium-carbon. The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C.,
It is preferably 0 ° C. to 80 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 1 hour to 24 hours, and preferably 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the catalyst is filtered off, the solvent is distilled off, or after the reaction is completed, the catalyst is filtered off, water is added to the reaction solution, and a solvent immiscible with water (for example, benzene, Ether, ethyl acetate, etc.) to extract the target compound, and then the extracted organic layer is washed with water,
After drying with anhydrous magnesium sulfate or the like, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The essential reaction (b), "removing a protecting group of a protected amino group", is generally carried out as follows according to a method well known in the art of synthetic organic chemistry.

The amino-protecting group is a formyl group, acetyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p −
When it is a nitrobenzyloxycarbonyl group, it can be removed by treating with an acid in an inert solvent or an aqueous solvent. At that time, the target compound can be obtained as a salt. The acid used can be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene,
Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether. Ethers such as; esters such as methyl acetate or ethyl acetate; methanol, ethanol, propanol,
Alcohols such as 2-propanol or butanol; formamide, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or a mixed solvent of water and the above solvent. Among them, preferred are halogenated hydrocarbons, ethers, alcohols, fatty acids or a mixed solvent of water and the above solvent, and more preferred halogenated hydrocarbons (particularly dichloromethane), Ethers (particularly tetrahydrofuran or dioxane), fatty acids (particularly acetic acid), alcohols (particularly methanol or ethanol), or water or a mixed solvent of water and the above solvent.
The reaction temperature varies depending on the raw material compound, the solvent or the acid used, but is usually −10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time varies depending on the starting compound, the solvent or the acid used, but usually 5
Minutes to 48 hours, preferably 10 minutes to 15 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is filtered, optionally neutralized appropriately, the solvent is distilled off and dried, or the reaction solution is poured into water, or if necessary, appropriately. Neutralize, add a solvent that is immiscible with water (eg benzene, ether, ethyl acetate, etc.) and extract, wash the organic layer containing the target compound with water, then dry with anhydrous magnesium sulfate, etc., and distill off the solvent. As a result, the target compound is obtained. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an alkanoyl group, an arylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aryldicarbonyl group, an aralkyl group or an aralkyloxycarbonyl group, it is used in an inert solvent or an aqueous solvent. It can be removed by treatment with a base in. Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; sodium hydrogen carbonate,
Alkali metal bicarbonates such as potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride;
Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl. Mercaptan alkali metals such as sodium mercaptan; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] organic bases such as undec-7-ene (DBU), preferably alkali metal carbonates (especially sodium or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or water). Potassium oxide), alkali metal alkoxides (especially sodium methoxide,
Sodium ethoxide or potassium-t-butoxide)
Alternatively, organic bases (especially hydrazine or methylamine). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as samethylphosphoric acid triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons, ethers, alcohols, or water And a mixed solvent of the above solvent, more preferably an ether (particularly tetrahydrofuran or dioxane), an alcohol (particularly methanol or ethanol), or a mixed solvent of water and the above solvent. The reaction temperature varies depending on the raw material compound, the solvent or the base used, but is usually −10 ° C. to 50 ° C.,
It is preferably -5 ° C to 10 ° C. The reaction time varies depending on the raw material compound, solvent or base used, but is usually 5 minutes to 20 hours, and preferably 10 minutes to 3
It's time. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is filtered or, if necessary, neutralized with an acid and then the solvent is distilled off, or water is poured into the reaction solution to adjust the pH of the aqueous layer. Filter the resulting precipitate, or
Or a solvent immiscible with water (eg benzene, ether,
Ethyl acetate etc.) is added for extraction, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

When the amino-protecting group is a t-butoxycarbonyl group, it can be removed by treatment with a silyl compound or a Lewis acid, particularly in an inert solvent. As the silyl compound used, for example,
Trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl trifluoromethanesulfonate can be mentioned, and the Lewis acid used is
For example, aluminum chloride etc. can be mentioned. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; diethyl ether, It may be an ether such as tetrahydrofuran or dioxane; or a nitrile such as acetonitrile, preferably a halogenated hydrocarbon (especially dichloromethane or chloroform) or a nitrile (especially acetonitrile).
The reaction temperature varies depending on the raw material compound, reagent, solvent, etc., but is usually −20 ° C. to 100 ° C., and preferably 0
C. to 50.degree. The reaction time depends on the starting compounds, reagents,
The time is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours, varying depending on the solvent, the reaction temperature and the like.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an allyloxycarbonyl group, it can be removed in the same manner as in the case of an aralkyl group or the like, by the catalytic reduction reaction. That is, it can be removed using palladium and triphenylphosphine or nickel tetracarbonyl.

The amino-protecting group is an aralkyl group or C
_{When it is a 7-} C ₁₁ aralkyloxycarbonyl group, it is usually contacted with a reducing agent (preferably, in an inert solvent).
Examples thereof include a method of removing by catalytic reduction) in the presence of a catalyst or a method of removing using an oxidizing agent. In the case of the reaction of removing the protective group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in this reaction, and examples thereof include aliphatic hydrocarbons such as hexane or cyclohexane; toluene. , Aromatic hydrocarbons such as benzene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane;
Esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or 2-propanol; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably Has
Aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids or mixed solvents of these organic solvents and water, more preferably alcohols (especially methanol or ethanol) , A fatty acid (particularly formic acid or acetic acid) or a mixed solvent of these organic solvents and water. The catalyst used is not particularly limited as long as it is used in a usual catalytic reduction reaction, and examples thereof include palladium-carbon, Raney-nickel, rhodium-aluminum oxide and palladium-barium sulfate. However, it is preferably palladium-carbon or Raney-nickel. The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm, preferably 1 atm. The reaction temperature varies depending on the raw material compound, the solvent, the reducing agent used, etc., but is usually 0 ° C. to 100 ° C., and preferably 1
The temperature is 0 to 50 ° C. The reaction time varies depending on the raw material compound, the solvent, the reducing agent used, the reaction temperature and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the catalyst is filtered off, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.). )
After extraction, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, and examples thereof include ketones such as acetone; halogenated carbonization such as dichloromethane, chloroform or carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; N, N-dimethylformamide, N, N
Amides such as dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons , Nitriles, ethers, amides, sulfoxides or mixed solvents of these organic solvents and water, more preferably ketones (especially acetone), halogenated hydrocarbons (especially dichloromethane), nitrile It is a solvent (especially acetonitrile), an amide (especially hexamethylphosphorotriamide), a sulfoxide (especially dimethylsulfoxide) or a mixed solvent of these organic solvents and water. The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably ,
CAN or DDQ. The reaction temperature varies depending on the raw material compound, the solvent, the oxidizing agent used, etc., but is usually 0.
C. to 150.degree. C., preferably 10.degree. C. to 50.degree. The reaction time varies depending on the compound, the solvent, the oxidizing agent used, etc., but is usually 15 minutes to 24 hours,
It is preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, water is poured into the reaction solution to make the aqueous layer alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate). Etc.), and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

In the essential reaction (c), "acetamidoidylation of amino group", the starting compound is treated with ethylacetate in an inert solvent in the presence or absence of a base (preferably in the presence of a base). It is achieved by reacting with imidate or ethylacetimidate hydrochloride, preferably ethylacetimidate hydrochloride. The solvent used in the reaction (c) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, an aliphatic such as hexane, cyclohexane, heptane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether ,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; methanol, ethanol, propanol, Alcohols such as 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformamide,
It may be an amide such as N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or a sulfoxide such as dimethylsulfoxide or sulfolane, preferably alcohols (especially ethanol). The base used in the reaction (c) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; water. Alkali metal hydroxides such as sodium oxide, potassium hydroxide or lithium hydroxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N,
N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] ] Octane (DABCO) or 1,
It may be an organic base such as 8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates (sodium carbonate or potassium carbonate) or organic bases (especially triethylamine). ). The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 1 hour to 48 hours, and preferably 5 hours to 15 hours. After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or after the reaction is completed, water is added to the reaction solution and a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.)
After extracting the target compound by adding the, the extracted organic layer was washed with water, dried with anhydrous magnesium sulfate or the like,
The target compound is obtained by distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization,
It can be further purified by reprecipitation and chromatography.

The desired reaction (d), "ester hydrolysis reaction", is carried out according to a method generally known in the art of organic synthetic chemistry by reacting the starting compound with an acid or base in an inert solvent or in the absence of a solvent. It can be achieved by hydrolysis below, but hydrolysis with an acid is more preferred. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol and It may be a mixed solvent of water, preferably hydrous methanol or hydrous ethanol. The acid used is, for example, hydrochloric acid,
Mineral acids such as hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; sulfones such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid An acid; or a carboxylic acid salt such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably a mineral acid (especially hydrochloric acid). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or sodium hydroxide. , Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide,
Preferred is sodium hydroxide. The reaction temperature varies depending on the raw material compounds, reagents, etc., but in the reaction using an acid,
Generally, 0 ° C to 150 ° C (preferably 50 ° C to 100 ° C)
C.), and in the reaction using a base, it is usually -10.degree. C. to 50.degree. C. (preferably -5.degree. C. to 10.degree. C.). The reaction time varies depending on the starting compounds, reagents, reaction temperature,
The reaction using an acid is usually 30 minutes to 48 hours (preferably 3 hours to 10 hours), and the reaction using a base is usually 5 minutes to 10 hours (preferably 10 minutes to 3 hours). ). After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or after the reaction is completed, the reaction solution is acidified with an acid (for example, hydrochloric acid), and the precipitated target compound is collected by filtration, or a solvent immiscible with water. (For example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound. To be After completion of the reaction, a carbonate salt of the target compound can be obtained by passing carbon dioxide gas in an aqueous solvent or adding sodium carbonate or potassium carbonate. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The desired reaction (e) "removing the protecting group of a protected hydroxyl group" is described in, for example, Protective Groups in Organic Synthesis, 3rd Edition, T.W. W. Green and P. G. M. Watts, John Wiley and Sons Inc. [Prot
ective Groups in Organic Synthesis, 3rd edition,
TWGreene &PGMWuts; John Wiley & Sons, Inc.]
Can be performed according to the method described in.

The hydroxyl protecting group is a formyl group, acetyl group, benzoyl group, tetrahydropyran-2-yl group,
3-bromotetrahydropyran-2-yl group, 4-methoxytetrahydropyran-4-yl group, tetrahydrothiopyran-2-yl group, 4-methoxytetrahydrothiopyran-4-yl group, tetrahydrofuran-2-yl group, Tetrahydrothiofuran-2-yl group, methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group, t-butoxymethyl group,
2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, 1-ethoxyethyl group, 1- (isopropoxy)
Ethyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group , Benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, in an inert solvent. Alternatively, it can be removed by treating with an acid in an aqueous solvent. The acid used may be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylform Amides, amides such as N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or a mixture of water with the above solvents. Can be a solvent,
Preferred are halogenated hydrocarbons, ethers, esters, alcohols, fatty acids or a mixed solvent of water and the above solvent, and more preferred are halogenated hydrocarbons (particularly dichloromethane) and ethers ( Particularly, tetrahydrofuran or dioxane), esters (especially ethyl acetate), fatty acids (especially acetic acid) or water or a mixed solvent of water and the above solvent. The reaction temperature varies depending on the raw material compound, the solvent or the acid used, but is usually -10 ° C to 15 ° C.
It is 0 ° C., and preferably 0 ° C. to 60 ° C. While the reaction time varies depending on the raw material compound, solvent or acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added, and then the target compound The organic layer containing is washed with water, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The hydroxyl-protecting group is an alkanoyl group, a carboxylated alkanoyl group, a halogenoalkanoyl group, an alkoxyalkanoyl group, an unsaturated alkanoyl group, an arylcarbonyl group, a halogenoarylcarbonyl group, an alkylated arylcarbonyl group, a carboxylated arylcarbonyl group, The nitrated arylcarbonyls, alkoxycarbonylated arylcarbonyls or arylated arylcarbonyls can be removed by treatment with a base in an inert solvent or an aqueous solvent. The base used is, for example, sodium carbonate,
Alkali metal carbonates such as potassium carbonate or lithium carbonate; Alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; Alkali metal hydrogen such as lithium hydride, sodium hydride or potassium hydride Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan Mercaptan alkali metals such as sodium or ethyl mercaptan sodium; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU), preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides. (Especially sodium methoxide, sodium ethoxide or potassium t-butoxide) or organic bases (especially hydrazine or methylamine). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as samethylphosphoric acid triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons, ethers, alcohols, or water And a mixed solvent of the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol),
Alternatively, it is a mixed solvent of water and the above solvent. The reaction temperature varies depending on the raw material compound, the solvent or the base used,
It is usually -10 ° C to 150 ° C, preferably 0 ° C to 5 ° C.
It is 0 ° C. The reaction time varies depending on the raw material compound, solvent or base used, but is usually 50 minutes to 20 hours, and preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, and the organic layer containing the target compound is washed with water. After that, the target compound is obtained by drying with anhydrous magnesium sulfate or the like and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

When the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contacting with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent. The method of removing or using an oxidizing agent is preferable. In the case of the reaction of removing the protective group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in the reaction, for example,
Aliphatic hydrocarbons such as hexane or cyclohexane; Aromatic hydrocarbons such as toluene, benzene or xylene; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Esters such as ethyl acetate or propyl acetate; Methanol , Alcohols such as ethanol or 2-propanol; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic carbonization Hydrogen, ethers, esters, alcohols, fatty acids or a mixed solvent of these organic solvents and water, more preferably alcohols (especially methanol or ethanol), fatty acids (especially formic acid or acetic acid) Or a mixed solvent of these organic solvents and water. The catalyst used is not particularly limited as long as it is used in a usual catalytic reduction reaction, but may be, for example, palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate, and is preferable. The palladium-
Carbon or Raney-Nickel. The pressure is not particularly limited, but is usually 1 to 10 atm, and preferably 1 atm. The reaction temperature varies depending on the raw material compound, solvent, reducing agent used, etc., but is usually 0 ° C. to 100 ° C., and preferably 10 ° C. to 50 ° C. The reaction time is
The time is usually 15 minutes to 10 hours, preferably 30 minutes to 3 hours, varying depending on the raw material compound, solvent, reducing agent used, reaction temperature and the like. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method.
For example, the catalyst is filtered off, the solvent is distilled off, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer containing the target compound is washed with water, and then anhydrous magnesium sulfate or the like is added. The compound of interest is obtained by drying using the solvent and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The solvent used for removal by oxidation is not particularly limited as long as it does not participate in this reaction, and examples thereof include ketones such as acetone; halogenated carbonization such as dichloromethane, chloroform or carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; N, N-dimethylformamide, N, N
Amides such as dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or mixed solvents of these organic solvents and water, preferably ketones, halogenated hydrocarbons , Nitriles, ethers, amides, sulfoxides, or a mixed solvent of these organic solvents and water,
More preferably, ketones (especially acetone), halogenated hydrocarbons (especially dichloromethane), nitrites (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide) or these It is a mixed solvent of an organic solvent and water. The oxidizing agent used is, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-.
p-benzoquinone (DDQ), preferably CA
N or DDQ. The reaction temperature varies depending on the raw material compound, the solvent, the oxidizing agent used, etc., but is usually 0 ° C. to 150 ° C., and preferably 10 ° C. to 50 ° C. While the reaction time varies depending on the compound, the solvent, the oxidizing agent used, etc., it is generally 15 minutes to 24 hours, preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the oxidant is filtered off, the solvent is distilled off, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer containing the target compound is washed with water, and then anhydrous magnesium sulfate, etc. The desired compound is obtained by drying with a solvent and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

When the hydroxyl-protecting group is a silyl group, a method of removing it by reacting with a compound which produces a fluorine anion in an inert solvent is suitable. There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene, toluene or xylene. Aromatic hydrocarbons;
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (suitably Is tetrahydrofuran).
The compound that produces the fluorine anion used is, for example,
It may be tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride, preferably tetrabutylammonium fluoride. The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −50 ° C. to 100 ° C.
℃, preferably -10 ℃ to 50 ℃. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 12 hours, preferably 10 minutes to 1
It's time. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water and anhydrous magnesium sulfate, etc. After drying with, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method B is a method for separately producing a compound having the general formula (Va), (Vb), (Vc) or (Vd) which is an intermediate in Method A.

The step B1 is carried out by reacting the compound (V) with R ³
Is a hydrogen atom, is a step of producing a compound having the general formula (Va), wherein the compound having the general formula (VI) is
(1) After condensation with a compound having the general formula (IVa) in the presence or absence (preferably in the presence) of molecular sieves (preferably powdered molecular sieves 5A) in an inert solvent, (2) This is achieved by reducing the obtained intermediate compound with a reducing agent in an inert solvent.

The solvent used in the step B1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include hexane, heptane, ligroin and petroleum ether. Aliphatic hydrocarbons;
Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide or hexamethylphosphoric triamide; may be sulfoxides such as dimethylsulfoxide or sulfolane, preferably halogen Hydrocarbons, ethers or aromatic hydrocarbons, more preferably ethers or aromatic hydrocarbons, and even more preferably aromatic hydrocarbons (especially benzene or toluene). is there. The reaction temperature varies depending on the raw material compound, the solvent or the acid used, but is usually 0 ° C to 150 ° C, preferably 50 ° C.
To 100 ° C. While the reaction time varies depending on the raw material compound, solvent or acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, water is poured into the reaction solution, then a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extract is washed with water. After that, the target compound is obtained by drying with anhydrous magnesium sulfate or the like and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography. The intermediate compound obtained in this step can be used in the next step without further purification.

The solvent used in the step B1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include hexane, heptane, ligroin and petroleum ether. Aliphatic hydrocarbons;
Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; or a mixed solvent of the above solvents, preferably halogenated hydrocarbons, ethers, alcohols Or a mixed solvent thereof, and more preferably alcohols (particularly, methanol or ethanol). The reducing agent used may be an aluminum hydride compound such as lithium aluminum hydride or diisobutylaluminum hydride, sodium borohydride or diborane and the like, preferably sodium borohydride. When sodium borohydride is used as the reducing agent, cerium chloride can be used as a catalyst. The reaction temperature varies depending on the raw material compound, the solvent or the acid used, but it is usually -50 ° C to 50 ° C, and preferably 0.
The temperature is from 30 ° C to 30 ° C. While the reaction time varies depending on the raw material compound, solvent or acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or the reaction solution is poured into ice water, followed by extraction by adding a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.), and washing the extract with water, The target compound is obtained by drying with anhydrous magnesium sulfate or the like and distilling off the solvent. If necessary, the obtained target compound is obtained by a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

Step B2 is the step of reacting R in the compound (V).
^3, C ₁ -C ₆ alkyl; protected hydroxyl group or (C ₁ -C ₆ alkoxy) C ₁ substituted with a carbonyl group
-C ₆ alkyl group; general formula

[0127]

[Chemical 18] (Wherein R ⁷ , m and n have the same meanings as described above); C ₇ -C ₁₅ aralkyl group; C ₁ -C ₆
An alkylsulfonyl group; or (C ₁ -C ₆ alkoxy)
A step of producing a compound having the general formula (Vb), which is a C ₁ -C ₆ alkylsulfonyl group substituted with a carbonyl group, wherein the compound (Va) is present in an inert solvent in the presence or absence of a base. (Preferably in the presence of a base), the general formula (VI
This is achieved by reacting with a compound having I).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-
Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone;
Alternatively, it may be a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably with halogenated hydrocarbons (especially dichloromethane), ethers (diethyl ether or tetrahydrofuran) or amides (especially N, N-dimethylformamide). is there. Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxy. Alkali metal alkoxides such as methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] Undec-7-ene (DBU), which may be organic bases, preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal bicarbonates (especially sodium hydrogen carbonate or hydrogen carbonate). Potassium) or alkali metal hydrides (particularly lithium hydride or sodium hydride). The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. While the reaction time varies depending on the raw material compounds, reagents, and reaction temperature, it is generally 10 minutes to 24 hours, and preferably 1 hour to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water and anhydrous magnesium sulfate, etc. After drying with, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step B3 is the step of reacting R in the compound (V).
³ is a step of producing a compound having the general formula (Vc), which is a C ₁ -C ₆ alkyl group or a C ₇ -C ₁₅ aralkyl group, wherein the compound (Va) is mixed with acetic acid and cyan This is achieved by reacting with a compound having the general formula (VIII) in the presence of sodium borohydride or sodium triacetoxyborohydride.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol,
Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; dimethylsulfoxide or It may be a sulfoxide such as sulfolane; or a mixed solvent of the above organic solvents, preferably halogenated hydrocarbons (particularly dichloromethane), alcohols (methanol or ethanol) or a mixed solvent thereof (particularly dichloromethane and methanol). Mixed solvent). The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually −10 ° C. to 150 ° C.
C., preferably 0 to 100.degree. The reaction time will differ depending on the starting compounds, reagents and reaction temperature, but will usually be 10 minutes to 24 hours, and preferably 1 hour to 12 hours.
It's time. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water and anhydrous magnesium sulfate, etc. After drying with, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step B4 is carried out by reacting the compound (V) with R ³
Is a C ₁ -C ₆ alkanoyl group or a C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group, the general formula (Vd)
Is a step of producing a compound having
After reacting (1) with a compound having the general formula (IX) or (X) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent, if desired, ( 2) It is achieved by removing the hydroxyl-protecting group of the compound obtained in (1) above.

The solvent used in the step B4 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene. Kinds; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N- Dimethylformamide, N, N-
Amides such as dimethylacetamide or N-methyl-2-pyrrolidinone; or may be sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (diethyl ether) Or tetrahydrofuran). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide. Alkali metal hydroxides such as potassium or lithium hydroxide; methylamine,
Dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-
Diethylaniline, 1,5-diazabicyclo [4.3.
0] nona-5-ene, 1,4-diazabicyclo [2.
2.2] Octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be organic bases, preferably alkali metal carbonates (especially carbonates). Sodium or potassium carbonate), alkali metal bicarbonates (especially sodium hydrogen carbonate or potassium hydrogen carbonate) or organic bases (especially triethylamine, pyridine or 4- (N, N-dimethylamino) pyridine). The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time will differ depending on the starting compounds, reagents and reaction temperature, but it is usually 10 minutes to 24 minutes.
Time, preferably 1 to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, and a solvent immiscible with water (for example, benzene, ether,
(Ethyl acetate etc.) is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound is obtained by a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation and chromatography.

In the step B4 (2), the removal of the hydroxyl-protecting group can be carried out under the same conditions as in the reaction (e) in the step A2.

Method C is a method for separately producing the compound (V) which is an intermediate in Method A.

The step C1 is a step for producing the compound (V), which comprises condensing the compound having the general formula (XI) with the compound (IV) in the presence of a palladium catalyst and phosphines in an inert solvent. Achieved by

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or nitrites such as acetonitrile or isobutyronitrile, preferably ethers (particularly tetrahydrofuran). The palladium catalyst used may be, for example, tris (dibenzylideneacetone) dipalladium chloroform complex, bis (dibenzylideneacetone) palladium, palladium acetate or pyaryl palladium chloride dimer, preferably tris (dibenzylidene). Acetone) dipalladium chloroform complex. The phosphines used are, for example, trimethylphosphine,
Tri C ₁ -C ₆ alkylphosphine such as triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; triC ₆ -C ₁₀ arylphosphine such as triphenylphosphine, triindenylphosphine or trinaphthylphosphine Or tri C ₆ which may have C ₁ -C ₄ alkyl as a substituent, such as tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine; -C be a ₁₀ arylphosphine, preferably tri C ₁ -C ₆ alkyl phosphines (particularly trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or tri C ₆ -C ₁₀ A reel phosphine (particularly triphenylphosphine, tri indenyl phosphine or trinaphthylphosphine), more preferably a tributylphosphine or triphenylphosphine are particularly preferably triphenylphosphine. The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually −10 ° C. to 100 ° C.
C., preferably 0 to 50.degree. The reaction time will vary depending on the starting compounds, reagents and reaction temperature, but is usually 1
It is 0 minutes to 10 hours, preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction,
The target compound is obtained by distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization,
It can be further purified by reprecipitation and chromatography.

Method D is a method for separately producing the compound (V) which is an intermediate in Method A.

Step D1 is a step for producing a compound having the general formula (XIII),
It is achieved by condensation with a compound having the general formula (XII) in the presence of a phosphine and an azo compound in an inert solvent, and is carried out under the same conditions as in step A1.

Step D2 is a step for producing a compound having the general formula (XIV), which is accomplished by removing the hydroxyl-protecting group of compound (XIII), and is similar to reaction (e) in step A2. It can be performed under the conditions of.

Step D3 is a step for producing compound (V), wherein compound (XIV) is condensed with a compound having general formula (XV) in the presence of a phosphine and an azo compound in an inert solvent. And is performed under the same conditions as in step A1.

The compound (II
I), (IV), (IVa), (VI), (XI) or (XII) can be easily produced, for example, according to the following method.

[0142]

[Chemical 19]

[0143]

[Chemical 20]

[0144]

[Chemical 21]

[0145]

[Chemical formula 22]

[0146]

[Chemical formula 23]

[0147]

[Chemical formula 24]

[0148]

[Chemical 25]

[0149]

[Chemical formula 26]

[0150]

[Chemical 27]

In the above, R ¹ , R ² , R ³ , R ³ a, R ³
b, R ³ c, R ³ d, R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ ,
R ¹¹ , R ¹² , R ¹³ and X have the same meanings as described above, R ² a represents a hydrogen atom, R ⁵ a represents a carboxyl group, and R ⁵ b represents (C _1- C ₆ alkoxy) carbonyl group, R ⁵ c represents a carbamoyl group, a (C ₁ -C ₆ alkyl) carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, and Z represents a hydroxyl group or a leaving group. Indicates.

[0152] In the above-mentioned, in the definition of R ⁵ b "(C
_“1- C ₆ alkoxy) carbonyl group”, “(C ₁ -C ₆ alkyl) carbamoyl group” and “di (C ₁ -C ₆ alkyl) carbamoyl group” in the definition of R ⁵ c are respectively R ⁵
Has the same meaning as defined in.

The "leaving group" in the definition of Z is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue.
For example, halogen atom such as chlorine atom, bromine atom or iodine atom; C ₁ -C ₄ alkanesulfonyloxy group such as methanesulfonyloxy group, ethanesulfonyloxy group, propanesulfonyloxy group or butanesulfonyloxy group; trifluoromethane Sulfonyloxy group,
2,2,2-trichloroethanesulfonyloxy group,
A halogeno C ₁ -C ₄ alkanesulfonyloxy group such as a 3,3,3-tribromopropanesulfonyloxy group or a 4,4,4-trifluorobutanesulfonyloxy group; or a benzenesulfonyloxy group, α C, such as -naphthylsulfonyloxy, β-naphthylsulfonyloxy, p-toluenesulfonyloxy, 4-t-butylbenzenesulfonyloxy, mesitylenesulfonyloxy or 6-ethyl-α-naphthylsulfonyloxy. _It may be a C ₆ -C ₁₀ arylsulfonyloxy group which may have 1 to 3 _1- C ₄ alkyl, and is preferably a halogen atom, a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyl group. Oxy group, 2,2,2-trichloroethanesulfonyloxy group, benze Sulfonyloxy group, toluenesulfonyloxy group or mesitylenesulfonyloxy group, more preferably halogen atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or mesitylenesulfonyl group. It is an oxy group, more preferably a halogen atom, and particularly preferably a fluorine atom or a chlorine atom.

Method E is a method for producing compound (VI), (III) or (XI).

Step E1 is a step for producing compound (VI), and is accomplished by reacting a compound having general formula (XVI) with a compound having general formula (XVII) in an inert solvent. .

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
It may be an ether such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or a nitrile such as acetonitrile, propionitrile or butyronitrile, preferably aromatic hydrocarbons (especially benzene or toluene). The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually 0 ° C. to 150 ° C.
C., preferably 30 to 100.degree. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, and preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after the reaction is completed. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step E2 is a step for producing compound (III) and is accomplished by reducing compound (VI) in the presence of a reducing agent in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is, for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol,
Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent of the above solvents, where the reducing agent is aluminum hydrides or diborane, aliphatic hydrocarbons (especially Hexane or cyclohexane), aromatic hydrocarbons (especially benzene, toluene or xylene) or ethers (especially diethyl ether, tetrahydrofuran or dioxane), and alcohols (especially methanol) when the reducing agent is sodium borohydride. Or ethanol) or a mixed solvent of halogenated hydrocarbons and alcohols (especially a mixed solvent of dichloromethane and ethanol)
Is. The reducing agent used may be an aluminum hydride compound such as lithium aluminum hydride or diisobutylaluminum hydride, sodium borohydride or diborane and the like, preferably sodium borohydride. When sodium borohydride is used as the reducing agent, cerium chloride can be used as a catalyst. The reaction temperature varies depending on the starting compounds, reagents, etc.,
It is usually -78 ° C to 100 ° C, preferably 0 ° C to 5
It is 0 ° C. While the reaction time varies depending on the raw material compounds, reagents, and reaction temperature, it is generally 10 minutes to 12 hours, and preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is added to the resulting residue, and then a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic The layer is washed with water, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step E3 is a step for producing the compound (XI), which comprises reacting the compound (III) in the presence of a base or in the absence of a base (preferably in the presence of a base) in the formula (XVIII). ).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-
Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone;
Alternatively, it may be a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetrahydrofuran). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or triethylamine, tributylamine. , Diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
-Organazins such as diazabicyclo [5.4.0] undec-7-ene (DBU), preferably
Organic amines (especially triethylamine or pyridine). The reaction temperature will differ depending on the raw material compounds, reagents, etc., but is usually −50 ° C. to 80 ° C., and preferably −20 ° C.
To 50 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, and preferably 30 minutes to 5 hours. After the reaction,
The target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water and anhydrous magnesium sulfate, etc. After drying with, the target compound is obtained by distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method G is the same as compound (III) in which R ²
Is a hydrogen atom, and is a method for separately producing a compound having the general formula (IIIa).

Step G1 is a step for producing a compound having the general formula (XXIV). After reacting with catecholborane (in the absence of a solvent), (2) the obtained intermediate compound is treated with a compound represented by the general formula (XX) in the presence of a palladium catalyst and a base in an inert solvent.
This is achieved by reacting with a compound having III).

The solvent used in the step G1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons such as benzene; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Alternatively, it may be an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons (especially hexane or petroleum ether) or aromatic hydrocarbons ( Especially with toluene) That. The reaction temperature in Step G1 (1) will differ depending on the raw material compounds, reagents, etc., but is usually −10 ° C.
To 100 ° C, preferably 30 ° C to 80 ° C. The reaction time of the step G1 (1) depends on the starting compound, the reagent,
Although it depends on the reaction temperature, it is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of the step G1 (1) is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after the reaction is completed. In addition, it can also be used in the next step without particular purification.

The solvent used in the G1 (2) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons such as benzene; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or above. It is a mixed solvent of the machine solvent, preferably an aromatic hydrocarbon (particularly toluene). G
The palladium catalyst used in the step 1 (2) is, for example,
Tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex, palladium chloride bis (diphenylphosphinoferrocene)
Complex or palladium phosphine complex such as palladium acetate bis (triphenylphosphine); or may be tris (dibenzylideneacetone) dipalladium chloroform complex, bis (dibenzylideneacetone) palladium, palladium acetate or pyaryl palladium chloride dimer Preferred are tetrakis (triphenylphosphine) palladium, palladium chloride-bis (triphenylphosphine) complex or palladium chloridebis (diphenylphosphinoferrocene) complex, and more preferred is tetrakis (triphenylphosphine) palladium.
The base used in Step G1 (2) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. ; Sodium methoxide, sodium ethoxide,
Alkali metal alkoxides such as potassium t-butoxide or lithium methoxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-).
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
-Organazins such as diazabicyclo [5.4.0] undec-7-ene (DBU), preferably
Alkali metal alkoxides (particularly sodium ethoxide). The reaction temperature in Step G1 (2) varies depending on the raw material compounds, reagents, etc., but is usually 0 ° C. to 150 ° C., and preferably 50 ° C. to 120 ° C. G1
The reaction time of the step (2) varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 10 minutes to 10 hours, and preferably 30 minutes to 5 hours. After the reaction, G1
The target compound of step (2) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution,
After extracting a target compound by adding a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.), the extracted organic layer is washed with water and dried with anhydrous magnesium sulfate, etc., and then the solvent is distilled off. As a result, the target compound is obtained. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step G2 is a step for producing compound (IIIa) and is accomplished by removing the protective group for the hydroxyl group of compound (XXIV), and under the same conditions as in reaction (e) of step A2. It can be carried out.

Method H is the same as formula (IVa), (IVb),
A method for producing a compound having (IVc) or (IVd).

Step H1 is a step for producing a compound having the general formula (XXVI), and in the compound having the general formula (XXV), when Z represents a leaving group, (1)
Compound (XXV) is reacted with Compound (XV) in the presence of a base in an inert solvent, or when Z is a hydroxyl group in Compound (XXV), (2) Compound (XX
V) is achieved by dehydration condensation with compound (XV) in the presence of phosphines and an azo compound in an inert solvent.

The solvent used in the step H1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons such as benzene; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N- Amides such as methylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably amides (especially N, N- Dimethylformamide or N, N-dimethylacetamide). H1 (1)
Bases used in the process include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium acetate. Alkali metal acetates; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide Alkali metal alkoxides such as sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, - dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.
0] nona-5-ene, 1,4-diazabicyclo [2.
2.2] organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium. Or it may be a lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal hydrides (especially lithium hydride or sodium hydride), metal alkoxides (especially sodium methoxide) or Alkyl lithiums (especially butyl lithium). The reaction temperature in the H1 (1) step varies depending on the raw material compounds, reagents, etc.
It is usually -10 ° C to 100 ° C, preferably -5 ° C to 50 ° C. The reaction time of the H1 (1) step varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours, and preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of the step H1 (1) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, and then a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water to remove anhydrous sulfuric acid. After drying with magnesium or the like, the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The solvent used in the H1 (2) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is, for example, hexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane or ethers such as diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably , Halogenated hydrocarbons (especially Chloromethane) or ethers (in particular diethyl ether or tetrahydrofuran).
The phosphine used in the H1 (2) step is, for example, triC ₁ -C ₆ alkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; A tri-C ₆ -C ₁₀ arylphosphine such as triindenylphosphine or trinaphthylphosphine; or a tolyldiphenylphosphine, tritolylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine. , C
Tri-C _6-, which may have _1- C ₄ alkyl as a substituent,
It may be a C ₁₀ arylphosphine, preferably tri-C _1-
C ₆ alkylphosphines (especially trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or tri-C ₆ -C ₁₀ arylphosphines (especially triphenylphosphine, triindenylphosphine or trinaphthylphosphine),
More preferably, it is tributylphosphine or triphenylphosphine. The azo compound used in the H1 (2) step is, for example, azodicarbonyldipiperidine, dimethyl azodicarboxylate, diethyl azodicarboxylate,
It may be di-C ₁ -C ₄ alkyl azodicarboxylate such as dipropyl azodicarboxylate or dibutyl azodicarboxylate, preferably dimethyl azodicarboxylate or diethyl azodicarboxylate. The reaction temperature in the H1 (2) step varies depending on the raw material compounds, reagents, etc., but is usually −
20 ° C to 100 ° C, preferably -10 ° C to 50 ° C
℃. The reaction time of Step H1 (2) varies depending on the raw material compounds, reagents and reaction temperature, but is usually 15 minutes to 48 hours, and preferably 30 minutes to 24 hours. After completion of the reaction, the target compound of the step H1 (2) is collected from the reaction mixture according to a conventional method. For example, if an insoluble substance is present, it is filtered off, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) After extraction with water, the product is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Step H2 is a step for producing compound (IVa), wherein compound (XXVI) is added to (1) an inert solvent under a hydrogen atmosphere at 1 atm to 5 atm (preferably 1 atm).
Atmospheric pressure), reduction using a catalytic reduction catalyst, or
(2) It is usually achieved by applying a method of organically known reduction of a nitro group to an amino group by stirring in acetic acid in the presence of a metal powder.

The solvent used in the catalytic reduction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane, cyclohexane,
Aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Halogenated hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or they A mixed solvent of alcohols (particularly methanol) or a mixed solvent of ethers and alcohols (particularly tetrahydrofuran and methanol or ethanol). A mixed solvent) of. The catalytic reduction catalyst used is not particularly limited as long as it is used in a usual catalytic reduction reaction, for example, palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, Raney nickel, rhodium. It may be aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferably palladium-carbon. The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually -10
C. to 100.degree. C., preferably 0.degree. C. to 50.degree. The reaction time will differ depending on the starting compounds, reagents and reaction temperature, but will usually be 10 minutes to 10 hours, and is preferably 3
It is from 0 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is filtered off, and the filtrate is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Further, the solvent used in the reduction using the metal powder may be acetic acid, hydrochloric acid water, water, alcohol, or a mixture with an organic solvent soluble in water, preferably acetic acid. The metal powder used can be, for example, zinc powder, tin powder or iron powder, preferably zinc powder or tin powder. The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually -10
C. to 100.degree. C., preferably 0.degree. C. to 50.degree. The reaction time will differ depending on the starting compounds, reagents and reaction temperature, but will usually be 10 minutes to 10 hours, and is preferably 3
It is from 0 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the insoluble matter is filtered off, and then the filtrate is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step H3 is a step for producing a compound having the general formula (IVb), wherein compound (IVa) is treated in an inert solvent in the presence or absence of a base (preferably in the presence of a base). It is achieved by reacting with compound (VII) and can be carried out under the same conditions as in step B2.

Step H4 is a step for producing a compound having the general formula (IVc), which is prepared by treating compound (IVa) in the presence of acetic acid and sodium triborohydride cyanide in the presence of compound (VIII). And can be carried out under the same conditions as in step B3.

The step H5 is a step for producing a compound having the general formula (IVd), wherein the compound (IVa) is
(1) After reacting with compound (IX) or (X) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent, (2) above (1) This can be achieved by removing the hydroxyl-protecting group of the compound obtained in 1. above, and can be carried out under the same conditions as in the reaction (e) of step B4 (1) or step A2, respectively.

Method J is a compound represented by the general formula (XIIa) or (XIIa
b), a method of producing a compound having (XIIc) or (XIId).

The step J1 is a step for producing a compound having the general formula (XXVII), and in the compound (XXV), the compound having the general formula (XXVa) wherein Z is a hydroxyl group is In the presence of a base or in the absence of a base (preferably in the presence of a base) in an inert solvent, a compound represented by the general formula R ¹² -Za
(In the formula, R ¹² has the same meaning as described above, and Za has the same meaning as Z except that it represents a leaving group.)
Or general formula compound with a ^{R 12 a-O-R 12} a ( wherein,
R ¹² a has the same meaning as R ¹² except that it represents an acyl group. )
Is reacted with, (2) in an inert solvent, condensing agent and a base in the presence or absence (preferably in the presence of a base) compounds having the general formula R ¹² a-OH (wherein, R ¹² a is The same meaning as described above.) Or (3) in the presence of a halogenated phosphoric acid dialkyl ester such as diethyl chlorophosphate and a base in an inert solvent, and a compound of the general formula R ¹² a-OH
(Wherein R ¹² a has the same meaning as described above)
Or (4) by reacting with dihydrofuran or dihydropyrans in the presence or absence of an acid (preferably in the presence of an acid) in an inert solvent.

The solvent used in the step J1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene. Kinds; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane Nitriles such as acetonitrile or isobutyronitrile; Alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as N-methyl-2-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably halogenated hydrocarbons ( Dichloromethane), an ether (particularly diethyl ether or tetrahydrofuran) or amides (particularly N, N- dimethylformamide). The base used in Step J1 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine, triethylamine Butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino)
Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]
It may be an organic amine such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal hydrides (especially sodium hydride). , Alkali metal alkoxides (particularly potassium t-butoxide) or organic amines (particularly triethylamine or pyridine).
In addition, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in catalytic amounts in combination with other bases, and in order to effectively carry out the reaction, benzyltriethyl It is also possible to add quaternary ammonium salts such as ammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like. J1 (1)
The reaction temperature of the step varies depending on the raw material compounds, reagents, etc., but is usually −20 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time in Step J1 (1) will differ depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 24 hours, and preferably 30 minutes to 12 hours. Specific examples of the compound having the general formula R ¹² -Za include, for example, acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, hexanoyl chloride, methoxycarbonyl chloride, methoxycarbonyl bromide, ethoxycarbonyl chloride,
Acyl halides such as propoxycarbonyl chloride, butoxycarbonyl chloride, hexyloxycarbonyl chloride, benzoyl chloride, benzoyl bromide or naphthoyl chloride; t-butyldimethylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, triethylsilyl bromide, triisopropylsilyl. Silyl halides such as chloride, dimethylisopropylsilyl chloride, diethylisopropylsilyl chloride, t-butyldiphenylsilyl chloride, diphenylmethylsilyl chloride, triphenylsilyl chloride or the corresponding silyltrifluoromethanesulfonates; like benzyl chloride, benzyl bromide Aralkyl halides; or methoxymethyl chloride, etoki Methyl chloride, pivaloyloxymethyl chloride, there may be mentioned alkyl halides such as ethoxycarbonyloxymethyl chloride,
Alkyl halides (particularly methoxymethyl chloride) are preferred. Specific examples of the compound having the general formula ^{R 12 a-O-R 12} a, for example, there may be mentioned acetic anhydride, propionic anhydride, valeryl anhydride, an aliphatic carboxylic acid anhydrides such as hexanoic acid Furthermore, it is also possible to use mixed acid anhydrides such as formic acid and acetic acid.

The solvent used in the step J1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene. Kinds; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N- Dimethylformamide, N, N-
Amides such as dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers (especially diethyl ether or tetrahydrofuran) or amides (especially N). , N-dimethylacetamide or N-methyl-2-pyrrolidinone).
The condensing agent used in the step J1 (2) can be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide. Examples of the base used in Step J1 (2) include the same bases used in Step J1 (1). No. J
The reaction temperature in step 1 (2) will differ depending on the starting compounds, reagents, etc., but is usually −20 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time in Step J1 (2) will differ depending on the raw material compounds, reagents and reaction temperature, but is usually 1
0 minutes to 24 hours, preferably 30 minutes to 12
It's time.

The solvent used in the step J1 (3) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene. Kinds; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; nitro compounds such as nitromethane Nitriles such as acetonitrile or isobutyronitrile; formamide, N, N
-Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers (especially diethyl ether or Tetrahydrofuran). The base used in the J1 (3) step is the Jth
The same thing as what is used in 1 (1) process can be mentioned. The reaction temperature in Step J1 (3) varies depending on the raw material compounds, reagents, etc., but is usually −20 ° C. to 1
The temperature is 00 ° C, preferably 0 ° C to 50 ° C. J1
The reaction time in the step (3) will differ depending on the starting compounds, reagents and reaction temperature, but will usually be 10 minutes to 24 hours, and is preferably 30 minutes to 12 hours.

The solvent used in the step J1 (4) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene. Kinds; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; nitro compounds such as nitromethane; or acetonitrile or isobutyro Can be nitriles such as nitriles,
Preference is given to halogenated hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetrahydrofuran). The acid used in the J1 (4) step is, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, Sulfonic acids such as trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid or benzoic acid It may be a carboxylic acid such as an acid, and is preferably a sulfonic acid (particularly p-toluenesulfonic acid). The reaction temperature in Step J1 (4) will differ depending on the raw material compounds, reagents, etc., but is usually −20 ° C. to 100 ° C.
C., preferably 0 to 50.degree. J1
The reaction time of the step (4) varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 10 minutes to 24 hours,
It is preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of each reaction in Step J1 is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step J2 is a step for producing compound (XIIa), wherein compound (XXVII) is added to (1) an inert solvent under a hydrogen atmosphere at 1 atm to 5 atm (preferably 1 atm), By reduction using a catalytic reduction catalyst, or (2) stirring in acetic acid in the presence of metal powder, etc., usually by applying a method of reducing a nitro group to an amino group which is organically known. Achieved and can be carried out under similar conditions to step H2.

Step J3 is a step for producing a compound having the general formula (XIIb), which is compound (XIIa).
Can be achieved by reacting with compound (VII) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent, and can be carried out under the same conditions as in step B2.

Step J4 is a step for producing a compound having the general formula (XIIc), and is compound (XIIa)
Can be performed by reacting with compound (VIII) in the presence of acetic acid and sodium triborohydride cyanide in an inert solvent, and can be carried out under the same conditions as in Step B3.

Step J5 is a step for producing a compound having the general formula (XIId), which is compound (XIIa).
(1) after reacting with compound (IX) or (X) in the presence or absence of a base (preferably in the presence of a base) in an inert solvent, and (2) above ( This can be achieved by removing the hydroxyl-protecting group of the compound obtained in 1), and can be carried out under the same conditions as in the reaction (e) of step B4 (1) or step A2, respectively.

The K method is represented by the general formula (XXVc) or (XXV
A method for producing a compound having d).

The step K1 is a step for producing the compound (XXVc), which comprises reacting the compound (XXVb) with an alcohol in the presence of an esterifying agent in (1) an inert solvent, or (2) inactivating the compound. After producing an active ester by reacting with an active esterifying agent in a solvent and then reacting with an alcohol in an inert solvent, or (3) reacting with a halogenating agent in an inert solvent to produce an acid halide. Reacting with an alcohol in an inert solvent, or (4) in an inert solvent or in the absence of a solvent (preferably in the absence of a solvent),
This is achieved by reacting with alcohol in the presence of acid.

The esterifying agent used in the step K1 (1) is not particularly limited as long as it is generally used in the technique of synthetic organic chemistry, and for example, diazoalkane or trialkylsilyl group. It may be a diazoalkane, preferably a C ₁ -C ₆ diazoalkane such as diazomethane, diazoethane, diazopropane, diazobutane, diazopentane or diazohexane or trimethylsilyldiazomethane, more preferably C ₁ -C ₄ Diazoalkane or trimethylsilyldiazomethane, particularly preferably diazomethane. The solvent used in the reaction using the diazo C ₁ -C ₆ alkane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; benzene,
Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol. Ethers such as dimethyl ether; esters such as methyl acetate or ethyl acetate; or a mixed solvent of the above solvents,
Preferred are halogenated hydrocarbons, ethers, esters and mixed solvents of the above solvents, and more preferred are ethers (particularly diethyl ether), esters (particularly ethyl acetate) or mixed solvents of the above solvents. . The solvent used in the reaction using trimethylsilyldiazomethane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methanol, ethanol, propanol, 2-propanol and butanol. , Alcohols such as isobutanol, t-butanol, pentanol or hexanol; or aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatics such as benzene, toluene or xylene. Hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol. It may be a mixed solvent of a solvent selected from the group consisting of ethers such as methyl ether; and esters such as methyl acetate or ethyl acetate, preferably alcohols (particularly, alcohols). It is a mixed solvent of (methanol) or aromatic hydrocarbons (especially benzene) and alcohols (especially methanol). K1 (1)
The reaction temperature of the step varies depending on the raw material compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., preferably 10 ° C.
To 50 ° C. The reaction time of the K1 (1) step varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10
Minutes to 10 hours, preferably 15 minutes to 2 hours. After completion of the reaction, the target compound of the step K1 (1) is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after the reaction is completed. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The active esterifying agent used in the step K1 (2) is not particularly limited as long as it is generally used in the technique of synthetic organic chemistry. For example, ethyl chloroformate, N -Hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-
N such as norbornene-2,3-dicarboximide
It can be a hydroxy compound or a disulfide compound such as dipyridyl disulfide and the active esterification reaction is suitably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The solvent used in both reactions in the K1 (2) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methylene chloride, chloroform and carbon tetrachloride. , Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N
-Amides such as dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; or nitrites such as acetonitrile, preferably ethers (especially tetrahydrofuran) or amides (especially N). , N-dimethylformamide). The reaction temperature in the K1 (2) step varies depending on the raw material compounds, reagents and the like, but usually in the active esterification reaction, -70 ° C to 150 ° C (preferably -10 ° C to 10 ° C)
0 ° C), and in the reaction between the active ester compound and the alcohol, -20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
℃). The reaction time of the step K1 (2) varies depending on the raw material compounds, reagents and reaction temperature, but both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 4 hours).
8 hours). After completion of the reaction, the target compound of the step K1 (2) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound is obtained by a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

The halogenating agent used in the step K1 (3) is not particularly limited as long as it is generally used in the technique of synthetic organic chemistry, and examples thereof include oxalyl chloride and thionyl chloride. , Phosphorus oxychloride or phosphorus pentachloride. The solvent used in both reactions of the step K1 (3) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, benzene, toluene or xylene. Aromatic hydrocarbons;
May be halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, Preferred are ethers (particularly tetrahydrofuran). K1
The reaction temperature in the step (3) varies depending on the raw material compounds, reagents, etc., but is usually -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the acid halide reaction.
-20 ° C to 10 for reaction of acid halide with alcohol
The temperature is 0 ° C (preferably 0 ° C to 50 ° C). K1 (3)
The reaction time of the step varies depending on the raw material compound, the reagent and the reaction temperature, but in both reactions, it is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of the step K1 (3) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The solvent used in the step K1 (4) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methylene chloride, chloroform and carbon tetrachloride. , Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N- Amides such as dimethylacetamide or hexamethylphosphoric triamide; or nitrites such as acetonitrile, preferably ethers (especially diethyl ether or tetrahydrofuran). The acid used in the step K1 (4) is, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, Sulfonic acids such as trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid or benzoic acid It may be a carboxylic acid such as an acid and is preferably a mineral acid (especially hydrochloric acid or sulfuric acid). The reaction temperature in the step K1 (4) varies depending on the raw material compounds, reagents, etc., but is usually 0.
C. to 150.degree. C. (preferably 30.degree. C. to 100.degree. C.). The reaction time of Step K1 (4) varies depending on the raw material compounds, reagents and reaction temperature, but is usually 30 minutes to 8 minutes.
It is 0 hour (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of the step K1 (4) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Step K2 is a step for producing compound (XXVd), which comprises reacting compound (XXVc) in an inert solvent in the presence or absence of a base (preferably in the presence of a base).
Ammonias, C ₁ -C ₆ alkylamine or a di (C ₁ -
This is achieved by reacting with a C ₆ alkyl) amine.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol Alcohols; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; or sulfoxides such as dimethylsulfoxide or sulfolane. Possible, preferably halogenated hydrocarbons or ethers,
More preferred are ethers (particularly tetrahydrofuran). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide. It may be an alkali metal hydroxide such as potassium or lithium hydroxide, preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate)
Is. The ammonia used may be, for example, ammonia gas or concentrated ammonia water, and is preferably ammonia water. C ₁ -C ₆ alkylamines used are, for example, methylamine, ethylamine, propylamine,
Isopropylamine, butylamine, isobutylamine, s-butylamine, t-butylamine, pentylamine or hexylamine. Used di (C ₁ −
C ₆ alkyl) amine, for example, N, N- dimethylamine, N- ethyl -N- methylamine, N, N- diethylamine, N, N- dipropylamine, N, N- diisopropylamine, N, N- Dibutylamine, N, N-diisobutylamine, N, N-di-s-butylamine,
N, N-di-t-butylamine, N, N-dipentylamine or N, N-dihexylamine. The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10 ° C
To 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, and preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Step K3 is a step for separately producing compound (XXVd) and is carried out by a method well known in synthetic organic chemistry. , Active ester method,
Mixed acid anhydride method or condensation method (preferably mixed acid anhydride method)] in an inert solvent, ammonia, C ₁ -C ₆
This is achieved by reacting with an alkyl amine or a di (C ₁ -C ₆ alkyl) amine.

In the above method, the azide method is an amide such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide, preferably in an inert solvent. Is N, N-dimethylformamide), hydrazine, -1
The hydrazide obtained by reacting at 0 ° C to 100 ° C (preferably 0 ° C to 50 ° C) is reacted with a nitrite compound to convert into an azide compound, and then ammonia, C
Is performed by treating with ₁ -C ₆ alkylamine or a di (C ₁ -C ₆ alkyl) amine. The nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent, the solvent used being, for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; dimethylsulfoxide. Or sulfoxides such as sulfolane;
Alternatively, it may be a pyrrolidone such as N-methyl-2-pyrrolidinone, preferably an amide (particularly N, N-dimethylformamide). Further, the two steps of this reaction [reaction with azidation and ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine] are usually carried out in one reaction solution. The reaction temperature will vary depending on the starting compounds, reagents, etc., but normally the azidation step is -70 ° C.
To 50 ° C (preferably -50 ° C to 0 ° C), and the reaction with ammonia and the like is -70 ° C to 50 ° C (preferably-).
10 ° C. to 10 ° C.). The time required for the reaction varies depending on the raw material compound, the reagent and the reaction temperature, but usually the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour).
And the reaction with ammonia etc. is 5 hours to 7 hours.
It is a day (preferably 10 hours to 5 days). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. After washing the organic layer with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

In the active ester method, the active ester is produced by reacting with an active esterifying agent in an inert solvent, and then ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C _{1) is} added in an inert solvent. ₆ alkyl) amine. The solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene. Halogenated hydrocarbons such as; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N-
It may be an amide such as dimethylacetamide or hexamethylphosphoric triamide; or a nitrile such as acetonitrile, preferably an ether (especially tetrahydrofuran) or an amide (especially N, N-dimethylformamide). Active esterifying agents used include, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or dipyridyl disulfides. Such a disulfide compound may be used, and the active esterification reaction is suitably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature varies depending on the raw material compounds, reagents, etc., but is usually -70 in the active esterification reaction.
C. to 150.degree. C. (preferably -10.degree. C. to 100.degree. C.), and -20.degree. C. to 100.degree. C. (preferably 0.degree. C. to 50.degree. C.) in the reaction between the active ester compound and ammonia. The time required for the reaction varies depending on the raw material compounds, reagents, and reaction temperature, but both reactions are usually 30 minutes to 8 minutes.
It is 0 hour (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. After washing the organic layer with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

In the mixed acid anhydride method, a mixed acid anhydride agent is reacted in the presence of a base in an inert solvent to produce a mixed acid anhydride, and then the mixed acid anhydride and ammonia, in an inert solvent, , C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine. The solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or formamide, N, N-dimethylformamide,
It may be an amide such as N, N-dimethylacetamide or hexamethylphosphoric triamide, preferably ethers (particularly tetrahydrofuran). Mixed acid anhydride agents are, for example, C ₁ -C ₄ alkyl halogenoformates such as ethyl chloroformate or isobutyl chloroformate, C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride or diethyl cyanophosphate or diphenyl. It may be a C ₁ -C ₄ alkyl such as cyanophosphate or a di C ₆ -C ₁₄ aryl cyanophosphate, preferably a halogenoformic acid C _1-.
C ₄ alkyl (especially ethyl chloroformate). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-
(N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2. 2.2] Octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7
It may be an organic amine such as -ene (DBU), preferably an organic amine (especially triethylamine). The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the raw material compounds, reagents, etc., but is usually -50 ° C to 1
The temperature is 00 ° C (preferably -10 ° C to 50 ° C). The reaction time in the reaction for producing the mixed acid anhydride varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours). The solvent used in the reaction of the mixed acid anhydride and ammonia or the like is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include diethyl ether, diisopropyl ether and tetrahydrofuran. , Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether or amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide, preferably ethers. (Especially tetrahydrofuran). The reaction temperature in the reaction of the mixed acid anhydride and ammonia and the like varies depending on the raw material compounds, reagents and the like, but is usually −30 ° C. to 100 ° C. (preferably 0 ° C.).
C. to 80.degree. C.). The reaction time in the reaction of the mixed acid anhydride and ammonia and the like varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The condensation method is carried out in an inert solvent in the presence of a condensing agent,
Ammonias, C ₁ -C ₆ alkylamine or a di (C ₁ -
It is carried out by reacting directly with a C ₆ alkyl) amine. The condensing agent used is, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-
It may be methyl-2-chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide. This reaction can be carried out under the same conditions as the reaction for producing the above-mentioned active ester. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. After washing the organic layer with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The L method is represented by the general formula (XXVIb) or (XX
VIc).

Step L1 is a step for producing the compound (XXVIb), and the compound having the general formula (XXVIa) is treated in an inert solvent or in the absence of a solvent according to a method generally known in the art of synthetic organic chemistry. It can be carried out under the same conditions as in the reaction (d) of the step A2, which is achieved by hydrolysis in the presence of an acid or a base.

The step L2 is a step for producing the compound (XXVIc), which is generally carried out according to the method well known in the art of synthetic organic chemistry, for example, the compound (XXVIb)
Ammonia, in an inert solvent, according to a conventional method for peptide synthesis [eg, azide method, active ester method, mixed acid anhydride method or condensation method (preferably mixed acid anhydride method)]
It is achieved by reacting with a C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine, and can be carried out under the same conditions as in step K3.

Method M is a method for producing a compound having the general formula (XVI) or a compound having the general formula (XXIII).

Step M1 is a step for producing compound (XVI) or compound (XXIII) and has the general formula (XX
Compounds or formula having VIII) a compound having a (XXIX), (1) in an inert solvent, a base in the presence or absence (preferably in the presence of a base), the general formula R ¹² -Za
Compound having (wherein, R ¹² and Za are. The same meanings as defined above) Compound (wherein with or general formula ^{R 12 a-O-R 12} a, R 12 a is as previously described Have the same meaning.) Or (2) in the presence or absence of a condensing agent and a base in an inert solvent (preferably in the presence of a base).
Compounds having the general formula R ¹² a-OH (wherein, R ¹² a
Indicates the same meaning as described above. ) Or
(3) an inert solvent, halogenated dialkyl phosphoric acid esters and the presence of a base such as chloride phosphodiesterase, compounds having the general formula ^{R 12 a-OH (R 12} a have the same meanings as those described above. ) Or (4)
This can be achieved by reacting with dihydrofuran or dihydropyran in the presence or absence of an acid (preferably in the presence of an acid) in an inert solvent, and can be carried out under the same conditions as in Step J1.

Method N is a method for separately producing the compound having the general formula (III).

Step N1 is a step for producing a compound having the general formula (XXXI), wherein the compound having the general formula (XXX) is hydrolyzed in an inert solvent or in the absence of a solvent, in the presence of an acid or a base. Achieved by disassembling, No. A2
It can be carried out under the same conditions as in step reaction (d).

Step N2 is a step for producing a compound having the general formula (XXXII), which is compound (XXXI).
Is achieved by reacting with a compound having the general formula (XVI) in the presence of a base in an inert solvent.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane, cyclohexane, heptane, ligroin or an aliphatic hydrocarbon such as petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or like dimethyl sulfoxide or sulfolane Sulfoxides, preferably ethers (especially diethyl ether or tetrahydrofuran). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N -Methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyl lithiums such as methyllithium, ethyllithium or butyllithium; lithium such as lithium diisopropylamide or lithium dicyclohexylamide. Alkyl amides; or may be alkali metal hexamethyldisilazides such as potassium hexamethyldisilazide or sodium hexamethyldisilazide, preferably alkyllithiums (especially butyllithium) or lithium alkylamides (Especially lithium diisopropylamide). The reaction temperature varies depending on the starting compounds, reagents, etc.,
It is usually −150 ° C. to 50 ° C., preferably −100 ° C.
To 0 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, and preferably 30 minutes to 5 hours. After the reaction,
The target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution to extract the target compound, and then the pH of the extracted aqueous layer is adjusted to acidic with an acid (for example, hydrochloric acid), and a solvent immiscible with water (for example, benzene, The target compound is obtained by adding (ether, ethyl acetate, dichloromethane or the like) to extract the target compound, washing the extracted organic layer with water, and drying with anhydrous magnesium sulfate and the like, and then distilling off the solvent. . The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step N3 is a step for producing compound (III), which comprises reacting (1) compound (XXXII) with C ₁ -C ₆ alkyl halogenocarbonate in the presence of a base in an inert solvent. , (2) It is achieved by reacting the obtained intermediate compound with sodium borohydride in an inert solvent.

The solvent used in the N3 (1) th step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane, cyclohexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons such as benzene; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Alternatively, it may be an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetra ether). It is a Dorofuran). Nth N3
The base used in the step (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N) -Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.
0] nona-5-ene, 1,4-diazabicyclo [2.
2.2] Octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be organic bases, preferably organic bases (especially triethylamine). is there. "Halogeno carbonate C ₁ -C ₆ alkyl" as used in the first N3 (1) step, for example, fluoro methyl carbonate, methyl chlorocarbonate, bromo methyl carbonate, methyl iodide carbonate, fluoroethyl carbonate, ethyl chlorocarbonate, bromo carbonate It can be ethyl, ethyl iodocarbonate, propyl fluorocarbonate, butyl chlorocarbonate, pentyl bromocarbonate or hexyl iodocarbonate, preferably methyl chlorocarbonate or ethyl chlorocarbonate. The reaction temperature will differ depending on the starting compounds, reagents, etc., but will usually be −10 ° C. to 150 ° C., and is preferably 0 ° C. to 100 ° C. While the reaction time varies depending on the raw material compounds, reagents and reaction temperature, it is generally 5 minutes to 12 hours, preferably 10 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the insoluble matter is filtered off as desired, and then the solvent is distilled off, or after completion of the reaction, water is added to the reaction solution, and a solvent immiscible with water (for example, benzene, ether,
(Ethyl acetate etc.) is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound is obtained by a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation and chromatography.

The solvent used in the N3 (2) th step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether. Aliphatic hydrocarbons such as benzene; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Alternatively, it may be an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably an ether (particularly diethyl ether or tetrahydrofuran). The reaction temperature will differ depending on the starting compounds, reagents, etc., but is usually -10 ° C.
To 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 1 hour to 48 hours, and preferably 6 hours to 24 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example,
After completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, and anhydrous magnesium sulfate or the like is used. After drying, the solvent is distilled off to obtain the target compound. The desired compound thus obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method O is a method for producing a compound having the general formula (XXVIII) which is a starting compound of Method M.

Step O1 is a step for producing compound (XXVIII) and is achieved by reacting the compound having general formula (XXXIII) with hexamethylenetetramine in trifluoroacetic acid.

The reaction temperature will differ depending on the starting compounds, reagents, etc., but the reaction with hexamethylenetetramine is usually
0 ° C to 150 ° C, preferably 50 ° C to 120 ° C
And the reaction with sulfuric acid is usually from -20 ° C to 100 ° C.
And preferably 0 ° C. to 50 ° C. The reaction time varies depending on the raw material compound, the reagent and the reaction temperature, but the reaction with hexamethylenetetramine is usually 1 hour to 24 hours, preferably 6 hours to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent after completion of the reaction, or by distilling off the solvent after completion of the reaction and pouring water into the resulting residue, a solvent immiscible with water (for example, benzene, diethyl ether or ethyl acetate). After extraction with water, the extract is washed with water, the organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If the desired compound obtained is necessary,
It can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Starting compounds (VII), (VIII), (IX) of the activated blood coagulation factor X inhibitor of the present invention,
(X), (XV), (XVI), (XVII), (XV
III), (XIX), (XXII), (XXII
I), (XXV), (XXVIII), (XXIX),
(XXX), (XXXIII) and the like are known or easily produced according to known methods. {For example, Bio-Organic and Medicinal Chemistry Letters, Vol. 8, p. 277 (1998) [ Bio
Med. Chem. Lett. , 8 , 277 (1998)], Tetrahedron Letters, 37, 6439 (1996).
Year) [ Tetrahedron Letters , 37 , 6439 (1996)] etc.}.

Since the activated blood coagulation factor X inhibitor of the present invention has an excellent activated blood coagulation factor X inhibitory action and weak toxicity, it is a blood coagulation disease (for example, cerebral infarction, myocardial infarction or It is useful as a preventive or therapeutic drug (particularly a therapeutic drug) for thrombotic diseases such as peripheral circulatory disorders.

The activated blood coagulation factor X inhibitor of the present invention is mixed with itself or an appropriate pharmacologically acceptable excipient, diluent or the like to give tablets, capsules, granules,
It can be administered orally by a powder or syrup or parenterally by an injection or a suppository. These formulations include excipients such as lactose, sucrose, glucose,
Sugar derivatives such as mannitol and sorbitol; corn starch, potato starch, α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; inorganics such as sulfates such as calcium sulfate Examples include system excipients. ), Lubricants (eg metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; sodium sulfate, etc.) Sulfate; glycol;
Examples include fumaric acid; sodium benzoate; DL leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives. ),
Binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (eg, low-substituted hydroxypropylcellulose, carboxy). Cellulose derivatives such as methylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; chemically modified starch / celluloses such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone can be mentioned.), Emulsifier ( For example, bentonite,
Colloidal clay such as veegum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cationic surfactants such as benzalkonium chloride. And nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester. ), Stabilizers (methylparaben,
Paraoxybenzoic acid esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid Can be mentioned. ), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.) and diluents and the like can be used to produce the compound by a known method. The amount used depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg per dose (preferably 10 m
g), an upper limit of 1000 mg (preferably 500 mg), and a lower limit of 0.5 mg per dose (preferably, in the case of intravenous administration)
5 mg), an upper limit of 500 mg (preferably 250 mg), is preferably administered to an adult 1 to 6 times daily depending on the symptoms.

[0217]

[Examples] Hereinafter, the compounds contained in the medicament of the present invention will be described in more detail by showing Examples and Formulation examples, but the scope of the present invention is not limited thereto.

In the NMR spectrum, tetramethylsilane was used as an internal standard, the δ value was shown in ppm, and the binding constant was shown in J value (Hz) (approximate to 0.5 Hz unit). Coupling patterns are: d: doublet, dd: double doublet, ddd: double double doublet, dt: double triplet, t: triplet, q: quartet, m: multiplet, s: singlet, bs: wide or shaped. It was abbreviated as a signal observed like a collapsed singlet.

Example 1 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] ethanesulfonamide 2 Hydrochloride (Exemplified Compound Number: 1080) (a) N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- (piperidine-4-
Iloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] ethanesulfonamide (955 mg) was added to dichloromethane (40 ml).
It was dissolved in a mixed solvent of ethanol and ethanol (20 ml), and hydrogen chloride was passed through the mixture under ice cooling for 1 hour.
Stir for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), an aqueous ammonium chloride solution (193 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.375 ml) were added, and the mixture was left at room temperature for 12 hours. did. The solvent was evaporated under reduced pressure, and the residue was added with methanol (2
0 ml) and 4M hydrogen chloride dioxane solution (2
(ml) was added, and the mixture was concentrated under reduced pressure. Preparative collection of residue HPL
After purification with C (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (1 ml) was added. This was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give the title compound 354m
g (44% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.
0), 1.83 (2H, m), 2.09 (2H, m), 3.03 (2H, m), 3.17
(2H, q, J = 7.0), 3.19 (2H, m), 4.45 (2H, d, J = 6.
0), 4.64 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55
(1H, d, J = 16.0), 7.00 (2H, d, J = 9.0), 7.37 (2H,
d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, m), 7.89
(1H, s); MS (FAB) m / z = 443 (M + H) ⁺ .

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] ethanesulfonamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidine) -4-yloxy) phenyl] ethanesulfonamide dihydrochloride (311
mg) was dissolved in ethanol (10 ml), ethylacetimidate hydrochloride (260 mg) and triethylamine (0.500 ml) were added, and the mixture was stirred at room temperature for 12 hr. 4M hydrogen chloride dioxane solution (1m
l) was added, and the mixture was concentrated under reduced pressure. Preparative HPLC of the residue
After purification with (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. Then, it was concentrated to dryness under reduced pressure.
The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to give the title compound (243 mg)
(Yield 62%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.
0), 1.72 (2H, m), 2.04 (2H, m), 2.30 (3H, s), 3.18
(2H, q, J = 7.0), 3.50-3.59 (2H, m), 3.72 (1H, m),
3.84 (1H, m), 4.45 (2H, d, J = 6.0), 4.70 (1H, m),
6.46 (1H, dt, J = 15.5, 6.0), 6.55 (1H, d, J = 15.5),
7.01 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.54 (1
H, t, J = 8.0), 7.71 (2H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1674, 1625.

Example 2 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] Ethanesulfonamide dihydrochloride (Exemplified compound number: 122
0)

(A) N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide (839 mg) was mixed with dichloromethane (40 ml) and ethanol (20 ml). The mixture was dissolved in a solvent, hydrogen chloride was passed through the mixture under ice cooling for 1 hour, the vessel was sealed, and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous ammonium chloride solution (166 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.320 ml) were added.
It was left at room temperature for 12 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent 15% acetonitrile / water), and the obtained amorphous solid was dissolved in methanol (20 ml) and 4M.
After adding a hydrogen chloride dioxane solution (1 ml), this was concentrated to dryness under reduced pressure. The amorphous solid obtained is treated with water (about 1
(0 ml) and then freeze-dried,
The title compound (514 mg, yield 63%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.
0), 1.84 (2H, m), 1.87 (3H, s), 2.09 (2H, m), 3.04
(2H, m), 3.16 (2H, q, J = 7.0), 3.20 (2H, m), 4.39
(2H, s), 4.64 (1H, m), 6.35 (1H, s), 7.01 (2H, d,
J = 9.5), 7.39 (2H, d, J = 9.5), 7.47 (1H, d, J = 8.0),
7.55 (2H, m), 7.64 (1H, d, J = 8.0); IR (KBr, cm ^-1 ): 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2-methyl-2- (E)
-Propenyl] ethanesulfonamide dihydrochloride N- [3- (3-amidinophenyl) -2-methyl-2
-(E) -Propenyl] -N- [4- (piperidine-4
-Iloxy) phenyl] ethanesulfonamide dihydrochloride (303 mg) was dissolved in ethanol (10 ml), ethyl acetimidate hydrochloride (246 mg) and triethylamine (0.460 ml) were added, and the mixture was stirred at room temperature for 1 hour.
Stir for 2 hours. After adding a 4M hydrogen chloride dioxane solution (0.9 ml) to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and a 4M hydrogen chloride dioxane solution (0. (4 ml) was added, and this was concentrated to dryness under reduced pressure. The obtained amorphous solid is treated with water (about 10 m
After dissolving in 1) and lyophilization, 170 mg (45% yield) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.
0), 1.71 (2H, m), 1.87 (3H, s), 2.04 (2H, m), 2.30
(3H, s), 3.17 (2H, q, J = 7.0), 3.53 (2H, m), 3.72
(1H, m), 3.83 (1H, m), 4.39 (2H, s), 4.70 (1H, m),
6.35 (1H, s), 7.01 (2H, d, J = 9.0), 7.39 (2H, d, J =
9.0), 7.47 (1H, d, J = 8.0), 7.55 (1H, s), 7.55 (1H,
t, J = 8.0), 7.65 (1H, d, J = 8.0); IR (KBr, cm ^-1 ): 1673, 1626.

Example 3 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 2 Hydrochloride (Exemplified compound number: 1410)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [ 4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate (1.46 g) was added to dichloromethane (50 m).
The mixture was dissolved in a mixed solvent of 1) and ethanol (25 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, the vessel was sealed and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (40 ml), and then an aqueous ammonium chloride solution (0.30 g was dissolved in 15 ml of water) and 28%.
Aqueous ammonia (0.58 ml) was added, and the mixture was left at room temperature for 12 hours. 4M hydrogen chloride dioxane solution (2m
l) was added, and the mixture was concentrated under reduced pressure. Preparative HPLC of the residue
0.98 g of the title compound by purification with (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water)
(68% yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.83 (2H, m), 2.10 (2H, m), 3.05 (2H, m), 3.19
(2H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45
(2H, d, J = 6.0), 4.66 (1H, m), 6.45 (1H, dt, J = 16.
0, 6.0), 6.55 (1H, d, J = 16.0), 7.04 (2H, d, J = 8.
5), 7.39 (2H, d, J = 8.5), 7.55 (1H, t, J = 8.0), 7.69
(1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.89 (1H, s)
IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidine -4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (1
090 mg) in ethanol (40 ml),
After adding ethyl acetimidate hydrochloride (705 mg) and triethylamine (1.30 ml), the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), then the obtained amorphous solid was dissolved in methanol (15 ml), and a 4M hydrogen chloride dioxane solution (1 ml) was dissolved. Was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (812 mg, yield 70%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.67-1.79 (2H, m), 2.04 (2H, m), 2.29 (3H, s),
3.50 (2H, m), 3.72 (1H, m), 3.81 (1H, m), 4.19 (2
H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 6.0),
4.70 (1H, m), 6.45 (1H, dt, J = 16.5, 6.0), 6.55 (1
H, d, J = 16.5), 7.04 (2H, d, J = 9.5), 7.39 (2H, d, J
= 9.5), 7.54 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0),
7.71 (1H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1673, 1626.

Example 4 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride Salt (Exemplified compound number: 1939) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid Ethyl dihydrochloride (440 mg) was added to 3M hydrochloric acid (30 m
It was dissolved in 1) and stirred at 80 ° C. for 3 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was collected by HPL.
After purification with C (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (15 ml), and 4M hydrogen chloride dioxane solution (1 ml) was added. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (about 15 ml) and freeze-dried to obtain 331 mg of the title compound (yield 78%). ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.0
4 (2H, m), 2.29 (3H, s), 3.51 (2H, m), 3.72 (1H,
m), 3.80 (1H, m), 4.18 (2H, s), 4.45 (2H, d, J = 6.
0), 4.70 (1H, m), 6.44 (1H, dt, J = 16.5, 6.0), 6.55
(1H, d, J = 16.5), 7.03 (2H, d, J = 8.5), 7.40 (2H, d,
J = 8.5), 7.54 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0),
7.71 (1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1733, 1673, 1627.

Example 5 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2)
-Fluorophenyl) -2- (E) -propenyl] ethanesulfonamide dihydrochloride (Exemplified compound number: 12)
80)

(A) N- [3- (5-amidino-2-
Fluorophenyl) -2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -propenyl]
Ethanesulfonamide (2.00 g) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), an aqueous ammonium chloride solution (0.39 g was dissolved in 25 ml of water) and 28% aqueous ammonia (0.76 ml) were added, and the mixture was stirred at room temperature for 12 hours. Left for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 20
% Amorphous / water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to give the title compound 1.
20 g (61% yield) was obtained as a light brown amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.
0), 1.82 (2H, m), 2.09 (2H, m), 3.04 (2H, m), 3.17
(2H, q, J = 7.0), 3.18 (2H, m), 4.49 (2H, d, J = 6.
0), 4.64 (1H, m), 6.55 (1H, dt, J = 16.0, 6.0), 6.61
(1H, d, J = 16.0), 7.01 (2H, d, J = 8.5), 7.37 (2H,
d, J = 8.5), 7.45 (1H, m), 7.78 (1H, m), 8.11 (1H, m)
IR (KBr, cm ^-1 ): 3056, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(5-amidino-2-fluorophenyl) -2-
(E) -Propenyl] ethanesulfonamide dihydrochloride N- [3- (5-amidino-2-fluorophenyl)-
2- (E) -propenyl] -N- [4- (piperidine-
4-yloxy) phenyl] ethanesulfonamide dihydrochloride (534 mg) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (371 mg) and triethylamine (0.70 ml) were added at room temperature, and then at the same temperature. It was stirred for 12 hours. After adding a 4M hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure.
The residue was subjected to preparative HPLC (YMC-Pack ODSYMC, elution solvent: 2
After purification with 0% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. It was The obtained amorphous solid was dissolved in water (about 10 ml), and then freeze-dried to obtain 415 mg (yield 75%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.28 (3H, t, J = 7.
0), 1.74 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.18
(2H, q, J = 7.0), 3.52 (2H, m), 3.72 (1H, m), 3.81
(1H, m), 4.50 (2H, d, J = 6.0), 4.70 (1H, m), 6.56
(1H, dt, J = 16.5, 6.0), 6.62 (1H, d, J = 16.5), 7.02
(2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.46 (1H, m),
7.78 (1H, m), 8.12 (1H, m); IR (KBr, cm ^-1 ): 3113, 1674, 1625.

Example 6 N- [4- (1-acetimidoylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
419)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [2-methyl-
4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -2-methylphenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.80 g) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), and hydrogen chloride was added for 1 hour under ice cooling. After passing through, the vessel was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), an aqueous ammonium chloride solution (0.32 g was dissolved in 25 ml of water) and 28% ammonia water (0.62 ml) were added, and then the mixture was stirred at room temperature for 12 hours. I left it. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 20
% Acetonitrile / water) to give 0.78 g (45% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.73 (2H, m), 2.04 (2H, m), 2.27 (3H, s), 3.00
(2H, m), 3.18 (2H, m), 4.20 (2H, q, J = 7.0), 4.25
(1H, m), 4.33 (1H, d, J = 14.5), 4.45 (1H, m), 4.46
(1H, d, J = 14.5), 4.59 (1H, m), 6.46 (2H, s), 6.88
(1H, d, J = 9.0), 6.90 (1H, s), 7.39 (1H, d, J = 9.0),
7.55 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.71 (1
H, d, J = 8.0), 7.81 (1H, s); IR (KBr, cm ^-1 ): 1737, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [2-methyl-4- (piperidine-4)
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (631 mg) was dissolved in ethanol (30 ml) and ethyl acetimidate hydrochloride (397 mg)
And triethylamine (0.75 ml) were added, and the mixture was stirred at room temperature for 64 hours. After adding a 4M hydrogen chloride dioxane solution (2 ml), the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 24%
After purification with acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (1 ml) was added, and this was concentrated to dryness under reduced pressure. The obtained amorphous solid was washed with water (about 15 m
It was dissolved in 1) and freeze-dried to obtain 423 mg (yield 60%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 6.
5), 1.65-1.79 (2H, m), 2.04 (2H, m), 2.28 (3H, s),
2.31 (3H, s), 3.48-3.59 (2H, m), 3.72 (1H, m), 3.
85 (1H, m), 4.21 (2H, q, J = 6.5), 4.28 (1H, dd, J = 1
4.5, 6.0), 4.34 (1H, d, J = 15.0), 4.43 (1H, dd, J = 1
4.5, 4.5), 4.49 (1H, d, J = 15.0), 4.70 (1H, m), 6.4
6 (1H, d, J = 15.5), 6.49 (1H, m), 6.90 (1H, dd, J =
9.0, 3.0), 6.93 (1H, d, J = 3.0), 7.41 (1H, d, J = 9.
0), 7.55 (1H, t, J = 8.0), 7.72 (2H, m), 7.88 (1H,
s); IR (KBr, cm ^-1 ): 1738, 1673, 1624.

Example 7 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3
-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number:
1442)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methoxy-4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride Salt N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methoxyphenyl] -N- [3
-(3-Cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate (985 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed under ice cooling for 40 minutes,
The reaction vessel was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (172 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.33 ml) were added, and the mixture was left at room temperature for 13 hours. did. The reaction solution is concentrated under reduced pressure,
The residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (1.5 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17% acetonitrile / water), and the obtained amorphous solid was dissolved in methanol (20 ml) and 4M hydrogen chloride dioxane solution (0.4 ml). After the reaction, this was concentrated to dryness to give the title compound (560 mg, yield 58%) as a pale-yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.84 (2H, m), 2.05 (2H, m), 3.03 (2H, m), 3.19
(2H, m), 3.79 (3H, s), 4.21 (2H, q, J = 7.0), 4.38
(2H, s), 4.46 (2H, d, J = 6.0), 4.56 (1H, m), 6.46
(1H, dt, J = 15.5, 6.0), 6.57 (1H, d, J = 15.5), 6.98
(1H, dd, J = 9.0, 2.0), 7.08 (1H, d, J = 9.0), 7.11 (1
H, d, J = 2.0), 7.55 (1H, t, J = 7.5), 7.69 (1H, d, J =
7.5), 7.73 (1H, d, J = 7.5), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methoxy-4- (piperidine-
4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (392 mg) was dissolved in ethanol (20 ml) to give ethylacetimidate hydrochloride (241 m).
g) and triethylamine (0.452 ml) were added, and the mixture was stirred at room temperature for 38 hours. After adding a 4M hydrogen chloride dioxane solution (0.8 ml) to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-PackODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was dissolved in methanol (20 ml),
After adding a 4M hydrogen chloride dioxane solution (0.3 ml), this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml), and then freeze-dried to obtain 317 mg (yield 76%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.66-1.80 (2H, m), 2.01 (2H, m), 2.30 (3H, s),
3.47-3.59 (2H, m), 3.72 (1H, m), 3.78 (3H, s), 3.
82 (1H, m), 4.21 (2H, q, J = 7.0), 4.39 (2H, s), 4.4
7 (2H, d, J = 5.5), 4.62 (1H, m), 6.47 (1H, dt, J = 1
5.5, 5.5), 6.57 (1H, d, J = 15.5), 6.99 (1H, dd, J = 9.
0, 3.0), 7.11 (2H, m), 7.55 (1H, t, J = 8.0), 7.71
(1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.91 (1H, s)
IR (KBr, cm ^-1 ): 1738, 1674, 1625.

Example 8 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
414)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-
4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-chlorophenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1200 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml), and hydrogen chloride was passed through for 2 hours under ice cooling. rear,
The reaction vessel was sealed and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (208 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.40 ml) were added, and the mixture was left at room temperature for 13 hours. did. The reaction solution is concentrated under reduced pressure,
The residue was dissolved in methanol (25 ml), 4M hydrogen chloride dioxane solution (1.6 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water) and the obtained amorphous solid was dissolved in methanol (20 ml).
After adding M hydrogen chloride dioxane solution (0.5 ml),
This was concentrated to dryness to give an amorphous solid. The title compound 6 was obtained by dissolving this in water and subjecting it to freeze-drying.
Obtained 62 mg (56% yield) as a pale yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.88 (2H, m), 2.10 (2H, m), 3.08 (2H, m), 3.17
(2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47
(2H, d, J = 6.5), 4.78 (1H, m), 6.44 (1H, dt, J = 16.
0, 6.5), 6.57 (1H, d, J = 16.0), 7.30 (1H, d, J = 9.
5), 7.41 (1H, dd, J = 9.5, 2.5), 7.55 (1H, t, J = 8.
0), 7.59 (1H, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.73
(1H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidine-4)
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (387 mg) was dissolved in ethanol (10 ml) and ethyl acetimidate hydrochloride (232 mg) was added.
And triethylamine (0.440 ml) were added,
Stir at room temperature for 5 hours. After adding a 4M hydrogen chloride dioxane solution (1 ml), the reaction solution was concentrated under reduced pressure. The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22%
After purification with acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (0.25 ml) was added, and this was concentrated to dryness under reduced pressure. The amorphous solid obtained is treated with water (about 1
5 ml) and then freeze-dried,
268 mg (66% yield) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.80 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.55
-3.78 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s),
4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.45 (1H, dt,
J = 15.5, 6.0), 6.58 (1H, d, J = 15.5), 7.33 (1H, d, J =
9.0), 7.41 (1H, dd, J = 9.0, 3.0), 7.55 (1H, t, J = 8.
0), 7.59 (1H, d, J = 3.0), 7.70 (1H, d, J = 8.0), 7.73
(1H, d, J = 8.0), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1673, 1623.

Example 9 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid dihydrochloride (Exemplary compound number: 194
3) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-
Ethyl amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (187 mg) was dissolved in 3M hydrochloric acid (7 ml), and this was stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15).
% Amorphous / water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. After dissolving this in water (about 10 ml),
By freeze-drying, the title compound (147 mg, yield 82%) was obtained. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.79 (2H, m), 2.0
5 (2H, m), 2.29 (3H, s), 3.54-3.75 (4H, m), 4.23 (2
H, s), 4.47 (2H, d, J = 6.0), 4.83 (1H, m), 6.45 (1H,
dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.32 (1H,
d, J = 9.0), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.6
0 (1H, m), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.
0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1734, 1673, 1625.

Example 10 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3
-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number:
1412)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-fluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride Salt N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-fluorophenyl] -N- [3
-(3-Cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate (1210 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml), and hydrogen chloride was passed under ice-cooling for 1 hour.
The reaction vessel was sealed and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (215 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.41 ml) were added,
It was left at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure.
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 1
(7% acetonitrile / water), dissolve the obtained amorphous solid in methanol (15 ml), add 4M hydrogen chloride dioxane solution (0.3 ml), and concentrate and dry it under reduced pressure. Gives the title compound 798 mg
(Yield 67%) was obtained as a pale yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85 (2H, m), 2.09 (2H, m), 3.06 (2H, m), 3.19
(2H, m), 4.19 (2H, q, J = 7.0), 4.40 (2H, s), 4.47
(2H, d, J = 7.0), 4.68 (1H, m), 6.43 (1H, m), 6.58
(1H, d, J = 16.0), 7.25 (1H, dd, J = 9.0, 2.5), 7.31
(1H, t, J = 9.0), 7.43 (1H, dd, J = 12.5,2.5), 7.55 (1
H, t, J = 8.0), 7.68 (1H, m), 7.73 (1H, d, J = 8.0),
7.88 (1H, bs); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-fluoro-4- (piperidine-
4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (467 mg) was dissolved in ethanol (25 ml) and ethyl acetimidate hydrochloride (293 m) was added.
g) and triethylamine (0.550 ml) were added, and the mixture was stirred at room temperature for 66 hours. After adding a 4M hydrogen chloride dioxane solution (1.5 ml) to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-PackODS YMC, elution solvent: 22% acetonitrile / water), and the obtained amorphous solid was dissolved in methanol (15 ml),
After adding a 4M hydrogen chloride dioxane solution (0.3 ml), this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 15 ml), and then freeze-dried to obtain 284 mg (yield 57%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.68-1.82 (2H, m), 2.06 (2H, m), 2.31 (3H, s),
3.51 (1H, m), 3.59 (1H, m), 3.71 (1H, m), 3.86 (1
H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2
H, d, J = 6.0), 4.76 (1H, m), 6.46 (1H, dt, J = 15.5,
6.0), 6.57 (1H, d, J = 15.5), 7.26 (1H, d, J = 9.0), 7.
35 (1H, t, J = 9.0), 7.43 (1H, dd, J = 12.0, 2.5), 7.5
4 (1H, t, J = 8.0), 7.73 (2H, m), 7.95 (1H, s); IR (KBr, cm ^-1 ): 1738, 1673, 1623.

Example 11 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3
-Amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplary compound number: 194)
1) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3
-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (199 mg) was dissolved in 3M hydrochloric acid (7 ml), and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was converted to methanol ( 10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 10 ml) and freeze-dried to give 163 mg of the title compound (yield 86
%) Was obtained. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.77 (2H, m), 2.0
5 (2H, m), 2.29 (3H, s), 3.52 (2H, m), 3.71 (1H,
m), 3.80 (1H, m), 4.23 (2H, s), 4.47 (2H, d, J = 6.
0), 4.73 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57
(1H, d, J = 16.0), 7.26 (1H, m), 7.32 (1H, t, J = 8.
5), 7.43 (1H, dd, J = 13.0, 2.0), 7.55 (1H, t, J = 8.
0), 7.68 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88
(1H, s); IR (KBr, cm ^-1 ): 3295, 1733, 1673, 1624.

Example 12 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2)
-Methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
771)

(A) N- [3- (5-amidino-2-
Methylphenyl) -2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (5-cyano-2-methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate (2.03 g) was added to dichloromethane (40 ml) and ethanol (40 ml). The mixture was dissolved in the mixed solvent of, and hydrogen chloride was passed through the mixture under ice cooling for 1 hour, then the vessel was sealed with a stopper and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), and an aqueous ammonium chloride solution (0.36 g was dissolved in 15 ml of water).
And 28% aqueous ammonia (0.68 ml) were added,
It was left at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride ethyl acetate solution (2 ml) was added, and the mixture was concentrated under reduced pressure.
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 2
(0% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), 4M hydrogen chloride ethyl acetate solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The title compound (1.49 g, yield 75%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.82 (2H, m), 2.09 (2H, m), 2.22 (3H, s), 3.05
(2H, m), 3.21 (2H, m), 4.19 (2H, q, J = 7.0), 4.34
(2H, s), 4.46 (2H, d, J = 6.5), 4.66 (1H, m), 6.30
(1H, dt, J = 16.0, 6.5), 6.66 (1H, d, J = 16.0), 7.05
(2H, d, J = 9.5), 7.37 (1H, d, J = 7.5), 7.38 (2H, d, J
= 9.5), 7.61 (1H, dd, J = 7.5, 2.0), 7.86 (1H, d, J =
2.0); IR (KBr, cm ^-1 ): 1738, 1674.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(5-amidino-2-methylphenyl) -2- (E)
-Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (5-amidino-2-methylphenyl) -2
-(E) -Propenyl] -N- [4- (piperidine-4
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (1.43 g) was dissolved in ethanol (40 ml) and ethyl acetimidate hydrochloride (0.60 g) was added.
And triethylamine (1.4 ml) were added, and the mixture was stirred at room temperature for 13 hours. After adding 4M hydrogen chloride ethyl acetate solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and the solution was diluted with 4M hydrogen chloride ethyl acetate solution (0 (1.8 ml) and then concentrated to dryness under reduced pressure to give the title compound (1.18 g, yield 77%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.67-1.80 (2H, m), 2.05 (2H, m), 2.22 (3H, s),
2.30 (3H, s), 3.49-3.61 (2H, m), 3.72 (1H, m),
3.83 (1H, m), 4.19 (2H, q, J = 7.0), 4.35 (2H, s),
4.46 (2H, d, J = 6.0), 4.72 (1H, m), 6.32 (1H, dt, J
= 16.0, 6.0), 6.66 (1H, d, J = 16.0), 7.06 (2H, d, J =
9.5), 7.38 (1H, d, J = 9.0), 7.39 (2H, d, J = 9.5), 7.
64 (1H, dd, J = 9.0, 2.0), 7.88 (1H, d, J = 2.0); IR (KBr, cm ^-1 ): 1738, 1675, 1626.

Example 13 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1440)

(A) Ethyl N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl acetate Dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-trifluoromethylphenyl]
-N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate (2.06g)
To dichloromethane (50 ml) and ethanol (25
(ml) in a mixed solvent, hydrogen chloride was passed through the mixture under ice-cooling for 1 hour, and the mixture was tightly closed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), and an ammonium chloride aqueous solution (0.34 g was added to water 1
Dissolved in 5 ml) and 28% ammonia water (0.63 m
After adding 1), the mixture was allowed to stand at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride dioxane solution (2.5 ml) was added, and the mixture was concentrated under reduced pressure. The residue was collected by preparative HPLC (YMC-Pack
Purified by ODS YMC, elution solvent: 25% acetonitrile / water) and the amorphous solid obtained was methanol (20 ml).
4M hydrogen chloride dioxane solution (0.5m
l) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (1.21 g, yield 60%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.87 (2H, m), 2.08 (2H, m), 3.11 (2H, m), 3.33
(2H, m), 4.18 (2H, q, J = 7.0), 4.44 (2H, s), 4.50
(2H, d, J = 6.5), 4.89 (1H, m), 6.44 (1H, dt, J = 16.
0, 6.5), 6.57 (1H, d, J = 16.0), 7.39 (1H, d, J = 9.
0), 7.55 (1H, t, J = 8.0), 7.66-7.73 (4H, m), 7.85 (1
H, s); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl)
2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) -3 Ethyl acetimidate hydrochloride (0.65 g) and triethylamine (1.20 m) were prepared by dissolving ethyl trifluoromethylphenyl] sulfamoyl acetate dihydrochloride (1.13 g) in ethanol (20 ml).
After 1) was added, the mixture was stirred at room temperature for 13 hours. 4 in the reaction solution
After adding a M hydrogen chloride dioxane solution (2 ml), the mixture was concentrated under reduced pressure. The residue was subjected to preparative HPLC (YMC-Pack ODS YMC,
After purification with an elution solvent: 30% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), 4M hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and this was reduced under reduced pressure. By concentration to dryness, 1.04 g (yield 87%) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.81 (2H, m), 2.07 (2H, m), 2.30 (3H, s), 3.59
-3.73 (4H, m), 4.19 (2H, q, J = 7.0), 4.46 (2H, s),
4.50 (2H, d, J = 6.5), 4.96 (1H, m), 6.47 (1H, dt, J
= 16.5, 6.5), 6.58 (1H, d, J = 16.5), 7.44 (1H, d, J =
9.5), 7.56 (1H, t, J = 8.0), 7.71 (4H, m), 7.90 (1H,
s); IR (KBr, cm ^-1 ): 1739, 1673, 1618.

Example 14 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
420)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-
4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methylphenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.90 g) was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (40 ml), and hydrogen chloride was cooled for 1 hour under ice cooling. After passing through, the vessel was sealed and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), and an aqueous ammonium chloride solution (0.34 g was dissolved in 15 ml of water).
And 28% aqueous ammonia (0.64 ml) were added,
It was left at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was concentrated under reduced pressure.
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 2
After purification with (0% acetonitrile / water), the obtained amorphous solid is dissolved in methanol (20 ml), 4M hydrogen chloride ethyl acetate solution (1 ml) is added, and this is concentrated to dryness under reduced pressure. Gives 1.36 g of the title compound
(73% yield) was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.87 (2H, m), 2.10 (2H, m), 2.17 (3H, s), 3.07
(2H, m), 3.17 (2H, m), 4.20 (2H, q, J = 7.0), 4.33
(2H, s), 4.44 (2H, d, J = 6.0), 4.65 (1H, m), 6.44
(1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.05
(1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0,2.5), 7.29 (1
H, d, J = 2.5), 7.54 (1H, t, J = 8.0), 7.71 (2H, m),
7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidine-4)
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (1.23 g) was dissolved in ethanol (40 ml) and ethyl acetimidate hydrochloride (0.52 g) was added.
And triethylamine (1.20 ml) were added, and the mixture was stirred at room temperature for 13 hours. After adding a 4M hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and the solution was diluted with 4M hydrogen chloride ethyl acetate solution (0 .6 ml) and then concentrated to dryness under reduced pressure to give 1.10 g of the title compound.
(Yield 84%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.77 (2H, m), 2.03 (2H, m), 2.16 (3H, s), 2.30
(3H, s), 3.60-3.80 (4H, m), 4.20 (2H, q, J = 7.
0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (1H,
m), 6.45 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.
0), 7.06 (1H, d, J = 9.0), 7.25 (1H, dd, J = 9.0, 2.
5), 7.29 (1H, d, J = 2.5), 7.55 (1H, t, J = 8.0), 7.71
(2H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1738, 1672, 1624.

Example 15 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5]
-Methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
711)

(A) N- [3- (3-amidino-5-
Methylphenyl) -2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyano-5-methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate (1.59 g) was added to dichloromethane (15 ml) and ethanol (15 ml). Was dissolved in the mixed solvent of, and hydrogen chloride was passed through the mixture under ice-cooling for 1 hour, and the vessel was tightly capped and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.21 g was dissolved in 4 ml of water) and 28% aqueous ammonia (0.53 ml) were added, and the mixture was stirred at room temperature overnight. I left it. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water) to give 1.10 g (80% yield) of the title compound as a colorless compound. Obtained as a solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85 (2H, m), 2.10 (2H, m), 2.36 (3H, s), 3.06
(2H, m), 3.18 (2H, m), 4.19 (2H, q, J = 7.0), 4.33
(2H, s), 4.44 (2H, d, J = 5.5), 4.66 (1H, m), 6.41
(1H, dt, J = 16.0, 5.5), 6.51 (1H, d, J = 16.0), 7.04
(2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.54 (1H, s),
7.58 (1H, s), 7.68 (1H, s); IR (KBr, cm ^-1 ): 1737, 1674.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidino-5-methylphenyl) -2- (E)
-Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidino-5-methylphenyl) -2
-(E) -Propenyl] -N- [4- (piperidine-4
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (800 mg) was dissolved in ethanol (25 ml) and ethyl acetimidate hydrochloride (1400 m) was added.
g) and triethylamine (2.2 ml) were added,
Stir at room temperature for 27 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20%
After purification with acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (20 ml), 4M hydrogen chloride ethyl acetate solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was suspended in ethyl acetate and collected by filtration to give the title compound (400 mg, yield 41%) as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.70 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 2.36
(3H, s), 3.45-3.65 (2H, m), 3.65-3.95 (2H, m), 4.
19 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 5.
5), 4.71 (1H, m), 6.41 (1H, dt, J = 16.0, 5.5), 6.51
(1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d,
J = 9.0), 7.56 (2H, 2s duplication), 7.70 (1H, s); IR (KBr, cm ^-1 ): 1738, 1672, 1625.

Example 16 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5]
-Methylphenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number: 220)
8) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5)
-Methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (200 mg) was dissolved in 1M hydrochloric acid (8 ml), and the mixture was stirred at 80 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack O
After purification with DS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in water, 4M hydrogen chloride ethyl acetate solution (0.2 ml) was added, and this was then under reduced pressure. By concentrating to dryness, the title compound 110
mg (yield 57%) was obtained as a colorless amorphous solid. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.60-1.85 (2H,
m), 2.05 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 3.40-
3.65 (2H, m), 3.65-3.95 (2H, m), 4.20 (2H, s), 4.4
4 (2H, d, J = 5.0), 4.70 (1H, m), 6.41 (1H, dt, J = 1
6.0, 5.0), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.
0), 7.39 (2H, d, J = 9.0), 7.55 (2H, duplication of 2 s),
7.69 (1H, s); MS (FAB) m / z = 528 (M + H) ⁺ .

Example 17 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-4]
-Fluorophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number:
1638)

(A) N- [3- (3-amidino-4-
Fluorophenyl) -2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate (1530 mg) was dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), hydrogen chloride was passed through the mixture under ice cooling for 1.25 hours, and the mixture was sealed and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (200 mg was added to 4 ml of water).
Solution) and 28% aqueous ammonia (0.50 ml) were added, and the mixture was left at room temperature overnight. The reaction solution is concentrated under reduced pressure,
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 2
The title compound (550 mg, yield 41%) was obtained as a colorless amorphous solid by purification with 0% acetonitrile / water). ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.75-1.95 (2H, m), 2.00-2.20 (2H, m), 2.95-3.1
5 (2H, m), 3.15-3.30 (2H, m), 4.19 (2H, q, J = 7.0),
4.33 (2H, s), 4.42 (2H, d, J = 6.0), 4.65 (1H, m),
6.35 (1H, dt, J = 16.0, 6.0), 6.53 (1H, d, J = 16.0),
7.03 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.42 (1
H, m), 7.73 (2H, m); IR (KBr, cm ^-1 ): 1737, 1677.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidino-4-fluorophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidino-4-fluorophenyl)-
2- (E) -propenyl] -N- [4- (piperidine-
Ethyl 4-yloxy) phenyl] sulfamoylacetate dihydrochloride (350 mg) was dissolved in ethanol (14 ml) to give ethylacetimidate hydrochloride (160 m).
g) and triethylamine (0.36 ml) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 20
% Amorphous / water), the obtained amorphous solid is dissolved in ethanol (8 ml), 4M hydrogen chloride ethyl acetate solution (0.5 ml) is added, and the mixture is concentrated to dryness under reduced pressure. By this, the title compound 279 mg
(65% yield) was obtained as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.73 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.40
-3.65 (2H, m), 3.65-3.90 (2H, m), 4.19 (2H, q, J =
7.0), 4.33 (2H, s), 4.42 (2H, d, J = 5.5), 4.71 (1H,
m), 6.35 (1H, dt, J = 16.0, 5.5), 6.54 (1H, d, J = 16.
0), 7.04 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.40
(1H, m), 7.73 (2H, m); IR (KBr, cm ^-1 ): 1738, 1675, 1618.

Example 18 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] acetamide dihydrochloride (Exemplified compound number: 948)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] acetamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] acetamide (1203 mg) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (30 ml) and iced. After passing hydrogen chloride under cooling for 1 hour, the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), an aqueous ammonium chloride solution (271 mg was dissolved in 25 ml of water) and 28% aqueous ammonia (0.51 ml) were added, and the mixture was left at room temperature for 12 hours. did. 4M hydrogen chloride dioxane solution (1.5m
1) was added, and the mixture was concentrated under reduced pressure. The residue is purified by preparative HPLC (YM
C-Pack ODS YMC, elution solvent: 13% acetonitrile /
After purification with water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (1.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml), and then freeze-dried to give the title compound 853 m.
g (72% yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.78 (3H, s), 1.8
3 (2H, m), 2.11 (2H, m), 2.90-3.30 (4H, m), 4.39 (2
H, m), 4.50-4.80 (1H, m), 6.40-6.60 (2H, m), 7.04
(2H, d, J = 9.0), 7.28 (2H, d, J = 9.0), 7.55 (1H, t,
J = 7.5), 7.71 (1H, d, J = 7.5), 7.73 (1H, d, J = 7.5),
7.94 (1H, s); IR (KBr, cm ^-1 ): 1675, 1626.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2- (E) -propenyl] acetamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidine-4) -Yloxy) phenyl] acetamide dihydrochloride (400 mg)
Was dissolved in methanol (20 ml), ethyl acetimidate hydrochloride (320 mg) and triethylamine (0.60 ml) were added at room temperature, and then the mixture was stirred at the same temperature for 12 hours. 4M hydrogen chloride dioxane solution (1m
l) was added and then concentrated under reduced pressure, and the residue was collected by preparative HPLC.
After purification with (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give the title compound 342.
mg (79% yield) was obtained as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.74 (2H, m), 1.7
8 (3H, s), 2.04 (2H, m), 2.31 (3H, s), 3.45-3.95 (4
H, m), 4.39 (2H, m), 4.60-4.80 (1H, m), 6.40-6.60
(2H, m), 7.05 (2H, d, J = 8.5), 7.28 (2H, d, J = 8.5),
7.55 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.95 (1H,
s); IR (KBr, cm ^-1 ): 1672, 1624.

Example 19 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] -2-hydroxy Acetamide dihydrochloride (Exemplified compound number: 1014)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] -2-hydroxyacetamide dihydrochloride N -[4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] -2-hydroxyacetamide (977 mg) was added to dichloromethane (3
It was dissolved in a mixed solvent of 0 ml) and ethanol (15 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the vessel was tightly closed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (213 mg was dissolved in 10 ml of water) and 28
% Ammonia water (0.40 ml) was added, and then 1 at room temperature.
It was left for 2 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture was concentrated under reduced pressure and the residue was collected by HP.
After purification by LC (YMC-Pack ODS YMC, eluting solvent: 11% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, it was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to give the title compound 6
Obtained 85 mg (72% yield) as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.84 (2H, m), 2.1
0 (2H, m), 2.90-3.80 (6H, m), 4.36 (2H, m), 4.65 (1
H, m), 6.50 (2H, m), 7.03 (2H, d, J = 8.5), 7.28 (2H,
d, J = 8.5), 7.55 (1H, t, J = 7.5), 7.65-7.80 (2H,
m), 7.92 (1H, s); IR (KBr, cm ^-1 ): 1673.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] -2-hydroxyacetamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (Piperidin-4-yloxy) phenyl] -2-hydroxyacetamide dihydrochloride (385 mg) was dissolved in methanol (20 ml), ethyl acetimidate hydrochloride (300 mg) and triethylamine (0.56 ml) were added at room temperature. After
The mixture was stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 14% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid is treated with water (about 10 m
It was dissolved in 1) and freeze-dried to obtain 336 mg (yield 80%) of the title compound as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.0
5 (2H, m), 2.30 (3H, s), 3.30-3.90 (6H, m), 4.39 (2
H, m), 4.69 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H,
d, J = 9.0), 7.28 (2H, d, J = 9.0), 7.55 (1H, t, J = 8.
0), 7.65-7.80 (2H, m), 7.93 (1H, s); IR (KBr, cm ^-1 ): 1671.

Example 20 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-benzylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplified compound number: 864)

(A) 3- [3- [N-benzyl-N-
[4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N-benzyl-N- [4- (1-t-butoxycarbonylpiperidine -4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (916 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was added thereto under ice cooling for 1 hour. After passing through, the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (187 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.46 ml) were added, and the mixture was left at room temperature for 12 hours. did. 4M hydrogen chloride dioxane solution (1 ml) in the reaction solution
After the addition, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography- [Cosmosil (registered trademark) 75C18-PRE.
P; Nacalai Tesque, elution solvent: 5% acetonitrile /
After purification with water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give the title compound 581 m.
g (60% yield) was obtained as a light brown amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.78 (2H, m), 2.0
3 (2H, m), 2.98 (2H, m), 3.15 (2H, m), 4.35 (2H, m)
m), 4.50 (1H, m), 4.76 (2H, m), 6.61 (1H, dt, J = 1
6.0, 6.5), 6.70 (1H, d, J = 16.0), 6.93 (2H, m), 7.2
0-7.35 (3H, m), 7.35-7.50 (4H, m), 7.57 (1H, t, J =
8.0), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.8
9 (1H, s); IR (KBr, cm ^-1 ): 1675.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-benzylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N-benzyl-N- [4- (piperidine-
4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (335 mg),
After dissolving in methanol (20 ml) and adding ethylacetimidate hydrochloride (230 mg) and triethylamine (0.51 ml) at room temperature, the mixture was stirred at the same temperature for 12 hours. 4M hydrogen chloride dioxane solution (1m
l) was added and then concentrated under reduced pressure, and the residue was collected by preparative HPLC.
After purification with (YMC-Pack ODS YMC, elution solvent: 30% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give the title compound 252.
mg (70% yield) was obtained as a colorless amorphous solid. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.50-1.75 (2H,
m), 1.96 (2H, m), 2.29 (3H, s), 3.40 -3.90 (4H, m),
4.40 (2H, m), 4.50-4.90 (3H, m), 6.63 (1H, dt, J = 1
6.0, 6.0), 6.74 (1H, d, J = 16.0), 6.97 (2H, d, J = 8.
5), 7.15-7.30 (3H, m), 7.40-7.60 (4H, m), 7.56 (1
H, t, J = 7.5), 7.66 (1H, d, J = 7.5), 7.77 (1H, d, J =
7.5), 7.92 (1H, s); IR (KBr, cm ^-1 ): 1672, 1624.

Example 21 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] amino] -1-
(E) -Propenyl] benzamidine trihydrochloride (Exemplified compound number: 177)

(A) 3- [3- [N- [4- (piperidin-4-yloxy) phenyl] amino] -1-
(E) -Propenyl] benzamidine trihydrochloride 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (900 mg)
With dichloromethane (30 ml) and ethanol (15
(ml) in a mixed solvent, hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the vessel was sealed with a stopper and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (222 mg was added to water 1
Dissolved in 0 ml) and 28% ammonia water (0.54 m
After adding 1), the mixture was allowed to stand at room temperature for 12 hours. 4 in the reaction solution
After adding M hydrogen chloride dioxane solution (1 ml), the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 15% acetonitrile / water),
The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (735 mg, yield 77%). Was obtained as a yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.82 (2H, m), 2.0
5 (2H, m), 3.03 (2H, m), 3.20 (2H, m), 3.95-4.10 (2
H, m), 4.50-4.65 (1H, m), 6.55 (1H, dt, J = 16.0, 6.
5), 6.79 (1H, d, J = 16.0), 7.05 (2H, m), 7.20-7.45
(2H, m), 7.61 (1H, t, J = 8.0), 7.70-7.80 (2H, m), 7.
87 (1H, s); IR (KBr, cm ^-1 ): 1675.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3 -[N- [4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (345 mg) was dissolved in methanol (20 ml) to give ethylacetimidate hydrochloride. (185 mg) and triethylamine (0.52 m
l) was added at room temperature and then stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS).
After purification with YMC, elution solvent: 30% acetonitrile / water), the amorphous solid obtained was methanol (10 ml).
4M hydrogen chloride dioxane solution (0.5m
After the addition of 1), this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give 272 mg of the title compound (yield 7
2%) as a yellow amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.0
5 (2H, m), 2.30 (S, 3H), 3.40-3.95 (4H, m), 4.06 (2
H, d, J = 6.5), 4.69 (1H, m), 6.56 (1H, dt, J = 16.0,
6.5), 6.80 (1H, d, J = 16.0), 7.10 (2H, d, J = 9.0),
7.35-7.55 (2H, m), 7.60 (1H, t, J = 8.0), 7.70-7.80 (2
H, m), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1672, 1625.

Example 22 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzamidine 3
Hydrochloride (Exemplified compound number: 358)

(A) 3- [3- [N-isopropyl-
N- [4- (piperidin-4-yloxy) phenyl]
Amino] -1- (E) -propenyl] benzamidine 3
The hydrochloride salt 3- [3- [N-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl-N-isopropylamino] -1- (E) -propenyl] benzonitrile (705 mg) was added to dichloromethane ( 30 ml) and ethanol (15 ml) mixed solvent, and under ice cooling,
After passing hydrogen chloride for 1 hour, the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (1
59 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.39 ml) was added, and the mixture was left at room temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa.
After purification with ck ODS YMC, eluting solvent: 15% acetonitrile / water), the obtained amorphous solid was purified with methanol (10
4M hydrogen chloride dioxane solution (0.
(5 ml) was added, and this was concentrated to dryness under reduced pressure. After dissolving the obtained amorphous solid in water (about 10 ml),
By freeze-drying, 570 mg (70% yield) of the title compound was obtained as a light brown amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.16 (3H, m), 1.4
0 (3H, m), 1.82 (2H, m), 2.07 (2H, m), 3.03 (2H, m
m), 3.18 (2H, m), 3.98 (1H, m), 4.41 (2H, m), 4.68
(1H, m), 6.40 (1H, m), 6.72 (1H, d, J = 16.0), 7.13
(2H, m), 7.50-7.65 (2H, m), 7.70-7.85 (4H, m); IR (KBr, cm ^-1 ): 1675.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N-isopropyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E)
-Propenyl] benzamidine trihydrochloride (310 mg)
Was dissolved in methanol (20 ml), ethyl acetimidate hydrochloride (229 mg) and triethylamine (0.52 ml) were added at room temperature, and then the mixture was stirred at the same temperature for 12 hours. 4M hydrogen chloride dioxane solution (1m
l) was added and then concentrated under reduced pressure, and the residue was collected by preparative HPLC.
After purification with (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give the title compound 259
mg (77% yield) was obtained as a light brown amorphous solid. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.17 (3H, d, J = 6.
0), 1.43 (3H, d, J = 6.0), 1.70 (2H, m), 2.04 (2H,
m), 2.31 (3H, s), 3.45-4.05 (5H, m), 4.41 (2H, m),
4.74 (1H, m), 6.42 (1H, dt, J = 16.0, 7.0), 6.73 (1
H, d, J = 16.0), 7.15 (2H, d, J = 8.5), 7.50-7.65 (2H,
m), 7.70-7.90 (4H, m); IR (KBr, cm ^-1 ): 1672, 1623.

Example 23 2- [N- [4- (1-acetimidoylpiperidine-
4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl acetate trihydrochloride (Exemplified compound number: 668)

(A) 2- [N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4-]
(Piperidin-4-yloxy) phenyl] amino] ethyl acetate trihydrochloride 2- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl acetate (1305 mg) was added to dichloromethane (30
(ml) and ethanol (15 ml), the mixture was dissolved, and hydrogen chloride was passed through the mixture under ice cooling for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (269 mg was dissolved in 10 ml of water) and 28%.
Ammonia water (0.66 ml) was added, and then at room temperature, 12
Left for hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture was concentrated under reduced pressure and the residue was collected by HP.
After purification by LC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, it was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to give the title compound 6
52 mg (48% yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.
0), 1.80 (2H, m), 2.04 (2H, m), 3.00 (2H, m), 3.17
(2H, m), 4.11 (2H, q, J = 7.0), 4.10-4.20 (4H, m),
4.42 (1H, m), 6.55 (1H, dt, J = 16.0, 5.0), 6.65 (2
H, d, J = 9.0), 6.67 (1H, d, J = 16.0), 6.87 (2H, d, J
= 9.0), 7.56 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.91
(1H, s); IR (KBr, cm ^-1 ): 1747, 1675.

(B) 2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N
-[3- (3-Amidinophenyl) -2- (E) -propenyl] amino] ethyl acetate 3-hydrochloride 2- [N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- (piperidine-4-
Iloxy) phenyl] amino] ethyl acetate trihydrochloride (400 mg) was dissolved in methanol (20 ml) and ethylacetimidate hydrochloride (270 mg) and triethylamine (0.61 ml) were added at room temperature,
The mixture was stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 24% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid is treated with water (about 10 m
After dissolving in 1) and freeze-drying, 350 mg (yield 81%) of the title compound was obtained as a pale yellow amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.
0), 1.70 (2H, m), 1.99 (2H, m), 2.31 (3H, s), 3.45
-3.85 (4H, m), 4.11 (2H, q, J = 7.0), 4.15-4.25 (4H,
m), 4.48 (1H, m), 6.56 (1H, dt, J = 16.0, 4.5), 6.6
6 (2H, d, J = 9.0), 6.67 (1H, d, J = 16.0), 6.88 (2H,
d, J = 9.0), 7.56 (1H, t, J = 8.0), 7.65-7.80 (2H, m),
7.92 (1H, s); IR (KBr, cm ^-1 ): 1747, 1672, 1623.

Example 24 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplified compound number: 297)

(A) 3- [3- [N-ethyl-N-
[4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy ) Phenyl] -N-ethylamino] -1- (E) -propenyl] benzonitrile (770 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and the mixture was cooled with ice.
After passing hydrogen chloride for 1 hour, the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (1
78 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.44 ml) was added, and the mixture was left at room temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa.
After purification with ck ODS YMC, eluting solvent: 20% acetonitrile / water, the obtained amorphous solid was purified with methanol (10
4M hydrogen chloride dioxane solution (0.
(5 ml) was added, and this was concentrated to dryness under reduced pressure. After dissolving the obtained amorphous solid in water (about 10 ml),
By freeze-drying, 570 mg (70% yield) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.07 (3H, t, J = 7.
0), 1.83 (2H, m), 2.10 (2H, m), 2.95-3.25 (4H, m),
3.60 (2H, m), 4.30 (2H, m), 4.69 (1H, m), 6.48 (1
H, dt, J = 16.0, 7.0), 6.72 (1H, d, J = 16.0), 7.15 (2
H, d, J = 8.5), 7.56 (1H, t, J = 7.5), 7.66 (1H, d, J =
7.5), 7.70-8.00 (4H, m); IR (KBr, cm ^-1 ): 1675.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl]
Benzamidine trihydrochloride 3- [3- [N-ethyl-N- [4- (piperidine-4
-Yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (420 mg) was dissolved in methanol (20 ml) and ethyl acetimidate hydrochloride (319 mg) and triethylamine (0.
(72 ml) was added at room temperature, and then the mixture was stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa.
After purification with ck ODS YMC, eluting solvent: 20% acetonitrile / water, the obtained amorphous solid was purified with methanol (10
4M hydrogen chloride dioxane solution (0.
(5 ml) was added, and this was concentrated to dryness under reduced pressure. After dissolving the obtained amorphous solid in water (about 10 ml),
By freeze-drying, 287 mg of the title compound (yield 63%) was obtained as a colorless amorphous solid. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.09 (3H, t, J = 7.
0), 1.71 (2H, m), 2.03 (2H, m), 2.32 (3H, s), 3.50
-3.95 (6H, m), 4.30 (2H, m), 4.75 (1H, m), 6.49 (1
H, dt, J = 16.0, 6.5), 6.73 (1H, d, J = 16.0), 7.00-7.
30 (2H, m), 7.58 (1H, t, J = 7.5), 7.67 (1H, d, J = 7.
5), 7.75-7.90 (4H, m); IR (KBr, cm ^-1 ): 1673, 1623.

Example 25 N- [4- (1-acetimidoylpyrrolidin-3-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 2 Hydrochloride (Exemplified compound number: 90)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (pyrrolidin-3-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [ 4- (1-t-butoxycarbonylpyrrolidine-
3-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate (2349 mg) was added to dichloromethane (60
(ml) and ethanol (30 ml), and the mixture was dissolved in a mixed solvent of hydrogen (1 ml) and ethanol (30 ml). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (100 ml), and an aqueous ammonium chloride solution (440 mg was dissolved in 50 ml of water) and 28
% Ammonia water (0.83 ml) was added, and then 1 at room temperature.
It was left for 2 hours. After adding 4M hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was collected by HP.
It was purified by LC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (272 mg, yield 12
%) As a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 2.05-2.25 (2H, m), 3.15-3.50 (4H, m), 4.20 (2
H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 5.5),
5.12 (1H, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.56 (1
H, d, J = 16.0), 7.01 (2H, d, J = 9.0), 7.42 (2H, d, J
= 9.0), 7.54 (1H, t, J = 8.0), 7.65-7.75 (2H, m), 7.90
(1H, s); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpyrrolidin-3-yloxy) phenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (pyrrolidine -3-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (4
(00 mg) was dissolved in methanol (20 ml), ethyl acetimidate hydrochloride (350 mg) and triethylamine (0.50 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hr. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was collected H.
After purification by PLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. After that, it was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml), and then freeze-dried to obtain 255 mg (yield 59%) of the title compound as a colorless amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 2.10-2.30 (2H, m), 2.26 and 2.29 (total 3H, each
s), 3.40-4.05 (4H, m), 4.19 (2H, q, J = 7.0), 4.34 (2
H, s), 4.45 (2H, d, J = 5.5), 5.10-5.30 (1H, m), 6.4
4 (1H, dt, J = 16.0, 5.5), 6.56 (1H, d, J = 16.0), 7.0
1 and 7.02 (total 2H, each d, J = 9.0), 7.42 and 7.43 (total
2H, each d, J = 9.0), 7.54 (1H, t, J = 7.5), 7.65-7.75 (2
H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1738, 1672, 1629.

Example 26 2- [N- [4- (1-acetimidoylpiperidine-
4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] propionate ethyl trihydrochloride (Exemplary compound No. 78)
8)

(A) 2- [N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4-]
Ethyl (piperidin-4-yloxy) phenyl] amino] propionate trihydrochloride 2- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl propionate (882 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (177 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.43 ml) were added, and the mixture was left at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 384 mg of the title compound and the title compound of low purity. 200 mg (41% yield or more) of each was obtained as a brown amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.16 (3H, t, J = 7.
0), 1.44 (3H, d, J = 7.0), 1.78 (2H, m), 2.04 (2H,
m), 3.01 (2H, m), 3.18 (2H, m), 4.09 (2H, q, J = 7.
0), 3.96-4.15 (2H, m), 4.42 (1H, m), 4.55 (1H, q,
J = 7.0), 6.55 (1H, dt, J = 16.0, 4.5), 6.64 (1H, d, J
= 16.0), 6.72 (2H, d, J = 8.5), 6.86 (2H, d, J = 8.5),
7.54 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.73 (1
H, d, J = 8.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1745, 1681.

(B) 2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N
-[3- (3-Amidinophenyl) -2- (E) -propenyl] amino] ethyl propionate trihydrochloride 2- [N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- (piperidine-4-
A mixture containing ethyl (oxy) phenyl] amino] propionate (544 mg) was added to methanol (30 ml).
Dissolved in ethylacetimidate hydrochloride (360 m
g) and triethylamine (0.81 ml) were added at room temperature, and then the mixture was stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODSYMC, elution solvent: 25% acetonitrile / water), and then obtained. Dissolve the amorphous solid in methanol (10 ml),
After adding a 4M hydrogen chloride dioxane solution (0.5 ml), this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and freeze-dried to give 468 mg of the title compound (yield: 2 steps, 47%).
Was obtained as a light brown amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.15 (3H, t, J = 7.
0), 1.45 (3H, d, J = 7.0), 1.68 (2H, m), 1.98 (2H,
m), 2.29 (3H, s), 3.45-3.60 (2H, m), 3.65-3.85 (2
H, m), 4.09 (2H, q, J = 7.0), 3.95-4.20 (2H, m), 4.4
9 (1H, m), 4.56 (1H, q, J = 7.0), 6.56 (1H, dt, J = 16.
0, 4.5), 6.64 (1H, d, J = 16.0), 6.76 (2H, d, J = 9.
0), 6.87 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70
(1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s)
IR (KBr, cm ^-1 ): 1745, 1673, 1623.

Example 27 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplified compound number: 237)

(A) 3- [3- [N-methyl-N-
[4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N-4- (1-t-butoxycarbonylpiperidin-4-yloxy) Phenyl-N-methylamino] -1- (E) -propenyl] benzonitrile (76
1 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling for 1 hour, and the vessel was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol (2
0 ml) and ammonium chloride aqueous solution (181
mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.44 ml) was added, and the mixture was left at room temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa.
ck ODS YMC, elution solvent: 8% acetonitrile / water). The obtained amorphous solid was added to methanol (10 m
l) and dissolved in 4M hydrogen chloride dioxane solution (0.5
(ml) and then concentrated to dryness under reduced pressure to give the title compound (401 mg, yield 50%) as a yellow amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.83 (2H, m), 2.0
8 (2H, m), 2.95-3.25 (7H, m), 4.22 (2H, m), 4.60 (1
H, m), 6.49 (1H, dt, J = 16.0, 6.5), 6.71 (1H, d, J =
16.0), 6.90-7.90 (8H, m); IR (KBr, cm ^-1 ): 1675.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl]
Benzamidine trihydrochloride 3- [3- [N-methyl-N- [4- (piperidine-4
-Yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (368 mg) was dissolved in methanol (20 ml) and ethyl acetimidate hydrochloride (290 mg) and triethylamine (0.
(65 ml) was added at room temperature, and then the mixture was stirred at the same temperature for 12 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa.
After purification with ck ODS YMC, eluting solvent: 10% acetonitrile / water), the obtained amorphous solid was purified with methanol (10
4M hydrogen chloride dioxane solution (0.
(5 ml) was added, and this was concentrated to dryness under reduced pressure. After dissolving the obtained amorphous solid in water (about 10 ml),
By freeze-drying, 288 mg (yield 72%) of the title compound was obtained as a light brown amorphous solid. ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.71 (2H, m), 2.0
2 (2H, m), 2.31 (3H, s), 3.13 (3H, s), 3.40-3.70 (4
H, m), 4.29 (2H, d, J = 7.0), 4.75 (1H, m), 6.50 (1H,
dt, J = 16.0, 7.0), 6.76 (1H, d, J = 16.0), 7.15 (2H,
d, J = 9.0), 7.58 (1H, t, J = 7.5), 7.69 (1H, d, J = 7.
5), 7.70-7.85 (3H, m), 7.92 (1H, s); IR (KBr, cm ^-1 ): 1672, 1625.

Example 28 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1- (E) -propenyl ] Benzamidine trihydrochloride (Exemplified compound number: 478)

(A) 3- [3- [N- (2-hydroxyethyl) -N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (2-
Hydroxyethyl) amino] -1- (E) -propenyl] benzonitrile (1098 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed under ice-cooling for 1 hour. The reaction vessel was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (246 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.60 ml) were added, and the mixture was left at room temperature for 12 hours. did. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 12% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid is treated with water (about 10 m
It was dissolved in 1) and freeze-dried to obtain 555 mg (yield 48%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.82 (2H, m), 2.0
7 (2H, m), 3.03 (2H, m), 3.18 (2H, m), 3.54 (2H, m
m), 3.60 (2H, m), 4.31 (2H, m), 4.62 (1H, m), 6.48
(1H, dt, J = 16.0, 6.5), 6.69 (1H, d, J = 16.0), 7.08
(2H, m), 7.50 (2H, m), 7.58 (1H, t, J = 8.0), 7.70
(1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s)
IR (KBr, cm ^-1 ): 1676.

(B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1-
(E) -Propenyl] benzamidine trihydrochloride 3- [3- [N- (2-hydroxyethyl) -N- [4
-(Piperidin-4-yloxy) phenyl] amino]
-1- (E) -Propenyl] benzamidine trihydrochloride (295 mg) was dissolved in methanol (20 ml) and ethylacetimidate hydrochloride (362 mg) and triethylamine (0.41 ml) were added at room temperature,
The mixture was stirred at the same temperature for 2 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 16% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid is treated with water (about 10 m
After dissolving in 1) and lyophilization, 175 mg (55% yield) of the title compound was obtained as a pale yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.71 (2H, m), 2.0
3 (2H, m), 2.31 (3H, s), 3.40-4.00 (8H, m), 4.32 (2
H, m), 4.67 (1H, m), 6.50 (1H, dt, J = 16.0, 6.5), 6.
70 (1H, d, J = 16.0), 7.08 (2H, m), 7.50 (2H, m), 7.
58 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.75 (1H,
d, J = 8.0), 7.89 (1H, s); IR (KBr, cm ^-1 ): 1673, 1626.

Example 29 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1450)

(A) Ethyl N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-ethoxycarbonyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate 2 Hydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-ethoxycarbonylphenyl]
Ethyl -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (2.45g) was added to dichloromethane (25ml) and ethanol (25m).
1) dissolved in a mixed solvent of 1), and under ice cooling, added hydrogen chloride to 1.5
After passing the time, the vessel was sealed and stirred at room temperature for 4.5 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol (20 m
l) and dissolved in ammonium chloride aqueous solution (0.44 g
Dissolved in 5 ml of water) and 28% aqueous ammonia (1.00
ml), the reaction is stirred at room temperature for 0.5 hours,
Then it was left for 13 hours. After concentrating the reaction solution under reduced pressure,
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 2
After purification with 2% acetonitrile / water), the obtained amorphous solid is dissolved in ethanol (20 ml), 4M hydrogen chloride ethyl acetate solution (1.90 ml) is added, and this is concentrated to dryness under reduced pressure. By this, 1.41 g of the title compound
(58% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.29 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-
2.15 (2H, m), 3.05-3.40 (4H, m), 4.19 (2H, q, J = 7.
0), 4.28 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H,
d, J = 6.0), 4.86 (1H, m), 6.45 (1H, dt, J = 16.0, 6.
0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.55 (1H,
m), 7.61 (1H, m), 7.65-7.80 (3H, m), 7.89 (1H, m); IR (KBr, cm ^-1 ): 1729, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-amidinophenyl)
2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-ethoxycarbonyl-4- (piperidine-4) -Yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (1.24 g) was added to ethanol (20
ml), and under ice cooling, ethylacetimidate hydrochloride (0.72 g) and triethylamine (1.70 m)
1) was added, the mixture was stirred at room temperature for 0.5 hour, and then left for 15 hours. The reaction mixture is concentrated under reduced pressure, and the residue is collected by HPL.
Purified by C (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride ethyl acetate solution (1.30 ml) was added. After that, this was concentrated to dryness under reduced pressure to give the title compound (1.01 g, yield 76%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.27 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 1.95-
2.10 (2H, m), 2.31 (3H, s), 3.60-3.70 (3H, m), 3.70
-3.80 (1H, m), 4.19 (2H, q, J = 7.0), 4.26 (2H, q, J
= 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.90 (1
H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J =
16.0), 7.32 (1H, m), 7.55 (1H, m), 7.62 (1H, m),
7.65-7.70 (3H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1730, 1673, 1624.

Example 30 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carboxyphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 1
975) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (0.30
g) was dissolved in 3M hydrochloric acid (6 ml) and stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 10% acetonitrile / water), and the obtained amorphous solid was 1M hydrochloric acid. After being dissolved in (1.10 ml), this was concentrated to dryness under reduced pressure to obtain 0.22 g (yield 79%) of the title compound as a colorless amorphous solid. 1H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H,
m), 1.90-2.10 (2H, m), 2.29 (3H, s), 3.55-3.75 (4H,
m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.87 (1H,
m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.
0), 7.28 (1H, m), 7.50-7.65 (2H, m), 7.65-7.80 (3
H, m), 7.86 (1H, m); IR (KBr, cm ^-1 ): 1726, 1673, 1627.

Example 31 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1
416)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-bromo-
4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (2.20 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), and hydrogen chloride was added to 1.5 ml under ice cooling. After going through the time,
The vessel was sealed and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml),
Aqueous ammonium chloride solution (0.40 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.90 ml) were added,
After stirring at room temperature for 0.5 hours, the mixture was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack
Purified with ODS YMC, elution solvent: 22% acetonitrile / water) and the amorphous solid obtained is ethanol (20 ml)
4M hydrogen chloride ethyl acetate solution (1.70 m
l) was added and the mixture was concentrated to dryness under reduced pressure to give the title compound (1.34 g, yield 61%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.2
0 (4H, m), 4.20 (2H, q, J = 7.0), 4.42 (2H, s), 4.47
(2H, d, J = 6.0), 4.80 (1H, m), 6.44 (1H, dt, J = 16.
0, 6.0), 6.58 (1H, d, J = 16.0), 7.27 (1H, m), 7.45
(1H, m), 7.55 (1H, m), 7.65-7.80 (3H, m), 7.90 (1
H, m); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-bromo-4- (piperidine-4)
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (1.17 g) was dissolved in ethanol (30 ml), and ethyl acetimidate hydrochloride (0.6
7 g) and triethylamine (1.50 ml) were added,
After stirring at room temperature for 2 hours, the mixture was left for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack ODS
Purified with YMC, elution solvent: 22% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride ethyl acetate solution (1.20 ml) was added.
After the addition of the above, the mixture was concentrated to dryness under reduced pressure to give the title compound (0.97 g, yield 77%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.70-1.90 (2H, m), 1.95-2.15 (2H, m), 2.30 (3
H, s), 3.55-3.75 (4H, m), 4.19 (2H, q, J = 7.0), 4.4
2 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H, m), 6.44
(1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.29
(1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.65-7.80 (3
H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1738, 1674, 1625.

Example 32 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid dihydrochloride (Exemplary compound number: 194
5) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-
Ethyl amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (0.80 g) was dissolved in 3M hydrochloric acid (15 ml), and the mixture was stirred at 90 ° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 22% acetonitrile / water), and the obtained amorphous solid was purified by ethanol (10 ml). ), A 4M solution of hydrogen chloride in ethyl acetate (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.37 g of the title compound (yield 48
%) As a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.70-1.85 (2H,
m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.55-3.75 (4H,
m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H,
m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.
0), 7.29 (1H, m), 7.46 (1H, m), 7.55 (1H, m), 7.65
-7.75 (3H, m), 7.89 (1H, m); IR (KBr, cm ^-1 ): 1732, 1672, 1626.

Example 33 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1426)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-isopropyl-4- (piperidin-4-yloxy) phenyl]
Sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-isopropylphenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.82 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), and hydrogen chloride was added under ice cooling. After passing through the mixture for 1.5 hours, the vessel was sealed and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.35 g was dissolved in 5 ml of water) and 28% aqueous ammonia (0.80 ml) were added, and the mixture was stirred at room temperature for 0.5 After stirring for an hour, the mixture was left for 13 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-
Pack ODS YMC, elution solvent: 25% acetonitrile / water)
The amorphous solid obtained was purified with ethanol (20 m
l) and dissolved in 4M hydrogen chloride ethyl acetate solution (1.4
(0 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.92 g, yield 51%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.15 (6H, d, J = 7.
0), 1.24 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.05-
2.20 (2H, m), 3.00-3.20 (4H, m), 3.21 (1H, m), 4.21
(2H, q, J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J = 6.
0), 4.68 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55
(1H, d, J = 16.0), 7.04 (1H, d, J = 9.0), 7.23 (1H, d
d, J = 9.0, 3.0), 7.29 (1H, d, J = 3.0), 7.54 (1H, m),
7.65-7.75 (2H, m), 7.89 (1H, m); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-isopropyl-4- (piperidin-4-yloxy) phenyl ] Sulfamoylethyl acetate dihydrochloride (0.78 g) was added to ethanol (30 ml)
Dissolved in ethyl acetate, and under ice cooling, ethyl acetimidate hydrochloride (0.50 g) and triethylamine (1.10 ml)
Was added, the mixture was stirred at room temperature for 7 hours, and then left for 12 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-
Pack ODS YMC, elution solvent: 25% acetonitrile / water)
The resulting amorphous solid was purified with ethanol (20 m
l) and dissolved in 4M hydrogen chloride ethyl acetate solution (0.9
(0 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.67 g, yield 80%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.14 (6H, d, J = 7.
0), 1.24 (3H, t, J = 7.0), 1.70-1.85 (2H, m), 1.95-
2.10 (2H, m), 2.30 (3H, s), 3.22 (1H, m), 3.50-3.6
0 (1H, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m),
4.21 (2H, q, J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J =
6.0), 4.74 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.
55 (1H, d, J = 16.0), 7.07 (1H, d, J = 9.0), 7.23 (1H,
dd, J = 9.0, 3.0), 7.28 (1H, d, J = 3.0), 7.55 (1H,
m), 7.71 (2H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1739, 1673, 1623.

Example 34 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 1
955) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoylethyl acetate dihydrochloride (0.51 g) was added to 3
It was dissolved in M hydrochloric acid (20 ml) and stirred at 90 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 25
% Amorphous / water), the obtained amorphous solid was dissolved in 1M hydrochloric acid (1.70 ml), and this was concentrated to dryness under reduced pressure to give 0.33 g of the title compound (yield 66%). Obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.14 (6H, d, J = 7.
0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3
H, s), 3.21 (1H, m), 3.50-3.60 (1H, m), 3.60-3.70
(2H, m), 3.70-3.80 (1H, m), 4.21 (2H, s), 4.44 (2
H, d, J = 6.0), 4.73 (1H, m), 6.46 (1H, dt, J = 16.0,
6.0), 6.54 (1H, d, J = 16.0), 7.06 (1H, d, J = 9.0), 7.
24 (1H, dd, J = 9.0, 3.0), 7.29 (1H, d, J = 3.0), 7.54
(1H, m), 7.71 (2H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1733, 1673, 1625.

Example 35 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1460)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl]
Sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (2.40 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was added under ice cooling. The mixture was stirred for 2.5 hours, then sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.50 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.10 ml) were added, and the reaction mixture was allowed to stand at room temperature. After stirring for 0.5 hour, the mixture was left for 13 hours. The reaction mixture is concentrated under reduced pressure, and the residue is collected by HPL.
Purified by C (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (0.90 ml) was added. Then, this was concentrated to dryness under reduced pressure to obtain 0.60 g (yield 25%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-2.00 (2H, m), 2.05-2.20 (2H, m), 3.00-3.1
0 (2H, m), 3.15-3.25 (2H, m), 4.20 (2H, q, J = 7.0),
4.38 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m),
6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0),
7.24 (1H, m), 7.50 (1H, m), 7.54 (1H, m), 7.65-7.75
(3H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1736, 1671, 1658.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl ] Ethyl sulfamoylacetate dihydrochloride (0.44 g) was added to ethanol (20 ml).
Dissolved in ethyl acetate and under ice cooling, ethylacetimidate hydrochloride (0.27 g) and triethylamine (0.60 ml)
Was added, the mixture was stirred at room temperature for 0.5 hour, and then left for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC.
(YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was purified with ethanol (1
0M), 4M hydrogen chloride ethyl acetate solution (0.50ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound 0.37g (yield 78%) as a colorless amorphous solid. Obtained. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (3
H, s), 3.45-3.65 (2H, m), 3.65-3.85 (2H, m), 4.20
(2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0),
4.86 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1
H, d, J = 16.0), 7.28 (1H, m), 7.45-7.60 (2H, m), 7.
70 (2H, m), 7.78 (1H, m), 7.88 (1H, m); IR (KBr, cm ^-1 ): 1737, 1672.

Example 36 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 1
989) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.20 g) was dissolved in 1.5 M hydrochloric acid (20 ml), and the mixture was stirred at 60 ° C. for 6 hr. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was diluted with 1M hydrochloric acid ( 0.75 ml) and concentrated to dryness under reduced pressure to give the title compound 0.14
g (71% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.95 (2H,
m), 2.00-2.15 (2H, m), 2.29 (3H, s), 3.45-3.65 (2H,
m), 3.65-3.85 (2H, m), 4.24 (2H, s), 4.47 (2H, d,
J = 6.0), 4.85 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0),
6.57 (1H, d, J = 16.0), 7.27 (1H, m), 7.45-7.60 (2
H, m), 7.70 (2H, m), 7.77 (1H, m), 7.88 (1H, m); IR (KBr, cm ^-1 ): 1729, 1672.

Example 37 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N'-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1462)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N'-
Methylcarbamoyl) -4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3- (N'-methylcarbamoyl)
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate (1.
50 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), hydrogen chloride was passed through the mixture under ice cooling for 1.5 hours, the vessel was sealed and stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol (2
0 ml), ammonium chloride aqueous solution (0.29 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.66 ml) were added, and after stirring at room temperature for 2 hours,
It was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml) to give 4M. A solution of hydrogen chloride in ethyl acetate (1.55 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.14 g of the title compound (yield 7
3%) as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.79 (3
H, m), 2.95-3.10 (2H, m), 3.10-3.25 (2H, m), 4.20
(2H, q, J = 7.0), 4.38 (2H, s), 4.47 (2H, d, J = 6.0),
4.79 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1
H, d, J = 16.0), 7.24 (1H, m), 7.48 (1H, m), 7.54 (1
H, m), 7.62 (1H, m), 7.12 (2H, m), 7.92 (1H, m); IR (KBr, cm ^-1 ): 1737, 1676, 1641.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N'-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N′-methylcarbamoyl)
Ethyl-4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (1.00 g) was dissolved in ethanol (30 ml), and ethyl acetimidate hydrochloride (0.60 g) and triethylamine ( 1.35 ml) was added and the mixture was stirred at room temperature for 8 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack
Purified with ODS YMC, eluting solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride ethyl acetate solution (1.00 m)
l) was added and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.79 g, yield 74%) as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.75-1.90 (2H, m), 1.95-2.10 (2H, m), 2.30 (3
H, s), 2.78 (3H, s), 3.50-3.80 (4H, m), 4.20 (2H,
q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.84
(1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d,
J = 16.0), 7.27 (1H, m), 7.50 (1H, m), 7.55 (1H, m),
7.65-7.75 (3H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1738, 1673, 1633.

Example 38 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N'-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number: 1991) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2-
Ethyl (E) -propenyl] sulfamoyl acetate dihydrochloride (0.53 g) was dissolved in 1.5 M hydrochloric acid (30 ml), and the mixture was stirred at 60 ° C. for 8 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack
ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was purified with 1M hydrochloric acid (2.20 ml).
Was dissolved in and concentrated to dryness under reduced pressure to obtain 0.42 g (yield: 82%) of the title compound as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H,
m), 1.95-2.10 (2H, m), 2.30 (3H, s), 2.78 (3H, s),
3.50-3.85 (4H, m), 4.25 (2H, s), 4.47 (2H, d, J = 6.
0), 4.84 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57
(1H, d, J = 16.0), 7.27 (1H, m), 7.45-7.60 (2H, m),
7.65-7.75 (3H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1732, 1673, 1628.

Example 39 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ', N'-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl)
-2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1466)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N ',
N'-dimethylcarbamoyl) -4- (piperidine-4)
-Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.70 g) was added to dichloromethane. The mixture was dissolved in a mixed solvent of (20 ml) and ethanol (20 ml), hydrogen chloride was passed through the mixture under ice cooling for 1.5 hours, and the vessel was sealed and stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.30 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.70 ml) were added, and the mixture was stirred at room temperature for 5 hours. After that, it was left for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 15
% Acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (20 ml), 4M hydrogen chloride ethyl acetate solution (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The title compound (0.75 g, yield 44%) was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.75-1.95 (2H, m), 1.95-2.15 (2H, m), 2.69 (3
H, s), 2.97 (3H, s), 2.95-3.15 (4H, m), 4.19 (2H,
q, J = 7.0), 4.38 (2H, s), 4.35-4.55 (2H, m), 4.75
(1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d,
J = 16.0), 7.22 (1H, d, J = 9.0), 7.30 (1H, d, J = 3.0),
7.45 (1H, dd, J = 9.0, 3.0), 7.54 (1H, t, J = 8.0),
7.70 (2H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1676, 1618.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ', N'-
Dimethylcarbamoyl) phenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N ', N' -Dimethylcarbamoyl) -4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (0.60 g)
Was dissolved in ethanol (20 ml), ethyl acetimidate hydrochloride (0.35 g) and triethylamine (0.80 ml) were added under ice cooling, and the mixture was stirred at room temperature for 0.5 hr and then left for 12 hr. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-PackODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml) and 4M chlorinated. After adding a hydrogen ethyl acetate solution (0.60 ml), the mixture was concentrated to dryness under reduced pressure to give the title compound 0.4
7 g (73% yield) was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.60-1.85 (2H, m), 1.85-2.10 (2H, m), 2.29 (3
H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H,
m), 4.19 (2H, q, J = 7.0), 4.35-4.55 (2H, m), 4.39
(2H, s), 4.79 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0),
6.55 (1H, d, J = 16.0), 7.25 (1H, d, J = 9.0), 7.29
(1H, d, J = 3.0), 7.45 (1H, dd, J = 9.0, 3.0), 7.54 (1
H, m), 7.65-7.75 (2H, m), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1673, 1618.

Example 40 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ', N'-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl)
-2- (E) -Propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number: 1995) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) ) Phenyl] -N- [3- (3-amidinophenyl)
2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride (0.30 g) was dissolved in 1.5 M hydrochloric acid (10 ml), and the mixture was stirred at 60 ° C. for 9.5 hr. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was collected by preparative HPLC.
(YMC-PackODS YMC, elution solvent: 10% acetonitrile / water), and the obtained amorphous solid was diluted with 1M hydrochloric acid (1.
(20 ml) and concentrated to dryness under reduced pressure to give the title compound (0.24 g, yield 83%) as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.65-1.85 (2H,
m), 1.90-2.10 (2H, m), 2.28 (3H, s), 2.69 (3H, s),
2.95 (3H, s), 3.50-3.70 (4H, m), 4.25 (2H, s), 4.3
5-4.55 (2H, m), 4.78 (1H, m), 6.43 (1H, dt, J = 16.
0, 6.0), 6.55 (1H, d, J = 16.0), 7.24 (1H, d, J = 9.
0), 7.29 (1H, d, J = 3.0), 7.46 (1H, dd, J = 9.0, 3.
0), 7.54 (1H, m), 7.65-7.75 (2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1733, 1672, 1614.

Example 41 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-
Amidino-2-hydroxyphenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1843)

(A) N- [3- (5-amidino-2-
Hydroxyphenyl) -2- (E) -propenyl] -N
-[3-Chloro-4- (piperidin-4-yloxy)
Phenyl] sulfamoylethyl acetate N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-chlorophenyl] -N- [3-
(5-Cyano-2-methoxymethoxyphenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate (1.
4 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), hydrogen chloride was passed under ice-cooling for 1.5 hours, and the vessel was sealed and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol (4
0 ml) and ammonium chloride aqueous solution (0.2
g in 10 ml of water) and 28% aqueous ammonia (0.
5 ml) was added, and the mixture was stirred at room temperature for 0.5 hour and then left standing for 12 hours. After concentrating the reaction solution under reduced pressure, the residue is collected H
Purification by PLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water) and concentration to dryness under reduced pressure gave the title compound (0.1 g, yield 4%) as a colorless amorphous solid. It was ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.1
5 (2H, m), 3.15-3.25 (2H, m), 4.19 (2H, q, J = 7.0),
4.40 (2H, s), 4.45 (2H, d, J = 6.0), 4.78 (1H, m),
6.38 (1H, dt, J = 16.0, 6.0), 6.66 (1H, d, J = 16.0),
7.04 (1H, d, J = 9.0), 7.31 (1H, d, J = 9.0), 7.38 (1
H, dd, J = 9.0, 3.0), 7.56 (1H, d, J = 3.0), 7.62 (1H,
dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.0).

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-amidino-2-hydroxyphenyl) -2- (E). -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (5-amidino-2-hydroxyphenyl)
-2- (E) -Propenyl] -N- [3-chloro-4-
Ethyl (piperidin-4-yloxy) phenyl] sulfamoyl acetate (0.05 g) was added to ethanol (10 m
l), and under ice cooling, ethylacetimidate hydrochloride (0.04 g) and triethylamine (0.08 m)
1) was added, and the mixture was stirred at room temperature for 5 hours and then left for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC.
(YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was purified with ethanol (1
0M) and 4M hydrogen chloride ethyl acetate solution (0.05ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.04g, yield 59%) as a colorless amorphous solid. Obtained. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.30 (3
H, s), 3.50-3.80 (4H, m), 4.19 (2H, q, J = 7.0), 4.4
1 (2H, s), 4.45 (2H, d, J = 6.0), 4.84 (1H, m), 6.39
(1H, dt, J = 16.0, 6.0), 6.65 (1H, d, J = 16.0), 7.08
(1H, d, J = 9.0), 7.33 (1H, d, J = 9.0), 7.38 (1H, dd,
J = 9.0, 2.0), 7.56 (1H, d, J = 2.0), 7.63 (1H, dd, J
= 9.0, 2.0), 7.95 (1H, d, J = 2.0); IR (KBr, cm ^-1 ): 1738, 1671.

Example 42 N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1484)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate (1.
50 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), hydrogen chloride was passed under ice-cooling for 1.5 hours, and the vessel was sealed and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol (2
0 ml) and ammonium chloride aqueous solution (0.2
6 g dissolved in 5 ml water) and 28% aqueous ammonia (0.
(60 ml) was added, and the mixture was stirred at room temperature for 4 hours and then left standing for 12 hours. After concentrating the reaction solution under reduced pressure, the residue is collected by HP.
Purified by LC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in 1M hydrochloric acid, and concentrated to dryness under reduced pressure to give the title compound (0.55 g). (Yield 37%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.95-3.0
5 (2H, m), 3.20-3.30 (2H, m), 4.19 (2H, q, J = 7.0),
4.35 (1H, m), 4.48 (2H, s), 4.51 (2H, d, J = 6.0),
6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0),
7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.88 (1H, m); IR (KBr, cm ^-1 ): 1737, 1672.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-
3-Chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl ] -N- [5-carbamoyl-3-chloro-4
Ethyl- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (0.51 g) was dissolved in ethanol (25 ml), and ethyl acetimidate hydrochloride (0.30 g) and triethylamine (0.
70 ml) was added, and the mixture was stirred at room temperature for 1 hour and then left for 12 hours. After concentrating the reaction solution under reduced pressure, the residue is collected by HP.
Purified by LC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride ethyl acetate solution (0.50 ml) was added. Then, this was concentrated to dryness under reduced pressure to obtain 0.36 g (yield 66%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.75-1.90 (2H, m), 1.90-2.05 (2H, m), 2.29 (3
H, s), 3.40-3.55 (2H, m), 3.75-3.90 (2H, m), 4.20
(2H, q, J = 7.0), 4.42 (1H, m), 4.48 (2H, s), 4.52
(2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1
H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H,
m), 7.89 (1H, m); IR (KBr, cm ^-1 ): 1738, 1671, 1622.

Example 43 N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 2013) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (0.
20 g) was dissolved in 3M hydrochloric acid (20 ml) and stirred at 70 ° C. for 1.5 hours. After cooling the reaction solution to room temperature,
After concentration under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YM
C, elution solvent: 15% acetonitrile / water),
The obtained amorphous solid was dissolved in 1M hydrochloric acid (0.80 ml), and this was concentrated to dryness under reduced pressure to give the title compound (0.16 g, yield 83%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H,
m), 1.90-2.05 (2H, m), 2.28 (3H, s), 3.40-3.55 (2H,
m), 3.75-3.90 (2H, m), 4.35 (2H, s), 4.42 (1H,
m), 4.51 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.
0), 6.61 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-
7.80 (3H, m), 7.87 (1H, m); IR (KBr, cm ^-1 ): 1730, 1671, 1628.

Example 44 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1498)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-5-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate (3.
20 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), hydrogen chloride was passed under ice-cooling for 1.5 hours, and the vessel was sealed and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), an aqueous ammonium chloride solution (0.59 g was dissolved in 8 ml of water) and 28% aqueous ammonia (1.34 ml) were added, and the mixture was stirred at room temperature for 0.5. After stirring for an hour, the mixture was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 20
% Acetonitrile / water), the resulting amorphous solid was dissolved in ethanol (10 ml), 4M hydrogen chloride dioxane solution (3.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 2.85 g (90% yield) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 2.26 (3
H, s), 2.90-3.00 (2H, m), 3.20-3.30 (2H, m), 4.15-
4.20 (1H, m), 4.20 (2H, q, J = 7.0), 4.39 (2H, s),
4.47 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0),
6.60 (1H, d, J = 16.0), 7.54 (2H, m), 7.57 (1H, m),
7.68 (1H, m), 7,73 (1H, m), 7.87 (1H, m); IR (KBr, cm ^-1 ): 1737, 1672.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-
5-Methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E)- Propenyl] -N- [3-carbamoyl-5-methyl-4
Ethyl-(piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (2.68 g) was dissolved in ethanol (40 ml), and under ice cooling, ethyl acetimidate hydrochloride (1.58 g) and triethylamine (3.
(55 ml) was added, and the mixture was stirred at room temperature for 1 hour and then left standing for 13 hours. After concentrating the reaction solution under reduced pressure, the residue is collected by HP.
After purification by LC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride dioxane solution (0.44 ml) was added. Then, this was concentrated to dryness under reduced pressure to obtain 0.38 g (yield 13%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.70-1.90 (2H, m), 1.90-2.00 (2H, m), 2.27 (3
H, s), 2.29 (3H, s), 3.35-3.45 (2H, m), 3.75-3.95
(2H, m), 4.20 (2H, q, J = 7.0), 4.25 (1H, m), 4.40
(2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.
0, 6.0), 6.60 (1H, d, J = 16.0), 7.43 (2H, m), 7.55
(1H, m), 7.69 (1H, m), 7.73 (1H, m), 7.88 (1H, m); IR (KBr, cm ^-1 ): 1738, 1672, 1625.

Example 45 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 2027) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (0.
24 g) was dissolved in 3M hydrochloric acid (20 ml), and the mixture was stirred at 70 ° C. for 2.5 hours. After cooling the reaction solution to room temperature,
After concentration under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YM
C, elution solvent: 15% acetonitrile / water),
The obtained amorphous solid was dissolved in 1M hydrochloric acid (1.00 ml), and this was concentrated to dryness under reduced pressure to give the title compound (0.18 g, yield 78%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.70-1.85 (2H,
m), 1.90-2.00 (2H, m), 2.27 (3H, s), 2.29 (3H, s),
3.30-3.45 (2H, m), 3.75-3.90 (2H, m), 4.25 (1H,
m), 4.27 (2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, d
t, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.43 (2H,
m), 7.55 (1H, m), 7.67 (1H, m), 7.72 (1H, m), 7.86
(1H, m); IR (KBr, cm ^-1 ): 1731, 1672.

Example 46 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplified compound number: 1474)

(A) Ethyl N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-difluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate Dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-difluorophenyl] -N
Ethyl-[3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1823 mg) was added to dichloromethane (30 ml) and ethanol (15 ml).
The mixture was dissolved in the mixed solvent of, and hydrogen chloride was passed through for 1 hour under ice-cooling, and the vessel was tightly closed and stirred at room temperature for 5.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (315 mg was added to water 10
(dissolved in ml) and 28% aqueous ammonia (0.59 ml)
After adding, the mixture was left at room temperature for 15 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution and concentrating under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). Dissolve the obtained amorphous solid in ethanol (20 ml) and
Hydrochloric acid (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (1214 mg, yield 68%) as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.21 (3H, t, J = 7.
0), 1.85-1.91 (2H, m), 2.04-2.10 (2H, m), 2.99-3.0
5 (2H, m), 3.18-3.24 (2H, m), 4.18 (2H, q, J = 7.0),
4.37 (1H, m), 4.50 (2H, s), 4.51 (2H, d, J = 6.0),
6.42 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0),
7.39 (2H, m), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J =
8.0), 7.74 (1H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-amidinophenyl) -2
-(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-difluoro-4- (piperidine-4- Iloxy) phenyl] sulfamoylethyl acetate dihydrochloride (1020 mg) was added to ethanol (30 m
l) and dissolved in ethyl acetimidate hydrochloride (62
0 mg) and triethylamine (1.17 ml) were added, and the mixture was stirred at room temperature for 15 hours. 4M Hydrogen chloride dioxane solution (1.0 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water). Dissolve the obtained amorphous solid in ethanol (15 ml) and
After adding hydrochloric acid (1.0 ml), the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to give 851 mg of the title compound (yield 78%).
Was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.76-1.83 (2H, m), 1.98-2.03 (2H, m), 2.30 (3
H, s), 3.52 (2H, m), 3.78 (2H, m), 4.18 (2H, q, J =
7.0), 4.46 (1H, m), 4.51 (2H, s), 4.52 (2H, d, J =
6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 1
6.0), 7.39 (2H, m), 7.55 (1H, t, J = 8.0), 7.70 (1H,
d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1739, 1673, 1624.

Example 47 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3
-(3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number: 2003) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5- Difluorophenyl] -N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (415 mg)
Was dissolved in 2M hydrochloric acid (20 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 15% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 20 ml) and freeze-dried to give the title compound 319.
mg (80% yield) was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.70-1.90 (2H,
m), 1.95-2.10 (2H, m), 2.29 (3H, s), 3.40-3.60 (2H,
m), 3.78 (2H, m), 4.37 (2H, s), 4.46 (1H, m), 4.5
2 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.62
(1H, d, J = 16.0), 7.38 (2H, m), 7.55 (1H, t, J = 8.
0), 7.69 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.89
(1H, s); IR (KBr, cm ^-1 ): 3123, 1733, 1674, 1626.

Example 48 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate dihydrochloride (Exemplified compound number: 1478)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dichloro-4- (piperidin-4-yloxy) phenyl]
Sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dichlorophenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (2057 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was added for 1 hour under ice cooling. After passing through, the vessel was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (40 ml), and an aqueous ammonium chloride solution (337 mg was added to 20 ml of water.
Dissolved in water) and 28% aqueous ammonia (0.63 ml) were added, and the mixture was left at room temperature for 15 hours. A 4M hydrogen chloride dioxane solution (2.0 ml) was added to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 23% acetonitrile / water). Dissolve the resulting amorphous solid in ethanol (20 ml) and
M hydrochloric acid (1.0 ml) was added, and this was concentrated to dryness under reduced pressure to give 1002 mg of the title compound (yield 49
%) As a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.21 (3H, t, J = 7.
0), 1.95-2.15 (4H, m), 2.95-3.10 (2H, m), 3.20-3.3
5 (2H, m), 4.18 (2H, q, J = 7.0), 4.46 (1H, m), 4.53
(4H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d,
J = 16.0), 7.55 (1H, t, J = 7.5), 7.67 (2H, s), 7.68 (1
H, d, J = 7.5), 7.74 (1H, d, J = 7.5), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dichloro-4- (piperidin-4-yloxy) ) Phenyl] sulfamoylethyl acetate dihydrochloride (800 mg) in ethanol (30 ml)
Dissolved in ethylacetimidate hydrochloride (462m
g) and triethylamine (0.87 ml) were added, and the mixture was stirred at room temperature for 15 hours. 4M Hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), and 1M hydrochloric acid (1.0 m
l) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to obtain 722 mg (yield 85%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.80-2.00 (2H, m), 2.00-2.10 (2H, m), 2.29 (3
H, s), 3.40-3.55 (2H, m), 3.80-4.00 (2H, m), 4.18
(2H, q, J = 7.0), 4.53 (5H, m), 6.43 (1H, dt, J = 16.
0, 6.0), 6.63 (1H, d, J = 16.0), 7.56 (1H, t, J = 8.
0), 7.67 (2H, s), 7.68 (1H, d, J = 8.0), 7.74 (1H,
d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1739, 1674, 1624.

Example 49 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 2
007) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoylethyl acetate dihydrochloride (300 mg) was added to 2
It was dissolved in M hydrochloric acid (20 ml) and stirred at 60 ° C. for 6 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 18
% Acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to give 233 mg of the title compound (yield 81
%) As a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.80-2.00 (2H,
m), 2.00-2.10 (2H, m), 2.30 (3H, s), 3.40-3.55 (2H,
m), 3.80-4.00 (2H, m), 4.39 (2H, s), 4.53 (2H, d,
J = 6.0), 4.53 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0),
6.62 (1H, d, J = 16.0), 7.56 (1H, t, J = 8.0), 7.67
(2H, s), 7.70 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0),
7.90 (1H, s); IR (KBr, cm ^-1 ): 3127, 1733, 1673, 1625.

Example 50 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Methyl sulfamoyl acetate dihydrochloride (Exemplified compound number: 2429)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dimethyl-4- (piperidin-4-yloxy) phenyl]
Sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dimethylphenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.75 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was added under ice cooling. After passing the mixture for 1 hour, the vessel was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), and an ammonium chloride aqueous solution (0.31 g was added to 15 ml of water).
Dissolved in water) and 28% aqueous ammonia (0.57 ml) were added, and the mixture was left at room temperature for 14 hours. After adding 4M hydrogen chloride dioxane solution (1 ml) to the reaction solution, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20).
% Acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.21 g (yield 70%) of the title compound as a colorless solid. Obtained as a solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.80-1.95 (2H, m), 2.00-2.10 (2H, m), 2.22 (6
H, s), 2.94 (2H, m), 3.26 (2H, m), 4.12 (1H, m),
4.19 (2H, q, J = 7.0), 4.35 (2H, s), 4.44 (2H, d, J =
6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 1
6.0), 7.17 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H,
d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] sulfamoyl acetate methyl dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dimethyl-4- (piperidin-4-yloxy) ) Phenyl] sulfamoylethyl acetate dihydrochloride (1.00 g) was added to methanol (30 ml).
Dissolved in ethyl acetimidate hydrochloride (0.62
g) and triethylamine (1.16 ml) were added, and the mixture was stirred at room temperature for 14 hours. After adding a 4 M hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (20 ml), and 1M hydrochloric acid (1.0 m
l) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to obtain 0.81 g (yield 78%) of the title compound as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.75 (2H, m), 1.9
8 (2H, m), 2.23 (6H, s), 2.29 (3H, s), 3.25-3.35 (2
H, m), 3.73 (3H, s), 3.85 (1H, m), 4.02 (1H, m),
4.18 (1H, m), 4.38 (2H, s), 4.44 (2H, d, J = 6.0),
6.42 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0),
7.16 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J =
8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1743, 1673, 1626.

Example 51 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 2
011) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Methyl sulfamoyl acetate dihydrochloride (620 mg)
It was dissolved in M hydrochloric acid (20 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 18
% Acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to give 220 mg of the title compound (yield 57%).
Was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75 (2H, m), 1.9
8 (2H, m), 2.23 (6H, s), 2.29 (3H, s), 3.25-3.40 (2
H, m), 3.85 (1H, m), 4.02 (1H, m), 4.17 (1H, m),
4.22 (2H, s), 4.44 (2H, d, J = 6.0), 6.43 (1H, dt, J
= 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.17 (2H, s),
7.55 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (1
H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 3131, 1733, 1673, 1626.

Example 52 4- [N- [4- (1-acetimidoylpiperidine-
4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] butyric acid ethyl trihydrochloride (Exemplary compound number: 849)

(A) 4- [N- [3- (3-amidinophenyl) -2- (E) -propenyl]-[N- [4-
Ethyl (piperidin-4-yloxy) phenyl] amino] butyrate trihydrochloride 4- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl butyrate (2.19g) was added to dichloromethane (30m
The mixture was dissolved in a mixed solvent of 1) and ethanol (15 ml), hydrogen chloride was passed through the mixture under ice-cooling for 1 hour, the vessel was sealed and stirred at room temperature for 5.5 hours. After concentrating the reaction solution under reduced pressure,
The residue was dissolved in ethanol (20 ml) and aqueous ammonium chloride solution (0.43 g dissolved in 10 ml water) and 2
After adding 8% aqueous ammonia (1.04 ml), the mixture was left at room temperature for 14 hours. To this, 4M hydrogen chloride dioxane solution (1 ml) was added, concentrated under reduced pressure, and the residue was collected on a preparative HP.
Purified by LC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. Water this (about 10m
After being dissolved in 1) and freeze-dried, 1.52 g (yield 66%) of the title compound was obtained as a pale yellow amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.19 (3H, t, J = 7.
0), 1.70-1.95 (4H, m), 2.00-2.15 (2H, m), 2.39 (2
H, m), 3.00-3.15 (2H, m), 3.15-3.30 (2H, m), 3.30-
3.40 (2H, m), 4.07 (2H, q, J = 7.0), 4.00-4.20 (2H,
m), 4.43 (1H, m), 6.52 (1H, dt, J = 16.0, 5.5), 6.55
-7.00 (5H, m), 7.59 (1H, t, J = 8.0), 7.65-7.80 (2H,
m), 7.88 (1H, s); IR (KBr, cm ^-1 ) :: 1728, 1674.

(B) 4- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N
-[3- (3-Amidinophenyl) -2- (E) -propenyl] amino] butyric acid ethyl trihydrochloride 4- [N- [3- (3-amidinophenyl) -2-
(E) -Propenyl]-[N- [4- (piperidine-4
Ethyl-yloxy) phenyl] amino] butyrate trihydrochloride (1378 mg) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (890 mg) and triethylamine (2.01 ml) were added, and the mixture was stirred at room temperature for 4 hr. did. To the reaction solution was added 4M hydrogen chloride dioxane solution (1 ml), the mixture was concentrated under reduced pressure, and the residue was collected by HP.
Purified by LC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This is water (about 20m
After dissolving in 1) and freeze-drying, 1072 mg of the title compound (yield 73%) was obtained as a pale yellow amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.16 (3H, t, J = 7.
0), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.29 (3
H, s), 2.30-2.40 (2H, m), 3.20-3.40 (2H, m), 3.45-
3.60 (2H, m), 3.70-3.85 (2H, m), 4.04 (2H, q, J = 7.
0), 4.00-4.10 (2H, m), 4.40-4.55 (1H, m), 6.49 (1
H, dt, J = 16.0, 6.0), 6.55-6.95 (5H, m), 7.57 (1H,
t, J = 7.5), 7.65-7.75 (2H, m), 7.85 (1H, s); IR (KBr, cm ^-1 ): 1727, 1673, 1624.

Example 53 4- [N- [4- (1-acetimidoylpiperidine-
4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] butyric acid trihydrochloride (Exemplified compound number: 663) 4- [N- [4- (1 -Acetimidoylpiperidine-
4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] butyric acid ethyl trihydrochloride (572 mg) was added to 2M hydrochloric acid (20 ml).
And was stirred at room temperature for 2 hours and then at 50 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml) and 1M hydrochloric acid (1.0 ml), and concentrated and dried under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to give 333 mg of the title compound (yield 61
%) As a light brown amorphous solid. ¹ H NMR (400MHz,
DMSO-d ₆ ) δppm: 1.40-1.95 (4H, m), 1.95-2.10 (2H,
m), 2.30 (3H, s), 2.25-2.35 (2H, m), 3.45-4.40 (8
H, m), 4.65-4.80 (1H, m), 6.50 (1H, dt, J = 15.5, 6.
5), 6.55-7.30 (5H, m), 7.58 (1H, t, J = 7.5), 7.65-
7.75 (2H, m), 7.85 (1H, s); IR (KBr, cm ^-1 ): 3119, 1726, 1673, 1625.

Example 54 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N-
[3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number:
1969) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (321 m
g) was dissolved in 3M hydrochloric acid (15 ml) and stirred at 80 ° C. for 3 hours. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC,
After purification with an elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. Let This is water (about 15m
It was dissolved in 1) and freeze-dried to obtain 231 mg (yield 75%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.79 (2H, m), 2.0
5 (2H, m), 2.31 (3H, s), 3.40-3.75 (4H, m), 4.32 (2
H, s), 4.50 (2H, d, J = 6.5), 4.96 (1H, m), 6.47 (1H,
dt, J = 17.0, 6.5), 6.57 (1H, d, J = 17.0), 7.43 (1H,
d, J = 10.0), 7.54 (1H, d, J = 7.5), 7.71 (4H, m), 7.9
2 (1H, s); IR (KBr, cm ^-1 ): 3102, 1734, 1675, 1617.

Example 55 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid dihydrochloride (Exemplary compound number: 194
9) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-
Ethyl amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (480 mg) was dissolved in 3M hydrochloric acid (15 ml), and the mixture was stirred at 80 ° C. for 3 hours. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS YMC, eluting solvent: 20).
% Acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 315 mg of the title compound (yield 6
9%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.78 (2H, m), 2.0
2 (2H, m), 2.14 (3H, s), 2.29 (3H, s), 3.62 (4H,
m), 3.71 (2H, s), 4.12 (1H, m), 4.46 (2H, d, J = 6.
0), 4.70 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.50
(1H, d, J = 16.0), 7.02 (1H, d, J = 8.5), 7.36 (1H,
s), 7.37 (1H, d, J = 8.5), 7.52 (1H, d, J = 8.0), 7.67
(1H, d, J = 7.5), 7.69 (1H, d, J = 8.0), 7.86 (1H,
s); IR (KBr, cm ^-1 ): 3067, 1678, 1608, 1497.

Example 56 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] Sulfamoylethyl acetate dihydrochloride (Exemplary compound number:
1509)

(A) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl]
Ethyl sulfamoyl acetate (1.41 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the mixture was sealed and stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous ammonium chloride solution (0.25 g dissolved in 10 ml of water) and 28% aqueous ammonia (0.47 ml) were added,
It was left at room temperature for 8 hours. A 4 M hydrogen chloride dioxane solution (2.0 ml) was added, the solvent was evaporated, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (1.00 g, yield 75
%) As a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.81 (2H, m), 2.08 (2H, m), 3.06 (2H, m), 3.22
(2H, m), 4.20 (2H, q, J = 7.0), 4.36 (2H, s), 4.56
(2H, d, J = 16.5), 4.65 (1H, m), 5.94 (1H, d, J = 39.
0), 7.05 (2H, d, J = 9.5), 7.40 (2H, d, J = 9.5), 7.56
(1H, d, J = 8.0), 7.74 (2H, m), 7.81 (1H, s); IR (KBr, cm ^-1 ): 3061, 2985, 1737, 1676, 1507.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2-fluoro-2-
(Z) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [4- (piperidine-
4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (800 mg) was dissolved in ethanol (20 ml) and ethyl acetimidate hydrochloride (515 mg) was added.
And triethylamine (0.97 ml) were added, and the mixture was stirred at room temperature for 4 hours. After adding 4M hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was collected by HP.
Purified by LC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (458 mg, yield 54%).
Was obtained as a pale yellow amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.74 (2H, m), 2.05 (2H, m), 2.28 (3H, s), 3.52
(2H, m), 3.72 (1H, m), 3.78 (1H, m), 4.20 (2H, q,
J = 7.0), 4.36 (2H, s), 4.59 (2H, d, J = 15.5), 4.71
(1H, m), 5.96 (1H, d, J = 39.0), 7.05 (2H, d, J = 9.
5), 7.41 (2H, d, J = 9.5), 7.59 (1H, t, J = 7.5), 7.67
(1H, d, J = 7.5), 7.76 (1H, d, J = 7.5), 7.80 (1H,
s); IR (KBr, cm ^-1 ): 3103, 1738, 1673, 1627, 1606.

Example 57 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] Sulfamoyl acetic acid dihydrochloride (Exemplary compound number: 203
8) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoylethyl acetate 2 The hydrochloride salt (265 mg) was dissolved in 3M hydrochloric acid (15 ml), and the mixture was stirred at 80 ° C. for 2 hours.
After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure,
The residue was subjected to preparative HPLC (YMC-Pack ODS YMC, elution solvent: 1
Purified with 5% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 15 ml) and then freeze-dried to give 218 mg of the title compound.
(Yield 86%) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.74 (2H, m), 2.0
5 (2H, m), 2.29 (3H, s), 3.52 (2H, m), 3.72 (1H,
m), 3.82 (1H, m), 4.20 (2H, s), 4.59 (2H, d, J = 15.
5), 4.71 (1H, m), 5.95 (1H, d, J = 38.0), 7.06 (2H,
d, J = 9.0), 7.42 (2H, d, J = 9.0), 7.59 (1H, t, J = 8.
0), 7.68 (1H, d, J = 8.0), 7.76 (1H, d, J = 8.0), 7.81
(1H, s); IR (KBr, cm ^-1 ): 1734, 1673, 1627.

Example 58 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1506)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dicarbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoylacetic acid Ethyl dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dicarbamoylphenyl]
Ethyl -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (0.84g) was added to dichloromethane (25ml) and ethanol (25m).
1) dissolved in a mixed solvent of 1), and under ice cooling, added hydrogen chloride to 1.5
After passing the time, the vessel was sealed and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was ethanol (25 ml).
, Ammonium chloride aqueous solution (0.15 g dissolved in 5 ml of water) and 28% ammonia water (0.35 m
1) was added, the mixture was stirred at room temperature for 2.5 hours, and then left for 12 hours. The reaction mixture is concentrated under reduced pressure and the residue is collected by preparative HPLC.
After purification with (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride dioxane solution (0.20 ml) was added. After the addition, this was concentrated to dryness under reduced pressure to give the title compound 0.17 g (yield 20
%) As a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.85-2.00 (4H, m), 2.95-3.05 (2H, m), 3.20-3.3
0 (2H, m), 4.20 (2H, q, J = 7.0), 4.25-4.35 (1H, m),
4.45 (2H, s), 4.50 (2H, d, J = 6.0), 6.45 (1H, dt, J
= 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.55 (1H, t, J =
8.0), 7.61 (2H, s), 7.67 (1H, d, J = 8.0), 7.72 (1H,
d, J = 8.0), 7.88 (1H, s); MASS (FAB, m / z): 587 [M + H].

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-amidinophenyl)
2- (E) -Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dicarbamoyl-4- (piperidine) -4-yloxy) phenyl] sulfamoylethyl acetate dihydrochloride (0.17 g) was added to ethanol (20
ml), ethyl acetimidate hydrochloride (1.67 g) and triethylamine (1.68 ml)
Was added and stirred at room temperature for 5.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (5 ml). After dissolution and addition of 4M hydrogen chloride dioxane solution (0.10 ml), this was concentrated to dryness under reduced pressure to obtain 0.08 g (yield 43%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.75-2.00 (4H, m), 2.28 (3H, s), 3.45-3.55 (2
H, m), 3.70-3.80 (2H, m), 4.20 (2H, q, J = 7.0), 4.3
0-4.40 (1H, m), 4.45 (2H, s), 4.51 (2H, d, J = 6.0),
6.44 (1H, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0),
7.55 (1H, t, J = 8.0), 7.64 (2H, s), 7.68 (1H, d, J =
8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s); MASS (FAB, m / z): 628 [M + H].

Example 59 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplified compound number: 2035) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3, 5-Dicarbamoylphenyl] -N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride (0.07
g) was dissolved in 3M hydrochloric acid (10 ml), and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 10% acetonitrile / water), and the obtained amorphous solid was adjusted to 1M. It was dissolved in hydrochloric acid (0.30 ml), and this was concentrated to dryness under reduced pressure to give the title compound (0.05 g, yield 69%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-2.00 (4H,
m), 2.27 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2
H, m), 4.32 (2H, s), 4.35-4.40 (1H, m), 4.51 (2H,
d, J = 6.0), 6.45 (1H, dt, J = 16.0, 6.0), 6.60 (1H,
d, J = 16.0), 7.55 (1H, t, J = 8.0), 7.63 (2H, s), 7.6
7 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.87 (1H,
s); IR (KBr, cm ^-1 ): 1729, 1668.

Example 60 N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1491)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-2-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate (2.
10 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed through the mixture under ice cooling for 1 hour, and the vessel was sealed and stirred at room temperature for 3 hours.
The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol (25 m
l) and dissolved in ammonium chloride aqueous solution (0.59 g
Dissolved in 5 ml of water) and 28% aqueous ammonia (1.34
ml) was added, and the mixture was stirred at room temperature for 7 hours and then left standing for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC.
Purify with (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), dissolve the obtained amorphous solid in ethanol (20 ml), and add 4M hydrogen chloride dioxane solution (1.40 ml). After that, it was concentrated to dryness under reduced pressure to give the title compound (1.18 g, yield 57%).
Was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.85-1.95 (2H, m), 2.10-2.20 (2H, m), 2.33 (3
H, s), 3.05-3.15 (2H, m), 3.20-3.30 (2H, m), 4.21
(2H, q, J = 7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J =
14.0), 4.45-4.50 (1H, m), 4.51 (1H, d, J = 14.0), 4.
80 (1H, m), 6.40-6.55 (2H, m), 6.48 (1H, s), 7.55
(1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d,
J = 8.0), 7,77 (1H, s), 7.83 (1H, s); IR (KBr, cm ^-1 ): 1737, 1673, 1657.

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-
2-Methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E)- Propenyl] -N- [5-carbamoyl-2-methyl-4
Ethyl-(piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (1.00 g) was dissolved in ethanol (50 ml), ethyl acetimidate hydrochloride (0.59 g) and triethylamine (1.33 m).
1) was added, and the mixture was stirred at room temperature for 1 hour and then left for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC.
After purification with (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M hydrogen chloride dioxane solution (1.00 ml) was added. By concentrating this to dryness under reduced pressure, 0.98 g (yield 92%) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.75-1.90 (2H, m), 2.00-2.15 (2H, m), 2.30 (3
H, s), 2.34 (3H, s), 3.50-3.60 (2H, m), 3.70-3.80
(1H, m), 3.80-3.90 (1H, m), 4.21 (2H, q, J = 7.0),
4.25-4.30 (1H, m), 4.36 (1H, d, J = 14.0), 4.45-4.50
(1H, m), 4.51 (1H, d, J = 14.0), 4.87 (1H, m), 6.40
-6.55 (2H, m), 7.19 (1H, s), 7.56 (1H, t, J = 8.0),
7.70 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7,82 (1H,
s), 7.84 (1H, s); IR (KBr, cm ^-1 ): 1737, 1672, 1622.

Example 61 N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 2020) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl]
-N- [3- (3-amidinophenyl) -2- (E)-
Propenyl] sulfamoylethyl acetate dihydrochloride (0.
80 g) was dissolved in 3M hydrochloric acid (40 ml) and stirred at 70 ° C. for 1.5 hours. After cooling the reaction solution to room temperature,
After concentration under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YM
C, elution solvent: 12.5% acetonitrile / water) and the obtained amorphous solid was purified with 1M hydrochloric acid (3.00 ml).
Was dissolved in and concentrated to dryness under reduced pressure to obtain 0.71 g (yield 92%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H,
m), 2.00-2.15 (2H, m), 2.30 (3H, s), 2.34 (3H, s),
3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 3.65-3.80 (1
H, m), 3.80-3.95 (1H, m), 4.20-4.30 (1H, m), 4.22
(1H, d, J = 15.0), 4.41 (1H, d, J = 15.0), 4.45-4.55
(1H, m), 4.86 (1H, m), 6.40-6.55 (2H, m), 7.18 (1H,
s), 7.55 (1H, t, J = 7.0), 7.70 (1H, d, J = 7.0), 7.7
2 (1H, d, J = 7.0), 7,83 (1H, s), 7.84 (1H, s); IR (KBr, cm ^-1 ): 1730, 1672.

Example 62 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplified compound number:
1577)

(A) N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] -N-
[4- (Piperidin-4-yloxy) phenyl] sulfamoylethyl acetate N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] sulfamoylethyl acetate (4.92 g) in dichloromethane (30 ml) and ethanol (30 ml). The mixture was dissolved in a mixed solvent, hydrogen chloride was passed under ice-cooling, the vessel was sealed, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (60 ml), aqueous ammonium chloride solution (0.79 g dissolved in 20 ml of water) and 28% aqueous ammonia (1.65 ml) were added, and the mixture was stirred at room temperature for 1 hour. I left it at night. The reaction mixture is concentrated under reduced pressure and the residue is collected by preparative HPLC.
(YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water) to give 3.52 g of the title compound (yield 83
%) As a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.78-1.92 (2H, m), 1.87 (3H, s), 2.05-2.16 (2
H, m), 2.98-3.10 (2H, m), 3.14-3.25 (2H, m), 4.20
(2H, q, J = 7.0), 4.32 (2H, s), 4.37 (2H, s), 4.66
(1H, m), 6.34 (1H, s), 7.04 (2H, d, J = 9.0), 7.40
(2H, d, J = 9.0), 7.48 (1H, d, J = 8.0), 7.52-7.59 (2
H, m), 7.66 (1H, d, J = 8.0).

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3
-(3-amidinophenyl) -2-methyl-2- (E)
-Propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2-methyl-2
-(E) -Propenyl] -N- [4- (piperidine-4
Ethyl -yloxy) phenyl] sulfamoyl acetate (2.48 g) was dissolved in ethanol (45 ml), ethyl acetimidate hydrochloride (1.31 g) and triethylamine (2.22 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC.
2.55 g of an amorphous solid by purification with (YMC-PackODS-A; YMC, elution solvent: 20% acetonitrile / water)
Got 0.20 g of this solid was dissolved in ethanol (4 ml) to prepare a 4M hydrogen chloride dioxane solution (0.28 m).
l) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and then freeze-dried to give the title compound (0.1%).
20 g (80% yield) was obtained as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.64-1.81 (2H, m), 1.87 (3H, s), 1.98-2.11 (2
H, m), 2.30 (3H, s), 3.47-3.62 (2H, m), 3.66-3.89
(2H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.37
(2H, s), 4.71 (1H, m), 6.34 (1H, s), 7.05 (2H, d,
J = 9.0), 7.40 (2H, d, J = 9.0), 7.48 (1H, d, J = 8.0),
7.52-7.58 (2H, m), 7.66 (1H, d, J = 8.0); IR (KBr, cm ^-1 ): 1738, 1672, 1349, 1158.

Example 63 N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 209
9) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] sulfamoylethyl acetate ( 1.97 g) with 3M hydrochloric acid (35
ml) and stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was collected by preparative HPLC.
(YMC-Pack ODS-A; YMC, elution solvent: 11% acetonitrile / water). The resulting amorphous solid was washed with water (30
ml) and a 4M hydrogen chloride dioxane solution (2.
(59 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and then freeze-dried to obtain 1.86 g (yield 87%) of the title compound as a colorless amorphous solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.64-1.82 (2H, m),
1.88 (3H, s), 1.98-2.11 (2H, m), 2.30 (3H, s), 3.
46-3.90 (4H, m), 4.19 (2H, s), 4.37 (2H, s), 4.71
(1H, m), 6.33 (1H, s), 7.04 (2H, d, J = 9.0), 7.41
(2H, d, J = 9.0), 7.48 (1H, d, J = 8.0), 7.52-7.58 (2H,
m), 7.67 (1H, d, J = 8.0); IR (KBr, cm ^-1 ): 1672, 1345, 1156.

Example 64 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-amidinophenyl) -2-fluoro-2- (Z)
-Propenyl] sulfamoylethyl acetate dihydrochloride (Exemplary compound number: 1559)

(A) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
[3-Carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoylethyl acetate N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-cyanophenyl) -2-fluoro-2-
(Z) -Propenyl] sulfamoyl ethyl acetate (4.
30 g) was dissolved in a mixed solvent of dichloromethane (35 ml) and ethanol (35 ml), hydrogen chloride was passed under ice-cooling, and the mixture was tightly capped and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), and an ammonium chloride aqueous solution (0.80 g was added to 5 ml of water).
Solution) and 28% aqueous ammonia (1.80 ml) were added, and the mixture was left at room temperature overnight. The reaction solution is concentrated under reduced pressure,
The residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water) to give 2.20 g (yield 58%) of the title compound as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.
0), 1.88-1.96 (2H, m), 2.09-2.17 (2H, m), 3.02-3.0
9 (2H, m), 3.17-3.24 (2H, m), 4.21 (2H, q, J = 7.0),
4.40 (2H, s), 4.62 (2H, d, J = 16.0), 4.81 (1H, m),
5.98 (1H, d, J = 38.0), 7.26 (1H, d, J = 9.0), 7.51 (1
H, dd, J = 9.0, 3.0), 7.57-7.71 (2H, m), 7.73-7.78
(2H, m), 7.81 (1H, s).

(B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2-
Fluoro-2- (Z) -propenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [3-carbamoyl-
Ethyl 4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate (2.20 g) was added to ethanol (50
ml), ethyl acetimidate hydrochloride (1.00 g) and triethylamine (2.20 ml)
Was added, the mixture was stirred at room temperature for 2 hours, and then left overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS
-A; YMC, elution solvent: 18% acetonitrile / water). 1 M hydrochloric acid (5.60 m was added to the obtained amorphous solid.
l) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (2.20 g, yield 93%) as a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ + D ₂ O) δppm: 1.24 (3H, t, J
= 7.0), 1.79-1.92 (2H, m), 2.02-2.13 (2H, m), 2.30
(3H, s), 3.50-3.58 (2H, m), 3.69-3.77 (1H, m), 3.78
-3.85 (1H, m), 4.21 (2H, q, J = 7.0), 4.39 (2H, s),
4.62 (2H, d, J = 16.0), 4.88 (1H, m), 5.98 (1H, d, J =
38.5), 7.31 (1H, d, J = 9.0), 7.53 (1H, dd, J = 9.0,
2.5), 7.59 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.
76 (1H, d, J = 8.0), 7.79-7.82 (2H, m); IR (KBr, cm ^-1 ): 1671, 1353, 1157.

Example 65 N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-amidinophenyl) -2-fluoro-2- (Z)
-Propenyl] sulfamoylacetic acid dihydrochloride (Exemplary compound number: 2088) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-amidinophenyl) -2-fluoro-2- (Z)
Ethyl-propenyl] sulfamoyl acetate dihydrochloride (2.20 g) was dissolved in 3M hydrochloric acid (40 ml) and
Stirred at 0 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS-A; YMC, eluting solvent: 10
% Acetonitrile / water). The obtained amorphous solid was dissolved in 1M hydrochloric acid (7.0 ml), and concentrated and dried under reduced pressure to give 1.70 g of the title compound (yield 72
%) As a colorless amorphous solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.80-1.92 (2H, m),
2.02-2.12 (2H, m), 2.30 (3H, s), 3.49-3.64 (2H,
m), 3.68-3.76 (1H, m), 3.78-3.84 (1H, m), 4.27 (2
H, s), 4.62 (2H, d, J = 16.0), 4.87 (1H, m), 5.98 (1
H, d, J = 39.0), 7.30 (1H, d, J = 9.0), 7.51-7.71 (3H,
m), 7.73-7.83 (3H, m); IR (KBr, cm ^-1 ): 1672, 1352, 1158.

Reference Example 1 3-Cyanocinnamic Aldehyde 3-Cyanobenzaldehyde (4.5 g) was dissolved in toluene (200 ml), triphenylphosphoranylidene acetaldehyde (13.6 g) was added, and the reaction solution was heated to 70 ° C. And stirred for 4 hours. The reaction solution is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane), and recrystallized from toluene and hexane to give 3.09 g (yield 57%) of the title compound as pale yellow needle crystals. . ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 6.76 (1H, dd, J = 16.
0, 7.5), 7.46 (1H, d, J = 16.0), 7.58 (1H, t, J = 8.
0), 7.73 (1H, d, J = 8.0), 7.80 (1H, d, J = 8.0), 7.84
(1H, s), 9.75 (1H, d, J = 7.5).

Reference Example 2 3- (3-Cyanophenyl) -2- (E) -propene-
1-ol 3-cyanocinnamic aldehyde (3.00 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (70 ml), and sodium borohydride (1.
32 g) and cerium chloride (2.49 g) were added,
The mixture was stirred at the same temperature for 1.5 hours. Saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane three times,
After the extract was washed with saturated saline, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with hexane / ethyl acetate = 3/2) gave 3.27 g (quantitative yield) of the title compound as a pale yellow oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.37 (2H, m), 6.43
(1H, dt, J = 16.0, 5.0), 6.62 (1H, d, J = 16.0), 7.43
(1H, t, J = 8.0), 7.52 (1H, d, J = 8.0), 7.60 (1H, d, J
= 8.0), 7.65 (1H, s).

Reference Example 3 Carbonic acid [3- (3-cyanophenyl) -2- (E) -propenyl] ethyl 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (403 mg) was added to dichloromethane (6 ml)
, Pyridine (1 ml) was added, and the mixture was cooled with ice,
Ethyl chloroformate (0.38 ml) was added dropwise and the temperature was adjusted to 2
Stir for hours. An aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline, and the organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane /
Purification with ethyl acetate = 4/1) gave the title compound (492 mg, yield 84%) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 4.24 (2H, q, J = 7.0), 4.80 (2H, d, J = 5.5), 6.36
(1H, dt, J = 16.0, 5.5), 6.67 (1H, d, J = 16.0), 7.44
(1H, t, J = 8.0), 7.55 (1H, d, J = 8.0), 7.61 (1H, d,
J = 8.0), 7.66 (1H, s).

Reference Example 4 Sodium 4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene hydride (2.2 g) was washed with hexane,
After suspending in N, N-dimethylacetamide (150 ml), 1-t-butoxycarbonyl-4-hydroxypiperidine (10.1 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Next, 4-fluoronitrobenzene was added to the reaction solution over 20 minutes, and then the dark brown reaction solution was stirred for 4 hours. After adding saturated aqueous ammonium chloride solution to the reaction solution to stop the reaction, extraction was performed 3 times with t-butyl methyl ether, the extract was washed with water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. Dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 11.9 g of the title compound (yield 74
%) As a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.43 (9H, s), 1.76
(2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.65 (2H, m),
4.56 (1H, m), 6.91 (2H, d, J = 9.0), 8.15 (2H, d, J
= 9.0).

Reference Example 5 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene (11.9 g) was dissolved in methanol (100 ml). After adding a palladium-carbon catalyst (1.9 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 10.7 g (yield 99%) of the title compound as a pale red solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.71
(2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m),
4.26 (1H, m), 6.63 (2H, d, J = 8.5), 6.76 (2H, d, J =
8.5).

Reference Example 6 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] ethanesulfonamide 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (10.6 g) and pyridine (8 m
l) was dissolved in dichloromethane (75 ml), ethanesulfonyl chloride (4.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hr. Methanol (1
(ml) and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give the title compound 1
1.7 g (yield 84%) was obtained as a pale pink solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.38 (3H, t, J = 8.
0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.07
(2H, q, J = 8.0), 3.34 (2H, m), 3.69 (2H, m), 4.42 (1
H, m), 6.88 (2H, d, J = 9.0), 7.17 (2H, d, J = 9.0).

Reference Example 7 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] ethanesulfonamide [3- (3-cyanophenyl) -2- (E) -propenyl] ethyl carbonate (1.04 g) and N- [4- (1-t
-Butoxycarbonylpiperidin-4-yloxy) phenyl] ethanesulfonamide (1.15 g) was suspended in tetrahydrofuran (9 ml) and tris (dibenzylideneacetone) palladium chloroform complex (0.0
77 g) and triphenylphosphine (0.039 g)
After adding, the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 8/1) to give 1.57 g (quantitative yield) of the title compound as a pale yellow oil. Obtained as a substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.
0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.06
(2H, q, J = 7.0), 3.34 (2H, m), 3.68 (2H, m), 4.42 (2
H, d, J = 7.0), 4.44 (1H, m), 6.28 (1H, dt, J = 15.5,
7.0), 6.42 (1H, d, J = 15.5), 6.89 (2H, d, J = 9.0), 7.
26 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.5), 7.52 (2H,
m), 7.56 (1H, s).

Reference Example 8 3- (3-Cyanophenyl) -2-methyl-2- (E)
-Propenal 3-cyanobenzaldehyde (2.62 g) was dissolved in toluene (90 ml), 2-triphenylphosphoranylidenepropionaldehyde (8.28 g) was added, and the mixture was stirred at 70 ° C for 11 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane) to give the title compound (2.61 g, yield 76%) as pale yellow needle crystals. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.07 (3H, s), 7.25
(1H, bs), 7.59 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0),
7.74 (1H, d, J = 8.0), 7.79 (1H, s), 9.63 (1H, s).

Reference Example 9 3- (3-Cyanophenyl) -2-methyl-2- (E)
-Propen-1-ol 3- (3-cyanophenyl) -2-methyl-2- (E)
-Propenal (2.00 g) with dichloromethane (30
(ml) and ethanol (60 ml), the mixture was dissolved, sodium borohydride (0.83 g) and cerium chloride (1.30 g) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane three times. The extract was washed with water and saturated saline, and the organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 2.05 g (quantitative yield) of the title compound. Obtained as a pale-yellow oil. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.87 (3H, s), 4.22
(2H, m), 6.52 (1H, bs), 7.42-7.52 (3H, m), 7.55
(1H, s).

Reference Example 10 Carbonic acid [3- (3-cyanophenyl) -2-methyl-2-
(E) -Propenyl] ethyl 3- (3-cyanophenyl) -2-methyl-2- (E)
-Propene-1-ol (2.00 g) was dissolved in dichloromethane (20 ml), pyridine (3 ml) was added, ethyl chloroformate (1.30 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 12 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give 2.46 g (yield 87%) of the title compound as a colorless oily substance. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.90 (3H, s), 4.25 (2H, q, J = 7.0), 4.70 (2H,
s), 6.53 (1H, bs), 7.43-7.55 (4H, m).

Reference Example 11 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide carbonate [3- (3-cyanophenyl) -2-methyl-2 −
(E) -Propenyl] ethyl (1.10 g) and N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) phenyl] ethanesulfonamide (1.1
5 g) was suspended in tetrahydrofuran (9 ml), and tris (dibenzylideneacetone) palladium chloroform complex (78 mg) and triphenylphosphine (39) were suspended.
(mg), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12 /
0.58 g of the title compound by purification in 1)
(36% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.
5), 1.47 (9H, s), 1.75 (2H, m), 1.89 (3H, s), 1.91
(2H, m), 3.07 (2H, q, J = 7.5), 3.34 (2H, m), 3.69 (2
H, m), 4.37 (2H, s), 4.45 (1H, m), 6.21 (1H, s),
6.89 (2H, d, J = 9.0), 7.26 (2H, d, J = 9.0), 7.32 (1
H, d, J = 8.0), 7.35 (1H, s), 7.38 (1H, t, J = 8.0),
7.48 (1H, d, J = 8.0).

Reference Example 12 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (4.39 g) and pyridine (2.
4 ml) was dissolved in dichloromethane (30 ml), ethyl chlorosulfonylacetate (2.4 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 13 hours. After adding methanol (0.5 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 4.96 g of the title compound. (Yield 75%) was obtained as a pale red oily substance. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34
(2H, m), 3.69 (2H, m), 3.89 (2H, s), 4.29 (2H, q,
J = 7.0), 4.44 (1H, m), 6.89 (2H, d, J = 8.5), 7.27 (2
H, d, J = 8.5).

Reference Example 13 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.80 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoylethyl acetate (2.21 g) and triphenylphosphine (1.70 g) were added to dichloromethane ( 40 ml), and diethyl azodicarboxylate (1.0 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: dichloromethane /
Purification with ethyl acetate = 10/1) gave the title compound (2.15 g, yield 74%) as a colorless oil. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34
(2H, m), 3.68 (2H, m), 3.98 (2H, s), 4.30 (2H, q,
J = 7.0), 4.45 (1H, m), 4.47 (2H, d, J = 6.0), 6.24 (1
H, dt, J = 15.5, 6.0), 6.40 (1H, d, J = 15.5), 6.90 (2
H, d, J = 8.5), 7.39 (3H, m), 7.51 (2H, m), 7.55 (1H,
s).

Reference Example 14 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (6.04 g), 3-methyl-4-nitro Phenol (4.59 g) and triphenylphosphine (10.2
0 g) was dissolved in dichloromethane (100 ml),
Diethyl azodicarboxylate (6.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give 6.04 g of the title compound (yield 60%).
Was obtained as a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.78
(2H, m), 1.94 (2H, m), 2.62 (3H, s), 3.38 (2H, m),
3.69 (2H, m), 4.58 (1H, m), 6.80 (2H, m), 8.08 (1
H, d, J = 9.5).

Reference Example 15 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylnitrobenzene (3.23 g) )
Was dissolved in methanol (30 ml), a palladium-carbon catalyst (0.21 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 3.02 g of the title compound (yield 99 %)
Was obtained as a pale red oily substance. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70
(2H, m), 1.87 (2H, m), 2.12 (3H, s), 3.27 (2H, m),
3.71 (2H, m), 4.26 (1H, m), 6.59-6.69 (3H, m).

Reference Example 16 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -2-methylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylaniline (3.00 g) and pyridine (1.6 ml) in dichloromethane (20 ml). And ethyl chlorosulfonyl acetate (1.
(6 ml) was added dropwise, and the mixture was stirred at room temperature for 13 hours. Methanol (1 ml) was added to the reaction solution, which was then concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give the title compound (2.35 g, yield 53%) as a pale-yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.
0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 2.38
(3H, s), 3.34 (2H, m), 3.68 (2H, m), 4.01 (2H, s),
4.29 (2H, q, J = 7.0), 4.43 (1H, m), 6.73 (1H, dd,
J = 8.5, 3.0), 6.80 (1H, d, J = 3.0), 7.34 (1H, d, J =
8.0).

Reference Example 17 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -2-methylphenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-Cyanophenyl) -2- (E) -propene-
1-ol (0.48 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylphenyl] sulfamoylethyl acetate (1.37)
g) and triphenylphosphine (0.94 g) were dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.57 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 11/1) to give 1.80 g (quantitative yield) of the title compound as a pale yellow compound. Obtained as a solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 2.35
(3H, s), 3.34 (2H, m), 3.68 (2H, m), 3.99 (1H, d,
J = 15.0), 4.12 (1H, d, J = 15.0), 4.27 (1H, dd, J = 15.
0, 6.0), 4.31 (2H, m), 4.44 (1H, m), 4.50 (1H, dd,
J = 15.0, 6.0), 6.28 (1H, dt, J = 16.5, 6.0), 6.32 (1
H, d, J = 16.5), 6.76 (1H, dd, J = 9.0, 3.0), 6.79 (1
H, d, J = 3.0), 7.39 (1H, d, J = 9.0), 7.41 (1H, d, J =
7.5), 7.52 (3H, m).

Reference Example 18 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxynitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-methoxy-4-nitro Phenol (2.54 g) and triphenylphosphine (10.
20 g) is dissolved in dichloromethane (60 ml),
Diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/2) to give 4.36 g of the title compound (yield 82%).
Was obtained as a pale yellow oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.83
(2H, m), 1.96 (2H, m), 3.33 (2H, m), 3.77 (2H, m),
3.94 (3H, s), 4.61 (1H, m), 6.94 (1H, d, J = 9.0),
7.76 (1H, d, J = 2.0), 7.87 (1H, dd, J = 9.0, 2.0).

Reference Example 19 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxynitrobenzene (4.36)
g) was dissolved in methanol (60 ml), a palladium-carbon catalyst (0.25 g) was added, and then under a hydrogen atmosphere,
Stir at room temperature for 65 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 2.03 g of the title compound (yield 51
%) As a pale red oil. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.71
(2H, m), 1.87 (2H, m), 3.18 (2H, m), 3.78 (2H, m),
3.80 (3H, s), 4.15 (1H, m), 6.19 (1H, dd, J = 8.5,
3.0), 6.29 (1H, d, J = 3.0), 6.76 (1H, d, J = 8.5).

Reference Example 20 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methoxyphenyl] sulfamoylethyl acetate ethyl 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyaniline (2.00 g) and pyridine (1.0 ml) in dichloromethane (40 ml).
The mixture was dissolved in water and ethyl chlorosulfonyl acetate (1.0 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane /
The title compound (2.56 g, yield 87%) was obtained as a pale red oily substance by purification with ethyl acetate = 2/1). ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.
0), 1.47 (9H, s), 1.76 (2H, m), 1.90 (2H, m), 3.25
(2H, m), 3.78 (2H, m), 3.85 (3H, s), 3.92 (2H, s),
4.29 (2H, q, J = 7.0), 4.36 (1H, m), 6.82 (1H, dd,
J = 9.0, 2.5), 6.88 (1H, d, J = 9.0), 6.96 (1H, d, J =
2.5).

Reference Example 21 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methoxyphenyl] -N- [3
-(3-Cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (338 mg), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyphenyl] sulfamoylethyl acetate (823 m
g) and triphenylphosphine (1000 mg),
It was dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.43 ml) was added dropwise under ice cooling,
The mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / ethyl acetate = 12/1) gave the title compound (985 mg, yield 76%) as a colorless amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.
0), 1.48 (9H, s), 1.78 (2H, m), 1.93 (2H, m), 3.27
(2H, m), 3.80 (2H, m), 3.84 (3H, s), 4.02 (2H, s),
4.32 (2H, q, J = 7.0), 4.43 (1H, m), 4.50 (2H, d, J
= 7.0), 6.27 (1H, dt, J = 15.5, 7.0), 6.42 (1H, d, J = 1
5.5), 6.92 (1H, d, J = 8.0), 7.03 (1H, dd, J = 8.0, 3.
0), 7.05 (1H, d, J = 3.0), 7.42 (1H, t, J = 8.0), 7.53
(2H, m), 7.58 (1H, s).

Reference Example 22 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-fluoronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-fluoro-4-nitro Phenol (2.36 g) and triphenylphosphine (5.1
1 g) was dissolved in dichloromethane (60 ml), diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/2) to give 3.71 g of the title compound (yield 73%).
Was obtained as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84
(2H, m), 1.97 (2H, m), 3.41 (2H, m), 3.71 (2H, m),
4.66 (1H, m), 7.05 (1H, m), 8.04 (2H, m).

Reference Example 23 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoronitrobenzene (3.71)
g) was dissolved in methanol (50 ml), a palladium-carbon catalyst (0.30 g) was added, and then under a hydrogen atmosphere,
Stir at room temperature for 4 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 3.27 g of the title compound (yield 97
%) As a pale red solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72
(2H, m), 1.86 (2H, m), 3.23 (2H, m), 3.75 (2H, m),
4.17 (1H, m), 6.35 (1H, dd, J = 8.5, 3.0), 6.44 (1H,
dd, J = 12.5, 3.0), 6.82 (1H, dd, J = 9.0, 8.5).

Reference Example 24 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-fluorophenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoroaniline (1.49 g) and pyridine (0.77 ml) were added to dichloromethane (30 m).
It was dissolved in 1), ethyl chlorosulfonyl acetate (0.77 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
3/8) to give the title compound 1.58
g (71% yield) was obtained as a pale red oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.
0), 1.47 (9H, s), 1.77 (2H, m), 1.90 (2H, m), 3.32
(2H, m), 3.72 (2H, m), 3.92 (2H, s), 4.29 (2H, q,
J = 7.0), 4.42 (1H, m), 6.97 (1H, dd, J = 9.0, 8.5),
7.04 (1H, dd, J = 9.0, 3.0), 7.17 (1H, dd, J = 11.5,
3.0).

Reference Example 25 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-fluorophenyl] -N- [3
-(3-Cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.40 g), ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluorophenyl] sulfamoylacetate (1.15
g) and triphenylphosphine (0.85 g) were dissolved in dichloromethane (20 ml) and diethyl azodicarboxylate (0.51 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 10/1) to give 1.21 g (yield 81%) of the title compound as a pale yellow compound. Obtained as a solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.77 (2H, m), 1.91 (2H, m), 3.34
(2H, m), 3.70 (2H, m), 3.98 (2H, s), 4.31 (2H, q,
J = 7.0), 4.46 (1H, m), 4.47 (2H, d, J = 7.0), 6.22 (1
H, dt, J = 16.0, 7.0), 6.41 (1H, d, J = 16.0), 6.98 (1
H, dd, J = 9.0, 8.5), 7.20 (1H, dd, J = 8.5, 2.0), 7.2
7 (1H, m), 7.40 (1H, dd, J = 8.0, 7.0), 7.52 (1H, d,
J = 7.0), 7.53 (1H, d, J = 8.0), 7.56 (1H, s).

Reference Example 26 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.32 g), 2-chloro-4-nitro Phenol (2.36 g) and triphenylphosphine (5.11)
g) was dissolved in dichloromethane (60 ml), diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/2) to give 3.90 g of the title compound (yield 76%) as a pale yellow solid. Got as. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84-
1.98 (4H, m) 3.54 (2H, m), 3.62 (2H, m), 4.73 (1H,
m), 7.00 (1H, d, J = 9.0), 8.14 (1H, dd, J = 9.0, 3.
0), 8.31 (1H, d, J = 3.0).

Reference Example 27 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene (2.40 g) )
Was dissolved in acetic acid (50 ml), and zinc powder (5.
60 g) was added in 4 portions and the mixture was stirred for 2 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 1.99 g of the title compound (yield 87 %) As an orange oil. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.77
(2H, m), 1.87 (2H, m), 3.31 (2H, m), 3.72 (2H, m),
4.26 (1H, m), 6.52 (1H, dd, J = 9.0, 3.0), 6.73 (1H,
d, J = 3.0), 6.80 (1H, d, J = 9.0).

Reference Example 28 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-chlorophenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline (1.50 g) and pyridine (0.56 ml) in dichloromethane (20 ml)
The mixture was dissolved in water, ethyl chlorosulfonyl acetate (0.74 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
3/2) to give the title compound 1.19.
g (54% yield) was obtained as a pale red oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.46 (2H, m),
3.64 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0),
4.52 (1H, m), 6.94 (1H, d, J = 9.0), 7.22 (1H, dd, J
= 9.0, 2.5), 7.40 (1H, d, J = 2.5).

Reference Example 29 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-chlorophenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-Cyanophenyl) -2- (E) -propene-
1-ol (0.40 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylethyl acetate (1.19)
g) and triphenylphosphine (0.79 g) were dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.50 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2.5 hr. After concentrating the reaction solution under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 10/1) to give 1.20 g of the title compound (yield 78%).
Was obtained as a pale red amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.47 (2H, m),
3.62 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0),
4.47 (2H, d, J = 6.5), 4.55 (1H, m), 6.23 (1H, dt, J
= 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.94 (1H, d, J =
9.0), 7.32 (1H, dd, J = 9.0, 3.0), 7.41 (1H, t, J = 7.
5), 7.50-7.58 (4H, m).

Reference Example 30 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (1.45 g), Journal of Organic・
chemistry. , 63, 4199 (1998
Year)) 2-Trifluoromethyl-4-nitrophenol (1.38 g) and triphenyl synthesized from 3-trifluoromethylnitrobenzene according to the method described in [ J. Org. Chem. , 63 , 4199 (1998)] . Phosphine (2.27
g) was dissolved in dichloromethane (65 ml), diethyl azodicarboxylate (1.4 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane) to give the title compound (2.28 g, yield 88%) as a pale-yellow oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.49 (9H, s), 1.88-
1.99 (4H, m), 3.51 (2H, m), 3.64 (2H, m), 4.83 (1
H, m), 7.09 (1H, d, J = 9.0), 8.41 (1H, dd, J = 9.0,
3.0), 8.53 (1H, d, J = 3.0).

Reference Example 31 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene (2.28 g) was dissolved in methanol (50 ml), and after adding a palladium-carbon catalyst (0.20 g),
The mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
3/2) to give the title compound 1.69.
g (yield 80%) was obtained as a pale red oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.76-
1.88 (4H, m), 3.43 (2H, m), 3.59 (2H, m), 4.46 (1
H, m), 6.78 (1H, dd, J = 9.0, 3.0), 6.83 (1H, d, J = 9.
0), 6.91 (1H, d, J = 3.0).

Reference Example 32 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-trifluoromethylphenyl]
Ethyl sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylaniline (1.6
9 g) and pyridine (0.49 ml) were dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (0.76 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give 1.74 g (yield 73%) of the title compound as a pale red oily substance. Got as. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.48 (9H, s), 1.83-1.94 (4H, m), 3.48-3.60 (4
H, m), 3.91 (2H, s), 4.31 (2H, q, J = 7.0), 4.65 (1
H, m), 6.99 (1H, d, J = 9.0), 7.52 (1H, dd, J = 9.0,
2.5), 7.56 (1H, d, J = 2.5).

Reference Example 33 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-trifluoromethylphenyl]
-N- [3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.57 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylethyl acetate (1.74 g) and triphenylphosphine (1. 07
g) was dissolved in dichloromethane (27 ml), diethyl azodicarboxylate (0.65 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12/1) to give 2.06 g of the title compound (yield 93
%) As a colorless amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.82-1.92 (4H, m), 3.46-3.62 (4
H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2
H, d, J = 6.5), 4.66 (1H, m), 6.22 (1H, dt, J = 16.0,
6.5), 6.41 (1H, d, J = 16.0), 6.98 (1H, d, J = 7.5), 7.
41 (1H, dd, J = 8.0, 7.5), 7.52 (2H, m), 7.57 (1H,
s), 7.58 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.
0).

Reference Example 34 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-nitro Phenol (2.55 g) and triphenylphosphine (5.25
g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (3.2 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane) to give the title compound (4.07 g) as a pale yellow oily substance contaminated with impurities. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84
(2H, m), 1.95 (2H, m), 2.29 (3H, s), 3.49 (2H, m),
3.62 (2H, m), 4.66 (1H, m), 6.86 (1H, d, J = 8.5),
8.07 (2H, m).

Reference Example 35 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylnitrobenzene (4.07 g) )
Is dissolved in methanol (40 ml) and palladium-
After adding a carbon catalyst (0.41 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 2.73 g of the title compound (reference to yield) Example 4
53% in 2 steps from 1) was obtained as a pale red oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.74
(2H, m), 1.87 (2H, m), 2.17 (3H, s), 3.30 (2H, m),
3.68 (2H, m), 4.25 (1H, m), 6.47 (1H, dd, J = 8.5,
2.5), 6.53 (1H, d, J = 2.5), 6.68 (1H, d, J = 8.5).

Reference Example 36 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline (1.63 g) and pyridine (0.81 ml) in dichloromethane (30 ml)
Was dissolved in ethyl acetate, ethyl chlorosulfonyl acetate (0.86 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hours. After adding methanol (0.5 ml) to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2).
The title compound (1.84 g, yield 76%) was obtained as a light brown amorphous solid by purification. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.22
(3H, s), 3.43 (2H, m), 3.62 (2H, m), 3.90 (2H, s),
4.29 (2H, q, J = 7.0), 4.48 (1H, m), 6.79 (1H, d, J
= 8.0), 7.12 (2H, m).

Reference Example 37 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methylphenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-Cyanophenyl) -2- (E) -propene-
1-ol (0.64 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] sulfamoylethyl acetate (1.84)
g) and triphenylphosphine (1.26 g) were dissolved in dichloromethane (40 ml), diethyl azodicarboxylate (0.76 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 12/1) to give 1.90 g (yield 79%) of the title compound as a colorless amorphous form. Obtained as a solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.21
(3H, s), 3.44 (2H, m), 3.60 (2H, m), 3.99 (2H, s),
4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5), 4.50 (1
H, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 1
6.0), 6.80 (1H, d, J = 8.0), 7.24 (2H, m), 7.40 (1H,
t, J = 8.0), 7.50 (1H, d, J = 7.5), 7.52 (1H, d, J = 8.
0), 7.56 (1H, s).

Reference Example 38 3-Bromo-5-cyanotoluene 3,5-dibromotoluene (10.00 g) was dissolved in 1-methyl-2-pyrrolidone (70 ml) to give copper (I) cyanide (5.20 g). ) At 200 ° C.
Stir for hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid, water and saturated brine in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was suspended in a mixed solvent of hexane and ethyl acetate (9/1), and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 9/1) to give 1.70 g of the title compound (yield 21%). ¹ H NMR (270MHz, CDCl ₃ ) δppm: 2.39 (3H, s), 7.40
(1H, s), 7.57 (1H, s), 7.60 (1H, s).

Reference Example 39 3- (3-Cyano-5-methylphenyl) -2- (E)
-Propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (1.
Catechol borane (1.07 ml) to 70 g),
The mixture was stirred at 60 ° C for 3 hours. The reaction solution was cooled to room temperature, then diluted with toluene (20 ml), and 3-bromo-5-
Cyanotoluene (1.40 g), tetrakis (triphenylphosphine) palladium complex (0.42 g), and sodium ethoxide 20% ethanol solution (3.40).
(ml) and then stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with ether. The extract was washed with a 1M aqueous sodium hydroxide solution, water and saturated saline solution in that order, and the organic layer was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 19 /
By purifying in 1), silyl ether body 1.5
0 g was obtained. Next, the obtained silyl ether compound was dissolved in tetrahydrofuran (30 ml) and cooled to 1M under ice cooling.
After adding a tetrabutylammonium fluoride / tetrahydrofuran solution (7 ml), the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give 0.54 g of the title compound (yield: 2 steps, 43%) as a yellow oil. Obtained as a substance. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 2.38 (3H, s), 4.35
(2H, d, J = 5.0), 6.40 (1H, dt, J = 16.0, 5.0), 6.58 (1
H, d, J = 16.0), 7.33 (1H, s), 7.40 (1H, s), 7.46 (1
H, s).

Reference Example 40 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyano-5-methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyano-5-methylphenyl) -2- ( E)
-Propen-1-ol (0.54g), N- [4-
Ethyl (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate (1.50
g) and triphenylphosphine (1.10 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.66 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4.5 hr. After concentrating the reaction solution under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 19/1) to give 1.70 g of the title compound (yield 91%).
Was obtained as an amorphous solid. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2
H, m), 2.36 (3H, s), 3.25-3.40 (2H, m), 3.60-3.75
(2H, m), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.40-
4.50 (3H, m), 6.21 (1H, dt, J = 16.0, 6.0), 6.36 (1H,
d, J = 16.0), 6.90 (2H, m), 7.30-7.45 (5H, m).

Reference Example 41 3- (3-Cyano-4-fluorophenyl) -2-
(E) -Propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (1.
Catechol borane (1.07 ml) to 70 g),
The mixture was stirred at 60 ° C for 4 hours. The reaction solution was cooled to room temperature, then diluted with toluene (20 ml), and 5-bromo-2-
Fluorobenzonitrile (1.43 g), tetrakis (triphenylphosphine) palladium complex (0.42
g) and 20% ethanol solution of sodium ethoxide (3.4 ml) were added, and the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with ether. The extract was washed with a 1M aqueous sodium hydroxide solution, water and saturated saline solution in that order, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 19/1) to obtain 1.33 g of a silyl ether compound. Then, the obtained silyl ether compound was dissolved in tetrahydrofuran (20 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (6 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3 / 2-1 / 1) to give 0.48 g of the title compound (yield: 2 steps, 37%). ) Was obtained as a yellow oil. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 4.30-4.40 (2H, m),
6.35 (1H, dt, J = 16.0, 5.0), 6.59 (1H, d, J = 16.0),
7.18 (1H, m), 7.55-7.65 (2H, m).

Reference Example 42 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyano-4-fluorophenyl) -2-
(E) -Propen-1-ol (0.48 g), N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) phenyl] sulfamoylethyl acetate (1.30 g) and triphenylphosphine (1.00
g) was dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.60 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19/1) to give 1.53 g of the title compound (yield 93
%) Was obtained as an amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2
H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 3.97
(2H, s), 4.30 (2H, q, J = 7.0), 4.40-4.50 (3H, m),
6.16 (1H, dt, J = 16.0, 6.0), 6.37 (1H, d, J = 16.0),
6.91 (2H, d, J = 9.0), 7.14 (1H, m), 7.38 (2H, d, J =
9.0), 7.45-7.55 (2H, m).

Reference Example 43 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile 3-cyanocinnamic aldehyde (6.0 g), 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (11.
3g) and powdered molecular sieves 5A (15.0).
g) was suspended in toluene (30 ml) and heated under reflux for 2 hours. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was recrystallized with dichloromethane and ether to give an imine compound (12.
9 g) was obtained. Then, the obtained imine form was suspended in ethanol (200 ml), a catalytic amount of cerium chloride was added, and then sodium borohydride (1.1
g) was added and the mixture was stirred at the same temperature. The reaction solution is concentrated under reduced pressure,
Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2), and the obtained yellow solid was washed with diisopropyl ether.
The title compound (10.0 g, yield 60%) was obtained as pale yellow crystals. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.60
-1.80 (2H, m), 1.80- 1.95 (2H, m), 3.20-3.35 (2
H, m), 3.65-3.80 (2H, m), 3.93 (2H, dd, J = 5.5, 1.
0), 4.28 (1H, m), 6.39 (1H, dt, J = 16.0, 5.5), 6.61
(1H, d, J = 16.0), 6.61 (2H, d, J = 9.0), 6.81 (2H,
d, J = 9.0), 7.41 (1H, t, J = 7.5), 7.51 (1H, d, J = 7.
5), 7.57 (1H, d, J = 7.5), 7.63 (1H, s).

Reference Example 44 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl] benzonitrile 3 -[3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1000 m
g) and paraformaldehyde (138 mg) were suspended in dichloromethane (20 ml), acetic acid (0.26 ml) and sodium triborohydride cyanide (144 mg) were added under ice cooling, and the mixture was stirred at room temperature overnight. . Methanol (20 ml) was added to the reaction solution, and the mixture was mixed at 30 ° C for 5
After stirring for an hour, water was added, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give 761 mg (yield 74%) of the title compound as a yellow oily substance. Got as. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.72
(2H, m), 1.87 (2H, m), 2.92 (3H, s), 3.28 (2H, m),
3.71 (2H, m), 4.02 (2H, d, J = 5.0), 4.29 (1H, m),
6.32 (1H, dt, J = 16.0, 5.0), 6.51 (1H, d, J = 16.0),
6.72 (2H, d, J = 9.0), 6.86 (2H, d, J = 9.0), 7.39 (1
H, t, J = 7.5), 7.49 (1H, d, J = 7.5), 7.56 (1H, d, J =
7.5), 7.62 (1H, s).

Reference Example 45 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzonitrile 3 -[3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1000 m
g) and acetaldehyde (0.52 ml) were dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml), and acetic acid (0.26 ml) and sodium triborohydride cyanide (144 mg) were added under ice cooling. The mixture was stirred at the same temperature for 2 hours and then at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4 / 1-2 / 1) to give 661 mg of the title compound (yield 62%).
Was obtained as a yellow oil. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.16 (3H, t, J = 7.
0), 1.46 (9H, s), 1.72 (2H, m), 1.87 (2H, m), 3.25
(2H, m), 3.36 (2H, q, J = 7.0), 3.71 (2H, m), 4.01 (2
H, d, J = 5.0), 4.26 (1H, m), 6.31 (1H, dt, J = 16.0,
5.0), 6.50 (1H, d, J = 16.0), 6.69 (2H, d, J = 9.0), 6.
84 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.49 (1H,
d, J = 7.5), 7.55 (1H, d, J = 7.5), 7.61 (1H, s).

Reference Example 46 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzonitrile 3 -[3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1500 m
g) was dissolved in acetone (20 ml), acetic acid (0.20 ml) and sodium triborohydride cyanide (214 mg) were added under ice cooling, and the mixture was stirred at room temperature overnight, and then heated under reflux for 8 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent hexane-ethyl acetate = 4: 1).
The compound (583 mg, yield 35%) was obtained as a pale yellow oily substance by purification. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 6.
5), 1.46 (9H, s), 1.60- 1.80 (2H, m), 1.80-1.95
(2H, m), 3.26 (2H, m), 3.71 (2H, m), 3.91 (2H, d,
J = 4.5), 4.00 (1H, m), 4.26 (1H, m), 6.33 (1H, dt,
J = 16.0, 4.5), 6.53 (1H, d, J = 16.0), 6.73 (2H, d, J
= 9.0), 6.82 (2H, d, J = 9.0), 7.38 (1H, t, J = 7.5), 7.
47 (1H, d, J = 7.5), 7.53 (1H, d, J = 7.5), 7.60 (1H,
s).

Reference Example 47 3- [3- [N-benzyl-N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile 3 -[3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1000 m
g) and benzaldehyde (0.52 ml) were dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml), and acetic acid (0.26 ml) and sodium triborohydride cyanide (144 mg) were added under ice cooling. After that, the mixture was heated under reflux for 10 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4 / 1-2 / 1) to give the title compound (924 mg, yield 76%). Was obtained as a yellow oil. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70
(2H, m), 1.87 (2H, m), 3.26 (2H, m), 3.69 (2H, m),
4.11 (2H, d, J = 5.0), 4.26 (1H, m), 4.52 (2H, s),
6.32 (1H, dt, J = 16.0, 5.0), 6.48 (1H, d, J = 16.0),
6.71 (2H, d, J = 9.0), 6.81 (2H, d, J = 9.0), 7.20-
7.60 (9H, m).

Reference Example 48 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] acetamide 3- [3- [N- [4- (1-t-butoxycarbonylpiperidine-4- Iloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (503 mg)
And pyridine (0.14 ml) with dichloromethane (10
ml), and acetic anhydride (0.13 ml) under ice cooling.
Was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent is evaporated under reduced pressure, the residue is purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1 / 1-ethyl acetate), and the obtained yellow crystals are washed with diisopropyl ether. This gave the title compound (403 mg, yield 50%) as pale-yellow crystals. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.88
(3H, s), 1.70-1.95 (4H, m), 3.33 (2H, m), 3.70 (2
H, m), 4.41 (2H, d, J = 5.5), 4.47 (1H, m), 6.32 (1H,
dt, J = 16.0, 5.5), 6.38 (1H, d, J = 16.0), 6.91 (2H,
d, J = 9.0), 7.07 (2H, d, J = 9.0), 7.40 (1H, t, J = 8.
0), 7.51 (1H, d, J = 8.0), 7.55 (1H, d, J = 8.0), 7.58
(1H, s).

Reference Example 49 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] -2-hydroxyacetamide 3- [3- [N- [4- (1-t-butoxycarbonyl] Piperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1000 m
g) and pyridine (0.28 ml) were dissolved in dichloromethane (20 ml), acetoxyacetyl chloride (0.27 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/3) to obtain 1232 mg of the intermediate compound as a colorless amorphous solid. Then, the obtained intermediate compound was treated with methanol (20 m
l), potassium carbonate (640 mg) was added,
Stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1.
/ 2) to give the title compound (977 mg)
(Yield 86%) was obtained as a colorless amorphous solid. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.76
(2H, m), 1.93 (2H, m), 3.28-3.40 (2H, m), 3.60-
3.80 (2H, m), 3.81 (2H, d, J = 4.5), 4.46 (2H, d, J
= 6.5), 4.47 (1H, m), 6.30 (1H, dt, J = 16.0, 6.5),
6.44 (1H, d, J = 16.0), 6.93 (2H, d, J = 9.0), 7.07 (2
H, d, J = 9.0), 7.42 (1H, t, J = 7.5), 7.53 (1H, d, J =
7.5), 7.56 (1H, d, J = 7.5), 7.59 (1H, s).

Reference Example 50 2- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl acetate 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1.00 g)
Was dissolved in N, N-dimethylformamide (20 ml), potassium carbonate (0.96 g) and ethyl bromoacetate (0.62 ml) were added, and the mixture was stirred at 70 ° C. for 9 hr.
Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 1.31 g (quantitative yield) of the title compound as yellow. Obtained as an oil. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.26 (3H, t, J = 7.
0), 1.46 (9H, s), 1.71 (2H, m), 1.88 (2H, m), 3.27
(2H, m), 3.71 (2H, m), 4.03 (2H, m), 4.15 -4.35 (5
H, m), 6.36 (1H, dt, J = 16.0, 5.0), 6.57 (1H, d, J =
16.0), 6.65 (2H, d, J = 9.0), 6.83 (2H, d, J = 9.0),
7.40 (1H, t, J = 7.5), 7.50 (1H, d, J = 7.5), 7.57 (1
H, d, J = 7.5), 7.63 (1H, s).

Reference Example 51 2- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl propionate 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1200 m
g) was dissolved in N, N-dimethylformamide (20 ml), potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml) were added, and then 10
Stirred at 0 ° C. for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate =
2/1) to give the title compound 882m.
g (60% yield) was obtained as a yellow oil. ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.24 (3H, t, J = 7.
0), 1.46 (9H, s), 1.50 (3H, d, J = 7.0), 1.71 (2H,
m), 1.87 (2H, m), 3.27 (2H, m), 3.70 (2H, m), 4.17
(2H, q, J = 7.0), 4.01-4.32 (3H, m), 4.38 (1H, q,
J = 7.0), 6.36 (1H, dt, J = 16.0, 4.5), 6.57 (1H, d, J =
16.0), 6.73 (2H, d, J = 9.0), 6.82 (2H, d, J = 9.0), 7.
39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.55 (1H,
d, J = 8.0), 7.61 (1H, s).

Reference Example 52 Ethyl N- (4-methoxymethoxyphenyl) sulfamoyl acetate 4-methoxymethoxyaniline (20.9 g) and pyridine (33 ml) were dissolved in dichloromethane (400 ml), and ethyl chlorosulfonylacetate was cooled with ice. (18.
0 ml) was added dropwise and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give 28.0 g of the title compound (yield 67%) as a brown color. Obtained as an oil. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.
0), 3.48 (3H, s), 3.90 (2H, s), 4.29 (2H, q, J = 7.
0), 5.16 (2H, s), 7.03 (2H, d, J = 9.0), 7.28 (2H,
d, J = 9.0).

Reference Example 53 N- [3- (3-Cyanophenyl) -2- (E) -propenyl] -N- (4-methoxymethoxyphenyl) sulfamoylethyl acetate 3- (3-Cyanophenyl) -2- (E) -Propene-
1-ol (0.525 g), ethyl N- (4-methoxymethoxyphenyl) sulfamoyl acetate (1.00
g) and triphenylphosphine (1.12 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.66 ml) was added dropwise, and the mixture was stirred at room temperature for 3.
Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 1.38 g (yield 94%) of the title compound as a yellow oily substance. Got as. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.
0), 3.48 (3H, s), 3.99 (2H, s), 4.32 (2H, q, J = 7.
0), 4.49 (2H, d, J = 6.0), 5.18 (2H, s), 6.25 (1H, d
t, J = 16.0, 6.0), 6.42 (1H, d, J = 16.0), 7.06 (2H,
d, J = 9.0), 7.40 (1H, t, J = 7.0), 7.41 (2H, d, J = 9.
0), 7.52 (1H, d, J = 7.0), 7.54 (1H, d, J = 7.0), 7.56
(1H, s).

Reference Example 54 N- [3- (3-Cyanophenyl) -2- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoylacetate N- [3- (3-cyanophenyl)- 2- (E) -Propenyl] -N- (4-methoxymethoxyphenyl) sulfamoylethyl acetate (10.7 g) was dissolved in ethyl acetate (120 ml), and 4M hydrogen chloride ethyl acetate solution (80 ml) under ice cooling. After adding, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine,
The organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1).
9.1 g of the title compound (yield 9
5%) as a yellow oil. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.46 (2H, d,
J = 6.0), 6.23 (1H, dt, J = 16.0, 6.0), 6.39 (1H, d,
J = 16.0), 6.84 (2H, d, J = 9.0), 7.34 (2H, d, J = 9.0),
7.39 (1H, t, J = 7.5), 7.50 (2H, m), 7.54 (1H, s).

Reference Example 55 N- [4- (1-t-butoxycarbonylpyrrolidine-
3-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate N- [3- (3-cyanophenyl) -2- (E) -propenyl] Ethyl -N- (4-hydroxyphenyl) sulfamoyl acetate (800 mg), 1-t-butoxycarbonyl-3-hydroxypyrrolidine (450 mg) and triphenylphosphine (680 mg) were dissolved in tetrahydrofuran (20 ml) to give azodicarboxylic acid. After adding diethyl (0.68 ml), the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 10/1) to obtain 900 mg (yield 79%) of the title compound as a colorless amorphous solid. It was ¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.46 (9H, s), 2.00-2.25 (2H, m), 3.40-3.70
(4H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2
H, d, J = 6.5), 4.85 (1H, m), 6.24 (1H, dt, J = 16.0,
6.5), 6.41 (1H, d, J = 16.0), 6.87 (2H, d, J = 9.0), 7.
35-7.45 (3H, m), 7.45-7.60 (3H, m).

Reference Example 56 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (2-
Hydroxyethyl) amino] -1- (E) -propenyl] benzonitrile 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1
-(E) -Propenyl] benzonitrile (1000 m
g) and glycol aldehyde dimer (277 mg)
Was dissolved in dichloromethane (20 ml), and under ice cooling,
Acetic acid (0.13 ml) and sodium triborohydride (72 mg) were added, and the mixture was stirred at the same temperature for 5 hours,
Stir at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4
/ 3) to give the title compound (1100 mg)
(Yield 50%) was obtained as a yellow oily substance. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72
(2H, m), 1.89 (2H, m), 3.28 (2H, m), 3.45 (2H, t,
J = 5.5), 3.71 (2H, m), 3.79 (2H, m), 4.07 (2H, m),
4.30 (1H, m), 6.31 (1H, dt, J = 16.0, 5.5), 6.48 (1
H, d, J = 16.0), 6.80 (2H, d, J = 9.0), 6.84 (2H, d, J =
9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.5
4 (1H, d, J = 8.0), 7.60 (1H, s).

Reference Example 57 Ethyl 5-nitrosalicylate 5-Nitrosalicylic acid (10.8 g) was added to ethanol (1
(00 ml), concentrated sulfuric acid (92.0 g) was added at room temperature, and the mixture was heated under reflux for 7.5 hr. Aqueous sodium hydroxide solution was added to the reaction solution to neutralize it, followed by extraction with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, 0.5 M hydrochloric acid and saturated saline solution, and the organic layer was washed with anhydrous magnesium sulfate. Used to dry. After filtration, the solvent was evaporated under reduced pressure to give the title compound (10.7 g, yield 85%) as a pale-yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (3H, t, J = 7.
0), 4.49 (2H, q, J = 7.0), 7.09 (1H, d, J = 9.0), 8.33
(1H, dd, J = 9.0, 3.0), 8.79 (1H, d, J = 3.0).

Reference Example 58 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (10.2 g), ethyl 5-nitrosalicylate ( 1
0.7 g) and triphenylphosphine (17.3 g)
Was dissolved in dichloromethane (200 ml) and cooled under ice,
After diethyl azodicarboxylate (10.4 ml) was added dropwise, the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
The mixture was purified with hexane / ethyl acetate = 3/1), and hexane was added to the obtained yellow solid and the crystals were collected by filtration to give the title compound (12.3 g, yield 61%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J = 7.
0), 1.47 (9H, s), 1.91 (4H, m), 3.58 (4H, m), 4.39
(2H, q, J = 7.0), 4.79 (1H, m), 7.04 (1H, d, J = 9.0),
8.32 (1H, dd, J = 9.0, 3.0), 8.69 (1H, d, J = 3.0).

Reference Example 59 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene (5 0.0 g) was dissolved in methanol (75 ml), a palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred at room temperature for 2.5 hr under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to give 4.6 g of the title compound (yield 9
9%) as a gray oil. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.
0), 1.46 (9H, s), 1.70-1.95 (4H, m), 3.25-3.40 (2
H, m), 3.60-3.75 (2H, m), 4.30-4.40 (1H, m), 4.34
(2H, q, J = 7.0), 6.77 (1H, dd, J = 9.0, 3.0), 6.83 (1
H, d, J = 9.0), 7.12 (1H, d, J = 3.0).

Reference Example 60 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-ethoxycarbonylphenyl]
Ethyl sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylaniline (4.6
g) and pyridine (2.0 ml) with dichloromethane (7
It was dissolved in 0 ml), ethyl chlorosulfonyl acetate (2.5 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours.
The reaction solution was concentrated under reduced pressure, the insoluble material was filtered (hexane-ethyl acetate = 1: 1), and the filtrate was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1).
/ 1) to give the title compound (5.9 g, yield 90%) as an orange amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95
(4H, m), 3.45-3.55 (2H, m), 3.55-3.65 (2H, m), 3.9
1 (2H, s), 4.30 (2H, q, J = 7.0), 4.35 (2H, q, J = 7.
0), 4.59 (1H, m), 6.97 (1H, d, J = 9.0), 7.47 (1H, d
d, J = 9.0, 3.0), 7.70 (1H, d, J = 3.0).

Reference Example 61 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-ethoxycarbonylphenyl]
-N- [3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (1.7 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] sulfamoylethyl acetate (5.9 g) and triphenylphosphine (4.5 g). )
Was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (2.7 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 5.7 g (yield 81%) of the title compound as a yellow amorphous solid. Got as. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 1.75-1.95
(4H, m), 3.45-3.65 (4H, m), 3.99 (2H, s), 4.31 (2
H, q, J = 7.0), 4.35 (2H, q, J = 7.0), 4.49 (2H, d, J =
7.0), 4.62 (1H, m), 6.23 (1H, dt, J = 16.0, 7.0), 6.
41 (1H, d, J = 16.0), 6.97 (1H, m), 7.40 (1H, m), 7.
45-7.60 (4H, m), 7.89 (1H, m).

Reference Example 62 3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.7 g), Journal of Organic Chemistry. ． , 63, 4199 (1998)
3-Bromo- synthesized from 3-bromonitrobenzene according to the method described in [ J. Org. Chem. , 63 , 4199 (1998)] .
4-Hydroxynitrobenzene (1.9 g) and triphenylphosphine (4.4 g) were added to dichloromethane (50 g).
ml) and dissolved in diethyl azodicarboxylate (2.7
(ml) was added dropwise, and the mixture was stirred at room temperature for 11.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 2).
/ 1) to obtain 3.1 g (yield 91%) of the title compound as a yellow oily substance. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.91
(4H, m), 3.59 (4H, m), 4.75 (1H, m), 6.96 (1H, d,
J = 9.0), 8.19 (1H, dd, J = 9.0, 3.0), 8.48 (1H, d, J =
3.0).

Reference Example 63 3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline 3-bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene (3.1 g Was dissolved in acetic acid (40 ml), zinc powder (10.0 g) was added in 10 batches, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite (registered trademark), the filtrate was extracted with ethyl acetate, the extract was washed successively with saturated aqueous potassium carbonate solution, water and saturated brine, and the organic layer was washed with anhydrous magnesium sulfate. Used to dry. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1).
The title compound (2.0 g, yield 69
%) As a brown amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70-
1.90 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H,
m), 4.30 (1H, m), 6.57 (1H, dd, J = 9.0, 3.0), 6.78
(1H, d, J = 9.0), 6.91 (1H, d, J = 3.0).

Reference Example 64 N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoylethyl acetate 3-Bromo-4- (1-t-butoxycarbonylpiperidine-4-) Iloxy) aniline (2.0 g) and pyridine (0.9 ml) were dissolved in dichloromethane (60 ml), and ethyl chlorosulfonylacetate (0.9
ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 2.1 g of the title compound (yield 74%) as a yellow amorphous solid. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2
H, m), 3.55-3.65 (2H, m), 3.92 (2H, s), 4.29 (2H,
q, J = 7.0), 4.55 (1H, m), 6.85-6.95 (2H, m), 7.56
(1H, m).

Reference Example 65 N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-Cyanophenyl) -2- (E) -propene-
1-ol (0.7 g), N- [3-bromo-4- (1
Ethyl -t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate (2.1 g)
And triphenylphosphine (1.4 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.9 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 19/1) to give 2.2 g (yield 82%) of the title compound as a colorless amorphous solid. Got as. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4
H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2
H, d, J = 6.0), 4.58 (1H, m), 6.22 (1H, dt, J = 16.0,
6.0), 6.42 (1H, d, J = 16.0), 6.90 (1H, m), 7.37 (1H,
m), 7.42 (1H, m), 7.45-7.60 (3H, m), 7.71 (1H,
m).

Reference Example 66 2-Isopropyl-4-nitrophenol 2-Isopropylphenol (4.1 ml) was mixed with acetic acid (3
0 ml), 69% nitric acid (4 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water and extracted with t-butyl methyl ether. The extract was washed with water and saturated saline solution in that order, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give 2.66 g of the title compound (yield 49%) as a yellow color. Obtained as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.30 (6H, d, J = 7.
0), 3.25 (1H, m), 6.82 (1H, d, J = 9.0), 8.01 (1H, d
d, J = 9.0, 2.5), 8.13 (1H, d, J = 2.5).

Reference Example 67 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.96 g), 2-isopropyl-4-nitro Phenol (2.66 g) and triphenylphosphine (5.00 g) were dissolved in dichloromethane (80 ml), diethyl azodicarboxylate (3.0 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane) to give the title compound (4.07 g, yield 76%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.26 (6H, d, J = 7.
0), 1.48 (9H, s), 1.80-1.90 (2H, m), 1.90-2.05 (2H,
m), 3.33 (1H, m), 352 (2H, m), 3.62 (2H, m), 4.67
(1H, m), 6.87 (1H, d, J = 9.0), 8.08 (1H, dd, J = 9.
0, 3.0), 8.12 (1H, d, J = 3.0).

Reference Example 68 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylnitrobenzene (4.1
g) was dissolved in methanol (70 ml), a palladium-carbon catalyst (0.4 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 2.8 g of the title compound (yield 74% ) Was obtained as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 7.
0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2
H, m), 3.20-3.40 (3H, m), 3.60-3.75 (2H, m), 4.29
(1H, m), 6.47 (1H, dd, J = 9.0, 3.0), 6.60 (1H, d, J
= 3.0), 6.68 (1H, d, J = 9.0).

Reference Example 69 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-isopropylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylaniline (2.8 g) and pyridine (1.4 ml) were added to dichloromethane (80 m).
It was dissolved in 1), ethyl chlorosulfonyl acetate (1.5 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours.
The title compound 3.3 was obtained by concentrating the reaction solution under reduced pressure and purifying the residue by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1).
g (80% yield) was obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.20 (6H, d, J = 7.
0), 1.37 (3H, t, J = 7.0), 1.48 (9H, s), 1.75-1.85
(2H, m), 1.85-1.95 (2H, m), 3.30 (1H, m), 3.40-3.5
0 (2H, m), 3.55-3.65 (2H, m), 3.90 (2H, s), 4.30
(2H, q, J = 7.0), 4.50 (1H, m), 6.80 (1H, d, J = 9.0),
7.13 (1H, dd, J = 9.0, 3.0), 7.17 (1H, d, J = 3.0).

Reference Example 70 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-isopropylphenyl] -N-
[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.5 g), ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylphenyl] sulfamoylacetate (1.5
g) and triphenylphosphine (1.1 g) were dissolved in dichloromethane (50 ml), diethyl azodicarboxylate (0.7 ml) was added dropwise under ice-cooling, and then 4
Stir for hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 19/1) to give 1.8 g (yield 96%) of the title compound as a yellow amorphous solid. Got as. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 7.
0), 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85
(2H, m), 1.85-1.95 (2H, m), 3.29 (1H, m), 3.40-3.5
0 (2H, m), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31
(2H, q, J = 7.0), 4.46 (2H, d, J = 6.0), 4.52 (1H, m),
6.25 (1H, dt, J = 16.0, 6.0), 6.40 (1H, d, J = 16.0),
6.81 (1H, d, J = 9.0), 7.22 (1H, dd, J = 9.0, 3.0),
7.31 (1H, d, J = 3.0), 7.40 (1H, m), 7.45-7.60 (3H,
m).

Reference Example 71 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene (1. 0 g) was dissolved in ethanol (10 ml), potassium hydroxide (0.2 g) aqueous solution (0.5 ml) was added, and the mixture was heated under reflux for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid, extracted with ethyl acetate, the extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.9 g of the title compound (yield 96%) as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-
1.95 (2H, m), 2.00-2.10 (2H, m), 3.45-3.55 (2H,
m), 3.65-3.75 (2H, m), 4.87 (1H, m), 7.13 (1H, d,
J = 9.0), 8.39 (1H, dd, J = 9.0, 3.0), 8.93 (1H, d, J =
3.0).

Reference Example 72 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene (0.9
g) was dissolved in dichloromethane (20 ml), isobutyl chloroformate (0.3 ml) and triethylamine (0.4 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hr, and then 28% aqueous ammonia (0.2 ml) was added. ) Was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give
0.9 g (98% yield) of the title compound was obtained as a pale yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.80-
1.90 (2H, m), 2.05-2.20 (2H, m), 3.30-3.40 (2H, m
m), 3.75-3.90 (2H, m), 4.81 (1H, m), 7.11 (1H, d,
J = 9.0), 8.33 (1H, dd, J = 9.0, 3.0), 9.09 (1H, d, J =
3.0).

Reference Example 73 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylnitrobenzene (5.7
g) was dissolved in methanol (80 ml), a palladium-carbon catalyst (0.6 g) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 4.8 g (yield 91%) of the title compound as a pale yellow amorphous solid. Obtained. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-
1.80 (2H, m), 1.95-2.05 (2H, m), 3.19 (2H, m), 3.7
5-3.85 (2H, m), 4.44 (1H, m), 6.78 (1H, dd, J = 9.0,
3.0), 6.84 (1H, d, J = 9.0), 7.50 (1H, d, J = 3.0).

Reference Example 74 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline (4.8 g) and pyridine (2.3 ml) in dichloromethane (80 m).
It was dissolved in l), ethyl chlorosulfonyl acetate (2.5 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 1.
After purification by 9/1), ether was added to the obtained orange solid, and then collected by filtration to obtain 3.7 g (yield 53%) of the title compound as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.
0), 1.47 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2
H, m), 3.27 (2H, m), 3.75-3.85 (2H, m), 3.94 (2H,
s), 4.28 (2H, q, J = 7.0), 4.65 (1H, m), 7.02 (1H,
d, J = 9.0), 7.59 (1H, dd, J = 9.0, 3.0), 8.12 (1H, d,
J = 3.0).

Reference Example 75 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.7 g), ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] sulfamoylacetate (2.0
g) and triphenylphosphine (1.5 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.9 ml) was added dropwise, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to give the title compound 2.
5 g (94% yield) was obtained as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2
H, m), 3.27 (2H, m), 3.75-3.85 (2H, m), 3.99 (2H,
s), 4.31 (2H, q, J = 7.0), 4.53 (2H, d, J = 7.0), 4.66
(1H, m), 6.22 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d,
J = 16.0), 7.01 (1H, m), 7.39 (1H, m), 7.45-7.60 (2
H, m), 7.65-7.75 (2H, m), 8.32 (1H, m).

Reference Example 76 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxy Nitrobenzene (3.3
g) was dissolved in dichloromethane (50 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.4 ml) were added under ice-cooling, the mixture was stirred at the same temperature for 0.5 hr, and then a 40% methylamine aqueous solution ( 1.1 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / methanol = 19/1) gave 3.5 g (quantitative yield) of the title compound as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.80-
1.90 (2H, m), 2.05-2.15 (2H, m), 3.04 (3H, m), 3.3
0-3.40 (2H, m), 3.75-3.85 (2H, m), 4.79 (1H, m),
7.08 (1H, d, J = 9.0), 8.29 (1H, dd, J = 9.0, 3.0), 9.
07 (1H, d, J = 3.0).

Reference Example 77 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- ( N-Methylcarbamoyl) nitrobenzene (3.5 g) was dissolved in methanol (50 ml), a palladium-carbon catalyst (0.4 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. After filtering the reaction solution,
The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol =
19/1) to give the title compound (2.9 g)
(92% yield) was obtained as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-
1.75 (2H, m), 1.95-2.05 (2H, m), 2.99 (3H, m), 3.2
0 (2H, m), 3.75-3.85 (2H, m), 4.40 (1H, m), 6.74
(1H, dd, J = 9.0, 3.0), 6.81 (1H, d, J = 9.0), 7.50 (1
H, d, J = 3.0).

Reference Example 78 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3- (N'-methylcarbamoyl)
Phenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) aniline (2.9 g) and pyridine (0.8 ml) were dissolved in dichloromethane (50 ml). Then, ethyl chlorosulfonyl acetate (1.3 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 2/1) to obtain 3.0 g (yield 72%) of the title compound as a pale yellow solid. It was ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.28 (3H, t, J = 7.
0), 1.48 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2
H, m), 3.05 (3H, m), 3.29 (2H, m), 3.70-3.85 (2H,
m), 3.95 (2H, s), 4.22 (2H, q, J = 7.0), 4.63 (1H,
m), 7.00 (1H, d, J = 9.0), 7.61 (1H, dd, J = 9.0, 3.
0), 8.27 (1H, d, J = 3.0).

Reference Example 79 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3- (N'-methylcarbamoyl)
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl ethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.5 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-
Ethyl (N′-methylcarbamoyl) phenyl] sulfamoylacetate (1.5 g) and triphenylphosphine (1.0 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.6 ml) was added under ice cooling.
Was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to give 1.5 g of the title compound (yield 77%) as a colorless amorphous solid. Got as. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2
H, m), 3.01 (3H, m), 3.30 (2H, m), 3.70-3.80 (2H,
m), 3.99 (2H, s), 4.32 (2H, q, J = 7.0), 4.53 (2H,
d, J = 7.0), 4.64 (1H, m), 6.22 (1H, dt, J = 16.0, 7.
0), 6.42 (1H, d, J = 16.0), 6.98 (1H, m), 7.35-7.45
(1H, m), 7.45-7.55 (4H, m), 8.33 (1H, m).

Reference Example 80 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3- (N, N-dimethylcarbamoyl) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3 -Carboxynitrobenzene (3.4
g) was dissolved in dichloromethane (60 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.5 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hr, and then a 50% dimethylamine aqueous solution ( 1.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to obtain 3.1 g (yield 83%) of the title compound as a pale yellow amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-
2.10 (4H, m), 2.89 (3H, s), 3.14 (3H, s), 3.35-3.6
5 (4H, m), 4.69 (1H, m), 7.00 (1H, d, J = 9.0), 8.20
(1H, d, J = 3.0), 8.25 (1H, dd, J = 9.0, 3.0).

Reference Example 81 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3- (N, N-dimethylcarbamoyl) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3 -(N, N-Dimethylcarbamoyl) nitrobenzene (3.1 g) was dissolved in methanol (30 ml), palladium-carbon catalyst (0.3 g) was added,
The mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to give 2.8 g of the title compound (yield 99%). Was obtained as a yellow amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.45 (9H, s), 1.55-
1.95 (4H, m), 2.89 (3H, s), 3.09 (3H, s), 3.25-3.4
0 (2H, m), 3.50-3.65 (2H, m), 4.20-4.30 (1H, m),
6.61 (1H, d, J = 3.0), 6.64 (1H, dd, J = 9.0, 3.0), 6.
76 (1H, d, J = 9.0).

Reference Example 82 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] sulfamoylethyl acetate 4- (1
-T-Butoxycarbonylpiperidin-4-yloxy) -3- (N, N-dimethylcarbamoyl) aniline (2.8 g) and pyridine (0.7 ml) were dissolved in dichloromethane (30 ml) and chlorosulfonyl was added under ice cooling. Ethyl acetate (1.2 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 1/1) to give 3.3 g (yield 79%) of the title compound as a yellow amorphous solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.
0), 1.46 (9H, s), 1.70-2.00 (4H, m), 2.87 (3H, s),
3.10 (3H, s), 3.30-3.50 (2H, m), 3.50-3.60 (2H,
m), 3.93 (2H, s), 4.28 (2H, q, J = 7.0), 4.48 (1H,
m), 6.91 (1H, d, J = 9.0), 7.22 (1H, d, J = 3.0), 7.34
(1H, dd, J = 9.0, 3.0).

Reference Example 83 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3- (N ', N'-dimethylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) ) -2- (E) -Propene-
1-ol (0.5 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-
Ethyl (N ′, N′-dimethylcarbamoyl) phenyl] sulfamoyl acetate (1.5 g) and triphenylphosphine (1.0 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.6
ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to give 1.7 g of the title compound (yield 88%).
Was obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.46 (9H, s), 1.75-2.00 (4H, m), 2.83 (3H, s),
3.10 (3H, s), 3.30-3.60 (4H, m), 3.95-4.05 (2H,
m), 4.30 (2H, q, J = 7.0), 4.47 (2H, d, J = 7.0), 4.52
(1H, m), 6.23 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d,
J = 16.0), 6.92 (1H, m), 7.35-7.55 (6H, m).

Reference Example 84 5-Cyano-2-hydroxybenzaldehyde 4-cyanophenol (25.0 g) was dissolved in trifluoroacetic acid (150 ml), hexamethylenetetramine (50.0 g) was added, and the mixture was heated at 100 ° C. for 9 hours. It was stirred.
The reaction solution was cooled to room temperature, sulfuric acid (50 ml) and water (300 ml) were added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted with dichloromethane, the extract was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate / dichloromethane = 1/19) to give 4.3 g (yield 13%) of the title compound as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 7.11 (1H, d, J = 9.
0), 7.78 (1H, dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.
0), 9.93 (1H, s).

Reference Example 85 5-Cyano-2-hydroxycinnamic aldehyde 5-Cyano-2-hydroxybenzaldehyde (4.3
g) and triphenylphosphoranylidene acetaldehyde (9.4 g) were dissolved in toluene (150 ml),
The mixture was stirred at 70 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / dichloromethane = 1/3) to obtain 2.3 g (yield 44%) of the title compound as a colorless solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 6.98 (1H, dd, J = 1
6.0, 8.0), 7.08 (1H, d, J = 9.0), 7.73 (1H, d, J = 9.
0), 7.83 (1H, d, J = 16.0), 8.22 (1H, s), 9.67 (1H,
d, J = 8.0).

Reference Example 86 5-Cyano-2-methoxymethoxycinnamic aldehyde 5-Cyano-2-hydroxycinnamic aldehyde (2.3
g) was dissolved in N, N-dimethylformamide (25 ml), and methoxymethoxy chloride (1.5 m) under ice cooling.
1) and triethylamine (2.8 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to give the title compound (2.8 g) (yield 9
8%) as a colorless solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 3.52 (3H, s), 5.36
(2H, s), 6.80 (1H, dd, J = 16.0, 8.0), 7.30 (1H, d,
J = 9.0), 7.66 (1H, dd, J = 9.0, 2.0), 7.75 (1H, d, J =
16.0), 7.84 (1H, d, J = 2.0), 9.74 (1H, d, J = 8.0).

Reference Example 87 3- (5-cyano-2-methoxymethoxyphenyl)-
2- (E) -propen-1-ol 5-cyano-2-methoxymethoxycinnamic aldehyde (2.8 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (40 ml), and cerium chloride ( 1.7 g) was added and the mixture was stirred at the same temperature for 0.5 hr, sodium borohydride (0.9 g) was added, and the mixture was further stirred at the same temperature for 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The extract was washed successively with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent hexane / ethyl acetate = 1/1) to give 2.6 g of the title compound (yield 93
%) As a yellow oil. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 3.49 (3H, s), 4.37
(2H, d, J = 5.0), 5.27 (2H, s), 6.41 (1H, dt, J = 16.0,
5.0), 6.90 (1H, d, J = 16.0), 7.18 (1H, d, J = 9.0),
7.49 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.0).

Reference Example 88 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-chlorophenyl] -N- [3-
(5-Cyano-2-methoxymethoxyphenyl) -2-
(E) -Propenyl] sulfamoylethyl acetate 3- (5-cyano-2-methoxymethoxyphenyl)-
2- (E) -propen-1-ol (0.6 g), N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) -3-chlorophenyl] sulfamoylethyl acetate (1.3 g) and triphenylphosphine (0.9 g) were dissolved in dichloromethane (40 ml) and diethyl azodicarboxylate (0.6 ml) under ice cooling.
Was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 9/1) to give 1.4 g of the title compound (yield 74
%) As a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2
H, m), 3.40-3.50 (2H, m), 3.44 (3H, s), 3.55-3.65
(2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.48
(2H, d, J = 7.0), 4.55 (1H, m), 5.23 (2H, s), 6.17
(1H, dt, J = 16.0, 7.0), 6.70 (1H, d, J = 16.0), 6.94
(1H, d, J = 9.0), 7.13 (1H, d, J = 9.0), 7.34 (1H, dd,
J = 9.0, 3.0), 7.47 (1H, dd, J = 9.0, 2.0), 7.55 (1H,
d, J = 3.0), 7.61 (1H, d, J = 2.0).

Reference Example 89 Methyl 3-chloro-5-nitrosalicylate 3-Chlorosalicylic acid (4.5 g) was added to methanol (10
ml) and benzene (40 ml), and the mixture was added with 2M trimethylsilyldiazomethane / hexane solution (20.0 ml) under ice cooling and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained colorless oily substance was
After adding to a mixed solution of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), the mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline solution in that order, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, hexane was added to the obtained yellow solid, and the crystals were collected by filtration to give the title compound (2.4 g, yield 39%) as a yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.07 (3H, s), 8.47
(1H, d, J = 3.0), 8.72 (1H, d, J = 3.0).

Reference Example 90 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-chloro-5-methoxycarbonylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (6.3 g), 3- Methyl chloro-5-nitrosalicylate (2.4 g) and triphenylphosphine (10.
8 g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (6.6 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the title compound (3.4 g, yield 79%) as a pink solid. It was ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-
1.85 (2H, m), 1.85-1.95 (2H, m), 3.11 (2H, m), 3.8
5-3.95 (2H, m), 3.97 (3H, s), 4.44 (1H, m), 8.43
(1H, d, J = 3.0), 8.56 (1H, d, J = 3.0).

Reference Example 91 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-3-chloronitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloro- 5-Methoxycarbonylnitrobenzene (3.4 g) was dissolved in concentrated hydrochloric acid (30 ml), and the mixture was stirred at 75 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, the obtained colorless solid was dissolved in a mixed solvent of water (15 ml) and acetone (15 ml), and under cooling with ice, sodium hydrogen carbonate (1.6 g) and di-t-butyldicarbonate. After adding carbonate (2.2g), it stirred at 40 degreeC for 1 hour.
The reaction mixture was extracted with ethyl acetate, and the extract was extracted with 0.5M hydrochloric acid,
After sequentially washing with water and saturated saline, the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, hexane was added to the obtained pale yellow solid, and the solid was collected by filtration to give 2.6 g of the title compound (yield 7
9%) as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-
1.95 (2H, m), 1.95-2.05 (2H, m), 3.16 (2H, m), 3.9
0-4.00 (2H, m), 4.54 (1H, m), 8.45 (1H, d, J = 3.0),
8.70 (1H, d, J = 3.0).

Reference Example 92 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloronitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy- 3-Chloronitrobenzene (2.6 g) was dissolved in dichloromethane (80 ml), isobutyl chloroformate (1.0 ml) and triethylamine (1.1 ml) were added under ice-cooling, and the temperature was 0.5.
After stirring for 28 hours, 28% aqueous ammonia (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to obtain 2.2 g (yield 84%) of the title compound as a pale yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-
1.85 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m), 4.0
5-4.15 (2H, m), 4.51 (1H, m), 8.42 (1H, d, J = 3.0),
8.79 (1H, d, J = 3.0).

Reference Example 93 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl- 3-Chloronitrobenzene (2.2 g) was dissolved in acetic acid (100 ml), tin powder (9.9 g) was added, and the mixture was stirred at room temperature for 11 hr.
The reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated under reduced pressure, the obtained pale yellow solid was dissolved in an aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. After sequentially washing with saturated saline, the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (1.7 g, yield 83%) as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.65-
1.75 (2H, m), 1.95-2.05 (2H, m), 2.77 (2H, m), 3.7
0-3.80 (2H, m), 4.17 (1H, m), 6.84 (1H, d, J = 3.0),
7.19 (1H, d, J = 3.0).

Reference Example 94 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-3-chlorophenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloroaniline (1.7 g) in dichloromethane (30 ml) After the addition, pyridine (0.7 ml) was added, ethyl chlorosulfonylacetate (0.7 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 1/1) to give
1.2 g (48% yield) of the title compound was obtained as a pale yellow solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.17 (3H, t, J = 7.
0), 1.40 (9H, s), 1.55-1.65 (2H, m), 1.80-1.90 (2
H, m), 2.95-3.05 (2H, m), 3.70-3.80 (2H, m), 4.10
(2H, q, J = 7.0), 4.21 (1H, m), 4.27 (2H, s), 7.28
(1H, d, J = 3.0), 7.36 (1H, d, J = 3.0).

Reference Example 95 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl ethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.4 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] sulfamoylethyl acetate (1.2 g) and triphenylphosphine (0 .8
g) was dissolved in a mixed solvent of dichloromethane (50 ml) and tetrahydrofuran (20 ml), diethyl azodicarboxylate (0.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 3/2) to give 1.5 g (quantitative yield) of the title compound as a yellow amorphous solid. Got as. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.46 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2
H, m), 2.79 (2H, m), 4.00 (2H, s), 4.00-4.15 (2H,
m), 4.31 (2H, q, J = 7.0), 4.38 (1H, m), 4.53 (2H,
d, J = 7.0), 6.21 (1H, dt, J = 16.0, 7.0), 6.46 (1H,
d, J = 16.0), 7.23 (1H, m), 7.41 (1H, m), 7.50-7.60
(3H, m), 8.03 (1H, m).

Reference Example 96 3-Methyl-5-nitrosalicylic acid Methyl 3-methylsalicylic acid (5.1 g) was added to methanol (10
ml) and benzene (40 ml), and the mixture was added with 2M trimethylsilyldiazomethane / hexane solution (25.0 ml) under ice cooling, and then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained colorless oily substance was added to a mixed solution of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline solution in that order, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
The mixture was purified with hexane / ethyl acetate = 2/1), hexane was added to the obtained yellow solid, and the crystals were collected by filtration to give the title compound (1.8 g, yield 25%) as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.35 (3H, s), 4.03
(3H, s), 8.21 (1H, d, J = 3.0), 8.66 (1H, d, J = 3.0).

Reference Example 97 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxycarbonyl-5-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (4.2 g), 3- Methyl methyl-5-nitrosalicylate (1.8 g) and triphenylphosphine (6.8
g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (4.1 ml) was added, and the mixture was stirred at room temperature for 3 hours.
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 3.1 g of the title compound (yield 91%) as a pink oily substance. Obtained. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-
1.75 (2H, m), 1.85-1.95 (2H, m), 2.39 (3H, s), 2.9
7 (2H, m), 3.90-4.00 (2H, m), 3.95 (3H, s), 4.16
(1H, m), 8.22 (1H, d, J = 3.0), 8.52 (1H, d, J = 3.0).

Reference Example 98 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxy-5-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxycarbonyl -5-Methylnitrobenzene (4.0 g) was dissolved in concentrated hydrochloric acid (40 ml), and the mixture was stirred at 75 ° C for 7 hours. The reaction solution is concentrated under reduced pressure,
The white solid obtained was washed with water (20 ml) and acetone (2
It was dissolved in a mixed solvent (0 ml), sodium hydrogen carbonate (1.9 g) and di-t-butyl dicarbonate (2.7 g) were added under ice cooling, and the mixture was stirred at 40 ° C. for 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed successively with 0.5 M hydrochloric acid, water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hexane was added to the obtained pale yellow solid,
The title compound (3.6 g, yield 79) was obtained by filtration.
%) As a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70-
1.85 (2H, m), 1.90-2.05 (2H, m), 2.43 (3H, s), 2.9
5 (2H, m), 4.00-4.10 (2H, m), 4.26 (1H, m), 8.26
(1H, d, J = 3.0), 8.69 (1H, d, J = 3.0).

Reference Example 99 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxy- 5-Methylnitrobenzene (3.6 g) was dissolved in dichloromethane (60 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.6 ml) were added under ice-cooling, and the temperature was 0.5.
After stirring for 28 hours, 28% aqueous ammonia (0.7 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to obtain 3.9 g (quantitative yield) of the title compound as a yellow oily substance. . ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70-
1.80 (2H, m), 1.90-2.00 (2H, m), 2.43 (3H, s), 2.7
9 (2H, m), 4.05-4.15 (2H, m), 4.17 (1H, m), 8.20
(1H, d, J = 3.0), 8.66 (1H, d, J = 3.0).

Reference Example 100 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl- 5-Methylnitrobenzene (3.9 g) was dissolved in methanol (100 ml), a palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hr. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to give the title compound 3.
5 g (97% yield) was obtained as a black-green amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.60-
1.70 (2H, m), 1.90-2.00 (2H, m), 2.23 (3H, s), 2.7
1 (2H, m), 3.62 (2H, m), 3.80-3.90 (1H, m), 6.65
(1H, d, J = 3.0), 7.11 (1H, d, J = 3.0).

Reference Example 101 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoyl-5-methylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylaniline (3.5 g) and pyridine (1 0.0 ml) was dissolved in dichloromethane (80 ml), ethyl chlorosulfonyl acetate (1.6 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to obtain 2.6 g (yield 51%) of the title compound as a pale yellow solid. . ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.31 (3H, t, J = 7.
0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.90-2.00 (2
H, m), 2.33 (3H, s), 2.74 (2H, m), 3.90-4.00 (1H,
m), 3.97 (2H, s), 4.00-4.15 (2H, m), 4.27 (2H, q,
J = 7.0), 7.44 (1H, d, J = 3.0), 7.72 (1H, d, J = 3.0).

Reference Example 102 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl ethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.8 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] sulfamoylethyl acetate (2.6 g) and triphenylphosphine ( 1.7
g) was dissolved in a mixed solvent of dichloromethane (50 ml) and tetrahydrofuran (50 ml), diethyl azodicarboxylate (1.0 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to give
3.2 g (96% yield) of the title compound was obtained as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2
H, m), 2.32 (3H, s), 2.73 (2H, m), 3.95-4.05 (1H,
m), 4.00 (2H, s), 4.05-4.15 (2H, m), 4.31 (2H, q,
J = 7.0), 4.52 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0,
7.0), 6.44 (1H, d, J = 16.0), 7.22 (1H, m), 7.40 (1
H, m), 7.50-7.60 (3H, m), 7.91 (1H, m).

Reference Example 103 2,6-difluoro-4-nitrophenol 2,6-difluorophenol (2.00 g) was dissolved in acetic acid (20 ml), and 60% nitric acid (1.2%) was added under ice cooling.
(0 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, ethyl acetate was added for extraction, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1 to 2/1).
The title compound 1.37 g (yield 5
1%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 7.95 (2H, m).

Reference Example 104 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), 2,6-difluoro -4-Nitrophenol (1.37 g) and triphenylphosphine (2.67 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (1.57 m was prepared under ice cooling.
After l) was added dropwise, the mixture was stirred at room temperature for 9 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 6/1) to give 2.13 g of the title compound (yield: 76
%) As a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.77-
1.85 (2H, m), 1.89-1.96 (2H, m), 3.35 (2H, m), 3.7
2 (2H, m), 4.62 (1H, m), 7.87 (2H, m).

Reference Example 105 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoronitrobenzene (2.
13 g) was dissolved in ethanol (40 ml), palladium-carbon catalyst (0.20 g) was added, and under a hydrogen atmosphere,
Stirred at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.70 g of the title compound (yield 87% )
Was obtained as a colorless solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72-
1.78 (2H, m), 1.83-1.89 (2H, m), 3.23 (2H, m), 3.7
7 (2H, m), 4.11 (1H, m), 6.21 (2H, m).

Reference Example 106 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-difluorophenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoroaniline (1.70
g) and pyridine (0.84 ml) were dissolved in dichloromethane (30 ml), ethyl chlorosulfonyl acetate (0.76 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the extract was washed with saturated saline and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 2.48 g (quantitative) of the title compound as a yellow oily substance. Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.47 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2
H, m), 3.28 (2H, m), 3.75 (2H, m), 3.95 (2H, s), 4.
30 (2H, q, J = 7.0), 4.31 (1H, m), 6.95 (2H, m).

Reference Example 107 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-difluorophenyl] -N
-[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.52 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5
-Difluorophenyl] sulfamoylethyl acetate (1.55g) and triphenylphosphine (1.02)
g) was dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.60 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 1.82 g (yield 91%) of the title compound as a colorless amorphous solid. Got as. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.46 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2
H, m), 3.29 (2H, m), 3.73 (2H, m), 3.99 (2H, s), 4.
31 (2H, q, J = 7.0), 4.37 (1H, m), 4.47 (2H, d, J = 6.
5), 6.20 (1H, dt, J = 16.0, 6.5), 6.43 (1H, d, J = 16.
0), 7.12 (2H, m), 7.41 (1H, t, J = 7.5), 7.53 (1H, d,
J = 7.5), 7.54 (1H, d, J = 7.5), 7.57 (1H, s).

Reference Example 108 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (677 mg), 2,6-dichloro-4 -Nitrophenol (700 mg) and triphenylphosphine (1
150 mg) was dissolved in dichloromethane (40 ml) and diethyl azodicarboxylate (0.67 m was prepared under ice cooling.
1) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 6/1) to give the title compound (950 mg, yield 72%) as a colorless solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-
2.00 (4H, m), 3.20 (2H, m), 3.91 (2H, m), 4.59 (1
H, m), 8.23 (2H, s).

Reference Example 109 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloronitrobenzene (1.9
5 g) was dissolved in acetic acid (50 ml), and zinc powder (11.10 g) was added in 5 portions at room temperature.
Stir for hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate and water were added to the residue for extraction, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. . After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give 1.40 g of the title compound (yield 78% )
Was obtained as a colorless solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.80-
1.95 (4H, m), 3.09 (2H, m), 3.92 (2H, m), 4.22 (1
H, m), 6.61 (2H, s).

Reference Example 110 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dichlorophenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloroaniline (1.40 g)
And pyridine (0.63 ml) into dichloromethane (30
ml), ethyl chlorosulfonyl acetate (0.57 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture for extraction, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 1.89 g of the title compound (yield 95
%) As a pale yellow amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.
0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.14 (2H, m),
3.92 (2H, m), 3.96 (2H, s), 4.30 (2H, q, J = 7.0),
4.37 (1H, m), 7.33 (2H, s).

Reference Example 111 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dichlorophenyl] -N-
[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.59 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5
-Dichlorophenyl] sulfamoylethyl acetate (1.
89 g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.68 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give 2.06 g (yield 86%) of the title compound as a colorless amorphous solid. Obtained. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.15 (2H, m),
3.90 (2H, m), 4.00 (2H, s), 4.31 (2H, q, J = 7.0),
4.41 (1H, m), 4.47 (2H, d, J = 6.5), 6.20 (1H, dt, J
= 16.0, 6.5), 6.44 (1H, d, J = 16.0), 7.42 (1H, t, J =
8.0), 7.47 (2H, s), 7.53 (2H, m), 7.58 (1H, s).

Reference Example 112 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.40 g), 2,6-dimethyl -4-Nitrophenol (1.50 g) and triphenylphosphine (3.06 g) were dissolved in dichloromethane (60 ml), and diethyl azodicarboxylate (1.80 m was prepared under ice cooling.
1) was added dropwise, and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/1) to obtain 2.25 g (yield 71%) of the title compound as a colorless solid. . ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.73
(2H, m), 1.93 (2H, m), 2.35 (6H, s), 2.93 (2H, m),
4.00-4.10 (3H, m), 7.92 (2H, s).

Reference Example 113 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylnitrobenzene (2.2
4 g) was dissolved in a mixed solvent of ethanol (30 ml) and tetrahydrofuran (10 ml), palladium-carbon catalyst (0.20 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere at room temperature for 1 hour.
Stir for hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.94 g of the title compound (yield 95% ) Was obtained as a pale pink solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.66
(2H, m), 1.92 (2H, m), 2.19 (6H, s), 2.86 (2H, m),
3.79 (1H, m), 4.02 (2H, m), 6.36 (2H, s).

Reference Example 114 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dimethylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylaniline (1.94 g)
And pyridine (0.98 ml) with dichloromethane (30
ml), ethyl chlorosulfonyl acetate (0.97 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate and water were added to the reaction mixture for extraction, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give 2.00 g of the title compound (yield 70%) as a pale product. Obtained as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.
0), 1.47 (9H, s), 1.69 (2H, m), 1.91 (2H, m), 2.26
(6H, s), 2.89 (2H, m), 3.90 (1H, m), 3.93 (2H, s),
4.03 (2H, m), 4.29 (2H, q, J = 7.0), 6.98 (2H, s).

Reference Example 115 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dimethylphenyl] -N-
[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.55 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5
-Dimethylphenyl] sulfamoylethyl acetate (1.
50 g) and triphenylphosphine (1.08 g) were dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.63 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with hexane / ethyl acetate = 2/1) gave the title compound (1.75 g, yield 90%) as a colorless amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.70 (2H, m), 1.91 (2H, m), 2.26
(6H, s), 2.90 (2H, m), 3.93 (1H, m), 3.99 (2H, s),
4.00 (2H, m), 4.30 (2H, q, J = 7.0), 4.47 (2H, d, J
= 6.5), 6.23 (1H, dt, J = 16.0, 6.5), 6.42 (1H, d, J = 1
6.0), 7.11 (2H, s), 7.40 (1H, t, J = 8.0), 7.52 (2H,
m), 7.56 (1H, s).

Reference Example 116 4- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-
Cyanophenyl) -2- (E) -propenyl] amino]
Ethyl butyrate 3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenylamino] -1-
(E) -Propenyl] benzonitrile (2.00 g) was dissolved in N, N-dimethylformamide (40 ml), and potassium carbonate (6.50 g) and ethyl bromobutyrate (5.00 ml) were added in 5 portions. 16 at 140 ° C
Stir for hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1).
The title compound (1.20 g, yield 4)
8%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.25 (3H, t, J = 7.
0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.80-2.00 (4
H, m), 2.36 (2H, t, J = 7.0), 3.20-3.35 (4H, m), 3.6
5-3.75 (2H, m), 4.02 (2H, d, J = 5.0), 4.13 (2H, q,
J = 7.0), 4.27 (1H, m), 6.29 (1H, dt, J = 16.0, 5.0),
6.47 (1H, d, J = 16.0), 6.70 (2H, d, J = 9.0), 6.84 (2
H, d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J =
8.0), 7.54 (1H, d, J = 8.0), 7.61 (1H, s).

Reference Example 117 3- (3-Cyanophenyl) -2-fluoro-2-
(Z) -Propene-1-All Journal of Organometallic Chemistry, Volume 332, page 1 (1987) [ J. Organomet. C
hem. , 332 , 1 (1987)] .
-Diethylphosphono-2-fluoroacetic acid (4.35 g)
Was dissolved in tetrahydrofuran (90 ml), and -7
A 1.6 M butyllithium hexane solution (28 ml) was added dropwise with stirring at 8 ° C, and the mixture was stirred at the same temperature for 1 hour. A solution of 3-cyanobenzaldehyde (2.66 g) in tetrahydrofuran (10 ml) was added dropwise to the reaction solution over 10 minutes,
After stirring at 78 ° C for 3 hours, the temperature was raised to 0 ° C. Water (40 ml) was added to the reaction solution, the aqueous layer was separated, and the organic layer was extracted twice with a saturated aqueous sodium hydrogen carbonate solution. After combining all the aqueous layers, the pH of the solution was adjusted to 4 with concentrated hydrochloric acid, and the solution was extracted 5 times with t-butyl methyl ether.
The extract was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an intermediate compound (3.47 g) as a white solid. Then, the obtained intermediate compound (1.15 g) and triethylamine (0.92 ml) were dissolved in dichloromethane (10 ml), and ethyl chlorocarbonate (0.63 ml) was stirred under ice cooling.
Was added and stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, ethyl acetate (10 ml) was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml), an aqueous sodium borohydride solution (0.45 g dissolved in 5 ml of water) was added under ice-cooling stirring, and the mixture was stirred at room temperature for 18 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with t-butyl methyl ether three times. The extract was washed with a saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane /
Purification with ethyl acetate = 3/2) gave the title compound 0.33 g (yield 31%) as a colorless solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 4.32 (2H, dd, J = 12.
5, 5.5), 5.82 (1H, d, J = 37.5), 7.45 (1H, t, J = 8.0),
7.53 (1H, d, J = 8.0), 7.70 (1H, d, J = 8.0), 7.81 (1
H, s).

Reference Example 118 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2-fluoro-2-
(Z) -Propen-1-ol (0.45 g), N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) phenyl] sulfamoylethyl acetate (1.12 g) and triphenylphosphine (0.80
g) was dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.48 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 15/1) to give 1.40 g of the title compound (yield 92%).
Was obtained as a colorless oily substance. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.34
(2H, m), 3.68 (2H, m), 4.00 (2H, s), 4.30 (2H, q,
J = 7.0), 4.46 (1H, m), 4.54 (2H, d, J = 15.0), 5.62
(1H, d, J = 36.5), 6.92 (2H, d, J = 9.5), 7.42 (3H, m),
7.51 (1H, d, J = 7.0), 7.63 (1H, d, J = 8.0), 7.71 (1
H, s).

Reference Example 119 2-Hydroxyisophthalic acid 2-Methoxyisophthalic acid (1.0 g) was dissolved in 55% hydroiodic acid (10 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was added to ice water, and the deposited precipitate was collected by filtration to give the title compound (0.9 g, yield 95%) as a pale-yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 6.93 (1H, t, J = 8.
0), 7.96 (2H, d, J = 8.0).

Reference Example 120 Dimethyl 2-hydroxyisophthalate 2-Hydroxyisophthalic acid (1.9 g) was dissolved in methanol (20 ml), and thionyl chloride (1.
5 ml) was added and the mixture was stirred at 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure to give the title compound (1.5 g, 68 g).
%) As a white solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 3.96 (6H, s), 6.94
(1H, t, J = 8.0), 8.06 (2H, d, J = 8.0).

Reference Example 121 Dimethyl 2-hydroxy-5-nitroisophthalate Dimethyl 2-hydroxyisophthalate (1.5 g)
It was added to a mixed solution of 69% nitric acid (5 ml) and concentrated sulfuric acid (5 ml), and the mixture was stirred under ice cooling for 0.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained yellow solid was added to hexane and collected by filtration.
1.6 g (89% yield) of the title compound was obtained as a yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.03 (6H, s), 8.94
(2H, s).

Reference Example 122 2- (1-t-Butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid dimethyl 1-t-butoxycarbonyl-4-hydroxypiperidine (2.6 g), 2-hydroxy-5 Dimethyl nitroisophthalate (1.6 g) and triphenylphosphine (4.4 g) were dissolved in a mixed solvent of dichloromethane (40 ml) and tetrahydrofuran (20 ml), diethyl azodicarboxylate (2.6 ml) was added, and the mixture was stirred at room temperature. Four
Stir for hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 19/1), and the obtained yellow solid was filtered with hexane and ethyl acetate (4/1). By taking 2.2 g of the title compound (yield 78%)
Was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70-
1.80 (2H, m), 1.85-1.95 (2H, m), 3.05 (2H, m), 3.8
0-3.95 (2H, m), 3.97 (6H, s), 4.29 (1H, m), 8.74
(2H, s).

Reference Example 123 2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid 2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid dimethyl ( 10.
7 g) is dissolved in concentrated hydrochloric acid (100 ml), and 1
Stir for 0 hours. The reaction solution was concentrated under reduced pressure, hexane was added to the residue, and a white solid was collected by filtration. Then, the obtained solid was dissolved in a mixed solvent of water (50 ml) and acetone (50 ml), and sodium hydrogencarbonate (4.6 ml) was added at room temperature.
g) and di-t-butyl dicarbonate (5.9 g) were added, and the mixture was stirred at 40 ° C. for 1 hr. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, hexane was added to the residue, and the crystals were collected by filtration to give the title compound (4.1 g, yield 40%) as a pale-yellow solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.40 (9H, s), 1.5
5-1.65 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H,
m), 3.55-3.65 (2H, m), 4.40 (1H, m), 8.54 (2H, s).

Reference Example 124 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylnitrobenzene 2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid (4.6 g) was dissolved in dichloromethane (150 ml), isobutyl chloroformate (4.3 ml) and triethylamine (4.8 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hr.
28% aqueous ammonia (1.9 ml) was added, and the mixture was further stirred at room temperature for 1 hr. The deposited precipitate was collected by filtration to give the title compound (3.0 g, yield 64%) as a pale-yellow solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.40 (9H, s), 1.6
0-1.70 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H,
m), 3.55-3.65 (2H, m), 4.48 (1H, m), 8.31 (2H, s).

Reference Example 125 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-di Carbamoylnitrobenzene (3.0 g) was dissolved in methanol (60 ml), a palladium-carbon catalyst (0.3 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.8 g, quantitative yield) as a yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.45 (9H, s), 1.55-
1.70 (2H, m), 1.85-2.00 (2H, m), 2.67 (2H, m), 3.8
0-3.90 (2H, m), 4.02 (1H, m), 7.34 (2H, s).

Reference Example 126 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dicarbamoylphenyl]
Ethyl sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylaniline (2.8
g) was dissolved in dichloromethane (80 ml), pyridine (1.4 ml) was added, ethyl chlorosulfonylacetate (2.4 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 4/1) to obtain 0.9 g of the title compound (yield 23%) as a pale yellow solid. . ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.
0), 1.40 (9H, s), 1.50-1.60 (2H, m), 1.75-1.85 (2
H, m), 2.90-3.00 (2H, m), 3.30 (2H, s), 3.65-3.75
(2H, m), 4.10 (2H, q, J = 7.0), 4.15-4.20 (1H, m),
7.43 (2H, s).

Reference Example 127 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3,5-dicarbamoylphenyl]
-N- [3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.9 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-
Dicarbamoylphenyl] sulfamoylethyl acetate (0.9 g) and triphenylphosphine (1.8 g)
Was dissolved in a mixed solvent of dichloromethane (30 ml) and tetrahydrofuran (30 ml), diethyl azodicarboxylate (1.1 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 1/2) to give 0.8 g of the title compound (yield 73%) as a yellow amorphous solid. Got as. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.26 (3H, t, J = 7.
0), 1.45 (9H, s), 1.60-1.75 (2H, m), 1.85-2.00 (2
H, m), 2.60-2.75 (2H, m), 4.00-4.15 (2H, m), 4.03
(2H, s), 4.15-4.25 (1H, m), 4.31 (2H, q, J = 7.0),
4.55 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0),
6.46 (1H, d, J = 16.0), 7.35-7.45 (2H, m), 7.50-7.60
(3H, m), 8.16 (1H, m).

Reference Example 128 4-Methyl-5-nitrosalicylic acid Methyl 4-methylsalicylic acid (3.5 g) was added to methanol (8 m).
l) and benzene (32 ml) dissolved in a mixed solvent,
A 2.0 M trimethylsilyldiazomethanehexane solution (15.0 ml) was added under ice cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated under reduced pressure, the obtained yellow oily substance was added to 69% nitric acid (20 ml) under ice cooling, and the mixture was stirred at the same temperature for 2
Stir for hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline solution in that order, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
4/1) to give 1.3 g of the title compound.
(21% yield) was obtained as a pale yellow solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.66 (3H, s), 4.01
(3H, s), 6.92 (1H, s), 8.66 (1H, s).

Reference Example 129 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-methoxycarbonyl-2-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (5.4 g), 4- Methyl methyl-5-nitrosalicylate (2.8 g) and triphenylphosphine (9.0
g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (5.4 ml) was added, and the mixture was stirred at room temperature for 9 minutes.
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give 4.9 g (yield 93%) of the title compound as a yellow oily substance. Obtained. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.85-
1.95 (4H, m), 2.68 (3H, s), 3.50-3.65 (4H, m), 3.9
1 (3H, s), 4.78 (1H, m), 6.84 (1H, s), 8.63 (1H,
s).

Reference Example 130 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-2-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-methoxycarbonyl 2-Methylnitrobenzene (4.9 g) was dissolved in concentrated hydrochloric acid (100 ml), and the mixture was stirred at 80 ° C for 5 hr. The reaction solution was concentrated under reduced pressure, the obtained white solid was dissolved in a mixed solvent of water (30 ml) and acetone (30 ml), and sodium hydrogencarbonate (2.3 g) and di-t-butyl dicarbonate were added at room temperature. (3.3 g) was added, and the mixture was stirred at 40 ° C for 1 hr. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 4.8 g (quantitative yield) of the title compound as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-
1.95 (2H, m), 2.05-2.15 (2H, m), 2.71 (3H, s), 3.3
5-3.45 (2H, m), 3.70-3.80 (2H, m), 4.85 (1H, m),
6.93 (1H, s), 8.84 (1H, s).

Reference Example 131 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy- 2-Methylnitrobenzene (4.8 g) was dissolved in dichloromethane (100 ml), isobutyl chloroformate (1.7 ml) and triethylamine (1.8 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hr, then 28 Aqueous ammonia solution (0.8 ml) was added, and the mixture was further stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / methanol = 19/1) gave 4.7 g (97% yield) of the title compound as a white solid. ¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.41 (9H, s), 1.7
5-1.85 (2H, m), 1.90-2.00 (2H, m), 2.61 (3H, s),
3.20-3.30 (2H, m), 3.60-3.70 (2H, m), 4.93 (1H, m),
7.35 (1H, s), 8.42 (1H, s).

Reference Example 132 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl- 2-Methylnitrobenzene (4.7 g) was dissolved in methanol (120 ml), a palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After filtering the reaction solution,
The filtrate was concentrated under reduced pressure to give 4.0 g of the title compound.
(93% yield) was obtained as a yellow amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-
1.75 (2H, m), 1.95-2.05 (2H, m), 2.20 (3H, s), 3.1
8 (2H, m), 3.75-3.85 (2H, m), 4.45 (1H, m), 6.74
(1H, s), 7.47 (1H, s).

Reference Example 133 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-2-methylphenyl] sulfamoylethyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylaniline (4.0 g) in dichloromethane (60 ml) ), Pyridine (1.2 ml) was added, ethyl chlorosulfonylacetate (1.9 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 19/1) to obtain 2.8 g (yield 48%) of the title compound as a pale yellow solid. . ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.
0), 1.48 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2
H, m), 2.49 (3H, s), 3.29 (2H, m), 3.75-3.85 (2H,
m), 4.06 (2H, s), 4.33 (2H, q, J = 7.0), 4.66 (1H,
m), 6.90 (1H, s), 8.16 (1H, s).

Reference Example 134 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl ethyl acetate 3- (3-cyanophenyl) -2- (E) -propene-
1-ol (0.9 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] sulfamoyl acetate (2.8 g) and triphenylphosphine ( 2.0
g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (1.2 ml) was added under ice cooling,
Stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
The title compound (2.1 g, yield 58%) was obtained as a yellow amorphous solid by purification with hexane / ethyl acetate = 1/4. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2
H, m), 2.41 (3H, s), 3.25-3.35 (2H, m), 3.75-3.85
(2H, m), 4.02 (1H, d, J = 14.0), 4.16 (1H, d, J = 14.
0), 4.20-4.25 (1H, m), 4.30-4.40 (2H, m), 4.65-4.75
(2H, m), 6.20-6.30 (1H, m), 6.35 (1H, d, J = 16.0),
6.88 (1H, s), 7.41 (1H, m), 7.50-7.55 (3H, m), 8.
30 (1H, s).

Reference Example 135 3- (5-Cyano-2-methylphenyl) -2- (E)
-Propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (2.
Catecholborane (1.5 ml) was added to 45 g, and 6
The mixture was stirred at 0 ° C for 4 hours. The reaction solution was cooled to room temperature, then diluted with toluene (40 ml), and 3-bromo-4-
Methylbenzonitrile (2.02g), tetrakis (triphenylphosphine) palladium complex (0.58g)
And sodium ethoxide 20% ethanol solution (5.
0 ml) was added, and the mixture was stirred at 90 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed successively with 1M sodium hydroxide aqueous solution, water and saturated saline, and then the organic layer was dried with anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 8 /
By purifying in 1), the intermediate compound (2.23
g) was obtained. Next, the obtained intermediate compound was dissolved in tetrahydrofuran (60 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (12 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction solution, followed by extraction with t-butyl methyl ether. The extract was washed with water and saturated saline solution in that order, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to give 0.64 g of the title compound (yield: 2 steps, 36%) as a colorless solid. Got as. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.41 (3H, s), 4.39
(2H, bs), 6.30 (1H, dt, J = 16.0, 5.5), 6.80 (1H, d,
J = 16.0), 7.25 (1H, d, J = 8.0), 7.43 (1H, dd, J = 8.0,
2.0), 7.70 (1H, d, J = 2.0).

Reference Example 136 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (5-cyano-2-methylphenyl) -2- (E) -propenyl] sulfamoylethyl acetate 3- (5-cyano-2-methylphenyl) -2- ( E)
-Propen-1-ol (0.64 g), N- [4-
Ethyl (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate (1.62
g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml), diethyl azodicarboxylate (0.70 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12/1),
2.03 g (yield 92%) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.
0), 1.47 (9H, s), 1.75 (2H, m), 1.91 (2H, m), 2.25
(3H, s), 3.43 (2H, m), 3.69 (2H, m), 3.98 (2H, s),
4.31 (2H, q, J = 7.0), 4.47 (1H, m), 4.49 (2H, d, J
= 6.5), 6.05 (1H, dt, J = 15.5, 6.5), 6.56 (1H, d, J = 1
5.5), 6.92 (2H, d, J = 10.0), 7.19 (1H, d, J = 7.5), 7.
40 (3H, m), 7.55 (1H, s).

Reference Example 137 3- (5-cyano-2-fluorophenyl) -2-
(E) -Propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (1.
Catechol borane (1.07 ml) to 70 g),
The mixture was stirred at 60 ° C for 3 hours. The reaction solution was cooled to room temperature and then diluted with toluene (20 ml), and 3-bromo-4-
Fluorobenzonitrile (1.40 g), tetrakis (triphenylphosphine) palladium complex (0.41
g) and 20% ethanol solution of sodium ethoxide (3.4 ml) were added, and the mixture was stirred at 100 ° C. for 6 hours. After adding 1M sodium hydroxide aqueous solution to the reaction solution,
The mixture was extracted with ether, the extract was washed with 1M aqueous sodium hydroxide solution, water and saturated brine in that order, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 10/1) to obtain an intermediate compound (1.29 g). Then, the obtained intermediate compound was treated with tetrahydrofuran (10
ml) and under ice cooling, 1M tetrabutylammonium fluoride / tetrahydrofuran solution (5.30 ml)
After adding, the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and brine in that order, and the organic layer was dried over anhydrous magnesium sulfate. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 0.46 g of the title compound (yield: 2 steps, 37%) as a colorless solid. Obtained. ¹ H NMR (400MHz, CDCl ₃ ) δppm: 4.40 (2H, m), 6.52
(1H, dt, J = 16.5, 5.0), 6.75 (1H, d, J = 16.5), 7.16
(1H, dd, J = 10.0, 8.5), 7.53 (1H, ddd, J = 8.5, 5.0,
2.0), 7.70 (1H, dd, J = 7.0, 2.0).

Reference Example 138 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -propenyl]
Ethanesulfonamide 3- (5-cyano-2-fluorophenyl) -2-
(E) -Propen-1-ol (0.72 g), N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) phenyl] ethanesulfonamide (1.6
3 g) and triphenylphosphine (1.37 g) were dissolved in dichloromethane (40 ml), diethyl azodicarboxylate (0.83 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 10/1) to obtain 2.00 g (yield 91%) of the title compound as a colorless oily substance. . ¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.
5), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.06
(2H, q, J = 7.5), 3.33 (2H, m), 3.68 (2H, m), 4.45 (3
H, m), 6.34 (1H, dt, J = 16.0, 6.0), 6.54 (1H, d, J =
16.0), 6.90 (2H, d, J = 9.0), 7.12 (1H, dd, J = 10.5,
9.0), 7.27 (2H, d, J = 9.0), 7.51 (1H, ddd, J = 9.0, 5.
0, 2.0), 7.68 (1H, dd, J = 6.5, 2.0).

Reference Example 139 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] sulfamoylethyl acetate 3- (3-cyanophenyl) -2-methyl-2- ( E)
-Propen-1-ol (1.50 g), N- [4-
Ethyl (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate (3.83
g) and triphenylphosphine (2.95 g) were dissolved in dichloromethane (70 ml), diethyl azodicarboxylate (1.77 ml) was added under ice-cooling, and then 1
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 1/10) to give 4.98 g (yield 96%) of the title compound as a yellow amorphous solid. Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.0),
1.47 (9H, s), 1.69-1.79 (2H, m), 1.84-1.96 (2H,
m), 1.88 (3H, s), 3.34 (2H, m), 3.69 (2H, m), 3.98
(2H, s), 4.32 (2H, q, J = 7.0), 4.40 (2H, s), 4.46
(1H, m), 6.20 (1H, s), 6.91 (2H, d, J = 9.0), 7.28-
7.34 (5H, m), 7.47 (1H, d, J = 7.5).

Reference Example 140 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-cyanophenyl) -2-fluoro-2-
Ethyl (Z) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2-fluoro-2-
(Z) -Propen-1-ol (0.80 g), N-
[4- (1-t-butoxycarbonylpiperidine-4-
Iloxy) -3-carbamoylphenyl] sulfamoylethyl acetate (2.20 g) and triphenylphosphine (1.50 g) were dissolved in dichloromethane (50 ml), and diethyl azodicarboxylate (0.86 m) was added under ice cooling.
After l) was added dropwise, the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/4).
˜1 / 2) to give the title compound 3.40.
g (quantitative yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.47 (9H, s), 1.75-1.84 (2H, m), 2.02-2.10 (2H,
m), 3.23-3.30 (2H, m), 3.76-3.84 (2H, m), 4.01 (2
H, s), 4.31 (2H, q, J = 7.0), 4.57-4.70 (3H, m), 5.6
5 (1H, d, J = 36.5), 7.03 (1H, d, J = 9.0), 7.38-7.74
(5H, m), 8.35 (1H, d, J = 3.0).

Test Example 1 Measurement of anti-factor Xa activity The anti-factor Xa activity was measured by the method of Hara et al. [Thrombosis and Hemostasis, Vol . 71 , p. 314 (1994) [ Thromb. Haemost. , 71 , 314 (1994)]]
Was partially modified. 0.9% sodium chloride, 0.4 mM
The chromogenic substrate S-2222 (Daiichi Pure Chemicals) and 50 mM Tris hydrochloric acid buffer solution (pH 8.4) containing the test compound were mixed to obtain 0.25
The reaction was started by adding unit / ml of human factor Xa (Cosmo Bio). In the control group, distilled water was added to the buffer instead of the test compound.
The reaction solution (total volume 0.1 ml) was incubated at room temperature for 5 minutes. The absorbance at 405 nm was continuously measured with a 96-well microplate reader (Model 550, Bio-Rad), and the increase in absorbance for 5 minutes was calculated as an index of Factor Xa activity. In order to evaluate the anti-factor Xa activity of the test compound, the concentration at which the test compound inhibited the factor Xa activity by 50% (IC ₅₀ value) was determined. As a result, it was found that the benzamidine derivative having the general formula (I) contained in the medicament of the present invention has an excellent activated blood coagulation factor X inhibitory action. Table 2 shows compounds having an IC ₅₀ of 12 nM or less. In the table, compound A is WO 98/31
661 (EP 976722), N- [4- [1-acetamidoyl-4-piperidyloxy] phenyl] -N-.
2 shows the dihydrochloride salt of [2- (3-amidinophenoxy) ethyl] sulfamoyl acetic acid.

[0508]

[Chemical 28]

[0509]

[Table 2] ────────────────────── Example compound Factor Xa inhibitory activity number [IC ₅₀ (nM)] ────────── ───────────── Example 3 8.6 Example 4 6.4 Example 8 4.5 Example 9 7.4 Example 10 4.6 Example 11 8.1 Implementation Example 22 8.3 Example 23 8.3 Example 28 9.0 Example 29 29 9.0 Example 31 10.0 Example 34 10.0 10.0 Example 36 7.1 Example 38 8.7 Example 41 7.5 Example 46 6.8 Example 47 3.7 Example 49 9.8 Example 54 4.6 Example 55 5.0 Example 56 10.0 Example 57 9.3 Example 63 10 Example Example 65 12 ────────────────────── Compound A 130 ───────────────────────

Test Example 2 Measurement of antitrypsin activity The measurement of antitrypsin activity was carried out by the method of Taniuchi et al. [Thrombosis and Hemostasis, Vol . 79 , p. 1998)]]
Was partially modified. 50 with 0.9% sodium chloride
85 μl of mM Tris HCl buffer (pH 8.4), 5 μl of chromogenic substrate
S-2222 (final concentration 0.4 mM, Daiichi Pure Chemicals) and 5 μl of test compound were mixed, and 5 μl of bovine trypsin (final concentration)
The reaction was started by adding 0.25 μg-protein / ml, Sigma). In the control group, distilled water was added to the buffer instead of the test compound. The reaction solution (total volume 0.1 ml) was incubated at room temperature. Absorbance at 405 nm for 96-well microplate reader (Model 55
(0, Bio-Rad), and the increase in absorbance for 5 minutes was calculated as an index of trypsin activity. To evaluate the antitrypsin activity of the test compound, the concentration required for the test compound to inhibit the trypsin activity by 50% (IC ₅₀ value)
I asked. The results are shown in Table 3.

[0511]

[Table 3] ────────────────────── Example compounds Antitrypsin activity number [IC ₅₀ (nM)] ────────── ──────────── Example 9 520 Example 11 840 ────────────────────────

Formulation Example 1 Hard capsules 50 mg of the compound of Example 9 in powder form, 128.7 mg lactose, 70 mg cellulose and 1.3 mg magnesium stearate were mixed and passed through a 60 mesh sieve,
This powder is put into a 250 mg No. 3 gelatin capsule to form a capsule.

Formulation Example 2 Tablets 50 mg of powdered compound of Example 9, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate were mixed and tableted by a tableting machine to give 1 tablet. Take 200 mg tablets. This tablet can be sugar-coated if necessary.

Formulation Example 3 Injections 1.5% by weight of the compound of Example 9 is stirred in 10% by volume of propylene glycol, adjusted to a certain volume with water for injection, and then sterilized to obtain injections.

[0515]

The activated blood coagulation factor X inhibitor comprising the benzamidine derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent activated blood coagulation factor X inhibitory action. It is useful as a prophylactic or therapeutic drug (particularly a therapeutic drug) for blood coagulation diseases (for example, thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulatory disorder) because it has weak toxicity.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 111 A61P 43/00 111 C07D 207/12 C07D 207/12 211/46 211/46 F term ( Reference) 4C054 AA02 CC06 DD01 EE01 FF25 4C069 AA12 BB03 BB42 BC05 4C086 AA01 AA02 BC07 BC21 MA01 MA04 NA14 ZA02 ZA36 ZA54 ZC20 ZC41

Claims (27)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a hydroxyl group, R ² represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, and R ³ represents hydrogen atom; C ₁ -C ₆ alkyl group; a hydroxyl group, a carboxyl group or a (C ₁ -C ₆ alkoxy) C ₁ -C substituted with a carbonyl group ₆ alkyl group; general formula 2] (In the formula, R ⁷ represents a C ₁ -C ₆ alkyl group, and m and n
Are the same or different and each represents an integer of 1 to 6. Group having C); C ₇ -C ₁₅ aralkyl group; C ₁ -C ₆ alkanoyl group; hydroxy C ₂ -C ₆ alkanoyl group; C ₁ -C ₆ alkylsulfonyl group; or (C ₁ -C ₆ alkoxy) carbonyl. C _1- substituted with a radical or a carboxyl group
C ₆ alkylsulfonyl group, wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group. , Carboxyl group, (C _1-
C ₆ alkoxy) carbonyl group, carbamoyl group, (C ₁
A -C ₆ alkyl) carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, and R ⁶ represents a 1-acetimidoylpyrrolidin-3-yl group or a 1-acetimidoylpiperidin-4-yl group. Show. ] The activated blood coagulation factor X inhibitor which consists of a benzamidine derivative or its pharmacologically acceptable salt. 2. A benzamidine derivative in which R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group or a hydroxyl group, or a pharmacologically acceptable salt thereof. An activated blood coagulation factor X inhibitor comprising: 3. The activated blood according to claim 1, wherein R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a hydroxyl group, or a benzamidine derivative or a pharmacologically acceptable salt thereof. Coagulation factor X inhibitor. 4. The activated blood coagulation factor X inhibitor according to claim 1, wherein R ¹ is a hydrogen atom, a fluorine atom, a methyl group or a hydroxyl group, or a pharmaceutically acceptable salt thereof. . 5. The activated blood coagulation factor X inhibitor according to claim 1, wherein R ¹ is a hydrogen atom or a hydroxyl group or a benzamidine derivative or a pharmacologically acceptable salt thereof. 6. A benzamidine derivative according to claim 1, wherein R ² is hydrogen atom, fluorine atom, chlorine atom, bromine atom or C ₁ -C ₄ alkyl group. An activated blood coagulation factor X inhibitor consisting of a pharmacologically acceptable salt thereof. 7. A benzamidine derivative according to claim 1, wherein R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, or a pharmaceutically acceptable derivative thereof. Activated blood coagulation X
Factor inhibitors. 8. The activity according to claim 1, wherein R ² is a hydrogen atom, a fluorine atom or a methyl group, or a benzamidine derivative or a pharmacologically acceptable salt thereof. Blood coagulation factor X inhibitor. 9. The activated blood coagulation according to claim 1, wherein R ² is a benzamidine derivative in which R ² is a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof. Factor X inhibitors. 10. An activated blood coagulation factor X according to claim 1, wherein R ² is a benzamidine derivative in which R ² is a hydrogen atom or a pharmaceutically acceptable salt thereof. Inhibitor. 11. A method according to claim 1, wherein R ³ is hydrogen atom; C ₁ -C ₄ alkyl group; hydroxy C ₁ -C ₄ alkyl group, carboxy C _1-.
C ₄ alkyl group or (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) group; general formula: (In the formula, R ⁷ represents a C ₁ -C ₄ alkyl group, and m and n
Are the same or different and each represents an integer of 1 to 4. Group having); benzyl group, naphthylmethyl group, diphenylmethyl group or phenethyl group; C ₁ -C ₄ alkanoyl group; hydroxyacetyl group, 3-hydroxypropionyl group or 4-hydroxybutyryl group; methanesulfonyl group, ethanesulfonyl group Group, propanesulfonyl group,
Butanesulfonyl group, pentane sulfonyl group or hexanesulfonyl group; or, C ₁ substituted with (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group -
An activated blood coagulation factor X inhibitor comprising a benzamidine derivative having a C ₄ alkylsulfonyl group or a pharmacologically acceptable salt thereof. 12. The method according to claim 1, wherein R ³ is hydrogen atom; C ₁ -C ₄ alkyl group; 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group. Group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group; general formula: (In the formula, R ⁷ represents a methyl group or an ethyl group, and m and n are the same or different and represent 1 or 2.); benzyl group or phenethyl group; formyl group or acetyl group; hydroxyacetyl Group; methanesulfonyl group, ethanesulfonyl group or butanesulfonyl group; or a benzamidine derivative which is a methanesulfonyl group or an ethanesulfonyl group substituted with a (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group, or a pharmacologically acceptable thereof. An activated blood coagulation factor X inhibitor consisting of a salt of 13. The method according to claim 1, wherein R ³ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group or a methoxycarbonyl group. Methyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group,
Butoxycarbonylmethyl group, acetyl group, hydroxyacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group,
Activated blood coagulation factor X inhibition comprising a benzamidine derivative which is a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group or a pharmaceutically acceptable salt thereof. Agent. 14. The method according to claim 1, wherein R ³ is isopropyl group, 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group or ethane. A benzamidine derivative which is a sulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group, or a pharmacologically derivative thereof. An activated blood coagulation factor X inhibitor consisting of an acceptable salt. 15. The method according to claim 1, wherein R ³ is an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group. An activated blood coagulation factor X inhibitor comprising a benzamidine derivative or a pharmaceutically acceptable salt thereof. 16. A benzamidine derivative in which R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group, or a pharmaceutically acceptable salt thereof according to one of the claims selected from 1 to 10. , An activated blood coagulation factor X inhibitor. 17. The method according to claim 1, wherein R ⁴ and R ⁵ are the same or different and are hydrogen atom, fluorine atom, chlorine atom, bromine atom, C ₁ -C. ₄ alkyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group,
Activation consisting of a benzamidine derivative which is a C ₁ -C ₄ alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group or a pharmacologically acceptable salt thereof. Blood coagulation factor X inhibitor. 18. A contract selected from claims 1 to 16.
In the request, R^FourBut hydrogen atom, fluorine atom, chlorine atom
Or a trifluoromethyl group, R^FiveIs a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C₁
-C_FourAlkyl group, fluoromethyl group, difluoromethyl
Group, trifluoromethyl group, 2-fluoroethyl group,
2,2-difluoroethyl group, 2,2,2-trifluoro
R-ethyl group, C ₁-C_FourAlkoxy group, carboxyl group,
Methoxycarbonyl group, ethoxycarbonyl group, carba
Moyl group, methylcarbamoyl group or N, N-dimethyl
A benzamidine derivative having a carbamoyl group or a derivative thereof
Activated blood coagulation factor X consisting of a pharmacologically acceptable salt
Inhibitor. 19. The method according to claim 1, wherein R ⁴ is a hydrogen atom, a fluorine atom or a chlorine atom, and R ⁵ is a hydrogen atom, a fluorine atom or a chlorine atom. An activated blood coagulation factor X inhibitor comprising a benzamidine derivative which is a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a carbamoyl group or a pharmaceutically acceptable salt thereof. 20. In one claim selected from claims 1 through 16, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, trifluoromethyl. A benzamidine derivative or a carbamoyl group or a pharmacologically acceptable salt thereof,
Activated blood coagulation factor X inhibitor. 21. A benzamidine derivative according to claim 1, wherein R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group. Alternatively, an activated blood coagulation factor X inhibitor consisting of a pharmacologically acceptable salt thereof. 22. A benzamidine derivative in which R ⁶ is a 1-acetimidoylpiperidin-4-yl group or a pharmacologically acceptable salt thereof according to one of claims 1 to 21. An activated blood coagulation factor X inhibitor comprising: 23. An activated blood coagulation factor X inhibitor consisting of a compound of the following group selected from claim 1 or a pharmaceutically acceptable salt thereof: N- [4- (1-acetimidoylpiperidine- 4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3 -Chlorophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylethyl acetate, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate, N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid, N- [ 4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3
-Amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N-
[3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl acetic acid, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoyl ethyl acetate, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3-
(3-Amidinophenyl) -2- (E) -propenyl]
Sulfamoylacetic acid and N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (E) -propenyl] sulfamoyl Acetic acid. 24. A therapeutic or prophylactic drug for a blood coagulation disease, which comprises the activated blood coagulation factor X inhibitor according to one of the claims 1 to 23. 25. A therapeutic or prophylactic agent for cerebral infarction, which comprises the activated blood coagulation factor X inhibitor according to one of claims 1 to 23. [26] A therapeutic or prophylactic agent for myocardial infarction, which comprises the activated blood coagulation factor X inhibitor according to one of [1] to [23]. 27. A therapeutic or prophylactic agent for peripheral circulatory disorders, which comprises the activated blood coagulation factor X inhibitor according to one of claims 1 to 23.