JPH08176149A - Thiazole derivative - Google Patents

Abstract

PURPOSE: To obtain a thiazole derivative useful as a preventive and a therapeutic agent for peptic diseases, having excellent antagonistic activity on a H2 receptor, antiulcer action and antibacterial action on Helicobacter pylori. CONSTITUTION: This compound is shown by formula I (R<1> is amino, a mono or di-1-6C alkanoylamino, a 3-8C cycloalkylcarbonylamino, a 5 or 6 membered cyclic heteroarylcarbonylamino; R<2> and R<3> are each H or a 1-10C alkyl; R<4> is H or a 1-6C alkyl; A is a 1-6C alkylene) or its salt such as 4-(4- acetylaminomethylpyrimidin-2-yl)-2[(amino)-(butylamino)methyleneamino] thiazole. The compound of formula I is obtained by reacting a compound of formula II (Y is a halogen) with a compound of formula III in an inert solvent (e.g. ethanol) at -20 to 100 deg.C for 10 minutes to 10 hours.

Description

Detailed Description of the Invention

[0001]

[Object of the invention]

[0002]

FIELD OF THE INVENTION The present invention provides an excellent H ₂ receptor antagonistic action, antiulcer action and Helicobacter pylori ( He
thiol derivative or a pharmacologically acceptable salt thereof having an antibacterial action against licobacter pylori ).

[0003]

2. Description of the Related Art It is said that peptic ulcer occurs when the balance between the attacking factor and the defense factor against the digestive mucosa is lost. Therefore, suppressing gastric acid secretion, which is an attack factor, can be a useful method for the prevention and treatment of ulcers. Hitherto, anticholinergic agents and histamine H ₂ receptor antagonists such as cimetidine have been widely clinically used as agents used for suppressing gastric acid secretion. Anticholinergics have side effects such as suppression of gastrointestinal motility, dry mouth, mydriasis, and suppression of sweating. Further, some histamine H ₂ receptor antagonists have undesired central actions, anti-androgen actions, etc., and there is a problem that the gastric mucosal protective factor is lowered by long-term administration, and ulcer recurrence is also seen after administration interruption. . In addition, it is known that eradication of Helicobacter pylori dramatically reduces recurrence of gastric ulcer and duodenal ulcer. A drug having both anti-gastric acid secretion and antibacterial activity against Helicobacter pylori Development is desired.

[0004]

DISCLOSURE OF THE INVENTION In order to solve the above problems, the present inventors have proposed an antiulcer agent having an H ₂ receptor antagonistic action, an antiulcer action and an antibacterial action against Helicobacter pylori . As a result of extensive research on the synthesis and pharmacological activity of the thiazole derivative aiming at development, as a result, the thiazole derivative having a specific substituent has an excellent gastric acid secretion inhibitory action, antiulcer action and Helicobacter pylori ( Helicobacter pylor).
The inventors have found that they have antibacterial activity against i ) and completed the present invention. The thiazole derivative having antiulcer action and the like is described in, for example, JP-A-3-141270 and JP-A-6-505724.

[0005]

The thiazole derivative of the present invention has the general formula

[0006]

Embedded image

Having

In the above formula, an amino group, mono- or di-C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkanoylamino group, (C ₁ -C ₆ alkoxy) -C ₂ -C ₅ alkanoylamino group, halogeno -C ₂ -C ₅ alkanoylamino group, an amino -C ₂ -C ₅ alkanoylamino group,
(Mono- or di-C ₁ -C ₆ alkylamino) -C
_2- C ₅ alkanoylamino group, (C ₁ -C ₆ alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆ alkoxycarbonyl-mono-C _1-)
C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆ alkanoyl) -C ₂ -C ₅ alkanoylamino group, C ₃ -C ₈ cycloalkyl carbonyl amino group, C ₆ -C ₁₀ aryl Carbonylamino group, C ₇
-C ₁₁ aralkylcarbonylamino group, 5- to 6-membered cyclic heteroarylcarbonylamino group containing nitrogen, oxygen or sulfur atom, C ₁ -C ₆ alkoxycarbonylamino group, (C ₁ -C ₆ alkoxycarbonyl) -mono-C ₁ -C ₆ alkylamino groups, C ₁ -C ₆ alkane sulfonylamino groups, C ₆ -C ₁₀ arylsulfonyl group, a ureido groups, C ₁ -C ₆ alkyl ureido groups, C
_7- C ₁₁ aralkyl ureido group, thioureido group, C ₁
-C ₆ alkyl thioureido group, C ₇ -C ₁₁ aralkyl thioureido group or a phthalimido group, R ² and R ³ are the same or different, a hydrogen atom or a C ₁ -C ₁₀
Represents an alkyl group, R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and A represents a C ₁ -C ₆ alkylene group.

In the general formula (I), the C ₁ -C ₆ alkyl group contained in R ¹ or R ⁴ is, for example, a methyl, ethyl, propyl, isopropyl, butyl, s-butyl, pentyl or hexyl group. And preferably C ₁
A -C ₄ alkyl group, more preferably a methyl or ethyl group, particularly preferably a methyl group.

The C ₁ -C ₆ alkanoyl group contained in R ¹ may be, for example, a formyl, acetyl, propionyl, butyryl, isobutyl, valeryl, isovaleryl, pivaloyl, hexanoyl group, preferably C ₂ -C ₅ It is an alkanoyl group, more preferably an acetyl or propionyl group, and particularly preferably an acetyl group.

The C ₂ -C ₅ alkanoyl group contained in R ¹ can be, for example, acetyl, propionyl, butyryl, isobutyl, valeryl, isovaleryl, pivaloyl group, preferably acetyl or propionyl group, particularly preferably Is an acetyl group.

The C ₁ -C ₆ alkoxy group contained in R ¹ may be, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, hexyloxy group, preferably C _1-. It is a C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group, and particularly preferably a methoxy group.

The halogen atom contained in R ¹ is, for example,
It may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The alkoxy moiety of the C ₁ -C ₆ alkoxycarbonyl group contained in R ¹ is as described above, more preferably C ₁ -C ₂ alkoxy or t-butoxy group, and particularly preferably. , Methoxy or t-butoxy group.

The C ₃ -C ₈ cycloalkyl group contained in R ¹ may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, preferably C ₃ -C ₇ cycloalkyl group. And more preferably a cyclopentyl or cyclohexyl group.

The C ₆ -C ₁₀ aryl group contained in R ¹ is
For example, it may be a phenyl group or a naphthyl group, preferably a phenyl group. In addition, a substituent (preferably 1
To 3 and particularly preferably 1),
They may be the aforementioned C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups or halogen atoms, preferably methyl groups, ethyl groups, methoxy groups, ethoxy groups, fluorine atoms or chlorine atoms. , Particularly preferably a methyl group, a methoxy group, a fluorine atom or a chlorine atom.

The C ₇ -C ₁₁ aralkyl group contained in R ¹ is, for example, a (C ₆ -C ₁₀ aryl) -C ₁ -C ₆ alkyl group, and the aryl moiety and the alkyl moiety are
The same as those described above, preferably a benzyl, phenethyl, phenylpropyl or naphthylmethyl group, more preferably a benzyl, phenethyl or phenylpropyl group, and particularly preferably a benzyl or phenethyl group. It is a base.

The 5- to 6-membered cyclic heteroaryl group containing a nitrogen, oxygen or sulfur atom contained in R ¹ contains ¹ to 3 heteroatoms, for example, furyl, thienyl, pyridyl, oxazolyl, isoxazolyl and thiazolyl. , Isothiazolyl, oxadiazolyl, thiadiazolyl, preferably furyl, thienyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group, more preferably furyl, thienyl or pyridyl group, particularly preferably, It is a furyl or thienyl group.

(C ₁ -C ₆ alkoxy) -C ₂ -of R ¹
The C ₅ alkanoylamino group is preferably methoxyacetylamino, ethoxyacetylamino, 3-methoxypropionylamino, 3-ethoxypropionylamino,
4-methoxybutyrylamino, 5-methoxyvalerylamino or 6-methoxyhexanoylamino group, more preferably methoxyacetylamino, ethoxyacetylamino or 3-methoxypropionylamino group, particularly preferably , 3-methoxypropionylamino group.

The halogeno-C ₂ -C ₅ alkanoylamino group for R ¹ is preferably fluoroacetylamino, difluoroacetylamino, trifluoroacetylamino,
A chloroacetylamino, dichloroacetylamino, trichloroacetylamino, bromoacetylamino, 3-fluoropropionylamino, 4-fluorobutyrylamino, 5-fluorovalerylamino or 6-fluorohexanoylamino group, more preferably , A fluoroacetylamino, difluoroacetylamino, trifluoroacetylamino, chloroacetylamino, dichloroacetylamino or trichloroacetylamino group, particularly preferably a fluoroacetylamino, trifluoroacetylamino or chloroacetylamino group.

R ¹ (amino-, mono-C ₁ -C ₆ alkylamino- or di-C ₁ -C ₆ alkylamino)
-C ₂ -C ₅ alkanoylamino group is preferably amino acetylamino, methylamino acetylamino, ethylamino acetylamino, dimethylamino acetylamino, 3-amino-propionylamino, 3-methylamino-propionylamino, 3-ethyl Aminopropionylamino, 3-dimethylaminopropionylamino, 4-aminobutyrylamino, 5-aminovalerylamino or 6
-Aminohexanoylamino group, more preferably,
Aminoacetylamino, methylaminoacetylamino,
Ethylaminoacetylamino, dimethylaminoacetylamino, 3-aminopropionylamino, 3-methylaminopropionylamino, 3-ethylaminopropionylamino or 3-dimethylaminopropionylamino group, particularly preferably aminoacetylamino, dimethyl Aminoacetylamino, 3-aminopropionylamino or 3-dimethylaminopropionylamino group.

The (C ₁ -C ₆ alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino group is preferably
Methoxycarbonylaminoacetylamino, ethoxycarbonylaminoacetylamino, propoxycarbonylaminoacetylamino, butoxycarbonylaminoacetylamino, t-butoxycarbonylaminoacetylamino, 3-methoxycarbonylaminopropionylamino, 3-ethoxycarbonylaminopropionylamino, t- Butoxycarbonylaminopropioniamino,
4-t-butoxycarbonylaminobutyrylamino, 5
-T-butoxycarbonylaminovalerylamino or 6
A -t-butoxycarbonylaminohexanoylamino group, more preferably methoxycarbonylaminoacetylamino, ethoxycarbonylaminoacetylamino, t-butoxycarbonylaminoacetylamino, 3
-Methoxycarbonylaminopropionylamino or t
-Butoxycarbonylaminopropioniamino group, particularly preferably methoxycarbonylaminoacetylamino or t-butoxycarbonylaminoacetylamino group.

The (C ₁ -C ₆ alkoxycarbonyl-mono-C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group is preferably methoxycarbonylmethylaminoacetylamino, ethoxycarbonylmethylaminoacetylamino, t-butoxycarbonylmethylaminoacetylamino, methoxycarbonylethylaminoacetylamino, ethoxycarbonylethylaminoacetylamino, t-butoxycarbonylethylaminoacetylamino, 3-methoxycarbonylmethylaminopropionylamino, 3-ethoxycarbonylmethylaminopropionylamino, t-butoxycarbonylmethylaminopropioniamino, t-butoxycarbonylethylaminopropioniamino, 4-t-butoxycarbonylmethylaminobutyrylua No, 5-t-butoxycarbonylmethylaminovalerylamino or 6-t-butoxycarbonylmethylaminohexanoylamino group, more preferably methoxycarbonylmethylaminoacetylamino, ethoxycarbonylmethylaminoacetylamino, t- Butoxycarbonylmethylaminoacetylamino, t-butoxycarbonylethylaminoacetylamino, 3-t-butoxycarbonylmethylaminopropionylamino or 3-t-butoxycarbonylethylaminopropioniamino group, particularly preferably methoxycarbonylmethyl. It is an aminoacetylamino, ethoxycarbonylmethylaminoacetylamino or t-butoxycarbonylmethylaminoacetylamino group.

(C ₁ -C ₆ alkanoyl) -C _{2 of} R ¹
The -C ₅ alkanoylamino group is preferably an acetylacetylamino, formylpropionylamino, acetylpropionylamino, acetylbutyrylamino, acetylvalerylamino or acetylhexanoylamino group, particularly preferably acetylpropionylamino. It is a base.

The (C ₁ -C ₆ alkoxycarbonyl) -mono-C ₁ -C ₆ alkylamino group is preferably methoxycarbonylmethylamino, ethoxycarbonylmethylamino, propoxycarbonylmethylamino, butoxycarbonylmethylamino, t-. Butoxycarbonylmethylamino, methoxycarbonylethylaminoamino, ethoxycarbonylethylamino, t-butoxycarbonylethylamino, t-butoxycarbonylpropylaminopropioniamino or t-butoxycarbonylbutylamino group, more preferably methoxycarbonyl. A methylamino, ethoxycarbonylmethylamino, t-butoxycarbonylmethylamino, methoxycarbonylethylaminoamino or t-butoxycarbonylethylamino group, especially Preferred is a methoxycarbonylmethylamino, ethoxycarbonylmethylamino or t-butoxycarbonylmethylamino group.

The C ₁ -C ₁₀ alkyl group for R ² and R ³ is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, nonyl, It may be a decyl group, preferably C ₁ -C
₇ alkyl groups, more preferably C ₄ -C ₆ alkyl groups, and particularly preferably pentyl groups.

The C ₁ -C ₆ alkylene group of A is, for example,
It may be a methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene or hexamethylene group, preferably a linear C ₁ -C ₄ alkylene group,
More preferred is a methylene or ethylene group, and particularly preferred is a methylene group.

The compound having the above general formula (I) can be converted into a pharmaceutically acceptable salt, if necessary. Such salts are preferably hydrofluoric acid salts, hydrochloride salts,
Inorganic acid salts such as hydrobromic acid salts such as hydrobromic acid salts, hydroiodic acid salts, nitrates, perchlorates, sulfates, phosphates, carbonates; methanesulfonates, trifluoromethanesulfonic acid Salts, lower alkyl sulfonates such as ethane sulfonate, benzene sulfonate, aryl sulfonates such as p-toluene sulfonate, fumarate, succinate, citrate, tartrate, oxalic acid Examples thereof include salts, organic acid salts such as maleate, and acid addition salts of organic acids such as glutamate and amino acid salts such as aspartate. When compound (I) has an optical isomer based on an asymmetric carbon atom, the present invention includes such stereoisomers and mixtures thereof. Further, there exist geometrical isomers based on the double bond of butenylene group, but the present invention includes such geometrical isomers and a mixture thereof, and the cis-form is preferable.

In the general formula (I), it is preferable that
(1) R ¹ is an amino group, mono- or di-C ₁ -C ₄
Alkylamino group, C ₂ -C ₅ alkanoylamino group,
(C ₁ -C ₄ alkoxy) -C ₂ -C ₃ alkanoylamino group, halogeno-C ₂ -C ₃ alkanoylamino group,
Amino -C ₂ -C ₃ alkanoylamino group, (mono- or di-C ₁ -C ₄ alkylamino) -C ₂ -C ₃ alkanoylamino groups, (C ₁ -C ₄ alkoxycarbonylamino) -C ₂ -C ₃ alkanoyl Amino group, (C ₁
-C ₄ alkoxycarbonyl over mono over C ₁ -C ₄ alkylamino) -C ₂ -C ₃ alkanoylamino groups, (C ₂
-C ₃ alkanoyl) -C ₂ -C ₃ alkanoylamino groups, C ₃ -C ₇ cycloalkyl carbonyl amino groups, C
₆ arylcarbonylamino group, C ₇ -C ₈ aralkyl carbonyl amino group, 1 or 2 nitrogen, oxygen or 5 or 6 membered cyclic heteroaryl carbonyl amino group containing a sulfur atom, C ₁ -C ₄ alkoxycarbonylamino group , C ₁ -C ₄ alkoxycarbonyl-mono-C _1-
C ₄ alkylamino group, C ₁ -C ₂ alkane sulfonylamino group, C ₆ arylsulfonylamino group, a ureido group, C ₁ -C ₄ alkyl ureido group, C ₇ -C ₈ aralkyl ureido group, thioureido group, C ₁ - A compound which is a C ₄ alkylthioureido group, a C ₇ -C ₈ aralkylthioureido group or a phthalimido group, (2) R ¹ is an amino group, a mono- or di-C ₁ -C ₂ alkylamino group,
C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₂ alkoxy) - acetylamino group, fluoro or chloro -
C ₂ -C ₃ alkanoylamino groups, amino acetylamino group, (mono- or di-C ₁ -C ₂ alkylamino) - acetylamino group, (C ₁ -C ₂ alkoxycarbonylamino) -C ₂ -C ₃ alkanoylamino group , T
- butoxycarbonylamino -C ₂ -C ₃ alkanoylamino groups, (C ₁ -C ₂ alkoxycarbonylmethyl amino) -C ₂ -C ₃ alkanoylamino group, (t-butoxycarbonyl -C ₁ -C ₂ alkylamino) - C ₂ −
C ₃ alkanoylamino group, acetyl-C ₂ -C ₃ alkanoylamino group, C ₅ -C ₆ cycloalkylcarbonylamino group, benzoylamino group, benzylcarbonylamino group, containing 1 to 2 nitrogen, oxygen or sulfur atoms 5- to 6-membered cyclic heteroarylcarbonylamino group, C ₁ -C ₄ alkoxycarbonylamino group, C ₁
-C ₂ alkoxycarbonyl - mono -C ₁ -C ₂ alkylamino group, t-butoxycarbonyl - mono -C ₁ -C
₂ alkylamino group, methanesulfonylamino group, ureido group, C ₁ -C ₄ alkylureido group, C ₇ -C ₈ aralkylureido group, thioureido group, C ₁ -C ₄ alkylthioureido group, C ₇ -C ₈ aralkylthio group A compound which is a ureido group or a phthalimido group, (3) R ¹ is
C ₂ -C ₅ alkanoylamino group, trifluoroacetyl group, trifluoroacetyl group, chloroacetyl amino groups, C ₅ -C ₆ cycloalkyl carbonyl amino group, a furyl carbonyl group, thienylcarbonyl group, pyridylcarbonyl amino groups, C ₁ -C ₄ alkoxycarbonylamino group, a ureido group, C ₁ -C ₄ alkyl ureido group, a benzyl ureido group, thioureido group,
A compound which is a C ₁ -C ₄ alkylthioureido group, a benzylthioureido group or a phthalimido group, (4) R ¹
There, C ₂ -C ₃ alkanoylamino group, trifluoroacetyl group, a furyl carbonyl group, thienylcarbonyl group, C ₁ -C ₂ alkoxycarbonyl group, a ureido group, C ₁ -C ₂ alkyl ureido group, a benzyl ureido A group, a thioureido group, a C ₁ -C ₂ alkylthioureido group or a benzylthioureido group, (5) R ¹ is a C ₂ -C ₃ alkanoylamino group,
A compound which is a C ₁ -C ₂ alkylureido group or a C ₁ -C ₂ alkylthioureido group, (6) R ² and R ³
Are the same or different and are hydrogen atoms or C ₁ -C ₇ alkyl groups, (7) R ² and R ³ are the same or different and are hydrogen atoms or C ₄ -C ₆ alkyl groups, (8) A compound in which R ² and R ³ are the same or different and each is a hydrogen atom or a pentyl group, (9) R ²
Is a hydrogen atom, R ³ is a hydrogen atom or a pentyl group, (10) R ⁴ is a hydrogen atom or C ₁ -C
_A compound having ₄ alkyl groups, (11) a compound having R ⁴ as a hydrogen atom or a methyl group, (12) a compound having R ⁴ as a hydrogen atom, (13) A having a straight chain C ₁ -C ₄ Examples thereof include a compound having an alkylene group and a compound having (14) A a methylene or ethylene group, and a compound having a methylene group (15) A.

Further, (1)-(5), (6)-(9),
A combination of those arbitrarily selected from the group consisting of (10)-(12) and (13)-(15) is also preferable.

Representative compounds of the present invention include, for example:
The compounds shown in the following Table 1 and Table 2 can be illustrated. In addition, Table 1 and Table 2 show the general formula (Ia) and
The compound having (Ib) is shown, and the abbreviations have the following meanings.

[0032]

Embedded image

[0033] Bu: butyl group Bu ^c: cyclobutyl group Bu ^i: isobutyl group Bu ^t: t-butyl group Et: ethyl group Fur: furyl Hp: heptyl Hp ^c: cycloheptyl Hp ^i: isoheptyl Hx: hexyl Group Hx ^c : Cyclohexyl group Hx ⁱ : Isohexyl group Me: Methyl group Oc: Octyl group Ph: Phenyl group PHID: Phthalidyl group Pn: Pentyl group Pn ^c : Cyclopentyl group Pn ⁱ : Isopentyl group Pr: Propyl group Pr ^c : Cyclopropyl Group Pr ⁱ : Isopropyl group Pyr: Pyridyl group Thir: Thienyl group.

[0034]

[Table 1] ──────────────────────────────────── No. R ² R ³ R ⁴ AR ¹ ──────────────────────────────────── 1-1 HHH CH ₂ NH ₂ 1-2 HHH CH ₂ NHMe 1-3 HHH CH ₂ NHEt 1-4 HHH CH ₂ NMe ₂ 1-5 HHH CH ₂ NHCOMe 1-6 HHH CH ₂ NHCOEt 1-7 HHH CH ₂ NHCOPr 1-8 HHH CH ₂ NHCOPr ⁱ 1-9 HHH _{CH 2 NHCOBu 1-10 HHH CH 2 NHCOBu} i 1-11 HHH CH 2 NHCOBu t 1-12 HHH CH 2 NHCOCH 2 OMe 1-13 HHH CH 2 NHCOCH 2 F 1-14 HHH CH 2 NHCOCF 3 1-15 HHH CH _{2 NHCOCH 2 Cl 1-16 HHH CH 2} NHCOCH 2 NH 2 1-17 HHH CH 2 NHCOCH 2 NHMe 1-18 HHH CH 2 NHCOCH 2 NHEt 1-19 HHH CH 2 NHCOCH 2 NMe 2 1-20 HHH CH 2 NHCOCH 2 COMe 1-21 HHH CH ₂ NHCOCH ₂ CH ₂ COMe 1-22 HHH CH ₂ NHCOPr ^c 1-23 HHH CH ₂ NHCOPn ^c 1-24 HHH CH ₂ NHCOHx ^c 1-25 HHH CH ₂ NHCOHp ^c 1-26 HHH CH ₂ NHCOPh 1-27 HHH CH ₂ NHCOCH ₂ Ph 1-28 HHH CH ₂ NHCOCH ₂ CH ₂ Ph 1-29 HHH CH ₂ NHCO (2-Fur) 1-30 HHH CH ₂ NHCO (3-Fur) 1-31 HHH CH ₂ NHCO ( 2-Thi) 1-32 HHH CH ₂ NHCO (3-Thi) 1-33 HHH CH ₂ NHCO (3-Pyr) 1-34 HHH CH ₂ NHCO (4-Pyr) 1-35 HHH CH ₂ NHCO ₂ Me 1 -36 HHH CH ₂ NHCO ₂ Et 1-37 HHH CH ₂ NHCO ₂ Pr 1-38 HHH CH ₂ NHCO ₂ Pr ⁱ 1-39 HHH CH ₂ NHCO ₂ Bu 1-40 HHH CH ₂ NHCO ₂ Bu ⁱ 1-41 HHH ^{_{CH 2 NHCO 2 Bu t 1-42 HHH}} CH 2 NHSO 2 Me 1-43 HHH CH 2 NHSO 2 Et 1-44 HHH CH 2 NHSO 2 Ph 1-45 HHH CH 2 NHCONH 2 1-46 HHH CH 2 NHCONHMe 1- 47 HHH CH ₂ NHCONHEt 1-48 HHH CH ₂ NHCONHPr 1-49 HHH CH ₂ NHCONHPr ⁱ 1-50 HHH CH ₂ NHCONHBu 1-51 HHH CH ₂ NHCONHCH ₂ Ph 1-52 HHH CH ₂ NHCONHCH ₂ CH ₂ Ph 1-53 HHH CH ₂ NHCSNH ₂ 1-54 HHH CH ₂ NHCSNHMe 1-55 HHH CH ₂ NHCSNHEt 1-56 HHH CH ₂ NHCSNHPr 1-57 HHH CH ₂ NHCSNHPr ⁱ 1-58 HHH CH ₂ NHCSNHBu 1-59 HHH CH ₂ NHCSNHCH ₂ Ph 1-60 HHH CH ₂ NHCSNHCH ₂ CH ₂ Ph 1-61 HHH CH ₂ PHID 1-62 HHH CH ₂ CH ₂ NH ₂ 1-63 HHH CH ₂ CH ₂ NHMe ₂ 1-64 HHH CH ₂ CH ₂ NHCOMe 1-65 HHH CH ₂ CH ₂ NHCOEt 1-66 HHH CH ₂ CH ₂ NHCOPr 1-67 HHH CH ₂ CH ₂ NHCOPr ⁱ 1-68 HHH CH ₂ CH ₂ NHCOBu 1-69 HHH CH ₂ CH ₂ NHCOCF ₃ 1-70 HHH CH ₂ CH ₂ NHCOCH ₂ NH ₂ 1-71 HHH CH ₂ CH ₂ NHCOCH ₂ COMe 1-72 HHH CH ₂ CH ₂ NHCOCH ₂ CH ₂ COMe 1-73 HHH CH ₂ CH ₂ NHCOPn ^c 1-74 HHH CH ₂ CH ₂ NHCOHx ^c 1-75 HHH CH ₂ CH ₂ NHCOHp ^c 1-76 HHH CH ₂ CH ₂ NHCOCH ₂ Ph 1-77 HHH CH ₂ CH ₂ NHCOCH ₂ CH ₂ Ph 1-78 HHH CH ₂ CH ₂ NHCO (2-Fur) 1-79 HHH CH ₂ CH ₂ NHCO (3 -Fur) 1-80 HHH CH ₂ CH ₂ NHCO (2-Thi) 1-81 HHH CH ₂ CH ₂ NHCO (3-Thi) 1-82 HHH CH ₂ CH ₂ NHCO (3-Pyr) 1-83 HHH CH ₂ CH ₂ NHCO ₂ Me 1-84 HHH CH ₂ CH ₂ NHCO ₂ Et 1-85 HHH CH ₂ CH ₂ NHCO ₂ Pr 1-86 HHH CH ₂ CH ₂ NHCO ₂ Pr ⁱ 1-87 HHH CH ₂ CH ₂ NHCO ₂ Bu 1-88 HHH CH ₂ CH ₂ NHSO ₂ Me 1-89 HHH CH ₂ CH ₂ NHCONH ₂ 1-90 HHH CH ₂ CH ₂ NHCONHMe 1-91 HHH CH ₂ CH ₂ NHCONHEt 1-92 HHH CH ₂ CH ₂ NHCONHCH ₂ Ph 1-93 HHH CH ₂ CH ₂ NHCONHCH ₂ CH ₂ Ph 1-94 HHH CH ₂ CH ₂ NHCSNH ₂ 1-95 HHH CH ₂ CH ₂ NHCSNHMe 1-96 HHH CH ₂ CH ₂ NHCSNHEt 1-97 HHH CH ₂ CH ₂ NHCSNHCH ₂ Ph 1-98 HHH CH ₂ CH ₂ NHCSNHCH ₂ CH ₂ Ph 1-99 HHH CH ₂ CH ₂ PHID 1-100 HH Me CH ₂ NH ₂ 1-101 HH Me CH ₂ NHCOMe 1-102 HH Me CH ₂ NHCOEt 1-103 HH Me CH ₂ NHCOCF ₃ 1-104 HH Me CH ₂ NHCOC H ₂ CH ₂ COMe 1-105 HH Me CH ₂ NHCOPn ^c 1-106 HH Me CH ₂ NHCOHx ^c 1-107 HH Me CH ₂ NHCOCH ₂ Ph 1-108 HH Me CH ₂ NHCO (2-Fur) 1-109 HH Me CH ₂ NHCO (2-Thi) 1-110 HH Me CH ₂ NHCO ₂ Me 1-111 HH Me CH ₂ NHCO ₂ Et 1-112 HH Me CH ₂ NHCONH ₂ 1-113 HH Me CH ₂ NHCONHMe 1-114 HH Me CH ₂ NHCONHCH ₂ Ph 1-115 HH Me CH ₂ NHCSNH ₂ 1-116 HH Me CH ₂ NHCSNHMe 1-117 HH Me CH ₂ NHCSNHCH ₂ Ph 1-118 HH Me CH ₂ PHID 1-119 HH Et CH ₂ NHCOMe 1 -120 HH Et CH ₂ NHCOEt 1-121 HH Et CH ₂ NHCOPn ^c 1-122 HH Et CH ₂ NHCOHx ^c 1-123 HH Et CH ₂ NHCO (2-Fur) 1-124 HH Et CH ₂ NHCO (2-Thi ) 1-125 HH Et CH ₂ NHCO ₂ Me 1-126 HH Et CH ₂ NHCO ₂ Et 1-127 HH Et CH ₂ NHCONHMe 1-128 HH Et CH ₂ NHCONHCH ₂ Ph 1-129 HH Et CH ₂ NHCSNHMe 1-130 _{HH Et CH 2 NHCSNHCH 2 Ph 1-131} H Me H CH 2 NHCOMe 1-132 H Me H CH 2 NHCOEt 1-133 H Me H CH 2 NHCOCF 3 1-134 H Me H CH 2 NHCOCH 2 CH 2 COMe 1- 135 H Me H CH ₂ NHCOPn ^c 1-136 H Me H CH ₂ NHCOHx ^c 1-137 H Me H CH ₂ NHCOCH ₂ Ph 1-138 H Me H CH ₂ NHCO (2-Fur) 1-139 H Me H CH ₂ NHCO (2-Thi) 1-140 H Me H CH ₂ NHC O ₂ Me 1-141 H Me H CH ₂ NHCO ₂ Et 1-142 H Me H CH ₂ NHCONH ₂ 1-143 H Me H CH ₂ NHCONHMe 1-144 H Me H CH ₂ NHCONHCH ₂ Ph 1-145 H Me H CH ₂ NHCSNH ₂ 1-146 H Me H CH ₂ NHCSNHMe 1-147 H Me H CH ₂ NHCSNHCH ₂ Ph 1-148 H Me H CH ₂ PHID 1-149 H Et H CH ₂ NHCOMe 1-150 H Et H CH _{2 NHCOEt 1-151 H Et H CH 2 NHCOCF} 3 1-152 H Et H CH 2 NHCOCH 2 CH 2 COMe 1-153 H Et H CH 2 NHCOPn c 1-154 H Et H CH 2 NHCOHx c 1-155 H Et H CH ₂ NHCOCH ₂ Ph 1-156 H Et H CH ₂ NHCO (2-Fur) 1-157 H Et H CH ₂ NHCO (2-Thi) 1-158 H Et H CH ₂ NHCO ₂ Me 1-159 H Et H CH ₂ NHCO ₂ Et 1-160 H Et H CH ₂ NHCONH ₂ 1-161 H Et H CH ₂ NHCONHMe 1-162 H Et H CH ₂ NHCONHCH ₂ Ph 1-163 H Et H CH ₂ NHCSNH ₂ 1-164 H Et H CH ₂ NHCSNHMe 1-165 H Et H CH ₂ NHCSNHCH ₂ Ph 1-166 H Et H CH ₂ PHID 1-167 H Pr H CH ₂ NHCOMe 1-168 H Pr H CH ₂ NHCOEt 1-169 H Pr H CH _{2 NHCOCF 3 1-170 H Pr H CH 2} NHCOCH 2 CH 2 COMe 1-171 H Pr H CH 2 NHCOPn c 1-172 H Pr H CH 2 NHCOHx c 1-173 H Pr H CH 2 NHCOCH 2 Ph 1-174 H Pr H CH ₂ NHCO (2-Fur) 1-175 H Pr H CH ₂ NHCO (2-Thi) 1-1 76 H Pr H CH ₂ NHCO ₂ Me 1-177 H Pr H CH ₂ NHCO ₂ Et 1-178 H Pr H CH ₂ NHCONH ₂ 1-179 H Pr H CH ₂ NHCONHMe 1-180 H Pr H CH ₂ NHCONHCH ₂ Ph 1-181 H Pr H CH ₂ NHCSNH ₂ 1-182 H Pr H CH ₂ NHCSNHMe 1-183 H Pr H CH ₂ NHCSNHCH ₂ Ph 1-184 H Pr H CH ₂ PHID 1-185 H Bu H CH ₂ NHCOMe 1- _{186 H Bu H CH 2 NHCOEt 1-187} H Bu H CH 2 NHCOCF 3 1-188 H Bu H CH 2 NHCOCH 2 CH 2 COMe 1-189 H Bu H CH 2 NHCOPn c 1-190 H Bu H CH 2 NHCOHx c 1-191 H Bu H CH ₂ NHCOCH ₂ Ph 1-192 H Bu H CH ₂ NHCO (2-Fur) 1-193 H Bu H CH ₂ NHCO (2-Thi) 1-194 H Bu H CH ₂ NHCO ₂ Me 1-195 H Bu H CH ₂ NHCO ₂ Et 1-196 H Bu H CH ₂ NHCONH ₂ 1-197 H Bu H CH ₂ NHCONHMe 1-198 H Bu H CH ₂ NHCONHCH ₂ Ph 1-199 H Bu H CH ₂ NHCSNH ₂ 1-200 H Bu H CH ₂ NHCSNHMe 1-201 H Bu H CH ₂ NHCSNHCH ₂ Ph 1-202 H Bu H CH ₂ PHID 1-203 H Bu H CH ₂ CH ₂ NHCOMe 1-204 H Bu H CH ₂ CH ₂ NHCOEt 1-205 H Bu H CH ₂ CH ₂ NHCOCF ₃ 1-206 H Bu H CH ₂ CH ₂ NHCO (2-Fur) 1-207 H Bu H CH ₂ CH ₂ NHCO (2-Thi) 1-208 H Bu H CH ₂ CH ₂ NHCO ₂ Me 1-209 H Bu H CH ₂ CH ₂ NHCO ₂ Et 1-210 H Bu H CH ₂ CH ₂ NHCONH ₂ 1-211 H Bu H CH ₂ CH ₂ NHCONHMe 1-212 H Bu H CH ₂ CH ₂ NHCONHEt 1-213 H Bu H CH ₂ CH ₂ NHCONHCH ₂ Ph 1-214 H Bu H CH ₂ CH ₂ NHCSNH ₂ 1-215 H Bu H CH ₂ CH ₂ NHCSNHMe 1-216 H Bu H CH ₂ CH ₂ NHCSNHEt 1-217 H Bu H CH ₂ CH ₂ NHCSNHCH ₂ Ph 1-218 H Bu H CH ₂ CH ₂ PHID 1- 219 H Bu Me CH ₂ NHCOMe 1-220 H Bu Me CH ₂ NHCOEt 1-221 H Bu Me CH ₂ NHCOCF ₃ 1-222 H Bu Me CH ₂ NHCO (2-Fur) 1-223 H Bu Me CH ₂ NHCO ( 2-Thi) 1-224 H Bu Me CH ₂ NHCO ₂ Me 1-225 H Bu Me CH ₂ NHCO ₂ Et 1-226 H Bu Me CH ₂ NHCONH ₂ 1-227 H Bu Me CH ₂ NHCONHMe 1-228 H Bu Me CH ₂ NHCONHEt 1-229 H Bu Me CH ₂ NHCONHCH ₂ Ph 1-230 H Bu Me CH ₂ NHCSNH ₂ 1-231 H Bu Me CH ₂ NHCSNHMe 1-232 H Bu Me CH ₂ NHCSNHEt 1-233 H Bu Me CH ₂ NHCSNHCH ₂ Ph 1-234 H Bu Me CH ₂ PHID 1-235 H Pn H CH ₂ NH ₂ 1-236 H Pn H CH ₂ NHMe 1-237 H Pn H CH ₂ NHEt 1-238 H Pn H CH ₂ NMe ₂ 1-239 H Pn H CH ₂ NHCOMe 1-240 H Pn H CH ₂ NHCOEt 1-241 H Pn H CH ₂ NHCOPr 1-242 H Pn H CH ₂ NHCOPr ⁱ 1-243 H Pn H CH ₂ NHCOBu 1-244 H Pn H CH ₂ NHCOBu ⁱ 1-245 H Pn H CH ^{_{2 NHCOBu t 1-246 H Pn H CH}} 2 NHCOCH 2 OMe 1-247 H Pn H CH 2 NHCOCH 2 F 1-248 H Pn H CH 2 NHCOCF 3 1-249 H Pn H CH 2 NHCOCH 2 Cl 1-250 H _{pn H CH 2 NHCOCH 2 NH 2} 1-251 H pn H CH 2 NHCOCH 2 NHMe 1-252 H pn H CH 2 NHCOCH 2 NHEt 1-253 H pn H CH 2 NHCOCH 2 NMe 2 1-254 H pn H CH 2 NHCOCH ₂ COMe 1-255 H Pn H CH ₂ NHCOCH ₂ CH ₂ COMe 1-256 H Pn H CH ₂ NHCOPr ^c 1-257 H Pn H CH ₂ NHCOPn ^c 1-258 H Pn H CH ₂ NHCOHx ^c 1-259 H Pn H CH ₂ NHCOHp ^c 1-260 H Pn H CH ₂ NHCOPh 1-261 H Pn H CH ₂ NHCOCH ₂ Ph 1-262 H Pn H CH ₂ NHCOCH ₂ CH ₂ Ph 1-263 H Pn H CH ₂ NHCO (2 -Fur) 1-264 H Pn H CH ₂ NHCO (3-Fur) 1-265 H Pn H CH ₂ NHCO (2-Thi) 1-266 H Pn H CH ₂ NHCO (3-Thi) 1-267 H Pn H CH ₂ NHCO (3-Pyr) 1-268 H Pn H CH ₂ NHCO (4-Pyr) 1-269 H Pn H CH ₂ NHCO ₂ Me 1-270 H Pn H CH ₂ NHCO ₂ Et 1-271 H Pn H CH ₂ NHCO ₂ Pr 1-272 H Pn H CH ₂ NHCO ₂ Pr ⁱ 1-273 H Pn H CH ₂ NHCO ₂ Bu 1-274 H Pn H CH ₂ NHCO ₂ Bu ⁱ 1-275 H Pn H CH ₂ NHCO ^{_{2 Bu t 1-276 H Pn H CH}} 2 NHSO 2 Me 1-277 H Pn H CH 2 NHSO 2 Et 1-278 H Pn H CH 2 NHSO 2 Ph 1-279 H Pn H CH ₂ NHCONH ₂ 1-280 H Pn H CH ₂ NHCONHMe 1-281 H Pn H CH ₂ NHCONHEt 1-282 H Pn H CH ₂ NHCONHPr 1-283 H Pn H CH ₂ NHCONHPr ⁱ 1-284 H Pn H CH ₂ NHCONHBu 1-285 H Pn H CH ₂ NHCONHCH ₂ Ph 1-286 H Pn H CH ₂ NHCONHCH ₂ CH ₂ Ph 1-287 H Pn H CH ₂ NHCSNH ₂ 1-288 H Pn H CH ₂ NHCSNHMe 1-289 H Pn H CH ₂ NHCSNHEt 1-290 H Pn H CH ₂ NHCSNHPr 1-291 H Pn H CH ₂ NHCSNHPr ⁱ 1-292 H Pn H CH ₂ NHCSNHBu 1-293 H Pn H CH ₂ NHCSNHCH ₂ Ph 1-294 H Pn H CH ₂ NHCSNHCH ₂ CH ₂ Ph 1-295 H Pn H CH ₂ PHID 1-296 H Pn H CH ₂ CH ₂ NH ₂ 1-297 H Pn H CH ₂ CH ₂ NHMe ₂ 1-298 H Pn H CH ₂ CH ₂ NHCOMe 1 -299 H Pn H CH ₂ CH ₂ NHCOEt 1-300 H Pn H CH ₂ CH ₂ NHCOPr 1-301 H Pn H CH ₂ CH ₂ NHCOPr ⁱ 1-302 H Pn H CH ₂ CH ₂ NHCOBu 1-303 H Pn H _{CH 2 CH 2 NHCOCF 3 1-304 H} Pn H CH 2 CH 2 NHCOCH 2 NH 2 1-305 H Pn H CH 2 CH 2 NHCOCH 2 COMe 1-306 H Pn H CH 2 CH 2 NHCOCH 2 CH 2 COMe 1- 307 H Pn H CH ₂ CH ₂ NHCOPn ^c 1-308 H Pn H CH ₂ CH ₂ NHCOHx ^c 1-309 H Pn H CH ₂ CH ₂ NHCOHp ^c 1-310 H Pn H CH ₂ CH ₂ NHCOCH ₂ Ph 1-311 H Pn H CH ₂ CH ₂ NHCOCH ₂ CH ₂ Ph 1-312 H Pn H CH ₂ CH ₂ NHCO (2-Fur) 1-313 H Pn H CH ₂ CH ₂ NHCO (3-Fur) 1-314 H Pn H CH ₂ CH ₂ NHCO (2-Thi ) 1-315 H Pn H CH ₂ CH ₂ NHCO (3-Thi) 1-316 H Pn H CH ₂ CH ₂ NHCO (3-Pyr) 1-317 H Pn H CH ₂ CH ₂ NHCO ₂ Me 1-318 H Pn H CH ₂ CH ₂ NHCO ₂ Et 1-319 H Pn H CH ₂ CH ₂ NHCO ₂ Pr 1-320 H Pn H CH ₂ CH ₂ NHCO ₂ Pr ⁱ 1-321 H Pn H CH ₂ CH ₂ NHCO ₂ Bu 1 -322 H Pn H CH ₂ CH ₂ NHSO ₂ Me 1-323 H Pn H CH ₂ CH ₂ NHCONH ₂ 1-324 H Pn H CH ₂ CH ₂ NHCONHMe 1-325 H Pn H CH ₂ CH ₂ NHCONHEt 1-326 H Pn H CH ₂ CH ₂ NHCONHCH ₂ Ph 1-327 H Pn H CH ₂ CH ₂ NHCONHCH ₂ CH ₂ Ph 1-328 H Pn H CH ₂ CH ₂ NHCSNH ₂ 1-329 H Pn H CH ₂ CH ₂ NHCSNHMe 1-330 H Pn H CH ₂ CH ₂ NHCSNHEt 1-331 H Pn H CH ₂ CH ₂ NHCSNHCH ₂ Ph 1-332 H Pn H CH ₂ CH ₂ NHCSNHCH ₂ CH ₂ Ph 1-333 H Pn H CH ₂ CH ₂ PHID 1-334 _{H Pn Me CH 2 NH 2 1-335} H Pn Me CH 2 NHCOMe 1-336 H Pn Me CH 2 NHCOEt 1-337 H Pn Me CH 2 NHCOCF 3 1-338 H Pn Me CH 2 NHCOCH 2 CH 2 COMe 1- 339 H Pn Me CH ₂ NHCOPn ^c 1-340 H Pn Me CH ₂ NHCOHx ^c 1-341 H Pn Me CH ₂ NHCOCH ₂ Ph 1-342 H Pn Me CH ₂ NHCO (2-Fur) 1-343 H Pn Me CH ₂ NHCO (2-Thi) 1-344 H Pn Me CH ₂ NHCO ₂ Me 1-345 H Pn Me CH ₂ NHCO ₂ Et 1-346 H Pn Me CH ₂ NHCONH ₂ 1-347 H Pn Me CH ₂ NHCONHMe 1-348 H Pn Me CH ₂ NHCONHCH ₂ Ph 1-349 H Pn Me CH ₂ NHCSNH ₂ 1-350 H Pn Me CH ₂ NHCSNHMe 1-351 H Pn Me CH ₂ NHCSNHCH ₂ Ph 1-352 H Pn Me CH ₂ PHID 1-353 H Pn Et CH ₂ NHCOMe 1-354 H Pn Et CH ₂ NHCOEt 1-355 H Pn Et CH ₂ NHCOPn ^c 1-356 H Pn Et CH ₂ NHCOHx ^c 1-357 H Pn Et CH ₂ NHCO (2-Fur) 1-358 H Pn Et CH ₂ NHCO (2-Thi) 1-359 H Pn Et CH ₂ NHCO ₂ Me 1-360 H Pn Et CH ₂ NHCO ₂ Et 1-361 H Pn Et CH ₂ NHCONHMe 1-362 H Pn Et CH ₂ NHCONHCH ₂ Ph 1-363 H Pn Et CH ₂ NHCSNHMe 1-364 H Pn Et CH ₂ NHCSNHCH ₂ Ph 1-365 H Hx H CH _{2 NH 2 1-366 H Hx H CH 2} NHCOMe 1-367 H Hx H CH 2 NHCOEt 1-368 H Hx H CH 2 NHCOCF 3 1-369 H Hx H CH 2 NHCOCH 2 CH 2 COMe 1-370 H Hx H CH ₂ NHCOPn ^c 1-371 H Hx H CH ₂ NHCOHx ^c 1-372 H Hx H CH ₂ NHCOCH ₂ Ph 1-373 H Hx H CH ₂ NHCO (2-Fur) 1-374 H Hx H CH ₂ NHCO (2- Thi) 1-375 H Hx H CH ₂ NHCO ₂ Me 1-376 H Hx H CH ₂ NHCO ₂ Et 1 -377 H Hx H CH ₂ NHCONH ₂ 1-378 H Hx H CH ₂ NHCONHMe 1-379 H Hx H CH ₂ NHCONHCH ₂ Ph 1-380 H Hx H CH ₂ NHCSNH ₂ 1-381 H Hx H CH ₂ NHCSNHMe 1- 382 H Hx H CH ₂ NHCSNHCH ₂ Ph 1-383 H Hx H CH ₂ PHID 1-384 H Hx H CH ₂ CH ₂ NHCOMe 1-385 H Hx H CH ₂ CH ₂ NHCOEt 1-386 H Hx H CH ₂ CH ₂ NHCOCF ₃ 1-387 H Hx H CH ₂ CH ₂ NHCO (2-Fur) 1-388 H Hx H CH ₂ CH ₂ NHCO (2-Thi) 1-389 H Hx H CH ₂ CH ₂ NHCO ₂ Me 1-390 H Hx H CH ₂ CH ₂ NHCO ₂ Et 1-391 H Hx H CH ₂ CH ₂ NHCONH ₂ 1-392 H Hx H CH ₂ CH ₂ NHCONHMe 1-393 H Hx H CH ₂ CH ₂ NHCONHEt 1-394 H Hx H CH ₂ CH ₂ NHCOCH ₂ Ph 1-395 H Hx H CH ₂ CH ₂ NHCSNH ₂ 1-396 H Hx H CH ₂ CH ₂ NHCSNHMe 1-397 H Hx H CH ₂ CH ₂ NHCSNHEt 1-398 H Hx H CH ₂ CH ₂ NHCSCH ₂ Ph 1-399 H Hx H CH ₂ CH ₂ PHID 1-400 H Hx Me CH ₂ NHCOMe 1-401 H Hx Me CH ₂ NHCOEt 1-402 H Hx Me CH ₂ NHCOCF ₃ 1-403 H Hx Me CH ₂ NHCO (2-Fur) 1-404 H Hx Me CH ₂ NHCO (2-Thi) 1-405 H Hx Me CH ₂ NHCO ₂ Me 1-406 H Hx Me CH ₂ NHCO ₂ Et 1-407 H Hx Me CH ₂ NHCONH ₂ 1-408 H Hx Me CH ₂ NHCONHMe 1-409 H Hx Me CH ₂ NHCONHEt 1-41 0 H Hx Me CH ₂ NHCOCH ₂ Ph 1-411 H Hx Me CH ₂ NHCSNH ₂ 1-412 H Hx Me CH ₂ NHCSNHMe 1-413 H Hx Me CH ₂ NHCSNHEt 1-414 H Hx Me CH ₂ NHCSCH ₂ Ph 1- _{415 H Hx Me CH 2 PHID 1-416} H Hp H CH 2 NHCOMe 1-417 H Hp H CH 2 NHCOEt 1-418 H Hp H CH 2 NHCOCF 3 1-419 H Hp H CH 2 NHCOCH 2 CH 2 COMe 1- 420 H Hp H CH ₂ NHCOPn ^c 1-421 H Hp H CH ₂ NHCOHx ^c 1-422 H Hp H CH ₂ NHCOCH ₂ Ph 1-423 H Hp H CH ₂ NHCO (2-Fur) 1-424 H Hp H CH ₂ NHCO (2-Thi) 1-425 H Hp H CH ₂ NHCO ₂ Me 1-426 H Hp H CH ₂ NHCO ₂ Et 1-427 H Hp H CH ₂ NHCONH ₂ 1-428 H Hp H CH ₂ NHCONHMe 1- 429 H Hp H CH ₂ NHCONHCH ₂ Ph 1-430 H Hp H CH ₂ NHCSNH ₂ 1-431 H Hp H CH ₂ NHCSNHMe 1-432 H Hp H CH ₂ NHCSNHCH ₂ Ph 1-433 H Hp H CH ₂ PHID 1- _{434 H Oc H CH 2 NHCOMe 1-435} H Oc H CH 2 NHCOEt 1-436 H Oc H CH 2 NHCOCF 3 1-437 H Oc H CH 2 NHCOCH 2 CH 2 COMe 1-438 H Oc H CH 2 NHCOPn c 1 -439 H Oc H CH ₂ NHCOHx ^c 1-440 H Oc H CH ₂ NHCOCH ₂ Ph 1-441 H Oc H CH ₂ NHCO (2-Fur) 1-442 H Oc H CH ₂ NHCO (2-Thi) 1- 443 H Oc H CH ₂ NHCO ₂ Me 1-444 H Oc H CH ₂ NHCO ₂ Et 1-445 H Oc H CH ₂ NHCONH ₂ 1-446 H Oc H CH ₂ NHCONHMe 1-447 H Oc H CH ₂ NHCONHCH ₂ Ph 1-448 H Oc H CH ₂ NHCSNH ₂ 1-449 H Oc H CH ₂ NHCSNHMe 1-450 H Oc H CH ₂ NHCSNHCH ₂ Ph 1-451 H Oc H CH ₂ PHID 1-452 H Bu ⁱ H CH ₂ NHCOMe 1-453 H Bu ⁱ H CH ₂ NHCOEt 1-454 H Bu ⁱ H CH ₂ NHCOCF ₃ 1-455 H Bu ⁱ H CH ₂ NHCOCH ₂ CH ₂ COMe 1-456 H Bu ⁱ H CH ₂ NHCOPn ^c 1-457 H Bu ⁱ H CH ₂ NHCOHx ^c 1-458 H Bu ⁱ H CH ₂ NHCOCH ₂ Ph 1-459 H Bu ⁱ H CH ₂ NHCO (2-Fur) 1-460 H Bu ⁱ H CH ₂ NHCO (2-Thi) 1-461 H Bu ⁱ H CH ₂ NHCO ₂ Me 1-462 H Bu ⁱ H CH ₂ NHCO ₂ Et 1-463 H Bu ⁱ H CH ₂ NHCONH ₂ 1-464 H Bu ⁱ H CH ₂ NHCONHMe 1-465 H Bu ⁱ H CH ₂ NHCONHCH ₂ Ph 1-466 H Bu ⁱ H CH ₂ NHCSNH ₂ 1-467 H Bu ⁱ H CH ₂ NHCSNHMe 1-468 H Bu ⁱ H CH ₂ NHCSNHCH ₂ Ph 1-469 H Bu ⁱ H CH ₂ PHID 1-470 H Pn ⁱ H CH ₂ NHCOMe 1-471 H Pn ⁱ H CH ₂ NHCOEt 1-472 H Pn ⁱ H CH ₂ NHCOCF ₃ 1-473 H Pn ⁱ H CH ₂ NHCOCH ₂ CH ₂ COMe 1-474 H Pn ⁱ H CH ₂ NHCOPn ^c 1-475 H Pn ⁱ H CH ₂ NHCOHx ^c 1-476 H Pn ⁱ H CH ₂ NHCOCH ₂ Ph 1-477 H Pn ⁱ H CH ₂ NHCO (2-Fur) 1-478 H Pn ⁱ H CH ₂ NHCO (2- Thi) 1-479 H Pn ⁱ H CH ₂ NHCO ₂ Me 1-480 H Pn ⁱ H CH ₂ NHCO ₂ Et 1-481 H Pn ⁱ H CH ₂ NHCONH ₂ 1-482 H Pn ⁱ H CH ₂ NHCONHMe 1-483 H Pn ⁱ H CH ₂ NHCONHCH ₂ Ph 1-484 H Pn ⁱ H CH ₂ NHCSNH ₂ 1-485 H Pn ⁱ H CH ₂ NHCSNHMe 1-486 H Pn ⁱ H CH ₂ NHCSNHCH ₂ Ph 1-487 H Pn ⁱ H CH ^{_{2 PHID 1-488 H Hx i H CH}} 2 NHCOMe 1-489 H Hx i H CH 2 NHCOEt 1-490 H Hx i H CH 2 NHCOCF 3 1-491 H Hx i H CH 2 NHCOCH 2 CH 2 COMe 1-492 H Hx ⁱ H CH ₂ NHCOPn ^c 1-493 H Hx ⁱ H CH ₂ NHCOHx ^c 1-494 H Hx ⁱ H CH ₂ NHCOCH ₂ Ph 1-495 H Hx ⁱ H CH ₂ NHCO (2-Fur) 1-496 H Hx ⁱ H CH ₂ NHCO (2-Thi) 1-497 H Hx ⁱ H CH ₂ NHCO ₂ Me 1-498 H Hx ⁱ H CH ₂ NHCO ₂ Et 1-499 H Hx ⁱ H CH ₂ NHCONH ₂ 1-500 H Hx ⁱ H CH ₂ NHCONHMe 1-501 H Hx ⁱ H CH ₂ NHCONHCH ₂ Ph 1-502 H Hx ⁱ H CH ₂ NHCSNH ₂ 1-503 H Hx ⁱ H CH ₂ NHCSNHMe 1-504 H Hx ⁱ H CH ₂ NHCSNHCH ₂ Ph 1-505 H Hx ⁱ H CH ₂ PHID 1-506 Pn Pn H CH ₂ NHCOMe 1-507 Pn Pn H CH ₂ NHCOEt 1-508 Pn Pn H CH ₂ NHCOCF ₃ 1-509 Pn Pn H CH ₂ NHCOCH ₂ CH ₂ COMe 1-510 Pn Pn H CH ₂ NHCOPn ^c 1-511 Pn Pn H CH ₂ NHCOHx ^c 1-512 P n Pn H CH ₂ NHCOCH ₂ Ph 1-513 Pn Pn H CH ₂ NHCO (2-Fur) 1-514 Pn Pn H CH ₂ NHCO (2-Thi) 1-515 Pn Pn H CH ₂ NHCO ₂ Me 1-516 Pn Pn H CH ₂ NHCO ₂ Et 1-517 Pn Pn H CH ₂ NHCONH ₂ 1-518 Pn Pn H CH ₂ NHCONHMe 1-519 Pn Pn H CH ₂ NHCOCH ₂ Ph 1-520 Pn Pn H CH ₂ NHCSNH ₂ 1- _{521 Pn Pn H CH 2 NHCSNHMe 1-522} Pn Pn H CH 2 NHCSCH 2 Ph 1-523 Pn Pn H CH 2 PHID 1-524 HHH CH 2 NHCOCH 2 NHCO 2 Me 1-525 HHH CH 2 NHCOCH 2 NHCO 2 Bu t _{1-526 HHH CH 2 NHCOCH 2 NMeCO 2} Me 1-527 HHH CH 2 NHCOCH 2 NMeCO 2 Bu t 1-528 HHH CH 2 NHCOCH 2 NEtCO 2 Bu t 1-529 HHH CH 2 NMeCO 2 Me 1-530 HHH CH 2 _{^{NMeCO 2 Bu t 1-531 HHH CH 2}} NEtCO 2 Bu t 1-532 H Pn H CH 2 NHCOCH 2 NHCO 2 Me 1-533 H Pn H CH 2 NHCOCH 2 NHCO 2 Bu t 1-534 H Pn H CH 2 NHCOCH _{2 NMeCO 2 Me 1-535 H Pn H} CH 2 NHCOCH 2 NMeCO 2 Bu t 1-536 H Pn H CH 2 NHCOCH 2 NEtCO 2 Bu t 1-537 H Pn H CH 2 NMeCO 2 Me 1-538 H Pn H CH ^{_{2 NMeCO 2 Bu t 1-539 H Pn}} H CH 2 NEtCO 2 Bu t ───────────────────────────────── ─.

[0035]

[Table 2] ──────────────────────────────────── No. R ² R ³ R ⁴ AR ¹ ──────────────────────────────────── 2-1 HHH CH ₂ NH ₂ 2-2 HHH CH ₂ NHMe 2-3 HHH CH ₂ NHEt 2-4 HHH CH ₂ NMe ₂ 2-5 HHH CH ₂ NHCOMe 2-6 HHH CH ₂ NHCOEt 2-7 HHH CH ₂ NHCOPr 2-8 HHH CH ₂ NHCOPr ⁱ 2-9 HHH _{CH 2 NHCOBu 2-10 HHH CH 2 NHCOBu} i 2-11 HHH CH 2 NHCOBu t 2-12 HHH CH 2 NHCOCH 2 OMe 2-13 HHH CH 2 NHCOCH 2 F 2-14 HHH CH 2 NHCOCF 3 2-15 HHH CH _{2 NHCOCH 2 Cl 2-16 HHH CH 2} NHCOCH 2 NH 2 2-17 HHH CH 2 NHCOCH 2 NHMe 2-18 HHH CH 2 NHCOCH 2 NHEt 2-19 HHH CH 2 NHCOCH 2 NMe 2 2-20 HHH CH 2 NHCOCH 2 COMe 2-21 HHH CH ₂ NHCOCH ₂ CH ₂ COMe 2-22 HHH CH ₂ NHCOPr ^c 2-23 HHH CH ₂ NHCOPn ^c 2-24 HHH CH ₂ NHCOHx ^c 2-25 HHH CH ₂ NHCOHp ^c 2-26 HHH CH ₂ NHCOPh 2-27 HHH CH ₂ NHCOCH ₂ Ph 2-28 HHH CH ₂ NHCOCH ₂ CH ₂ Ph 2-29 HHH CH ₂ NHCO (2-Fur) 2-30 HHH CH ₂ NHCO (3-Fur) 2-31 HHH CH ₂ NHCO ( 2-Thi) 2-32 HHH CH ₂ NHCO (3-Thi) 2-33 HHH CH ₂ NHCO (3-Pyr) 2-34 HHH CH ₂ NHCO (4-Pyr) 2-35 HHH CH ₂ NHCO ₂ Me 2 -36 HHH CH ₂ NHCO ₂ Et 2-37 HHH CH ₂ NHCO ₂ Pr 2-38 HHH CH ₂ NHCO ₂ Pr ⁱ 2-39 HHH CH ₂ NHCO ₂ Bu 2-40 HHH CH ₂ NHCO ₂ Bu ⁱ 2-41 HHH ^{_{CH 2 NHCO 2 Bu t 2-42 HHH}} CH 2 NHSO 2 Me 2-43 HHH CH 2 NHSO 2 Et 2-44 HHH CH 2 NHSO 2 Ph 2-45 HHH CH 2 NHCONH 2 2-46 HHH CH 2 NHCONHMe 2- 47 HHH CH ₂ NHCONHEt 2-48 HHH CH ₂ NHCONHPr 2-49 HHH CH ₂ NHCONHPr ⁱ 2-50 HHH CH ₂ NHCONHBu 2-51 HHH CH ₂ NHCONHCH ₂ Ph 2-52 HHH CH ₂ NHCONHCH ₂ CH ₂ Ph 2-53 HHH CH ₂ NHCSNH ₂ 2-54 HHH CH ₂ NHCSNHMe 2-55 HHH CH ₂ NHCSNHEt 2-56 HHH CH ₂ NHCSNHPr 2-57 HHH CH ₂ NHCSNHPr ⁱ 2-58 HHH CH ₂ NHCSNHBu 2-59 HHH CH ₂ NHCSNHCH ₂ Ph 2-60 HHH CH ₂ NHCSNHCH ₂ CH ₂ Ph 2-61 HHH CH ₂ PHID 2-62 HHH CH ₂ CH ₂ NH ₂ 2-63 HHH CH ₂ CH ₂ NHMe ₂ 2-64 HHH CH ₂ CH ₂ NHCOMe 2-65 HHH CH ₂ CH ₂ NHCOEt 2-66 HHH CH ₂ CH ₂ NHCOPr 2-67 HHH CH ₂ CH ₂ NHCOPr ⁱ 2-68 HHH CH ₂ CH ₂ NHCOBu 2-69 HHH CH ₂ CH ₂ NHCOCF ₃ 2-70 HHH CH ₂ CH ₂ NHCOCH ₂ NH ₂ 2-71 HHH CH ₂ CH ₂ NHCOCH ₂ COMe 2-72 HHH CH ₂ CH ₂ NHCOCH ₂ CH ₂ COMe 2-73 HHH CH ₂ CH ₂ NHCOPn ^c 2-74 HHH CH ₂ CH ₂ NHCOHx ^c 2-75 HHH CH ₂ CH ₂ NHCOHp ^c 2-76 HHH CH ₂ CH ₂ NHCOCH ₂ Ph 2-77 HHH CH ₂ CH ₂ NHCOCH ₂ CH ₂ Ph 2-78 HHH CH ₂ CH ₂ NHCO (2-Fur) 2-79 HHH CH ₂ CH ₂ NHCO (3 -Fur) 2-80 HHH CH ₂ CH ₂ NHCO (2-Thi) 2-81 HHH CH ₂ CH ₂ NHCO (3-Thi) 2-82 HHH CH ₂ CH ₂ NHCO (3-Pyr) 2-83 HHH CH ₂ CH ₂ NHCO ₂ Me 2-84 HHH CH ₂ CH ₂ NHCO ₂ Et 2-85 HHH CH ₂ CH ₂ NHCO ₂ Pr 2-86 HHH CH ₂ CH ₂ NHCO ₂ Pr ⁱ 2-87 HHH CH ₂ CH ₂ NHCO ₂ Bu 2-88 HHH CH ₂ CH ₂ NHSO ₂ Me 2-89 HHH CH ₂ CH ₂ NHCONH ₂ 2-90 HHH CH ₂ CH ₂ NHCONHMe 2-91 HHH CH ₂ CH ₂ NHCONHEt 2-92 HHH CH ₂ CH ₂ NHCONHCH ₂ Ph 2-93 HHH CH ₂ CH ₂ NHCONHCH ₂ CH ₂ Ph 2-94 HHH CH ₂ CH ₂ NHCSNH ₂ 2-95 HHH CH ₂ CH ₂ NHCSNHMe 2-96 HHH CH ₂ CH ₂ NHCSNHEt 2-97 HHH CH ₂ CH ₂ NHCSNHCH ₂ Ph 2-98 HHH CH ₂ CH ₂ NHCSNHCH ₂ CH ₂ Ph 2-99 HHH CH ₂ CH ₂ PHID 2-100 HH Me CH ₂ NH ₂ 2-101 HH Me CH ₂ NHCOMe 2-102 HH Me CH ₂ NHCOEt 2-103 HH Me CH ₂ NHCOCF ₃ 2-104 HH Me CH ₂ NHCOC H ₂ CH ₂ COMe 2-105 HH Me CH ₂ NHCOPn ^c 2-106 HH Me CH ₂ NHCOHx ^c 2-107 HH Me CH ₂ NHCOCH ₂ Ph 2-109 HH Me CH ₂ NHCO (2-Thi) 2-110 HH Me CH ₂ NHCO ₂ Me 2-111 HH Me CH ₂ NHCO ₂ Et 2-112 HH Me CH ₂ NHCONH ₂ 2-113 HH Me CH ₂ NHCONHMe 2-114 HH Me CH ₂ NHCONHCH ₂ Ph 2-115 HH Me CH ₂ NHCSNH ₂ 2-116 HH Me CH ₂ NHCSNHMe 2-117 HH Me CH ₂ NHCSNHCH ₂ Ph 2-118 HH Me CH ₂ PHID 2-119 HH Et CH ₂ NHCOMe 2-120 HH Et CH ₂ NHCOEt 2-121 HH Et CH ₂ NHCOPn ^c 2-122 HH Et CH ₂ NHCOHx ^c 2-123 HH Et CH ₂ NHCO (2-Fur) 2-124 HH Et CH ₂ NHCO (2-Thi) 2-125 HH Et CH ₂ NHCO ₂ Me 2- 126 HH Et CH ₂ NHCO ₂ Et 2-127 HH Et CH ₂ NHCONHMe 2-128 HH Et CH ₂ NHCONHCH ₂ Ph 2-129 HH Et CH ₂ NHCSNHMe 2-130 HH Et CH ₂ NHCSNHCH ₂ Ph 2-131 H Me H _{CH 2 NHCOMe 2-132 H Me H CH} 2 NHCOEt 2-133 H Me H CH 2 NHCOCF 3 2-134 H Me H CH 2 NHCOCH 2 CH 2 COMe 2-135 H Me H CH 2 NHCOPn c 2-136 H Me H CH ₂ NHCOHx ^c 2-137 H Me H CH ₂ NHCOCH ₂ Ph 2-138 H Me H CH ₂ NHCO (2-Fur) 2-139 H Me H CH ₂ NHCO (2-Thi) 2-140 H Me H CH ₂ NHCO ₂ Me 2-141 H Me H CH ₂ NHCO ₂ Et 2-142 H Me H CH ₂ NHCONH ₂ 2-143 H Me H CH ₂ NHCONHMe 2-144 H Me H CH ₂ NHCONHCH ₂ Ph 2-145 H Me H CH ₂ NHCSNH ₂ 2-146 H Me H CH ₂ NHCSNHMe 2-147 H Me H CH ₂ NHCSNHCH ₂ Ph 2-148 H Me H CH ₂ PHID 2-149 H Et H CH ₂ NHCOMe 2-150 H Et H CH ₂ NHCOEt 2-151 H Et H CH ₂ NHCOCF ₃ 2 -152 H Et H CH ₂ NHCOCH ₂ CH ₂ COMe 2-153 H Et H CH ₂ NHCOPn ^c 2-154 H Et H CH ₂ NHCOHx ^c 2-155 H Et H CH ₂ NHCOCH ₂ Ph 2-156 H Et H CH ₂ NHCO (2-Fur) 2-157 H Et H CH ₂ NHCO (2-Thi) 2-158 H Et H CH ₂ NHCO ₂ Me 2-159 H Et H CH ₂ NHCO ₂ Et 2-160 H Et H CH ₂ NHCONH ₂ 2-161 H Et H CH ₂ NHCONHMe 2-162 H Et H CH ₂ NHCONHCH ₂ Ph 2-163 H Et H CH ₂ NHCSNH ₂ 2-164 H Et H CH ₂ NHCSNHMe 2-165 H Et H CH ₂ NHCSNHCH ₂ Ph 2-166 H Et H CH ₂ PHID 2-167 H Pr H CH ₂ NHCOMe 2-168 H Pr H CH ₂ NHCOEt 2-169 H Pr H CH ₂ NHCOCF ₃ 2-170 H Pr H CH ₂ NHCOCH ₂ CH ₂ COMe 2-171 H Pr H CH ₂ NHCOPn ^c 2-172 H Pr H CH ₂ NHCOHx ^c 2-173 H Pr H CH ₂ NHCOCH ₂ Ph 2-174 H Pr H CH ₂ NHCO (2-Fur) 2- 175 H Pr H CH ₂ NHCO (2-Thi) 2-176 H Pr H CH ₂ NHCO ₂ Me 2-17 7 H Pr H CH ₂ NHCO ₂ Et 2-178 H Pr H CH ₂ NHCONH ₂ 2-179 H Pr H CH ₂ NHCONHMe 2-180 H Pr H CH ₂ NHCONHCH ₂ Ph 2-181 H Pr H CH ₂ NHCSNH ₂ 2 -182 H Pr H CH ₂ NHCSNHMe 2-183 H Pr H CH ₂ NHCSNHCH ₂ Ph 2-184 H Pr H CH ₂ PHID 2-185 H Bu H CH ₂ NHCOMe 2-186 H Bu H CH ₂ NHCOEt 2-187 H Bu H CH ₂ NHCOCF ₃ 2-188 H Bu H CH ₂ NHCOCH ₂ CH ₂ COMe 2-189 H Bu H CH ₂ NHCOPn ^c 2-190 H Bu H CH ₂ NHCOHx ^c 2-191 H Bu H CH ₂ NHCOCH ₂ Ph 2-192 H Bu H CH ₂ NHCO (2-Fur) 2-193 H Bu H CH ₂ NHCO (2-Thi) 2-194 H Bu H CH ₂ NHCO ₂ Me 2-195 H Bu H CH ₂ NHCO ₂ Et 2-196 H Bu H CH ₂ NHCONH ₂ 2-197 H Bu H CH ₂ NHCONHMe 2-198 H Bu H CH ₂ NHCONHCH ₂ Ph 2-199 H Bu H CH ₂ NHCSNH ₂ 2-200 H Bu H CH ₂ NHCSNHMe 2 -201 H Bu H CH ₂ NHCSNHCH ₂ Ph 2-202 H Bu H CH ₂ PHID 2-203 H Bu H CH ₂ CH ₂ NHCOMe 2-204 H Bu H CH ₂ CH ₂ NHCOEt 2-205 H Bu H CH ₂ CH ₂ NHCOCF ₃ 2-206 H Bu H CH ₂ CH ₂ NHCO (2-Fur) 2-207 H Bu H CH ₂ CH ₂ NHCO (2-Thi) 2-208 H Bu H CH ₂ CH ₂ NHCO ₂ Me 2- 209 H Bu H CH ₂ CH ₂ NHCO ₂ Et 2-210 H Bu H CH ₂ CH ₂ NHCONH ₂ 2-211 H Bu H CH ₂ CH ₂ NHCONHMe 2-212 H Bu H CH ₂ CH ₂ NHCONHEt 2-213 H Bu H CH ₂ CH ₂ NHCONHCH ₂ Ph 2-214 H Bu H CH ₂ CH ₂ NHCSNH ₂ 2-215 H Bu H CH ₂ CH ₂ NHCSNHMe 2-216 H Bu H CH ₂ CH ₂ NHCSNHEt 2-217 H Bu H CH ₂ CH ₂ NHCSNHCH ₂ Ph 2-218 H Bu H CH ₂ CH ₂ PHID 2-219 H Bu Me CH ₂ NHCOMe 2-220 H Bu Me CH ₂ NHCOEt 2-221 H Bu Me CH ₂ NHCOCF ₃ 2-222 H Bu Me CH ₂ NHCO (2-Fur) 2-223 H Bu Me CH ₂ NHCO (2-Thi) 2-224 H Bu Me CH ₂ NHCO ₂ Me 2-225 H Bu Me CH ₂ NHCO ₂ Et 2-226 H Bu Me CH ₂ NHCONH ₂ 2-227 H Bu Me CH ₂ NHCONHMe 2-228 H Bu Me CH ₂ NHCONHEt 2-229 H Bu Me CH ₂ NHCONHCH ₂ Ph 2-230 H Bu Me CH ₂ NHCSNH ₂ 2-231 H Bu Me CH ₂ NHCSNHMe 2-232 H Bu Me CH ₂ NHCSNHEt 2-233 H Bu Me CH ₂ NHCSNHCH ₂ Ph 2-234 H Bu Me CH ₂ PHID 2-235 H Pn H CH ₂ NH ₂ 2-236 H Pn H CH ₂ NHMe 2-237 H Pn H CH ₂ NHEt 2-238 H Pn H CH ₂ NMe ₂ 2-239 H Pn H CH ₂ NHCOMe 2 -240 H Pn H CH ₂ NHCOEt 2-241 H Pn H CH ₂ NHCOPr 2-242 H Pn H CH ₂ NHCOPr ⁱ 2-243 H Pn H CH ₂ NHCOBu 2-244 H Pn H CH ₂ NHCOBu ⁱ 2-245 H ^{_{Pn H CH 2 NHCOBu t 2-246 H}} Pn H CH 2 _{NHCOCH 2 OMe 2-247 H Pn H CH} 2 NHCOCH 2 F 2-248 H Pn H CH 2 NHCOCF 3 2-249 H Pn H CH 2 NHCOCH 2 Cl 2-250 H Pn H CH 2 NHCOCH 2 NH 2 2-251 _{H Pn H CH 2 NHCOCH 2 NHMe} 2-252 H Pn H CH 2 NHCOCH 2 NHEt 2-253 H Pn H CH 2 NHCOCH 2 NMe 2 2-254 H Pn H CH 2 NHCOCH 2 COMe 2-255 H Pn H CH 2 NHCOCH ₂ CH ₂ COMe 2-256 H Pn H CH ₂ NHCOPr ^c 2-257 H Pn H CH ₂ NHCOPn ^c 2-258 H Pn H CH ₂ NHCOHx ^c 2-259 H Pn H CH ₂ NHCOHp ^c 2-260 H Pn H CH ₂ NHCOPh 2-261 H Pn H CH ₂ NHCOCH ₂ Ph 2-262 H Pn H CH ₂ NHCOCH ₂ CH ₂ Ph 2-263 H Pn H CH ₂ NHCO (2-Fur) 2-264 H Pn H CH ₂ NHCO (3-Fur) 2-265 H Pn H CH ₂ NHCO (2-Thi) 2-266 H Pn H CH ₂ NHCO (3-Thi) 2-267 H Pn H CH ₂ NHCO (3-Pyr) 2- 268 H Pn H CH ₂ NHCO (4-Pyr) 2-269 H Pn H CH ₂ NHCO ₂ Me 2-270 H Pn H CH ₂ NHCO ₂ Et 2-271 H Pn H CH ₂ NHCO ₂ Pr 2-272 H Pn ^{_{H CH 2 NHCO 2 Pr i 2-273}} H Pn H CH 2 NHCO 2 Bu 2-274 H Pn H CH 2 NHCO 2 Bu i 2-275 H Pn H CH 2 NHCO 2 Bu t 2-276 H Pn H CH 2 NHSO ₂ Me 2-277 H Pn H CH ₂ NHSO ₂ Et 2-278 H Pn H CH ₂ NHSO ₂ Ph 2-279 H Pn H CH ₂ NHCONH ₂ 2-280 H Pn H CH ₂ NHCONHMe 2-281 H Pn H CH ₂ NHCONHEt 2-282 H Pn H CH ₂ NHCONHPr 2-283 H Pn H CH ₂ NHCONHPr ⁱ 2-284 H Pn H CH ₂ NHCONHBu 2-285 H Pn H CH ₂ NHCONHCH ₂ Ph 2-286 H Pn H CH ₂ NHCONHCH ₂ CH ₂ Ph 2-287 H Pn H CH ₂ NHCSNH ₂ 2-288 H Pn H CH ₂ NHCSNHMe 2-289 H Pn H CH ₂ NHCSNHEt 2-290 H Pn H CH ₂ NHCSNHPr 2-291 H Pn H CH ₂ NHCSNHPr ⁱ 2-292 H Pn H CH ₂ NHCSNHBu 2-293 H Pn H CH ₂ NHCSNHCH ₂ Ph 2-294 H Pn H CH ₂ NHCSNHCH ₂ CH ₂ Ph 2-295 H Pn H CH ₂ PHID 2-296 H Pn H CH ₂ CH ₂ NH ₂ 2-297 H Pn H CH ₂ CH ₂ NHMe ₂ 2-298 H Pn H CH ₂ CH ₂ NHCOMe 2-299 H Pn H CH ₂ CH ₂ NHCOEt 2 -300 H Pn H CH ₂ CH ₂ NHCOPr 2-301 H Pn H CH ₂ CH ₂ NHCOPr ⁱ 2-302 H Pn H CH ₂ CH ₂ NHCOBu 2-303 H Pn H CH ₂ CH ₂ NHCOCF ₃ 2-304 H Pn _{H CH 2 CH 2 NHCOCH 2 NH} 2 2-305 H Pn H CH 2 CH 2 NHCOCH 2 COMe 2-306 H Pn H CH 2 CH 2 NHCOCH 2 CH 2 COMe 2-307 H Pn H CH 2 CH 2 NHCOPn c 2 -308 H Pn H CH ₂ CH ₂ NHCOHx ^c 2-309 H Pn H CH ₂ CH ₂ NHCOHp ^c 2-310 H Pn H CH ₂ CH ₂ NHCOCH ₂ Ph 2-312 H Pn H CH ₂ CH ₂ NHCO (2- Fur) 2-313 H Pn H CH ₂ CH ₂ NHC O (3-Fur) 2-314 H Pn H CH ₂ CH ₂ NHCO (2-Thi) 2-315 H Pn H CH ₂ CH ₂ NHCO (3-Thi) 2-316 H Pn H CH ₂ CH ₂ NHCO ( 3-Pyr) 2-317 H Pn H CH ₂ CH ₂ NHCO ₂ Me 2-318 H Pn H CH ₂ CH ₂ NHCO ₂ Et 2-319 H Pn H CH ₂ CH ₂ NHCO ₂ Pr 2-320 H Pn H CH ₂ CH ₂ NHCO ₂ Pr ⁱ 2-321 H Pn H CH ₂ CH ₂ NHCO ₂ Bu 2-322 H Pn H CH ₂ CH ₂ NHSO ₂ Me 2-323 H Pn H CH ₂ CH ₂ NHCONH ₂ 2-324 H Pn H CH ₂ CH ₂ NHCONHMe 2-325 H Pn H CH ₂ CH ₂ NHCONHEt 2-326 H Pn H CH ₂ CH ₂ NHCONHCH ₂ Ph 2-327 H Pn H CH ₂ CH ₂ NHCONHCH ₂ CH ₂ Ph 2-328 H Pn H CH ₂ CH ₂ NHCSNH ₂ 2-329 H Pn H CH ₂ CH ₂ NHCSNHMe 2-330 H Pn H CH ₂ CH ₂ NHCSNHEt 2-331 H Pn H CH ₂ CH ₂ NHCSNHCH ₂ Ph 2-332 H Pn H CH ₂ CH ₂ NHCSNHCH ₂ CH ₂ Ph 2-333 H Pn H CH ₂ CH ₂ PHID 2-334 H Pn Me CH ₂ NH ₂ 2-335 H Pn Me CH ₂ NHCOMe 2-336 H Pn Me CH ₂ NHCOEt 2-337 H Pn Me CH ₂ NHCOCF ₃ 2-338 H Pn Me CH ₂ NHCOCH ₂ CH ₂ COMe 2-339 H Pn Me CH ₂ NHCOPn ^c 2-340 H Pn Me CH ₂ NHCOHx ^c 2-341 H Pn Me CH ₂ NHCOCH ₂ Ph 2-342 H Pn Me CH ₂ NHCO (2-Fur) 2-343 H Pn Me CH ₂ NHCO (2-Thi) 2-344 H Pn Me CH ₂ NHCO ₂ Me 2-345 H Pn Me CH ₂ NHCO ₂ Et 2-346 H Pn Me CH ₂ NHCONH ₂ 2-347 H Pn Me CH ₂ NHCONHMe 2-348 H Pn Me CH ₂ NHCOCH ₂ Ph 2-349 H Pn Me CH ₂ NHCSNH ₂ 2-350 H Pn Me CH ₂ NHCSNHMe 2-351 H Pn Me CH ₂ NHCSNHCH ₂ Ph 2-352 H Pn Me CH ₂ PHID 2-353 H Pn Et CH ₂ NHCOMe 2-354 H Pn Et CH ₂ NHCOEt 2-355 H Pn Et CH ₂ NHCOPn ^c 2-356 H Pn Et CH ₂ NHCOHx ^c 2-357 H Pn Et CH ₂ NHCO (2-Fur) 2-358 H Pn Et CH ₂ NHCO (2-Thi) 2-359 H Pn Et CH ₂ NHCO ₂ Me 2-360 H Pn Et CH ₂ NHCO ₂ Et 2-361 H Pn Et CH ₂ NHCONHMe 2-362 H Pn Et CH ₂ NHCOCH ₂ Ph 2-363 H Pn Et CH ₂ NHCSNHMe 2-364 H Pn Et CH ₂ NHCSCH ₂ Ph 2-365 H Hx H CH ₂ NH ₂ 2-366 H Hx H CH ₂ NHCOMe 2-367 H Hx H CH ₂ NHCOEt 2-368 H Hx H CH ₂ NHCOCF _{3 2-369 H Hx H CH 2 NHCOCH 2} CH 2 COMe 2-370 H Hx H CH 2 NHCOPn c 2-371 H Hx H CH 2 NHCOHx c 2-372 H Hx H CH 2 NHCOCH 2 Ph 2-373 H Hx H CH ₂ NHCO (2-Fur) 2-374 H Hx H CH ₂ NHCO (2-Thi) 2-375 H Hx H CH ₂ NHCO ₂ Me 2-376 H Hx H CH ₂ NHCO ₂ Et 2-377 H Hx H CH ₂ NHCONH ₂ 2-378 H Hx H CH ₂ NHCONHMe 2-379 H Hx H CH ₂ NHCO NHCH ₂ Ph 2-380 H Hx H CH ₂ NHCSNH ₂ 2-381 H Hx H CH ₂ NHCSNHMe 2-382 H Hx H CH ₂ NHCSNHCH ₂ Ph 2-383 H Hx H CH ₂ PHID 2-384 H Hx H CH ₂ CH ₂ NHCOMe 2-385 H Hx H CH ₂ CH ₂ NHCOEt 2-386 H Hx H CH ₂ CH ₂ NHCOCF ₃ 2-387 H Hx H CH ₂ CH ₂ NHCO (2-Fur) 2-388 H Hx H CH ₂ CH ₂ NHCO (2-Thi) 2-389 H Hx H CH ₂ CH ₂ NHCO ₂ Me 2-390 H Hx H CH ₂ CH ₂ NHCO ₂ Et 2-391 H Hx H CH ₂ CH ₂ NHCONH ₂ 2-392 H Hx H CH ₂ CH ₂ NHCONHMe 2-393 H Hx H CH ₂ CH ₂ NHCONHEt 2-394 H Hx H CH ₂ CH ₂ NHCONHCH ₂ Ph 2-395 H Hx H CH ₂ CH ₂ NHCSNH ₂ 2-396 H Hx H CH ₂ CH ₂ NHCSNHMe 2-397 H Hx H CH ₂ CH ₂ NHCSNHEt 2-398 H Hx H CH ₂ CH ₂ NHCSNHCH ₂ Ph 2-399 H Hx H CH ₂ CH ₂ PHID 2-400 H Hx Me CH ₂ NHCOMe 2- 401 H Hx Me CH ₂ NHCOEt 2-402 H Hx Me CH ₂ NHCOCF ₃ 2-403 H Hx Me CH ₂ NHCO (2-Fur) 2-404 H Hx Me CH ₂ NHCO (2-Thi) 2-405 H Hx Me CH ₂ NHCO ₂ Me 2-406 H Hx Me CH ₂ NHCO ₂ Et 2-407 H Hx Me CH ₂ NHCONH ₂ 2-408 H Hx Me CH ₂ NHCONHMe 2-409 H Hx Me CH ₂ NHCONHEt 2-410 H Hx Me CH ₂ NHCONHCH ₂ Ph 2-411 H Hx Me CH ₂ NHCSNH ₂ 2-412 H Hx Me CH ₂ NHCSNHMe 2-413 H Hx Me CH ₂ NHCSNHEt 2-414 H Hx Me CH ₂ NHCSNHCH ₂ Ph 2-415 H Hx Me CH ₂ PHID 2-416 H Hp H CH ₂ NHCOMe 2-417 H Hp H CH ₂ NHCOEt _{2-418 H Hp H CH 2 NHCOCF 3} 2-419 H Hp H CH 2 NHCOCH 2 CH 2 COMe 2-420 H Hp H CH 2 NHCOPn c 2-421 H Hp H CH 2 NHCOHx c 2-422 H Hp H CH ₂ NHCOCH ₂ Ph 2-423 H Hp H CH ₂ NHCO (2-Fur) 2-424 H Hp H CH ₂ NHCO (2-Thi) 2-425 H Hp H CH ₂ NHCO ₂ Me 2-426 H Hp H CH ₂ NHCO ₂ Et 2-427 H Hp H CH ₂ NHCONH ₂ 2-428 H Hp H CH ₂ NHCONHMe 2-429 H Hp H CH ₂ NHCONHCH ₂ Ph 2-430 H Hp H CH ₂ NHCSNH ₂ 2-431 H Hp H CH ₂ NHCSNHMe 2-432 H Hp H CH ₂ NHCSNHCH ₂ Ph 2-433 H Hp H CH ₂ PHID 2-434 H Oc H CH ₂ NHCOMe 2-435 H Oc H CH ₂ NHCOEt 2-436 H Oc H CH ₂ NHCOCF ₃ 2-437 H Oc H CH ₂ NHCOCH ₂ CH ₂ COMe 2-438 H Oc H CH ₂ NHCOPn ^c 2-439 H Oc H CH ₂ NHCOHx ^c 2-440 H Oc H CH ₂ NHCOCH ₂ Ph 2-441 H Oc H CH ₂ NHCO (2-Fur) 2-442 H Oc H CH ₂ NHCO (2-Thi) 2-443 H Oc H CH ₂ NHCO ₂ Me 2-444 H Oc H CH ₂ NHCO ₂ Et 2-445 H Oc H CH ₂ NHCONH ₂ 2-446 H Oc H CH ₂ NHCONHMe 2-447 H Oc H CH ₂ NHCONH CH ₂ Ph 2-448 H Oc H CH ₂ NHCSNH ₂ 2-449 H Oc H CH ₂ NHCSNHMe 2-450 H Oc H CH ₂ NHCSNHCH ₂ Ph 2-451 H Oc H CH ₂ PHID 2-452 H Bu ⁱ H CH ^{_{2 NHCOMe 2-453 H Bu i H CH}} 2 NHCOEt 2-454 H Bu i H CH 2 NHCOCF 3 2-455 H Bu i H CH 2 NHCOCH 2 CH 2 COMe 2-456 H Bu i H CH 2 NHCOPn c 2- 457 H Bu ⁱ H CH ₂ NHCOHx ^c 2-458 H Bu ⁱ H CH ₂ NHCOCH ₂ Ph 2-459 H Bu ⁱ H CH ₂ NHCO (2-Fur) 2-460 H Bu ⁱ H CH ₂ NHCO (2-Thi ) 2-461 H Bu ⁱ H CH ₂ NHCO ₂ Me 2-462 H Bu ⁱ H CH ₂ NHCO ₂ Et 2-463 H Bu ⁱ H CH ₂ NHCONH ₂ 2-464 H Bu ⁱ H CH ₂ NHCONHMe 2-465 H Bu ⁱ H CH ₂ NHCONHCH ₂ Ph 2-466 H Bu ⁱ H CH ₂ NHCSNH ₂ 2-467 H Bu ⁱ H CH ₂ NHCSNHMe 2-468 H Bu ⁱ H CH ₂ NHCSNHCH ₂ Ph 2-469 H Bu ⁱ H CH _{2 ^{PHID 2-470 H Pn i H CH 2}} NHCOMe 2-471 H Pn i H CH 2 NHCOEt 2-472 H Pn i H CH 2 NHCOCF 3 2-473 H Pn i H CH 2 NHCOCH 2 CH 2 COMe 2-474 H Pn ⁱ H CH ₂ NHCOPn ^c 2-475 H Pn ⁱ H CH ₂ NHCOHx ^c 2-476 H Pn ⁱ H CH ₂ NHCOCH ₂ Ph 2-477 H Pn ⁱ H CH ₂ NHCO (2-Fur) 2-478 H Pn ⁱ H CH ₂ NHCO (2-Thi) 2-479 H Pn ⁱ H CH ₂ NHCO ₂ Me 2-480 H Pn ⁱ H CH ₂ NHCO ₂ Et 2- 481 H Pn ⁱ H CH ₂ NHCONH ₂ 2-482 H Pn ⁱ H CH ₂ NHCONHMe 2-483 H Pn ⁱ H CH ₂ NHCONHCH ₂ Ph 2-484 H Pn ⁱ H CH ₂ NHCSNH ₂ 2-485 H Pn ⁱ H CH ₂ NHCSNHMe 2-486 H Pn ⁱ H CH ₂ NHCSNHCH ₂ Ph 2-487 H Pn ⁱ H CH ₂ PHID 2-488 H Hx ⁱ H CH ₂ NHCOMe 2-489 H Hx ⁱ H CH ₂ NHCOEt 2-490 H Hx ⁱ H CH ₂ NHCOCF ₃ 2-491 H Hx ⁱ H CH ₂ NHCOCH ₂ CH ₂ COMe 2-492 H Hx ⁱ H CH ₂ NHCOPn ^c 2-493 H Hx ⁱ H CH ₂ NHCOHx ^c 2-494 H Hx ⁱ H CH ₂ NHCOCH ₂ Ph 2-495 H Hx ⁱ H CH ₂ NHCO (2-Fur) 2-496 H Hx ⁱ H CH ₂ NHCO (2-Thi) 2-497 H Hx ⁱ H CH ₂ NHCO ₂ Me 2-498 H Hx ⁱ H CH ₂ NHCO ₂ Et 2-499 H Hx ⁱ H CH ₂ NHCONH ₂ 2-500 H Hx ⁱ H CH ₂ NHCONHMe 2-501 H Hx ⁱ H CH ₂ NHCONHCH ₂ Ph 2-502 H Hx ⁱ H CH ₂ NHCSNH ₂ 2-503 H Hx ⁱ H CH ₂ NHCSNHMe 2-504 H Hx ⁱ H CH ₂ NHCSNHCH ₂ Ph 2-505 H Hx ⁱ H CH ₂ PHID 2-506 Pn Pn H CH ₂ NHCOMe 2-507 Pn Pn H CH _{2 NHCOEt 2-508 Pn Pn H CH 2 NHCOCF} 3 2-509 Pn Pn H CH 2 NHCOCH 2 CH 2 COMe 2-510 Pn Pn H CH 2 NHCOPn c 2-511 Pn Pn H CH 2 NHCOHx c 2-512 Pn Pn H CH ₂ NHCOCH ₂ Ph 2-513 Pn Pn H CH ₂ NHCO (2-Fur) 2-514 Pn Pn H CH ₂ NHCO (2-Thi) 2-515 Pn Pn H CH ₂ NHCO ₂ Me 2-516 Pn Pn H CH ₂ NHCO ₂ Et 2-517 Pn Pn H CH ₂ NHCONH ₂ 2-518 Pn Pn H CH ₂ NHCONHMe 2-519 Pn Pn H CH ₂ NHCONHCH ₂ Ph 2-520 Pn Pn H CH ₂ NHCSNH ₂ 2-521 Pn Pn H CH ₂ NHCSNHMe 2-522 Pn Pn H CH ₂ NHCSNHCH ₂ Ph 2-523 Pn Pn H CH ₂ PHID _{2-524 HHH CH 2 NHCOCH 2 NHCO 2} Me 2-525 HHH CH 2 NHCOCH 2 NHCO 2 Bu t 2-526 HHH CH 2 NHCOCH 2 NMeCO 2 Me 2-527 HHH CH 2 NHCOCH 2 NMeCO 2 Bu t 2-528 HHH ^{_{CH 2 NHCOCH 2 NEtCO 2 Bu t}} 2-529 HHH CH 2 NMeCO 2 Me 2-530 HHH CH 2 NMeCO 2 Bu t 2-531 HHH CH 2 NEtCO 2 Bu t 2-532 H Pn H CH 2 NHCOCH 2 NHCO 2 Me _{2-533 H Pn H CH 2 NHCOCH 2} NHCO 2 Bu t 2-534 H Pn H CH 2 NHCOCH 2 NMeCO 2 Me 1-535 H Pn H CH 2 NHCOCH 2 NMeCO 2 Bu t 2-536 H Pn H CH 2 NHCOCH ^{_{2 NEtCO 2 Bu t 2-537 H Pn}} H CH 2 NMeCO 2 Me 2-538 H Pn H CH 2 NMeCO 2 Bu t 2-539 H Pn H CH 2 NEtCO 2 Bu t ────────── ────────────────────────.

In the above table, preferably the compound number N
o. 1-149, 1-150, 1-160, 1-16
1, 1-167, 1-168, 1-169, 1-17
1, 1-172, 1-174, 1-175, 1-17
6, 1-177, 1-178, 1-179, 1-18
0, 1-182, 1-183, 1-185, 1-18
6, 1-187, 1-189, 1-190, 1-19
2, 1-193, 1-194, 1-195, 1-19
6, 1-197, 1-198, 1-200, 1-20
1, 1-239, 1-240, 1-241, 1-24
2, 1-243, 1-244, 1-248, 1-25
6, 1-257, 1-258, 1-259, 1-26
0, 1-261, 1-262, 1-263, 1-26
4, 1-265, 1-266, 1-269, 1-27
0, 1-271, 1-272, 1-276, 1-27
7, 1-278, 1-279, 1-280, 1-28
1, 1-282, 1-283, 1-284, 1-28
5, 1-288, 1-289, 1-290, 1-29
1, 1-293, 1-298, 1-299, 1-32
3, 1-324, 1-366, 1-367, 1-36
8, 1-370, 1-371, 1-373, 1-37
4, 1-375, 1-376, 1-377, 1-37
8, 1-379, 1-381, 1-382, 1-41
6, 1-417, 1-418, 1-420, 1-42
1, 1-423, 1-424, 1-425, 1-42
6, 1-427, 1-428, 1-429, 1-43
1, 1-432, 1-434, 1-435, 1-43
6, 1-438, 1-439, 1-441, 1-44
2, 1-443, 1-444, 1-445, 1-44
6, 1-447, 1-449, 1-450, 1-45
2, 1-453, 1-470, 1-471, 1-47
2, 1-474, 1-475, 1-477, 1-47
8, 1-479, 1-480, 1-481, 1-48
2, 1-483, 1-485, 1-488, 1-48
9, 1-490, 1-492, 1-493, 1-49
5, 1-496, 1-497, 1-498, 1-49
9, 1-500, 1-501, 1-503, 1-50
4, 2-149, 2-150, 2-160, 2-16
1, 2-167, 1-168, 2-169, 2-17
1, 2-172, 2-174, 2-175, 1-17
6, 2-177, 2-178, 2-179, 2-18
0, 2-182, 2-183, 2-185, 2-18
6, 2-187, 2-189, 2-190, 2-19
2, 2-193, 2-194, 2-195, 2-19
6, 2-197, 2-198, 2-200, 2-20
1, 2-239, 2-240, 2-241, 2-24
2, 2-243, 2-244, 2-248, 2-25
6, 2-257, 2-258, 2-259, 2-26
0, 2-261, 2-262, 2-263, 2-26
4, 2-265, 2-266, 2-269, 2-27
0, 2-271, 2-272, 2-276, 2-27
7, 2-278, 2-279, 2-280, 2-28
1, 2-282, 2-283, 2-284, 2-28
5, 2-288, 2-289, 2-290, 2-29
1, 2-293, 2-298, 2-299, 2-32
3, 2-324, 2-366, 2-367, 2-36
8, 2-370, 2-371, 2-373, 2-37
4, 2-375, 2-376, 2-377, 2-37
8, 2-379, 2-381, 2-382, 2-41
6, 2-417, 2-418, 2-420, 2-42
1, 2-423, 2-424, 2-425, 2-42
6, 2-427, 2-428, 2-429, 2-43
1, 2-432, 2-434, 2-435, 2-43
6, 2-438, 2-439, 2-441, 2-44
2, 2-443, 2-444, 2-445, 2-44
6, 2-447, 2-449, 2-450, 2-45
2, 2-453, 2-463, 2-464, 2-47
0, 2-471, 2-472, 2-474, 2-47
5, 2-477, 2-478, 2-479, 2-48
0, 2-481, 2-482, 2-483, 2-48
5, 2-486, 2-488, 2-489, 2-49
0, 2 -492, 2-493, 2 -495, 2-49
6, 2-497, 2-498, 2-499, 2-50
0, 2-501, 2-503 and 2-504 can be mentioned, More preferably, compound number No.
1-167, 1-168, 1-178, 1-179, 1
-185, 1-186, 1-187, 1-192, 1-
193, 1-194, 1-195, 1-196, 1-1
97, 1-200, 1-239, 1-240, 1-24
1, 1-242, 1-243, 1-244, 1-24
8, 1-256, 1-257, 1-258, 1-25
9, 1-260, 1-261, 1-262, 1-26
3, 1-264, 1-265, 1-266, 1-26
9, 1-270, 1-279, 1-280, 1-28
1, 1-282, 1-283, 1-288, 1-28
9, 1-290, 1-291, 1-366, 1-36
7, 1-368, 1-373, 1-374, 1-37
5, 1-376, 1-377, 1-378, 1-38
1, 1-416, 1-417, 1-418, 1-42
3, 1-424, 1-425, 1-426, 1-42
7, 1-428, 1-431, 1-434, 1-43
5, 1-445, 1-446, 1-470, 1-47
1, 1-481, 1-482, 1-488, 1-48
9, 1-499, 1-500, 2-167, 1-16
8, 2-178, 2-179, 2-185, 2-18
6, 2-187, 2-196, 2-197, 2-20
0, 2-239, 2-240, 2-241, 2-24
2, 2-243, 2-244, 2-248, 2-25
6, 2-257, 2-258, 2-259, 2-26
0, 2-261, 2-262, 2-263, 2-26
4, 2-265, 2-266, 2-269, 2-27
0, 2-279, 2-280, 2-281, 2-28
2, 2-283, 2-288, 2-289, 2-29
0, 2-291, 2-366, 2-367, 2-36
8, 2-373, 2-374, 2-375, 2-37
6, 2-377, 2-378, 2-381, 2-41
6, 2-417, 2-418, 2-423, 2-42
4, 2-425, 2-426, 2-427, 2-42
8, 2-431, 2-434, 2-435, 2-44
5, 2-446, 2-470, 2-471, 2-48
1,2-482,2-488,2-489,2-499
And 2-500, and even more preferably, compound number No. 1-185, 1-18
6, 1-196, 1-197, 1-239, 1-24
0, 1-241, 1-242, 1-279, 1-28
0, 1-281, 1-282, 1-283, 1-28
8, 1-289, 1-366, 1-367, 1-37
7, 1-378, 1-381, 1-416, 1-41
7, 1-427, 1-428, 1-431, 1-43
4, 2-185, 2-186, 2-196, 2-19
7, 2-239, 2-240, 2-241, 2-24
2, 2-279, 2-280, 2-281, 2-28
2, 2-283, 2-288, 2-289, 2-36
6, 2-367, 2-377, 2-378, 2-38
1, 2-416, 2-417, 2-427, 2-42
Compounds Nos. 8, 2-431 and 2-434 can be mentioned, and particularly preferably, Compound No. 1-185: 4- (4-acetylaminomethylpyrimidin-2-yl) -2-[(amino) (butylamino) methyleneamino] thiazole, 1-186: 2-[(amino) (butylamino) methyleneamino ] -4- (4-Propionylaminomethylpyrimidin-2-yl) thiazole, 1-239: 4- (4-acetylaminomethylpyrimidin-2-yl) -2-[(amino) (pentylamino)
Methyleneamino] thiazole, 1-240: 2-[(amino) (pentylamino) methyleneamino] -4- (4-propionylaminomethylpyrimidin-2-yl) thiazole, 1-279: 2-[(amino) ( Pentylamino) methyleneamino] -4- (4-ureidomethylpyrimidine-
2-yl) thiazole, 1-280: 2-[(amino) (pentylamino) methyleneamino] -4- [4- (3-methylureido) methylpyrimidin-2-yl) thiazole, 1-281: 2- [(Amino) (pentylamino) methyleneamino] -4- [4- (3-ethylureido) methylpyrimidin-2-yl) thiazole, 1-288: 2-[(amino) (pentylamino) methyleneamino]- 4- [4- (3-methylthioureido)
Methylpyrimidin-2-yl) thiazole, 1-289: 2-[(amino) (pentylamino) methyleneamino] -4- [4- (3-ethylthioureido)
Methylpyrimidin-2-yl) thiazole, 1-366: 4- (4-acetylaminomethylpyrimidin-2-yl) -2-[(amino) (hexylamino)
Methyleneamino] thiazole, 1-367: 2-[(amino) (hexylamino) methyleneamino] -4- (4-propionylaminomethylpyrimidin-2-yl) thiazole, 1-377: 2-[(amino) ( Hexylamino) methyleneamino] -4- (4-ureidomethylpyrimidine-
2-yl) thiazole, 1-378: 2-[(amino) (hexylamino) methyleneamino] -4- [4- (3-methylureido) methylpyrimidin-2-yl) thiazole, 2-239: 4- (2-Acetylaminomethylpyrimidin-4-yl) -2-[(amino) (pentylamino)
Methyleneamino] thiazole, 2-240: 2-[(amino) (pentylamino) methyleneamino] -4- (2-propionylaminomethylpyrimidin-4-yl) thiazole, 2-279: 2-[(amino) ( Pentylamino) methyleneamino] -4- (2-ureidomethylpyrimidine-
4-yl) thiazole, 2-280: 2-[(amino) (pentylamino) methyleneamino] -4- [2- (3-methylureido) methylpyrimidin-4-yl) thiazole, 2-281: 2- [(Amino) (pentylamino) methyleneamino] -4- [2- (3-ethylureido) methylpyrimidin-4-yl) thiazole, 2-288: 2-[(amino) (pentylamino) methyleneamino]- 4- [2- (3-methylthioureido)
Methylpyrimidin-4-yl) thiazole and 2-289: 2-[(amino) (pentylamino) methyleneamino] -4- [2- (3-ethylthioureido)
An example is a compound of methylpyrimidin-4-yl) thiazole.

The compound (I) of the present invention can be easily produced according to the following method.

[0038]

[Chemical 4]

[0039]

Embedded image

In the above formula, R ¹ , R ² , R ³ , R ⁴ and A
Represents the same meaning as described above, and R ¹ a represents C ₁ -C
₆ alkanoylamino group, (C ₁ -C ₆ alkoxy)-
C ₂ -C ₅ alkanoylamino group, a halogeno -C ₂ -C ₅
Alkanoylamino group, (di-C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆
Alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆ alkoxycarbonyl - mono- C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆ alkanoyl) -C ₂ -C
₅ alkanoylamino group, C ₃ -C ₈ cycloalkyl carbonyl amino group, C ₆ -C ₁₀ arylcarbonylamino group, C ₇ -C ₁₁ aralkylcarbonyl group, nitrogen, 5 or 6 membered cyclic containing oxygen or sulfur atom A heteroarylcarbonylamino group, a C ₁ -C ₆ alkoxycarbonylamino group, a (C ₁ -C ₆ alkoxycarbonyl) -mono-C ₁ -C ₆ alkylamino group or a phthalimido group, and R ⁵ represents C ₁ -C ₆ It represents an alkyl group, and Y represents a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom).

Method A is a method for producing a compound (I). Step A1 is a step of producing a compound having the general formula (III) and is accomplished by reacting the compound having the general formula (II) with a halogenating agent in the presence of water in an inert solvent.

The halogenating agent used is, for example, N-
Chlorosuccinimide, N-bromosuccinimide, N
-N-halogenosuccinimides such as iodosuccinimide, halogens such as chlorine, bromine, sodium chloride-lead tetraacetate, sodium bromide-lead tetraacetate, alkali metals such as sodium iodide-lead tetraacetate It may be halide-lead tetraacetate, preferably N-halogenosuccinimide (particularly N-bromosuccinimide).

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform, ethers, ethers such as tetrahydrofuran and dioxane, and ethyl acetate. Such esters, alcohols such as methanol, ethanol, isopropanol, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, or nitriles such as acetonitrile, preferably ethers ( In particular, tetrahydrofuran). The reaction temperature is generally -20 ° C to 100 ° C (preferably -10 ° C to 2 ° C).
The reaction time is usually 5 minutes to 2 hours (preferably 10 minutes to 30 minutes), although it depends on the reaction temperature and the like.

After completion of the reaction, the target compound of this step can be collected from the reaction mixture by a conventional method. For example, by appropriately neutralizing, distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture,
It can be obtained by pouring the reaction mixture into water, extracting with a water-insoluble organic solvent, drying and distilling the solvent from the extract. Further, if necessary, it can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

The step A2 is a step for producing the compound (I) and is accomplished by reacting the compound (III) with a compound having the general formula (IV) in an inert solvent.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, for example, benzene, toluene,
Aromatic hydrocarbons such as xylene, dichloromethane,
Halogenated hydrocarbons such as chloroform, ethers such as ether, tetrahydrofuran and dioxane, esters such as ethyl acetate and propyl acetate, alcohols such as methanol, ethanol and isopropanol, dimethylformamide, dimethylacetamide, hexa It may be an amide such as methylphosphorotriamide or a nitrile such as acetonitrile, preferably alcohols (especially ethanol). The reaction temperature is generally -20 ° C to 100 ° C (preferably 20 ° C).
The reaction time is usually 10 minutes to 10 hours (preferably 30 minutes to 5 hours), although the time required for the reaction varies depending on the reaction temperature and the like.

After completion of the reaction, the target compound of this step can be collected from the reaction mixture by a conventional method. For example, by appropriately neutralizing, distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture,
It can be obtained by pouring the reaction mixture into water, extracting with a water-insoluble organic solvent, drying and distilling the solvent from the extract. Further, if necessary, it can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Method B is a method for separately producing compound (I). Step B1 is a step of producing compound (I),
Amino group or mono-C of compound having general formula (Ia)
By removing a portion corresponding to the protecting group ₁ -C ₆ alkylamino group, it is accomplished by acylation or alkylation if desired. It is also possible to alkylate the amino group and acylate the mono-C ₁ -C ₆ alkylamino compound. R ¹ a is, C ₁ -C ₆ alkanoylamino group,
(C ₁ -C ₆ alkoxy) -C ₂ -C ₅ alkanoylamino group, halogeno-C ₂ -C ₅ alkanoylamino group,
(Gee C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆ alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino group (provided that, t-
Excluding butoxycarbonylamino -C ₂ -C ₅ alkanoylamino group. ), (C ₁ -C ₆ alkoxycarbonyl-mono-C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group (provided t-butoxycarbonyl-mono-C ₁ -C ₆ alkylamino-C ₂ -C ₅ excluding alkanoylamino groups), (C ₁ -C ₆ alkanoyl)-
5 containing C ₂ -C ₅ alkanoylamino group, C ₃ -C ₈ cycloalkyl carbonyl amino group, C ₆ -C ₁₀ arylcarbonylamino group, C ₇ -C ₁₁ aralkylcarbonyl group, nitrogen, oxygen or sulfur atom To 6-membered cyclic heteroarylcarbonylamino group, C ₁ -C ₆ alkoxycarbonylamino group (excluding t-butoxycarbonylamino group) or (C ₁ -C ₆ alkoxycarbonyl) -mono-C ₁ -C ₆ alkyl When it is an amino group (however, excluding t-butoxycarbonyl-mono-C ₁ -C ₆ alkylamino group), the amino group is obtained by reacting the corresponding compound with a base in the presence of water in an inert solvent. Alternatively, the portion corresponding to the protecting group for the C ₁ -C ₆ alkylamino group is removed.

The base used is, for example, sodium
Methoxide, sodium ethoxide, potassium t-
Alkali metal alkoxides such as butoxide, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, aqueous ammonia, ammonia-methanol Ammonias such as, and preferably alkali metal hydroxides.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include water, ethers such as ether, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol and isopropanol, or water. It may be a mixed solvent with the above organic solvent, and is preferably hydrous alcohol. The reaction temperature is usually 0
C. to 150.degree. C. (preferably 20.degree. C. to 100.degree. C.), and the time required for the reaction varies depending on the reaction temperature etc., but is usually 30 minutes to 48 hours (preferably 1 hour to 2 hours).
4 hours).

[0051] R ¹ a is, t-butoxycarbonylamino -C ₂ -C ₅ alkanoylamino group, (t-butoxycarbonyl - mono- C ₁ -C ₆ alkylamino) -C ₂ -
C ₅ alkanoylamino group, t-butoxycarbonylamino group or t-butoxycarbonyl-mono-C ₁ -C ₆
When it is an alkylamino group, the corresponding compound is treated with an acid or tri (C ₁ -C ₆ alkyl) silyl halide (preferably trimethylsilyl iodide or triethylsilyl iodide, particularly preferably trimethylsilyl) in an inert solvent. By reacting with iodide), the portion corresponding to the protective group of the amino group or C ₁ -C ₆ alkylamino group is removed. The acid used can be a mineral acid such as hydrochloric acid, nitric acid, sulfuric acid, an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, preferably hydrochloric acid or trifluoroacetic acid. ..

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as ether, tetrahydrofuran and dioxane. It is preferably a halogenated hydrocarbon. The reaction temperature is usually -20 ° C to 100 ° C.
(Preferably 0 ° C to 50 ° C), and the time required for the reaction varies depending on the reaction temperature and the like, but is usually 5 minutes to 1
It is 0 hours (preferably 10 minutes to 5 hours).

When R ¹ a is a phthalimido group,
By reacting the corresponding compound with a base in an inert solvent, the portion corresponding to the protective group of the amino group is removed.
Examples of the base used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, organic amines such as ethylamine, propylamine, butylamine and methylhydrazine, or inorganic amines such as hydrazine. It may be a class, preferably hydrazine.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers, tetrahydrofuran, ethers such as dioxane, alcohols such as methanol, ethanol and isopropanol, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphorotriamide, nitriles such as acetonitrile, sulfoxides such as dimethylsulfoxide, or water, and preferably,
They are alcohols. Further, it is also possible to use an excess of organic amines or inorganic amines as a solvent.

The reaction temperature is usually from -20 ° C to 150 ° C.
(Preferably 0 ° C. to 100 ° C.), and the time required for the reaction is usually 10 minutes to 30 hours (preferably 30 minutes to 24 hours), although it varies depending on the reaction temperature and the like.

In the reaction of removing the portion corresponding to the protective group of the amino group of the compound (Ia) and acylating the produced amino group, R ¹ is a C ₁ -C ₆ alkanoylamino group, (C ₁
-C ₆ alkoxy) -C ₂ -C ₅ alkanoylamino group, a halogeno -C ₂ -C ₅ alkanoylamino group, (di C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ - C ₆ alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆
Alkoxycarbonyl-mono-C ₁ -C ₆ alkylamino) -C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₆
Alkanoyl) -C ₂ -C ₅ alkanoylamino group, C ₃
-C ₈ cycloalkylcarbonyl amino group, C ₆ -C
₁₀ arylcarbonylamino group, C ₇ -C ₁₁ aralkylcarbonylamino group, 5- to 6-membered cyclic heteroarylcarbonylamino group containing nitrogen, oxygen or sulfur atom, C ₁ -C ₆ alkoxycarbonylamino group, (C ₁
-C ₆ alkoxycarbonyl) -mono-C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkanesulfonylamino group or C ₆ -C ₁₀ arylsulfonylamino group, an amino compound corresponding to the corresponding acid or its It is achieved by reacting with a reactive derivative, and R ¹ is a ureido group, a C ₁ -C ₆ alkylureido group, a C ₇ -C ₁₁ aralkylureido group, a thioureido group, a C ₁ -C ₆ alkylthioureido group or C ₇ In the case of a -C ₁₁ aralkylthioureido group, the amino compound may be an alkali metal cyanate such as sodium cyanate or potassium cyanate, a C ₁ -C ₆ alkylisocyanate, a C ₇ -C ₁₁ aralkylisocyanate, or thiocyanic acid. Sodium, alkali metal thiocyanates such as potassium thiocyanate, C ₁ -C ₆ alkylisothiates Cyanate or C ₇ −
This is accomplished by reacting with C ₁₁ aralkyl isothiocyanate.

The acid used is, for example, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, hexanoic acid, methoxyacetic acid, ethoxyacetic acid, 3-methoxypropionic acid, 3
-Ethoxypropionic acid, 4-methoxybutyric acid, 5-methoxyvaleric acid, fluoroacetic acid, trifluoroacetic acid, chloroacetic acid, 3-fluoropropionic acid, 3-chloropropionic acid, 4-fluorobutyric acid, 5-fluorovaleric acid, dimethyl Aminoacetic acid, diethylaminoacetic acid, 3-dimethylaminopropionic acid, 3-diethylaminopropionic acid, 4
-Dimethylaminobutyric acid, 5-dimethylaminovaleric acid, methoxycarbonylaminoacetic acid, ethoxycarbonylaminoacetic acid, t-butoxycarbonylaminoacetic acid, 3-methoxycarbonylaminopropionic acid, 3-ethoxycarbonylaminopropionic acid, 3-t-butoxy Carbonylaminopropionic acid, 4-t-butoxycarbonylaminobutyric acid, 5-t-butoxycarbonylaminovaleric acid,
Methoxycarbonylmethylaminoacetic acid, methoxycarbonylethylaminoacetic acid, ethoxycarbonylmethylaminoacetic acid, ethoxycarbonylethylaminoacetic acid, t-butoxycarbonylmethylaminoacetic acid, t-butoxycarbonylethylaminoacetic acid, t-butoxycarbonylpropylaminoacetic acid, 3- Methoxycarbonylmethylaminopropionic acid, 3-methoxycarbonylethylaminopropionic acid, 3-ethoxycarbonylmethylaminopropionic acid, 3-ethoxycarbonylethylaminopropionic acid, 3-t-butoxycarbonylmethylaminopropionic acid, 3-t-butoxy Carbonylethylaminopropionic acid, 4-t-butoxycarbonylmethylaminobutyric acid, 5-t-butoxycarbonylmethylaminovaleric acid, acetylacetic acid, -Acetylpropionic acid, 3-propionylpropionic acid, 4-acetylbutyric acid, 5-acetylvaleric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, cycloheptanecarboxylic acid, cyclooctanecarboxylic acid, Benzoic acid, naphthyl carboxylic acid, phenyl acetic acid, 3-phenyl propionic acid, furyl carboxylic acid, thienyl carboxylic acid, pyridyl carboxylic acid, mono-methyl carbolute, mono-ethyl carbo root, mono-propyl carbo root, mono-isopropyl carbo root, mono-butyl. Carbolute, mono-isobutyl carbolute, mono-pentyl carbolute, mono-hexyl carbolute, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesul Phosphate, pentanoic acid, hexanoic acid, benzenesulfonic acid, toluenesulfonic acid or naphthyl sulfonate.

The reaction of an acid corresponding to an amino compound or a reactive derivative thereof is carried out, for example, by an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method.

In the acid halide method, a corresponding acid is reacted with a halogenating agent (eg, thionyl chloride, phosphorus pentachloride, etc.) to produce an acid halide, which is then mixed with an amino compound in an inert solvent in the presence of a base or It is achieved by reacting in the absence of the compound. Examples of the base used include organic amines such as triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, sodium bicarbonate, alkali metal bicarbonates such as potassium bicarbonate, sodium carbonate and potassium carbonate. Alkali metal carbonates, preferably organic amines.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated compounds such as methylene chloride, dichloroethane and chloroform. Hydrocarbons, ethers, tetrahydrofuran, ethers such as dioxane, ketones such as acetone,
It may be amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, sulfoxides such as dimethylsulfoxide, preferably aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides. It is a kind.

The reaction temperature varies depending on the starting amine compound, the type of solvent, etc., but the reaction between the halogenating agent and the corresponding acid and the reaction between the acid halide and the amine compound,
Usually, it is -20 ° C to 150 ° C, preferably, the reaction between the halogenating agent and the corresponding acid is -10 ° C to 50 ° C, and the reaction between the acid halide and the amine compound is 0 ° C to 10 ° C.
0 ° C. The reaction time depends on the reaction temperature, etc.,
Usually 15 minutes to 24 hours (preferably 30 minutes to 1 hour)
6 hours).

The mixed acid anhydride method is achieved by reacting a carbonic acid lower alkyl halide or di-lower alkyl cyanophosphoric acid with the corresponding acid to prepare a mixed acid anhydride, and then reacting it with an amine compound. The reaction for producing a mixed acid anhydride is carried out by a lower carbonic acid alkyl halide such as ethyl chlorocarbonate, isobutyl chlorocarbonate, a dilower alkylcyanophosphoric acid such as diethylcyanophosphoric acid or diphenylphosphoryl azide, di (p-nitrophenyl). It is carried out by reacting a diarylphosphoryl azide such as phosphoryl azide or dinaphthyl phosphoryl azide with a corresponding acid, and preferably in an inert solvent in the presence of a base.

The base and inert solvent used are the same as those used in the above acid halide method. The reaction temperature will differ depending on the type of acid and solvent corresponding to the raw materials, but is usually -20 ° C to 50 ° C (preferably 0 ° C to 3 ° C).
The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

The reaction between the mixed acid anhydride and the amine compound is
It is preferably carried out in an inert solvent in the presence or absence of a base, and the base and inert solvent used are the same as those used in the acid halide method above. The reaction temperature will differ depending on such factors as the starting amine compound and the type of solvent, but it is usually -20 ° C to 100 ° C (preferably -1 ° C).
0 ° C to 50 ° C), and the reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 3 minutes).
0 minutes to 16 hours). Also, in this method,
When di-lower alkyl cyanophosphoric acid or diaryl phosphoryl azide is used, the amine compound and the corresponding acid can be directly reacted in the presence of a base.

The active ester method is based on a condensing agent (eg, dicyclohexylcarbodiimide, carbonyldiimidazo-
The corresponding acid with an active esterifying agent (for example, N-hydroxy compound such as N-hydroxysuccinimide, N-hydroxybenzotriazole, etc.) to produce an active ester. After that, it is achieved by reacting with an amine compound. The reaction to produce the active ester is preferably carried out in an inert solvent and the inert solvent used is similar to that used in the acid halide method above. Although the reaction temperature varies depending on the type of the starting amine compound and the solvent, it is usually -20 ° C to 50 ° C (preferably -10 ° C to 30 ° C) in the active esterification reaction. In the reaction with the compound, -20 ° C to 50 ° C (preferably -10 ° C)
The reaction time is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours) for both reactions, although the reaction time varies depending on the reaction temperature and the like.

The condensation method is carried out by using a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 1-
In the presence of (N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or the like), the reaction is carried out by directly reacting the amine compound with the corresponding acid. This reaction is
It is carried out in the same manner as the reaction for producing the above-mentioned active ester.

The reaction between the amino compound and the alkali metal cyanate or the alkali metal thiocyanate can be achieved by reacting both compounds in the presence of an acid in an inert solvent.

Acids used include mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid,
It can be an organic acid such as toluene sulfonic acid, preferably hydrochloric acid.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and for example, water, dichloromethane,
It can be halogenated hydrocarbons such as dichloroethane, chloroform, ethers such as ether, tetrahydrofuran, dioxane, preferably water. The reaction temperature is usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 40 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but is usually 1 hour to 48 hours (preferably,
5 minutes to 24 hours).

Amino compound and C ₁ -C ₆ alkyl isocyanate, C ₇ -C ₁₁ aralkyl isocyanate, C ₁
-C ₆ reaction of an alkyl isothiocyanate or C ₇ -C ₁₁ aralkyl isothiocyanate is accomplished by reacting both compounds in an inert solvent.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated compounds such as methylene chloride, dichloromethane and chloroform. Hydrocarbons, ethers such as ether, tetrahydrofuran, dioxane, alcohols such as methanol and ethanol, esters such as ethyl acetate and propyl acetate, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Amides such as or nitriles such as acetonitrile, preferably alcohols. The reaction temperature is usually -10.
C. to 50.degree. C. (preferably 10 to 30.degree. C.), and the reaction time is usually 30 minutes to 24 hours (preferably 1 to 15 hours), varying depending on the reaction temperature and the like.

The reaction of removing the portion corresponding to the protecting group of the amino group of the compound (Ia) and alkylating the produced amino group is carried out by reacting the amino compound with a C ₁ -C ₆ alkyl halide (preferably, in an inert solvent). Is methyl iodide, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, isopropyl iodide, butyl chloride, butyl iodide, isobutyl iodide, pentyl iodide, hexyl iodide)
It is achieved by reacting with.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated compounds such as methylene chloride, dichloroethane and chloroform. Hydrocarbons, ethers, tetrahydrofuran, ethers such as dioxane, ketones such as acetone,
It may be amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, sulfoxides such as dimethylsulfoxide, preferably aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides. It is a kind.

The reaction temperature will differ depending on such factors as the starting amine compound and the type of solvent, but it is usually -10 ° C to 150 ° C.
(Preferably 10 ° C to 50 ° C), and the reaction time is
Although it varies depending on the reaction temperature and the like, it is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours).

In this reaction, about 1 alkyl halide was used.
By using an equivalent amount and performing the reaction under mild conditions (for example, near room temperature), a mono-alkyl compound is obtained, and by using an alkyl halide in an amount of 2 equivalents or more, the reaction is performed.
A dialkyl body is obtained. After completion of the reaction, the target compound of each reaction can be collected from the reaction mixture according to a conventional method. For example, distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, the reaction mixture is poured into water, extracted with a water-insoluble organic solvent, dried, the solvent from the extract. Can be obtained by distilling off. Further, if necessary, a conventional method such as recrystallization,
It can be further purified by reprecipitation or chromatography.

The starting compound (II) is produced by the following method, and the starting compound (IV) is known or easily prepared according to a known method (for example, Japanese Patent Publication No. 5-85545) or a method similar thereto. Manufactured to.

[0077]

[Chemical 6]

[0078]

[Chemical 7]

[0079]

Embedded image

[0080]

[Chemical 9]

In the above formula, R ¹ , R ⁴ , R ⁵ , A and Y
Represents the same meaning as described above, and R ⁶ represents C ₁ -C ₆
An alkyl group (preferably a butyl group), and R ⁷ is C
Indicates ₁ -C ₆ alkyl group, R ⁸ is a hydrogen atom or a C ₁
-C ₆ represents an alkyl group, R ⁹ represents a C ₆ -C ₁₀ aryl group, R ¹⁰ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, Z is a halogen atom (preferably chlorine Or a bromine atom), and Za is a halogen atom (preferably chlorine or bromine atom), a C ₁ -C ₆ alkylsulfonyloxy group (preferably a methanesulfonyloxy group or an ethanesulfonyloxy group) or C ₆ A -C ₁₀ arylsulfonyloxy group (preferably a benzenesulfonyloxy group or a toluenesulfonyloxy group) is shown. However, when R ⁸ and R ¹⁰ represent a C ₁ -C ₆ alkyl group, the total number of carbon atoms of them and the alkylene group to which they are bonded is 6
It is the following.

Method C is a method for producing compound (II). Step C1 is a step of producing a compound having the general formula (VI), and is carried out by catalytic reduction or by reacting the compound having the general formula (V) with a reducing agent.

The catalytic reduction is carried out in an inert solvent (preferably alcohols such as methanol and ethanol) in the presence of a catalytic reduction catalyst (preferably palladium-calcium carbonate, palladium-barium sulfate such as Lindlar. Catalyst) and compound (V) with hydrogen gas (preferably 1 to 3 atm) and -20 ° C to 50 ° C (preferably 0 ° C to 30 atm).
C.) for 1 to 24 hours (preferably 2 to 1
It is carried out by reacting for 2 hours.

The reaction of compound (v) with a reducing agent is carried out by reacting compound (V) with a reducing agent (eg, sodium borohydride, cyano) in an inert solvent (preferably ether, ethers such as tetrahydrofuran). Hydrides such as sodium borohydride, phosphines such as tributylphosphine and triphenylphosphine, preferably phosphines, and -20 ° C to 100 ° C (preferably 0 ° C to 5).
The reaction is carried out at 0 ° C. for 5 minutes to 5 hours (preferably 10 minutes to 2 hours).

Step C2 is a step of producing a compound having the general formula (VII) except R ¹ being an amino group, and is carried out by acylating or alkylating compound (VI). This reaction is carried out in the same manner as the corresponding reaction in the above-mentioned Method B, step B1.

The step C3 is a step for producing the compound (II) in the presence of a palladium catalyst in an inert solvent (preferably aromatic hydrocarbons such as benzene, toluene and xylene). Is tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tri-o-tolylphosphine) palladium], compound (VII) with a compound having the general formula (VIII), and 0 ° C to 200 ° C ( Suitably at 50 ° C
To 150 ° C for 30 minutes to 24 hours (preferably
The reaction is performed for 1 to 12 hours.

Method D is a method for producing a compound (Va) in which A is a methylene group in the compound (V). Step D1 is a step of producing a compound having the general formula (X), in an inert solvent (preferably methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride), a radical initiator In the presence (preferably benzoyl peroxide,
2,2'-azobisisobutyronitrile), general formula (IX)
A compound having a halogenating agent (preferably N-chlorosuccinimide, N-bromosuccinimide, N-halogenosuccinimide such as N-iodosuccinimide) and 0 ° C to 200 ° C. (Preferably, 20 ° C to 10
The reaction is carried out at 0 ° C. for 2 hours to 100 hours (preferably 5 hours to 40 hours).

When a dihalide is obtained in this step, the dihalide is reduced with a reducing agent (preferably borohydride) in an inert solvent (preferably alcohols such as methanol and ethanol). Sodium, hydrides such as sodium cyanoborohydride) and -20 ° C to 100 ° C (preferably 0 ° C to 30 ° C) for 15 minutes to 5 hours (preferably 30 minutes to 2 hours). Compound (X) can also be produced by reacting.

Step D2 is a step for producing compound (Va), which is carried out in an inert solvent (preferably dimethylformamide,
Dimethylacetamide, amides such as hexamethylphosphorotriamide), compound (X) as an alkali metal azide (preferably sodium azide, potassium azide) or tri (C ₁ -C ₆ alkyl) silyl azide (preferably By reacting with trimethylsilyl azide or triethylsilyl azide at −20 ° C. to 100 ° C. (preferably 20 ° C. to 50 ° C.) for 15 minutes to 5 hours (preferably 30 minutes to 2 hours). Done.

Method E is a method for producing a compound having the general formula (Xa) including the intermediate of Method D. Step E1 is a step of producing a compound having the general formula (XII):
In II), the compound in which R ⁸ is a hydrogen atom has the general formula
A compound having (XI) is reacted with a reducing agent (preferably a hydride such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride) to produce a compound ( XI
In (I), the compound in which R ⁸ is a C ₁ -C ₆ alkyl group is the same as the compound (XI) or the compound (XII) in which R ⁸ is a hydrogen atom is oxidized in the same manner as in the F method F1 step described later. The compound thus obtained is treated with a Grignard reagent (preferably C ₃ -C ₆ alkylmagnesium chloride, C _2-
C ₆ alkyl magnesium bromide, C ₁ -C ₆ alkyl magnesium iodide,).

The reaction between the compound (XI) and the reducing agent is carried out in an inert solvent (preferably alcohols such as methanol and ethanol) -20 ° C to 100 ° C (preferably 0 ° C to 70 ° C). At a reaction temperature of 15 minutes to 5 hours (preferably 30 minutes to 2 hours).

The reaction between the compound (XI) and the like and the Grignard reagent is carried out in an inert solvent (preferably ethers such as ether, tetrahydrofuran and dioxane) at -20 ° C to 80 ° C (preferably 0 ° C). At a reaction temperature of
15 minutes to 5 hours (preferably 30 minutes to 2 hours)
Reaction time.

The step E2 is a step for producing the compound (Xa). When Za is a halogen atom, the compound (XII) is mixed with an inert solvent (preferably ethers such as ether, tetrahydrofuran and dioxane). ) Is a halogenating agent (eg, thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, etc.)
And -20 ° C to 100 ° C (preferably 0 ° C to 30 ° C)
The reaction is carried out for 15 minutes to 5 hours (preferably 30 minutes to 2 hours) at (° C.). When Za is a sulfonyloxy group, it may be reacted in the presence of a base (preferably pyridine or triethylamine). Organic amines), in an inert solvent (preferably ethers such as ether, tetrahydrofuran, dioxane), compound (XII) to a sulfonyl halide (preferably methanesulfonyl chloride,
Methanesulfonyl bromide, ethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, etc.) and -20 ° C to 100 ° C (preferably 0
C. to 50.degree. C., 15 minutes to 5 hours (preferably 3
The reaction is performed for 0 minutes to 2 hours).

Method F is the compound (V) wherein A is the formula
—CH (R ⁸ ) CH (R ¹⁰ ) — (wherein R ⁸ and R ^8
10 has the same meaning as described above. And a compound (Vb) which is a group having Step F1 is a step of producing a compound having the general formula (XIII), which is carried out in an inert solvent (preferably methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride), compound (XI
I) is an oxidizing agent [preferably pyridinium chlorochromate (PCC), pyridinium dichromate (PDC)
Chromic acid, such as dimethylsulfoxide oxalyl chloride (swenic acid)], -100 ° C to 100 ° C
The reaction is carried out at (preferably −780 ° C. to 30 ° C.) for 15 minutes to 10 hours (preferably 30 minutes to 5 hours).

Step F2 is a step for producing a compound having the general formula (XV), in the presence of a base in an inert solvent (preferably ethers such as ether, tetrahydrofuran, dioxane). Is a lithium salt such as lithium diitopropylamide or butyl lithium), compound (XIII) is a compound having the general formula (XIV)
To 100 ° C (preferably -78 ° C to 30 ° C), 1
5 minutes to 10 hours (preferably 30 minutes to 5 hours)
It is carried out by reacting.

The step F3 is a step for producing a compound having the general formula (XVI), and is carried out in an inert solvent (preferably methylene chloride, chloroform, halogenated hydrocarbon such as carbon tetrachloride or ether, Tetrahydrofuran, ethers such as dioxane), in the presence of water, the compound (X
V) with an acid (preferably a mineral acid such as hydrochloric acid or sulfuric acid, a sulfonic acid such as p-toluenesulfonic acid or pyridinium p-toluenesulfonic acid), and -20 ° C to 100 ° C (preferably 0 ° C). The reaction is carried out at 15 ° C to 30 ° C for 15 minutes to 5 hours (preferably 30 minutes to 2 hours).

Step F4 is a step for producing a compound having the general formula (XVII) and is achieved by reducing compound (XVI). This reaction is carried out in the same manner as in Method E, Step E1.

Step F5 is a step for producing a compound having the general formula (XVIII) and is accomplished by halogenating compound (XVII). This reaction is carried out in the same manner as in Method E, Step E2. .

Step F6 is a step for producing compound (Vb) and is accomplished by azidating compound (XVIII). This reaction is carried out in the same manner as in method D, step D2.

Further, in the compound (V), a compound having a larger number of carbon atoms than the compound (Vb) can be produced by sequentially carrying out the reaction of the F2 to F6 steps using the compound (XVI).

After completion of the reaction, the target compound of each step can be collected from the reaction mixture according to a conventional method. For example, when an insoluble matter is present, it is appropriately filtered, and when the reaction solution is acidic or alkaline, it is appropriately neutralized and the solvent is distilled off from the reaction mixture or, if necessary, the solvent is removed from the reaction mixture. After distilling off, the reaction mixture is poured into water, extracted with a water-insoluble organic solvent, dried and the solvent is distilled off from the extract. Further, if necessary, it can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

The compounds (VIII), (IX) and (XI) are known or known methods [eg, tetrahedron letters, 24, 2361, 1983: Tetrahedron Let.
t., 24 , 2361 (1983), Heterocycles, Volume 22, Volume 7
9 pages, 1984: Heterocycles, 22 , 79 (1984), Collection Czechoslovak Chemical Communication, Volume 26, 2871, 1961: Collection Czechos
Chem. Commun., 26 , 2871 (1961), etc.] or a method similar thereto.

[0103]

The thiourea derivative of the present invention has excellent histamine H ₂ antagonistic activity, gastric acid secretion inhibitory activity and excellent antibacterial activity against Helicobacter pylori, and has peptic ulcer, acute or chronic gastric ulcer, Useful as a preventive agent for ulcerative diseases such as duodenal ulcer, gastritis, reflux esophagitis, gastroesophageal reflex disease, dyspepsia, hyperacidity, Solinger-Ellison syndrome, etc. Is. Compound of the present invention
The dosage form of (I) includes, for example, tablets, capsules,
Oral administration by granules, powders, syrups and the like, or parenteral administration by injections and the like can be mentioned. These formulations include excipients (eg lactose, mannitol, corn starch, crystalline cellulose etc.), binders (eg cellulose derivatives, gum arabic, gelatin etc.),
Additives such as disintegrants (eg, carboxymethylcellulose calcium), lubricants (eg, talc, magnesium stearate, etc.), stabilizers, flavoring agents, solvents for injections (eg, water, ethanol, glycerin, etc.) Is manufactured by a known method. Although the amount used varies depending on symptoms, age and the like, 1 mg to 2000 mg (preferably 10 to 400 mg) per day can be administered to an adult once or several times a day. Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples.

[0104]

【Example】

Example 1 4- (4-acetylaminomethylpyrimidin-2-i
) -2- ( Diaminomethyleneamino ) thiazole 4-acetylaminomethyl-2- (1-ethoxyvinyl) pyrimidine (416 mg) was dissolved in a mixed solution of 20 ml of tetrahydrofuran and 2 ml of water, and N-bromosuccinimide was cooled under ice cooling. 325 mg was added, and the mixture was stirred under ice cooling for 10 minutes. Water was added and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-acetylaminomethyl-2-bromoacetylpyrimidine as a crude product. Dissolve the above residue in 20 ml of ethanol, add 222 mg of diaminomethylene thiourea, and 40 ° C.
For 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in water, made alkaline with a 20% aqueous potassium carbonate solution, extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with methanol-ethyl acetate-triethylamine (2: 5: 0.3) to obtain 370 mg of the target compound as a powder (yield 68%). Melting point: 195-200 ° C (decomposition). NMR spectrum, δppm (DMSO-d ₆ ): 1.93 (3H, s), 4.35
(2H, d, J = 5.8Hz), 7.21 (1H, d, J = 5.1Hz), 6.98-7.35 (4H, b
r), 7.67 (1H, s), 8.57 (1H, t, J = 5.8Hz), 8.73 (1H, d, J = 5.
1Hz). IR spectrum, ν _max cm ^-1 (KBr): 3321, 2926, 1656,
1551, 1513, 1487, 1460, 1440, 1407, 1250, 1028, 980
. The target compound obtained above was dissolved in methanol, 2 equivalents of 4N-hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes, diisopropyl ether was added, and the resulting precipitate was collected by filtration to obtain the target compound. The hydrochloride salt was obtained. Melting point: 205
-208 ° C.

Example 2 4- (4-cyclohexylcarbonylaminomethylpyridin
Midin-2-yl) -2- (diaminomethyleneamino)
Thiazole 4-cyclohexylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine was reacted in the same manner as in Example 1 to give the target compound as a powder in a yield of 7
Obtained at 4%. Melting point: 263-265 [deg.] C. (decomposition). NMR spectrum, δppm (DMSO-d ₆ ): 1.10-1.88 (10H,
m), 2.25 (1H, tt, J = 11.2Hz and 3.2Hz), 4.34 (2H, d, J =
5.9Hz), 7.13 (1H, d, J = 5.2Hz), 6.84-7.38 (4H, br), 7.64
(1H, s), 8.40 (1H, t, J = 5.9Hz), 8.73 (1H, d, J = 5.2Hz). IR spectrum, ν _max cm ^-1 (KBr): 3352, 3136, 2923,
1665, 1550, 1516,1464, 1437, 1407, 1339, 1256, 124
4, 980, 733.

Example 3 4- (4-Cycloheptylcarbonylaminomethylpyri
Midin-2-yl) -2- (diaminomethyleneamino)
Thiazole 4-cycloheptylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine was reacted in the same manner as in Example 1 to give the target compound as a powder in a yield of 7
Obtained in 9%. Melting point: 235-240 ° C (decomposition). NMR spectrum, δppm (DMSO-d ₆ ): 1.30-2.00 (12H,
m), 2.34-2.49 (1H, m), 4.33 (2H, d, J = 5.9Hz), 7.14 (1H, d,
J = 5.1Hz), 6.90-7.38 (4H, br), 7.64 (1H, s), 8.41 (1H, t, J
= 5.9Hz), 8.73 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (KBr): 3449, 3387, 3266,
2923, 1636, 1570, 1531, 1454, 1416, 1244, 1224, 750
.

Example 4 4- (4-Acetylaminomethyl-6-methylpyrimidimy
N-2-yl) -2- (diaminomethyleneamino) thia
Zol 4-acetylaminomethyl-2- (1-ethoxyvinyl) -6-methylpyrimidine was reacted in the same manner as in Example 1 to give the target compound as a powder in a yield of 8
Obtained at 8%. Melting point; 150-160 [deg.] C. NMR spectrum, δppm (DMSO-d ₆ ): 1.95 (3H, s), 2.47
(3H, s), 4.31 (2H, d, J = 6.0Hz), 7.08 (1H, s), 6.92-7.40
(4H, br), 7.64 (1H, s), 8.51 (1H, t, J = 6.0Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3322, 2926, 165
6, 1613, 1588, 1542,1516, 1487, 1459, 1372, 1263,
1027, 788.

Example 5 4- (4-acetylaminomethylpyrimidin-2-i)
) -2-[(amino) (propylamino) methylenea
Mino] thiazole (amino) (propylamino) methylenethiourea was used and reacted in the same manner as in Example 1 to obtain the target compound as a powder in a yield of 66%. Melting point: 90-95 ° C (decomposition). NMR spectrum, δppm (CDCl ₃ ): 1.05 (3H, t, J = 7.2H
z), 1.71 (2H, sextet, J = 7.2Hz), 2.11 (3H, s), 3.21 (2H, t
d, J = 7.2Hz and 5.1Hz), 4.57 (2H, d, J = 5.3Hz), 6.58-
6.76 (1H, br), 7.11 (1H, d, J = 5.1Hz), 7.71 (1H, s), 8.68
(1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3429, 2994, 297
1, 1672, 1622, 1557, 1514, 1473, 1439.

Example 6 4- (4-acetylaminomethylpyrimidin-2-i)
) -2-[(amino) (pentylamino) methylenea
Mino] thiazole 4-acetylaminomethyl-2- (1-ethoxyvinyl) pyrimidine (480 mg) was dissolved in a mixed solution of tetrahydrofuran (20 ml) and water (2 ml), and N-bromosuccinimide (375 mg) was added under ice-cooling. Stir for 10 minutes. Water was added and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-acetylaminomethyl-2-bromoacetylpyrimidine as a crude product. The above residue was dissolved in 40 ml of ethanol, 409 mg of (N-pentylguanyl) thiourea was added, and the mixture was stirred at 40 ° C. for 2.5 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in water, made alkaline with a 20% aqueous potassium carbonate solution, extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with methanol-ethyl acetate (1: 6) to obtain 500 mg of the target compound as a powder (yield 63%). Melting point; 75-80 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 2.11 (3H, s), 3.22 (2
H, td, J = 6.8Hz and 5.1Hz), 4.57 (2H, d, J = 5.3Hz), 6.63
-6.78 (1H, br), 7.15 (1H, d, J = 4.9Hz), 7.70 (1H, s), 8.68
(1H, d, J = 4.9Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3492, 3427, 299
6, 2962, 2935, 2864,1672, 1622, 1556, 1513, 1471,
1439. The target compound obtained above was dissolved in methanol, 2 equivalents of 4N-hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes, diisopropyl ether was added, and the formed precipitate was collected by filtration to obtain the target compound. A hydrochloric acid weir was obtained. Melting point: 138
-140 ° C.

Example 7 2-[(amino) (pentylamino) methyleneamino]
-4- (4-cyclohexylcarbonylaminomethylpi)
Limidin-2-yl) thiazole 4-cyclohexylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine was reacted in the same manner as in Example 6 to obtain the target compound as a powder with a yield of 87%. Melting point; 80-85 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 0.91 (3H, t, J = 6.9H
z), 1.18-2.00 (16H, m), 2.22 (1H, tt, J = 11.5Hz and 3.4
Hz), 3.21 (2H, td, J = 6.9Hz and 5.2Hz), 4.56 (2H, d, J =
5.2Hz), 6.63-6.83 (1H, br), 7.09 (1H, d, J = 5.1Hz), 7.69
(1H, s), 8.67 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3500, 3429, 299
5, 2960, 2935, 2859,1661, 1621, 1555, 1510, 1472,
1439.

Example 8 2-[(amino) (pentylamino) methyleneamino]
-4- (4-cycloheptylcarbonylaminomethylpi
Limidin-2-yl) thiazole 4-cycloheptylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine was reacted in the same manner as in Example 6 to obtain the target compound as a powder in a yield of 57%. Melting point; 85-90 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 0.91 (3H, t, J = 7.0H
z), 1.30-2.02 (18H, m), 2.29-2.43 (1H, m), 3.22 (2H, td, J
= 7.1Hz and 5.3Hz), 4.56 (2H, d, J = 5.3Hz), 6.55-6.68
(1H, br), 7.09 (1H, d, J = 5.1Hz), 7.69 (1H, s), 8.67 (1H,
d, J = 5.1 Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3429, 2932, 286
1, 1660, 1621, 1556,1513, 1472, 1439, 1412, 1344,
1146.

Example 9 2-[(amino) (pentylamino) methyleneamino]
-4- [4- (3-ethylureido) methylpyrimidine
2-yl] thiazole 2- (1-ethoxyvinyl) -4- (3-ethylureido) methylpyrimidine was reacted in the same manner as in Example 6 to give the target compound as a powder in a yield of 66%. Obtained. Melting point; 110-117 [deg.] C. NMR spectrum, δppm (DMSO-d ₆ ): 0.89 (3H, t, J = 7.1H
z), 1.06 (3H, t, J = 7.1Hz), 1.22-1.39 (4H, m), 1.41-1.59
(2H, m), 3.05 (2H, qd, J = 7.1Hz and 5.6Hz), 3.17 (2H, t
d, J = 6.6Hz and 5.8Hz), 4.30 (2H, d, J = 5.9Hz), 6.20 (1
H, t, J = 5.6Hz), 6.5 (1H, t, J = 5.9Hz), 7.17 (1H, d, J = 5.1H
z), 7.66 (1H, s), 8.72 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (KBr): 3332, 2957, 2930,
1629, 1553, 1512, 1467, 1439, 1411, 1384, 1346, 124
Five.

Example 10 2-[(amino) (pentylamino) methyleneamino]
-4- (4-t-butoxycarbonylaminomethylpyri
Midin-2-yl) thiazole 4-t-butoxycarbonylaminomethyl-2- (1-
(Ethoxyvinyl) pyrimidine was reacted in the same manner as in Example 6 to give the target compound as a powder in a yield of 9
Obtained at 2%. Melting point; 69-74 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 0.92 (3H, t, J = 7.0H
z), 1.48 (9H, s), 1.31-1.51 (4H, m), 1.59-1.73 (2H, m),
3.23 (2H, td, J = 6.7Hz and 5.1Hz), 4.45 (2H, d, J = 5.6H
z), 5.41-5.55 (1H, br), 7.12 (1H, d, J = 5.1Hz), 7.73 (1H,
s), 8.69 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3440, 2982, 293
5, 1710, 1622, 1556, 1509, 1473, 1166.

Example 11 4- (4-acetylaminomethyl-6-methylpyrimidimy
N-2-yl) -2-[(amino) (pentylamino)
Methyleneamino] thiazole 4-acetylaminomethyl-2- (1-ethoxyvinyl) -6-methylpyrimidine was reacted in the same manner as in Example 6 to give the target compound as a powder in a yield of 7
Obtained in 9%. Melting point; 60-70 ° C. NMR spectrum, δppm (CDCl ₃ ): 0.89 (3H, t, J = 7.0H
z), 1.21-1.47 (4H, m), 1.52-1.72 (2H, m), 2.09 (3H, s),
2.54 (3H, s), 3.20 (2H, td, J = 6.9Hz and 5.0Hz), 4.51
(2H, d, J = 5.3Hz), 6.79-6.92 (1H, br), 6.97 (1H, s), 7.68
(1H, s). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3494, 3428, 296
3, 2935, 2864, 1669,1622, 1590, 1549, 1513, 1471,
1396, 1372, 1272.

Example 12 2-[(amino) (pentylamino) methyleneamino]
-4- [4- (3-ethylthioureido) methylpyrimi
Din-2-yl] thiazole 2-[(amino) (pentylamino) methyleneamino]
220 mg of -4- (4-t-butoxycarbonylaminomethylpyrimidin-2-yl) thiazole was dissolved in 10 ml of chloroform, 0.1 ml of iodotrimethylsilane was added, and the mixture was stirred at room temperature for 40 minutes. After adding a 10% aqueous sodium hydroxide solution, the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained residue was dissolved in 10 ml of ethanol, 54 mg of ethyl isothiocyanate was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. After adding water, the solvent was distilled off, and the obtained residue was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, and eluted with methanol-ethyl acetate (1:19) to give the target compound as a powder in 1
40 mg was obtained (yield 72%). Melting point; 95-98 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 0.92 (3H, t, J = 7.0H
z), 1.28 (3H, t, J = 6.8Hz), 1.33-1.49 (4H, m), 1.54-1.76
(2H, m), 3.22 (2H, td, J = 6.9Hz and 4.8Hz), 3.48 (2H, q
d, J = 6.8Hz and 5.4Hz), 4.86 (2H, d, J = 3.9Hz), 6.27-6.
42 (1H, br), 7.08-7.18 (1H, br), 7.16 (1H, d, J = 5.1Hz),
7.65 (1H, s), 8.70 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3431, 2964, 162
1, 1557, 1516, 1474, 1439, 1058.

Example 13 2-[(amino) (pentylamino) methyleneamino]
-4- [4- (3-benzylthioureido) methylpyri
By using benzyl [midin-2-yl] thiazole isothiocyanate and reacting in the same manner as in Example 12, the target compound was obtained as a powder in a yield of 5
Obtained at 7%. Melting point; 91-94 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 0.90 (3H, t, J = 6.9H
z), 1.28-1.42 (4H, m), 1.51-1.65 (2H, m), 3.10 (2H, td, J =
6.8Hz and 5.0Hz), 4.70 (2H, d, J = 4.8Hz), 4.83 (2H, s),
6.15-6.72 (1H, br), 6.90-7.13 (1H, br), 7.08 (1H, d, J =
5.1Hz), 7.22-7.48 (6H, m), 8.63 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3436, 2963, 293
5, 1621, 1557, 1471, 1439, 1343.

Example 14 2-[(amino) (pentylamino) methyleneamino]
-4- [4- (2-thiophene) carbonylaminomethyi
Lupyrimidin-2-yl] thiazole 2-[(amino) (pentylamino) methyleneamino]
445 mg of 4- (4-t-butoxycarbonylaminomethylpyrimidin-2-yl) thiazole was dissolved in 15 ml of chloroform, 0.5 ml of iodotrimethylsilane was added, and the mixture was stirred at room temperature for 30 minutes. After adding a 10% aqueous sodium hydroxide solution, the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained residue was dissolved in 10 ml of N, N-dimethylformamide and 163 mg of thenoic acid and diethyl cyanophosphate were added under ice cooling.
90 mg and 0.12 ml of triethylamine were added, and the mixture was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with methanol-ethyl acetate (1: 9) to obtain 180 mg of the target compound as a powder (yield 40
%). NMR spectrum, δppm (CDCl ₃ ): 0.91 (3H, t, J = 7.3H
z), 1.28-1.48 (4H, m), 1.54-1.75 (2H, m), 3.20 (2H, td, J =
7.3Hz and 5.3Hz), 4.76 (2H, d, J = 5.3Hz), 7.11-7.18 (2
H, m), 7.33-7.44 (1H, br), 7.53 (1H, d, J = 5.1Hz), 7.64 (1
H, d, J = 4.0Hz), 7.72 (1H, s), 8.70 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3434, 2964, 162
1, 1557, 1502, 1473, 1439.

Reference Example 1 4-Bromomethyl-2-chloropyrimidine and 2-ku
Lolo-4-dibromomethylpyrimidine 11.4 g of 2-chloro-4-methylpyrimidine was dissolved in 200 ml of carbon tetrachloride to give N-bromosuccinimide 3
9.3g and benzoyl peroxide 1.43g were added, and it heated and refluxed for 20 hours. After cooling, the precipitate was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 5) to give 1.89 g of 4-bromomethyl-2-chloropyrimidine as an oil (yield 10%),
9.39 g of 2-chloro-4-dibromomethylpyrimidine was obtained as an oil (37% yield). 4-Bromomethyl-2-chloropyrimidine NMR spectrum, δppm (CDCl ₃ ): 4.43 (2H, s), 7.46 (1
H, d, J = 5.1Hz), 8.67 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3000, 1570, 154
6, 1430, 1344, 1185, 1170, 916, 843. 2-chloro-4-dibromomethyl-pyrimidine NMR _{spectrum, δppm (CDCl 3): 6.45} (1H, s), 7.77 (1
H, d, J = 5.1Hz), 8.76 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3000, 1567, 154
4, 1430, 1342, 1186, 1175, 920, 848.

Reference Example 2 4-Bromomethyl-2-chloropyrimidine 2-chloro-4-dibromomethylpyrimidine 6.43 g
Was dissolved in 100 ml of ethanol, 0.850 g of sodium borohydride was added under ice cooling, and the mixture was stirred under ice cooling for 90 minutes. After adding water, the mixture was concentrated under reduced pressure, and the residue was extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, and eluted with ethyl acetate-hexane (1: 5) to give the object compound as an oil.
50 g was obtained (yield 54%). NMR spectrum, δppm (CDCl ₃ ): 4.43 (2H, s), 7.46 (1
H, d, J = 5.1Hz), 8.67 (1H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3000, 1570, 154
6, 1430, 1344, 1185, 1170, 916, 843.

Reference Example 3 4-Azidomethyl-2-chloropyrimidine To a solution of 69 mg of sodium azide in 5 ml of N, N-dimethylformamide, a solution of 200 mg of 4-bromomethyl-2-chloropyrimidine in 2 ml of N, N-dimethylformamide was ice-cooled. After dropping, the mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with a mixed solution of ethyl acetate-hexane (1: 1). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, and eluted with ethyl acetate-hexane (1: 4) to give 160 mg of the target compound as white crystals (yield 98%). Melting point: 34-35 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 4.54 (2H, s), 7.39 (1
H, d, J = 4.9Hz), 8.67 (1H, d, J = 4.9Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3000, 2113, 157
4, 1548, 1431, 1352, 1285, 1184, 837.

Reference Example 4 4- Acetylaminomethyl-2-chloropyrimidine 720 mg of 4-azidomethyl-2-chloropyrimidine was dissolved in 15 ml of tetrahydrofuran, 1.22 g of triphenylphosphine was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. did. After adding water, the mixture was stirred for 10 minutes and extracted with chloroform. After drying the extract over anhydrous magnesium sulfate,
Concentration under reduced pressure gave 4-aminomethyl-2-chloropyrimidine as a crude product. The above residue was dissolved in 9 ml of pyridine, and 866 mg of acetic anhydride was slowly added dropwise under ice cooling, followed by stirring at room temperature for 3 hours. After concentration under reduced pressure, water was added and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, eluted with methanol-methylene chloride (1:40), and the target compound was crystallized in an amount of 610 mg.
Obtained (yield 78%). Melting point: 114-115 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 2.11 (3H, s), 4.54 (2
H, d, J = 5.6Hz), 6.32-6.59 (1H, br), 7.25 (1H, d, J = 5.0H
z), 8.58 (1H, d, J = 5.0Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3454, 3346, 300
0, 1675, 1576, 1545,1514, 1433, 1358, 1338, 1272,
1152, 901.

Reference Example 5 4-Acetylaminomethyl-2- (1-ethoxyvinyl)
1) Pyrimidine 4-acetylaminomethyl-2-chloropyrimidine 1.
12 g was dissolved in 30 ml of toluene, 4.36 g of (1-ethoxyvinyl) tributyltin and 0.21 g of bis (triphenylphosphine) palladium (II) chloride were added, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with methanol-ethyl acetate (1: 9) to obtain 1.22 g of the target compound as yellow crystals (yield 91%). Melting point: 90-92 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.52 (3H, t, J = 7.3H
z), 2.11 (3H, s), 4.06 (2H, q, J = 7.3Hz), 4.58 (2H, d, J = 5.
3Hz), 4.67 (1H, d, J = 2.0Hz), 5.70 (1H, d, J = 2.0Hz), 6.48
-6.74 (1H, br), 7.18 (1H, d, J = 4.7Hz), 8.73 (1H, d, J = 4.7H
z). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3453, 2995, 167
3, 1576, 1559, 1512, 1441, 1220, 1061.

Reference Example 6 2-Chloro-4-cyclohexylcarbonylaminomethyi
1.46 g of rubilimidine 4-azidomethyl-2-chloropyrimidine was dissolved in 25 ml of ethanol, 0.20 g of 5% palladium-calcium carbonate was added as a catalyst, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After separating the catalyst by filtration, concentration under reduced pressure,
4-Aminomethyl-2-chloropyrimidine was obtained. 1.26 g of the above residue was dissolved in a mixed solution of 30 ml of methylene chloride and 15 ml of N, N-dimethylformamide, 1.21 g of cyclohexanecarboxylic acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.
98 g and a catalytic amount of dimethylaminopyridine are added,
The mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 1) to give 1.30 g of the desired compound as crystals (yield 60%). Melting point: 139-141 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 1.19-1.95 (10H, m),
2.21 (1H, tt, J = 11.4Hz and 3.5Hz), 4.53 (2H, d, J = 5.7H
z), 6.32-6.50 (1H, br), 7.23 (1H, d, J = 5.0Hz), 8.56 (1H,
d, J = 5.0 Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3454, 3050, 293
6, 2858, 1672, 1576,1547, 1509, 1452, 1434, 1360,
1341.

Reference Example 7 4-Cyclohexylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine 2-chloro-4-cyclohexylcarbonylaminomethylpyridine was reacted in the same manner as in Reference Example 5 to obtain the target compound as a yellow powder in a yield of 76%. Melting point: 133-135 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.50 (3H, t, J = 7.3H
z), 1.21-2.05 (10H, m), 2.22 (1H, tt, J = 11.5Hz and 3.3
Hz), 4.04 (2H, q, J = 7.3Hz), 4.56 (1H, d, J = 5.3Hz), 4.65
(1H, d, J = 2.0Hz), 5.69 (1H, d, J = 2.0Hz), 6.61-6.80 (1H, b
r), 7.15 (1H, d, J = 5.3Hz), 8.70 (1H, d, J = 5.3Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3452, 2990, 293
5, 2858, 1661, 1576, 1559, 1510, 1440, 1308, 1200,
1062, 830.

Reference Example 8 2-Chloro-4-cycloheptylcarbonylaminomethyi
By reacting with rupyrimidine cycloheptanecarboxylic acid in the same manner as in Reference Example 6, the target compound was obtained as a crystal in a yield of 81.
Earned in%. Melting point: 98-101 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.40-1.83 (10H, m),
1.85-2.01 (2H, m), 2.28-2.43 (1H, m), 4.52 (2H, d, J = 5.7H
z), 6.27-6.48 (1H, br), 7.24 (1H, d, J = 5.1Hz), 8.57 (1H,
d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3454, 3000, 293
1, 2860, 1672, 1576, 1547, 1505, 1434, 1360, 1341,
1094.

Reference Example 9 4-Cycloheptylcarbonylaminomethyl-2- (1
-Ethoxyvinyl) pyrimidine 2-chloro-4-cycloheptylcarbonylaminomethylpyrimidine was reacted in the same manner as in Reference Example 5 to obtain the target compound as a yellow powder in a yield of 54%. Melting point: 98-101 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.51 (3H, t, J = 7.3H
z), 1.48-1.98 (10H, m), 1.90-2.06 (2H, m), 2.33-2.44 (1
H, m), 4.05 (2H, q, J = 7.3Hz), 4.55 (2H, d, J = 5.3Hz), 4.65
(1H, d, J = 1.9Hz), 5.69 (1H, d, J = 1.9Hz), 6.52-6.70 (1H, b
r), 7.16 (1H, d, J = 5.3Hz), 8.71 (1H, d, J = 5.3Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3452, 2994, 293
1, 2859, 1665, 1576, 1559, 1505, 1440, 1308, 1200,
1062, 860.

Reference Example 10 2-Chloro-4- (3-ethylureido) methylpyrimi
1.50 g of gin 4-azidomethyl-2-chloropyrimidine was dissolved in 40 ml of ethanol, 0.20 g of 5% palladium-calcium carbonate was added as a catalyst, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After separating the catalyst by filtration, concentration under reduced pressure,
4-Aminomethyl-2-chloropyrimidine was obtained. The above residue was mixed with 6 ml of methanol and 18 ml of tetrahydrofuran.
The resulting mixture was dissolved in a mixed solution of 1), 0.75 g of ethyl isocyanate and 3.7 ml of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Water was added and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography,
It was eluted with ethyl acetate to obtain 0.62 g of the desired product as a powder (yield 33%). Melting point: 150-152 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.17 (3H, t, J = 7.2H
z), 3.25 (2H, qd, J = 7.2Hz and 5.5Hz), 4.49 (2H, d, J = 5.
7Hz), 4.35-4.51 (1H, br), 5.09-5.20 (1H, br), 7.30 (1H,
d, J = 5.2Hz), 8.56 (1H, d, J = 5.2Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3450, 3010, 167
5, 1577, 1538, 1535, 1434, 1354, 1340.

Reference Example 11 2- (1-ethoxyvinyl) -4- (3-ethylurei)
De) Methylpyrimidine 2-chloro-4- (3-ethylureido) methylpyrimidine is reacted in the same manner as in Reference Example 5,
The target compound was obtained as a white solid with a yield of 82%. Melting point: 156-158 [deg.] C. NMR spectrum, δppm (CDCl ₃ ): 1.18 (3H, t, J = 7.3H
z), 1.50 (3H, t, J = 7.0Hz), 3.26 (2H, qd, J = 7.3Hz and 5.
7Hz), 4.05 (2H, q, J = 7.0Hz), 4.51 (2H, d, J = 5.4Hz), 4.44
-4.55 (1H, br), 4.64 (1H, d, J = 2.1Hz), 5.27-5.38 (1H, b
r), 5.67 (1H, d, J = 2.1Hz), 7.21 (1H, d, J = 5.1Hz), 8.71 (1
H, d, J = 5.1Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3455, 2993, 167
0, 1576, 1559, 1534, 1442, 1309, 1190, 1061.

Reference Example 12 4-t-Butoxycarbonylaminomethyl-2-chloro
2.01 g of pyrimidine 4-azidomethyl-2-chloropyrimidine was dissolved in 20 ml of ethanol, 0.20 g of 5% palladium-calcium carbonate was added as a catalyst, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After separating the catalyst by filtration, concentration under reduced pressure,
4-Aminomethyl-2-chloropyrimidine was obtained as a crude product. 30 ml of dichloromethane and N, N
-Dissolved in a mixed solution of 20 ml of dimethylformamide, added 2.24 g of di-t-butyl-dicarbonate, and stirred at room temperature for 16 hours. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 3) to obtain 1.28 g of the desired product as crystals (yield 45%). Melting point: 60-61 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.47 (9H, s), 4.42 (2
H, d, J = 6.0Hz), 5.23-5.48 (1H, br), 7.28 (1H, d, J = 5.2H
z), 8.58 (1H, d, J = 5.2Hz). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3460, 2984, 171
4, 1576, 1549, 1504, 1369, 1344, 1165, 860.

Reference Example 13 4-t-butoxycarbonylaminomethyl-2- (1-
Ethoxyvinyl) pyrimidine 4-t-butoxycarbonylaminomethyl-2-chloropyrimidine was reacted in the same manner as in Reference Example 5 to obtain the target compound as an oil in a yield of 95%. NMR spectrum, δppm (CDCl ₃ ): 1.48 (9H, s), 1.50 (3
H, t, J = 7.0Hz), 4.05 (2H, q, J = 7.0Hz), 4.45 (2H, d, J = 5.8H
z), 4.64 (1H, d, J = 2.0Hz), 5.32-5.48 (1H, br), 5.70 (1H,
d, J = 2.0Hz), 7.19 (1H, d, J = 5.2Hz), 8.73 (1H, d, J = 5.2H
z). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3459, 2985, 293
4, 1711, 1576, 1559, 1505, 1442, 1369, 1309, 1166,
1061.

Reference Example 14 2-Chloro-4-hydroxymethyl-6-methylpyrimi
2.19 g of gin 2-chloro-4-methoxycarbonyl-6-methylpyrimidine was dissolved in 100 ml of methanol, 0.665 g of sodium borohydride was added under ice cooling, and the mixture was stirred under ice cooling for 1 hour. After adding water, the mixture was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.54 g of the desired compound as an oily substance (yield 83%). NMR spectrum, δppm (CDCl ₃ ): 2.56 (3H, s), 4.74 (2
H, d, J = 5.0Hz), 7.27 (1H, s). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3627, 3000, 159
1, 1537, 1444, 1418, 1346, 1260, 1070, 875.

Reference Example 15 2-chloro-4-azidomethyl- 6-methylpyrimidine 1.54 g of 2-chloro-4-hydroxymethyl-6-methylpyrimidine was dissolved in 50 ml of tetrahydrofuran,
Methanesulfonyl chloride (1.34 g) and triethylamine (1.63 ml) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours.
After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 5 ml of N, N-dimethylformamide. This solution was cooled with ice to give 0.761 g of N, N sodium azide.
-Dripping into a solution of 20 ml of dimethylformamide, the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with a mixed solution of ethyl acetate-hexane (1: 1). The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, and eluted with ethyl acetate-hexane (4: 1) to give 1.68 g of the desired compound as an oil (yield 94%). NMR spectrum, δppm (CDCl ₃ ): 2.58 (3H, s), 4.49 (2
H, s), 7.23 (1H, s). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3000, 1588, 153
7, 1429, 1324, 1240, 874.

Reference Example 16 4-Acetylaminomethyl-2-chloro-6-methylpi
Limidin 4-azidomethyl-2-chloro-6-methylpyrimidine was used and reacted in the same manner as in Reference Example 4 to obtain the target compound as crystals in a yield of 71%. Melting point: 91-93 ° C. NMR spectrum, δppm (CDCl ₃ ): 2.10 (3H, s), 2.53 (3
H, s), 4.48 (2H, d, J = 5.7Hz), 6.35-6.55 (1H, br), 7.10 (1
H, s). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3455, 3000, 167
6, 1589, 1535, 1512, 1262.

Reference Example 17 4-Acetylaminomethyl-2- (1-ethoxyvinyl)
Le) -6-Methylpyrimidine 4-acetylaminomethyl-2-chloro-6-methylpyrimidine was reacted in the same manner as in Reference Example 5 to obtain the target compound as yellow crystals in a yield of 83%. Melting point: 106-108 ° C. NMR spectrum, δppm (CDCl ₃ ): 1.50 (3H, t, J = 7.0H
z), 2.09 (3H, s), 2.55 (3H, s), 4.05 (2H, q, J = 7.0Hz), 4.
52 (2H, d, J = 5.2Hz), 4.63 (1H, D, J = 1.9Hz), 5.64 (1H, d, J =
1.9Hz), 6.63-6.76 (1H, br), 7.04 (1H, s). IR spectrum, ν _max cm ^-1 (CHCl ₃ ): 3453, 2995, 293
3, 1670, 1588, 1549, 1512, 1447, 1378, 1273, 1063.

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[Procedure amendment]

[Submission date] January 11, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0038

[Correction method] Change

[Correction content]

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[Chemical 4]

Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C07D 417/14 239 (72) Inventor Keiichi Tabata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. Within

Claims (41)

[Claims] 1. A general formula: [In the formula, R ¹ is an amino group, mono- or di-C _1-
C ₆ alkylamino group, C ₁ -C ₆ alkanoylamino group, (C ₁ -C ₆ alkoxy) -C ₂ -C ₅ alkanoylamino group, a halogeno -C ₂ -C ₅ alkanoylamino group, an amino -C ₂ -C ₅ Alkanoylamino group, (mono- or di-C ₁ -C ₆ alkylamino) -C ₂ -C
₅ alkanoylamino groups, (C ₁ -C ₆ alkoxycarbonylamino) -C ₂ -C ₅ alkanoylamino groups,
(C ₁ -C ₆ alkoxycarbonyl-mono-C ₁ -C ₆
Alkylamino) -C ₂ -C ₅ alkanoylamino group,
(C ₁ -C ₆ alkanoyl) -C ₂ -C ₅ alkanoylamino group, C ₃ -C ₈ cycloalkyl carbonyl amino group, C ₆ -C ₁₀ arylcarbonylamino group, C ₇ -C
₁₁ Aralkylcarbonylamino group, 5- or 6-membered cyclic heteroarylcarbonylamino group containing nitrogen, oxygen or sulfur atom, C ₁ -C ₆ alkoxycarbonylamino group, (C ₁ -C ₆ alkoxycarbonyl) -mono-C
₁ -C ₆ alkylamino group, C ₁ -C ₆ alkanesulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a ureido group, C ₁ -C ₆ alkyl ureido group, C ₇
-C ₁₁ aralkyl ureido group, thioureido group, C ₁ -
C ₆ alkyl thioureido group, C ₇ -C ₁₁ aralkyl thioureido group or a phthalimido group, R ² and R ³ are the same or different and each represents a hydrogen atom or a C ₁ -C ₁₀ alkyl group, R ⁴ is, It represents a hydrogen atom or a C ₁ -C ₆ alkyl group, a is a C ₁ -C ₆ alkylene group. ] The thiazole derivative which has these, or its pharmacologically acceptable salt. 2. R ¹ is an amino group, mono- or di-C _1.
-C ₄ alkylamino group, C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₄ alkoxy) -C ₂ -C ₃ alkanoylamino group, a halogeno -C ₂ -C ₃ alkanoylamino groups, amino -C ₂ - C ₃ alkanoylamino group, (mono- or di-C ₁ -C ₄ alkylamino) -C ₂ -
A C ₃ alkanoylamino group, a (C ₁ -C ₄ alkoxycarbonylamino) -C ₂ -C ₃ alkanoylamino group,
(C ₁ -C ₄ Alkoxycarbonyl-mono-C ₁ -C ₄
Alkylamino) -C ₂ -C ₃ alkanoylamino group,
(C ₂ -C ₃ alkanoyl) -C ₂ -C ₃ alkanoylamino groups, C ₃ -C ₇ cycloalkyl carbonyl amino group, C ₆ aryl carbonylamino group, C ₇ -C ₈ aralkyl carbonyl amino group, 1 or 2 5 to 6-membered cyclic heteroarylcarbonylamino group containing a nitrogen, oxygen or sulfur atom, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄ alkoxycarbonyl-mono-C ₁ -C ₄ alkylamino group, C ₁ -C ₂ alkane sulfonylamino group, C ₆ arylsulfonylamino group, a ureido group, C ₁ -C ₄ alkyl ureido group, C ₇ -C ₈
The thiazole derivative according to claim 1, which is an aralkylureido group, a thioureido group, a C ₁ -C ₄ alkylthioureido group, a C ₇ -C ₈ aralkylthioureido group or a phthalimido group, or a pharmaceutically acceptable salt thereof. 3. R ¹ is an amino group, mono- or di-C _1.
-C ₂ alkylamino groups, C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₂ alkoxy) - acetylamino group,
Fluoro or chloro-C ₂ -C ₃ alkanoylamino group, aminoacetylamino group, (mono- or di-C ₁ -C ₂ alkylamino) -acetylamino group, (C
_1- C ₂ alkoxycarbonylamino) -C ₂ -C ₃ alkanoylamino group, t-butoxycarbonylamino-
C ₂ -C ₃ alkanoylamino groups, (C ₁ -C ₂ alkoxycarbonylmethyl amino) -C ₂ -C ₃ alkanoylamino group, (t-butoxycarbonyl -C ₁ -C ₂ alkylamino) -C ₂ -C ₃ alkanoylamino group, acetyl -C ₂ -C ₃ alkanoylamino groups, C ₅ -C ₆
Cycloalkylcarbonylamino group, benzoylamino group, benzylcarbonylamino group, 1 to 2 nitrogens,
5- or 6-membered cyclic heteroaryl carbonylamino group containing oxygen or sulfur atom, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₂ alkoxycarbonyl-
Mono-C ₁ -C ₂ alkylamino group, t-butoxycarbonyl-mono-C ₁ -C ₂ alkylamino group, methanesulfonylamino group, ureido group, C ₁ -C ₄ alkylureido group, C ₇ -C ₈ aralkyl Ureido group, thioureido group, C ₁ -C ₄ alkylthioureido group, C ₇ -C
_8. The thiazole derivative according to claim 1, which is an aralkylthioureido group or a phthalimido group, or a pharmaceutically acceptable salt thereof. 4. R ¹ is a C ₂ -C ₅ alkanoylamino group, a fluoroacetyl group, a trifluoroacetyl group, a chloroacetylamino group, a C ₅ -C ₆ cycloalkylcarbonylamino group, a furylcarbonylamino group, a thienylcarbonyl group. Amino group, pyridylcarbonylamino group, C
₁ -C ₄ alkoxycarbonylamino group, a ureido group,
C ₁ -C ₄ alkylureido group, benzylureido group,
Thioureido group, C ₁ -C ₄ alkylthioureido group,
The thiazole derivative according to claim 1, which is a benzylthioureido group or a phthalimido group, or a pharmaceutically acceptable salt thereof. 5. R ¹ is a C ₂ -C ₃ alkanoylamino group, trifluoroacetyl group, furylcarbonylamino group, thienylcarbonylamino group, C ₁ -C ₂ alkoxycarbonylamino group, ureido group, C ₁ -C ₂ alkylureido group, benzylureido group, thioureido group,
The thiazole derivative according to claim 1, which is a C ₁ -C ₂ alkylthioureido group or a benzylthioureido group, or a pharmaceutically acceptable salt thereof. 6. The thiazole derivative according to claim 1 or a pharmacologically acceptable thereof, wherein R ¹ is a C ₂ -C ₃ alkanoylamino group, a C ₁ -C ₂ alkylureido group or a C ₁ -C ₂ alkylthioureido group. salt. 7. R ² and R ³ are the same or different,
The thiazole derivative according to claim 1, which is a hydrogen atom or a C ₁ -C ₇ alkyl group, or a pharmaceutically acceptable salt thereof. 8. R ² and R ³ are the same or different,
The thiazole derivative according to claim 1, which is a hydrogen atom or a C ₄ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof. 9. R ² and R ³ are the same or different,
The thiazole derivative according to claim 1, which is a hydrogen atom or a pentyl group, or a pharmaceutically acceptable salt thereof. 10. A thiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is a hydrogen atom and R ³ is a hydrogen atom or a pentyl group. 11. The thiazole derivative according to claim ₁ , wherein R ⁴ is a hydrogen atom or a C ₁ -C ₄ alkyl group, or a pharmaceutically acceptable salt thereof. 12. The thiazole derivative according to claim 1, wherein R ⁴ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. 13. The thiazole derivative according to claim 1, wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 14. A thiazole derivative or a pharmaceutically acceptable salt thereof according to claim ₁ , wherein A is a linear C ₁ -C ₄ alkylene group. 15. The thiazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein A is a methylene or ethylene group. 16. The thiazole derivative according to claim 1, wherein A is a methylene group, or a pharmaceutically acceptable salt thereof. 17. R ¹ is an amino group, mono- or di-C
₁ -C ₄ alkylamino group, C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₄ alkoxy) -C ₂ -C ₃ alkanoylamino group, a halogeno -C ₂ -C ₃ alkanoylamino groups, amino -C ₂ -C ₃ alkanoylamino group,
(Mono or di C ₁ -C ₄ alkylamino) -C
_2- C ₃ alkanoylamino group, (C ₁ -C ₄ alkoxycarbonylamino) -C ₂ -C ₃ alkanoylamino group, (C ₁ -C ₄ alkoxycarbonyl-mono-C _1-)
C ₄ alkylamino) -C ₂ -C ₃ alkanoylamino groups, (C ₂ -C ₃ alkanoyl) -C ₂ -C ₃ alkanoylamino groups, C ₃ -C ₇ cycloalkyl carbonyl amino group, C ₆ arylcarbonylamino group , C ₇ -C ₈
Aralkylcarbonylamino group, 5- to 6-membered cyclic heteroarylcarbonylamino group containing 1 to 2 nitrogen, oxygen or sulfur atoms, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄ alkoxycarbonyl-mono-C ₁ -C ₄ alkylamino group, C ₁ -C ₂ alkane sulfonylamino group, C ₆ arylsulfonylamino group, a ureido group, C ₁ -C ₄ alkyl ureido group, C ₇
-C ₈ aralkyl ureido group, thioureido group, C ₁ -
A C ₄ alkylthioureido group, a C ₇ -C ₈ aralkylthioureido group or a phthalimido group, R ² and R ³ are the same or different and each is a hydrogen atom or a C ₁ -C ₇ alkyl group, and R ⁴ is A thiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a hydrogen atom or a C ₁ -C ₄ alkyl group, and A is a linear C ₁ -C ₄ alkylene group. 18. R ¹ is an amino group, mono- or di-C
_1- C ₂ alkylamino group, C ₂ -C ₅ alkanoylamino group, (C ₁ -C ₂ alkoxy) -acetylamino group, fluoro or chloro-C ₂ -C ₃ alkanoylamino group, aminoacetylamino group, (mono- Or a di C ₁ -C ₂ alkylamino) -acetylamino group,
(C ₁ -C ₂ alkoxycarbonylamino) -C ₂ -C
₃ alkanoylamino group, t-butoxycarbonylamino -C ₂ -C ₃ alkanoylamino groups, (C ₁ -C ₂ alkoxycarbonylmethyl amino) -C ₂ -C ₃ alkanoylamino group, (t-butoxycarbonyl -C ₁ - C
₂ alkylamino) -C ₂ -C ₃ alkanoylamino group, acetyl -C ₂ -C ₃ alkanoylamino groups, C ₅
-C ₆ cycloalkylcarbonyl group, a benzoylamino group, benzylcarbonyl group, 1 to 2 nitrogen, oxygen or 5 or 6 membered cyclic heteroaryl carbonyl amino group containing a sulfur atom, C ₁ -C ₄ alkoxycarbonyl Amino group, C ₁ -C ₂ alkoxycarbonyl-mono-C ₁ -C ₂ alkylamino group, t-butoxycarbonyl-mono-C ₁ -C ₂ alkylamino group, methanesulfonylamino group, ureido group, C ₁ -C ₄ alkylureido group, C ₇ -C ₈ aralkyl ureido group, thioureido group, C ₁ -C ₄ alkylthioureido group, C
_7- C ₈ aralkylthioureido group or phthalimido group, R ² and R ³ are the same or different and each is a hydrogen atom or a C ₁ -C ₇ alkyl group, and R ⁴ is a hydrogen atom or C ₁ -C _4. A thiazole derivative or a pharmaceutically acceptable salt thereof according to claim ₁ , which is a _4- alkyl group and A is a linear C ₁ -C ₄ alkylene group. 19. R ¹ is a C ₂ -C ₅ alkanoylamino group, a fluoroacetyl group, a trifluoroacetyl group, a chloroacetylamino group, a C ₅ -C ₆ cycloalkylcarbonylamino group, a furylcarbonylamino group, a thienylcarbonyl group. Amino group, pyridylcarbonylamino group, C
₁ -C ₄ alkoxycarbonylamino group, a ureido group,
C ₁ -C ₄ alkylureido group, benzylureido group,
Thioureido group, C ₁ -C ₄ alkylthioureido group,
A benzylthioureido group or a phthalimido group, R ² and R ³ are the same or different and each is a hydrogen atom or a C ₄ -C ₆ alkyl group, and R ⁴ is a hydrogen atom or a C ₁ -C ₄ alkyl group. And A is a linear C ₁ -C ₄ alkylene group, and the thiazole derivative or the pharmaceutically acceptable salt thereof according to claim 1. 20. R ¹ is C ₂ -C ₃ alkanoylamino group, trifluoroacetyl group, furylcarbonylamino group, thienylcarbonylamino group, C ₁ -C ₂ alkoxycarbonylamino group, ureido group, C ₁ -C ₂ alkylureido group, benzylureido group, thioureido group,
A C ₁ -C ₂ alkylthioureido group or a benzylthioureido group, R ² and R ³ are the same or different and each is a hydrogen atom or a pentyl group, R ⁴ is a hydrogen atom or a methyl group, and A is A A thiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a methylene or ethylene group. 21. R ¹ is a C ₂ -C ₃ alkanoylamino group, a C ₁ -C ₂ alkylureido group or a C ₁ -C ₂ alkylthioureido group, R ² is a hydrogen atom, and R ³ is , A hydrogen atom or a pentyl group, R ⁴ is a hydrogen atom, and A is a methylene group, The thiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1. 22. 4- (4-acetylaminomethylpyrimidin-2-yl) -2-[(amino) (butylamino)
Methyleneamino] thiazole or a pharmacologically acceptable salt thereof. 23. 2-[(Amino) (butylamino) methyleneamino] -4- (4-propionylaminomethylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 24. 4- (4-Acetylaminomethylpyrimidin-2-yl) -2-[(amino) (pentylamino) methyleneamino] thiazole or a pharmaceutically acceptable salt thereof. 25. 2-[(Amino) (pentylamino) methyleneamino] -4- (4-propionylaminomethylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 26. 2-[(amino) (pentylamino) methyleneamino] -4- (4-ureidomethylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 27. 2-[(Amino) (pentylamino) methyleneamino] -4- [4- (3-methylureido) methylpyrimidin-2-yl) thiazole or a pharmacologically acceptable salt thereof. 28. 2-[(amino) (pentylamino) methyleneamino] -4- [4- (3-ethylureido) methylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 29. 2-[(Amino) (pentylamino) methyleneamino] -4- [4- (3-methylthioureido) methylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 30. 2-[(Amino) (pentylamino) methyleneamino] -4- [4- (3-ethylthioureido) methylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 31. 4- (4-Acetylaminomethylpyrimidin-2-yl) -2-[(amino) (hexylamino) methyleneamino] thiazole or a pharmaceutically acceptable salt thereof. 32. 2-[(Amino) (hexylamino) methyleneamino] -4- (4-propionylaminomethylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 33. 2-[(Amino) (hexylamino) methyleneamino] -4- (4-ureidomethylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 34. 2-[(amino) (hexylamino) methyleneamino] -4- [4- (3-methylureido) methylpyrimidin-2-yl) thiazole or a pharmaceutically acceptable salt thereof. 35. 4- (2-Acetylaminomethylpyrimidin-4-yl) -2-[(amino) (pentylamino) methyleneamino] thiazole or a pharmaceutically acceptable salt thereof. 36. 2-[(Amino) (pentylamino) methyleneamino] -4- (2-propionylaminomethylpyrimidin-4-yl) thiazole or a pharmaceutically acceptable salt thereof. 37. 2-[(Amino) (pentylamino) methyleneamino] -4- (2-ureidomethylpyrimidin-4-yl) thiazole or a pharmaceutically acceptable salt thereof. 38. 2-[(Amino) (pentylamino) methyleneamino] -4- [2- (3-methylureido) methylpyrimidin-4-yl) thiazole or a pharmaceutically acceptable salt thereof. 39. 2-[(Amino) (pentylamino) methyleneamino] -4- [2- (3-ethylureido) methylpyrimidin-4-yl) thiazole or a pharmaceutically acceptable salt thereof. 40. 2-[(Amino) (pentylamino) methyleneamino] -4- [2- (3-methylthioureido) methylpyrimidin-4-yl) thiazole or a pharmaceutically acceptable salt thereof. 41. 2-[(Amino) (pentylamino) methyleneamino] -4- [2- (3-ethylthioureido) methylpyrimidin-4-yl) thiazole or a pharmacologically acceptable salt thereof.