JPH1095777A - Thiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound, having inhibiting actions on protein kinases and useful as a preventing and therapeutic agent, etc., for chronic artercular rheumatism, etc. SOLUTION: This compound is represented by formula I R<1> and R<2> are each H, a lower alkyl, etc.; R<3> is a group represented by formula II [(p) is 0 or 1; R<11b> is H or a lower alkyl; R<11a> is OH, a lower alkoxy, etc.], etc.; R<4> is H or a lower alkanoyloxy-lower alkyl; T is a lower alkylene; (n) is 0 or 1}, concretely 2- [3-methoxy-4- 3-[4-(4-methyl-1-homopiperazinyl)-1 piperidinylacarbonyl]acryloyl}phenoxy]methylcarbonylamino}benzothiazole, etc. The compound is preferably obtained by carrying out a Friedel-Crats reaction of, e.g. a compound represented by formula III [A is a lower alkylene; Z is 0 or S; R<5> is H, an alkyl, etc.; (s) is 0 or 1; (m) is 1 or 2] with a compound represented by formula IV, etc., in the presence of a Lewis acid at 0-120 deg.C for about 0.5-24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazole derivative.

[0002]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel thiazole derivative useful as a pharmaceutical.

[0003]

The thiazole derivative of the present invention is a novel compound which has not been described in any literature, and is represented by the following general formula (1).

[0004]

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Wherein R ¹ and R ² are the same or different,
It represents a hydrogen atom or a lower alkyl group. R ¹ and R ² may combine to form a group — (CH ₂ ) _n — (n represents 4 or 5) or a benzene ring. The benzene ring may be substituted by a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, and a halogen atom as a substituent. .

R ³ is a group

[0007]

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Or group

[0009]

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[0010] is shown. Here, p represents 0 or 1. R
^11b represents a hydrogen atom or a lower alkyl group. R ^11a represents a hydroxyl group, a lower alkoxy group or a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen, oxygen or sulfur atoms. The heterocycle includes:
As the substituent, (a) a lower alkyl group, (a) a group
(B) ₁ -NR ¹² R ¹³ (1 represents 0 or 1. B represents a group-
CO-A- (A represents a lower alkylene group), a carbonyl group or a lower alkylene group. R ¹² and R ¹³ are the same or different and represent a hydrogen atom, a lower alkyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent. R ¹² and R ¹³ may form a 5- to 12-membered saturated monocyclic, binomial or spiro heterocyclic ring with or without a nitrogen atom or an oxygen atom to which they are bonded. Good. In the heterocycle, a lower alkyl group, a lower alkoxycarbonyl group,
It may have a lower alkoxy group-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent, and a group selected from the group consisting of a hydroxyl group-substituted lower alkyl group. ), (C) lower alkoxycarbonyl group, (d)
A hydroxyl-substituted lower alkyl group, (e) a pyridyl group which may have a lower alkyl group which may have a halogen atom as a substituent on the pyridine ring, (f) a halogen-substituted lower alkyl group, (g) a lower alkoxy group, (C) cycloalkyl group, (K) hydroxyl group, (co) tetrahydropyranyloxy group-substituted lower alkyl group, (sa) pyrimidyl group, (S) lower alkoxy-substituted lower alkyl group, (S)
Carboxy group, (se) phenyl lower alkoxy group,
(So) a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring,
It may have (1) a lower alkanoyloxy group and (1) one to three groups selected from a piperidinyl group which may have a lower alkyl group as a substituent on the piperidine ring. A is the same as above. Z represents an oxygen atom or a sulfur atom. s represents 0 or 1. m represents 1 or 2. R
⁵ is the same or different and is (a) a hydrogen atom, (b) an alkyl group which may have a hydroxyl group as a substituent, (c) a halogen atom, (d) group-(O) _t -A- (CO) _l -NR
⁷ R ⁸ (wherein the same .R ⁷ is .A and l t wherein represents 0 or 1 and R ⁸ are the same or different and represent a hydrogen atom or a lower alkyl group. Alternatively R ⁷ and R ^8, A 5- to 7-membered saturated heterocyclic ring may be formed with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded, and the heterocyclic ring has a group-(A) _l- as a substituent. NR ⁹
R ¹⁰ (A and l are the same as above; R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a lower alkyl group; or R ⁹ and R ¹⁰ are a nitrogen atom or an oxygen together with a nitrogen atom to which they are bonded. 5-7 with or without atoms
A membered saturated heterocyclic ring (which may be substituted with a lower alkyl group as a substituent on the heterocyclic ring), a lower alkyl group which may have a hydroxyl group as a substituent, May have a group selected from the group consisting of a hydroxyl group and a lower alkanoyl group), (e) a lower alkoxycarbonyl lower alkyl group, (f) a lower alkanoyloxy lower alkyl group, and (g) having a halogen atom as a substituent. Lower alkoxy group, (h) halogen-substituted lower alkyl group, (i) carboxy-substituted lower alkyl group, (j) lower alkoxycarbonyl group, (k) lower alkenyloxy group, (l) phenyl lower alkoxy group,
(M) a cycloalkyloxy group, (n) a phenyl group,
(O) a phenyloxy group, (p) a hydroxyl group, (q) a lower alkylthio group, (r) a lower alkenyl group, or (s) an amino group which may have a lower alkyl group as a substituent. R ⁶ represents the group (1) —CO—CH ＝ CR ^11b — (CO) _p —
R ^11a or (2) a group —CO—C≡C—COR ¹⁴ is shown. Here, p, R ^11a and R ^11b are the same as above. R ¹⁴ represents a hydroxyl group or a lower alkoxy group. When m represents 1, A and R ⁵
Are bonded to each other,

[0011]

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(R ⁶ is the same as above, and r represents 0, 1 or 2). When m represents 2, two groups R ⁵ may combine to form a lower alkylenedioxy group, a lower alkylene group, or a group — (CH ₂ ) ₂ CONH—. R ⁵ and R ⁶ are bonded to each other to form a group

[0013]

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(R ^28a and R ^28b represent a hydrogen atom or a carboxyl group, provided that R ^28a and R ^28b do not simultaneously represent a carboxyl group.

[0015]

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Is shown. R ^29a represents a hydrogen atom or a lower alkyl group. R ^29b represents a lower alkyl group. X represents a halogen atom. ) May be formed.

R ⁴ represents a hydrogen atom or a lower alkanoyloxy lower alkyl group.

T represents a lower alkylene group.

U represents 0 or 1. (1) In the general formula (1), u is 0, R ¹ and R ² are the same or different, and a hydrogen atom or a lower alkyl group;
R ³ based

[0020]

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(R ^11b , p and R ^11a are as defined above) or a salt thereof.

(2) In the above general formula (1), u is 0, R ¹ and R ² are the same or different and a hydrogen atom or a lower alkyl group, and R ³ is

[0023]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 0) or a thiazole derivative or a salt thereof.

[0025] (3) Among the above general formula (1), u is 0, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, R ³ is a group

[0026]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1, and Z is an oxygen atom), or a thiazole derivative or a salt thereof is preferred.

(4) In the above general formula (1), u is 0, R ¹ and R ² are the same or different and a hydrogen atom or a lower alkyl group and R ³ are

[0029]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1, and Z is a sulfur atom).

(5) In the above general formula (1), u is 0 and R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 4).
And R ³ is a group

[0032]

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(R ^11b , p and R ^11a are the same as above) or a thiazole derivative or a salt thereof.

(6) In general formula (1), u is 0, and R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 4).
And R ³ is a group

[0035]

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(A, R ⁵ , m and R ⁶ are the same as above, and s is 0) or a salt thereof.

(7) In the general formula (1), u is 0, and R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 4).
And R ³ is a group

[0038]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1 and Z is an oxygen atom), or a thiazole derivative or a salt thereof is preferred.

(8) In the general formula (1), u is 0, and R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 4).
And R ³ is a group

[0041]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1 and Z is a sulfur atom), or a thiazole derivative or a salt thereof is preferred.

(9) In the general formula (1), u is 0, and R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 5).
And R ³ is a group

[0044]

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(R ^11b , p and R ^11a are the same as described above), or a salt thereof.

(10) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 5), and R ³ is a group

[0047]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 0) or a salt thereof.

(11) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 5), and R ³ is a group

[0050]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1, and Z is an oxygen atom), or a thiazole derivative or a salt thereof is preferred.

(12) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 5), and R ³ is a group

[0053]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1 and Z is a sulfur atom), or a thiazole derivative or a salt thereof is preferred.

(13) In the above general formula (1), u
Is 0, R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group, a lower alkoxy group, a nitro group as a substituent, an amino group which may have a lower alkyl group as a substituent, group selected from the atoms consisting the group may be substituted.) to form, R ³ is a group

[0056]

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(R ^11b , p and R ^11a are as defined above) or a salt thereof.

(14) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group, a lower alkoxy group, a nitro group as a substituent, an amino group which may have a lower alkyl group as a substituent, group selected from the atoms consisting the group may be substituted.) to form, R ³ is a group

[0059]

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(A, R ⁵ , m and R ⁶ are the same as above and s is 0) or a salt thereof.

(15) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group, a lower alkoxy group, a nitro group as a substituent, an amino group which may have a lower alkyl group as a substituent, group selected from the atoms consisting the group may be substituted.) to form, R ³ is a group

[0062]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1, and Z is an oxygen atom).

(16) In the general formula (1), u
Is 0, R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group, a lower alkoxy group, a nitro group as a substituent, an amino group which may have a lower alkyl group as a substituent, group selected from the atoms consisting the group may be substituted.) to form, R ³ is a group

[0065]

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(A, R ⁵ , m and R ⁶ are the same as above, s is 1 and Z is a sulfur atom), or a thiazole derivative or a salt thereof is preferred.

(17) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b and p are the same as above. R ^11a represents a hydroxyl group or a lower alkoxy group. The thiazole derivative according to the above (3) or a salt thereof is preferred.

(18) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b is the same as above. p represents 1. R ^11a is a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (in the heterocyclic ring, as a substituent, Substituents (A), (A),
(C), (d), (o), (f), (g), (h),
(K), (ko), (sa), (shi), (su), (se),
It may have 1 to 3 groups selected from the group consisting of (so), (ta) and (h). ). The thiazole derivative according to the above (3) or a salt thereof is preferred.

(19) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b is the same as above. p represents 0. R ^11a is a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (in the heterocyclic ring, as a substituent, Substituents (A), (A),
(C), (d), (o), (f), (g), (h),
(K), (ko), (sa), (shi), (su), (se),
It may have 1 to 3 groups selected from the group consisting of (so), (ta) and (h). ). The thiazole derivative according to the above (3) or a salt thereof is preferred.

(20) In the general formula (1), R
The thiazole derivative or salt thereof according to the above (3), wherein ⁶ is a group —CO—C≡C—COR ¹⁴ (R ¹⁴ is as defined above), is preferable.

(21) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b and p are the same as above. R ^11a represents a hydroxyl group or a lower alkoxy group. The thiazole derivative or the salt thereof according to the above (15), which is the above-mentioned (15), is preferable.

(22) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b is the same as above. p represents 1. R ^11a is a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (in the heterocyclic ring, as a substituent, Substituents (A), (A),
(C), (d), (o), (f), (g), (h),
(K), (ko), (sa), (shi), (su), (se),
It may have 1 to 3 groups selected from the group consisting of (so), (ta) and (h). ). The thiazole derivative or the salt thereof according to the above (15), which is the above-mentioned (15), is preferable.

(23) In the general formula (1), R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b is the same as above. p represents 0. R ^11a is a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (in the heterocyclic ring, as a substituent, Substituents (A), (A),
(C), (d), (o), (f), (g), (h),
(K), (ko), (sa), (shi), (su), (se),
It may have 1 to 3 groups selected from the group consisting of (so), (ta) and (h). ). The thiazole derivative or the salt thereof according to the above (15), which is the above-mentioned (15), is preferable.

(24) In the general formula (1), R
The thiazole derivative or salt thereof according to the above (15), wherein ⁶ is a group —CO—C≡C—COR ¹⁴ (R ¹⁴ is as defined above), is preferable.

(25) In the general formula (1), u
Is 1, R ³ is a group

[0076]

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(R ^11b , p and R ^11a are as defined above) or a salt thereof.

(26) In the general formula (1), u
Is 1, R ¹ and R ² are the same or different, and a hydrogen atom or a lower alkyl group, and R ³ is a group

[0079]

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(A, Z, s, R ⁵ , m and R ⁶ are the same as defined above) or a salt thereof.

(27) In the general formula (1), u
Is 1, R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 4), and R ³ is a group

[0082]

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(A, Z, s, R ⁵ , m and R ⁶ are as defined above) or a salt thereof.

(28) In the general formula (1), u
Is 1, R ¹ and R ² are bonded to form a group — (CH ₂ ) _n — (n is 5), and R ³ is a group

[0085]

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The thiazole derivative (A, Z, s, R ⁵ , m and R ⁶ are the same as described above) or a salt thereof is preferred.

(29) In the general formula (1), u
Is a benzene ring wherein R ¹ and R ² are bonded to each other (the benzene ring may have a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, group selected from the atoms consisting the group may be substituted.) to form, R ³ is a group

[0088]

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The thiazole derivative (A, Z, s, R ⁵ , m and R ⁶ are the same as described above) or a salt thereof is preferred.

(30) In the general formula (1), R
^The heterocyclic residue represented by ^11a is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1-azacyclooctyl, homopiperazinyl, homomorpholino, 1,4-diazabicyclo [4,3,0] nonyl, 1,4-diazabicyclo [4 , 4,0] decyl, pyridyl, 1,2,5
6-tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3
4-triazolyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, pyrrolinyl, carbostyryl, 1,3
-Dioxolanyl, thiomorpholino, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl , Benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, naphthyridinyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, Imidazolyl, pyrazolidinyl, benzofuryl, 2,3-dihydrobenzo [b] furyl, benzothienyl, tetrahydropyranyl, 4H-chromenyl, 1H-in Zoriru, isoindolinyl, 2
-Imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,
Isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4- Benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthale Nil, 1,4-dithianaphthalenyl, 2,5-
Dihydrofurano [3,4-c] pyridyl, 2,3,4
5,6,7-hexahydro-1H-azepinyl, 1,
2,3,4,5,6,7,8-octahydroazocinyl, 1,2,3,4,5,6-hexahydrooxevinyl, 1,3-dioxolanyl, 3,4,5,6 -Tetrahydro-2H-pyranyl and 5,6-dihydro-2H-
The above (1), (2), which is a group selected from a pyranyl group,
The thiazole derivatives or salts thereof described in (5) to (14), (16) to (28) or (29) are preferred.

(31) In the general formula (1), 2
-{[3-methoxy-4- {3- [4- (4-methyl-
1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[2-isopropyl-4
-{3- [4- (4-methyl-1-piperazinyl) -1
-Piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-
{[2-methoxy-4- {3- [2- (4-methyl-1
-Piperazinyl) methyl-4-morpholinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[2-ethoxy-4-
{3- [4- (4-methyl-1-piperazinyl) -1-
Piperidinylcarbonyl] acryloyl｝ phenoxy)
Methylcarbonylamino dibenzothiazole, 2-
｛[3-methyl-4- {3- [4- (4-methyl-1-
Homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[3-methoxy-6-ethyl-
4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-[{3-methoxy-6-ethyl-4- [3-
(4-methyl-1-piperazinyl) acryloyl {phenoxy] methylcarbonylamino} benzothiazole,
2-[{2-trifluoromethyl-4- [3- (4-hydroxy-1-piperazinyl) acryloyl} phenoxy] methylcarbonylamino} benzothiazole, 2-
｛[2-fluoro-4- {3- [2- (4-methyl-1
-Piperazinyl) methyl-4-morpholinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2- {2-methoxy-4-} 3
-[4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[2
3-dimethyl-4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[3-methoxy-4- ｛3- [4
-(3,4-dimethyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-[{3-
Methoxy-6-isopropyl-4- [3- (4-methyl-1-piperazinyl) carbonyl] acryloyl] phenoxy {methylcarbonylamino] benzothiazole,
2-{[2-methoxy-4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl} phenoxy] methylcarbonylamino} benzothiazole and 2-{[2- n-butyl-4
-{3- [4- (4-methyl-1-homopiperazinyl)
Thiazole derivatives or salts thereof selected from the group consisting of -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole are preferred.

The thiazole derivative represented by the above general formula (1) or a salt thereof is a protein kinase C (PKC, C
a ²⁺ / phospholipid-dependent serine / threonine protein kinase)
Useful as inhibitors.

Protein kinase C plays an important role in the regulation of various biological functions such as the release reaction of hormones, cytokines, neurotransmitters and the like, as well as the regulation of metabolism, cell proliferation, differentiation and the like. Therefore, the protein kinase C inhibitor is useful as an agent for preventing or treating various diseases caused by excessive action of these biological reactions involving protein kinase C.

More specifically, a protein kinase C inhibitor containing the compound of the present invention as an active ingredient is a protein kinase C inhibitor such as IL-2.
By suppressing the production of cell-derived cytokines and inflammatory cytokines, including TNF-α, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, asthma,
Therapeutic agent for allergic diseases such as atopic dermatitis; rejection reaction in organ transplantation, prophylactic agent for GVHD reaction; for ischemic disease in organs such as heart, liver, kidney, brain, acute pancreatitis, pulmonary blood, burns, etc. Multiple organ failure,
It is useful as a prophylactic or therapeutic agent for ARDS and the like.

Further, prevention or prevention of cancer, diabetes, Alzheimer's dementia, arteriosclerosis, HIV infection, nephritis, vasculitis, etc. caused by other biological reactions involving protein kinase C, such as cell proliferation, hormone secretion, and metabolic regulation. Useful as a therapeutic.

[0096]

BEST MODE FOR CARRYING OUT THE INVENTION Each group represented by the above general formula (1) is more specifically as follows.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms, such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

Examples of the halogen atom include a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

The lower alkanoyloxy group-substituted lower alkyl group includes, for example, acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl,
-Acetyloxypropyl, 4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-t
tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-
Carbon number 2 such as 3-acetyloxypropyl, diacetyloxymethyl, 1,3-diacetyloxypropyl, etc.
From 6 to 6 linear or branched alkanoyloxy groups from 1 to 2
And a straight or branched alkoxy group having 1 to 6 carbon atoms.

Examples of the alkyl group which may have a hydroxyl group as a substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, hydroxymethyl, 2-hydroxyethyl , 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 1,3-dihydroxypropyl, 5,5,4-trihydroxypentyl , 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, 7-hydroxyheptyl, 8-hydroxyoctyl, etc. ~ 8
A straight-chain or branched-chain alkyl group.

The lower alkylene group includes, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene C1 of group etc.
To 6 linear or branched alkylene groups.

A 5- to 7-membered saturated heterocyclic group formed by bonding together with or without a nitrogen atom or an oxygen atom together with a nitrogen atom to which R ⁷ and R ⁸ or R ⁹ and R ¹⁰ is bonded is as follows. Examples thereof include a pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl, homomorpholino group and the like.

Examples of the lower alkyl group which may have a hydroxyl group as a substituent include, for example, hydroxymethyl, 2-hydroxyethyl, 1-
Hydroxyethyl, 3-hydroxypropyl, 2,3-
Dihydroxypropyl, 4-hydroxybutyl, 1,1
-Dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-
A hydroxyl group such as a methyl-3-hydroxypropyl group is 1 to 3
Examples thereof include straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms.

Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl.

Group-(A) ₁ -NR ⁹ R ¹⁰ (A is a lower alkylene group, 1 is 0 or 1. R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a lower alkyl group. Alternatively, R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached,
A 7-membered saturated heterocyclic ring may be formed. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. The above heterocyclic group substituted by a group selected from the group consisting of a lower alkyl group which may have a hydroxyl group as a substituent, a hydroxyl group and a lower alkanoyl group;
-Methylpiperazinyl, 2- (4-methyl-1-piperazinyl) methylmorpholino, 4- (4-methyl-1-piperazinyl) piperidinyl, 4-methylhomopiperazinyl, 4- (2-hydroxyethyl) piperazinyl , 4-
Morpholinopiperidinyl, 2-[(1-pyrrolidinyl)
Methyl] morpholino, 4-hydroxypiperidinyl, 4
-Acetylpiperazinyl, 4-dimethylaminopiperidinyl, 4- (4-methyl-1-homopiperazinyl) piperidinyl, 4- (4,5-dimethyl-1-homopiperazinyl) piperidinyl, 4- (3-methyl-4 -Ethyl-
1-piperazinyl) piperidinyl, 4- (3-methyl-
4-n-propyl-1-piperazinyl) piperidinyl,
4- (3,4-dimethyl-1-piperazinyl) piperidinyl, 4- (4-isopropyl-3-methylpiperazinyl) piperidinyl, 4- (4-methyl-3-isopropylpiperazinyl) piperidinyl, 2-methyl Pyrrolidinyl, 3-ethylpyrrolidinyl, 2,3-dimethylpyrrolidinyl, 2,3,4-trimethylpyrrolidinyl, 2-propylmorpholino, 3- (1-pyrrolidinyl) pyrrolidinyl, 3-isopropylmorpholino, 2,3-dimethylmorpholino, 4-n-butylpiperidinyl, 3,4,5
-Trimethylpiperidinyl, 3-pentylpiperidinyl, 4-methylhomopiperazinyl, 4,5-dimethylhomopiperazinyl, 4-hexylhomopiperazinyl, 3-
Methyl-4-ethylpiperazinyl, 3-methyl-4-n
-Propyl-1-piperazinyl, 3,4-dimethylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-
Methyl homomorpholino, 3-propionylpyrrolidinyl, 4-butyrylpiperidinyl, 4-pentanoylpiperazinyl, 3-hexanoylmorpholino, 4-acetylhomopiperazinyl, 3-hydroxymorpholino, 4-hydroxyhomopipe Radinyl, 4-hydroxypiperazinyl, 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3- (3-hydroxypropyl) morpholino, 2-hydroxymethylhomomorpholino, 2-
(4-methyl-1-piperazinyl) methyl homomorpholino, 4- (1,3-dihydroxy-2-propyl) piperazinyl, 4-ethylhomopiperazinyl, 3- (4-methyl-1-homopiperazinyl) pyrrolidinyl, 4 -Methyl-3- (1-piperidinyl) methylpiperazinyl, 4
-Methyl-3- (4-methyl-1-homopiperazinyl)
Methylpiperazinyl, 4-methyl-3- (4-methyl-
A group such as 1-piperazinyl) methylpiperazinyl group
(A) _l- NR ⁹ R ¹⁰ (A is a linear or branched alkylene group having 1 to 6 carbon atoms, 1 is 0 or 1. R ⁹ and R ¹⁰
Is the same or different and represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. Or R ⁹ and R ¹⁰
May form a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may have 1 to 3 straight or branched alkyl groups having 1 to 6 carbon atoms as substituents. A) a linear or branched alkyl group having 1 to 6 carbon atoms, which may have 1 to 3 hydroxyl groups as a substituent, a hydroxyl group and a linear or branched alkanoyl group having 1 to 6 carbon atoms. Examples of the above heterocyclic ring having 1 to 3 groups selected from the above can be given.

The heterocyclic ring substituted by a lower alkyl group includes, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methylpyrrolidinyl Zinyl, 3,4,5
-Trimethylpiperidinyl, 4-butylpiperidinyl,
3-pentylmorpholino, 4-ethylhomopiperazinyl, 4-methylhomopiperazinyl, 4-hexylpiperazinyl, 4-methylhomopiperazinyl, 4,5-dimethylhomopiperazinyl, 3-methyl- 4-ethylpiperazinyl, 3-methyl-4-n-propylpiperazinyl, 4
Substitution of 1 to 3 straight or branched alkyl groups having 1 to 6 carbon atoms such as -isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-methylhomomorpholino group The above-mentioned heterocyclic groups can be exemplified.

The lower alkyl group substituted with a lower alkoxycarbonyl group includes, for example, methoxycarbonylmethyl, 3
-Methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-
An alkoxycarbonyl moiety such as 3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl group has 1 to 1 carbon atoms.
A straight-chain or branched-chain alkoxycarbonylalkyl group having 1 to 6 carbon atoms, which is a straight-chain or branched-chain alkoxycarbonyl group of 6 can be exemplified.

Examples of the lower alkanoyloxy-substituted lower alkyl group include acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl,
Acetyloxypropyl, 4-acetyloxybutyl,
4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-ter
t-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-
A straight-chain or branched alkanoyloxy group having 2 to 6 carbon atoms such as an acetyloxypropyl group can be exemplified by a straight-chain or branched alkyl group having 1 to 6 carbon atoms.

Examples of the lower alkoxy group which may have a halogen atom as a substituent include, for example, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, in addition to the above-mentioned lower alkoxy groups. , Dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy,
3-chloropropoxy, 2,3-dichloropropoxy,
Halogen atoms such as 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy and 5,6-dichlorohexyloxy are A straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, which may have three, may be exemplified.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-
Trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-
Examples of the substituent such as methylpropyl, 5-bromohexyl, and 5,6-dichlorohexyl include a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms and having 1 to 3 halogen atoms.

As the carboxy-substituted lower alkyl group,
For example, carboxymethyl, 2-carboxyethyl, 1-
Alkyl moieties such as carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, and 2-methyl-3-carboxypropyl have carbon atoms. Examples thereof include carboxyalkyl groups that are 1 to 6 linear or branched alkyl groups.

Examples of the lower alkoxycarbonyl group include linear groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. Or a branched alkoxycarbonyl group.

Examples of the aminocarbonyl-substituted lower alkoxy group which may have a lower alkyl group as a substituent include, for example, aminocarbonylmethoxy, 2-aminocarbonylethoxy, 1-aminocarbonylethoxy,
-Aminocarbonylpropoxy, 4-aminocarbonylbutoxy, 5-aminocarbonylpentyloxy, 6-
Aminocarbonylhexyloxy, 1,1-dimethyl-
2-aminocarbonylethoxy, 2-methyl-3-aminocarbonylpropoxy, methylaminocarbonylmethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonylbutoxy, 5 -Pentylaminocarbonylpentyloxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethoxy, 2-diethylaminocarbonylethoxy, 2-dimethylaminocarbonylethoxy, (N-ethyl-N-propylamino) carbonylmethoxy, 2- (N -Methyl-N-hexylamino)
A straight-chain or branched-chain having 1 to 6 carbon atoms having an aminocarbonyl group which may have 1 to 2 straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms as a substituent such as a carbonylethoxy group; An alkoxy group can be exemplified.

Examples of the amino-substituted lower alkyl group which may have a lower alkyl group as a substituent include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6
-Aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylamino Butyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino) methyl, 2- (N-methyl-
(N-hexylamino) ethyl or other straight or branched chain having 1 to 6 carbon atoms having an amino group which may have 1 or 2 straight or branched alkyl groups as substituents. A branched alkyl group can be exemplified.

Together with the nitrogen atom to which R ¹² and R ¹³ are attached,
Examples of the 5- to 12-membered saturated monocyclic, binomial or spiro heterocyclic ring formed by bonding to each other via or without a nitrogen atom or an oxygen atom include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl , Homomorpholino, 1,4-diazabicyclo [4,3,0] nonyl, 1,4-diazabicyclo [4,
4,0] decyl and 1,4-diazaspiro [5,5] undecyl groups.

Examples of the lower alkyl group substituted with a lower alkoxy group include methoxymethyl, 3-methoxypropyl, ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl, and 6-propoxy. C1-C6 linear or branched as a substituent such as hexyl, 1,1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl group, etc. 1 to 6 carbon atoms having 1 to 3 chain alkoxy groups
A straight-chain or branched-chain alkyl group.

Examples of the amino group which may have a lower alkyl group as a substituent include, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino , Diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-
Examples of the substituent such as N-butylamino and N-methyl-N-hexylamino group include an amino group which may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms.

Examples of the hydroxyl-substituted lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl and 1,1-dimethyl-2- Carbon which may have 1 to 3 hydroxyl groups such as hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl group Examples include straight-chain or branched-chain alkyl groups of the formulas 1 to 6.

A group selected from the group consisting of a lower alkyl group, a lower alkoxy group-substituted lower alkyl group, a lower alkoxycarbonyl group as a substituent, an amino group which may have a lower alkyl group as a substituent, and a hydroxyl group-substituted lower alkyl group. Examples of the heterocyclic ring having 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-ethylpiperazinyl, 4-methylhomopiperazinyl,
Dimethylaminopiperidinyl, 4-tert-butoxycarbonylhomopiperazinyl, 4-n-butylhomopiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 3-methylpiperazinyl, 4- (1,3 -Dihydroxy-2-propyl) piperazinyl, 4- (1,3-dihydroxy-2-propyl) homopiperazinyl, 3,
4,5-trimethylpiperazinyl, 4-isopropylpiperazinyl, 3,3,4-trimethylpiperazinyl,
4,5-dimethylhomopiperazinyl, 3-methyl-4-
Ethyl piperazinyl, 3-methyl-4-n-propylpiperazinyl, 3-n-propyl-4-methylpiperazinyl, 3-methyl-4-isopropylpiperazinyl, 3-
Ethyl-4-methylpiperazinyl, 3-methyl-4-
(2-methoxyethyl) piperazinyl, 3-methyl-4
-(2-hydroxyethyl) piperazinyl, 3-isopropyl-4-methylpiperazinyl, 4-methyl-1,4
-Diazaspiro [5,5] undecyl, 3-amino-
1,4-diazabicyclo [4,4,0] decyl, 5-hydroxymethyl-1,4-diazabicyclo [4,3,
0] nonyl, 3-ethoxycarbonyl homomorpholino,
A straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent such as 3-diethylaminomorpholino or 3-methoxymethylpyrrolidinyl group; a straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent 1 to 3 carbon atoms having 1 to 3 alkoxy groups
6 straight-chain or branched-chain alkyl group, a straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms, and a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms as a substituent. Examples of the above heterocyclic ring having 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms having 1 to 3 amino groups and 1 to 3 hydroxyl groups, which may have 2 amino groups. it can.

Examples of the lower alkyl group which may have a halogen atom as a substituent include the above-mentioned lower alkyl groups and halogen-substituted lower alkyl groups.

The pyridyl group which may have a lower alkyl group which may have a halogen atom as a substituent on the pyridine ring includes, for example, pyridyl, 3-methylpyridyl, 4-ethylpyridyl, 2-propylpyridyl,
-Butylpyridyl, 4-pentylpyridyl, 4-hexylpyridyl, 3,4-dimethylpyridyl, 3,4,5-
Trimethylpyridyl, 3-trifluoromethylpyridyl, 2-chloromethylpyridyl, 4- (5-bromohexyl) pyridyl, 3-iodomethylpyridyl, 4-
(2,2,2-trifluoroethyl) pyridyl, 4-
A linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as a substituent on a pyridine ring such as a (5,6-dichlorohexyl) pyridyl group;
Examples include pyridyl groups that may have up to 3 pyridyl groups.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

Examples of the tetrahydropyranyloxy-substituted lower alkyl group include (2-tetrahydropyranyl)
Oxymethyl, 2- (3-tetrahydropyranyl) oxyethyl, 1- (4-tetrahydropyranyl) oxyethyl, 3- (2-tetrahydropyranyl) oxypropyl, 4- (3-tetrahydropyranyl) oxybutyl,
5- (4-tetrahydropyranyl) oxypentyl, 6
-(2-tetrahydropyranyl) oxyhexyl, 1,
An alkyl moiety such as a 1-dimethyl-2- (3-tetrahydropyranyl) oxyethyl or 2-methyl-3- (4-tetrahydropyranyl) oxypropyl group has 1 to 1 carbon atoms.
And a tetrahydropyranyloxy-substituted alkyl group which is a straight or branched alkyl group of No. 6.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
An alkyl moiety such as 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, or 2-methyl-3-phenylpropyl has 1 to 6 carbon atoms. And a phenylalkyl group which is a linear or branched alkyl group.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1- A phenylalkoxy group which is a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety such as dimethyl-2-phenylethoxy and 2-methyl-3-phenylpropoxy groups can be exemplified.

Examples of the lower alkanoyloxy group include straight-chain alkanoyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups. A chain or branched alkanoyloxy group may be mentioned.

The piperidinyl group which may have a lower alkyl group as a substituent on the piperidine ring includes piperidinyl, 1-methyl-4-piperidinyl, 1-ethyl-3-piperidinyl, 1-ethyl-2-piperidinyl,
1-propyl-4-piperidinyl, 1-butyl-4-piperidinyl, 1-pentyl-4-piperidinyl, 1-hexyl-4-piperidinyl, 1-isobutyl-3-piperidinyl, 1-tert-butyl-2-piperidinyl group And a piperidinyl group which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the piperidine ring.

The phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring includes, in addition to the phenyl lower alkyl group,
3,4-methylenedioxybenzyl, 2- (3,4-ethylenedioxyphenyl) ethyl, 1- (3,4-ethylenedioxyphenyl) ethyl, 3- (2,3-trimethylenedioxyphenyl) Propyl, 4- (3,4-tetramethylenedioxyphenyl) butyl, 5- (3,4
-Methylenedioxyphenyl) pentyl, 6- (2,3
-Trimethylenedioxyphenyl) an alkyl moiety which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on a phenyl ring such as a hexyl group has 1 to 6 carbon atoms. A phenylalkyl group which is a linear or branched alkyl group can be exemplified.

As the lower alkylenedioxy group, a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy group and the like can be used. No.

A nitrogen atom, an oxygen atom or a sulfur atom
Examples of the 5- or 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1-azacyclooctyl, homopiperazinyl, homomorpholino, 1,4 −
Diazabicyclo [4,3,0] nonyl, 1,4-diazabicyclo [4,4,0] decyl, pyridyl, 1,2,2
5,6-tetrahydropyridyl, thienyl, 1,2,4
-Triazolyl, 1,2,3,4-tetrazolyl, 1,
3,4-triazolyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, pyrrolinyl, carbostyryl,
1,3-dioxolanyl, thiomorpholino, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, Indolizinyl, indazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, naphthyridinyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl,
Chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-
Thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuryl, 2,3-dihydrobenzo [b] furyl, benzothienyl, tetrahydropyranyl, 4H-
Chromenil, 1H-indazolyl, isoindolinyl,
2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-
Pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzo Thiazinyl, 1,2,3,4
-Tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, 1,4-dithianaphthalenyl, 2,
5-dihydrofurano [3,4-c] pyridyl, 2,3
4,5,6,7-hexahydro-1H-azepinyl,
1,2,3,4,5,6,7,8-octahydroazocinyl, 1,2,3,4,5,6-hexahydrooxepinyl, 1,3-dioxolanyl, 3,4,5 , 6-Tetrahydro-2H-pyranyl, 5,6-dihydro-2H-
Examples thereof include a pyranyl group.

(A) lower alkyl group, (A) group- (B)
_l -NR ¹² R ¹³ _(l is as .B said the group -CO-A-
(A is the same as above.), A carbonyl group or a lower alkylene group. R ¹² and R ¹³ are the same or different and represent a hydrogen atom, a lower alkyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent. Alternatively, a 5- to 12-membered saturated monocyclic, binomial or spiro heterocyclic ring may be formed together with or without a nitrogen atom to be bonded via a nitrogen atom or an oxygen atom. The heterocycle is selected from the group consisting of a lower alkyl group as a substituent, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent, and a hydroxyl-substituted lower alkyl group. It may have a group. ), (C) a lower alkoxycarbonyl group, (d) a hydroxyl-substituted lower alkyl group, (e) a pyridyl group which may have a lower alkyl group which may have a halogen atom as a substituent on a pyridine ring, (f) Halogen-substituted lower alkyl group, (g) lower alkoxy group,
(C) cycloalkyl group, (K) hydroxyl group, (co) tetrahydropyranyloxy group-substituted lower alkyl group, (sa) pyrimidyl group, (si) lower alkoxy-substituted lower alkyl group, (su) carboxy group, (se) A phenyl lower alkoxy group, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the (so) phenyl ring, a (ta) lower alkanoyloxy group and a lower alkyl as a substituent on the (thi) piperidine ring Examples of the heterocycle having 1 to 3 groups selected from the group consisting of piperidinyl groups which may have a group include 4-methylpiperazinyl, 4- (4-methyl-1-piperazinyl) piperidinyl, 2- ( 4-methyl-1-piperazinylmethyl) morpholino, 2- (4-methyl-1-piperazinylmethyl)
Pyrrolidinyl, 3- (4-methyl-1-piperazinyl)
Pyrrolidinyl, 1-ethyl-1,2,3,4-tetrazolyl, 1-tert-butoxycarbonylpiperidinyl, 1-methylpiperidinyl, 2,2-dimethyl-1,
3-dioxolanyl, 4- (3,4-dimethyl-1-piperazinyl) piperidinyl, (4-ethyl-1-piperazinyl) piperidinyl, 4- [N- (2-diethylaminoethyl) -N-methylamino] piperidinyl, −
(4-methyl-1-homopiperazinyl) piperidinyl,
2- (4-ethyl-1-piperazinylmethyl) morpholino, 4-dimethylaminopiperidinyl, 2-morpholinomethylpyrrolidinyl, 4- (1-pyrrolidinyl) piperidinyl, 4-isopentylpiperazinyl, 4 -(2-hydroxyethyl) piperazinyl, 2- (1-pyrrolidinylmethyl) morpholino, 4-morpholinopiperidinyl,
2-aminomethylmorpholino, 1-dimethylaminomethylcarbonylpiperidinyl, 1-methylimidazolyl,
4- (2-pyridyl) piperazinyl, 4- (3,4-methylenedioxybenzyl) piperazinyl, 1- (4-chlorobutyl) -1,2,3,4-tetrazolyl, 2-methoxycarbonylpyridyl, 2-carboxy Pyridyl,
4-isopropylpyridyl, 4-hydroxypiperidinyl, 2-methyl-3-hydroxy-2,5-dihydrofuran [3,4-c] pyridyl, 1-cyclohexyl-
1,2,3,4-tetrazolyl, 3- (4-methyl-1
-Piperazinyl) pyrrolidinyl, 1-[(3-3,4,
5,6-tetrahydro-2H-pyranyl) methyl]-
1,2,3,4-tetrazolyl, 1- (3-chloropropyl) -1,2,3,4-tetrazolyl, 2-carbamoylpyrrolidinyl, 4- (3-trifluoromethyl-2
-Pyridyl) piperazinyl, 4-benzylpiperidinyl, 4-n-butyl-1,2,3,4-tetrazolyl,
4-carbamoylpiperidinyl, 2- (4-methyl-1
-Piperazinyl) homomorpholino, 2-methylmorpholino, 2-methoxymethylmorpholino, 2-chloromethylmorpholino, 2-hydroxymethylmorpholino, 2-n
-Butoxymethylmorpholino, 2- (4-methyl-1-
Homopiperazinylmethyl) morpholino, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl, 2
-(4-methyl-1-homopiperazinylmethyl) homomorpholino, 2-chloromethyl homomorpholino, 2-hydroxymethyl homomorpholino, 4-hydroxypiperazinyl, 2-methoxymethyl-1,2,3,4 , 5,6-
Hexahydrooxepinyl, 4- (2-phenylethoxy) piperidinyl, 4-benzyloxypiperidinyl,
4-hydroxy-3-methylpiperazinyl, 4-methylhomopiperazinyl, 4-acetyloxypiperazinyl,
4-methoxypiperazinyl, 4- (4-tert-butoxycarbonyl-1-homopiperazinyl) piperidinyl, 4- (4-n-butyl-1-homopiperazinyl) piperidinyl, 4- (1-methyl-4-piperidinyl) homopiperazinyl , 3- (4-methyl-1-homopiperazinyl) piperidinyl, 2- (4-dimethylamino-1-
Piperidinylmethyl) morpholino, 2- (4-methyl-
1-piperazinylmethyl) homomorpholino, 2- [4-
(2-hydroxyethyl) -1-piperazinylmethyl]
Morpholino, 4- (3-methyl-1-piperazinyl) piperidinyl, 4- (4-ethyl-1-homopiperazinyl) piperidinyl, 3- (4-methyl-1-homopiperazinyl) pyrrolidinyl, 4- [4- (1,3 -Dihydroxy-2-propyl) -1-piperazinyl] piperidinyl, 4- [4- (1,3-dihydroxy-2-propyl) -1-homopiperazinyl] piperidinyl, 4-methyl-3- (1-piperidinylmethyl ) Piperazinyl, 4
-Methyl-3- (4-methyl-1-piperazinylmethyl) piperazinyl, 4-methyl-3- (4-methyl-1
-Homopiperazinylmethyl) piperazinyl, 3,4,5
-Trimethoxypiperazinyl, 4-isopropylpiperazinyl, 4- (1,4-diazabicyclo [4,3,0]
Nonyl) piperidinyl, (3,3,4-trimethyl-1)
-Piperazinyl) piperidinyl, 4- (1,4-diazabicyclo [4,4,0] decyl) piperidinyl, 4-
(3-methyl-4-ethyl-1-piperazinyl) piperidinyl, 4- (3-methyl-4-propyl-1-piperazinyl) piperidinyl, 4- (3-propyl-4-methyl-1-piperazinyl) piperidinyl, -(3-methyl-4-isopropyl-1-piperazinyl) piperidinyl, 4- (3-ethyl-4-methyl-1-piperazinyl) piperidinyl, 4- [3-methyl-4- (2-methoxyethyl) -1 -Piperazinyl] piperidinyl, 4-
[3-methyl-4- (2-hydroxyethyl) -1-piperazinyl] piperidinyl, 4- (4-methyl-1-
(A) carbon number of 1 to 6 such as 1,4-diazaspiro [5,5] undecyl) piperidinyl, 4- (4-methyl-3-isopropyl-1-piperazinyl) piperidinyl, 4- (2-pyrimidyl) piperazinyl group A linear or branched alkyl group represented by the following formula: (a) group-(B) ₁ -NR ¹² R ¹³ (l is the same as above; B is a group -CO-A- (A is the same as above);
It represents a carbonyl group or a linear or branched alkyl group having 1 to 6 carbon atoms. R ¹² and R ¹³ are the same or different and each represent a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, and a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent. 1 to 1 carbon atoms having an amino group which may have 2
6 represents a linear or branched alkyl group. Alternatively, R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 5- to 12-membered saturated monocyclic, binomial or spiro heterocyclic ring with or without a nitrogen or oxygen atom. Is also good. The heterocycle has a straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, and a carbon atom having 1 to 3 straight-chain or branched alkoxy groups having 1 to 6 carbon atoms as a substituent. A linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, and a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent. 1-2
It may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms and having 1 to 3 amino groups and 1 to 3 hydroxyl groups. ), (C)
A linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, (d) a linear or branched alkyl group having 1 to 3 carbon atoms having 1 to 3 carbon atoms, and (e) a pyridine ring A pyridyl group having from 1 to 3 straight or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as a substituent; A linear or branched alkyl group having 1 to 6 carbon atoms,
(G) a linear or branched alkoxy group having 1 to 6 carbon atoms,
(H) a cycloalkyl group having 3 to 8 carbon atoms, (q) a hydroxyl group, a (co) tetrahydropyranyloxy-substituted alkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl portion, (Sa) pyrimidyl group, (si) 1 to 1 carbon atoms
A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms having 1 to 6 straight-chain or branched-chain alkoxy groups having 6 to 6 carbon atoms; A phenylalkoxy group which is a straight-chain or branched-chain alkoxy group having 6 or an alkyl which may have a straight-chain or branched-chain alkylenedioxy group having 1 to 4 carbon atoms as a substituent on a (so) phenyl ring; A phenylalkyl group in which a portion is a linear or branched alkyl group having 1 to 6 carbon atoms;
6 linear or branched alkanoyloxy groups and (h)
The above heterocyclic ring having 1 to 3 groups selected from a piperidinyl group which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the piperidine ring can be exemplified.

Examples of the lower alkenyloxy group include vinyloxy, 1-methylvinyloxy, 2,2-dimethylvinyloxy, 1,2-dimethylvinyloxy,
-Propylvinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-ethylvinyloxy, 1-methylallyloxy, 1-pentenyloxy,
Examples thereof include linear or branched alkenyloxy groups having 2 to 6 carbon atoms, such as 2-pentenyloxy, 2-hexenyloxy, 3-methyl-1-butenyloxy, and 1-butenyloxy groups.

Examples of the cycloalkyloxy group include those having 3 to 8 carbon atoms such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy groups.
Can be exemplified.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio and hexylthio. Can be exemplified.

Examples of the lower alkenyl group include vinyl, 1-methylvinyl, 2,2-dimethylvinyl,
2-dimethylvinyl, 1-propenylvinyl, allyl,
2-butenyl, 3-butenyl, 1-ethylvinyl, 1-
Methylallyl, 1-pentenyl, 2-pentenyl, 2-
Examples thereof include linear or branched alkenyl groups having 2 to 6 carbon atoms, such as hexenyl, 3-methyl-1-butenyl and 1-butenyl groups.

The thiazole derivatives of the general formula (1) of the present invention include the compounds of the following various embodiments.

[0138] (1) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0139]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0141] (2) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0142]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0144] (3) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0145]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

[0147] (4) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0148]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(5) R ¹ and R ² are bonded to form a group — (CH
₂ ) _n- (n represents 4), and R ³ is a group

[0151]

Embedded image

(R ^11b , p and R ^11a are the same as those represented by the general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(6) R ¹ and R ² are bonded to form a group — (CH
₂ ) _n- (n represents 4), and R ³ is a group

[0154]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(7) R ¹ and R ² are bonded to form a group — (CH
₂ ) _n- (n represents 4), and R ³ is a group

[0157]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(8) R ¹ and R ² are bonded to form a group — (CH
₂ ) _n- (n represents 4), and R ³ is a group

[0160]

Embedded image

(R ^11b , p and R ^11a are the same as those represented by the general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(9) R ¹ and R ² are bonded to form a group — (CH
₂ ) _n- (n represents 5), and R ³ is a group

[0163]

Embedded image

(R ^11b , p and R ^11a are the same as those of the general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(10) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0166]

Embedded image

(R ^11b , p and R ^11a are the same as those of the above formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(11) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0169]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(12) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0172]

Embedded image

(R ^11b , p and R ^11a are the same as those of the above formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(13) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0175]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(14) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0178]

Embedded image

(R ^11b , p and R ^11a are the same as those in the general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(15) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0181]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(16) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0184]

Embedded image

(R ^11b , p and R ^11a are those represented by the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0186] (17) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0187]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0189] (18) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0190]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0192] (19) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0193]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

[0195] (20) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0196]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(21) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0199]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(22) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0202]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(23) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0205]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(24) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0208]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(25) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0211]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(26) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0214]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(27) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0219]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(28) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0220]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(29) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0223]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(30) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0226]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(31) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0229]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(32) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0232]

Embedded image

(S represents 0. R ⁶ represents a group —CO—CH ＝
CR ^11b- (CO) _p -R ^11a (R ^11b , p and R ^11a are the same as defined in the general formula (1)). R ⁵ ,
m, A and Z are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0234] (33) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0235]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

[0237] (34) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0238]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0240] (35) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0241]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

[0243] (36) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0244]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(37) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0247]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(38) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0250]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(39) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0253]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(40) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0256]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(41) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0259]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(42) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0262]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(43) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0265]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(44) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0268]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(45) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0271]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(46) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0274]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(47) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0277]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(48) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0280]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0282] (49) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0283]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

[0285] (50) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0286]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0288] (51) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0289]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

[0291] (52) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0292]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(53) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0295]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(54) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0298]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(55) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0301]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(56) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0304]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(57) R ¹ and R ² are bonded to form a group-(C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0307]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(58) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0310]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(59) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0313]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(60) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0316]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(61) R ¹ and R ² are bonded to form a benzene ring (this benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0319]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(62) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0322]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(63) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0325]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u
Is a thiazole derivative represented by the general formula (1) or a salt thereof.

(64) R ¹ and R ² are bonded to each other to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0328]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—CH ＝ CR ^11b — (CO) _p —R ^11a (R
^11b , p and R ^11a are the same as defined in the general formula (1). ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0330] (65) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0331]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0333] (66) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0334]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0336] (67) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0337]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

[0339] (68) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0340]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(69) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0343]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(70) R ¹ and R ² are bonded to form a group-(C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0346]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(71) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0349]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(72) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0352]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(73) R ¹ and R ² are bonded to form a group-(C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0355]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(74) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0358]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(75) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0361]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(76) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0364]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(77) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0367]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(78) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0370]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(79) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0373]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(80) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0376]

Embedded image

(S represents 0. R ⁶ represents a group —CO—C≡C
OR ¹⁴ (R ¹⁴ is the same as defined in the general formula (1)). R ⁵ , m, A and Z are as defined in the above general formula (1)
Same as the definition in ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0378] (81) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0379]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0381] (82) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0382]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(83) R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ³ represents a group

[0385]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

[0387] (84) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0388]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(85) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0391]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(86) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0394]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(87) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0397]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(88) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 4), and R ³ is a group

[0400]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(89) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0403]

Embedded image

(S represents 1. Z represents an oxygen atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(90) R ¹ and R ² are bonded to form a group-(C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0406]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(91) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0409]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(92) R ¹ and R ² are bonded to form a group — (C
H ₂ ) _n — (n represents 5), and R ³ is a group

[0412]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(93) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0415]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(94) R ¹ and R ² are bonded to form a benzene ring (this benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0418]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(95) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0421]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(96) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group as a substituent,
A group selected from the group consisting of a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent and a halogen atom may be substituted. ) To form
R ³ based

[0424]

Embedded image

(S represents 1; Z represents an oxygen atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

[0426] (97) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0427]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0429] (98) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0430]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

[0432] (99) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0433]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

[0435] (100) R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a group

[0436]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(101) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n — (n represents 4), and R ³ is a group

[0439]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(102) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n — (n represents 4), and R ³ is a group

[0442]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(103) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n — (n represents 4), and R ³ is a group

[0445]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(104) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n — (n represents 4), and R ³ is a group

[0448]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(105) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n- (n represents 5), and R ³ is a group

[0451]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(106) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n- (n represents 5), and R ³ is a group

[0454]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(107) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n- (n represents 5), and R ³ is a group

[0457]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(108) R ¹ and R ² are bonded to form a group
(CH ₂ ) _n- (n represents 5), and R ³ is a group

[0460]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

(109) R ¹ and R ² are bonded to form a benzene ring (the benzene ring may be a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having a lower alkyl group as a substituent, group selected from the group consisting group and a halogen atom may be substituted.) to form, R ³ is a group

[0463]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(110) R ¹ and R ² are bonded to form a benzene ring (the benzene ring has a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, group selected from the group consisting group and a halogen atom may be substituted.) to form, R ³ is a group

[0466]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 0, or a thiazole derivative represented by the general formula (1) or a salt thereof.

(111) R ¹ and R ² are bonded to form a benzene ring (the benzene ring may be a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, group selected from the group consisting group and a halogen atom may be substituted.) to form, R ³ is a group

[0469]

Embedded image

(S represents 1; Z represents a sulfur atom; R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), R ⁴ represents a hydrogen atom, and u is 1. A thiazole derivative represented by the general formula (1) or a salt thereof.

(112) R ¹ and R ² are bonded to form a benzene ring (the benzene ring may be a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, group selected from the group consisting group and a halogen atom may be substituted.) to form, R ³ is a group

[0472]

Embedded image

(S represents 1. Z represents a sulfur atom. R
⁶ is a group —CO—C≡COR ¹⁴ (R ¹⁴ is the above-mentioned general formula (1)
Same as the definition in ). R ⁵ , m and A are the same as defined in the general formula (1). ), Wherein R ⁴ represents a lower alkanoyloxy lower alkyl group, and u is 1;

The compound of the present invention can be produced by various methods.

[0475]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s,
T, u and A are the same as above. R ¹⁵ is a group —CH ＝ C (R
^11b ) (COR ¹⁶ ) (R ^11b is the same as above; R ¹⁶ represents a hydroxyl group or a lower alkoxy group) or a group —C−C—CO
R ¹⁴ (R ¹⁴ is as defined above) is shown. X represents a halogen atom. The reaction between compound (2) and compound (3) or (4) is generally carried out by a Friedel-Craft reaction (Friedel-Craft reaction).
fts Reaction), which can be performed in a suitable solvent in the presence of a Lewis acid. As the Lewis acid used here, any Lewis acid generally used in this type of Friedel-Crafts reaction can be used. For example, aluminum chloride, zinc chloride, iron chloride,
Examples thereof include tin chloride, boron tribromide, boron trifluoride, and concentrated sulfuric acid. As the solvent used, for example, carbon disulfide,
Examples thereof include aromatic hydrocarbons such as nitrobenzene and chlorobenzene, halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloroethane; aliphatic nitro compounds such as nitroethane and nitromethane; and mixed solvents thereof. The amount of compound (3) or (4) to be used is at least equimolar, preferably equimolar to 5 times the molar amount of compound (2). The amount of the Lewis acid to be used is generally 1 to 6 times the molar amount of the compound (2). The reaction is carried out usually at 0 to 120 ° C, preferably at about 0 to 70 ° C, for 0.5
It ends in about 24 hours.

R ¹⁵ is a group —CH ＝ C (R ^11b ) (CO
R ¹⁶ ) and the compound (1a) in which the double bond in the group is a cis form,
By heating to around 100 ° C., the compound (1a) in which the corresponding R ¹⁵ represents a group —CH ＝ C (R ^11b ) (COR ¹⁶ ) and the double bond in the group represents a trans form can be easily isomerized. Can be

R ¹⁵ is a group —CH ＝ C (R ^11b ) (CO
R ¹⁶ ) or a compound (1a) which represents a group —C≡C—COR ¹⁴ and R ¹⁶ or R ¹⁴ represents a lower alkoxy group leads to a compound (1e) which is a compound (1d) in the following reaction formula-4. By treating under the same conditions as in the reaction, it is possible to lead to the compound (1a) in which the corresponding R ¹⁶ or R ¹⁴ represents a hydroxyl group.

[0479]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ^11b , Z,
m, s, T, u and A are the same as above. R ¹⁷ represents a heterocyclic residue defined in R ^11a having at least one group —N <in the heterocyclic ring. The method represented by the reaction formula-2 is a method in which a thiazole compound of the general formula (1b) and an amine of the general formula (5) are reacted by a usual amide bond formation reaction. Known conditions for the amide bond formation reaction can be easily applied to the acid amide bond formation reaction. For example, (a) a mixed acid anhydride method, that is, a method of reacting a carboxylic acid (1b) with an alkylhalocarbonate to form a mixed acid anhydride and reacting the mixed acid anhydride with an amine (5); A method in which the acid (1b) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester and the like and an amine (5) is reacted therewith; (c) a carbodiimide method, A method in which the amine (5) is condensed with the acid (1b) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; A carboxylic acid anhydride, and reacting the carboxylic acid anhydride with an amine (5). A method of reacting under pressure and temperature of the amine (5) to the ester of the call, acid halide of the carboxylic acid (1b), can be exemplified That method in which reacting a carboxylic acid halide to the amine (5).

The mixed acid anhydride used in the mixed acid anhydride method (a) is obtained by a reaction similar to the usual Schotten-Baumann reaction, and this is reacted with the amine (5) without isolation. Thereby, the compound of the present invention of the general formula (1) is produced. The Schotten-Baumann reaction is performed in the presence of a basic compound. Examples of the basic compound used include compounds commonly used in the Schotten-Baumann reaction, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5.
Organic bases such as (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO);
Inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like can be mentioned. The reaction is usually carried out at about -20 to 100 ° C, preferably at -20 to 5
The reaction is performed at about 0 ° C., and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (5) is usually carried out at -20 to 15
The reaction is performed at about 0 ° C., preferably about −20 to 50 ° C., and the reaction time is about 5 minutes to 35 hours, preferably 5 minutes to
It is about 30 hours. The mixed acid anhydride method is generally performed in a solvent in the presence of a basic compound. As the basic compound used, any of the basic compounds used in the Schotten-Baumann reaction can be used. As the solvent, any of the solvents commonly used in the mixed acid anhydride method can be used. Specifically, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and aromatic solvents such as benzene, p-chlorobenzene, toluene and xylene can be used. Group hydrocarbons, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoric triamide, 1- An aprotic polar solvent such as methyl-2-pyrrolidinone (NMP) or a mixed solvent thereof may be used. Examples of the alkyl halocarbonate used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. The use ratio of the carboxylic acid (1b), the alkyl halocarbonate and the amine (5) in the method is usually preferably equimolar, but the ratio of the alkyl halocarbonate and the amine (5) to the carboxylic acid (1b) is relatively small. Each can be used in the range of about 1 to 1.5 times the molar amount.

When the method of reacting a carboxylic acid halide with an amine (5) is employed among the other methods (d), the reaction is carried out in the presence of a basic compound in a suitable solvent. As the basic compound to be used, known compounds can be widely used.For example, in addition to the basic compound used for the above-mentioned Schotten-Baumann reaction, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like can be used. Can be illustrated. Examples of the solvent used include, in addition to the solvent used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; pyridine; Acetone, water and the like can be exemplified. The ratio of the amine (5) and the carboxylic acid halide to be used is not particularly limited and can be appropriately selected within a wide range. Usually, the former is at least about equimolar, preferably about equimolar to about 5 times the molar amount of the latter. Good to use. The reaction is usually carried out at about -70 to 180 ° C, preferably at about -50 to 150 ° C, and is generally completed in about 5 minutes to 30 hours.

Further, in the amide bond forming reaction shown in the above reaction formula-2, the carboxylic acid (1b) and the amine (5) are reacted with phenylphosphine-2,2'-dithiodipyridine, diphenylphosphinyl chloride, phenyl- N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphate azide,
N, N'-bis (2-oxo-3-oxazolidinyl)
It can also be carried out by a method of reacting a phosphorus compound such as phosphinic chloride in the presence of a condensing agent.

The reaction is usually carried out at about -20 to 150 ° C., preferably at about 0 to 100 ° C., in the presence of a solvent and a basic compound used in the method of reacting the amine (5) with the carboxylic acid halide. 5 minutes to 3 days
The reaction is completed in about 0 hours. The amounts of the condensing agent and the amine (5) to be used are at least about an equimolar amount, and preferably about an equimolar to 2 times the molar amount, of the carboxylic acid (1b).

[0485]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s,
T, u, R ¹⁶ and A are the same as above. R ¹⁸ and R ¹⁹ each represent a lower alkoxy group. R ²² are the same as described below. The reaction between the compound (6) and the compound (7) is performed in an appropriate solvent in the presence of a basic compound. Examples of the basic compound used include metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium methylate,
Metal alcoholates such as sodium ethylate and potassium t-butoxide; alkyl and aryl lithium or lithium amides such as methyllithium, n-butyllithium, phenyllithium and lithium diisopropylamide; pyridine, piperidine, quinoline, triethylamine, N, N -Organic bases such as dimethylaniline. Any solvent can be used as long as it does not affect the reaction.For example, water, diethyl ether, dioxane, tetrahydrofuran, monoglyme,
Ethers such as diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, n-hexane, heptane,
Aliphatic hydrocarbons such as cyclohexane, pyridine, N,
Amines such as N-dimethylaniline, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol , Alcohols such as isopropanols, ureas such as N, N'-dimethylpropylene urea (DMPU), 1,3-dimethyl-3,
Examples thereof include 4,5,6-tetrahydro-2 (1H) -pyrimidinone and a mixed solvent thereof. Compound (7)
Is used at least in an equimolar amount, preferably in an equimolar to 5-fold molar amount, relative to compound (6). The reaction temperature is usually -80 to 150C, preferably -80 to 120.
C., and the reaction is generally completed in about 0.5 to 15 hours.

The reaction for converting the compound (8) to the compound (10) is carried out in a suitable solvent in the presence of an oxidizing agent. The oxidizing agent used here is 2,3-dichloro-5,6
Benzoquinones such as -dicyano-1,4-benzoquinone (DDQ), pyridinium chromates such as pyridinium chlorochromate and pyridinium dichlorochromate;
Dimethyl sulfoxide-oxalyl chloride, dichromate such as dichromic acid, sodium dichromate, potassium dichromate, permanganate such as permanganate, potassium permanganate, sodium permanganate, manganese dioxide, etc. Can be exemplified. Examples of the solvent used include water, formic acid, acetic acid, organic acids such as trifluoroacetic acid, alcohols such as methanol and ethanol, chloroform, halogenated hydrocarbons such as dichloromethane, tetrahydrofuran, diethyl ether, and dioxane. Examples thereof include ethers, dimethyl sulfoxide, dimethylformamide, and a mixed solvent thereof. The oxidizing agent is usually used in a large excess usually with respect to the starting materials. The reaction is completed usually at about 0 to 200 ° C, preferably about 0 to 150 ° C, for about 1 to 10 hours.

The reaction of compound (9) with compound (7)
The reaction is carried out under the same reaction conditions as in the reaction between compound (6) and compound (7).

The reaction between the compound (10) and the compound (12) is carried out under the same reaction conditions as in the reaction between the compound (6) and the compound (7).

The reaction between the compound (10) and the compound (20) is carried out under the same reaction conditions as in the reaction between the compound (6) and the compound (7).

[0490]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , Z, m, s,
T, u and A are the same as described above, and R ²⁰ represents a lower alkoxy group. M represents an alkali metal such as lithium, sodium and potassium. R ^16a represents a lower alkoxy group. The reaction between compound (6) and compound (13) is carried out in a suitable solvent in the presence of a basic compound, generally at -80 ° C to around room temperature for 5 minutes to 6 hours. As the solvent used herein, for example, diethyl ether, dioxane, ethers such as tetrahydrofuran, benzene, aromatic hydrocarbons such as toluene, hexane, heptane, pentane,
Examples include saturated hydrocarbons such as cyclohexane and ureas such as N, N'-dimethylpropylene urea (DMPU). As the basic compound used here, any of the basic compounds used in the reaction of the compound (6) with the compound (7) in the above Reaction Scheme-3 can be used. The amount of compound (13) to be used is generally at least equimolar, preferably equimolar to 5-fold molar amount, relative to compound (6).

The reaction for converting the compound (11) into the compound (1d ′) is carried out in a suitable solvent in the presence of a basic compound. Examples of the basic compound used herein include organic compounds such as triethylamine, trimethylamine, diisopropylamine, tri-n-butylamine, ethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, and DABCO. Bases can be exemplified. As the solvent used,
Examples thereof include water, alcohols such as ethanol, methanol, and isopropyl alcohol, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and a mixed solvent thereof. The reaction is usually carried out at room temperature to 15
It is completed at about 0 ° C., preferably at about room temperature to 100 ° C., for about 1 to 5 hours.

The reaction for converting the compound (11) into the compound (1f) is carried out under the same reaction conditions as the reaction for converting the compound (8) into the compound (10) in the above Reaction Formula-3. The reaction for converting the compound (1d ′) to the compound (1e) can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; dioxane; tetrahydrofuran; and ethylene glycol dimethyl ether. And fatty acids such as acetic acid and formic acid, and a mixed solvent thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and aromatic sulfonic acid.Examples of the basic compound include sodium carbonate And metal carbonates such as potassium carbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. The reaction is usually carried out at room temperature to 2
The process suitably proceeds at about 00 ° C., preferably at room temperature to about 150 ° C., and generally ends in about 10 minutes to 25 hours.

The reaction for converting the compound (1f) to the compound (1g) is carried out under the same reaction conditions as those for converting the compound (1d ′) to the compound (1e).

[0496]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , A, Z, m,
s, T, u and X are the same as above. X ¹ represents a halogen atom. R ²¹ represents a phenyl group. R ²² is a 5- to 10-membered monocyclic or dicyclic saturated or unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms (in the heterocyclic ring, as a substituent, (A) lower alkyl group, (A) group-
_{^{(B) l -NR 12 R 13}} (l is as .B said the group -CO
-A- (A is the same as above), a carbonyl group or a lower alkylene group. R ¹² and R ¹³ are the same or different and represent a hydrogen atom, a lower alkyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent.
R ¹² and R ¹³ may be 5 to 1 with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bound.
It may form a two-membered saturated monocyclic, binomial or spiro heterocyclic ring. The heterocycle is selected from the group consisting of a lower alkyl group as a substituent, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent, and a hydroxyl-substituted lower alkyl group. It may have a group. ), (C)
A lower alkoxycarbonyl group, (d) a hydroxyl-substituted lower alkyl group, (e) a pyridyl group which may have a lower alkyl group which may have a halogen atom as a substituent on a pyridine ring, and (f) a halogen-substituted lower alkyl group ,
(G) lower alkoxy group, (C) cycloalkyl group,
(G) hydroxyl group, (co) tetrahydropyranyloxy group-substituted lower alkyl group, (sa) pyrimidyl group, (si) lower alkoxy-substituted lower alkyl group, (s) carboxy group,
(Se) a phenyl lower alkoxy group, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the (so) phenyl ring, a (ta) lower alkanoyloxy group, a substituent on the (thi) piperidine ring May have 1 to 3 groups selected from the group consisting of piperidinyl groups which may have a lower alkyl group. ). Reaction of Compound (2) with Compound (14) and Compound (2)
The reaction of the compound (15) with the compound (15) can be carried out under the same conditions as in the reaction of the compound (2) with the compound (3) or (4) in the aforementioned Reaction Formula-1.

The halogenation of compound (16) is carried out in a suitable solvent in the presence of a halogenating agent. Examples of the halogenating agent used here include halogen molecules such as bromine and chlorine, copper compounds such as iodine chloride, sulfuryl chloride, cupric bromide, N-bromosuccinimide, and N-bromosuccinimide.
Examples include N-halogenated succinimides such as chlorosuccinimide. Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, fatty acids such as acetic acid and propionic acid, and carbon disulfide. The amount of the halogenating agent to be used is generally equimolar to 10-fold molar amount, preferably equimolar to 5-fold molar amount, relative to compound (16). The reaction is completed usually at 0 ° C. to the boiling point of the solvent, preferably at about 0 to 100 ° C., usually for about 5 minutes to 20 hours.

The reaction between compound (17) and compound (18) is completed in a suitable solvent, usually at room temperature to 150 ° C., preferably at room temperature to about 100 ° C., generally for about 1 to 10 hours. As the solvent used herein, any of the solvents used in the method of reacting the amine (5) with the carboxylate during the reaction between the compound (1b) and the compound (5) in the above Reaction Formula-2 is used. be able to. The amount of compound (18) to be used is at least equimolar, preferably equimolar to 1.5-fold molar with respect to compound (17).

In the above reaction, the general formula

[0501]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , A, Z, m,
R ²¹ , s, T, u and X are the same as above. Which is then treated in a suitable solvent in the presence of a basic compound to give compound (19). The solvent and the basic compound used here are the same as those described in the reaction formula-2.
In the reaction between the compound (1b) and the compound (5) in the above, any of the solvent and the basic compound used in the method of reacting the amine (5) with the carboxylic acid halide can be used. The reaction is usually carried out at 0 to 100 ° C, preferably at 0 to 70 ° C.
C., and generally ends in about 1 to 5 hours.

The reaction between the compound (19) and the compound (20) is carried out under the same reaction conditions as the reaction between the compound (6) and the compound (7) in the above Reaction Scheme-3.

Alternatively, compound (19) and compound (20)
The reaction proceeds in a suitable solvent, usually at 0 to 150 ° C., preferably at room temperature to around 100 ° C., and is generally completed in about 0.5 to 8 hours. As the solvent used here, any solvent that does not affect the reaction can be used, for example, water, methanol, ethanol,
Alcohols such as isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, diglyme and monoglyme, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, and dimethyl Examples thereof include polar solvents such as formamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Compound (20) is usually used in an amount at least equimolar, preferably equimolar to 5-fold molar amount, relative to compound (19). The reaction proceeds advantageously when paraaldehyde is added to the reaction system.

[0505]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , Z,
s, T, u and A are the same as above. q represents 1. R
^5a represents a halogen-substituted lower alkyl group. R ^5b is a group-
A-NR ⁷ R ⁸ (A, R ⁷ and R ⁸ are as defined above) or a lower alkanoyloxy lower alkyl group. R ²³ is a group -NR ⁷ R ⁸ (R ⁷ and R ⁸ are the same. Above) shows a or a lower alkanoyloxy group. The reaction between compound (1i) and compound (22) is generally carried out in a suitable inert solvent or without solvent, in the presence or absence of a basic compound. As the inert solvent used, for example, benzene, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, dichloromethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, methanol, Examples thereof include lower alcohols such as ethanol, isopropanol, butanol, and tert-butanol, water, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and a mixed solvent thereof. . Examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonates such as potassium hydrogen carbonate, sodium hydroxide, metal hydroxides such as potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, and the like. Metal alcoholates such as sodium methylate, pyridine,
N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU),
1,4-diazabicyclo [2,2,2] octane (DA
And organic bases such as BCO). The use ratio of the compound (1i) to the compound (22) is not particularly limited and may be appropriately selected in a wide range. The amount of the latter is at least about equimolar, preferably about 10 to 10 times the amount of the former. It is better to use about the amount. The reaction is usually performed at 0
The reaction is carried out at about 200 ° C., preferably about 0-170 ° C., and the reaction is completed in about 30 minutes to 75 hours. An alkali metal halide such as sodium iodide and potassium iodide, copper powder and the like may be added to the reaction system.

[0507]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , T, u and m
Is the same as above. The reaction between the compound (23) and the compound (24) is carried out under the same reaction conditions as the reaction between the compound (1b) and the compound (5) in the aforementioned Reaction Formula-2.

[0509]

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[Wherein R ¹ , R ² , R ³ , T, u and X are as defined above. R ^4a represents a lower alkanoyloxy lower alkyl group. The reaction between the compound (1k) and the compound (25) is carried out under the same reaction conditions as the reaction between the compound (1i) and the compound (22) in the aforementioned Reaction Formula-6.

[0511]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
⁸ , Z, s, T, u and q are the same as above. R ^5c represents a carboxy-substituted lower alkyl group. R ^5d is a group -A-CO-
NR ⁷ R ⁸ (R ⁷ and R ⁸ are as defined above). The reaction between the compound (1m) and the compound (26) is carried out under the same reaction conditions as the reaction between the compound (1b) and the compound (5) in the aforementioned Reaction Formula-2.

In each of the above reaction formulas, compounds (2), (6) and (23) as starting materials are produced, for example, by the following reaction formulas.

[0514]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , X, Z, T,
u and m are the same as above. R ²⁴ represents a hydroxyl group, a lower alkoxy group or a phenyl lower alkoxy group. A 'represents a lower alkylene group. The reaction between the compound (27) and the compound (28) is carried out under the same reaction conditions as the reaction between the compound (1i) and the compound (22) in the aforementioned Reaction Formula-6.

Compounds wherein R ²⁴ represents a lower alkoxy group (2
The reaction for converting 9) to the compound (30) is carried out under the same reaction conditions as the reaction for converting the compound (1d) to the compound (1e) in the aforementioned Reaction Formula-4.

The reaction for converting the compound (29), in which R ²⁴ represents a phenyl lower alkoxy group, to the compound (30) is carried out under the same reaction conditions as the reaction for converting the compound (5b) into the compound (5c) in Reaction Scheme-13 described later. Done in

The reaction of the compound (30) with the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) with the compound (5) in the aforementioned reaction formula-2.

[0519]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , A ′, Z, R
²⁴ , T, u and m are the same as above. The reaction between the compound (31) and the compound (28) is carried out under the same reaction conditions as the reaction between the compound (27) and the compound (28) in the aforementioned Reaction Formula-10.

Compounds wherein R ²⁴ represents a lower alkoxy group (3
The reaction for converting 2) to the compound (33) is carried out according to the above reaction formula -10
Wherein R ²⁴ represents a lower alkoxy group (29)
Is carried out under the same reaction conditions as in the reaction leading to compound (30).

The reaction for converting the compound (32), in which R ²⁴ represents a phenyl lower alkoxy group, to the compound (33) is carried out under the same reaction conditions as the reaction for converting the compound (5b) into the compound (5c) in the following Reaction Scheme-13. Done in

The reaction of the compound (33) with the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (30) with the compound (24) in the aforementioned Reaction Formula-10.

[0524]

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[Wherein R ⁵ , R ⁶ , m, A ′, X, Z and R
²⁴ is the same as above. The reaction between (34) and compound (28) is performed according to the reaction formula-1
The reaction is carried out under the same reaction conditions as in the reaction of compound (27) with compound (28) at 0.

Compounds wherein R ²⁴ represents a lower alkoxy group (3
The reaction for introducing 5) into compound (23a) is carried out according to the above-mentioned reaction formula-1.
0 is a compound wherein R ²⁴ represents a lower alkoxy group (2
The reaction is carried out under the same reaction conditions as in the reaction for converting 9) to compound (30).

The reaction for converting the compound (35) in which R ²⁴ represents a phenyl lower alkoxy group to the compound (23a) is carried out under the same reaction conditions as the reaction for converting the compound (5b) to the compound (5c) in Reaction Scheme-13 described later. Done in

Compound (5) used as starting material
Is produced, for example, by the method shown in the following reaction formula.

[0529]

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[Wherein R ¹² and R ¹³ are as defined above. R
^17a represents R ¹⁷ having at least one oxo group on the heterocyclic ring. R ^17b represents a group —NR ¹² R ¹³ on the heterocyclic ring
(R ¹² and R ¹³ are the same. Above) show the R ¹⁷ having at least one. R ²⁵ represents a phenyl lower alkyl group. The reaction between compound (5a) and compound (36) is carried out without a solvent or in a suitable solvent in the presence of a reducing agent. Examples of the solvent used herein include water, alcohols such as methanol, ethanol, and isopropanol; acetonitrile, formic acid, acetic acid, dioxane, diethyl ether, diglyme, and ethers such as tetrahydrofuran; and aromatic hydrocarbons such as benzene, toluene, and xylene. Examples thereof include hydrogens and a mixed solvent thereof. As the reducing agent, for example, formic acid, alkali metal salts of fatty acids such as sodium formate, sodium borohydride, sodium cyanoborohydride, hydrogenation reducing agents such as lithium aluminum hydride, palladium-
Examples thereof include catalytic reducing agents such as black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.

In the case of using formic acid as a reducing agent, the reaction temperature is usually from room temperature to about 200 ° C., preferably from 50 to 150 ° C.
C. is appropriate, and the reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably a large excess with respect to compound (5a).

In the case of using a hydride reducing agent, the reaction temperature is usually about -30 to 100 ° C, preferably 0 to 70 ° C.
The reaction is properly performed, and the reaction is completed in about 30 minutes to 12 hours. The amount of the reducing agent to be used is generally about equimolar to 20-fold molar quantity, preferably about 1- to 6-fold molar quantity, relative to compound (5a). In particular, when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme as solvents, and aromatic hydrocarbons such as benzene, toluene, and xylene.

When a catalytic reducing agent is further used, it is usually in a hydrogen atmosphere at normal pressure to about 20 atm, preferably normal pressure to about 10 atm, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene or hydrazine hydrate. The reaction is usually carried out at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C, and the reaction is usually completed in about 1 to 12 hours. The amount of the catalytic reducing agent used may be the compound (5
It is usually about 0.1 to 40% by weight, preferably about 0.1 to 20% by weight, based on a).

The amount of compound (36) to be used is generally at least equimolar, preferably equimolar to 3-fold molar with respect to compound (5a).

The reaction for converting the compound (5b) into the compound (5c) can be carried out, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst. As the solvent used, for example, water, acetic acid, methanol, ethanol, alcohols such as isopropanol, hexane, hydrocarbons such as cyclohexane, dioxane, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol dimethyl ether, ethyl acetate, Esters such as methyl acetate; aprotic polar solvents such as dimethylformamide; and mixed solvents thereof. As the catalyst used, for example, palladium, palladium-
Black, palladium hydroxide, palladium hydroxide-carbon, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like are used. The amount of the catalyst to be used is generally about 0.02 to 1 times that of compound (5b). The reaction temperature is usually about -20 to 100 ° C, preferably about 0 to 70 ° C, and the hydrogen pressure is usually 1 to 10 atm. The reaction is generally completed in about 0.5 to 20 hours.

[0536]

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[Wherein R ¹² , R ¹³ and R ²⁵ are as defined above.
R ^17c represents R ¹⁷ having at least one carboxy group on the heterocyclic ring. R ^17d represents a group —CON on the heterocycle.
The above R ¹⁷ having at least one of R ¹² R ¹³ (R ¹² and R ¹³ are the same as described above) is shown. R ^17e represents a group-
The above R ¹⁷ having at least one CH ₂ NR ¹² R ¹³ (R ¹² and R ¹³ are the same as described above) is shown. The reaction between the compound (5d) and the compound (36) is carried out under the same reaction conditions as the reaction between the compound (1b) and the compound (5) in the aforementioned Reaction Formula-2.

The reaction for converting the compound (5e) to the compound (5f) and the reaction for converting the compound (5g) to the compound (5h) are as follows.
Compound (5b) in the above Reaction Scheme-13 was replaced with compound (5
The reaction is carried out under the same reaction conditions as the reaction leading to c).

In the reaction for converting the compound (5e) to the compound (5g), a reduction method using a hydride reducing agent is suitably used. The hydride reducing agent used includes, for example, lithium aluminum hydride, sodium borohydride, diborane, and the like, and the amount thereof is at least equimolar, preferably equimolar to 15-fold molar with respect to the raw material compound. is there. This reduction reaction is usually carried out using an appropriate solvent, for example, water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether and diglyme, and a mixed solvent thereof. The reaction is carried out at a temperature of １５０150 ° C., preferably -30-100 ° C., for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, tetrahydrofuran,
It is preferable to use an anhydrous solvent such as diethyl ether, diisopropyl ether, and diglyme.

[0540]

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[Wherein R ¹² , R ¹³ and R ²⁵ are as defined above.
R ^17f represents R ¹⁷ having at least one halogen-substituted lower alkyl group on the heterocyclic ring. R ^17g represents R ¹⁷ having at least one group -B'-NR ¹² R ¹³ (B 'represents a lower alkylene group; R ¹² and R ¹³ are the same as described above) on the heterocyclic ring. The reaction between the compound (5i) and the compound (36) is performed under the same reaction conditions as the reaction between the compound (1i) and the compound (22) in the aforementioned Reaction Formula-6.

The reaction for converting the compound (5j) into the compound (5k) is carried out under the same reaction conditions as the reaction for converting the compound (5b) into the compound (5c) in the aforementioned Reaction Formula-13.

When R ⁶ is

[0544]

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(R ^11b , P and R ^11a are the same as described above.)
In the compound represented by the general formula (1), a compound showing a trans form at a double bond in the group is a compound showing a cis form at a corresponding double bond by irradiation with sunlight in an appropriate solvent. Can be isomerized. As the solvent used herein, any of the solvents used in the reaction between the carboxylic acid halide and the amine (5) during the reaction between the compound (1b) and the compound (5) in the above Reaction Formula-2 may be used. it can. The reaction is completed at about 0 to 70 ° C, preferably about 0 ° C to room temperature, for about 1 to 10 hours.

Certain of the compounds (32) used as starting materials in Reaction Scheme-11 are also produced, for example, by the following method.

[0547]

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[Wherein R ⁵ , m, X, A ′, M and R ²⁴ are the same as above. R ²⁶ and R ²⁷ are the same or different and represent a lower alkyl group. The reaction for converting the compound (37) into the compound (38) can be carried out in a suitable solvent in the presence of a basic compound. Examples of the solvent used include water, methanol,
Lower alcohols such as ethanol and isopropanol,
Examples thereof include ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, and mixed solvents thereof. Examples of the basic compound include metal carbonates such as sodium carbonate and potassium carbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. The reaction proceeds normally at room temperature to about 200 ° C., preferably at room temperature to about 150 ° C.
It ends in about 25 minutes to 25 hours.

The reaction of the compound (38) with the compound (28) is carried out under the same reaction conditions as the reaction of the compound (27) with the compound (28) in the aforementioned Reaction Formula-10.

In a series of reactions represented by the above reaction formula-16,
The reaction can be carried out in two consecutive steps without taking out compound (38).

[0551]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , q,
Z, s, A, T and u are the same as above. R ^5e represents a lower alkenyloxy group. R ^5f represents a hydroxyl group. The reaction for converting the compound (1o) into the compound (1p) is carried out, for example, in a suitable solvent in the presence of a catalyst and an acid. As the solvent used, for example, water, acetic acid, methanol, ethanol, alcohols such as isopropanol, hexane,
Examples include hydrocarbons such as cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as dimethylformamide; and mixed solvents thereof. . As the catalyst used, for example, palladium, palladium-black, palladium hydroxide, palladium hydroxide-carbon, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like are used. Examples of the acid include p
An organic acid such as toluenesulfonic acid is used. The amount of the catalyst to be used is generally 0.04 relative to compound (1o).
The amount is preferably about 2 to 1 times. The amount of acid used is
It is preferable to use a catalytic amount. The reaction temperature is usually -20 to 15
The temperature is preferably around 0 ° C, preferably around 0 to 120 ° C, and the reaction is generally completed in 0.5 to 20 hours.

[0553]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, A ′,
Z, R ²¹ , R ²⁴ , X, T and u are the same as described above. The reaction between the compound (39) and the compound (28) is carried out under the same reaction conditions as the reaction between the compound (1i) and the compound (22) in the aforementioned Reaction Formula-6.

The reaction for converting the compound (40) into the compound (41) is carried out under the same reaction conditions as in the reaction for converting the compound (16) into the compound (17) in the aforementioned Reaction Formula-5.

The reaction of the compound (41) with the compound (18) is carried out under the same reaction conditions as in the reaction of the compound (17) with the compound (18) in the above Reaction Scheme-5.

Compounds wherein R ²⁴ represents a lower alkoxy group (4
In the case of 2), the compound (42) is treated under the same reaction conditions as the reaction for converting the compound (1d) into the compound (1e) in the above-mentioned reaction formula-4 to give the corresponding compound (43). I can guide you.

In the case of the compound (42) in which R ²⁴ represents a phenyl lower alkoxy group, the same reaction conditions as in the reaction for converting the compound (42) from the compound (5b) to the compound (5c) in the aforementioned Reaction Formula-13 are used. The following treatment can lead to the corresponding compound (43).

The reaction of the compound (43) with the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) with the compound (5) in the aforementioned reaction formula-2.

The reaction of the compound (19a) with the compound (44) is carried out usually in an appropriate solvent in the presence of a basic compound.
Proceeds at 150 ° C., preferably at room temperature to around 100 ° C.,
Generally, the reaction is completed in about 0.5 to 8 hours. As the solvent used here, any solvent that does not affect the reaction can be used.For example, alcohols such as water, methanol, ethanol and isopropanol, and aromatic hydrocarbons such as benzene, toluene and xylene can be used. Hydrogens, ethers such as diethyl ether, tetrahydrofuran, dioxane, diglyme, and monoglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; and polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Can be illustrated. Further, as the basic compound, the above-mentioned reaction formula-3
And the same basic compound as the basic compound used in the reaction of the compound (6) with the compound (7). The compound (44) is usually used at least in an equimolar amount, preferably an equimolar to 5-fold molar amount, relative to the compound (19a).

Compound (9) used as starting material
Is produced, for example, by the method shown in the following reaction formulas -19 and -20.

[0562]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, A ′,
Z, R ¹⁹ , R ²⁴ , T, u and X are the same as described above. The reaction between the compound (45) and the compound (28) is carried out under the same reaction conditions as the reaction between the compound (1i) and the compound (22) in the aforementioned Reaction Formula-6.

Compounds wherein R ²⁴ represents a lower alkoxy group (4
In the case of 6), the compound (46) is treated under the same reaction conditions as in the reaction for converting the compound (1d) into the compound (1e) in the aforementioned Reaction Formula-4 to give the corresponding compound (47). I can guide you.

In the case where the compound (46) in which R ²⁴ represents a phenyl lower alkoxy group, the same reaction conditions as in the reaction for converting the compound (46) into the compound (5c) in the reaction formula -13 are carried out. The following treatment can lead to the corresponding compound (47).

The reaction of the compound (47) with the compound (24) is carried out under the same reaction conditions as in the reaction of the compound (1b) with the compound (5) in the aforementioned reaction formula-2.

[0567]

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[Wherein R ⁵ , m and R ¹⁹ are as defined above. R
^19a represents a lower alkoxy group. The reaction between compound (48) and compound (49) is performed in a suitable solvent in the presence of a basic compound. As the solvent and the basic compound used herein, any of the solvent and the basic compound used in the reaction between the compound (6) and the compound (7) in the above Reaction Formula-3 can be used. Compound (49) is generally used in an amount of at least equimolar, preferably equimolar to 3 times the molar amount of compound (48). This reaction proceeds usually at 0 to 200 ° C., preferably at room temperature to around 150 ° C., and is generally completed in about 1 to 60 hours.

The reaction for converting the compound (50) into the compound (9b) is carried out under the same reaction conditions as the reaction for converting the compound (5b) into the compound (5c) in the aforementioned Reaction Scheme-13.

The reaction between compound (51) and compound (52) is carried out in a suitable solvent in the presence of a basic compound and a catalyst. As the solvent used, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, benzene, toluene,
Examples thereof include aromatic hydrocarbons such as xylene, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane; polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixed solvents thereof. . As the basic compound, any of the basic compounds used in the reaction using a carboxylic acid halide during the reaction between the compound (1b) and the compound (5) in the above Reaction Formula-2 can be used. Examples of the catalyst include palladium chloride, tetrakis (triphenylphosphine) palladium, palladium acetate,
Examples thereof include 1,3-bis (diphenylphosphino) propane and the like, and a mixture thereof. Compound (52)
Is usually at least equimolar, preferably equimolar to 10-fold molar amount, relative to compound (51). The basic compound is usually used in an amount at least equimolar to the compound (51), preferably in an equimolar to 3-fold molar amount, and the catalyst is usually used in a large excess amount relative to the compound (51). . This reaction proceeds usually at 0 to 200 ° C., preferably at room temperature to around 150 ° C., and is generally completed in about 1 to 20 hours.

The reaction for converting the compound (53) into the compound (50) is carried out under the same reaction conditions as the reaction for converting the compound (1d) into the compound (1e) in the aforementioned Reaction Formula-4.

[0572]

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[Wherein R ¹ , R ² , R ⁴ , R ⁵ , q, Z, s,
A, R ¹⁸ , T, u and W are the same as above. R ^5g represents an amino group which may have a lower alkyl group as a substituent. Further, a group (R ¹⁸ ) ₂ P (＝ O) —CH ₂ —C (＝ O) —
Is substituted at the o-position to R ^5g . The reaction between the compound (10a) and the compound (44) is carried out under the same reaction conditions as the reaction between the compound (10) and the compound (12) in the aforementioned Reaction Formula-3.

[0574] W is based

[0575]

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Compound (1r) showing (R ^29b and X are the same as described above) can be obtained by treating the above reaction with a hydrohalic acid such as hydrochloric acid or hydrobromic acid.

[0577]

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[Wherein R ¹ , R ² , R ⁴ , T, u, R ¹⁶ , R
¹⁸ and R ²² are as defined above. The reaction between the compound (54) and the compound (12) is carried out under the same reaction conditions as the reaction between the compound (10) and the compound (12) in the aforementioned Reaction Scheme-3.

Compounds wherein R ¹⁶ represents a lower alkoxy group (1
In the case of s), the compound (1s) is treated under the same reaction conditions as in the reaction for converting the compound (1d) into the compound (1e) in the aforementioned reaction formula-4 to give the corresponding compound (1t). I can guide you.

The reaction of the compound (54) with the compound (20) is carried out under the same reaction conditions as in the reaction of the compound (10) with the compound (20) in the aforementioned Reaction Scheme-3.

In the above reaction formula-22, compound (54) used as a starting material is produced, for example, according to the following method.

[0582]

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[Wherein R ¹ , R ² , M, R ¹⁸ and R ¹⁹ are as defined above. For the halogenation reaction of compound (58), any of the usual conditions for halogenation of carboxylic acids can be applied. The reaction between the carboxylic acid halide of the compound (58) thus obtained and the compound (55) is carried out in a suitable solvent in the presence or absence of a basic compound. As the solvent used herein, for example, methylene chloride, halogenated hydrocarbons such as chloroform, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane, methyl acetate, methyl acetate,
Esters such as ethyl acetate, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, methanol, ethanol, propanol, butanol, 3-methoxy-1-
Alcohols such as butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile,
Examples thereof include water and the like and a mixed solvent thereof. Examples of the basic compound include, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DABCO, potassium carbonate, sodium carbonate, potassium hydroxide,
Examples thereof include inorganic bases such as sodium hydroxide, potassium hydride, sodium hydride, and silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. Compound (55) is generally used in an amount of at least equimolar, preferably equimolar to 3 times the molar amount of carboxylic acid halide of compound (58). This reaction proceeds usually at -30 to 180 ° C, preferably at about 0 to 150 ° C, and is generally completed in about 5 minutes to 30 hours.

The compound of the formula (58a) and the compound of the formula (5)
The reaction with the compound of 6) is carried out in a suitable solvent or without solvent.
Usually, it is carried out at 0 to 200 ° C, preferably at room temperature to around 150 ° C. As the solvent used herein, any of the solvents used in the reaction of the compound (58) with the carboxylic acid halide and the compound (55) can be used. Compound (56) is generally used at least in an equimolar amount, preferably in an equimolar to 1.5-fold molar amount, relative to compound (58a). The reaction is generally completed in about 1 to 5 hours.

The reaction between the compound (58b) and the compound (7) is carried out under the same reaction conditions as in the reaction between the compound (9) and the compound (7) in the aforementioned Reaction Formula-3.

[0586]

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[Wherein R ¹ , R ² , R ⁴ , R ^11b , T, u and R ¹⁷ are as defined above. The reaction between the compound (1u) and the compound (5) is carried out under the same reaction conditions as the reaction between the compound (1b) and the compound (5) in the aforementioned Reaction Formula-2.

Compound (24) used as starting material
Is produced, for example, according to the method shown in the following reaction formula-25.

[0589]

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[Wherein R ¹ , R ² , X, T and M are as defined above. R ³⁰ represents a lower alkylsulfonyl group. The reaction between compound (59) and compound (61) and the reaction between compound (61) and compound (62) are the same as the reaction between compound (1i) and compound (22) in the aforementioned Reaction Formula-6. Under the reaction conditions of

The reaction for converting the compound (63) into the compound (24a) can be carried out by reacting the compound (63) with hydrazine or hydrolyzing it in a suitable solvent.

As a solvent used in the reaction of hydrazine, in addition to water, the solvent used in the reaction between the compound (1b) and the compound (5) in the reaction formula-2 using a carboxylic acid halide can be used. Any of the same solvents as those described above can be used. Hydrazine is compound (6)
It is usually preferable to use at least equimolar, preferably equimolar to 6-fold molar amount to 3). The reaction is usually carried out at room temperature to
The reaction proceeds at 120 ° C, preferably around 0 to 100 ° C, and the reaction is completed in about 0.5 to 5 hours.

The above hydrolysis is carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether, dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether; and fatty acids such as acetic acid and formic acid. And a mixed solvent thereof.
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid and aromatic sulfonic acid.Examples of the basic compound include sodium carbonate and potassium carbonate And metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. The reaction is usually carried out at room temperature to 20
The process suitably proceeds at about 0 ° C., preferably about room temperature to about 150 ° C., and generally ends in about 10 minutes to 25 hours.

Of the compounds (1) of the present invention, those having an acidic group can form salts with pharmacologically acceptable basic compounds. Such basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate and sodium hydrogen carbonate, sodium methylate And alkali metal alcoholates such as potassium ethylate. In addition, among the compounds (1) of the present invention, a compound having basicity can easily form a salt with a usual pharmacologically acceptable acid. Such acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid,
Organic acids such as succinic acid and benzoic acid can be exemplified. These salts can also be used as the active ingredient compound in the present invention, similarly to the free form of the compound (1). The compound (1) includes stereoisomers and optical isomers, and these can also be used as active ingredient compounds.

The target compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by usual separation means and can be further purified. Such separation and purification means include, for example, distillation, recrystallization, column chromatography, ion exchange chromatography,
Gel chromatography, affinity chromatography, preparative thin-layer chromatography, solvent extraction and the like can be employed.

The active compound thus obtained is effective as a protein kinase C inhibitor, and these drugs are used in the form of general pharmaceutical preparations. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrating agents such as sodium, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors, such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, absorption promoting agents, such as sodium lauryl sulfate; Emissions, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablet can be made into a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet. When molding into pill form,
As the carrier, those conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin, talc, binders such as gum arabic, tragacanth, gelatin, ethanol, disintegrants such as laminaran, agar, etc. Can be used. In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Capsules are prepared according to a conventional method, usually by mixing an active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like. When prepared as an injection, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used as diluents in the art when formed into these forms. And water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 1 to 70% by weight in the pharmaceutical composition. The content is preferably 5 to 50% by weight.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited, and may include various preparation forms, patient age, gender and other conditions,
The drug is administered according to the degree of the disease. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of the disease, etc. Usually, the amount of the active compound is about 0 to 1 kg / body weight per day. It is preferable to be about 0.6 to 50 mg.
In addition, the active ingredient compound is contained in a dosage unit form preparation in an amount of about 10%.
Desirably, it is contained in the range of １０００1000 mg.

[0600]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the pharmaceutical preparation of the present invention will be given, followed by production examples of the above-mentioned active ingredient compounds, and test examples of the active ingredient compounds.

Formulation Example 1 2- [2-methoxy-4- {3- [4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl} phenoxymethylcarbonylamino] benzothiazole 150 g Avicel ( 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Ethanol 40g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating R10m
Tablet with m-kine. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
0, coating with a film coating agent consisting of castor oil and ethanol to produce film-coated tablets.

Formulation Example 2 2- [3-methoxy-4- {3- [4- (3,4-dimethyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl} phenoxymethylcarbonylamino] benzozimidazole 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinyl pyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbo) Wax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount Active compound of the present invention, citric acid, lactose, dicalcium phosphate, pull Mixing the nick F-68 and sodium lauryl sulfate.

The above mixture was designated as No. Sieve through a 60 screen and wet granulate with an alcoholic solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was no. Pass through 10 screens, place in trays and dry in oven at 100 ° C. for 12-14 hours. The dried particles were no. Sieve through 16 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress to desired shape on tablet press.

The above core is treated with varnish, and talc is sprayed to prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 2- {2- (3-morpholinopropyl) -4- [3- (4-pyridyl) acryloyl] phenoxymethyl carbonylamino} benzothiazole 5 g Polyethylene glycol (molecular weight: 4000) 0.3 g Chloride Sodium 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml The above parabens, sodium metabisulfite and The sodium chloride is dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to make the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Reference Example 1 A solution of 39.5 g of o-isopropylphenol, 40 g of potassium carbonate and 40 ml of α-ethyl bromoacetate in 300 ml of dimethylformamide was stirred at 80 ° C. for 8 hours.
Water was added, the mixture was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off. This is made up of 20 g of sodium hydroxide in 300
The mixture was dissolved in a mixed solution of ethanol and 200 ml of ethanol, and heated under reflux for 1.5 hours. After cooling, concentrated hydrochloric acid was added to make the mixture acidic, and the precipitated crystals were collected by filtration to obtain 37 g of α- (2-isopropylphenoxy) acetic acid.

White powder ¹ H-NMR (CDCl ₃ ) δ ppm: 1.24 (6H,
d, J = 7 Hz), 3.39 (1H, sept, J = 7
Hz), 4.69 (2H, s), 6.75 (1H, d
d, J = 1 Hz, J = 8 Hz), 6.95-7.3 (3
H, m).

Reference Example 2 A solution of 13.1 g of α- (2-isopropylphenoxy) acetic acid in 30 ml of thionyl chloride was heated under reflux for 30 minutes. After distilling off excess thionyl chloride under reduced pressure, the residue was dissolved in 50 ml of dichloromethane, and 9.1 g of 2-aminobenzothiazole and 7.2 ml of pyridine in dichloromethane were added.
The solution was added dropwise to a 0 ml solution under ice cooling. After stirring at the same temperature for 5 hours, the reaction solution was washed with water, dried and evaporated. Ethanol was added to the residue, and yellow powder of 2- (2-isopropylphenoxymethylcarbonylamino) benzothiazole was added.
66 g were obtained.

[0609] Yellow powder _{^{1 H-NMR (CDCl 3)}} δppm: 1.32 (6H,
d, J = 7 Hz), 3.43 (1H, sept, J = 7)
Hz), 4.78 (2H, s), 6.85 (1H, d
d, J = 1 Hz, J = 8 Hz), 7.0-7.55 (5
H, m), 7.8-7.9 (2H, m), 9.74 (1
H, br).

Reference Example 3 A solution of 19.5 ml of dimethylmethylphosphonate in 300 ml of anhydrous tetrahydrofuran at -50 ° C. was obtained at 1.72M.
107 ml of n-hexane solution of n-butyllithium was added dropwise. 30 minutes later, 2- (2-methoxy-4-formylphenoxymethylcarbonylamino) benzothiazole 2
0.5 g was added little by little under a nitrogen stream. 1 at -50 ° C
After stirring for an hour, water was added, the mixture was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 200: 1 to 30: 1) to give dimethyl {2- [3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) phenyl]-. 19.0 g of 2-hydroxyethyl diphosphonate was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.
05-2.35 (2H, m), 3.73, 3.76,
3.78 and 3.81 (6H, each s), 3.98 (2
H, d, J = 2.5 Hz), 4.01 (3H, s),
4.77 (2H, s), 5.0-5.15 (1H,
m), 6.90 (1H, dd, J = 2 Hz, J = 8H)
z), 6.98 (1H, d, J = 8 Hz), 7.07
(1H, d, J = 2 Hz), 7.25-7.5 (2H,
m), 7.8-7.9 (2H, m), 10.66 (1
H, br).

The dimethyl {2- [3-methoxy-4- (2
-Benzothiazolylaminocarbonylmethoxy) phenyl] -2-hydroxyethyl} phosphonate 19.0 g
Activated manganese dioxide in 300 ml of chloroform
7.7 g was added, and the mixture was heated under reflux for 3 hours. After adding 18 g of activated manganese dioxide and heating under reflux for 3 hours, further adding 20 g of activated manganese dioxide and heating under reflux for 3 hours. Manganese dioxide was collected by filtration and washed with chloroform. Chloroform is distilled off, and the residue is subjected to silica gel column chromatography (eluent; dichloromethane: methanol = 200: 1).
５０50: 1). Dimethyl} [3-methoxy-
There were obtained 7.76 g of 4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyl} phosphonate.

[0613] White powder _{^{1 H-NMR (CDCl 3)}} δppm: 3.62 (2H,
d, J = 22.5 Hz), 3.79 (6H, d, J = 1)
1.2 Hz), 4.04 (3H, s), 4.85 (2
H, s), 7.02 (1H, d, J = 8.5 Hz),
7.3-7.55 (2H, m), 7.6-7.7 (2
H, m), 7.8-7.9 (2H, m), 10.31
(1H, br).

Reference Example 4 To a solution of 10.0 ml of chloroacetyl chloride in 250 ml of anhydrous 1,2-dichloroethane was added 12 g of aluminum chloride at room temperature, and the mixture was stirred for 20 minutes and then 20 g of 2- (2-isopropylphenoxymethylcarbonylamino) benzothiazole. Was added all at once, followed by stirring at room temperature for 1 hour. The reaction solution was poured into water, n-hexane was added, the mixture was filtered, washed with water and dried to give 2- [2-isopropyl-4- white powder.
25.9 g of (2-chloroacetyl) phenoxymethylcarbonylamino] benzothiazole were obtained.

¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.24 (6H, d, J = 7 Hz), 3.38 (1H,
m), 5.12 (4H, s), 7.01 (1H, d, J
= 9 Hz), 7.25-7.55 (2H, m), 7.7
−7.95 (3H, m), 7.97 (1H, d, J = 8)
Hz), 13.00 (1H, br).

Reference Example 5 2- [2-isopropyl-4- (2-chloroacetyl)
A suspension of 4.0 g of [phenoxymethylcarbonylamino] benzimidazole and 2.8 g of triphenylphosphine in 100 ml of chloroform was heated under reflux for 7 hours. After distilling off the reaction solution, it was crystallized from dichloromethane-diethyl ether to obtain 3.8 g of [3-isopropyl-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyltriphenylphosphonium chloride.

¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.23 (6H, d, J = 7 Hz), 3.40 (1H,
m), 5.18 (2H, s), 6.19 (2H, d, J
= 13.5 Hz), 7.09 (1H, d, J = 9H)
z), 7.25-7.5 (2H, m), 7.6-8.0
5 (19H, m), 12.77 (1H, s).

To a solution of [3-isopropyl-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyltriphenylphosphonium chloride (3.3 g) in methanol (50 ml) was added DBU (1 ml).
Stirred for hours. The precipitated crystals were collected by filtration, washed with methanol, and dried to obtain 2.27 g of [3-isopropyl-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methylenetriphenylphosphorane.

[0619] White powder _{^{1 H-NMR (CDCl 3)}} δppm: 1.32 (6H,
d, J = 7 Hz), 3.42 (1H, sept, J = 7)
Hz), 4.2-4.6 (1H, m), 4.73 (2
H, s), 6.75 (1H, d, J = 8.5 Hz),
7.25-8.0 (21H, m), 10.01 (1H,
br).

The following compounds were obtained in the same manner as in Reference Example 5 using appropriate starting materials.

[3- (3-chloropropyl) -4- (2
-Benzothiazolylaminocarbonylmethoxy) benzoyl] methylenetriphenylphosphonium chloride White powder ¹ H-NMR (CDCl ₃ ) δ ppm: 2.11 (2H,
tt, J = 6.6 Hz, J = 8.0 Hz), 2.86
(2H, t, J = 8.0 Hz), 3.71 (2H, t,
J = 6.6 Hz), 5.20 (2H, s), 6.17
(2H, d, J = 12.8 Hz), 7.13 (1H,
d, J = 8.7 Hz), 7.34 (1H, t, J = 7.
5 Hz), 7.48 (1H, t, J = 7.0 Hz),
7.76-8.02 (19H, m), 12.75 (1
H, br).

Reference Example 6 2-methoxy-4 in 200 ml of dimethylformamide
-20 g of acetylphenol, ethyl α-bromoacetate 1
After 5 ml and 18.3 g of potassium carbonate were added and the stirring reaction was completed overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with aqueous sodium bicarbonate, the extract was dried over magnesium sulfate, and the solvent was distilled off. The obtained crystal is n
-Α- by washing with hexane-diethyl ether
23.86 g of ethyl-(2-methoxy-4-acetylphenoxy) acetate were obtained.

To 230 ml of chloroform were added 23 g of ethyl α- (2-methoxy-4-acetylphenoxy) acetate and 55 g of cupric bromide, and the mixture was refluxed for 3.5 hours. After completion of the reaction, the precipitate was filtered through celite, washed with sodium hypochlorite, the dry solvent was distilled off over magnesium sulfate, and crystallization was carried out to give α- [2-methoxy-4-.
(2-bromoacetyl) phenoxy] ethyl acetate 21.
28 g were obtained.

In an ice bath, add α-
[2-methoxy-4- (2-bromoacetyl) phenoxy] ethyl acetate 20 g and triphenylphosphine 2
0.6 g was added and the mixture was stirred for 1 hour. After confirming that the raw materials had disappeared, the mixture was washed with aqueous potassium carbonate. Next, drying with magnesium sulfate was performed to distill off the solvent. Again methanol 2
Then, sodium hydroxide was added dropwise in an ice bath, and after confirming that the raw materials had disappeared, concentrated hydrochloric acid was added. The obtained crystals were washed with water and diethyl ether, and dried to obtain 25 g of (3-methoxy-4-carboxymethoxybenzoyl) methylenetriphenylphosphorane.

(3-methoxy-4-carboxymethoxybenzoyl) methylenetriphenylphosphorane 5 g, 2-aminobenzothiazole 1.9 g, bis (2-oxo-3-oxazolidinyl) in 50 ml of dichloromethane
2.93 g of phosphinic chloride and 3.3 ml of triethylamine were added and stirred overnight. After completion of the reaction, the mixture was washed with aqueous sodium hydrogencarbonate, and then the dry solvent was distilled off over magnesium sulfate, and recrystallized using toluene to give [3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy). 5.17 g) Benzoyl] methylenetriphenylphosphorane.

Light yellow powder ¹ H-NMR (CDCl ₃ ) δ ppm: 4.03 (3H,
s), 4.12-4.62 (1H, m), 4.79 (2
H, s), 6.96 (1H, d, J = 8.3 Hz),
7.25-7.90 (22H, m).

Reference Example 7 To a solution of 8.0 g of N-benzyl-4-piperidone and 9.5 g of 3,4-dimethylpiperazine in 100 ml of ethanol was added 2 g of 5% platinum-carbon and 14.4 ml of acetic acid, and the mixture was contacted at normal temperature and normal pressure. Reduced. The catalyst was filtered off and the filtrate was distilled off. Add water, make it basic with 5% aqueous sodium hydroxide,
Extracted with diethyl ether. After washing with water and drying, the solvent was distilled off, the residue was dissolved in ethanol, and concentrated hydrochloric acid was added to obtain a hydrochloride. The white powder was collected by filtration, dissolved in water, basified with 5% aqueous sodium hydroxide, extracted with diethyl ether, washed with water and dried, and the solvent was distilled off to give 4- (3,4-dimethyl-1-piperazinyl). 3.)-1-benzylpiperidine
2 g were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.
04 (3H, d, J = 6 Hz), 1.45-2.5 (1
2H, m), 2.27 (3H, s), 2.7-3.05
(4H, m), 3.48 (2H, s), 7.31 (5
H, m).

4- (3,4-Dimethyl-1-piperazinyl) -1-benzylpiperidine 4.2 g of ethanol 5
0.4 g of 20% palladium hydroxide-carbon was added to the 0 ml solution, and the mixture was catalytically reduced at 50 ° C. and normal pressure. The catalyst was filtered off and the filtrate was distilled off. The residue was distilled to obtain 1.65 g of 4- (3,4-dimethyl-1-piperazinyl) piperidine.

Colorless oil bp 145 ° C. (0.3 mmHg) ¹ H-NMR (CDCl ₃ ) δ ppm: 1.05 (3H,
d, J = 6 Hz), 1.25 to 1.55 (2H, m),
1.75-3.3 (14H, m), 2.31 (3H,
s).

Reference Example 8 Dichloromethane 3 of 50 g of 1-benzyl-L-proline
The 00 ml solution was ice-cooled. N-methylmorpholine 22.
5 g was added, and 30 g of isobutyl chloroformate was added dropwise.
After stirring at the same temperature for about 1 hour, pyrrolidine 18.8 ml
Was added dropwise at the same temperature. The mixture was returned to room temperature and stirred for 2 days and nights. It was washed twice with 250 ml of water and dried over magnesium sulfate.
After the solvent was distilled off, the residue was recrystallized from ethyl acetate-n-hexane to give 2
31 g of-(1-pyrrolidinyl) carbonyl-1-benzylpyrrolidine were obtained. White powder.

[0632] 3 g of 5% palladium-carbon was added to ethanol 3
The mixture was suspended in 00 ml, and 30 g of 2- (1-pyrrolidinyl) carbonyl-1-benzylpyrrolidine was added, and the mixture was reduced at normal temperature and normal pressure. After filtration and removal of the solvent, about 18 g of 2- (1-
(Pyrrolidinyl) carbonylpyrrolidine was obtained as an oil.

[0633] 9 g of lithium aluminum hydride was suspended in 100 ml of dry tetrahydrofuran under ice-cooling.
33 g of 2- (1-pyrrolidinyl) carbonylpyrrolidine
Dissolved in 80 ml of dry tetrahydrofuran was added dropwise. Reflux under a nitrogen atmosphere for 4 hours. After cooling with ice, about 15 ml of saturated aqueous sodium sulfate was added, and then the mixture was stirred at room temperature for 3 hours. When sodium sulfate precipitated, it was filtered off. The precipitated sodium sulfate was thoroughly washed with chloroform, and the filtrates were combined and the solvent was distilled off.
22 g of-(1-pyrrolidinyl) methylpyrrolidine was obtained.

Colorless oil bp 99 to 101 ° C. (20 mmHg) Reference Example 9 15 g of 4-benzyl-2-chloromethylmorpholine and 25 ml of 4- (2-hydroxyethyl) piperazine were mixed and stirred at 130 ° C. for 5 hours. After completion of the reaction, chloroform extraction was performed, and the mixture was dried over magnesium sulfate. The solvent was distilled off to obtain 16 g of 4-benzyl-2- [4- (2-hydroxyethyl) -1-piperazinyl] methylmorpholine.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.
86 (1H, t, J = 10.6 Hz), 2.07-2.
27 (2H, m), 2.37-3.05 (14H,
m), 3.49 (2H, d, J = 2.3 Hz), 3.5
7-3.89 (5H, m), 7.24-7.33 (5
H, m).

4-Benzyl-2- [4- (2-hydroxyethyl) -1-piperazinyl] methylmorpholine 16
g was dissolved in 160 ml of ethanol, 1.6 g of palladium hydroxide was added, and debenzylation was performed at 50 ° C. in a hydrogen atmosphere. After 5 hours, the mixture was filtered through celite, the solvent was distilled off, and the obtained crystals were washed with diethyl ether-n-hexane to give 2- [4- (2-hydroxyethyl) -1-piperazinyl] methylmorpholine. 09g
I got

Mp 73-75.5 ° C. White powder ¹ H-NMR (CDCl ₃ ) δ ppm: 2.25 (1H,
dd, J = 4.2 Hz, J = 13.0 Hz), 2.37
-2.74 (11H, m), 2.74-3.02 (6
H, m), 3.49-3.77 (4H, m), 3.85
-3.93 (1H, m).

The compounds shown in Tables 1 to 4 were obtained in the same manner as in Reference Example 1 using appropriate starting materials.

[0639]

[Table 1]

[0640]

[Table 2]

[0641]

[Table 3]

[0642]

[Table 4]

¹ H-NMR of each compound shown in Tables 1 to 4
The spectra (NMR (1) to NMR (6)) are as follows.

NMR (1) (DMSO-d ₆ ) δpp
m: 2.19 (3H, s), 4.68 (2H, s),
6.83 (2H, dd, J = 7.8 Hz, J = 13.2
Hz), 7.12 (2H, t, J = 7.8 Hz), 1
2.96 (1H, s).

NMR (2) (DMSO-d ₆ ) δpp
m: 1.14 (3H, t, J = 7.5 Hz), 2.61
(2H, q, J = 7.5 Hz), 4.69 (2H, q, J = 7.5 Hz)
s), 6.78-6.95 (2H, m), 7.05-
7.20 (2H, m), 12.97 (1H, s).

NMR (3) (CDCl ₃ ) δ ppm:
0.95 (3H, t, J = 7.4 Hz), 1.5-1.
8 (2H, m), 2.65 (2H, t, J = 7.4H
z), 4.65 (2H, s), 6.73 (1H, d, J
= 8.3 Hz), 6.9-7.05 (1H, m), 7.
15 (2H, t, J = 7.2 Hz), 9.4-10.1.
(1H, m).

NMR (4) (DMSO-d ₆ ) δpp
m: 4.77 (2H, s), 6.88-7.30 (4
H, m), 13.09 (1H, s).

NMR (5) (CDCl ₃ ) δ ppm:
4.76 (2H, s), 6.89 (1H, dd, J =
1.5 Hz, J = 8.0 Hz), 6.99 (1 H, d
t, J = 1.5 Hz, J = 7.6 Hz), 7.23 (1
H, dt, J = 1.5 Hz, J = 7.6 Hz), 7.4
1 (1H, dd, J = 1.5 Hz, J = 8.0 Hz),
8.16 (1H, br).

NMR (6) (DMSO-d ₆ ) δpp
m: 1.6-1.85 (4H, m), 2.55-2.7
5 (4H, m), 4.63 (2H, s), 6.57 (1
H, d, J = 8 Hz), 6.65 (1H, d, J = 7.
5 Hz), 6.9-7.05 (1H, m), 12.94
(1H, br).

NMR (7) (DMSO-d ₆ ) δpp
m: 2.10 (3H, s), 2.20 (3H, s),
4.63 (2H, s), 6.64 (1H, d, J = 8H)
z), 6.75 (1H, d, J = 7.5 Hz), 6.9
5-7.1 (1H, m), 12.9 (1H, br) NM
R (8) (DMSO-d ₆ ) δ ppm: 2.22 (6
H, s), 4.35 (2H, s), 6.87-7.06
(3H, m), 12.87 (1H, s).

NMR (9) (DMSO-d ₆ ) δpp
m: 2.22 (6H, s), 4.48 (2H, s),
6.48 (2H, s), 6.60 (1H, s).

NMR (10) (DMSO-d ₆ ) δpp
m: 2.26 (3H, s), 4.62 (2H, s),
6.60-6.80 (3H, m), 7.11-7.18
(1H, m).

NMR (11) (DMSO-d ₆ ) δpp
m: 0.85 (3H, t, J = 7.2 Hz), 1.17
-1.38 (2H, m), 1.45-1.60 (2H,
m), 2.49-2.57 (2H, m), 4.63 (2
H, s), 6.66-6.79 (3H, m), 7.13
-7.21 (1H, m), 13.00 (1H, br).

NMR (12) (CDCl ₃ ) δ ppm:
1.22 (6H, d, J = 6.9 Hz), 2.77−
3.00 (1H, m), 4.68 (2H, s), 6.6
6-6.76 (1H, m), 6.81-6.95 (2
H, m), 7.17-7.29 (1H, m), 8.65
(1H, brs).

NMR (13) (CDCl ₃ ) δ ppm:
4.69 (2H, s), 6.79-6.85 (1H,
m), 6.85-7.04 (2H, m), 7.19-
7.28 (1H, m), 8.00 (1H, br).

NMR (14) (CDCl ₃ ) δ ppm:
4.69 (2H, s), 6.62-6.79 (3H,
m), 7.20-7.32 (1H, m), 9.07 (1
H, br).

NMR (15) (CDCl ₃ ) δ ppm:
3.79 (3H, s), 4.67 (2H, s), 6.4
7-6.61 (3H, m), 7.16-7.26 (1
H, m), 9.12 (1H, br).

NMR (16) (CDCl ₃ ) δ ppm:
1.40 (3H, t, J = 7.0 Hz), 4.01 (2
H, q, J = 7.0 Hz), 4.66 (2H, s),
6.45-6.62 (3H, m), 7.13-7.25
(1H, m), 8.34 (1H, br).

Compounds shown in Tables 5 to 9 were obtained in the same manner as in Reference Example 2 by using appropriate starting materials.

[0660]

[Table 5]

[0661]

[Table 6]

[0662]

[Table 7]

[0663]

[Table 8]

[0664]

[Table 9]

¹ H-NMR of each compound shown in Tables 5 to 9
The spectra (NMR (1) to NMR (20)) are as follows.

NMR (1) (DMSO-d ₆ ) δpp
m: 2.45 (3H, s), 4.95 (2H, s),
6.81-6.95 (2H, m), 7.10-7.22
(2H, m), 7.32 (1H, t, J = 6.1H)
z), 7.45 (1H, t, J = 6.4 Hz), 7.7
7 (1H, d, J = 6.4 Hz), 7.99 (1H,
d, J = 6.3 Hz), 12.60 (1H, s).

NMR (2) (DMSO-d ₆ ) δpp
m: 1.18 (3H, t, J = 7.5 Hz), 2.67
(2H, q, J = 7.5 Hz), 4.96 (2H,
s), 6.89 (2H, dd, J = 8.0 Hz, J = 1)
2.5 Hz), 7.09-7.23 (2H, m), 7.
28-7.38 (1H, m), 7.40-7.52 (1
H, m), 7.77 (1H, d, J = 8.0 Hz),
7.98 (1H, d, J = 7.8 Hz), 12.58
(1H, s).

NMR (3) (CDCl ₃ ) δ ppm:
1.03 (3H, t, J = 7.4 Hz), 1.6-1.
8 (2H, m), 2.73 (2H, t, J = 7.4H
z), 4.76 (2H, s), 6.84 (1H, d, J
= 8.0 Hz), 7.01-7.50 (5H, m),
7.79-7.86 (2H, m), 9.6-9.8 (1
H, s).

NMR (4) (CDCl ₃ ) δ ppm:
0.95 (3H, t, J = 7.2 Hz), 1.37-
1.55 (2H, m), 1.59-1.74 (2H,
m), 2.71 (2H, d, J = 7.2 Hz), 4.7
7 (2H, s), 6.82 (1H, d, J = 8.1H)
z), 6.98-7.06 (1H, m), 7.16-
7.26 (2H, m), 7.30-7.38 (1H,
m), 7.41-7.50 (1H, m), 7.79-
7.86 (2H, m), 9.78 (1H, brs).

NMR (5) (CDCl ₃ ) δ ppm:
4.76 (2H, s), 6.95-7.11 (3H,
m), 7.26-7.47 (4H, m), 7.79-
7.87 (2H, m), 9.92 (1H, br).

NMR (6) (CDCl ₃ ) δ ppm:
0.92 (3H, t, J = 6.8 Hz), 1.30 −
1.55 (4H, m), 1.55-1.90 (2H,
m), 2.71 (2H, t, J = 7.6 Hz), 4.7
7 (2H, s), 6.82 (1H, d, J = 8.0H)
z), 6.98-7.05 (1H, m), 7.17-
7.26 (2H, m), 7.31-7.38 (1H,
m), 7.42-7.50 (1H, m), 7.79-
7.87 (2H, m), 9.73 (1H, brs).

NMR (7) (DMSO-d ₆ ) δpp
m: 5.03 (2H, s), 6.90-7.07 (1
H, m), 7.07-7.20 (2H, m), 7.20
−7.50 (2H, m), 7.45 (1H, dt, J =
1.3 Hz, J = 7.3 Hz), 7.77 (1H, d,
J = 7.8 Hz), 7.99 (1H, dd, J = 0.7)
Hz, J = 7.7 Hz), 12.63 (1H, s).

NMR (8) (CDCl ₃ ) δ ppm:
4.80 (2H, s), 6.95-7.10 (2H,
m), 7.23-7.49 (4H, m), 7.85 (2
H, dd, J = 2.0 Hz, J = 6.6 Hz), 9.9
7 (1H, br).

NMR (9) (CDCl ₃ ) δ ppm:
1.75-2.0 (4H, m), 2.75-2.9 (4
H, m), 4.74 (2H, s), 6.63 (1H,
d, J = 8 Hz), 6.82 (1H, d, J = 8H)
z), 7.05-7.15 (1H, m), 7.3-7.
5 (2H, m), 7.75-7.9 (2H, m), 9.
73 (1H, br).

NMR (10) (CDCl ₃ ) δ ppm:
2.29 (3H, s), 2.32 (3H, s), 4.7
5 (2H, s), 6.70 (1H, d, J = 8 Hz),
6.90 (1H, d, J = 7.5 Hz), 7.05-
7.15 (1H, m), 7.3-7.5 (2H, m),
7.75-7.9 (2H, m), 9.76 (1H, b
r).

NMR (11) (DMSO-d ₆ ) δpp
m: 2.27 (6H, s), 4.63 (2H, s),
6.90-7.12 (3H, s), 7.29-7.40
(1H, m), 7.42-7.52 (1H, s), 7.
76 (1H, d, J = 7.8 Hz), 8.02 (1H, d, J = 7.8 Hz)
d, J = 7.4 Hz), 12.49 (1H, s).

NMR (12) (CDCl ₃ ) δ ppm:
2.32 (6H, s), 4.73 (2H, s), 6.6
1 (2H, s), 6.72 (1H, s), 7.3-7.
55 (2H, m), 7.8-7.95 (2H, m),
9.86 (1H, br).

NMR (13) (CDCl ₃ ) δ ppm:
2.18 (2H, tt, J = 7.0 Hz, J = 8.0H
z), 2.96 (2H, t, J = 7.0 Hz), 3.6
3 (2H, t, J = 8.0 Hz), 4.80 (2H, t, J = 8.0 Hz)
s), 6.87 (1H, d, J = 8.5 Hz), 7.0
4 (1H, t, J = 7.2 Hz), 7.15-7.29
(2H, m), 7.34 (1H, t, J = 8.9H)
z), 7.43 (1H, t, J = 8.0 Hz), 7.7
9-7.87 (2H, m), 9.73 (1H, br).

NMR (14) (CDCl ₃ ) δ ppm:
3.22 (2H, t, J = 7.0 Hz), 3.82 (2
H, t, J = 7.0 Hz), 4.81 (2H, s),
6.86 (1H, d, J = 8.2 Hz), 7.05 (1
H, t, J = 7.2 Hz), 7.15-7.52 (4
H, m), 7.81 (2H, t, J = 8.4 Hz),
9.78 (1H, br).

NMR (15) (CDCl ₃ ) δ ppm:
2.37 (3H, s), 4.74 (2H, s), 6.7
4-6.85 (2H, m), 6.85 (1H, d, J =
7.3 Hz), 7.17-7.30 (1H, m), 7.
30-7.40 (1H, m), 7.40-7.54 (1
H, m), 7.77-7.90 (2H, m), 9.88
(1H, brs).

NMR (16) (CDCl ₃ ) δ ppm:
1.25 (3H, t, J = 7.6 Hz), 2.65 (2
H, q, J = 7.6 Hz), 4.74 (2H, s),
6.74-6.84 (2H, m), 6.88-6.95
(1H, m), 7.21-7.50 (3H, m), 7.
79-7.86 (2H, m), 9.94 (1H, b
r).

NMR (17) (CDCl ₃ ) δ ppm:
4.73 (2H, s), 6.75-6.84 (1H,
m), 6.84-6.98 (1H, m), 7.01-
7.08 (1H, m), 7.21-7.46 (3H,
m), 7.82 (2H, t, J = 8.4 Hz), 10.
09 (1H, br).

NMR (18) (DMSO-d ₆ ) δpp
m: 4.94 (2H, s), 6.75-6.92 (3
H, m), 7.27-7.47 (3H, m), 7.75
(1H, d, J = 8.0 Hz), 7.97 (1H, d,
J = 8.0 Hz).

NMR (19) (CDCl ₃ ) δ ppm:
3.81 (3H, s), 4.73 (2H, s), 6.5
3-6.65 (3H, m), 7.20-7.51 (3
H, m), 7.79-7.86 (2H, m), 9.89
(1H, br).

NMR (20) (CDCl ₃ ) δ ppm:
1.43 (3H, t, J = 7.0 Hz), 4.04 (2
H, q, J = 7.0 Hz), 4.73 (2H, s),
6.50-6.66 (3H, m), 7.18-7.51
(3H, m), 7.78-7.90 (2H, m), 9.
87 (1H, br).

Using the appropriate starting materials, the compounds shown in Table 10 were obtained in the same manner as in Reference Example 3.

[0687]

[Table 10]

The ¹ H-NMR spectra (NMR (1) to NMR (5)) of each compound shown in Table 10 are as follows.

NMR (1) (CDCl ₃ ) δ ppm:
1.58 (3H, t, J = 7.0 Hz), 3.61 (2
H, d, J = 22.8 Hz), 3.76 (3H, s),
3.82 (3H, s), 4.25 (2H, q, J = 7.
0 Hz), 4.85 (2H, s), 7.04 (1H,
d, J = 8.6 Hz), 7.33 (1H, t, J = 7.
5 Hz), 7.46 (1H, t, J = 7.5 Hz),
7.60-7.65 (2H, m), 7.79-7.86
(2H, m), 10.28 (1H, br).

NMR (2) (CDCl ₃ ) δ ppm:
1.47 (6H, d, J = 6.0 Hz), 3.74 (3
H, s), 3.79 (3H, s), 3.85 (2H,
d, J = 20.2 Hz), 4.69 (1H, sept,
J = 6.0 Hz), 4.79 (2H, s), 6.51-
6.56 (2H, m), 7.36 (1H, t, J = 7.
0 Hz), 7.49 (1H, t, J = 7.0 Hz),
7.79-7.88 (3H, m), 9.98 (1H, b
r).

NMR (3) (CDCl ₃ ) δ ppm:
3.76 (2H, d, J = 21.3 Hz), 3.75
(3H, s), 3.80 (3H, s), 4.40 (2
H, q, J = 7.9 Hz), 4.79 (2H, s),
6.44 (1H, d, J = 2.2 Hz), 6.60 (1
H, dd, J = 2.2 Hz, J = 8.8 Hz), 7.3
4 (1H, dt, J = 1.3 Hz, J = 7.3 Hz),
7.45 (1H, dt, J = 1.3 Hz, J = 7.3H
z), 7.75-7.86 (3H, m).

NMR (4) (DMSO-d ₆ ) δpp
m: 3.62 (3H, s), 3.68 (3H, s),
3.93 (2H, d, J = 22.5 Hz), 5.27
(2H, s), 7.3-7.55 (3H, m), 7.7
8 (1H, d, J = 8 Hz), 7.98 (1H, d, J)
= 8 Hz), 8.2-8.35 (2H, m), 12.6
8 (1H, br).

NMR (5) (CDCl ₃ ) δ ppm:
3.74 (3H, s), 3.80 (3H, s), 3.8
1 (2H, d, J = 21 Hz), 3.95 (3H,
s), 4.81 (2H, s), 6.5-6.65 (2
H, m), 7.25-7.55 (2H, m), 7.75
-7.95 (3H, m), 10.01 (1H, s).

Using the appropriate starting materials, compounds shown in Tables 11 to 13 were obtained in the same manner as in Reference Example 4.

[0696]

[Table 11]

[0696]

[Table 12]

[0697]

[Table 13]

[0698] ¹ H-N of each compound shown in Tables 11 to 13
The MR spectra (NMR (1) to NMR (8)) are as follows.

NMR (1) (CDCl ₃ ) δ ppm:
4.41 (2H, s), 4.84 (2H, s), 7.0
7 (2H, d, J = 9.0 Hz), 7.36 (1H,
t, J = 7.3 Hz), 7.45 (1H, t, J = 7.
3 Hz), 7.88 (2H, t, J = 8.5 Hz),
8.03 (2H, d, J = 9.0 Hz).

NMR (2) (DMSO-d ₆ ) δpp
m: 2.30 (3H, s), 5.11 (4H, s),
7.00-7.10 (1H, m), 7.28-7.40
(1H, m), 7.40-7.55 (1H, m), 7.
70-7.93 (3H, m), 7.98 (1H, d, J)
= 7.1 Hz), 12.68 (1H, s).

NMR (3) (DMSO-d ₆ ) δpp
m: 1.21 (3H, t, J = 7.4 Hz), 2.72
(2H, q, J = 7.4 Hz), 5.12, 5.13
(4H, each s), 7.02 (1H, d, J = 8.6H)
z), 7.31 (1H, dt, J = 1.2 Hz, J =
7.3 Hz), 7.45 (1H, dt, J = 1.3H)
z, J = 7.3 Hz), 7.75-7.92 (3H,
m), 7.95-8.00 (1H, m), 12.68
(1H, brs).

NMR (4) (CDCl ₃ ) δ ppm:
0.97 (3H, t, J = 7.2 Hz), 1.39-
1.59 (2H, m), 1.59-1.86 (2H,
m), 2.77 (2H, t, J = 7.6 Hz), 4.6
7 (2H, s), 4.86 (2H, s), 6.89 (1
H, d, J = 8.6 Hz), 7.32-7.39 (1
H, m), 7.43-7.51 (1H, m), 7.79
−7.87 (4H, m), 9.10-10.01 (1
H, brs).

NMR (5) (CDCl ₃ ) δ ppm:
3.16 (2H, t, J = 6.9 Hz), 3.92 (2
H, t, J = 6.9 Hz), 4.83 (2H, s),
5.13 (2H, s), 7.07 (1H, d, J = 9.
4Hz), 7.31 (1H, t, J = 6.9Hz),
7.45 (1H, t, J = 8.3 Hz), 7.76 (1
H, d, J = 7.9 Hz), 7.82-8.06 (3
H, m).

NMR (6) (CDCl ₃ ) δ ppm:
2.17 (2H, tt, J = 6.1 Hz, J = 7.5H
z), 3.03 (2H, t, J = 7.5 Hz), 3.6
4 (2H, t, J = 6.1 Hz), 4.40 (2H,
s), 4.88 (2H, s), 6.95 (1H, d, J
= 9.3 Hz), 7.35 (1H, t, J = 6.8H)
z), 7.47 (1H, t, J = 9.4 Hz), 7.8
0-7.94 (4H, m), 9.68 (1H, br).

NMR (7) (CDCl ₃ ) δ ppm:
2.75 (2H, t, J = 7.0 Hz), 3.13 (2
H, t, J = 7.0 Hz), 3.74 (3H, s),
4.65 (2H, s), 4.89 (2H, s), 6.8
9 (1H, d, J = 8.4 Hz), 7.30-7.37
(1H, m), 7.41-7.48 (1H, m), 7.
78-7.89 (4H, m), 9.00-11.30
(1H, brs).

NMR (8) (CDCl ₃ ) δ ppm:
2.00 (3H, s), 2.09 (3H, s), 3.0
8 (1H, dd, J = 8 Hz, J = 14 Hz), 3.2
3 (1H, dd, J = 6 Hz, J = 14 Hz), 4.1
4 (1H, dd, J = 5.5 Hz, J = 12 Hz),
4.33 (1H, dd, J = 3 Hz, J = 12 Hz),
4.64 (2H, s), 4.5 (2H, s), 5.49
(1H, m), 6.90 (1H, d, J = 9 Hz),
7.3-8.0 (6H, m), 8.79 (1H, b
r).

Using the appropriate starting materials, compounds shown in Tables 14 to 22 were obtained in the same manner as in Reference Example 5 or 6.

[0708]

[Table 14]

[0709]

[Table 15]

[0710]

[Table 16]

[0711]

[Table 17]

[0712]

[Table 18]

[0713]

[Table 19]

[0714]

[Table 20]

[0715]

[Table 21]

[0716]

[Table 22]

[0717] ¹ H-N of each compound shown in Table 14 to Table 22
The MR spectra (NMR (1) to NMR (35)) are as follows.

NMR (1) (CDCl ₃ ) δ ppm:
4.37 (1H, d, J = 24 Hz), 4.77 (2
H, s), 6.91 (2H, d, J = 8.8 Hz),
7.16 (1H, t, J = 7.3 Hz), 7.32 (1
H, t, J = 7.3 Hz), 7.38-7.82 (17
H, m), 7.89 (2H, d, J = 8.8 Hz).

NMR (2) (CDCl ₃ ) δ ppm:
2.35 (3H, s), 4.41 (1H, brs),
4.70 (2H, s), 6.70 (1H, d, J = 8.
2 Hz), 7.20-8.00 (21H, m).

NMR (3) (DMSO-d ₆ ) δpp
m: 1.19 (3H, t, J = 7.4 Hz), 2.69
(2H, q, J = 7.4 Hz), 4.43 (1H, d,
J = 2.5 Hz), 5.00 (2H, s), 6.83
(1H, d, J = 8.9 Hz), 7.25-7.38
(1H, m), 7.38-7.85 (19H, m),
7.98 (1H, d, J = 7.1 Hz), 12.65
(1H, brs).

NMR (4) (CDCl ₃ ) δ ppm:
1.32 (6H, d, J = 7 Hz), 3.42 (1H,
sept, J = 7 Hz), 4.2-4.6 (1H,
m), 4.73 (2H, s), 7.25-8.0 (21
H, m), 10.01 (1H, br).

NMR (5) (CDCl ₃ ) δ ppm:
0.86 (3H, t, J = 7.2 Hz), 1.31-
1.51 (2H, m), 1.51-1.72 (2H,
m), 2.65-2.72 (2H, m), 3.76 (3
H, s), 4.34 (1H, br-d, J = 24.7H)
z), 4.66 (2H, s), 5.98 (1H, br-)
s), 6.66 (1H, d, J = 8.3 Hz), 6.9
9-7.10 (1H, m), 7.19-7.31 (1
H, m), 7.38-7.60 (11H, m), 7.6
0-7.87 (8H, m).

NMR (6) (DMSO-d ₆ ) δpp
m: 4.52 (1H, d, J = 23 Hz), 5.12
(2H, s), 7.07 (1H, d, J = 8.4H
z), 7.31 (1H, td, J = 7.6 Hz, J =
1.0 Hz), 7.45 (1H, td, J = 7.6H)
z, J = 1.4 Hz), 7.45-8.15 (19H,
m), 12.68 (1H, s).

NMR (7) (DMSO-d ₆ ) δpp
m: 4.34 (1H, d, J = 22 Hz), 4.79
(2H, s), 6.97 (1H, t, J = 8.4H)
z), 7.30-7.38 (2H, m), 7.38-
7.92 (19H, m), 9.97 (1H, br).

NMR (8) (DMSO-d ₆ ) δpp
m: 3.16 (2H, t, J = 7.0 Hz), 3.92
(2H, t, J = 7.0 Hz), 4.83 (2H,
s), 5.13 (2H, s), 7.07 (1H, d, J
= 9.4 Hz), 7.34 (1H, t, J = 6.5H)
z), 7.44 (1H, t, J = 6.5 Hz), 7.6
0-8.12 (19H, m), 12.70 (1H, b
r).

NMR (9) (CDCl ₃ ) δ ppm:
1.67-1.90 (4H, m), 2.64-2.82
(2H, m), 3.68 (1H, bt, J = 6.0H
z), 5.19 (2H, s), 6.12 (2H, d, J
= 14.0 Hz), 7.10 (1H, d, J = 10.0)
Hz), 7.29-7.41 (1H, m), 7.41-
7.52 (1H, m), 7.69-7.95 (17H,
m), 7.95-8.06 (2H, m), 12.74
(1H, br-s).

NMR (10) (DMSO-d ₆ ) δpp
m: 1.10 (3H, t, J = 7.1 Hz), 2.62
(2H, t, J = 8.0 Hz), 2.90 (2H, t, J
J = 8.0 Hz), 4.00 (2H, q, J = 7.1H)
z), 4.33 (1H, d, J = 30.0 Hz);
01 (2H, s), 6.82 (1H, d, J = 14.0)
Hz), 7.29-7.38 (1H, m), 7.40-
7.50 (1H, m), 7.50-7.80 (18H,
m), 8.00-8.02 (1H, d, J = 4.0H)
z), 12.61 (1H, brs).

NMR (11) (CDCl ₃ ) δ ppm:
2.00 (3H, s), 2.05 (3H, s), 3.0
−3.15 (2H, m), 4.0−4.35 (2H,
m), 4.93, 5.05 (2H, ABq, J = 16
Hz), 5.40 (1H, m), 6.1-6.6 (2
H, br), 6.98 (1H, d, J = 8 Hz), 7.
2-8.5 (2H, m).

NMR (12) (CDCl ₃ ) δ ppm:
2.54-2.78 (6H, m), 2.87-3.12
(2H, m), 3.69-3.90 (4H, m), 4.
36 (1H, d, J = 24.0 Hz), 4.78 (2
H, s), 6.77 (1H, d, J = 8.5 Hz),
7.27-7.88 (21H, m).

NMR (13) (CDCl ₃ ) δ ppm:
2.27 (3H, s), 2.32-2.76 (10H,
m), 2.76-3.05 (2H, m), 4.36 (1
H, d, J = 26.0 Hz), 4.71 (2H, s),
6.77 (1H, d, J = 8.3 Hz), 7.27-
8.02 (21H, m).

NMR (14) (CDCl ₃ ) δ ppm:
1.00 (6H, t, J = 7.1 Hz), 1.80 −
2.00 (2H, m), 2.48-2.62 (6H,
m), 2.78 (2H, t, J = 6.2 Hz), 4.3
7 (1H, d, J = 24.4 Hz), 4.76 (2H,
s), 6.80 (1H, d, J = 6.8 Hz), 7.3
2 (1H, t, J = 7.3 Hz), 7.39-7.93
(20H, m).

NMR (15) (CDCl ₃ ) δ ppm:
1.72-2.05 (2H, m), 2.30-2.57
(4H, m), 2.70-2.89 (2H, m), 3.
54-3.83 (4H, m), 4.37 (1H, d, J
= 28.0 Hz), 4.74 (2H, s), 6.77
(1H, d, J = 8.3 Hz), 7.33 (1H, t,
J = 7.3 Hz), 7.40-7.96 (20H,
m).

NMR (16) (CDCl ₃ ) δ ppm:
1.81-2.01 (2H, m), 2.22 (3H,
s) 2.28-2.68 (10H, m), 2.79
(2H, t, J = 6.9 Hz), 4.37 (1H, d,
J = 24.0 Hz), 4.76 (2H, s), 6.79
(1H, d, J = 8.4 Hz), 7.33 (1H, t,
J = 8.8 Hz), 7.40-7.64 (10H,
m), 7.64-7.95 (10H, m).

NMR (17) (CDCl ₃ ) δ ppm:
1.7-3.3 (16H, m), 3.59 (2H,
m), 4.81 (2H, s), 6.82 (1H, d, J
= 8.5 Hz), 7.2-8.0 (21H, m).

NMR (18) (CDCl ₃ ) δ ppm:
1.4-1.7 (2H, m), 1.75-2.0 (4
H, m), 2.2-2.4 (2H, m), 2.4-2.
6 (2H, m), 2.65-2.9 (4H, m), 3.
65 (1H, m), 4.1-4.8 (2H, br),
4.68 (2H, s), 6.70 (1H, d, J = 8.
5 Hz), 7.2-7.9 (21H, m).

NMR (19) (CDCl ₃ ) δ ppm:
1.41-2.31 (9H, m), 2.24 (6H,
s), 2.46 (2H, t, J = 7.5 Hz), 2.7
7 (2H, t, J = 7.5 Hz), 2.93-3.12
(2H, m), 4.23-4.60 (1H, br),
4.73 (2H, s), 6.75 (1H, d, J = 8.
5Hz), 7.23-7.92 (21H, m).

NMR (20) (CDCl ₃ ) δ ppm:
1.48-2.28 (9H, m), 2.36-2.61
(6H, m), 2.77 (2H, t, J = 7.5H
z), 2.92-3.13 (2H, m), 3.65 (4
H, t, J = 4.5 Hz), 4.19-4.58 (1
H, m), 4.70 (2H, s), 6.71 (1H,
d, J = 8.5 Hz), 7.02-7.94 (21H,
m).

NMR (21) (CDCl ₃ ) δ ppm:
1.41-2.03 (8H, m), 2.05-2.80
(13H, m), 2.77 (2H, t, J = 7.6H
z), 2.88-3.07 (2H, m), 4.73 (2
H, s), 6.75 (1H, d, J = 8.5 Hz),
7.32 (1H, t, J = 6.4 Hz), 7.40 −
7.90 (20H, m).

NMR (22) (CDCl ₃ ) δ ppm:
1.62-2.23 (8H, m), 2.29-2.97
(12H, m), 3.48-3.93 (3H, m),
4.22-4.57 (1H, br), 4.69 (2H, br)
s), 6.70 (1H, d, J = 8.5 Hz), 7.2
2-8.04 (21H, m).

NMR (23) (CDCl ₃ ) δ ppm:
1.69-2.00 (3H, m), 2.00-2.62
(16H, m), 2.62-2.87 (4H, m),
3.50-3.92 (3H, m), 4.37 (1H,
d, J = 26.8 Hz), 4.75 (2H, s), 6.
77 (1H, d, J = 8.4 Hz), 7.28-7.9
2 (21H, m).

NMR (24) (CDCl ₃ ) δ ppm:
1.82-2.22 (4H, m), 2.50 (3H,
s), 2.54-3.12 (12H, m), 4.73.
(2H, s), 6.71 (1H, d, J = 8.6H)
z), 7.29-7.88 (21H, m).

NMR (25) (CDCl ₃ ) δ ppm:
1.55-1.85 (4H, m), 2.3-2.5 (6
H, m), 2.7-2.9 (2H, m), 3.67 (4
H, t, J = 4.5 Hz), 4.25-4.55 (2
H, m), 4.76 (2H, s), 6.78 (1H,
d, J = 8.5 Hz), 7.25-7.95 (21H,
m).

NMR (26) (DMSO-d ₆ ) δpp
m: 1.37-1.70 (4H, m), 2.08 (3
H, s), 2.14-2.43 (10H, m), 2.6
0-2.77 (2H, m), 4.33 (1H, d, J =
26.0 Hz), 4.96 (2H, s), 6.80 (1
H, d, J = 10.0 Hz), 7.27-7.38 (1
H, m), 7.38-7.80 (19H, m), 7.9
0-8.03 (1H, m).

NMR (27) (CDCl ₃ ) δ ppm:
1.00 (3H, t, J = 7.0 Hz), 1.01 (3
H, t, J = 7.0 Hz), 2.68 (2H, t, J =
6.9 Hz), 3.12-3.27 (4H, m),
35-3.46 (2H, m), 4.25-4.60 (1
H, m), 4.96 (2H, s), 6.67 (1H,
d, J = 8.5 Hz), 7.23-7.27 (1H,
m), 7.29-7.57 (10H, m), 7.68-
7.81 (9H, m), 7.92 (1H, brs), 1
1.97 (1H, brs).

NMR (28) (CDCl ₃ ) δ ppm:
2.14-2.39 (4H, m), 2.22 (3H,
s), 2.74 (2H, t, J = 6.3 Hz), 2.9
8-3.20 (2H, m), 3.29-3.48 (2
H, m), 3.63-3.80 (2H, m), 4.17
-4.54 (1H, m), 4.73 (2H, s), 6.
67 (1H, d, J = 8.6 Hz), 7.26-7.3
3 (1H, m), 7.33-7.62 (10H, m),
7.62-7.85 (9H, m), 7.90 (1H, b
rs).

NMR (29) (CDCl ₃ ) δ ppm:
0.89 (3H, t, J = 7.1 Hz), 1.00 (3
H, t, J = 7.1 Hz), 2.35-4.47 (15
H, m), 4.73 (2H, s), 6.67-6.74.
(1H, m), 7.20-7.61 (11H, m),
7.61-7.85 (9H, m), 7.85-7.93
(1H, m).

NMR (30) (CDCl ₃ ) δ ppm:
1.01-1.47 (2H, m), 1.65-1.90
(2H, m), 2.29 (3H, s), 2.35-2.
65 (11H, m), 2.65-2.91 (2H,
m), 3.03-3.22 (2H, m), 3.73-
3.91 (1H, m), 4.22-4.54 (1H,
m), 4.73 (2H, s), 4.75-4.92 (1
H, m), 6.69 (1H, d, J = 8.6 Hz),
7.22-7.63 (11H, m), 7.63-7.8
8 (9H, m), 7.88-8.00 (1H, m).

NMR (31) (CDCl ₃ ) δ ppm:
2.18-3.50 (20H, m), 3.50-3.7
1 (1H, m), 3.71-3.95 (1H, m),
4.20-4.82 (4H, m), 6.65-6.74
(1H, m), 7.20-7.63 (12H, m),
7.63-7.86 (9H, m), 7.86-7.98
(1H, m).

NMR (32) (CDCl ₃ ) δ ppm:
4.09 (3H, s), 4.42 (1H, d, J = 2
2.9 Hz), 4.85 (2H, s), 6.93 (1
H, d, J = 8.7 Hz), 7.00-7.18 (1
H, m), 7.18-7.98 (18H, m), 8.1
9 (1H, dd, J = 2.2 Hz, J = 8.7 Hz),
8.60 (1H, d, J = 2.2 Hz), 11.55
(1H, br).

NMR (33) (CDCl ₃ ) δ ppm:
2.73 (2H, t, J = 7.4 Hz), 3.37 (2
H, t, J = 7.4 Hz), 4.06 (1H, d, J =
20.6 Hz), 4.84 (2H, s), 6.77 (1
H, d, J = 8.6 Hz), 7.28-7.77 (20
H, m), 10.85 (1H, br), 12.16 (1
H, br).

NMR (35) (DMSO-d ₆ ) δpp
m: 2.03-2.46 (2H, m), 2.67-3.
06 (2H, m), 4.28-4.52 (1H, m),
4.94-5.24 (1H, m), 6.83-8.11
(22H, m), 12.61 (1H, brs).

Using the appropriate starting materials, the compounds shown in Tables 23 to 31 were obtained in the same manner as in Reference Example 2.

[0753]

[Table 23]

[0754] The ¹ H-NMR spectrum (NMR (1)) of the compound shown in Table 23 is as follows.

NMR (1) (CDCl ₃ ) δ ppm:
4.81 (2H, s), 7.05 (1H, d, J = 3.
5Hz), 7.25-7.35 (2H, m), 7.45
−7.65 (2H, m), 7.50 (1H, d, J =
3.5Hz), 10.00 (1H, s), 10.06
(1H, brs).

[0756]

[Table 24]

[0757]

[Table 25]

[0758]

[Table 26]

[0759]

[Table 27]

[0760]

[Table 28]

[0761]

[Table 29]

[0762]

[Table 30]

[0763]

[Table 31]

[0764] ¹ H-N of each compound shown in Tables 24 to 31
The MR spectra (NMR (1) to NMR (30)) are as follows.

[0765] NMR (1) (DMSO-d ₆ ) δpp
m: 2.08 (2H, q, J = 6.6 Hz), 2.62
(2H, t, J = 7.2 Hz), 4.13 (2H, t,
J = 4.1 Hz), 7.10 (2H, d, J = 8.6H)
z), 7.19 (1H, d, J = 3.6 Hz), 7.4
5 (1H, d, J = 3.6 Hz), 7.85 (2H,
d, J = 8.6 Hz), 9.86 (1H, s), 12.
13 (1H, s).

NMR (2) (DMSO-d ₆ ) δpp
m: 5.07 (2H, s), 7.19 (2H, d, J =
8.7 Hz), 7.27-7.40 (1H, m), 7.
40-7.56 (1H, m), 7.77 (1H, d, J
= 7.5 Hz), 7.90 (2H, d, J = 8.8H)
z), 7.98 (1H, d, J = 7.1 Hz), 9.8
9 (1H, s), 12.1-13.0 (1H, br).

NMR (3) (CDCl ₃ ) δ ppm:
2.38 (6H, s), 4.57 (2H, s), 7.0
6 (1H, d, J = 3.6 Hz), 7.51 (1H, d, J = 3.6 Hz)
d, J = 3.6 Hz), 7.61 (2H, s), 9.9
2 (1H, s), 10.10 (1H, brs).

NMR (4) (CDCl ₃ ) δ ppm:
1.13 (6H, t, J = 7.1 Hz), 2.93 (4
H, q, J = 7.1 Hz), 3.79 (2H, s),
5.01 (2H, s), 7.08 (1H, d, J = 8.
2Hz), 7.23-7.35 (1H, m), 7.35
−7.45 (1H, m), 7.74-7.87 (4H,
m), 9.92 (1H, s), 10.71 (1H,
s).

NMR (5) (CDCl ₃ ) δ ppm:
2.33 (3H, s), 2.42-2.88 (8H,
m), 3.71 (2H, s), 4.92 (2H, s),
7.02 (1H, d, J = 8.2 Hz), 7.27 −
7.40 (1H, m), 7.40-7.59 (1H,
m), 7.67-7.93 (1H, m), 9.93 (1
H, s).

NMR (6) (CDCl ₃ ) δ ppm:
1.29 (6H, t, J = 7.1 Hz), 2.98−
3.48 (8H, m), 5.20 (2H, s), 7.2
2 (1H, d, J = 9.0 Hz), 7.35 (1H,
d, J = 7.6 Hz), 7.49 (1H, d, J = 7.
6Hz), 7.80 (1H, d, J = 7.8Hz),
7.85-7.98 (2H, m), 8.01 (1H,
d, J = 7.4 Hz), 9.91 (1H, s), 10.
36 (1H, br), 12.84 (1H, br).

NMR (7) (CDCl ₃ ) δ ppm:
2.86 (3H, s), 3.14-4.00 (12H,
m), 5.21 (2H, s), 7.22 (1H, d, J
= 7.8 Hz), 7.35 (1H, t, J = 7.6H)
z), 7.49 (1H, t, J = 7.6 Hz), 7.7
8-7.87 (3H, m), 8.01 (1H, d, J =
8.1 Hz), 9.90 (1 H, s), 11.60 (2
H, br), 12.75 (1H, br).

NMR (8) (CDCl ₃ ) δ ppm:
1.83-2.11 (2H, m), 3.06 (2H,
t, J = 7.3 Hz), 3.85 (2H, t, J = 5.
2Hz), 4.22 (1H, br), 4.85 (2H,
s), 6.98 (1H, d, J = 8.2 Hz), 7.2
8-7.41 (1H, m), 7.41-7.49 (1
H, m), 7.74-7.86 (4H, m), 9.92
(1H, s), 11.84 (1H, br).

NMR (9) (CDCl ₃ ) δ ppm:
1.83-2.06 (2H, m), 2.25 (3H,
s), 2.32-2.76 (10H, m), 2.88
(2H, t, J = 7.7 Hz), 4.87 (2H, t, J = 7.7 Hz)
s), 6.97 (1H, d, J = 8.3 Hz), 7.3
0-7.42 (1H, m), 7.42-7.51 (1
H, m), 7.72-7.87 (4H, m), 9.94
(1H, s).

NMR (10) (CDCl ₃ ) δ ppm:
0.99 (6H, t, J = 7.1 Hz), 1.40-
1.61 (2H, m), 1.70-1.92 (4H,
m), 2.43-2.63 (6H, m), 3.56 (2
H, s), 3.95 (2H, t, J = 6.3 Hz),
6.86 (1H, d, J = 8.5 Hz), 7.28-
7.40 (1H, m), 7.40-7.51 (1H,
m), 7.70-7.91 (3H, m), 7.95 (1
H, d, J = 2.1 Hz), 9.89 (1H, s), 1
0.39-13.00 (1H, brs).

NMR (11) (CDCl ₃ ) δ ppm:
0.97 (6H, t, J = 7.1 Hz), 2.10-
2.40 (2H, m), 2.40-2.68 (6H,
m), 3.54 (2H, s), 3.95-4.23 (2
H, m), 6.84 (1H, t, J = 8.5 Hz),
7.20-7.40 (2H, m), 7.58-7.88
(3H, m), 7.90 (1H, d, J = 2.1H)
z), 9.87 (1H, s).

NMR (12) (CDCl ₃ ) δ ppm:
1.38-1.76 (2H, m), 1.76-2.13
(6H, m), 2.13-2.70 (14H, m),
2.88 (2H, t, J = 7.6 Hz), 2.95−
3.18 (2H, m), 4.86 (2H, s), 6.9
7 (1H, d, J = 8.2 Hz), 7.31-7.42
(1H, m), 7.42-7.57 (1H, m), 7.
73-7.87 (4H, m), 9.91 (1H, s).

NMR (13) (DMSO-d ₆ ) δpp
m: 1.92-2.45 (6H, m), 2.60-3.
21 (9H, m), 3.21-3.76 (4H, m),
3.76-4.16 (4H, m), 5.17 (2H,
s), 7.15 (1H, d, J = 8.8 Hz), 7.3
1 (1H, t, J = 6.9 Hz), 7.45 (1H,
t, J = 6.9 Hz), 7.68-7.92 (3H,
m), 7.99 (1H, d, J = 7.0 Hz), 9.8
7 (1H, s), 10.73 (1H, br), 11.7
8 (1H, br), 12.80 (1H, s).

NMR (14) (DMSO-d ₆ ) δpp
m: 1.28 (6H, t, J = 7.1 Hz), 2.00
-2.38 (6H, m), 2.68-2.90 (2H,
m), 2.90-3.25 (8H, m), 3.47-
3.83 (3H, m), 5.18 (2H, s), 7.1
8 (1H, d, J = 8.7 Hz), 7.34 (1H,
t, J = 7.7 Hz), 7.45 (1H, t, J = 7.
7Hz), 7.78-7.86 (3H, m), 8.00
(1H, d, J = 7.0 Hz), 9.90 (1H,
s), 10.78 (2H, br), 12.80 (1H,
br).

NMR (15) (DMSO-d ₆ ) δpp
m: 2.40 (3H, s), 5.06 (2H, s),
7.15-7.40 (3H, m), 7.65 (1H,
d, J = 8.4 Hz), 7.77 (1H, s), 7.8
9 (2H, d, J = 8.6 Hz), 9.88 (1H,
s), 12.61 (1H, s).

NMR (16) (DMSO-d ₆ ) δpp
m: 2.27 (3H, d, J = 0.9 Hz), 4.98
(2H, s), 6.79 (1H, d, J = 1.0H
z), 7.12-7.25 (2H, m), 7.82-
7.96 (2H, m), 9.88 (1H, s), 12.
0-12.7 (1H, br).

NMR (17) (DMSO-d ₆ ) δpp
m: 1.26 (9H, s), 4.98 (2H, s),
6.78 (1H, s), 7.15 (2H, d, J = 8.
8 Hz), 7.90 (2H, d, J = 8.8 Hz),
9.88 (1H, s), 12.42 (1H, s).

NMR (18) (DMSO-d ₆ ) δpp
m: 5.05 (2H, s), 7.19 (2H, d, J =
8.8 Hz), 7.25-7.55 (3H, m), 7.
69 (1H, s), 7.80-8.02 (4H, m),
9.89 (1H, s), 12.60 (1H, s).

NMR (19) (DMSO-d ₆ ) δpp
m: 1.57-1.84 (7H, m), 1.84-2.
05 (3H, m), 2.20 (1H, q, J = 8.5H
z) 2.30-2.72 (8H, m), 2.74-
3.12 (3H, m), 3.16-3.30 (1H,
m), 4.87 (2H, s), 6.97 (1H, d, J
= 8.3 Hz), 7.27-7.41 (1H, m),
7.41-7.53 (1H, m), 7.70-7.93
(4H, m), 9.91 (1H, s).

NMR (20) (CDCl ₃ ) δ ppm:
1.67-2.95 (20H, m), 3.55-3.9
5 (3H, m), 4.90 (2H, s), 6.96 (1
H, d, J = 8.3 Hz), 7.25-7.53 (2
H, m), 7.55-7.95 (4H, m), 9.90
(1H, s).

NMR (21) (CDCl ₃ ) δ ppm:
1.55-3.80 (23H, m), 4.91 (2H,
s), 6.96 (1H, d, J = 8.4 Hz), 7.2
5-7.52 (2H, m), 7.65-7.78 (4
H, m), 9.88 (1H, s).

NMR (22) (CDCl ₃ ) δ ppm:
1.75-2.95 (16H, m), 3.55-3.9
5 (7H, m), 4.88 (2H, s), 6.95 (1
H, d, J = 8.3 Hz), 7.28-7.55 (2
H, m), 7.65-7.95 (4H, m), 9.90
(1H, s).

NMR (23) (CDCl ₃ ) δ ppm:
1.75-3.00 (20H, m), 2.27 (3H,
s), 3.58-3.98 (3H, m), 4.88 (2
H, s), 6.95 (1H, d, J = 8.3 Hz),
7.30-7.52 (2H, m), 7.65-7.90
(4H, m), 9.89 (1H, s).

NMR (24) (CDCl ₃ ) δ ppm:
1.5-3.4 (15H, m), 2.40 (4H, t,
J = 4.5 Hz), 3.61 (4H, t, J = 4.5H)
z), 4.88 (2H, s), 6.99 (1H, d, J
= 8.5 Hz), 7.3-7.55 (2H, m), 7.
7-7.9 (4H, m), 9.92 (1H, s).

NMR (25) (CDCl ₃ ) δ ppm:
1.5-3.1 (23H, m), 2.24 (3H,
s), 4.91 (2H, s), 7.00 (1H, d, J
= 8 Hz), 7.3-7.5 (2H, m), 7.7-
7.9 (4H, m), 9.91 (1H, s).

NMR (26) (CDCl ₃ ) δ ppm:
1.7-2.0 (4H, m), 2.33 (3H, s),
2.5-3.0 (12H, m), 4.87 (2H,
s), 6.97 (1H, d, J = 8 Hz), 7.3-
7.9 (6H, m), 9.91 (1H, s).

NMR (27) (DMSO-d ₆ ) δpp
m: 1.30-3.51 (25H, m), 3.51-
3.75 (2H, m), 5.16 (2H, s), 7.0
9 (1H, d, J = 8.9 Hz), 7.27-7.39
(1H, m), 7.39-7.52 (1H, m), 7.
70-7.84 (3H, m), 7.98-8.09 (1
H, m), 9.86 (1H, s), 10.58-11.
17 (3H, m).

NMR (28) (DMSO-d ₆ ) δpp
m: 1.45 (6H, s), 2.68-3.01 (2
H, m), 2.77 (3H, s), 3.21-3.85
(10H, m), 5.24 (2H, s), 7.10 (1
H, d, J = 8.3 Hz), 7.29-7.40 (1
H, m), 7.40-7.52 (1H, m), 7.74
-7.89 (3H, m), 7.93-8.05 (1H,
m), 9.89 (1H, s), 11.10-13.00
(3H, m).

[0793] _{NMR (29) (CDCl 3)} δppm:
1.86 (2H, quint, J = 7.5 Hz);
18-2.63 (10H, m), 2.30 (3H,
s), 3.05 (2H, t, J = 7.5 Hz), 4.8
2 (2H, s), 6.24-7.01 (2H, m),
7.10-7.59 (3H, m), 7.73-7.93
(3H, m) 10.17 (1H, s).

NMR (30) (CDCl ₃ ) δ ppm:
3.46 (1H, dd, J = 6.5 Hz, J = 16.5)
Hz), 3.68 (1H, dd, J = 10.5 Hz, J
= 16.5 Hz), 5.67 (1H, dd, J = 6.5)
Hz, J = 10.5 Hz), 7.08 (1H, d, J =
8.5 Hz), 7.25-7.55 (2H, m), 7.
75-7.85 (3H, m), 7.99 (2H, d, J
= 8.5 Hz), 9.84 (1 H, s).

Using the appropriate starting materials, compounds shown in Tables 32 to 37 were obtained in the same manner as in Reference Example 7, 8 or 9.

[0796]

[Table 32]

[0797]

[Table 33]

[0798]

[Table 34]

[0799]

[Table 35]

[0800]

[Table 36]

[0801]

[Table 37]

¹ H-N of each compound shown in [0802] Table 32 to Table 37
The MR spectra (NMR (1) to NMR (22)) are as follows.

NMR (1) (CDCl ₃ ) δ ppm:
1.05 (3H, d, J = 6 Hz), 1.25-1.5
5 (2H, m), 1.75-3.3 (14H, m),
2.31 (3H, s).

NMR (2) (CDCl ₃ ) δ ppm:
0.89 (3H, t, J = 7.5 Hz), 1.17-
1.54 (3H, m), 1.54-1.78 (1H,
m), 1.78-1.94 (2H, m), 1.94-
2.18 (3H, m), 2.18-2.49 (6H,
m), 2.49-2.72 (2H, m), 2.72-
2.95 (3H, m), 3.03-3.27 (2H,
m).

NMR (3) (CDCl ₃ ) δ ppm:
0.91 (3H, t, J = 7 Hz), 1.15-1.7
(5H, m), 1.75-2.15 (6H, m), 2.
28 (3H, s), 2.15 to 2.45 (3H, m),
2.45-2.65 (2H, m), 2.7-2.95
(3H, m), 3.05-3.25 (2H, m).

NMR (4) (CDCl ₃ ) δ ppm:
0.85-0.94 (6H, m), 1.23-1.54
(2H, m), 1.62 (1H, br), 1.80-
1.96 (3H, m), 1.96-2.18 (2H,
m), 2.18-2.45 (6H, m), 2.45-
2.68 (2H, m), 2.68-2.92 (3H,
m) 3.00-3.24 (2H, m).

NMR (5) (CDCl ₃ ) δ ppm:
1.06-1.98 (15H, m), 2.20-2.4
7 (5H, m), 2.47-2.61 (1H, m),
2.61-2.90 (6H, m), 3.09-3.33
(2H, m).

NMR (6) (CDCl ₃ ) δ ppm:
1.06 (6H, d, J = 6.5 Hz), 1.25-
1.55 (2H, m), 1.75-1.95 (2H,
m), 2.2-2.4 (1H, m), 2.45-2.7
5 (11H, m), 3.05-3.2 (2H, m).

NMR (7) (CDCl ₃ ) δ ppm:
1.25-1.6 (3H, m), 1.6-2.75 (1
4H, m), 2.85 (1H, dd, J = 2 Hz, J =
11.5 Hz), 2.9-3.3 (5H, m).

NMR (8) (CDCl ₃ ) δ ppm:
1.00 (3H, t, J = 7.3 Hz), 1.04 (3
H, d, J = 6.3 Hz), 1.24 to 1.51 (2
H, m), 1.70-1.92 (3H, m), 2.03
(1H, t, J = 10.7 Hz), 2.20-2.50
(5H, m), 2.50-2.69 (2H, m), 2.
69-3.00 (4H, m), 3.07-3.22 (2
H, m).

NMR (9) (CDCl ₃ ) δ ppm:
0.84 (3H, t, J = 7.3 Hz), 1.03 (3
H, d, J = 6.2 Hz), 1.25-1.65 (4
H, m), 1.65-1.93 (3H, m), 2.02
(1H, q, J = 10.7 Hz), 2.19-2.48
(5H, m), 2.48-2.95 (6H, m), 3.
05-3.21 (2H, m).

[0812] _{NMR (10) (CDCl 3)} δppm:
0.89 (3H, d, J = 6.5 Hz), 1.03 (6
H, dd, J = 6.5 Hz, J = 15.1 Hz);
44-1.69 (2H, m), 1.80-2.00 (2
H, m), 2.05-2.24 (2H, m), 2.24
−2.50 (2H, m), 2.50-2.95 (6H,
m), 3.13-3.30 (3H, m), 4.85 (1
H, br).

[0813] _{NMR (11) (CDCl 3)} δppm:
1.03 (3H, d, J = 6.2 Hz), 1.33-
1.52 (2H, m), 1.72-3.08 (16H,
m), 3.08-3.23 (2H, m), 3.45-
3.80 (2H, m).

[0814] _{NMR (12) (CDCl 3)} δppm:
1.04 (3H, d, J = 6.2 Hz), 1.49−
1.68 (2H, m), 1.80-1.99 (2H,
m), 2.06 (1H, t, J = 10.1 Hz), 2.
24-2.55 (5H, m), 2.57-2.88 (4
H, m), 2.90-3.10 (2H, m), 3.15
-3.31 (3H, m), 3.34 (3H, s), 3.
44-3.62 (2H, m).

NMR (13) (CDCl ₃ ) δ ppm:
1.07 (3H, t, J = 7.1 Hz), 1.40 (2
H, dq, J = 3.8 Hz, J = 12.0 Hz);
65-1.98 (5H, m), 2.39-2.72 (9
H, m), 2.72-2.84 (4H, m), 3.05
-3.22 (2H, m).

[0816] _{NMR (14) (CDCl 3)} δppm:
0.91 (3H, t, J = 7.1 Hz), 1.14
1.58 (5H, m), 1.58-2.13 (5H,
m), 2.22-2.87 (13H, m), 3.01-
3.24 (2H, m).

NMR (15) (CDCl ₃ ) δ ppm:
2.0-3.2 (17H, m), 2.26 (3H,
s), 2.32 (3H, s).

NMR (16) (CDCl ₃ ) δ ppm:
1.8-1.9 (2H, m), 2.0-3.2 (17
H, m), 2.33 (3H, s), 2.34 (3H,
s).

[0819] NMR (17) (DMSO-d 6) δpp
m: 1.94-2.46 (6H, m), 2.69 (3
H, d, J = 3.7 Hz), 2.84-3.16 (2
H, m), 3.16-4.30 (11H, m), 9.5
6 (1H, br), 9.99 (1H, br), 11.0
4 (1H, br), 12.06 (1H, br).

[0820] _{NMR (18) (CDCl 3)} δppm:
1.08 (3H, d, J = 6.2 Hz), 1.28−
1.55 (2H, m), 1.55-1.95 (5H,
m), 2.38 (3H, s), 2.40-2.99 (1
0H, m), 3.02-3.22 (2H, m).

[0821] _{NMR (19) (CDCl 3)} δppm:
1.05 (3H, d, J = 6 Hz), 1.25-1.5
5 (2H, m), 1.75-3.3 (14H, m),
2.31 (3H, s).

[0822] _{NMR (20) (CDCl 3)} δppm:
1.05 (3H, d, J = 6 Hz), 1.25-1.5
5 (2H, m), 1.75-3.3 (14H, m),
2.31 (3H, s).

[0823] NMR (21) (DMSO-d 6) δpp
m: 1.78-2.47 (6H, m), 2.68-3.
06 (2H, m), 3.14-4.32 (16H,
m), 5.20-5.78 (2H, m), 9.1-9.
82 (2H, m), 10.54-11.36 (1H,
m), 11.82-12.38 (1H, m).

[0824] _{NMR (22) (CDCl 3)} δppm:
1.3-1.7 (6H, m), 2.0-3.2 (13
H, m), 2.32 (3H, s).

Reference Example 182 To a solution of 9.7 g of t-butyl propiolate in 300 ml of tetrahydrofuran was added dropwise 48 ml of a 1.6 M n-butyllithium solution in n-hexane at -70 ° C., and the mixture was reacted for 10 minutes. -{(2-methoxy-4-formylphenoxy) methylcarbonylamino} benzothiazole 10 g of tetrahydrofuran (200 ml and N, N
-A solution of 20 ml of dimethylpropylene urea was added dropwise over 20 minutes. After further reacting for 20 minutes, the reaction vessel was taken out of the cooling bath and stirred for 20 minutes. 5 ml of acetic acid was added, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying over sodium sulfate, the mixture was concentrated, and the residue was recrystallized from ethyl acetate-n-hexane. This was collected by filtration and white powder 2- [2-methoxy-4- (3-
13 g of [t-butoxycarbonyl-1-hydroxypropargyl) phenoxymethylcarbonylamino] benzothiazole were obtained.

Reference Example 183 A solution of 4.92 g of sodium hydroxide in 5 ml of water was diluted with 80 ml of ethanol, degassed, and then subjected to a nitrogen atmosphere. 20 g of 3-methoxy-4-dimethylaminocarbonylthiobenzaldehyde was added to this solution, and the mixture was refluxed for 14 hours.
After cooling with ice, 9.74 ml of ethyl bromoacetate was added dropwise, and the mixture was stirred at room temperature for 3 hours. Ethanol, 1.5N hydrochloric acid and water were added and extracted with chloroform. After drying over sodium sulfate and concentration, the residue is subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1 → 5.6: 1).
→ 4: 1) to give a white solid 3-methoxy-4-ethoxycarbonylmethylthiobenzaldehyde 11.8.
g was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.
21 (3H, t, J = 7.1 Hz), 3.74 (2H,
s), 3.99 (3H, s), 4.14 (2H, q, J
= 7.1 Hz), 7.32-7.48 (3H, m),
9.92 (1H, s).

Reference Example 184 The following compounds were obtained in the same manner as in Reference Example 1 using appropriate starting materials.

Α- (2-Methoxy-4-formylphenoxymethyl) acetic acid yellow powder ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.84 (3
H, s), 4.82 (2H, s), 7.05 (1H,
d, J = 8 Hz), 7.41 (1H, d, J = 2H)
z), 7.51 (1H, dd, J = 2 Hz, J = 8H)
z), 9.83 (1H, s), 13.14 (1H, b
r).

Reference Example 185 The following compounds were obtained in the same manner as in Reference Example 2 using appropriate starting materials.

2- (2-Methoxy-4-formylphenoxymethylcarbonylamino) benzimidazole yellow powder ¹ H-NMR (CDCl ₃ ) δ ppm: 4.06 (3H,
s), 4.86 (2H, s), 7.09 (1H, d, J
= 8.5 Hz), 7.3-7.55 (4H, m), 7.
8-7.9 (2H, m), 9.91 (1H, s), 1
0.25 (1H, br).

2- (2-ethoxy-4-formylphenoxymethylcarbonylamino) benzimidazole white powder ¹ H-NMR (CDCl ₃ ) δ ppm: 1.60 (3H,
t, J = 7.0 Hz), 4.26 (2H, q, J = 7.
0 Hz), 4.87 (2H, s), 7.11 (1H,
d, J = 8.3 Hz), 7.30-7.49 (4H,
m), 7.79-7.88 (2H, m), 9.90 (1
H, s), 10.34 (1H, br).

2- [2- (Diethylaminocarbonylmethoxy) -4-formylphenoxymethylcarbonylamino] benzimidazole White powder ¹ H-NMR (CDCl ₃ ) δ ppm: 1.16 (3H,
t, J = 7 Hz), 1.30 (3H, t, J = 7H)
z), 3.35 (2H, q, J = 7 Hz), 3.49
(2H, q, J = 7 Hz), 4.92 (2H, s),
5.00 (2H, s), 7.09 (1H, d, J = 8H)
z), 7.25-7.55 (4H, m), 7.7-7.
85 (2H, m), 9.86 (1H, s).

Reference Example 186 The following compounds were obtained in the same manner as in Reference Example 5 using appropriate starting materials.

[3- (2-chloroethyl) -4- (2-
Benzothiazolylaminocarbonylmethoxy) benzoyl] methyltriphenylphosphonium bromide ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.16 (2
H, t, J = 7.0 Hz), 3.92 (2H, t, J =
7.0 Hz), 5.18 (2H, s), 6.12 (2
H, d, J = 13.1 Hz), 7.14 (1H, d, J)
= 9.4 Hz), 7.31 (1H, t, J = 6.5H)
z), 7.44 (1H, t, J = 6.5 Hz), 7.6
0-8.12 (19H, m), 12.70 (1H, b
r).

[3- (2,3-Diacetyloxypropyl) -4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyltriphenylphosphonium chloride ¹ H-NMR (CDCl ₃ ) δ ppm: 2.00 ( 3H,
s), 2.05 (3H, s), 3.0-3.15 (2
H, m), 4.0-4.35 (2H, m), 4.93,
5.05 (2H, AB-q, J = 16 Hz), 5.40
(1H, m), 6.1-6.6 (2H, br), 6.9
8 (1H, d, J = 8 Hz), 7.2-8.5 (21
H, m).

Reference Example 187 To a solution of 25.1 g of methyl 2,4-dihydroxybenzoate in 250 ml of acetone were added 14.9 ml of methyl bromoacetate and 21.7 g of potassium carbonate, and the mixture was heated under reflux for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; n-hexane-ethyl acetate = 3: 1) to give 31.5.
g of ethyl 2- (3-hydroxy-4-methoxycarbonylphenoxy) acetate was obtained.

[0838] White solid ¹ H-NMR (CDCl ₃ ) δ ppm: 3.81 (3H,
s), 3.91 (3H, s), 4.65 (2H, s),
6.39 (1H, d, J = 2.6 Hz), 6.45 (1
H, dd, J = 2.6 Hz, J = 8.8 Hz), 7.7
3 (1H, d, J = 8.8 Hz), 10.97 (1H,
s).

Reference Example 188 2- (2-phthalimide) was dissolved in 50 ml of ethanol.
3.37 g of methylbenzothiazole and 3 ml of hydrazine monohydrate were added, and the mixture was heated under reflux for 30 minutes. After the disappearance of the raw materials, the precipitated solid was removed, and the filtrate was concentrated. An aqueous potassium carbonate solution was added to the residue, extracted with dichloromethane, and dried over magnesium sulfate. The solvent was distilled off to obtain 1.42 g of 2-aminomethylbenzothiazole.

[0840] Yellow powder _{^{1 H-NMR (CDCl 3)}} δppm: 1.83 (2H,
br), 4.30 (2H, s), 7.33-7.51
(2H, m), 7.85-7.99 (2H, m).

Reference Example 189 2 g of 2-hydroxymethylbenzothiazole and 2.5 ml of triethylamine were added to 50 ml of dichloromethane, and further, under ice-cooling, methanesulfonyl chloride 1.03 m
was added and stirred at the same temperature for 1 hour. After the completion of the reaction, the resultant was washed with hydrochloric acid and dried with magnesium sulfate. After evaporating the solvent, the obtained crude product was dissolved in 50 ml of dimethylformamide, 5.6 g of potassium phthalimide was added, and the mixture was heated with stirring at 70 ° C. for 1 hour. After the completion of the reaction, the reaction solution was poured into water, and the precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate, and the residue obtained by evaporating the solvent and the previous crystal were combined and washed with n-hexane-diethyl ether to give 3.37 g of 2- (2-phthalimide). ) Methylbenzothiazole was obtained.

[0842] Yellow powder _{^{1 H-NMR (CDCl 3)}} δppm: 5.30 (2H,
s), 7.35-7.47 (2H, m), 7.74-
8.02 (6H, m).

Reference Example 190 A solution of 12.33 g of methyl p-formylbenzoate, 16 g of malonic acid and 1 ml of piperidine in 100 ml of pyridine was heated under reflux for 2 hours. The reaction solution was poured into ice water, and the precipitated white powder was collected by filtration, washed with water and dried.
-Methoxycarbonylcinnamic acid was obtained.

[0844] White powder ^{1 H-NMR (DMSO-d} 6) δppm: 3.85 (3
H, s), 6.65 (1H, d, J = 16 Hz), 7.
63 (1H, d, J = 16 Hz), 7.82 (2H,
d, J = 8 Hz), 8.01 (2H, d, J = 8H)
z) 12.57 (1H, br).

Reference Example 191 4.64 g of 4-methoxycarbonylcinnamic acid 300 parts of acetic acid
0.5 g of 10% palladium-carbon was added to the ml solution, and hydrogenated at normal pressure at 70 ° C. for 2 hours. The catalyst was filtered off, and the filtrate was distilled off under reduced pressure. Water was added to the obtained residue, and the precipitated white powder was collected by filtration to obtain 3.87 g of 3- (4-methoxycarbonylphenyl) propionic acid.

[0846] White powder _{^{1 H-NMR (CDCl 3)}} δppm: 2.71 (2H,
t, J = 7.5 Hz), 3.02 (2H, t, J = 7.
5Hz), 3.91 (3H, s), 7.29 (2H,
d, J = 8.5 Hz), 7.97 (2H, d, J = 8.
5 Hz).

Reference Example 192 Oxalyl chloride 3.2 was added to a suspension of 6.5 g of 2-carboxybenzothiazole in 100 ml of anhydrous dichloromethane.
ml and one drop of dimethylformamide were added, and the mixture was stirred at room temperature for 3 hours. Dichloromethane is distilled off, and the residue is treated with acetone 1
The solution was added dropwise to a solution of 5 g of sodium azide in 20 ml of water under ice-cooling. After stirring at the same temperature for 3 hours, water was added to the reaction solution, and the crystals were collected by filtration. The obtained crystals were dissolved in 50 ml of dichloromethane, dried, the solvent was distilled off, 50 ml of benzene was added, and the mixture was heated under reflux for 4 hours. 5.7 g of ethyl 4-piperidinecarboxylate was added, and the mixture was further heated under reflux for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 200: 1 → 100: 1) to obtain 4.0.
g of 2- (4-ethoxycarbonyl-1-piperidinyl) carbonylaminobenzothiazole was obtained.

[0848] White powder _{^{1 H-NMR (CDCl 3)}} δppm: 1.25 (3H,
t, J = 7 Hz), 1.65-2.05 (4H, m),
2.4-2.6 (1H, m), 2.95-3.2 (2
H, m), 4.0-4.2 (2H, m), 4.14 (2
H, q, J = 7 Hz), 7.15-7.45 (2H,
m), 7.58 (1H, d, J = 8 Hz), 7.75
(1H, d, J = 8 Hz) 10.11 (1H, b
r).

Reference Example 193 In a solution of 26.8 g of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate, 62.5 ml of t-butyl acrylate and 25 ml of triethylamine in 100 ml of anhydrous dimethylformamide, 100 ml of anhydrous palladium acetate was added under argon atmosphere. 4 g and 0.74 g of 1,3-bis (diphenylphosphino) propane were added,
Stirred at 75 ° C. for 16 hours. The reaction solution was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 5).
There were obtained 23.5 g of t-butyl 4-methoxy-4-methoxycarbonylcinnamate.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.
54 (9H, s), 3.90 (3H, s), 3.94
(3H, s), 6.42 (1H, d, J = 16 Hz),
7.07 (1H, d, J = 1.5 Hz), 7.13 (1
H, dd, J = 1.5 Hz, J = 8 Hz), 7.55
(1H, d, J = 16 Hz), 7.80 (1H, d, J)
= 8 Hz).

Reference Example 194 50 ml of trifluoroacetic acid was added to a solution of 23.5 g of t-butyl 3-methoxy-4-methoxycarbonylcinnamate in 100 ml of anhydrous dichloromethane under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was distilled off under reduced pressure, and the residue was crystallized from ethanol to obtain 8.35 g of 3-methoxy-4-methoxycarbonylcinnamic acid.

[0832] White powdery ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ ppm:
3.88 (3H, s), 3.94 (3H, s), 6.5
0 (1H, d, J = 16 Hz), 7.13 (1H,
s), 7.15 (1H, d, J = 8 Hz), 7.62
(1H, d, J = 16 Hz), 7.78 (1H, d, J)
= 8 Hz).

Reference Example 195 3-methoxy-4-methoxycarbonylcinnamic acid 8.35
1.0 g of 10% palladium-carbon was added to 200 g of acetic acid suspension in 200 ml, and hydrogenated at room temperature. After filtering off the catalyst,
The filtrate was evaporated, and the residue was crystallized from diethyl ether-n-hexane to give 7.5 g of 3- (3-methoxy-4-.
(Methoxycarbonylphenyl) propionic acid was obtained.

[0854] White powder _{^{1 H-NMR (CDCl 3)}} δppm: 2.70 (2H,
t, J = 7.5 Hz), 2.98 (2H, t, J = 7.
5 Hz), 3.88 (3H, s), 3.89 (3H,
s), 5.71 (1H, br), 6.75-6.9 (2
H, m), 7.75 (1H, d, J = 8 Hz).

Reference Example 196 A dimethylmethylphosphonate (7.7 ml) solution in anhydrous tetrahydrofuran (100 ml) was treated with a 1.66 M n-butyllithium (43 ml) n-hexane solution at −50 to −60.
It was added dropwise at ° C. Subsequently, 2- [2- (3-methoxy-4)
-Methoxycarbonylphenyl) ethyl] carbonylaminobenzothiazole (8.72 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise. Since a yellow rubbery substance was separated in the reaction solution, 1,3-dimethyl-3,4,5,5
6-tetrahydro-2 (1H) -pyrimidinone 10 ml
Was added and stirred at the same temperature for 2 hours. After adding a saturated aqueous ammonium chloride solution to the reaction solution, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off.
The residue was subjected to silica gel column chromatography (eluent;
Dichloromethane: methanol = 100: 1 → 10: 1)
And dimethyl [｛3
6.4 g of -methoxy-4- [2- (2-benzothiazolyl) aminocarbonylethyl] benzoyl} methyl] phosphonate was obtained.

[0856] Yellow powder _{^{1 H-NMR (CDCl 3)}} δppm: 2.80 (2H,
t, J = 7.5 Hz), 3.05 (2H, t, J = 7.5 Hz).
5Hz), 3.73 (3H, s), 3.78 (3H,
s), 3.79 (3H, s), 3.82 (2H, d, J
= 21.5 Hz), 6.65-6.8 (2H, m),
7.25-7.45 (2H, m), 7.60 (1H,
d, J = 8.5 Hz), 7.64 (1H, d, J = 7.
5Hz), 7.82 (1H, dd, J = 1 Hz, J =
7.5 Hz), 11.49 (1H, br).

Reference Example 197 3.9 ml of dimethyl methylphosphonate, 1.65 M
Using 22 ml of n-butyllithium and 4.0 g of 2- (4-ethoxycarbonyl-1-piperidinyl) carbonylaminobenzothiazole, dimethyl [1- (2-benzothiazolyl) aminocarbonyl) -4 was obtained in the same manner as in Reference Example 196. -Piperidinylcarbonylmethyl] phosphonate (2.5 g) was obtained.

[0858] _{^{1 H-NMR (CDCl 3)}} δppm: 1.
5-2.05 (4H, m), 2.75-3.1 (3H,
m), 3.16 (2H, d, J = 28 Hz), 3.76
(3H, s), 3.82 (3H, s), 4.1-4.3
5 (2H, m), 7.15-7.45 (2H, m),
7.57 (1H, d, J = 7.5 Hz), 7.74 (1
H, d, J = 8 Hz), 10.04 (1H, br).

The following compounds were obtained in the same manner as in Reference Example 1 using appropriate starting materials.

[0860]

[Table 38]

[0861]

[Table 39]

[0862]

[Table 40]

[0863]

[Table 41]

The following compounds were obtained in the same manner as in Reference Example 2 using appropriate starting materials.

[0865]

[Table 42]

[0866]

[Table 43]

[0867]

[Table 44]

[0868]

[Table 45]

[0869]

[Table 46]

[0870]

[Table 47]

[0871]

[Table 48]

[0873]

[Table 49]

[0873]

[Table 50]

[0874]

[Table 51]

[0875]

[Table 52]

[0876]

[Table 53]

The following compounds were obtained in the same manner as in Reference Example 3 using appropriate starting materials.

[0878]

[Table 54]

[0877]

[Table 55]

[0880]

[Table 56]

[0881]

[Table 57]

[0882]

[Table 58]

[0883]

[Table 59]

[0884]

[Table 60]

[0885]

[Table 61]

[0887] The following compounds were obtained in the same manner as in Reference Example 5 or Reference Example 6 using appropriate starting materials.

[0887]

[Table 62]

[0888]

[Table 63]

The following compounds were obtained in the same manner as in Reference Example 7, Reference Example 8 or Reference Example 9 using appropriate starting materials.

[0890]

[Table 64]

The following compounds were obtained in the same manner as in Reference Example 187 using appropriate starting materials.

[0892]

[Table 65]

[0893]

[Table 66]

[0894]

[Table 67]

[0895]

[Table 68]

[0896]

[Table 69]

[0897]

[Table 70]

[0898]

[Table 71]

[0899]

[Table 72]

[0900]

[Table 73]

The following compounds were obtained in the same manner as in Reference Example 1 or Reference Example 194 using appropriate starting materials.

[0902]

[Table 74]

[0903]

[Table 75]

[0904]

[Table 76]

[0905]

[Table 77]

[0906]

[Table 78]

[0907] ¹ of each compound shown in Table 38 to Table 78 H
-The NMR spectra ((1) to (77)) are as follows.

(1) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.88 (3H, t, J = 7.2 Hz), 1.26
-1.47 (2H, m), 1.47-1.66 (2H,
m), 2.56 (2H, t, J = 7.5 Hz), 3.7
8 (3H, s), 4.66 (2H, s), 6.33 (1
H, d, J = 2.4 Hz), 6.46 (1H, dd, J)
= 2.4 Hz, J = 8.3 Hz), 7.05 (1H,
d, J = 8.3 Hz).

(2) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 2.02 (3H, s), 3.75 (3H, s),
4.64 (2H, s), 6.47 (1H, d, J = 8.
3Hz), 6.60 (1H, d, J = 8.3Hz),
7.07 (1H, t, J = 8.3 Hz), 12.93
(1H, brs).

(3) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 0.86 (3H, t, J = 7.2 Hz), 1.1
3-1.51 (4H, m), 2.59 (2H, t, J =
7.6 Hz), 3.74 (3H, s), 4.63 (2
H, s), 6.46 (1H, d, J = 8.3 Hz),
6.59 (1H, d, J = 8.3 Hz), 7.06 (1
H, t, J = 8.3 Hz), 12.89 (1H, br)
s).

(4) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 1.13 (6H, d, J = 7.0 Hz), 3.0
8-3.35 (1H, m), 3.69 (3H, s),
4.66 (2H, s), 6.38 (1H, d, J = 2.
4 Hz), 6.48 (1H, dd, J = 2.4 Hz, J
= 8.4 Hz), 7.07 (1H, d, J = 8.4H)
z), 12.93 (1H, s).

(5) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 0.69-1.00 (3H, m), 1.08-
1.62 (8H, m), 2.32-2.63 (2H,
m), 3.68 (3H, s), 4.65 (2H, s),
6.30-6.53 (2H, m), 7.00 (1H,
d, J = 8.2 Hz), 12.92 (1H, s).

(6) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 2.09 (3H, s), 3.68 (3H, s),
4.66 (2H, s), 6.32-6.52 (2H,
m), 7.02 (1H, d, J = 8.1 Hz), 12.
95 (1H, s).

(7) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 3.66 (3H, s), 3.70 (3H, s),
4.64, 4.73 (all 1H, each s), 6.34-6.
52 (2H, m), 6.79-6.96 (1H, m),
12.88-13.03 (1H, m).

(8) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 1.27 (3H, t, J = 7.0 Hz), 3.6
5 (3H, s), 3.92 (2H, q, J = 7.0H
z), 4.65 (2H, s), 6.32-6.52 (2
H, m), 6.78-6.93 (1H, m), 12.8.
1-13.01 (1H, brs).

(9) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.97 (3H, t, J = 7.1 Hz), 1.31
-1.68 (4H, m), 2.77 (2H, t, J =
7.0 Hz), 3.84 (3H, s), 4.75 (2
H, s), 6.51 (1H, d, J = 8.2 Hz),
6.64 (1H, d, J = 8.2 Hz), 7.14 (1
H, t, J = 8.2 Hz), 7.26-7.39 (1
H, m), 7.39-7.52 (1H, m), 7.73
-7.90 (2H, m), 9.70 (1H, brs).

(10) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.24 (3H, s), 3.85 (3H, s),
4.75 (2H, s), 6.51 (1H, d, J = 8.
3Hz), 6.63 (1H, d, J = 8.3Hz),
7.14 (1H, t, J = 8.3 Hz), 7.29-
7.40 (1H, m), 7.40-7.52 (1H,
m), 7.74-7.91 (2H, m).

(11) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.69 (3H, d, J = 7 Hz), 3.80 (3
H, s), 4.95 (1H, q, J = 7 Hz), 6.4
5-6.7 (3H, m), 7.15-7.5 (3H,
m), 7.7-7.9 (2H, m), 9.77 (1H,
br).

(12) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.31 (3H, s), 3.78 (3H, s),
4.74 (2H, s), 6.42 (1H, d, J = 2.
4Hz), 6.52 (1H, dd, J = 2.4Hz, J
= 8.8 Hz), 7.12 (1H, d, J = 8.8H)
z), 7.25-7.53 (2H, m), 7.72-
7.94 (2H, m), 9.71 (1H, s).

(13) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.30 (6H, d, J = 6.9 Hz), 3.19
-3.46 (1H, m), 3.79 (3H, s), 4.
75 (2H, s), 6.44 (1H, d, J = 2.4H
z), 6.60 (1H, dd, J = 2.4 Hz, J =
8.5Hz), 7.20 (1H, d, J = 8.5H)
z), 7.24-7.53 (2H, m), 7.72-
7.94 (2H, m), 9.51-9.82 (1H, b
rs).

(14) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.78-0.99 (3H, m), 1.18-1.
77 (8H, m), 2.67 (2H, t, J = 7.9H
z), 3.78 (3H, s), 4.74 (2H, s),
6.43 (1H, d, J = 2.4 Hz), 6.55 (1
H, dd, J = 2.4 Hz, J = 8.3 Hz), 7.1
2 (1H, d, J = 8.3 Hz), 7.23-7.52
(2H, m), 7.75-7.92 (2H, m), 9.
56-9.80 (1H, brs).

(15) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.77 (3H, s), 3.97 (3H, s),
4.78 (2H, s), 6.51-6.72 (2H,
m), 6.89 (1H, d, J = 8.8 Hz), 7.2
1-7.56 (2H, m), 7.73-7.92 (2
H, m).

(16) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.48 (3H, s), 3.90 (3H, s),
4.82 (2H, s), 6.69 (1H, dd, J =
8.7 Hz, J = 2.4 Hz), 6.86 (1H, d,
J = 2.4 Hz), 7.36 (1H, dt, J = 1.2)
Hz, J = 7.7 Hz), 7.48 (1H, dt, J =
1.2 Hz, J = 7.7 Hz), 7.84 (2H, t,
J = 7.7 Hz), 8.05 (1H, d, J = 8.7H)
z), 9.91 (1H, brs).

(17) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.99 (3H, t, J = 7.1 Hz), 1.37
-1.71 (4H, m), 2.80 (2H, t, J =
6.9 Hz), 3.87 (3H, s), 3.91 (3
H, s), 4.82 (2H, s), 6.66 (1H,
d, J = 8.8 Hz), 7.34 (1H, dt, J =
1.3 Hz, J = 7.7 Hz), 7.46 (1 H, d
t, J = 1.3 Hz, J = 7.7 Hz), 7.69−
7.90 (3H, m), 9.62 (1H, brs).

(18) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.31 (3H, s), 3.85 (3H, s),
3.90 (3H, s), 4.82 (2H, s), 6.6
5 (1H, d, J = 8.8 Hz), 7.34 (1H, d
t, J = 1.2 Hz, J = 7.6 Hz), 7.46 (1
H, dt, J = 1.2 Hz, J = 7.6 Hz), 7.6
9-7.89 (3H, m), 9.79 (1H, br)
s).

(19) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.27 (3H, t, J = 7.6 Hz), 2.83
(2H, q, J = 7.6 Hz), 3.87 (3H,
s), 3.91 (3H, s), 4.83 (2H, s),
6.66 (1H, d, J = 8.8 Hz), 7.30 (1
H, dt, J = 1.3 Hz, J = 7.3 Hz), 7.4
6 (1H, dt, J = 1.3 Hz, J = 7.3 Hz),
7.70-7.90 (3H, m), 9.72 (1H, b
rs).

(20) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.91 (6H, s), 3.88 (3H, s),
3.89 (3H, s), 4.80 (2H, s), 6.6
4 (1H, d, J = 8.7 Hz), 7.30-7.38
(2H, m), 7.42-7.51 (1H, m), 7.
80-7.89 (2H, m), 10.24 (1H, b
r).

(21) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.03 (6H, s), 3.91 (3H, s),
4.72 (2H, s), 7.12 (1H, d, J = 8.
3 Hz), 7.29 (1H, dt, J = 1.2 Hz, J
= 7.8 Hz), 7.43 (1H, dt, J = 1.2H)
z, J = 7.8 Hz), 7.78-7.86 (4H,
m), 13.22 (1H, br).

(22) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.86 (3H, s), 3.89 (3H, s),
4.65 (2H, s), 4.97 (1H, d, J = 5.
9Hz), 6.49-6.55 (2H, m), 7.34
−7.54 (3H, m), 7.84-7.89 (1H,
m), 7.98 (1H, d, J = 7.3 Hz).

(23) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.78 (2H, t, J = 7.5 Hz), 3.09
(2H, t, J = 7.5 Hz), 3.90 (3H,
s), 7.15 (2H, d, J = 8.5 Hz), 7.2
5-7.45 (2H, m), 7.68 (1H, d, J =
7.5 Hz), 7.8-7.95 (1H, m), 7.9
0 (2H, d, J = 8.5 Hz).

(24) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.79 (2H, t, J = 7.5 Hz), 3.06
(2H, t, J = 7.5 Hz), 3.76 (3H,
s), 3.86 (3H, s), 6.65 (1H, d, J
= 8 Hz), 6.72 (1H, s), 7.25-7.5
(2H, m), 7.6-7.75 (2H, m), 7.8
5 (1H, d, J = 7.5 Hz), 11.40 (1H,
br).

(25) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.65-2.12 (8H, m), 3.74 (3
H, s), 3.78 (3H, s), 3.70-3.88
(2H, m), 4.79 (2H, s), 4.83-4.
94 (1H, m), 6.40-6.62 (2H, m),
7.32-7.42 (1H, m), 7.44-7.52
(1H, m), 7.79-7.90 (3H, m), 8.
31-10.20 (1H, brs).

(26) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.50-3.70 (8H, m), 4.79 (2
H, s), 6.77-6.97 (2H, m), 7.09
−7.49 (8H, m), 7.58-7.89 (2H,
m), 9.97-10.81 (1H, brs).

(27) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.72 (3H, s), 3.77 (3H, s),
3.81 (2H, d, J = 21.6 Hz), 4.68
(2H, s), 6.34 (1H, d, J = 2.4H)
z), 6.62 (1H, dd, J = 2.4 Hz, J =
8.8 Hz), 7.04-7.15 (2H, m), 7.0.
15-7.47 (5H, m), 7.68-7.83 (2
H, m), 7.86 (1H, d, J = 8.8 Hz), 1
0.65 (1H, brs).

(28) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.41 (3H, s), 3.63 (2H, d, J =
22.6 Hz), 3.80 (6H, d, J = 11.2H)
z), 4.82 (2H, s), 6.71 (1H, dd,
J = 8.8 Hz, J = 2.4 Hz), 6.85 (1H,
d, J = 2.4 Hz), 7.34 (1H, dt, J =
1.3 Hz, J = 9.2 Hz), 7.47 (1H, d
t, J = 1.3 Hz, J = 9.2 Hz), 7.82 (2
H, t, J = 9.2 Hz), 8.01 (1H, d, J =
8.8 Hz).

(29) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.00 (3H, t, J = 7.0 Hz), 1.39
-1.73 (4H, m), 2.78 (2H, t, J =
8.0 Hz), 3.76 (6H, d, J = 11.4H)
z), 3.79 (3H, s), 3.81 (2H, d, J
= 22.1 Hz), 4.82 (2H, s), 6.69
(1H, d, J = 8.8 Hz), 7.34 (1H, t,
J = 8.6 Hz), 7.46 (1H, t, J = 8.6H)
z), 7.57 (1H, d, J = 8.8 Hz), 7.8
2 (2H, t, J = 8.6 Hz), 9.87 (1H, b
rs).

(30) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.33 (3H, s), 3.77 (6H, d, J =
11.1 Hz), 3.80 (3H, s), 3.81 (2
H, d, J = 22.0 Hz), 4.82 (2H, s),
6.69 (1H, d, J = 8.8 Hz), 7.35 (1
H, dt, J = 1.3 Hz, J = 7.9 Hz), 7.4
7 (1H, dt, J = 1.3 Hz, J = 7.9 Hz),
7.61 (1H, d, J = 8.8 Hz), 7.82 (2
H, t, J = 7.9 Hz), 9.87 (1H, br)
s).

(31) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.29 (3H, t, J = 7.5 Hz), 2.83
(2H, q, J = 7.5 Hz), 3.76 (6H, d,
J = 11.2 Hz), 3.80 (2H, d, J = 22.
1 Hz), 3.81 (3H, s), 4.83 (2H,
s), 6.70 (1H, d, J = 8.8 Hz), 7.3
8 (1H, dt, J = 1.4 Hz, J = 8.6 Hz),
7.47 (1H, dt, J = 1.4 Hz, J = 8.6H
z), 7.59 (1H, d, J = 8.8 Hz), 7.8
3 (2H, t, J = 8.6 Hz), 9.73 (1H, b
rs).

(32) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.90 (6H, s), 3.69 (3H, s),
3.74 (2H, d, J = 21.7 Hz), 3.75
(3H, s), 3.90 (3H, s), 4.83 (2
H, s), 6.74 (1H, d, J = 8.6 Hz),
7.26 (1H, d, J = 8.6 Hz), 7.34 (1
H, t, J = 9.1 Hz), 7.43 (1H, t, J =
9.1 Hz), 7.80-7.90 (2H, m), 1
0.10 (1H, br).

(33) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.03 (6H, s), 3.61 (2H, d, J =
22.7 Hz), 3.77 (3H, s), 3.81 (3
H, s), 4.94 (2H, s), 7.15 (1H,
d, J = 8.4 Hz), 7.30 (1H, t, J = 7.
8Hz), 7.43 (1H, t, J = 7.8Hz),
7.76-7.86 (4H, m).

(34) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.62 (2H, d, J = 22.5 Hz), 3.7
7, 3.82 (6H, each s), 4.04 (3H, s),
4.85 (2H, s), 7.02 (1H, d, J = 8.
5Hz), 7.3-7.55 (2H, m), 7.6-
7.7 (2H, m), 7.8-7.9 (2H, m), 1
0.31 (1H, br).

(35) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.72 (3H, s), 3.78 (3H, s),
3.79 (2H, d, J = 21.7 Hz), 3.92
(3H, s), 4.66 (2H, s), 4.97 (2
H, d, J = 5.9 Hz), 6.53-6.61 (2
H, m), 7.39-7.54 (3H, m), 7.82
−7.90 (2H, m), 7.98 (1H, d, J =
7.6 Hz).

(36) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.77 (2H, t, J = 7.5 Hz), 3.06
(2H, t, J = 7.5 Hz), 3.66 (2H, d,
J = 22.6 Hz), 3.75 (3H, s), 3.81
(3H, s), 7.10-7.22 (2H, m), 7.
26-7.49 (2H, m), 7.63-7.68 (1
H, m), 7.81-7.90 (3H, m).

(37) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.80 (2H, t, J = 7.5 Hz), 3.05
(2H, t, J = 7.5 Hz), 3.73 (3H,
s), 3.78 (3H, s), 3.79 (3H, s),
3.82 (2H, d, J = 21.5 Hz), 6.65-
6.8 (2H, m), 7.25-7.45 (2H,
m), 7.60 (1H, d, J = 8.5 Hz), 7.6
4 (1H, d, J = 7.5 Hz), 7.82 (1H, d
d, J = 1 Hz, J = 7.5 Hz), 11.49 (1
H, br).

(38) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.96 (3H, s), 4.03 (3H, s),
4.55 (1H, brd, J = 27.4 Hz), 4.7
6 (2H, s), 6.71 (1H, d, J = 8.7H)
z), 7.25-7.38 (1H, m), 7.39-
7.88 (19H, m), 10.50 (1H, br)
s).

(39) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.10-2.30 (2H, m), 3.58 (2
H, t, J = 6.6 Hz), 4.04-4.19 (2
H, m), 4.38-4.72 (1H, m), 4.65
(2H, s), 6.39 (1H, dd, J = 2.3H)
z, J = 8.6 Hz), 6.52 (1H, d, J = 2.
3 Hz), 7.28-7.95 (20H, m), 10.
58 (1H, brs).

(40) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.82 to 2.11 (2H, m), 2.11-2.
38 (4H, m), 2.38-2.62 (2H, m),
3.49-3.75 (4H, m), 4.04 (2H,
t, J = 5.9 Hz), 4.50-4.93 (1H,
m), 4.68 (2H, s), 6.40 (1H, dd,
J = 2.2 Hz, J = 8.6 Hz), 6.54 (1H,
d, J = 2.2 Hz), 7.23-7.37 (1H,
m), 7.37-7.62 (10H, m), 7.62-
7.96 (9H, m), 10.37 (1H, brs).

(41) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.00 (6H, s), 3.89 (3H, s),
4.70 (2H, s), 6.49 (1H, dd, J =
2.5 Hz, J = 8.5 Hz), 6.57 (1H, d,
J = 2.5 Hz), 6.93 (1H, dd, J = 2.5)
Hz, J = 9 Hz), 7.08 (1H, d, J = 2.5)
Hz), 7.20-8.05 (16H, m), 8.55
-8.65 (1H, m), 9.90 (1H, br).

(42) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.21-1.56 (2H, m), 1.67 (1
H, br), 1.75-1.94 (2H, m), 2.0
1 (1H, t, J = 10.6 Hz), 2.01-2.8
9 (14H, m), 3.02-3.28 (2H, m),
3.55-3.78 (2H, m), 3.85-4.02
(1H, m).

(43) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.83 (1H, br), 2.15 (1H, dd,
J = 4.1 Hz, J = 12.8 Hz), 2.26 (6
H, s), 2.43 (1H, dd, J = 7.8 Hz, J
= 12.8 Hz), 2.53 (1H, dd, J = 10.
2 Hz, J = 12.1 Hz), 2.68-2.98 (3
H, m), 3.50-3.72 (2H, m), 3.78
-3.99 (1H, m).

(44) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.81 (3H, s), 3.91 (3H, s),
4.65 (2H, s), 6.39 (1H, d, J = 2.
6 Hz), 6.45 (1H, dd, J = 2.6 Hz, J
= 8.8 Hz), 7.73 (1H, d, J = 8.8H)
z) 10.97 (1H, s).

(45) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.80 (3H, s), 3.87 (3H, s),
4.64 (2H, s), 5.16 (2H, s), 6.4
2 (1H, dd, J = 2.4 Hz, J = 8.7 Hz),
6.60 (1H, d, J = 2.4 Hz), 7.30 −
7.43 (3H, m), 7.49-7.52 (2H,
m), 7.85 (1H, d, J = 8.7 Hz).

(46) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.82 (3H, s), 3.86 (3H, s),
4.58-4.62 (2H, m), 4.66 (2H,
s), 5.28-5.58 (2H, m), 5.98-
6.19 (1H, m), 6.41 (1H, dd, J =
2.4 Hz, J = 8.7 Hz), 6.54 (1H, d,
J = 2.4 Hz), 7.83 (1H, d, J = 8.7H)
z).

(47) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.52-2.00 (8H, m), 3.82 (3
H, s), 3.84 (3H, s), 4.66 (2H,
s), 4.73-4.84 (1H, m), 6.37 (1
H, dd, J = 2.4 Hz, J = 8.7 Hz), 6.5
3 (1H, d, J = 2.4 Hz), 7.79 (1H,
d, J = 8.7 Hz).

(48) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.61 (3H, s), 3.81 (3H, s),
4.70 (2H, s), 6.83-6.97 (2H,
m), 7.22-7.33 (2H, m), 7.33-
7.45 (3H, m), 7.85 (1H, d, J = 8.
8 Hz).

(49) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.92 (3H, t, J = 7.4 Hz), 1.48
-1.70 (2H, m), 2.65-2.78 (2H,
m), 3.79 (3H, s), 3.90 (3H, s),
4.70 (2H, s), 6.25 (1H, d, J = 8.
9 Hz), 7.65 (1H, d, J = 8.9 Hz), 1
1.08 (1H, s).

(50) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.94 (3H, t, J = 7.3 Hz), 1.49
-1.71 (2H, m), 2.63-2.77 (2H,
m), 3.80 (3H, s), 3.83 (3H, s),
3.89 (3H, s), 4.70 (2H, s), 6.4
8 (1H, d, J = 8.8 Hz), 7.70 (1H,
d, J = 8.8 Hz).

(51) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.77 (3H, s), 3.79 (3H, s),
4.59 (2H, s), 6.45 (1H, d, J = 2.
5 Hz), 6.65 (1H, dd, J = 2.5 Hz, J
= 8.8 Hz), 6.92-7.03 (2H, m),
7.03-7.17 (1H, m), 7.26-7.40
(2H, m), 7.91 (1H, d, J = 8.8H)
z).

(52) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.43 (3H, s), 3.82 (3H, s),
3.88 (3H, s), 4.70 (2H, s), 6.5
9 (1H, dd, J = 8.8 Hz, J = 2.4 Hz),
6.81 (1H, d, J = 2.4 Hz), 8.00 (1
H, t, J = 8.8 Hz).

(53) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.93 (3H, t, J = 7.0 Hz), 1.19
-1.62 (4H, m), 2.73 (2H, t, J =
7.0 Hz), 3.79 (3H, s), 3.91 (3
H, s), 4.70 (2H, s), 6.27 (1H,
d, J = 9.0 Hz), 7.67 (1H, d, J = 9.
0 Hz), 11.07 (1H, s).

(54) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.94 (3H, t, J = 7.2 Hz), 1.29
-1.63 (4H, m), 2.72 (2H, t, J =
7.1 Hz), 3.80 (3H, s), 3.83 (3
H, s), 3.89 (3H, s), 4.70 (2H,
s), 6.50 (1H, d, J = 8.8 Hz), 7.7
2 (1H, d, J = 8.8 Hz).

(55) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.14 (3H, t, J = 7.5 Hz), 2.75
(2H, q, J = 7.5 Hz), 3.80 (3H,
s), 3.91 (3H, s), 4.71 (2H, s),
6.28 (1H, d, J = 9.0 Hz), 7.67 (1
H, d, J = 9.0 Hz), 11.08 (1H, s).

(56) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.18 (3H, s), 3.80 (3H, s),
3.91 (3H, s), 4.71 (2H, s), 6.2
8 (1H, d, J = 9.0 Hz), 7.67 (1H,
d, J = 9.0 Hz), 11.11 (1H, s).

(57) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.34 (3H, s), 3.81 (3H, s),
3.82 (3H, s), 3.89 (3H, s), 4.7
0 (2H, s), 6.51 (1H, d, J = 8.8H)
z), 7.71 (1H, d, J = 8.8 Hz).

(58) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.18 (3H, t, J = 7.5 Hz), 2.76
(2H, q, J = 7.5 Hz), 3.80 (3H,
s), 3.84 (3H, s), 3.89 (3H, s),
4.71 (2H, s), 6.51 (1H, d, J = 8.
8 Hz), 7.73 (1H, d, J = 8.8 Hz).

(59) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.30 (3H, t, J = 7 Hz), 3.91 (3
H, s), 4.27 (2H, q, J = 7 Hz), 4.6
3 (2H, s), 6.41 (1H, d, J = 2.5H
z), 6.48 (1H, dd, J = 2.5 Hz, J = 9)
Hz), 7.75 (1H, t, J = 9 Hz), 10.9
6 (1H, s).

(60) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.30 (3H, t, J = 7 Hz), 3.86 (3
H, s), 3.89 (3H, s), 4.28 (2H,
q, J = 7 Hz), 6.43 (1H, dd, J = 2.5)
Hz, J = 8.5 Hz), 6.58 (1H, d, J =
2.5 Hz), 7.84 (1H, d, J = 8.5H)
z).

(61) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.80 (3H, s), 3.84 (3H, s),
3.88 (3H, s), 4.73 (2H, s), 5.9
8 (2H, br), 6.12 (1H, d, J = 9.1H)
z), 7.59 (1H, d, J = 9.1 Hz).

(62) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.88 (6H, s), 3.80 (3H, s),
3.83 (3H, s), 3.87 (3H, s), 4.7
1 (2H, s), 6.48 (1H, d, J = 8.7H)
z), 7.29 (1H, d, J = 8.7 Hz).

(63) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.82 (3H, s), 3.93 (3H, s),
4.73 (2H, s), 6.34 (1H, s), 8.0
2 (1H, s), 10.93 (1H, s).

(64) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.82, 3.86, 3.88 (each 3H, each s),
4.77 (2H, s), 6.40 (1H, s), 8.0
7 (1H, d, J = 3.1 Hz).

(65) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.73, 3.74 (each 3H, each s), 4.6
3 (2H, s), 6.76 (1H, s), 7.30 (1
H, s), 10.66 (1H, brs).

(66) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.84 (6H, s), 3.89 (3H, s),
4.81 (2H, s), 5.23 (2H, s), 6.7
0 (1H, d, J = 9.0 Hz), 7.26-7.40
(5H, m), 7.60-7.64 (2H, m).

(67) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.76 (3H, s), 4.76 (2H,
s), 5.19 (2H, s), 6.54 (1H, dd,
J = 2.3 Hz, J = 8.7 Hz), 6.76 (1H,
d, J = 2.3 Hz), 7.27-7.44 (3H,
m), 7.49-7.53 (2H, m), 7.69 (1
H, d, J = 8.7 Hz), 13.07 (1H, br)
s).

(68) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.74 (3H, s), 4.59-4.63
(2H, s), 4.75 (2H, s), 5.21-5.
29 (2H, m), 5.93-6.09 (1H, m),
6.52 (1H, dd, J = 2.3 Hz, J = 8.7H
z), 6.64 (1H, d, J = 2.3 Hz), 7.6
7 (1H, d, J = 8.7 Hz), 13.05 (1H, d, J = 8.7 Hz)
brs).

(69) ¹ H-NMR (CDCl ₃ ) δpp
m: 1.52-2.03 (8H, m), 3.84 (3
H, s), 4.71 (2H, s), 4.30-5.20
(2H, m), 6.40 (1H, dd, J = 2.4H)
z, J = 8.7 Hz), 6.54 (1H, d, J = 2.
4 Hz), 7.80 (1H, d, J = 8.7 Hz).

(70) ¹ H-NMR (CDCl ₃ ) δpp
m: 0.93 (3H, t, J = 7.3 Hz), 1.47
-1.70 (2H, m), 2.62-2.76 (2H,
m), 3.83 (3H, s), 3.90 (3H, s),
4.74 (2H, s), 6.51 (1H, d, J = 8.
8Hz), 7.20 (1H, brs), 7.72 (1
H, d, J = 8.8 Hz).

(71) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.39 (3H, s), 3.77 (3H, s)
s), 4.81 (2H, s), 6.62-6.83 (2
H, m), 7.89 (1H, d, J = 9.1 Hz), 1
3.14 (1H, brs).

(72) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.88 (3H, t, J = 7.1 Hz);
19-1.61 (4H, m), 2.60 (2H, t, J
= 6.7 Hz), 3.70 (3H, s), 3.78 (3
H, s), 4.77 (2H, s), 6.71 (1H,
d, J = 8.8 Hz), 7.60 (1H, d, J = 8.
8 Hz), 13.05 (1H, brs).

(73) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.10 (3H, s), 3.70 (3H,
s), 3.78 (3H, s), 4.78 (2H, s),
6.72 (1H, d, J = 8.9 Hz), 7.59 (1
H, d, J = 8.9 Hz), 13.11 (1H, br)
s).

(74) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.08 (3H, t, J = 7.4 Hz), 2.
62 (2H, q, J = 7.4 Hz), 3.72 (3H,
s), 3.78 (3H, s), 4.79 (2H, s),
6.72 (1H, d, J = 8.9 Hz), 7.60 (1
H, d, J = 8.9 Hz), 13.09 (1H, br)
s).

(75) ¹ H-NMR (CDCl ₃ ) δpp
m: 3.38 (2H, d, J = 6.5 Hz), 3.84
(3H, s), 3.86 (3H, s), 4.74 (2
H, s), 4.95-5.15 (2H, m), 5.85
-6.1 (1H, m), 6.34 (1H, s), 7.6
9 (1H, s), 9.28 (1H, br).

(76) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.74, 3.82 (each 3H, each s), 4.9
7 (2H, s), 6.74 (1H, s), 7.85 (1
H, d, J = 3.6 Hz), 12.82-13.44
(1H, br).

(77) ¹ H-NMR (CDCl ₃ ) δpp
m: 2.91 (6H, s), 3.93 (3H, s),
4.73 (2H, s), 7.14 (1H, d, J = 7.
8 Hz), 7.90-7.94 (2H, m), 9.72
(1H, br).

Reference Example 303 The following compounds were obtained in the same manner as in Reference Example 6, using appropriate starting materials.

• α- (2,3-dihydroxy-4-acetylphenoxy) methyl acetate White powder ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3
H, s), 3.69 (3H, s), 4.91 (2H,
s), 6.49 (1H, d, J = 9.1 Hz), 7.3
5 (1H, d, J = 9.1 Hz), 8.79 (1H,
s), 12.31 (1H, s).

Methyl α- (2,3-dimethoxy-4-acetylphenoxy) acetate White solid ¹ H-NMR (CDCl ₃ ) δ ppm: 2.60 (3H,
s), 3.81 (3H, s), 3.93 (3H, s),
3.99 (3H, s), 4.75 (2H, s), 6.5
7 (1H, d, J = 8.9 Hz), 7.48 (1H,
d, J = 8.9 Hz).

Α- [2,3-dimethoxy-4- (2-
Bromoacetyl) phenoxy] methyl acetate colorless oil ¹ H-NMR (CDCl ₃ ) δ ppm: 3.81 (3H,
s), 3.93 (3H, s), 4.07 (3H, s),
4.57 (2H, s), 4.76 (2H, s), 6.5
8 (1H, d, J = 8.9 Hz), 7.54 (1H,
d, J = 8.9 Hz).

(2,3-Dimethoxy-4-methoxycarbonylmethoxybenzoyl) methylenetriphenylphosphorane Colorless amorphous ¹ H-NMR (CDCl ₃ ) δ ppm: 3.77 (3H,
s), 3.94 (6H, s), 4.61 (1H, br)
d, J = 27.8 Hz), 4.70 (2H, s), 6.
56 (1H, d, J = 8.8 Hz), 7.38-7.8
0 (16H, m).

Α- [3- (3-chloropropoxy)-
4-acetylphenoxy) methyl acetate yellow oil ¹ H-NMR (CDCl ₃ ) δ ppm: 1.31 (3H,
t, J = 7 Hz), 2.2-2.5 (2H, m), 2.
57 (3H, s), 3.77 (2H, t, J = 6.5H
z), 4.30 (2H, t, J = 7 Hz), 4.66
(2H, s), 6.47 (1H, dd, J = 2 Hz, J
= 8.5 Hz), 6.57 (1H, d, J = 2 Hz),
7.81 (1H, d, J = 8.5 Hz).

Α- [3- (3-chloropropoxy)-
4- (2-Bromoacetyl) phenoxy] ethyl acetate colorless oil ¹ H-NMR (CDCl ₃ ) δ ppm: 1.31 (3H,
t, J = 7 Hz), 2.25-2.55 (2H, m),
3.55-3.85 (2H, m), 4.15-4.4
(4H, m), 4.50 (2H, s), 4.68 (2
H, s), 6.51 (1H, dd, J = 2 Hz, J = 9)
Hz), 6.59 (1H, d, J = 2 Hz), 7.89
(1H, d, J = 9 Hz).

[2- (3-chloropropoxy) -4-
Ethoxycarbonylmethoxybenzoyl] methylenetriphenylphosphorane pale brown amorphous ¹ H-NMR (CDCl ₃ ) δ ppm: 1.31 (3H,
t, J = 7 Hz), 2.2-2.7 (2H, m), 3.
67 (2H, d, J = 5.5 Hz), 4.27 (2H, d, J = 5.5 Hz)
q, J = 7 Hz), 4.2-4.4 (2H, m), 4.
66 (2H, s), 6.20 (1H, br), 6.47
(1H, dd, J = 2 Hz, J = 9 Hz), 6.57
(1H, d, J = 2 Hz), 7.4-8.0 (16H,
m).

(2,3-Dimethoxy-4-carboxymethoxybenzoyl) methyltriphenylphosphonium chloride Colorless prism (recrystallized from dilute hydrochloric acid) mp 137-151 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm : 3.78 (3
H, s), 3.81 (3H, s), 4.69 (2H,
s), 6.63 (1H, d, J = 8.9 Hz), 7.2
8 (1H, d, J = 8.9 Hz), 7.50-7.80
(15H, m).

[2- (3-chloropropoxy) -4-
Carboxymethoxybenzoyl] methyltriphenylphosphonium chloride pale yellow amorphous ¹ H-NMR (CDCl ₃ ) δ ppm: 2.1-2.45
(2H, m), 3.63 (2H, t, J = 6.5H
z), 4.04 (2H, t, J = 5 Hz), 4.49
(2H, s), 6.35 (1H, dd, J = 2 Hz, J
= 7 Hz), 6.48 (1H, d, J = 2 Hz), 7.
35-7.9 (16H, m).

Example 1 6.5 g of 2- (2-isopropylphenoxymethylcarbonylamino) benzothiazole, maleic anhydride
A solution of 9 g and 8.0 g of aluminum chloride in 50 ml of 1,2-dichloroethane was stirred at room temperature for 7 hours. After water was added to decompose aluminum chloride, ethyl acetate was added and stirred. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried. 7.3 g of a mixture of the trans form and the cis form was obtained. This was dissolved in dimethylformamide (50 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 60 ° C for 30 minutes. Water about 10
0 ml was added, and the precipitated crystals were collected by filtration, washed with methanol, and dried to give 2- [2-isopropyl-4- (trans 3
-Carboxyacryloyl) phenoxymethylcarbonylamino] benzothiazole (6.2 g) was obtained.

[0996] ^{1 H-NMR (DMSO-d} 6) δppm:
1.25 (6H, d, J = 7 Hz), 3.40 (1H,
sept, J = 7 Hz), 5.12 (2H, s), 6.
64 (1H, d, J = 15.5 Hz), 7.03 (1
H, d, J = 8.5 Hz), 7.25-7.5 (2H,
m), 7.77 (1H, d, J = 7.5 Hz), 7.8
5-8.05 (4H, m), 12.70 (1H, b
r), 13.10 (1H, br).

Example 2 To a solution of 1.0 g of 2- [2-isopropyl-4- (3-carboxyacryloyl) phenoxymethylcarbonylamino] benzothiazole and 0.4 ml of triethylamine in 20 ml of dichloromethane was added 0.32 ml of isobutyl chloroformate on ice. It was added dropwise under water cooling. At the same temperature, 0.27 ml of N-methylpiperazine was added, and the mixture was stirred for 2.5 hours. After the reaction solution was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; dichloromethane → dichloromethane: methanol = 30: 1). Recrystallization from ethanol gave 0.80 g of 2- {2-isopropyl-4- [3- (4-methyl-1-piperazinylcarbonyl) acryloyl] phenoxymethylcarbonylamino} benzothiazole. Light brown powder, mp 190-192 ° C.

Example 3 1.0 g of 2- [4- (3-carboxyacryloyl) phenoxymethylcarbonylamino] benzothiazole,
A solution of 0.23 ml of thionyl chloride and 1 drop of dimethylformamide in 20 ml of dichloromethane was added at room temperature to 10 ml.
Stirred for hours. This solution was added dropwise to a solution of 0.5 g of 4- (4-methyl-1-piperazinyl) piperidine and 1 ml of pyridine in 20 ml of dichloromethane under ice-water cooling. Water was added to the reaction solution, made basic with 5% aqueous sodium hydroxide, and extracted with dichloromethane. After washing with water and drying, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (eluent; dichloromethane: methanol = 50: 1 → 1).
0: 1). The obtained compound was converted into a hydrochloride according to a conventional method, and recrystallized from ethanol-diethyl ether to give 2- [4- {3- [4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl). 0.14 g of [acryloyl {phenoxymethylcarbonylamino] benzothiazole dihydrochloride was obtained.

White powder mp 202.5-225 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.35-
1.8 (2H, m), 2.0-2.3 (2H, m),
2.6-3.9 (11H, m), 2.81 (3H,
s), 4.1-4.3 (1H, m), 4.5-4.7
(1H, m), 5.08 (2H, s), 7.15 (2
H, d, J = 9 Hz), 7.3-7.55 (3H,
m), 7.76 (1H, d, J = 14 Hz), 7.77
(1H, d, J = 8.5 Hz), 7.98 (1H, d,
J = 8 Hz), 8.05 (2H, d, J = 9 Hz), 1
2.67 (1H, br).

Example 4 4- (4-Methyl-1-piperazinyl) piperidine was added to a solution of 0.97 g of 2- [2-isopropyl-4- (3-carboxyacryloyl) phenoxymethylcarbonylamino] benzothiazole in 10 ml of dimethylformamide. 0.65 g and 0.6 ml of diethyl cyanophosphate were added dropwise at room temperature. 0.5 ml of triethylamine was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent; dichloromethane: methanol = 1).
00: 1 → 10: 1). The obtained compound is converted into a hydrochloride in ethanol according to a conventional method, and recrystallized from ethanol-diethyl ether to give 2- {2-isopropyl-4- [3- [4- (4-methyl-1-piperazinyl)].
0.45 g of -1-piperidinylcarbonyl] acryloyl] phenoxymethylcarbonylamino {benzothiazole dihydrochloride was obtained.

Yellow powder: mp 186-190 ° C (decomposition).

Example 5 A solution of 3.0 g of sodium periodate in 30 ml of water was added to a solution of 4.0 g of dibutyl tartrate in 100 ml of methanol, and the mixture was stirred for 10 minutes and extracted with ethyl acetate. A suspension of dimethyl {[3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyl} phosphonate (5.7 g) in tetrahydrofuran (100 ml) was ice-cooled and 5% sodium hydroxide until the reaction mixture became homogeneous. Water was added, and a solution of glyoxalate prepared from dibutyl tartrate in 30 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring for 30 minutes, the mixture was acidified with 5% hydrochloric acid and tetrahydrofuran was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with dichloromethane. The dichloromethane layer was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 200: 1) to give 2- [2-methoxy-4- (3-butoxycarbonylacryloyl) phenoxymethyl. 2.85 g of [carbonylamino] benzothiazole were obtained. This is the condition of tetrahydrofuran-5% sodium hydroxide aqueous solution,
By stirring at room temperature for 30 minutes, 2.9 g of 2- [2-methoxy-4- (3-carboxyacryloyl) phenoxymethylcarbonylamino] benzothiazole was obtained.

[1003] ^{1 H-NMR (DMSO-d} 6) δppm:
3.89 (3H, s), 5.09 (2H, s), 6.6
7 (1H, d, J = 15.5 Hz), 7.08 (1H,
d, J = 8.5 Hz), 7.25-7.55 (2H,
m), 7.57 (1H, m), 7.7-8.1 (4H,
m), 11.68 (1H, br).

Example 6 To a solution of 17.7 ml of ethyl propiolate in 450 ml of tetrahydrofuran was added dropwise, at -78 ° C, 102 ml of a 1.71 M solution of n-butyllithium in n-hexane.
Stirred for minutes. To this solution was added 2- (2-methoxy-) at the same temperature.
A solution of 20 g of 4-formylphenoxymethylcarbonylamino) benzothiazole in 400 ml of tetrahydrofuran and 40 ml of N, N-dimethylpropyleneurea was added dropwise over 15 minutes. Stir for another 10 minutes, then remove the reaction vessel from the cooling bath, stir for 20 minutes, and then add 11 ml of acetic acid.
Was added. After dilution with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium carbonate, dried over sodium sulfate and concentrated.
Purification by silica gel column chromatography (eluent; dichloromethane: methanol = 100: 1 → 50: 1) gave 2- [2-methoxy-) as a dark brown oil.
There were obtained 33.7 g of 4- (3-methoxycarbonyl-1-hydroxypropargyl) phenoxymethylcarbonylamino] benzothiazole.

33.7 g of 2- [2-methoxy-4- (3-methoxycarbonyl-1-hydroxypropargyl) phenoxymethylcarbonylamino] benzothiazole
Was added to a solution of dimethylformamide in 150 ml, and the mixture was stirred at room temperature for 1.5 hours. After diluting with ethyl acetate and washing with 0.15N hydrochloric acid,
It was dried over sodium sulfate. The precipitated crystals during the evaporation of the solvent were collected by filtration to obtain 5.5 g of 2- [2-methoxy-4- (trans-3-methoxycarbonylacryloyl) phenoxymethylcarbonylamino] benzothiazole (compound A) as a pale yellow powder. Was. On the other hand, the filtrate is concentrated and crystallized from ethanol-diethyl ether to give 2- [2-methoxy-4- (cis-3-methoxycarbonylacryloyl) phenoxymethylcarbonylamino] benzothiazole (compound) as a pale yellow powder. B) 6.0 g were obtained.

Compound A; ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.26 (3
H, t, J = 7.1 Hz), 3.92 (3H, s),
4.21 (2H, q, J = 7.1 Hz), 5.11 (2
H, s), 6.71 (1H, d, J = 15.5 Hz),
7.08 (1H, d, J = 8.6 Hz), 7.31 −
7.37 (1H, m), 7.44-7.50 (1H,
m), 7.59 (1H, d, J = 2.0 Hz), 7.7
5-7.81 (2H, m), 7.98 (1H, d, J =
15.5 Hz), 8.00-8.02 (1H, m), 1
2.67 (1H, brs).

Compound B; ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.05 (3
H, t, J = 7.1 Hz), 3.89 (3H, s),
3.97 (2H, q, J = 7.1 Hz), 5.11 (2
H, s), 6.35 (1H, d, J = 12.3 Hz),
7.05 (1H, d, J = 8.8 Hz), 7.21 (1
H, d, J = 12.3 Hz), 7.31-7.37 (1
H, m), 7.44-7.50 (3H, m), 7.78
-7.81 (1H, m), 7.99-8.02 (1H,
m), 12.62 (1H, brs). Example 7 2- {2-isopropyl-4- [trans-3- (4-
Methyl-1-piperazinyl) carbonylacryloyl]
A solution of 100 mg of phenoxymethylcarbonylaminodibenzothiazole in 10 ml of dimethylformamide was allowed to stand for 6.5 hours in direct sunlight near the window. Water was added, the crystals were collected by filtration and recrystallized from ethanol to give 2
-{2-isopropyl-4- [cis-3- (4-methyl-1-piperazinyl) carbonylacryloyl] phenoxymethylcarbonylamino} benzothiazole 45m
g was obtained.

Light yellow powder: mp 114-115 ° C.

Example 8 1.7 g of dimethyl {[3-methoxy-4- (2-benzothiazolylaminocarbonylmethoxy) benzoyl] methyl} phosphonate and 0.1 g of pyridine-4-aldehyde were prepared.
5% of a solution of 5 g of tetrahydrofuran in 30 ml under ice-cooling
6 ml of sodium hydroxide was added and stirred for 5 hours. After neutralization with acetic acid, the precipitated crystals were collected by filtration. Recrystallization from dichloromethane-ethanol-diethyl ether gave 1.3 g of 2- {2-methoxy-4- [3- (4-pyridyl) acryloyl] phenoxymethylcarbonylamino} benzothiazole.

[1010] pale yellow powder, mp 206-207 ° C.

Example 9 1 g of activated manganese dioxide was added to a 50 ml solution of 1 g of 2- [2-methoxy-4- (3-t-butoxycarbonyl-1-hydroxypropargyl) phenoxymethylcarbonylamino] benzothiazole in 50 ml of chloroform. Refluxed for hours. Add 1 g of manganese dioxide and add 1.5 g
Reflux continued for hours. The mixture was filtered through Celite, and the filtrate was concentrated.
The residue was recrystallized from ethanol to give 2- [2-
0.5 g of methoxy-4- (3-t-butoxycarbonylpropiolyl) phenoxymethylcarbonylamino] benzothiazole was obtained.

Example 10 0.5 g of 2- [2-methoxy-4- (3-t-butoxycarbonylpropioloyl) phenoxymethylcarbonylamino] benzothiazole in 30 ml of methylene chloride
10 ml of trifluoroacetic acid was added to the solution, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated, methylene chloride was added to the residue, and the mixture was stirred. The precipitated crystals were collected by filtration and recrystallized from dichloromethane-trifluoroacetic acid to give 2- [2-methoxy-
0.26 g of 4- (3-carboxypropioloyl) phenoxymethylcarbonylamino] benzothiazole was obtained.

Mp 174-176 ° C. The following compounds were obtained in the same manner as in Example 1 or 5, using appropriate starting materials.

[1014]

[Table 79]

[1015]

[Table 80]

[1016]

[Table 81]

[1017]

[Table 82]

[1018]

[Table 83]

[1019]

[Table 84]

[1020]

[Table 85]

[1021]

[Table 86]

[1022]

[Table 87]

[1023]

[Table 88]

[1024]

[Table 89]

[1025]

[Table 90]

[1026] ¹ H-N of each compound shown in Tables 79 to 90
The MR spectra (NMR (1) to NMR (29)) are as follows.

[1027] NMR (1) (DMSO-d 6) δpp
m: 0.92 (3H, t, J = 7.4 Hz), 1.58
-1.69 (2H, m), 2.69 (2H, t, J =
7.4 Hz), 5.12 (2H, s), 6.65 (1
H, d, J = 15.4 Hz), 7.03 (1H, d, J)
= 8.6 Hz), 7.31 (1H, t, J = 7.6H)
z), 7.44 (1H, t, J = 7.7 Hz), 7.7
6 (1H, d, J = 7.7 Hz), 7.87-7.99
(4H, m).

[1028] NMR (2) (DMSO-d 6) δpp
m: 1.25 (6H, d, J = 7 Hz), 3.40 (1
H, sept, J = 7 Hz), 5.12 (2H, s),
6.64 (1H, d, J = 15.5 Hz), 7.03
(1H, d, J = 8.5 Hz), 7.25-7.5 (2
H, m), 7.77 (1H, d, J = 7.5 Hz),
7.85-8.05 (4H, m), 12.70 (1H,
br), 13.10 (1H, br).

[1029] NMR (3) (DMSO-d 6) δpp
m: 5.07 (2H, s), 6.65 (1H, d, J =
15.5 Hz), 7.15 (2H, d, J = 9 Hz),
7.15-7.5 (2H, m), 7.76 (1H, d,
J = 7 Hz), 7.89 (1H, d, J = 15.5H)
z), 7.99 (1H, d, J = 7 Hz), 8.05
(2H, d, J = 9 Hz), 12.70 (1H, b
r), 13.04 (1H, br).

[1030] NMR (4) (DMSO-d 6) δpp
m: 0.89 (3H, t, J = 6.4 Hz), 1.21
−1.50 (4H, m), 1.53-1.79 (2H,
m), 2.69 (2H, t, J = 8.0 Hz), 5.1
4 (2H, s), 6.64 (1H, d, J = 15.5H)
z), 7.04 (1H, d, J = 8.5 Hz), 7.3
0-7.38 (1H, m), 7.43-7.51 (1
H, m), 7.78-7.82 (1H, d, J = 7.9)
Hz), 7.85-8.10 (4H, m).

[1031] NMR (5) (DMSO-d 6) δpp
m: 5.22 (2H, s), 6.67 (1H, d, J =
15.5 Hz), 7.24-7.49 (3H, m),
7.77 (1H, d, J = 7.6 Hz), 7.89 (1
H, d, J = 15.5 Hz), 7.96-8.12 (3
H, m), 12.83 (1H, br).

[1032] NMR (6) (DMSO-d 6) δpp
m: 1.6-1.9 (4H, m), 2.65-3.0
(4H, m), 5.06 (2H, s), 6.45 (1
H, d, J = 16 Hz), 6.82 (1H, d, J =
8.5 Hz), 7.25-7.65 (4H, m), 7.
75 (1H, d, J = 8 Hz), 7.97 (1H, d,
J = 8 Hz), 12.85 (1H, br).

The NMR (7) (DMSO-d ₆ ) δpp
m: 2.22 (3H, s), 2.31 (3H, s),
5.05 (2H, s), 6.44 (1H, d, J = 1)
5.5 Hz), 6.85 (1H, d, J = 8.5H)
z), 7.25-7.6 (4H, m), 7.76 (1
H, d, J = 8 Hz), 7.98 (1H, d, J = 8H)
z), 12.83 (1H, br).

[1034] NMR (8) (DMSO-d 6) δpp
m: 2.36 (6H, s), 4.75 (2H, s),
6.67 (1H, d, J = 15.5 Hz), 7.30−
7.53 (2H, m), 7.77 (1H, d, J = 8.
9Hz), 7.79 (2H, s), 7.91 (1H,
d, J = 15.5 Hz), 8.00 (1H, d, J =
7.00 Hz), 12.09-13.2 (2H, b
r).

[1035] NMR (9) (DMSO-d 6) δpp
m: 2.10 (6H, s), 4.95 (2H, s),
6.22 (1H, d, J = 16 Hz), 6.78 (2
H, s), 7.02 (1H, d, J = 16 Hz), 7.0.
25-7.5 (2H, m), 7.76 (1H, d, J =
8 Hz), 7.98 (1H, d, J = 7.5 Hz), 1
2.9 (2H, br).

[1036] _{NMR (10) (CDCl 3)} δppm:
1.37 (3H, d, J = 7.0 Hz), 4.14 (2
H, q, J = 7.0 Hz), 5.09 (2H, s),
6.65 (1H, d, J = 15.5 Hz), 7.06
(1H, d, J = 8.6 Hz), 7.31 (1H, d,
J = 7.4 Hz), 7.44 (1H, t, J = 7.4H)
z), 7.55 (1H, s), 7.67-7.78 (2
H, m), 7.90 (1H, d, J = 15.5 Hz),
7.98 (1H, d, J = 7.4 Hz), 12.74
(2H, br).

[1037] NMR (11) (DMSO-d 6) δpp
m: 2.45 (3H, s), 5.03 (2H, s),
6.45 (1H, d, J = 15.6 Hz), 6.90 −
7.06 (2H, m), 7.28-7.35 (1H,
m), 7.41-7.48 (1H, m), 7.56 (1
H, d, J = 15.6 Hz), 7.75 (2H, t, J)
= 7.4 Hz), 7.97-8.00 (1H, m), 1
2.80 (2H, brs).

[1038] NMR (12) (DMSO-d 6) δpp
m: 1.13 (3H, t, J = 7.4 Hz), 2.80
(2H, q, J = 7.4 Hz), 5.03 (2H,
s), 6.47 (1H, d, J = 15.6 Hz), 6.
94 (1H, dd, J = 2.5 Hz, J = 8.6H
z), 7.01 (1H, d, J = 2.5 Hz), 7.2
7-7.50 (2H, m), 7.53 (1H, t, J =
15.6 Hz), 7.68-7.81 (2H, m),
7.92-8.03 (1H, m), 12.86 (2H,
br).

[1039] NMR (14) (DMSO-d 6) δpp
m: 0.82 (3H, t, J = 7.2 Hz), 1.17
-1.40 (2H, m), 1.40-1.61 (2H,
m), 2.72-2.90 (2H, m), 5.06 (2
H, s), 6.46 (1H, d, J = 15.7 Hz),
6.91-7.07 (2H, m), 7.30-7.41
(1H, m), 7.41-7.54 (1H, m), 7.
51 (1H, d, J = 15.7 Hz), 7.74-7.
82 (2H, m), 8.00-8.04 (1H, m).

NMR (15) (DMSO-d ₆ ) δpp
m: 5.08 (2H, s), 6.50 (1H, d, J =
15.7 Hz), 7.13 (1H, dd, J = 2.5H)
z, J = 8.7 Hz), 7.27-7.49 (4H,
m), 7.71 (1H, d, J = 8.7 Hz), 7.7
6 (1H, d, J = 7.0 Hz), 7.99 (1H,
d, J = 7.0 Hz), 12.85 (1H, br).

NMR (16) (DMSO-d ₆ ) δpp
m: 5.09 (2H, s), 6.61 (1H, d, J =
15.6 Hz), 6.98-7.13 (2H, m),
7.30 (1H, t, J = 7.1 Hz), 7.44 (1
H, t, J = 7.1 Hz), 7.63 (1H, dd, J)
= 3.4 Hz, J = 15.6 Hz), 7.74-7.9
0 (2H, m), 7.97 (1H, d, J = 7.1H)
z), 12.88 (1H, br).

[1042] NMR (17) (DMSO-d 6) δpp
m: 3.89 (3H, s), 5.06 (2H, s),
6.51 (1H, d, J = 15.5 Hz), 6.71
(1H, dd, J = 2.2 Hz, J = 8.7 Hz),
6.82 (1H, d, J = 2.2 Hz), 7.25 −
7.50 (2H, m), 7.66 (1H, d, J = 8.
7 Hz), 7.70 (1H, d, J = 15.5 Hz),
7.74-7.81 (1H, m), 7.94-8.03
(1H, m), 12.80 (2H, br).

NMR (18) (DMSO-d ₆ ) δpp
m: 1.34 (3H, t, J = 6.9 Hz), 4.15
(2H, q, J = 6.9 Hz), 5.05 (2H,
s), 6.45 (1H, d, J = 15.5 Hz), 6.
68 (1H, dd, J = 2.0 Hz, J = 8.7H
z), 6.77 (1H, d, J = 2.0 Hz), 7.2
6-7.50 (2H, m), 7.66 (1H, d, J =
8.7 Hz), 7.72-7.81 (1H, m), 7.
79 (1H, d, J = 15.5 Hz), 7.91-8.
05 (1H, m), 12.77 (2H, br).

NMR (19) (DMSO-d ₆ ) δpp
m: 3.89 (3H, s), 5.09 (2H, s),
6.67 (1H, d, J = 15.5 Hz), 7.08
(1H, d, J = 8.5 Hz), 7.25-7.55
(2H, m), 7.57 (1H, m), 7.7-8.1
(4H, m), 11.68 (1H, br).

[1045] NMR (20) (DMSO-d 6) δpp
m: 1.29 (6H, d, J = 6.0 Hz), 4.82
(1H, sept, J = 6.0 Hz), 5.05 (2
H, s), 6.43 (1H, d, J = 15.5 Hz),
6.89 (1H, dd, J = 2.3 Hz, J = 8.7H
z), 6.78 (1H, d, J = 2.3 Hz), 7.3
1 (1H, t, J = 7.0 Hz), 7.45 (1H,
t, J = 7.0 Hz), 7.66 (1H, d, J = 8.
7 Hz), 7.78 (1H, d, J = 15.5 Hz),
7.80 (1H, d, J = 7.0 Hz), 7.99 (1
H, d, J = 7.0 Hz), 12.76 (1H, b
r).

[1046] NMR (21) (DMSO-d 6) δpp
m: 4.92 (2H, q, J = 8.7 Hz), 5.07
(2H, s), 6.48 (1H, d, J = 15.5H)
z), 6.81 (1H, dd, J = 2.3 Hz, J =
8.8 Hz), 6.93 (1H, d, J = 2.3H)
z), 7.32 (1H, t, J = 7.0 Hz), 7.4
5 (1H, t, J = 7.0 Hz), 7.62-7.79
(3H, m), 7.99 (1H, d, J = 7.0H)
z), 12.78 (1H, br).

[1047] NMR (22) (DMSO-d 6) δpp
m: 5.28 (2H, s), 6.69 (1H, d, J =
15.5 Hz), 7.25-7.55 (3H, m),
7.77 (1H, d, J = 8 Hz), 7.92 (1H, d, J = 8 Hz)
d, J = 15.5 Hz), 7.98 (1H, d, J =
7.5 Hz), 8.15-8.45 (2H, m), 1
2.88 (1H, br).

[1048] NMR (23) (DMSO-d 6) δpp
m: 1.03 (3H, t, J = 7 Hz), 1.18 (3
H, t, J = 7 Hz), 3.1-3.5 (4H, m),
4.96 (2H, s), 5.10 (2H, s), 6.6
3 (1H, d, J = 15.5 Hz), 7.10 (1H, d, J = 15.5 Hz)
d, J = 8.5 Hz), 7.25-7.55 (3H,
m), 7.7-7.85 (2H, m), 7.86 (1
H, d, J = 15.5 Hz), 7.98 (1H, d, J)
= 7.5 Hz), 12.66 (1H, br).

[1049] NMR (24) (DMSO-d 6) δpp
m: 3.90 (3H, s), 5.18 (2H, s),
6.67 (1H, d, J = 15.5 Hz), 7.28-
7.36 (2H, m), 7.46 (1H, t, J = 7.
6Hz), 7.78 (1H, d, J = 7.6Hz),
7.89 (1H, d, J = 15.5 Hz), 7.99
(1H, t, J = 7.6 Hz), 8.25 (1H, d
d, J = 2.3 Hz, J = 8.9 Hz), 8.38 (1
H, d, J = 2.3 Hz).

[1050] NMR (25) (DMSO-d 6) δpp
m: 2.48 (2H, t, J = 7.5 Hz), 3.12
(2H, t, J = 7.5 Hz), 5.04 (2H, t, J = 7.5 Hz)
s), 6.52 (1H, d, J = 15.7 Hz), 7.
13 (1H, d, J = 8.7 Hz), 7.34 (1H,
t, J = 7.2 Hz), 7.42-7.63 (3H,
m), 7.80 (1H, d, J = 7.6 Hz), 8.0
2 (1H, d, J = 7.2 Hz), 10.33 (1H,
br), 12.98 (1H, br).

[1051] NMR (26) (DMSO-d 6) δpp
m: 2.71 (2H, t, J = 7.6 Hz), 2.98
(2H, t, J = 7.6 Hz), 3.59 (3H,
s), 5.13 (2H, s), 6.60-6.75 (1
H, m), 7.04-7.08 (1H, m), 7.27
−7.38 (1H, m), 7.38−7.51 (1H,
m), 7.55-7.78 (1H, m), 7.84-
7.99 (4H, m), 9.40 (2H, brs).

[1052] NMR (27) (DMSO-d 6 + CDC
l ₃ ) δ ppm: 2.66 (2H, t, J = 8.8H)
z), 2.84 (3H, s), 2.89-3.06 (5
H, m), 5.01 (2H, s), 6.57-6.75.
(1H, m), 6.90-7.10 (1H, m), 7.
18-7.30 (1H, m), 7.30-7.41 (1
H, m), 7.63-7.72 (1H, m), 7.72
-7.90 (3H, m), 7.96 (1H, s), 1
1.50-13.00 (2H, brs).

[1053] NMR (28) (DMSO-d 6) δpp
m: 1.00 (3H, t, J = 7.0 Hz), 1.07
(3H, t, J = 7.0 Hz), 2.68 (2H, t,
J = 7.4 Hz), 3.01 (2H, t, J = 7.4H)
z), 3.15-3.46 (4H, m), 5.06 (2
H, s), 6.78 (2H, d, J = 15.4 Hz),
6.95-6.99 (1H, m), 7.25-7.30
(1H, m), 7.38-7.43 (1H, m), 7.
72-7.85 (5H, m).

NMR (29) (DMSO-d ₆ ) δpp
m: 1.12 (3H, t, J = 7.1 Hz), 2.69
(2H, t, J = 7.8 Hz), 2.98 (2H, t,
J = 7.8 Hz), 4.00 (2H, q, J = 7.1H)
z), 5.13 (2H, s), 6.61 (1H, d, J
= 15.4 Hz), 7.04 (1H, d, J = 8.8H)
z), 7.30-7.40 (1H, m), 7.55 (1
H, m), 7.75 (1H, d, J = 7.3 Hz),
7.86 (1H, d, J = 15.4 Hz), 7.91-
8.10 (3H, m), 12.40-13.30 (2
H, m).

Using the appropriate starting materials, compounds shown in the following Tables 91 to 166 were obtained in the same manner as in Example 3 or 4.

[1056]

[Table 91]

[1057]

[Table 92]

[1058]

[Table 93]

[1059]

[Table 94]

[1060]

[Table 95]

[1061]

[Table 96]

[1062]

[Table 97]

[1063]

[Table 98]

[1064]

[Table 99]

[1065]

[Table 100]

[1066]

[Table 101]

[1067]

[Table 102]

[1068]

[Table 103]

[1069]

[Table 104]

[1070]

[Table 105]

[1071]

[Table 106]

[1072]

[Table 107]

[1073]

[Table 108]

[1074]

[Table 109]

[1075]

[Table 110]

[1076]

[Table 111]

[1077]

[Table 112]

[1078]

[Table 113]

[1079]

[Table 114]

[1080]

[Table 115]

[1081]

[Table 116]

[1082]

[Table 117]

[1083]

[Table 118]

[1084]

[Table 119]

[1085]

[Table 120]

[1086]

[Table 121]

[1087]

[Table 122]

[1088]

[Table 123]

[1089]

[Table 124]

[1090]

[Table 125]

[1091]

[Table 126]

[1092]

[Table 127]

[1093]

[Table 128]

[1094]

[Table 129]

[1095]

[Table 130]

[1096]

[Table 131]

[1097]

[Table 132]

[1098]

[Table 133]

[1099]

[Table 134]

[1100]

[Table 135]

[1101]

[Table 136]

[1102]

[Table 137]

[1103]

[Table 138]

[1104]

[Table 139]

[1105]

[Table 140]

[1106]

[Table 141]

[1107]

[Table 142]

[1108]

[Table 143]

[1109]

[Table 144]

[1110]

[Table 145]

[1111]

[Table 146]

[1112]

[Table 147]

[1113]

[Table 148]

[1114]

[Table 149]

[1115]

[Table 150]

[1116]

[Table 151]

[1117]

[Table 152]

[1118]

[Table 153]

[1119]

[Table 154]

[1120]

[Table 155]

[1121]

[Table 156]

[1122]

[Table 157]

[1123]

[Table 158]

[1124]

[Table 159]

[1125]

[Table 160]

[1126]

[Table 161]

[1127]

[Table 162]

[1128]

[Table 163]

[1129]

[Table 164]

[1130]

[Table 165]

[1131]

[Table 166]

[1132] Compounds shown in the following Tables 167 to 169 were obtained in the same manner as in Example 5 using appropriate starting materials.

[1133]

[Table 167]

[1134]

[Table 168]

[1135]

[Table 169]

Using the appropriate starting materials, compounds shown in the following Tables 170 to 190 were obtained in the same manner as in Example 8.

[1137]

[Table 170]

[1138]

[Table 171]

[1139]

[Table 172]

[1140]

[Table 173]

[1141]

[Table 174]

[1142]

[Table 175]

[1143]

[Table 176]

[1144]

[Table 177]

[1145]

[Table 178]

[1146]

[Table 179]

[1147]

[Table 180]

[1148]

[Table 181]

[1149]

[Table 182]

[1150]

[Table 183]

[1151]

[Table 184]

[1152]

[Table 185]

[1153]

[Table 186]

[1154]

[Table 187]

[1155]

[Table 188]

[1156]

[Table 189]

[1157]

[Table 190]

[1158] Each compound shown in Table 91 to Table 190 ¹ H-
The NMR spectra (NMR (1) to NMR (55)) are as follows.

[1158] NMR (1) (CDCl ₃ ) δ ppm:
2.33 (3H, s), 2.45 (4H, t, J = 5H
z), 3.6-3.8 (4H, m), 4.85 (2H,
s), 7.09 (2H, d, J = 9 Hz), 7.3-
7.55 (2H, m), 7.50 (1H, d, J = 15
Hz), 7.8-7.95 (2H, m), 7.93 (1
H, d, J = 15 Hz), 8.10 (2H, d, J = 9)
Hz), 9.88 (1H, br).

[1160] NMR (2) (DMSO-d ₆ ) δpp
m: 1.35-1.8 (2H, m), 2.0-2.3
(2H, m), 2.6-3.9 (11H, m), 2.8
1 (3H, s), 4.1-4.3 (1H, m), 4.5
-4.7 (1H, m), 5.08 (2H, s), 7.1
5 (2H, d, J = 9 Hz), 7.3-7.55 (3
H, m), 7.76 (1H, d, J = 14 Hz), 7.
77 (1H, d, J = 8.5 Hz), 7.98 (1H,
d, J = 8 Hz), 8.05 (2H, d, J = 9H)
z), 12.67 (1H, br).

NMR (3) (DMSO-d ₆ ) δpp
m: 2.32 (3H, s), 2.45-4.50 (20
H, m, 2.50 (s)), 5.14 (2H, s),
7.04 (1H, d, J = 9.3 Hz), 7.26-
7.52 (3H, m), 7.70-8.10 (5H,
m), 11.30-12.35, 12.35-13.2.
0 (all 3H, br).

NMR (4) (DMSO-d ₆ ) δpp
m: 2.60-4.50 (20H, m), 5.23 (2
H, s), 7.20-7.55 (4H, m), 7.70.
−8.10 (5H, m), 11.30-13.20 (3
H, br).

NMR (5) (DMSO-d ₆ ) δpp
m: 0.926 (3H, t, J = 7.4 Hz), 1.5
-1.9 (4H, m), 2.05-2.3 (2H,
m), 2.6-2.8 (3H, m), 2.81 (3H,
s), 3.0-3.3 (1H, m), 3.3-3.9.
(9H, m), 4.15-4.35 (1H, m), 4.
5-4.8 (1H, m), 5.12 (2H, s), 7.
02 (1H, d, J = 8.6 Hz), 7.27-7.4
7 (3H, m), 7.74-7.99 (4H, m),
7.91 (1H, d, J = 15 Hz), 11.5-1
3.0 (3H, br).

NMR (6) (DMSO-d ₆ ) δpp
m: 0.93 (3H, t, J = 7.4 Hz), 1.5
5-1.75 (2H, m), 2.6-2.8 (4H,
m), 2.79 (3H, s), 3.0-4.15 (14
H, m), 4.2-4.4 (1H, m), 5.12 (2
H, s), 7.03 (1H, d, J = 8.5 Hz),
7.25-7.55 (2H, m), 7.45 (1H,
s), 7.75-7.9 (4H, m), 7.79 (1
H, d, J = 8.5 Hz).

NMR (7) (DMSO-d ₆ ) δpp
m: 1.25 (6H, d, J = 7 Hz), 1.3-2.
0 (4H, m), 2.6-3.5 (6H, m), 5.1
2 (2H, s), 6.77 (1H, dd, J = 6 Hz,
J = 15.5 Hz), 7.00 (1H, d, J = 8.5)
Hz), 7.17 (1H, d, J = 15.5 Hz),
7.25-7.5 (2H, m), 7.7-8.05 (4
H, m), 9.14 (2H, br), 12.73 (1
H, br).

NMR (8) (CDCl ₃ ) δ ppm:
1.62 (3H, t, J = 7.3 Hz), 1.76 −
2.03 (4H, m), 2.85-3.09 (2H,
m), 3.95-4.11 (2H, m), 4.52 (2
H, q, J = 7.3 Hz), 4.88 (2H, s),
5.28 (1H, brs), 6.98 (1H, d, J =
7.5 Hz), 7.32-7.43 (1H, m), 7.
43-7.55 (1H, m), 7.56 (1H, d, J
= 15.2 Hz), 7.77-7.93 (2H, m),
8.00-8.12 (2H, m), 8.35 (1H,
d, J = 15.2 Hz), 10.85 (1H, br)
s).

NMR (9) (DMSO-d ₆ ) δpp
m: 0.93 (3H, t, J = 7.4 Hz), 1.5-
1.8 (2H, m), 1.8-2.2 (4H, m),
2.69 (2H, t, J = 7.4 Hz), 2.8 (3
H, s), 3.0-4.3 (12H, m), 4.3-
4.6 (1H, m), 5.13 (2H, s), 7.03
(1H, d, J = 8.6 Hz), 7.17 (1H, d,
J = 15.1 Hz), 7.30 (1H, t, J = 7H)
z), 7.74-7.99 (5H, m), 11.5-1
2.3 (1H, br), 12.3-13.3 (1H, b
r).

NMR (10) (DMSO-d ₆ ) δpp
m: 1.56-1.91 (4H, m), 2.70-2.
90 (7H, m), 3.10-3.52 (8H, m),
5.14 (2H, s), 6.65-6.75 (1H,
m), 6.99-7.15 (2H, m), 7.28-
7.40 (1H, m), 7.40-7.52 (1H,
m), 7.52-7.60 (2H, m), 7.72-
7.85 (1H, m), 7.90-8.08 (4H,
m), 10.90-13.18 (3H, m).

NMR (11) (DMSO-d ₆ ) δpp
m: 1.40-1.89 (2H, m), 1.96-2.
32 (2H, m), 2.58-2.96 (4H, m),
2.96-3.83 (10H, m), 3.89 (3H,
s), 4.06-4.34 (1H, m), 4.42-
4.71 (1H, m), 5.08 (2H, s), 7.0
7 (1H, d, J = 8.5 Hz), 7.31 (1H,
t, J = 7.0 Hz), 7.38-7.69 (3H,
m), 7.69-7.92 (3H, m), 7.98 (1
H, d, J = 8.5 Hz), 11.76 (2H, b
r), 12.71 (1H, br). NMR (12) (D
_{MSO-d 6) δppm: 1.40-1.85} (2H,
m), 2.00-2.23 (2H, m), 2.40 (3
H, s), 2.60-2.88 (1H, m), 2.81
(3H, s), 3.00-3.80 (10H, m),
3.89 (3H, s), 4.10-4.30 (1H,
m), 4.48-4.78 (1H, m), 5.06 (2
H, s), 7.04 (1H, d, J = 8.5 Hz),
7.21-7.31 (1H, m), 7.40 (1H,
d, J = 15.2 Hz), 7.52-7.60 (1H,
m), 7.60-7.88 (4H, m), 11.02-
12.33 (2H, m), 12.33-12.80 (1
H, m).

[1170] NMR (13) (DMSO-d ₆ ) δpp
m: 2.40 (3H, s), 2.81 (3H, s),
2.90-4.35 (15H, m), 3.89 (3H,
s), 5.07 (2H, s), 6.99-7.12 (1
H, m), 7.12-7.35 (2H, m), 7.52.
−7.60 (1H, m), 7.60−7.91 (4H,
m), 11.00-13.28 (3H, m).

NMR (14) (CDCl ₃ ) δ ppm:
1.31-1.64 (2H, m), 1.77-2.07
(2H, m), 2.21-2.87 (10H, m),
2.29 (3H, s), 2.67 (3H, s), 3.0
6-3.26 (1H, m), 3.96-4.28 (1
H, m), 4.10 (3H, s), 4.62-4.78.
(1H, m), 4.87 (2H, s), 7.07 (1
H, d, J = 8.1 Hz), 7.14-7.32 (2
H, m), 7.52 (1H, d, J = 14.9 Hz),
7.61-7.77 (3H, m), 7.91 (1H,
d, J = 14.9 Hz).

NMR (15) (CDCl ₃ ) δ ppm:
1.20-2.16 (4H, m), 2.31-2.72
(3H, m), 2.44 (3H, s), 2.72-3.
34 (2H, m), 4.85 (2H, s), 6.76-
7.06 (3H, m), 7.21-7.58 (2H,
m), 7.72-8.00 (4H, m).

NMR (16) (CDCl ₃ ) δ ppm:
1.43-2.13 (4H, m), 2.28 (6H,
s), 2.45 (3H, s), 2.53-3.28 (5
H, m), 3.56-4.56 (2H, m), 4.86
(2H, s), 6.80-7.11 (3H, m), 7.
28-7.53 (2H, m), 7.74-7.93 (4
H, m).

[1174] NMR (17) (CDCl ₃ ) δ ppm:
1.3-1.5 (2H, m), 1.7-1.9 (2H,
m), 2.6-2.8 (2H, m), 2.8-3.3.
(2H, m), 3.90 (3H, s), 4.80 (2
H, s), 6.5-6.65 (2H, m), 6.73.
(1H, d, J = 15.5 Hz), 6.87 (1H, d
d, J = 15.5 Hz, J = 6 Hz), 7.3-7.5
5 (2H, m), 7.6-7.95 (4H, m).

[1176] NMR (18) (CDCl ₃ ) δ ppm:
1.12 (3H, t, J = 5.9 Hz), 1.28−
3.78 (11H, m), 4.97 (1H, t, J =
5.3 Hz), 6.68-7.53 (5H, m), 7.
70-8.14 (4H, m).

[1176] NMR (19) (DMSO-d 6) δpp
m: 1.29-2.11 (4H, m), 2.32 (3
H, s), 2.60-3.08 (3H, m), 3.08
-3.56 (3H, m), 3.91 (6H, s), 4.
85 (2H, s), 6.73-6.93 (1H, m),
7.19-7.54 (5H, m), 7.71-7.83
(1H, m), 7.93-8.05 (1H, m), 8.
29-8.80 (1H, m), 12.14 (1H, br)
s).

[1177] NMR (20) (CDCl ₃ ) δ ppm:
1.86-2.13 (2H, m), 2.39 (3H,
s), 2.48-3.06 (12H, m), 3.82.
(3H, s), 4.87 (2H, s), 6.82-8.
09 (9H, m), 7.04 (1H, s), 7.21
(1H, s).

[1178] NMR (21) (DMSO-d ₆ ) δpp
m: 1.4-2.2 (6H, m), 2.35 (3H,
s), 2.65-2.85 (2H, m), 2.95-
4.05 (14H, m), 5.07 (2H, s), 6.
78 (1H, dd, J = 7 Hz, J = 15.5 Hz),
7.02 (1H, d, J = 8.5 Hz), 7.16 (1
H, d, J = 15.5 Hz), 7.26 (1H, d, J)
= 3.5 Hz), 7.50 (1H, d, J = 3.5H)
z), 7.8-8.0 (2H, m), 9.58 (1H,
br), 12.45 (1H, br).

[1179] NMR (22) (DMSO-d ₆ ) δpp
m: 1.33-1.71 (5H, m), 1.80-2.
00 (1H, m), 2.00-2.21 (2H, m),
2.65-2.77 (2H, m), 2.80 (3H,
s), 2.88-3.10 (4H, m), 3.10-
4.00 (14H, m), 4.00-4.23 (1H,
m), 4.47-4.66 (1H, m), 5.13 (2
H, s), 6.71-6.87 (1H, m), 6.98.
−7.09 (1H, m), 7.09−7.22 (1H,
m), 7.26-7.40 (1H, m), 7.40-
7.52 (1H, m), 7.72-7.83 (1H,
m), 7.83-7.97 (2H, m), 7.97-
8.08 (1H, m), 11.32-12.55 (2
H, m), 12.70 (1H, brs).

[1180] NMR (23) (CDCl ₃ ) δ ppm:
1.43-2.28 (12H, m), 2.28-3.0
1 (13H, m), 3.23-3.56 (2H, m),
3.56-4.09 (5H, m), 4.87 (2H,
s), 6.74-7.02 (3H, m), 7.22-
7.53 (2H, m), 7.70-7.97 (4H,
m).

NMR (24) (CDCl ₃ ) δ ppm:
1.43-2.18 (12H, m), 2.37-2.6
8 (8H, m), 2.86 (2H, t, J = 7.7H)
z), 2.97-3.16 (2H, m), 3.25-
3.53 (2H, m), 3.56-3.80 (4H,
m), 3.82-4.03 (2H, m), 4.85 (2
H, s), 6.79-7.00 (3H, m), 7.22.
-7.53 (2H, m), 7.68-7.93 (4H,
m).

[1182] _{NMR (25) (CDCl 3)} δppm:
1.48-3.22 (19H, m), 1.62 (3H,
t, J = 7.4 Hz), 3.57-3.78 (4H,
m), 4.54 (2H, q, J = 7.4 Hz), 4.8
9 (2H, s), 6.99 (1H, d, J = 8.5H)
z), 7.22-7.53 (3H, m), 7.59 (1
H, d, J = 15.2 Hz), 7.76-7.90 (2
H, m), 7.92-8.09 (1H, m), 8.36.
(1H, d, J = 15.2 Hz).

[1183] NMR (26) (DMSO-d 6) δpp
m: 2.65-2.8 (1H, m), 2.9-3.05
(1H, m), 3.3-3.45 (2H, m), 3.8
(1H, m), 4.65 (2H, br), 5.11 (2
H, s), 7.06 (1H, d, J = 8.5 Hz),
7.25-7.5 (2H, m), 7.64 (1H, d,
J = 15.5 Hz), 7.75-7.9 (3H, m),
7.95-8.2 (4H, m), 8.66 (2H, b
r) 12.58 (1H, br).

[1184] NMR (27) (CDCl ₃ ) δ ppm:
1.36 (3H, t, J = 7.5 Hz), 2.6-3.
6 (6H, m), 2.86 (2H, q, J = 7.5H
z), 4.05 (1H, m), 4.50 (1H, m),
4.87 (2H, s), 6.93 (1H, d, J = 8H)
z), 7.3-7.55 (3H, m), 7.8-8.0
(5H, m), 9.66 (1H, br).

[1185] NMR (28) (DMSO-d ₆ ) δpp
m: 1.67-1.97 (2H, m), 2.80 (3
H, s), 2.88-4.35 (17H, m), 3.9.
0 (3H, s), 5.10 (2H, s), 7.08 (1
H, d, J = 8.6 Hz), 7.20-7.66 (4
H, m), 7.66-7.95 (3H, m), 7.99
(1H, d, J = 7.1 Hz), 12.70 (1H,
s).

[1186] NMR (29) (DMSO-d ₆ ) δpp
m: 2.05-2.35 (2H, m), 2.55-4.
18 (22H, m), 4.18-4.42 (1H,
m), 5.09 (2H, s), 7.07 (1H, d, J
= 8.6 Hz), 7.27-7.57 (4H, m),
7.74-7.77 (3H, m), 7.98 (1H,
d, J = 7.1 Hz), 11.52 (2H, br), 1
2.55 (1H, br).

NMR (30) (CDCl ₃ ) δ ppm:
1.1-1.4 (3H, m), 1.37 (3H, t, J
= 7.5 Hz), 2.5-2.8 (2H, m), 2.8
6 (2H, q, J = 7.5 Hz), 2.9-3.1 (1
H, m), 3.2-3.6 (2H, m), 3.8-4.
1 (1H, m), 4.5-4.8 (1H, m), 4.8
7 (2H, s), 5.35 (1H, br), 6.93
(1H, d, J = 9 Hz), 7.25-7.6 (3H,
m), 7.75-8.05 (5H, m), 9.60 (1
H, br).

[1188] NMR (31) (DMSO-d ₆ ) δpp
m: 0.74-0.91 (3H, m), 1.12-1.
44 (6H, m), 1.50-1.71 (2H, m),
2.55-2.90 (3H, m), 2.79 (3H,
s), 2.90-3.80 (13H, m), 3.80-
4.12 (4H, m), 4.19-4.42 (1H,
m), 5.11 (2H, s), 7.01 (1H, d, J
= 8.7 Hz), 7.27-7.51 (3H, m),
7.71-8.02 (5H, m), 11.00-13.
00 (3H, m).

[1189] NMR (32) (DMSO-d ₆ ) δpp
m: 1.45-1.89 (2H, m), 2.00-2.
38 (6H, m), 2.55-2.86 (6H, m),
3.01-3.22 (1H, m), 3.22-3.94
(9H, m), 3.77 (3H, s), 3.99-4.
50 (3H, m), 4.50-4.70 (1H, m),
7.07-7.20 (1H, m), 7.20-7.37
(1H, m), 7.37-7.54 (3H, m), 7.
67-7.89 (3H, m), 7.89-8.03 (1
H, m), 11.06-12.62 (3H, m).

NMR (33) (DMSO-d ₆ ) δpp
m: 1.40-1.92 (2H, m), 1.92-2.
30 (4H, m), 2.31 (3H, s), 2.55-
2.90 (4H, m), 2.90-4.03 (10H,
m), 4.03-4.34 (1H, m), 4.44-
4.73 (1H, m), 5.11 (2H, s), 7.2
3 (1H, d, J = 9.3 Hz), 7.31 (1H,
t, J = 6.9 Hz), 7.32-7.48 (2H,
m), 7.74-7.86 (2H, m), 7.86-
8.05 (3H, m), 10.88-12.00 (2
H, m), 12.70 (1H, br).

[1191] NMR (34) (DMSO-d ₆ ) δpp
m: 1.48-1.94 (2H, m), 2.00-2.
39 (4H, m), 2.57-2.85 (4H, m),
2.85-4.03 (10H, m), 4.10-4.3
9 (1H, m), 4.48-4.71 (1H, m),
5.29 (2H, s), 7.21-7.57 (4H,
m), 7.75-7.83 (2H, m), 7.98 (1
H, d, J = 7.4 Hz), 8.23 (1H, s),
8.32 (1H, d, J = 8.7 Hz), 10.89-
12.06 (2H, m), 12.76 (1H, br).

[1192] NMR (35) (DMSO-d ₆ ) δpp
m: 2.88-3.28 (4H, m), 3.73-4.
31 (4H, m), 5.30 (2H, s), 7.31
(1H, t, J = 6.9 Hz), 7.35-7.48
(3H, m), 7.75-7.85 (2H, m), 7.
97 (1H, d, J = 7.1 Hz), 8.23 (1H,
s), 8.33 (1H, d, J = 8.7 Hz), 9.3
7 (2H, br), 12.78 (1H, br).

[1193] NMR (36) (DMSO-d ₆ ) δpp
m: 1.2-1.5 (2H, m), 1.6-1.85
(8H, m), 2.31 (3H, s), 2.5-3.1
5 (15H, m), 3.9-4.0 (1H, m), 4.
4-4.5 (1H, m), 5.04 (2H, s), 6.
81 (1H, d, J = 8.5 Hz), 7.20 (1H, d, J = 8.5 Hz)
d, J = 15.5 Hz), 7.25-7.5 (3H,
m), 7.55 (1H, d, J = 8.5 Hz), 7.7
5 (1H, d, J = 7.5 Hz), 7.97 (1H,
d, J = 7 Hz).

[1194] NMR (37) (DMSO-d ₆ ) δpp
m: 1.4-1.9 (2H, m), 2.12 (6H,
s), 2.0-4.0 (19H, m), 4.45-4.
6 (1H, m), 4.95 (2H, s), 6.77 (2
H, s), 6.88 (1H, d, J = 16 Hz), 7.
03 (1H, d, J = 16 Hz), 7.35-7.5
(2H, m), 7.76 (1H, d, J = 7.5H
z), 7.99 (1H, d, J = 8 Hz), 11.2
4, 12.04 (all 1H, br), 11.74 (1H,
br), 12.64 (1H, br).

[1195] NMR (38) (DMSO-d 6) δpp
m: 2.54-2.93 (5H, m), 2.93-3.
78 (10H, m), 3.78-4.17 (7H,
m), 4.17-4.44 (1H, m), 5.07 (2
H, s), 6.65-6.78 (1H, m), 6.78.
−6.90 (1H, m), 7.18-7.71 (5H,
m), 7.76 (1H, d, J = 7.5 Hz), 7.9
8 (1H, d, J = 7.1 Hz), 11.28 (2H,
br), 12.68 (1H, br).

[1196] NMR (39) (DMSO-d 6) δpp
m: 2.22 (3H, s), 2.33 (3H, s),
2.36 (3H, s), 2.80 (3H, d, J = 4H)
z), 2.9-3.6 (6H, m), 4.15-4.3
(1H, m), 4.4-4.55 (1H, m), 5.0
6 (2H, s), 6.85 (1H, d, J = 9 Hz),
7.24 (1H, d, J = 15.5 Hz), 7.37
(1H, d, J = 15.5 Hz), 7.25-7.55
(3H, m), 7.76 (1H, d, J = 7 Hz),
7.98 (1H, d, J = 7 Hz), 9.76 (1H,
br), 12.60 (1H, br).

NMR (40) (DMSO-d ₆ ) δpp
m: 2.05-2.35 (2H, m), 2.54-2.
98 (5H, m), 2.98-3.85 (10H,
m), 3.85-4.19 (7H, m), 4.19-
4.47 (1H, m), 5.07 (2H, s), 6.6
5-6.79 (1H, m), 6.79-6.90 (1
H, m), 7.18-7.71 (5H, m), 7.77.
(1H, d, J = 7.7 Hz), 8.00 (1H, d,
J = 7.8 Hz), 11.22 (2H, br), 12.
68 (1H, br).

NMR (41) (DMSO-d ₆ ) δpp
m: 1.89-2.44 (4H, m), 2.53-3.
78 (16H, m), 3.78-4.13 (6H,
m), 4.13-4.42 (1H, m), 5.07 (2
H, s), 6.70 (1H, dd, J = 2.2 Hz, J
= 8.7 Hz), 6.81 (1H, d, J = 2.2H)
z), 7.19-7.73 (5H, m), 7.76 (1
H, d, J = 7.8 Hz), 7.98 (1H, d, J =
7.0Hz), 10.61 (1H, br), 11.27
(1H, br), 12.71 (1H, br).

NMR (42) (DMSO-d ₆ ) δpp
m: 1.30 (6H, d, J = 5.9 Hz), 2.55
-4.19 (19H, m), 4.19-4.41 (1
H, m), 4.82 (1H, sept, J = 5.9H)
z), 5.07 (2H, s), 6.60-6.71 (1
H, m), 6.76-6.79 (1H, m), 7.22.
−7.49 (3H, m), 7.64 (1H, d, J =
8.7 Hz), 7.71-7.90 (2H, m), 7.
98 (1H, d, J = 7.1 Hz), 11.81 (2
H, br), 12.58 (1H, br).

NMR (43) (DMSO-d ₆ ) δpp
m: 1.35 (3H, d, J = 6 Hz), 1.5-2.
2 (4H, m), 2.5-3.8 (13H, m), 3.
88 (3H, s), 4.1-4.3 (1H, m), 4.
45-4.65 (1H, m), 5.06 (2H, s),
6.70 (1H, d, J = 9 Hz), 6.81 (1H, d, J = 9 Hz)
s), 7.27 (1H, d, J = 15.5 Hz), 7.
25-7.5 (2H, m), 7.56 (1H, d, J =
15.5 Hz), 7.64 (1H, d, J = 8.5H)
z), 7.77 (1H, d, J = 8 Hz), 7.99
(1H, d, J = 8 Hz), 12.5-13 (3H, b
r).

[1201] NMR (44) (DMSO-d 6) δpp
m: 1.30 (3H, d, J = 6.5 Hz), 1.5−
2.3 (4H, m), 2.55-2.8 (1H, m),
3.0-4.7 (13H, m), 3.88 (3H,
s), 5.07 (2H, s), 6.70 (1H, d, J
= 9 Hz), 6.81 (1H, m), 7.27 (1H,
d, J = 15.5 Hz), 7.25-7.5 (2H,
m), 7.56 (1H, d, J = 15.5 Hz), 7.
64 (1H, d, J = 8.5 Hz), 7.77 (1H,
d, J = 8 Hz), 7.98 (1 H, d, J = 7.5 H)
z), 9.85 (1H, br), 10.01 (1H, b
r), 12.25 (1H, br).

[1202] NMR (45) (DMSO-d 6) δpp
m: 2.05-2.20 (2H, m), 2.5-4.0
(18H, m), 3.88 (3H, s), 4.1-4.
25 (1H, m), 4.5-4.65 (1H, m),
5.06 (2H, s), 6.70 (1H, d, J = 8.
5 Hz), 6.81 (1H, m), 7.28 (1H,
d, J = 15 Hz), 7.25-7.5 (2H, m),
7.56 (1H, d, J = 15 Hz), 7.64 (1
H, d, J = 8.5 Hz), 7.77 (1H, d, J =
8 Hz), 7.99 (1H, d, J = 7.5 Hz), 1
0.78 (1H, br), 11.94 (1H, br),
12.66 (1H, br).

[1203] NMR (46) (DMSO-d 6) δpp
m: 1.43-1.85 (2H, m), 1.97-2.
42 (4H, m), 2.58-2.82 (1H, m),
2.82-4.08 (18H, m), 4.08-4.3
0 (1H, m), 4.42-4.72 (1H, m),
5.06 (2H, s), 5.22-5.68 (2H,
m), 6.62-6.78 (1H, m), 6.78-
6.95 (1H, m), 7.24-7.70 (5H,
m), 7.77 (1H, d, J = 6.2 Hz), 7.9
9 (1H, d, J = 5.8 Hz), 10.35 (2H,
br), 11.48 (1H, br).

NMR (47) (DMSO-d ₆ ) δpp
m: 1.3-2.0 (6H, m), 2.37 (6H,
s), 2.8-4.2 (16H, m), 3.88 (3
H, s), 5.07 (2H, s), 6.71 (1H, d
d, J = 7 Hz, J = 2 Hz), 6.81 (1H, d,
J = 2 Hz), 7.25 (1 H, d, J = 15 Hz),
7.25-7.5 (3H, m), 7.65-7.75
(2H, m), 7.77 (1H, d, J = 7 Hz),
7.98 (1H, d, J = 6 Hz), 9.40 (1H, d, J = 6 Hz)
br).

[1205] NMR (48) (DMSO-d 6) δpp
m: 2.4-4.5 (23H, m), 3.88 (3H,
s), 5.09 (2H, s), 6.71 (1H, d, J
= 9 Hz), 6.82 (1H, s), 7.2-7.75
(5H, m), 7.77 (1H, d, J = 8 Hz),
7.98 (1H, d, J = 7 Hz), 10.98 (1
H, br), 11.58 (1H, br), 12.71
(1H, br).

[1206] NMR (49) (DMSO-d ₆ ) δpp
m: 2.16 (3H, s), 2.23 (3H, s),
2.74 (3H, d, J = 4 Hz), 2.85-3.7
(6H, m), 3.86 (3H, s), 4.15-4.
6 (2H, m), 4.95 (2H, s), 6.66 (1
H, d, J = 8.5 Hz), 6.79 (1H, m),
7.27 (1H, d, J = 15 Hz), 7.61 (1
H, d, J = 15 Hz), 7.63 (1H, d, J =
8.5 Hz), 11.42 (1 H, br).

[1207] NMR (50) (DMSO-d ₆ ) δpp
m: 1.39-1.90 (2H, m), 1.98-2.
37 (4H, m), 2.58-2.90 (4H, m),
2.98-3.99 (10H, m), 4.11-4.3
2 (1H, m), 4.48-4.70 (1H, m),
5.09 (2H, s), 6.93-7.15 (2H,
m), 7.20-7.62 (4H, m), 7.80-
7.92 (2H, m), 7.99 (1H, d, J = 7.
3Hz), 10.80-11.95 (2H, m), 1
2.68 (1H, br).

[1208] NMR (51) (DMSO-d ₆ ) δpp
m: 1.67-1.03 (2H, m), 2.80 (3
H, s), 2.99-4.35 (20H, m), 5.0.
7 (2H, s), 6.70 (1H, dd, J = 2.2H)
z, J = 8.7 Hz), 6.82 (1H, d, J = 2.
2Hz), 7.19-7.74 (5H, m), 7.77
(1H, d, J = 7.5 Hz), 7.99 (1H, d,
J = 7.9 Hz), 10.80-12.32 (2H, b
r), 12.69 (1H, br).

[1209] NMR (52) (DMSO-d ₆ ) δpp
m: 2.15 (3H, s), 2.22 (3H, s),
2.83 (3H, s), 2.5-4.4 (17H,
m), 3.86 (3H, s), 4.94 (2H, s),
6.65 (1H, d, J = 8.5 Hz), 6.78 (1
H, s), 7.2-7.7 (3H, m), 12.05
(1H, br).

[1210] NMR (53) (DMSO-d 6) δpp
m: 2.36 (6H, s), 2.55-4.45 (20
H, m), 4.92 (2H, q, J = 8.9 Hz),
5.08 (2H, s), 6.80 (1H, dd, J =
2.3 Hz, J = 8.9 Hz), 6.94 (1H, d,
J = 2.3 Hz), 7.21-7.75 (5H, m),
7.77 (1H, d, J = 8.1 Hz), 7.98 (1
H, d, J = 7.1 Hz), 9.95 (2H, br),
12.63 (1H, br).

[1211] NMR (54) (DMSO-d 6) δpp
m: 1.40 (6H, d, J = 6.0 Hz), 1.51
-1.86 (2H, m), 2.05-2.30 (2H,
m), 2.57-2.73 (1H, m), 2.79 (3
H, s), 2.98-3.87 (8H, m), 3.88.
(3H, s), 4.14-4.25 (1H, m), 4.
40-4.70 (1H, m), 5.06 (2H, s),
6.70 (1H, dd, J = 2.2 Hz, J = 8.8H
z), 6.81 (1H, d, J = 2.2 Hz), 7.2
3-7.66 (5H, m), 7.77 (1H, d, J =
7.6 Hz), 8.00 (1H, d, J = 7.0H)
z), 11.40-13.10 (3H, m).

[1212] NMR (55) (DMSO-d 6) δpp
m: 1.4-2.4 (4H, m), 2.34 (3H,
s), 2.7-5.0 (9H, m), 3.88 (3H,
s), 5.06 (2H, s), 6.71 (1H, dd,
J = 2 Hz, J = 9 Hz), 6.82 (1H, d, J =
2Hz), 7.2-7.5 (3H, m), 7.55-
7.8 (3H, m), 7.99 (1H, d, J = 7H
z), 9.6-10.2 (1H, m), 12.60 (1
H, br).

[1213] NMR (56) (DMSO-d 6) δpp
m: 1.40-1.84 (2H, m), 2.00-2.
42 (4H, m), 2.67 (1H, t, J = 12.5
Hz), 2.77 (3H, s), 3.12 (1H, t,
J = 12.5 Hz), 3.24-4.05 (12H,
m), 4.10-4.31 (1H, m), 4.48-
4.71 (1H, m), 5.07 (2H, s), 6.7
0 (1H, dd, J = 2.1 Hz, J = 8.7 Hz),
6.82 (1H, d, J = 2.1 Hz), 7.19-
7.62 (4H, m), 7.64 (1H, d, J = 8.
6 Hz), 7.77 (1H, d, J = 8.1 Hz),
7.99 (1H, d, J = 7.9 Hz), 11.05-
12.10 (2H, m), 12.68 (1H, br).

Example 344 0.55 g of 2- {3-allyloxy-4- [3- (1-piperidinyl) carbonylacryloyl] phenoxymethylcarbonylamino} benzothiazole was dissolved in 70 ml of methanol and 40 ml of dioxane.
0.15 g of 0% palladium-carbon, 70 mg of p-toluenesulfonic acid monohydrate and 3 ml of water were added. After deaeration,
The mixture was refluxed overnight under a nitrogen atmosphere. After filtration through celite, water-methylene chloride was added, the mixture was separated, and dried over sodium sulfate. After crystallization with ethanol-methylene chloride, recrystallization with dimethylformamide-ethanol gave 120
mg of 2- {3-hydroxy-4- [3- (1-piperidinyl) carbonylacryloyl] phenoxymethylcarbonylamino} benzothiazole was obtained.

[1215] Yellow powder: mp 207.3-210 ° C.

Example 345 6.4 g of dimethyl [{2-methoxy-4- [2- (2-benzothiazolylaminocarbonyl) ethyl] benzoyl} methyl] phosphonate in tetrahydrofuran 10
After 7.7 ml of 40% glyoxylic acid was added to the 0 ml solution, 70 ml of 5% sodium hydroxide was added dropwise under ice cooling.
After stirring for 30 minutes, the mixture was acidified with 5% hydrochloric acid, the yellow powder was collected by filtration, washed with ethanol, dried, and recrystallized from dimethylformamide-ethanol to obtain 4.0 g of 2- {2-
[3-Methoxy-4- (trans-3-carboxyacryloyl) phenyl] ethylcarbonylamino} benzothiazole was obtained.

[1217] Yellow powder: mp 260-261 ° C.

Example 346 To 50 ml of tetrahydrofuran was added 4.70 g of dimethyl [{2-dimethylamino-4-[(2-benzothiazolyl) aminocarbonylmethoxy] benzoyl} methyl] phosphonate, and the mixture was cooled with ice and cooled with 5% sodium hydroxide. 4
0 ml and glyoxylic acid 3.5 ml were added.
Stirred for 0 minutes. After the disappearance of the raw materials, hydrochloric acid was added to make the mixture acidic, and tetrahydrofuran was distilled off. The precipitated crystals were collected by filtration and dissolved in 100 ml of dimethylformamide.
The mixture was heated and stirred at 30 ° C. for 30 minutes. After cooling, isopropyl alcohol was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from dimethylformamide-isopropyl alcohol to give 2.46 g of 1,1-dimethyl-2-carboxy-4-oxo-7. -[(2-benzothiazolyl) aminocarbonylmethoxy] -1,2,3,4-tetrahydroquinolinium chloride was obtained.

Mp 184.5-186.5 ° C. Light green powder.

Using the appropriate starting materials, the following compound was obtained in the same manner as in Example 1 or 5.

[1221]

[Table 191]

[1222]

[Table 192]

[1223]

[Table 193]

[1224]

[Table 194]

[1225]

[Table 195]

[1226]

[Table 196]

[1227]

[Table 197]

[1228]

[Table 198]

[1229]

[Table 199]

[1230]

[Table 200]

[1231]

[Table 201]

[1232]

[Table 202]

[1233]

[Table 203]

[1234]

[Table 204]

[1235]

[Table 205]

[1236]

[Table 206]

Using the appropriate starting materials, the following compounds were obtained in the same manner as in Example 3 or 4.

[1238]

[Table 207]

[1239]

[Table 208]

[1240]

[Table 209]

[1241]

[Table 210]

[1242]

[Table 211]

[1243]

[Table 212]

[1244]

[Table 213]

[1245]

[Table 214]

[1246]

[Table 215]

[1247]

[Table 216]

[1248]

[Table 217]

[1249]

[Table 218]

[1250]

[Table 219]

[1251]

[Table 220]

[1252]

[Table 221]

[1253]

[Table 222]

[1254]

[Table 223]

[1255]

[Table 224]

[1256]

[Table 225]

[1257]

[Table 226]

[1258]

[Table 227]

[1259]

[Table 228]

[1260]

[Table 229]

[1261]

[Table 230]

[1262]

[Table 231]

[1263]

[Table 232]

[1264]

[Table 233]

[1265]

[Table 234]

[1266]

[Table 235]

[1267]

[Table 236]

[1268]

[Table 237]

[1269]

[Table 238]

[1270]

[Table 239]

[1271]

[Table 240]

[1272]

[Table 241]

[1273]

[Table 242]

[1274]

[Table 243]

[1275]

[Table 244]

[1276]

[Table 245]

[1277]

[Table 246]

[1278]

[Table 247]

[1279]

[Table 248]

[1280]

[Table 249]

[1281]

[Table 250]

[1282]

[Table 251]

[1283]

[Table 252]

[1284]

[Table 253]

[1285]

[Table 254]

[1286]

[Table 255]

[1287]

[Table 256]

Using the appropriate starting materials, the following compounds were obtained in the same manner as in Example 8.

[1289]

[Table 257]

Using the appropriate starting materials, the following compounds were obtained in the same manner as in Example 3 or 4.

[1291]

[Table 258]

[1292: ¹ H of each compound shown in Table 191 to Table 258
-NMR spectrum (NMR (1) to NMR (49))
Is as follows.

(1) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 4.61-4.78 (2H, m), 5.05 (2
H, s), 5.18-5.50 (2H, m), 5.91
−6.17 (1H, m), 6.46 (1H, d, J = 1)
5.5 Hz), 6.62-6.78 (1H, m), 6.
78-6.88 (1H, m), 7.28-7.39 (1
H, m), 7.39-7.52 (1H, m), 7.54
−7.81 (2H, m), 7.71 (1H, d, J = 1)
5.5 Hz), 7.92-8.05 (1H, m), 1
2.72 (2H, brs).

(2) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 4.97 (2H, s), 6.40-6.58 (2
H, m), 6.91 (1H, dd, J = 2.4 Hz, J
= 8.8 Hz), 7.00-7.22 (3H, m),
7.22-7.51 (4H, m), 7.61-7.89
(3H, m), 7.89-8.04 (1H, m), 1
2.75 (2H, brs).

(3) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 1.12 (3H, t, J = 7.4 Hz), 2.6
0 (2H, q, J = 7.4 Hz), 3.85 (3H,
s), 5.15 (2H, s), 6.46 (1H, d, J
= 15.5 Hz), 6.71 (1H, s), 7.26-
7.39 (1H, m), 7.39-7.50 (1H,
m), 7.51 (1H, s), 7.68 (1H, d, J
= 15.5 Hz), 7.72-7.81 (1H, m),
7.91-8.03 (1H, m), 12.75 (2H,
brs).

(4) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 2.19 (3H, s), 3.64 (3H, s),
5.07 (2H, s), 6.54 (1H, d, J = 1
5.6 Hz), 6.85 (1H, d, J = 8.7H)
z), 7.25-7.40 (1H, m), 7.40-
7.51 (1H, m), 7.54 (1H, d, J = 8.
8 Hz), 7.68 (1H, d, J = 15.6 Hz),
7.76 (1H, d, J = 7.5 Hz), 7.98 (1
H, d, J = 7.5 Hz), 12.41-13.16
(2H, m).

(5) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 2.16 (3H, s), 3.88 (3H, s),
4.64 (2H, s), 6.52 (1H, d, J = 1)
5.6 Hz), 6.95 (1H, d, J = 8.8H)
z), 7.21-7.38 (1H, m), 7.38-
7.51 (1H, m), 7.55-7.80 (3H,
m), 7.98 (1H, d, J = 7.1 Hz).

(6) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 0.91 (3H, t, J = 7.3 Hz), 1.2
0-1.65 (4H, m), 2.54-2.78 (2
H, m), 3.63 (3H, s), 5.07 (2H,
s), 6.58 (1H, d, J = 15.6 Hz);
84 (1H, d, J = 8.7 Hz), 7.21-7.3
9 (1H, m), 7.39-7.51 (1H, m),
7.55 (1H, d, J = 8.7 Hz), 7.67 (1
H, d, J = 15.6 Hz), 7.76 (1H, d, J)
= 7.8 Hz), 7.97 (1H, d, J = 7.8H)
z) 12.05-13.51 (2H, m).

(7) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 2.41 (3H, s), 5.10 (2H, s),
6.56 (1H, d, J = 15.5 Hz), 6.90
(1H, dd, J = 8.8 Hz, J = 2.2 Hz),
6.98 (1H, d, J = 2.2 Hz), 7.32 (1
H, t, J = 7.2 Hz), 7.45 (1H, t, J =
7.2 Hz), 7.65-7.85 (2H, m), 7.
99 (1H, d, J = 7.7 Hz), 8.05 (1H,
d, J = 8.8 Hz), 12.06 to 13.45 (2
H, m).

(8) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 1.17 (3H, t, J = 7.5 Hz), 2.7
0 (2H, q, J = 7.5 Hz), 3.65 (3H,
s), 5.09 (2H, s), 6.57 (1H, d, J
= 15.6 Hz), 6.85 (1H, d, J = 8.9H)
z), 7.30 (1H, dt, J = 1.2 Hz, J =
7.1 Hz), 7.43 (1H, dt, J = 1.2H)
z, J = 7.1 Hz), 7.56 (1H, d, J = 8.
9 Hz), 7.67 (1H, d, J = 15.6 Hz),
7.76 (1H, t, J = 7.1 Hz), 7.97 (1
H, d, J = 7.1 Hz), 12.51-13.12
(2H, m).

(9) ¹ H-NMR (DMSO-d ₆ ) δp
pm: 3.79 (3H, s), 3.83 (3H, s),
5.12 (2H, s), 6.51 (1H, d, J = 1)
5.5 Hz), 6.84 (1H, s), 7.15-7.
54 [3H, m, 7.26 (1H, s)], 7.61-
7.86 [2H, m, 7.26 (1H, d, J = 15.
5 Hz)], 7.99 (1H, d, J = 7.1 Hz),
12.20-13.25 (2H, m).

(10) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.19 (3H, s), 3.85 (3H, s)
s), 5.14 (2H, s), 6.49 (1H, d, J
= 15.5Hz), 6.70 (1H, s), 7.20-
7.56 [3H, m, 7.52 (1H, s)], 7.6
0-7.82 [2H, m, 7.71 (1H, d, J = 1)
5.5 Hz)], 7.98 (1H, d, J = 7.0H)
z), 12.41-13.17 (2H, m).

(11) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.19 (6H, d, J = 6.9 Hz), 3.
10-3.42 (1H, m), 3.86 (3H, s),
5.16 (2H, s), 6.50 (1H, d, J = 1)
5.5 Hz), 6.70 (1H, s), 7.21-7.
60 [3H, m, 7.55 (1H, s)], 7.65-
7.82 [2H, m, 7.73 (1H, d, J = 15.
5 Hz)], 7.89-8.08 (1H, m), 12.
42-13.12 (2H, m).

(12) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.68-0.92 (3H, m), 1.08-
1.64 (8H, m), 2.38-2.68 (2H,
m), 3.85 (3H, s), 5.14 (2H, s),
6.49 (1H, d, J = 15.5 Hz), 6.71
(1H, s), 7.20-7.57 (3H, m), 7.
62-7.85 [2H, m, 7.72 (1H, d, J =
15.5 Hz)], 7.88-8.05 (1H, m),
12.45-13.12 (2H, m).

(13) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.17 (6H, s), 5.28 (2H,
s), 6.71 (1H, d, J = 15.5 Hz), 7.
29-7.49 (3H, m), 7.78 (1H, d, J
= 8.0 Hz), 7.91-8.06 (2H, m),
8.09 (1H, d, J = 8.4 Hz), 8.25 (1
H, s).

(14) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 3.87 (3H, s), 4.75 (2H, d,
J = 5.1 Hz), 4.77 (2H, s), 6.50
(1H, d, J = 15.5 Hz), 6.72 (1H, d
d, J = 2.2 Hz, J = 8.6 Hz), 6.78 (1
H, d, J = 2.2 Hz), 7.33-7.57 (2
H, m), 7.66 (1H, d, J = 8.6 Hz),
7.69 (1H, d, J = 15.5 Hz), 7.94
(1H, d, J = 7.4 Hz), 8.05 (1H, d,
J = 6.9 Hz), 9.18 (1H, t, J = 5.1H)
z), 12.99 (1H, br).

(15) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.65-2.8 (4H, m), 3.06 (9
H, s), 3.87 (3H, s), 4.15-4.65
(4H, m), 5.07 (2H, s), 6.70 (1
H, dd, J = 2 Hz, J = 8.5 Hz), 6.81
(1H, d, J = 2 Hz), 7.29 (1H, d, J =
15 Hz), 7.48 (1H, br), 7.62 (1
H, d, J = 15 Hz), 7.65 (1H, d, J =
8.5 Hz), 7.77 (1 H, d, J = 9 Hz),
7.93 (1H, br), 11.0 (1H, br), 1
2.7 (1H, br).

(16) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.65 (2H, br), 2.05-2.40
(4H, m), 2.55-2.9 (4H, m), 3.1
3 (6H, s), 3.25-4.8 (15H, m),
5.10 (2H, s), 6.70 (1H, dd, J = 2)
Hz, J = 9 Hz), 6.81 (1H, d, J = 2H)
z), 7.26 (1H, d, J = 15 Hz), 7.55
(1H, d, J = 15 Hz), 7.64 (1H, d, J)
= 8.5 Hz), 7.7-7.8 (1H, m), 7.8
8 (1H, d, J = 9 Hz), 8.31 (1H, b
r) 11.2-12.2 (2H, m).

(17) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.61 (3H, d, J = 6.5 Hz);
6 (2H, br), 2.12 (4H, br), 2.5-
2.85 (4H, m), 2.95-4.05 (13H,
m), 4.1-4.3 (1H, m), 4.4-4.7
(1H, m), 5.35 (1H, q, J = 6.5H
z), 6.63 (1H, dd, J = 2 Hz, J = 9H)
z), 6.77 (1H, d, J = 2 Hz), 7.15-
7.7 (4H, m), 7.69 (1H, d, J = 9H
z), 7.76 (1H, d, J = 7.5 Hz), 7.9
8 (1H, d, J = 7.5 Hz), 11.1-13.1
(3H, m).

(18) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.61 (3H, d, J = 6.5 Hz);
73 (3H, d, J = 4 Hz), 2.8-4.1 (6
H, m), 3.85 (3H, s), 4.1-4.35
(1H, m), 4.35-4.6 (1H, m), 5.3
8 (1H, q, J = 6.5 Hz), 6.63 (1H, d
d, J = 2 Hz, J = 9 Hz), 6.78 (1H, d,
J = 2 Hz), 7.26 (1H, d, J = 15 Hz),
7.25-7.5 (2H, m), 7.59 (1H, d,
J = 15 Hz), 7.63 (1H, d, J = 9 Hz),
7.76 (1H, d, J = 7.5 Hz), 7.97 (1
H, d, J = 7 Hz), 11.40 (1H, br), 1
2.9 (1H, br).

(19) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.61 (3H, d, J = 6.5 Hz);
35-4.4 (23H, m), 5.37 (1H, q, J
= 6.5 Hz), 6.63 (1H, dd, J = 2 Hz,
J = 8.5 Hz), 6.78 (1H, d, J = 2H)
z), 7.1-7.7 (5H, m), 7.76 (1H,
d, J = 7.5 Hz), 7.98 (1H, d, J = 7H)
z), 11.85 (2H, br), 12.90 (1H,
br).

(20) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.42 (6H, s), 2.82 (3H, d,
J = 4 Hz), 2.9-3.25 (3H, m), 3.3
-3.6 (3H, m), 4.15-4.6 (6H,
m), 5.03 (2H, s), 6.68 (1H, d, J
= 9Hz), 7.23 (1H, d, J = 9Hz), 7.
31 (1H, d, J = 15 Hz), 7.15-7.5
(2H, m), 7.61 (1H, d, J = 15 Hz),
7.76 (1H, d, J = 7.5 Hz), 7.98 (1
H, d, J = 7 Hz), 9.85 (1H, br).

(21) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.64 (2H, br), 2.17 (4H, b
r), 2.55-2.9 (4H, m), 2.95-4.
0 (10H, m), 4.05-4.7 (6H, m),
5.03 (2H, s), 6.68 (1H, d, J = 9H)
z), 7.22 (1H, d, J = 9 Hz), 7.25-
7.6 (4H, m), 7.76 (1H, d, J = 7.5)
Hz), 7.98 (1H, d, J = 7.5 Hz), 1
1.1-12.2 (2H, m), 12.65 (1H, b
r).

(22) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.55-2.7 (1H, m), 2.79 (3
H, s), 2.85-4.5 (20H, m), 5.04
(2H, s), 6.68 (1H, d, J = 8.5H)
z), 7.15-7.7 (5H, m), 7.76 (1
H, d, J = 7.5 Hz), 7.98 (1H, d, J =
7.5 Hz), 11.4-13.1 (2H, m).

(23) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.35 (3H, d, J = 5.5 Hz), 1.
64 (2H, br), 2.14 (2H, br), 2.5
5-2.95 (4H, m), 2.95-4.0 (9H,
m), 4.05-4.7 (6H, m), 5.03 (2
H, s), 6.68 (1H, d, J = 9 Hz), 7.2
2 (1H, d, J = 9 Hz), 7.29 (1H, d, J
= 15.5 Hz), 7.4-7.5 (1H, m), 7.
53 (1H, d, J = 15.5 Hz), 7.76 (1
H, d, J = 7.5 Hz), 7.98 (1H, d, J =
7 Hz), 11.5-13.0 (2H, m).

(24) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.16 (3H, s), 2.37 (3H,
s), 2.77 (3H, d, J = 4.2 Hz), 2.8
3-3.19 (3H, m), 3.29-3.58 (3
H, m), 3.88 (3H, s), 4.12-4.57
(2H, m), 4.65 (2H, s), 6.95 (1
H, d, J = 8.8 Hz), 7.19-7.37 (2
H, m), 7.37-7.50 (1H, m), 7.50
−7.66 (2H, m), 7.75 (1H, d, J =
7.9 Hz), 7.99 (1H, d, J = 7.9H)
z), 9.82 (1H, brs), 11.95-12.
71 (1H, m).

(25) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.17 (2H, br), 2.34 (3H, br)
s), 2.82 (3H, s), 3.05 (4H, b
r), 3.4 (2H, br), 4.05-4.4 (5
H, m), 4.49 (1H, br), 5.05 (2H,
s), 6.83 (1H, d, J = 9 Hz), 7.28
(1H, d, J = 15 Hz), 7.29 (1H, d, J)
= 9 Hz), 7.25-7.35 (1H, m), 7.3
5-7.5 (1H, m), 7.52 (1H, d, J = 1)
5 Hz), 7.76 (1H, d, J = 7.5 Hz),
7.98 (1H, d, J = 7 Hz), 9.81 (1H, d, J = 7 Hz)
br), 12.6 (1H, br).

(26) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.61 (2H, br), 2.15 (4H, b
r), 2.55-2.9 (4H, m), 3.0-4.3
(11H, m), 4.4-4.7 (1H, m), 5.0
9 (2H, s), 7.12 (1H, dd, J = 2.5H)
z, J = 8.5 Hz), 7.25-7.4 (4H,
m), 7.4-7.5 (1H, m), 7.69 (1H,
d, J = 8.5 Hz), 7.77 (1H, d, J = 7.
5 Hz), 7.99 (1H, d, J = 7 Hz), 11.
0-12.2. (2H, m).

(27) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.91 (3H, t, J = 7.2 Hz), 1.
20-1.86 (6H, m), 1.93-2.39 (4
H, m), 2.58-2.89 (4H, m), 2.76
(3H, s), 2.95-3.98 (9H, m), 3.
64 (3H, s), 4.07-4.31 (1H, m),
4.41-4.69 (1H, m), 5.09 (2H,
s), 6.83 (1H, d, J = 8.9 Hz), 7.2
0-7.64 (5H, m), 7.76 (1H, d, J =
7.9 Hz), 7.97 (1H, d, J = 7.9H)
z) 11.11-12.29 (2H, m), 12.7
2 (1H, brs).

(28) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.0-2.2 (2H, m), 2.34 (3
H, s), 2.68 (2H, t, J = 7 Hz), 2.8
1 (3H, d, J = 3 Hz), 2.9-3.2 (2H,
m), 3.3-3.65 (4H, m), 3.79 (3
H, s), 4.15 (2H, t, J = 6 Hz), 4.2
-4.4 (1H, m), 4.4-4.6 (1H, m),
6.55-6.7 (2H, m), 7.2-7.35 (1
H, m), 7.27 (1H, d, J = 15 Hz), 7.
35-7.5 (1H, m), 7.63 (1H, d, J =
9.5 Hz), 7.63 (1 H, d, J = 15 Hz),
7.72 (1H, d, J = 7.5 Hz), 7.9-8.
0 (1H, m), 9.79 (1H, br), 13.38
(1H, br).

(29) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.64 (2H, br), 2.0-2.4 (6
H, m), 2.55-2.9 (6H, m), 2.95-
4.0 (13H, m), 4.0-4.35 (3H,
m), 4.4-4.7 (1H, m), 6.55-6.7
5 (2H, m), 7.01 (1H, br), 7.2-
7.35 (2H, m), 7.35-7.45 (1H,
m), 7.5-7.65 (2H, m), 7.65-7.
75 (1H, m), 7.9-8.0 (1H, m), 1
1.2-12.6 (2H, m).

(30) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.0-2.2 (2H, m), 2.69 (2
H, t, J = 7 Hz), 2.80 (3H, s), 2.9
-4.4 (22H, m), 6.4-6.75 (2H,
m), 7.15-7.5 (3H, m), 7.5-7.8
(3H, m), 7.96 (1H, d, J = 7 Hz), 1
1.95 (1H, br), 12.41 (1H, br).

(31) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.45-1.9 (2H, m), 2.0-2.
35 (4H, m), 2.55-2.95 (6H, m),
2.95-3.25 (1H, m), 3.3-3.95
(12H, m), 4.0-4.35 (3H, m);
4-4.65 (1H, m), 6.4-6.75 (2H,
m), 7.25 (1H, d, J = 15 Hz), 7.2-
7.5 (2H, m), 7.55 (1H, d, J = 15H
z), 7.61 (1H, d, J = 9.5 Hz), 7.7
1 (1H, d, J = 7.5 Hz), 7.96 (1H,
d, J = 7 Hz), 11.9-12.8 (2H, m).

(32) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.16 (3H, t, J = 7.5 Hz), 1.
9-2.2 (2H, m), 2.48 (3H, s), 2.
62 (2H, q, J = 7.5 Hz), 2.82 (3H,
d, J = 4.5 Hz), 3.0-3.8 (5H, m),
3.84 (3H, s), 3.9-4.3 (3H, m),
5.16 (2H, s), 6.71 (1H, s), 7.2
2 (1H, d, J = 15 Hz), 7.25-7.35
(1H, m), 7.4-7.5 (1H, m), 7.51
(1H, s), 7.66 (1H, dd, J = 5.5H)
z, J = 15 Hz), 7.77 (1H, d, J = 7.5)
Hz), 7.98 (1H, d, J = 7 Hz), 9.55
(1H, br), 11.7 (1H, br).

(33) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.15 (3H, t, J = 7.5 Hz), 1.
35-1.7 (2H, m), 1.9-2.1 (2H,
m), 2.36 (3H, s), 2.5-2.7 (3H,
m), 2.73 (3H, s), 2.75 (3H, s),
3.0-3.2 (1H, m), 3.3-3.55 (1
H, m), 3.84 (3H, s), 4.05-4.25
(1H, m), 4.45-4.65 (1H, m), 5.
16 (2H, s), 6.71 (1H, s), 7.26
(1H, d, J = 15 Hz), 7.25-7.35 (1
H, m), 7.4-7.5 (1H, m), 7.50 (1
H, s), 7.58 (1H, d, J = 15 Hz), 7.5.
77 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7.5 Hz)
d, J = 7 Hz), 9.58 (1H, br).

(34) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.90 (3H, t, J = 7.5 Hz), 1.
57 (2H, tq, J = 7.5 Hz, J = 8 Hz),
2.35 (3H, s), 2.57 (2H, t, J = 8H)
z), 2.81 (3H, d, J = 3.5 Hz), 2.9
-3.25 (3H, m), 3.3-3.7 (3H,
m), 3.83 (3H, s), 4.15-4.4 (1
H, m), 4.4-4.65 (1H, m), 5.16
(2H, s), 6.70 (1H, s), 7.28 (1
H, d, J = 15 Hz), 7.25-7.4 (1H,
m), 7.4-7.5 (1H, m), 7.49 (1H,
s), 7.66 (1H, d, J = 15 Hz), 7.77
(1H, d, J = 8 Hz), 7.98 (1H, d, J =
7.5 Hz), 9.85 (1H, br), 12.6 (1
H, br).

(35) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.89 (3H, t, J = 7.5 Hz), 1.
4-1.9 (4H, m), 2.0-2.4 (4H,
m), 2.5-2.85 (6H, m), 3.0-4.0
5 (10H, m), 3.84 (3H, s), 4.05-
4.3 (1H, m), 4.45-4.7 (1H, m),
5.17 (2H, s), 6.71 (1H, s), 7.1
5-7.35 (2H, m), 7.35-7.5 (1H,
m), 7.48 (1H, s), 2.58 (1H, d, J
= 15 Hz), 7.77 (1H, d, J = 7.5H)
z), 7.98 (1H, d, J = 7 Hz), 11.1-
13.2 (2H, m).

(36) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.90 (3H, t, J = 7.5 Hz), 1.
4-1.8 (4H, m), 1.95-2.25 (2H,
m), 2.57 (2H, t, J = 8 Hz), 2.6-
2.9 (1H, m), 2.81 (3H, s), 2.95
-4.0 (10H, m), 3.84 (3H, s), 4.
05-4.3 (1H, m), 4.4-4.65 (1H,
m), 5.16 (2H, s), 6.70 (1H, s),
7.26 (1H, d, J = 15 Hz), 7.25-7.
35 (1H, m), 7.35-7.5 (1H, m),
7.48 (1H, s), 7.58 (1H, d, J = 15)
Hz), 7.77 (1H, d, J = 7.5 Hz), 7.
98 (1H, d, J = 7 Hz), 11.4-13.0
(3H, m).

(37) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 0.90 (3H, t, J = 7.5 Hz), 1.
57 (2H, tq, J = 7.5 Hz, J = 8 Hz),
2.57 (2H, t, J = 8 Hz), 2.65-4.4
(17H, m), 2.79 (3H, s), 3.84 (3
H, s), 5.18 (2H, s), 6.71 (1H,
s), 7.15-7.5 (3H, m), 7.48 (1
H, s), 7.5-7.8 (2H, m), 7.98 (1
H, d, J = 7 Hz), 11.0-13.0 (3H,
m).

(38) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.11 (3H, t, J = 7.4 Hz), 2.
53-4.17 (16H, m), 2.59 (2H, q,
J = 7.4 Hz), 2.79 (3H, s), 3.84
(3H, s), 4.17-4.40 (1H, m), 5.
20 (2H, s), 6.73 (1H, s), 7.18-
7.38 (2H, m), 7.38-7.54 (2H,
m), 7.54-7.74 (1H, m), 7.74-
7.81 (1H, m), 7.92-8.05 (1H,
m), 11.32-13.11 (3H, m).

(39) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.35 (3H, s), 2.80 (3H, d,
J = 3.5 Hz), 2.85-3.6 (6H, m),
3.85 (3H, s), 4.04 (2H, br),
2-4.6 (2H, m), 5.0-5.25 (4H,
m), 5.81-6.1 (1H, m), 6.74 (1
H, s), 7.28 (1H, d, J = 15 Hz), 7.
25-7.55 (2H, m), 7.48 (1H, s),
7.65 (1H, d, J = 15 Hz), 7.77 (1
H, d, J = 7.5 Hz), 7.98 (1H, d, J =
7 Hz), 9.99 (1H, br), 12.6 (1H,
br).

(40) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.65 (2H, br), 2.0-2.4 (4
H, m), 2.55-2.95 (4H, m), 3.0-
3.25 (1H, m), 3.25-4.05 (14H,
m), 4.05-4.3 (1H, m), 4.45-4.
7 (1H, m), 4.95-5.3 (4H, m), 5.
85-6.1 (1H, m), 6.75 (1H, s),
7.15-7.7 (5H, m), 7.77 (1H, d,
J = 8 Hz), 7.98 (1H, d, J = 7.5H)
z) 11.1-13.0 (3H, m).

(41) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.4-1.85 (2H, m), 1.95-
2.3 (2H, m), 2.55-2.95 (4H,
m), 2.95-3.2 (1H, m), 3.2-3.9
5 (11H, m), 5.86 (3H, s), 4.1-
4.3 (1H, m), 4.45-4.7 (1H, m),
4.95-5.25 (4H, m), 5.86-6.1
(1H, m), 6.74 (1H, s), 7.26 (1
H, d, J = 15 Hz), 7.25-7.55 (3H,
m), 7.56 (1H, d, J = 15 Hz), 7.77
(1H, d, J = 7.5 Hz), 7.98 (1H, d,
J = 7 Hz), 11.1-13.0 (3H, m).

(42) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.55-4.45 (25H, m), 4.9-
5.3 (4H, m), 5.85-6.1 (1H, m),
6.75 (1H, s), 7.15-7.85 (6H,
m), 7.98 (1H, d, J = 7 Hz), 11.0-
13.3 (3H, m).

(43) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.32 (3H, t, J = 7 Hz), 2.33
(3H, s), 2.80 (3H, s), 2.9-3.2
(3H, m), 3.3-3.5 (3H, m), 3.81
(3H, s), 4.03 (2H, q, J = 7 Hz),
4.2-4.65 (2H, m), 5.15 (2H,
s), 6.83 (1H, s), 7.2-7.4 (3H,
m), 7.44 (1H, t, J = 8 Hz), 7.69
(1H, d, J = 15 Hz), 7.77 (1H, d, J)
= 8 Hz), 7.98 (1H, d, J = 8 Hz), 9.
83 (1H, br), 12.60 (1H, br).

(44) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.32 (3H, t, J = 7 Hz), 1.4
1.9 (2H, m), 2.05-2.4 (4H, m),
2.6-3.9 (4H, m), 3.05-3.95 (1
3H, m), 4.03 (2H, q, J = 7 Hz);
1-4.3 (1H, m), 4.5-4.7 (1H,
m), 5.17 (2H, s), 6.83 (1H, s),
7.2-7.4 (3H, m), 7.44 (1H, t, J
= 8 Hz), 7.60 (1H, d, J = 15.5H)
z), 7.76 (1H, d, J = 8 Hz), 7.98
(1H, d, J = 8 Hz), 11.25 to 12.2 (2
H, m).

(45) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.32 (3H, t, J = 7 Hz), 2.55
-4.5 (19H, m), 2.80 (3H, s), 3.
82 (3H, s), 5.17 (2H, s), 6.84
(1H, s), 7.2-7.4 (3H, m), 7.44
(1H, t, J = 8 Hz), 7.64 (1H, d, J =
15.5 Hz), 7.76 (1 H, d, J = 8 Hz),
7.98 (1H, d, J = 8 Hz), 11.5-12.
5 (2H, m).

(46) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.32 (3H, s), 2.81 (3H, s)
s), 3.4-3.7 (4H, m), 3.25-3.6
(2H, m), 3.86 (3H, s), 4.15-4.
65 (2H, m), 5.26 (2H, s), 6.89
(1H, s), 7.32 (1H, d, J = 15 Hz),
7.32 (1H, t, J = 7.5 Hz), 7.45 (1
H, t, J = 8 Hz), 7.61 (1H, d, J = 15)
Hz), 7.77 (1H, d, J = 8 Hz), 7.83
(1H, s), 7.98 (1H, d, J = 7.5H)
z), 9.78 (1H, br), 12.65 (1H, b
r).

(47) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.4-1.85 (2H, m), 2.1-2.
4 (4H, m), 2.6-3.9 (4H, m), 3.0
5-4.5 (14H, m), 4.5-4.65 (1H,
m), 5.27 (2H, s), 6.89 (1H, s),
7.2-7.4 (2H, m), 7.4-7.6 (2H,
m), 7.77 (1H, d, J = 8 Hz), 7.81
(1H, s), 7.98 (1H, d, J = 8 Hz), 1
1.1-12.1. (2H, m).

(48) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 2.35 (6H, s), 2.82 (3H,
s), 2.92-3.27 (9H, m), 3.30-
3.59 (3H, m), 4.18 (1H, br),
19-4.34 (1H, m), 4.47-4.65 (1
H, m), 5.24 (2H, s), 7.33 (2H,
t, J = 7.6 Hz), 7.44 (1H, d, J = 7.
3 Hz), 7.46 (1H, d, J = 15.1 Hz),
7.78 (1H, d, J = 8.0 Hz), 7.84 (1
H, d, J = 15.1 Hz), 7.96-8.15 (3
H, m), 9.82 (1H, br), 12.66 (1
H, br).

(491) ¹ H-NMR (DMSO-d ₆ ) δ
ppm: 1.42-1.88 (2H, m), 1.93-
2.39 (4H, m), 2.59-2.85 (4H,
m), 3.13 (6H, s), 3.26-3.96 (1
0H, m), 4.05-4.28 (1H, m), 4.5
1-4.68 (1H, m), 5.26 (2H, s),
7.29-7.35 (2H, m), 7.42-7.48
(2H, m), 7.74-7.80 (2H, m), 7.
96-8.04 (2H, m), 8.19 (1H, b
r), 11.35-12.13 (2H, m).

(1) Inhibitory activity of protein kinase C (PKC) Method for measuring PKC activity Purification of PKC using a soluble fraction of rat brain was performed using Kikk
Away et al. [Ushio Kikkawa, Yos
himi Takai, Ryoji Minakuch
i, Shinichi Inohara, and Ya
sutomiNishizuka: The Journal
al of BiologicalChemistry
vol257, no. 22, pp 13341-133
48 (1982)]. PKC activity is
20 mM Tris-HCl buffer (pH 7.5), 200μ
g / ml calf thymus-derived H1 histone, 10 μM [γ-
³² P] adenosine triphosphate (ATP), 5 mM
Magnesium acetate, 8 μg / ml phosphatidylserine, 2 μg / ml diacylglycerol and 0.3 mM
It was determined by the transfer of radioactivity from [γ- ³² P] ATP to Hl histones from calf thymus in the presence of Ca ²⁺ . Test compounds were dissolved in dimethylformamide and added to the assay system to a final concentration of 0.8%. 3
After incubation at 0 ° C. for 30 minutes, the reaction was stopped by adding 25% trichloroacetic acid, and the acid-insoluble protein was captured on a nitrocellulose membrane by suction filtration. The radioactivity of ³² P was measured with a scintillation counter. The results are shown in Table 259.

[1343]

[Table 259]

(2) Mouse Collagen Arthritis 0.1% bovine type II collagen (collagen workshop) was applied to the ridge of a mouse (DBA / 1JNCrj) by CFA.
(Complete Freund's Adjuvant) (Adjuvant, DI
Emulsion with 50% FCO) and intradermal injection (1
Next sensitization) and 3 weeks later, bovine type II collagen 0.1
% Were injected intraperitoneally (secondary sensitization). Three weeks after the secondary sensitization, the degree of swelling of the limbs of the mice was evaluated on a four-point scale of 0 to 3 and scored as an index of arthritis (the maximum score was 12). The test compound was orally administered once a day from two weeks after the primary sensitization.

As a result, the compound of Example 182 contained 30 to
The administration of 50 mg / kg significantly suppressed the arthritis score as compared with the control group.

The compounds of Example 160, Example 192 and Example 197 significantly suppressed the arthritis score by administration of 50 mg / kg as compared with the control group.

(3) Mouse cGVHD (chromic)
Graft-versus-host disease
e model) A female mouse (DBA / 2NCrj) was dislocated from the cervical vertebra and the spleen was removed to prepare spleen cells. Cell number 37.5 × 10
^It was adjusted to ⁷ cells / ml, and 200 μl was administered per mouse via the tail vein of BDF1 female mice. Two weeks later, blood was collected in the absence of heparin, and anti-DNA antibodies were measured by ELISA.

The compound of Example 182 was treated in an amount of 30 to 50 mg /
After oral administration once a day for 2 weeks, the effect on cGVHD was examined.

As a result of measuring the amount of anti-DNA antibody in blood at OD ₄₀₅ , 0.348 ± 0.111 in the control group.
(Mean ± se), compound 30m of Example 182
In the g / kg administration group, 0.255 ± 0.062 (mean
± s. e. ) And 0.094 ± 0.026 (mean ± s.d.) In the group administered with 50 mg / kg of the compound of Example 182.
e. ), And the group administered with the compound of Example 182 suppressed the amount of anti-DNA antibody in blood in a dose-dependent manner as compared with the control group.

The compound of Example 100 was used in an amount of 30 mg /
After oral administration once a day for 2 weeks, the effect on cGVHD was examined.

As a result of measuring the amount of anti-DNA antibody in blood at OD ₄₀₅ , 0.258 ± 0.084 was obtained in the control group.
(Mean ± se), compound 30m of Example 100
In the g / kg administration group, 0.177 ± 0.061 (mean
± s. e. ), And the compound-administered group of Example 100 suppressed the amount of anti-DNA antibody in blood as compared with the control group.

(4) Rat renal ischemia-reperfusion model The right kidney of an SD male rat was excised, the left renal artery was clamped for a certain period of time, and reperfusion was performed to prepare a renal ischemia-reperfusion model. The effects of the compound, the compound of Example 89, and the compound of Example 100 were examined.

The compound of Example 71 was 3 mg 5 minutes before ischemia.
/ Kg dose. Twenty-four hours later, venous blood was collected from the tail vein, and the blood creatinine and urea nitrogen contents were determined. As a result, blood creatinine was 2.19 ± 0.21 (mean ± se) in the control group, and Example 7
1 compound administration group was 1.4 ± 0.11 (mean ± s.
e. ), The amount of urea nitrogen was 78.8 ± 5.6 in the control group.
(Mean ± se), the compound administration group of Example 71 was 54.1 ± 5.0 (mean ± se), and the compound administration group of Example 71 was smaller than the control group. It was significantly lower. The compound of Example 89 was administered intravenously at a dose of 3 mg / kg 5 minutes before ischemia and reperfusion.
Forty-eight hours later, venous blood was collected from the tail vein, and the blood creatinine and urea nitrogen contents were determined. As a result, the blood creatinine was 4.31 ± 0.53 (mean ±
s. e. ), The administration group of the compound of Example 89 was 2.34 ±
0.46 (mean ± se), and the amount of urea nitrogen was 155.1 ± 15.4 (mean ± s.
e. ), The compound administration group of Example 89 was 99.1 ± 16.
0 (mean ± se), and the compound-administered group of Example 89 was significantly lower than the control group.

The compound of Example 100 was orally administered at a dose of 30 mg / kg one hour before ischemia. 48 hours later,
Blood creatinine was 2.48 ± 0.59 in the control group
(Mean ± se), the compound administration group of Example 100 was 1.53 ± 0.20 (mean ± se), and the urea nitrogen amount was 91.3 ± 20.1 (mean ± se).
s. e. ), The compound administration group of Example 100 was 63.1 ±
10.3 (mean ± se).
Each of the compound administration groups tended to be lower than the control group.

(5) TPA-induced mouse pinna edema, epidermal hyperplasia model One side of the ear of a female mouse (ICR) was applied with 200 μg / ml phorbol ester (TPA) in an amount of 10 μl each.
24 hours after PA application, the pinna thickness was measured using a dial thickness gauge to determine the increased pinna thickness. The test compound was dissolved in acetone and applied to both sides of the ear 30 minutes before TPA application.

The compound of Example 88 contains 0.3% and 1%
Was applied at a dose of 20 μl. The auricle thickness increased 24 hours after TPA application was 215 ± 40 μm (me
an ± s. e. ), Whereas 0.3% of the compound of Example 88 was 87 ± 53 μm (mean ± se),
At 1%, it was 67 ± 23 μm (mean ± se), and the thickness of the pinna was significantly suppressed in the compound-administered group of Example 88 as compared with the control group.

(6) Mouse Atopic Dermatitis Model Female mice (Balb / c) were applied with 10 μl of 1% trinitrochlorobenzene (TNCB) on both sides of the ear once every two days for 24 days. After 24 days, the animals were divided into groups, and the pinna thickness was measured using a dial thickness gauge to determine the increased pinna thickness. The compounds of Example 88 and Example 89 were dissolved in acetone at a dose of 1%, and 1 day 2 days after 24 days.
The TNCB was applied to both sides of the ear 30 minutes before and 30 minutes after application. The compound of Example 182 was dissolved in acetone: methanol 1: 1 at a dose of 0.75%. As a result, a therapeutic effect was observed on the pinna thickened by continuous application of TNCB by administration of the test compound. That is, the inhibition rate of the compound of Example 88 against auricle thickness was 25 to 30%, and the inhibition rate of the compound of Example 89 and the compound of Example 182 was about 25%.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI C07D 417/12 213 C07D 417/12 213 233 233 239 239 243 243 257 257 265 265 267 267 307 307 309 309 311 311 313 313 317 317 (72) Inventor Kaoru Abe 7-76, Miyanoya, Hachiman-cho, Tokushima City, Tokushima Prefecture (72) Kenji Nakaya 48, Kamibetsugu-Kita, Kawauchi-cho, Tokushima City, Tokushima Prefecture (72) Inventor Isao Takemura 1 Minamiyukiya, Ota-ku, Tokyo −15−7 (72) Inventor: Yuichi Shinohara 140 Maehama, Kokuwajima, Nadu-cho, Naruto City, Tokushima Prefecture (72) Inventor: Kiku Tanada 193--3, East, Saida, Nadu-cho, Naruto City, Tokushima Prefecture (72) Inventor: Yamauchi Takahito 92-1, Haihama-ji, Hara, Kitajima-cho, Itano-gun, Tokushima

Claims (2)

[Claims] 1. A compound of the general formula [Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkyl group. R ¹ and R ² may combine to form a group — (CH ₂ ) _n — (n represents 4 or 5) or a benzene ring. The benzene ring may be substituted by a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a nitro group, an amino group which may have a lower alkyl group as a substituent, and a halogen atom as a substituent. . R ³ is a group Or group Is shown. Here, p represents 0 or 1. R ^11b represents a hydrogen atom or a lower alkyl group. R ^11a represents a hydroxyl group, a lower alkoxy group or a nitrogen atom, an oxygen atom or a sulfur atom of 1 to
A 5- or 10-membered monocyclic or binomial saturated or unsaturated heterocyclic residue having 4 members is shown. The heterocyclic ring has, as substituents, (a) a lower alkyl group, (a) a group-(B) ₁ -NR
¹² R ¹³ (l represents 0 or 1. B represents a group -CO-A- (A
Represents a lower alkylene group), a carbonyl group or a lower alkylene group. R ¹² and R ¹³ are the same or different and represent a hydrogen atom, a lower alkyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent. R ¹² and R ¹³ are, together with the nitrogen atom to which they are attached, 5 or not with or without a nitrogen or oxygen atom.
It may form a saturated monocyclic, binomial or spirocyclic heterocyclic ring having from 12 to 12 members. The heterocycle is selected from the group consisting of a lower alkyl group as a substituent, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent, and a hydroxyl-substituted lower alkyl group. It may have a group. ),
(C) a lower alkoxycarbonyl group, (d) a hydroxyl-substituted lower alkyl group, (e) a pyridyl group which may have a lower alkyl group which may have a halogen atom as a substituent on a pyridine ring, and (f) halogen substitution Lower alkyl group, (g) lower alkoxy group, (c) cycloalkyl group, (q) hydroxyl group, (co) tetrahydropyranyloxy group-substituted lower alkyl group, (sa) pyrimidyl group, (si) lower alkoxy-substituted lower alkyl Group, (su) carboxy group, (se) phenyl lower alkoxy group, (so) phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, (t) lower alkanoyloxy group, H) a group selected from the group consisting of a piperidinyl group which may have a lower alkyl group as a substituent on the piperidine ring; It may have to three. A is the same as above. Z represents an oxygen atom or a sulfur atom. s represents 0 or 1. m represents 1 or 2. R ⁵ is the same or different and is (a) a hydrogen atom, (b) an alkyl group which may have a hydroxyl group as a substituent, (c) a halogen atom,
(D) group _{- (O) t -A- (CO} ) l -NR 7 R 8 ( wherein t
Represents 0 or 1. A and 1 are the same as above. R ⁷ and R ⁸
Represents the same or different and represents a hydrogen atom or a lower alkyl group. Alternatively, R ⁷ and R ⁸ may form a 5- to 7-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. In the heterocyclic ring, a group-(A) ₁ -NR ⁹ R ¹⁰ (A and 1
Is the same as above. R ⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom or a lower alkyl group. Or R ⁹ and R
¹⁰ is a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded (this heterocyclic ring may be substituted with a lower alkyl group as a substituent) Or a group selected from the group consisting of a lower alkyl group which may have a hydroxyl group as a substituent, a hydroxyl group and a lower alkanoyl group), and (e) a lower alkoxycarbonyl A lower alkyl group, (f) a lower alkanoyloxy lower alkyl group, (g) a lower alkoxy group which may have a halogen atom as a substituent, (h) a halogen-substituted lower alkyl group, (i) a carboxy-substituted lower alkyl group, j)
Lower alkoxycarbonyl group, (k) lower alkenyloxy group, (l) phenyl lower alkoxy group, (m) cycloalkyloxy group, (n) phenyl group, (o) phenyloxy group, (p) hydroxyl group, (q) A lower alkylthio group, (r) a lower alkenyl group or (s) an amino group which may have a lower alkyl group as a substituent. R ⁶
Is (1) group ^{-CO-CH = CR 11b - (} CO) p -R 11 a or
(2) A group -CO-C≡C-COR ¹⁴ is shown. Where p, R
^11a and R ^11b are the same as above. R ¹⁴ represents a hydroxyl group or a lower alkoxy group. When m represents 1, A and R ⁵ are bonded to each other to form a group (R ⁶ is the same as above, and r represents 0, 1 or 2). When m represents 2, two groups R ⁵ may combine to form a lower alkylenedioxy group, a lower alkylene group, or a group — (CH ₂ ) ₂ CONH—. R ⁵ and R ⁶ are bonded to each other to form a group (R ^28a and R ^28b represent a hydrogen atom or a carboxyl group, provided that R ^28a and R ^28b do not simultaneously represent a carboxyl group. Is shown. R ^29a represents a hydrogen atom or a lower alkyl group.
R ^29b represents a lower alkyl group. X represents a halogen atom. ) May be formed. R ⁴ represents a hydrogen atom or a lower alkanoyloxy lower alkyl group. T represents a lower alkylene group. u represents 0 or 1. Or a salt thereof. 2. The method according to claim 1, wherein the thiazole derivative or a salt thereof is 2-
{[3-methoxy-4- {3- [4- (4-methyl-1
-Homopiperazinyl) -1-piperidinylcarbonyl]
Acryloyl {phenoxy] methylcarbonylamino}
Benzothiazole, 2-{[2-isopropyl-4-
{3- [4- (4-methyl-1-piperazinyl) -1-
Piperidinylcarbonyl] acryloyl｝ phenoxy)
Methylcarbonylamino dibenzothiazole, 2-
{[2-methoxy-4- {3- [2- (4-methyl-1
-Piperazinyl) methyl-4-morpholinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[2-ethoxy-4-
{3- [4- (4-methyl-1-piperazinyl) -1-
Piperidinylcarbonyl] acryloyl｝ phenoxy)
Methylcarbonylamino dibenzothiazole, 2-
｛[3-methyl-4- {3- [4- (4-methyl-1-
Homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[3-methoxy-6-ethyl-
4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-[{3-methoxy-6-ethyl-4- [3-
(4-methyl-1-piperazinyl) acryloyl {phenoxy] methylcarbonylamino} benzothiazole,
2-[{2-trifluoromethyl-4- [3- (4-hydroxy-1-piperazinyl) acryloyl} phenoxy] methylcarbonylamino} benzothiazole, 2-
｛[2-fluoro-4- {3- [2- (4-methyl-1
-Piperazinyl) methyl-4-morpholinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2- {2-methoxy-4-} 3
-[4- (4-methyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[2
3-dimethyl-4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-{[3-methoxy-4- ｛3- [4
-(3,4-dimethyl-1-piperazinyl) -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole, 2-[{3-
Methoxy-6-isopropyl-4- [3- (4-methyl-1-piperazinyl) carbonyl] acryloyl] phenoxy {methylcarbonylamino] benzothiazole,
2-{[2-methoxy-4- {3- [4- (4-methyl-1-homopiperazinyl) -1-piperidinylcarbonyl] acryloyl} phenoxy] methylcarbonylamino} benzothiazole and 2-{[2- n-butyl-4
-{3- [4- (4-methyl-1-homopiperazinyl)
The thiazole derivative according to claim 1, which is a thiazole derivative selected from the group consisting of -1-piperidinylcarbonyl] acryloyl {phenoxy] methylcarbonylamino} benzothiazole or a salt thereof.