JPH09235276A - Oxazole derivative, production of the same and use of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having IL-6 activity inhibitory activity effective to heart trouble and various autoimmune diseases, etc., caused by IL-6. SOLUTION: The compound are the oxazole derivatives having a group bonded through sulfinyl or sulfonyl group at the 5 position expressed in formula I (R<1> is a (substituted) hydrocarbon, heterocyclic group, etc.,; R<2> and R<3> are each a (substituted) hydrocvarbon, heterocyclic group, etc.,; n is 1 or 2). For example, 3,3-dichloro-2hexanoylaminoacrylonitrile. The compound of formula I is obtained by dissolving an oxazole derivative of formula II in the solvent (e.g. dichloromethane, carbontetrachloride, etc.), oxidizing the derivative for 1-20hrs. using 1-3mol of an oxidizing agent (for example, methachloroperbenzoic acid, etc.) per mol of the derivative and purifying the reaction product by a conventional method such as solvent extraction, distillation, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has an interleukin 6 activity inhibitory action and a nitric oxide synthase-induced cell nitric oxide production inhibitory action, and is effective in treating heart diseases, autoimmune diseases, inflammatory diseases and granulomas. The present invention relates to an oxazole derivative useful as a prophylactic / therapeutic agent for associated diseases, a method for producing the same, and a medicine containing the derivative.

[0002]

2. Description of the Related Art Interleukin 6 (hereinafter abbreviated as IL-6) is a 26 kD glycoprotein cloned as a B cell stimulating factor.
It is produced by monocytes, fibroblasts, skin keratinocytes, vascular endothelial cells, renal mesangial cells, brain astrocytes, and osteoblasts. Physiological activity is immune system, hematopoietic system, cranial nervous system,
1) Antibody production inducer, 2) Hybridoma / plasmacytoma / myeloma growth factor, 3) T lymphocyte growth factor and killer T lymphocyte differentiation factor, 4) Hematopoietic stem cell differentiation factor 5) megakaryocyte differentiation factor and thrombocytosis factor, 6) nerve cell stimulating factor, 7) hepatocyte stimulating factor, 8) osteoclast growth factor, 9) renal mesangial cell growth factor, 10) adrenocortical hormone ACTH producing factor And other activities [The Cytokine Handbook, 2nd Edition, Academic
Press, USA, 145-168 (1994)]. Recently, IL-
6, heart disease such as cardiomyopathy, cardiac hypertrophy, myocardial infarction, angina,
Rheumatoid arthritis, systemic erythematosus, systemic sclerosis, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease and autoimmune hemolytic anemia. , Mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic cirrhosis, gout, and various encephalitis It has become clear that inflammatory diseases, multiple myeloma, intra-atrial mucosa, renal cancer, lung adenocarcinoma, malignant mesothelioma, ovarian cancer, and cancer cachexia are associated with diseases associated with granulomas.

[0003] In fact, in rheumatoid arthritis, a high concentration of IL-6 was found in the synovial fluid of patients, and synovial tissue was IL-6m.
RNA was expressed. Administration of anti-IL-6 antibody to these patients improved their symptoms [The Journal.
The Journal of Rheumatolog
y), Volume 20, pp. 259-261 (1993)]. In glomerulonephritis, IL-6 transgenic mice showed mesangial proliferative nephritis accompanied by high proteinuria, and administration of anti-IL-6 antibody improved the symptoms [Japanese clinical, No. 50.
2840-2841 (1992)]. In human proliferative glomerulonephritis including IgA nephritis, urinary IL-6 is higher as tissue damage is more progressive, and is used as a clinical marker. In postmenopausal osteoporosis with reduced estrogen production, IL-6 acts as an osteoclast growth factor and exerts a strong bone resorption activity. In ovariectomized mice, osteoclasts proliferated and anti-IL-6 antibody suppressed it (Science, Vol. 257, pp. 88-91 (1992)).
Bone destruction did not occur in the IL-6 gene-deficient mice even after ovariectomy. These reports indicate that IL-6 is involved in the above-mentioned diseases, and it has been shown that inhibition of the physiological activity of IL-6 can improve symptoms. Methods for inhibiting the biological activity of IL-6 include IL-
6 production inhibition and IL-6 activity inhibition are considered. In the former, a 4H-1-benzopyran-4-one derivative which is a production inhibitor has been reported [JP-A-2-497].
No. 78]. On the other hand, in the latter, the search system is an unexplored field and is more unique than ever, and thus reports are mostly on macromolecules such as antibodies and peptides that are disadvantageous for administration [The European Journal of・ Immunology (The European Journal of Immunology), No.18
Vol. 951-956 (1988)].

[0004] Nitric oxide (hereinafter abbreviated as NO) is a physiological activity in the body of mammals, for example, as a vasodilator in the vascular system [Pharmacol. Rev. 43, 109-142].
(1991)], as a factor showing tumoricidal cell bactericidal action in leukocytes [Curr. Opin. Immunol. Vol. 3, pp. 65-70 (199).
1)], as a neurotransmitter in the nervous system [Neuron Vol. 8,
3-11 (1992)] and so on. NO is NO synthase (hereinafter abbreviated as NOS)
Is produced from L-arginine. at present,
The existence of three types of isoforms, namely, neuronal NOS, vascular endothelial NOS, and inducible NOS (hereinafter abbreviated as iNOS) has been genetically revealed [Cell
70, 705-707 (1992)], the former two are constitutive in comparison with the latter iNOS due to its production mode.
It is also called NOS (hereinafter, abbreviated as cNOS). cN
OS is present in vascular endothelial cells and nerve cells, and is said to be calcium / calmodulin-dependent and activated by various receptor stimuli to produce a small amount of NO, which is responsible for the above-mentioned physiological regulatory action. On the other hand, iNOS is induced in macrophages, neutrophils, etc. by various cytokines and bacterial lipopolysaccharide (LPS), and a large amount of N
Since O is continuously produced, it has been pointed out that not only the above-mentioned physiological activity but also a damaging action on cells and tissues at the production site [Immunol. Today Vol. 13, 157-160]
Page (1992)]. In addition to the above cells, cells / tissues expressing iNOS include hepatocytes, Kupffer cells, glial cells, vascular smooth muscle cells, vascular endothelial cells, myocardial intima, cardiomyocytes, mesangial cells, chondrocytes, synovial cells, pancreas β cells and osteoclasts are known [FASEB J. Volume 6, 3
051-3064 (1992), Arch Surg. Volume 128, 396-401.
(1993), J. Biol. Chem. 44, 27580-27588 (199
4), J. Cell. Biochem. 57, 399-408 (199
5)], it is assumed that NO excessively produced in these cells / tissues is involved in many diseases and pathological conditions. Therefore,
The substance that suppresses NO production from iNOS-induced cells is, for example, arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, rheumatoid arthritis, osteoarthritis, gastric ulcer. It is considered to be effective as a prophylactic / therapeutic agent for various diseases such as, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection or pain. From this point of view, as a compound that inhibits iNOS, L-
arginineanalogue [Pharmacol. Rev. Volume 43, 109-14
2 (1991)], aminoguanidine [Br. J. Pharmacol.
110, 963-968 (1993)], S-ethylisothiourea
[J. Biol. Chem. 43, 26669-26676 (1994)] and the like are reported. However, these compounds have problems that they are not very strong in activity or that they inhibit not only iNOS but also cNOS responsible for physiological activity. Also, [Chem. Mater., 1994, 6 (7) 1023-1
032], [Chem. Abs. 107: 96787] and [EP-A 8795.
[3] describes oxazole derivatives.
No mention is made of L-6 activity inhibitory action and NO production inhibitory action.

[0005]

[0005] Drugs for treating heart diseases, autoimmune diseases, inflammatory diseases, and diseases involving granuloma have been used, but their effects and safety are still insufficient. Nevertheless, with respect to these points, there is a demand for the development of further improved drugs for preventing and treating heart diseases, autoimmune diseases, inflammatory diseases, and diseases involving granuloma.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group is Unexpectedly excellent IL-6
It was found that it has an activity-inhibiting action and an NO production-inhibiting action from iNOS-induced cells, and is effective for heart diseases, autoimmune diseases, inflammatory diseases, diseases associated with granulomas, and as a result of further studies, the present invention Has been completed.

That is, the present invention provides 1) an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group (provided that when the 4-position is a hydrogen atom, the 2-position is a 4-methoxyphenyl group or 4 A compound in which the 5-position is a nonafluorobutylsulfonyl group in the -methoxyphenylethynyl group, a compound in which the 2-position is a phenyl group and the 5-position is (2-phenyl-5-thiazolyl) sulfonyl group, and 3- [5- (2,3-
Epoxy-5-hydroxy-4-methylhexyl)-
3,4-dihydroxytetrahydropyran-2-yl]
2-methyl-1- (E) -propenyl group having 4-position at 4-position
2) The oxazole derivative described in 1) above, which may be substituted at the 2-position with a halogen atom or a group through which a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom is present, 3) The oxazole derivative described in 1) above, which may be substituted at the 4-position with a halogen atom or a group through which a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom is present,

4) The oxazole derivative has the formula

Embedded image [In the formula, R ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted amino group, n is 1 or 2, R ² is a hydrogen atom, Cyano group, acyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted A good amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or formula-S
(O) m-R (In the formula, R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, m is 0,
An oxazole derivative according to the above 1), which is a compound represented by 1) or 2)

5) R ¹ is a C _1-19 hydrocarbon group which may be substituted, a nitrogen atom which may be substituted, an oxygen atom,
R 5 is a 5- to 8-membered heterocyclic group having at least one atom selected from a sulfur atom or an optionally substituted amino group, R ² is a hydrogen atom, a cyano group, an acyl group derived from an organic carboxylic acid, or a substituted group. Optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted C _1-19 hydrocarbon group, _optionally substituted atom selected from nitrogen atom, oxygen atom and sulfur atom. A 5- to 8-membered heterocyclic group having at least one of the above, an optionally substituted amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom, a halogen atom,
_Optionally substituted C _1-19 hydrocarbon group, _optionally substituted nitrogen atom, oxygen atom, 5- to 8-membered heterocyclic group having at least one atom selected from sulfur atom, optionally substituted A good C _1-19 hydrocarbon oxy group, an optionally substituted amino group, an optionally esterified carboxyl group or the formula —S (O) m—R ′ (wherein R ′ is substituted) An optionally substituted C _1-19 hydrocarbon group or an optionally substituted 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
m represents a group represented by 0, 1 or 2), and the oxazole derivative according to 4) above,

6) R ¹ is (1) (i) 5 to 6 membered sulfur-containing heterocyclic group, (ii) C _1-12 alkyl or 5 to 6 optionally substituted with cyano
Member oxygen-containing and nitrogen heterocyclic groups, (iii) carboxyl,
(iv) C _6-14 arylcarbonyl, (v) cyano, (vi) C
Carbamoyl which may be mono- or di-substituted by _1-12 alkyl and (vii) C _1-19 alkyl group which may be substituted by a group selected from C _1-12 alkoxycarbonyl, (2) mono- or di- -C _1-12 alkylamino optionally substituted C _2-12 alkenyl group, (3) C _2-12 alkynyl group, (4) C _3-10 cycloalkyl group, (5) (i) halogen atom , (Ii) C _1-12 alkoxy, (iii) (a)
Carbamoyl substituted with C _1-12 alkyl or C _3-10 cycloalkyl, (b) optionally substituted with halogen, C _6-14 arylsulfonyl or (c) C _1-12 alkylsulfonyl as a substituent. Amino that may be, (i
v) optionally C _1-12 alkyl optionally substituted with a halogen atom, (v) nitro, and (vi) group optionally substituted C _6-14 aryl group selected from hydroxyl, (6) (i) Halogen atom, (ii) C _1-12 alkoxy, (iii) (a)
C _1-12 substituted alkyl an optionally substituted C _6-14 arylsulfonyl, or (b) C _1-12 amino optionally having alkylsulfonyl as a substituent and (iv) a group selected from nitro An optionally _substituted C _7-19 aralkyl group, (7) a 5- or 6-membered nitrogen-containing or oxygen heterocyclic group, (8) (i) (a) C _1-12 alkoxycarbonyl, (b) mono- or di- -C _1-12 alkylamino, or (c) C _1-12 alkyl optionally having a 5- to 6-membered nitrogen-containing heterocyclic group as a substituent, (ii) a halogen atom or C _1-12 alkoxy substituted C _7-19 aralkyl which may have as a group, (ii
i) an amino group which may be substituted with a group selected from a C _4-12 bridged cyclic hydrocarbon group, (iv) C _6-14 aryl and (v) C _3-10 cycloalkyl, or (9) C The oxazole derivative according to 4) above, which is a thienopyrimidylhydrazino group optionally substituted with _1-12 alkyl.

7) R ¹ is (1) (i) thienyl, (ii) oxazolyl optionally substituted with C _1-6 alkyl or cyano, (iii) carboxyl, (iv) C _6-12 arylcarbonyl , (V) cyano, (vi)
Carbamoyl optionally mono- or di-substituted by C _1-6 alkyl and (vii) C _1-12 alkyl group optionally substituted by a group selected from C _1-6 alkoxycarbonyl, (2) mono- or C _2-6 alkenyl group _optionally substituted by di-C _1-6 alkylamino, (3) C _2-6 alkynyl group, (4) C _3-8 cycloalkyl group, (5) (i) halogen , (Ii) C _1-6 alkoxy, (iii) (a) C _1-6
Carbamoyl substituted by alkyl or C _3-8 cycloalkyl, (b) optionally halogen-containing C _6-12 arylsulfonyl or (c) C _1-6 alkylsulfonyl as a substituent Good amino, (iv) C _1-6 alkyl _optionally substituted with halogen, (v) nitro and
(vi) C _6-12 aryl group which may be substituted with a group selected from hydroxyl group, (6) (i) halogen, (ii) C _1-6 alkoxy, (iii) (a) C _1-6
C _6-12 arylsulfonyl optionally substituted with alkyl or (b) amino optionally substituted with C _1-6 alkylsulfonyl as a substituent and optionally substituted with a group selected from (iv) nitro A good C _7-13 aralkyl group, (7) a heterocyclic group selected from pyrimidyl, piperidino, morpholino and 1-piperazinyl, (8) (i) (a) C _1-6 alkoxycarbonyl, (b) mono- or di- C _1-6 alkylamino, or (c) pyridyl a C _1-6 alkyl as a substituent, (ii) C _{6-12
Optionally} substituted with a group selected from aryl, (iii) halogen or C _7-13 aralkyl optionally substituted with C _1-6 alkoxy, (iv) adamantyl and (v) C _3-8 cycloalkyl The oxazole derivative according to the above 4), which is an amino group or (9) a thienopyrimidylhydrazino group optionally substituted with C _1-6 alkyl,

8) R ² is (1) a cyano group, (2) a C _1-12 alkanoyl group, (3) a C _1-12 alkyl optionally substituted with a 5- to 6-membered nitrogen-containing heterocyclic group. , C _1-12 alkanoyl or C _7-19
A carbamoyl group optionally having aralkyl as a substituent, (4) C _6-14 aryl _optionally having a substituent,
5- to 6-membered nitrogen-containing saturated heterocyclic group-carbonyl group, (5) thiocarbamoyl group optionally having C _1-12 alkyl or C _7-19 aralkyl as a substituent, (6) 5- to 6-membered Nitrogen-containing saturated heterocyclic group-thiocarbonyl group, (7) (i) C _6-14 arylcarbonyl-acylated hydroxy, (ii) halogen, (iii) carboxyl, (iv) cyano, ( v) an amino _optionally substituted with a C _1-12 alkyl or a C _7-19 aralkyl _optionally substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (vi)
A 5- to 6-membered saturated heterocyclic group containing two nitrogen atoms, which may have C _6-14 aryl as a substituent, (v
ii) Substituted with a group selected from phthalimide, (viii) C _6-14 arylsulfonyl _optionally having C _1-12 alkyl, and (ix) C _6-14 aryloxy _optionally substituted with halogen. _Optionally substituted C _1-12 alkyl group, (8) halogen or hydroxyl substituted C _7-19 aralkyl group, (9) C _1-12 alkoxycarbonyl or C _6-14 aryl substituted group A 5- to 6-membered nitrogen-containing and sulfur heterocyclic group which may be possessed as, (10) an amino group which may be substituted by C _1-12 alkoxycarbonyl, (11) a carboxyl group or (12) C An oxazole derivative as described in 4) above, which is _1-12 alkoxycarbonyl;

9) R ² is (1) cyano group, (2) C _1-6 alkanoyl group, (3) (i) C _1-6 alkyl optionally substituted with pyridyl, (ii) C _{7 -13} aralkyl and (iii) carbamoyl group optionally having C _1-6 alkylcarbonyl as a substituent, (4) piperidinocarbonyl group, (5) _optionally substituted by C _6-12 aryl 1-piperazinylcarbonyl group, (6) (i) C _1-6 alkyl and (ii) thiocarbamoyl group optionally having C _7-13 aralkyl as a substituent, (7) piperidinothiocarbonyl group , (8) (i) C _6-12 arylcarbonyl-acylated hydroxy, (ii) halogen, (iii) carboxyl,
(iv) Cyano, (v) C _1-6 optionally substituted with pyridyl
Amino _optionally having alkyl or C _7-13 aralkyl as a substituent, (vi) 1-piperazinyl optionally substituted with C _6-12 aryl, (vii) phthalimide, (vi
ii) C _1-6 which may have an alkyl C _6-12 arylsulfonyl, (ix) optionally C _6-12 optionally substituted with halogen
C _1-6 alkyl group optionally substituted with a group selected from aryloxy, (9) C _7-13 aralkyl group optionally substituted with halogen or hydroxyl, (10) C _1-6 alkoxycarbonyl or A thiazolyl group optionally having C _6-12 aryl as a substituent, (11) an amino group optionally substituted by C _1-6 alkoxycarbonyl, (12) a carboxyl group, or (13) C _1- An oxazole derivative as described in 4) above, which is a _6- alkoxycarbonyl group,

10) R ³ is (1) a hydrogen atom, (2) a halogen atom, (3) (i) C _7-19 aralkyl or C _1-12 alkyl _optionally substituted amino. (ii) 5- to 6-membered saturated heterocyclic group containing 2 nitrogen atoms, which may have C _6-14 aryl as a substituent, (iii) phthalimide, (iv) C _1-12 alkyl _Optionally substituted by C _6-14
Arylsulfonyl, (v) hydroxy optionally acylated with C _1-12 alkanoyl, (vi) 5- to 6-membered saturated heterocyclic group containing a nitrogen atom and / or an oxygen atom,
(vii) a 5- or _6- membered halogen atom, (viii) C _1-12 alkoxycarbonyl and (ix) C _1-6 alkyl or cyano-containing optionally substituted nitrogen atom and / or oxygen atom. C _1-12 alkyl group _optionally substituted with a group selected from unsaturated heterocyclic groups, (4) C _2-12 alkenyl group _optionally substituted with C _6-14 aryl, (5) C _{1 -12} has a C _6-14 aryl group optionally substituted by alkoxy, (6) (i) amino, (ii) nitro, (iii) C _1-12 alkoxy or (iv) halogen as a substituent. May be C
_7-19 aralkyl group, (7) C _3-10 cycloalkyl group, (8) C _3-10 cycloalkyl-C _1-12 alkyl group, (9) C _4-12 bridged cyclic hydrocarbon group, (10 ) A 5- or 6-membered unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom, (11) C _1-12 alkoxy group, (12) (i) (a) C _1-12 alkoxycarbonyl or (b ) 5
To an amino group optionally substituted with a group selected from C _1-12 alkyl optionally having a 6-membered nitrogen-containing heterocyclic group as a substituent and (ii) C _7-19 aralkyl, or (13 ) An oxazole derivative according to the above 4), which is a C _1-12 alkoxycarbonyl group,

11) R ³ is (1) a hydrogen atom, (2) a halogen atom, (3) (i) C _7-13 aralkyl or C _1-6 alkyl _optionally substituted amino. (ii) 1-piperazinyl substituted with C _6-12 aryl, (iii) phthalimido, (iv) C _6-12 arylsulfonyl optionally having C _1-6 alkyl, (v) C _{1- 6} Hydroxy optionally acylated with alkanoyl, (vi) morpholino, (vii) piperidino, (viii) halogen, (ix) C _1-6 alkoxycarbonyl and (x) C _1-6 alkyl or cyano as substituents A C _1-6 alkyl group optionally substituted by a group selected from oxazolyl, (4) a C _2-6 alkenyl group _optionally substituted by C _6-12 aryl (5) C _1-6 alkoxy optionally substituted C _6-12 also be an aryl group, (6) (i) amino, (ii) nitro, (iii) C _1-6 alkoxy Shi or (iv) a halogen atom which may be substituted C _7-13 arachidyl group, (7) C _3-8 cycloalkyl group, (8) C _3-8 cycloalkyl -C _1-6 alkyl group, ( 9) adamantyl group, (10) oxadiazolyl, (11) C _1-6 alkoxy group, (12) (i) C _1-6 alkoxycarbonyl or C _1-6 alkyl optionally having pyridyl as a substituent Group and (ii) an amino group optionally substituted with a group selected from a C _7-13 aralkyl group, or (13) a C _1-6 alkoxycarbonyl group, the oxazole derivative according to 4) above, 12) R ¹ Is C optionally substituted with (1) (i) 2-thienyl or (ii) carboxyl
_1-6 alkyl group, (2) (i) halogen, (ii) C _1-6 alkoxy or (iii) C _1-6 alkyl optionally substituted with carbamoylamino optionally substituted C _{6- 12} aryl groups, (3) nitro optionally substituted C _7-13 aralkyl groups, (4) (i) C _1-6 alkyl, (ii) C _6-12 aryl or (iii) C _3-8 The oxazole derivative according to the above 4), which is an amino group optionally substituted with cycloalkyl or a (5) morpholino group,

13) R ² is a cyano group, a thiocarbamoyl group, a carbamoyl group, a C _1-6 alkyl group _optionally substituted with halogen, and the oxazole derivative according to 4) above, 14) R ³ is 1) a hydrogen atom, (2) a C _1-6 alkyl group or a C _1-6 alkyl group which may be substituted with an amino which may have a C _7-13 aralkyl as a substituent, (3) C _{3- 6}
Cycloalkyl group or C _6-12 aryl group optionally substituted with (4) C _1-6 alkoxy or C optionally substituted with (5) (i) halogen or (ii) C _1-6 alkoxy
_7-13 The oxazole derivative described in 4) above which is an aralkyl group, 15) The oxazole derivative described in 4) above, wherein n is 2.

16) Equation (1)

Embedded image [Wherein R ¹ , R ² and R ³ have the same meanings as described in 4) above, and the compound represented by the formula

[0018]

Embedded image [Wherein R ¹ , R ² and R ³ have the same meanings as described above, and n has the same meaning as described in 4) above, or

Equation (2)

Embedded image [Wherein R ² and R ³ have the same meanings as described above, R ¹² represents a lower alkyl group or a phenyl group, and n ¹ represents 0, 1 or 2] and a compound represented by the formula R ¹ -SO ₂ M [wherein R ¹ has the same meaning as defined above and M represents an alkali metal]

[0020]

Embedded image [Wherein R ¹ , R ² and R ³ are as defined above], or

Equation (3)

Embedded image [Wherein R ² , R ³ and n have the same meanings as defined above, and X represents a leaving group] and a compound of the formula HNR ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or Which are different from each other, represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ and R ⁵ may form a ring together with the adjacent nitrogen atom]. React with a compound to give a formula

[0022]

Embedded image [Wherein R ² , R ³ , n, R ⁴ and R ⁵ have the same meanings as described above], and a process for producing the oxazole derivative according to 4) above,

17) Equation (1)

Embedded image [In the formula, R ² and R ³ have the same meaning as described in 4) above.]
A compound represented by the formula M ₂ S [wherein M has the same meaning as described in 16) above and a compound represented by the formula R ¹ X [wherein R ¹ has the same meaning as described in 4) above. Where X is 1 above
6) has the same meaning as described above], or

Equation (2)

[Chemical 21]

[Wherein R ² and R ³ have the same meanings as described above,
R ¹² and n ¹ have the same meanings as described in 16) above] and a compound represented by the formula R ¹ -SH [wherein R ¹ has the same meanings as described above] are reacted. Or

Equation (3)

Embedded image [Wherein R ² , R ³ , R ¹² and n ¹ are as defined above]

A compound represented by the formula M ₂ S [wherein M has the same meaning as defined above] and a compound represented by the formula R ¹ X [wherein R ¹ and X have the same meanings as defined above]. Formula characterized by reacting with a compound

Embedded image [Wherein R ¹ , R ² and R ³ have the same meanings as described above],

18) A drug comprising an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group, 19) an oxazole derivative represented by the formula:

Embedded image [Wherein R ¹ represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted, n is 1 or 2, and R ² ′ is a hydrogen atom. A cyano group, an acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted An amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or -S (O)
m-R (R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and m represents a group represented by 0, 1 or 2)]. The drug according to the above 18),

20) The drug according to the above 18) or 19), which is a preventive / therapeutic drug for a heart disease, an autoimmune disease, an inflammatory disease, or a disease associated with granuloma, 21) cardiomyopathy, cardiac hypertrophy, myocardial infarction, angina. , Rheumatoid arthritis, systemic erythematosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease, autoimmune hemolytic anemia, mesangial proliferation Nephritis, IgA nephritis,
Lupus nephritis, osteoporosis, amyloidosis, bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis,
Prevention against atherosclerosis, active chronic hepatitis, alcoholic liver cirrhosis, gout, encephalitis, multiple myeloma, atrial mucosa, renal cancer, lung adenocarcinoma, malignant mesothelioma, ovarian cancer or cancer cachexia 22) The drug according to the above 18) or 19) which is a therapeutic agent, 22) an interleukin-6 activity inhibitor containing an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group, 23) arteriosclerosis, Myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, The drug according to the above 18) or 19), which is a preventive / therapeutic drug for hepatitis, graft rejection or pain, and 24) a sulfinyl group or a sulfonyl group at the 5-position. About nitric oxide production inhibitor comprising the oxazole derivative having binding to group by.

The oxazole ring which is the skeleton of the compound of the present invention is represented by the following formula.

Embedded image

The compounds of the present invention A is a sulfinyl group at the 5-position (-SO-) or sulfonyl group (-SO ₂ -) oxazole derivatives having a binding group via the (however,
A compound in which the 4-position is a hydrogen atom, the 2-position is a 4-methoxyphenyl group or a 4-methoxyphenylethynyl group, and the 5-position is a nonafluorobutylsulfonyl group, the 2-position is a phenyl group, and the 5-position is (2-phenyl-5 A compound that is a -thiazolyl) sulfonyl group and 3- [5- (2,3
-Epoxy-5-hydroxy-4-methylhexyl)-
3,4-dihydroxytetrahydropyran-2-yl]
2-methyl-1- (E) -propenyl group having 4-position at 4-position
(Excluding compounds that are methylphenylsulfonyl groups). The 2-position of the oxazole ring may be unsubstituted,
It may be substituted with a specific substituent, for example, a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. The 4-position of the oxazole ring may be unsubstituted, but may be substituted with a specific substituent, for example, a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. The group bonded via the sulfinyl group or the sulfonyl group, which is the substituent at the 5-position of the oxazole ring, may be any group as long as it is bonded via the sulfinyl group or the sulfonyl group. Such groups include, for example, the formula R ¹ —S (O) n— (wherein R ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group). And the amino group, n is 1 or 2, and the like.

Examples of the halogen atom include fluorine,
Chlorine, bromine, iodine, etc. are used. The group having a carbon atom at the 2-position or the 4-position is, for example, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group (the heterocyclic group is Bonded to the 2-position or 4-position of the oxazole derivative), -CN, -CO
^{OR a, -CO-R a,} -CO-NR a R b, -CS-NR
^{a R b, -CO-SR a} , -CS-SR a, -CO-NR a
^{-CO-R b, -C (=} NH) such as -NR ^a R ^b is used. Examples of the group via the nitrogen atom at the 2-position or 4-position include, for example, —NR ^a R ^b , —NR ^a —CO—R ^b , and —NR ^a —C.
^{S-R b, -NR c -CO} -NR a R b, -NR c -CS-
NR ^a R ^b , -NR ^a -CO-OR ^b , -NR ^a -CS-O
^{R b, -NR a -CO-SR} b, -NR a -CS-SR b,
^{-NR c -C (= NH) -NR} a R b, -NR a -SO 2 R b,
Etc. -NR ^c -NR ^a R ^b is used. Examples of the group via the oxygen atom at the 2-position or 4-position include, for example, -OR ^a ,-
O-CO- ^Ra , -O-CS- ^Ra , -O-CO-O
^{R a, -O-CO-NR} a R b, -O-C (= NH) -NR a
Are used. Examples of the substituent via the 2-position or 4-position sulfur atom include, for example, —SR ^a , —SO—R ^a , and —S.
_{^{O 2 -R a, -SO 2 NR}} a R b, -S-CO-R a, -S-
CS-R ^a , -S-CO-NR ^a R ^b , -S-CS-NR ^{a
R b, -S-C (=} NH) NR a R b, etc. -SCN is used. The above R ^a , R ^b and R ^c are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. Further, when it has —NR ^a R ^b as ^a partial structure of the substituent, R ^a and R ^b may form a ring together with the adjacent nitrogen atom.

A hydrocarbon group and R ¹ in "a group through a carbon atom" defined as a substituent at the 2- and 4-positions,
As the hydrocarbon group represented by R ^a , R ^b and R ^c ,
Examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, an aralkyl group, and a crosslinked cyclic hydrocarbon group. Of these, a C _1-24 hydrocarbon group is preferable, and a C _1-19 hydrocarbon group is more preferable. The alkyl group has, for example, 1 to 1 carbon atoms.
24 linear or branched alkyl groups (C _1-24 alkyl groups) are preferred, and specific examples include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, n-hexyl, isohexyl,
n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,
N-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-eicosyl, n-docosyl, n-tetracosyl and the like are used. As the alkyl group, a linear or branched alkyl group having 1 to 19 carbon atoms (C _1-19 alkyl group) is preferable, and a linear or branched alkyl group having 1 to 12 carbon atoms is particularly preferable. (C _1-12 alkyl group) is preferable, and particularly, a linear or branched alkyl group having 1 to 6 carbon atoms (C _1-6
Alkyl group) and the like are preferable.

The alkenyl group has, for example, 2 carbon atoms.
To 24 linear or branched alkenyl groups (C _2-24 alkenyl groups), and specific examples thereof include vinyl, propenyl (1-, 2-), and butenyl (1-, 2-, 3)
-), Pentenyl, octenyl, butadienyl (1,3
−) And the like are used. Here, as the alkenyl group,
For example, a straight-chain or branched alkenyl group having 2 to 19 carbon atoms (C _2-19 alkenyl group) is preferable.
_2-12 alkenyl group) is preferable, and a linear or branched alkenyl group having 2 to 6 carbon atoms (C _2-6 alkenyl group) is particularly preferable. As the alkynyl group, for example,
A linear or branched alkynyl group having 2 to 24 carbon atoms (C _2-24 alkynyl group) is preferred.
Ethynyl, propynyl (1-, 2-), butynyl (1
-, 2-, 3-), pentynyl, octynyl, decynyl and the like are used. Here, as the alkynyl group, for example, a straight-chain or branched alkynyl group having 2 to 19 carbon atoms (C _2-19 alkynyl group) is preferable. Alkynyl group (C _2-12
Alkynyl group), more preferably a straight-chain or branched alkynyl group having 2 to 6 carbon atoms (C _2-6 alkynyl group).

The cycloalkyl group is preferably, for example, one having 3 to 10 carbon atoms (C _3-10 cycloalkyl group), and specific examples include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are used. Here, as cycloalkyl, for example, those having 3 to 8 carbon atoms (C _3-8 cycloalkyl group) are preferable, and those having 3 to 6 carbon atoms (C 3
_3-6 cycloalkyl group) is more preferred. As the aryl group, for example, a monocyclic or condensed polycyclic group is used, and an aryl group having 6 to 18 carbon atoms (C _6-18 aryl group) is preferable. Examples of the aryl group include phenyl, biphenylyl, And naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Here, as the aryl group, for example, phenyl, naphthyl and the like have 6 to 1 carbon atoms.
4 (C _6-14 aryl group) is preferable and has 6 to 6 carbon atoms.
Twelve (C _6-12 aryl groups) are more preferred.

As the aralkyl group, an alkyl group substituted with a 1 to 3 ring aromatic hydrocarbon group and the like are used.
Among them, an alkyl group having 1 to 24 carbon atoms (C _6-18 aryl-C _1-24 alkyl group) substituted with an aryl group having 6 to 18 carbon atoms is preferable. Specific examples of such an aralkyl group include benzyl, biphenylylmethyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl,
Naphthylmethyl and the like. Among these aralkyl groups, for example, a C _7-19 aralkyl group is preferable, and a C _7-13 aralkyl group is particularly preferable. As the crosslinked cyclic hydrocarbon group, for example, a crosslinked cyclic hydrocarbon group having 4 to 19 carbon atoms (C _4-19 crosslinked cyclic hydrocarbon group) and the like are preferable, and above all, a crosslinked cyclic carbon group having 4 to 12 carbon atoms. Hydrogen group (C
_4-12 bridged cyclic hydrocarbon groups) are more preferable. Specific examples of such a crosslinked cyclic hydrocarbon group include 1-adamantyl, 2-adamantyl, 2-norbornanyl, 5-norbornen-2-yl and the like.

A heterocyclic group in "a group through a carbon atom" defined as a substituent at the 2- and 4-positions and R ¹ , R ^a ,
Examples of the heterocyclic group represented by R ^b and R ^c include, for example,
A 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, etc. in addition to carbon atoms, or a condensed ring group thereof (eg, 6 to 8-membered carbocycle) Alternatively, a condensed ring group with a heterocyclic group, etc.) is used. Specifically, for example, 2
-Or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2
-, 4- or 5-pyrimidinidyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,
3-, 4- or 5-pyrazolyl, 2-, 4- or 5
-Imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5 -(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,
2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, N-oxide-
2-, 3- or 4-pyridyl, N-oxide-2-,
4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, triazinyl, oxotriazinyl, tetrazolo [1,5-b ] Pyridazinyl, triazolo [1,5
-B] pyridazinyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl,
Thiopyranyl, 1,4-oxazinyl, morpholinyl,
1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, acridinyl Phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, thienopyrimidinyl and the like are used. Preferable examples of the heterocyclic group include a heterocyclic group containing at least one 5- or 6-membered nitrogen atom, and specific examples include pyrimidinyl, thiazolyl, oxadiazolyl and the like.

The above-mentioned "hydrocarbon group" and "heterocyclic group"
Examples of the substituent of are C _1-12 alkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably C _1-6 alkyl, and more preferably C _1-6 alkyl. _1-4 alkyl), C _3-8 cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl etc., preferably C _3-6 cycloalkyl), halogen atom (eg fluorine, chlorine, bromine, iodine etc.), cyano group, optionally acylated hydroxyl group (eg C _1-12 alkanoyl, Hydroxyl optionally acylated with C _6-14 arylcarbonyl, C _7-13 aralkylcarbonyl and the like, specifically, for example, carboxyl, C _1-12 alkanoyloxy (eg,
Acetyloxy, etc.), C _6-14 arylcarbonyloxy (eg, benzoyloxy etc.), C _7-13 aralkylcarbonyloxy (eg, benzylcarbonyloxy etc.)
Etc.), C _1-12 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc., preferably C _1-6 alkoxy), C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy etc.), carboxyl group , C
_1-12 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Butoxycarbonyl etc., preferably C _1-6 alkoxy-carbonyl), nitro group, carbamoyl group optionally substituted by C _1-12 alkyl (eg butylcarbamoyl etc.), C _1-12 alkanoyl group (eg formyl) , Acetyl, propionyl, butyryl, etc., preferably C _1-6 alkanoyl), C _6-14 aryl group (eg,
Phenyl, naphthyl etc.), C _6-14 arylcarbonyl (eg benzoyl, naphthoyl etc.), C _7-13 aralkylcarbonyl (eg benzylcarbonyl, naphthylmethylcarbonyl etc.), heterocyclic group [eg nitrogen in addition to carbon atom 3 to 8 containing 1 to 4 heteroatoms selected from atoms, oxygen atoms, sulfur atoms, etc.
Membered heterocyclic group or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group, specifically, for example, furyl (2-, 3-), thienyl (2-, 3-), Pyridyl (2-, 3-, 4-), thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl, oxazolyl (2-, 4-, 5-) etc.], -NR ^d R ^e [R ^d and R ^e are the same or different. A hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or a group represented by -SO ₂ R ^f (R ^f represents an optionally substituted hydrocarbon group) , R ^d and R ^e may form a ring with the adjacent nitrogen atom], C _1-12 alkylthio, C _1-12 alkylsulfinyl, C _1-12 alkylsulfonyl, C _6-14 arylthio, C _{6 -14} arylsulfinyl, C _6-14 aryl Sulfonyl and the like are used.

Among the above substituents, C _1-12 alkyl group, C
_3-8 cycloalkyl and C _1-12 alkylthio, C
_1-12 alkyl group alkylsulfinyl or C _1-12 alkylsulfonyl, for example, C _3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl group), a halogen atom (e.g., fluorine , Chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-12 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc., preferably C _1-6 alkoxy), carboxyl, C _1-12 alkoxy-carbonyl (eg. , Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like, preferably C _1-6 alkoxy-carbonyl), nitro, amino,
Carbamoyl, C _1-12 alkanoyl (eg formyl, acetyl, propionyl, butyryl, etc., preferably C
_1-6 alkanoyl) and the like.

Among the above substituents, a C _6-14 aryl group,
C _6-14 arylcarbonyl group, C _{6- 14} arylthio, C
_6-14 C _6-14 aryl arylsulfinyl or C _6-14 arylsulfonyl, for example, C _1-6 alkyl (e.g. methyl, ethyl, propyl, butyl, etc., preferably C
_1-4 alkyl), C _3-8 cycloalkyl (eg cyclopentyl, cyclohexyl etc., preferably C _3-6 cycloalkyl), halogen atom (eg fluorine, chlorine, bromine, iodine etc.), cyano, hydroxyl, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc., preferably C _1-4 alkoxy), carboxyl, C
_1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc., preferably C _1-4 alkoxy-carbonyl), nitro, amino, carbamoyl, C _1-6 alkanoyl (eg, formyl, acetyl) , Propionyl,
It may be further substituted with, for example, butyryl, preferably C _1-4 alkanoyl).

Among the above substituents, the heterocyclic group is, for example,
C _1-6 alkyl (eg, methyl, ethyl, propyl, butyl, etc., preferably C _1-4 alkyl), C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl), Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc., C _1-4 alkoxy), carboxyl, C _1-6 alkoxy -Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc., preferably C _1-4 alkoxy-carbonyl), nitro, amino, carbamoyl,
It may be further substituted with C _1-6 alkanoyl (eg formyl, acetyl, propionyl, butyryl and the like, preferably C _1-4 alkanoyl) and the like.

Of the above substituents, --NR ^{d Re} or --S
The hydrocarbon group and the heterocyclic group represented by R ^d , R ^e or R ^f in the group represented by O ₂ -R ^f have the same meanings as the hydrocarbon group and the heterocyclic group represented by R ¹ , respectively. . When R ^d and R ^e form a ring with an adjacent nitrogen atom, the ring (that is, a nitrogen-containing ring) is selected from the group consisting of carbon atom, nitrogen atom, oxygen atom and sulfur atom in addition to nitrogen atom. A 5- to 8-membered nitrogen-containing ring which may contain 1 to 4 atoms is used, and the nitrogen-containing ring may be further condensed with a 6- to 8-membered carbocyclic or heterocyclic group. Good. When R ^d and R ^e together with the nitrogen atom form a nitrogen-containing ring in this way, the group —NR ^d R ^e itself constitutes a cyclic amino group. Specific examples of the cyclic amino group (—NR ^d R ^e ) include, for example, 1-
Pyrrolidyl, 1-imidazolyl, piperidino (1-piperidyl), 1-piperazinyl, 3-oxazolidinyl,
Hexamethyleneimino, heptamethyleneimino, morpholino (4-morpholinyl), 1-indolinyl, phthalimide and the like can be mentioned. These cyclic amino groups may have a substituent.

The substituent of the hydrocarbon group represented by R ^d or R ^e , the heterocyclic group or the cyclic amino group formed by —NR ^d R ^e is, for example, C _1-4 alkyl (eg, methyl, ethyl , Propyl, butyl etc.), C _3-8 cycloalkyl (eg cyclopentyl, cyclohexyl etc., preferably C _1-6 cycloalkyl group), halogen atom (eg fluorine, chlorine, bromine, iodine etc.), cyano, hydroxyl , C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), nitro, amino, di -C _1-4 alkylamino, carbamoyl, C _1-4 alkanoyl (eg, formyl, acetyl, propionyl, bromo) Cylyl, etc.), C _6-12
Aryl (eg, phenyl, naphthyl, etc.), 2-pyridyl and the like can be mentioned. The C _1-4 alkyl and C _3-8 cycloalkyl include, for example, C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl), halogen atom (eg, fluorine, Chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl) , Butoxycarbonyl), nitro, amino, carbamoyl, C _1-4 alkanoyl (eg, formyl, acetyl, propionyl, butyryl, etc.) and the like. The C _6-12 aryl is, for example, C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), C
_3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-4 alkoxy (eg, Methoxy,
Ethoxy, propoxy, butoxy, etc.), carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Butoxycarbonyl etc.), nitro, amino, carbamoyl, C _1-4 alkanoyl (eg formyl, acetyl,
(Eg, propionyl, butyryl, etc.) and the like. As the ring formed by R ^a and R ^b together with the adjacent nitrogen atom, the same ring as the ring formed by R ^d and R ^e with the adjacent nitrogen atom can be used.

Examples of the optionally substituted amino group represented by R ¹ include, for example, the formulas —NR ⁴ R ⁵ and —NR ^a —C.
^{O-R b, -NR a -CO} -NR 4 R 5, -NR a -CS-
^{NR 4 R 5, -NR a -NR} 4 R 5 or -NR ^a -CO-O
R ^b (wherein R ^a , R ^b , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, ^Four
And R ⁵ may be a group represented by the formula (may form a ring with the adjacent nitrogen atom). The optionally substituted hydrocarbon group represented by R ⁴ or R ⁵ and the optionally substituted heterocyclic group are each represented by the above R ^a.
Alternatively, those similar to the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R ^b are used. The ring formed by R ⁴ and R ⁵ together with the adjacent nitrogen atom may be the same ring as the ring formed by R ^d and R ^e together with the adjacent nitrogen atom.

The "group bonded via a sulfinyl group or a sulfonyl group" at the 5-position of the compound A of the present invention is:
A group represented by the formula R ¹ -S (O) n- is preferred. R ¹
As, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or the like is used, and in particular, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group is used. Amino group which may be present is preferable. As n, either 1 or 2 is preferable, but 2 is particularly preferable. Compound A of the present invention 2
As the substituent at the position, for example, a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydrocarbonoxy group (for example, -OR ^a group represented by a), an optionally substituted amino group (for example, —NR ^a R ^b, etc.), an optionally esterified carboxyl group (—COOR ^a )
Are preferred. Examples of the substituent at the 4-position of the compound A of the present invention include a hydrogen atom, a cyano group, an acyl group (-CO
R ^a ), an optionally substituted carbamoyl group (—CO
-NR ⁶ R ^7), an optionally substituted thiocarbamoyl group ^{(-CS-NR 6 R 7)} , optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, optionally substituted also an amino group (such as -NR ^a -CO-OR ^b), esterified carboxyl group which may be (-COOR ^a)
Are preferred. In particular, a cyano group and an acyl group (-COR
^a ), an optionally substituted carbamoyl group (—CO—
NR ⁶ R ^7), an optionally substituted thiocarbamoyl group ^{(-CS-NR 6 R 7)} , optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, optionally esterified And a carboxyl group (—COOR ^a ) and the like are preferable.

More specifically, as the substituent at the 5-position,
A group represented by the formula R ¹ —S (O) n— is preferable, and R ¹
For example, the following (1) to (9) are preferable. (1) (i) 5- or 6-membered sulfur-containing heterocyclic group, (ii) C _1-12 alkyl or 5-6 optionally substituted with cyano
Member oxygen-containing and nitrogen heterocyclic groups, (iii) carboxyl,
(iv) C _6-14 arylcarbonyl, (v) cyano, (vi) C
Carbamoyl which may be mono- or di-substituted by _1-12 alkyl, and (vii) C _1-19 alkyl group which may be substituted by a group selected from C _1-12 alkoxycarbonyl, (2) mono- or di- -C _1-12 C _2-12 alkenyl group _optionally substituted by alkylamino, (3) C _2-12 alkynyl group, (4) C _3-10 cycloalkyl group, (5) (i) halogen atom , (Ii) C _1-12 alkoxy, (iii) (a)
Carbamoyl substituted with C _1-12 alkyl or C _3-10 cycloalkyl, (b) optionally substituted with halogen, C _6-14 arylsulfonyl or (c) C _1-12 alkylsulfonyl as a substituent. Amino that may be, (i
v) a C _1-12 alkyl group _optionally substituted with a halogen atom, (v) nitro and (v) a C _6-14 aryl group _optionally substituted with a group selected from hydroxyl group, (6) (i) Halogen atom, (ii) C _1-12 alkoxy, (iii) (a)
C _1-12 substituted alkyl an optionally substituted C _6-14 arylsulfonyl, or (b) C _1-12 amino optionally having alkylsulfonyl as a substituent and (iv) a group selected from nitro An optionally _substituted C _7-19 aralkyl group, (7) a 5- or 6-membered nitrogen-containing or oxygen heterocyclic group, (8) (i) (a) C _1-12 alkoxycarbonyl, (b) mono- or di- -C _1-12 alkylamino, or (c) C _1-12 alkyl optionally having a 5- to 6-membered nitrogen-containing heterocyclic group as a substituent, (ii) a halogen atom or C _1-12 alkoxy substituted C _7-19 aralkyl which may have as a group, (ii
i) an amino group which may be substituted with a group selected from a C _4-12 bridged cyclic hydrocarbon group, (iv) C _6-14 aryl or (v) C _3-10 cycloalkyl, (9) C _{1 -12} Thienopyrimidylhydrazino groups optionally substituted with alkyl

More preferably, R ¹ is, for example,
(1) to (9) are preferred. (1) (i) thienyl, (ii) oxazolyl optionally substituted with C _1-6 alkyl or cyano, (iii) carboxyl, (iv) C _6-12 arylcarbonyl, (v) cyano, (v
i) carbamoyl mono- or di-substituted with C _1-6 alkyl and (vii) C _1-12 alkyl group optionally substituted with a group selected from C _1-6 alkoxycarbonyl, (2) mono- Alternatively, a C _2-6 alkenyl group _optionally substituted with di-C _1-6 alkylamino, (3) C _2-6 alkynyl group, (4) C _3-8 cycloalkyl group, (5) (i) Halogen, (ii) C _1-6 alkoxy, (iii) (a) C _1-6
Carbamoyl substituted with alkyl or C _3-8 cycloalkyl, (b) optionally substituted C _6-12 arylsulfonyl, or (c) C _1-6 alkylsulfonyl as a substituent Optionally substituted amino, (iv) halogen-substituted C _1-6 alkyl, (v) nitro and (v) hydroxyl-substituted C _6-12 aryl group, (6 ) (i) halogen, (ii) C _1-6 alkoxy, (iii) (a) C _1-6
C _6-12 arylsulfonyl optionally substituted by alkyl, or (b) optionally substituted by a group selected from amino and (iv) nitro optionally having C _1-6 alkylsulfonyl as a substituent. A heterocyclic group selected from C _7-13 aralkyl group, (7) pyrimidyl, piperidino, morpholino and 1-piperazinyl, (8) (i) (a) C _1-6 alkoxycarbonyl, (b) mono- or di -C _1-6 alkylamino, or (c) C _1-6 alkyl optionally having a pyridyl as a substituent, (ii) C
_6-12 aryl, (iii) substituted by a group selected from C _7-13 aralkyl optionally substituted with halogen or C _1-6 alkoxy, (iv) adamantyl and (v) C _3-8 cycloalkyl Optionally an amino group, or (9) a thienopyrimidylhydrazino group optionally substituted by C _1-6 alkyl.

More preferably, R ¹ is, for example, (1) (i) 2-thienyl or (ii) a C _1-6 alkyl group optionally substituted with carboxyl, (2) (i) halogen, (ii) ) C _1-6 alkoxy or (iii) C
_1-6 alkyl optionally substituted carbamoylamino C _6-12 aryl group _optionally substituted, (3) nitro optionally substituted C _7-13 aralkyl group, (4) (i ) C _1-6 alkyl, (ii) C _6-12 aryl or (ii
i) Amino group which may be substituted with C _3-8 cycloalkyl, (5) morpholino group and the like are preferable.

As n, either 1 or 2 is preferable, and 2 is particularly preferable. When n is 1, R ¹ is particularly C which may be substituted with (1) a cyano group or the like.
Substitute carbamoyl substituted with _1-12 alkyl group, (2) C _2-12 alkynyl group, (3) C _3-8 cycloalkyl group, (4) (i) halogen, (ii) C _1-6 alkyl Amino optionally having as a group, (iii) C optionally substituted with halogen
C optionally substituted with a group selected from _1-6 alkyl
_{A 6-12} aryl group or (5) pyrimidinyl is preferred.

Examples of the substituent at the 2-position include the following (1)
(13) and the like are preferable. (1) hydrogen atom (2) halogen atom (3) (i) amino _optionally having C _7-19 aralkyl or C _1-12 alkyl as a substituent, (ii) C _6-14 aryl as a substituent may have as the two nitrogen atoms of 5 to 6-membered saturated heterocyclic group containing, (iii) phthalimide, (iv) C _1-12 optionally C _6-14 optionally substituted with alkyl
Arylsulfonyl, (v) hydroxy optionally acylated with C _1-12 alkanoyl, (vi) 5- to 6-membered saturated heterocyclic group containing a nitrogen atom and / or an oxygen atom,
(vii) a 5- or _6- membered halogen atom, (viii) C _1-12 alkoxycarbonyl and (ix) C _1-6 alkyl or cyano-containing optionally substituted nitrogen atom and / or oxygen atom. C _1-12 alkyl group _optionally substituted with a group selected from unsaturated heterocyclic groups (4) C _6-14 C _2-12 alkenyl group _optionally substituted with aryl (5) C _1-12 C _6-14 aryl group optionally substituted with alkoxy (6) (i) amino, (ii) nitro, (iii) C _1-12 alkoxy or (iv) optionally having halogen as a substituent C
_7-19 Aralkyl group (7) C _3-10 cycloalkyl group (8) C _3-10 cycloalkyl-C _1-12 alkyl group (9) C _4-12 bridged cyclic hydrocarbon group (10) Nitrogen atom or 5- and 6-membered unsaturated heterocyclic group containing / and an oxygen atom (11) C _1-12 alkoxy group (12) (i) (a) C _1-12 alkoxycarbonyl or (b) 5
To C _1-12 alkyl _optionally having a 6-membered nitrogen-containing heterocyclic group as a substituent and (ii) an amino group _optionally substituted with a group selected from C _7-19 aralkyl (13) C _1-12 alkoxycarbonyl group

More preferably, for example, the following (1) to (1
3) etc. are used. (1) hydrogen atom (2) halogen atom (3) (i) C _7-13 aralkyl or amino _optionally having C _1-6 alkyl as a substituent, (ii) C _6-12 aryl substituted 1-piperazinyl, (iii) phthalimide, (iv) C _6-12 arylsulfonyl optionally having C _1-6 alkyl, (v) hydroxy optionally acylated with C _1-6 alkanoyl , (Vi) morpholino, (vii) piperidino, (viii) halogen, (ix) C _1-6 alkoxycarbonyl and (x) C _1-6 alkyl or cyano which may have a substituent as an oxazolyl. C _1-6 alkyl group optionally substituted with group (4) C _2-6 alkenyl group optionally substituted with C _6-12 aryl (5) optionally substituted with C _1-6 alkoxy C _6-12 aryl group (6) (i) amino, (ii) nitro, substituted with (iii) C _1-6 alkoxy or (iv) a halogen atom There good C _7-13 arachidyl group (7) be a C _3-8 cycloalkyl group (8) C _3-8 cycloalkyl -C _1-6 alkyl group (9) adamantyl (10) oxadiazolyl (11) C _{1 -6} alkoxy group (12) (i) substituted by a group selected from C _1-6 alkyl group optionally having C _1-12 alkoxycarbonyl or pyridyl as a substituent and (ii) C _7-13 aralkyl group _Optionally substituted amino group (13) C _1-12 alkoxycarbonyl group

More preferably, (1) hydrogen atom, (2) C _1-6
Alkyl or C _1-6 alkyl group _optionally substituted with amino, which may have C _7-13 aralkyl as a substituent, (3) C _3-6 cycloalkyl group, (4) C _1-6 A C _6-12 aryl group optionally substituted with alkoxy, or
(5) (i) a halogen atom or (ii) a C _7-13 aralkyl group optionally substituted by C _1-6 alkoxy is used.

When the 5-position is a group bonded via a sulfinyl group, the substituent at the 2-position is (1) hydroxy optionally acylated with C _1-12 alkanoyl (eg acetoxy etc.). Optionally substituted C _1-12 alkyl group, (2) C _6-12 aryl optionally substituted C _2-12 alkenyl group, (3) optionally substituted by C _1-12 alkoxy C _6-14 aryl group, (4) C _7-19 aralkyl group, (5) C _3-10 cycloalkyl group, (6) nitrogen atom or /
And a 5- to 6-membered saturated heterocyclic group containing an oxygen atom (for example, oxadiazolyl etc.) is preferable.

Examples of the substituent at the 4-position include the following (1)
To (11) are preferred. (1) Cyano group (2) C _1-12 alkanoyl group (3) C _1-12 alkyl optionally substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, C _1-12 alkanoyl or C _7-19
Carbamoyl group optionally having aralkyl as a substituent (4) C _6-14 aryl _optionally having a substituent,
5- to 6-membered nitrogen-containing saturated heterocyclic group-carbonyl group (5) C _1-12 alkyl or C _7-19 thiocarbamoyl group optionally having as a substituent (6) 5- or 6-membered thiocarbamoyl group Nitrogen-saturated heterocyclic group-thiocarbonyl group (7) (i) C _6-14 hydroxy _optionally acylated with arylcarbonyl, (ii) halogen, (iii) carboxyl, (iv) cyano, (v) 5 To amino _optionally having C _1-12 alkyl _optionally substituted with a 6-membered nitrogen-containing heterocyclic group or C _7-19 aralkyl as a substituent, (vi)
A 5- to 6-membered saturated heterocyclic group containing two nitrogen atoms, which may have C _6-14 aryl as a substituent, (v
ii) phthalimide, is optionally substituted with a group selected from (viii) C _1-12 optionally C _6-14 arylsulfonyl optionally having alkyl and (ix) C _6-14 aryloxy optionally substituted by halogen _{Optionally a} C _1-12 alkyl group (8) having a C _7-19 aralkyl group optionally substituted with halogen or hydroxyl (9) having a C _1-12 alkoxycarbonyl or C _6-14 aryl as a substituent _Optionally substituted 5- or 6-membered nitrogen-containing and sulfur heterocyclic group (10) amino group optionally substituted by C _1-12 alkoxycarbonyl (11) carboxyl group (12) C _1-12 alkoxycarbonyl group

More preferably, for example, the following (1) to (1
2) etc. are used. (1) Cyano group (2) C _1-6 alkanoyl group (3) (i) C _1-6 alkyl optionally substituted with pyridyl, (ii) C _3-17 aralkyl and (iii) C _1-6 Carbamoyl group optionally having alkanoyl as a substituent (4)
1-piperazinylcarbonyl group substituted with a piperidinocarbonyl group (5) C _6-12 aryl (6) (i) C _1-6 alkyl and (ii) C _3-17 aralkyl as substituents Optionally thiocarbamoyl group (7) piperidinothiocarbonyl group (8) (i) C _6-12 aryl optionally acylated hydroxy, (ii) halogen, (iii) carboxyl, (iv) Cyano, (v) C _1-6 alkyl _optionally substituted with pyridyl or amino _optionally having C _7-13 aralkyl as a substituent, (vi) 1 substituted with C _6-12 aryl −
Piperazinyl, (vii) phthalimide, (viii) C _1-12 arylsulfonyl optionally having C _1-6 alkyl, (ix)
Halogen-substituted C _1-6 alkyl group (9) optionally substituted by a group also selected from optionally C _6-12 aryloxy optionally halogenated or optionally substituted C _7-13 also be an aralkyl group with a hydroxyl , (10) Thiazolyl group optionally having C _1-6 alkoxycarbonyl or C _6-12 aryl as a substituent (11) Amino group optionally substituted by C _1-6 alkoxycarbonyl (12) carboxyl Group (13) C _1-6 alkoxycarbonyl group

More preferably, a cyano group, a thiocarbamoyl group, a carbamoyl group or a C _1-6 alkyl group optionally substituted with halogen is used, and a cyano group or a thiocarbamoyl group is particularly preferable. When the 5-position is a group bonded via a sulfinyl group, the substituent at the 4-position is preferably a cyano group, an optionally substituted C _1-12 alkyl group such as a halogen atom, or a thiocarbamoyl group. Of these, a cyano group is particularly preferable. Compound A of the present invention is a compound in which 2-position is 4-methoxyphenyl group or 4-methoxyphenylethynyl group and 5-position is nonafluorobutylsulfonyl group, 2-position is phenyl group and 5-position is (2-phenyl A compound which is a -5-thiazolyl) sulfonyl group and 3- [5- (2,3
-Epoxy-5-hydroxy-4-methylhexyl)-
3,4-dihydroxytetrahydropyran-2-yl]
2-methyl-1- (E) -propenyl group having 4-position at 4-position
Does not include compounds that are methylphenylsulfonyl groups,
The compound A of the present invention is a novel compound.

The compound A used in the present invention is, for example,
formula

Embedded image [In the formula, R ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted amino group, n is 1 or 2, R ² is a hydrogen atom, Cyano group, acyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted A good amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or -S (O)
m-R (R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, m represents a group represented by 0, 1 or 2)] (However, a compound in which R ² is a hydrogen atom, n is 2, R ³ is a 4-methoxyphenyl group or a 4-methoxyphenylethynyl group, and R ¹ is a nonafluorobutyl group,
A compound in which R ³ is a phenyl group and R ¹ is a 5- (2-phenylthiazolyl) group, and R ³ is 3- [5- (2,3
-Epoxy-5-hydroxy-4-methylhexyl)-
3,4-dihydroxytetrahydropyran-2-yl]
2-Methyl-1- (E) -propenyl group in which R ¹ is 4-
(Excluding compounds that are methylphenyl groups) and the like are preferable.

In the above formula (I), the optionally substituted hydrocarbon group represented by R ¹ , the optionally substituted heterocyclic group and the optionally substituted amino group are as described above. . Examples of the optionally substituted amino group represented by R ³ include, for example, formula —NR ⁴ R ⁵ [wherein, R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon. Group or a heterocyclic group which may be substituted, and R ⁴ and R ⁵ may form a ring with adjacent nitrogen atoms]. As the acyl group represented by R ² , for example, an acyl group derived from an organic carboxylic acid or the like is used, and those having 1 to 19 carbon atoms (C _1-19 alkanoyl) and the like are preferable. Specifically, formyl, acetyl, ethylcarbonyl, propylcarbonyl and the like are used, and have 1 to 1 carbon
2 (C _1-12 alkanoyl) and the like are preferable, and those having 1 to 6 carbon atoms (C _1-6 alkanoyl group) and the like are particularly preferable. The optionally substituted carbamoyl group represented by R ² includes, for example, the formula —CONR ⁶ R ⁷ (in the formula, R
⁶ and R ⁷ are the same or different and each represents a hydrogen atom, an acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁶ and R ⁷ are a ring together with an adjacent nitrogen atom. May be formed) and the like.

The optionally substituted thiocarbamoyl group represented by R ² is, for example, the formula —CS—NR ⁶ R ⁷
(In the formula, R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁶ and R ⁷ are adjacent to each other. And may form a ring together with the nitrogen atom). Examples of the optionally esterified carboxyl group represented by R ² or R ³ include, for example, formula —COOR ¹⁰ (wherein, R ¹⁰ is a hydrogen atom, an optionally substituted hydrocarbon group or a substituted Group which represents a heterocyclic group which may also be used. R
^As the substituent of the optionally substituted amino group represented by 2, for example, a C _1-12 alkoxycarbonyl (preferably C _1-6 alkoxycarbonyl) group and the like can be used. Among them, for example, butoxycarbonyl and the like. Is preferred. Examples of the halogen atom represented by R ³ include fluorine, chlorine, bromine, iodine and the like. The hydrocarbon oxy group which may be substituted has the formula —OR
A group represented by ¹¹ (R ¹¹ represents an optionally substituted hydrocarbon group) and the like are used. R, R ² , R ³ , R ⁴ ,
The “optionally substituted hydrocarbon group” represented by R ⁵ , R ⁶ , R ⁷ , R ¹⁰ or R ^{11 includes} the “optionally substituted hydrocarbon group” for R ¹ described above. Similar ones are used.

The "optionally substituted heterocyclic group" represented by R, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ¹⁰ is "the above-mentioned R ¹ ". The same as the "heterocyclic group which may be substituted" is used. The ring formed by R ⁴ and R ⁵ or R ⁶ and R ⁷ together with the adjacent nitrogen atom is the same as the ring formed by R ^d and R ^e together with the adjacent nitrogen atom. As the acyl group represented by R ⁶ or R ⁷ , the same acyl groups as those represented by R ² are used. Examples of -S (O) m-R represented by R ³ include C _1-12 alkylthio group (eg, methylthio, ethylthio, etc.), C
_6-14 arylthio group (eg, phenylthio etc.), C
_6-14 aryl-C _1-6 alkylthio group (eg, benzylthio etc.), C _1-12 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl etc.),
C _6-14 arylsulfinyl group (eg phenylsulfinyl etc.), C _6-14 aryl-C _1-6 alkylsulfinyl group (eg benzylsulfinyl etc.), C
_1-12 alkylsulfonyl group (eg methylsulfonyl, ethylsulfonyl etc.), C _6-14 arylsulfonyl group (eg phenylsulfonyl etc.), C _6-14 aryl-C _1-6 alkylsulfonyl group (eg benzylsulfonyl) Etc.) are used.

In the above formula (I), preferred examples of R ¹ include those represented by the formula R ¹ —S (O) n of the substituent at the 5-position.
The same as the preferable examples of R ^{1 in} the group represented by — are mentioned. As the preferable example of R ^2, the same as the above-mentioned substituent at the 4-position is used. As preferred examples of R ³ , those similar to the above-mentioned substituent at the 2-position are used. Examples of the compound (I) of the present invention include R ¹ and R ² described above.
All compounds in which R ³ and R ³ are optionally combined are preferred.

In the compound (I) of the present invention, R ² is a hydrogen atom, n is 2, R ³ is a 4-methoxyphenyl group or a 4-methoxyphenylethynyl group, and R ¹ is a nonafluorobutyl group. Some compounds, R ³ is a phenyl group, R ¹
Is a 4- (2-phenylthiazolyl) group and R ³ is 3- [5- (2,3-epoxy-5-hydroxy-4-methylhexyl) -3,4-dihydroxytetrahydropyran-2. -Yl] -2-methyl-1-
(E) - R ¹ does not contain the compound is 4-methylphenyl group propenyl group, compound (I) of the present invention are novel compounds. Compound B used in the present invention, 5-position group or a sulfonyl group via a sulfinyl group (-SO-) - oxazole derivatives having a binding group via a (-SO _2). The 2-position of the oxazole ring may be unsubstituted, but may be substituted with a specific substituent, for example, a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. The 4-position of the oxazole ring may be unsubstituted, but may be substituted with a specific substituent, for example, a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. The group bonded via the sulfinyl group or the sulfonyl group which is the 5-position substituent of the oxazole ring is a group bonded via the sulfinyl group or the sulfonyl group which is the 5-position substituent of the oxazole ring in the above compound A. The same as is used.

As the group via the halogen atom and carbon atom, the nitrogen atom, the oxygen atom and the sulfur atom at the 2-position or 4-position of the oxazole ring, the halogen atom and carbon atom at the 2-position or 4-position in the compound A, respectively,
The same groups as those through the nitrogen atom, oxygen atom and sulfur atom are used. The compound B used in the present invention has a hydrogen atom at the 4-position, a 4-methoxyphenyl group or a 4-methoxyphenylethynyl group at the 2-position, and a nonafluorobutylsulfonyl group at the 5-position, which have been removed from the compound A. Is a phenyl group at the 2-position and a (2-phenyl-5-thiazolyl) sulfonyl group at the 5-position, and 3- [5- (2,3-epoxy-
5-hydroxy-4-methylhexyl) -3,4-dihydroxytetrahydropyran-2-yl] -2-methyl-1- (E) -propenyl group and a compound in which the 5-position is a 4-methylphenylsulfonyl group is also included. Has been.

As the compound B, for example, compounds of the formula

Embedded image [Wherein R ¹ represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted, n is 1 or 2, and R ² ′ is a hydrogen atom. A cyano group, an acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted An amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or -S (O)
m-R (R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, m represents a group represented by 0, 1 or 2)] and the like. preferable. R ¹ and R ³ in the above formula (I ′) have the same meanings as described above, and R ² ′ has the same meaning as R ² described above.

When the compound of the present invention has an acidic group (eg, carboxyl group, phenolic hydroxyl group, sulfo group, etc.) or basic group (eg, amino group, etc.) as a substituent, a suitable base or acid is used. It is possible to form salts with these, and these salts are also included in the compound of the present invention. As the type of the salt, a pharmacologically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid,
Examples thereof include salts with organic acids and salts with basic or acidic amino acids. Examples of the salt with an inorganic base include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.)
Or an ammonium salt etc. are mentioned. Examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, dicyclohexylamine and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like. Examples of the salt with an organic acid include salts with formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. The salt with a basic amino acid includes, for example, a salt with arginine, lysine, ornithine, and the salt with an acidic amino acid includes, for example, a salt with aspartic acid, glutamic acid and the like.

[0066]

BEST MODE FOR CARRYING OUT THE INVENTION The compound A of the present invention can be produced according to the production method of the compound (I) of the present invention described below. The compound (I) of the present invention is, for example, the following (1)
It can be manufactured by the method (4). (1)

Embedded image [Wherein, R ¹ , R ² , R ³ and n have the same meaning as described above. ]

This method is a method for producing the compound (I) of the present invention by oxidizing the oxazole derivative (II). More specifically, it is a method of producing compound (I) by dissolving derivative (II) in a solvent and then reacting with an oxidizing agent. Examples of the oxidizing agent include metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, potassium peroxysulfate, potassium permanganate, sodium perborate, sodium periodate, sodium hypochlorite, Halogen or the like is used. The amount of the oxidizing agent is usually about 1 to 3 mol with respect to 1 mol of the compound (II). Particularly, when n = 1, it is usually about 1 to 1.5 mol, preferably about 1 to 1.2 mol, and when n = 2, it is usually about 2 to 3 mol, preferably about 2 to 2.5 mol. use. The reaction solvent is not particularly limited as long as it does not react with an oxidizing agent, and examples thereof include dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane,
Aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbons such as pentane, hexane, petroleum ether, alcohols such as methanol, ethanol, i-propanol, t-butanol, acetic acid, trifluoroacetic acid, etc. Carboxylic acids, ethers such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, water or a mixed solvent thereof are used. In the present oxidation reaction, for example, vanadium pentoxide, benzene selenic acid, ruthenium oxide, osmium oxide, or the like may be used as a catalyst. The reaction is carried out under cooling, at room temperature or under heating, and is usually carried out from room temperature to under heating. The reaction time is generally about 1-20 hours, preferably about 1-10 hours. After the reaction, the target compound can be isolated and purified with high purity from the reaction solution by known means, for example, solvent extraction, distillation, column chromatography, recrystallization and the like.

(2)

Embedded image [Wherein R ¹ , R ² , R ³ and n have the same meanings as described above, R 1
¹² is a lower alkyl group or a phenyl group, and n ¹ is 0,1
Or 2, M is an alkali metal. ]

In the above formula, the alkali metal represented by M is, for example, lithium, sodium, potassium or cesium. Examples of the lower alkyl group represented by R ¹² include C such as methyl, ethyl and propyl.
_{A 1-6} alkyl group is used. This method is a method for producing a compound (n = 2) of the compound (I) of the present invention by reacting the sulfinate salt (IV) with the oxazole derivative (III) in a solvent. The reaction solvent is preferably a polar solvent, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, alcohols such as methanol, ethanol, i-propanol and t-butanol, and acetone. , Acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof and the like are used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is usually about 1 to
20 hours, preferably about 1-10 hours. After the reaction, the desired product can be isolated and purified with high purity from the reaction solution by known means such as solvent extraction, distillation, column chromatography, and recrystallization.

(3)

Embedded image [In the formula, R ¹ ″, R ² ″ and R ³ ″ have the same meanings as the above R ¹ , R ² and R ³ . R ¹ ″ ″, R ² ″ ″ and R ³ ″ ″
Has the same meaning as R ¹ , R ² and R ³ above. R ¹ '' and R
^{1 ''', R 2'} ' and R ^2' '' or R ³ '' and R ³ '''is may be the same, at least one set of the three sets are not identical. This method is a compound (I ″ ′) obtained by introducing a substituent into 1 to ³ of R ¹ ′, R ² ′ or R ³ ′ of the oxazole derivative (I ″) or converting the functional group. ) Is a method of manufacturing. The substituent introduction reaction and the functional group conversion reaction can be carried out by applying a conventional method. As a conventional method, for example, the following reaction can be mentioned as a typical example.

[0071]

[Table 1]

[0072]

[Table 2]

[0073]

[Table 3] Here, R ^g , R ^h and R ⁱ are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.

(4)

Embedded image [Wherein R ¹ , R ² , R ³ , R ¹² , R ⁴ , R ⁵ , n and M
Is as defined above, and X is a leaving group. In the above formula, X is a halogen atom such as chlorine, bromine or iodine, p-toluenesulfonyloxy, methanesulfonyloxy or the like. Among them, a halogen atom is preferable, and a chlorine atom is more preferable.

In this method, R
^This is a method for producing a compound (VII), wherein ¹ is an amino group (—NR ⁴ R ⁵ ) which may be substituted. More specifically, the compound (III) is reacted with M ₂ S such as sodium sulfide or potassium sulfide and then treated with an acid to give a thiol intermediate (V), which is then subjected to a known method (Chem. Lett. 1992). ， 1483
Compound (VII) by converting to intermediate (VI) and then reacting with primary and secondary amines in the presence of a base according to
It is a method of manufacturing. At this time, the intermediates (V) and (VI) can be isolated and purified to obtain a pure product, but there is no problem if they are not particularly purified. Compound (III)
As a reaction solvent in the reaction with M ₂ S in the step of converting a compound to a compound (V), a polar solvent is preferable, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. methanol,
Alcohols such as ethanol and i-propanol, acetone, acetonitrile, water or a mixed solvent thereof are used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1-20 hours, preferably about 1-10 hours. Next, the acid used in the acid treatment step is not particularly limited, but an aqueous solution of hydrochloric acid, sulfuric acid, nitric acid, acetic acid or the like is generally used.

In the step of converting the compound (III) to the compound (V), MSH such as sodium hydrosulfide or potassium hydrosulfide may be used instead of M ₂ S. The reaction conditions in this case are the same as those for M ₂ S, but the acid treatment step is not required. The step of converting compound (V) to compound (VI) can be carried out according to a known method using sulfuryl chloride and a nitrate as described above. The base used in the step from compound (VI) to compound (VII) includes, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, sodium methoxide, Sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide and the like are used. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; and fats such as pentane, hexane, and petroleum ether. Group hydrocarbons, diethyl ether,
Ethers such as tetrahydrofuran and dioxane, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, a mixed solvent thereof and the like are used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1-20 hours, preferably about 1-10 hours. After the reaction, the desired product can be isolated and purified with high purity from the reaction solution by known means such as solvent extraction, distillation, column chromatography, and recrystallization.

The starting compound (II) used in the production method (1) can be produced by a known method or a method analogous thereto. As a known method, a method of converting 2-amino-3,3-dichloroacrylonitrile as a starting material into a 3,3-bis (substituted mercapto) derivative and then cyclizing the derivative with a silver salt [Matsumura et al. Chem. Pharm. Bull.
24, 912 (1976), ibid., 948] and a method for S-alkylating 5-mercaptooxazole [TK Vino
gradova et al., Zh. Org. Khim. 18: 1864 (1982)].

Further, the raw material compound (II) can be obtained by the process represented by the following formula.

Embedded image [Wherein R ¹ , R ² , R ³ and M have the same meanings as described above, X
Represents a leaving group. ]

In the above formula, R ² is preferably an electron-withdrawing group such as cyano, alkyloxycarbonyl or carbamoyl. X is preferably a halogen atom such as chlorine, bromine or iodine, p-toluenesulfonyloxy, methanesulfonyloxy or the like. This law
Matsumura et al. [Chem. Pharm. Bull. 24, 912 (197
6)] or a compound obtained by a method analogous thereto (VII
Sodium sulfide I) in a solvent, M _2, such as potassium sulfide
This is a method of obtaining a compound (II) by reacting with S and then treating with R ₃ X. The reaction solvent is preferably a polar solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, alcohols such as methanol, ethanol, i-propanol, t-butanol, and acetone. , Acetonitrile, N, N-dimethylformamide,
Dimethyl sulfoxide, hexamethylphosphoramide,
Water or a mixed solvent thereof is used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1-20 hours, preferably about 1-10 hours.

Further, the starting compound (II) can be obtained by the steps shown in the following formula.

Embedded image [In the formula, R ¹ , R ² , R ³ , R ¹² , n ¹ , M and X have the same meanings as described above. ]

That is, the compound (III) is reacted with a thiol in a solvent in the presence of a base (method A) or with M ₂ S such as sodium sulfide or potassium sulfide and then treated with R ₃ X. (Method B), the compound (I
I) is the way to get. In both methods A and B, the reaction solvent is
Polar solvents are preferred, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, alcohols such as methanol, ethanol, i-propanol, t-butanol, acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof is used, and the reaction is carried out under cooling, at room temperature or under heating, and the reaction time is usually about 1 to 1.
It is 20 hours, preferably 1 to 10 hours. Examples of the base in Method A include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, hydrogenation. Sodium, sodium amide, etc. are used. Alternatively, the thiol may be treated with a base in advance and reacted with the compound (III) as a thiol anion (RS ⁻ ).

The compound (II) thus obtained has the same method as in the production method (3) of the compound (I) for 1 to ³ of the substituents R ¹ , R ² and R ^3. A compound having a different substituent can be converted by introducing a substituent with or converting the functional group. Production method (2),
Of the starting compound (III) of (4), those having n ¹ = 0 are included in the compound (II), and those having n ¹ = 1 and 2 are included in the compound (I). It can be manufactured according to the manufacturing method. The starting compound (I ″) of the production method (3) can be produced by the production method (1) or (2). The oxazole derivative (I) of the present invention can be produced as described above.

In the formula (I), the preferred compounds are shown in more detail below. R ¹ is (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl-substituted C _1-12 alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro C _3-8 cycloalkyl optionally substituted with (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 Shikuroa Kill, (c) halogen, (d) cyano, (e) hydrate Rokishiru, (f) C _1-6 alkoxy,
(g) carboxyl, (h) C _1-6 alkoxy-carbonyl,
(i) nitro, (j) amino, (k) carbamoyl or (l) C
_1-6 substituted with C _6-14 aryloxy optionally substituted with alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 alkyl Carbamoyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' [R ^d 'and R ^e ' are the same or different and are (A) a hydrogen atom, (B) (a) (i) C _3-8 cycloalkyl, (ii ) Halogen, (iii)
Cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (vi)
Carboxyl, (vii) C _1-4 alkoxy-carbonyl, (v
iii) nitro, (ix) amino, (x) carbamoyl or (xi)
C _1-4 alkanoyl optionally substituted by optionally C _1-4 alkyl, (b) (i) C 3-8 cycloalkyl, (ii) halogen, (ii
i) cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (v
i) carboxyl, (vii) C _1-4 alkoxy-carbonyl,
(viii) nitro, (ix) amino, (x) carbamoyl or (x
i) C _3-8 cycloalkyl optionally substituted with C _1-4 alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-4 alkoxy, (g) carboxyl, (h) C _1-4
Alkoxy-carbonyl, (i) nitro, (j) di-C _1-4 alkylamino, (k) carbamoyl, (l) C _1-4 alkanoyl, (m) (i) C _1-4 alkyl, (ii) C _3-8 cycloalkyl,
(iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C
Optionally substituted with _1-4 alkoxy, (vii) carboxyl, (viii) C _1-4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl or (xii) C _1-4 alkanoyl Good C _6-12 aryl and C _1-19 hydrocarbon group _optionally substituted with a group selected from (n) 2-pyridyl, (C) (a) (i) C _3-8 cycloalkyl, (ii ) Halogen, (iii)
Cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (vi)
Carboxyl, (vii) C _1-4 alkoxy-carbonyl, (v
iii) nitro, (ix) amino, (x) carbamoyl or (xi)
C _1-4 alkanoyl optionally substituted by optionally C _1-4 alkyl, (b) (i) C 3-8 cycloalkyl, (ii) halogen, (iii)
Cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (vi)
Carboxyl, (vii) C _1-4 alkoxy-carbonyl, (v
iii) nitro, (ix) amino, (x) carbamoyl or (xi)
C _3-8 cycloalkyl optionally substituted with C _1-4 alkanoyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-4 alkoxy, (g) carboxyl, (h ) C _1-4
Alkoxy-carbonyl, (i) nitro, (j) di-C _1-4 alkylamino, (k) carbamoyl, (l) C _1-4 alkanoyl, (m) (i) C _1-4 alkyl, (ii) C _3-8 cycloalkyl,
(iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C
Optionally substituted with _1-4 alkoxy, (vii) carboxyl, (viii) C _1-4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl or (xii) C _1-4 alkanoyl A heterocyclic group which may be substituted with a group selected from good C _6-12 aryl and (n) 2-pyridyl, or

(D) -SO ₂ R ^f '(R ^f ' is (a) (i) C _3-8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C _{1 -4} alkoxy, (vi) carboxyl, (vi
i) C _1-4 alkoxy-carbonyl, (viii) nitro, (ix)
Amino, (x) carbamoyl or (xi) C _1-4 alkyl optionally substituted with C _1-4 alkanoyl, (b) (i) C _3-8
Cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (vi) carboxyl,
(vii) C _1-4 alkoxy-carbonyl, (viii) nitro, (i
x) amino, (x) carbamoyl or (xi) C _1-4 optionally substituted by alkanoyl C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-4 alkoxy, (g) carboxyl, (h) C _1-4 alkoxy-carbonyl, (i) nitro, (j) di-C _1-4 alkylamino, (k) carbamoyl, (l) C _1-4 Alkanoyl, (m) (i) C _1-4 alkyl, (ii) C _3-8 cycloalkyl, (iii) halogen, (iv)
Cyano, (v) hydroxyl, (vi) C _1-4 alkoxy, (vi
i) carboxyl, (viii) C _1-4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl or
(xii) C _1-4 C _6-12 optionally substituted with alkanoyl
Aryl and (n) represents a C _1-19 hydrocarbon group which may be substituted with a group selected from (2) pyridyl), wherein R ^d 'and R ^e ' are together with adjacent nitrogen atoms,
1-pyrrolidyl, 1-imidazolyl, piperidino, 1-
A nitrogen-containing heterocycle selected from piperazinyl, 3-oxazolidinyl, hexamethyleneimino, heptamethyleneimino, morpholino, 1-indolinyl or phthalimide may be formed, and (a) (i) C _3-8 cycloalkyl,
(ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C
Optionally substituted with _1-4 alkoxy, (vi) carboxyl, (vii) C _1-4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl or (xi) C _1-4 alkanoyl Good C _1-4 alkyl, (b) (i) C _3-8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl,
(v) C _1-4 alkoxy, (vi) carboxyl, (vii) C _1-4 alkoxy-carbonyl, (viii) nitro, (ix) amino,
(x) carbamoyl or (xi) C _1-4 alkanoyl-substituted C _3-8 cycloalkyl, (c) halogen,
(d) cyano, (e) hydroxyl, (f) C _1-4 alkoxy,
(g) carboxyl, (h) C _1-4 alkoxy-carbonyl,
(i) nitro, (j) di-C _1-4 alkylamino, (k) carbamoyl, (l) C _1-4 alkanoyl, (m) (i) C _1-4 alkyl,
(ii) C _3-8 cycloalkyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C _1-4 alkoxy, (vii) carboxyl, (viii) C _1-4 alkoxy-carbonyl, (i
x) nitro, (x) amino, (xi) carbamoyl or (xii) C
_1-4 C _6-12 aryl optionally substituted with alkanoyl and optionally substituted with a group selected from (n) 2-pyridyl],

(17) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1 -12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k)
C _1-12 alkanoyl with optionally substituted C _1-12 alkylthio, (18) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, (e) C _Optionally substituted with _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy - carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally substituted with alkanoyl C _1-12 alkylsulfonyl, (20 ) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl,

(1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1 -12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k)
C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, (e) C _Optionally substituted with _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl A good C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 aralkylcarbonyl Optionally acylated hydroxyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
5- to 8-membered heterocyclic group having at least one atom selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with a group selected from arylsulfonyl,

--NR ⁴ 'R ⁵ ' [R ⁴ 'and R ⁵ ' are the same or different, and (A) a hydrogen atom, (B) (1) (a) C _3-8 cycloalkyl, (b) halogen , (C) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, Substituted with (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl. _Optionally substituted C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _{7- 19} aralkylcarbonyl may be acylated Dorokishiru, (6) C _1-12 alkoxy, (7) (a) C 1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f ) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' [R ^d 'and R ^e ' have the same meanings as defined above], (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro,
(i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl, (b) C _{3- 8} cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl, or

(C) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g ) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or
(k) C _1-12 optionally C _1-12 optionally substituted with alkanoyl
Alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1- 12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) Cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 Alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g ) Carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with a group selected from arylsulfonyl,
R ⁴ 'and R ⁵ ' together with adjacent nitrogen atoms are selected from 1-pyrrolidyl, 1-imidazolyl, piperidino, 1-piperazinyl, 3-oxazolidinyl, hexamethyleneimino, heptamethyleneimino, morpholino, 1-indolinyl or phthalimido. A nitrogen-containing heterocycle may be formed, and (a) (i) C _3-8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, ( vi) Carboxyl, (vii) C _1-4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl or (xi) C _1-4 alkyl optionally substituted by C _1-4 alkanoyl , (B) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-4 alkoxy, (g) carboxyl, (h) C _1-4 alkoxy-carbonyl , (I) nitro, (j) di-C _1-4 alkylamino, (k) carbamo Yl, (l) C _1-4 alkanoyl, (m) (i) C _1-4 alkyl, (ii) (i) C _3-8 cycloalkyl, (ii) halogen, (ii
i) cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (v
i) carboxyl, (vii) C _1-4 alkoxy-carbonyl,
(viii) nitro, (ix) amino, (x) carbamoyl or (x
i) C _3-8 cycloalkyl optionally substituted with C _1-4 alkanoyl, (iii) halogen, (iv) cyano, (v) hydroxyl, (vi) C _1-4 alkoxy, (vii) carboxyl, (vii
i) C _1-4 alkoxy-carbonyl, (ix) nitro, (x) amino, (xi) carbamoyl or (xii) C _6-12 aryl optionally substituted with C _1-4 alkanoyl and (n) 2 -May be substituted with a group selected from pyridyl],

[0093] -NR ^a '-CO-R ^b' [R ^a ', R ^b' are the same or different, (A) a hydrogen atom, (B) (1) ( a) C 3-8 cycloalkyl, ( b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, ( j) carbamoyl or (k) C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d ) Hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12. C _3-8 cycloalkyl optionally substituted with alkanoyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 have been acylated with aralkylcarbonyl Even from a hydroxyl, (6) C _1-12 alkoxy, (7) (a) C 1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxy, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d' R ^e '[R ^d ' and R ^e 'have the same meanings as defined above], (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro,
(i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl with optionally substituted C _1-12 alkylsulfinyl, (19) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) optionally substituted with C _1-12 alkanoyl C _1-12 alkylsulfonyl, (20) (a) C 1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl, or

(C) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g ) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or
(k) C _1-12 optionally C _1-12 optionally substituted with alkanoyl
Alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1- 12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) Cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 Alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g ) Carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Represents a 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with a group selected from arylsulfonyl],

[0097] ^{-NR a '-CO-NR 4'} R 5 ' [wherein, R
^a ', R ^4' and R ⁵ 'has the same significance as described ^{above], -NR a' -CS-NR 4} 'R 5' wherein, R ^a ', R ^4' and R ⁵ ', are as defined ^{above], -NR a '-NR 4' R} 5 ' wherein, R ^a', R ⁴ 'and R ^5'
Has the same significance as described above] or -NR ^a '-CO-OR ^b' wherein,, R ^a 'and R ^b' are,
The same meaning as above] is shown.

[0098] R ² is a hydrogen atom, a cyano group, an acyl group derived from an organic carboxylic acid, -CONR ⁶ 'R ^7' wherein, R ⁶ 'and R ^7' are the same or different, (A) Hydrogen atom, (B) C _1-12 alkanoyl, (C) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 Alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl-substituted C _{1 -12} alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, ( 4) cyano, (5) (a) _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 optionally hydroxylated be acylated with aralkylcarbonyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _{1- 6} alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' [R ^d 'and R ^e ' have the same meanings as defined above], (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro,
(i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl with optionally substituted C _1-12 alkylsulfinyl, (19) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) optionally substituted with C _1-12 alkanoyl C _1-12 alkylsulfonyl, (20) (a) C 1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl, or

(D) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g ) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or
(k) C _1-12 optionally C _1-12 optionally substituted with alkanoyl
Alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1- 12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) Cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 Alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g ) Carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with a group selected from arylsulfonyl,

R ⁶ 'and R ⁷ ' together with the adjacent nitrogen atom
1-pyrrolidyl, 1-imidazolyl, piperidino, 1-
A nitrogen-containing heterocycle selected from piperazinyl, 3-oxazolidinyl, hexamethyleneimino, heptamethyleneimino, morpholino, 1-indolinyl or phthalimide may be formed, and (a) (i) C _3-8 cycloalkyl,
(ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C
Optionally substituted with _1-4 alkoxy, (vi) carboxyl, (vii) C _1-4 alkoxy-carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl or (xi) C _1-4 alkanoyl Good C _1-4 alkyl, (b) C _3-8 cycloalkyl,
(c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-4
Alkoxy, (g) carboxyl, (h) C _1-4 alkoxy-
Carbonyl, (i) nitro, (j) di-C _1-4 alkylamino, (k) carbamoyl, (l) C _1-4 alkanoyl, (m) (i)
C _1-4 alkyl, (ii) (i) C _3-8 cycloalkyl, (ii) halogen, (iii) cyano, (iv) hydroxyl, (v) C _1-4 alkoxy, (vi) carboxyl, (vii ) C _1-4 alkoxy-
C _3-8 cycloalkyl optionally substituted with carbonyl, (viii) nitro, (ix) amino, (x) carbamoyl or (xi) C _1-4 alkanoyl, (iii) halogen, (iv) cyano, ( v) hydroxyl, (vi) C _1-4 alkoxy, (vii) carboxyl, (viii) C _1-4 alkoxy-carbonyl, (i
x) nitro, (x) amino, (xi) carbamoyl or (xii) C
_1-4 C _6-12 aryl optionally substituted with alkanoyl and optionally substituted with a group selected from (n) 2-pyridyl],

[0103] -CSNR ⁶ 'R ^7' [R ⁶ 'and R ^7' is,
Has the same meaning as above], (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkyl optionally substituted with C _1-12 alkanoyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, ( b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, ( i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro,
(i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl with optionally substituted C _1-12 alkylthio, (18) (a) C 3-8 cycloalkyl, (b) halogen, ( c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or ( k) C _1-12 alkanoyl with optionally substituted C _1-12 alkylsulfinyl, (19) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, ( substituted with e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl _{Optionally substituted} C _1-12 alkylsulfonyl, (20) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl,

(1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1 -12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k)
C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, (e) C _Optionally substituted with _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl With a good C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 aralkylcarbonyl Optionally acylated hydroxyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
5- to 8-membered heterocyclic group having at least one atom selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with a group selected from arylsulfonyl, and is substituted with C _1-19 hydrocarbonoxycarbonyl. It represents an optionally substituted amino group or an optionally esterified carboxyl group.

R ³ is a hydrogen atom, a halogen atom, (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy - carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 optionally substituted with alkanoyl Alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1- 12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) Cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 Arcoki , (7) (a) C 1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) Carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl,

(1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1 -12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k)
C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, (e) C _Optionally substituted with _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl A good C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 aralkylcarbonyl Optionally acylated hydroxyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
5- to 8-membered heterocyclic group having at least one atom selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with a group selected from arylsulfonyl,

(1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1 -12alkoxy-} carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k)
C _1-12 alkanoyl with optionally substituted C _1-12 alkyl, (2) (a) C 3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxy, (e) C _Optionally substituted with _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl A good C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 aralkylcarbonyl Optionally acylated hydroxyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' [R ^d 'and R ^e ' have the same meanings as defined above], (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbonoxy group which may be substituted with a group selected from arylsulfonyl,

--NR ⁴ 'R ⁵ ' (R ⁴ 'and R ⁵ ' have the same meanings as described in 25) above, an optionally esterified carboxyl group, or -S (O) m-R ″ [R ”is (A) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f ) Carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl-substituted C _1-12 alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy -Carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-8 alkanoyl-substituted C _3-8 cycloalkyl, (3) halogen, (4) cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro , (J) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' where R ^d 'and R ^e ' have the same meanings as defined above, (17) (a) C _3-8 cycloalkyl, (b) halogen, (c ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A C _1-19 hydrocarbon group which may be substituted with a group selected from arylsulfonyl, or

(B) (1) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g ) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or
(k) C _1-12 optionally C _1-12 optionally substituted with alkanoyl
Alkyl, (2) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _{1- 12} alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _3-8 cycloalkyl optionally substituted with C _1-12 alkanoyl, (3) halogen, (4) Cyano, (5) (a) C _1-12 alkanoyl, (b) C _6-14 arylcarbonyl or (c) C _7-19 hydroxyl optionally acylated with aralkylcarbonyl, (6) C _1-12 Alkoxy, (7) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c) halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g ) Carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) carbamoyl or
(l) C _6-14 aryloxy optionally substituted with C _1-6 alkanoyl, (8) carboxyl, (9) C _1-12 alkoxy-carbonyl, (10) nitro, (11) C _1-12 Carbamoyl optionally substituted with alkyl, (12) C _1-12 alkanoyl, (13) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Aryl, (14) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylcarbonyl, (15) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) Carbamoyl or (l) C _1-6 alkanoyl-substituted 3 to 8 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like,
Or a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic group,

(16) -NR ^d 'R ^e ' [R ^d 'and R ^e ' have the same meanings as defined above], (17) (a) C _3-8 cycloalkyl, (b) halogen, (c) ) Cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k ) C _1-12 alkanoyl-substituted C _1-12 alkylthio, (18) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) Substituted with C _1-12 alkoxy, (f) carboxyl, (g) C _1-12 alkoxy-carbonyl, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 alkanoyl Good C _1-12 alkylsulfinyl, (19) (a) C _3-8 cycloalkyl, (b) halogen, (c) cyano, (d) hydroxyl, (e) C _1-12 alkoxy, (f) carboxyl , (G) C _1-12 alkoxy-carboni Le, (h) nitro, (i) amino, (j) carbamoyl or (k) C _1-12 optionally C _1-12 alkylsulfonyl optionally substituted by alkanoyl, (20) (a) C 1-6 alkyl , (B) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylthio, (21) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
Arylsulfinyl, and (22) (a) C _1-6 alkyl, (b) C _3-8 cycloalkyl, (c)
Halogen, (d) cyano, (e) hydroxyl, (f) C _1-6 alkoxy, (g) carboxyl, (h) C _1-6 alkoxy-carbonyl, (i) nitro, (j) amino, (k) C _6-14 optionally substituted with carbamoyl or (l) C _1-6 alkanoyl
A 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with a group selected from arylsulfonyl, and m represents 0, 1 or 2] Represents a group represented by.

Compound B, especially Compound A, has excellent
L-6 activity inhibitory action and NO from iNOS-induced cells
It has an inhibitory action on production and has low toxicity, and can be used in humans and mammals (for example, mouse, rat, guinea pig, rabbit,
It can be used as a safe IL-6 activity inhibitor or NO production inhibitor against dogs, cats, cows, pigs, sheep, monkeys, chimpanzees, etc.). Further, compound B is a disease caused by IL-6, for example, heart diseases such as cardiomyopathy, cardiac hypertrophy, myocardial infarction, angina pectoris, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, rheumatism. Fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, various autoimmune diseases such as Castleman's disease or autoimmune hemolytic anemia, mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis, Bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic liver cirrhosis, inflammatory diseases such as gout or various encephalitis, or multiple myeloma, atrial mucosa , Prophylactic / therapeutic agent for diseases associated with granulomas such as renal cancer, lung adenocarcinoma, malignant mesothelioma, ovarian cancer or cancer cachexia or NO Diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes , As a medicine such as a prophylactic / therapeutic agent for glomerulonephritis, osteoporosis, pneumonia, hepatitis, transplant rejection or pain, etc., humans and mammals (eg, mouse, rat, guinea pig,
Rabbit, dog, cat, cow, pig, sheep, monkey, chimpanzee, etc.).
When compound B is used as a medicine, it is mixed with itself or with a suitable pharmacologically acceptable carrier, excipient, diluent and molded into tablets, capsules, granules, powders, etc. For example, it is parenterally administered by molding it into an injection.

In the production of the above oral preparations such as tablets, binders (eg hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol etc.), disintegrants (eg starch, carboxymethylcellulose calcium etc.), excipients, etc. A shaping agent (eg, lactose, starch, etc.), a lubricant (eg, magnesium stearate, talc, etc.) and the like can be appropriately mixed. In the case of producing parenteral preparations such as injections, aqueous solvents (eg, distilled water), water-soluble solvents (eg, physiological saline, Ringer's solution, etc.), isotonic agents (eg, glucose, D-). Sorbitol, D
-Mannitol, sodium chloride, etc., stabilizers (eg,
Human serum albumin, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol, etc.),
A buffering agent (eg, phosphate buffer, sodium acetate buffer, etc.), soothing agent (eg, benzalkonium chloride, procaine hydrochloride, etc.) and the like can be appropriately added. The daily dose of compound B varies depending on the target disease, target human or mammal, condition, etc., but when orally administered, it is usually about 1 to 10 per 1 kg body weight of human or mammal.
0 mg, more preferably about 1 to 50 mg, which can be administered in 1 to 3 divided doses. In the case of parenteral administration, generally, for example, about 0.1 to 10 mg, and more preferably about 0.1 to 5 mg per kg body weight of a human or mammal is administered once a day.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but these are merely examples and do not limit the present invention. The compounds obtained in Reference Examples and Examples are shown in [Table 4] to [Table 25]. IR spectra were measured by liquid film or KBr tablet method. Ph in the table indicates a phenyl group.

[0120]

Reference Example 1 3,3-Dichloro-2-hexanoylaminoacrylonitrile Method of Matsumura et al. [Chem. Pharm. Bull., 24, 924 (197
6)], 2-amino-3,3-dichloroacrylonitrile (50.0 g) and hexanoic acid anhydride (84.9 g) and concentrated sulfuric acid (0.5 ml) were used as an acid catalyst to give crude crystals of the title compound.
4 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.0Hz, 3H), 1.25-1.45 (m,
4H), 1.55-1.85 (m, 2H), 2.35 (t, J = 7.5Hz, 2H), 6.83 (bs, 1
H) The compound of Reference Example 5 was produced in the same manner.

[0121]

Reference Example 2 2-Benzoylamino-3,3-dichloroacrylonitrile 2-amino-3,3-dichloroacrylonitrile 5.0
0 g was dissolved in 100 ml of dichloromethane, and 5.64 g of benzoyl chloride was added under ice cooling, and then 5.36 g of anhydrous aluminum chloride was added. After stirring at 0 ° C for 1 hour, water 20
0 ml was added and the mixture was extracted 3 times with dichloromethane. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: dichloromethane).
Then, it was recrystallized from dichloromethane / n-hexane to obtain 4.45 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.43-7.70 (m, 4H), 7.84 (d, 2H) Elemental analysis value (%): Calculated as C ₁₀ H ₆ N ₂ OCl ₂ : C, 49.82; H, 2.51; N, 11.62 Actual value: C, 49.97; H, 2.27; N, 11.70 The compounds of Reference Examples 3 to 4 were produced in the same manner.

[0122]

Reference Example 6 3,3-dichloro-2-methoxycarbonylaminoacrylonitrile 2-amino-3,3-dichloroacrylonitrile 20.0
g was added to 200 ml of methyl chloroformate, and the mixture was heated under reflux for 48 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate / n-hexane to give the title compound 23.
7 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (s, 3H), 6.26 (bs, 1H) Elemental analysis value (%): Calculated as C ₅ H ₄ N ₂ O ₂ Cl ₂ value: C, 30.80; H, 2.07; N, 14.37 Found: C, 30.71; H, 2.14; N, 14.30

[0123]

Reference Example 7 N '-(1-Cyano-2,2-dichlorovinyl) ureidobutyl acetate In the same manner as in Reference Example 2, 2-amino-3,3-dichloroacrylonitrile (20.92 g) and isocyanate butyl acetate were used. By reacting 24.0 g with 20.37 g of anhydrous aluminum chloride, 23.6 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, 3H), 1.25-1.48 (m, 2H), 1.5
6-1.73 (m, 2H), 4.05 (d, 2H), 4.17 (t, 2H), 6.12 (t, 1H),
7.21 (bs, 1H) Elemental analysis _{(%): C 10 H 13} N 3 O 3 Cl 2 Calculated: C, 40.83; H, 4.45 ; N, 14.29 Found: C, 40.64; H, 4.55 ; N , 14.25

[0124]

Reference Example 8 2-Acetylamino-3,3-bis (pentylthio) acrylonitrile Method of Matsumura et al. [Chem. Pharm. Bull., 24, 948 (197
6)], 2-acetylamino-3,3-dichloroacrylonitrile 2.00 g and pentanethiol 2.56 g
This gave 3.44 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 7.3Hz, 6H), 1.15-1.50 (m,
8H), 1.50-1.75 (m, 4H), 2.14 (s, 3H), 2.85 (t, J = 7.4Hz, 2
H), 2.91 (t, J = 7.5Hz, 2H), 7.30 (bs, 1H) Elemental analysis value (%): Calculated value as C ₁₅ H ₂₆ N ₂ OS ₂ : C, 57.28; H, 8.33; N, 8.91 Found: C, 57.06; H, 8.36; N, 8.67 The compounds of Reference Examples 9 to 13 and 16 were produced in the same manner.

[0125]

Reference Example 14 3,3-bis (methylthio) -2-chloroacetylaminoacrylonitrile 7.39 g of chloroacetic acid chloride was added to 100 ml of a dichloromethane solution of 9.98 g of 2-amino-3,3-bis (methylthio) acrylonitrile. After stirring for 10 minutes under ice cooling, 8.72 g of aluminum chloride was added, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution to stop the reaction, and the organic layer was washed with cold water three times. Next, this organic layer is dried and concentrated, and the residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane =
3/1) and recrystallized from dichloromethane / n-hexane = 1/2 to give the title compound 8.8.
6 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 2.48 (s, 3H), 4.17 (s, 2
H), 8.23 (bs, 1H) Elemental analysis value (%): Calculated as C ₇ H ₉ N ₂ OS ₂ Cl: C, 35.51; H, 3.83; N, 11.83 Measured value: C, 35.33; H, 3.74 N, 11.68 The compound of Reference Example 15 was produced in the same manner.

[0126]

Reference Example 17 2-Methyl-5-pentylthio-4-oxazolecarbonate Matsumura et al. [Chem. Pharm. Bull., 21: 924 (1
976)], 2-acetylamino-3,3-bis (pentylthio) acrylonitrile 1.99 g and silver carbonate 6.9.
By acting 8 g, 1.25 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.2Hz, 3H), 1.24-1.52 (m,
4H), 1.67 (qin, J = 7.0Hz, 2H), 2.50 (s, 3H), 2.99 (t, J = 7.
2Hz, 2H) Elemental analysis value (%): Calculated value as C ₁₀ H ₁₄ N ₂ OS: C, 57.11; H, 6.71; N, 13.32 Measured value: C, 56.98; H, 6.72; N, 13.34 The compounds of Reference Examples 18 to 21 and 23 to 26 were produced by the same method.

[0127]

Reference Example 27 2-Methyl-5-phenethylthio-4-
Oxazolecarbonitrile Phenethyl mercaptan 0.98 g in ethanol solution 2
To 0 ml, 0.41 g of sodium ethylate was added, and the solution stirred at room temperature for 15 minutes was gradually added to 20 ml of an ethanol solution of 1.0 g of 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile at room temperature. Stir for 2.5 hours. Ethyl acetate and water were added to the residue obtained by distilling off the solvent of this reaction solution to remove salt, and the organic layer was dried and concentrated to give a yellow oil. Column chromatography (silica gel, developing solvent: ethyl acetate / n)
Purification by -hexane = 1/10) gave 1.13 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (s, 3H), 2.99 (t, J = 7.5Hz, 2H),
3.25 (t, J = 7.5Hz, 2H), 7.15-7.35 (m, 5H) Elemental analysis value (%): Calculated as C ₁₃ H ₁₂ N ₂ OS: C, 63.91; H, 4.95; N, 11.47 Actual measurement Value: C, 63.89; H, 4.93; N, 11.44 In the same manner, Reference Examples 30, 31, 53, 72, 85-
The compounds 103, 107, 110 were prepared.

[0128]

Reference Example 28 2-Methyl-5- (3-phenylpropylthio) -4-oxazolecarbonitrile 0.93 g of 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile prepared in Example 1 was mixed with 20 ml of methanol. After heating and melting, add sodium sulfide 9
1.32 g of the hydrate was added. 1-Bromo-3-
Phenylpropane (1.0 g) was added and the mixture was stirred for 2 hours at 50 ° C., 100 ml of ethyl acetate was added, and the mixture was washed twice with 50 ml of water. The organic layer is dried and concentrated, and the residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate /
By purifying with n-hexane = 1/3), 0.72 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.96 (t, 2H), 2.47 (s, 3H), 2.77 (t, 2
H), 2.96 (t, 2H), 7.15-7.32 (m, 5H) Elemental analysis value (%): Calculated as C ₁₄ H ₁₄ N ₂ OS: C, 65.09; H, 5.46; N, 10.84 Measured value: C, 65.12; H, 5.52; N, 10.74 The compounds of Reference Examples 29, 32-52 and 75-81 were produced in the same manner.

[0129]

Reference Example 54 5-Methylthio-2-trifluoromethyl-4-oxazolecarbonitrile 5.8 g of 3,3-dichloro-2-trifluoroacetylaminoacrylonitrile was dissolved in 60 ml of N, N-dimethylformamide and then sulfurized. Sodium nonahydrate 12.
What melt | dissolved 5 g in 8 ml of water was dripped under ice-cooling, and it stirred for 30 minutes. Add 7.5 g of methyl iodide and add 3 more.
The mixture was stirred for 0 minutes under ice cooling. Then, 200 ml of water was added and the mixture was extracted twice with 200 ml of ethyl acetate. Ethyl acetate layer is water 1
The extract was washed with 00 ml, dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/3) to obtain 4.98 g of the title compound. . ¹ H-NMR (CDCl ₃ ) δ: 2.75 (s, 3H) Elemental analysis value (%): Calculated as C ₆ H ₃ N ₂ OSF ₃ : C, 34.62; H, 1.45; N, 13.46 Measured value: C , 34.51; H, 1.44; N, 13.17 By a similar method, the compounds of Reference Examples 22, 55 to 60 were produced.

[0130]

Reference Example 61 5-Methylthio-2-phthalimidomethyl-4-oxazolecarbonitrile 2-chloromethyl-5-methylthio-4-oxazolecarbonitrile 20 ml of a solution of 0.20 g of N, N-dimethylformamide under ice cooling. , Potassium phthalimide 0.2
2 ml of N, N-dimethylformamide solution (10 ml) was gradually added, and the mixture was stirred at room temperature for 2 hours.
Was diluted with ethyl acetate and extracted three times with ethyl acetate. The residue obtained by drying and concentrating this extract was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 2/5) to give 0.23 g of the title compound.
I got ¹ H-NMR (CDCl ₃ ) δ: 2.61 (s, 3H), 4.97 (s, 2H), 7.75-7.8
5 (m, 2H), 7.85-7.98 (m, 2H) Elemental analysis value (%): Calculated as C ₁₄ H ₉ N ₃ O ₃ S: C, 56.18; H, 3.03; N, 14.04 Measured value: C , 56.01; H, 3.02; N, 13.72

[0131]

[Reference Example 62] 4-hydroxymethyl-2-methyl-5
-Methylthiooxazole 2-methyl-5-methylthio-4 prepared in Reference Example 26
2.00 g of methyl oxazolecarboxylate was dissolved in 25 ml of dry tetrahydrofuran, and 0.34 g of lithium aluminum hydride was added little by little under ice cooling. After stirring for 2 hours under ice-cooling, 0.34 ml of water, 0.34 ml of 15% aqueous sodium hydroxide solution and 1 ml of water were added. After stirring for 30 minutes, the reaction solution was filtered to remove insoluble materials and the filtrate was concentrated. By purifying the residue by column chromatography (silica gel, developing solvent: ethyl acetate),
0.73 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.37 (s, 3H), 2.46 (s, 3H), 3.25 (bs, 1
H), 4.57 (d, J = 4.2Hz, 2H) Elemental analysis value (%): C ₆ H ₉ NO
Calculated as ₂ S: C, 45.27; H, 5.70; N, 8.80 Measured value: C, 45.42; H, 5.61; N, 8.79 The compound of Reference Example 67 was produced in the same manner.

[0132]

Reference Example 63 Benzoic acid 2-methyl-5-methylthio-4-oxazolyl methyl ester 0.360 g of 4-hydroxymethyl-2-methyl-5-methylthiooxazole prepared in Reference Example 62 and 0.380 g of benzoyl chloride. Was dissolved in 10 ml of dichloromethane, and a solution of 0.310 g of triethylamine in dichloromethane (1 ml) was added dropwise under ice cooling. After stirring overnight at room temperature,
Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2) to obtain 0.533 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (s, 3H), 2.48 (s, 3H), 5.27 (s, 2
H), 7.42 (t, J = 7.5Hz, 2H), 7.55 (t, J = 7.5Hz, 1H), 8.07
(d, J = 7.5Hz, 2H) Elemental analysis value (%): Calculated value as C ₁₃ H ₁₃ NO ₃ S: C, 59.30; H, 4.98; N, 5.32 measured value: C, 59.23; H, 5.11; N, 5.28

[0133]

Reference Example 64 (A) 4- (4-chlorophenyloxymethyl) -2-
Methyl-5-methylthiooxazole (B) 4- (5-chloro-2-hydroxyphenylmethyl) -2-methyl-5-methylthiooxazole 4-hydroxymethyl-2-methyl-5-methylthiooxazole prepared in Reference Example 62 0.606 g, p-chlorophenol 0.636 g and triphenylphosphine 1.50 g were dissolved in dry tetrahydrofuran 20 ml,
With cooling with ice, 0.995 g of diethyl azodicarboxylate was added dropwise. After stirring for 1 hour under ice cooling, the reaction solution was concentrated.
The residue was subjected to column chromatography twice (silica gel, developing solvent: the first time, ethyl acetate / n-hexane = 1/2,
2nd time (dichloromethane) to give the title compound (A)
0.213 g (oil) and 0.449 g (solid) of (B) were obtained. (B) was recrystallized from dichloromethane / n-hexane. (A) ¹ H-NMR (CDCl ₃ ) δ: 2.37 (s, 3H), 2.47 (s, 3H), 4.
93 (s, 2H), 6.95 (d, J = 6.8Hz, 2H), 7.23 (d, J = 6.8Hz, 2H) (B) ¹ H-NMR (CDCl ₃ ) δ: 2.34 (s, 3H), 2.43 (s, 3H), 3.
80 (s, 2H), 6.89 (d, J = 9.0Hz, 1H), 7.10 (m, 2H), 9.66 (s, 1
H) Elemental analysis value (%): Calculated value as C ₁₂ H ₁₂ NO ₂ SCl: C, 53.43; H, 4.48; N, 5.19 Found value: C, 53.01; H, 4.39; N, 4.94

[0134]

[Reference Example 65] 4-Bromomethyl-2-methyl-5-methylthiooxazole 1.76 g of 4-hydroxymethyl-2-methyl-5-methylthiooxazole prepared in Reference Example 62 and 4.37 g of triphenylphosphine were dried on tetrahydrofuran 2
It was dissolved in 5 ml and 4.05 g of carbon tetrabromide was added under ice cooling. After stirring under ice cooling for 1.5 hours, the insoluble solid was removed by filtration, and the filtrate was concentrated. The residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n
Purification with -hexane = 1/2) gave 1.95 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (s, 3H), 2.46 (s, 3H), 4.41 (s, 2
H)

[0135]

Reference Example 66 Butyl 4- (2-methyl-5-methylthiooxazolyl) ketone 2-Methyl-5-methylthio-4-oxazolecarbonitrile 1.0 g N, N-dimethylformamide solution 1
To 0 ml in a dry ice-ethanol bath under a nitrogen stream,
1.6M n-butyllithium-n-hexane solution 2.1
ml was added and stirred, the temperature was raised to room temperature over 1.5 hours, and the mixture was further stirred for 10 minutes. The solvent was distilled off from the reaction solution, and the resulting residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/9) to obtain 0.23 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 7.2Hz, 3H), 1.38 (m, J = 7.4
Hz, 2H), 1.67 (qin, J = 7.4Hz, 2H), 2.49 (s, 3H), 2.56 (s, 3
H), 1.67 (t, J = 7.5Hz, 2H) Elemental analysis value (%): Calculated as C ₁₀ H ₁₅ NO ₂ S: C, 56.31; H, 7.09; N, 6.57 Measured value: C, 56.16; H, 7.04; N, 6.86

[0136]

Reference Example 68 4-chloromethyl-2-methyl-5-phenylthiooxazole 3.02 g of 4-hydroxymethyl-2-methyl-5-phenylthiooxazole prepared in Reference Example 67 was dissolved in 50 ml of chloroform and iced. Thionyl chloride 3.24 under cold conditions
g was added dropwise. After stirring under ice cooling for 0.5 hours, the reaction solution was concentrated. The residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1 /
By purifying in 2), 2.25 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 4.55 (s, 2H), 7.17-7.3
3 (m, 5H) Elemental analysis value (%): Calculated as C ₁₁ H ₁₀ NOSCl: C, 55.11; H, 4.20; N, 5.84 Found: C, 54.85; H, 4.12; N, 6.10

[0137]

Reference Example 69 2-Methyl-5-phenylthio-4-oxazolylacetonitrile 4-chloromethyl-2-methyl-prepared in Reference Example 68
5-phenylthiooxazole (1.00 g) was dissolved in dimethyl sulfoxide (7 ml), and sodium cyanide (0.31) was added.
g, and the mixture was stirred overnight at room temperature. The reaction solution was poured into brine and extracted 3 times with ethyl acetate. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2) to obtain 0.656 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (s, 3H), 3.68 (s, 2H), 7.19-7.3
4 (m, 5H) Elemental analysis value (%): Calculated value as C ₁₂ H ₁₀ N ₂ OS: C, 62.59; H, 4.38; N, 12.16 Found value: C, 62.32; H, 4.39; N, 11.93

[0138]

Reference Example 71 N-isobutyl- (4-cyano-2-methyl-5-oxazolyl) thioacetamide (4-cyano-2-methyl-5-) produced in Reference Example 70.
Oxazolyl) thioglycolic acid 0.79 g was dissolved in dichloromethane 16 ml, and under ice cooling, 1-hydroxybenzotriazole (HOBt) 0.60 g, 1-ethyl-3.
0.84 g of-(3-dimethylaminopropyl) -carbodiimide hydrochloride (WSCD-HCl) and 0.32 g of isobutylamine were added in that order and the mixture was stirred for 1 hour, then, the reaction solution was dried under reduced pressure. This residue was subjected to column chromatography (silica gel, developing solvent: methanol / chloroform =
1/50) to obtain 1.00 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (d, 6H), 1.84 (m, 1H), 2.50 (s, 3
H), 3.14 (t, 2H), 3.65 (s, 2H), 6.55 (broad, 1H) Elemental analysis value (%): Calculated as C ₁₁ H ₁₅ N ₃ O ₂ S: C, 52.15; H, 5.97 N, 16.59 Found: C, 50.34; H, 5.84; N, 15.77 Similarly, the compound of Reference Example 74 was produced.

[0139]

Reference Example 82 4-cyano-5-methylthio-2-oxazole carbohydrazide Methyl 4-cyano-5-methylthio-2-oxazolecarboxylate 1.49 prepared in the same manner as in Reference Example 54.
g was dissolved in 30 ml of methanol, and 1.87 g of hydrazine hydrate was added at room temperature. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and dried to obtain 0.77 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.74 (s, 3H), 4.09 (s, 2H), 8.11 (s,
1H) Elemental analysis value (%): Calculated value as C ₆ H ₆ N ₄ O ₂ S: C, 36.36; H, 3.05; N, 28.27 Actual value: C, 36.28; H, 3.06; N, 28.32

[0140]

Reference Example 83 4-cyano-N'-formyl-5-methylthio-2-oxazole carbohydrazide 4-cyano-5-methylthio-2 prepared in Reference Example 82
-Oxazole carbohydrazide 1.18g formic acid 15m
It was dissolved in 1 and heated to reflux for 1 hour. The reaction solution was dried under reduced pressure and 50 ml of methanol was added for crystallization. This was filtered and dried to obtain 0.53 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.75 (s, 3H), 8.12 (s, 1H), 10.2 (s, 1
H), 11.1 (s, 1H) Elemental analysis value (%): Calculated value as C ₇ H ₆ N ₄ O ₃ S: C, 37.17; H, 2.67; N, 24.7
7 Found: C, 37.09; H, 2.66; N, 24.7.
9

[0141]

[Reference Example 84] 5-methylthio-2- (2- [1,3,
4] -Oxadiazolyl) -4-oxazolecarbonitrile 4-cyano-N′-formyl-5 prepared in Reference Example 83
-Methylthio-2-oxazole carbohydrazide 1.
250 ml of xylene was added to 12 g, and phosphorous pentoxide was 0.7
g was added, and the mixture was heated under reflux for 3 hours while dehydrating with a Soxhlet filled with Molecular Sieve 3A. The reaction solution was distilled off under reduced pressure and the product dissolved in ethyl acetate was purified by column chromatography (silica gel, developing solvent; ethyl acetate / n-hexane = 1/2) to obtain 0.17 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.80 (s, 3H), 8.63 (s, 1H) Elemental analysis value (%): Calculated as C ₇ H ₄ N ₄ O ₂ S: C, 40.38; H, 1.94 N, 26.91 Found: C, 40.08; H, 1.98; N, 26.80

[0142]

Reference Example 105 N-4- [5- (4-cyano-2-methyloxazolyl) thio] phenylmethanesulfonamide 5- (4-aminophenylthio) -2-methyl-prepared in Reference Example 103 0.6 g of 4-oxazolecarbonitrile was dissolved in 10 ml of pyridine, 0.39 g of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 7 hours.
After the pyridine was distilled off under reduced pressure, the residue was dissolved in 50 ml of chloroform and washed twice with 50 ml of water. The organic layer was dried and concentrated, and the residue was subjected to column chromatography (silica gel, developing solvent; chloroform / ethyl acetate = 10).
/ 1). Then, it was recrystallized from n-hexane / toluene to obtain 0.62 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (s, 3H), 3.06 (s, 3H), 6.83 (b, 1
H), 7.20-7.28 (m, 2H ), 7.50-7.56 (m, 2H) Elemental analysis _{(%): C 12 H 11} N 3 O 3 S 2 Calculated: C, 46.59; H, 3.58 ; N , 13.58 Found: C, 46.65; H, 3.48; N, 13.5
5 By a similar method, the compound of Reference Example 106 was produced.

[0143]

Reference Example 111 N-3- [5- (4-cyano-2-methyloxazolyl) thio] phenyl-N'-propylurea 5- (3-aminophenylthio) -2 prepared in Reference Example 110 0.5 g of methyl-4-oxazolecarbonitrile and 0.84 g of n-propyl isocyanate are dissolved in 20 ml of chloroform. Aluminum chloride (0.04 g) was added thereto, and the mixture was stirred at room temperature for one day. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, developing solvent; dichloromethane / n-hexane /
It was purified with ethyl acetate = 2/2/1). Then, it was recrystallized from toluene to obtain 0.57 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (t, 3H), 1.54-1.65 (m, 2H), 2.46
(s, 3H), 3.26 (dt, 2H), 5.12 (b, 1H), 6.96-7.68 (m, 4H),
8.29 (dd, 1H) Elemental analysis value (%): Calculated as C ₁₅ H ₁₆ N ₄ O ₂ S: C, 56.95; H, 5.10; N, 17.71 Actual value: C, 56.98; H, 5.06; N, 17.78 The compounds of Reference Examples 104, 108 and 109 were produced in the same manner.

[0144]

Example 1 2-methyl-5-methylsulfonyl-4-
Oxazolecarbonitrile 10.0 g of 2-methyl-5-methylthio-4-oxazolecarbonitrile were added to 400 ml of chloroform.
28.0 g of m-chloroperbenzoic acid was added under ice cooling, and the mixture was stirred at room temperature for 2 hours and then refluxed for 4 hours. The reaction mixture was washed twice with a 10% aqueous sodium thiosulfate solution and three times with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried and concentrated, the residue was washed with diethyl ether, and dried under reduced pressure to give the title compound as crude crystals 9.
8 g was obtained. A part of the crude crystal was recrystallized from toluene to obtain a pure product. ¹ H-NMR (CDCl ₃ ) δ: 2.65 (s, 3H), 3.30 (s, 3H) Elemental analysis value (%): Calculated as C ₆ H ₆ N ₂ O ₃ S: C, 38.71; H, 3.25 N, 15.05 Found: C, 39.16; H, 3.31; N, 14.59 In a similar manner, Examples 2-19, 21-55, 65, 7
5 to 78, 84 to 86, 99, 100, 116, 11
7, 119-121, 123, 125-128, 13
0, 142-146, 148-154, 157, 15
9, 160, 162, 164, 165, 167, 181
~ 183, 185-187 compounds were prepared.

[0145]

Example 20 5-Methylsulfonyl-2-phenyl-
4-Oxazolecarboxamide 5-Methylthio-2-phenyl-4-oxazolecarboxamide To 5 ml of acetic acid solution of 0.13 g, a mixed solution of 0.23 g of 30% hydrogen peroxide and 25 ml of acetic acid was added, and the mixture was heated at 70 ° C. in an oil bath at 7 ° C. Stir for hours. After adding a 0.5% aqueous sodium thiosulfate solution thereto, 200 ml of ethyl acetate was added for extraction, and the extract was dried and concentrated. The residue was recrystallized from methanol to obtain 0.10 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.52 (s, 3H), 7.58-7.88 (m, 4H),
7.97 (bs, 2H), 8.06-8.18 (m, 2H) Elemental analysis value (%): Calculated as C ₁₁ H ₁₀ N ₂ O ₄ S: C, 49.62; H, 3.79; N, 10.52 Measured value: C , 49.48; H, 3.54; N, 10.65

[0146]

Example 56 (A) 5-Methylsulfonyl-2- (4-nitrobenzyl) -4-oxazolecarbonitrile (B) 5-Methylsulfonyl-2- (2-nitrobenzyl) -4-oxazolecarbonitrile nitric acid 6 ml of a concentrated sulfuric acid solution of 0.39 g of sodium was stirred under ice cooling, and 2-benzyl-5-methylsulfonyl-4 was added thereto.
-1.01 g of oxazolecarbonitrile was added slowly. After stirring for 1 hour under ice cooling, 50 g of ice water was added to dilute the reaction solution, and the mixture was extracted 3 times with dichloromethane. The extract was dried and concentrated, and the residue was separated and purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / dichloromethane = 1/1/1), and then dichloromethane / n-hexane = 1 respectively. Recrystallized from H.1 / 0.88 g of the title compound (A) and 0.3 of (B).
7 g were obtained. (A) ¹ H-NMR (CDCl ₃ ) δ: 3.29 (s, 3H), 4.35 (s, 2H), 7.5
3 (d, J = 8.7Hz, 2H), 8.26 (d, J = 8.7Hz, 2H) Elemental analysis value (%): Calculated as C ₁₂ H ₉ N ₃ O ₅ S: C, 46.90; H, 2.95 N, 13.67 Found: C, 46.35; H, 2.89; N, 13.39 (B) ¹ H-NMR (CDCl ₃ ) δ: 3.31 (s, 3H), 4.59 (s, 2H), 7.4
5-7.80 (m, 3H), 8.15-8.30 (m, 1H) Elemental analysis value (%): Calculated as C ₁₂ H ₉ N ₃ O ₅ S: C, 46.90; H, 2.95; N, 13.67 Measured value : C, 46.48; H, 3.10; N, 13.43

[0147]

Example 58 2-Bromo-5-methylsulfonyl-4
-Oxazolecarbonitrile 5-methylsulfonyl-4-oxazolecarbonitrile To a solution of 0.30 g of tetrahydrofuran in 30 ml of tetrahydrofuran, in a dry ice-ethanol bath under a nitrogen stream, 1.6 M n.
1.2 ml of -butyllithium-n-hexane solution was added and stirred for 30 minutes. 0.31 g of bromine was added dropwise to this,
After stirring for another 30 minutes under the same conditions, 10% aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted 3 times with ethyl acetate. The extract was dried and concentrated, and the resulting residue was purified by column chromatography (silica gel, developing solvent: chloroform) to obtain 0.07 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.34 (s, 3H) Elemental analysis value (%): Calculated as C ₅ H ₃ N ₂ O ₃ SBr: C, 23.92; H, 1.20; N, 11.16 Measured value: C, 24.00; H, 1.15; N, 11.0
5

[0148]

Example 59 2-Methylamino-5-methylsulfonyl-4-oxazolecarbonitrile 2-bromo-5-methylsulfonyl-4-oxazolecarbonitrile 1.0 ml of a dichloromethane solution 80 ml
Then, under ice cooling, a 40% methylamine methanol solution 0.3
A mixed solution of 3 g and 0.42 g of triethylamine was added dropwise, and the mixture was stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent of this reaction solution was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / dichloromethane = 1/1/1) to give the title compound 0.68.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (d, J = 5.1Hz, 3H), 3.23 (s, 3H),
5.22 (bs, 1H) Elemental analysis value (%): Calculated as C ₆ H ₇ N ₃ O ₃ S: C, 35.82; H, 3.51; N, 20.88 Found: C, 35.57; H, 3.53; N, 20.68 The compounds of Examples 60 and 61 were prepared in a similar manner.

[0149]

Example 62 2- (N-Benzyl-N-methylaminomethyl) -5-methylsulfonyl-4-oxazolecarbonitrile 2-chloromethyl-5-methylsulfonyl-4-oxazolecarbonitrile 0.23 g in dichloromethane solution A solution of benzylmethylamine (0.15 g) and triethylamine (0.13 g) in dichloromethane (60 ml) on ice was cooled to 20 m.
l was added slowly and it was heated to reflux overnight. The yellow residue obtained by distilling off the solvent of the reaction solution was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / dichloromethane = 1/1/1) to obtain 0.03 g of the title compound. It was ¹ H-NMR (CDCl ₃ ) δ: 2.43 (s, 3H), 3.29 (s, 3H), 3.67 (s, 2
H), 3.83 (s, 2H), 7.25-7.40 (m, 5H) Elemental analysis value (%): Calculated as C ₁₄ H ₁₅ N ₃ O ₃ S: C, 55.07; H, 4.95; N, 13.76 Measured Values: C, 55.26; H, 4.96; N, 13.50 The compounds of Examples 131-133 were prepared in a similar manner.

[0150]

Example 63 5-Methylsulfonyl-2- (4-phenyl-1-piperazinylmethyl) -4-oxazolecarbonitrile 2-chloromethyl-5-methylsulfonyl-4-oxazolecarbonitrile 0.30 g of acetonitrile To 50 ml of the solution was added 0.05 g of potassium iodide, 0.23 g of phenylpiperazine, and 0.20 g of potassium carbonate,
Stir for 30 minutes at room temperature. The reaction mixture was filtered and the solvent was evaporated to give a yellow residue, which was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane /
Purification by dichloromethane = 1/1/1) and recrystallization from dichloromethane / n-hexane = 1/1 gave 0.48 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (t, J = 4.9Hz, 4H), 3.24 (t, J = 5.0H
z, 4H), 3.33 (s, 3H), 3.89 (s, 2H), 6.83-7.00 (m, 3H), 7.
22-7.33 (m, 2H) Elemental analysis value (%): Calculated as C ₁₆ H ₁₈ N ₄ O ₃ S: C, 55.48; H, 5.24; N, 16.17 Found: C, 55.27; H, 5.25; N, 16.14

[0151]

Example 64 (A) 2- (4-methylphenylsulfonylmethyl)-
5-Methylsulfonyl-4-oxazolecarbonitrile (B) 5- (4-methylphenylsulfonyl) -2-
(4-Methylphenylsulfonylmethyl) -4-oxazolecarbonitrile 2-chloromethyl-5-methylsulfonyl-4-oxazolecarbonitrile A solution of 0.16 g of N, N-dimethylformamide in 30 ml of p-toluene under ice cooling. After 0.19 g of sodium sulfinate was added and stirred at room temperature for 20 minutes, 100 ml of water was added to the reaction solution to dilute it, and the mixture was extracted three times with ethyl acetate. The residue obtained by drying and concentrating this extract was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2), and then recrystallized from dichloromethane / n-hexane to give the title. 0.12 g of compound (A) and 0.03 g of (B) were obtained. (A) ¹ H-NMR (CDCl ₃ ) δ: 2.50 (s, 3H), 3.30 (s, 3H), 4.6
4 (s, 2H), 7.42 (d, J = 8.6Hz, 2H), 7.72 (d, J = 8.6Hz, 2H) Elemental analysis value (%): Calculated as C ₁₃ H ₁₂ N ₂ O ₅ S: C, 45.87; H, 3.55; N, 8.23 Found: C, 45.69; H, 3.56; N, 8.29 (B) ¹ H-NMR (CDCl ₃ ) δ: 2.48 (s, 3H), 2.50 (s, 3H ), 4.5
4 (s, 2H), 7.32 (d, J = 8.6Hz, 2H), 7.46 (d, J = 8.6Hz, 2H),
7.58 (d, J = 8.6Hz, 2H), 7.95 (d, J = 8.6Hz, 2H) Elemental analysis _{(%): C 19 H 16} N 2 O 5 S 2 Calculated: C, 54.79; H, 3.87; N, 6.78 Found: C, 54.28; H, 3.84; N, 6.68.

[0152]

Example 66 2-Methyl-5-methylsulfonyl-4
-Oxazolecarboxamide 1.0 g of 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile was gradually added to 3 ml of concentrated sulfuric acid under ice cooling, and stirred at room temperature for 3 hours. 20 ice water in this reaction solution
ml was added, the precipitated solid was filtered, washed with a small amount of cold water, dried under reduced pressure, and recrystallized from methanol to obtain 0.49 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.55 (s, 3H), 3.56 (s, 3H), 7.92 (b
s, 1H), 8.02 (bs, 1H) Elemental analysis value (%): Calculated as C ₆ H ₈ N ₂ O ₄ S: C, 35.29; H, 3.95; N, 13.72 Found: C, 35.30; H , 3.75; N, 13.75 The compound of Example 67 was prepared in a similar manner.

[0153]

Example 68 2-Methyl-5-methylsulfonyl-4
-Oxazolecarboxylic acid 1 to 3.44 g of methyl 2-methyl-5-methylsulfonyl-4-oxazolecarboxylate prepared in Example 19
4.61 g of 5% sodium hydroxide and 30 ml of water were added, and the mixture was stirred at room temperature for 1 hour. After adding dilute sulfuric acid to make the mixture acidic, the mixture was extracted 10 times with ethyl acetate. The extract was dried and concentrated, and the residue was recrystallized from methanol / diethyl ether / hexane to give 2.66 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.55 (s, 3H), 3.50 (s, 3H) Elemental analysis value (%): Calculated as C ₆ H ₇ NO ₅ S: C, 35.12; H, 3.44 N, 6.83 Actual value: C, 35.16; H, 3.44; N, 6.90 The compounds of Example 98 and Reference Examples 70 and 73 were produced in the same manner.

[0154]

Example 69 N-benzyl-2-methyl-5-methylsulfonyl-4-oxazolecarboxamide To 1.00 g of 2-methyl-5-methylsulfonyl-4-oxazolecarboxylic acid prepared in Example 68, 10 ml of thionyl chloride is added. In addition, the mixture was heated under reflux for 6 hours. Thionyl chloride was distilled, the obtained solid was dissolved in 15 ml of dichloromethane, and a solution of 0.57 g of benzylamine and 0.54 g of triethylamine in dichloromethane (1 ml) was added dropwise under ice cooling. After stirring for 1 hour under ice-cooling, the reaction solution was poured into water and extracted 3 times with dichloromethane. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate). Then, it was recrystallized from ethanol to obtain 1.36 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (s, 3H), 3.56 (s, 3H), 4.61 (d, J
= 6.0Hz, 2H), 7.34 (m, bs, 6H) Elemental analysis value (%): Calculated as C ₁₃ H ₁₄ N ₂ O ₄ S: C, 53.05; H, 4.79; N, 9.52 Measured value: C , 52.97; H, 4.80; N, 9.59 In a similar manner, the compounds of Examples 70 to 74 were prepared.

[0155]

Example 79 4- (N-benzyl-N-methylaminomethyl) -2-methyl-5-methylsulfonyloxazole 4-bromomethyl-2-methyl-prepared in Example 78
0.35 g of 5-methylsulfonyloxazole was dissolved in 15 ml of dichloromethane, and a solution of 0.217 g of N-methylbenzylamine and 0.182 g of triethylamine in dichloromethane (1 ml) was added dropwise under ice cooling. After stirring under ice cooling for 1 hour and then at room temperature for 1 hour, the reaction solution was concentrated. The residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate) to obtain 0.322 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (s, 3H), 2.68 (s, 3H), 3.17 (s, 3
H), 3.64 (s, 2H), 3.78 (s, 2H), 7.20-7.38 (m, 5H) In the same manner, the compounds of Examples 80 and 81 were produced.

[0156]

Example 83 2-Methyl-4- (4-methylphenylsulfonylmethyl) -5-methylsulfonyloxazole 4-Bromomethyl-2-methyl-prepared in Example 78
5-methylsulfonyloxazole 0.250 g was added to N, N
-Dissolved in 5 ml of dimethylformamide, and under ice cooling, p-toluenesulfinic acid sodium salt tetrahydrate 0.258
g was added. After stirring for 1 hour under ice cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate). Then, it was recrystallized from dichloromethane / diethyl ether / n-hexane to obtain 0.231 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 2.58 (s, 3H), 3.30 (s, 3
H), 4.62 (s, 2H), 7.39 (d, J = 8.4Hz, 2H), 7.82 (d, J = 8.4H
z, 2H) Elemental analysis _{(%): C 13 H 15} NO 5 S 2 Calculated: C, 47.40; H, 4.59 ; N, 4.25 Found: C, 47.16; H, 4.47 ; N, 4.37 the same By a method, the compound of Example 82 was prepared.

[0157]

Example 87 2-Methyl-5-phenylsulfonyl-4-oxazolylacetic acid 0.200 g of 2-methyl-5-phenylsulfonyl-4-oxazolylacetonitrile prepared in Example 86 was added to 10 ml of concentrated sulfuric acid to give 115 Heated at ° C for 2 hours. The reaction solution was added little by little to ice-cold water and extracted twice with ethyl acetate. The extract was washed once with brine, dried and concentrated, and the residue was recrystallized from dichloromethane / n-hexane to give 0.151 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 4.06 (s, 2H), 6.80 (b, 1
H), 7.50-7.72 (m, 3H), 7.96-8.05 (m, 2H) Elemental analysis value (%): Calculated as C ₁₂ H ₁₁ NO ₅ S: C, 51.24; H, 3.94; N, 4.98 Actual measurement Value: C, 50.84; H, 3.88; N, 4.79

[0158]

Example 88 2-Methyl-5-methylsulfonyl-4
-Oxazolecarbothioamide 2.00 g of 2-methyl-5-methylsulfonyl-4-oxazolecarboxamide prepared in Example 66 and 2.77 g of Lawesson's reagent were added to 80 ml of dry tetrahydrofuran and heated under reflux for 6 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/1). Then recrystallize from ethyl acetate to give 60 g of the title compound.
I got ¹ H-NMR (DMSO-d ₆ ) δ: 2.51 (s, 3H), 3.49 (s, 3H), 9.78 (b
s, 1H), 10.31 (bs , 1H) Elemental analysis _{(%): C 6 H 8} N 2 O 3 S 2 Calculated: C, 32,72; H, 3.66 ; N, 12.72; S, 29.11 Found Values: C, 32.83; H, 3.55; N, 12.52; S, 28.75 The compounds of Examples 89-92 were prepared in a similar manner.

[0159]

Example 93 2-Methyl-5-pentylsulfonyl-
4-Oxazolecarbothioamide 0.170 g of 2-methyl-5-pentylsulfonyl-4-oxazolecarboxamide prepared in Example 4 was dissolved in 6.6 ml of a tetrahydrofuran / water = 10/1 solution to give dithiophosphoric acid O, O'-. Diethyl 0.390 g was added, and the mixture was heated under reflux for 9 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/1) to obtain 0.108 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 7.0Hz, 3H), 1.25-1.50 (m,
4H), 1.70-1.90 (m, 2H), 2.60 (s, 3H), 3.56-3.67 (m, 2H),
7.70 (bs, 1H), 8.60 (bs, 1H) MS m / z 276 (M ⁺ ) In a similar manner, the compounds of Examples 94, 95, 135-139 were prepared.

[0160]

Example 96 2-Methyl-5-methylsulfonyl-4
-(4-Phenylthiazolyl) oxazole 0.15 g of 2-methyl-5-methylsulfonyl-4-oxazole carbothioamide prepared in Example 88 and 0.162 g of phenacyl bromide were dissolved in 20 ml of ethanol and heated for 1 hour. Refluxed. The reaction solution was concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2). Then
Recrystallization from dichloromethane / n-hexane gave 0.112 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.64 (s, 3H), 3.67 (s, 3H), 7.33-7.5
4 (m, 3H), 7.67 (s, 1H), 7.89-8.00 (m, 2H) Elemental analysis value (%): C ₁₄ H ₁₂ N ₂ O ₃ S ₂ calculated value: C, 52.48; H, 3.78; N, 8.74 Found: C, 52.18; H, 3.92; N, 8.82 The compound of Example 97 was prepared in a similar manner.

[0161]

Example 101 (E) -5- (2-N, N-Dimethylaminoethenylsulfonyl) -2-methyl-4-oxazolecarbonitrile 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile 1. 0.83 g of N, N-dimethylformamide dimethylacetal was added to 10 ml of 0 g of N, N-dimethylformamide solution, and the mixture was stirred at room temperature for 4 hours and further at 50 ° C. for 15 minutes in an oil bath. The residue obtained by distilling off the solvent of the reaction solution was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 4/5) to obtain 0.64 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (s, 3H), 2.88 (s, 3H), 3.18 (s, 3
H), 4.97 (d, J = 12Hz, 1H), 7.44 (d, J = 12Hz, 1H) Elemental analysis value (%): Calculated value as C ₉ H ₁₁ N ₃ O ₃ S: C, 44.80; H, 4.60; N, 17.42 Found: C, 44.63; H, 4.44; N, 17.24

[0162]

Example 102 2-Methyl-5- (2-methyl-4-
Cyano-5-oxazolyl) methylsulfonyl-4-oxazolecarbonitrile 0.93 g of 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile prepared in Example 1 was added to N, N-
It was dissolved in 20 ml of dimethylformamide, and 0.24 g of sodium hydride (ca. 60%) was added under ice cooling. The mixture was stirred under ice cooling for 1 hour and further at room temperature for 1 hour. 100 ml of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 50 ml of water. The organic layer is dried and concentrated, and the residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane =
Purified by 1/2). Then, it was recrystallized from ethyl acetate / n-hexane to obtain 0.12 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.58 (s, 3H), 2.69 (s, 3H), 4.77 (s, 2
H) Elemental analysis value (%): Calculated value as C ₁₁ H ₈ N ₄ O ₄ S: C, 45.21; H, 2.76; N, 19.17 Actual value: C, 45.17; H, 2.76; N, 19.20 Similar method Thus, the compound of Example 188 was prepared.

[0163]

Example 104 2-Methyl-5- [2- (4-methylsulfonamidophenyl) ethylsulfonyl] -4-oxazolecarbonitrile 2-Methyl-5- [2- (4-
Aminophenyl) ethylsulfonyl] -4-oxazolecarbonitrile (0.25 g) was dissolved in pyridine (5 ml),
0.12 g of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 1 hour. 50 ml of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 50 ml of water. The organic layer was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2). Then, it was recrystallized from methanol to obtain 0.20 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (s, 3H), 3.05 (s, 3H), 3.20 (t, 2
H), 3.65 (t, 2H ), 6.04 (s, 1H), 7.16 (s, 2H) Elemental analysis _{(%): C 14 H 15} N 3 O 5 S 2 Calculated: C, 45.52; H, 4.09; N, 11.37 Found: C, 45.44; H, 4.07; N, 11.24 The compounds of Examples 105 and 106 were prepared in a similar manner.

[0164]

Example 107 5- (4-aminophenylsulfonyl) -2-methyl-4-oxazolecarbonitrile 2-Methyl-5- (4-nitrophenylsulfonyl) -4-oxazolecarbonitrile prepared in Example 40 0 0.20 g was dissolved in 10 ml of tetrahydrofuran, and 1.3 ml of concentrated hydrochloric acid and 0.15 g of iron powder were added under cooling. After stirring for 1 hour under ice cooling, saturated aqueous sodium hydrogen carbonate solution was added to neutralize. After concentrating the reaction mixture, 100 ml of ethyl acetate
Was added and washed with a 15% aqueous sodium hydroxide solution. The organic layer was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: n-hexane / dichloromethane / ethyl acetate = 2/2/1). Then
Recrystallization from n-hexane / toluene gave 0.044 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (s, 3H), 4.20 (b, 2H), 6.71-6.7
6 (m, 2H), 7.80-7.85 (m, 2H) The compounds of Examples 57 and 103 were produced in the same manner.

[0165]

Example 108 N-isobutyl-4-cyano-2-methyl-5-oxazolesulfonamide 1.00 g of 2-methyl-5-methylsulfonyl-4-oxazolecarbonitrile prepared in Example 1 is heated to 20 ml of methanol. After dissolution, 1.40 g of sodium sulfide nonahydrate was added. After stirring at room temperature for 1 hour, 1N-H
Cl was added to make the solution acidic at pH 3 or less. The reaction solution was dried under reduced pressure, 6 ml of acetonitrile was added, and insoluble salts were removed by filtration. The filtrate is cooled to -10 ° C and potassium nitrate 1.35.
g, and 1.81 g of thionyl chloride were added. After the insoluble material in the reaction solution was filtered off, 40 ml of pyridine was added to this filtered solution, 0.46 g of isobutylamine was added, and the mixture was stirred for 1 hour at room temperature. 200 ml of ethyl acetate was added to the reaction solution, and 100 parts of water was added.
It was washed twice with ml. The organic layer was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/3). Then, it was recrystallized from ethyl acetate / n-hexane to obtain 0.095 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, 6H), 1.84 (m, 1H), 2.60 (s, 3
H), 3.05 (t, 2H), 5.28 (t, 1H) Elemental analysis value (%): Calculated as C ₉ H ₁₃ N ₃ O ₃ S: C, 44.43; H, 5.39; N, 17.27 Found: C, 44.15; H, 5.17; N, 17.15 In a similar manner, Examples 109-112, 189-205.
Was prepared.

[0166]

Example 113 4-Bromomethyl-2-methyl-5-
Methylsulfinyloxazole 4-bromomethyl-2-methyl-produced in Reference Example 65
3.55 g of 5-methylthiooxazole was dissolved in 30 ml of dichloromethane, and m-chloroperbenzoic acid 2.7 was cooled under cooling.
6 g were added. After stirring at room temperature for 1 hour, the reaction solution was mixed with 10
% Sodium thiosulfate aqueous solution once, and saturated sodium hydrogencarbonate aqueous solution twice. Dry and concentrate the organic layer,
The residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate). Then recrystallize from dichloromethane / hexane to give the title compound 1.10
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.57 (s, 3H), 3.01 (s, 3H), 4.47 (s, 2
H) Elemental analysis value (%): Calculated value as C ₆ H ₈ NO ₂ SBr: C, 30.27; H, 3.39; N, 5.88 Actual value: C, 30.01; H, 3.46; N, 5.86 By the same method, Examples 114, 115, 118, 12
2,124,129,147,155,156,15
The compounds of 8, 161, 163, 166, 184 were prepared.

[0167]

Example 134 (A) 5-Methylsulfinyl-2- (2- [1,3,4]
-Oxadiazolyl) -4-oxazolecarbonitrile (B) 5-methylsulfonyl-2- (2- [1,3,4]-
Oxadiazolyl) -4-oxazolecarbonitrile 5-methylthio-2- (2- [1,
3,4] -Oxadiazolyl) -4-oxazolecarbonitrile (0.90 g) was dissolved in chloroform and cooled to m.
-0.90 g of chloroperbenzoic acid was added. After reacting at room temperature for 2 hours, the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution, the chloroform layer was dried and concentrated, and the residue was subjected to column chromatography (silica gel, developing solvent; ethyl acetate / n-hexane = 1/2). ) And was separated and purified to obtain 0.25 g of the title compound (A) and 0.057 g of (B). (A) ¹ H-NMR (CDCl ₃ ) δ: 3.24 (s, 3H), 8.71 (s, 1H) Elemental analysis value (%): Calculated as C ₇ H ₄ N ₄ O ₃ S: C, 37.50; H, 1.80; N, 24.99 Actual value: C, 37.20; H, 1.94; N, 24.49 (B) ¹ H-NMR (CDCl ₃ ) δ: 3.43 (s, 3H), 8.73 (s, 1H) Elemental analysis value (%): Calculated as C ₇ H ₄ N ₄ O ₄ S: C, 35.00; H, 1.68; N, 23.33 Measured value: C, 35.42; H, 1.73; N, 23.34

[0168]

Example 140 2-Methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid The title compound was prepared in the same manner as in Example 68, and the obtained oily substance was crystallized from methanol. ¹ H-NMR (CDCl ₃ ) δ: 2.59 (s, 3H), 7.76-7.90 (m, 3H), 8.14
(m, 2H) Elemental analysis value (%): Calculated value as C ₁₁ H ₉ NO ₅ S.CH ₃ OH: C, 48.15; H, 4.38; N, 4.68 Measured value: C, 47.76; H, 4.13; N , 4.77

[0169]

Example 141 t-Butyl 4- (2-methyl-5-phenylsulfonyloxazolyl) -carbamate 0.65 g of 2-methyl-5-phenylsulfonyl-4-oxazolecarboxylic acid prepared in Example 140 t-
Add to 15 ml butanol, then 0.23 g diphenylphosphoryl azide (DPPA), 0.03 triethylamine.
9 g was added and the mixture was heated under reflux for 2 hours. After distilling off the solvent, the residue was dissolved in 30 ml of dichloromethane and washed with 5% citric acid and saturated aqueous sodium hydrogen carbonate solution. The organic layer is dried and concentrated, and the residue is purified by column chromatography (silica gel, developing solvent; ethyl acetate / n-hexane = 1/1), and then dichloromethane / n.
Recrystallized from hexane to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.55 (s, 9H), 2.48 (s, 3H), 7.53-7.67
(m, 3H), 7.84 (bs, 1H), 7.93-8.00 (m, 2H) Elemental analysis value (%): Calculated as C ₁₅ H ₁₈ N ₂ O ₅ S: C, 53.24; H, 5.36; N , 8.28 Found: C, 53.18; H, 5.34; N, 8.29

[0170]

Example 168 2- (2-methoxybenzyl) -5-
Methylsulfonyl-4-oxazolecarbonitrile 1.86 g of 2-methoxyphenylacetic acid in 8 g of thionyl chloride
l was added and the mixture was heated under reflux for 1 hour. Thionyl chloride was distilled off, and the obtained oily substance was dissolved in 50 ml of ethyl acetate to give 2-
Amino-3,3-dichloroacrylonitrile (1.50 g) was added, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was recrystallized from diethyl ether / n-hexane to obtain 1.57 g of needle crystals. According to Reference Example 54, the needle crystals were treated with 50 ml of N, N-dimethylformamide.
Then, 2.76 g of sodium sulfide nonahydrate dissolved in 5 ml of water was added dropwise under ice cooling and the mixture was stirred for 5 minutes. After adding 1.60 g of methyl iodide and further stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, 100 ml of ethyl acetate and 50 ml of water were added to the residue, and the ethyl acetate layer was taken.
This was washed twice with 50 ml of water, dried and concentrated.
The obtained oily substance was treated with 100 ml of chloroform in accordance with Example 1.
The mixture was dissolved in water, 3.80 g of m-chloroperbenzoic acid was added under ice cooling, and the mixture was heated under reflux for 4 hours. The reaction solution was washed twice with 10% aqueous sodium thiosulfate solution and three times with saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried and concentrated, and the obtained residue was subjected to column chromatography (silica gel, developing solvent;
The product was separated and purified with ethyl acetate / n-hexane = 1/2) and then recrystallized from ethyl acetate / n-hexane = 1/1 to obtain 0.53 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.26 (s, 3H), 3.81 (s, 3H), 4.21 (s, 2
H), 6.80-7.40 (m, 4H) Elemental analysis value (%): Calculated as C ₁₃ H ₁₂ N ₂ O ₄ S: C, 53.42; H, 4.14; N, 9.58 Actual value: C, 53.41; H , 4.11; N, 9.65 The compounds of Examples 169 to 178 were produced in the same manner.

[0171]

Example 179 2- (3-methoxybenzyl) -5-
Methylsulfonyl-4-oxazolecarbonitrile 2-amino-3,3-dichloroacrylonitrile 0.7 g
Was dissolved in 50 ml of ethyl acetate, 0.98 g of 3-methoxyphenylacetic acid chloride was added thereto, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from diethyl ether / n-hexane = 1/3 to obtain 1.1 g of needle crystals. According to Reference Example 54, the needle crystals were dissolved in 50 ml of N, N-dimethylformamide, and then 1.95 g of sodium sulfide nonahydrate dissolved in 5 ml of water was added dropwise under ice cooling for 5 minutes. The mixture was stirred, 1.2 g of methyl iodide was added, and the mixture was further stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 50 ml of water was added to the residue and the mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed twice with 50 ml of water, dried and concentrated. The obtained oily substance was dissolved in 100 ml of chloroform according to Example 1 and m-
2.34 g of chloroperbenzoic acid was added, and the mixture was heated under reflux for 4 hours. The reaction mixture was diluted with 10% aqueous sodium thiosulfate solution to 2
Once, washed 3 times with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated the organic layer, and the resulting residue was separated and purified by column chromatography (silica gel, developing solvent; ethyl acetate / n-hexane = 1/2). , Then ethyl acetate /
Recrystallized from n-hexane = 1/2 to give the title compound 0.1
2 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.27 (s, 3H), 3.82 (s, 3H), 4.18 (s, 2
H), 6.80-6.95 (m, 3H), 7.20-7.40 (m, 1H) Elemental analysis value (%): Calculated as C ₁₃ H ₁₂ N ₂ O ₄ S: C, 53.42; H, 4.14; N, 9.58 Found: C, 53.56; H, 4.13; N, 9.47 The compound of Example 180 was prepared in a similar manner.

[0172]

[Table 4]

[0173]

[Table 5]

[0174]

[Table 6]

[0175]

[Table 7]

[0176]

[Table 8]

[0177]

[Table 9]

[0178]

[Table 10]

[0179]

[Table 11]

[0180]

[Table 12]

[0181]

[Table 13]

[0182]

[Table 14]

[0183]

[Table 15]

[0184]

[Table 16]

[0185]

[Table 17]

[0186]

[Table 18]

[0187]

[Table 19]

[0188]

[Table 20]

[0189]

[Table 21]

[0190]

[Table 22]

[0191]

[Table 23]

[0192]

[Table 24]

[0193]

[Table 25]

[0194]

[Test Example 1] Inhibitory effect on IL-6 activity The test compound was dissolved in N, N-dimethylformamide to a concentration of 10 mM, and R was adjusted to 0.1 mM.
It was diluted with PMI-1640 medium. Further, the medium was prepared so that the final concentration became 20 μM to 0.16 μM by 2-fold dilution, and added to the culture solution. Using the IL-6-dependent cell line MH60, the inhibition rate of the test compound on IL-6-dependent proliferation was measured. On the day before the experiment, cells were 1 × 10 ⁵
10% RPMI with inactivated fetal bovine serum at 10ml / mL
Prepared in I-1640 medium, 37 ° C in culture flask,
The cells were cultured in 5% CO ₂ /95% air. On the day of the experiment, the cultured cells were placed in a 96-well plate at 1 × 10 ⁴ cells / well.
Seeded to 0.1 mL. Next, the prepared test compound was added, and IL-6 was added to a final concentration of 0.25 ng / mL, followed by culturing. After culturing for 2 days, 5m with PBS
0.02 mL of dimethyl thiazolyl diphenyl tetrazolium bromide (MTT) dissolved in g / mL was added to each well, and the mixture was further cultured for 3 hours. Then 10
% Sodium dodecyl sulfate / 0.01N hydrochloric acid solution 1
After adding 0.1 mL per well and incubating at 37 ° C. overnight, the absorbance at 560 nm was measured by multiscan to measure the cell viability. As a result, the test compound effectively inhibited the growth of the cell line MH60. The results are shown in [Table 26]. IC
₅₀ indicates the concentration of the test substance showing 50% growth inhibition.

[0195]

[Table 26] From Table 26, it was found that the oxazole derivative of the present invention has an excellent IL-6 activity inhibitory action.

[0196]

[Test Example 2] Inhibitory effect on acute phase protein production The living body produces acute phase protein due to infection, tissue damage, malignant tumor, immune abnormality and the like, and IL-
6 is known to be the most important factor in inducing the production of this protein. It is known that in amyloidosis secondary to chronic inflammatory disease, serum amyloid A protein, which is an acute-phase protein, fibrils and deposits in extracellular stroma to cause organ damage. Therefore, the effect of the test compound on the production of serum amyloid A protein was examined using experimental animals. Female C57BL / 6 mice (6 weeks old) were pre-bred for 1 week and divided into groups of 5 mice. In the test group, the test compound was suspended in a 5% aqueous solution of gum arabic and orally administered once. The control group was similarly administered with the solvent alone.
One hour later, 0.25 mg of LPS, a bacterial component, was intraperitoneally administered to the test group and the control group. Blood was collected 7 hours after the administration of the bacterial cell components, and the serum amyloid A protein concentration was quantified by a sandwich ELISA method. The results are shown in [Table 27]. * Indicates that there is a significant difference from the control group (p
<0.01; Student t-test).

[0197]

[Table 27] From Table 27, it was found that the oxazole derivative of the present invention has an excellent inhibitory effect on the acute phase protein production.

[0198]

[Test Example 3] Inhibitory effect on NO production Using a mouse macrophage cell line RAW264.7 as an iNOS-inducing cell, the inhibitory rate of a test compound on NO production was measured. The test compound was dissolved in N, N-dimethylformamide at 10 mM and diluted with RPMI-1640 medium to 0.1 mM. Further, it was prepared in a medium so that the final concentration was about 10 nM from 10 μM by 10-fold dilution, and added to the culture solution. On the day before the experiment, cells were prepared in RPMI-1640 medium supplemented with 10% inactivated fetal bovine serum so that the cells became 5 × 10 ⁵ cells / ml.
Cells were seeded in a well plate at 1 × 10 ⁵ cells / 0.2 ml per well. After overnight culturing at 37 ° C., 5% CO ₂ /95% air, the prepared test compound was added, and LPS and interferon gamma were each added to a final concentration of 5 ng / m 2.
1 and 1 U / ml. After further culturing overnight, the concentration of nitrite ion (stable metabolite of NO) in the culture supernatant was measured and used as an index of NO production. The nitrite ion concentration was determined by adding 25 μl of 20 μg / ml 2,3-diaminonaphthalene (DAN) to 50 μl of the culture supernatant,
It was quantified by measuring the fluorescence at an excitation wavelength of 365 nm. The results are shown in [Table 28]. IC ₅₀ is 50%
2 shows the concentration of a test compound showing suppression of NO production in.

[0199]

[Table 28] From Table 28, the oxazole derivative of the present invention is
It was found that it strongly inhibits NO production from W264.7 cells and has an excellent NO production inhibitory action.

[0200]

[Test Example 4] Effect on increase in blood nitrogen oxide concentration When NO is produced in the body due to biological defense reaction against infection or immune abnormality, it is immediately metabolized to nitrite and nitric acid, Nitrogen oxide concentration (NOx) rises.
Therefore, the effect of the test compound on the increase in blood NOx concentration was examined using experimental animals. Female BALB / c mice (6 weeks old) were pre-bred for one week and divided into groups of 6 to 8 mice. The test compound is included in the test group (Example compounds 8 and 8).
8, 123 and 132) were suspended in a 0.5% aqueous solution of methylcellulose, and 30 mg / kg was intraperitoneally administered. The control group was similarly administered with the solvent. 30 minutes later, LPS
(30 mg / kg) was intraperitoneally administered to the test group and the control group, and blood was collected 6 hours after LPS administration, and the nitrate ion + nitrite ion concentration in the serum was measured. Nitrate is nit
It is converted to nitrite ion by the rate rectase,
The total nitrite ion concentration was quantified by the fluorescence method using the above DAN. As a result, it was shown that the oxazole derivative of the present invention showed a significant inhibition against NO production even in vivo, showing significant inhibition (Student t-test) relative to the control group.

[0201]

INDUSTRIAL APPLICABILITY The oxazole derivative of the present invention has an excellent inhibitory effect on IL-6 activity and N from cells induced by iNOS.
A safe inhibitor of IL-6 activity having an O production inhibitory effect on humans and mammals (eg, mouse, rat, guinea pig, rabbit, dog, cat, cow, pig, sheep, monkey, chimpanzee, etc.) or It can be used as an NO production inhibitor. Further, the oxazole derivative (I ′) is associated with diseases caused by IL-6, for example, cardiomyopathy, cardiac hypertrophy, myocardial infarction, angina, and other heart diseases, rheumatoid arthritis, systemic erythematosus, and systemic strength. Dermatosis,
Rheumatic fever, polymyositis, periarteritis nodosa, Sjögren's syndrome, Behcet's disease, various autoimmune diseases such as Castleman's disease or autoimmune hemolytic anemia, mesangial proliferative nephritis, IgA nephritis, lupus nephritis, osteoporosis, amyloidosis , Bronchial asthma, atopic dermatitis, psoriasis, pleurisy, ulcerative colitis, atherosclerosis,
Inflammatory diseases such as active chronic hepatitis, alcoholic cirrhosis, gout or various encephalitis, or multiple myeloma, intra-atrial mucosa, renal cancer, lung adenocarcinoma, malignant mesothelioma, ovarian cancer or cancer cachexia Agent for preventing / treating diseases associated with granulomas of the above or diseases caused by NO, for example, arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, rheumatoid arthritis, deformity Humans and mammals as drugs such as prophylactic / therapeutic agents for diseases such as osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia, hepatitis, graft rejection or pain. Animals (eg, mouse, rat, guinea pig, rabbit, dog, cat, cow, pig, sheep,
It can be used safely against monkeys, chimpanzees, etc.).

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/42 ABB A61K 31/42 ABB ABC ABC ABC ABE ABE ABG ABG ABCJ ABB ABB ABR ABR ABR A ACD ACD ACJ ACJ ACL ACL ACL ACS ACS ACV ACV ADD ADD ADM ADM ADP ADP ADP ADS ADS ADU ADU AED AED 31/425 31/425 31/44 31/44 31/445 31/445 31/495 31/495 31/505 31 / 505 31/535 31/535 C07D 263/48 C07D 263/48 413/04 263 413/04 263 413 413/06 209 413/06 209 413/12 213 413/12 213 333 333 417/04 263 417/04 263 495/04 105 495/04 105Z (72) Inventor Yukimasa Nozaki 11-23 Muromachi, Ikeda-shi, Osaka (72) Inventor Yuzo Ichimori 5, 7 Hamachiji-machi, Sakai-shi, Osaka No. 25 (72) Inventor Masayuki Ii 6-571 Minoh, Minoh City, Osaka Prefecture Heights 305

Claims (24)

[Claims] 1. An oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group (provided that when the 4-position is a hydrogen atom, the 2-position is a 4-methoxyphenyl group or a 4-methoxyphenylethynyl group). A compound in which the 5-position is a nonafluorobutylsulfonyl group, the 2-position is a phenyl group, and the 5-position is (2-phenyl-5-thiazolyl).
A compound which is a sulfonyl group and 3- [5-
(2,3-Epoxy-5-hydroxy-4-methylhexyl) -3,4-dihydroxytetrahydropyran-2
-Yl] -2-methyl-1- (E) -propenyl group with 5
Except the compound in which the position is a 4-methylphenylsulfonyl group). 2. The oxazole derivative according to claim 1, wherein the 2-position may be substituted with a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. 3. The oxazole derivative according to claim 1, which may be substituted at the 4-position with a halogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. 4. The oxazole derivative has the formula: [In the formula, R ¹ is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted amino group, n is 1 or 2, R ² is a hydrogen atom, Cyano group, acyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted A good amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or formula-S
(O) m-R (In the formula, R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, m is 0,
An oxazole derivative according to claim 1, which is a compound represented by the formula [1 or 2]. 5. A 5- to 8-membered complex in which R ¹ has at least one atom selected from _optionally substituted C _1-19 hydrocarbon group, _optionally substituted nitrogen atom, oxygen atom and sulfur atom. A cyclic group or an optionally substituted amino group,
R ² is a hydrogen atom, a cyano group, an acyl group derived from an organic carboxylic acid, an optionally substituted carbamoyl group,
Optionally substituted thiocarbamoyl group, optionally substituted C _1-19 hydrocarbon group, _optionally substituted,
A 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, an optionally substituted amino group or an optionally esterified carboxyl group, and R ³ is a hydrogen atom. , A halogen atom, an _optionally substituted C _1-19 hydrocarbon group, an _optionally substituted nitrogen atom, an oxygen atom, a 5- to 8-membered heterocyclic group having at least one atom selected from a sulfur atom, a substituent _Optionally substituted C _1-19 hydrocarbon oxy group, optionally substituted amino group, optionally esterified carboxyl group or formula —S (O) m—R ′ (wherein R ′ is An optionally substituted C _1-19 hydrocarbon group or an optionally substituted 5- to 8-membered heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, m is 0, Indicates 1 or 2 ) A group represented by
The oxazole derivative described. 6. R ¹ is (1) (i) 5 to 6 membered sulfur-containing heterocyclic group, (ii) 5 to 6 optionally substituted with C _1-12 alkyl or cyano.
Member oxygen-containing and nitrogen heterocyclic groups, (iii) carboxyl,
(iv) C _6-14 arylcarbonyl, (v) cyano, (vi) C
Carbamoyl which may be mono- or di-substituted by _1-12 alkyl and (vii) C _1-19 alkyl group which may be substituted by a group selected from C _1-12 alkoxycarbonyl, (2) mono- or di- -C _1-12 alkylamino optionally substituted C _2-12 alkenyl group, (3) C _2-12 alkynyl group, (4) C _3-10 cycloalkyl group, (5) (i) halogen atom , (Ii) C _1-12 alkoxy, (iii) (a)
Carbamoyl substituted with C _1-12 alkyl or C _3-10 cycloalkyl, (b) optionally substituted with halogen, C _6-14 arylsulfonyl or (c) C _1-12 alkylsulfonyl as a substituent. Amino that may be, (i
v) optionally C _1-12 alkyl optionally substituted with a halogen atom, (v) nitro, and (vi) group optionally substituted C _6-14 aryl group selected from hydroxyl, (6) (i) Halogen atom, (ii) C _1-12 alkoxy, (iii) (a)
C _1-12 substituted alkyl an optionally substituted C _6-14 arylsulfonyl, or (b) C _1-12 amino optionally having alkylsulfonyl as a substituent and (iv) a group selected from nitro An optionally _substituted C _7-19 aralkyl group, (7) a 5- or 6-membered nitrogen-containing or oxygen heterocyclic group, (8) (i) (a) C _1-12 alkoxycarbonyl, (b) mono- or di- -C _1-12 alkylamino, or (c) C _1-12 alkyl optionally having a 5- to 6-membered nitrogen-containing heterocyclic group as a substituent, (ii) a halogen atom or C _1-12 alkoxy substituted C _7-19 aralkyl which may have as a group, (ii
i) an amino group which may be substituted with a group selected from a C _4-12 bridged cyclic hydrocarbon group, (iv) C _6-14 aryl and (v) C _3-10 cycloalkyl, or (9) C The oxazole derivative according to claim 4, which is a thienopyrimidylhydrazino group optionally substituted with _1-12 alkyl. 7. R ¹ is (1) (i) thienyl, (ii) oxazolyl optionally substituted with C _1-6 alkyl or cyano, (iii) carboxyl, (iv) C _6-12 arylcarbonyl. , (V) cyano, (vi)
Carbamoyl optionally mono- or di-substituted by C _1-6 alkyl and (vii) C _1-12 alkyl group optionally substituted by a group selected from C _1-6 alkoxycarbonyl, (2) mono- or C _2-6 alkenyl group _optionally substituted by di-C _1-6 alkylamino, (3) C _2-6 alkynyl group, (4) C _3-8 cycloalkyl group, (5) (i) halogen , (Ii) C _1-6 alkoxy, (iii) (a) C _1-6
Carbamoyl substituted by alkyl or C _3-8 cycloalkyl, (b) optionally halogen-containing C _6-12 arylsulfonyl or (c) C _1-6 alkylsulfonyl as a substituent Good amino, (iv) C _1-6 alkyl _optionally substituted with halogen, (v) nitro and
(vi) C _6-12 aryl group which may be substituted with a group selected from hydroxyl group, (6) (i) halogen, (ii) C _1-6 alkoxy, (iii) (a) C _1-6
C _6-12 arylsulfonyl optionally substituted with alkyl or (b) amino optionally substituted with C _1-6 alkylsulfonyl as a substituent and optionally substituted with a group selected from (iv) nitro A good C _7-13 aralkyl group, (7) a heterocyclic group selected from pyrimidyl, piperidino, morpholino and 1-piperazinyl, (8) (i) (a) C _1-6 alkoxycarbonyl, (b) mono- or di- C _1-6 alkylamino, or (c) pyridyl a C _1-6 alkyl as a substituent, (ii) C _{6-12
Optionally} substituted with a group selected from aryl, (iii) halogen or C _7-13 aralkyl optionally substituted with C _1-6 alkoxy, (iv) adamantyl and (v) C _3-8 cycloalkyl The oxazole derivative according to claim 4, which is an amino group or a thienopyrimidylhydrazino group optionally substituted with (9) C _1-6 alkyl. Is 8. R ^2, (1) cyano group, (2) C _1-12 alkanoyl group, (3) 5 to 6-membered nitrogen-containing heterocyclic optionally C _1-12 alkyl optionally substituted with a group , C _1-12 alkanoyl or C _7-19
A carbamoyl group optionally having aralkyl as a substituent, (4) C _6-14 aryl _optionally having a substituent,
5- to 6-membered nitrogen-containing saturated heterocyclic group-carbonyl group, (5) thiocarbamoyl group optionally having C _1-12 alkyl or C _7-19 aralkyl as a substituent, (6) 5- to 6-membered Nitrogen-containing saturated heterocyclic group-thiocarbonyl group, (7) (i) C _6-14 arylcarbonyl-acylated hydroxy, (ii) halogen, (iii) carboxyl, (iv) cyano, ( v) an amino _optionally substituted with a C _1-12 alkyl or a C _7-19 aralkyl _optionally substituted with a 5- or 6-membered nitrogen-containing heterocyclic group, (vi)
A 5- to 6-membered saturated heterocyclic group containing two nitrogen atoms, which may have C _6-14 aryl as a substituent, (v
ii) Substituted with a group selected from phthalimide, (viii) C _6-14 arylsulfonyl _optionally having C _1-12 alkyl, and (ix) C _6-14 aryloxy _optionally substituted with halogen. _Optionally substituted C _1-12 alkyl group, (8) halogen or hydroxyl substituted C _7-19 aralkyl group, (9) C _1-12 alkoxycarbonyl or C _6-14 aryl substituted group A 5- to 6-membered nitrogen-containing and sulfur heterocyclic group which may be possessed as, (10) an amino group which may be substituted by C _1-12 alkoxycarbonyl, (11) a carboxyl group or (12) C The oxazole derivative according to claim 4, which is _1-12 alkoxycarbonyl. 9. R ² is (1) cyano group, (2) C _1-6 alkanoyl group, (3) (i) C _1-6 alkyl optionally substituted with pyridyl, (ii) C _{7 -13} aralkyl and (iii) carbamoyl group optionally having C _1-6 alkylcarbonyl as a substituent, (4) piperidinocarbonyl group, (5) _optionally substituted by C _6-12 aryl 1-piperazinylcarbonyl group, (6) (i) C _1-6 alkyl and (ii) thiocarbamoyl group optionally having C _7-13 aralkyl as a substituent, (7) piperidinothiocarbonyl group , (8) (i) C _6-12 arylcarbonyl-acylated hydroxy, (ii) halogen, (iii) carboxyl,
(iv) Cyano, (v) C _1-6 optionally substituted with pyridyl
Amino _optionally having alkyl or C _7-13 aralkyl as a substituent, (vi) 1-piperazinyl optionally substituted with C _6-12 aryl, (vii) phthalimide, (vi
ii) C _1-6 which may have an alkyl C _6-12 arylsulfonyl, (ix) optionally C _6-12 optionally substituted with halogen
C _1-6 alkyl group optionally substituted with a group selected from aryloxy, (9) C _7-13 aralkyl group optionally substituted with halogen or hydroxyl, (10) C _1-6 alkoxycarbonyl or A thiazolyl group optionally having C _6-12 aryl as a substituent, (11) an amino group optionally substituted by C _1-6 alkoxycarbonyl, (12) a carboxyl group, or (13) C _1- The oxazole derivative according to claim 4, which is a _6- alkoxycarbonyl group. 10. R ³ is (1) a hydrogen atom, (2) a halogen atom, (3) (i) C _7-19 aralkyl or C _1-12 alkyl _optionally substituted amino, (ii) 5- to 6-membered saturated heterocyclic group containing 2 nitrogen atoms, which may have C _6-14 aryl as a substituent, (iii) phthalimide, (iv) C _1-12 alkyl _Optionally substituted by C _6-14
Arylsulfonyl, (v) hydroxy optionally acylated with C _1-12 alkanoyl, (vi) 5- to 6-membered saturated heterocyclic group containing a nitrogen atom and / or an oxygen atom,
(vii) a 5- or _6- membered halogen atom, (viii) C _1-12 alkoxycarbonyl and (ix) C _1-6 alkyl or cyano-containing optionally substituted nitrogen atom and / or oxygen atom. C _1-12 alkyl group _optionally substituted with a group selected from unsaturated heterocyclic groups, (4) C _2-12 alkenyl group _optionally substituted with C _6-14 aryl, (5) C _{1 -12} has a C _6-14 aryl group optionally substituted by alkoxy, (6) (i) amino, (ii) nitro, (iii) C _1-12 alkoxy or (iv) halogen as a substituent. May be C
_7-19 aralkyl group, (7) C _3-10 cycloalkyl group, (8) C _3-10 cycloalkyl-C _1-12 alkyl group, (9) C _4-12 bridged cyclic hydrocarbon group, (10 ) A 5- or 6-membered unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom, (11) C _1-12 alkoxy group, (12) (i) (a) C _1-12 alkoxycarbonyl or (b ) 5
To an amino group optionally substituted with a group selected from C _1-12 alkyl optionally having a 6-membered nitrogen-containing heterocyclic group as a substituent and (ii) C _7-19 aralkyl, or (13 ) The oxazole derivative according to claim 4, which is a C _1-12 alkoxycarbonyl group. 11. R ³ is (1) a hydrogen atom, (2) a halogen atom, (3) (i) C _7-13 aralkyl or C _1-6 alkyl _optionally substituted amino. (ii) 1-piperazinyl substituted with C _6-12 aryl, (iii) phthalimide, (iv) C _6-12 arylsulfonyl optionally having C _1-6 alkyl, (v) C _{1- 6} Hydroxy optionally acylated with alkanoyl, (vi) morpholino, (vii) piperidino, (viii) halogen, (ix) C _1-6 alkoxycarbonyl and (x) C _1-6 alkyl or cyano as substituents A C _1-6 alkyl group optionally substituted by a group selected from oxazolyl, (4) a C _2-6 alkenyl group _optionally substituted by C _6-12 aryl (5) C _1-6 alkoxy optionally substituted C _6-12 aryl group, (6) (i) amino, (ii) nitro, (iii) C _1-6 alkoxy Others (iv) a halogen atom which may be substituted C _7-13 arachidyl group, (7) C _3-8 cycloalkyl group, (8) C _3-8 cycloalkyl -C _1-6 alkyl group, ( 9) adamantyl group, (10) oxadiazolyl, (11) C _1-6 alkoxy group, (12) (i) C _1-6 alkoxycarbonyl or C _1-6 alkyl optionally having pyridyl as a substituent The oxazole derivative according to claim 4, which is a group and (ii) an amino group which may be substituted with a group selected from a C _7-13 aralkyl group, or (13) a C _1-6 alkoxycarbonyl group. 12. R ¹ is (1) (i) 2-thienyl or (ii)
C _1-6 alkyl group optionally substituted with carboxyl, (2) (i) halogen, (ii) C _1-6 alkoxy or (iii)
C _6-12 aryl group _optionally substituted with carbamoylamino optionally substituted with C _1-6 alkyl, (3) C _7-13 aralkyl group _optionally substituted with nitro, (4)
(i) C _1-6 alkyl, (ii) C _6-12 aryl or (iii) C
The oxazole derivative according to claim 4, which is an amino group which may be substituted with _3-8 cycloalkyl or a (5) morpholino group. 13. The oxazole derivative according to claim 4, wherein R ² is a cyano group, a thiocarbamoyl group, a carbamoyl group or a C _1-6 alkyl group _optionally substituted with halogen. Is 14. R ^3, (1) a hydrogen atom, (2) C _1-6 alkyl or C _7-13 aralkyl and optionally substituted by amino optionally having as a substituent C _{1- 6} alkyl groups,
(3) C _3-6 cycloalkyl group or (4) C _1-12 aryl group optionally substituted with C _1-6 alkoxy or (5) (i) halogen or (ii) C _1-6 alkoxy The oxazole derivative according to claim 4, which is an _optionally substituted C _7-13 aralkyl group. 15. The oxazole derivative according to claim 4, wherein n is 2. 16. A formula (1): [Wherein R ¹ , R ² and R ³ have the same meanings as defined in claim 4], and the compound represented by the formula: [Wherein R ¹ , R ² and R ³ have the same meanings as described above, and n has the same meaning as in claim 4], or a compound represented by the formula (2) [Wherein R ² and R ³ have the same meanings as described above, R ¹² represents a lower alkyl group or a phenyl group, and n ¹ represents 0, 1 or 2] and a compound represented by the formula R ¹ -SO ₂ M is reacted with a compound represented by the formula: wherein R ¹ has the same meaning as above and M represents an alkali metal, [Wherein R ¹ , R ² and R ³ have the same meanings as described above] or a compound of the formula (3) [Wherein R ² , R ³ and n have the same meanings as described above, and X represents a leaving group] and a compound of the formula HNR ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or Which are different from each other, represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ and R ⁵ may form a ring together with the adjacent nitrogen atom]. Reacting with a compound of formula The method for producing an oxazole derivative according to claim 4, wherein a compound represented by the formula: wherein R ² , R ³ , n, R ⁴ and R ⁵ have the same meanings as defined above is produced. 17. A formula (1): [In the formula, R ² and R ³ have the same meaning as in claim 4]
A compound represented by the formula M ₂ S [wherein M has the same meaning as in claim 16] and a compound represented by the formula R ¹ X [wherein R ¹ has the same meaning as in claim 4]. Where X is claim 1
6 has the same meaning as described in [6] or by reacting with a compound represented by the formula (2) [Wherein R ² and R ³ have the same meanings as described above, R ¹² and n
¹ represents the same meaning as in claim 16] and a compound represented by the formula R ¹ -SH [wherein R ¹ represents the same meaning as described above], or Formula (3) [Wherein, R ² , R ³ , R ¹² and n ¹ have the same meanings as described above] and a compound of formula M ₂ S [wherein M has the same meanings as described above] A compound represented by the formula R ¹ X [wherein R ¹ and X have the same meanings as defined above]; [Wherein R ¹ , R ² and R ³ have the same meanings as described above]. 18. A medicine comprising an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group. 19. The oxazole derivative has the formula: [Wherein R ¹ represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted, n is 1 or 2, and R ² ′ is a hydrogen atom. A cyano group, an acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted An amino group or an optionally esterified carboxyl group, R ³ is a hydrogen atom,
Halogen atom, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted hydrocarbon oxy group, optionally substituted amino group, optionally esterified Carboxyl group or -S (O)
m-R (wherein R represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and m represents 0, 1 or 2)]. The medicine according to claim 18. 20. A preventive / therapeutic drug for heart diseases, autoimmune diseases, inflammatory diseases or diseases associated with granulomas.
8. The medicine according to 8 or 19. 21. Cardiomyopathy, cardiac hypertrophy, myocardial infarction, angina, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, Behcet's disease, Castleman's disease,
Autoimmune hemolytic anemia, mesangial proliferative nephritis, Ig
A nephritis, lupus nephritis, osteoporosis, amyloidosis,
Bronchial asthma, atopic dermatitis, psoriasis, pleuritis, ulcerative colitis, atherosclerosis, active chronic hepatitis, alcoholic liver cirrhosis, gout, encephalitis, multiple myeloma, atrial mucosa, renal cancer, lung gland 20. The medicine according to claim 18 or 19, which is a prophylactic / therapeutic drug for cancer, malignant mesothelioma, ovarian cancer, or cancer cachexia. 22. An interleukin 6 activity inhibitor containing an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group. 23. Atherosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer,
Ulcerative colitis, diabetes, glomerulonephritis, osteoporosis, pneumonia,
20. The medicine according to claim 18 or 19, which is a preventive / therapeutic drug for hepatitis, graft rejection or pain. 24. A nitric oxide production inhibitor containing an oxazole derivative having a group bonded to the 5-position via a sulfinyl group or a sulfonyl group.