JP2007210929A - Medicine containing urea compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having an excellent DGAT (diacyl glycerol acyl transferase) inhibitory activity. <P>SOLUTION: This medicine is provided by containing a urea derivative expressed by general formula (I) [wherein, R<SP>1</SP>is a 6-10C aryl or the like; R<SP>2</SP>is a 6-10C ary or the like; R<SP>3</SP>, R<SP>4</SP>are each H or the like; A is a 2-4C alkylene or the like; Q is a group expressed by formula: -N(Me)- or S; T is a group expressed by formula: =CH- or N; U, V are each the same or different and are each a group expressed by formula: =CH- or the like] or it pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  INDUSTRIAL APPLICABILITY The present invention effectively uses a urea derivative having a specific chemical structure having an excellent acylcoenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory action or a pharmacologically acceptable salt thereof. The present invention relates to a medicine contained as an ingredient.

  In obesity, triglycerides (triacylglycerol or triglyceride, TG) accumulate in adipocytes due to the persistence of excess energy compared to energy consumption, resulting in a normal body weight. It is the state which increased remarkably compared with (nonpatent literature 1). Obesity is hyperlipidemia, hyperTGemia, diabetes, hypertension, arteriosclerosis and other lifestyle-related diseases, cerebrovascular disorders, coronary artery disease, respiratory abnormalities, low back pain, knee osteoarthritis, gout, cholelithiasis, etc. Any obesity that has these complications or that may cause these complications in the future is defined as obesity and is treated as a disease.

  In recent years, it has been clarified that obesity is one of the main causes of lifestyle-related diseases called metabolic syndrome (Non-patent Document 2). In obese individuals, accumulated visceral fat releases factors such as fatty acids and TNF-α, which cause insulin resistance in skeletal muscle, liver and adipose tissue, and promotes synthesis of neutral fat in the liver. It has been reported to cause hyperlipidemia. In addition, elevated blood insulin levels caused by insulin resistance cause impaired glucose tolerance and diabetes, and also increase peripheral vascular resistance through increased Na ion reabsorption and activation of sympathetic nerves in the kidney, Causes hypertension. Hyperlipidemia, diabetes, and hypertension caused by obesity are thought to cause vascular disorders such as cerebrovascular disorders and coronary artery diseases based on arteriosclerosis, resulting in serious life-threatening medical conditions. Yes.

  As anti-obesity drugs currently used, central appetite suppressants such as mazindol (Non-patent Document 3) and sibutramine (Non-patent Document 4) and pancreatic lipase inhibitors such as orlistat are known. However, central appetite suppressants have side effects such as dry mouth, constipation, stomach discomfort, sometimes hallucinations, and hallucinations. Therefore, it is desired to develop an effective drug with fewer side effects.

  Animals and plants store lipids as insoluble TGs and break down TGs to produce energy as needed. TG ingested by meals is broken down into free fatty acids and monoacylglycerol by the action of bile acids and pancreatic lipase in the lumen of the small intestine. Micelles consisting of free fatty acids, monoacylglycerols and bile acids are absorbed by small intestinal epithelial cells, and in the endoplasmic reticulum by the action of acylcoenzyme A synthase (hereinafter referred to as ACS), acylcoenzyme A: monoacylglycerol acyltransferase and DGAT TG is newly synthesized. TG, in combination with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. Furthermore, TG is secreted into the blood via the lymph main duct and is transported to the periphery for use. On the other hand, also in adipose tissue, TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 6). Thus, TG ingested excessively accumulates in adipose tissue, resulting in obesity.

  DGAT is an enzyme that is present in the endoplasmic reticulum in the cell and catalyzes the most important final step of the TG synthesis pathway, ie, the reaction of transferring the acyl group of acylcoenzyme A to the 3-position of 1,2-diacylglycerol (Non-Patent Documents 7 to 9). It has been reported that DGAT has two types of isozymes DGAT1 (Non-Patent Document 10) and DGAT2 (Non-Patent Document 11). Since DGAT1 is highly expressed in the small intestine and adipose tissue, and DGAT2 is highly expressed in the liver and adipose tissue, DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation in the adipose tissue. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue. Although the difference in the roles of DGAT1 and DGAT2 has not yet been clarified in detail, the relationship between DGAT and obesity, lipid metabolism, sugar metabolism, etc. has been suggested (Non-patent Document 12). DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue, and drugs that inhibit DGAT suppress fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue by inhibiting TG synthesis, obesity , Obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, diabetes, or hyperlipidemia caused by obesity, hyperTGemia, dyslipidemia, insulin resistance It is expected to be useful as a therapeutic or prophylactic agent for syndrome, diabetes, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, etc. (Non-patent Documents 13 to 16).

  So far, several compounds having a DGAT inhibitory action are known, but all have structures different from the compounds of the present invention (for example, Patent Document 1 or Non-Patent Documents 17 to 20).

  In addition, although compounds having a structure similar to the compound of the present invention are known, it is not known that they exhibit a DGAT inhibitory action (for example, Patent Document 2).

Furthermore, a compound having an action of inhibiting fat absorption from the small intestine by mainly inhibiting DGAT1 among DGAT has not been known.
JP 2002-306199 A International Publication No. 03/045926 Pamphlet Eiji Itagaki, "STEP metabolism and endocrine", Kaiba Shobo, 1st edition, 1998, p.105 Zimmet, P. et al., Nature, 2001, 414, p. 782-787 Engstrom, RG et al., Arch. Intern. Pharmacodyn., 1975, 214, p.308-321 Bray, GA et al., Obes. Res., 1996, Vol. 4, p.263-270 Davidson, MH et al., The Journal of the American Medical Association, 1999, 281, p.235-242 Coleman, R., Bell, R., J. Biol. Chem., 1976, Vol. 251, p.4537-4543 Coleman, R., Methods in Enzymology, 1992, 209, p.98-104 Lehner, R., Kuksis, A., Prog. Lipid Res., 1996, Vol. 35, p.169-201 R. Bell., Ann. Rev. Biochem., 1980, 49, p.459-487 Cases, S. et al., Proc. Natl. Acad. Sci. USA., 1998, Vol. 95, p.13018-13023 Cases, S. et al., J. Biol. Chem., 2001, 276, p.38870-38876 Coleman, RA, Lee, DP, Progress in Lipid Research, 2004, Vol. 43, p.134-176 Smith, SJ et al., Nat. Genet., 2000, 25, p.87-90 Chen, HC, J. Clin. Invest., 2002, 109, p.1049-1055 Buhman, KK, J. Biol. Chem., 2002, 277, p.25474-25479 Gaziano, J., et al., Circulation, 1997, 96, p.2520-2525 Tomoda, H. et al., J. Antibiot. (Tokyo), 1995, Vol. 48, p.937-941 Yang, DJ et al., J. Antibiot. (Tokyo), 1996, 49, p.223-229 Tomoda, H. et al., J. Antibiot. (Tokyo), 1999, Vol. 52, p.689-694 Tabata, N. et al., Phytochemistry, 1997, 46, p.683-687

  As a result of intensive studies on compounds having a DGAT inhibitory effect, the inventors have found that a urea compound having a specific chemical structure has an excellent DGAT inhibitory action, particularly a high inhibitory action on DGAT1. I found out. In addition, the present inventors have found that this urea compound is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic Peripheral neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases shown above and below) The following diseases caused by obesity as active ingredients of drugs for the prevention and / or treatment of diseases selected from the group consisting of: atherosclerosis, and diabetic arteriosclerosis: hyperlipidemia , HyperTG, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) Cataract, pregnancy Gestational Diabetes, Polycystic Ovarian Syndrome, Arteriosclerosis (including arteriosclerosis caused by the diseases shown above and below), Atherosclerosis, Diabetic arteriosclerosis, Hypertension, Cerebrovascular disorder, Coronary artery disease, It has been found that it is useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, and cholelithiasis. The present invention has been completed based on the above findings.

  The present invention comprises (1) a general formula

[Where:
R ¹ is a C ₆ -C ₁₀ aryl group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b; one group and / or one or two optionally substituted heterocyclic group with a group selected independently from substituent group b is selected from the substituent group a, C ₁ -C ₁₀ alkyl group, A C ₇ -C ₁₆ aralkyl group which may be substituted with one group selected from the substituent group a and / or one to four groups independently selected from the substituent group b, or one A C ₃ -C ₆ cycloalkyl group optionally substituted with a C ₆ -C ₁₀ aryl group of
R ² is a C ₆ -C ₁₀ aryl group optionally substituted with one group selected from substituent group a and / or 1 to 4 groups independently selected from substituent group b, Or a heterocyclic group which may be substituted with one group selected from substituent group a and / or one or two groups independently selected from substituent group b;
R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a halogen atom,
R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
A is a methylene group, vinylene group, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, or one of the main chain methylene groups is replaced by a vinylene group, oxygen atom, sulfur atom, sulfinyl group or sulfonyl group. indicates even better _C 2 -C ₄ alkylene group,
Q represents a group represented by the formula -N (Me)-or a sulfur atom,
T represents a group represented by the formula = CH- or a nitrogen atom,
U and V are the same or different and represent a group represented by the formula = CH- or a nitrogen atom (provided that U and V do not represent a nitrogen atom at the same time),
The substituent group a is a C ₆ -C ₁₀ aryl group which may be substituted with 1 to 3 groups independently selected from the substituent group c, and 1 to 3 independently selected from the substituent group c. It represents the group consisting of pieces of one nitrogen-containing heterocyclic group optionally substituted by a group selected from optionally C ₆ -C ₁₀ aryl group and substituent group c substituted with one,
Substituent group b is a halogen _atom, C 1 _{-C 10} alkyl _group, C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl _{group, -P (= O) (O} -C 1 -C 6 _{alkyl) 2} in 1-substituted _C 1 -C ₆ alkyl _group, C 3 -C ₆ cycloalkyl _group, C 1 _{-C 10} alkoxy _group, C 1 -C ₆ halogenated alkoxy group, one or two hydroxy groups _C 1 -C ₆ alkoxy group _{substituted, C} 1 -C ₆ alkoxy group which is one substituted with C 3 -C ₆ cycloalkyl, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyl oxy _{group, (C} 1 -C ₆ alkoxy) - _(C 1 -C ₆ alkyl) _group, C 1 -C ₆ alkylthio group, a carboxyl _group, C 2 -C ₇ alkylcarbonyl _group, C 2 -C ₇ alkoxycarbonyl group A Amino group, _mono--C 2 -C ₇ alkylcarbonylamino group, a mono _-C 1 -C ₆ alkylsulfonylamino group, a mono _-C 1 -C ₆ alkylamino group, di - _(C 1 -C ₆ alkyl) amino group N- (C ₁ -C ₆ alkyl) -N- (C ₁ -C ₆ hydroxyalkyl) amino group, di- (C ₁ -C ₆ hydroxyalkyl) amino group, cyano group, nitro group, carbamoyl group, mono -C ₂ -C ₇ represents the group consisting alkylaminocarbonyl group and oxo group,
Substituent group c show a group consisting of halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl group and hydroxy group. ]
The present invention relates to a pharmaceutical comprising a urea derivative having a pharmaceutically acceptable salt or a pharmacologically acceptable salt thereof as an active ingredient.

In the present invention, preferably,
(2) In (1),
A pharmaceutical comprising as an active ingredient a urea derivative or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ia),

(3) In (1) or (2),
R ¹ is a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ halogenated alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogenated alkoxy group and a C ₂ -C ₅ alkylcarbonyl group. A C ₆ -C ₁₀ aryl group optionally substituted with 1 to 3 groups independently selected from the group consisting of: independently substituted with 1 to 3 C ₁ -C ₆ alkyl groups Good heterocyclic group; C ₁ -C ₆ alkyl group; halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ halogenated alkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ halogenated alkoxy A C ₇ -C ₁₄ aralkyl group optionally substituted with 1 to 3 groups independently selected from the group consisting of a group and a C ₂ -C ₅ alkylcarbonyl group; or substituted with one phenyl group May ₃ -C ₆ medicament containing a cycloalkyl group in which urea derivative or a pharmacologically acceptable salt thereof as an active ingredient,
(4) In (1) or (2),
^{1 or 2 in} which R ¹ is independently selected from the group consisting of a fluorine atom, a chlorine atom, a C ₁ -C ₄ alkyl group, a trifluoromethyl group, a C ₁ -C ₄ alkoxy group, a trifluoromethoxy group, and a methylcarbonyl group Phenyl group or naphthyl group which may be substituted with one group; independently a 5-membered aromatic heterocyclic group or condensed bicyclic heterocyclic group which may be substituted with 1 or 2 C ₁ -C ₄ alkyl groups ring _group; C 2 -C ₆ alkyl _group; is or permitted one urea derivative substituted with a phenyl group also optionally _C 3 -C ₆ cycloalkyl group, or a pharmacologically; C 7 _{-C 14} aralkyl group A medicine containing a salt as an active ingredient,
(5) In (1) or (2),
R ¹ is a phenyl group; a phenyl group substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group; a fluorine atom, a chlorine atom, a methyl group, and substituted by or one phenyl group; a thienyl group; two phenyl group substituted with a group selected independently from the group consisting of a methoxy group C ₂ -C ₆ alkyl group; C ₇ -C ₈ aralkyl group A pharmaceutical comprising a urea derivative which is a C ₃ -C ₆ cycloalkyl group which may be prepared, or a pharmacologically acceptable salt thereof as an active ingredient,
(6) In (1) or (2),
R ¹ is phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 2,4-difluorophenyl, 5-fluoro-2-methylphenyl, 5-chloro-2- A pharmaceutical comprising a urea derivative which is a methoxyphenyl group, 2-methoxy-5-methylphenyl group, n-hexyl group, 1-phenylethyl group or 2-phenylcyclopropyl group or a pharmacologically acceptable salt thereof as an active ingredient ,
(7) In any one item selected from (1) to (6),
R ² is a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₂ halogenated alkyl group, C ₁ -C ₆ alkoxy group, carboxyl group, C ₂ -C ₇ alkoxycarbonyl group, mono-C ₂ -C _A C ₆ -C ₁₀ aryl group optionally substituted by 1 to 3 groups independently selected from the group consisting of ₇ alkylaminocarbonyl group, cyano group, carbamoyl group and 5- (1H-tetrazolyl) group; or halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₂ halogenated alkyl _group, C 1 -C ₆ alkoxy group, a carboxyl _group, C 2 -C ₇ alkoxycarbonyl group, _mono--C 2 -C ₇ alkyl 1 or 2 groups independently selected from the group consisting of aminocarbonyl group, cyano group, carbamoyl group, 5- (1H-tetrazolyl) group and oxo group A pharmaceutical containing a urea derivative which is an optionally substituted heterocyclic group or a pharmacologically acceptable salt thereof as an active ingredient,
(8) In any one item selected from (1) to (6),
R ² is a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₂ halogenated alkyl group, a C ₁ -C ₆ alkoxy group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, a carbamoyl group, and A phenyl or pyridyl group optionally substituted with one or two groups independently selected from the group consisting of 5- (1H-tetrazolyl) groups; or independently selected from the group consisting of halogen atoms and oxo groups A pharmaceutical comprising, as an active ingredient, a urea derivative which is a condensed bicyclic heterocyclic group optionally substituted with one or two groups, or a pharmacologically acceptable salt thereof,
(9) In any one item selected from (1) to (6),
R ² is independently selected from the group consisting of fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carbamoyl group and 5- (1H-tetrazolyl) group A phenyl group substituted at the 2- and 6-positions, the 2- and 5-positions, or the 2- and 4-positions; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group , A phenyl group substituted at the 2-position with a group selected from the group consisting of a methoxycarbonyl group, a methylaminocarbonyl group, a carbamoyl group and a 5- (1H-tetrazolyl) group; a fluorine atom, a chlorine atom, a methyl group, Fluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carba 2-pyridyl group substituted at the 3-position with a group selected from the group consisting of moyl group and 5- (1H-tetrazolyl) group; or 1 or 2 independently selected from the group consisting of chlorine atom and oxo group A pharmaceutical comprising, as an active ingredient, a urea derivative which is a 1,3-dihydro-1-isobenzofuranyl group, 1-indolyl group or 1-indolinyl group substituted with one group or a pharmacologically acceptable salt thereof ,
(10) In any one item selected from (1) to (6),
R ² is 2,6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2-chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6-chlorophenyl group or 2-chloro-6- [5- (1H -Tetrazolyl)] a pharmaceutical containing a urea derivative which is a phenyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(11) In any one item selected from (1) to (10),
A pharmaceutical comprising a urea derivative in which R ³ is a hydrogen atom or a pharmacologically acceptable salt thereof as an active ingredient,
(12) In any one item selected from (1) to (11),
A pharmaceutical comprising a urea derivative in which R ⁴ is a hydrogen atom or a pharmacologically acceptable salt thereof as an active ingredient,
(13) In any one item selected from (1) to (12),
A is vinylene group, or one methylene group in the main chain, but a vinylene group, an oxygen atom or a urea derivative or a pharmacologically acceptable salt thereof is a good C ₂ -C ₄ alkylene group optionally substituted by a sulfur atom A medicament containing as an active ingredient,
(14) In any one item selected from (1) to (12),
A pharmaceutical comprising as an active ingredient a urea derivative in which A is a vinylene group, ethylene group, methyleneoxy group or methylenethio group, or a pharmacologically acceptable salt thereof,
(15) In any one item selected from (1) to (12),
A pharmaceutical comprising a urea derivative in which A is a vinylene group, an ethylene group or a methylenethio group or a pharmacologically acceptable salt thereof as an active ingredient,
(16) In any one item selected from (1) to (12),
A medicament comprising as an active ingredient a urea derivative in which A is a vinylene group or an ethylene group, or a pharmacologically acceptable salt thereof,
(17) In any one item selected from (1) to (16),
A pharmaceutical comprising a urea derivative or a pharmacologically acceptable salt thereof as an active ingredient, wherein U is a group represented by the formula = CH-
(18) In any one item selected from (1) to (17),
A pharmaceutical comprising a urea derivative or a pharmacologically acceptable salt thereof as an active ingredient, wherein V is a group represented by the formula = CH-
(19) In (1),
The general formula (I) is the general formula (Ia), and R ¹ is substituted with ^one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b. A C ₆ -C ₁₀ aryl group which may be substituted, one group selected from substituent group a and / or one or two groups independently selected from substituent group b A heterocyclic group, a C ₁ -C ₁₀ alkyl group, _one group selected from substituent group a and / or 1 to 4 groups independently selected from substituent group b A good C ₇ -C ₁₆ aralkyl group, or a C ₃ -C ₆ cycloalkyl group optionally substituted by one C ₆ -C ₁₀ aryl group, and R ² is selected from the substituent group a It may be substituted with 1 to 4 groups independently selected from one group and / or substituent group b. C ₆ -C ₁₀ aryl group, or, one group and / or one or two heterocyclic ring which may be substituted with a group independently selected from substituent group b is selected from the substituent group a R ³ is a hydrogen atom, a C ₁ -C ₆ alkyl group or a halogen atom, R ⁴ is a hydrogen atom or a C ₁ -C ₆ alkyl group, A is a methylene group, a vinylene group, an oxygen atom, sulfur atom, a sulfinyl group, a sulfonyl group, or one methylene group in the main chain, but vinylene group, an oxygen atom, a sulfur atom, a C ₂ -C ₄ alkylene group optionally substituted sulfinyl group or a sulfonyl group, U and V are the same or different and are a group represented by the formula = CH- or a nitrogen atom (however, U and V do not represent a nitrogen atom at the same time), and the substituent group a is independent of the substituent group c. Selected That from 1-3 which may be C ₆ -C ₁₀ aryl group substituted by a group, one to three optionally C ₆ -C be substituted with a group selected independently from substituent group c ₁₀ a group consisting of one nitrogen-containing heterocyclic group optionally substituted with a group selected from aryl group and substituent group c, substituent group b is a halogen atom, C ₁ -C ₁₀ alkyl group, A C ₁ -C ₆ alkyl halide group, a C ₁ -C ₆ hydroxyalkyl group, a C ₁ -C ₆ alkyl group that is 1-substituted with —P (═O) (O—C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₆ cycloalkyl _group, C 1 _{-C 10} alkoxy _group, C 1 -C ₆ halogenated alkoxy group, _C 1 -C ₆ alkoxy group which is one or two substituted with a hydroxy _group, C 3 -C ₆ C ₁ -C substituted with one cycloalkyl group ₆ alkoxy group, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyloxy group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₁ -C ₆ alkylthio group, carboxyl _group, C 2 -C ₇ alkylcarbonyl _group, C 2 -C ₇ alkoxycarbonyl group, an amino group, a mono _-C 2 -C ₇ alkylcarbonylamino group, a mono _-C 1 -C ₆ alkylsulfonylamino group, a mono -C ₁ -C ₆ alkylamino group, di - _(C 1 -C ₆ alkyl) amino group, _N-(C 1 -C _{6 alkyl)-N-(C} 1 -C ₆ hydroxyalkyl) amino group, di - (C _1- C ₆ hydroxyalkyl) A group consisting of an amino group, a cyano group, a nitro group, a carbamoyl group, a mono-C ₂ -C ₇ alkylaminocarbonyl group and an oxo group, and a substituent group c Pharmaceutical but containing a halogen atom, a C ₁ -C ₆ alkyl group, C ₁ -C ₆ urea derivative or a pharmacologically acceptable salt thereof is a group consisting of a halogenated alkyl group and hydroxy group as an active ingredient,
(20) In (1),
^{1 or 2 in} which R ¹ is independently selected from the group consisting of a fluorine atom, a chlorine atom, a C ₁ -C ₄ alkyl group, a trifluoromethyl group, a C ₁ -C ₄ alkoxy group, a trifluoromethoxy group, and a methylcarbonyl group Phenyl group or naphthyl group which may be substituted with one group; independently a 5-membered aromatic heterocyclic group or condensed bicyclic heterocyclic group which may be substituted with 1 or 2 C ₁ -C ₄ alkyl groups A cyclic group; a C ₂ -C ₆ alkyl group; a C ₇ -C ₁₄ aralkyl group; or a C ₃ -C ₆ cycloalkyl group optionally substituted with one phenyl group, and R ² is a halogen atom, C ₁ -C ₆ alkyl _group, C 1 -C ₂ halogenated alkyl _group, C 1 -C ₆ alkoxy group, a carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, a cyano group, mosquitoes A phenyl group or a pyridyl group optionally substituted with one or two groups independently selected from the group consisting of a vamoyl group and a 5- (1H-tetrazolyl) group; or independent from the group consisting of a halogen atom and an oxo group A condensed bicyclic heterocyclic group optionally substituted with one or two groups selected from: R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, A is a vinylene group, an ethylene group A urea derivative or a pharmacologically acceptable salt thereof, which is a methyleneoxy group or a methylenethio group, U is a group represented by the formula = CH-, and V is a group represented by the formula = CH- or a nitrogen atom A medicine containing as an ingredient,
(21) In (1),
The general formula (I) is the general formula (Ia), and R ¹ is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group. and which phenyl group; a thienyl group;; C ₂ -C ₆ alkyl group; a fluorine atom, a chlorine atom, a phenyl group is substituted with two groups independently selected from the group consisting of methyl group and methoxy group C ₇ -C ₈ aralkyl group; or C ₃ -C ₆ cycloalkyl optionally substituted by one phenyl group, and R ² is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group A group independently selected from the group consisting of a group, a methoxycarbonyl group, a methylaminocarbonyl group, a carbamoyl group and a 5- (1H-tetrazolyl) group; Or phenyl group substituted at the 2-position and 4-position; fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carbamoyl group and 5 A phenyl group substituted at the 2-position with a group selected from the group consisting of-(1H-tetrazolyl) group; fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, 2-pyridyl group substituted at the 3-position with a group selected from the group consisting of methylaminocarbonyl group, carbamoyl group and 5- (1H-tetrazolyl) group; or independently selected from the group consisting of chlorine atom and oxo group 1,3-dihydro-1-isobenzofuranyl group substituted with 1 or 2 groups A Ndoriru group or 1-indolinyl group, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, A is a vinylene group, an ethylene group or a methylenethio group, a group U is represented by the formula = CH- A drug containing a urea derivative or a pharmacologically acceptable salt thereof as an active ingredient, wherein V is a group represented by the formula = CH- or a nitrogen atom;
(22) In (1),
The general formula (I) is the general formula (Ia), and R ¹ is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group. and which phenyl group; a thienyl group;; C ₂ -C ₆ alkyl group; a fluorine atom, a chlorine atom, a phenyl group is substituted with two groups independently selected from the group consisting of methyl group and methoxy group C ₇ -C ₈ aralkyl group; a or one good _C 3 -C ₆ cycloalkyl optionally substituted with a phenyl group, ^{R 2} is 2,6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2- chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6-chlorophenyl or 2-chloro-6- [5-(1H-tetrazolyl) phenyl group, ^{R 3} is a hydrogen atom Ri, R ⁴ is a hydrogen atom, A is a vinylene group or an ethylene group, a group U is represented by the formula = CH-, urea derivatives V is a group or a nitrogen atom represented by the formula = CH- Or a medicament containing a pharmacologically acceptable salt thereof as an active ingredient,
(23) In (1),
The general formula (I) is the general formula (Ia), and R ¹ is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 2-trifluoromethylphenyl group, 2,4-difluorophenyl group, 5- fluoro-2-methylphenyl group, 5-chloro-2-methoxyphenyl group, a 2-methoxy-5-methylphenyl group, n- hexyl group, 1-phenylethyl or 2-phenyl cyclopropyl group, ^{R 2} Is 2,6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2-chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6-chlorophenyl group or 2-chloro-6- [5- (1H-tetrazolyl) )] phenyl group, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, a is a vinylene group or an ethylene group, U is the formula = CH- A it is the group, medicine containing salt V is allowed urea derivative or a pharmacologically a group or a nitrogen atom represented by the formula = CH- as an active ingredient,
(24) In (1),
1- (4- {5- [2- (2,6-dichloro-phenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2- Methoxy-5-methylphenyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-trifluoromethylphenyl) urea,
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid,
3-Chloro-2- [2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] triazole-3- Yl) ethyl] benzoic acid methyl ester,
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester,
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzamide,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3-hexyl Urea,
1- [4- (5- {2- [2-Chloro-6- (1H-tetrazol-5-yl) phenyl] ethyl} -4-methyl-4H- [1,2,4] triazol-3-yl ) Phenyl] -3- (2-methoxy-5-methylphenyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 3,5-dimethylphenyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2,4-difluorophenyl) urea,
1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-fluorophenyl Urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-fluorophenyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-phenyl-cyclopropyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3-phenyl Urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( (R) -1-phenylethyl) urea,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 3-fluorophenyl) urea,
1- (5-Chloro-2-methoxyphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4 ] Triazol-3-yl} phenyl) urea,
N- (4- {5-[(E) -2- (2-trifluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N ' -(2-methoxy-5-methylphenyl) urea,
N- (4- {5-[(E) -2- (2-chlorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N '-( 2-methoxy-5-methylphenyl) urea,
N- (4- {5-[(E) -2- (2,4-difluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N '-(2-methoxy-5-methylphenyl) urea,
N- (4- {5-[(E) -2- (2-methylphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N'- (2-methoxy-5-methylphenyl) urea,
1- (6- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-yl) -3- ( 2-methoxy-5-methylphenyl) urea,
1- (5- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-2-yl) -3- ( 2-methoxy-5-methylphenyl) urea,
1- (6- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-yl) -3- (2-methoxy-5-methylphenyl) urea,
1- {5- [5- (2,6-dichlorobenzsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] pyridin-2-yl} -3- (2-methoxy -5-methylphenyl) urea,
3-chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] -pyridin-3-yl} -4-methyl-4H- [1,2,4] triazole- 3-ylsulfanylmethyl) benzoic acid,
3-Chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] pyridin-3-yl} -4-methyl-4H- [1,2,4] triazole-3 -Ylsulfanylmethyl) benzamide,
1- (2-methoxy-5-methylphenyl) -3- (6- {4-methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2, 4] triazol-3-yl} pyridin-3-yl) urea,
1- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-fluorophenyl) urea,
1- (5-chloro-2-methoxyphenyl) -3- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) urea,
1- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-methoxy-5-methylphenyl) urea,
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-fluorophenyl) urea,
1- (5-Chloro-2-methoxyphenyl) -3- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} Phenyl) urea,
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-methoxy-5-methyl Phenyl) urea,
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] thiazol-5-yl} phenyl) -3- (2-methoxy-5-methylphenyl) urea, or
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl]-[1,3,4] thiadiazol-2-yl} phenyl) -3- (2-methoxy-5- A pharmaceutical comprising a urea derivative represented by (methylphenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient,
(25) In (1),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-trifluoromethylphenyl) urea,
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester,
1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-fluorophenyl ) Urea, or
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( A pharmaceutical comprising a urea derivative represented by (2-fluorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient,
(26) An acyl coenzyme A: diacylglycerol acyltransferase inhibitor comprising, as an active ingredient, the urea derivative described in any one of (1) to (25) or a pharmacologically acceptable salt thereof,
(27) A medicament comprising, as an active ingredient, the urea derivative described in any one of (1) to (25) or a pharmacologically acceptable salt thereof,
(28) The medicament according to (27), wherein the medicament has an acylcoenzyme A: diacylglycerol acyltransferase inhibitory action,
(29) The drug is obesity, obesity, hyperlipidemia, hyperTGemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases mentioned above and below), atherosclerosis The medicament according to (28) for the treatment and / or prevention of infectious disease or diabetic arteriosclerosis,
(30) The following diseases caused by obesity: hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases mentioned above and below), atheroma For the treatment and / or prevention of atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis (28 ) Medicines described in
(31) The medicament according to (28) for treating and / or preventing obesity, obesity or hyperlipidemia caused by obesity, hyperTGemia, diabetes, hypertension or arteriosclerosis,
(32) The medicament according to (28) for treating and / or preventing obesity or obesity,
(33) The medicament according to (28), which is for suppressing fat absorption from the small intestine.

In the present invention, the “C ₆ -C ₁₀ aryl group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms such as a phenyl, indenyl or naphthyl group, preferably a phenyl or naphthyl group. More preferably a phenyl group.

In the present invention, the “heterocyclic group” refers to a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atom, oxygen atom and / or nitrogen atom. For example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl "5-membered aromatic heterocyclic group" such as oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl or thiadiazolyl group, "6-membered" such as pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group Aromatic heterocyclic group ", tetrahydropyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl A “partially or fully reduced saturated heterocyclic group” such as a benzene, dioxolanyl, or dioxanyl group, and the heterocyclic group may be condensed with another cyclic group such as a benzene ring (“ Fused bicyclic heterocyclic groups ") such as benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, 1,3-dihydroisobenzofuranyl, quinolyl, 1,3-benzodioxolanyl, 1, 4-benzodioxanyl, indolyl, isoindolyl or indolinyl group, and R ¹ is preferably a 5-membered aromatic heterocyclic group or a condensed bicyclic heterocyclic group, more preferably a thienyl group. , still more preferably a 2-thienyl group, in R ² is preferably a 6-membered aromatic heterocyclic group or a fused bicyclic heterocyclic group, more preferably a pyridinium 1,3-dihydroisobenzofuranyl, indolyl or indolinyl group, even more preferably 2-pyridyl group, 1,3-dihydro-1-isobenzofuranyl group, 1-indolyl group or 1-indolyl group. Indolinyl group.

In the present invention, the “C ₁ -C ₁₀ alkyl group” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethyl. Propyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 A linear or branched chain having 1 to 10 carbon atoms such as dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl or decyl group An alkyl group, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (C ₁ -C ₆ R ¹ is more preferably a linear or branched alkyl group having 2 to 6 carbon atoms (C ₂ -C ₆ alkyl group), and even more preferably hexyl. In the substituent group b, a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group) is more preferable, and methyl is more preferable. Group or an ethyl group (C ₁ -C ₂ alkyl group), and particularly preferably a methyl group.

In the present invention, “C ₇ -C ₁₆ aralkyl group” refers to a group in which one “C ₆ -C ₁₀ aryl group” is bonded to the “C ₁ -C ₆ alkyl group”. α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1 -Naphtylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4 -Naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl Til, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenyl Hexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl or 6-naphthylhexyl, preferably 1 The “C ₆ -C ₁₀ aryl group” is a group (C ₇ -C ₁₄ aralkyl group) bonded to the “C ₁ -C ₄ alkyl group”, more preferably benzyl, 1-phenylethyl 2-phenylethyl or 1-phenylpropyl group, and even more preferably benzyl, 1 Phenylethyl or 2-phenylethyl group _(C 7 -C ₈ aralkyl group), particularly preferably a 1-phenylethyl group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, and preferably a cyclohexyl group.

In the present invention, "one C ₆ -C ₁₀ aryl group optionally substituted C ₃ -C be the ₆ cycloalkyl group", optionally substituted by one of the "C ₆ -C ₁₀ aryl group" The above-mentioned “C ₃ -C ₆ cycloalkyl group” may be represented by, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-phenylcyclopropyl, 2-phenylcyclobutyl, 2-phenylcyclopentyl, 2-phenylcyclohexyl, It is a 4-phenylcyclohexyl or 2-naphthylcyclopropyl group, preferably a cyclohexyl or 2-phenylcyclopropyl group, and more preferably a 2-phenylcyclopropyl group.

In the present invention, the “C ₁ -C ₆ alkyl group” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethyl. Propyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 A straight-chain or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group), more preferably methyl group or An ethyl group (C ₁ -C ₂ alkyl group), even more preferably more, a methyl group.

  In the present invention, the “halogen atom” is a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably a fluorine atom, chlorine atom or bromine atom, more preferably a fluorine atom or chlorine atom. is there.

In the present invention, the “C ₂ -C ₄ alkylene group” means, for example, an ethylene group, a propylene group, a 1,2-dimethylethylene group, an ethylethylene group, a trimethylene group or a tetramethylene group having 2 to 4 carbon atoms. A divalent group formed by losing two hydrogen atoms from two different carbon atoms of an aliphatic hydrocarbon, preferably from two different carbon atoms of an aliphatic hydrocarbon having 2 or 3 carbon atoms It is a divalent group (“C ₂ -C ₃ alkylene group”) generated by losing two hydrogen atoms, and more preferably an ethylene group.

In the present invention, the “main chain” of the “methylene group of the main chain” is a carbon chain excluding the side chain in the structure connecting the triazole ring of the general formula (I) and R ² .

In the present invention, “a C ₂ -C ₄ alkylene group in which one of the methylene groups of the main chain may be replaced by a vinylene group, an oxygen atom, a sulfur atom, a sulfinyl group, or a sulfonyl group” refers to the “methylene group of the main chain”. One of the “groups” is the “C ₂ -C ₄ alkylene group” which may be substituted with a vinylene group, an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, for example, an ethylene group, a propenylene group, a methyleneoxy group , Methylenethio group, methylenesulfinyl group, methylenesulfonyl group, trimethylene group, butenylene group, ethyleneoxy group, ethylenethio group, ethylenesulfinyl group or ethylenesulfonyl group, preferably ethylene group, methyleneoxy group or methylenethio group More preferably, with an ethylene group or a methylenethio group That.

  In the present invention, the “vinylene group” includes both the Z-conformation and the E-conformation, but is preferably the E-conformation.

In the present invention, the “C ₆ -C ₁₀ aryloxy group” refers to a group in which the “C ₆ -C ₁₀ aryl group” is bonded to an oxygen atom, such as a phenyloxy, indenyloxy or naphthyloxy group. An aryloxy group having 6 to 10 carbon atoms, preferably a phenyloxy group or a naphthyloxy group, and more preferably a phenyloxy group.

  In the present invention, the “nitrogen-containing heterocyclic group” refers to a 4- to 7-membered heterocyclic group containing 1 to 4 nitrogen atoms. For example, an “aromatic group” such as tetrazolyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl or piperazinyl group. Group heterocyclic group "or" partially or completely reduced saturated heterocyclic group ", preferably a tetrazolyl or pyrrolidinyl group, more preferably a 5- (1H-tetrazolyl) group or a 1-pyrrolidinyl group. It is.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” refers to a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. Fluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, pentafluoroethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl group, preferably the same or different 1 to 5 “halogen atoms” There is said group attached to the "C ₁ -C ₄ alkyl group" (C ₁ -C ₄ halogenated alkyl group), more preferably the same or different one to five of the "C A group Gen atom "is bonded to the" C ₁ -C ₂ alkyl group "(C ₁ -C ₂ halogenated alkyl group), even more preferably more, a trifluoromethyl group.

In the present invention, the “C ₁ -C ₆ hydroxyalkyl group” refers to a group in which one hydroxyl group is bonded to the “C ₁ -C ₆ alkyl group”, for example, a hydroxymethyl, hydroxyethyl or hydroxypropyl group And preferably a group in which one hydroxyl group is bonded to a linear or branched alkyl group having 1 to 3 carbon atoms (C ₁ -C ₃ hydroxyalkyl group), more preferably hydroxymethyl , 2-hydroxyethyl or 3-hydroxypropyl group, and more preferably a hydroxymethyl group.

In the present invention, “—P (═O) (O—C ₁ -C ₆ alkyl) ₂ ” means that two oxygen atoms bonded to _one “C ₁ -C ₆ alkyl group” are bonded to a phosphoryl group. Phosphonic acid diethyl ester or phosphonic acid dimethyl ester, more preferably phosphonic acid diethyl ester.

In the present invention, “—P (═O) (O—C ₁ -C ₆ alkyl) ₂ monosubstituted by C ₁ -C ₆ alkyl group” refers to one “—P (═O) (O -C ₁ -C ₆ alkyl) ₂ ”represents a group bonded to the“ C ₁ -C ₆ alkyl group ”, preferably phosphonic acid diethyl ester methyl or phosphonic acid diethyl ester ethyl, more preferably , Phosphonic acid diethyl ester methyl.

In the present invention, the “C ₁ -C ₁₀ alkoxy group” refers to a group in which the “C ₁ -C ₁₀ alkyl group” is bonded to an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, heptyloxy, octyloxy, nonyloxy or Linear or branched chain having 1 to 10 carbon atoms such as decyloxy group A chain alkoxy group, preferably a straight or branched alkoxy group having 1 to 6 carbon atoms (C ₁ -C ₆ alkoxy group), more preferably having 1 to 4 straight-carbon A chain or branched chain alkoxy group (C ₁ -C ₄ alkoxy group), even more preferably a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group), and particularly preferably a methoxy group is there.

In the present invention, the “C ₁ -C ₆ halogenated alkoxy group” refers to a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkoxy group”. Trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2- Fluoroethoxy, 2-iodoethoxy, pentafluoroethoxy, 3-chloropropoxy, 4-fluorobutoxy, 6-iodoheptyloxy or 2,2-dibromoethoxy groups, preferably 1 to 5 identical or different wherein a group of "halogen atom" is bonded to the "C ₁ -C ₄ alkoxy group" (C ₁ -C ₄ halogenated alkoxy group), Ri preferably, are the same or different one to five of the "halogen atom" is bonded to the "C ₁ -C ₂ alkoxy group" group (C ₁ -C ₂ halogenated alkoxy group), preferably more than Is a trifluoromethoxy group.

In the present invention, “C ₁ -C ₆ alkoxy group substituted with 1 or 2 hydroxy groups” means a group in which 1 or 2 hydroxy groups are bonded to the “C ₁ -C ₆ alkoxy group”. For example, hydroxyethoxy, hydroxypropoxy, dihydroxypropoxy, hydroxybutoxy or dihydroxybutoxy group, preferably one or two hydroxyl groups bonded to a linear or branched alkoxy group having 2 to 4 carbon atoms a group (C ₂ -C ₄ hydroxyalkoxy group substituted one or two hydroxy groups), more preferably a 2-hydroxyethoxy or 2,3-dihydroxy-propoxy group.

In the present invention, “a C ₁ -C ₆ alkoxy group which is substituted with one C ₃ -C ₆ cycloalkyl group” means that one “C ₃ -C ₆ cycloalkyl group” is the above “C ₁ -C ₆ cycloalkyl group”. shows the attached group on C ₆ alkoxy group ", for example, cyclopropylmethyloxy, cyclobutylmethyl oxy, cyclopentylmethyl oxy, cyclohexylmethyloxy, 2-cyclopropyl-ethoxy, 2-cyclobutyl-ethoxy, 1-cyclopropyl-ethoxy, 1-cyclobutylethoxy, 3-cyclopropylpropoxy or 3-cyclobutylpropoxy group, and preferably one of the “C ₃ -C ₆ cycloalkyl group” is the above “C ₁ -C ₄ alkoxy group”. a bonded group, more preferably, one of the "C ₃ -C ₆ cycloalkyl group" is the "C ₁ -C A group attached to an alkoxy group ", further preferably more, cyclopropylmethyl group.

In the present invention, the “C ₂ -C ₆ alkenyloxy group” is a group having 2 to 6 carbon atoms and having one double bond among the above “C ₁ -C ₆ alkoxy groups”. are shown, for example, 1-ethenyloxy, 2-propenyloxy, 1-propenyloxy, 3-butenyloxy, 2-butenyloxy, 1-butenyloxy or 5-hexenyl group, preferably, C ₂ -C ₄ alkenyloxy More preferably a 2-propenyloxy group.

In the present invention, the “C ₂ -C ₆ alkynyloxy group” is a group having 2 to 6 carbon atoms and having one triple bond among the above “C ₁ -C ₆ alkoxy groups”. shows, for example, 1-ethynyl-oxy, 2-propynyloxy, 1-propynyloxy, 3-butynyloxy, 2-butynyloxy, 1-butynyloxy or 5-hexynyloxy group, preferably, C ₂ -C ₄ alkynyloxy group And more preferably a 2-propynyloxy group.

In the present invention, the “(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group” means that one “C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkyl group”. For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, s-butoxymethyl, t-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2 -Propoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2- (s-butoxy) ethyl, 2- (t-butoxy) ethyl, 1-methoxyethyl, 1-ethoxyethyl, 1 -Propoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl, 1- (s-butoxy) Le, a 1-(t-butoxy) ethyl or 3- isopropoxypropyl group, preferably, coupled to the _"C 1 -C ₄ alkyl group" is one of the _"C 1 -C ₄ alkoxy group" Group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group), and more preferably, one of said “C ₁ -C ₂ alkoxy group” is the above “C ₁ -C A group ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkyl) group) bonded to “ ₂ alkyl group”, and more preferably a methoxymethyl group.

In the present invention, “C ₁ -C ₆ alkylthio group” refers to a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a sulfur atom, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio , Isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio, 3-methylpentyl Ruthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3- Dimethylbutylthio, 2,3-dimethylbutylthio, 1-ethylbutylthio or 2-ethyl Chiruchio a linear or branched alkylthio group having 1 to 6 carbon atoms such as groups, preferably, of 1 to 4 carbon atoms straight-chain or branched-chain alkylthio group (C ₁ -C ₄ alkylthio groups ), and more preferably a methylthio group or an ethylthio group (C ₁ -C ₂ alkylthio group), even more preferably more, a methylthio group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyl group” refers to a group in which the “C ₁ -C ₆ alkyl group” is bonded to a carbonyl group, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, A valeryl or isovaleryl group, preferably a group in which the “C ₁ -C ₄ alkyl group” is bonded to a carbonyl group (C ₂ -C ₅ alkylcarbonyl group), more preferably an acetyl or propionyl group a _(C 2 -C ₃ alkylcarbonyl group), even more preferably more, an acetyl group.

In the present invention, “C ₂ -C ₇ alkoxycarbonyl group” refers to a group in which the above “C ₁ -C ₆ alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl. , Butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3 -Methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbut Aryloxycarbonyl, 1,3 is dimethyl-butoxycarbonyl or 2,3-dimethyl-butoxycarbonyl group, Preferably, the "C ₁ -C ₄ alkoxy group" is bonded to a carbonyl group group _(C 2 -C ₅ alkoxy A carbonyl group), more preferably a methoxycarbonyl or ethoxycarbonyl group (C ₂ -C ₃ alkoxycarbonyl group), and even more preferably a methoxycarbonyl group.

In the present invention, “mono-C ₂ -C ₇ alkylcarbonylamino group” means a group in which one carbonyl group to which the above “C ₁ -C ₆ alkyl group” is bonded is bonded to an amino group. Ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, pentylcarbonylamino, isopentylcarbonylamino, 2-methylbutylcarbonylamino, neo Pentylcarbonylamino, 1-ethylpropylcarbonylamino, hexylcarbonylamino, isohexylcarbonylamino, 4-methylpentylcarbonylamino, 3-methylpentylcarbonylamino, 2-methylpentyl Carbonylamino, 1-methylpentylcarbonylamino, 3,3-dimethylbutylcarbonylamino, 2,2-dimethylbutylcarbonylamino, 1,1-dimethylbutylcarbonylamino, 1,2-dimethylbutylcarbonylamino, 1,3- A dimethylbutylcarbonylamino, 2,3-dimethylbutylcarbonylamino or 2-ethylbutylcarbonylamino group, preferably a carbonyl group to which one of the above-mentioned “C ₁ -C ₄ alkyl groups” is bonded to the amino group; A bonded group (mono-C ₂ -C ₅ alkylcarbonylamino group), more preferably an acetamide or ethylcarbonylamino group (mono-C ₂ -C ₃ alkylcarbonylamino group), and even more preferably. Is an acetamide group.

In the present invention, the “mono-C ₁ -C ₆ alkylsulfonylamino group” refers to a group in which one sulfonyl group to which the “C ₁ -C ₆ alkyl group” is bonded is bonded to an amino group, for example, methyl Sulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, s-butylsulfonylamino, t-butylsulfonylamino, pentylsulfonylamino, isopentylsulfonylamino, 2-methylbutylsulfonylamino Neopentylsulfonylamino, 1-ethylpropylsulfonylamino, hexylsulfonylamino, isohexylsulfonylamino, 4-methylpentylsulfonylamino, 3-methylpentylsulfonylamino, 2-methyl Rupentylsulfonylamino, 1-methylpentylsulfonylamino, 3,3-dimethylbutylsulfonylamino, 2,2-dimethylbutylsulfonylamino, 1,1-dimethylbutylsulfonylamino, 1,2-dimethylbutylsulfonylamino, 1, 3-dimethylbutylsulfonylamino, 2,3-dimethylbutylsulfonylamino or 2-ethylbutylsulfonylamino group, and preferably a sulfonyl group to which one of the above-mentioned “C ₁ -C ₄ alkyl groups” is bonded is amino A group bonded to a group (mono-C ₁ -C ₄ alkylsulfonylamino group), more preferably a methylsulfonylamino or ethylsulfonylamino group (mono-C ₁ -C ₂ alkylsulfonylamino group), Even more preferred is a methylsulfonylamino group.

In the present invention, “mono-C ₁ -C ₆ alkylamino group” refers to a group in which _one “C ₁ -C ₆ alkyl group” is bonded to an amino group, such as methylamino, ethylamino, propyl Amino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1 , 2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3 A dimethylbutylamino or 2-ethylbutyl group, preferably, with one group the the "C ₁ -C ₄ alkyl group" bonded to an amino group (mono--C ₁ -C ₄ alkylamino group) More preferably a methylamino group or an ethylamino group (mono-C ₁ -C ₂ alkylamino group), and even more preferably a methylamino group.

In the present invention, “di- (C ₁ -C ₆ alkyl) amino group” refers to a group in which two identical or different “C ₁ -C ₆ alkyl groups” are bonded to an amino group. , Diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, diisopentylamino, dineopentylamino, dihexylamino, diisohexylamino, N-ethyl-N-methylamino, N-methyl- N-propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-isobutyl-N-methylamino, N-methyl-N-pentylamino, N-isopentyl-N-methylamino, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-butyl N- ethylamino, N- ethyl -N- isobutyl amino, N- ethyl -N- pentylamino or N- ethyl -N- isopentyl group, preferably, identical or different two aforementioned "C ₁ a -C ₄ alkyl group "is bonded to an amino group group (di -C ₁ -C ₄ alkylamino group), more preferably, dimethylamino group, diethylamino group or N- ethyl -N- methylamino group ( A di-C ₁ -C ₂ alkylamino group), and even more preferably a dimethylamino group.

In the present invention, “N- (C ₁ -C ₆ alkyl) -N— (C ₁ -C ₆ hydroxyalkyl) amino group” means one “C ₁ -C ₆ alkyl group” and one said “C ₁ -C ₆ hydroxyalkyl group” represents a group bonded to an amino group, for example, N- (2-hydroxyethyl) -N-methylamino, N- (3-hydroxypropyl) -N-methylamino N-ethyl-N- (2-hydroxyethyl) amino, N-ethyl-N- (3-hydroxypropyl) amino, N- (2-hydroxyethyl) -N-propylamino or N- (3-hydroxypropyl) ) -N- propyl amino group, preferably, one of the "C ₁ -C ₄ alkyl group" and one of the "C ₁ -C ₃ hydroxyalkyl group" is bonded respectively to an amino group group A N- _(C 1 -C ₄ alkyl) -N- _(C 1 -C ₃ hydroxyalkyl) amino group), more preferably, N- (2-hydroxyethyl) -N- methylamino or N- ( 3-hydroxypropyl) -N-methylamino group.

In the present invention, “di- (C ₁ -C ₆ hydroxyalkyl) amino group” means a group in which two identical or different “C ₁ -C ₆ hydroxyalkyl groups” are bonded to an amino group, for example, Di- (2-hydroxyethyl) amino, di- (3-hydroxypropyl) amino, di- (2-hydroxypropyl) amino, di- (4-hydroxybutyl) amino, di- (5-hydroxypentyl) amino, Di- (6-hydroxyhexyl) amino, N- (2-hydroxyethyl) -N- (3-hydroxypropyl) amino, N- (2-hydroxyethyl) -N- (2-hydroxypropyl) amino or N- (4-hydroxybutyl) -N- (2-hydroxyethyl) amino group, preferably two identical or different “C ₁ -C ₃ hydroxyalkyl” groups. Le group "is a group attached to an amino group (di -C ₁ -C ₃ hydroxyalkyl amino group), more preferably, di - (2-hydroxyethyl) amino group.

In the present invention, “mono-C ₂ -C ₇ alkylaminocarbonyl group” refers to a group in which one amino group to which the above “C ₁ -C ₆ alkyl group” is bonded is bonded to a carbonyl group, for example, methyl Aminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, s-butylaminocarbonyl, t-butylaminocarbonyl, pentylaminocarbonyl, isopentylaminocarbonyl, 2-methylbutylaminocarbonyl Neopentylaminocarbonyl, 1-ethylpropylaminocarbonyl, hexylaminocarbonyl, isohexylaminocarbonyl, 4-methylpentylaminocarbonyl, 3-methylpentylaminocarbonyl, 2-methyl Rupentylaminocarbonyl, 1-methylpentylaminocarbonyl, 3,3-dimethylbutylaminocarbonyl, 2,2-dimethylbutylaminocarbonyl, 1,1-dimethylbutylaminocarbonyl, 1,2-dimethylbutylaminocarbonyl, 1, 3-dimethylbutylaminocarbonyl, 2,3-dimethylbutylaminocarbonyl or 2-ethylbutylaminocarbonyl group, and preferably an amino group to which one of the above-mentioned “C ₁ -C ₄ alkyl groups” is bonded is carbonyl A group bonded to a group (mono-C ₁ -C ₄ alkylaminocarbonyl group), more preferably a methylaminocarbonyl or ethylaminocarbonyl group (mono-C ₁ -C ₂ alkylaminocarbonyl group), Even more preferred is a methylaminocarbonyl group.

In the present invention, the “C ₆ -C ₁₀ aryl group optionally substituted with 1 to 3 groups independently selected from substituent group c” is 1 to 1 independently selected from substituent group c. The above-mentioned “C ₆ -C ₁₀ aryl group” which may be substituted with three groups is shown, preferably consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group or a trifluoromethyl group It is a phenyl group which may be substituted at the 2-position, 3-position or 4-position with a group selected from the group.

In the present invention, the “C ₆ -C ₁₀ aryloxy group optionally substituted with 1 to 3 groups independently selected from substituent group c” is independently selected from substituent group c 1 Or the above-mentioned “C ₆ -C ₁₀ aryloxy group” which may be substituted with 3 groups, preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group or a trifluoromethyl group. A phenyloxy group which may be substituted at the 2-position, 3-position or 4-position with a group selected from the group consisting of:

  In the present invention, the “nitrogen-containing heterocyclic group optionally substituted with one group selected from substituent group c” may be substituted with one group selected from substituent group c. Good examples of the above “nitrogen-containing heterocyclic group” include, for example, 3-hydroxy-1-azetidinyl, 3-fluoro-1-pyrrolidinyl, 3-methyl-1-pyrrolidinyl, 3-trifluoromethyl-1-pyrrolidinyl, 3- Hydroxy-1-pyrrolidinyl, 4-hydroxy-1-piperidinyl, 4-hydroxy-1-pyrazolidinyl, 3-hydroxy-1-piperazinyl or 5- (1H-tetrazolyl) group, preferably 3-hydroxy-1 -A pyrrolidinyl group or a 5- (1H-tetrazolyl) group.

In the present invention, “a C ₆ -C ₁₀ aryl group optionally substituted with one group selected from substituent group a and / or 1 to 4 groups independently selected from substituent group b” “Is a group selected from the substituent group a and / or the above-mentioned“ C ₆ -C ₁₀ aryl group optionally substituted by 1 to 4 groups independently selected from the substituent group b ”. R ¹ is preferably a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ halogenated alkyl group, a C ₁ -C ₄ alkoxy group, or a C ₁ -C ₄ halogenated alkoxy. A C ₆ -C ₁₀ aryl group optionally substituted with 1 to 3 groups independently selected from the group consisting of a group and a C ₂ -C ₅ alkylcarbonyl group, more preferably a fluorine atom, _chlorine, C 1 -C ₄ alkyl group, trifluoperazine Romechiru group, a C ₁ -C ₄ alkoxy group, a trifluoromethoxy group, and one or two phenyl group which may be substituted with a group selected independently from the group consisting of methyl group, even more preferably Is a phenyl group; a phenyl group substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a methoxy group; or a fluorine atom, a chlorine atom, a methyl group And a phenyl group substituted by two groups independently selected from the group consisting of a methoxy group, and particularly preferably a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 2-trifluoro group. Methylphenyl group, 2,4-difluorophenyl group, 5-fluoro-2-methylphenyl group, 5-chloro-2-methoxyphenyl group or 2-methoxy group 5-methyl phenyl group, in ^{R 2} is preferably a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₂ halogenated alkyl _group, C 1 -C ₆ alkoxy group, a carboxyl group, C ₂ -C ₇ alkoxycarbonyl group, _mono--C 2 -C ₇ alkylaminocarbonyl group, a cyano group, a carbamoyl group and 5-(1H-tetrazolyl) 1 to 3 groups selected from the group consisting of groups independently A C ₆ -C ₁₀ aryl group which may be substituted with, more preferably a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₂ halogenated alkyl group, a C ₁ -C ₆ alkoxy group Independently selected from the group consisting of: a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, a carbamoyl group and a 5- (1H-tetrazolyl) group. A phenyl group optionally substituted by one or two groups, and more preferably a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group, a methoxycarbonyl group, a methyl group A group independently selected from the group consisting of an aminocarbonyl group, a carbamoyl group and a 5- (1H-tetrazolyl) group is substituted at the 2-position and 6-position, the 2-position and the 5-position, or the 2-position and the 4-position Phenyl group; or selected from the group consisting of fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carbamoyl group and 5- (1H-tetrazolyl) group A phenyl group substituted at the 2-position with a group selected from the group consisting of 2,6-dichlorophenyl group, 6-chlorophenyl group, 2-chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6-chlorophenyl or 2-chloro-6- [5-(1H-tetrazolyl)] phenyl group.

In the present invention, “a heterocyclic group optionally substituted with one group selected from substituent group a and / or one or two groups independently selected from substituent group b” is substituted one group and / or said that may be substituted with one or two groups independently selected from substituent group b is selected from the group a indicates "heterocyclic group" in R ¹ is Preferably a 5-membered heterocyclic group or a bicyclic heterocyclic group which may be independently substituted with 1 or 2 C ₁ -C ₄ alkyl groups, more preferably a thienyl group. Even more preferably, it is a 2-thienyl group, and R ² is preferably a halogen atom, a C ₁ -C ₆ alkyl group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, or a carbamoyl group. From a group and a 5- (1H-tetrazolyl) group Substituted with 1 or 2 groups independently selected from the group consisting of 6-membered aromatic heterocyclic groups or halogen atoms and oxo groups optionally substituted with 1 or 2 groups independently selected from the group A fused bicyclic heterocyclic group which may be substituted, more preferably a fluorine atom, a chlorine atom, a methyl group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a carbamoyl group and 5- (1H-tetrazolyl). 1) substituted with 1 or 2 groups independently selected from the group consisting of a 2-pyridyl group, a chlorine atom and an oxo group substituted at the 3-position with a group selected from the group consisting of A 3-dihydro-1-isobenzofuranyl group, a 1-indolyl group or a 1-indolinyl group, and even more preferably a 3-chloro-2-pyridyl group, a 7-chloro-1-indolyl group, - oxo-1-indolinyl group, or a 7-chloro-3-oxo-1,3-dihydro-1-isobenzofuranyl.

In the present invention, “a C ₇ -C ₁₆ aralkyl group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b”. "Is a group selected from the substituent group a and / or the above-mentioned" C ₇ -C ₁₆ aralkyl group optionally substituted by 1 to 4 groups independently selected from the substituent group b ". Preferably, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₂ halogenated alkyl group, a C ₁ -C ₃ hydroxyalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₂ halogenated alkoxy group, a carboxyl group, an amino group, a mono _-C 2 -C ₃ alkylcarbonylamino group, di _-C 1 -C ₂ alkylamino group, a cyano group, independently from the group consisting of nitro and phenyl group 1 to selected Benzyl group or 1-phenylethyl group which may be substituted with one group, more preferably fluorine atom, chlorine atom, bromine atom, methyl group, trifluoromethyl group, hydroxymethyl group, carboxyl group, A benzyl group substituted at the 2 and 6 positions with a group independently selected from the group consisting of an amino group or a nitro group; selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a trifluoromethyl group Or a 1-phenylethyl group, and even more preferably a 2-fluorophenylmethyl group, a 2,6-difluorophenylmethyl group or a 1-phenylethyl group. And particularly preferred is a 1-phenylethyl group.

  In the present invention, the preferred general formula (I) is the general formula (Ia).

In the present invention, R ¹ is preferably a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ halogenated alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ halogenated alkoxy group and a C _2. A C ₆ -C ₁₀ aryl group optionally substituted by 1 to 3 groups independently selected from the group consisting of —C ₅ alkylcarbonyl groups; independently 1 to 3 C ₁ -C ₆ alkyl groups in an optionally substituted heterocyclic _group; C 1 -C ₆ alkyl group; a halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ halogenated alkyl _group, C 1 -C ₄ alkoxy groups, _{C 1} -C ₄ halogenated alkoxy group and a C ₂ -C ₅ 1 to 3 substituents which may be C ₇ -C ₁₄ aralkyl group with a group selected from the group consisting of alkylcarbonyl groups independently; or one Phenyl group In substituted it is also good _C 3 -C ₆ cycloalkyl group, more preferred ^{R 1} is a fluorine atom, a chlorine _atom, C 1 -C ₄ alkyl group, trifluoromethyl _group, C 1 -C ₄ alkoxy group A phenyl group or a naphthyl group optionally substituted with 1 or 2 groups independently selected from the group consisting of a trifluoromethoxy group and a methylcarbonyl group; independently 1 or 2 C ₁ -C ₄ alkyl substituted by or one phenyl group; 5-membered aromatic may be substituted by a heterocyclic group or a Chijimigoni heterocyclic group; C ₂ -C ₆ alkyl group; C ₇ -C ₁₄ aralkyl group and it is also good C ₃ -C ₆ cycloalkyl group, still more preferred R ¹ is a phenyl group; a fluorine atom, a chlorine atom, or the group consisting of methyl group, trifluoromethyl group and methoxy group A phenyl group substituted with one selected group; a phenyl group substituted with two groups independently selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group and a methoxy group; a thienyl group; A C ₂ -C ₆ alkyl group; a C ₇ -C ₈ aralkyl group; or a C ₃ -C ₆ cycloalkyl group optionally substituted by one phenyl group, and particularly preferred R ¹ is a phenyl group, 2 -Fluorophenyl group, 3-fluorophenyl group, 2-trifluoromethylphenyl group, 2,4-difluorophenyl group, 5-fluoro-2-methylphenyl group, 5-chloro-2-methoxyphenyl group, 2-methoxy A 5-methylphenyl group, an n-hexyl group, a 1-phenylethyl group or a 2-phenylcyclopropyl group;

In the present invention, suitable R ² is a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₂ halogenated alkyl group, a C ₁ -C ₆ alkoxy group, a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group, C ₆ optionally substituted by 1 to 3 groups independently selected from the group consisting of mono-C ₂ -C ₇ alkylaminocarbonyl group, cyano group, carbamoyl group and 5- (1H-tetrazolyl) group -C ₁₀ aryl group; or a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₂ halogenated alkyl _group, C 1 -C ₆ alkoxy group, a carboxyl _group, C 2 -C ₇ alkoxycarbonyl group, a mono - C ₂ -C ₇ alkylaminocarbonyl group, a cyano group, a carbamoyl group, are independently selected from the group consisting of 5-(1H-tetrazolyl) group and oxo group More preferably R ² is a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₂ halogenated alkyl group, or a C _1- group. C ₆ alkoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, cyano group, carbamoyl group and substituted with 1 or 2 groups independently selected from the group consisting of 5- (1H-tetrazolyl) group An optionally substituted phenyl group or pyridyl group; or a fused bicyclic heterocyclic group optionally substituted with one or two groups independently selected from the group consisting of a halogen atom and an oxo group; a R ² is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group A phenyl group substituted at the 2-position and 6-position, 2-position and 5-position, or 2-position and 4-position with a group independently selected from the group consisting of a carbamoyl group and a 5- (1H-tetrazolyl) group; fluorine 2-position selected from the group consisting of an atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carbamoyl group and 5- (1H-tetrazolyl) group A phenyl group substituted with: fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methylaminocarbonyl group, carbamoyl group and 5- (1H-tetrazolyl) group A 2-pyridyl group substituted at the 3-position with a group selected from the group; or consisting of a chlorine atom and an oxo group 1,3-dihydro-1-isobenzofuranyl group, 1-indolyl group or 1-indolinyl group substituted by 1 or 2 groups independently selected from the group, particularly preferred R ² is 2,6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2-chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6-chlorophenyl group or 2-chloro-6- [5- (1H-tetrazolyl) ] A phenyl group.

In the present invention, preferred R ³ is a hydrogen atom.

In the present invention, preferred R ⁴ is a hydrogen atom.

In the present invention, preferable A is a vinylene group or a C ₂ -C ₄ alkylene group in which one of the methylene groups in the main chain may be replaced with a vinylene group, an oxygen atom or a sulfur atom, and more preferable A Is a vinylene group, ethylene group, methyleneoxy group or methylenethio group, even more preferred A is a vinylene group, ethylene group or methylenethio group, and particularly preferred A is a vinylene group or ethylene group.

  In the present invention, preferred Q is a group represented by the formula -N (Me)-.

  In the present invention, preferred T is a nitrogen atom.

  In the present invention, preferred U is a group represented by the formula = CH-.

  In the present invention, preferred V is a group represented by the formula = CH-.

  The “pharmacologically acceptable salt” means that the urea derivative having the general formula (I) of the present invention has a basic group such as an amino group, and is reacted with an acid. When it has an acidic group such as a group, it can be converted into a salt by reacting with a base, so that the salt is shown.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates and aspartates.

  On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, etc. Amine salts such as machine salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.

  The urea derivative having the general formula (I) or the pharmacologically acceptable salt thereof of the present invention absorbs moisture by being left in the atmosphere or recrystallized, and adsorbed water is attached. In some cases, such hydrates are also included in the salts of the present invention.

  The urea derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present in the present invention. It is included in the salt.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1, Table 2 and Table 3 below, but the present invention is not limited to these groups. Absent.
The meanings of the abbreviations in Tables 1 to 3 below are as follows.
-CH _2- : Methylene group
-CH ₂ -CH _2- : Ethylene group
(E) -CH = CH-: (E) -Vinylene group
-CH ₂ -S-: Methylenethio group
Me: Methyl group
Et: Ethyl group
i-Pr: i-propyl group
n-Bu: n-butyl group
t-Bu: t-butyl group
n-Hex: n-hexyl group
CycHex: cyclohexyl group
2-Ph-CycPr: 2-phenylcyclopropyl group
Ph: Phenyl group
1-Naph: 1-naphthyl group
Bn: benzyl group
1-Ph-Et: 1-phenylethyl group
2-F-Ph: 2-fluorophenyl group
3-F-Ph: 3-fluorophenyl group
2-Cl-Ph: 2-chlorophenyl group
2-Me-Ph: o-Toluyl group
2-i-Pr-Ph: 2- (i-propyl) phenyl group
4-n-Bu-Ph: 4- (n-butyl) phenyl group
2-CF ₃ -Ph: 2-trifluoromethylphenyl group
2-OMe-Ph: 2-methoxyphenyl group
4-On-Bu-Ph: 4- (n-butoxy) phenyl group
4-OCF ₃ -Ph: 4-trifluoromethoxyphenyl group
4-COMe-Ph: 4-acetylphenyl group
2,4-di-F-Ph: 2,4-difluorophenyl group
5-F-2-Me-Ph: 5-fluoro-2-methylphenyl group
2,6-di-Cl-Ph: 2,6-dichlorophenyl group
2-COOH-6-Cl-Ph: 2-carboxy-6-chlorophenyl group
2-Cl-6- (5-tetra) -Ph: 2-chloro-6- [5- (1H-tetrazolyl)] phenyl group
2,6-di-Me-Ph: 2,6-dimethylphenyl group
2-OMe-5-Me-Ph: 2-methoxy-5-methylphenyl group
2-Pyr: 2-pyrimidinyl group
3-CF ₃ -2-Py: 3-trifluoromethyl-2-pyridyl group
3,5-di-Me-4-Isoxa: 3,5-dimethyl-4-isoxazolyl group
2-Thi: 2-thienyl group
5-Dioxo: 5-benzo [1,3] dioxolyl group
7-Cl-1-Indoly: 7-Chloro-1-indolyl group
2-oxo-1-Indolin: 2-oxo-1-indolinyl group
7-Cl-3-oxo-1-Isoben: 7-chloro-3-oxo-1,3-dihydro-1-isobenzofuranyl group
N: Nitrogen atom
S: Sulfur atom
CH: group represented by the formula = CH-
NMe: a group represented by the formula -NMe-.

  (Table 1)

――――――――――――――――――――――――――――――――――――
Compound number R ² AR ¹
――――――――――――――――――――――――――――――――――――
1-1 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-2 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-Me-Ph
1-3 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-4 2,6-di-Cl-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-5 2,6-di-Cl-Ph (E) -CH = CH- 2-Me-Ph
1-6 2,6-di-Cl-Ph (E) -CH = CH- 2-CF ₃ -Ph
1-7 2,6-di-Cl-Ph -CH ₂ -S- 2-OMe-5-Me-Ph
1-8 2,6-di-Cl-Ph -CH ₂ -S- 2-Me-Ph
1-9 2,6-di-Cl-Ph -CH ₂ -S- 2-CF ₃ -Ph
1-10 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
1-11 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-Me-Ph
1-12 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-13 2-COOH-6-Cl-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-14 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Me-Ph
1-15 2-COOH-6-Cl-Ph (E) -CH = CH- 2-CF ₃ -Ph
1-16 2-COOH-6-Cl-Ph -CH ₂ -S- 2-OMe-5-Me-Ph
1-17 2-COOH-6-Cl-Ph -CH ₂ -S- 2-Me-Ph
1-18 2-COOH-6-Cl-Ph -CH ₂ -S- 2-CF ₃ -Ph
1-19 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
1-20 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-Me-Ph
1-21 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-22 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-23 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Me-Ph
1-24 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-CF ₃ -Ph
1-25 2-Cl-6-CO ₂ Me-Ph -CH ₂ -S- 2-OMe-5-Me-Ph
1-26 2-Cl-6-CO ₂ Me-Ph -CH ₂ -S- 2-Me-Ph
1-27 2-Cl-6-CO ₂ Me-Ph -CH ₂ -S- 2-CF ₃ -Ph
_{1-28 2-CONH 2 -6-Cl} -Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
_{1-29 2-CONH 2 -6-Cl} -Ph -CH 2 -CH 2 - 2-Me-Ph
1-30 2-CONH ₂ -6-Cl-Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-31 2-CONH ₂ -6-Cl-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-32 2-CONH ₂ -6-Cl-Ph (E) -CH = CH- 2-Me-Ph
1-33 2-CONH ₂ -6-Cl-Ph (E) -CH = CH- 2-CF ₃ -Ph
1-34 2-CONH ₂ -6-Cl-Ph -CH ₂ -S- 2-OMe-5-Me-Ph
1-35 2-CONH ₂ -6-Cl-Ph -CH ₂ -S- 2-Me-Ph
1-36 2-CONH ₂ -6-Cl-Ph -CH ₂ -S- 2-CF ₃ -Ph
1-37 2,6-di-Cl-Ph -CH ₂ -CH ₂ -n-Hex
1-38 2,6-di-Cl-Ph (E) -CH = CH- n-Hex
1-39 2,6-di-Cl-Ph -CH ₂ -S- n-Hex
1-40 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -n-Hex
1-41 2-COOH-6-Cl-Ph (E) -CH = CH- n-Hex
1-42 2-COOH-6-Cl-Ph -CH ₂ -S- n-Hex
1-43 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -n-Hex
1-44 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- n-Hex
1-45 2-Cl-6-CO ₂ Me-Ph -CH ₂ -S- n-Hex
1-46 2-CONH ₂ -6-Cl-Ph -CH ₂ -CH ₂ -n-Hex
1-47 2-CONH ₂ -6-Cl-Ph (E) -CH = CH- n-Hex
1-48 2-CONH ₂ -6-Cl-Ph -CH ₂ -S- n-Hex
1-49 2-Cl-6-CN -Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
1-50 2-Cl-6-CN -Ph -CH 2 -CH 2 - 2-Me-Ph
1-51 2-Cl-6-CN-Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-52 2-Cl-6-CN-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-53 2-Cl-6-CN-Ph (E) -CH = CH- 2-Me-Ph
1-54 2-Cl-6-CN-Ph (E) -CH = CH- 2-CF ₃ -Ph
1-55 2-Cl-6- (5 -tetra) -Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
1-56 2-Cl-6- (5 -tetra) -Ph -CH 2 -CH 2 - 2-Me-Ph
1-57 2-Cl-6- (5-tetra) -Ph -CH ₂ -CH ₂ -2-CF ₃ -Ph
1-58 2-Cl-6- (5-tetra) -Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-59 2-Cl-6- (5-tetra) -Ph (E) -CH = CH- 2-Me-Ph
1-60 2-Cl-6- (5-tetra) -Ph (E) -CH = CH- 2-CF ₃ -Ph
_{1-61 2-Pyr -CH 2 -CH 2} - 2-OMe-5-Me-Ph
1-62 2-Pyr (E) -CH = CH- 2-OMe-5-Me-Ph
1-63 2-Pyr -CH ₂ -S- 2-OMe-5-Me-Ph
1-64 2,6-di-Cl-Ph -CH 2 -CH 2 - 2-Cl-5-CF 3 -Ph
1-65 2,6-di-Cl-Ph (E) -CH = CH- 2-Cl-5-CF ₃ -Ph
1-66 2,6-di-Cl-Ph -CH 2 -CH 2 - 2,5-di-OMe-Ph
1-67 2,6-di-Cl-Ph (E) -CH = CH-2,5-di-OMe-Ph
1-68 2,6-di-Cl-Ph -CH 2 -CH 2 - 5-F-2-Me-Ph
1-69 2,6-di-Cl-Ph (E) -CH = CH-5-F-2-Me-Ph
1-70 2,6-di-Cl-Ph -CH ₂ -CH ₂ -t-Bu
1-71 2,6-di-Cl-Ph (E) -CH = CH- t-Bu
1-72 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -OCF ₃ -Ph
1-73 2,6-di-Cl-Ph (E) -CH = CH- 4-OCF ₃ -Ph
1-74 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -CF ₃ -Ph
1-75 2,6-di-Cl-Ph (E) -CH = CH- 4-CF ₃ -Ph
1-76 2,6-di-Cl-Ph -CH 2 -CH 2 - 2,4-di-F-Ph
1-77 2,6-di-Cl-Ph (E) -CH = CH-2,4-di-F-Ph
1-78 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -i-Pr-Ph
1-79 2,6-di-Cl-Ph (E) -CH = CH- 4-i-Pr-Ph
1-80 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-F-Ph
1-81 2,6-di-Cl-Ph (E) -CH = CH- 2-F-Ph
1-82 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-Ph-CycPr
1-83 2,6-di-Cl-Ph (E) -CH = CH- 2-Ph-CycPr
1-84 2,6-di-Cl-Ph -CH ₂ -CH ₂ -Et
1-85 2,6-di-Cl-Ph (E) -CH = CH- Et
1-86 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -OMe-Ph
1-87 2,6-di-Cl-Ph (E) -CH = CH- 4-OMe-Ph
1-88 2,6-di-Cl-Ph -CH ₂ -CH ₂ -Ph
1-89 2,6-di-Cl-Ph (E) -CH = CH- Ph
1-90 2,6-di-Cl-Ph -CH ₂ -CH ₂ -n-Bu
1-91 2,6-di-Cl-Ph (E) -CH = CH- n-Bu
1-92 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-OMe-Ph
1-93 2,6-di-Cl-Ph (E) -CH = CH- 2-OMe-Ph
1-94 2,6-di-Cl-Ph -CH 2 -CH 2 - 1-Ph-Et
1-95 2,6-di-Cl-Ph (E) -CH = CH- 1-Ph-Et
1-96 2,6-di-Cl-Ph -CH ₂ -CH ₂ -i-Pr
1-97 2,6-di-Cl-Ph (E) -CH = CH- i-Pr
1-98 2,6-di-Cl-Ph -CH 2 -CH 2 - 2,6-di-Me-Ph
1-99 2,6-di-Cl-Ph (E) -CH = CH-2,6-di-Me-Ph
1-100 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CycHex
1-101 2,6-di-Cl-Ph (E) -CH = CH- CycHex
1-102 2,6-di-Cl-Ph -CH ₂ -CH ₂ -Bn
1-103 2,6-di-Cl-Ph (E) -CH = CH- Bn
1-104 2,6-di-Cl-Ph -CH ₂ -CH ₂ -3-F-Ph
1-105 2,6-di-Cl-Ph (E) -CH = CH- 3-F-Ph
1-106 2,6-di-Cl-Ph -CH 2 -CH 2 - 2,3-di-Cl-Ph
1-107 2,6-di-Cl-Ph (E) -CH = CH- 2,3-di-Cl-Ph
1-108 2,6-di-Cl-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-109 2,6-di-Cl-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-110 2,6-di-Cl-Ph -CH 2 -CH 2 - 1-Naph
1-111 2,6-di-Cl-Ph (E) -CH = CH- 1-Naph
1-112 2,6-di-Cl-Ph -CH ₂ -CH ₂ -3-Cl-Ph
1-113 2,6-di-Cl-Ph (E) -CH = CH- 3-Cl-Ph
1-114 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-Et-Ph
1-115 2,6-di-Cl-Ph (E) -CH = CH- 2-Et-Ph
1-116 2,6-di-Cl-Ph -CH ₂ -CH ₂ -OMe-Ph
1-117 2,6-di-Cl-Ph (E) -CH = CH- 3-OMe-Ph
1-118 2,6-di-Cl-Ph -CH 2 -CH 2 - 2-i-Pr-Ph
1-119 2,6-di-Cl-Ph (E) -CH = CH- 2-i-Pr-Ph
1-120 2,6-di-Cl-Ph -CH 2 -CH 2 - 5-Dioxo
1-121 2,6-di-Cl-Ph (E) -CH = CH-5-Dioxo
1-122 2,6-di-Cl-Ph -CH 2 -CH 2 - 3,5-di-Me-4-Isoxa
1-123 2,6-di-Cl-Ph (E) -CH = CH- 3,5-di-Me-4-Isoxa
1-124 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-Thi
1-125 2,6-di-Cl-Ph (E) -CH = CH- 2-Thi
1-126 2,6-di-Cl-Ph -CH ₂ -CH ₂ -3-Me-Ph
1-127 2,6-di-Cl-Ph (E) -CH = CH- 3-Me-Ph
1-128 2,6-di-Cl-Ph -CH ₂ -CH ₂ -3-CF ₃ -Ph
1-129 2,6-di-Cl-Ph (E) -CH = CH- 3-CF ₃ -Ph
1-130 2,6-di-Cl-Ph -CH ₂ -CH ₂ -2-Cl-Ph
1-131 2,6-di-Cl-Ph (E) -CH = CH- 2-Cl-Ph
1-132 2,6-di-Cl-Ph -CH 2 -CH 2 - 2,6-di-Cl-Ph
1-133 2,6-di-Cl-Ph (E) -CH = CH- 2,6-di-Cl-Ph
1-134 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -COMe-Ph
1-135 2,6-di-Cl-Ph (E) -CH = CH- 4-COMe-Ph
1-136 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -On-Bu-Ph
1-137 2,6-di-Cl-Ph (E) -CH = CH- 4-On-Bu-Ph
1-138 2,6-di-Cl-Ph -CH ₂ -CH _2-4 -n-Bu-Ph
1-139 2,6-di-Cl-Ph (E) -CH = CH- 4-n-Bu-Ph
1-140 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-Cl-5-CF 3 -Ph
1-141 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Cl-5-CF ₃ -Ph
1-142 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2,5-di-OMe-Ph
1-143 2-COOH-6-Cl-Ph (E) -CH = CH-2,5-di-OMe-Ph
1-144 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 5-F-2-Me-Ph
1-145 2-COOH-6-Cl-Ph (E) -CH = CH-5-F-2-Me-Ph
1-146 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -t-Bu
1-147 2-COOH-6-Cl-Ph (E) -CH = CH- t-Bu
1-148 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -4-OCF ₃ -Ph
1-149 2-COOH-6-Cl-Ph (E) -CH = CH- 4-OCF ₃ -Ph
1-150 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -4-CF ₃ -Ph
1-151 2-COOH-6-Cl-Ph (E) -CH = CH- 4-CF ₃ -Ph
1-152 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2,4-di-F-Ph
1-153 2-COOH-6-Cl-Ph (E) -CH = CH- 2,4-di-F-Ph
1-154 2-COOH-6-Cl-Ph -CH ₂ -CH _2-4 -i-Pr-Ph
1-155 2-COOH-6-Cl-Ph (E) -CH = CH- 4-i-Pr-Ph
1-156 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-F-Ph
1-157 2-COOH-6-Cl-Ph (E) -CH = CH- 2-F-Ph
1-158 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-Ph-CycPr
1-159 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Ph-CycPr
1-160 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -Et
1-161 2-COOH-6-Cl-Ph (E) -CH = CH- Et
1-162 2-COOH-6-Cl-Ph -CH ₂ -CH _2-4 -OMe-Ph
1-163 2-COOH-6-Cl-Ph (E) -CH = CH- 4-OMe-Ph
1-164 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -Ph
1-165 2-COOH-6-Cl-Ph (E) -CH = CH- Ph
1-166 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -n-Bu
1-167 2-COOH-6-Cl-Ph (E) -CH = CH- n-Bu
1-168 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -2-OMe-Ph
1-169 2-COOH-6-Cl-Ph (E) -CH = CH- 2-OMe-Ph
1-170 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 1-Ph-Et
1-171 2-COOH-6-Cl-Ph (E) -CH = CH- 1-Ph-Et
1-172 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -i-Pr
1-173 2-COOH-6-Cl-Ph (E) -CH = CH- i-Pr
1-174 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2,6-di-Me-Ph
1-175 2-COOH-6-Cl-Ph (E) -CH = CH-2,6-di-Me-Ph
1-176 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -CycHex
1-177 2-COOH-6-Cl-Ph (E) -CH = CH- CycHex
1-178 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -Bn
1-179 2-COOH-6-Cl-Ph (E) -CH = CH- Bn
1-180 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -3-F-Ph
1-181 2-COOH-6-Cl-Ph (E) -CH = CH- 3-F-Ph
1-182 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2,3-di-Cl-Ph
1-183 2-COOH-6-Cl-Ph (E) -CH = CH-2,3-di-Cl-Ph
1-184 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-185 2-COOH-6-Cl-Ph (E) -CH = CH- 5-Cl-2-OMe-Ph
1-186 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 1-Naph
1-187 2-COOH-6-Cl-Ph (E) -CH = CH- 1-Naph
1-188 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -3-Cl-Ph
1-189 2-COOH-6-Cl-Ph (E) -CH = CH- 3-Cl-Ph
1-190 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -2-Et-Ph
1-191 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Et-Ph
1-192 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -3-OMe-Ph
1-193 2-COOH-6-Cl-Ph (E) -CH = CH- 3-OMe-Ph
1-194 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-i-Pr-Ph
1-195 2-COOH-6-Cl-Ph (E) -CH = CH- 2-i-Pr-Ph
1-196 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 5-Dioxo
1-197 2-COOH-6-Cl-Ph (E) -CH = CH-5-Dioxo
1-198 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 3,5-di-Me-4-Isoxa
1-199 2-COOH-6-Cl-Ph (E) -CH = CH- 3,5-di-Me-4-Isoxa
1-200 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -2-Thi
1-201 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Thi
1-202 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 3-Me-Ph
1-203 2-COOH-6-Cl-Ph (E) -CH = CH- 3-Me-Ph
1-204 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -3-CF ₃ -Ph
1-205 2-COOH-6-Cl -Ph (E) -CH = CH- 3-CF 3 -Ph
1-206 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2-Cl-Ph
1-207 2-COOH-6-Cl-Ph (E) -CH = CH- 2-Cl-Ph
1-208 2-COOH-6-Cl -Ph -CH 2 -CH 2 - 2,6-di-Cl-Ph
1-209 2-COOH-6-Cl-Ph (E) -CH = CH- 2,6-di-Cl-Ph
1-210 2-COOH-6-Cl-Ph -CH ₂ -CH _2-4 -COMe-Ph
1-211 2-COOH-6-Cl-Ph (E) -CH = CH- 4-COMe-Ph
1-212 2-COOH-6-Cl-Ph -CH ₂ -CH _2-4 -On-Bu-Ph
1-213 2-COOH-6-Cl-Ph (E) -CH = CH- 4-On-Bu-Ph
1-214 2-COOH-6-Cl-Ph -CH ₂ -CH _2-4 -n-Bu-Ph
1-215 2-COOH-6-Cl-Ph (E) -CH = CH- 4-n-Bu-Ph
1-216 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-Cl-5-CF 3 -Ph
1-217 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Cl-5-CF ₃ -Ph
1-218 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2,5-di-OMe-Ph
1-219 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH-2,5-di-OMe-Ph
1-220 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 5-F-2-Me-Ph
1-221 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH-5-F-2-Me-Ph
1-222 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -t-Bu
1-223 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- t-Bu
1-224 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -4-OCF ₃ -Ph
1-225 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-OCF ₃ -Ph
1-226 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -4-CF ₃ -Ph
1-227 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-CF ₃ -Ph
1-228 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2,4-di-F-Ph
1-229 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2,4-di-F-Ph
1-230 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH _2-4 -i-Pr-Ph
1-231 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-i-Pr-Ph
1-232 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-F-Ph
1-233 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-F-Ph
1-234 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-Ph-CycPr
1-235 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Ph-CycPr
1-236 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -Et
1-237 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- Et
1-238 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH _2-4 -OMe-Ph
1-239 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-OMe-Ph
1-240 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -Ph
1-241 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- Ph
1-242 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -n-Bu
1-243 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- n-Bu
1-244 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -2-OMe-Ph
1-245 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-OMe-Ph
1-246 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 1-Ph-Et
1-247 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 1-Ph-Et
1-248 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -i-Pr
1-249 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- i-Pr
1-250 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2,6-di-Me-Ph
1-251 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2,6-di-Me-Ph
1-252 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CycHex
1-253 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CycHex
1-254 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -Bn
1-255 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- Bn
1-256 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -3-F-Ph
1-257 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3-F-Ph
1-258 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2,3-di-Cl-Ph
1-259 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH-2,3-di-Cl-Ph
1-260 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-261 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 5-Cl-2-OMe-Ph
1-262 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 1-Naph
1-263 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 1-Naph
1-264 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -3-Cl-Ph
1-265 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3-Cl-Ph
1-266 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-Et-Ph
1-267 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Et-Ph
1-268 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -3-OMe-Ph
1-269 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3-OMe-Ph
1-270 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-i-Pr-Ph
1-271 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-i-Pr-Ph
1-272 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 5-Dioxo
1-273 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 5-Dioxo
1-274 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 3,5-di-Me-4-Isoxa
1-275 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3,5-di-Me-4-Isoxa
1-276 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -2-Thi
1-277 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Thi
1-278 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 3-Me-Ph
1-279 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3-Me-Ph
1-280 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -3-CF ₃ -Ph
1-281 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 3-CF ₃ -Ph
1-282 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2-Cl-Ph
1-283 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 2-Cl-Ph
1-284 2-Cl-6-CO 2 Me-Ph -CH 2 -CH 2 - 2,6-di-Cl-Ph
1-285 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH-2,6-di-Cl-Ph
1-286 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH _2-4 -COMe-Ph
1-287 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-COMe-Ph
1-288 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH _2-4 -On-Bu-Ph
1-289 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-On-Bu-Ph
1-290 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH _2-4 -n-Bu-Ph
1-291 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- 4-n-Bu-Ph
1-292 7-Cl-1-Indoly -CH ₂ -2-OMe-5-Me-Ph
1-293 7-Cl-1-Indoly -CH ₂ -2-Me-Ph
1-294 7-Cl-1-Indoly -CH ₂ -2-CF ₃ -Ph
1-295 7-Cl-1-Indoly -CH ₂ -2-F-Ph
1-296 7-Cl-1-Indoly -CH ₂ -n-Hex
1-297 7-Cl-1-Indoly -CH ₂ -i-Pr
1-298 2-oxo-1-Indolin -CH 2 - 2-OMe-5-Me-Ph
1-299 2-oxo-1-Indolin -CH 2 - 2-Me-Ph
1-300 2-oxo-1-Indolin -CH ₂ -2-CF ₃ -Ph
1-301 2-oxo-1-Indolin -CH 2 - 2-F-Ph
1-302 2-oxo-1-Indolin -CH ₂ -n-Hex
1-303 2-oxo-1-Indolin -CH ₂ -i-Pr
1-304 7-Cl-3-oxo-1-Isoben -CH ₂ -2-OMe-5-Me-Ph
1-305 7-Cl-3-oxo-1-Isoben -CH ₂ -2-Me-Ph
1-306 7-Cl-3-oxo-1-Isoben -CH ₂ -2-CF ₃ -Ph
1-307 7-Cl-3-oxo-1-Isoben -CH ₂ -2-F-Ph
1-308 7-Cl-3-oxo-1-Isoben -CH ₂ -n-Hex
1-309 7-Cl-3-oxo-1-Isoben -CH ₂ -i-Pr
_{1-310 2-CF 3 -Ph -CH 2} -CH 2 - 2-OMe-5-Me-Ph
1-311 2-CF ₃ -Ph (E) -CH = CH- 2-OMe-5-Me-Ph
_{1-312 2-Cl-Ph -CH 2} -CH 2 - 2-OMe-5-Me-Ph
1-313 2-Cl-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-314 2,4-di-Cl-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-315 2,4-di-Cl-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-316 2,4-di-F-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-317 2,4-di-F-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-318 2,4-di-OMe-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-319 2,4-di-OMe-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-320 2,5-di-OMe-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-321 2,5-di-OMe-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
_{1-322 2-OMe-Ph -CH 2} -CH 2 - 2-OMe-5-Me-Ph
1-323 2-OMe-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
_{1-324 2-Me-Ph -CH 2} -CH 2 - 2-OMe-5-Me-Ph
1-325 2-Me-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-326 2-F-6-CF 3 -Ph -CH 2 -CH 2 - 2-OMe-5-Me-Ph
1-327 2-F-6-CF ₃ -Ph (E) -CH = CH- 2-OMe-5-Me-Ph
1-328 4-OMe-2-Me-Ph -CH ₂ -CH ₂ -2-OMe-5-Me-Ph
1-329 4-OMe-2-Me-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
_{1-330 2-F-Ph -CH 2} -CH 2 - 2-OMe-5-Me-Ph
1-331 2-F-Ph (E) -CH = CH- 2-OMe-5-Me-Ph
_{1-332 2-CF 3 -Ph -CH 2} -CH 2 - 2-F-Ph
1-333 2-CF ₃ -Ph (E) -CH = CH- 2-F-Ph
_{1-334 2-Cl-Ph -CH 2} -CH 2 - 2-F-Ph
1-335 2-Cl-Ph (E) -CH = CH- 2-F-Ph
1-336 2,4-di-Cl-Ph -CH ₂ -CH ₂ -2-F-Ph
1-337 2,4-di-Cl-Ph (E) -CH = CH- 2-F-Ph
1-338 2,4-di-F-Ph -CH 2 -CH 2 - 2-F-Ph
1-339 2,4-di-F-Ph (E) -CH = CH- 2-F-Ph
1-340 2,4-di-OMe-Ph -CH 2 -CH 2 - 2-F-Ph
1-341 2,4-di-OMe-Ph (E) -CH = CH- 2-F-Ph
1-342 2,5-di-OMe-Ph -CH 2 -CH 2 - 2-F-Ph
1-343 2,5-di-OMe-Ph (E) -CH = CH- 2-F-Ph
1-344 2-OMe-Ph -CH ₂ -CH ₂ -2-F-Ph
1-345 2-OMe-Ph (E) -CH = CH- 2-F-Ph
_{1-346 2-Me-Ph -CH 2} -CH 2 - 2-F-Ph
1-347 2-Me-Ph (E) -CH = CH- 2-F-Ph
1-348 2-F-6-CF 3 -Ph -CH 2 -CH 2 - 2-F-Ph
1-349 2-F-6-CF ₃ -Ph (E) -CH = CH- 2-F-Ph
1-350 4-OMe-2-Me-Ph -CH ₂ -CH ₂ -2-F-Ph
1-351 4-OMe-2-Me-Ph (E) -CH = CH- 2-F-Ph
_{1-352 2-F-Ph -CH 2} -CH 2 - 2-F-Ph
1-353 2-F-Ph (E) -CH = CH- 2-F-Ph
_{1-354 2-CF 3 -Ph -CH 2} -CH 2 - 5-Cl-2-OMe-Ph
1-355 2-CF ₃ -Ph (E) -CH = CH-5-Cl-2-OMe-Ph
_{1-356 2-Cl-Ph -CH 2} -CH 2 - 5-Cl-2-OMe-Ph
1-357 2-Cl-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-358 2,4-di-Cl-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-359 2,4-di-Cl-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-360 2,4-di-F-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-361 2,4-di-F-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-362 2,4-di-OMe-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-363 2,4-di-OMe-Ph (E) -CH = CH- 5-Cl-2-OMe-Ph
1-364 2,5-di-OMe-Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-365 2,5-di-OMe-Ph (E) -CH = CH- 5-Cl-2-OMe-Ph
_{1-366 2-OMe-Ph -CH 2} -CH 2 - 5-Cl-2-OMe-Ph
1-367 2-OMe-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
_{1-368 2-Me-Ph -CH 2} -CH 2 - 5-Cl-2-OMe-Ph
1-369 2-Me-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-370 2-F-6-CF 3 -Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-371 2-F-6-CF ₃ -Ph (E) -CH = CH-5-Cl-2-OMe-Ph
1-372 4-OMe-2-Me -Ph -CH 2 -CH 2 - 5-Cl-2-OMe-Ph
1-373 4-OMe-2-Me-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
_{1-374 2-F-Ph -CH 2} -CH 2 - 5-Cl-2-OMe-Ph
1-375 2-F-Ph (E) -CH = CH-5-Cl-2-OMe-Ph
――――――――――――――――――――――――――――――――――――

  (Table 2)

――――――――――――――――――――――――――――――――――――
Compound number R ² AUVR ^3b R ^3a R ⁴ R ¹
――――――――――――――――――――――――――――――――――――
2-1 2,6-di-Cl-Ph -CH ₂ -CH ₂ -N CH HHH 2-OMe-5-Me-Ph
2-2 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH NHHH 2-OMe-5-Me-Ph
2-3 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH Me HH 2-OMe-5-Me-Ph
2-4 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH FHH 2-OMe-5-Me-Ph
2-5 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH H Me H 2-OMe-5-Me-Ph
2-6 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH HFH 2-OMe-5-Me-Ph
2-7 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH HH Me 2-OMe-5-Me-Ph
2-8 2,6-di-Cl-Ph -CH ₂ -CH ₂ -N CH HHH 2-Me-Ph
2-9 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH NHHH 2-Me-Ph
2-10 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH Me HH 2-Me-Ph
2-11 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH FHH 2-Me-Ph
2-12 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH H Me H 2-Me-Ph
2-13 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH HFH 2-Me-Ph
2-14 2,6-di-Cl-Ph -CH ₂ -CH ₂ -CH CH HH Me 2-Me-Ph
2-15 2,6-di-Cl-Ph (E) -CH = CH- N CH HHH 2-OMe-5-Me-Ph
2-16 2,6-di-Cl-Ph (E) -CH = CH- CH NHHH 2-OMe-5-Me-Ph
2-17 2,6-di-Cl-Ph (E) -CH = CH- CH CH Me HH 2-OMe-5-Me-Ph
2-18 2,6-di-Cl-Ph (E) -CH = CH- CH CH FHH 2-OMe-5-Me-Ph
2-19 2,6-di-Cl-Ph (E) -CH = CH- CH CH H Me H 2-OMe-5-Me-Ph
2-20 2,6-di-Cl-Ph (E) -CH = CH- CH CH HFH 2-OMe-5-Me-Ph
2-21 2,6-di-Cl-Ph (E) -CH = CH- CH CH HH Me 2-OMe-5-Me-Ph
2-22 2,6-di-Cl-Ph (E) -CH = CH- N CH HHH 2-Me-Ph
2-23 2,6-di-Cl-Ph (E) -CH = CH- CH NHHH 2-Me-Ph
2-24 2,6-di-Cl-Ph (E) -CH = CH- CH CH Me HH 2-Me-Ph
2-25 2,6-di-Cl-Ph (E) -CH = CH- CH CH FHH 2-Me-Ph
2-26 2,6-di-Cl-Ph (E) -CH = CH- CH CH H Me H 2-Me-Ph
2-27 2,6-di-Cl-Ph (E) -CH = CH- CH CH HFH 2-Me-Ph
2-28 2,6-di-Cl-Ph (E) -CH = CH- CH CH HH Me 2-Me-Ph
2-29 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -N CH HHH 2-OMe-5-Me-Ph
2-30 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH NHHH 2-OMe-5-Me-Ph
2-31 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH Me HH 2-OMe-5-Me-Ph
2-32 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH FHH 2-OMe-5-Me-Ph
2-33 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH H Me H 2-OMe-5-Me-Ph
2-34 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH HFH 2-OMe-5-Me-Ph
2-35 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH HH Me 2-OMe-5-Me-Ph
2-36 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -N CH HHH 2-Me-Ph
2-37 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH NHHH 2-Me-Ph
2-38 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH Me HH 2-Me-Ph
2-39 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH FHH 2-Me-Ph
2-40 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH H Me H 2-Me-Ph
2-41 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH HFH 2-Me-Ph
2-42 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -CH CH HH Me 2-Me-Ph
2-43 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- N CH HHH 2-OMe-5-Me-Ph
2-44 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH NHHH 2-OMe-5-Me-Ph
2-45 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH Me HH 2-OMe-5-Me-Ph
2-46 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH FHH 2-OMe-5-Me-Ph
2-47 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH H Me H 2-OMe-5-Me-Ph
2-48 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH HFH 2-OMe-5-Me-Ph
2-49 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH HH Me 2-OMe-5-Me-Ph
2-50 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- N CH HHH 2-Me-Ph
2-51 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH NHHH 2-Me-Ph
2-52 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH Me HH 2-Me-Ph
2-53 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH FHH 2-Me-Ph
2-54 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH H Me H 2-Me-Ph
2-55 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH HFH 2-Me-Ph
2-56 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- CH CH HH Me 2-Me-Ph
2-57 2,6-di-Cl-Ph -CH ₂ -S- CH CH HH Me Ph
2-58 2,6-di-Cl-Ph -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-59 2-Cl-6-CO ₂ Me-Ph -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-60 2-COOH-6-Cl-Ph -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-61 2-Cl-6-CONHMe-Ph -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-62 2-CONH ₂ -6-Cl-Ph -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-63 2-Pyr -CH ₂ -S- CH NHHH 2-OMe-5-Me-Ph
2-64 3-CF ₃ -2-Py -CH ₂ -CH ₂ -N CH HHH 2-OMe-5-Me-Ph
――――――――――――――――――――――――――――――――――――

  (Table 3)

――――――――――――――――――――――――――――――――――――
Compound number R ² AQTR ¹
――――――――――――――――――――――――――――――――――――
3-1 2,6-di-Cl-Ph -CH ₂ -CH ₂ -NMe CH 2-F-Ph
3-2 2,6-di-Cl-Ph -CH ₂ -CH ₂ -NMe CH 5-F-2-Me-Ph
3-3 2,6-di-Cl-Ph -CH ₂ -CH ₂ -NMe CH 5-Cl-2-OMe-Ph
3-4 2,6-di-Cl-Ph -CH ₂ -CH ₂ -NMe CH 2-OMe-5-Me-Ph
3-5 2,6-di-Cl-Ph (E) -CH = CH- NMe CH 2-F-Ph
3-6 2,6-di-Cl-Ph (E) -CH = CH- NMe CH 5-F-2-Me-Ph
3-7 2,6-di-Cl-Ph (E) -CH = CH- NMe CH 5-Cl-2-OMe-Ph
3-8 2,6-di-Cl-Ph (E) -CH = CH- NMe CH 2-OMe-5-Me-Ph
3-9 2,6-di-Cl-Ph -CH ₂ -CH ₂ -S CH 2-F-Ph
3-10 2,6-di-Cl-Ph -CH ₂ -CH ₂ -S CH 5-F-2-Me-Ph
3-11 2,6-di-Cl-Ph -CH ₂ -CH ₂ -S CH 5-Cl-2-OMe-Ph
3-12 2,6-di-Cl-Ph -CH ₂ -CH ₂ -S CH 2-OMe-5-Me-Ph
3-13 2,6-di-Cl-Ph (E) -CH = CH- S CH 2-F-Ph
3-14 2,6-di-Cl-Ph (E) -CH = CH- S CH 5-F-2-Me-Ph
3-15 2,6-di-Cl-Ph (E) -CH = CH- S CH 5-Cl-2-OMe-Ph
3-16 2,6-di-Cl-Ph (E) -CH = CH- S CH 2-OMe-5-Me-Ph
3-17 2,6-di-Cl-Ph -CH ₂ -CH ₂ -SN 2-F-Ph
3-18 2,6-di-Cl-Ph -CH ₂ -CH ₂ -SN 5-F-2-Me-Ph
3-19 2,6-di-Cl-Ph -CH ₂ -CH ₂ -SN 5-Cl-2-OMe-Ph
3-20 2,6-di-Cl-Ph -CH ₂ -CH ₂ -SN 2-OMe-5-Me-Ph
3-21 2,6-di-Cl-Ph (E) -CH = CH- SN 2-F-Ph
3-22 2,6-di-Cl-Ph (E) -CH = CH- SN 5-F-2-Me-Ph
3-23 2,6-di-Cl-Ph (E) -CH = CH- SN 5-Cl-2-OMe-Ph
3-24 2,6-di-Cl-Ph (E) -CH = CH- SN 2-OMe-5-Me-Ph
3-25 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -NMe CH 2-F-Ph
3-26 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -NMe CH 5-F-2-Me-Ph
3-27 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -NMe CH 5-Cl-2-OMe-Ph
3-28 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -NMe CH 2-OMe-5-Me-Ph
3-29 2-COOH-6-Cl-Ph (E) -CH = CH- NMe CH 2-F-Ph
3-30 2-COOH-6-Cl-Ph (E) -CH = CH- NMe CH 5-F-2-Me-Ph
3-31 2-COOH-6-Cl-Ph (E) -CH = CH- NMe CH 5-Cl-2-OMe-Ph
3-32 2-COOH-6-Cl-Ph (E) -CH = CH- NMe CH 2-OMe-5-Me-Ph
3-33 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -S CH 2-F-Ph
3-34 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -S CH 5-F-2-Me-Ph
3-35 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -S CH 5-Cl-2-OMe-Ph
3-36 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -S CH 2-OMe-5-Me-Ph
3-37 2-COOH-6-Cl-Ph (E) -CH = CH- S CH 2-F-Ph
3-38 2-COOH-6-Cl-Ph (E) -CH = CH- S CH 5-F-2-Me-Ph
3-39 2-COOH-6-Cl-Ph (E) -CH = CH- S CH 5-Cl-2-OMe-Ph
3-40 2-COOH-6-Cl-Ph (E) -CH = CH- S CH 2-OMe-5-Me-Ph
3-41 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -SN 2-F-Ph
3-42 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -SN 5-F-2-Me-Ph
3-43 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -SN 5-Cl-2-OMe-Ph
3-44 2-COOH-6-Cl-Ph -CH ₂ -CH ₂ -SN 2-OMe-5-Me-Ph
3-45 2-COOH-6-Cl-Ph (E) -CH = CH- SN 2-F-Ph
3-46 2-COOH-6-Cl-Ph (E) -CH = CH- SN 5-F-2-Me-Ph
3-47 2-COOH-6-Cl-Ph (E) -CH = CH- SN 5-Cl-2-OMe-Ph
3-48 2-COOH-6-Cl-Ph (E) -CH = CH- SN 2-OMe-5-Me-Ph
3-49 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -NMe CH 2-F-Ph
3-50 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -NMe CH 5-F-2-Me-Ph
3-51 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -NMe CH 5-Cl-2-OMe-Ph
3-52 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -NMe CH 2-OMe-5-Me-Ph
3-53 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- NMe CH 2-F-Ph
3-54 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- NMe CH 5-F-2-Me-Ph
3-55 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- NMe CH 5-Cl-2-OMe-Ph
3-56 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- NMe CH 2-OMe-5-Me-Ph
3-57 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -S CH 2-F-Ph
3-58 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -S CH 5-F-2-Me-Ph
3-59 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -S CH 5-Cl-2-OMe-Ph
3-60 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -S CH 2-OMe-5-Me-Ph
3-61 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- S CH 2-F-Ph
3-62 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- S CH 5-F-2-Me-Ph
3-63 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- S CH 5-Cl-2-OMe-Ph
3-64 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- S CH 2-OMe-5-Me-Ph
3-65 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -SN 2-F-Ph
3-66 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -SN 5-F-2-Me-Ph
3-67 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -SN 5-Cl-2-OMe-Ph
3-68 2-Cl-6-CO ₂ Me-Ph -CH ₂ -CH ₂ -SN 2-OMe-5-Me-Ph
3-69 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- SN 2-F-Ph
3-70 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- SN 5-F-2-Me-Ph
3-71 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- SN 5-Cl-2-OMe-Ph
3-72 2-Cl-6-CO ₂ Me-Ph (E) -CH = CH- SN 2-OMe-5-Me-Ph
――――――――――――――――――――――――――――――――――――

In Tables 1 to 3, suitable compounds are compound numbers 1-1, 1-5, 1-6, 1-13, 1-14, 1-15, 1-19, 1-22, 1-23, 1 -24, 1-31, 1-32, 1-33, 1-37, 1-38, 1-49, 1-55, 1-65, 1-67, 1-69, 1-71, 1-73 , 1-75, 1-77, 1-79, 1-80, 1-81, 1-83, 1-85, 1-87, 1-89, 1-91, 1-93, 1-95, 1 -96, 1-97, 1-99, 1-101, 1-103, 1-105, 1-107, 1-109, 1-111, 1-113, 1-115, 1-117, 1-119 , 1-121, 1-123, 1-125, 1-127, 1-129, 1-131, 1-133, 1-135, 1-137, 1-139, 1-295, 1-311, 1 -313, 1-317, 1-325, 2-1, 2-2, 2-15, 2-58, 2-60, 2-62, 2-64, 3-1, 3-3, 3-4 3-5, 3-7, 3-8, 3-16, or 3-24,
More preferred compounds are compound numbers 1-1, 1-5, 1-6, 1-13, 1-14, 1-15, 1-19, 1-22, 1-24, 1-31, 1- 32, 1-38, 1-55, 1-69, 1-71, 1-77, 1-80, 1-81, 1-83, 1-85, 1-87, 1-89, 1-91, 1-93, 1-95, 1-97, 1-101, 1-105, 1-109, 1-125, 1-131, 1-311, 1-313, 1-317, 1-325, 2- 1, 2-2, 2-15, 2-58, 2-60, 2-62, 2-64, 3-1, 3-3, 3-4, 3-5, 3-7, 3-8, 3-16 or 3-24,
Even more preferred compounds are
1- (4- {5- [2- (2,6-dichloro-phenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2- Methoxy-5-methylphenyl) urea (compound number 1-1),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-trifluoromethylphenyl) urea (compound number 1-6),
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid (Compound No. 1-13),
3-Chloro-2- [2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] triazole-3- Yl) ethyl] benzoic acid methyl ester (Compound No. 1-19),
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester (Compound No. 1-22),
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzamide (Compound No. 1-31),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3-hexyl Urea (compound number 1-38),
1- [4- (5- {2- [2-Chloro-6- (1H-tetrazol-5-yl) phenyl] ethyl} -4-methyl-4H- [1,2,4] triazol-3-yl ) Phenyl] -3- (2-methoxy-5-methylphenyl) urea (compound number 1-55),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 3,5-dimethylphenyl) urea (compound number 1-69),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2,4-difluorophenyl) urea (compound number 1-77),
1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-fluorophenyl ) Urea (compound number 1-80),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-fluorophenyl) urea (compound number 1-81),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-phenyl-cyclopropyl) urea (compound number 1-83),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3-phenyl Urea (compound number 1-89),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( (R) -1-phenylethyl) urea (compound number 1-95),
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 3-fluorophenyl) urea (compound number 1-105),
1- (5-Chloro-2-methoxyphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4 ] Triazol-3-yl} phenyl) urea (Compound No. 1-109),
N- (4- {5-[(E) -2- (2-trifluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N ' -(2-methoxy-5-methylphenyl) urea (compound number 1-311),
N- (4- {5-[(E) -2- (2-chlorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N '-( 2-methoxy-5-methylphenyl) urea (compound number 1-313),
N- (4- {5-[(E) -2- (2,4-difluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-317),
N- (4- {5-[(E) -2- (2-methylphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N'- (2-methoxy-5-methylphenyl) urea (Compound No. 1-325),
1- (6- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-yl) -3- ( 2-methoxy-5-methylphenyl) urea (compound number 2-1),
1- (5- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-2-yl) -3- ( 2-methoxy-5-methylphenyl) urea (compound number 2-2),
1- (6- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-yl) -3- (2-methoxy-5-methylphenyl) urea (compound number 2-15),
1- {5- [5- (2,6-dichlorobenzsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] pyridin-2-yl} -3- (2-methoxy -5-methylphenyl) urea (compound number 2-58),
3-chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] -pyridin-3-yl} -4-methyl-4H- [1,2,4] triazole- 3-ylsulfanylmethyl) benzoic acid (Compound No. 2-60),
3-Chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] pyridin-3-yl} -4-methyl-4H- [1,2,4] triazole-3 -Ylsulfanylmethyl) benzamide (Compound No. 2-62),
1- (2-methoxy-5-methylphenyl) -3- (6- {4-methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2, 4] triazol-3-yl} pyridin-3-yl) urea (compound number 2-64),
1- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-fluorophenyl) urea (Compound No. 3- 1),
1- (5-Chloro-2-methoxyphenyl) -3- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) urea ( Compound No. 3-3),
1- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-methoxy-5-methylphenyl) urea ( Compound number 3-4),
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-fluorophenyl) urea ( Compound number 3-5),
1- (5-Chloro-2-methoxyphenyl) -3- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} Phenyl) urea (compound number 3-7),
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-methoxy-5-methyl Phenyl) urea (compound number 3-8),
1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] thiazol-5-yl} phenyl) -3- (2-methoxy-5-methylphenyl) urea compound number 3- 16) or
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl]-[1,3,4] thiadiazol-2-yl} phenyl) -3- (2-methoxy-5- Methylphenyl) urea (Compound No. 3-24)
And
Particularly suitable compounds are
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-trifluoromethylphenyl) urea (compound number 1-6),
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester (Compound No. 1-22),
1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-fluorophenyl ) Urea (compound number 1-80), or
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-Fluorophenyl) urea (Compound No. 1-81)
It is.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is described below in warm-blooded animals (preferably mammals, including humans). Diseases: obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetes Retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis resulting from the diseases described above and below), atherosclerosis, and Diseases selected from the group consisting of diabetic arteriosclerosis, or the following diseases caused by obesity: hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetes Disease (diabetes mellitus) Peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases mentioned above and below) Selected from the group consisting of atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, and cholelithiasis It is useful as a medicament for the prevention and / or treatment of diseases. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and is a warm-blooded animal (preferably a mammal). It is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases in humans (including humans). Preferred diseases include those selected from the group consisting of obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, diabetes, and arteriosclerosis, or the following diseases caused by obesity: high fat Is a disease selected from the group consisting of diabetes, hyperTGemia, dyslipidemia, diabetes, arteriosclerosis, hypertension, cerebrovascular disease, and coronary artery disease, more preferably obesity, obesity, or The following diseases caused by obesity are hyperlipidemia, hyperTGemia, diabetes, or arteriosclerosis, and more preferably obesity or obesity. Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.

  The compound having the general formula (I) of the present invention can be produced according to the method described below.

  Method A is a method for producing a compound having the general formula (IA).

In the present invention, R ¹ , R ² , R ³ , R ⁴ , U and V have the same meaning as described above, and R ^1a and R ^2a are included as substituents in the groups R ¹ and R ^2. Amino group, hydroxy group and / or carboxyl group is an amino group, hydroxy group and / or carboxyl group which may be protected, and represents the same group as the group in the definition of R ¹ and R ² , R ⁵ represents a C ₁ -C ₆ alkyl group (preferably a methyl group or an ethyl group), and A ¹ represents a methylene group, a vinylene group, an oxygen atom, a sulfur atom, or a main chain methylene group. one of a vinylene group, an oxygen atom or optionally C ₂ -C ₄ alkylene group optionally substituted by a sulfur atom, X is a halogen atom (preferably a chlorine atom.) shows a.

Step A1 This step is a step of producing a compound having the general formula (V).

  This step is performed by reacting a compound having the general formula (IV) with hydrazine hydrate in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, n-propanol, isopropanol Alcohol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, and preferably ethanol. It is le.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually room temperature to 150 ° C., and preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually from 30 minutes to 48 hours, and preferably from 1 hour to 24 hours.

Step A2 This step is a step of producing a compound having the general formula (V) separately from the step A1.

  This step is performed by reacting a compound having the general formula (VI) with hydrazine hydrate in the presence of a condensing agent in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and the like. Halogenated hydrocarbons, preferably dichloromethane.

The condensing agent used in this step is, for example,
(1) A combination of a phosphate ester such as diethyl phosphoryl cyanide and diphenyl phosphoryl azide and the following base;
(2) carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride); Combinations of the above carbodiimides and N-hydroxys such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide combination;
(3) Combination of disulfides such as 2,2′-dipyridyl disulfide, 2,2′-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine and tributylphosphine;
(4) Like N, N′-disuccinimidyl carbonate, diethyl pyrocarbonate, di-2-pyridyl carbonate, S, S′-bis (1-phenyl-1H-tetrazol-5-yl) dithiocarbonate Carbonates;
(5) Phosphonic chlorides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphonic chloride;
(6) N, N′-disuccinimidyl oxalate, N, N′-diphthalimidyl oxalate, N, N′-bis (5-norbornene-2,3-dicarboxyimidyl) oxalate, 1 , 1′-bis (benzotriazolyl) oxalate, 1,1′-bis (6-chlorobenzotriazolyl) oxalate, 1,1′-bis (6-trifluoromethylbenzotriazolyl) oxalate Oxalates;
(7) A combination of the phosphine and an azodicarboxylic acid ester such as diethyl azodicarboxylate, or an azodicarboxamide such as 1,1 ′-(azodicarbonyl) dipiperidine; A combination of the following bases:
(8) N-lower alkyl-5-arylisoxazolium-3′-sulfonates such as N-ethyl-5-phenylisoxazolium-3′-sulfonate;
(9) Diheteroaryl diselenides such as di-2-pyridyl diselenide;
(10) Arylsulfonyl triazolides such as p-nitrobenzenesulfonyl triazolide;
(11) 2-halogeno-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium chloride;
(12) Imidazoles such as 1,1′-oxalyldiimidazole and N, N′-carbonyldiimidazole;
(13) 3-Lower alkyl-2-halogeno-benzothiazolium fluoroborates such as 3-ethyl-2-chloro-benzothiazolium fluoroborate;
(14) 3-lower alkyl-benzothiazole-2-thelones such as 3-methyl-benzothiazole-2-thelone;
(15) Phosphate such as phenyl dichlorophosphate, polyphosphate ester;
(16) halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate;
(17) Halogenosilanes such as trimethylsilyl chloride and triethylsilyl chloride;
(18) A combination of a lower alkanesulfonyl halide such as methanesulfonyl chloride and the following base; or
(19) N, N, N ′, N′-tetra lower alkyl halogenoformamidium chlorides such as N, N, N ′, N′-tetramethylchloroformamidium chloride,
Preferred is carbonyldiimidazole (CDI).

  Examples of the base used in combination with the condensing agent include alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. Or N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6- Organic bases such as di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, preferably organic bases, more preferably , Triethylamine, diisopropylethylamine or pyridine.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 60 ° C., preferably room temperature.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 30 minutes to 20 hours, preferably 1 hour to 10 hours.

Step A3 This step is a step of producing a compound having the general formula (VIII).

  This step is carried out in the same manner as in a known method using a known compound or a known compound as a starting material in an inert solvent in the presence or absence (preferably in the presence) of a base. ) Is reacted with methylamine.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane and heptane; benzene, toluene, Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; ketones such as acetone, methyl ethyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile, etc. Nitriles; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; dimethyl sulfoxide, sulfolane and the like Or a mixed solvent thereof, preferably an amide, a sulfoxide or a mixed solvent thereof, and more preferably N, N-dimethylformamide or N, N-dimethylacetamide.

  The base used in this step is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; or N -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, preferably organic bases, more preferably pyridine or N , N-dimethylaniline.

  In this step, the reaction may be performed using an organic base as a solvent without using an inert solvent.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually from 30 minutes to 48 hours, and preferably from 1 hour to 24 hours.

Step A4 This step is a step of producing a compound having the general formula (IX).

  This step involves reacting a compound having the general formula (VIII) with thionyl chloride in an inert solvent or without using an inert solvent, Journal; Mills, John E .; Cosgrove, Robin M .; Shah, Rekha Maryanoff, Cynthia A .; Paragamian, Vasken; JOCEAH; J.Org.Chem .; EN; 49; 3; 1984; 546-547.

Step A5 This step is a step of producing a compound having the general formula (X).

  This step is performed by reacting a compound having the general formula (IX) with a compound having the general formula (V) obtained in the step A1 or step A2 in the presence of a base in an inert solvent. It is.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, it is an aromatic hydrocarbon such as benzene and toluene, and is preferably Is toluene.

  The base used in this step is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; or N -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline and the like, preferably organic bases, more preferably triethylamine .

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 150 ° C., preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 1 hour to 40 hours, preferably 10 hours to 30 hours.

Step A6 This step is a step of producing a compound having the general formula (XI).

  This step is performed by reacting a compound having the general formula (X) with a reducing agent in the presence of an acid in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, n-propanol, isopropanol Alcohols such as alcohol, n-butanol, isobutanol, t-butanol and isoamyl alcohol, preferably methanol.

  The reducing agent used in this step is, for example, a metal such as zinc, tin, or iron, and preferably zinc.

  The acid used in this step is, for example, a mineral acid such as hydrochloric acid or an organic acid such as acetic acid, and preferably acetic acid.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 30 minutes to 10 hours, preferably 1 hour to 2 hours.

  The reaction in this step can also be performed in a hydrogen atmosphere in the presence of palladium such as palladium-carbon or a catalyst such as platinum (IV) oxide.

Step A7 This step is a step of producing a compound having the general formula (IA).

In this step, a compound having the general formula (XI) in the presence of a base in an inert solvent is converted into a general formula (XII) that can be easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material. After reacting with the compound having, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a and R ^2a is optionally removed.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane and heptane; benzene, toluene, Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; ketones such as acetone, methyl ethyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile, etc. Nitriles; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; dimethyl sulfoxide, sulfolane and the like Or a mixed solvent thereof, preferably an amide, a sulfoxide or a mixed solvent thereof, and more preferably N, N-dimethylformamide or N, N-dimethylacetamide.

  The base used in this step is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; or N -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, preferably organic bases, more preferably pyridine or N , N-dimethylaniline.

  In this step, the reaction may be performed using an organic base as a solvent without using an inert solvent.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 120 ° C., preferably room temperature to 100 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 1 hour to 30 hours, preferably 10 hours to 20 hours.

  Method B is a method for producing a compound having the general formula (IB).

In the present invention, R ¹ , R ² , R ³ , R ^1a , R ^2a , A ¹ , U and V have the same meaning as described above.

Step B1 This step is a step of producing a compound having the general formula (IB).

In this step, in the presence of a base in an inert solvent, the compound having the general formula (XI) obtained in the above-mentioned Method A, Step A6 is treated in the same manner as in a known method using a known compound or a known compound as a starting material. After reacting with a compound having the general formula (XIII) that can be easily obtained, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a and R ^2a is optionally removed.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane and heptane; benzene, toluene, Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; ketones such as acetone, methyl ethyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile, etc. Nitriles; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; dimethyl sulfoxide, sulfolane and the like Or a mixed solvent thereof, preferably an amide, a sulfoxide or a mixed solvent thereof, and more preferably N, N-dimethylformamide or N, N-dimethylacetamide.

  The base used in this step is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; or N -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, preferably organic bases, more preferably pyridine or N , N-dimethylaniline.

  In this step, the reaction may be performed using an organic base as a solvent without using an inert solvent.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., preferably room temperature.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 1 hour to 30 hours, preferably 10 hours to 20 hours.

In the method C, a compound having the general formula (IC) in which A ¹ represents A ² among the compounds having the general formulas (IA) and (IB) separately from the methods A and B It is a method of manufacturing.

In the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^1a , R ^2a , U and V have the same meaning as described above, and A ² represents a methylene group, a vinylene group, or , One of the methylene groups of the main chain represents a C ₂ -C ₄ alkylene group which may be replaced with a vinylene group, an oxygen atom or a sulfur atom.

Step C1 This step is a step of producing a compound having the general formula (XLVIII).

  This step is performed by reacting a compound having the general formula (XLVII) with a base in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin , Octanol, cyclohexanol, alcohols such as methyl cellosolve; or a mixed solvent thereof, preferably methanol, tetrahydrofuran, or a mixed solvent thereof, more preferably a mixed solvent of methanol and tetrahydrofuran. is there. If necessary, it can be a mixed solvent with water (mixing ratio is 1: 100 to 100: 1, preferably 80:20).

  In this step, the reaction may be performed using only water as a solvent without using an inert solvent.

  The base used in this step is, for example, an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and preferably an aqueous solution of sodium hydroxide.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., and preferably 40 ° C. to 80 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 1 hour to 48 hours, preferably 10 hours to 24 hours.

Step C2 This step is a step of producing a compound having the general formula (XIV).

  This step is carried out by reacting the compound having the general formula (XLVIII) with a chlorinating agent in the presence or absence (preferably in the presence) of N, N-dimethylformamide in an inert solvent. It is.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethyl sulfoxide, sulfolane Sulfoxides such as: nitriles such as acetonitrile; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; halo such as dichloromethane, 1,2-dichloroethane, dichlorobenzene Genated hydrocarbons; or aromatic hydrocarbons such as benzene, toluene and xylene, preferably halogenated hydrocarbons, and more preferably dichloromethane.

  The chlorinating agent used in this step is, for example, an inorganic acid such as hydrochloric acid; a halogen molecule such as chlorine; a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride; Sulfinic acid reagents such as thionyl chloride and toluenesulfonic acid chloride; or sulfonic acid reagents such as sulfonyl chloride, preferably chloride, more preferably oxalyl chloride. is there.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 0 ° C. to 130 ° C., preferably 10 ° C. to 80 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 10 minutes to 24 hours, and preferably 30 minutes to 5 hours.

Step C3 This step is a step of producing a compound having the general formula (XV).

  This step comprises reacting the compound having the general formula (XIV) with methylamine in an inert solvent in the presence or absence of a base (preferably in the presence) with step A3 of the above method A. The same is done.

Step C4 This step is a step of producing a compound having the general formula (XVI).

  This step is performed by reacting a compound having the general formula (XV) with a chlorinating agent in an inert solvent under nitrogen pressure.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and the like. Halogenated hydrocarbons, preferably chloroform.

  The chlorinating agent used in this step is, for example, phosphorus reagents such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and preferably phosphorus pentachloride.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 30 ° C. to 160 ° C., and preferably 50 ° C. to 120 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 10 minutes to 24 hours, and preferably 30 minutes to 5 hours.

Step C5 This step is a step of producing a compound having the general formula (XVIII).

  This step is performed by reacting a compound having the general formula (XVII) in an inert solvent in the same manner as in Step A7 of Method A or Step B1 of Method B.

Step C6 This step is a step of producing a compound having the general formula (XIX).

  This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XVIII) with hydrazine hydrate in an inert solvent.

Step C7 This step is a step of producing a compound having the general formula (IC).

In this step, a compound having the general formula (XIX) is reacted with a compound having the general formula (XVI) obtained in the above-mentioned Method C, Step C4 in an inert solvent in the presence of a base, and then optionally. It is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R ^1a and R ^2a .

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane and heptane; benzene, toluene, Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; ketones such as acetone, methyl ethyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile, etc. Nitriles; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; dimethyl sulfoxide, sulfolane and the like Sulfoxides; or a mixed solvent thereof, preferably halogenated hydrocarbons, and more preferably chloroform.

  The base used in this step is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; or N -Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline and the like, preferably organic bases, more preferably triethylamine .

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., and preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 30 minutes to 40 hours, preferably 10 hours to 20 hours.

In the method D, among the compound having the general formula (IV) which is the raw material compound of the method A and the compound having the general formula (XLVII) which is the raw material compound of the method C, A ¹ and A ² are vinylene groups, or This is a method for producing a compound having the general formula (XXII) in which one of the methylene groups of the main chain represents a C ₂ -C ₄ alkylene group in which a vinylene group is substituted.

In the present invention, R ⁵ and R ^2a are as defined above, and G ¹ and G ² are simultaneously a single bond or a group represented by the formula —G ¹ —CH═CH—G ² —. as one of the methylene groups in the main chain shows a C ₂ -C ₄ alkylene group are replaced by vinylene group.

Step D1 This step is a step of producing a compound having the general formula (XXII).

  In this step, in the presence of a base in an inert solvent, a known compound or a compound having the general formula (XX) easily obtained in the same manner as a known method using a known compound as a starting material is converted into a known compound or a known compound. This is carried out by reacting the starting material with a compound having the general formula (XXI) which can be easily obtained in the same manner as in the known method.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin , Octanol, cyclohexanol, alcohols such as methyl cellosolve; or a mixed solvent thereof, preferably tetrahydrofuran or ethanol.

  The active methylene compound used in this step is not particularly limited as long as it is usually used for the synthesis of an α, β-unsaturated carboxylic acid compound. For example, the active methylene compound is an active methylene compound having the general formula (XXI). is there.

  Examples of the base used in this step include alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride. Is potassium carbonate or sodium hydride.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −78 ° C. to 50 ° C., preferably −20 ° C. to 20 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 10 minutes to 5 hours, preferably 30 minutes to 1 hour.

In the method E, among the compound having the general formula (IV) that is the raw material compound of the method A and the compound having the general formula (XLVII) that is the raw material compound of the method C, A ¹ and A ² are oxygen atoms, or , A method for producing a compound having the general formula (XXV) in which one of the methylene groups of the main chain represents a C ₂ -C ₄ alkylene group in which an oxygen atom is replaced.

In the present invention, R ⁵ and R ^2a are as defined above, and G ³ and G ⁴ simultaneously represent a single bond or as a group represented by the formula —G ³ —O—G ⁴ —, one of methylene groups in the main chain but shows the C ₂ -C ₄ alkylene group are replaced by oxygen atom, Y is a halogen atom (preferably a chlorine atom or a bromine atom.), an aryl sulfonate group (e.g., A C ₁ -C ₆ alkyl group and a phenyl sulfonate group which may be independently substituted with a group selected from a halogen atom, preferably a tosyl group.) Or C ₁ -C ₆ An alkyl sulfonate group (preferably a mesyl group) is shown.

Step E1 This step is a step of producing a compound having the general formula (XXV).

  In this step, a known compound or a compound having the general formula (XXIII) that is easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material in the presence of a base in an inert solvent is converted into a known compound or a known compound. The reaction is carried out by reacting the starting material with a compound having the general formula (XXIV) which can be easily obtained in the same manner as in a known method.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or dimethyl sulfoxide, Sulfoxides such as sulfolane; or a mixed solvent thereof, preferably amides or ethers, and more preferably N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this step include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride; Alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; sodium fluoride, potassium fluoride Inorganic bases such as alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide Class: Methyl mercaptan natriu Mercaptan alkali metals such as sodium ethyl mercaptan; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- ( N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3. .0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Such organic bases; or butyl lithium, lithium diisopropyl amino , An organometallic bases, such as lithium bis (trimethylsilyl) amide, preferably an alkali metal hydride or alkali metal alkoxides, more preferably, sodium hydride.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used, the type of base and the like, but is usually 0 ° C. to 130 ° C., and preferably 10 ° C. to 50 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the type of base, the reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step E2 This step is a step of producing a compound having the general formula (XXV) separately from the step E1.

  In this step, a known compound or a compound having the general formula (XXVI) that is easily obtained in the same manner as a known method using a known compound or a known compound as a starting material in the presence of a base in an inert solvent is converted to the known compound or the known compound. The reaction is carried out by reacting the starting material in the same manner as in Step E1 with a compound having the general formula (XXVII) which can be easily obtained in the same manner as in the known method.

In the method F, among the compound having the general formula (IV) that is the raw material compound of the method A and the compound having the general formula (XLVII) that is the raw material compound of the method C, A ¹ and A ² are sulfur atoms, or , A method for producing a compound having the general formula (XXX) in which one of the methylene groups of the main chain represents a C ₂ -C ₄ alkylene group in which a sulfur atom is replaced.

In the present invention, R ⁵ , R ^2a and Y are as defined above, and G ⁵ and G ⁶ are simultaneously a single bond or a group represented by the formula -G ⁵ -SG ^6-. Represents a C ₂ -C ₄ alkylene group in which one of the methylene groups of the main chain is replaced by a sulfur atom.

Step F1 This step is a step of producing a compound having the general formula (XXX).

  In this step, in the presence of a base in an inert solvent, a known compound or a compound having the general formula (XXVIII) easily obtained in the same manner as a known method using a known compound as a starting material is converted into a known compound or a known compound. This is carried out by reacting the starting material in the same manner as in the known method with a compound having the general formula (XXIX) which can be easily obtained in the same manner as in Step E1 of Method E.

Step F2 This step is a step of producing a compound having the general formula (XXX) separately from the Step F1.

  In this step, a known compound or a compound having the general formula (XXXI) easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material in the presence of a base in an inert solvent, The reaction is carried out by reacting the starting material in the same manner as in the known method with a compound having the general formula (XXXII) which can be easily obtained in the same manner as in Step E1 of Method E.

Method G is a method for separately producing a compound having the general formula (XXXV) in which A ¹ represents A ³ -S among the compounds having the general formula (XI) of the methods A and B.

In the present invention, R ³ , R ^2a , U, V and Y are as defined above, and A ³ represents a methylene group or a C ₂ -C ₃ alkylene group.

Step G1 This step is a step of producing a compound having the general formula (XXXV).

  This step is carried out in the same manner as in a known method using a known compound (for example, Bioorg. Med. Chem. Lett., 11 (2001) 1703-1707) or a known compound in an inert solvent in the presence of a base. The reaction is carried out by reacting a compound having the general formula (XXXIII) easily obtained with a compound having the general formula (XXXIV) easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin , Octanol, cyclohexanol, alcohols such as methyl cellosolve; or a mixed solvent thereof, preferably ethanol, tetrahydrofuran, or a mixed solvent thereof, more preferably ethanol and tetrahydrofuran. It is a mixed solvent.

  The base used in this step is, for example, an alkali metal hydroxide or an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and preferably an aqueous solution of potassium hydroxide or sodium hydroxide. More preferably, an aqueous solution of sodium hydroxide is used.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., more preferably room temperature. It is.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 30 minutes to 18 hours, and preferably 1 hour to 10 hours.

In the method H, among the compounds having the general formulas (IA), (IB), and (IC) separately from the methods A, B, and C, A ¹ and A ² are A ³ − It is a method for producing a compound having the general formula (IH) representing S.

In the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^1a , R ^2a , A ³ , U, V and Y have the same meaning as described above.

Step H1 This step is a step of producing a compound having the general formula (XXXVII).

  This step is performed by reacting a compound having the general formula (XXXVI) in an inert solvent in the same manner as in Step A7 of Method A or Step B1 of Method B.

Step H2 This step is a step of producing a compound having the general formula (XXXVIII).

  This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XXXVII) with hydrazine hydrate in an inert solvent.

Step H3 This step is a step of producing a compound having the general formula (XXXIX).

  This step is performed by reacting a compound having the general formula (XXXVIII) with methyl isothiocyanate in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether, preferably tetrahydrofuran.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 10 ° C. to 100 ° C., and preferably about 25 ° C. to 70 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually from 30 minutes to 48 hours, and preferably from 1 hour to 24 hours.

Step H4 This step is a step of producing a compound having the general formula (XL).

  This step is performed by reacting a compound having the general formula (XXXIX) with hydrazine hydrate in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide are preferred, and N, N-dimethylacetamide is preferred.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually room temperature to 100 ° C., preferably 60 ° C. to 80 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually from 30 minutes to 48 hours, and preferably from 1 hour to 24 hours.

Step H5 This step is a step of producing a compound having the general formula (IH).

In this step, a compound having the general formula (XL) in the presence of a base in an inert solvent is converted into a general formula (XXXIV) which can be easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material. The reaction is carried out in the same manner as in Step G1 of the above-mentioned method G, and then the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a and R ^2a is optionally removed.

  Method I is a method for producing a compound having the general formula (II).

In the present invention, R ¹ , R ² , R ³ , R ⁴ , U and V are as defined above, and A ⁴ is a sulfur atom or one of the main chain methylene groups is a sulfur atom. A C ₂ -C ₄ alkylene group in which is substituted, and A ⁵ is a sulfinyl group, a sulfonyl group, or a C ₂ -C ₄ alkylene in which one of the methylene groups of the main chain is replaced with a sulfinyl group or a sulfonyl group Indicates a group.

Step I1 This step is a step of producing a compound having the general formula (II).

  This step is performed by reacting a compound having the general formula (IS) with an oxidizing agent in an inert solvent.

The compound having the general formula (IS) used in this step is the compound having the general formulas (IA), (IB) and (IC), wherein A ¹ and A ² are A compound having a sulfur atom or a C ₂ -C ₄ alkylene group in which one of the methylene groups of the main chain is replaced with a sulfur atom, and a compound having the general formula (IH).

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n Alcohols such as -propanol, i-propanol, n-butanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; dimethyl sulfoxide, sulfora Sulfoxides such as acetonitrile; nitriles such as acetonitrile; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene Or aromatic hydrocarbons such as benzene, toluene and xylene, preferably halogenated hydrocarbons, and more preferably dichloromethane.

  The oxidizing agent used in this step is, for example, an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide solution or oxone, and preferably m-chloroperbenzoic acid.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −30 ° C. to 130 ° C., and preferably 0 ° C. to 70 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 10 minutes to 24 hours, and preferably 30 minutes to 3 hours.

  Method J is a method for producing a compound having the general formula (XX), which is a raw material compound of Method D.

In the present invention, R ^2a and G ¹ are as defined above.

Step J1 This step is a step of producing a compound having the general formula (XX).

  This step can be easily performed in the same manner as in a known method using a known compound or a known compound as a starting material in the presence of a lithium amide reagent (eg, lithium-2,2,6,6-tetramethylpiperidine) in an inert solvent. Is carried out according to the method of Tetrahedron Letters, 38, 1559-1562 (1997), in which the compound having the general formula (XLI) obtained in the above is reacted with an N-formyl compound (for example, 1-formylpiperidine).

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether, preferably tetrahydrofuran.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −78 ° C. to 0 ° C., and preferably −90 ° C. to −60 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 10 minutes to 3 hours, preferably 30 minutes to 1 hour.

The method K has a general formula (XLVI) in which A ¹ represents a vinylene group and R ^2a represents a phenyl group having a carboxyl group at the 2-position among compounds having the general formula (XI) separately from the method A. A method for producing a compound.

In the present invention, R ³ , U and V have the same meaning as described above.

Step K1 This step is a step of producing a compound having the general formula (XLIII).

  This step is performed by reacting a compound having the general formula (XLII) with a cyano compound (for example, copper (I) cyanide) in an inert solvent.

  The compound having the general formula (XLII) used in this step can be synthesized in the same manner as the compound having the general formula (X) of Method A.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide are preferred, and N, N-dimethylformamide is preferred.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 200 ° C., and preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 1 hour to 40 hours, preferably 5 hours to 30 hours.

Step K2 This step is a step of producing a compound having the general formula (XLIV).

  This step is performed by reacting a compound having the general formula (XLIII) with an acid.

  The acid used in this step is, for example, an aqueous solution of a mineral acid such as sulfuric acid, an organic acid such as acetic acid, or a mixture thereof, and preferably an aqueous solution of sulfuric acid, acetic acid, or a mixture thereof. More preferred is a 1: 1: 1 mixture of water, sulfuric acid and acetic acid.

  The reaction temperature in this step varies depending on the raw material compound, the acid used and the like, but is usually −20 ° C. to 200 ° C., and preferably 100 ° C. to 150 ° C.

  The reaction time in this step varies depending on the raw material compound, the acid used, the reaction temperature and the like, but is usually 10 to 40 hours, preferably 20 to 30 hours.

Step K3 This step is a step of producing a compound having the general formula (XLV).

  This step is performed by reacting a compound having the general formula (XLIV) in an inert solvent in the presence of an acid in the same manner as in Step A6 of Method A above.

Step K4 This step is a step of producing a compound having the general formula (XLVI).

  This step is carried out by reacting a compound having the general formula (XLV) in the presence of a base (for example, sodium methoxide, aqueous potassium hydroxide) in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol and ethanol; ethers such as dioxane and ether Or a mixed solvent thereof, preferably methanol, dioxane or a mixed solvent thereof, and more preferably a mixed solvent of methanol and dioxane.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 120 ° C., and preferably the reflux temperature of the solvent.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.

R ^{1 of} the compound obtained in each of the above steps is substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b. A C ₆ -C ₁₀ aryl group, one group selected from the substituent group a and / or a heterocyclic ring optionally substituted with one or two groups independently selected from the substituent group b A C ₇ -C ₁₆ aralkyl group which may be substituted with a group, or one group selected from substituent group a and / or one to four groups independently selected from substituent group b If, and / or, R ² is optionally substituted with one to four groups independently selected from one group and / or a substituent group b is selected from the substituent group a C ₆ -C ₁₀ aryl group, or one group selected from substituent group a and / or a substituent group From one or two substituents on these heterocyclic group with a group independently selected, for example, it is possible to convert a substituent at each of the following steps (1) to (8).

(1) Step of hydrolyzing a cyano group to convert it to a carbamoyl group The hydrolysis reaction can be performed, for example, in the presence of water and a base. As the base, for example, an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably an aqueous solution of potassium hydroxide can be used. The reaction can be carried out in a solvent, for example, preferably in a mixture of alcohols and ethers. Examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol. Ethers such as dimethyl ether, preferably tetrahydrofuran can be used. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, Alcohols such as isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve, preferably ethanol can be used. Particularly preferred is a 3: 1 mixture of tetrahydrofuran and methanol.

  The reaction may be performed under microwave irradiation under pressure (eg, 5 Bar to 30 Bar).

  While the reaction temperature varies depending on the solvent, starting materials, reagents and the like, it is generally 20 ° C. to 250 ° C., preferably 100 ° C. to 200 ° C.

  The reaction time varies depending on the solvent, starting materials, reagents, reaction temperature, and the like, but is usually 30 seconds to 1 hour, and preferably 1 minute to 10 minutes.

(2) Step of treating a cyano group with a nitrogen-containing reagent to convert it to a tetrazolyl group Examples of the nitrogen-containing reagent include sodium azide, a combination of sodium azide and an inorganic chlorine compound such as ammonium chloride, and azide A tin azide compound such as trimethyltin or tributyltin azide can be used, and a combination of an inorganic chlorine compound such as sodium azide and ammonium chloride can be preferably used.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane and heptane; aromatics such as benzene, toluene and xylene Group hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; acetone, Ketones such as methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, Isopropanol, -Alcohols such as butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane Water; or a mixture thereof; and amides are preferable, and N, N-dimethylformamide or N, N-dimethylacetamide is more preferable.

  While the reaction temperature varies depending on the solvent, starting materials, reagents and the like, it is generally 20 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.

  While the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature and the like, it is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours.

(3) The process of converting a cyano group with an acid to convert it into a carboxyl group This is carried out by reacting in the same manner as in the above-mentioned Method K, Step K2.

(4) Step of esterifying carboxyl group to convert to C ₂ -C ₇ alkoxycarbonyl group Esterification is performed in the presence of a halogenating agent such as thionyl chloride using alcohols to form an ester as a solvent. be able to. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, and the like. Preferably, methanol can be used.

  While the reaction temperature varies depending on the solvent, reagent and the like, it is generally −20 ° C. to 100 ° C., preferably 40 ° C. to 60 ° C.

  While the reaction time varies depending on the solvent, reagent, reaction temperature and the like, it is generally 1 hour to 48 hours, preferably 10 hours to 24 hours.

(5) Step of converting a carboxyl group into a carbamoyl group and converting it to an carbamoyl group Inert solvent (for example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone Amides such as hexamethylphosphorotriamide, preferably N, N-dimethylformamide, etc.) in the presence of 1-hydroxybenzotriazole (HOBt) and sequentially adding WSC and aqueous ammonia. .

  The reaction temperature varies depending on starting materials, solvents, reagents and the like, but is usually −20 ° C. to 100 ° C.

  The reaction time varies depending on the starting material, solvent, reagent, reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

(6) An amine compound in which the carboxyl group is represented by the general formula R ⁶ —NH—R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group). ) To convert to an optionally substituted carbamoyl group in the presence of a condensing agent such as carbonyldiimidazole (CDI), such as formamide, N, N-dimethylformamide, N , N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, amides such as hexamethylphosphorotriamide, preferably N, N-dimethylformamide.

  The reaction temperature varies depending on the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  While the reaction time varies depending on the solvent, reaction temperature and the like, it is usually 10 minutes to 24 hours, preferably 30 minutes to 6 hours.

(7) Step of converting bromine atom or iodine atom into aryl group or aromatic heterocyclo group by carbon-carbon coupling reaction, usually used for carbon-carbon coupling reaction such as tetrakis (triphenylphosphine) palladium (0) In the presence of the palladium compound, a boron compound such as a compound represented by the general formula R ⁸ B (OH) ₂ (R ⁸ represents an aryl group such as a phenyl group or an aromatic heterosilyl group such as a thienyl group) And a substitution reaction with iodine atoms. The reaction can be carried out in a solvent in the presence of a base. Examples of the base include alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate, alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. Sodium can be used. As the solvent, for example, a mixture of aromatic hydrocarbons and alcohols can be used, and as the aromatic hydrocarbons, for example, aromatic hydrocarbons such as benzene and toluene can be used, As the alcohols, for example, alcohols such as methanol and ethanol can be used. A mixture of toluene and ethanol can be preferably used, and a 1: 1: 1 mixture of 2M aqueous sodium carbonate, toluene and ethanol is particularly preferably used.

  The reaction temperature varies depending on starting materials, solvents, reagents and the like, but is usually −20 ° C. to 150 ° C.

  The reaction time varies depending on the starting material, solvent, reagent, reaction temperature and the like, but is usually 30 minutes to 10 hours, preferably 1 hour to 4 hours.

(8) An iodine atom is treated with an amine compound represented by the general formula R ⁶ —NH—R ⁷ (wherein R ⁶ and R ⁷ have the same meaning as described above) to give a substituent. Step of converting to an amino group A substitution reaction with an iodine atom is carried out by allowing an amine compound to act in the presence of a copper reagent such as copper (I) iodide and a phosphate such as tripotassium phosphate. It is a process. The reaction can be carried out in an inert solvent, preferably alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- The reaction can be carried out in a solvent such as butanol or isoamyl alcohol. Preferably, a mixture (1: 1) of ethanol and isopropanol can be used.

  The reaction temperature varies depending on starting materials, solvents, reagents and the like, but is usually −20 ° C. to 150 ° C.

  The reaction time varies depending on the starting material, solvent, reagent, reaction temperature, etc., but is usually 1 hour to 40 hours, preferably 10 hours to 30 hours.

  Method L is a method for separately producing a compound having the general formula (X) of Method A.

In the present invention, R ³ , R ^2a , A ¹ , U, V and Y have the same meaning as described above.

Step L1 This step is a step of producing a compound having the general formula (L).

  This step is performed by reacting the compound having the general formula (VIII) obtained in Step A3 of Method A in an inert solvent with a sulfurizing agent.

  The compound having the general formula (VIII) used in this step is a known compound (for example, J. Med. Chem., 20 (1977) 483-487) or a known compound as a starting material in the same manner as a known method. Can also be obtained.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; nitriles such as acetonitrile and isobutyronitrile; nitroethane and nitrobenzene Nitro compounds; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; Is a mixture of these solvents, preferably an aromatic hydrocarbon, more preferably toluene.

  The sulfurizing agent used in this step is, for example, Lawson reagent or diphosphorus pentasulfide, and preferably Lawson reagent.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 20 ° C. to 100 ° C., preferably 40 ° C. to 60 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 96 hours, preferably 6 to 24 hours.

Step L2 This step is a step of producing a compound having the general formula (LII).

  In this step, in the presence of a base in an inert solvent, the compound having the general formula (L) is converted into the general formula (LI) that can be easily obtained in the same manner as in the known method using known compounds or known compounds as starting materials. It is carried out by reacting with a compound having it.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol Alcohols such as cyclohexanol and methyl cellosolve; Sulfoxides such as dimethyl sulfoxide and sulfolane; Nitriles such as acetonitrile and isobutyronitrile; Ethyl formate , Esters such as ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro such as nitroethane and nitrobenzene Compounds; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; or a mixed solvent thereof Alcohols are preferable, and ethanol is more preferable.

  Examples of the base used in this step include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride; Alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; sodium fluoride and potassium fluoride Inorganic bases such as alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide Sodium trimethylsiloxy Alkali metal trialkylsiloxides such as sodium, potassium trimethylsiloxide and lithium trimethylsiloxide; mercaptan alkali metals such as methyl mercaptan sodium and ethyl mercaptan sodium; N-methylmorpholine, triethylamine, tripropylamine and tributylamine , Diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, Quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO Organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); or organometallic bases such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, Preferred are alkali metal alkoxides, and more preferred is sodium ethoxide.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 20 ° C. to 100 ° C., preferably 40 ° C. to 80 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 96 hours, preferably 2 to 24 hours.

Step L3 This step is a step of producing a compound having the general formula (X).

  This step is performed by reacting a compound having the general formula (LII) with a compound having the general formula (V) obtained in Step A1 or Step A2 of Method A in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Ethers such as dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexano Alcohols such as methyl and cellosolve; Sulfoxides such as dimethyl sulfoxide and sulfolane; Nitriles such as acetonitrile and isobutyronitrile; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate Ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, dichlorobenzene, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; or a mixed solvent thereof, preferably alcohols, more preferably n -Butanol

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 60 ° C to 140 ° C, preferably 80 ° C to 120 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 96 hours, preferably 6 to 24 hours.

  Method M is a method for producing a compound having the general formula (IM).

In the present invention, R ¹ , R ² , R ³ , R ⁴ , R ^2a , A ² , U and V have the same meaning as described above.

Step M1 This step is a step of producing a compound having the general formula (LIV).

  This step can be easily carried out in the same manner as in a known method using a known compound (for example, J. Med. Chem., 25 (1982) 1045-1050) or a known compound as a starting material in an inert solvent in the presence of a base. The reaction is carried out by reacting the obtained compound having the general formula (LIII) with the compound having the general formula (XIV) obtained in Step C2 of Method C.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; nitriles such as acetonitrile and isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, dicarbonate Esters such as ethyl; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; or a mixed solvent thereof, preferably ethers and hydrogen halides It is kind.

  Examples of the base used in this step include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride; Alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; sodium fluoride and potassium fluoride Inorganic bases such as alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide Sodium trimethylsiloxy Alkali metal trialkylsiloxides such as sodium, potassium trimethylsiloxide and lithium trimethylsiloxide; mercaptan alkali metals such as methyl mercaptan sodium and ethyl mercaptan sodium; N-methylmorpholine, triethylamine, tripropylamine and tributylamine , Diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, Quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO , Organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); or organometallic bases such as butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide Preferred are organometallic bases, and more preferred is triethylamine.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually −20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 72 hours, preferably 2 to 24 hours.

Step M2 This step is a step of producing a compound having the general formula (LV).

  This step is performed by reacting a compound having the general formula (LIV) with methylamine in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; nitriles such as acetonitrile and isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, dicarbonate Esters such as ethyl; nitro compounds such as nitroethane and nitrobenzene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene, chloroform and carbon tetrachloride; such as benzene, toluene and xylene Aromatic hydrocarbons; carboxylic acids such as acetic acid, formic acid or trifluoroacetic acid or mixed solvents thereof, preferably ethers, amides or carboxylic acids, more preferably tetrahydrofuran, N , N-dimethylformamide or acetic acid.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 20 ° C. to 150 ° C., preferably 120 ° C. to 140 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 96 hours, preferably 6 to 24 hours.

Step M3 This step is a step of producing a compound having the general formula (LVI).

  This step is performed by reacting a compound having the general formula (LV) in an inert solvent in the presence of an acid in the same manner as in Step A6 of Method A above.

Step M4 This step is a step of producing a compound having the general formula (IM).

In this step, after reacting a compound having the general formula (LVI) in an inert solvent in the same manner as in Step A7 of Method A or Step B1 of Method B, amino in R ^1a and R ^2a is optionally formed. It is carried out by removing the protecting group of the group, hydroxy group and / or carboxyl group.

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

In the present invention, R ¹ , R ² , R ³ , R ⁴ , R ^2a , A ² , U and V have the same meaning as described above.

Step N1 This step is a step of producing a compound having the general formula (LVII).

  This step is performed by reacting the compound having the general formula (LIV) obtained in Step M1 of Method M with a Lawson reagent in an inert solvent.

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; nitriles such as acetonitrile and isobutyronitrile; nitroethane and nitrobenzene Nitro compounds; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; Is a mixed solvent thereof, preferably, ethers, aromatic hydrocarbons, or a mixture of these solvents, more preferably a mixed solvent of dioxane and toluene.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 20 ° C. to 150 ° C., preferably 100 ° C. to 120 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 72 hours, preferably 12 to 24 hours.

Step N2 This step is a step of producing a compound having the general formula (LVIII).

  This step is performed by reacting the compound having the general formula (LVII) in an inert solvent in the presence of an acid in the same manner as in Step A6 of Method A described above.

Step N3 This step is a step of producing a compound having the general formula (IN).

In this step, after reacting a compound having the general formula (LVIII) in an inert solvent in the same manner as in Step A7 of Method A or Step B1 of Method B, amino in R ^1a and R ^2a is optionally obtained. It is carried out by removing the protecting group of the group, hydroxy group and / or carboxyl group.

  The method O is a method for producing a compound having the general formula (I—O).

In the present invention, R ¹ , R ² , R ³ , R ⁴ , R ^2a , A ¹ , U and V have the same meaning as described above.

Step O1 This step is a step of producing a compound having the general formula (LIX).

  In this step, a known compound or a compound having the general formula (VII) that can be easily obtained in the same manner as a known method using a known compound as a starting material is obtained by the general formula obtained in Step A1 or Step A2 of Method A above. It is carried out by reacting with a compound having (V).

  The inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as pentane, hexane, octane, petroleum ether, and ligroin are used. Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; nitriles such as acetonitrile and isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, dicarbonate Esters such as ethyl; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; or a mixed solvent thereof, preferably amides, and more N, N-dimethylacetamide is preferred.

  The reaction temperature in this step varies depending on the raw material compound, the inert solvent used and the like, but is usually 0 ° C. to 80 ° C., preferably 20 ° C. to 30 ° C.

  The reaction time in this step varies depending on the raw material compound, the inert solvent used, the reaction temperature and the like, but is usually 0.5 to 72 hours, preferably 2 to 24 hours.

Step O2 This step is a step of producing a compound having the general formula (LX).

  This step is performed by reacting a compound having the general formula (LIX) in an inert solvent with Lawesson's reagent in the same manner as in Step N1 of Method N.

Step O3 This step is a step of producing a compound having the general formula (LXI).

  This step is performed by reacting a compound having the general formula (LX) in an inert solvent in the presence of an acid in the same manner as in Step A6 of Method A above.

Step O4 This step is a step of producing a compound having the general formula (IO).

In this step, a compound having the general formula (LXI) is reacted in the same manner as in Step A7 of Method A or Step B1 of Method B in an inert solvent, and then, if desired, amino in R ^1a and R ^2a It is carried out by removing the protecting group of the group, hydroxy group and / or carboxyl group.

  In each of the above steps, after completion of the reaction, each target compound may be isolated from the reaction mixture and purified according to a conventional method and used in the next step, or the crude product after the reaction may be used as it is in the next step. May be. Usually, the reaction mixture is appropriately neutralized, and if insolubles are present, after removal by filtration, water and an organic solvent immiscible with water (for example, benzene, diethyl ether, ethyl acetate, etc.) are added, The organic layer containing the target compound is separated, washed with water, etc., dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc., filtered, and then distilled off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent.

  Processes that require protection and deprotection are known methods (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, A Wiley-Interscience Publication)) It is done according to.

  Starting compounds (IV), (VI), (VII), (VIII), (XII), (XIII), (XIV), (XVII), (XX), (XXI), (XXIII), (XXIV), (XXVI), (XXVII), (XXVIII), (XXXIX), (XXXXI), (XXXII), (XXXIII), (XXXIV), (XXXVI), (XLI), (XLVII), (XLVIII), (LI ) And (LIII) are known compounds, or can be easily produced according to known methods or similar methods using known compounds as starting materials.

In the above, "a protected or an amino group" in the definition of R ^1a and R ^2a, "in the definition of the protective group and R ^6a of the" protected which may be hydroxy group "and" protected which may be a carboxyl group " The protecting group of “optionally protected hydroxy group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, the “protecting group” of the “optionally protected hydroxy group” in the definition of R ^1a , R ^2a and R ^6a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of synthetic organic chemistry. For example, “a general protecting group for esters of hydroxy groups”, preferably formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3 -Methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpenta Decanoyl, 13, 13 -Alkanoyl groups such as dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, heinacosanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl Such as halogenated alkylcarbonyl groups, alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl, etc. Substitutable alkylcarbonyl groups ”; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, etc. Halogenated arylcarbonyl group, 2,4,6-trimethylbenzoyl, _C 1 -C ₆ alkylated ants such as 4-toluoyl - ylcarbonyl group, _4-C 1 -C ₆ alkoxylated arylcarbonyl group such as anisoyl , 4-nitrobenzoyl, 2-nitrobenzoyl nitrated arylcarbonyl group such as yl, 2-C ₂ -C ₇ alkoxycarbonyl arylcarbonyl group such as (methoxycarbonyl) benzoyl, arylation, such as 4-phenylbenzoyl A “substituted arylacyl group” such as an arylcarbonyl group; a halogen such as the aforementioned “C ₂ -C ₇ alkoxycarbonyl group”, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or tri- (C ₁ substituted with -C ₆ alkyl) silyl group "Alkoxycarbonyl group" such as ₂ -C ₇ alkoxycarbonyl group; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl” "; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl dimethylsilyl, methyl diisopropylsilyl, methyldi -t- butylsilyl, tri as triisopropylsilyl - _(C 1 -C ₆ alkyl) silyl group, diphenyl Methylpropenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, (C ₁ -C ₆ alkyl) diarylsilyl or di- such as phenyl diisopropylsilyl - "silyl group" such as (C ₁ -C ₆ alkyl) aryl silyl group; methoxy C ₁ -C ₆ alkoxymethyl groups such as methyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, such as 2-methoxyethoxymethyl C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxymethyl groups, “alkoxymethyl” such as C ₂ -C ₆ halogenated alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl Group "; 1-ethoxyethyl, 1- (isopropo A “substituted ethyl group” such as a C ₁ -C ₆ alkoxyethyl group such as xyl) ethyl, an ethyl halide group such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, C ₁ -C ₆ alkyl groups substituted with 1 to 3 aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4 , 6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyano _C 1 -C ₆ alkyl such as _benzyl, C 1 -C ₆ alkoxy, nitro, halogen, a cyano group ant - Le ring "Aralkyl groups" such conversion has been from 1-3 C ₁ -C ₆ alkyl group substituted with an allyl group, vinyl oxycarbonyl, "alkenyloxycarbonyl group" such as allyloxycarbonyl; benzyloxycarbonyl , 1 or 2 C ₁ -C ₆ alkoxy or nitro groups such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl -It is an “aralkyloxycarbonyl group” which may be substituted on the ring, preferably a substituted alkylcarbonyl group, a silyl group or an aralkyl group.

In the above, the “protecting group” of the “optionally protected carboxyl group” in the definition of R ^1a and R ^2a is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of synthetic organic chemistry, for example, a "such general protective groups in the ester of carboxyl group", preferably, the "C ₁ -C ₆ alkyl group"; ethenyl, 1-propenyl, "C ₂ -C such as 2-propenyl ₆ alkenyl group "; ethynyl, 1-propynyl, 2-" _C 2 -C ₆ alkynyl group "such as propynyl; the" _C 1 -C ₆ halogenated alkyl group "; 2-hydroxyethyl, 2,3-dihydroxy propyl, 3-hydroxypropyl, 3,4-dihydroxy-butyl, hydroxy _"C 1 -C ₆ alkyl group" such as 4-hydroxybutyl; acetylmethyl _"C 2 -C ₇ alkylcarbonyl" as - _"C 1 -C ₆ alkyl group"; the "aralkyl group"; a or the "silyl group", _preferably, C 1 -C ₆ alkyl group or an aralkyl It is a group.

In the above, the “protecting group” of the “amino group that may be protected” in the definition of R ^1a and R ^2a is not particularly limited as long as it is an amino protecting group used in the field of organic synthetic chemistry, For example, “alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “alkenyloxycarbonyl group”; “aralkyloxycarbonyl group” in the above “general protecting group for esters of hydroxy group”; “Silyl group”; or a group similar to “aralkyl group” or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, “Schiff salts such as (5-chloro-2-hydroxyphenyl) phenylmethylene A substituted methylene group forming "a, preferably, an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and most preferably, an alkoxycarbonyl group.

  When the urea derivative having the above general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a medicine, it is itself or an appropriate pharmacologically acceptable excipient, dilution. It can be mixed with an agent or the like and administered, for example, orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories.

  These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; calcium carbonate And inorganic excipients such as sulfates such as calcium sulfate), lubricants (for example, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Colloidal silica; Veegum, Gay wax Such as wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; And silicic acids such as silicic acid hydrate; and the starch derivatives mentioned above), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above excipients) And the like, and disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; And chemically modified starch and cellulose such as carboxymethyl starch, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chloro; Alcohols such as butanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, , Normally used sweeteners, acidulants, flavors, etc.), and can be produced by known methods using additives such as diluents.

  The amount used varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.0015 mg / kg body weight (preferably 0.008 mg / kg body weight) per day, and the upper limit is 70 mg / kg body weight ( Preferably, 7 mg / kg body weight), and in the case of intravenous administration, a lower limit of 0.00015 mg / kg body weight per day (preferably 0.0008 mg / kg body weight) and an upper limit of 8.5 mg / kg per day It is desirable to administer body weight (preferably 5 mg / kg body weight) to adults 1 to 6 times per day depending on symptoms.

  EXAMPLES Hereinafter, although an Example, a test example, and a reference example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

  In the following examples, nuclear magnetic resonance (hereinafter, 1H-NMR) spectra were measured using a JNM-GX 270 FT-NMR measuring apparatus (JEOL). Using tetramethylsilane as a standard substance, the chemical shift value is described in δ value (ppm). The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, and sep for seven lines.

  High performance liquid chromatography-mass spectrometry (hereinafter LC / MS) was performed using HP-1100 LC / MSD (Agilent Technologies). The measurement conditions of high performance liquid chromatography (hereinafter referred to as HPLC) are as follows. Rt indicates a retention time.

Column: CD-C18 (intact)
Moving bed: acetonitrile / water [with 0.01% trifluoroacetic acid and 0.5% acetic acid (v / v)] = 8 / 92-99 / 1 (v / v) (linear gradient for 10 minutes)
Flow rate: 1.5ml / min
Column temperature: 40 ° C
Detection wavelength: 254nm
Mass spectrometry (hereinafter referred to as MS) was performed by atmospheric pressure chemical ionization (hereinafter referred to as APCI) or ESi (electron spray ionization).

Example 1 3- {4- [5- (2,6-dichlorobenzoylsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenyl} -1-methyl-1 -Phenylurea (Compound No. 2-57)
36 mg (0.100 mmol) of the compound 4- [5- (2,6-dichlorobenzoylsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine of Reference Example 5 was added to N, It melt | dissolved in 1 ml of N-dimethylacetamide, 25 mg (0.150 mmol) of N-methyl-N-phenylcarbamoyl chloride was added, and it stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by preparative thin phase chromatography (ethyl acetate), and the obtained crystal was finely pulverized and washed with a mixed solvent of isopropyl ether-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 498 (M + 1) ⁺ , 500 (M + 1) ⁺ .
HPLC: Rt = 4.60 min.
Example 2 3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1 , 2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester (Compound No. 1-22)
Compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid methyl ester 160 of Reference Example 40 mg (0.434 mmol) was dissolved in 4 ml of pyridine under nitrogen pressure, 0.095 ml (0.651 mmol) of 2-methoxy-5-methylphenyl isocyanate was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: ethanol = 10: 1) to obtain the title compound.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ .
HPLC: Rt = 4.77 min.
Example 3 3-Chloro-2-((E) -2- {4-methyl-5- [4- (3-o-tolylureido) phenyl] -4H- [1,2,4] triazole- 3-yl} vinyl) benzoic acid methyl ester (Compound No. 1-23)
Compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid methyl ester of Reference Example 40 Reaction was carried out in the same manner as in Example 2 using o-tolyl isocyanate to obtain the title compound.
MS (APCI, m / z): 502 (M + 1) ⁺ , 504 (M + 1) ⁺ .
HPLC: Rt = 4.44 min.
Example 4 3-Chloro-2-[(E) -2- (4-methyl-5- {4- [3- (2-trifluoromethylphenyl) ureido] phenyl} -4H- [1,2 , 4] Triazol-3-yl) vinyl] benzoic acid methyl ester (Compound No. 1-24)
Compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid methyl ester of Reference Example 40 Using 2- (trifluoromethyl) phenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 556 (M + 1) ⁺ , 558 (M + 1) ⁺ .
HPLC: Rt = 4.68 min.
Example 5 3-chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1 , 2,4] Triazol-3-yl) vinyl] benzoic acid (Compound No. 1-13)
Example 3-Compound 3-chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1 , 2,4] triazol-3-yl) vinyl] benzoic acid methyl ester 160 mg (0.301 mmol) dissolved in a mixed solvent of 4 ml of methanol and 1 ml of tetrahydrofuran, and 1.20 ml of 1N aqueous sodium hydroxide solution was added for 3 hours. Heated to reflux. The reaction solution was cooled to room temperature, and 1.20 ml of 1N-hydrochloric acid aqueous solution was added. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by preparative thin-phase chromatography (dichloromethane: methanol: acetic acid = 5: 1: 0.01), and the resulting crystals were finely pulverized and washed with a mixed solvent of isopropanol-ethyl acetate to obtain the title compound. .
MS (APCI, m / z): 518 (M + 1) ⁺ , 520 (M + 1) ⁺ .
HPLC: Rt = 4.30 min.

Example 6 3-Chloro-2-((E) -2- {4-methyl-5- [4- (3-o-tolyl-ureido) phenyl] -4H- [1,2,4] triazole -3-yl} vinyl) benzoic acid (Compound No. 1-14)
The title compound was obtained by reacting in the same manner as in Example 5 using the compound of Example 3.
MS (APCI, m / z): 488 (M + 1) ⁺ , 490 (M + 1) ⁺ .
HPLC: Rt = 4.04 min.
Example 7 3-Chloro-2-[(E) -2- (4-methyl-5- {4- [3- (2-trifluoromethylphenyl) ureido] phenyl} -4H- [1,2 , 4] Triazol-3-yl) vinyl] benzoic acid (Compound No. 1-15)
The title compound was obtained by reacting in the same manner as in Example 5 using the compound of Example 4.
MS (APCI, m / z): 542 (M + 1) ⁺ , 544 (M + 1) ⁺ .
HPLC: Rt = 4.25 min.
Example 8 1- (4- {5- [2- (2,6-dichloro-phenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl)- 3- (2-Methoxy-5-methylphenyl) urea (Compound No. 1-1)
The compound of Reference Example 20 4- {5- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and 2-methoxy- The reaction was carried out in the same manner as in Example 2 using 5-methylphenyl isocyanate to obtain the title compound.
MS (APCI, m / z): 510 (M + 1) ⁺ , 512 (M + 1) ⁺ .
HPLC: Rt = 4.58 min.
Example 9 3-Chloro-2-((E) -2- {4-methyl-5- [4- (3-o-tolyl-ureido) phenyl] -4H- [1,2,4] triazole -3-yl} vinyl) benzamide (Compound No. 1-32)
73 mg (0.150 mmol) of the compound of Example 6 and 57 mg (0.300 mmol) of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride were dissolved in 1.5 ml of N, N-dimethylformamide, and aqueous ammonia (28% ) 0.1 ml was added, then added and stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by preparative thin phase chromatography (dichloromethane: methanol = 4: 1) to obtain the title compound.
MS (APCI, m / z): 487 (M + 1) ⁺ , 489 (M + 1) ⁺ .
HPLC: Rt = 3.68 min.
Example 10 3-Chloro-2-[(E) -2- (4-methyl-5- {4- [3- (2-trifluoromethylphenyl) ureido] phenyl} -4H- [1,2 , 4] Triazol-3-yl) vinyl] benzamide (Compound No. 1-33)
Using the compound of Example 7, the reaction was conducted in the same manner as in Example 9 to obtain the title compound.
MS (APCI, m / z): 541 (M + 1) ⁺ , 543 (M + 1) ⁺ .
HPLC: Rt = 3.89 min.

Example 11 3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1 , 2,4] Triazol-3-yl) vinyl] benzamide (Compound No. 1-31)
8.3 mg (0.0160 mmol) of the compound of Example 5 was dissolved in 1 ml of dry N, N-dimethylformamide, and 5.2 mg (0.0320 mmol) of 1,1′-carbonylbis-1H-imidazole was added and stirred for 30 minutes. To this reaction solution, 0.3 ml of aqueous ammonia (28%) was added and stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was finely pulverized and washed with an isopropanol-ethyl acetate mixed solvent to obtain the title compound.
MS (APCI, m / z): 517 (M + 1) ⁺ , 519 (M + 1) ⁺ .
HPLC: Rt = 3.94 min.
Example 12 1- (5- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-2-yl ) -3- (2-Methoxy-5-methylphenyl) urea (Compound No. 2-2)
37 mg (0.159 mmol) of the compound 3- (2,6-dichlorophenyl) -N-methylpropanamide of Reference Example 41 was dissolved in 2.0 ml of dry chloroform under nitrogen pressure, and 33 mg (0.159 mmol) of phosphorus pentachloride was added for 2 hours. Heated to reflux. The reaction solution was cooled in an ice bath, and 50 mg (0.159 mmol) of Compound 1- (4-hydrazinocarbonyl-pyridin-2-yl) -3- (2-methoxy-5-methylphenyl) urea of Reference Example 43 was added. Triethylamine 0.3 ml was added and stirred for 5 minutes. Thereafter, the mixture was heated to reflux for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue is purified by preparative thin-phase chromatography (dichloromethane: methanol: acetic acid = 10: 1: catalyst amount), and the resulting crystals are finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain the title compound. It was.
MS (APCI, m / z): 511 (M + 1) ⁺ , 513 (M + 1) ⁺ .
HPLC: Rt = 4.83 min.
Example 13 1- {5- [5- (2,6-Dichlorobenzsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] pyridin-2-yl} -3 -(2-Methoxy-5-methylphenyl) urea (Compound No. 2-58)
Example using Reference Example 46 compound 5- [5- (2,6-dichlorobenzylsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] pyridin-2-ylamine Reaction was performed in the same manner as 2 to obtain the title compound.
MS (APCI, m / z): 529 (M + 1) ⁺ , 531 (M + 1) ⁺ .
HPLC: Rt = 5.04 min.
Example 14 1- (4- {5- [2- (2-Chloro-6-cyanophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-Methoxy-5-methylphenyl) urea (Compound No. 1-49)
The compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzonitrile of Reference Example 16 was used. In the same manner as in Example 2, the title compound was obtained.
MS (APCI, m / z): 501 (M + 1) ⁺ , 503 (M + 1) ⁺ .
HPLC: Rt = 4.31 min.
Example 15 1- [4- (5- {2- [2-Chloro-6- (1H-tetrazol-5-yl) phenyl] ethyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) phenyl] -3- (2-methoxy-5-methylphenyl) urea (Compound No. 1-55)
The compound of Example 14 1- (4- {5- [2- (2-chloro-6-cyanophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-Methoxy-5-methylphenyl) urea 54 mg (0.108 mmol) was dissolved in N, N-dimethylformamide 1.5 ml, sodium azide 70 mg (1.08 mmol) and ammonium chloride 58 mg (1.08 mmol) ) And heated and stirred at 120 ° C. for 2 hours. Once again, sodium azide 70 mg (1.08 mmol) and ammonium chloride 58 mg (1.08 mmol) were added, and the mixture was heated and stirred at 120 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue is purified by preparative thin-phase chromatography ((dichloromethane: methanol: acetic acid = 5: 1: 0.01)). The resulting crystals are finely crushed and washed with a mixed solvent of n-hexane-ethyl acetate to give the title compound. Got.
MS (APCI, m / z): 544 (M + 1) ⁺ , 546 (M + 1) ⁺ .
HPLC: Rt = 4.02 min.

Example 16 3-Chloro-2- (5- {6- [3- (2-methoxy-5-methyl-phenyl) ureido] -pyridin-3-yl} -4-methyl-4H- [1, 2,4] Triazol-3-ylsulfanylmethyl) benzoic acid methyl ester (Compound No. 2-59)
Compound 2- [5- (6-aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid methyl ester of Reference Example 25 Was used in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 553 (M + 1) ⁺ , 555 (M + 1) ⁺ .
HPLC: Rt = 5.02 min.
Example 17 3-Chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] -pyridin-3-yl} -4-methyl-4H- [1,2 , 4] Triazol-3-ylsulfanylmethyl) benzoic acid (Compound No. 2-60)
The reaction was conducted in the same manner as in Example 5 using the compound of Example 16, and the title compound was obtained.
MS (APCI, m / z): 539 (M + 1) ⁺ , 541 (M + 1) ⁺ .
HPLC: Rt = 4.42 min.
Example 18 3-Chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] pyridin-3-yl} -4-methyl-4H- [1,2, 4] Triazol-3-ylsulfanylmethyl) -N-methylbenzamide (Compound No. 2-61)
Using the compound of Example 17 and methylamine (40% -methanol solution), the reaction was carried out in the same manner as in Example 11 to obtain the title compound.
MS (APCI, m / z): 552 (M + 1) ⁺ , 554 (M + 1) ⁺ .
HPLC: Rt = 4.17 min.
Example 19 3-Chloro-2- (5- {6- [3- (2-methoxy-5-methylphenyl) ureido] pyridin-3-yl} -4-methyl-4H- [1,2, 4] Triazol-3-ylsulfanylmethyl) benzamide (Compound No. 2-62)
The reaction was conducted in the same manner as in Example 11 using the compound of Example 17, and the title compound was obtained.
MS (APCI, m / z): 538 (M + 1) ⁺ , 540 (M + 1) ⁺ .
HPLC: Rt = 4.04 min.
Example 20 3-Chloro-2- [2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4 ] Triazol-3-yl) ethyl] benzoic acid methyl ester (Compound No. 1-19)
The compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzoic acid methyl ester of Reference Example 32 And the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 534 (M + 1) ⁺ , 536 (M + 1) ⁺ .
HPLC: Rt = 4.53 min.

Example 21 1- (2-Methoxy-5-methylphenyl) -3- {4- [4-methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazole -3-yl] phenyl} urea (Compound No. 1-63)
Example 2 with the compound 4- [4-methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazol-3-yl] -phenylamine of Reference Example 33 The reaction was carried out in the same manner to obtain the title compound.
MS (APCI, m / z): 461 (M + 1) ⁺ .
HPLC: Rt = 3.46 min.
Example 22 1- (2-Methoxy-5-methylphenyl) -3- {5- [4-methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazole -3-yl] -pyridin-2-yl} urea (Compound No. 2-63)
Performed using compound 5- [4-methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazol-3-yl] -pyridin-2-ylamine of Reference Example 34 The reaction was conducted in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 462 (M + 1) ⁺ .
HPLC: Rt = 3.19 min.
Example 23 1- (2-Chloro-5-trifluoromethylphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H -[1,2,4] Triazol-3-yl} phenyl) urea (Compound No. 1-65)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and 2-Chloro-5- (trifluoromethyl) phenyl isocyanate was used in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 566 (M + 1) ⁺ , 568 (M + 1) ⁺ .
HPLC: Rt = 5.80 min.
Example 24 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2,5-Dimethoxyphenyl) urea (Compound No. 1-67)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2,4-dimethoxyphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 524 (M + 1) ⁺ , 526 (M + 1) ⁺ .
HPLC: Rt = 4.66 min.
Example 25 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (3,5-Dimethylphenyl) urea (Compound No. 1-69)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 5-fluoro-2-methylphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 496 (M + 1) ⁺ , 498 (M + 1) ⁺ .
HPLC: Rt = 5.02 min.

Example 26 1-tert-Butyl-3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazole -3-yl} phenyl) urea (Compound No. 1-71)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The reaction was carried out in the same manner as in Example 2 using isocyanate tert-butyl ester to obtain the title compound.
MS (APCI, m / z): 444 (M + 1) ⁺ , 446 (M + 1) ⁺ .
HPLC: Rt = 4.49 min.
Example 27 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (4-Trifluoromethoxyphenyl) urea (Compound No. 1-73)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and 4- (Trifluoromethoxy) phenyl isocyanate was used in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 548 (M + 1) ⁺ , 550 (M + 1) ⁺ .
HPLC: Rt = 5.40 min.
Example 28 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (4-Trifluoromethylphenyl) urea (Compound No. 1-75)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 4- (trifluoromethyl) phenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ .
HPLC: Rt = 5.36 min.
Example 29 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Trifluoromethylphenyl) urea (Compound No. 1-6)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2- (trifluoromethyl) phenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ .
HPLC: Rt = 5.03 min.
Example 30 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2,4-Difluorophenyl) urea (Compound No. 1-77)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2,4-difluorophenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 500 (M + 1) ⁺ , 502 (M + 1) ⁺ .
HPLC: Rt = 4.86 min.

Example 31 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (4-Isopropylphenyl) urea (Compound No. 1-79)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 4-isopropylphenyl isocyanate, the reaction was performed in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 506 (M + 1) ⁺ , 508 (M + 1) ⁺ .
HPLC: Rt = 5.49 min.
Example 32 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Fluorophenyl) urea (Compound No. 1-81)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2-fluorophenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 482 (M + 1) ⁺ , 484 (M + 1) ⁺ .
HPLC: Rt = 4.83 min.
Example 33 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Phenyl-cyclopropyl) urea (Compound No. 1-83)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was conducted in the same manner as in Example 2 using trans-2-phenylcyclopropyl isocyanate to obtain the title compound.
MS (APCI, m / z): 504 (M + 1) ⁺ , 506 (M + 1) ⁺ .
HPLC: Rt = 4.78 min.
Example 34 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Ethylurea (Compound No. 1-85)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using ethyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 416 (M + 1) ⁺ , 418 (M + 1) ⁺ .
HPLC: Rt = 3.95 min.
Example 35 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Hexylurea (Compound No. 1-38)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using isocyanic acid n-hexyl ester to obtain the title compound.
MS (APCI, m / z): 472 (M + 1) ⁺ , 474 (M + 1) ⁺ .
HPLC: Rt = 5.05 min.

Example 36 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (4-Methoxyphenyl) urea (Compound No. 1-87)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using 4-methoxyphenyl ester of isocyanate to obtain the title compound.
MS (APCI, m / z): 494 (M + 1) ⁺ , 496 (M + 1) ⁺ .
HPLC: Rt = 4.52 min.
Example 37 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Phenylurea (Compound No. 1-89)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using phenyl isocyanate to obtain the title compound.
MS (APCI, m / z): 464 (M + 1) ⁺ , 466 (M + 1) ⁺ .
HPLC: Rt = 4.52 min.
Example 38 1-Butyl-3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazole-3 -Il} phenyl) urea (Compound No. 1-91)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using n-butyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 444 (M + 1) ⁺ , 446 (M + 1) ⁺ .
HPLC: Rt = 4.44 min.
Example 39 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Methoxyphenyl) urea (Compound No. 1-93)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2-methoxyphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 494 (M + 1) ⁺ , 496 (M + 1) ⁺ .
HPLC: Rt = 4.88 min.
Example 40 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-((R) -1-Phenylethyl) urea (Compound No. 1-95)
Compound of Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using (R)-(+)-alpha-methylbenzyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 492 (M + 1) ⁺ , 494 (M + 1) ⁺ .
HPLC: Rt = 4.65 min.

Example 41 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Isopropylurea (Compound No. 1-97)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was performed in the same manner as in Example 2 using isopropyl isocyanate to obtain the title compound.
MS (APCI, m / z): 430 (M + 1) ⁺ , 432 (M + 1) ⁺ .
HPLC: Rt = 4.16 min.
Example 42 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2,6-Dimethylphenyl) urea (Compound No. 1-99)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using 2,6-dimethylphenyl isocyanate to obtain the title compound.
MS (APCI, m / z): 492 (M + 1) ⁺ , 494 (M + 1) ⁺ .
HPLC: Rt = 4.66 min.
Example 43 1-cyclohexyl-3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazole-3 -Il} phenyl) urea (Compound No. 1-101)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using cyclohexyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 470 (M + 1) ⁺ , 472 (M + 1) ⁺ .
HPLC: Rt = 4.71 min.
Example 44 1-Benzyl-3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazole-3 -Il} phenyl) urea (Compound No. 1-103)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using benzyl isocyanate to obtain the title compound.
MS (APCI, m / z): 478 (M + 1) ⁺ , 480 (M + 1) ⁺ .
HPLC: Rt = 4.52 min.
Example 45 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (3-Fluorophenyl) urea (Compound No. 1-105)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 3-fluorophenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 482 (M + 1) ⁺ , 484 (M + 1) ⁺ .
HPLC: Rt = 4.88 min.

Example 46 1- (2,3-Dichlorophenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2 , 4] Triazol-3-yl} phenyl) urea (Compound No. 1-107)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2,3-dichlorophenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ , 536 (M + 1) ⁺ .
HPLC: Rt = 5.52 min.
Example 47 1- (5-Chloro-2-methoxyphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [ 1,2,4] triazol-3-yl} phenyl) urea (Compound No. 1-109)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 5-chloro-2-methoxyphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 528 (M + 1) ⁺ , 530 (M + 1) ⁺ .
HPLC: Rt = 5.38 min.
Example 48 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Naphthalen-1-ylurea (Compound No. 1-111)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using isocyanic acid 1-naphthyl ester to obtain the title compound.
MS (APCI, m / z): 514 (M + 1) ⁺ , 516 (M + 1) ⁺ .
HPLC: Rt = 5.00 min.
Example 49 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-o-Tolylurea (Compound No. 1-5)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Reaction was carried out in the same manner as in Example 2 using isocyanic acid o-tolyl ester to obtain the title compound.
MS (APCI, m / z): 478 (M + 1) ⁺ , 480 (M + 1) ⁺ .
HPLC: Rt = 4.74 min.
Example 50 1- (3-Chlorophenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4 ] Triazol-3-yl} phenyl) urea (Compound No. 1-113)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The title compound was obtained in the same manner as in Example 2 except that 3-chlorophenyl isocyanate was used.
MS (APCI, m / z): 498 (M + 1) ⁺ , 500 (M + 1) ⁺ .
HPLC: Rt = 5.17 min.

Example 51 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Ethylphenyl) urea (Compound No. 1-115)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2-ethylphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 492 (M + 1) ⁺ , 494 (M + 1) ⁺ .
HPLC: Rt = 4.96 min.
Example 52 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (3-Methoxyphenyl) urea (Compound No. 1-117)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The title compound was obtained by reacting in the same manner as in Example 2 using 3-methoxyphenyl isocyanate.
MS (APCI, m / z): 494 (M + 1) ⁺ , 496 (M + 1) ⁺ .
HPLC: Rt = 4.60 min.
Example 53 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (2-Isopropylphenyl) urea (Compound No. 1-119)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2-isopropylphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 506 (M + 1) ⁺ , 508 (M + 1) ⁺ .
HPLC: Rt = 5.10 min.
Example 54 1-Benzo [1,3] dioxol-5-yl-3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] Triazol-3-yl} phenyl) urea (Compound No. 1-121)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 3,4- (methylenedioxy) phenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 508 (M + 1) ⁺ , 510 (M + 1) ⁺ .
HPLC: Rt = 4.52 min.
Example 55 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (3,5-Dimethyl-isoxazol-4-yl) urea (Compound No. 1-123)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The title compound was obtained in the same manner as in Example 2 using 3,5-dimethylisoxazol-4-yl isocyanate.
MS (APCI, m / z): 483 (M + 1) ⁺ , 485 (M + 1) ⁺ .
HPLC: Rt = 4.05 min.

Example 56 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-Thiophen-2-ylurea (Compound No. 1-125)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2-thienyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 470 (M + 1) ⁺ , 472 (M + 1) ⁺ .
HPLC: Rt = 4.57 min.
Example 57 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3-m-Tolylurea (Compound No. 1-127)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using the isocyanic acid m-tolyl ester, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 478 (M + 1) ⁺ , 480 (M + 1) ⁺ .
HPLC: Rt = 4.94 min.
Example 58 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl ) -3- (3-Trifluoromethylphenyl) urea (Compound No. 1-129)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The title compound was obtained in the same manner as in Example 2 using 3-isocyanate 3-trifluoromethylphenyl ester.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ .
HPLC: Rt = 5.33 min.
Example 59 1- (2-Chlorophenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4 ] Triazol-3-yl} phenyl) urea (Compound No. 1-131)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and The title compound was obtained in the same manner as in Example 2 using 2-isocyanate 2-chlorophenyl ester.
MS (APCI, m / z): 498 (M + 1) ⁺ , 500 (M + 1) ⁺ .
HPLC: Rt = 5.09 min.
Example 60 1- (2,6-Dichlorophenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2 , 4] Triazol-3-yl} phenyl) urea (Compound No. 1-133)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 2,6-dichlorophenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 532 (M + 1) ⁺ , 534 (M + 1) ⁺ , 536 (M + 1) ⁺ .
HPLC: Rt = 4.69 min.

Example 61 1- (4-Acetylphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2, 4] Triazol-3-yl} phenyl) urea (Compound No. 1-135)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 4-acetylphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 506 (M + 1) ⁺ , 508 (M + 1) ⁺ .
HPLC: Rt = 4.45 min.
Example 62 1- (4-Butoxyphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2, 4] Triazol-3-yl} phenyl) urea (Compound No. 1-137)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 4-n-butoxyphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 536 (M + 1) ⁺ , 538 (M + 1) ⁺ .
HPLC: Rt = 5.53 min.
Example 63 1- (4-Butylphenyl) -3- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2, 4] Triazol-3-yl} phenyl) urea (Compound No. 1-139)
Reference Example 13 Compound 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and Using 4-n-butylphenyl isocyanate, the reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 520 (M + 1) ⁺ , 522 (M + 1) ⁺ .
HPLC: Rt = 5.95 min.
Example 64 1- {4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenyl} -3- (2 -Methoxy-5-methylphenyl) urea (Compound No. 1-292)
Example 2 was prepared using 4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine of Reference Example 38. Reaction was performed in the same manner to obtain the title compound.
MS (APCI, m / z): 501 (M + 1) ⁺ , 503 (M + 1) ⁺ .
HPLC: Rt = 4.83 min.
Example 65 1- {4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenyl} -3- (2 -Fluorophenyl) urea (Compound No. 1-295)
Using the compound of Reference Example 38, 4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine and 2-fluorophenyl isocyanate In the same manner as in Example 2, the title compound was obtained.
MS (APCI, m / z): 475 (M + 1) ⁺ , 477 (M + 1) ⁺ .
HPLC: Rt = 4.53 min.

Example 66 1- {4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenyl} -3-isopropylurea (Compound No. 1-297)
Performed using compound 4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine and isopropyl isocyanate of Reference Example 38 The reaction was conducted in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 423 (M + 1) ⁺ , 425 (M + 1) ⁺ .
HPLC: Rt = 3.94 min.
Example 67 1- {4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenyl} -3-hexylurea (Compound No. 1-296)
Using the compound of Reference Example 38, 4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine and n-butyl isocyanate The reaction was carried out in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 465 (M + 1) ⁺ , 467 (M + 1) ⁺ .
HPLC: Rt = 4.75 min.
Example 68 1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-Fluorophenyl) urea (Compound No. 1-80)
Compound 4- {5- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and 2-fluorophenyl of Reference Example 20 A reaction was carried out in the same manner as in Example 2 using isocyanate to obtain the title compound.
MS (APCI, m / z): 484 (M + 1) ⁺ , 486 (M + 1) ⁺ .
HPLC: Rt = 4.46 min.
Example 69 1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- Isopropyl urea (Compound No. 1-96)
Using the compound of Reference Example 20 4- {5- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and isopropyl isocyanate In the same manner as in Example 2, the title compound was obtained.
MS (APCI, m / z): 432 (M + 1) ⁺ , 434 (M + 1) ⁺ .
HPLC: Rt = 3.88 min.
Example 70 1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- Hexylurea (Compound No. 1-37)
Compound of Reference Example 20 4- {5- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine and n-butyl isocyanate Was used in the same manner as in Example 2 to obtain the title compound.
MS (APCI, m / z): 474 (M + 1) ⁺ , 476 (M + 1) ⁺ .
HPLC: Rt = 4.62 min.

Example 71 N- (4- {5-[(E) -2- (2-trifluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-311)
Compound of Reference Example 48 3-[(E) -2- (2-trifluorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 80 mg (0.21 mmol) Dissolved in 5 ml of methanol, added with 230 mg (3.5 mmol) of zinc and stirred at room temperature, added 0.30 ml of acetic acid over 1 minute, and heated to reflux for 1 hour. The reaction mixture was filtered through celite, and the mother liquor was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate-tetrahydrofuran (10: 1), and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was finely pulverized and washed with a hexane-ethyl acetate mixed solvent. The obtained compound was dissolved in 3 ml of pyridine under nitrogen pressure, 0.07 ml (0.42 mmol) of 2-methoxy-5-methylphenyl isocyanate was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: ethanol = 10: 1) to obtain 28 mg (26%) of the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 9.59 (1H, s), 8.25 (1H, s), 8.21 (1H, d, J = 7.8 Hz), 7.98 (1H, d, J = 2.0Hz), 7.81-7.74 (4H, m), 7.64-7.61 (1H, m), 7.59-7.52 (1H, m), 7.40 (1H, d, J = 16.0Hz), 6.89 (1H, d, J = 8.3Hz), 6.75 (1H, d, J = 8.3Hz), 3.85 (3H, s), 3.78 (3H, s), 2.24 (3H, s)
Melting point 300 ° C or higher
MS (ESi) m / z: 508 (M + 1) ⁺
Example 72 N- (4- {5-[(E) -2- (2-chlorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N '-(2-Methoxy-5-methylphenyl) urea (Compound No. 1-313)
Compound of Reference Example 50 3-[(E) -2- (2-chlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 117 mg (0.34 The reaction was carried out in the same manner as in Example 71 to obtain 18 mg (11%) of the title compound.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 9.58 (1H, s), 8.25 (1H, s), 8.09 (1H, dd, J = 7.6 and 1.8Hz), 7.98 (1H, d, J = 2.0Hz), 7.95 (1H, d, J = 16.0Hz), 7.92 (1H, s), 7.67-7.61 (3H, m), 7.53 (1H, dd, J = 7.8 and 1.6Hz), 7.44- 7.36 (2H, m), 7.37 (1H, d, J = 16.0Hz), 6.90 (1H, d, J = 8.2Hz), 6.76 (1H, d, J = 8.6Hz), 3.85 (3H, s), 3.77 (3H, s), 2.24 (3H, s)
Melting point 224 ° C
MS (ESi) m / z: 474 (M + 1) ⁺
Example 73 N- (4- {5-[(E) -2- (2,4-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-315)
Compound of Reference Example 52 3-[(E) -2- (2,4-dichlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 70 mg (0.19 mmol) was used in the same manner as in Example 71 to obtain the title compound 14 mg (15%).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 9.58 (1H, s), 8.25 (1H, s), 8.13 (1H, d, J = 8.6 Hz), 7.98 (1H, d, J = 2.0Hz), 7.89 (1H, d, J = 16.1Hz), 7.71 (1H, d, J = 2.4Hz), 7.67-7.61 (4H, m), 7.53 (1H, dd, J = 8.7 and 2.0Hz) , 7.41 (1H, d, J = 16.1Hz), 6.90 (1H, d, J = 8.2Hz), 6.76 (1H, dd, J = 8.2 and 1.5Hz), 3.85 (3H, s), 3.77 (3H, s), 2.24 (3H, s)
Melting point 156 ° C
MS (ESi) m / z: 509 (M + 1) ⁺
Example 74 N- (4- {5-[(E) -2- (2,4-difluorophenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl } Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-317)
Compound 3-[(E) -2- (2,4-difluorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole of Reference Example 54 Reaction was carried out in the same manner as in Example 71 using 68 mg (0.20 mmol), and 11 mg (12%) of the title compound was obtained.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 9.58 (1H, s), 8.25 (1H, s), 8.10-8.04 (1H, m), 7.98 (1H, s), 7.68 (1H, d, J = 16.4Hz), 7.64-7.61 (3H, m), 7.38-7.31 (1H, m), 7.32 (1H, d, J = 16.4Hz), 7.22 (2H, dd, J = 8.8 and 2.5Hz ), 6.90 (1H, d, J = 8.2Hz), 6.76 (1H, d, J = 8.6Hz), 3.76 (3H, s), 2.24 (3H, s),
Melting point 123 ° C
MS (ESi) m / z: 476 (M + 1) ⁺
Example 75 N- (4- {5-[(E) -2- (2,4-dimethoxyphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl } Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-319)
Compound 3-[(E) -2- (2,4-dimethoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole of Reference Example 56 The reaction was conducted in the same manner as in Example 71 using 111 mg (0.30 mmol), and 21 mg (14%) of the title compound was obtained.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 9.56 (1H, s), 8.24 (1H, s), 7.98 (1H, d, J = 2.4Hz), 7.82 (1H, d, J = 16.5Hz), 7.76 (1H, d, J = 8.2Hz), 7.64-7.58 (4H, m), 7.06 (1H, d, J = 16.5Hz). 6.90 (1H, d, J = 8.2Hz), 6.76 (1H, dd, J = 8.2 and 2.0Hz), 6.67-6.58 (2H, m), 3.89 (3H, s), 3.85 (3H, s) 3 82 (3H, s), 2,24 (3H, s )
Melting point 300 ° C or higher
MS (ESi) m / z: 500 (M + 1) ⁺ .

Example 76 N- (4- {5-[(E) -2- (2,5-dimethoxyphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl } Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-321)
Compound 3-[(E) -2- (2,5-dimethoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole of Reference Example 58 Reaction was carried out in the same manner as in Example 71 using 88 mg (0.24 mmol), and 24 mg (21%) of the title compound was obtained.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 9.57 (1H, s), 8.25 (1H, s), 7.98 (1H, d, J = 2.0 Hz), 7.89 (1H, d, J = 16.4Hz), 7.66-7.60 (4H, m), 7.66-7.60 (4H, m), 7.43 (1H, d, J = 2.7Hz), 7.24 (1H, d, J = 16.0Hz), 7.01 (1H, d, J = 9.0Hz), 6.94 (1H, d, J = 3.2Hz), 6.90 (1H, d, J = 8.2Hz), 6.76 (1H, d, J = 9.4Hz), 3.85 (3H, s) , 3.83 (3H, s), 3.78 (3H, s), 3.75 (3H, s), 2.24 (3H, s)
Melting point 259 ° C
MS (ESi) m / z: 500 (M + 1) ⁺
Example 77 N- (4- {5-[(E) -2- (2-methoxyphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl ) -N '-(2-Methoxy-5-methylphenyl) urea (Compound No. 1-323)
56 mg of the compound of Reference Example 60 3-[(E) -2- (2-methoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 0.17 mmol) was used in the same manner as in Example 71 to obtain 11 mg (14%) of the title compound.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 9.29 (1H, s), 8.25 (1H, s), 7.97 (1H, s), 7.58 (2H, d, J = 8.2Hz), 7.49 (2H, d, J = 7.8Hz), 7.45 (1H, d, J = 8.2Hz), 7.30 (1H, t, J = 7.8H z), 7.24 (1H, s), 7.02 (1H, d, J = 16.1Hz), 6.96 (1H, t, J = 7.7Hz), 6.90 (1H, d, J = 8.2Hz), 6.73 (1H, d, J = 8.2Hz), 6.66 (1H, d, J = 8.2 Hz), 3.83 (3H, s), 3.64 (3H, s), 2.26 (3H, s)
Melting point 277 ° C
MS (ESi) m / z: 470 (M + 1) ⁺
Example 78 N- (4- {5-[(E) -2- (2-methylphenyl) vinyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl ) -N '-(2-Methoxy-5-methylphenyl) urea (Compound No. 1-325)
Compound of Reference Example 62 3-[(E) -2- (2-methylphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 99 mg ( 0.31 mmol) was used in the same manner as in Example 71 to obtain 15 mg (11%) of the title compound.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 9.57 (1H, s), 8.25 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J = 15.7Hz), 7.86 -7.84 (2H, m), 7.65-7.61 (4H, m), 7.28-7.25 (2H, m), 7.15 (1H, d, J = 15.7Hz), 6.90 (1H, d, J = 8.3Hz), 6.75 (1H, d, J = 8.3Hz), 3.85 (3H, s), 3.76 (3H, s), 2.43 (3H, s), 2.24 (3H, s)
Melting point 300 ° C or higher
MS (ESi) m / z: 454 (M + 1) ⁺
Example 79 N- (4- {5- [2- (2-trifluoromethyl-6-fluorophenyl) ethyl] -4-methyl-4H- [1,2,4] -triazol-3-yl } Phenyl) -N '-(2-methoxy-5-methylphenyl) urea (Compound No. 1-326)
Compound of Reference Example 64 3- [2- (2-trifluoromethyl-6-fluorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 130 mg (0.33 mmol) was used in the same manner as in Example 71 to obtain 8 mg (5%) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.13 (1H, s), 8.13 (1H, s), 7.95 (1H, s), 7.53 (2H, d, J = 8.6 Hz), 7.47 ( 1H, d, J = 7.8Hz), 7.43 (2H, d, J = 8.6Hz), 7.38-7.32 (1H, m), 7.26 (1H, d, J = 7.8Hz), 6.26 (1H, d, J = 8.2Hz), 6.71 (1H, d, J = 8.2Hz), 3.69 (3H, s), 3.57 (3H, s), 3.33 (2H, d, J = 9.0Hz), 3.07 (2H, d, J = 7.1Hz), 2.26 (3H, s)
Melting point 121 ° C
MS (ESi) m / z: 528 (M + 1) ⁺
Example 80 N- (4- {5- [2- (5-methoxy-2-methylphenyl) ethyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl ) -N '-(2-Methoxy-5-methylphenyl) urea (Compound No. 1-328)
Compound of Reference Example 66 3- [2- (5-methoxy-2-methylphenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 166 mg (0.47 mmol) was used in the same manner as in Example 71 to obtain 13 mg (6%) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.57 (1H, s), 8.37 (1H, s), 7.93 (1H, s), 7.57 (2H, d, J = 8.6 Hz), 7.37 ( 2H, d, J = 8.6Hz), 6.97 (1H, d, J = 8.2Hz), 6.75-6.64 (4H, m), 3.76 (3H, s), 3.63 (3H, s), 3.50 (3H, s ), 3.28 (3H, s), 3.06 (2H, d, J = 7.4Hz), 3.02 (2H, d, J = 7.4Hz), 2.23 (3H, s)
Melting point 118 ° C
MS (ESi) m / z: 486 (M + 1) ^<+> .

Example 81 N- (4- {5- [2- (2-fluorophenyl) ethyl] -4-methyl-4H- [1,2,4] -triazol-3-yl} phenyl) -N ′ -(2-Methoxy-5-methylphenyl) urea (Compound No. 1-330)
Using the compound of Reference Example 68, 3- [2- (2-fluorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole 139 mg (0.38 mmol) Then, the reaction was carried out in the same manner as in Example 71 to obtain 26 mg (15%) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.54 (1H, s), 8.33 (1H, s), 7.92 (1H, s), 7.53 (2H, d, J = 8.6 Hz), 7.36 ( 2H, d, J = 8.6Hz), 7.21-7.16 (1H, m), 7.13-7.10 (1H, m), 7.01 (1H, d, J = 7.5Hz), 6.98 (1H, d, J = 3.1Hz ), 6.72 (1H, d, J = 8.6Hz), 6.65 (1H, d, J = 8.2Hz), 3.62 (3H, s), 3.41 (3H, s), 3.11 (2H, d, J = 16.1Hz) ), 3.08 (2H, d, J = 2.3Hz), 2.22 (3H, s)
Melting point 116 ° C
MS (ESi) m / z: 460 (M + 1) ⁺
Example 82 1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl]-[1,3,4] thiadiazol-2-yl} phenyl) -3- (2 -Methoxy-5-methylphenyl) urea (Compound No. 3-24)
Compound of Reference Example 71 4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl]-[1,3,4] thiazol-2-yl} phenylamine and 2-methoxy-5-methyl Reaction was performed in the same manner as in Example 2 using phenyl isocyanate to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.85 (3H, s), 6.76 (1H, brd, J = 7.8 Hz), 6.90 (1H, d, J = 7.0Hz), 7.42 (1H, dd, J = 9.0 and 9.0Hz), 7.69-7.45 (6H, m), 8.03-7.90 (3H, m), 8.28 (1H, s), 9.69 (1H, s)
MS (APCI) m / z: 511, 513 (M + 1) ⁺ .
HPLC: Rt = 7.49 min.
Melting point: 245-247 ° C
Example 83 1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] thiazol-5-yl} phenyl) -3- (2-methoxy-5-methylphenyl) Urea (Compound No. 3-16)
Example using compound 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] thiazol-5-yl} phenylamine and 2-methoxy-5-methylphenyl isocyanate of Reference Example 74 Reaction was performed in the same manner as 2 to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.84 (3H, s), 6.75 (1H, d, J = 7.8 Hz), 6.89 (1H, d, J = 8.2Hz), 7.42-7.35 (2H, m), 7.47 (1H, d, J = 16.8Hz), 7.54 (2H, d, J = 8.6Hz), 7.57 (2H, d, J = 7.8Hz), 7.64 (2H, d, J = 8.6Hz), 7.98 (1H, brs), 8.23-8.20 (2H, m), 9.51 (1H, s)
MS (APCI) m / z: 510, 512 (M + 1) ⁺ .
HPLC: Rt = 7.95 min.
Melting point: 127-130 ℃
Example 84 1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2- Methoxy-5-methylphenyl) urea monohydrochloride (hydrochloride of compound number 3-8)
The compound of Reference Example 76, 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenylamine 34 mg (0.10 mmol) was added to 1.0 Dissolve in ml, add 0.022 ml (0.15 mmol) of 2-methoxy-5-methylphenyl isocyanate and stir at 50 ° C. for 3 hours, and then add 0.015 ml (0.10 mmol) of 2-methoxy-5-methylphenyl isocyanate and 50 Stir at 24 ° C. for 24 hours. Methanol was added to the reaction solution to terminate the reaction, and the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was filtered using a pad carrying a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 4.0 ml of tetrahydrofuran, 0.125 ml (0.50 mmol) of 4N hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was washed with an ethyl acetate-ethanol mixed solvent system to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.80 (3H, s), 3.84 (3H, s), 6.76 (1H, dd, J = 8.4 and 1.8 Hz) , 6.90 (1H, d, J = 8.2Hz), 7.41 (1H, d, J = 16.4Hz), 7.44 (1H, dd, J = 8.2 and 8.2Hz), 7.50 (2H, d, J = 9.0Hz) , 7.67-7.60 (4H, m), 7.76 (1H, d, J = 16.4Hz), 7.90 (1H, s), 7.97 (1H, d, J = 2.0Hz), 8.28 (1H, s), 9.69 ( 1H, s)
MS (APCI) m / z: 507, 509 (M + 1) ⁺ .
HPLC: Rt = 4.04 min.
Melting point: 208-213 ℃
Example 85 1- (5-Chloro-2-methoxyphenyl) -3- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazole -4-yl} phenyl) urea monohydrochloride (hydrochloride of compound number 3-7)
Compound 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenylamine and 5-chloro-2-methoxyphenyl of Reference Example 76 The title compound was obtained in the same manner as in Example 84 using isocyanate.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 3.80 (3H, s), 3.89 (3H, s), 6.99 (1H, dd, J = 8.6 and 2.4Hz), 7.04 (1H, d, J = 8.6Hz), 7.41 (1H, d, J = 16.4Hz), 7.44 (1H, dd, J = 8.2 and 8.2Hz), 7.52 (2H, d, J = 8.6Hz), 7.62 (2H, d, J = 8.2Hz), 7.65 (2H, d, J = 9.0Hz), 7.78 (1H, d, J = 16.9Hz), 7.92 (1H, s), 8.23 (1H, d, J = 2.7Hz), 8.54 (1H, s), 9.84 (1H, s)
MS (APCI) m / z: 527, 529 (M + 1) ⁺ .
HPLC: Rt = 4.17 min.
Melting point: 198-203 ° C.

Example 86 1- (4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2- Fluorophenyl) urea monohydrochloride (hydrochloride of compound number 3-5)
Compound 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenylamine and 2-fluorophenyl isocyanate of Reference Example 76 were used. In the same manner as in Example 84, the title compound was obtained.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 3.80 (3H, s), 7.06-6.99 (1H, m), 7.15 (1H, dd like, J = 7.6 and 7.6Hz), 7.24 (1H , ddd, J = 11.3, 8.2 and 1.5Hz), 7.41 (1H, d, J = 16.8Hz), 7.45 (1H, dd, J = 8.1 and 8.0Hz), 7.52 (2H, d, J = 9.0Hz) , 7.62 (2H, d, J = 8.2Hz), 7.66 (2H, d, J = 8.6Hz), 7.76 (1H, d, J = 16.8Hz), 7.92 (1H, s), 8.12 (1H, ddd, J = 8.2, 8.2 and 1.5Hz), 8.74 (1H, d, J = 2.7Hz), 9.59 (1H, s)
MS (APCI) m / z: 481, 483 (M + 1) ⁺ .
HPLC: Rt = 3.83 min.
Melting point: 208-212 ℃
Example 87 1- (4- {2- [2- (2,6-Dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-methoxy-5- Methylphenyl) urea monohydrochloride (hydrochloride of compound number 3-4)
Using the compound 4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenylamine and 2-methoxy-5-methylphenyl isocyanate of Reference Example 79 In the same manner as in Example 84, the title compound was obtained.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.41-3.29 (4H, m), 3.64 (3H, s), 3.84 (3H, s), 6.76 (1H, dd, J = 8.2 and 1.5Hz), 6.90 (1H, d, J = 8.2Hz), 7.35 (1H, dd, J = 8.6 and 7.8Hz), 7.42 (2H, d, J = 8.6Hz), 7.50 ( 2H, d, J = 7.8Hz), 7.64 (2H, d, J = 8.6Hz), 7.70 (1H, s), 7.96 (1H, d, J = 1.6Hz), 8.28 (1H, s), 9.71 ( 1H, s)
MS (APCI) m / z: 509, 511 (M + 1) ⁺ .
HPLC: Rt = 3.94 min.
Melting point: 159-161 ℃
Example 88 1- (5-Chloro-2-methoxyphenyl) -3- (4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl } Phenyl) urea monohydrochloride (hydrochloride of compound number 3-3)
Using the compound 4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenylamine and 5-chloro-2-methoxyphenyl isocyanate of Reference Example 79 In the same manner as in Example 84, the title compound was obtained.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 3.42-3.28 (4H, m), 3.64 (3H, s), 3.89 (3H, s), 6.99 (1H, dd, J = 8.6 and 2.3 Hz), 7.04 (1H, d, J = 9.0Hz), 7.35 (1H, dd, J = 8.7 and 7.4Hz), 7.44 (2H, d, J = 8.6Hz), 7.50 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 9.0Hz), 7.71 (1H, s), 8.22 (1H, d, J = 2.3Hz), 8.55 (1H, s), 9.88 (1H, s)
MS (APCI) m / z: 529, 531 (M + 1) ⁺ .
HPLC: Rt = 4.05 min.
Melting point: 159-162 ℃
Example 89 1- (4- {2- [2- (2,6-Dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenyl) -3- (2-fluorophenyl) urea 1 Hydrochloride (hydrochloride of Compound No. 3-1)
Example 84 using the compound 4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenylamine and 2-fluorophenyl isocyanate of Reference Example 79 To give the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 3.42-3.29 (4H, m), 3.64 (3H, s), 7.05-6.98 (1H, m), 7.14 (1H, dd, J = 7.6 and 7.6Hz), 7.24 (1H, ddd, J = 11.3, 8.2 and 1.2Hz), 7.35 (1H, dd, J = 8.0 and 8.0Hz), 7.44 (2H, d, J = 8.6Hz), 7.50 (2H , d, J = 7.8Hz), 7.65 (2H, d, J = 8.6Hz), 7.71 (1H, s), 8.11 (1H, ddd, J = 8.2, 8.2 and 1.2Hz), 8.78 (1H, d, J = 2.3Hz), 9.72 (1H, s)
MS (APCI) m / z: 483, 485 (M + 1) ⁺ .
HPLC: Rt = 3.72 min.
Melting point: 199-204 ℃
Example 90 1- (6- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridine -3-yl) -3- (2-methoxy-5-methylphenyl) urea (Compound No. 2-15)
The compound of Reference Example 83 6- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridine-3- Reaction was carried out in the same manner as in Example 2 using ylamine and 2-methoxy-5-methylphenyl isocyanate to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.85 (3H, s), 4.04 (3H, s), 6.77 (1H, dd, J = 8.9 and 1.8 Hz) , 6.91 (1H, d, J = 8.2Hz), 7.25 (1H, d, J = 16.4Hz), 7.39 (1H, dd, J = 8.0 and 8.0Hz), 7.59 (2H, d, J = 8.2Hz) , 7.67 (1H, d, J = 16.4Hz), 7.98 (1H, brs), 8.09 (1H, d, J = 8.6Hz), 8.14 (1H, dd, J = 8.6 and 2.7Hz), 8.37 (1H, d, J = 1.9Hz), 8.72 (1H, d, J = 2.4Hz), 9.77 (1H, d, J = 3.1Hz)
MS (APCI) m / z: 509, 511 (M + 1) ⁺ .
HPLC: Rt = 5.30 min.
Melting point:> 300 ° C.

Example 91 1- (6- {5- [2- (2,6-Dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-yl ) -3- (2-Methoxy-5-methylphenyl) urea (Compound No. 2-1)
Compound 6- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-ylamine of Reference Example 85 and 2- Reaction was performed in the same manner as in Example 2 using methoxy-5-methylphenyl isocyanate to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.03 (2H, t, J = 7.8 Hz), 3.36-3.28 (2H, m), 3.85 (3H, s) , 3.91 (3H, s), 6.77 (1H, dd, J = 8.2 and 1.6Hz), 6.91 (1H, d, J = 7.8Hz), 7.31 (1H, dd, J = 8.2 and 8.2Hz), 7.48 ( 2H, d, J = 7.8Hz), 7.97 (1H, brs), 8.01 (1H, d, J = 8.6Hz), 8.10 (1H, dd, J = 8.8 and 2.5Hz), 8.34 (1H, s), 8.70 (1H, d, J = 2.3Hz), 9.71 (1H, brs)
MS (APCI) m / z: 511, 513 (M + 1) ⁺ .
HPLC: Rt = 5.00 min.
Melting point:> 300 ℃
Example 92 1- (2-Methoxy-5-methylphenyl) -3- (6- {4-methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2,4] Triazol-3-yl} pyridin-3-yl) urea (Compound No. 2-64)
The compound of Reference Example 90 6- {4-methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2,4] triazol-3-yl} pyridine-3 Using 2-ylamine and 2-methoxy-5-methylphenyl isocyanate, a reaction was carried out in the same manner as in Example 2 to obtain the title compound.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.24 (3H, s), 3.35-3.24 (2H, m), 3.45 (2H, t, J = 7.6 Hz), 3.85 (3H, s) , 3.93 (3H, s), 6.77 (1H, brd, J = 7.4Hz), 6.91 (1H, d, J = 8.2Hz), 7.52-7.48 (1H, m), 8.01-7.96 (2H, m), 8.09 (1H, dd, J = 8.6 and 2.7Hz), 8.15 (1H, dd, J = 8.0 and 1.0Hz), 8.34 (1H, s), 8.70 (1H, d, J = 2.7Hz), 8.80 (1H , d, J = 4.7Hz), 9.70 (1H, brs)
MS (APCI) m / z: 512 (M + 1) ⁺ .
HPLC: Rt = 4.13 min.
Melting point: 201-205 ° C.

(Reference Example 1) 4-[(Naphthalene-1-carbonyl) amino] benzoic acid ethyl ester
4-aminobenzoic acid ethyl ester (9.53 g, 50.0 mmol) was dissolved in N, N-dimethylacetamide (100 ml), 1-naphthoyl chloride (7.84 ml, 60.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 1 ml of ylchloride was further added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid (about 5%), saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with a mixed solvent of hexane-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 320 (M + 1) ⁺ .
HPLC: Rt = 5.16 min.
Reference Example 2 Naphthalene-1-carboxylic acid (4-hydrazinocarbonylphenyl) amide 17.1 g of 4-[(naphthalene-1-carbonyl) amino] benzoic acid ethyl ester obtained in Reference Example 1 was mixed with 50 ml of ethanol. It was dissolved in 50 ml of hydrazine monohydrate and heated to reflux for 16 hours. The title compound was obtained by washing the crystals obtained by concentrating the solvent under reduced pressure with hexane.
MS (APCI, m / z): 306 (M + 1) ⁺ .
HPLC: Rt = 3.39 min.
Reference Example 3 2- [5- (6-Aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzonitrile Reference Example 45 compounds of 5- (6-aminopyridin-3-yl) -4-methyl-2,4-dihydro- [1,2,4] triazole-3-thione and the compound of Reference Example 6 2-bromomethyl-3- Reaction was carried out in the same manner as in Reference Example 5 using chlorobenzonitrile to obtain the title compound.
MS (APCI, m / z): 357 (M + 1) ⁺ , 359 (M + 1) ⁺ .
HPLC: Rt = 2.60 min.
(Reference Example 4) 3- (2-Bromo-6-chlorophenyl) propionic acid Sodium hydride (55% or more, oily) 2.47 g (54.4 mmol) was suspended in 200 ml of dry tetrahydrofuran under a nitrogen stream and cooled in an ice bath. did. Diethyl malonate (8.25 ml, 54.4 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled again in an ice bath, and a solution of 12.9 g (45.3 mmol) of 1-bromo-2- (bromomethyl) -3-chlorobenzene in 50 ml of dry tetrahydrofuran was added dropwise over 10 minutes. After stirring at room temperature for 1.5 hours, the mixture was cooled in an ice bath, water was added, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 5% aqueous tartaric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of ethanol, a solution obtained by dissolving 7.25 g (181 mmol) of sodium hydroxide in 100 ml of water was added, and the mixture was heated to reflux for 1 hour. After cooling to room temperature, about 1000 ml of water was added and washed with ethyl ether. Hydrochloric acid was added to the water bath to PH = 1.0, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in 200 ml of xylene and heated to reflux for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was finely pulverized and washed with a hexane-ethyl ether mixed solvent to obtain the title compound.
1H-NMR (CDCl3) δ (ppm) = 7.48 (dd, 1H, J = 7.8 Hz, 1.1Hz), 7.33 (dd, 1H, J = 7.8 Hz, 1.1Hz), 7.03 (t, 1H, J = 8.1 Hz), 3.32 (t, 2H, J = 8.4 Hz), 2.65 (t, 2H, J = 8.4 Hz).
Reference Example 5 4- [5- (2,6-dichlorobenzylsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine
5- (4-aminophenyl) -4-methyl-2,4-dihydro [1,2,4] triazole-3-thione (synthesized with reference to Bioorg. Med. Chem. Lett. 11 (2001) 1703-1707) 1.02 g (4.94 mmol) was dissolved in 20 ml of ethanol and 5.44 ml of 1N aqueous sodium hydroxide solution. A solution of 1.19 g (4.94 mmol) of 2,6-dichlorobenzyl bromide in 10 ml of ethanol was added dropwise over 5 minutes, followed by stirring at room temperature for 18 hours. About 100 ml of water was added, filtered and dried to obtain the title compound.
MS (APCI, m / z): 365 (M + 1) ⁺ , 367 (M + 1) ⁺ .
HPLC: Rt = 3.85 min.

Reference Example 6 2-Bromomethyl-3-chlorobenzonitrile
Dissolve 1.51 g (10.0 mmol) of 3-chloro-2-methylbenzonitrile in 50 ml of carbon tetrachloride, add 1.87 g (10.5 mmol) of N-bromosuccinimide and about 30 mg of 2,2'-azobisisobutyronitrile. (0.183 mmol) was added and the mixture was heated to reflux for 2.5 hours under the irradiation of a Stanley infrared bulb (100-110 V, 375 W). The reaction mixture was cooled to room temperature and filtered through celite. The mother liquor was concentrated under reduced pressure to obtain the title compound. It was used for the next reaction without further purification.
1H-NMR (CDCl3) δ: 7.51 (dd, 1H, J = 8.1Hz, 1.1Hz), 7.37 (dd, 1H, J = 8.1Hz, 1.1Hz), 7.10 (t, 1H, J = 7.8Hz), 4.80 (s, 2H).
Reference Example 7 2- [5- (4-Aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzonitrile Compound 2 of Reference Example 6 Using -bromomethyl-3-chlorobenzonitrile, the reaction was carried out in the same manner as in Reference Example 5 to obtain the title compound.
MS (APCI, m / z): 356 (M + 1) ⁺ , 358 (M + 1) ⁺ .
HPLC: Rt = 3.37 min.
(Reference Example 8) (2,6-Dichlorophenyl) acetoacetic acid hydrazide Methyl-2,6-dichlorophenylacetate was used in the same manner as in Reference Example 2 to obtain the title compound.
MS (APCI, m / z): 219 (M + 1) ⁺ , 221 (M + 1) ⁺ .
HPLC: Rt = 2.73 min.
Reference Example 9 3- (2,6-dichlorobenzyl) -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole
N-methyl-4-nitrobenzimidoyl chloride (synthesized according to J. Org. Chem .; EN; 49, 3; 1984, 546-547.) 254 mg (1.28 mmol) and the compound of Reference Example 8 ( 2,6-Dichlorophenyl) acetoacetic acid hydrazide 255 mg (1.16 mmol) was suspended in 10 ml of toluene, 1 ml of triethylamine was added, and the mixture was heated to reflux for 3 days under nitrogen pressure. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate), and the obtained crystal was finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain the title compound.
1H-NMR (DMSO-d6) δ (ppm) = 8.38 (d, 2H, J = 8.9Hz), 8.04 (d, 2H, J = 8.9Hz), 7.54 (dd, 2H, J = 8.6Hz, 1.1Hz ), 7.40 (dd, 1H, J = 8.9Hz, 7.3Hz), 4.41 (s, 2H), 3.82 (s, 3H).
MS (APCI, m / z): 363 (M + 1) ⁺ , 365 (M + 1) ⁺ .
HPLC: Rt = 4.16 min.
Reference Example 10 3- [2- (2-Bromo-6-chlorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole Compound of Reference Example 4 Dissolve 6.00 g (22.8 mmol) of 3- (2-bromo-6-chlorophenyl) propionic acid in 100 ml of anhydrous dichloromethane and cool with ice under nitrogen pressure to 5.54 g (34.2 mmol) of 1,1'-carbonylbis-1H-imidazole And stirred at room temperature for 30 minutes. To this reaction solution, 100 ml of dichloromethane and 20 ml of hydrazine monohydrate were added dropwise over 5 minutes while stirring with ice cooling. The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with a mixed solvent of hexane-ethyl acetate. The obtained crystals and N-methyl-4-nitrobenzimidoyl chloride ( J.Org.Chem .; synthesized according to EN; 49, 3; 1984, 546-547.) Refluxed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate) to obtain the title compound.
MS (APCI, m / z): 421 (M + 1) ⁺ , 423 (M + 1) ⁺ .
HPLC: Rt = 4.51 min.

Reference Example 11 (E) -3- (2,6-dichlorophenyl) acrylic hydrazide
(E) -3- (2,6-Dichlorophenyl) acrylic acid (1.00 g, 4.61 mmol) was dissolved in anhydrous dichloromethane (10 ml) and 1,1'-carbonylbis-1H-imidazole (747 mg, 4.61 mmol) at room temperature under nitrogen pressure. ) Was added and stirred for 30 minutes. To this reaction solution, 10 ml of dichloromethane and 4 ml of hydrazine monohydrate were added dropwise over 3 minutes while stirring at room temperature. The mixture was then stirred for 30 minutes, diluted with dichloromethane and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting crystals were finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain the title compound.
MS (APCI, m / z): 231 (M + 1) ⁺ , 233 (M + 1) ⁺ .
HPLC: Rt = 3.24 min.
Reference Example 12 3-[(E) -2- (2,6-Dichlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole Reference Example Using the 11 compound (E) -3- (2,6-dichlorophenyl) acrylic hydrazide, the reaction was carried out in the same manner as in Reference Example 9 to obtain the title compound.
1H-NMR (DMSO-d6) δ (ppm) = 8.41 (d, 2H, J = 8.9Hz), 8.07 (d, 2H, J = 8.9Hz), 7.69 (d, 1H, J = 16.5Hz), 7.60 (d, 2H, J = 7.8Hz), 7.41 (t, 1H, J = 7.6Hz), 7.26 (d, 1H, J = 16.5Hz), 3.79 (s, 3H).
MS (APCI, m / z): 375 (M + 1) ⁺ , 377 (M + 1) ⁺ .
HPLC: Rt = 4.68 min.
Reference Example 13 4- {5-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine Reference Compound of Example 12 3-[(E) -2- (2,6-dichlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole 2.40 g ( 6.40 mmol) Dissolved in 150 ml of methanol, added 6.69 g (102 mmol) of zinc, stirred at room temperature, added 6 ml of acetic acid over 1 minute, and heated to reflux for 1 hour. The reaction mixture was filtered through celite, and the mother liquor was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate-tetrahydrofuran (10: 1), and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain the title compound.
MS (APCI, m / z): 345 (M + 1) ⁺ , 347 (M + 1) ⁺ .
HPLC: Rt = 3.73 min.
Reference Example 14 3-Chloro-2- {2- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-yl] ethyl} benzonitrile Reference Example 10 Using Reference Example 27 and 3- [2- (2-bromo-6-chlorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole The reaction was carried out in the same manner to obtain the title compound.
MS (APCI, m / z): 368 (M + 1) ⁺ , 370 (M + 1) ⁺ .
HPLC: Rt = 4.00 min.
Reference Example 15 2- [5- (4-Aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid Compound 2 of Reference Example 7 -[5- (4-Aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzonitrile 10.0 g (28.1 mmol) in acetic acid 50 ml, water The mixture was dissolved in 50 ml and 50 ml of concentrated sulfuric acid and stirred at 110 ° C. for 2 days. The reaction mixture was concentrated under reduced pressure, the residue was ice-cooled, and 10% aqueous sodium hydroxide solution was added until PH = 6.0. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting crystals were finely pulverized and washed with a mixed solvent of isopropyl ether and ethanol to obtain the title compound.
MS (APCI, m / z): 375 (M + 1) ⁺ , 377 (M + 1) ⁺ .
HPLC: Rt = 3.29 min.

Reference Example 16 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzonitrile Reference Example 14 Reference Example Using Compound 3-Chloro-2- {2- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-yl] ethyl} benzonitrile The reaction was carried out in the same manner as in 13 to obtain the title compound.
MS (APCI, m / z): 338 (M + 1) ⁺ , 340 (M + 1) ⁺ .
HPLC: Rt = 3.23 min.
Reference Example 17 2- [5- (6-Aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid Reference Example Using 3 compounds 2- [5- (6-aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzonitrile The reaction was carried out in the same manner as in Reference Example 15 to obtain the title compound.
MS (APCI, m / z): 376 (M + 1) ⁺ , 378 (M + 1) ⁺ .
HPLC: Rt = 2.65 min.
Reference Example 18 3- (2,6-Dichlorophenyl) -propionic acid hydrazide
The title compound was obtained in the same manner as in Reference Example 11 using 3- (2,6-dichlorophenyl) -propionic acid.
MS (APCI, m / z): 233 (M + 1) ⁺ , 235 (M + 1) ⁺ .
HPLC: Rt = 2.89 min.
Reference Example 19 3- [2- (2,6-Dichlorophenyl) -ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole Compound 3 of Reference Example 18 Using-(2,6-dichlorophenyl) -propionic acid hydrazide, the reaction was carried out in the same manner as in Reference Example 9 to obtain the title compound.
MS (APCI, m / z): 377 (M + 1) ⁺ , 379 (M + 1) ⁺ .
HPLC: Rt = 4.41 min.
Reference Example 20 4- {5- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenylamine Compound of Reference Example 19 Reaction similar to Reference Example 13 using 3- [2- (2,6-dichlorophenyl) -ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole To obtain the title compound.
MS (APCI, m / z): 347 (M + 1) ⁺ , 349 (M + 1) ⁺ .
HPLC: Rt = 3.46 min.

Reference Example 21 2-Bromo-6-chlorobenzaldehyde
2,2,6,6-Tetramethylpiperidine (26.3 ml, 156 mmol) was dissolved in dry tetrahydrofuran (400 ml) under nitrogen pressure. After cooling the reaction to −78 ° C., 100 ml (156 mmol) of n-butyllithium / n-hexane solution (1.56M) was added dropwise over 15 minutes. After stirring at −78 ° C. for 15 minutes, 18.3 ml (156 mmol) of 1-bromo-3-chlorobenzene was added dropwise over 5 minutes and then stirred for 2 hours. 19.1 ml (172 mmol) of 1-formylpiperidine was added dropwise over 10 minutes, followed by stirring for 30 minutes. Thereafter, the temperature was slowly raised to room temperature. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with 5% aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with hexane to obtain the title compound.
1H-NMR (CDCl3) δ (ppm) = 10.38 (s, 1H), 7.60 (dd, 1H, J = 8.1Hz, 1.1Hz), 7.44 (dd, 1H, J = 8.1Hz, 1.1Hz), 7.31 ( t, 1H, J = 7.8Hz).
(Reference Example 22) (E) -3- (2-Bromo-6-chlorophenyl) acrylic acid 4.47 g (103 mmol) of sodium hydride (55% or more, oily) was suspended in 100 ml of dry tetrahydrofuran under a nitrogen stream. Cooled in an ice bath. Ethyl diethylphosphonoacetate (20.3 ml, 103 mmol) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled again in an ice bath, and a solution of the compound 2-bromo-6-chlorobenzaldehyde of Reference Example 21 (15.0 g, 68.3 mmol) in 100 ml of dry tetrahydrofuran was added dropwise over 20 minutes. After stirring at room temperature for 15 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in 300 ml of ethanol, a solution of 8.20 g (205 mmol) of sodium hydroxide in 80 ml of water was added, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, about 1000 ml of water was added and washed with ethyl ether. Hydrochloric acid was added to the water bath to PH = 1.0, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with a hexane-ethyl ether mixed solvent to obtain the title compound.
1H-NMR (CDCl3) δ (ppm) = 7.84 (d, 1H, J = 16.2Hz), 7.56 (d, 1H, J = 7.6Hz), 7.28 (d, 1H, J = 7.6Hz), 7.13 (t , 1H, J = 7.8Hz), 6.54 (d, 1H, J = 16.2Hz), 2.74 (brs, 1H).
(Reference Example 23) (E) -3- (2-Bromo-6-chlorophenyl) acrylic acid hydrazide Reference was made using the compound (E) -3- (2-bromo-6-chlorophenyl) acrylic acid of Reference Example 22. The reaction was conducted in the same manner as in Example 11 to obtain the title compound.
1H-NMR (DMSO-d6) δ: 9.54 (s, 1H), 7.70 (d, 1H, J = 8.1Hz), 7.58 (d, 1H, J = 7.8Hz), 7.38 (d, 1H, J = 15.9 Hz), 7.29 (t, 1H, J = 7.8Hz), 6.49 (d, 1H, J = 15.9Hz), 4.52 (brs, 2H).
Reference Example 24 3-[(E) -2- (2-Bromo-6-chlorophenyl) vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole The title compound was obtained in the same manner as in Reference Example 9 using Compound (E) -3- (2-bromo-6-chlorophenyl) acrylic acid hydrazide of Reference Example 23.
1H-NMR (DMSO-d6) δ (ppm) = 8.40 (d, 2H, J = 8.9Hz), 8.06 (d, 2H, J = 8.9Hz), 7.76 (dd, 1H, J = 8.1Hz, 1.1Hz ), 7.64 (dd, 1H, J = 8.1Hz, 1.1Hz), 7.63 (d, 1H, J = 16.5Hz), 7.33 (t, 1H, J = 8.1Hz), 7.19 (d, 1H, J = 16.5 Hz), 3.80 (s, 3H).
MS (APCI, m / z): 419 (M + 1) ⁺ , 421 (M + 1) ⁺ .
HPLC: Rt = 4.73 min.
Reference Example 25 2- [5- (6-Aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid methyl ester Use of the compound 2- [5- (6-aminopyridin-3-yl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid of Reference Example 17 Then, the reaction was carried out in the same manner as in Reference Example 31 to obtain the title compound.
MS (APCI, m / z): 390 (M + 1) ⁺ , 392 (M + 1) ⁺ .
HPLC: Rt = 2.76 min.

Reference Example 26 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzoic acid Reference Example 16 Reference example using 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzonitrile The reaction was carried out in the same manner as in 15 to give the title compound.
MS (APCI, m / z): 357 (M + 1) ⁺ , 359 (M + 1) ⁺ .
HPLC: Rt = 3.11 min.
Reference Example 27 3-Chloro-2- {2- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-yl] vinyl} benzonitrile Reference Example 24 Compound 3-[(E) -2- (2-bromo-6-chlorophenyl) vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazole 13.2 g ( 31.4 mmol) was dissolved in 100 ml of N, N-dimethylformamide under nitrogen pressure, 3.10 g (34.6 mmol) of copper (I) cyanide was added, and the mixture was heated and stirred at 160 ° C. for 20 hours. After cooling to room temperature, about 1500 ml of water was added, filtered and dried to obtain the title compound.
MS (APCI, m / z): 366 (M + 1) ⁺ , 368 (M + 1) ⁺ .
HPLC: Rt = 4.08 min.
Reference Example 28 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzonitrile Reference Example 27 Reference Example Using Compound 3-Chloro-2- {2- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-yl] vinyl} benzonitrile The reaction was carried out in the same manner as in 13 to obtain the title compound.
MS (APCI, m / z): 336 (M + 1) ⁺ , 338 (M + 1) ⁺ .
HPLC: Rt = 3.40 min.
Reference Example 29 4-Chloro-3- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-ylmethyl] -3H-isobenzofuran-1-one Reference Using the compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzonitrile of Example 28 The reaction was carried out in the same manner as in Reference Example 15 to obtain the title compound.
MS (APCI, m / z): 385 (M + 1) ⁺ , 387 (M + 1) ⁺ .
HPLC: Rt = 3.61 min.
Reference Example 30 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzonitrile Reference Example 29 Using the compound 4-chloro-3- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-ylmethyl] -3H-isobenzofuran-1-one The reaction was carried out in the same manner as in Reference Example 13 to obtain the title compound.
MS (APCI, m / z): 355 (M + 1) ⁺ , 357 (M + 1) ⁺ .
HPLC: Rt = 2.81 min.

Reference Example 31 2- [5- (4-Aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid methyl ester of Reference Example 15 Compound 2. [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-ylsulfanylmethyl] -3-chlorobenzoic acid 6.20 g (16.5 mmol) under nitrogen flow It was dissolved in 150 ml of methanol and cooled on ice. After thionyl chloride (6.03 ml, 82.7 mmol) was added dropwise over 15 minutes, the mixture was heated to reflux for 4 days. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with a mixed solvent of isopropyl ether-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 389 (M + 1) ⁺ , 357 (M + 1) ⁺ .
HPLC: Rt = 3.72 min.
Reference Example 32 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzoic acid methyl ester Reference Using the compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] ethyl} -3-chlorobenzoic acid of Example 26 The reaction was carried out in the same manner as in Reference Example 31 to obtain the title compound.
MS (APCI, m / z): 371 (M + 1) ⁺ , 372 (M + 1) ⁺ .
HPLC: Rt = 3.51 min.
Reference Example 33 4- [4-Methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazol-3-yl] -phenylamine
5- (4-aminophenyl) -4-methyl-2,4-dihydro [1,2,4] triazole-3-thione (synthesized with reference to Bioorg. Med. Chem. Lett. 11 (2001) 1703-1707) 206 mg (1.00 mmol) was dissolved in 4 ml of ethanol and 1.00 ml of 1N sodium hydroxide aqueous solution. A solution of 3- (chloromethyl) pyridine hydrochloride (164 mg, 1.00 mmol) in ethanol (3 ml) was added dropwise over 3 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Used in the next reaction without further purification.
MS (APCI, m / z): 298 (M + 1) ⁺ .
HPLC: Rt = 1.95 min.
Reference Example 34 5- [4-Methyl-5- (pyridin-2-ylmethylsulfanyl) -4H- [1,2,4] triazol-3-yl] -pyridin-2-ylamine Compound of Reference Example 45 5- (6-Aminopyridin-3-yl) -4-methyl-2,4-dihydro- [1,2,4] triazole-3-thione was used in the same manner as in Reference Example 33, and the notation A compound was obtained.
MS (APCI, m / z): 299 (M + 1) ⁺ .
HPLC: Rt = 0.73 min.
Reference Example 35 (7-chloroindol-1-yl) acetoacetic acid ethyl ester Turbid and cooled in an ice bath. 7-Chloroindole 300 mg (1.98 mmol) was added in small portions and stirred at room temperature for 30 minutes. Ethyl chloroacetate 0.21 ml (2.38 mmol) was added dropwise over 3 minutes. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound.
MS (APCI, m / z): 238 (M + 1) ⁺ , 240 (M + 1) ⁺ .
HPLC: Rt = 5.28 min.

(Reference Example 36) (7-Chloroindol-1-yl) acetoacetic acid hydrazide Using the compound of Reference Example 35 (7-chloroindol-1-yl) acetoacetic acid ethyl ester, the reaction was carried out in the same manner as in Reference Example 2. The title compound was obtained.
MS (APCI, m / z): 224 (M + 1) ⁺ , 226 (M + 1) ⁺ .
HPLC: Rt = 2.97 min.
Reference Example 37 7-chloro-1- [4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-ylmethyl] -1H-indole Compound of Reference Example 36 ( 7-Chloroindol-1-yl) acetoacetic acid hydrazide was used in the same manner as in Reference Example 9 to obtain the title compound.
MS (APCI, m / z): 368 (M + 1) ⁺ , 370 (M + 1) ⁺ .
HPLC: Rt = 4.25 min.
Reference Example 38 4- [5- (7-chloroindol-1-ylmethyl) -4-methyl-4H- [1,2,4] triazol-3-yl] phenylamine Compound 7-chloro of Reference Example 37 -1- [4-Methyl-5- (4-nitrophenyl) -4H- [1,2,4] triazol-3-ylmethyl] -1H-indole was used for the reaction as in Reference Example 13, The title compound was obtained.
MS (APCI, m / z): 338 (M + 1) ⁺ , 340 (M + 1) ⁺ .
HPLC: Rt = 4.76 min.
Reference Example 39 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid Reference Example 30 Compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzonitrile 1.78 g (5.03 mmol) Was dissolved in a mixed solvent of 20 ml of methanol and 20 ml of 1,4-dioxane, 2.87 ml of sodium methoxide (28% methanol solution) was added, and the mixture was heated to reflux for 1 hour. Sodium methoxide (28% methanol solution) 2.87 ml was added once more, and the mixture was heated to reflux for 2 hours. The reaction solution was cooled in an ice bath, and 1N aqueous hydrochloric acid solution was added until PH = 7.0. Toluene was added to the reaction solution and concentrated under reduced pressure. Methanol was added to the resulting residue, and the salt was removed by filtration. The mother liquor was concentrated under reduced pressure, and the residue was used in the next reaction without purification.
MS (APCI, m / z): 355 (M + 1) ⁺ , 357 (M + 1) ⁺ .
HPLC: Rt = 3.21 min.
Reference Example 40 2- {2- [5- (4-Aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid methyl ester Reference Using the compound 2- {2- [5- (4-aminophenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] vinyl} -3-chlorobenzoic acid of Example 39 The reaction was carried out in the same manner as in Reference Example 31 to obtain the title compound.
MS (APCI, m / z): 369 (M + 1) ⁺ , 371 (M + 1) ⁺ .
HPLC: Rt = 3.47 min.

Reference Example 41 3- (2,6-Dichlorophenyl) -N-methylpropanamide
1.50 g (6.85 mmol) of 3- (2,6-dichlorophenyl) propionic acid was dissolved in 20 ml of dry dichloromethane, and 1.67 g (10.3 mmol) of 1,1′-carbonylbis-1H-imidazole was added and stirred for 30 minutes. To this reaction solution, 2.0 ml of methylamine (40% -methanol solution) was added and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was finely pulverized and washed with an isopropanol-ethyl acetate mixed solvent to obtain the title compound.
MS (APCI, m / z): 232 (M + 1) ⁺ , 234 (M + 1) ⁺ .
HPLC: Rt = 3.79 min.
(Reference Example 42) 4- [3- (2-Methoxy-5-methylphenyl) -ureido] nicotinic acid methyl ester 200 mg (1.31 mmol) of methyl-6-aminonicotinate was dissolved in 2 ml of pyridine under nitrogen pressure. Then, 0.289 ml (1.97 mmol) of 2-methoxy-5-methylphenyl isocyanate was added and stirred at 70 ° C. for 2 hours. When the reaction solution was diluted with water, crystals were precipitated and filtered to obtain the title compound.
MS (APCI, m / z): 316 (M + 1) ⁺ .
HPLC: Rt = 4.88 min.
Reference Example 43 1- (4-hydrazinocarbonyl-pyridin-2-yl) -3- (2-methoxy-5-methylphenyl) urea Compound 4- [3- (2-methoxy-5) of Reference Example 42 -Methylphenyl l) -ureido] nicotinic acid methyl ester was used in the same manner as in Reference Example 11 to obtain the title compound.
1H-NMR (DMSO-d6) δ (ppm) = 11.06 (brs, 1H), 10,08 (brs, 1H), 9,81 (brs, 1H), 8.74 (d, 1H, J = 1.9Hz), 8.13 (dd, 1H, J = 8.6Hz, 2.4Hz), 8.06 (d, 1H, J = 1.9Hz), 7.35 (d, 1H, J = 9.2Hz), 6.92 (d, 1H, J = 8.4Hz) , 6.80 (dd, 1H, J = 8.1Hz, 1.6Hz), 4.50 (brs, 2H), 3.90 (s, 3H), 2.25 (s, 3H).
(Reference Example 44) 6-benzoylaminonicotinic acid methyl ester 5.00 g (29.0 mmol) of methyl-6-aminonicotinate was dissolved in 60 ml of pyridine under nitrogen pressure, and 4.19 ml (36.1 mmol) of benzoyl chloride was added for 16 hours at room temperature Stir. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water, 5% -tartaric acid aqueous solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was finely pulverized and washed with isopropyl ether to obtain the title compound.
MS (APCI, m / z): 257 (M + 1) ⁺ .
HPLC: Rt = 4.15 min.
Reference Example 45 5- (6-Aminopyridin-3-yl) -4-methyl-2,4-dihydro- [1,2,4] triazole-3-thione Compound 6- obtained in Reference Example 44 7.43 g (29.0 mmol) of benzoylaminonicotinic acid methyl ester was dissolved in 100 ml of ethanol and 100 ml of hydrazine monohydrate, and heated to reflux for 1 hour. The solvent was concentrated under reduced pressure, and the resulting crystals were washed with hexane. This was dissolved in 100 ml of N, N-acetamide, 2.98 ml (43.5 mmol) of methyl isothiocyanate was added, and the mixture was stirred with heating at 80 ° C. for 1 hour. Further, 1.00 ml of methyl isothiocyanate was added and stirred with heating at 80 ° C. for 30 minutes. The solvent was concentrated under reduced pressure, and the resulting crystals were washed with a hexane-ethyl acetate mixed solvent. This was dissolved in 150 ml of 1N sodium hydroxide aqueous solution and heated to reflux for 18 hours. The reaction solution was cooled in an ice bath, 150 ml of 1N hydrochloric acid aqueous solution was added, and the precipitated crystals were filtered. The crystals were finely pulverized and washed with ethyl acetate to obtain the title compound.
MS (APCI, m / z): 208 (M + 1) ⁺ .
HPLC: Rt = 1.08 min.

Reference Example 46 5- [5- (2,6-dichlorobenzylsulfanyl) -4-methyl-4H- [1,2,4] triazol-3-yl] pyridin-2-ylamine Compound 5 of Reference Example 45 -(6-Aminopyridin-3-yl) -4-methyl-2,4-dihydro- [1,2,4] triazole-3-thione 500 mg (2.41 mmol) in 10 ml ethanol and 1N sodium hydroxide Dissolved in 2.65 ml of aqueous solution. A solution of 2,6-dichlorobenzyl bromide (579 mg, 2.41 mmol) in ethanol (5 ml) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 16 hours. About 100 ml of water was added, filtered and dried to obtain the title compound.
MS (APCI, m / z): 366 (M + 1) ⁺ , 368 (M + 1) ⁺ .
HPLC: Rt = 3.00 min.

Reference Example 47 (2E) -3- (2-trifluoromethylphenyl) acrylohydrazide
216 mg (1 mmol) of 2-trifluoromethylbenzaldehyde was dissolved in 10 ml of anhydrous dichloromethane, ice-cooled under nitrogen pressure, 243 mg (1.5 mmol) of 1,1′-carbonylbis-1H-imidazole was added, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution, 10 ml of dichloromethane and 1 ml of hydrazine monohydrate were added dropwise over 5 minutes while stirring with ice cooling. The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained crystals were finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain 89 mg (39%) of the title compound.
MS (ESi): 231 (M + 1) ⁺
Reference Example 48 3-[(E) -2- (2-trifluorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference 89 mg (0.39 mmol) of the compound (2E) -3- (2-trifluorophenyl) acrylohydrazide of Example 47 and N-methyl-4-nitrobenzimidoyl chloride (J. Org. Chem .; EN; 49, 3; synthesized according to 1984, 546-547.) 78 mg (0.39 mmol) was suspended in 10 ml of toluene, 1 ml of triethylamine was added, and the mixture was heated to reflux for 16 hours under nitrogen pressure. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate) to obtain 80 mg (55%) of the title compound.
MS (ESi): 375 (M + 1) ⁺
Reference Example 49 (2E) -3- (2-Chlorophenyl) acrylohydrazide
140 mg (1 mmol) of 2-chlorobenzaldehyde was dissolved in 5 ml of ethanol, 207 mg (1.5 mmol) of potassium carbonate and 218 mg (1.2 mmol) of trimethylphosphonoacetate were added, and the mixture was stirred at 70 degrees for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 5 ml of ethanol, an aqueous sodium hydroxide solution (1N 1.5 ml) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was diluted with dichloromethane, and hydrochloric acid (1N 2.5 ml) was added. The resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in anhydrous dichloromethane (10 ml), ice-cooled under nitrogen pressure, 1,1′-carbonylbis-1H-imidazole (243 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution, 10 ml of dichloromethane and 1 ml of hydrazine monohydrate were added dropwise over 5 minutes while stirring with ice cooling. The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystals were finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain 87 mg (44%) of the title compound.
MS (ESi): 197 (M + 1) ⁺
Reference Example 50 3-[(E) -2- (2-Chlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference Example 49 The compound (2E) -3- (2-chlorophenyl) acrylohydrazide 87 mg (0.44 mmol) was used and the reaction was carried out in the same manner as in Reference Example 48 to obtain the title compound 117 mg (78%).
MS (ESi): 341 (M + 1) ⁺ .

(Reference Example 51) (2E) -3- (2,4-dichlorophenyl) acrylohydrazide
Using 175 mg (1 mmol) of 2,4-dichlorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 49 to obtain the title compound 74 mg (32%).
MS (ESi): 232 (M + 1) ⁺
Reference Example 52 3-[(E) -2- (2,4-dichlorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference The reaction was conducted in the same manner as in Reference Example 48 using the compound (2E) -3- (2,4-dichlorophenyl) acrylohydrazide 74 mg (0.32 mmol) of Example 51, and 70 mg (58%) of the title compound was obtained.
MS (ESi): 374 (M-1) ⁺ , 376 (M + 1) ⁺
Reference Example 53 (2E) -3- (2,4-difluorophenyl) acrylohydrazide
The reaction was carried out in the same manner as in Reference Example 49 using 142 mg (1 mmol) of 2,4-difluorobenzaldehyde to obtain 68 mg (34%) of the title compound.
MS (ES ⁺ , m / z): 199 (M + 1) ⁺
Reference Example 54 3-[(E) -2- (2,4-difluorophenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Using 68 mg (0.34 mmol) of the compound (2E) -3- (2,4-difluorophenyl) acrylohydrazide of Reference Example 53, the reaction was carried out in the same manner as in Reference Example # 2, and 68 mg (59%) of the title compound was obtained. Obtained.
MS (ESi): 343 (M + 1) ⁺
Reference Example 55 (2E) -3- (2,4-dimethoxyphenyl) acrylohydrazide
The reaction was carried out in the same manner as in Reference Example 49 using 166 mg (1 mmol) of 2,4-dimethoxybenzaldehyde to obtain 86 mg (38%) of the title compound.
MS (ESi): 223 (M + 1) ⁺ .

Reference Example 56 3-[(E) -2- (2,4-Dimethoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole The reaction was conducted in the same manner as in Reference Example 48 using 86 mg (0.38 mmol) of the compound (2E) -3- (2,4-dimethoxyphenyl) acrylohydrazide of Reference Example 55, and 110 mg (80%) of the title compound was obtained. It was.
MS (ESi): 366 (M + 1) ⁺
Reference Example 57 (2E) -3- (2,5-dimethoxyphenyl) acrylohydrazide
The reaction was carried out in the same manner as in Reference Example 49 using 2,166-dimethoxybenzaldehyde (166 mg, 1 mmol) to obtain 94 mg (42%) of the title compound.
MS (ES ⁺ , m / z): 223 (M + 1) ⁺
Reference Example 58 3-[(E) -2- (2,5-dimethoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole The reaction was conducted in the same manner as in Reference Example 48 using 94 mg (0.42 mmol) of the compound (2E) -3- (2,5-dimethoxyphenyl) acrylohydrazide in Reference Example 57 to obtain the title compound 88 mg (57%). It was.
MS (ESi): 367 (M + 1) ⁺
(Reference Example 59) (2E) -3- (2-methoxyphenyl) acrylohydrazide
The reaction was carried out in the same manner as in Reference Example 49 using 136 mg (1 mmol) of 2-methoxybenzaldehyde to obtain 65 mg (34%) of the title compound.
MS (ESi): 193 (M + 1) ⁺
Reference Example 60 3-[(E) -2- (2-methoxyphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference Example The reaction was performed in the same manner as in Reference Example 48 using 59 compound (2E) -3- (2-methoxyphenyl) acrylohydrazide (65 mg, 0.34 mmol) to obtain 56 mg (49%) of the title compound.
MS (ESi): 337 (M + 1) ⁺ .

Reference Example 61 (2E) -3- (2-Methylphenyl) acrylohydrazide
The reaction was carried out in the same manner as in Reference Example 49 using 2-methylbenzaldehyde (120 mg, 1 mmol) to obtain the title compound (90 mg, 51%).
MS (ESi): 177 (M + 1) ⁺
Reference Example 62 3-[(E) -2- (2-Methylphenyl) -vinyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference Example The reaction was carried out in the same manner as in Reference Example 49 using 61 mg of compound (2E) -3- (2-methylphenyl) acrylohydrazide, to give 99 mg (60%) of the title compound.
MS (ESi): 321 (M + 1) ⁺
Reference Example 63 3- (2-Trifluoromethyl-6-fluorophenyl) propanohydrazide
384 mg (2 mmol) of 2-trifluoromethyl-6-fluorobenzaldehyde was dissolved in 10 ml of ethanol, 414 mg (3.0 mmol) of potassium carbonate and 436 mg (2.4 mmol) of trimethylphosphonoacetate were added, and the mixture was stirred at 70 degrees for 3 hours. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 10 ml of ethanol, 30 mg of 10% Pd-C was added, and the mixture was stirred at room temperature for 3 hours under hydrogen pressure. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of ethanol, an aqueous sodium hydroxide solution (1N 3.0 ml) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was diluted with dichloromethane, and hydrochloric acid (1N 5.0 ml) was added. The resulting precipitate was collected by filtration and dried under reduced pressure. The precipitate was dissolved in anhydrous dichloromethane (20 ml), ice-cooled under nitrogen pressure, 1,1′-carbonylbis-1H-imidazole (486 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To this reaction solution, 20 ml of dichloromethane and 2 ml of hydrazine monohydrate were added dropwise over 5 minutes while stirring with ice cooling. The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting crystals were finely pulverized and washed with a hexane-ethyl acetate mixed solvent to obtain 242 mg (24%) of the title compound.
MS (ESi): 251 (M + 1) ⁺
Reference Example 64 3- [2- (2-trifluoromethyl-6-fluorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference Using the compound of Example 63 (3- (2-trifluoromethyl-6-fluorophenyl) propanohydrazide 100 mg (0.40 mmol), the reaction was carried out in the same manner as in Reference Example 48 to obtain the title compound 130 mg (82%). It was.
MS (ESi): 395 (M + 1) ⁺
Reference Example 65 3- (5-Methoxy-2-methylphenyl) propanohydrazide
Using 300 mg (2 mmol) of 2-methoxy-5-methylbenzaldehyde, the reaction was carried out in the same manner as in Reference Example 63 to obtain 193 mg (23%) of the title compound.
MS (ESi): 209 (M + 1) ⁺ .

Reference Example 66 3- [2- (5-Methoxy-2-methylphenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Reference Example 65 The compound (3- (5-methoxy-2-methyl) propanohydrazide 100 mg (0.48 mmol)) was used and reacted in the same manner as in Reference Example 48 to obtain the title compound 166 mg (98%).
MS (ESi): 353 (M + 1) ⁺
Reference Example 67 3- (2-Fluorophenyl) propanohydrazide
Using 248 mg (2 mmol) of 2-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 63 to obtain 143 mg (16%) of the title compound.
MS (ESi): 217 (M + 1) ⁺
Reference Example 68 3- [2- (2-Fluorophenyl) ethyl] -4-methyl-5- (4-nitrophenyl) -4H- [1,2,4] -triazole Compound 3- of Reference Example 67 Using 100 mg (0.46 mmol) of (2-fluorophenyl) propanohydrazide, the reaction was carried out in the same manner as in Reference Example 48 to obtain 139 mg (83%) of the title compound.
MS (ESi): 360 (M + 1) ⁺
Reference Example 69 4-Nitrobenzoic acid N ′-[3- (2,6-dichlorophenyl) propionyl] hydrazide Compound (E) -3- (2,6-dichlorophenyl) acrylic hydrazide in Reference Example 11 231 mg 1.00 mmol) was dissolved in 5.0 ml of N, N-dimethylacetamide, 279 mg (1.50 mmol) of commercially available 4-nitrobenzoyl chloride was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained compound was washed with a mixed solvent system of hexane-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 380 (M + 1) ⁺ , 382 (M + 1) ⁺ .
HPLC: Rt = 4.31 min.
Reference Example 70 2-[(E) -2- (2,6-dichlorophenyl) vinyl] -5- (4-nitrophenyl)-[1,3,4] thiadiazole Compound 4-nitrobenzoate of Reference Example 69 Acid N '-[3- (2,6-dichlorophenyl) propionyl] hydrazide 38 mg (0.10 mmol) was suspended in 1.6 ml of toluene-1,4-dioxane (1: 1) mixed solvent, and Lawesson reagent 24 mg (0.060 mmol) was added, and the mixture was stirred for 17 hours with heating under reflux. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was filtered using a pad carrying a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was used for the next reaction without purification.
MS (APCI, m / z): 378 (M + 1) ⁺ , 380 (M + 1) ⁺ .
HPLC: Rt = 7.01 min.

Reference Example 71 4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl]-[1,3,4] thiazol-2-yl} phenylamine Compound 2- [of Reference Example 70 (E) -2- (2,6-Dichlorophenyl) vinyl] -5- (4-nitrophenyl)-[1,3,4] thiadiazole was used in the same manner as in Reference Example 13 to obtain the title compound. Obtained.
MS (APCI, m / z): 348 (M + 1) ⁺ , 350 (M + 1) ⁺ .
HPLC: Rt = 5.77 min.
Reference Example 72 (E) -3- (2,6-dichlorophenyl) -N- [2- (4-nitrophenyl) -2-oxoethyl] acrylamide Commercially available (E) -3- (2,6-dichlorophenyl ) 1.50 g (6.92 mmol) of acrylic acid was dissolved in a mixed solvent of dichloromethane-tetrahydrofuran (3: 1), 0.624 ml (7.27 mmol) of oxalyl chloride was added and stirred at room temperature for 30 minutes, and then N, N-dimethylformamide (catalyst) The mixture was stirred for 1.5 hours. After adding 1.00 g (4.62 mmol) of 2-amino-1- (4-nitrophenyl) ethanone monohydrochloride (see J. Med. Chem. 1982, 25, 1045-1050) to the reaction system at 0 ° C Then, 8.0 ml of a mixed solution of 3.20 ml (23.1 mmol) of triethylamine in dichloromethane-tetrahydrofuran (3: 1) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained compound was washed with a mixed solvent system of hexane-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 379 (M + 1) ⁺ , 381 (M + 1) ⁺ .
HPLC: Rt = 4.70 min.
Reference Example 73 2-[(E) -2- (2,6-dichlorophenyl) -vinyl] -5- (4-nitrophenyl) thiazole Compound (E) -3- (2,6- 45 mg (0.12 mmol) of dichlorophenyl) -N- [2- (4-nitrophenyl) -2-oxoethyl] acrylamide was suspended in 1.8 ml of a toluene-1,4-dioxane (1: 1) mixed solvent, Lawesson Reagent 29 mg (0.071 mmol) was added and stirred with heating under reflux for 18 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was filtered using a pad carrying a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was used for the next reaction without purification.
MS (APCI, m / z): 377 (M + 1) ⁺ , 379 (M + 1) ⁺ .
HPLC: Rt = 7.65 min.
Reference Example 74 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] thiazol-5-yl} phenylamine Compound 2-[(E) -2- (2 , 6-Dichlorophenyl) -vinyl] -5- (4-nitrophenyl) thiazole was used in the same manner as in Reference Example 13 to obtain the title compound.
MS (APCI, m / z): 347 (M + 1) ⁺ , 349 (M + 1) ⁺ .
HPLC: Rt = 6.18 min.
Reference Example 75 2-[(E) -2- (2,6-dichlorophenyl) vinyl] -1-methyl-5- (4-nitrophenyl) -1H-imidazole Compound (E) -3 in Reference Example 72 -(2,6-dichlorophenyl) -N- [2- (4-nitrophenyl) -2-oxoethyl] acrylamide 900 mg (2.37 mmol) in N, N-dimethylformamide-acetic acid (1: 1) mixed solvent 18 ml Then, methylamine (2.0 M in tetrahydrofuran; 5.9 ml, 11.9 mmol) was added, and the mixture was stirred for 16 hours while heating at 130 ° C. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 15 ml of tetrahydrofuran, 3.0 ml (12.0 mmol) of 4N hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate to obtain the hydrochloride of the title compound. The obtained hydrochloride was adjusted to 10 ml of a mixed solvent of tetrahydrofuran-methanol (1: 1), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered through a funnel with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was used in the next reaction without further purification.
MS (APCI, m / z): 374 (M + 1) ⁺ , 376 (M + 1) ⁺ .
HPLC: Rt = 4.02 min.

Reference Example 76 4- {2-[(E) -2- (2,6-dichlorophenyl) vinyl] -3-methyl-3H-imidazol-4-yl} phenylamine Compound 2-[( E) -2- (2,6-Dichlorophenyl) vinyl] -1-methyl-5- (4-nitrophenyl) -1H-imidazole was used in the same manner as in Reference Example 13 to obtain the title compound. .
MS (APCI, m / z): 344 (M + 1) ⁺ , 346 (M + 1) ⁺ .
HPLC: Rt = 3.15 min.
(Reference Example 77) N- [2- (4-aminophenyl) -2-oxoethyl] -3- (2,6-dichlorophenyl) propionamide Using commercially available 3- (2,6-dichlorophenyl) propionic acid The reaction was carried out in the same manner as in Reference Example 72 to obtain the title compound.
MS (APCI, m / z): 381 (M + 1) ⁺ , 383 (M + 1) ⁺ .
HPLC: Rt = 4.72 min.
Reference Example 78 2- [2- (2,6-dichlorophenyl) ethyl] -1-methyl-5- (4-nitrophenyl) -1H-imidazole N- [2- (4-aminophenyl] of Reference Example 77 ) -2-Oxoethyl] -3- (2,6-dichlorophenyl) propionamide was used in the same manner as in Reference Example 75 to obtain the title compound.
MS (APCI, m / z): 376 (M + 1) ⁺ , 378 (M + 1) ⁺ .
HPLC: Rt = 3.39 min.
Reference Example 79 4- {2- [2- (2,6-dichlorophenyl) ethyl] -3-methyl-3H-imidazol-4-yl} phenylamine Compound 2- [2- (2, 6-Dichlorophenyl) ethyl] -1-methyl-5- (4-nitrophenyl) -1H-imidazole was used in the same manner as in Reference Example 13 to obtain the title compound.
MS (APCI, m / z): 346 (M + 1) ⁺ , 348 (M + 1) ⁺ .
HPLC: Rt = 3.02 min.
Reference Example 80 5-Nitropyridine-2-carbothioic acid methylamide
600 mg (3.31 mmol) of 5-nitropyridine-2-carboxylic acid methylamide (see J. Med. Chem. 1977, 20, 483-487.) Was suspended in 7.0 ml of toluene, and 804 mg (1.99 mmol) of Lawesson reagent. ) Was added and stirred for 16 hours under reflux. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed successively with water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained compound was washed with a mixed solvent system of hexane-ethyl acetate to obtain the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 3.42 (3H, d, J = 5.1 Hz), 8.57 (1H, dd, J = 8.7 and 2.8 Hz), 8.90 (1H, d, J = 8.6 Hz), 9.30 (1H, d, J = 2.3Hz), 10.1 (1H, brs).

(Reference Example 81) N-methyl-5-nitropyridine-2-carboximidothioic acid ethyl ester 80 mg (0.41 mmol) of the compound 5-nitropyridine-2-carbothioic acid methylamide of Reference Example 80 was dissolved in 1.5 ml of ethanol. , Sodium ethoxide (21 wt% in ethanol; 0.155 ml, 0.41 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 0.031 ml (0.41 mmol) of ethyl bromide, and the mixture was stirred at 50 ° C. for 18 hours, diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The obtained residue was immediately used in the next reaction without further purification.

Reference Example 82 2- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} -5-nitro Pyridine Reference using N-methyl-5-nitropyridine-2-carboximidothioic acid ethyl ester of Reference Example 81 and Compound (E) -3- (2,6-dichlorophenyl) acrylic acid hydrazide of Reference Example 11 The reaction was conducted in the same manner as in Example 84 to obtain the title compound.
MS (APCI, m / z): 376 (M + 1) ⁺ , 378 (M + 1) ⁺ .
HPLC: Rt = 5.11 min.
Reference Example 83 6- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridine-3- Ilamine Compound of Reference Example 2- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} -5- The reaction was carried out in the same manner as in Reference Example 13 using nitropyridine to obtain the title compound.
MS (APCI, m / z): 346 (M + 1) ⁺ , 348 (M + 1) ⁺ .
HPLC: Rt = 3.84 min.
Reference Example 84 2- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} -5-nitropyridine Reference Example 81 Compound N-methyl-5-nitropyridine-2-carboximidothioic acid ethyl ester 61 mg (0.27 mmol) and Reference Example 18 compound 3- (2,6-dichlorophenyl) propionic acid hydrazide 63 mg (0.27 mmol) The mixture was stirred in 1.5 ml of 1-butanol for 18 hours with heating under reflux. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained compound was washed with a mixed solvent system of hexane-ethyl acetate to obtain the title compound.
MS (APCI, m / z): 378 (M + 1) ⁺ , 380 (M + 1) ⁺ .
HPLC: Rt = 4.72 min.
Reference Example 85 6- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} pyridin-3-ylamine Reference Example 84 Example of using 2- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} -5-nitropyridine The reaction was carried out in the same manner as in 13 to obtain the title compound.
MS (APCI, m / z): 348 (M + 1) ⁺ , 350 (M + 1) ⁺ .
HPLC: Rt = 3.53 min.

Reference Example 86 (E) -3- (3-Trifluoromethylpyridin-2-yl) acrylic acid ethyl ester 600 mg (3.31 mmol) of commercially available 2-chloro-3-trifluoromethylpyridine dissolved in N, To a solution of N-dimethylformamide 2.5 ml, add 0.720 ml (6.61 mmol) of ethyl acrylate, 0.920 ml (6.61 mmol) of triethylamine, 101 mg (0.331 mmol) of tri-ortho-tolylphosphine, and 37 mg (0.166 mmol) of palladium acetate. The mixture was stirred at 130-140 ° C. for 17 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed successively with water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered using a funnel filled with a small amount of silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 1.35 (3H, t, J = 7.0 Hz), 4.29 (2H, q, J = 7.0 Hz), 7.19 (1H, d, J = 14.9 Hz) , 7.41-7.34 (1H, m), 8.00-7.91 (2H, m), 8.77 (1H, d, J = 4.3Hz).
Reference Example 87 3- (3-Trifluoromethylpyridin-2-yl) propionic acid ethyl ester Compound (E) -3- (3-trifluoromethylpyridin-2-yl) acrylic acid ethyl ester of Reference Example 86 130 mg (0.530 mmol) was dissolved in 3.0 ml of ethanol, 70% of 10% palladium-carbon was added, and the mixture was vigorously stirred for 10 hours in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered using celite, the celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained residue was used in the next reaction without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 1.24 (3H, t, J = 7.2 Hz), 2.86 (2H, t, J = 7.4 Hz), 3.32 (2H, t, J = 7.4 Hz) , 4.15 (2H, q, J = 7.1Hz), 7.29-7.24 (1H, m), 7.92 (1H, d, J = 7.8Hz), 8.69 (1H, d, J = 5.1Hz).
(Reference Example 88) 3- (3-Trifluoromethylpyridin-2-yl) propionic acid hydrazide Compound 3- (3-trifluoromethylpyridin-2-yl) propionic acid ethyl ester of Reference Example 87 98 mg (0.40 mmol ) Was dissolved in ethanol (2.0 ml), hydrazine monohydrate (0.39 ml, 8.00 mmol) was added, and the mixture was stirred for 22 hours under heating to reflux. After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure. The obtained residue was used in the next reaction without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 2.72 (2H, t, J = 7.0 Hz), 3.35 (2H, t, J = 7.0 Hz), 3.88 (2H, brs), 7.27 (1H, dd, J = 7.8 and 4.7Hz), 7.33 (1H, brs), 7.91 (1H, d, J = 8.6Hz), 8.67 (1H, d, J = 4.7Hz).
Reference Example 89 2- {4-Methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2,4] triazol-3-yl} -5- Nitropyridine Using N-methyl-5-nitropyridine-2-carboximidothioic acid ethyl ester of Reference Example 81 and Compound 3- (3-trifluoromethylpyridin-2-yl) propionic acid hydrazide of Reference Example 88 In the same manner as in Reference Example 84, the title compound was obtained.
MS (APCI, m / z): 379 (M + 1) ⁺ .
HPLC: Rt = 3.91 min.
Reference Example 90 6- {4-Methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2,4] triazol-3-yl} pyridine-3 -Ilamine Compound of Reference Example 2- {4-methyl-5- [2- (3-trifluoromethylpyridin-2-yl) ethyl] -4H- [1,2,4] triazol-3-yl}- The reaction was carried out in the same manner as in Reference Example 13 using 5-nitropyridine to obtain the title compound.
MS (APCI, m / z): 349 (M + 1) ⁺ .
HPLC: Rt = 2.99 min.

(Test Example 1)
(1) Preparation of DGAT1 According to a reported method, a microsomal fraction in which mouse DGAT1 was highly expressed was prepared as follows (Cases, S. et al., Proc. Natl. Acad. Sci. US A. 1998, 95, p.13018-13023). A cDNA encoding mouse DGAT1 was cloned from a mouse cDNA library by a polymerase chain reaction (hereinafter referred to as “PCR”) and introduced into an insect cell virus vector (baculovirus expression system, Invitrogen). After infecting insect cells (High Five, Sf9, Sf21, etc., Invitrogen) with the virus, the cells are buffer A [0.1 M sucrose, 50 mM KCl, 40 mM potassium phosphate (pH 7.4), 30 mM EDTA, 1% Protease inhibitor cocktail (SIGMA, P-8340)] and crushed with a Polytron homogenizer. The supernatant obtained by subjecting the homogenate to low speed centrifugation (10,000 × g, 30 minutes) was further centrifuged at high speed (100,000 × g, 60 minutes), and the precipitate was resuspended in buffer A as a microsomal fraction, which was combined with DGAT1 enzyme. did. DGAT1 enzyme was divided into small volumes and stored at -80 ° C.
(2) DGAT1 inhibitory activity test Reaction solution [175 mM Tris-HCl (pH 8.0), 8 mM MgCl ₂ , 1 mg / ml BSA, 0.5 mM 1,2-dioleoyl-sn-glycerol (10-fold concentration] 10% EtOH solution), 30 μM [ ¹⁴ C] -oleoyl-CoA (about 50 mCi / mmol), 0.5% triton X-100, DGAT1 enzyme (10 μg) obtained in Test Example 1 (1), test compound Or a vehicle (DMSO / MeOH, 7: 3 solution, 5% added), total volume 50 μl] was incubated at room temperature (23 ° C.) for 30 minutes. To the reaction mixture was added a reaction stop solution (70 μl) consisting of isopropanol / 1-heptane / water (80: 20: 2, v / v / v) and stirred, then water (30 μl) and 1-heptane (100 μl) Was added and stirred. A 1-heptane layer (50 μl) was spotted on a TLC plate and developed with a developing solvent consisting of 1-hexane / diethyl ether / acetic acid (85: 15: 1, v / v / v). The radioactivity of the triglyceride fraction was quantified using a BAS2000 bioimage analyzer (Fuji Film), and the inhibitory activity of the test compound was calculated by the following formula by comparing with the control. The unreacted (0 minute incubation) radioactivity was used as the background.

Inhibition rate = 100 − [(radioactivity when test compound is added) − (background)] / [(control radioactivity) − (background)] × 100
Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 19, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 65, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, The compounds of 84, 85, 86, 87, 88, 89, 90, 91 and 92 showed an inhibition rate of 40% or more at a test compound concentration of 1 μg / ml.

  The DGAT inhibitory activity test is not limited to the above method, and for example, microsomes prepared from the small intestine, adipose tissue or liver of animals such as rats and mice may be used as the DGAT enzyme. Alternatively, microsomes prepared from cultured cells (3T3-L1 adipocytes, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells highly expressing DGAT can also be used as the DGAT enzyme. Further, in order to efficiently evaluate a large number of test compounds in a short time, a flash plate (PerkinElmer) in which the extraction operation is omitted can be used.

(Test Example 2)
Male C57BL / 6N mice (7-15 weeks old, body weight 17-35 g, Nippon Charles River), compound (30 mg / kg) and 20% neutral fat-containing emulsion (Intralipid 20%: Terumo Corporation) Was orally administered (0.3 mL / mouse). One hour after administration, laparotomy was performed under isoflurane (Foren: Abbott Japan Co., Ltd.) under inhalation anesthesia, and 1-10 μL of small intestinal lymph was collected from the small intestinal lymphatic vessel. The neutral fat concentration in the lymph was measured using a commercially available kit (Triglyceride E Test Wako: Wako Pure Chemical Industries, Ltd.), and the rate of decrease in neutral fat concentration relative to the 20% emulsion administration group (control group) was calculated. Neutral fat absorption inhibitory activity.

  The compounds of Examples 2, 29, 32, 68, 84 and 86 showed neutral fat absorption inhibitory activity of 60% or more.

  From the above results, the compound of the present invention has an excellent DGAT inhibitory action and is effective in obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, diabetes, arteriosclerosis, or obesity. It is useful as a therapeutic or prophylactic agent for the resulting hyperlipidemia, hyperTGemia, dyslipidemia, diabetes, arteriosclerosis, or hypertension.

Formulation Example 1: Capsule 50 mg of the compound of Example 15 or 16
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg No. 3 gelatin capsule to form a capsule.

Formulation Example 2: Tablet Example 15 or 16 Compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
200mg
The powder of the above formulation is mixed, wet granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is used for warm-blooded animals (particularly humans), obesity, obesity, hyperlipidemia. , HyperTG, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, etc. ), Cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases shown above and below), atherosclerosis, diabetic arteriosclerosis, or obesity Hyperlipidemia, hyperTGemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macrovascular Cataract, pregnancy sugar) Disease, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases shown above and below), atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fat Liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, or cholelithiasis, preferably obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, diabetes, arteriosclerosis, Or, hyperlipidemia, hyperTG caused by obesity, dyslipidemia, diabetes, arteriosclerosis, or hypertension, more preferably obesity, obesity, hyperlipidemia, high TG blood It is useful as a therapeutic agent or preventive agent (especially therapeutic agent) for infectious diseases, diabetes, or arteriosclerosis.

Claims (20)

General formula

[Where:
R ¹ is a C ₆ -C ₁₀ aryl group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b; one group and / or one or two optionally substituted heterocyclic group with a group selected independently from substituent group b is selected from the substituent group a, C ₁ -C ₁₀ alkyl group, A C ₇ -C ₁₆ aralkyl group which may be substituted with one group selected from the substituent group a and / or one to four groups independently selected from the substituent group b, or one A C ₃ -C ₆ cycloalkyl group optionally substituted with a C ₆ -C ₁₀ aryl group of
R ² is a C ₆ -C ₁₀ aryl group optionally substituted with one group selected from substituent group a and / or 1 to 4 groups independently selected from substituent group b, Or a heterocyclic group which may be substituted with one group selected from substituent group a and / or one or two groups independently selected from substituent group b;
R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a halogen atom,
R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
A is a methylene group, vinylene group, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, or one of the main chain methylene groups is replaced by a vinylene group, oxygen atom, sulfur atom, sulfinyl group or sulfonyl group. indicates even better _C 2 -C ₄ alkylene group,
Q represents a group represented by the formula -N (Me)-or a sulfur atom,
T represents a group represented by the formula = CH- or a nitrogen atom,
U and V are the same or different and represent a group represented by the formula = CH- or a nitrogen atom (provided that U and V do not represent a nitrogen atom at the same time),
The substituent group a is a C ₆ -C ₁₀ aryl group which may be substituted with 1 to 3 groups independently selected from the substituent group c, and 1 to 3 independently selected from the substituent group c. It represents the group consisting of pieces of one nitrogen-containing heterocyclic group optionally substituted by a group selected from optionally C ₆ -C ₁₀ aryl group and substituent group c substituted with one,
Substituent group b is a halogen _atom, C 1 _{-C 10} alkyl _group, C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl _{group, -P (= O) (O} -C 1 -C 6 _{alkyl) 2} in 1-substituted _C 1 -C ₆ alkyl _group, C 3 -C ₆ cycloalkyl _group, C 1 _{-C 10} alkoxy _group, C 1 -C ₆ halogenated alkoxy group, one or two hydroxy groups _C 1 -C ₆ alkoxy group _{substituted, C} 1 -C ₆ alkoxy group which is one substituted with C 3 -C ₆ cycloalkyl, C ₂ -C ₆ alkenyloxy group, C ₂ -C ₆ alkynyl oxy _{group, (C} 1 -C ₆ alkoxy) - _(C 1 -C ₆ alkyl) _group, C 1 -C ₆ alkylthio group, a carboxyl _group, C 2 -C ₇ alkylcarbonyl _group, C 2 -C ₇ alkoxycarbonyl group A Amino group, _mono--C 2 -C ₇ alkylcarbonylamino group, a mono _-C 1 -C ₆ alkylsulfonylamino group, a mono _-C 1 -C ₆ alkylamino group, di - _(C 1 -C ₆ alkyl) amino group N- (C ₁ -C ₆ alkyl) -N- (C ₁ -C ₆ hydroxyalkyl) amino group, di- (C ₁ -C ₆ hydroxyalkyl) amino group, cyano group, nitro group, carbamoyl group, mono -C ₂ -C ₇ represents the group consisting alkylaminocarbonyl group and oxo group,
Substituent group c show a group consisting of halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl group and hydroxy group. ]
And a pharmacologically acceptable salt thereof as an active ingredient. The medicament according to claim 1, wherein the general formula (I) is a urea derivative represented by the general formula (Ia) or a pharmacologically acceptable salt thereof as an active ingredient.

3. The method according to claim 1, wherein R ¹ is independent of the group consisting of a fluorine atom, a chlorine atom, a C ₁ -C ₄ alkyl group, a trifluoromethyl group, a C ₁ -C ₄ alkoxy group, a trifluoromethoxy group, and a methylcarbonyl group. 1 or two is a phenyl group or naphthyl group optionally substituted with a group selected; independently one or two C ₁ -C ₄ alkyl are 5-membered aromatic may be heterocyclic optionally substituted with a group A urea group which is a C ₃ -C ₆ cycloalkyl group optionally substituted by a group or a fused bicyclic heterocyclic group; a C ₂ -C ₆ alkyl group; a C ₇ -C ₁₄ aralkyl group; or a phenyl group A medicament comprising a derivative or a pharmacologically acceptable salt thereof as an active ingredient. According to claim 1 or 2, R ¹ is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 2-trifluoromethylphenyl group, 2,4-difluorophenyl group, 5-fluoro-2-methylphenyl group , Urea derivatives which are 5-chloro-2-methoxyphenyl group, 2-methoxy-5-methylphenyl group, n-hexyl group, 1-phenylethyl group or 2-phenylcyclopropyl group, or pharmacologically acceptable salts thereof As an active ingredient. In any one selected from claims 1 to 4, ^{R 2} is a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₂ halogenated alkyl _group, C 1 -C ₆ alkoxy group, a carboxyl group, Phenyl or pyridyl group optionally substituted by 1 or 2 groups independently selected from the group consisting of methoxycarbonyl group, methylaminocarbonyl group, cyano group, carbamoyl group and 5- (1H-tetrazolyl) group Or a urea derivative which is a fused bicyclic heterocyclic group optionally substituted with one or two groups independently selected from the group consisting of a halogen atom and an oxo group, or a pharmacologically acceptable salt thereof. Pharmaceuticals contained as an ingredient. 5. The compound according to claim 1, wherein R ² is 2,6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2-chloro-6-methoxycarbonylphenyl group, 2-carbamoyl-6. A pharmaceutical comprising a urea derivative which is a chlorophenyl group or 2-chloro-6- [5- (1H-tetrazolyl)] phenyl group or a pharmacologically acceptable salt thereof as an active ingredient. 7. A medicament comprising, as an active ingredient, a urea derivative or a pharmacologically acceptable salt thereof, wherein R ³ is a hydrogen atom according to any one of claims 1 to 6. 8. The medicine according to any one of claims 1 to 7, wherein the urea derivative or a pharmacologically acceptable salt thereof in which R ⁴ is a hydrogen atom is contained as an active ingredient.   9. A medicament according to claim 1, wherein A is a vinylene group or ethylene group, or a pharmacologically acceptable salt thereof as an active ingredient.   10. The medicament according to any one of claims 1 to 9, wherein U is a urea derivative or a pharmacologically acceptable salt thereof, wherein U is a group represented by the formula = CH-.   11. The medicament according to any one of claims 1 to 10, which contains, as an active ingredient, a urea derivative or a pharmacologically acceptable salt thereof, wherein V is a group represented by the formula = CH-. In claim 1,
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( 2-trifluoromethylphenyl) urea,
3-Chloro-2-[(E) -2- (5- {4- [3- (2-methoxy-5-methylphenyl) ureido] phenyl} -4-methyl-4H- [1,2,4] Triazol-3-yl) vinyl] benzoic acid methyl ester,
1- (4- {5- [2- (2,6-dichlorophenyl) ethyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- (2-fluorophenyl ) Urea, or
1- (4- {5-[(E) -2- (2,6-dichlorophenyl) vinyl] -4-methyl-4H- [1,2,4] triazol-3-yl} phenyl) -3- ( A pharmaceutical comprising a urea derivative represented by 2-fluorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient.   An acylcoenzyme A: diacylglycerol acyltransferase inhibitor comprising the urea derivative according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient.   A medicament comprising the urea derivative according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient.   The medicament according to claim 14, wherein the medicament has an inhibitory action on acylcoenzyme A: diacylglycerol acyltransferase.   Medicine is obesity, obesity, hyperlipidemia, hypertriglyceridemia (hereinafter referred to as hyperTGemia), dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral Neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases listed above and below) ), A medicament according to claim 15 for the treatment and / or prevention of atherosclerosis or diabetic arteriosclerosis.   The following diseases are caused by obesity: hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases mentioned above and below), atherosclerosis 16. Treatment for and / or prevention of diabetes mellitus, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis Medicines.   The medicament according to claim 15, for treating and / or preventing obesity, obesity or hyperlipidemia, hyperTGemia, diabetes, hypertension or arteriosclerosis caused by obesity.   The medicament according to claim 15, for treating and / or preventing obesity or obesity.   The medicament according to claim 15, for suppressing fat absorption from the small intestine.