JP2006045203A - Substituted benzene compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a substituted benzene compound that ameliorates lipid metabolism abnormality by modulating action of liver X receptors (LXR) and exhibits excellent anti-arteriosclerotic action and antiinflammation action by controlling formation of inflammation mediator or its pharmaceutically permissible salt or ester and is useful as an LXR modulator. <P>SOLUTION: The compound is represented by the general formula [R<SP>1</SP>is COR<SP>9</SP>(R<SP>9</SP>is an alkyl, an alkoxy which may be substituted, an amino which may be substituted or the like), an aryl which may be substituted or the like; R<SP>2</SP>is H, OH, an alkoxy or the like; R<SP>3</SP>is H, an alkyl which may be substituted, an alkenyl, an alkoxy which may be substituted or the like; R<SP>4</SP>and R<SP>5</SP>are each H, an alkyl which may be substituted, a halogeno or the like; R<SP>6</SP>and R<SP>7</SP>are each H, an alkyl or the like; R<SP>8</SP>is an N(R<SP>10</SP>)ZR<SP>11</SP>, a ZN(R<SP>10</SP>)R<SP>12</SP>, an X<SP>2</SP>N(R<SP>10</SP>)ZR<SP>11</SP>or the like; (R<SP>10</SP>is H, an alkyl which may be substituted or the like; R<SP>11</SP>is H, an alkyl which may be substituted, a cycloalkyl which may be substituted, an alkenyl which may be substituted, an alkoxy which may be substituted, an amino which may be substituted, a phenyl which may be substituted or the like; R<SP>12</SP>is H, an alkyl which may be substituted, an alkenyl which may be substituted or the like; X<SP>2</SP>is an alkylene; Z is CO, CS or SO<SB>2</SB>); X<SP>1</SP>is a single bond or a methylene which may be substituted; Y is a phenyl which may be substituted or a heterocyclyl which may be substituted]. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention shows excellent anti-atherosclerotic action and anti-inflammatory action by improving lipid metabolism abnormality by regulating the action of Liver X receptors (LXR) or by controlling the production of inflammatory mediators. And a novel substituted benzene compound or a pharmacologically acceptable salt or ester thereof.

  Furthermore, the present invention relates to a pharmaceutical composition containing a substituted benzene compound or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably arteriosclerosis; atherosclerosis; arteriosclerosis caused by diabetes Hyperlipidemia; hypercholesterolemia; lipid-related diseases; inflammatory diseases that are diseases caused by inflammatory cytokines such as rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis; Autoimmune diseases such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease; cardiovascular diseases such as ischemic heart disease and heart failure; cerebrovascular disease; kidney disease; diabetes; retinopathy, nephropathy, neurosis Diabetes complications such as coronary artery disease; obesity; nephritis; hepatitis; cancer; or pharmaceutical composition for the treatment or prevention of Alzheimer's disease; Includes arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, or Pharmaceutical composition for the treatment or prevention of diabetes; most preferably relates to a pharmaceutical composition for the treatment or prevention of arteriosclerosis.

  Furthermore, the present invention relates to the use of a substituted benzene compound or a pharmacologically acceptable salt or ester thereof for the manufacture of a pharmaceutical composition, preferably a pharmaceutical composition for the treatment or prevention of the above diseases.

  Furthermore, the present invention relates to a disease caused by administering a pharmacologically effective amount of a substituted benzene compound or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human), preferably the treatment of the above-mentioned disease. Or relates to preventive methods.

Furthermore, the present invention relates to a method for producing a substituted benzene compound or a pharmacologically acceptable salt or ester thereof.

  In advanced civilized countries, cardiovascular diseases (for example, heart diseases, cerebrovascular diseases, kidney diseases, etc.) caused by hypertension, hyperlipidemia, hyperglycemia, etc. are a major problem. Antihypertensive drugs, antihyperlipidemic drugs, and antidiabetic drugs are used for the treatment of hypertension, hyperlipidemia, and hyperglycemia, respectively. In the clinical field, α and β blockers, diuretics, calcium antagonists, ACE inhibitors, A-II antagonists and the like are used as antihypertensive agents, and HMG-CoA reductase inhibitors are used as antihyperlipidemic agents. , Anion exchange resins, nicotinic acid derivatives, probucol, and fibrates, and insulin, sulfonylureas, metformin, and glitazones are used as antidiabetic agents. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels. However, the mortality due to heart disease, cerebrovascular disease and kidney disease has not been greatly improved even by the use of these medicines, and development of better therapeutic agents for these diseases is desired.

  A direct risk factor for cardiovascular disease is arteriosclerosis with thickening of the arterial wall, which is caused by plaque formation due to accumulation of oxidized low density lipoprotein cholesterol (LDL-C) in the arterial wall (Ross, R., Annu. Rev. Physiol. 1995, 57, p. 791-804; Steinberg, D., J. Biol. Chem. 1997, 272, p. 20963-20966). This plaque inhibits blood flow and promotes thrombus formation.

  Recently, it has become clear that the nuclear receptor LXR plays an important role in the regulation of lipid metabolism (Janowski, BA, Willy, PJ, Falck, JR, Mangelsdorf, DJ, Nature, 1996, No. 1). 383, p.728-731). LXR has two isoforms, LXRα and LXRβ. LXRα is distributed in the liver, small intestine, spleen and adrenal gland in a small proportion in the liver of mammals, and LXRβ is distributed in organs and tissues throughout the body. LXR undergoes transcriptional regulation of oxidized sterols in macrophages on the vascular wall, induces expression of ABCA1 (ATP Binding Cassette Transpoter-1) and ApoE (Apolipoprotein E), pulls out cholesterol from the vascular wall and enters the liver (Lu, TT, Repa, JJ, Mangelsdorf, DJ, J. Biol. Chem., 2001, Vol. 276, pp. 37735-37738). LXR also induces ABCA1 expression in the small intestine and inhibits absorption of dietary cholesterol from the digestive tract (Repa, JJ, Turley, SD, Lobaccaro, JA, Medina, J., Li, L. Lustig, K., Shan, B., Heyman, RA, Dietschy, JM, Mangelsdorf, DJ, Science, 2002, Vol. 289, p.1524-1529). Considering the importance of LXR in such cholesterol metabolism, drugs that modulate LXR can be used to treat arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia or lipid-related diseases or Expected to be useful in prevention.

  Atherosclerosis is also considered a chronic inflammatory disease (Ross, R., N. Engl. J. Med., 1986, 314, p.488-500). In recent years, LXR regulates immune function by regulating the expression of inflammatory mediators such as nitric oxide synthase, cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6). (Mangelsdorf, DJ, Tontonoz, P. et. Al., Nat. Med., 2003, Vol. 9, p.213-219). Therefore, LXR modulators are expected to suppress the development and progression of arteriosclerosis by anti-inflammatory action in addition to improving lipid metabolism. Furthermore, naturally occurring and synthetic LXR activators have been shown to reduce chemically generated dermatitis in animal models (Fowler, AJ, et. Al., J. Invest Dermatol. 2003, 120, 246-255). Thus, LXR modulators are expected to be useful for the treatment of various inflammatory diseases.

A substituted benzene compound having an LXR-regulating action (that is, acting on ABCA1 expression) has been known so far, but has a structure different from that of the compound of the present invention (see Patent Document 1, etc.).
International Publication No. 2004/026816 Pamphlet

As a result of intensive studies on the synthesis and pharmacological activity of substituted benzene compounds in order to find compounds having excellent binding activity to LXR, the inventors have found that substituted benzene compounds having a specific structure are The present invention was completed.

  The present invention relates to a substituted benzene compound that exhibits an excellent anti-atherosclerotic action and anti-inflammatory action by regulating the function of nuclear receptor LXR to improve lipid metabolism abnormality or control the production of inflammatory mediators Alternatively, a pharmacologically acceptable salt or ester thereof is provided.

  Furthermore, the present invention relates to a pharmaceutical composition containing a substituted benzene compound or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably arteriosclerosis; atherosclerosis; arteriosclerosis caused by diabetes; Hyperlipidemia; hypercholesterolemia; lipid-related diseases; inflammatory diseases that are diseases caused by inflammatory cytokines such as rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis, etc .; Autoimmune diseases such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease, etc .; cardiovascular diseases such as ischemic heart disease, heart failure, etc .; cerebrovascular disease; kidney disease; diabetes; retinopathy, nephropathy, Diabetes complications such as neurosis, coronary artery disease, etc. Obesity; nephritis; hepatitis; cancer; or pharmaceutical composition for treatment or prevention of Alzheimer's disease; More preferably, arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, Alternatively, a pharmaceutical composition for the treatment or prevention of diabetes; most preferably a pharmaceutical composition for the treatment or prevention of arteriosclerosis is provided.

  The present invention further provides the use of a substituted benzene compound or a pharmacologically acceptable salt or ester thereof for the manufacture of a pharmaceutical composition, preferably a pharmaceutical composition for the treatment or prevention of the above diseases.

  Furthermore, the present invention relates to a disease caused by administering a pharmacologically effective amount of a substituted benzene compound or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human), preferably treatment of the above-mentioned disease or Provide prevention methods.

Furthermore, the present invention provides a method for producing a substituted benzene compound or a pharmacologically acceptable salt or ester thereof.

The present invention
(1) General formula (I)

[Wherein R ¹ represents a formula —COR ⁹ , wherein R ⁹ represents a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, (C ₃ -C ₆ cycloalkyl)-(C _1- C ₄ alkyl) oxy group, halogeno C ₁ -C ₁₀ alkoxy group (the halogeno C ₁ -C ₁₀ alkoxy group represents a C ₁ -C ₁₀ alkoxy group substituted with 1 to 7 halogeno groups), phenyl - (C ₁ -C ₁₀ alkoxy) group, C ₃ -C ₆ cycloalkyl group, (C ₁ -C ₄ alkyl) - (C ₃ -C ₆ cycloalkyl) oxy groups, C ₁ -C ₁₀ alkyl amino group , Di (C ₁ -C ₁₀ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group consist of a nitrogen atom, an oxygen atom and a sulfur atom) 5- to 7-membered saturated heterocycles containing 1 to 3 atoms selected from the group May form a Le group), a phenyl group or a substituted phenyl group (said substituents may be the same or different, represents 1 to a 3 radicals) selected from the substituent group beta. A group having
C ₆ -C ₁₀ aryl group, substituted C ₆ -C ₁₀ aryl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α), 5 to 10-membered aromatic A heterocyclyl group or a substituted 5- to 10-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
R ² represents a hydrogen atom, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group represents a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups), hydroxyl group group, C ₁ -C ₄ alkoxy group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (wherein the alkyl groups are the same or different), or represents a halogeno group;
R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group (the halogeno C ₁ -C ₆ alkyl group is a C ₁ -C substituted with 1 to 7 halogeno groups) ₆ alkyl group), (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group, (C _1- C ₄ alkylthio)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylsulfinyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylsulfonyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylamino)-(C ₁ -C ₄ alkyl) group, [di (C ₁ -C ₄ alkyl) amino]-(C ₁ -C ₄ alkyl) group (the alkyl groups are the same or different), C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, hydroxyl group, C ₁ -C ₆ alkoxy group A halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), a phenyloxy group, C _1- C ₆ alkylthio group, a phenylthio group, C ₁ -C ₆ alkylsulfinyl group, phenylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, phenylsulfonyl group, an amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl groups, taken with together with the nitrogen atom of the amino group, selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed), (C ₁ -C ₆ alkoxy) carbonyl group, cyano group, nitro group, halogeno group , A phenyl group, or a 5- to 6-membered aromatic heterocyclyl group;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is 1 to 5 halogeno groups). showing a substituted C ₁ -C ₄ alkyl group), C ₃ -C ₆ cycloalkyl group, a hydroxyl group, C ₁ -C ₄ alkoxy groups, halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ An alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), or a halogeno group;
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ⁶ and R ⁷ may together form an ethylene group or a trimethylene group;
R ⁸ has the formula —N (R ¹⁰ ) ZR ¹¹ , —ZN (R ¹⁰ ) R ¹² , —ZR ¹² , —X ² N (R ¹⁰ ) ZR ¹¹ , —X ² ZN (R ¹⁰ ) R ¹² , or , -X ² ZR ¹²
[Wherein, R ¹⁰ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different, and 1 to 3 selected from the substituent group β) a group), (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₂ alkyl) group, C ₃ -C ₆ cycloalkyl group or a substituted C ₃ -C ₆ cycloalkyl group (the substituent, the Are the same or different and are 1 to 3 groups selected from the substituent group β),
R ¹¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a substituted C ₁ -C ₆ alkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group γ) , (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, substituted (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group (the substituents may be the same or different 1 to 3 groups selected from the substituent group γ), a phenyl- (C ₁ -C ₄ alkyl) group, a substituted phenyl- (C ₁ -C ₄ alkyl) group (substituent of the phenyl group) Are the same or different and are 1 to 3 groups selected from the substituent group β, and the substituents of the alkyl group are the same or different and are 1 to 3 groups selected from the substituent group γ present), (4-10 membered heterocyclyl) - (C ₁ -C ₄ alkyl) group, a substituted (4 to 10 membered heterocyclyl) - (C ₁ C ₄ alkyl) group (the substituent of the heterocyclyl group may be the same or different and are 1 to 3 groups selected from Substituent group beta, substituents of the alkyl groups may be the same or different, substituent group 1 to 3 groups selected from γ), a C ₃ -C ₆ cycloalkyl group, a substituted C ₃ -C ₆ cycloalkyl group (the substituents may be the same or different and selected from the substituent group γ). 1 to 3 groups), a C ₂ -C ₆ alkenyl group, a substituted C ₂ -C ₆ alkenyl group (the substituents are the same or different and are selected from 1 to 3 groups selected from the substituent group γ) A C ₁ -C ₆ alkoxy group, a substituted C ₁ -C ₆ alkoxy group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group γ), ( C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₃ -C ₆ A cycloalkyloxy group, a C ₃ -C ₆ alkenyloxy group, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed together with the nitrogen atom of the amino group. ), (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) amino group, C ₃ -C ₆ cycloalkylamino group, C ₃ -C ₆ alkenylamino group, N- (C ₁ -C ₆₎ Alkyl) -N-[(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, N- (C ₁ -C ₆ alkyl) -N- (C ₃ -C ₆ cycloalkyl) amino, N- (C ₁ -C ₆ alkyl) -N- (C ₃ -C ₆ alkenyl) amino group, off Nyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group β), 4 to 10 membered heterocyclyl group, or substituted (4 to 10 membered heterocyclyl) ) Groups (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), provided that the formulas —N (R ¹⁰ ) ZR ¹¹ and —X ² N (R ¹⁰ ) When Z is —SO ₂ — in ZR ¹¹ , R ¹¹ is not a hydrogen atom,
R ¹² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a substituted C ₁ -C ₆ alkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β) , (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, substituted (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group (the substituents may be the same or different 1 to 3 groups selected from substituent group β), phenyl- (C ₁ -C ₄ alkyl) group, substituted phenyl- (C ₁ -C ₄ alkyl) group (the substituents are the same) Or, it is 1 to 3 groups selected from the substituent group β), (5- to 7-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group, substituted (5- to 7-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group (said substituents may be the same or different and are 1 to 3 groups selected from substituent group beta), C ₃ -C _{A 6} cycloalkyl group, a substituted C ₃ -C ₆ cycloalkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a C ₂ -C ₆ alkenyl group, A substituted C ₂ -C ₆ alkenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a phenyl group, a substituted phenyl group (the substituents are the same or 5 to 7-membered heterocyclyl group or substituted (5- to 7-membered heterocyclyl) group (the substituents may be the same or different, Wherein R ¹² is not a hydrogen atom when Z is —SO ₂ — in the formulas —ZR ¹² and —X ² ZR ¹² ;
X ² represents a C ₁ -C ₂ alkylene group,
Z represents a group having the formula —CO—, —CS— or —SO ₂ —. A group having the formula:
X ¹ represents a single bond, a methylene group, or a substituted methylene group (the substituents are the same or different 1 to 2 C ₁ -C ₃ alkyl groups, and the two substituents are An ethylene group or a trimethylene group may be formed);
Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α), a 5- to 6-membered aromatic heterocyclyl group, or a substituted 5 group. To a 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
Substituent group α is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is a C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different), a formyl group, (C ₁ - A group consisting of a C ₄ alkyl) carbonyl group and a halogeno group;
Substituent group β is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), and show the group consisting of halogeno groups;
Substituent group γ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), C ₁ -C ₄ alkylthio groups, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different), a carboxyl group, (C ₁ -C ₄ alkoxy) carbonyl group, a cyano group, and shows a group consisting of halogeno group. ]
Or a pharmacologically acceptable salt or ester thereof.

  The present invention also provides a pharmaceutical composition comprising an effective amount of a pharmacological activity of the compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof, and a carrier or diluent. To do. In particular, the present invention provides the above-mentioned pharmaceutical composition for treatment or prevention in a warm-blooded animal, which is a human being a disease that can be treated or prevented by regulating LXR function in the warm-blooded animal. obtain. Preferably, the pharmaceutical composition is for treatment or prevention in a warm-blooded animal, the warm-blooded animal being atherosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia Hypercholesterolemia; lipid-related diseases; inflammatory diseases that are caused by inflammatory cytokines; autoimmune diseases; cardiovascular diseases; cerebrovascular diseases; kidney diseases; diabetes; diabetes complications; obesity; It can be a human being a disease selected from the group consisting of hepatitis; cancer; and Alzheimer's disease. More preferably, the pharmaceutical composition is for treatment or prevention in a warm-blooded animal, the warm-blooded animal being atherosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia Hypercholesterolemia; lipid-related diseases; inflammatory diseases that are caused by inflammatory cytokines; and humans that are diseases selected from the group consisting of diabetes. Most preferably, the pharmaceutical composition is for treatment or prevention in a warm-blooded animal, and the warm-blooded animal can be a human who has arteriosclerosis.

  The present invention also provides a compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof for use as a medicament.

  The present invention also provides use of one or more compounds represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof in the manufacture of a medicament for treatment or prevention in warm-blooded animals, The warm-blooded animal can be a human being a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal. Preferably, the disease that can be treated or prevented by modulation of LXR function in warm-blooded animals is arteriosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia; hypercholesterolemia; Lipid-related diseases; inflammatory diseases caused by inflammatory cytokines; autoimmune diseases; cardiovascular diseases; cerebrovascular diseases; kidney diseases; diabetes; diabetic complications; obesity; nephritis; Selected from the group consisting of Alzheimer's disease. More preferably, the disease is a disease caused by arteriosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia; hypercholesterolemia; lipid-related disease; inflammatory cytokines An inflammatory disease; and selected from the group consisting of diabetes. Most preferably, the disease is arteriosclerosis.

  The present invention also provides a method for treating or preventing a warm-blooded animal by administering to the warm-blooded animal an effective amount of the compound represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof. The warm-blooded animal provided can be a human being a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal. Preferably, the disease that can be treated or prevented by modulation of LXR function in warm-blooded animals is arteriosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia; hypercholesterolemia; Lipid-related diseases; inflammatory diseases caused by inflammatory cytokines; autoimmune diseases; cardiovascular diseases; cerebrovascular diseases; kidney diseases; diabetes; diabetic complications; obesity; nephritis; Selected from the group consisting of Alzheimer's disease. More preferably, the disease is a disease caused by arteriosclerosis; atherosclerosis; arteriosclerosis resulting from diabetes; hyperlipidemia; hypercholesterolemia; lipid-related disease; inflammatory cytokines An inflammatory disease; and selected from the group consisting of diabetes. Most preferably, the disease is arteriosclerosis.

The present invention also provides a compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof; an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a plasma HDL-elevating agent, a cholesterol Synthesis inhibitor, squalene epoxidase inhibitor, squalene synthetase inhibitor, hypercholesterolemia treatment agent, acyl-coenzyme A, cholesteryl ester transfer protein inhibitor (hereinafter referred to as CETP inhibitor), ACAT inhibitor, probucol, cholesterol Absorption inhibitor, bile acid adsorption ion exchange resin, fibrate, nicotinic acid derivative, niacinamide, LDL receptor inducer, vitamin B ₆ , vitamin B ₁₂ , antioxidant vitamin, angiotensin II inhibitor, angiotensin converting enzyme inhibitor , Β-blockers, fibrinogen inhibitors, aspirin, diuretics, and And a pharmaceutical selected from the group consisting of combinations thereof; and a pharmaceutical composition comprising a carrier or diluent.

In the compound represented by the general formula (I) of the above (1) of the present invention or a pharmacologically acceptable salt or ester thereof, a suitable compound is:
(2) R ¹ is a formula —COR ^9a [wherein R ^9a is a C ₁ -C ₆ alkyl group, a C ₁ -C ₈ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) oxy group, halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₃ —C ₅ cycloalkyloxy group, (C ₁ -C ₂ alkyl)-(C ₃ -C ₅ cycloalkyl) oxy group, C ₁ -C ₆ alkylamino group, or di (C ₁ -C ₆ alkyl) amino A group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom); A 5- to 7-membered saturated heterocyclyl group may be formed. A group having
Phenyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α1), 5 to 6-membered aromatic heterocyclyl group, or substituted 5 to 6-membered An aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α1);
Substituent group α1 is a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, an amino group, The compound described in (1), which represents a group consisting of a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a formyl group, an acetyl group, a fluoro group, a chloro group, and a bromo group;
(3) R ¹ is a formula —COR ^9b [wherein R ^9b is a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is 1 to 5) A C ₁ -C ₄ alkoxy group substituted with one halogeno group). A group having
A phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α2);
The substituent group α2 is a compound described in (1), which represents a group consisting of a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a fluoro group, and a chloro group,
(4) The compound according to ( ¹ ), wherein R ¹ is a group having the formula —COR ^9c (wherein R ^9c represents a C ₂ -C ₆ alkoxy group),
(5) R ¹ is (wherein, R ^9d is 2-methyl show a 2-propoxy group.) Formula -COR ^9d compounds described in a group (1) with (6) R ² is , A hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group. Compound,
(7) The compound according to any one of (1) to (5), wherein R ² is a hydrogen atom or a hydroxyl group,
(8) The compound according to any one of (1) to (5), wherein R ² is a hydroxyl group,
(9) R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C substituted with 1 to 5 halogeno groups) ₄ alkyl group), (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, hydroxyl group, C ₁ -C ₄ alkoxy groups, halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ alkoxy group, 1 to 5 substituents C ₁ -C ₄ alkoxy substituted with halogeno group a group), C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ Alkyl) amino group (the alkyl groups may be the same or different, The kill group together with the nitrogen atom of the amino group forms a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Or a compound described in any one of (1) to (8), which is a fluoro group, a chloro group, or a bromo group,
(10) R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C substituted with 1 to 5 halogeno groups) shows a ₄ alkyl group), one C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy, fluoro, or chloro groups (1) to (8) A compound described in
(11) R ³ is methyl group, ethyl group, 2-propyl group, 1-butyl group, 2-methyl-2-propyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoro The compound according to any one of (1) to (8), which is an ethyl group, a cyclopropyl group, or a vinyl group;
(12) R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group (1) to (11) A compound described in any of the above,
(13) The compound according to any one of (1) to (11), wherein R ⁴ and R ⁵ are a hydrogen atom,
(14) The compound according to any one of (1) to (13), wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group,
(15) The compound according to any one of (1) to (13), wherein R ⁶ and R ⁷ are a hydrogen atom,
(16) R ⁸ is of the formula ^{-N (R 10a) ZR 11a,} -ZN (R 10a) R 12a, -ZR 12a, -X 2 N (R 10a) ZR 11a, -X 2a ZN (R 10a) R ^12a or -X ^2a ZR ^12a
[Wherein, R ^10a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₃ alkyl group (the substituent is one group selected from the substituent group β1), ( C ₃ -C ₄ cycloalkyl) methyl group, C ₃ -C ₄ cycloalkyl group, or substituted C ₃ -C ₄ cycloalkyl group (the substituent is one group selected from substituent group β1) Is)
R ^11a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group γ1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different Or a phenyl- (C ₁ -C ₂ alkyl) group, a substituted phenyl- (C ₁ -C ₂ alkyl) group (substituent of the phenyl group). Are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different and are 1 to 2 groups selected from the substituent group γ1. A) (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, substituted (5- to 7-membered heterocyclyl)-( C ₁ -C ₂ alkyl) group (the substituents of the heterocyclyl group are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different, 1 or 2 groups selected from the substituent group γ1), a C ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (the substituents may be the same or different, and the substituent group γ1 A C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (the substituents are the same or different and are selected from the substituent group γ1). 2 groups), a C ₁ -C ₄ alkoxy group, a substituted C ₁ -C ₄ alkoxy group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ1) ), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) Oki Group, C ₃ -C ₄ alkenyloxy group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group is the amino group Together with the nitrogen atom, a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed), C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) amino group, C ₃ -C ₄ alkenyl group, a phenyl group or represents a 5 to 7-membered heterocyclyl group, provided that the formula -N (R ^10a) ZR ^11a and -X ^2a N (R ^10a) in ZR ^11a Z is -SO ₂ - when is, R ^11a is not hydrogen atom,
R ^12a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group β1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different A phenyl- (C ₁ -C ₂ alkyl) group, a (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, a C 1 -2 group selected from the substituent group β 1 ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (said substituents may be the same or different, from 1 to 2 groups selected from substituent group β1), C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (said substituents may be the same or different, 1乃selected from substituent group β1 A two group), a phenyl group or represents a 5 to 7-membered heterocyclyl group, however, Z in formula -ZR ^12a and -X ^2a ZR ^12a is -SO ₂ - when is, R ^12a is a hydrogen atom not,
X ^2a represents a methylene group. And a group having
Substituent group β1 is methyl group, ethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, hydroxyl group, methoxy group, ethoxy group, trifluoromethoxy group, fluoro group, A group consisting of a chloro group and a bromo group,
Substituent group γ1 includes methyl group, ethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, hydroxy group, methoxy group, ethoxy group, trifluoromethoxy group, methylthio group, , Ethylthio group, methylsulfinyl group, ethylsulfinyl group, methanesulfonyl group, ethanesulfonyl group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, cyano A compound according to any one of (1) to (15), which represents a group consisting of a group, a fluoro group, a chloro group, and a bromo group;
(17) R ⁸ is a group of the formula -N (R ^10b ) ZR ^11b or -ZN (R ^10b ) R ^12b
[Wherein, R ^10b represents a C ₁ -C ₄ alkyl group, a methoxymethyl group, a 2,2,2-trifluoroethyl group, a cyclopropylmethyl group, or a cyclopropyl group;
R ^11b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ2), (C ₃ -C ₄ cycloalkyl) ) Methyl group, substituted (C ₃ -C ₄ cycloalkyl) methyl group (the substituent is one group selected from substituent group γ2), C ₃ -C ₄ cycloalkyl group, C _2- C ₄ alkenyl group, C ₁ -C ₄ alkoxy group, (C ₃ -C ₄ cycloalkyl) methyloxy group, or C ₁ -C ₄ alkylamino group,
R ^12b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group β2), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or shows a C ₂ -C ₃ alkenyl group. And a group having
The substituent group β2 represents a group consisting of a methyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, a trifluoromethoxy group, a fluoro group, and a chloro group,
Substituent group γ2 is composed of a methyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an amino group, a methylamino group, a dimethylamino group, a fluoro group, and a chloro group. A compound described in any one of (1) to (15),
(18) R ⁸ is a compound of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
The substituent group γ3 is a compound described in any one of (1) to (15), which represents a group consisting of a methoxy group, a methylthio group, a methylamino group, and a dimethylamino group,
(19) R ⁸ is represented by the formula —N (R ^10d ) COR ^11d , —N (R ^10d ) CSR ^11d , or —N (R ^10d ) SO ₂ R ^11d.
[Wherein R ^10d represents a methyl group or an ethyl group,
R ^11d represents a methyl group, an ethyl group, a 2-propyl group, a methoxymethyl group, a methylthiomethyl group, a cyclopropylmethyl group, or a cyclopropyl group. Or a compound according to any one of (1) to (15),
(20) The compound according to any one of (1) to (19), wherein X ¹ is a single bond or a methylene group,
(21) The compound according to any one of (1) to (19), wherein X ¹ is a single bond,
(22) Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from the substituent group α1), a pyridyl group, or a substituted pyridyl group (the relevant The substituents are the same or different and are 1 to 2 groups selected from the substituent group α1, and the compounds according to any one of (1) to (21),
(23) Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from the substituent group α3), or a pyridyl group,
The substituent group α3 is a compound described in any one of (1) to (21), which represents a group consisting of a methoxy group, a methylamino group, a dimethylamino group, a fluoro group, and a chloro group, or
(24) The compound according to any one of (1) to (21), wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group).

In the compound represented by the general formula (I) of the above (1) of the present invention or a pharmacologically acceptable salt or ester thereof, R ¹ selected from (2) to (5), (6) to R ² selected from (8), R ³ selected from (9) to (11), R ⁴ and R ⁵ selected from (12) to (13), and selected from (14) to (15) R ⁶ and R ⁷ , R ⁸ selected from (16) to (19), X ¹ selected from (20) to (21), and Y selected from (22) to (24) A compound obtained by arbitrarily combining or a pharmacologically acceptable salt or ester thereof is more preferred. Such more preferred compounds are, for example,
(25) R ¹ is a formula —COR ^9a [wherein R ^9a is a C ₁ -C ₆ alkyl group, a C ₁ -C ₈ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) oxy group, halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₃ —C ₅ cycloalkyloxy group, (C ₁ -C ₂ alkyl)-(C ₃ -C ₅ cycloalkyl) oxy group, C ₁ -C ₆ alkylamino group, or di (C ₁ -C ₆ alkyl) amino A group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom); A 5- to 7-membered saturated heterocyclyl group may be formed. A group having
Phenyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α1), 5 to 6-membered aromatic heterocyclyl group, or substituted 5 to 6-membered An aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α1);
R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group,
R ³ is, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, one to five C ₁ -C ₄ alkyl group substituted with halogeno group shown), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group, C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, hydroxyl Group, C ₁ -C ₄ alkoxy group, halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups) ), C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino Groups (the alkyl groups are the same or different, Together with the nitrogen atom of the amino group to form a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom Good), a fluoro group, a chloro group, or a bromo group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group,
R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group,
R ⁸ is represented by the formula -N (R ^10a ) ZR ^11a , -ZN (R ^10a ) R ^12a , -ZR ^12a , -X ² N (R ^10a ) ZR ^11a , -X ^2a ZN (R ^10a ) R ^12a , or , -X ^2a ZR ^12a
[Wherein, R ^10a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₃ alkyl group (the substituent is one group selected from the substituent group β1), ( C ₃ -C ₄ cycloalkyl) methyl group, C ₃ -C ₄ cycloalkyl group, or substituted C ₃ -C ₄ cycloalkyl group (the substituent is one group selected from substituent group β1) Is)
R ^11a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group γ1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different Or a phenyl- (C ₁ -C ₂ alkyl) group, a substituted phenyl- (C ₁ -C ₂ alkyl) group (substituent of the phenyl group). Are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different and are 1 to 2 groups selected from the substituent group γ1. A) (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, substituted (5- to 7-membered heterocyclyl)-( C ₁ -C ₂ alkyl) group (the substituents of the heterocyclyl group are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different, 1 or 2 groups selected from the substituent group γ1), a C ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (the substituents may be the same or different, and the substituent group γ1 A C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (the substituents are the same or different and are selected from the substituent group γ1). 2 groups), a C ₁ -C ₄ alkoxy group, a substituted C ₁ -C ₄ alkoxy group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ1) ), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) Oki Group, C ₃ -C ₄ alkenyloxy group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group is the amino group Together with the nitrogen atom, a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed), C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) amino group, C ₃ -C ₄ alkenyl group, a phenyl group or represents a 5 to 7-membered heterocyclyl group, provided that the formula -N (R ^10a) ZR ^11a and -X ^2a N (R ^10a) in ZR ^11a Z is -SO ₂ - when is, R ^11a is not hydrogen atom,
R ^12a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group β1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different A phenyl- (C ₁ -C ₂ alkyl) group, a (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, a C 1 -2 group selected from the substituent group β 1 ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (said substituents may be the same or different, from 1 to 2 groups selected from substituent group β1), C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (said substituents may be the same or different, 1乃selected from substituent group β1 A two group), a phenyl group or represents a 5 to 7-membered heterocyclyl group, however, Z in formula -ZR ^12a and -X ^2a ZR ^12a is -SO ₂ - when is, R ^12a is a hydrogen atom not,
X ^2a represents a methylene group. And a group having
X ¹ is a single bond or a methylene group,
Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from the substituent group α1), a pyridyl group, or a substituted pyridyl group (the substituent is Are the same or different and are 1 to 2 groups selected from the substituent group α1, and the compounds described in (1),
(26) R ¹ is the formula —COR ^9b [wherein R ^9b is a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is 1 to 5) pieces of C ₁ -C substituted with halogeno group ₄ denotes an alkoxy group indicates a). A group having
A phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α2);
R ² is a hydrogen atom or a hydroxyl group,
R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups) the illustrated), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or a chloro group,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10b ) ZR ^11b or —ZN (R ^10b ) R ^12b
[Wherein, R ^10b represents a C ₁ -C ₄ alkyl group, a methoxymethyl group, a 2,2,2-trifluoroethyl group, a cyclopropylmethyl group, or a cyclopropyl group;
R ^11b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ2), (C ₃ -C ₄ cycloalkyl) ) Methyl group, substituted (C ₃ -C ₄ cycloalkyl) methyl group (the substituent is one group selected from substituent group γ2), C ₃ -C ₄ cycloalkyl group, C _2- C ₄ alkenyl group, C ₁ -C ₄ alkoxy group, (C ₃ -C ₄ cycloalkyl) methyloxy group, or C ₁ -C ₄ alkylamino group,
R ^12b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group β2), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or shows a C ₂ -C ₃ alkenyl group. And a group having
X ¹ is a single bond,
The compound according to (1), wherein Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from substituent group α3), or a pyridyl group,
(27) R ¹ is a group having the formula —COR ^9c (wherein R ^9c represents a C ₂ -C ₆ alkoxy group);
R ² is a hydrogen atom or a hydroxyl group,
R ³ is methyl group, ethyl group, 2-propyl, 2-methyl-2-propyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, a cyclopropyl group, or be a vinyl group ,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
X ¹ is a single bond,
The compound according to (1), wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group);
(28) R ¹ is a group having the formula —COR ^9d (wherein R ^9d represents a 2-methyl-2-propoxy group);
R ² is a hydroxyl group,
R ³ is a methyl group, an ethyl group, a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, or a vinyl group. ,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10d ) COR ^11d , —N (R ^10d ) CSR ^11d , or —N (R ^10d ) SO ₂ R ^11d
[Wherein R ^10d represents a methyl group or an ethyl group,
R ^11d represents a methyl group, an ethyl group, a 2-propyl group, a methoxymethyl group, a methylthiomethyl group, a cyclopropylmethyl group, or a cyclopropyl group. And a group having
The compound according to claim 1, wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group).
(29) tert-butyl 2-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3-isopropylbenzoate,
tert-butyl 3-tert-butyl-6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxybenzoate,
tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [methyl (propionyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [butyryl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [isobutyryl (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4-[(methoxyacetyl) (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-[(4- {methyl [(methylthio) acetyl] amino} phenoxy) methyl] -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylacetyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [methyl (methylsulfonyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonothioyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [ethyl (methylsulfonyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylsulfonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -2-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate, and
tert-Butyl 6-({4-[(Cyclopropylcarbonyl) (methyl) amino] -3-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (1 ) Or a compound described in
(30) R ¹ is a formula —COR ^9b [wherein R ^9b is a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is 1 to 5) Represents a C ₁ -C ₄ alkoxy group substituted with one halogeno group). And a group having
R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group,
R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups) the illustrated), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or a chloro group,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
X ¹ is a single bond,
The compound described in (1), wherein Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from substituent group α3), or a pyridyl group.

The present invention also provides:
(31) A pharmaceutical comprising the compound according to any one of (1) to (30) or a pharmacologically acceptable salt or ester thereof as an active ingredient,
(32) Inflammatory diseases in which the medicament is a disease caused by arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, hypercholesterolemia, lipid-related diseases, inflammatory cytokines For the treatment or prevention of a disease selected from the group consisting of: autoimmune disease, cardiovascular disease, cerebrovascular disease, kidney disease, diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, and Alzheimer's disease The medicine described in (31), which is a medicine of
(33) an inflammatory disease in which the medicament is a disease caused by arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, hypercholesterolemia, lipid-related disease, inflammatory cytokine, And the medicament described in (31), which is a medicament for treating or preventing a disease selected from the group consisting of diabetes, or
(34) The medicament according to (31), wherein the medicament is a medicament for treating or preventing a disease selected from the group consisting of arteriosclerosis, atherosclerosis and arteriosclerosis caused by diabetes Also provide.

Furthermore, the present invention provides
(35) The compound described in any one of (1) to (30) or a pharmacologically acceptable salt or ester thereof; and an HMG-CoA reductase inhibitor, CETP inhibitor, ACAT inhibitor, cholesterol absorption inhibition A drug selected from the group consisting of an agent, a bile acid-adsorbing ion exchange resin, a fibrate, a nicotinic acid derivative, an angiotensin II inhibitor, a diuretic, and combinations thereof, simultaneously or separately A pharmaceutical composition of
(36) The pharmaceutical composition according to (35), wherein the drug is an HMG-CoA reductase inhibitor,
(37) The pharmaceutical composition according to (35), wherein the drug is pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, or rosuvastatin,
(38) The pharmaceutical composition according to (35), wherein the drug is pravastatin, atorvastatin or rosuvastatin.

The “C ₁ -C ₁₀ alkyl group” in R ⁹ of the general formula (I) is a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, 1- Propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group 2-methyl-2-butyl group, 3-methyl-2-butyl group, 1,1-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1 -Pentyl group, 3-methyl-3-pentyl group, 2-ethyl-1-butyl group, 2,3-dimethyl-1-butyl group, 3-heptyl group, 4-heptyl group, 3-methyl-3-hexyl Group, 3-ethyl-3-pentyl group, 3-octyl group, 4-octyl group Group, 3-ethyl-3-hexyl group, 4-nonyl group, 5-nonyl group, 4-ethyl-4-heptyl group, 4-decyl group, 5-decyl group, or 4- (1-propyl) It is a 4-heptyl group, preferably a C ₁ -C ₆ alkyl group, more preferably a C ₂ -C ₆ alkyl group, more preferably, C ₃ -C ₅ alkyl group It is.

The “C ₁ -C ₁₀ alkoxy group” in R ⁹ of the general formula (I) is a hydroxyl group substituted with the above C ₁ -C ₁₀ alkyl group, and examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, 2-methyl-1-propoxy group, 2-methyl-2-propoxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group 2-methyl-2-butoxy group, 3-methyl-2-butoxy group, 2-methyl-2-butoxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl- 1-pentyloxy group, 3-methyl-3-pentyloxy group, 2-ethyl-1-butoxy group, 2,3-dimethyl-1-butoxy group, 1-heptyloxy group, 3-heptyloxy group, 4- F Butyloxy group, 3-methyl-3-hexyloxy group, 3-ethyl-3-pentyloxy group, 3-octyloxy group, 4-octyloxy group, 3-ethyl-3-hexyloxy group, 4-nonyloxy group, It may be a 5-nonyloxy group, a 4-ethyl-4-heptyloxy group, a 4-decyloxy group, a 5-decyloxy group, or a 4- (1-propyl) -4-heptyloxy group, preferably C ₁ a -C ₆ alkoxy group, more preferably a C ₂ -C ₆ alkoxy group, more preferably a C ₃ -C ₆ alkoxy group, even more preferably, C ₃ -C ₅ alkoxy Group (particularly 2-propoxy group, 2-methyl-2-propoxy group or 2-methyl-2-butoxy group), and most preferably 2-methyl-2-propoxy group.

R ³ in the general formula ^{(I), R 4, R} 5, R 10, R 11, and, "C ₃ -C ₆ cycloalkyl group" in R ^12, and, C ₃ -C ₆ cycloalkyl in each substituent The moiety is a cyclic alkyl group having 3 to 6 carbon atoms, and may be, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and preferably a C ₃ -C ₅ cycloalkyl group. More preferably a C ₃ -C ₄ cycloalkyl group, and most preferably a cyclopropyl group.

Formula R ⁴ in ^{(I), R 5, R} 10, Substituent group alpha, Substituent group beta, and "C ₁ -C ₄ alkyl group" in Substituent group gamma, and, C ₁ in the respective substituent The —C ₄ alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, It can be a 2-butyl group, a 2-methyl-1-propyl group, or a 2-methyl-2-propyl group, preferably a C ₁ -C ₃ alkyl group, more preferably a methyl group or An ethyl group, most preferably a methyl group.

General formula (I) of ^{R 2, R 4, R 5} , Substituent group alpha, Substituent group beta, and "C ₁ -C ₄ alkoxy group" in Substituent group gamma, and, C ₁ in the respective substituent The —C ₄ alkoxy moiety or C ₁ -C ₄ alkyloxy moiety is a hydroxyl group substituted with one of the above C ₁ -C ₄ alkyl groups, for example, methoxy group, ethoxy group, 1-propoxy group, 2 It can be a propoxy group, a 1-butoxy group, a 2-butoxy group, or a 2-methyl-2-propoxy group. The “C ₁ -C ₄ alkoxy group” in the substituent group α, the substituent group β and the substituent group γ is preferably a C ₁ -C ₃ alkoxy group, more preferably a methoxy group or an ethoxy group. And most preferably a methoxy group.

The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy group” in R ⁹ and R ¹¹ of the general formula (I) is substituted with one of the above C ₃ -C ₆ cycloalkyl groups. The above-mentioned C ₁ -C ₄ alkoxy group, for example, cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxy group, 1-cyclohexane Butylethoxy group, 2-cyclobutylethoxy group, 1-cyclopentylethoxy group, 2-cyclopentylethoxy group, 1-cyclohexylethoxy group, 2-cyclohexylethoxy group, 1-cyclopropyl-1-propoxy group, 2-cyclopropyl- 1-propoxy group, 3-cyclopropyl-1-propoxy group, 1-cyclopropyl-2-propoxy group Si group, 2-cyclopropyl-2-propoxy group, 1-cyclobutyl-1-propoxy group, 3-cyclobutyl-1-propoxy group, 3-cyclopentyl-1-propoxy group, 3-cyclohexyl-1-propoxy group, 1 -Cyclopropyl-1-butoxy group, 4-cyclopropyl-1-butoxy group, 4-cyclopropyl-2-butoxy group, 3-cyclopropyl-2-methyl-1-propoxy group, 1-cyclopropyl-2- It may be a methyl-2-propoxy group, a 1-cyclobutyl-1-butoxy group, a 4-cyclobutyl-1-butoxy group, a 4-cyclopentyl-1-butyl group, or a 4-cyclohexyl-1-butyl group. The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy group” in R ⁹ is preferably (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) oxy. More preferably a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy group. The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy group” in R ¹¹ is preferably (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) oxy. Group, more preferably a (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy group, and still more preferably a cyclopropylmethyloxy group or a cyclobutylmethyloxy group. .

The “halogeno C ₁ -C ₁₀ alkoxy group” in R ⁹ of the general formula (I) is the above C ₁ -C ₁₀ alkoxy group substituted with 1 to 7 of the following halogeno groups, such as a fluoromethoxy group, Difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-bromoethoxy group, 2-chloroethoxy group, 2-iodoethoxy group, 2,2-difluoro Ethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoro-1-propoxy group, 1,1,1-tri Fluoro-2-propoxy group, 1,1,1-trichloro-2-propoxy group, 4,4,4-trifluoro-1-butoxy group, 4,4,4-trifluoro-2 Butoxy group, 2-trifluoromethyl-1-propoxy group, 2-trifluoromethyl-2-propoxy group, 5,5,5-trifluoro-1-pentyloxy group, 5,5,5-trifluoro-2 -Pentyloxy group, 1,1,1-trifluoro-3-pentyloxy group, 4,4,4-trifluoro-2-methyl-2-butoxy group, 4,4,4-trifluoro-3-methyl 2-butoxy group, 4,4,4-trifluoro-2-methyl-2-butoxy group, 6,6,6-trifluoro-1-hexyloxy group, 6,6,6-trifluoro-2- Hexyloxy group, 6,6,6-trifluoro-3-hexyloxy group, 5,5,5-trifluoro-2-methyl-1-pentyloxy group, 1,1,1-trifluoro-3-methyl -3-pentyloxy group, 6,6,6-trifluoro-2- Tyl-1-butoxy group, 6,6,6-trifluoro-2,3-dimethyl-1-butoxy group, 7,7,7-trifluoro-1-heptyloxy group, 7,7,7-trifluoro -3-heptyloxy group, 1,1,1-trifluoro-4-heptyloxy group, 6,6,6-trifluoro-3-methyl-3-hexyloxy group, 1,1,1-trifluoro- 3-ethyl-3-pentyloxy group, 8,8,8-trifluoro-3-octyloxy group, 8,8,8-trifluoro-4-octyloxy group, 6,6,6-trifluoro-3 -Ethyl-3-hexyloxy group, 9,9,9-trifluoro-4-nonyloxy group, 9,9,9-trifluoro-5-nonyloxy group, 1,1,1-trifluoro-4-ethyl- 4-heptyloxy group, 9,9,9-trifluoro-4-decyloxy group, 9 , 9,9-trifluoro-5-decyloxy group, or 1,1,1-trifluoro-4- (1-propyl) -4-heptyloxy group, preferably halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), more preferably halogeno C ₁ -C ₄ An alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), and more preferably a halogeno C ₃ -C ₄ alkoxy group Group (wherein the halogeno C ₃ -C ₄ alkoxy group represents a C ₃ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), most preferably 1,1,1-trifluoro 2-propoxy group or 2-trifluoromethyl 2-propoxy.

The “phenyl- (C ₁ -C ₁₀ alkoxy) group” in R ⁹ of the general formula (I) is the above C ₁ -C ₁₀ alkoxy group substituted with one phenyl group, such as a phenylmethoxy group, Phenylethoxy group, 3-phenyl-1-propoxy group, 1-phenyl-2-propoxy group, 4-phenyl-1-butoxy group, 1-phenyl-2-butoxy group, 3-phenyl-2-methyl-1- Propoxy group, 1-phenyl-2-methyl-2-propoxy group, 5-phenyl-1-pentyloxy group, 5-phenyl-2-pentyloxy group, 1-phenyl-3-pentyloxy group, 4-phenyl- 2-methyl-2-butoxy group, 4-phenyl-3-methyl-2-butoxy group, 4-phenyl-2-methyl-2-butoxy group, 6-phenyl-1-hexyloxy group, 6-phenyl Ru-2-hexyloxy group, 6-phenyl-3-hexyloxy group, 5-phenyl-2-methyl-1-pentyloxy group, 1-phenyl-3-methyl-3-pentyloxy group, 4-phenyl- 2-ethyl-1-butoxy group, 4-phenyl-2,3-dimethyl-1-butoxy group, 7-phenyl-1-heptyloxy group, 7-phenyl-3-heptyloxy group, 1-phenyl-4- Heptyloxy group, 6-phenyl-3-methyl-3-hexyloxy group, 1-phenyl-3-ethyl-3-pentyloxy group, 8-phenyl-3-octyloxy group, 8-phenyl-4-octyloxy group Group, 6-phenyl-3-ethyl-3-hexyloxy group, 9-phenyl-4-nonyloxy group, 1-phenyl-5-nonyloxy group, 1-phenyl-4-ethyl- -Heptyloxy group, 9-phenyl-4-decyloxy group, 1-phenyl-5-decyloxy group, or 1-phenyl-4- (1-propyl) -4-heptyloxy group, A phenyl- (C ₁ -C ₆ alkoxy) group, more preferably a phenyl- (C ₁ -C ₄ alkoxy) group, and even more preferably a phenyl- (C ₁ -C ₃ alkoxy) group And most preferably a 1-phenyl-1-ethyl group or a 2-phenyl-2-propyl group.

The “C ₃ -C ₆ cycloalkyloxy group” in R ⁹ and R ¹¹ of the general formula (I) is a hydroxyl group substituted with one of the above C ₃ -C ₆ cycloalkyl groups, for example, cyclopropyl It may be an oxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group, preferably a C ₃ -C ₅ cycloalkyloxy group, more preferably a C ₃ -C _A cycloalkyloxy group, most preferably a cyclopropyloxy group.

The “(C ₁ -C ₄ alkyl)-(C ₃ -C ₆ cycloalkyl) oxy group” in R ⁹ of the general formula (I) is the above C substituted with _one C ₁ -C ₄ alkyl group. ₃ -C ₆ cycloalkyloxy group, for example, 1-methylcyclopropyloxy group, 2-methylcyclopropyloxy group, 1-ethylcyclopropyloxy group, 2-ethylcyclopropyloxy group, 1- (1- Propyl) cyclopropyloxy group, 1- (1-butyl) cyclopropyloxy group, 1-methylcyclobutyloxy group, 2-methylcyclobutyloxy group, 3-methylcyclobutyloxy group, 1-ethylcyclobutyloxy group 2-ethylcyclobutyloxy group, 3-ethylcyclobutyloxy group, 1- (1-propyl) cyclobutyloxy group, 1-methylcyclopentyloxy group, It may be a rucyclopentyloxy group, 1- (1-propyl) cyclopentyloxy group, 1-methylcyclohexyloxy group, 1-ethylcyclohexyloxy group, or 1- (1-propyl) cyclohexyloxy group, (C ₁ -C ₂ alkyl)-(C ₃ -C ₅ cycloalkyl) oxy group, more preferably 1-methyl- (C ₃ -C ₅ cycloalkyl) oxy group or 1-ethyl- (C a ₃ -C ₅ cycloalkyl) oxy group, and most preferably, is 1-methyl-1-cyclopropyl group, 1-methyl-1-cyclobutyl group or 1-methyl-1-cyclopentyloxy .

The “C ₁ -C ₁₀ alkylamino group” in R ⁹ of the general formula (I) is an amino group substituted with _one C ₁ -C ₁₀ alkyl group, for example, a methylamino group, an ethylamino group 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, 2-methyl-1-propylamino group, 2-methyl-2-propylamino group, 1-pentylamino group, 2-pentyl Amino group, 3-pentylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 2-methyl-2-butylamino group, 1-hexylamino group, 2-hexylamino group 3-hexylamino group, 2-methyl-1-pentylamino group, 3-methyl-3-pentylamino group, 2-ethyl-1-butylamino group, 2,3-dimethyl-1-butylamino group, 1 -Hepti Ruamino group, 3-heptylamino group, 4-heptylamino group, 3-methyl-3-hexylamino group, 3-ethyl-3-pentylamino group, 3-octylamino group, 4-octylamino group, 3-ethyl -3-hexylamino group, 4-nonylamino group, 5-nonylamino group, 4-ethyl-4-heptylamino group, 4-decylamino group, 5-decylamino group, or 4- (1-propyl) -4-heptyl obtained an amino group, preferably a C ₁ -C ₆ alkylamino group, more preferably a C ₂ -C ₆ alkylamino group, more preferably, C ₃ -C ₆ alkylamino group , still more preferably, C ₃ -C ₅ alkylamino group (particularly, 2-propylamino group, 2-methyl-2-propylamino group or a 2-methyl-2-butylamino group) der , Most preferably a 2-methyl-2-propylamino group.

The “di (C ₁ -C ₁₀ alkyl) amino group” in R ⁹ of the general formula (I) is an amino group substituted with the same or different two C ₁ -C ₁₀ alkyl groups, for example, dimethyl Amino group, methylethylamino group, methylpropylamino group [for example, N- (1-propyl) -N-methylamino group and the like], methylbutylamino group [for example, N- (1-butyl) -N-methylamino Group, N-methyl-N- (2-methyl-2-propyl) amino group and the like], N-methyl-N- (2-methyl-2-butyl) amino group, N-methyl-N- (3-methyl -3-pentyl) amino group, N-methyl-N- (3-ethyl-3-pentyl) amino group, N-methyl-N- (3-ethyl-3-hexyl) amino group, N-methyl-N- (4-Ethyl-4-heptyl) amino group, N-methyl-N- [4- (1-pro Pyr) -4-heptyl] amino group, diethylamino group, ethylpropylamino group [for example, N- (1-propyl) -N-ethylamino group, etc.], N-ethyl-N- (2-methyl-2-propyl) ) Amino group, N-ethyl-N- (2-methyl-2-butyl) amino group, N-ethyl-N- (3-methyl-3-pentyl) amino group, N-ethyl-N- (3-ethyl) -3-pentyl) amino group, dipropylamino group [for example, di (1-propyl) amino group, di (2-propyl) amino group, etc.], N- (1-propyl) -N- (2-methyl- 2-propyl) amino group, dibutylamino group [eg, di (1-butyl) amino group, di (2-butyl) amino group, etc.], di (2-methyl-1-propyl) amino group, di (2- Methyl-2-propyl) amino group, N- (1-butyl) -N- (2-methyl-2-propyl) Amino group, dipentylamino group [eg, di (1-pentyl) amino group, di (2-pentyl) amino group, di (3-pentyl) amino group, etc.], di (2-methyl-1-butyl) amino group , Di (2-ethyl-1-propyl) amino group, N- (1-pentyl) -N- (2-methyl-2-propyl) amino group, dihexylamino group [for example, di (1-hexyl) amino group , Di (2-hexyl) amino group, di (3-hexyl) amino group, etc.], di (2-methyl-1-pentyl) amino group, di (3-methyl-1-pentyl) amino group, di (4 -Methyl-1-pentyl) amino group, di (2-methyl-2-pentyl) amino group, di (3-methyl-2-pentyl) amino group, di (4-methyl-2-pentyl) amino group, di (2,2-dimethyl-1-butyl) amino group, di (3,3-dimethyl-1-butyl) amino group, di (2, 3-dimethyl-1-butyl) amino group, di (2-ethyl-1-butyl) amino group, N- (1-hexyl) -N- (2-methyl-2-propyl) amino group, diheptylamino group [For example, di (1-heptyl) amino group, di (2-heptyl) amino group, etc.], di (3-ethyl-3-pentyl) amino group, dioctylamino group [for example, di (1-octyl) amino group , Di (2-octyl) amino group, di (4-octyl) amino group, etc.], di (3-ethyl-3-hexyl) amino group, dinonylamino group [eg, di (5-nonyl) amino group, etc.], It may be a di (4-ethyl-4-heptyl) amino group, a didecylamino group [for example, a di (5-decyl) amino group or the like], or a di [4- (1-propyl) -4-heptyl] amino group. , preferably a di (C ₁ -C ₆ alkyl) amino group, more preferably a di (C ₂ C ₆ alkyl) amino group or N- (C ₁ -C ₄ alkyl) -N- (C ₂ -C ₆ alkyl) amino group, more preferably a di (C ₃ -C ₆ alkyl) amino group or N- (C ₁ -C ₄ alkyl) -N- (C ₃ -C ₆ alkyl) amino group, and even more preferably a di (C ₃ -C ₅ alkyl) amino group or N- (C _1- C ₄ alkyl) -N- (C ₃ -C ₅ alkyl) amino group, most preferably N-methyl-N- (2-methyl-2-propyl) amino group, N-ethyl-N- ( 2-methyl-2-propyl) amino group, N- (1-propyl) -N- (2-methyl-2-propyl) amino group, N- (1-butyl) -N- (2-methyl-2- A propyl) amino group or a di (2-methyl-2-propyl) amino group. In addition, the “di (C ₁ -C ₁₀ alkyl) amino group” is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, wherein the two alkyl groups together with the nitrogen atom of the amino group A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed. Examples of the 5- to 7-membered saturated heterocyclyl group include a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group. A 5- to 6-membered saturated heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and preferably a perhydroazepinyl group More preferably, it is a pyrrolidinyl group, piperidyl group, morpholinyl group, or thiomorpholinyl group, and more preferably a piperidyl group or morpholinyl group. Is a group.

The “C ₆ -C ₁₀ aryl group” in R ¹ of the general formula (I) is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and may be, for example, a phenyl group or a naphthyl group, Is a phenyl group.

The “5- to 10-membered aromatic heterocyclyl group” in R ¹ of the general formula (I) is a 5- to 10-membered aromatic containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. For example, furyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, 1,2,3 -Thiadiazolyl, triazolyl, tetrazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl, azosinyl, azoninyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxa Zolyl group, benzisoxazolyl group, benzothiazolyl group, ben It may be a zoisothiazolyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, and preferably a 5 to 6 member containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An aromatic heterocyclyl group, more preferably a 5- to 6-membered aromatic heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and more preferably Is an imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group or pyridyl group.

The “halogeno C ₁ -C ₄ alkyl group” in R ² , R ⁴ , R ⁵ , substituent group α, substituent group β, and substituent group γ of the general formula (I) is 1 to 5 is the C ₁ -C ₄ alkyl group substituted with halogeno group, for example, fluoromethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-bromoethyl group, 2-chloroethyl group, 2-iodoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, 3 -Fluoropropyl group, 3-chloropropyl group, 3,3,3-trifluoropropyl group, 4-fluorobutyl group, or 4,4,4-trifluorobutyl group, preferably halogen C ₁ -C ₂ alkyl group (said halogeno C ₁ -C ₂ alkyl group has 1 to show the five C ₁ -C ₂ alkyl group substituted with halogeno group), more preferably, trifluoromethyl A methyl group, a 2,2,2-trifluoroethyl group, or a pentafluoroethyl group, and most preferably a trifluoromethyl group.

R ^{2 in the} general formula (I), the “C ₁ -C ₄ alkylamino group” in the substituent group α and the substituent group γ, and the C ₁ -C ₄ alkylamino moiety in each substituent group are the above C ₁ — An amino group substituted with a C ₄ alkyl group, for example, a methylamino group, an ethylamino group, a propylamino group (for example, a 1-propylamino group, a 2-propylamino group), a 1-butylamino group, 2- butylamino group, 2-methyl-1-propylamino group, or, can be a 2-methyl-2-propylamino group, preferably a C ₁ -C ₃ alkylamino group, and more preferably, methyl An amino group or an ethylamino group, and most preferably a methylamino group.

“Di (C ₁ -C ₄ alkyl) amino group” in R ² , substituent group α, and substituent group γ of general formula (I) is substituted with the same or different two C ₁ -C ₄ alkyl groups. For example, a dimethylamino group, a methylethylamino group, a methylpropylamino group [for example, N- (1-propyl) -N-methylamino group etc.], a methylbutylamino group [for example, N- (1-butyl) -N-methylamino group etc.], diethylamino group, ethylpropylamino group [eg N- (1-propyl) -N-ethylamino group etc.], dipropylamino group [eg di (1 -Propyl) amino group, di (2-propyl) amino group, etc.], di (1-butyl) amino group, di (2-butyl) amino group, di (2-methyl-1-propyl) amino group, or Di (2-methyl-2-propyl) amino group Preferably, di (C ₁ -C ₃ alkyl) amino group (said alkyl group may be the same or different), more preferably, dimethylamino group, methylethylamino group, methylpropylamino group, a diethylamino group , Ethylpropylamino group or dipropylamino group, more preferably dimethylamino group or diethylamino group, and most preferably dimethylamino group.

The “halogeno group” in R ² , R ³ , R ⁴ , R ⁵ , substituent group α, substituent group β, and substituent group γ of the general formula (I) is a fluoro group, a chloro group, a bromo group, Alternatively, it may be an iodo group, preferably a fluoro group, a chloro group or a bromo group, more preferably a fluoro group or a chloro group, and most preferably a fluoro group.

The “C ₁ -C ₆ alkyl group” in R ³ , R ¹¹ and R ¹² of the general formula (I) is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group Ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-pentyl group, 2-pentyl Group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3 -Methyl-1-pentyl group, 2-ethyl-1-butyl group, 2,2-dimethyl-1-butyl group, or 2,3-dimethyl-1-butyl group, preferably C ₁ a -C ₄ alkyl group, more preferably, C ₁ -C ₃ alkyl group (especially, methyl , An ethyl group or a propyl group), more preferably, a methyl group or an ethyl group, and most preferably a methyl group.

The “halogeno C ₁ -C ₆ alkyl group” in R ³ of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted with 1 to 7 of the above halogeno groups, such as a fluoromethyl group, Difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-bromoethyl group, 2-chloroethyl group, 2-iodoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, trichloroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 3-chloropropyl group, 3,3,3-trifluoropropyl group, 4-fluorobutyl group, 4 , 4,4-trifluorobutyl group, 5-fluoropentyl group, 5,5,5-trifluoropentyl group, 6-fluorohexyl group, or 6,6,6 Be a trifluoromethyl hexyl group, preferably a halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups a shown), and more preferably a halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, 1 to 5 fluoro, C ₁ -C substituted with chloro or bromo groups ₄ is a trifluoromethyl group, 2,2,2-trifluoroethyl group, or a pentafluoroethyl group, and most preferably a trifluoromethyl group. is there.

The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group” in R ³ , R ¹¹ and R ¹² of the general formula (I) represents one of the above C ₃ -C ₆ cycloalkyl groups. The C ₁ -C ₄ alkyl group substituted with, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylmethyl group, 1-cyclopropylethyl group, 2-cyclopropyl Ethyl group, 2-cyclobutylethyl group, 2-cyclopentylethyl group, 2-cyclohexylethyl group, 3-cyclopropyl-1-propyl group, 2-cyclopropyl-1-propyl group, 1-cyclopropyl-2-propyl group Group, 2-cyclopropyl-2-propyl group, 3-cyclobutyl-1-propyl group, 3-cyclopentyl-1-propyl group, 3-cyclohex Sil-1-propyl group, 4-cyclopropyl-1-butyl group, 4-cyclopropyl-2-butyl group, 3-cyclopropyl-2-methyl-1-propyl group, 1-cyclopropyl-2-methyl- It can be a 2-propyl group, a 4-cyclobutyl-1-butyl group, a 4-cyclopentyl-1-butyl group, or a 4-cyclohexyl-1-butyl group, preferably (C ₃ -C ₅ cycloalkyl) A — (C ₁ -C ₂ alkyl) group, more preferably a (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) group, and even more preferably a (C ₃ -C ₂ ) group. ₄ cycloalkyl) methyl group, most preferably a cyclopropylmethyl group.

R ³ in the general formula (I) "(C ₁ -C ₄ alkoxy) - (C ₁ -C ₄ alkyl) group", one of the C ₁ -C ₄ above C ₁ substituted with an alkoxy group - C ₄ alkyl group, for example, methoxymethyl group, ethoxymethyl group, (1-propoxy) methyl group, (2-propoxy) methyl group, (1-butoxy) methyl group, (2-butoxy) methyl group, ( 2-methyl-2-propoxy) methyl group, methoxyethyl group, ethoxyethyl group, (1-propoxy) ethyl group, (2-propoxy) ethyl group, (1-butoxy) ethyl group, (2-butoxy) ethyl group , (2-methyl-2-propoxy) ethyl group, methoxy (1-propyl) group, ethoxy (1-propyl) group, (1-propoxy)-(1-propyl) group, (1-butoxy)-(1 -Propyl) group, methoxy (1-butyl) group, ethoxy (1-butyl) group, (1 -Propoxy)-(1-butyl) group or (1-butoxy)-(1-butyl) group, preferably (C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkyl) More preferably a methoxymethyl group or an ethoxymethyl group, and most preferably a methoxymethyl group.

The “C ₁ -C ₄ alkylthio group” in the substituent group γ of the general formula (I) and the C ₁ -C ₄ alkylthio moiety in R ³ were substituted with one of the above C ₁ -C ₄ alkyl groups. A mercapto group, for example, a methylthio group, an ethylthio group, a 1-propylthio group, a 2-propylthio group, a 1-butylthio group, a 2-butylthio group, or a 2-methyl-2-propylthio group, preferably a C ₁ -C ₃ alkylthio group, more preferably a methylthio group or an ethylthio group, and most preferably a methylthio group.

R ³ in the general formula (I) "(C ₁ -C ₄ alkylthio) - (C ₁ -C ₄ alkyl) group", one of the C ₁ -C ₄ above C ₁ substituted with an alkylthio group - is a C ₄ alkyl group, for example, methylthiomethyl group, ethylthiomethyl group, (1-propylthio) methyl group, (2-propylthio) methyl group, (1-butylthio) methyl group, (2-butylthio) methyl group, (2-methyl-2-propylthio) methyl group, methylthioethyl group, ethylthioethyl group, (1-propylthio) ethyl group, (2-propylthio) ethyl group, (1-butylthio) ethyl group, (2-butylthio) Ethyl group, (2-methyl-2-propylthio) ethyl group, methylthio (1-propyl) group, ethylthio (1-propyl) group, (1-propylthio)-(1-propyl) group, (1-butylthio)- (1-propyl) group, methylthio It may be a (1-butyl) group, an ethylthio (1-butyl) group, a (1-propylthio)-(1-butyl) group, or a (1-butylthio)-(1-butyl) group, A (C ₁ -C ₂ alkylthio)-(C ₁ -C ₂ alkyl) group, more preferably a methylthiomethyl group or an ethylthiomethyl group, and most preferably a methylthiomethyl group.

"C ₁ -C ₄ alkylsulfinyl group" in Substituent group of the general formula (I) gamma, and, C ₁ -C ₄ alkylsulfinyl moiety in R ³ is substituted by one of the C ₁ -C ₄ alkyl group Sulfinyl group (-SO-), for example, methylsulfinyl group, ethylsulfinyl group, 1-propylsulfinyl group, 2-propylsulfinyl group, 1-butylsulfinyl group, 2-butylsulfinyl group, or 2- It is a methyl-2-propyl sulfinyl group, preferably a C ₁ -C ₃ alkylsulfinyl group, more preferably a methylsulfinyl group or an ethylsulfinyl group, and most preferably, at methylsulfinyl group is there.

The “(C ₁ -C ₄ alkylsulfinyl)-(C ₁ -C ₄ alkyl) group” in R ³ of the general formula (I) is the above C substituted with _one C ₁ -C ₄ alkylsulfinyl group. ₁ -C a _alkyl group, for example, methylsulfinyl methyl, ethyl sulfinyl methyl group, (1-propyl-sulfinyl) methyl group, (2-propyl-sulfinyl) methyl group, (1-butylsulfinyl) methyl group, (2 -Butylsulfinyl) methyl group, (2-methyl-2-propylsulfinyl) methyl group, methylsulfinylethyl group, ethylsulfinylethyl group, (1-propylsulfinyl) ethyl group, (2-propylsulfinyl) ethyl group, (1 -Butylsulfinyl) ethyl group, (2-butylsulfinyl) ethyl group, (2-methyl-2-propylsulfinyl) ethyl group, methyl Rufinyl (1-propyl) group, ethylsulfinyl (1-propyl) group, (1-propylsulfinyl)-(1-propyl) group, (1-butylsulfinyl)-(1-propyl) group, methylsulfinyl (1- Butyl) group, ethylsulfinyl (1-butyl) group, (1-propylsulfinyl)-(1-butyl) group, or (1-butylsulfinyl)-(1-butyl) group, A (C ₁ -C ₂ alkylsulfinyl)-(C ₁ -C ₂ alkyl) group, more preferably a methylsulfinylmethyl group or an ethylsulfinylmethyl group, and most preferably a methylsulfinylmethyl group. .

"C ₁ -C ₄ alkylsulfonyl group" in Substituent group of the general formula (I) gamma, and, C ₁ -C ₄ alkylsulfonyl moiety in R ³ is substituted by one of the C ₁ -C ₄ alkyl group Sulfonyl group (—SO ₂ —), for example, methanesulfonyl group, ethanesulfonyl group, 1-propanesulfonyl group, 2-propanesulfonyl group, 1-butanesulfonyl group, 2-butanesulfonyl group, or 2 - be a methyl-2-propanesulfonyl group, preferably a C ₁ -C ₃ alkylsulfonyl group, more preferably a methanesulfonyl group or an ethanesulfonyl group, and most preferably, methanesulfonyl group It is.

The “(C ₁ -C ₄ alkylsulfonyl)-(C ₁ -C ₄ alkyl) group” in R ³ of the general formula (I) is the above C substituted with _one C ₁ -C ₄ alkylsulfonyl group. ₁ -C a _alkyl group, for example, methanesulfonyl methyl, ethanesulfonyl methyl group, (1-propanesulfonyl) methyl group, (2-propanesulfonyl) methyl group, (1-butanesulfonyl) methyl group, (2 -Butanesulfonyl) methyl group, (2-methyl-2-propanesulfonyl) methyl group, methanesulfonylethyl group, ethanesulfonylethyl group, (1-propanesulfonyl) ethyl group, (2-propanesulfonyl) ethyl group, (1 -Butanesulfonyl) ethyl group, (2-butanesulfonyl) ethyl group, (2-methyl-2-propanesulfonyl) ethyl group, methanesulfonyl (1-propyl) group, ethane Sulfonyl (1-propyl) group, (1-propanesulfonyl)-(1-propyl) group, (1-butanesulfonyl)-(1-propyl) group, methanesulfonyl (1-butyl) group, ethanesulfonyl (1- Butyl) group, (1-propanesulfonyl)-(1-butyl) group, or (1-butanesulfonyl)-(1-butyl) group, preferably (C ₁ -C ₂ alkylsulfonyl) A — (C ₁ -C ₂ alkyl) group, more preferably a methanesulfonylmethyl group or an ethanesulfonylmethyl group, and most preferably a methanesulfonylmethyl group.

The “(C ₁ -C ₄ alkylamino)-(C ₁ -C ₄ alkyl) group” in R ³ of the general formula (I) is the above C substituted with _one C ₁ -C ₄ alkylamino group. ₁ -C a _alkyl group, for example, methylaminomethyl group, ethylaminomethyl group, (1-propylamino) methyl group, (2-propylamino) methyl group, (1-butylamino) methyl group, (2 -Butylamino) methyl group, (2-methyl-2-propylamino) methyl group, methylaminoethyl group, ethylaminoethyl group, (1-propylamino) ethyl group, (2-propylamino) ethyl group, (1 -Butylamino) ethyl group, (2-butylamino) ethyl group, (2-methyl-2-propylamino) ethyl group, methylamino (1-propyl) group, ethylamino (1-propyl) group, (1- Propylamino)-(1-propyl) group, (1- Tilamino)-(1-propyl) group, methylamino (1-butyl) group, ethylamino (1-butyl) group, (1-propylamino)-(1-butyl) group, or (1-butylamino) -(1-butyl) group, preferably (C ₁ -C ₂ alkylamino)-(C ₁ -C ₂ alkyl) group, more preferably methylaminomethyl group or ethylaminomethyl group A group, most preferably a methylaminomethyl group.

The “di (C ₁ -C ₄ alkylamino)-(C ₁ -C ₄ alkyl) group” in R ³ of the general formula (I) is substituted with two identical or different C ₁ -C ₄ alkylamino groups. The above-mentioned C ₁ -C ₄ alkyl group, for example, dimethylaminomethyl group, methylethylaminomethyl group, methylpropylaminomethyl group [for example, [N- (1-propyl) -N-methylamino] methyl group Etc.], methylbutylaminomethyl group [eg [N- (1-butyl) -N-methylamino] methyl group etc.], diethylaminomethyl group, ethylpropylaminomethyl group [eg [N- (1-propyl) -N-ethylamino] methyl group etc.], dipropylaminomethyl group [eg di (1-propyl) aminomethyl group, di (2-propyl) aminomethyl group etc.], dibutylaminomethyl group [eg di ( 1-Buchi ) Aminomethyl group, di (2-butyl) aminomethyl group], di (2-methyl-1-propyl) aminomethyl group, di (2-methyl-2-propyl) aminomethyl group, dimethylaminoethyl group [for example , 2-dimethylaminoethyl group and the like], methylethylaminoethyl group [for example, 2- (N-methyl-N-ethylamino) ethyl group and the like], methylpropylaminoethyl group [for example, 2- [N-methyl- N- (1-propyl) amino] ethyl group etc.], methylbutylaminoethyl group [eg 2- [N-methyl-N- (1-butyl) amino] ethyl group etc.], diethylaminoethyl group (eg 2 -Diethylaminoethyl group, etc.), ethylpropylaminoethyl group [for example, 2- [N- (1-propyl) -N-ethylamino] ethyl group, etc.], dipropylaminoethyl group [for example, 2- [di (1 − Propyl) amino] ethyl group etc.], dibutylaminoethyl group [eg 2-di (1-butyl) aminoethyl group etc.], di (2-methyl-1-propyl) aminoethyl group [eg 2-di ( 2-methyl-1-propyl) aminoethyl group etc.], di (2-methyl-2-propyl) aminoethyl group [eg 2-di (2-methyl-2-propyl) aminoethyl group etc.], dimethylamino Propyl group [for example, 3-dimethylamino-1-propyl group and the like], Methylethylaminopropyl group [for example, 3- (N-methyl-N-ethylamino) -1-propyl group and the like], Diethylaminopropyl group [for example , 3-diethylamino-1-propyl group, etc.], dipropylaminopropyl group [eg, 3-di (1-propyl) amino-1-propyl group, etc.], dibutylaminopropyl group [eg, 3- (1-butyl) amino-1-propyl group etc.], dimethylaminobutyl group [eg 4-dimethylamino-1-butyl group etc.], methylethylaminobutyl group [eg 4- (N-methyl-N- Ethylamino) -1-butyl group etc.], diethylaminobutyl group [eg 4-diethylamino-1-butyl group etc.], dipropylaminobutyl group [eg 4-di (1-propyl) amino-1-butyl group Etc.] or a dibutylaminobutyl group [eg, 4-di (1-butyl) amino-1-butyl group etc.], preferably di (C ₁ -C ₂ alkylamino)-(C ₁ a -C ₂ alkyl) group, more preferably a dimethylaminomethyl group or diethylaminomethyl group, and most preferably a dimethylaminomethyl group.

The “C ₂ -C ₆ alkenyl group” in R ³ , R ¹¹ and R ¹² of the general formula (I) is an alkenyl group having 1 to 2 carbon-carbon double bonds and 2 to 6 carbon atoms. Yes, for example, vinyl group, 2-propenyl group, 2-butenyl group, 1,3-butadiene-1-yl group, 2-methyl-2-propenyl group, 2-pentenyl group, 2-methyl-2-butenyl group or it can be a 2-hexenyl group, preferably is a C ₂ -C ₄ alkenyl group, more preferably a C ₂ -C ₃ alkenyl group, and most preferably a vinyl group.

The “C ₂ -C ₆ alkynyl group” in R ³ of the general formula (I) is an alkynyl group having 1 to 2 carbon-carbon triple bonds and 2 to 6 carbon atoms, such as an ethynyl group, 1-propynyl group, 1-butynyl group, 1,3-butadiin-1-yl group, 1-pentynyl group, or 1-hexynyl group, preferably C ₂ -C ₄ alkynyl group, More preferred is a C ₂ -C ₃ alkynyl group, and most preferred is an ethynyl group.

The “C ₁ -C ₆ alkoxy group” in R ³ and R ¹¹ of the general formula (I) is a hydroxyl group substituted by one of the above C ₁ -C ₆ alkyl groups, for example, methoxy group, ethoxy group 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, 2-methyl-1-propoxy group, 2-methyl-2-propoxy group, 1-pentyloxy group, 2-pentyloxy group 3-pentyloxy group, 2-methyl-2-butoxy group, 3-methyl-2-butoxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl-1-pentyl It may be an oxy group, a 3-methyl-1-pentyloxy group, a 2-ethyl-1-butoxy group, a 2,2-dimethyl-1-butoxy group, or a 2,3-dimethyl-1-butoxy group. the, C ₁ C ₄ alkoxy group, more preferably, C ₁ -C ₃ alkoxy groups (particularly, methoxy, ethoxy or propoxy group), more preferably, a methoxy group or ethoxy group, most suitably Is a methoxy group.

The “halogeno C ₁ -C ₆ alkoxy group” in R ³ of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted with 1 to 7 of the above halogeno groups, such as a fluoromethoxy group, Difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-bromoethoxy group, 2-chloroethoxy group, 2-iodoethoxy group, 2,2-difluoro Ethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoro-1-propoxy group, 1,1,1-tri Fluoro-2-propoxy group, 1,1,1-trichloro-2-propoxy group, 4,4,4-trifluoro-1-butoxy group, 4,4,4-trifluoro-2-butyl Toxi group, 2-trifluoromethyl-1-propoxy group, 2-trifluoromethyl-2-propoxy group, 5,5,5-trifluoro-1-pentyloxy group, 5,5,5-trifluoro-2 -Pentyloxy group, 1,1,1-trifluoro-3-pentyloxy group, 4,4,4-trifluoro-2-methyl-2-butoxy group, 4,4,4-trifluoro-3-methyl 2-butoxy group, 4,4,4-trifluoro-2-methyl-2-butoxy group, 6,6,6-trifluoro-1-hexyloxy group, 6,6,6-trifluoro-2- Hexyloxy group, 6,6,6-trifluoro-3-hexyloxy group, 5,5,5-trifluoro-2-methyl-1-pentyloxy group, 1,1,1-trifluoro-3-methyl -3-pentyloxy group, 6,6,6-trifluoro-2-ethyl 1-butoxy group, 6,6,6 be a tri-fluoro-2,3-dimethyl-1-butoxy group, preferably a halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ alkoxy Group is a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), more preferably a halogeno C ₁ -C ₂ alkoxy group (the halogeno C ₁ -C ₂ alkoxy group). is 1 to 5 fluoro, chloro or showing a C ₁ -C ₂ alkoxy group substituted with a bromo group), and even more preferably, a trifluoromethoxy group, 2,2,2-trifluoroethoxy Group or a pentafluoroethoxy group, and most preferably a trifluoromethoxy group.

The “C ₁ -C ₆ alkylthio group” in R ³ of the general formula (I) is a mercapto group substituted with one of the above C ₁ -C ₆ alkyl groups, for example, methylthio group, ethylthio group, 1- Propylthio group, 2-propylthio group, 1-butylthio group, 2-butylthio group, 2-methyl-1-propylthio group, 2-methyl-2-propylthio group, 1-pentylthio group, 2-pentylthio group, 3-pentylthio group 2-methyl-2-butylthio group, 3-methyl-2-butylthio group, 1-hexylthio group, 2-hexylthio group, 3-hexylthio group, 2-methyl-1-pentylthio group, 3-methyl-1-pentylthio group group, 2-ethyl-1-butylthio group, 2,2-dimethyl-1-butylthio group, or, it can be a 2,3-dimethyl-1-butylthio group, preferably, C ₁ A C ₄ alkylthio group, more preferably, C ₁ -C ₃ alkylthio group (in particular, methylthio group, ethylthio group or propylthio group), more preferably a methylthio group or an ethylthio group, and most preferably Is a methylthio group.

The “C ₁ -C ₆ alkylsulfinyl group” in R ³ of the general formula (I) is a sulfinyl group (—SO—) substituted with one of the above C ₁ -C ₆ alkyl groups, for example, methylsulfinyl Group, ethylsulfinyl group, 1-propylsulfinyl group, 2-propylsulfinyl group, 1-butylsulfinyl group, 2-butylsulfinyl group, 2-methyl-1-propylsulfinyl group, 2-methyl-2-propylsulfinyl group, 1-pentylsulfinyl group, 2-pentylsulfinyl group, 3-pentylsulfinyl group, 2-methyl-2-butylsulfinyl group, 3-methyl-2-butylsulfinyl group, 1-hexylsulfinyl group, 2-hexylsulfinyl group, 3-hexylsulfinyl group, 2-methyl-1-pentylsulfinyl group, 3-methyl 1-pentylsulfinyl group, 2-ethyl-1-butylsulfinyl group, 2,2-dimethyl-1-butylsulfinyl group, or 2,3-dimethyl-1-butylsulfinyl group, preferably C ₁ -C ₄ alkylsulfinyl group, more preferably C ₁ -C ₃ alkylsulfinyl group (particularly, methylsulfinyl group, ethylsulfinyl group or propylsulfinyl group), and more preferably methylsulfinyl group. Group or ethylsulfinyl group, and most preferably methylsulfinyl group.

The “C ₁ -C ₆ alkylsulfonyl group” in R ³ of the general formula (I) is a sulfonyl group (—SO ₂ —) substituted with one of the above C ₁ -C ₆ alkyl groups. Sulfonyl group, ethanesulfonyl group, 1-propanesulfonyl group, 2-propanesulfonyl group, 1-butanesulfonyl group, 2-butanesulfonyl group, 2-methyl-1-propanesulfonyl group, 2-methyl-2-propanesulfonyl group 1-pentanesulfonyl group, 2-pentanesulfonyl group, 3-pentanesulfonyl group, 2-methyl-2-butanesulfonyl group, 3-methyl-2-butanesulfonyl group, 1-hexanesulfonyl group, 2-hexanesulfonyl group , 3-hexanesulfonyl group, 2-methyl-1-pentanesulfonyl group, 3-methyl-1-pentanesulfonyl group, 2- Chill-1-butanesulfonyl group, 2,2-dimethyl-1-butanesulfonyl group, or may be a 2,3-dimethyl-1-butanesulfonyl group, preferably it is a C ₁ -C ₄ alkylsulfonyl group More preferably a C ₁ -C ₃ alkylsulfonyl group (particularly a methanesulfonyl group, an ethanesulfonyl group or a propanesulfonyl group), more preferably a methanesulfonyl group or an ethanesulfonyl group, most preferably Is a methanesulfonyl group.

The “C ₁ -C ₆ alkylamino group” in R ³ and R ¹¹ of the general formula (I) is an amino group substituted with one of the above C ₁ -C ₆ alkyl groups, for example, a methylamino group, Ethylamino group, 1-propylamino group, 2-propylamino group, 1-butylamino group, 2-butylamino group, 2-methyl-1-propylamino group, 2-methyl-2-propylamino group, 1- Pentylamino group, 2-pentylamino group, 3-pentylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 1-hexylamino group, 2-hexylamino group, 3- Hexylamino group, 2-methyl-1-pentylamino group, 3-methyl-1-pentylamino group, 2-ethyl-1-butylamino group, 2,2-dimethyl-1-butylamino group, or 2, 3-di It is a chill-1-butylamino group, preferably a C ₁ -C ₄ alkylamino group, more preferably, C ₁ -C ₃ alkylamino group (particularly, methylamino group, or an ethylamino group Propylamino group), more preferably a methylamino group or an ethylamino group, and most preferably a methylamino group.

The “di (C ₁ -C ₆ alkyl) amino group” in R ³ and R ¹¹ of the general formula (I) is an amino group substituted with the same or different two C ₁ -C ₆ alkyl groups, For example, dimethylamino group, methylethylamino group, methylpropylamino group [for example, N- (1-propyl) -N-methylamino group etc.], methylbutylamino group [for example, N- (1-butyl) -N -Methylamino group etc.], diethylamino group, ethylpropylamino group [eg N- (1-propyl) -N-ethylamino group etc.], dipropylamino group [eg di (1-propyl) amino group, di (2-propyl) amino group, etc.], dibutylamino group [eg, di (1-butyl) amino group, di (2-butyl) amino group, etc.], di (2-methyl-1-propyl) amino group, dipentyl An amino group [eg di (1-pe Til) amino group, di (2-pentyl) amino group, di (3-pentyl) amino group, etc.] or dihexylamino group [eg, di (1-hexyl) amino group, di (2-hexyl) amino group Di (3-hexyl) amino group and the like], preferably a di (C ₁ -C ₄ alkyl) amino group, and more preferably a di (C ₁ -C ₃ alkyl) amino group More preferably a dimethylamino group or a diethylamino group, and most preferably a dimethylamino group. In addition, the “di (C ₁ -C ₆ alkyl) amino group” is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, wherein the two alkyl groups together with the nitrogen atom of the amino group A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed. Examples of the 5- to 7-membered saturated heterocyclyl group include pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group. A 5- to 6-membered saturated heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and preferably a perhydroazepinyl group More preferably, it is a pyrrolidinyl group, piperidyl group, morpholinyl group, or thiomorpholinyl group, and more preferably a piperidyl group or morpholinyl group. Nyl group.

The “(C ₁ -C ₆ alkoxy) carbonyl group” in R ³ of the general formula (I) is a carbonyl group (—CO—) substituted with _one C ₁ -C ₆ alkoxy group, for example, Methoxycarbonyl group, ethoxycarbonyl group, 1-propoxycarbonyl group, 2-propoxycarbonyl group, 1-butoxycarbonyl group, 2-butoxycarbonyl group, 2-methyl-1-propoxycarbonyl group, 2-methyl-2-propoxycarbonyl group Group, 1-pentyloxycarbonyl group, 2-pentyloxycarbonyl group, 3-pentyloxycarbonyl group, 2-methyl-2-butoxycarbonyl group, 3-methyl-2-butoxycarbonyl group, 1-hexyloxycarbonyl group, 2-hexyloxycarbonyl group, 3-hexyloxycarbonyl group, 2-methyl-1-pen Ruoxycarbonyl group, 3-methyl-1-pentyloxycarbonyl group, 2-ethyl-1-butoxycarbonyl group, 2,2-dimethyl-1-butoxycarbonyl group, or 2,3-dimethyl-1-butoxycarbonyl group Group, preferably a (C ₁ -C ₄ alkoxy) carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, and most preferably a methoxycarbonyl group.

The “5- to 6-membered aromatic heterocyclyl group” in R ³ and Y in the general formula (I) contains 5 to 6 atoms containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A membered aromatic heterocyclic group, for example, furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, thiadiazolyl group, It may be a tetrazolyl group, a pyranyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, or a pyrazinyl group, preferably a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group, and more Preferably, an imidazolyl group, an oxazolyl group, a thiazolyl group, Other is a pyridyl group, most preferably a pyridyl group.

The “halogeno C ₁ -C ₄ alkoxy group” in R ⁴ , R ⁵ , substituent group α, substituent group β, and substituent group γ of the general formula (I) is 1 to 5 of the above halogeno groups. Substituted C ₁ -C ₄ alkoxy groups such as fluoromethoxy group, difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-bromo Ethoxy group, 2-chloroethoxy group, 2-iodoethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 3 1,3,3-trifluoro-1-propoxy group, 1,1,1-trifluoro-2-propoxy group, 1,1,1-trichloro-2-propoxy group, 4,4,4-trifluoro It may be a ro-1-butoxy group, a 4,4,4-trifluoro-2-butoxy group, a 2-trifluoromethyl-1-propoxy group, or a 2-trifluoromethyl-2-propoxy group, and preferably Is a halogeno C ₁ -C ₂ alkoxy group (wherein the halogeno C ₁ -C ₂ alkoxy group represents a C ₁ -C ₂ alkoxy group substituted with 1 to 5 halogeno groups), more preferably , A trifluoromethoxy group, a 2,2,2-trifluoroethoxy group or a pentafluoroethoxy group, and most preferably a trifluoromethoxy group.

The “C ₁ -C ₃ alkyl group” in R ⁶ and R ⁷ of the general formula (I) is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl group, an ethyl group 1-propyl group or 2-propyl group, preferably a methyl group or an ethyl group, and most preferably a methyl group.

The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₂ alkyl) group” in R ¹⁰ of the general formula (I) is C ₁ substituted with one C ₃ -C ₆ cycloalkyl group. a -C ₂ alkyl group, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2-cyclobutyl ethyl group, 2-cyclopentylethyl group, or, can be a 2-cyclohexylethyl group, preferably, (C ₃ -C ₅ cycloalkyl) - and (C ₁ -C ₂ alkyl) group, more preferably the (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) group, more preferably a (C ₃ -C ₄ cycloalkyl) methyl group, most preferably cyclopropylmethyl. Group .

The “phenyl- (C ₁ -C ₄ alkyl) group” in R ¹¹ and R ¹² of the general formula (I) is the above C ₁ -C ₄ alkyl group substituted with one phenyl group, for example, phenyl Methyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenyl-1-propyl group, 1-phenyl-2-propyl group, 4-phenyl-1-butyl group, 4-phenyl-2-butyl group , A 3-phenyl-2-methyl-1-propyl group or a 1-phenyl-2-methyl-2-propyl group, preferably a phenyl- (C ₁ -C ₃ alkyl) group, More preferred is a phenyl- (C ₁ -C ₂ alkyl) group (particularly a benzyl group, 1-phenylethyl group or 2-phenylethyl group), and most preferred is a benzyl group.

The “4- to 10-membered heterocyclyl group” in R ¹¹ of the general formula (I) and the 4- to 10-membered heterocyclyl moiety in R ¹¹ are 1 to 4 selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. A 4- to 10-membered heterocyclic group containing, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- Oxadiazolyl group, 1,2,3-thiadiazolyl group, triazolyl group, tetrazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, azepinyl group, azosinyl group, azoninyl group, indolyl group, benzofuranyl group, benzothienyl Group, benzimidazolyl group, benzoisoxazolyl group, benzo Unsaturated heterocyclic group such as soxazolyl group, benzothiazolyl group, benzoisothiazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, or quinazolinyl group, or azetidinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group , Pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, perhydroazepinyl group, perhydroazosinyl group, perhydroazoninyl group, 1,4,5,6-tetrahydropyrimidinyl group, Alternatively, the unsaturated heterocyclic group such as a 1,2,3,6-tetrahydropyridyl group may be a partially or completely reduced group, preferably from a nitrogen atom, an oxygen atom and a sulfur atom. Contains 1 to 4 atoms selected from the group consisting of A 5- to 7-membered heterocyclyl group, more preferably a 5- to 6-membered heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Is an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, a pyridyl group, a pyrrolidinylmethyl group, a piperidinyl group, a morpholinyl group, or a thiomorpholinyl group.

The “(4 to 10-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group” in R ¹¹ of the general formula (I) is the above C ₁ -C ₄ substituted with one of the above 4 to 10-membered heterocyclyl groups. An alkyl group, for example, furylmethyl group, thienylmethyl group, pyrrolylmethyl group, pyrazolylmethyl group, imidazolylmethyl group, imidazolylethyl group, imidazolylpropyl group, imidazolylbutyl group, oxazolylmethyl group, oxazolylethyl group, Oxazolylpropyl group, isoxazolylmethyl group, thiazolylmethyl group, thiazolylethyl group, thiazolylpropyl group, isothiazolylmethyl group, 1,2,3-oxadiazolylmethyl group, 1,2,3-thia Diazolylmethyl group, triazolylmethyl group, triazolylethyl group, tetrazolylmethyl group, pyranylmethyl group, Lysylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, azepinylmethyl, azosinylmethyl, azoninylmethyl, indolylmethyl, benzofuranylmethyl, benzo Thienylmethyl group, benzimidazolylmethyl group, benzoisoxazolylmethyl group, benzoisoxazolylmethyl group, benzothiazolylmethyl group, benzisothiazolylmethyl group, quinolylmethyl group, isoquinolyllmethyl group, quinoxalyl Nylmethyl, quinazolinylmethyl, azetidinylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolinylmethyl, imidazolidinylmethyl, imidazolinylmethyl, pyrazolidinylmethyl Group, pyrazoli Rumethyl, azetidinylmethyl, piperidylmethyl, piperidylethyl, piperidylpropyl, piperidylbutyl, piperazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, perhydroazepinylmethyl Group, perhydroazosinylmethyl group, perhydroazoninylmethyl group, 1,4,5,6-tetrahydropyrimidinylmethyl group, or 1,2,3,6-tetrahydropyridylmethyl group, preferably 5- to 7-membered heterocyclyl- (C ₁ -C ₂ alkyl) group (wherein the heterocyclyl group contains 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) More preferably a 5- to 6-membered heterocyclyl- (C ₁ -C ₂ alkyl) group (the heterocyclyl group). And the alkyl group represents a 5- to 6-membered heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and more preferably an imidazolylmethyl group Oxazolylmethyl group, thiazolylmethyl group, triazolylmethyl group, pyridylmethyl group, pyrrolidinylmethyl group, piperidinylmethyl group, morpholinylmethyl group, or thiomorpholinylmethyl group.

The “C ₃ -C ₆ alkenyloxy group” in R ¹¹ of the general formula (I) is a hydroxyl group substituted with one C ₃ -C ₆ alkenyl group, such as a 2-propenyloxy group, 2- It may be a butenyloxy group, a 2-methyl-2-propenyloxy group, a 2-pentenyloxy group, a 2-methyl-2-butenyloxy group, or a 2-hexenyloxy group, and preferably a C ₃ -C ₄ alkenyloxy group. Most preferably a 2-propenyloxy group or a 2-butenyloxy group.

The “(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) amino group” in R ¹¹ of the general formula (I) represents one of the above (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) amino group substituted with a group, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylmethyl group, 1-cyclopropylethyl-amino Group, 2-cyclopropylethylamino group, 2-cyclobutylethylamino group, 2-cyclopentylethylamino group, 2-cyclohexylethylamino group, 3-cyclopropyl-1-propylamino group, 2-cyclopropyl-1- Propylamino group, 1-cyclopropyl-2-propylamino group, 2-cyclopropyl-2-propylamino group, 3 Cyclobutyl-1-propylamino group, 3-cyclopentyl-1-propylamino group, 3-cyclohexyl-1-propylamino group, 4-cyclopropyl-1-butylamino group, 4-cyclopropyl-2-butylamino group, 3-cyclopropyl-2-methyl-1-propylamino group, 1-cyclopropyl-2-methyl-2-propylamino group, 4-cyclobutyl-1-butylamino group, 4-cyclopentyl-1-butylamino group, Alternatively, it may be a 4-cyclohexyl-1-butylamino group, preferably a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) amino group, more preferably (C ₃ -C ₄ cycloalkyl) - and (C ₁ -C ₂ alkyl) amino group, more preferably, (a C ₃ -C ₄ cycloalkyl) methyl group, most preferably, Black propyl methylamino group.

The “C ₃ -C ₆ cycloalkylamino group” in R ¹¹ of the general formula (I) is an amino group substituted with one C ₃ -C ₆ cycloalkyl group, for example, a cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, or, can be a cyclohexylamino group, preferably a C ₃ -C ₅ cycloalkyl amino group, and more preferably, preferably, C ₃ -C ₄ cycloalkyl An amino group, most preferably a cyclopropylamino group.

The “C ₃ -C ₆ alkenylamino group” in R ¹¹ of the general formula (I) is an amino group substituted with one C ₃ -C ₆ alkenyl group, such as a 2-propenylamino group, 2- It can be a butenylamino group, a 2-methyl-2-propenylamino group, a 2-pentenylamino group, a 2-methyl-2-butenylamino group, or a 2-hexenylamino group, preferably a C ₃ -C ₄ alkenylamino group. A 2-propenylamino group or 2-butenylamino group, most preferably a group.

“N- (C ₁ -C ₆ alkyl) -N-[(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group” in R ¹¹ of the general formula (I) is one An amino group substituted with one of the above-mentioned C ₁ -C ₆ alkyl group and one of the above-mentioned (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) groups, for example, N-methyl-N— Cyclopropylmethylamino group, N-ethyl-N-cyclopropylmethylamino group, N- (1-propyl) -N-cyclopropylmethylamino group, N- (2-propyl) -N-cyclopropylmethylamino group, N- (1-butyl) -N-cyclopropylmethylamino group, N- (1-pentyl) -N-cyclopropylmethylamino group, N- (1-hexyl) -N-cyclopropylmethylamino group, N- Methyl-N-cyclobutylmethylamino group, N-ethyl-N-cycl Butylmethylamino group, N-methyl-N-cyclopentylmethylamino group, N-ethyl-N-cyclopentylmethylamino group, N-methyl-N-cyclohexylmethylamino group, N-ethyl-N-cyclohexylmethylamino group, N -Methyl-N- (1-cyclopropylethyl) amino group, N-ethyl-N- (1-cyclopropylethyl) amino group, N- (1-propyl) -N- (1-cyclopropylethyl) amino group N- (1-butyl) -N- (1-cyclopropylethyl) amino group, N-methyl-N- (2-cyclopropylethyl) amino group, N-ethyl-N- (2-cyclopropylethyl) Amino group, N- (1-propyl) -N- (2-cyclopropylethyl) amino group, N- (1-butyl) -N- (2-cyclopropylethyl) amino group, N-methyl-N- ( 2-shi (Robutylethyl) amino group, N-methyl-N- (2-cyclopentylethyl) amino group, N-methyl-N- (3-cyclopropyl-1-propyl) amino group, N-methyl-N- (4-cyclopropyl) -1-butyl) amino group, preferably N- (C ₁ -C ₄ alkyl) -N-[(C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl)] amino group N- (C ₁ -C ₄ alkyl) -N-[(C ₃ -C ₄ cycloalkyl) methyl] amino group, more preferably N- (C ₁ -C ₂ alkyl) -N-cyclopropylmethylamino group.

The “N- (C ₁ -C ₆ alkyl) -N— (C ₃ -C ₆ cycloalkyl) amino group” in R ¹¹ of the general formula (I) represents one of the above C ₁ -C ₆ alkyl groups and 1 Amino groups substituted with the above-mentioned C ₃ -C ₆ cycloalkyl groups, such as N-methyl-N-cyclopropylamino group, N-ethyl-N-cyclopropylamino group, N- (1-propyl group) ) -N-cyclopropylamino group, N- (2-propyl) -N-cyclopropylamino group, N- (1-butyl) -N-cyclopropylamino group, N- (1-pentyl) -N-cyclo Propylamino group, N- (1-hexyl) -N-cyclopropylamino group, N-methyl-N-cyclobutylamino group, N-ethyl-N-cyclobutylamino group, N- (1-propyl) -N -Cyclobutylamino group, N- (2-propyl) -N-cyclo Tylamino group, N- (1-butyl) -N-cyclobutylamino group, N- (1-pentyl) -N-cyclobutylamino group, N- (1-hexyl) -N-cyclobutylamino group, N- It may be a methyl-N-cyclopentylamino group or an N-ethyl-N-cyclohexylamino group, preferably N- (C ₁ -C ₄ alkyl) -N- (C ₃ -C ₅ cycloalkyl) amino More preferably an N- (C ₁ -C ₄ alkyl) -N- (C ₃ -C ₄ cycloalkyl) amino group, and even more preferably an N- (C ₁ -C ₂ alkyl) group. ) -N-cyclopropylamino group.

The “N— (C ₁ -C ₆ alkyl) -N— (C ₃ -C ₆ alkenyl) amino group” in R ¹¹ of the general formula (I) means one above-mentioned C ₁ -C ₆ alkyl group and one An amino group substituted with a C ₃ -C ₆ alkenyl group, such as N-methyl-N- (2-propenyl) amino group, N-ethyl-N- (2-propenyl) amino group, N- ( 1-propyl) -N- (2-propenyl) amino group, N- (2-propyl) -N- (2-propenyl) amino group, N- (1-butyl) -N- (2-propenyl) amino group N- (1-pentyl) -N- (2-propenyl) amino group, N- (1-hexyl) -N- (2-propenyl) amino group, N-methyl-N- (2-butenyl) amino group N-ethyl-N- (2-butenyl) amino group, N- (1-propyl) -N- (2-butenyl) amino group, N- (2-propyl) -N- (2- Tenenyl) amino group, N- (1-butyl) -N- (2-butenyl) amino group, N- (1-pentyl) -N- (2-butenyl) amino group, N- (1-hexyl) -N -(2-butenyl) amino group, N-methyl-N- (2-methyl-2-propenyl) amino group, N-methyl-N- (2-pentenyl) amino group, N-methyl-N- (2- Methyl-2-butenyl) amino group or N-methyl-N- (2-hexenyl) amino group, preferably N- (C ₁ -C ₄ alkyl) -N- (C ₃ -C ₅ alkenyl) amino group, more preferably N- (C ₁ -C ₄ alkyl) -N- (C ₃ -C ₄ alkenyl) amino group, still more preferably N- (C _1- C ₂ alkyl) -N- (C ₃ -C ₄ alkenyl) amino group.

The “5- to 7-membered heterocyclyl group” in R ¹² of the general formula (I) and the 5- to 7-membered heterocyclyl moiety in R ¹¹ are 1 to 4 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A 5- to 7-membered heterocyclic group containing, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- Unsaturated heterocyclic group such as oxadiazolyl group, 1,2,3-thiadiazolyl group, triazolyl group, tetrazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group or azepinyl group, or pyrrolidinyl group , Pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl , Piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, perhydroazepinyl group, 1,4,5,6-tetrahydropyrimidinyl group, or 1,2,3,6-tetrahydropyridyl group. The saturated heterocyclic group may be a partially or fully reduced group, preferably 5 to 6 containing 1 to 2 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms It is a membered heterocyclyl group, more preferably an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, a pyridyl group, a pyrrolidinylmethyl group, a piperidinyl group, a morpholinyl group, or a thiomorpholinyl group.

The “(5 to 7-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group” in R ¹² of the general formula (I) is the above C ₁ -C ₄ substituted with one 5 to 7-membered heterocyclyl group. An alkyl group, for example, furylmethyl group, thienylmethyl group, pyrrolylmethyl group, pyrazolylmethyl group, imidazolylmethyl group, imidazolylethyl group, imidazolylpropyl group, imidazolylbutyl group, oxazolylmethyl group, oxazolylethyl group, Oxazolylpropyl group, isoxazolylmethyl group, thiazolylmethyl group, thiazolylethyl group, thiazolylpropyl group, isothiazolylmethyl group, 1,2,3-oxadiazolylmethyl group, 1,2,3-thia Diazolylmethyl group, triazolylmethyl group, triazolylethyl group, tetrazolylmethyl group, pyranylmethyl group, pyridi Rumethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, azepinylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolinylmethyl, imidazo Lydinylmethyl group, imidazolinylmethyl group, pyrazolidinylmethyl group, pyrazolinylmethyl group, azetidinylmethyl group, piperidylmethyl group, piperidylethyl group, piperidylpropyl group, piperidylbutyl group, piperazinylmethyl Group, morpholinylmethyl group, thiomorpholinylmethyl group, perhydroazepinylmethyl group, 1,4,5,6-tetrahydropyrimidinylmethyl group, or 1,2,3,6-tetrahydropyridylmethyl group in and obtained, preferably, 5 to 6-membered heterocyclyl - (C ₁ -C ₂ Alkyl group) (the heterocyclyl group is a 5- to 6-membered heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), and more preferably Is imidazolylmethyl, oxazolylmethyl, thiazolylmethyl, triazolylmethyl, pyridylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, or thiomorpholinylmethyl It is a group.

The “C ₁ -C ₂ alkylene group” in X ² of the general formula (I) is an alkylene group having 1 to 2 carbon atoms, such as a methylene group, an ethylene group [— (CH ₂ ) ₂ —]. , A methylmethylene group [—CH (Me) —], preferably a methylene group.

The “(C ₁ -C ₄ alkyl) carbonyl group” in the substituent group α of the general formula (I) is a carbonyl group (—CO—) substituted with _one C ₁ -C ₄ alkyl group, For example, a methylcarbonyl group (acetyl group), an ethylcarbonyl group, a 1-propylcarbonyl group, a 2-propylcarbonyl group, a 1-butylcarbonyl group, a 2-butylcarbonyl group, or a 2-methyl-2-propylcarbonyl group It is preferably a (C ₁ -C ₃ alkyl) carbonyl group, more preferably a methylcarbonyl group or an ethylcarbonyl group, and most preferably a methylcarbonyl group.

The “(C ₁ -C ₄ alkoxy) carbonyl group” in the substituent group α of the general formula (I) is a carbonyl group (—CO—) substituted with _one C ₁ -C ₄ alkoxy group, For example, methoxycarbonyl group, ethoxycarbonyl group, 1-propoxycarbonyl group, 2-propoxycarbonyl group, 1-butoxycarbonyl group, 2-butoxycarbonyl group, or 2-methyl-2-propoxycarbonyl group may be suitable. Is a (C ₁ -C ₃ alkoxy) carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, and most preferably a methoxycarbonyl group.

In the general formula (I), when Y is a phenyl group, a substituted phenyl group, a pyridyl group, or a substituted pyridyl group, when the substitution position of X ¹ is the 1-position, the substitution position of R ⁸ is preferably The third or fourth position, more preferably the fourth position.

  When the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable ester thereof has a basic group, it can be converted into a salt by reacting with an acid. ) Or a pharmacologically acceptable ester thereof can be converted into a salt by reacting with a base. If these salts are used in the treatment of disease, they must be pharmacologically acceptable.

The salt formed with the basic group of the compound represented by the general formula (I) of the present invention is preferably a hydrohalic acid such as hydrochloride, hydrobromide, hydroiodide, etc. Salt; nitrate; perchlorate; sulfate; or inorganic acid salt such as phosphate; C ₁ − which may be substituted with a fluorine atom such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc. Salt with C ₆ alkane sulfonic acid; salt with C ₆ -C ₁₀ aryl sulfonic acid optionally substituted with C ₁ -C ₄ alkyl such as benzene sulfonate, p-toluene sulfonate, acetate; Malate; fumarate: succinate; citrate; tartrate; oxalate; or organic acid salts such as maleate; or glycine, lysine, arginine, ornithine, glutamic acid Amino such as salt and aspartate It can be an acid salt, more preferably a hydrohalide salt.

  The salt formed with the acidic group of the compound represented by the general formula (I) of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; calcium salt, magnesium salt or the like. Alkaline earth metal salt; aluminum salt; iron salt; zinc salt; copper salt; nickel salt; or metal salt such as cobalt salt; inorganic amine salt such as ammonium salt; or t-octylamine salt, dibenzylamine salt Morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, Procaine salt, diethanolamine salt, N-benzylphenethylamine salt, Amine salts such as organic amine salts such as perazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt; or amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate salt, etc. It can be a salt, more preferably an alkali metal salt.

  The compound represented by the general formula (I) of the present invention, or a pharmacologically acceptable salt or ester thereof, is allowed to stand in the air or adsorbs moisture during recrystallization to form a hydrate. However, these hydrates are also included in the present invention. Furthermore, although the compounds of the present invention may incorporate other solvents to form solvates, these solvates are also included in the present invention.

Where a compound of the invention has one or more asymmetric centers, optical isomers (including diastereomers) may exist and these isomers and mixtures thereof may be represented by a single formula such as formula (I) It is described in. The present invention encompasses each of these isomers and any mixture thereof (including racemates) in any proportion.

The present invention includes esters of the compound represented by formula (I). These esters are compounds in which the hydroxyl group or carboxyl group of the compound represented by the general formula (I) is modified by addition of a protecting group according to a method well known in the art (for example, “Protective Groups in Organic Synthesis”). , Second Editio ", Theodora W. Greene and Peter GM Wuts, 1991, John Wiley & Sons, Inc.).

  There are no particular limitations on the nature of the protecting group. However, when this ester is used for the treatment of disease, it must be pharmacologically acceptable. For example, this protecting group is metabolized when the compound is administered in vivo to a mammal. It must be able to be eliminated by a process (for example, hydrolysis) to produce a compound represented by the general formula (I) or a salt thereof. That is, the pharmacologically acceptable ester is a “prodrug” of the compound represented by the general formula (I) of the present invention. However, when the ester of the compound represented by the general formula (I) of the present invention is used for other than the treatment of diseases (for example, when used as an intermediate for the production of other compounds), the ester is It need not be pharmacologically acceptable.

  It is easily determined whether or not the ester of the compound represented by the general formula (I) of the present invention is pharmacologically acceptable. The compound was intravenously administered to an experimental animal such as a rat or mouse, and the blood or body fluid of the animal was examined. The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof was detected. In this case, the compound is judged to be a pharmacologically acceptable ester.

  The compound represented by the general formula (I) of the present invention can be converted into an ester, and the ester can be, for example, a compound in which the hydroxyl group of the compound is esterified. The ester residue can be a general protecting group when the esterified compound is used as an intermediate, and when the esterified compound is pharmacologically acceptable, It may be a protecting group that can be removed by an in vivo metabolic process (for example, hydrolysis).

The general protecting groups are ester protecting groups that can be removed under chemical conditions such as hydrolysis, hydrogenolysis, electrolysis, and photolysis. These general protecting groups used for the preparation of the compounds of general formula (I) in which the hydroxyl group has been modified may suitably be, for example:
(I) an alkylcarbonyl group having 1 to 25 carbon atoms, an ester-forming residue of a saturated or unsaturated C ₂ -C ₁₀ dicarboxylic acid, a halogenoalkylcarbonyl group having 1 to 25 carbon atoms, 1 to 25 An aliphatic acyl group such as a lower alkoxyalkylcarbonyl group having 1 carbon atom or an unsaturated alkylcarbonyl group having 1 to 25 carbon atoms;
(Ii) Aromatic acyl such as arylcarbonyl group, halogenoarylcarbonyl group, lower alkylarylcarbonyl group, lower alkoxyarylcarbonyl group, nitrated arylcarbonyl group, lower alkoxycarbonylarylcarbonyl group, or arylated arylcarbonyl group Group;
(Iii) (C ₁ -C ₆ alkoxy) carbonyl group, or substituted with one or more substituents selected from the group consisting of a halogeno group and a tri (C ₁ -C ₆ alkyl) silyl group (C ₁ alkoxycarbonyl groups such as -C ₆ alkoxy) carbonyl group;
(Iv) a tetrahydropyranyl group or a tetrahydrothiopyranyl group optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogeno and C ₁ -C ₆ alkoxy;
(V) a tetrahydrofuranyl group or a tetrahydrothiofuranyl group which may be substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, halogeno and C ₁ -C ₆ alkoxy;
(Vi) a silyl group such as a tri (C ₁ -C ₆ alkyl) silyl group, a di (C ₁ -C ₆ alkyl) aryl silyl group or a diaryl (C ₁ -C ₆ alkyl) silyl group;
(Vii) (C ₁ -C ₆ alkoxy) methyl group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) methyl group, or (C ₁ -C ₆ alkoxy) substituted with a halogeno group An alkoxymethyl group such as a methyl group;
(Viii) substituted ethyl groups such as the (C ₁ -C ₆ alkoxy) ethyl group, or substituted with halogeno group (C ₁ -C ₆ alkoxy) ethyl groups;
(Ix) C ₁ -C ₆ alkyl, halogeno and C ₁ -C ₆ 1 or more may be substituted with a substituent triphenylmethyl group selected from the group consisting of alkoxy or,, C ₁ -C ₆ alkyl An aralkyl group such as a benzyl group optionally substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkoxy, nitro, halogeno and cyano;
(X) an alkenyloxycarbonyl group having 3 to 6 carbon atoms;
(Xi) C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halogeno and one or more may be substituted with a substituent aralkyloxycarbonyl group selected from the group consisting of cyano;
(Xii) an ester-forming residues of C ₁ -C ₁₀ acid;
(Xiii) carbonate ester;
(Xiv) carbonic acid mono (C ₁ -C ₆ alkyl) ester or ester with carbonic acid di (C ₁ -C ₆ alkyl) ester;
(Xv) an ester of a carbonic acid mono (C ₆ -C ₁₀ aromatic hydrocarbon) ester or a di (C ₆ -C ₁₀ aromatic hydrocarbon) ester;
(Xvi) phosphate ester;
(Xvii) an ester with phosphoric acid mono (C ₁ -C ₆ alkyl) ester or phosphoric acid di (C ₁ -C ₆ alkyl) ester; or
(Xviii) an ester of phosphoric acid mono (C ₆ -C ₁₀ aromatic hydrocarbon) ester or a phosphoric acid di (C ₆ -C ₁₀ aromatic hydrocarbon) ester.

An ester group that can be eliminated in a metabolic process (for example, hydrolysis) in a living body is eliminated in the metabolic process (for example, hydrolysis) when administered into a mammal, and is represented by the general formula (I). An ester group that forms a compound or a salt thereof. Such protecting groups as ester residues may suitably be, for example:
(I) 1-[(C ₁ -C ₆ alkyl) carbonyloxy]-(C ₁ -C ₆ alkyl) group, 1-[(C ₃ -C ₈ cycloalkyl) carbonyloxy]-(C ₁ -C ₆ alkyl) group _{or,, 1 - [(C 6} -C 12 aryl) carbonyloxy] - (C ₁ -C ₆ alkyl), such as a group 1 (acyloxy) - (C ₁ -C ₆ alkyl) group;
(Ii) a (C ₁ -C ₆ alkoxy) carbonyloxyalkyl group or an optionally substituted oxodioxolenylmethyl group (the substituent is a C ₁ -C ₆ alkyl group and a C ₁ -C substituted carbonyloxy group such as substituted with _alkyl or halogeno by a group selected from the group consisting of an aryl group);
(Iii) a phthalidyl group optionally substituted by C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
(Iv) an aliphatic acyl group as indicated in the general protecting groups for hydroxyl groups;
(V) an aromatic acyl group as shown in the general protecting groups for hydroxyl groups;
(Vi) a half ester residue of succinic acid;
(Vii) a phosphate ester residue;
(Viii) ester-forming residues of amino acids such as glutamate and aspartate;
(Ix) a carbamoyl group optionally substituted by _{1 to} 2 C ₁ -C ₆ alkyl groups; or
(X) 1- (acyloxy) alkoxycarbonyl group (the acyloxy group represents the aliphatic acyloxy group or the aromatic acyloxy group).

Among the above protecting groups that can be removed by in vivo metabolic processes (for example, hydrolysis), which are used to produce a compound represented by the general formula (I) having a modified hydroxyl group, an aliphatic acyl group (in particular, C ₁ -C ₂₅ alkyl group) and a substituted carbonyloxy group is preferred.

Among the compounds represented by the general formula (I), suitable compounds may be compounds shown in Tables 1 to 3 below. However, the compound of the present invention is not limited to these compounds.

In Tables 1 and 2 below, the following abbreviations are used:
Ac: Acetyl
cBu: Cyclobutyl
cPr: Cyclopropyl
Et: ethyl
Ety: Ethinyl
iPr: 2-propyl
iBu: 2-methyl-1-propyl
Mbu: 2-methyl-2-butyl
Me: methyl
Nap: Naphthyl
nPr: 1-propyl
Ph: Phenyl
Prd: pyrrolidinyl
Pyl: pyrrolyl
Pyr: Pyridyl
Qin: Quinazolyl
tBu: 2-methyl-2-propyl
Tfe: 2,2,2-trifluoroethyl
Thi: Thienyl
Thz: Thiazolyl
Vin: Vinyl.

[Table 1]

_____________________________________________________
Exemplary compound R ¹ R ² R ³ R ⁴ R ⁵ R ⁸
Item number ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
1-1 COCH ₂ tBu H CF ₃ HHN (Me) Ac
1-2 COCH ₂ tBu OH CF ₃ HHN (Me) COEt
1-3 COCH ₂ tBu OH CF ₃ HHN (Me) COcPr
1-4 COOiPr OH Me HHN (Me) COEt
1-5 COOiPr OH Me HHN (Me) COcPr
1-6 COOiPr OH Et HHN (Me) COEt
1-7 COOiPr OH Et HHN (Me) COcPr
1-8 COOiPr OH iPr HHN (Me) COEt
1-9 COOiPr OH iPr HHN (Me) COcPr
1-10 COOiPr OH CF ₃ HHN (Me) Ac
1-11 COOiPr OH CF ₃ HHN (Me) COEt
1-12 COOiPr OH CF ₃ HHN (Me) COCH ₂ cPr
1-13 COOiPr OH CF ₃ HHN (Me) COcPr
1-14 COOiPr OH cPr HHN (Me) COEt
1-15 COOiPr OH cPr HHN (Me) COcPr
1-16 COOtBu HHH Br N (Me) Ac
1-17 COOtBu H Me HHN (Me) Ac
1-18 COOtBu H Me HHN (Me) COEt
1-19 COOtBu H Me HHN (Me) COcPr
1-20 COOtBu H Et HHN (Me) Ac
1-21 COOtBu H Et HHN (Me) COEt
1-22 COOtBu H Et HHN (Me) COcPr
1-23 COOtBu H iPr HHN (Me) Ac
1-24 COOtBu H iPr HHN (Me) COEt
1-25 COOtBu H iPr HHN (Me) COcPr
1-26 COOtBu H tBu HHN (Me) Ac
1-27 COOtBu H tBu HHN (Me) COEt
1-28 COOtBu H tBu HHN (Me) COcPr
1-29 COOtBu H CF ₃ HHN (Me) Ac
1-30 COOtBu H CF ₃ HHN (Me) COEt
1-31 COOtBu H CF ₃ HHN (Et) COEt
1-32 COOtBu H CF ₃ HHN (Me) COnPr
1-33 COOtBu H CF ₃ HHN (Me) COiPr
1-34 COOtBu H CF ₃ HHN (Me) COCH ₂ SO ₂ Me
1-35 COOtBu H CF ₃ HHN (Me) COCH ₂ NMe ₂
1-36 COOtBu H CF ₃ HHN (Me) COCF ₃
1-37 COOtBu H CF ₃ HHN (Me) COCH ₂ cPr
1-38 COOtBu H CF ₃ HHN (Me) COcPr
1-39 COOtBu H CF ₃ HHN (Et) COcPr
1-40 COOtBu H CF ₃ HHN (Me) COOMe
1-41 COOtBu H CF ₃ HHN (Me) COOCH ₂ CH = CH ₂
1-42 COOtBu H CF ₃ HHN (Me) CONMe ₂
1-43 COOtBu H CF ₃ HHN (Me) SO ₂ Me
1-44 COOtBu H CF ₃ HH CONMe ₂
1-45 COOtBu H CF ₃ Cl HN (Me) Ac
1-46 COOtBu H Tfe HHN (Me) Ac
1-47 COOtBu H Tfe HHN (Me) COEt
1-48 COOtBu H Tfe HHN (Me) COcPr
1-49 COOtBu H CH ₂ OMe HHN (Me) Ac
1-50 COOtBu H CH ₂ SMe HHN (Me) Ac
1-51 COOtBu H cPr HHN (Me) Ac
1-52 COOtBu H cPr HHN (Me) COEt
1-53 COOtBu H cPr HHN (Me) COcPr
1-54 COOtBu H Vin HHN (Me) Ac
1-55 COOtBu H Ety HHN (Me) Ac
1-56 COOtBu H OMe HHN (Me) Ac
1-57 COOtBu H OMe HHN (Me) COEt
1-58 COOtBu H OMe HHN (Me) COcPr
1-59 COOtBu H OtBu HHN (Me) Ac
1-60 COOtBu H SMe HHN (Me) Ac
1-61 COOtBu H SPh HHN (Me) Ac
1-62 COOtBu H SOPh HHN (Me) Ac
1-63 COOtBu H SO ₂ Ph HHN (Me) Ac
1-64 COOtBu H NH ₂ HHN (Me) Ac
1-65 COOtBu H NMe ₂ HHN (Me) Ac
1-66 COOtBu H COOMe HHN (Me) Ac
1-67 COOtBu H CN HHN (Me) Ac
1-68 COOtBu H NO ₂ HHN (Me) Ac
1-69 COOtBu H Cl HHN (Me) Ac
1-70 COOtBu HIHHN (Me) Ac
1-71 COOtBu H Ph HHN (Me) Ac
1-72 COOtBu H 2-Thz HHN (Me) Ac
1-73 COOtBu H 2-Pyr HHN (Me) Ac
1-74 COOtBu OH Me HHN (Me) Ac
1-75 COOtBu OH Me HHN (Me) COEt
1-76 COOtBu OH Me HHN (Me) COCH ₂ cPr
1-77 COOtBu OH Me HHN (Me) COcPr
1-78 COOtBu OH Et HHN (Me) Ac
1-79 COOtBu OH Et HHN (Me) COEt
1-80 COOtBu OH Et HHN (Me) COCH ₂ cPr
1-81 COOtBu OH Et HHN (Me) COcPr
1-82 COOtBu OH iPr HHN (Me) Ac
1-83 COOtBu OH iPr HHN (Me) COEt
1-84 COOtBu OH iPr HHN (Me) COCH ₂ cPr
1-85 COOtBu OH iPr HHN (Me) COcPr
1-86 COOtBu OH tBu HHN (Me) Ac
1-87 COOtBu OH tBu HHN (Me) COEt
1-88 COOtBu OH tBu HHN (Me) COCH ₂ cPr
1-89 COOtBu OH tBu HHN (Me) COcPr
1-90 COOtBu OH CF ₃ HHN (Me) Ac
1-91 COOtBu OH CF ₃ HHN (Et) Ac
1-92 COOtBu OH CF ₃ HHN (Tfe) Ac
1-93 COOtBu OH CF ₃ HHN (Me) COEt
1-94 COOtBu OH CF ₃ HHN (Et) COEt
1-95 COOtBu OH CF ₃ HHN (Me) COnPr
1-96 COOtBu OH CF ₃ HHN (Me) COiPr
1-97 COOtBu OH CF ₃ HHN (Me) COiBu
1-98 COOtBu OH CF ₃ HHN (Me) COCH ₂ OH
1-99 COOtBu OH CF ₃ HHN (Me) COCH ₂ OMe
1-100 COOtBu OH CF ₃ HHN (Me) COCH ₂ OCF ₃
1-101 COOtBu OH CF ₃ HHN (Me) COCH ₂ SMe
1-102 COOtBu OH CF ₃ HHN (Me) COCH ₂ SOMe
1-103 COOtBu OH CF ₃ HHN (Me) COCH ₂ SO ₂ Me
1-104 COOtBu OH CF ₃ HHN (Me) COCH ₂ NH ₂
1-105 COOtBu OH CF ₃ HHN (Me) COCH ₂ NHMe
1-106 COOtBu OH CF ₃ HHN (Me) COCH ₂ NMe ₂
1-107 COOtBu OH CF ₃ HHN (Me) COCH ₂ COOH
1-108 COOtBu OH CF ₃ HHN (Me) COCH ₂ COOMe
1-109 COOtBu OH CF ₃ HHN (Me) COCH ₂ CN
1-110 COOtBu OH CF ₃ HHN (Me) COTfe
1-111 COOtBu OH CF ₃ HHN (Me) COCF ₃
1-112 COOtBu OH CF ₃ HHN (Me) COCH ₂ cPr
1-113 COOtBu OH CF ₃ HHN (Et) COCH ₂ cPr
1-114 COOtBu OH CF ₃ HHN (Me) COcPr
1-115 COOtBu OH CF ₃ HHN (Et) COcPr
1-116 COOtBu OH CF ₃ HHN (Me) COcBu
1-117 COOtBu OH CF ₃ HHN (Me) COVin
1-118 COOtBu OH CF ₃ HHN (Me) COCH ₂ CH = CH ₂
1-119 COOtBu OH CF ₃ HHN (Me) COOMe
1-120 COOtBu OH CF ₃ HHN (Me) COOCH ₂ CH = CH ₂
1-121 COOtBu OH CF ₃ HHN (Me) CONMe ₂
1-122 COOtBu OH CF ₃ HHN (Me) SO ₂ Me
1-123 COOtBu OH CF ₃ HHN (Me) SO ₂ Et
1-124 COOtBu OH CF ₃ HHN (Me) SO ₂ CF ₃
1-125 COOtBu OH CF ₃ HH CONMe ₂
1-126 COOtBu OH CF ₃ FHN (Me) COEt
1-127 COOtBu OH CF ₃ FHN (Me) COcPr
1-128 COOtBu OH CF ₃ Cl HN (Me) COEt
1-129 COOtBu OH CF ₃ Cl HN (Me) COcPr
1-130 COOtBu OH Tfe HHN (Me) Ac
1-131 COOtBu OH Tfe HHN (Me) COEt
1-132 COOtBu OH Tfe HHN (Me) COCH ₂ cPr
1-133 COOtBu OH Tfe HHN (Me) COcPr
1-134 COOtBu OH CH ₂ OMe HHN (Me) Ac
1-135 COOtBu OH CH ₂ OMe HHN (Me) COEt
1-136 COOtBu OH CH ₂ OMe HHN (Me) COCH ₂ cPr
1-137 COOtBu OH CH ₂ OMe HHN (Me) COcPr
1-138 COOtBu OH CH ₂ SMe HHN (Me) Ac
1-139 COOtBu OH CH ₂ SMe HHN (Me) COEt
1-140 COOtBu OH CH ₂ SMe HHN (Me) COCH ₂ cPr
1-141 COOtBu OH CH ₂ SMe HHN (Me) COcPr
1-142 COOtBu OH cPr HHN (Me) Ac
1-143 COOtBu OH cPr HHN (Me) COEt
1-144 COOtBu OH cPr HHN (Me) COCH ₂ cPr
1-145 COOtBu OH cPr HHN (Me) COcPr
1-146 COOtBu OH OMe HHN (Me) Ac
1-147 COOtBu OH OMe HHN (Me) COEt
1-148 COOtBu OH OMe HHN (Me) COCH ₂ cPr
1-149 COOtBu OH OMe HHN (Me) COcPr
1-150 COOtBu OH OtBu HHN (Me) Ac
1-151 COOtBu OH OtBu HHN (Me) COEt
1-152 COOtBu OH OtBu HHN (Me) COCH ₂ cPr
1-153 COOtBu OH OtBu HHN (Me) COcPr
1-154 COOtBu OH NMe ₂ HHN (Me) Ac
1-155 COOtBu OH NMe ₂ HHN (Me) COEt
1-156 COOtBu OH NMe ₂ HHN (Me) COCH ₂ cPr
1-157 COOtBu OH NMe ₂ HHN (Me) COcPr
1-158 COOtBu NH ₂ HHHN (Me) Ac
1-159 COOCH ₂ CMe ₃ H CF ₃ HHN (Me) Ac
1-160 COOCH ₂ CMe ₃ OH CF ₃ HHN (Me) Ac
1-161 COOCH ₂ CMe ₃ OH CF ₃ HHN (Me) COEt
1-162 COOCH ₂ CMe ₃ OH CF ₃ HHN (Me) COCH ₂ cPr
1-163 COOCH ₂ CMe ₃ OH CF ₃ HHN (Me) COcPr
1-164 COOMbu OH Me HHN (Me) COEt
1-165 COOMbu OH Me HHN (Me) COcPr
1-166 COOMbu OH Et HHN (Me) COEt
1-167 COOMbu OH Et HHN (Me) COcPr
1-168 COOMbu OH iPr HHN (Me) COEt
1-169 COOMbu OH iPr HHN (Me) COcPr
1-170 COOMbu OH CF ₃ HHN (Me) Ac
1-171 COOMbu OH CF ₃ HHN (Me) COEt
1-172 COOMbu OH CF ₃ HHN (Me) COCH ₂ cPr
1-173 COOMbu OH CF ₃ HHN (Me) COcPr
1-174 COOMbu OH cPr HHN (Me) COEt
1-175 COOMbu OH cPr HHN (Me) COcPr
1-176 COOC (Et) ₃ H CF ₃ HHN (Me) Ac
1-177 COOC (Et) ₃ OH Me HHN (Me) COEt
1-178 COOC (Et) ₃ OH Me HHN (Me) COcPr
1-179 COOC (Et) ₃ OH Et HHN (Me) COEt
1-180 COOC (Et) ₃ OH Et HHN (Me) COcPr
1-181 COOC (Et) ₃ OH iPr HHN (Me) COEt
1-182 COOC (Et) ₃ OH iPr HHN (Me) COcPr
1-183 COOC (Et) ₃ OH CF ₃ HHN (Me) Ac
1-184 COOC (Et) ₃ OH CF ₃ HHN (Me) COEt
1-185 COOC (Et) ₃ OH CF ₃ HHN (Me) COCH ₂ cPr
1-186 COOC (Et) ₃ OH CF ₃ HHN (Me) COcPr
1-187 COOC (Et) ₃ OH cPr HHN (Me) COEt
1-188 COOC (Et) ₃ OH cPr HHN (Me) COcPr
1-189 COOC (CF ₃ ) Me ₂ H CF ₃ HHN (Me) Ac
1-190 COOC (CF ₃ ) Me ₂ OH CF ₃ HHN (Me) COEt
1-191 COOC (CF ₃ ) Me ₂ OH CF ₃ HHN (Me) COcPr
1-192 CONHtBu H CF ₃ HHN (Me) Ac
1-193 CONHtBu OH CF ₃ HHN (Me) COEt
1-194 CONHtBu OH CF ₃ HHN (Me) COcPr
1-195 CON (Me) tBu H CF ₃ HHN (Me) Ac
1-196 CON (Me) tBu OH CF ₃ HHN (Me) COEt
1-197 CON (Me) tBu OH CF ₃ HHN (Me) COcPr
1-198 Ph H CF ₃ HHN (Me) Ac
1-199 2-Me-Ph H CF ₃ HHN (Me) Ac
1-200 2-Me-Ph OH CF ₃ HHN (Me) COEt
1-201 2-Me-Ph OH CF ₃ HHN (Me) COcPr
1-202 2-Cl-Ph H CF ₃ HHN (Me) Ac
1-203 2-Cl-Ph OH CF ₃ HHN (Me) COEt
1-204 2-Cl-Ph OH CF ₃ HHN (Me) COcPr
1-205 2,6-di-Me-Ph H CF ₃ HHN (Me) Ac
1-206 2,6-di-Me-Ph H CF ₃ HHN (Me) COEt
1-207 2,6-di-Me-Ph H CF ₃ HHN (Me) COcPr
1-208 2,6-di-Me-Ph OH CF ₃ HHN (Me) COEt
1-209 2,6-di-Me-Ph OH CF ₃ HHN (Me) COcPr
1-210 1-Nap H CF ₃ HHN (Me) Ac
1-211 8-Qin H CF ₃ HHN (Me) Ac
1-212 COOtBu H CF ₃ HHN (Tfe) Ac
1-213 COOtBu OH CF ₃ HHN (Me) COCH ₂ (2-Thi)
1-214 COOtBu OH CF ₃ HHN (Me) CO (1-Me-2-Pyl)
1-215 COOtBu OH CF ₃ HHN (Me) CScPr
1-216 COOtBu OH CF ₃ HH CONHMe
1-217 COOtBu OH CF ₃ HH CO (1-Prd)
1-218 COOtBu OH CF ₃ HHN (Et) SO ₂ Me
1-219 COOtBu OH CF ₃ HH CONMeEt
1-220 COOtBu OH CF ₃ HHN (Me) SO ₂ cPr
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

[Table 2]

_____________________________________________________
Example Compound ^{R 2 R 3 R 6 R 7} R 8 R 9 X 1 Y 1
Item number ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
2-1 H CF ₃ HH 4- [N (Me) Ac] H bond N
2-2 H CF ₃ HH 4- [N (Me) CoEt] H bond N
2-3 H CF ₃ HH 4- [N (Me) COcPr] H bond N
2-4 H CF ₃ HH 4- [N (Me) Ac] H CH ₂ CH
2-5 H CF ₃ HH 4- [N (Me) COEt] H CH ₂ CH
2-6 H CF ₃ HH 4- [N (Me) COcPr] H CH ₂ CH
2-7 H CF ₃ HH 4- [N (Me) Ac] 2-F bond CH
2-8 H CF ₃ HH 4- [N (Me) COEt] 2-F bond CH
2-9 H CF ₃ HH 4- [N (Me) COcPr] 2-F bond CH
2-10 H CF ₃ Me H 4- [N (Me) Ac] H bond CH
2-11 H CF ₃ Me H 4- [N (Me) COEt] H bond CH
2-12 H CF ₃ Me H 4- [N (Me) COcPr] H bond CH
2-13 OH Me HH 4- [N (Me) COEt] 2-F bond CH
2-14 OH Me HH 4- [N (Me) COEt] 2-Cl bond CH
2-15 OH Me HH 4- [N (Me) COEt] H bond N
2-16 OH Me HH 4- [N (Me) COcPr] 2-F bond CH
2-17 OH Me HH 4- [N (Me) COcPr] 2-Cl bond CH
2-18 OH Me HH 4- [N (Me) COcPr] H bond N
2-19 OH iPr HH 4- [N (Me) COEt] 2-F bond CH
2-20 OH iPr HH 4- [N (Me) COEt] 2-Cl bond CH
2-21 OH iPr HH 4- [N (Me) COEt] H bond N
2-22 OH iPr HH 4- [N (Me) COcPr] 2-F bond CH
2-24 OH iPr HH 4- [N (Me) COcPr] 2-Cl bond CH
2-25 OH iPr HH 4- [N (Me) COcPr] H bond N
2-26 OH CF ₃ HH 4- [N (Me) Ac] 2-F bond CH
2-27 OH CF ₃ HH 4- [N (Me) Ac] H bond N
2-28 OH CF ₃ HH 4- [N (Me) COEt] 2-Me bond CH
2-29 OH CF ₃ HH 4- [N (Me) COEt] 3-Me bond CH
2-30 OH CF ₃ HH 4- [N (Me) COEt] 2-CF ₃ bond CH
2-31 OH CF ₃ HH 4- [N (Me) COEt] 3-CF ₃ bond CH
2-32 OH CF ₃ HH 4- [N (Me) COEt] 2-F bond CH
2-33 OH CF ₃ HH 4- [N (Me) COEt] 3-F bond CH
2-34 OH CF ₃ HH 4- [N (Me) COEt] 2-Cl bond CH
2-35 OH CF ₃ HH 4- [N (Me) COEt] 3-Cl bond CH
2-36 OH CF ₃ HH 4- [N (Me) COEt] H bond N
2-37 OH CF ₃ HH 3- [N (Me) COEt] H bond CH
2-38 OH CF ₃ HH 4- [CH ₂ N (Me) COEt] H bond CH
2-39 OH CF ₃ HH 4- [N (Me) COEt] H CH ₂ CH
2-40 OH CF ₃ Me H 4- [N (Me) COEt] H bond CH
2-41 OH CF ₃ Me Me 4- [N (Me) COEt] H bond CH
2-42 OH CF ₃ HH 4- [N (Me) COcPr] 2-Me bond CH
2-43 OH CF ₃ HH 4- [N (Me) COcPr] 3-Me bond CH
2-44 OH CF ₃ HH 4- [N (Me) COcPr] 2-CF ₃ bond CH
2-45 OH CF ₃ HH 4- [N (Me) COcPr] 3-CF ₃ bond CH
2-46 OH CF ₃ HH 4- [N (Me) COcPr] 2-F bond CH
2-47 OH CF ₃ HH 4- [N (Me) COcPr] 3-F bond CH
2-48 OH CF ₃ HH 4- [N (Me) COcPr] 2-Cl bond CH
2-49 OH CF ₃ HH 4- [N (Me) COcPr] 3-Cl bond CH
2-50 OH CF ₃ HH 4- [N (Me) COcPr] H bond N
2-51 OH CF ₃ HH 3- [N (Me) COcPr] H bond CH
2-52 OH CF ₃ HH 4- [CH ₂ N (Me) COcPr] H bond CH
2-53 OH CF ₃ HH 4- [N (Me) COcPr] H CH ₂ CH
2-54 OH CF ₃ Me H 4- [N (Me) COcPr] H bond CH
2-55 OH CF ₃ Me Me 4- [N (Me) COcPr] H bond CH
2-56 OH cPr HH 4- [N (Me) COEt] 2-F bond CH
2-57 OH cPr HH 4- [N (Me) COEt] 2-Cl bond CH
2-58 OH cPr HH 4- [N (Me) COEt] H bond N
2-59 OH cPr HH 4- [N (Me) COcPr] 2-Cl bond CH
2-60 OH cPr HH 4- [N (Me) COcPr] H bond N
2-61 OH CF ₃ HH 4- [N (Me) COcPr] 3-NH ₂ bond CH
2-62 OH CF ₃ HH 4- [N (Me) COcPr] 3-NMe ₂ bond CH
2-63 OH CF ₃ HH 4- [N (Me) COcPr] 3-Cl bond CH
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

Among the above exemplified compounds, suitable compounds are exemplified compound numbers 1-20, 1-23, 1-29, 1-30, 1-32, 1-33, 1-38, 1-82, 1-89, 1 -90, 1-93, 1-95, 1-96, 1-97, 1-99, 1-101, 1-112, 1-114, 1-117, 1-122, 1-123, 1-215 , 1-218, 1-220, 2-46, or 2-47, and a more preferred compound is
Exemplified compound number 1-38: tert-butyl 2-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate,
Illustrative compound number 1-82: tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3-isopropylbenzoate,
Illustrative compound number 1-89: tert-butyl 3-tert-butyl-6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxybenzoate,
Exemplified compound number 1-90: tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-93: tert-butyl 2-hydroxy-6-({4- [methyl (propionyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
Exemplary Compound No. 1-95: tert-butyl 6-({4- [butyryl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-96: tert-butyl 2-hydroxy-6-({4- [isobutyryl (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
Illustrative compound number 1-99: tert-butyl 2-hydroxy-6-({4-[(methoxyacetyl) (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
Illustrative compound number 1-101: tert-butyl 2-hydroxy-6-[(4- {methyl [(methylthio) acetyl] amino} phenoxy) methyl] -3- (trifluoromethyl) benzoate,
Illustrative compound number 1-112: tert-butyl 6-({4-[(cyclopropylacetyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-114: tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-122: tert-butyl 2-hydroxy-6-({4- [methyl (methylsulfonyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
Exemplified compound number 1-215: tert-butyl 6-({4-[(cyclopropylcarbonothioyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-218: tert-butyl 6-({4- [ethyl (methylsulfonyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 1-220: tert-butyl 6-({4-[(cyclopropylsulfonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
Illustrative compound number 2-46: tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -2-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate, or ,
Exemplary Compound No. 2-47: Compound of tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate It is.

The compound represented by the general formula (I) of the present invention can be produced according to the following methods A to M.

In the structural formulas of the compounds of Method A to Method M, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , and Y are the same as those described above. R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group, R ^b represents a C ₁ -C ₁₀ alkyl group, a phenyl group or a substituted phenyl group in R ⁹ , and R ^c represents R C ₁ -C ₁₀ alkoxy group in the ^9, (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, a halogeno C ₁ -C ₁₀ alkoxy groups, phenyl - (C ₁ -C ₁₀ alkoxy) Group, C ₃ -C ₆ cycloalkyloxy group, (C ₁ -C ₄ alkyl)-(C ₃ -C ₆ cycloalkyl) oxy group, C ₁ -C ₁₀ alkylamino group, or di (C ₁ -C ₁₀ alkyl) amino group, R ^d is a C ₆ -C ₁₀ aryl group, a substituted C ₆ -C ₁₀ aryl group in R ¹ , 5 to 1 A 0-membered heterocyclyl group or a substituted 5- to 10-membered heterocyclyl group, R ^e represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and two R ^e together represent an ethylene group or a trimethylene group ( The ethylene group or trimethylene group may be substituted with 1 to 4 methyl groups), and R ^f represents 1 to 3 groups selected from the substituent group α; R ^g represents a tetrahydrofuranyl group, a tetrahydropyranyl group or a methoxymethyl group, and R ^h is a silyl group substituted with three groups selected from the group consisting of a C ₁ -C ₆ alkyl group and a phenyl group (Preferably, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group or triilopropylsilyl group), wherein R ⁱ is a phenyl group in R ³ or a 5- to 6-membered aromatic hetero Represents a cyclyl group, R ^j represents a C ₁ -C ₆ alkyl group, X ^a represents a chloro group, a bromo group or an iodo group, and X ^b represents a fluoro group, a chloro group, a bromo group or an iodo group. Represents a group, Alloc represents an allyloxycarbonyl group, t-Bu represents a tert-butyl group, and MOM represents a methoxymethyl group.

X ^c is a chloro group; a bromo group; an iodo group; a lower alkylsulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; a halogeno lower alkylsulfonyloxy group such as trifluoromethanesulfonyloxy; an aryl such as benzenesulfonyloxy A sulfonyloxy group; a lower alkylated arylsulfonyloxy group such as p-toluenesulfonyloxy; or a halogenoarylsulfonyloxy group such as p-chlorobezensulfonyloxy, preferably a chloro group, a bromo group, An iodo group, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group, and more preferably a bromo group or an iodo group.

  In the reaction of each step of the following methods A to M, when the compound serving as a reaction substrate has a group that inhibits the target reaction such as an amino group, a hydroxyl group, or a carboxyl group, the group is appropriately converted to those groups as necessary. These protecting groups may be introduced, or the introduced protecting groups may be removed as necessary. Such a protecting group is not particularly limited as long as it is a protecting group that is usually used to advance the reaction. For example, TH Greene, PG Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons , Inc., and the like. The introduction reaction of these protecting groups and the removal reaction of the protecting groups can be carried out according to conventional methods such as the methods described in the above-mentioned documents.

  The solvent used in the reaction in each step of the following methods A to M is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group. Solvent groups include aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate Esters such as butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; Cals such as acetic acid and propionic acid Acids; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, dimethylformamide, dimethyl Amides such as acetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.

  The acid used in the reaction in each step of the following methods A to M is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. Acid groups include organic acids such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and hydrochloric acid, bromide It consists of inorganic acids such as hydroacid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

  The base used in the reaction in each step of the following methods A to M is not particularly limited as long as it does not inhibit the reaction, and is selected from the following base group. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; Lithium methoxide, sodium methoxide, sodium ethoxide, alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; Lithium such as lithium diisopropylamide Lithium alkylamides such as n-butyllithium, sec-butyllithium and tert-butyllithium; and triethylamine, tributylamine, diisopropylethylamine, lithium alkylamides such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 4-pyrrolidinopyridine, 2,6-di (tert-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] Consisting of organic amines, such as deca-7-ene (DBU).

  In the reaction of each step of the following methods A to M, the reaction temperature varies depending on the solvent, starting material, reagent and the like, and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature and the like.

In the reaction in each step of the following methods A to M, after completion of the reaction, the target compound in each step is isolated from the reaction mixture according to a conventional method. For example, (i) if necessary, insoluble matters such as a catalyst are removed by filtration, and (ii) water and a solvent immiscible with water (for example, methylene chloride, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. The compound is extracted, (iii) the organic layer is washed with water, dried using a desiccant such as anhydrous magnesium sulfate, and (iv) the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary. In addition, the target compound in each step can be directly used in the next reaction without purification.

(Method A)
Method A is a method for producing compound (Ia) in which R ⁶ and R ⁷ are hydrogen atoms and X ¹ is a single bond in formula (I).
(Step A-1)
Step A-1 is a step of producing compound (2) by halogenating compound (1) which is known or easily obtained from a known compound with a halogenating agent.

  The halogenating agent to be used is not particularly limited as long as it is usually used in a halogenation reaction. For example, N-halogenosuccinimide such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, or , Halogen such as bromine and iodine, preferably N-halogenosuccinimide, more preferably N-bromosuccinimide. Step A-1 can be performed in the presence of a radical reaction initiation reagent (preferably, azoisobutyronitrile) such as azoisobutyronitrile, if necessary.

  The solvent used is selected from the above solvent group, and is preferably an aromatic hydrocarbon or a halogenated hydrocarbon, and more preferably benzene or carbon tetrachloride.

  The reaction temperature is usually 20 to 200 ° C, preferably 50 to 150 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 hour to 9 hours.
(Step A-2)
Step A-2 is a step of producing compound (Ia) by reacting compound (2) obtained in step A-1 with compound (3) in the presence of a base. The compound (3) is known, can be easily obtained from a known compound, or can be produced by the L method.

  The base to be used is not particularly limited as long as it is selected from the above group of bases and is usually used for the alkylation reaction of phenols. Preferably, alkali metal carbonate, alkali metal hydrogencarbonate or alkali metal is used. A hydride, more preferably potassium carbonate or cesium carbonate.

  The solvent used is selected from the above solvent group and is preferably an amide, more preferably dimethylformamide.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 50 ° C.

The reaction time is usually 30 minutes to 48 hours, preferably 1 to 24 hours.

(Method B)
Method B is a method for producing compound (Ib) in which R ¹ is —COR ^b , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is a single bond in formula (I).
(Process B-1)
In step B-1, compound (4), which is known or easily obtained from a known compound, is converted to a diazonium salt by reacting with nitrite in the presence of an acid, and then iodinated to give compound (5 ). Step B-1 is usually performed in the absence of a solvent.

  The nitrite used is not particularly limited as long as it is usually used in the diazotization reaction, and may be, for example, an alkali metal nitrite such as sodium nitrite or potassium nitrite, preferably sodium nitrite. It is.

  The acid to be used is not particularly limited as long as it is selected from the above acid group and is usually used for diazotization reaction, and may be preferably an inorganic acid, more preferably sulfuric acid or acetic acid. Most preferably, it is sulfuric acid.

  The iodination reagent to be used is not particularly limited as long as it is usually used for the iodination reaction of a diazo compound. For example, it can be an alkali metal iodide such as sodium iodide or potassium iodide. Is potassium iodide.

  The reaction temperature is usually −20 to 50 ° C. (preferably 0 to 20 ° C.) for the diazotization reaction, and 20 to 200 ° C. (preferably 5 to 150 ° C.) for the iodination reaction.

The reaction time is usually 30 minutes to 12 hours (preferably 1 hour to 6 hours) for the diazotization reaction, and 30 minutes to 12 hours (preferably 1 hour to 4 hours) for the iodination reaction. is there.
(Step B-2)
Step B-2 is a step of producing compound (6) by reducing compound (5) obtained in step B-1 with a reducing agent.

  The reducing agent to be used is not particularly limited as long as it is usually used for a reduction reaction of a carboxyl group or an ester group, and examples thereof include borane, borane-tetrahydrofuran complex, borane-methyl sulfide complex, and borane-pyridine complex. Boranes, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, alkali metal borohydrides such as lithium borohydride, lithium aluminum hydride, lithium triethoxide aluminum hydride It can be an aluminum hydride compound or an organoaluminum hydride compound such as di (isobutyl) aluminum hydride, di (methoxyethoxy) aluminum sodium dihydride, preferably boranes, more preferably borane. -Tetrahydr Lofuran complex.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually 0 to 200 ° C., preferably 20 to 150 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.
(Step B-3)
Process B-3
(Step B-3a): a step of halogenating the compound (6) obtained in Step B-2 with a halogenating agent in the presence of triphenylphosphine; and
(Step B-3b): The step comprises the step of producing the compound (7) by reacting the compound obtained in the step B-3a with the compound (3) in the presence of a base. The compound (3) is known, can be easily obtained from a known compound, or can be produced by the L method.

  The halogenating agent used in the step B-3a is not particularly limited as long as it is usually used in the halogenation reaction of alcohol. For example, carbon tetrachloride, carbon tetrabromide, carbon tetraiodide, etc. N-halogenosuccinimide such as carbon tetrahalide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, or halogen such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide May be phosphorous chloride, preferably carbon tetrahalide, more preferably carbon tetrabromide.

  The solvent used in the step B-3a is selected from the above solvent group, and is preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature in the step B-3a is usually −20 to 100 ° C., preferably 0 to 50 ° C.

  The reaction time in the step B-3a is usually 1 hour to 12 hours, preferably 2 hours to 6 hours.

B-3b process can be performed according to the method similar to A-2 process.
(Step B-4)
Process B-4
(Step B-4a): Compound (7) obtained in Step B-3 is converted into a Grignard reagent and then reacted with compound (8) which is known or easily obtained from a known compound. And a step of causing;
(Step B-4b): The step comprises the step of producing the compound (Ib) by oxidizing the compound obtained in the step B-4a with an oxidizing agent.
(Step B-4a)
The reagent for converting to the Grignard reagent to be used is not particularly limited as long as it is usually used. For example, alkyllithium such as n-butyllithium, sec-butyllithium, tert-butyllithium; And a combination of isopropyl magnesium chloride or isopropyl magnesium bromide, preferably a combination of n-butyl lithium and isopropyl magnesium chloride, or a combination of n-butyl lithium and isopropyl magnesium bromide, and more preferable. Is a combination of n-butyllithium and isopropylmagnesium chloride.

  The solvent used in is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually −100 to 50 ° C., preferably −80 to 20 ° C.

The reaction time is usually 30 minutes to 6 hours, preferably 1 hour to 4 hours.
(Step B-4b)
The oxidizing agent used is not particularly limited as long as it is usually used for the oxidation reaction of hydroxyl group or benzyl alcohol. For example, 1,1,1-tris (acetyloxy) -1,1-dihydro-1 , 2-Benziodoxol-3- (1H) -one (Dess-Martin periodinate, Dess, DB et al., J. Org. Chem., 1983, 48, p. 4155-4156), anhydrous Chromic acid (CrO ₃ ), chromic anhydride-pyridine complex, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), manganese dioxide, a combination of oxalyl chloride and dimethyl sulfoxide, or SO ₃ -pyridine and dimethyl sulfoxide Preferably, 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Dess-Martin periodinate ).

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 50 ° C.

The reaction time is usually 30 minutes to 6 hours, preferably 1 hour to 4 hours.

(Method C)
The method C is a method for producing the compound (Ic) in which R ¹ is —COR ^c , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is a single bond in the formula (I).
(Step C-1)
Process C-1 is a process for producing compound (10) by treating compound (9) obtained by Method A, Method F, Method J, or Method K with an acid.

  The acid used is not particularly limited as long as it is selected from the above acid group and used for the elimination reaction of the tert-butyl group, and is preferably trifluoroacetic acid or hydrochloric acid, more preferably Trifluoroacetic acid.

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.
(Step C-2)
In the step C-2, the compound (10) obtained in the step C-1 is reacted with a compound (11) which is known or easily obtained from a known compound in the presence of a condensing agent, to give a compound ( Ic).

The condensing agent to be used is not particularly limited as long as it is usually used for the condensation reaction of carboxylic acid and amine, or carboxylic acid and alcohol. RC Larock, Comprehensive Organic Transformations. Second Edition, 1999, John Wiley And a condensing agent described in & Sons, Inc. The condensing agent used is, for example,
(I) A combination of a phosphate ester such as diethyl phosphoryl cyanide and diphenyl phosphoryl azide and the following base:
(Ii) carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC); a combination of the above carbodiimides and the following bases; Combinations of the above carbodiimides with N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide;
(Iii) A combination of disulfides such as 2,2′-dipyridyl disulfide, 2,2′-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine and tributylphosphine;
(Iv) a combination of 2-halogen-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium chloride and the following bases; or
(V) imidazoles such as 1,1′-oxalyldiimidazole, N, N′-carbonyldiimidazole; or
(Vi) It may be a combination of sulfonyl chlorides such as p-toluenesulfonyl chloride, 2,4,6-trimethylsulfonyl chloride and 2,4,6-triisopropylsulfonyl chloride and the following bases, preferably carbodiimide And a combination of 2-halogeno-1-lower alkylpyridinium halides and a base, or a combination of sulfonyl chlorides and a base, more preferably 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide and base, 2-chloro-1-methylpyridinium iodide and base, or 2,4,6-triisopropylsulfonyl chloride and base.

  The base used in combination with the condensing agent is preferably an organic amine of the base group, more preferably triethylamine, diisopropylethylamine, pyridine, 4- (N, N-dimethylamino) pyridine, Or a mixture thereof, most preferably triethylamine, 4- (N, N-dimethylamino) pyridine, or a mixture thereof. When compound (11) is an amine in step C-2, an excess amount of compound (11) can be used as a base.

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

  The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.

In step C-2, compound (10) is converted into acid chloride with oxalyl chloride, thionyl chloride, etc. in a solvent (methylene chloride, etc.) and then compound (11) or in the presence of a base (triethylamine, etc.) It can also be carried out by reacting with an alkali metal alkoxide.

(Method D)
Method D is a method for producing a compound (Id) in which R ¹ is R ^d , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is a single bond in formula (I).
(Process D-1)
In step D-1, compound (7) obtained in step B-3 is reacted with compound (12) which is known in the presence of a palladium catalyst and a base or can be easily obtained from a known compound, This is a process for manufacturing (Id).

  The palladium catalyst to be used is not particularly limited as long as it is usually used for a carbon-carbon bond formation reaction. For example, tetrakis (triphenylphosphine) palladium (0), bis [1,2-bis (diphenylphosphine). Fino) ethane] palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (tri-t-butylphosphine) palladium (0), bis (tricyclohexylphosphine) palladium (0), palladium chloride (II ), Palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (II), dichlorobis [methylenebis (diphenylphosphine)] dipalladium-dichloromethane adduct, [1,2-bis (diphenylphosphino) ethane] dichloropalladium ( II), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane Adduct, palladium (II) acetylacetonate, bis (benzonitrile) palladium (II) chloride, bis (acetate) bis (triphenylphosphine) palladium (II), bis (acetonitrile) dichloropalladium (II), or bis It may be (benzonitrile) dichloropalladium (II), preferably tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0).

  In the step D-1, a phosphorus ligand capable of coordinating with the palladium catalyst may be used as necessary. Examples of the phosphorus ligand used include triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine, tris (2,6-dimethoxyphenyl) phosphine, and tris [2 -(Diphenylphosphino) ethyl] phosphine, bis (2-methoxyphenyl) phenylphosphine, 2- (di-t-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2- (diphenylphosphino)- 2 ′-(N, N-dimethylamino) biphenyl, tri-t-butylphosphine, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane, 1,2-bis (dimethylphosphino) Ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,5-bis ( Phenylphosphino) pentane, 1,6-bis (diphenylphosphino) hexane, 1,2-bis (dimethylphosphino) ethane, 1,1′-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphino) Ethyl) phenylphosphine, or bis (2-diphenylphosphinophenyl) ether, preferably with triphenylphosphine, tri-o-tolylphosphine, or 1,3-bis (diphenylphosphino) propane. is there.

  The base used is selected from the above base group and is preferably an alkali metal carbonate, more preferably sodium carbonate or potassium carbonate.

  The solvent used is selected from the above solvent group, preferably hydrocarbons, alcohols, amides, water, or a mixture thereof, more preferably toluene, ethanol, dimethylacetamide, water. Or a mixture thereof, most preferably a mixture of toluene and ethanol, or a mixture of dimethylacetamide and water.

  The reaction temperature is usually 20 to 200 ° C, preferably 50 to 150 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.

(E method)
In the method E, in formula (I), R ¹ is —COR ^c , R ⁶ and R ⁷ are hydrogen atoms, R ⁸ is —N (R ¹⁰ ) ZR ¹¹ , and X ¹ is a single bond And Y is a method for producing a compound (Ie) in which Y is a pyridyl group optionally substituted with R ^f .
(Step E-1)
In step E-1, compound (6) obtained in step B-2 is reacted with compound (13) which is known in the presence of a base or can be easily obtained from a known compound, to give compound (14). It is a manufacturing process.

  The base used is not particularly limited as long as it is selected from the above group of bases and used for the arylation reaction of an alcoholic hydroxyl group, preferably an alkali metal hydride, more preferably a hydrogenation. Sodium.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 60 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 2 hours to 12 hours.
(Step E-2)
Step E-2
(Step E-2a): A step of converting the compound (14) obtained in Step E-1 into an ester compound by reacting with an alcohol compound in the presence of a palladium catalyst and a base in a carbon monoxide atmosphere. ;
(Step E-2b): Step of hydrolyzing the ester compound obtained in Step E-2a in the presence of a base;
(Step E-2c): a step of reacting the compound obtained in Step E-2b with compound (11) in the presence of a condensing agent; and
(Step E-2d): The step comprises the step of producing the compound (15) by reducing the nitro group of the compound obtained in the step E-2c in the presence of a catalyst and in a hydrogen atmosphere.
(E-2a process)
The palladium catalyst used may be the same as that shown in step D-1, preferably palladium (II) acetate or dichlorobis (triphenylphosphine) palladium (II), more preferably Dichlorobis (triphenylphosphine) palladium (II). Further, as in the step D-1, a phosphorus ligand can be appropriately used as necessary, and the phosphorus ligand used is preferably 1,3-bis (diphenylphosphino) propane. It is.

  The base used is selected from the above group of bases, preferably an organic amine, and more preferably triethylamine.

  The alcohol compound used is not particularly limited as long as it is a lower primary alcohol, and is preferably methanol.

  The solvent used is selected from the above solvent group and is preferably an amide, more preferably dimethylformamide. The alcohol compound can also be used as a solvent together with amides (preferably dimethylformamide).

  The reaction temperature is usually 20 to 150 ° C., preferably 50 to 100 ° C.

The reaction time is usually 1 hour to 36 hours, preferably 2 hours to 24 hours.
(E-2b process)
The base used can be an alkali metal hydroxide of the above base group, preferably sodium hydroxide or potassium hydroxide.

  The solvent used is selected from the above solvent group, preferably ethers or alcohols, and more preferably tetrahydrofuran. Water is always used in the E-2b process.

  The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 1 hour to 36 hours, preferably 2 hours to 24 hours.
(E-2c process)
The condensing agent used can be the same as that shown in Step C-2, preferably a combination of carbodiimides and an organic base, more preferably 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide (WSC) and 4- (N, N-dimethylamino) pyridine.

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 1 hour to 36 hours, preferably 2 hours to 24 hours.
(E-2d process)
The catalyst used is not particularly limited as long as it is usually used in a hydrogenation reaction. For example, palladium black, palladium-carbon, palladium-barium sulfate, palladium hydroxide, palladium hydroxide-carbon, platinum-carbon. , Platinum oxide or Raney nickel, preferably palladium-carbon.

  The step E-2d is usually performed in a hydrogen atmosphere at normal pressure to 10000 hPa, preferably at normal pressure to 5000 hPa.

  The solvent used is selected from the above solvent group and is preferably an ester, more preferably ethyl acetate.

  The reaction temperature is usually 0 to 10 ° C, preferably 20 to 60 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 2 hours to 12 hours.
(Step E-3)
In step E-3, compound (15) obtained in step E-2 is reacted with compound (16) which is known in the presence of a base or can be easily obtained from a known compound, to give compound (17). It is a manufacturing process.

  The base used is selected from the above base group and is preferably an organic amine, more preferably triethylamine, 4- (N, N-dimethylamino) pyridine, or a mixture thereof.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C.

  The reaction time is usually 1 to 24 hours, preferably 2 to 12 hours.

In step E-3, when Z is —CO— or —SO ₂ — in compound (17),
(Step E-3a): It can also be carried out by a step of reacting compound (15) with compound (R ¹¹ Z) ₂ O in the presence of a base (preferably pyridine).

In step E-3, when Z is —CO— in compound (17),
(Step E-3b): Compound (15) is converted into a condensing agent [preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide] and a base [preferably triethylamine or 4- (N , N-dimethylamino) pyridine] can also be carried out by reacting with compound R ¹¹ COOH.
(Step E-4)
In step E-4, compound (17) obtained in step E-3 is reacted in the presence of a base with compound (18) that is known or easily obtained from a known compound, and compound (Ie) is reacted with compound (Ie). It is a manufacturing process.

  The base used is selected from the above group of bases, preferably an alkali metal hydride, and more preferably sodium hydride.

  The solvent used is selected from the above solvent group and is preferably an amide, more preferably dimethylformamide.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 60 ° C.

  The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.

In Method E, Step E-3 and Step E-4 can also be performed by the following method;
(Step E-5a): a step of reacting compound (15) with allyloxycarbonyl chloride in the presence of a base (particularly triethylamine);
(Step E-5b): A step of reacting the compound obtained in Step E-5a with compound (18) according to the same method as in Step E-4;
(Step E-5c): A step of removing the Alloc group from the compound obtained in Step E-5b according to the same method as in Step F-5a; and
(Step E-5d): A step of reacting the compound obtained in step E-5c with compound (16) according to the same method as in step E-3.

Steps E-2 to E-4 and steps E-5a to E-5d can also be applied to compounds in which Y is a phenyl group in formula (I).

(F method)
In the method F, in formula (I), R ¹ is —COO (t-Bu), R ² is a hydroxyl group, R ⁶ and R ⁷ are hydrogen atoms, and R ⁸ is —N (R ¹⁰ This is a method for producing a compound (If) which is ZR ¹¹ and X ¹ is a single bond.
(Step F-1)
Step F-1 is a step of producing compound (20) by reacting compound (19), which is known or easily obtained from a known compound, with dimethylformamide in the presence of alkyllithium and a base. is there.

  The alkyllithium used is selected from the alkyllithiums shown in the above base group and is preferably n-butyllithium.

  The base used may have a property of coordinating to lithium ions, and is preferably tetramethylethylenediamine.

  The solvent used is selected from the above solvent group and is preferably an ether, more preferably diethyl ether.

  The reaction temperature is usually −80 to 50 ° C., preferably −50 to 20 ° C.

  The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.

In step F-1, depending on the type of the compound (19), a compound having a hydroxy group of -OR ^g in the compound (20) may be obtained. In this case, in the obtained compound, R ^g removal reaction is performed in the presence of an acid (preferably an inorganic acid, more preferably hydrochloric acid) to obtain a compound (20). Can do.
(Step F-2)
Step F-2
(Step F-2a): a step of reacting the compound (20) obtained in Step F-1 with methyl orthoformate in the presence of an acid; and
(Step F-2b): The step consists of a step of producing the compound (21) by reacting the compound obtained in the step F-2a with chloromethyl methyl ether in the presence of a base.
(F-2a process)
The acid used is selected from the above acid group, preferably an organic sulfonic acid, and more preferably camphorsulfonic acid.

  The solvent used is selected from the above solvent group, preferably alcohols, and more preferably methanol.

  The reaction temperature is usually 20 to 150 ° C., preferably 50 to 100 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 2 hours to 12 hours.
(F-2b process)
The base used is selected from the above group of bases and is preferably an organic amine, more preferably diisopropylethylamine.

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 50 ° C.

The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.
(Step F-3)
F-3 process
(Step F-3a): a step of reacting compound (21) obtained in Step F-2 with dimethylformamide in the presence of alkyllithium and a base; and
(Step F-3b): The step comprises the step of producing the compound (22) by reducing the compound obtained in the step F-3a with a reducing agent.
(F-3a process)
The alkyllithium used is selected from the alkyllithiums shown in the above base group and is preferably n-butyllithium. In the step F-3a, the ratio of the number of moles of the compound (21) and n-butyllithium is preferably 1: 2 to 1: 3, and more preferably 1: 2 to 1: 2.5. It is.

  The base used can have the property of taking care of lithium ions, and is preferably tetramethylethylenediamine. In the step F-3a, the ratio of the number of moles of the compound (21) and tetramethylethylenediamine is preferably 1: 2 to 1: 3, more preferably 1: 2 to 1: 2.5. is there.

  The solvent used is selected from the above solvent group and is preferably an ether, more preferably diethyl ether.

  The reaction temperature is usually −80 to 60 ° C., preferably −50 to 40 ° C.

The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
(F-3b process)
The reducing agent to be used is not particularly limited as long as it is usually used in a formyl group reduction reaction. For example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride An alkali metal borohydride such as sodium borohydride is preferred.

  The solvent used is selected from the above solvent group, preferably ethers, alcohols or a mixture thereof, more preferably tetrahydrofuran, methanol or a mixture thereof, most preferably tetrahydrofuran. And a mixture of methanol.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
(Step F-4)
In the step F-4, the compound (22) obtained in the step F-3 is known or easily obtained from a known compound in the presence of an azodicarboxylate reagent and a phosphine reagent (23). This is a step for producing a compound (24) by reacting with.

  The azodicarboxylate reagent to be used is not particularly limited as long as it is usually used for Mitsunobu reaction. For example, dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate, diisopropyl azodi Carboxylates, dialkyl azodicarboxylates such as di (tert-butyl) azodicarboxylate; bis (2,2,2-trichloroethyl) azodicarboxylate; diphenylazodicarboxylate; 1,1 ′-( Azodicarbonyl) dipiperidine; N, N, N ′, N ′-(tetramethylazodicarboxamide); or dibenzylazodicarboxylate, preferably dialkylazodicarboxylate, more preferred Is diethyl azodicarboxylate. As an azodicarboxylate reagent, an azodicarboxylate reagent immobilized on a polymer such as polystyrene [preferably, polystyrene such as ethoxycarbonylazocarboxymethyl polystyrene (Nova Biochem, product number 01-64-0371) is used. An immobilized azodicarboxylate reagent] can also be used.

  The phosphine reagent used is not particularly limited as long as it is usually used for Mitsunobu reaction. For example, triphenylphosphine, tolylphosphine, tris (methoxyphenyl) phosphine, tris (chlorophenyl) phosphine, tri-n- It can be butylphosphine or 2- (di-t-butylphosphino) biphenyl, preferably triphenylphosphine or tri-n-butylphosphine. As the phosphine reagent, a phosphine reagent immobilized on a polymer such as polystyrene (preferably triphenylphosphine immobilized on polystyrene such as triphenylphosphine polystyrene) can also be used.

  The solvent used is selected from the above solvent group and is preferably an aromatic hydrocarbon or an ether, and more preferably tetrahydrofuran.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
(Step F-5)
The F-5 process is
(Step F-5a): In the compound (24) obtained in Step F-4, a step of removing the Alloc group in the presence of a palladium reagent; and
(Step F-5b): The compound obtained in Step F-5a is reacted with a compound (16) which is known in the presence of a base or can be easily obtained from a known compound to produce compound (25). It consists of a process.
(Step F-5a)
The palladium reagent to be used is not particularly limited as long as it is usually used for the elimination reaction of the Alloc group. For example, tetrakis (triphenylphosphine) palladium (0), bis [1,2-bis (diphenyl) is used. Phosphino) ethane] palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (tri-t-butylphosphine) palladium (0), palladium (II) chloride, palladium (II) acetate, dichlorobis ( Triphenylphosphine) palladium (II), dichlorobis [methylenebis (diphenylphosphine)] dipalladium-dichloromethane adduct, [1,2-bis (diphenylphosphino) ethane] dichloropalladium (II), [1,1′-bis (Diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct, palladium (II) acetylacetonate, bis (benzoni Ryl) palladium (II) chloride, bis (acetate) bis (triphenylphosphine) palladium (II), bis (acetonitrile) dichloropalladium (II), or bis (benzonitrile) dichloropalladium (II), suitable Is tetrakis (triphenylphosphine) palladium (0).

  In the F-5a step, a supplement can be appropriately used as necessary. Examples of supplements used include pyrrolidine, piperidine, morpholine, diethylamine, formic acid, acetic acid, 2-ethylhexanoic acid, 2-methylhexanoic acid sodium salt, 5,5-dimethyl-1,3-cyclohexanedione, and malonic acid. It can be dimethyl or tributyltin hydride, preferably pyrrolidine.

  The solvent used is selected from the above solvent group, preferably ethers or a mixture of ethers and water, more preferably a mixture of dioxane and water.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
(F-5b process)
F-5b process can be performed according to the method similar to E-3 process.
(Step F-6)
F-6 process is
(Step F-6a): In the compound (25) obtained in Step F-5, in the presence of an acid, a step of converting a dimethoxymethyl group into a formyl group and removing the methoxymethyl group;
(Step F-6b): a step of oxidizing the compound obtained in Step F-6a with sodium hypochlorite (NaClO ₂ ) in the presence of sodium dihydrogen phosphate and 2-methyl-2-butene; and,
(Step F-6c): The compound obtained in Step F-6b is reacted with the compound N, N-dimethylformamide ditert-butyl acetal [Me ₂ NC [O (t-Bu)] ₂ ] to give the compound ( If).
(Step F-6a)
The acid used is selected from the above acid group, preferably an inorganic acid, more preferably a hydrochloric acid or hydrogen chloride-tetrahydrofuran solution, and most preferably hydrochloric acid.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
(Step F-6b)
The solvent used is selected from the above solvent group and is preferably an alcohol, water or a mixture thereof, more preferably a mixture of 2-methyl-2-propanol and water.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
(Step F-6c)
The solvent used is selected from the above solvent group and is preferably an aromatic hydrocarbon, more preferably toluene.

  The reaction temperature is usually 50 to 200 ° C., preferably 80 to 150 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.

(G method)
Method G is a method for producing a compound (Ig) in which R ¹ is —COR ^c , R ⁷ is a hydrogen atom, and X ¹ is a single bond in formula (I).
(Step G-1)
G-1 process is
(Step G-1a): Step of oxidizing the compound (6) obtained in Step B-2 with manganese dioxide (MnO ₂ ); and
(Step G-1b): The step comprises the step of producing the compound (27) by reacting the compound obtained in the step G-1a with the compound (26).
(Step G-1a)
The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.
(Step G-1b)
The solvent used is selected from the above solvent group and is preferably an ether, more preferably tetrahydrofuran.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

  The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.

In the step G-1b, compound R ⁶ MgCl can be used instead of compound (26).
(Step G-2)
Step G-2 is a step of producing compound (28) by reacting compound (27) obtained in step G-1 with compound (3) in the presence of an azodicarboxylate reagent and a phosphine reagent. It is. The compound (3) is known, can be easily obtained from a known compound, or can be produced by the L method.

G-2 process can be performed according to the method similar to F-4 process.
(Step G-3)
G-3 process
(Step G-3a): The step of converting the compound (28) obtained in Step G-2 into an ester compound by reacting with an alcohol compound in the presence of a palladium catalyst and a base in a carbon monoxide atmosphere. ;
(Step G-3b): a step of hydrolyzing the ester compound obtained in Step G-3a in the presence of a base; and
(Step G-3c): The step comprises the step of producing the compound (Ig) by reacting the compound obtained in the step G-3b with the compound (11) in the presence of a condensing agent.

The G-3a step, the G-3b step, and the G-3c step can be performed according to the same method as the E-2a step, the E-2b step, and the E-2c step, respectively.

(Method H)
Method H is a method for producing a compound (Ih) in which R ⁶ and R ⁷ are hydrogen atoms and X ¹ is a methylene group in formula (I).
(Process H-1)
Step H-1 is a step of producing compound (30) by reducing compound (29) that is known or easily obtained from a known compound with a reducing agent.

  The reducing agent used is not particularly limited as long as it is usually used for ester reduction reaction. For example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride Alkali metal borohydride, lithium aluminum hydride, aluminum hydride compounds such as lithium hydride triethoxide aluminum, or hydrogen such as di (isobutyl) aluminum hydride, di (methoxyethoxy) aluminum sodium dihydride An organoaluminum compound can be used, preferably an alkali metal borohydride, and more preferably lithium borohydride.

  The solvent used is selected from the above solvent group, preferably ethers, alcohols or mixtures thereof, more preferably a mixture of tetrahydrofuran and methanol.

  The reaction temperature is usually 20 to 200 ° C, preferably 50 to 150 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.
(Process H-2)
Step H-2 is a step of producing compound (Ih) by reacting compound (30) obtained in step H-1 with compound (2) obtained in step A-1 in the presence of a base. is there.

  The base used is selected from the above group of bases, preferably an alkali metal hydride, and more preferably sodium hydride.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually −20 to 150 ° C., preferably 0 to 100 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.

(Method I)
In the method I, in formula (I), R ¹ is the formula —COO (t-Bu), R ² is a hydroxyl group, R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is a single bond. This is a method for producing compound (Ii).
(Step I-1)
In step I-1, compound (31) which is known or easily obtained from a known compound is converted to di-tert-butyl dicarbonate [(t-BuOCO) ₂ O in the presence of alkyllithium and a base. ] To produce compound (33).

Step I-1 can be performed according to the same method as Step F-1.
(Step I-2)
Step I-2 is a step of producing compound (33) by carrying out a silyl group removal reaction in compound (32) obtained in step I-1.

The reagent to be used is not particularly limited as long as it is usually used for silyl group removal reaction. For example, the acid shown in the acid group, tetra-n-butylammonium fluoride, potassium fluoride and the like can be used. a fluoride ion (F ^-) reagent to produce or, is obtained, preferably a mixture thereof, acetic acid, a tetra -n- butylammonium fluoride or a mixture thereof, more preferably, acetic acid and It is a mixture of tetra-n-butylammonium fluoride.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran. As a combination of the reagent and solvent used in Step I-2, a mixture of acetic acid, tetrahydrofuran and water is also suitable.

  The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.
(Process I-3)
Step I-3 is a step for producing compound (6) by reacting compound (33) obtained in step I-2 with compound (3) in the presence of a base. The compound (3) is known, can be easily obtained from a known compound, or can be produced by the L method.

Step I-3 can be performed according to the same method as Step F-4.
(Step I-4)
Step I-4 is a step of producing compound (Ii) by carrying out a methoxymethyl group removal reaction in compound (34) obtained in step I-3.

  The reagent used is usually used for the removal reaction of the methoxymethyl group, and is not particularly limited as long as it does not affect the -COO (t-Bu) group. For example, trimethylsilyl chloride, trimethylsilyl bromide And combinations of ammonium halides such as tetra-n-butylammonium chloride and tetra-n-butylammonium bromide, preferably trimethylsilyl chloride and tetra-n-butylammonium A combination of bromides.

  The solvent used is selected from the above solvent group, preferably a halogenated hydrocarbon, and more preferably methylene chloride.

  The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 2 hours to 12 hours.

(J method)
Method J, in formula (I), R ³ is R ^i, R ⁶ and R ⁷ are hydrogen atom, a process for preparing a compound X ¹ is a single bond (Ij).
(Step J-1)
In step J-1, compound (35) obtained in methods A to F is reacted with compound (36) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base. In this step, compound (Ij) is produced.

  The palladium catalyst used can be similar to that shown in step D-1, preferably tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0). More preferably, it is tris (dibenzylideneacetone) dipalladium (0). Moreover, a phosphorus ligand can be used suitably as needed like the D-1 process, and the phosphorus ligand used is preferably tri-o-tolylphosphine.

  The base used is selected from the above group of bases, preferably an alkali metal carbonate, and more preferably sodium carbonate.

  The solvent used is selected from the above solvent group, preferably aromatic hydrocarbons, alcohols, water, or a mixture thereof, more preferably toluene, ethanol, water, or these Most preferred is a mixture of toluene, ethanol and water.

  The reaction temperature is usually 20 to 200 ° C, preferably 50 to 150 ° C.

  The reaction time is usually 30 minutes to 24 hours, preferably 2 hours to 12 hours.

In Step J-1, compound (35) is converted into a palladium reagent [particularly [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct] and a metal salt [particularly, It can also be carried out by reacting with a compound R ⁱ MgCl or R ⁱ MgBr in a solvent (particularly tetrahydrofuran) in the presence of a combination of zinc chloride and copper (I) iodide].

(K method)
Method K is a method for producing a compound (Ik) in which R ⁶ and R ⁷ are hydrogen atoms and X ¹ is a single bond in formula (I).
(Step K-1)
In step K-1, compound (35) obtained in methods A to F is reacted with compound (37) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base. In this step, compound (38) is produced.

  The palladium catalyst used can be similar to that shown in step D-1, preferably with [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct. is there. Moreover, a phosphorus ligand can be used suitably as needed similarly to D-1 process.

  The base used is a base shown in the above base group or an alkali metal acetate such as sodium acetate or potassium acetate, preferably an alkali metal acetate, more preferably potassium acetate. It is.

  The solvent used is selected from the above solvent group and is preferably an amide, more preferably dimethylformamide.

  The reaction temperature is usually 20 to 200 ° C, preferably 50 to 150 ° C.

The reaction time is usually 30 minutes to 24 hours, preferably 2 hours to 12 hours.
(Step K-2)
In the step K-2, the compound (38) obtained in the step K-1 is reacted with a compound (39) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base. This is a step for producing compound (Ik).

Step K-2 can be performed according to the same method as step J-1.

(L method)
Method L is a compound in which R ⁸ is —N (R ¹⁰ ) ZR ¹¹ in compound (3) used in Step A-2, Step B-3, Step G-2, or Step 1-3. 3a).
(L-1 process)
Step L-1
(Step L-1a): a step of protecting a hydroxyl group by reacting a known compound or a compound (40) easily obtained from a known compound with a silylating reagent in the presence of a base;
(Step L-1b): a step of reducing a nitro group with a reducing agent in the compound obtained in Step L-1a;
(Step L-1c): a step of reacting the compound obtained in Step L-1b with compound (16) in the presence of a base; and
(Step L-1d): The step comprises the step of producing the compound (41) by reacting the compound obtained in the step L-1c with the compound (18) in the presence of a base.
(L-1a process)
The silylation reagent used is not particularly limited as long as it is usually used for hydroxyl group protection reaction, and may be, for example, R ^h Cl or R ^h OTf, preferably R ^h Cl, More preferably, it is triisopropylsilyl chloride.

  The base used is selected from the above group of bases, preferably an alkali metal hydride, and more preferably sodium hydride.

  The solvent used is selected from the above solvent group, preferably ethers, and more preferably tetrahydrofuran.

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 60 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.
(L-1b process)
The reducing agent used is not particularly limited as long as it is usually used for the reduction reaction of a nitro group. Combination].

  The solvent used is selected from the above solvent group, preferably alcohols, and more preferably methanol.

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.

  The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.

The L-1b step can also be performed according to the same method as the E-2d step.
(L-1c process)
L-1c process can be performed according to the method similar to E-3 process.
(L-1d process)
L-1d process can be performed according to the method similar to E-4 process.
(Step L-2)
Step L-2 is a step of producing compound (3a) by carrying out a silyl group removal reaction in compound (41) obtained in step L-1.

L-2 process can be performed according to the method similar to I-2 process.

(M method)
Method M is a method for producing compound (1a) in which R ¹ is —COR ^c in compound (1) used in step A-1.
(Step M-1)
Step M-1
(Step M-1a): a step of reducing a nitro group in the presence of a catalyst and in a hydrogen atmosphere in a compound (43) that is known or easily obtained from a known compound; and
(Step M-1b): The step comprises reacting the compound obtained in Step M-1a with a nitrite in the presence of an acid to convert it to a diazonium salt, followed by iodination to produce the compound (44).
(M-1a process)
M-1a process can be performed in accordance with the method similar to E-2d process.
(M-1b process)
M-1b process can be performed according to the method similar to B-1 process.
(Step M-2)
In step M-2, compound (44) obtained in step M-1 is reacted with compound R ^j OH in the presence of a palladium catalyst and a base in a carbon monoxide atmosphere to give compound (45). It is a manufacturing process.

M-2 process can be performed according to the method similar to E-2a process.
(M-3 process)
Step M-3 is a step of producing compound (46) by hydrolyzing compound (45) obtained in step M-2 in the presence of a base.

M-3 process can be performed according to the method similar to E-2b process.
(Step M-4)
Step M-4 is a step for producing compound (1a) by reacting compound (46) obtained in step M-3 with compound (11) in the presence of a condensing agent.

M-4 process can be performed in accordance with the method similar to C-2 process, E-2c process, or F-6c process.

In addition, a substituent conversion reaction under the following reaction conditions can be appropriately applied to the above-mentioned methods A to M as required.
(A) Amino group to chloro group: (i) sulfuric acid, sodium nitrite, (ii) potassium iodide, (iii) sodium nitrite, hydrochloric acid, copper (I) chloride;
(B) iodo group to cyclopropyl group: propargyl bromide, 9-borabicyclo [3.3.1] nonane, tetrakistriphenylphosphine palladium (0), sodium hydroxide;
(C) From an iodo group to a formyl group: carbon monoxide, tri-n-octylsilane, palladium (II) acetate, 1,3-bis (diphenylphosphino) propane;
(D) Formyl group to 2,2,2-trifluoroethyl group: (i) Trimethylsilyl trifluoromethane, tetra-n-butylammonium fluoride, (ii) p-toluenesulfonyl chloride, sodium hydride, (iii) hydrogen Palladium-carbon;
(E) an iodo group to an ethynyl group: (i) trimethylsilylacetylene, dichlorobis (triphenylphosphine) palladium (II), copper (I) iodide, diisopropylamine, (ii) tetra-n-butylammonium fluoride;
(F) iodo group to phenylthio group, phenylsulfinyl group, or phenylsulfonyl group: (i) mercaptobenzene, tris (dibenzylideneacetone) dipalladium (0), (oxydi-2,1-phenylene) bis (diphenylphosphine) ) (DEPphos), potassium t-butoxy, (ii) m-chloroperbenzoic acid;
(G) From an iodo group to a vinyl group: palladium (II) acetate, tetra-n-butylammonium fluoride, vinyltrimethoxysilane, 1,3-bis (2,6-diisopropylphenyl) imidazolium chloride;
(H) an amino group to a dimethylamino group: formalin, sodium cyanoborohydride; or
(I) 2,2,2-trifluoroethylamino group from amino group; trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester.

In the present invention, “arteriosclerosis” means (i) arteriosclerosis caused by various factors (including complex factors); and (ii) hyperlipidemia, hypercholesterolemia, lipid-related diseases, It includes arteriosclerosis caused by diseases that can cause arteriosclerosis such as inflammatory diseases, diabetes and hypertension.

  When the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is used as a medicine, it is combined with the following drugs according to the purpose, simultaneously or at intervals. Pharmaceutical compositions can be formed for separate administration.

  When the above pharmaceutical composition of the present invention is “administered simultaneously”, the dosage form is not particularly limited as long as it can be administered at approximately the same time. For example, the general formula (I) of the present invention which is a composition component Or a pharmacologically acceptable salt or ester thereof and the following drugs can be administered in the form of a combination of separate preparations or in the form of a single preparation (compound) It is preferably administered in the form of a combination of these preparations.

  When the above pharmaceutical composition of the present invention is "administered separately at different times", the dosage form is not particularly limited as long as it can be administered separately at different times. The compound represented by (I) or a pharmacologically acceptable salt or ester thereof is administered, and after a predetermined time, the following drug is administered, or the following drug is administered first, After this time, the compound represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof can be administered.

The drug that can be administered in combination with the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is particularly limited as long as it meets the purpose and exhibits a desired effect. For example, HMG-CoA reductase inhibitor, HMG-CoA synthase inhibitor, plasma HDL elevating agent, cholesterol biosynthesis inhibitor, squalene epoxidase inhibitor, squalene synthetase inhibitor, hypercholesterolemia therapeutic agent, Acyl-coenzyme A, CETP inhibitor, ACAT inhibitor, probucol, cholesterol absorption inhibitor, bile acid adsorption ion exchange resin, fibrate, nicotinic acid derivative, niacinamide, LDL receptor inducer, vitamin B ₆ , vitamin B _12, antioxidant vitamins, angiotensin II inhibitor, angiotensin converting enzyme inhibitors, beta-blockers, off It can be a blinogen inhibitor, aspirin, diuretic, or a combination thereof, preferably an HMG-CoA reductase inhibitor, CETP inhibitor, ACAT inhibitor, cholesterol absorption inhibitor, bile acid adsorption ion exchange resin , A fibrate, a nicotinic acid derivative, an angiotensin II inhibitor, a diuretic, or a combination thereof, more preferably an HMG-CoA reductase inhibitor, a CETP inhibitor, a cholesterol absorption inhibitor, or A combination thereof, more preferably an HMG-CoA reductase inhibitor, a CETP inhibitor, a cholesterol absorption inhibitor, or a combination thereof, most preferably an HMG-CoA reductase inhibitor It is an agent.

  A pharmaceutical composition for administering a compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof and an HMG-CoA reductase inhibitor simultaneously or separately over time The pharmaceutical composition may contain a CETP inhibitor or a cholesterol absorption inhibitor as necessary) atherosclerosis; atherosclerosis; arteriosclerosis due to diabetes; hyperlipidemia; Cholesterolemia; lipid-related diseases; ischemic heart disease, cardiovascular diseases such as heart failure; coronary artery disease; or cerebrovascular disease, preferably due to arteriosclerosis, atherosclerosis or diabetes It is useful as a pharmaceutical composition for the treatment or prevention of arteriosclerosis. In addition, the pharmaceutical composition is useful as a pharmaceutical composition for warm-blooded animals (particularly for humans).

The HMG-CoA reductase inhibitor is not limited as long as it has an HMG-CoA reductase inhibitory action and can be used as a medicine. For example, JP-A-57-2240 (US Pat. No. 4,346,227) (+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6-hydroxy-2-methyl-8- [ (S) -2-Methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoic acid (pravastatin) [(+)-(3R, 5R) -3,5- Dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6-hydroxy-2-methyl-8-[(S) -2-methylbutyryloxy] -1,2,6,7,8, 8a-hexahydro-1-naphthyl] heptanoic acid monosodium salt (including pravastatin sodium salt), which is described in JP-A-57-163374 (US Pat. No. 4231938). +)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4 -Hydroxy-6-oki -2H-pyran-2-yl] ethyl] -1-naphthyl (S) -2-methylbutyrate (lovastatin), described in JP-A-56-122375 (US Pat. No. 4,444,784) ( +)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4 -Hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl 2,2-dimethylbutyrate (simvastatin), JP 60-500015 (US Pat. No. 4,473,907) (±)-(3R ^* , 5S ^* , 6E) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -3,5 -Dihydroxy-6-heptenoic acid (fluvastatin), (3R, 5S, 6E) -7- [4- (4-fluorophenyl) described in JP-A-1-216974 (US Pat. No. 5,006,530) ) -2,6-di- (1-methylethyl) -5-methoxymethylpyridin-3-yl] -3,5-dihydroxy-6-heptenoic acid (cerivastatin), JP 3-58967 (3R, 5S) -7- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-phenylaminocarbonyl- described in US Pat. 1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid (atorvastatin), described in JP-A-1-279866 (US Pat. Nos. 5,854,259 and 5,856,336) (E) -3, 5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] -6-heptenoic acid (pitavastatin), JP-A-5-78841 (US Patent No. (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine- 5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid (rosuvastatin) or a pharmacologically acceptable salt thereof, preferably pravastatin, atorvastatin or rosbastati By weight, more preferably, pravastatin.

  The CETP inhibitor is not limited as long as it has a CETP inhibitory action and can be used as a medicine. For example, cis-4-[(3,5- Bistrifluoromethylbenzyl) methoxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or ethyl (2R, 4S) -4-[[3 , 5-bis (trifluoromethyl) benzyl] (methoxycarbonyl) amino] -2-ethyl-6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylate, or JP-A-11 2-methylthiopropionic acid S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester described in JP-A-49743 or JP-A-11-222428.

  The ACAT inhibitor is not limited as long as it has an ACAT inhibitory action and can be used as a medicine. For example, (±) -N- (1,2) described in WO 92/09561 -Diphenylethyl) -2- (2-octyloxyphenyl) acetamide, U.S. Pat. No. 5,491,172, U.S. Pat. No. 5,633,287, U.S. Pat. No. 6093719, U.S. Pat. No. 6,124,309 or U.S. Pat. 2,6-bis (1-methylethyl) phenyl N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate described in US Pat. No. 6,143,755, US Pat. No. 5,120,738 (1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl 3- [N- (2,2,5,5) described in the specification -Tetramethi Ru-1,3-dioxane-4-carbonyl) amino] propionate, (S) -2 ′, 3 ′, 5′-trimethyl-4′-hydroxy-α-dodecylthio- described in US Pat. No. 5,990,173. α-Phenylacetanilide, 2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert- described in US Pat. No. 5,849,732 Butylphenol and its hydrochloride, (−)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4, described in WO 96/26948 5-dimethyl-1,3-dioxolan-2-yl} phenyl phosphate and its monosodium salt, N- [2,4-bis (methyl) described in EP 0987254 Thio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin-2-ylthio) ethyl] piperazin-1-yl] acetamide, US Pat. No. 5,475,130 N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide described in the specification, trans-1,4-bis [[1-cyclohexyl- 3- (4-Dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2 described in WO 96/10559 , 4-Bis (methylthio) -6-methylpyridin-3-yl] urea, N- (4,6-dimethyl-1 as described in US Pat. No. 5,990,150 or US Pat. No. 6,127,403. Pentylindoline-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5-carboxymethyl-4, described in US Pat. No. 6063806 or US Pat. No. 6,2009,885. 6-dimethylindoline-7-yl) -2,2-dimethylpropanamide and its sulfate, N- [4- (3,4-dimethylphenyl) -1,4-diazacyclohexyl]-(2E) -3 -(3,5-dimethoxy-4-octyloxyphenyl) -2-propenamide, or a pharmacologically acceptable salt thereof, preferably N- (1-octyl-5-carboxymethyl-4 , 6-dimethylindoline-7-yl) -2,2-dimethylpropanamide and its sulfate.

  The angiotensin II inhibitor is not particularly limited as long as it has an angiotensin II inhibitory activity and can be used as a medicament. For example, in European Patent Application Publication No. 0459136 or European Patent Application Publication No. 0520423 Candesartan or 2-ethoxy-1- [p- (o-1H-tetrazol-5-ylphenyl) benzyl] -7-benzimidazolecarboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl ester (candesartan cilexetil) 2-n-butyl-4-spirocyclopentane-1-[((2'-tetrazol-5-yl) biphenyl-4-yl) methyl] -2- described in WO 91/14679 Imidazolin-5-one (irbesartan), olmesartan or (5-methyl-2-oxo-1,3-dioxo) described in JP-A-5-78328 (US Pat. No. 5,459,148) N-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole- 5-carboxylate (olmesartan medoxomil), 2-propyl-8-oxo-1-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) described in JP-A-5-320139 Methyl] -4,5,6,7-tetrahydrocycloheptimidazole (Pratosartan), 4 ′-[(1,4′-dimethyl-2′-propyl) described in EP 0502314 [2,6′-bi-1H-benzimidazole] -1′-yl) methyl]-[1,1′-biphenyl] -2-carboxylic acid (telmisartan), described in European Patent Application No. 0443983 (S) -N-valeryl-N-([2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl) valine (valsartan), described in EP 0403159 , Ep Sultan or 3- [1- (4-carboxyphenylmethyl) -2-n-butylimidazol-5-yl] -2-thienylmethyl-2-propenoic acid methanesulfonate (eprosartan mesylate), European Patent Application Publication No. 0253310 Losartan or 2-butyl-4-chloro-1-[[2 ′-(1H-tetrazol-5-yl)-[1,1 ′], which is described in U.S. Pat. -Biphenyl] -4-yl] methyl] -1H-imidazole-5-methanol monopotassium salt (losartan potassium) or a pharmacologically acceptable salt thereof, preferably olmesartan or olmesartan medoxomil .

  The cholesterol absorption inhibitor is not limited as long as it has an action of inhibiting the absorption of dietary cholesterol from the digestive tract and can be used as a medicine. For example, 1- (4-fluorophenyl) -3 ( It may be R)-[3- (4-fluorophenyl) -3 (S) -hydroxypropyl] -4 (S)-(4-hydroxyphenyl) -2-azetidinone (ezetimibe).

  The bile acid-adsorbing ion exchange resin is not limited as long as it has an action of increasing the excretion of bile acid, which is an in vitro excretion route of cholesterol, and can be used as a medicine. For example, cholestyramine, colestimide, or colesevelam hydrochloride It can be.

  The fibrate is not limited as long as it can be used as a medicine, and may be, for example, clofibrate, clinofibrate, bezafibrate, fenofibrate, or semfibrate.

  The nicotinic acid derivative is not limited as long as it can be used as a medicine, and may be, for example, niceritrol or nicomol.

  The diuretic is not limited as long as it has a diuretic action and can be used as a medicine. For example, it can be chlorothiazide, hydrochlorothiazide, furosemide, piretanide, or azosemide.

  The above HMG-CoA reductase inhibitor, CETP inhibitor, ACAT inhibitor, angiotensin II inhibitor, cholesterol absorption inhibitor, fibrate, nicotinic acid derivative, or diuretic may form a salt with an acid or base In some cases, these agents include salts thereof. In addition, when stereoisomers exist in the above drugs, these drugs include all stereoisomers and mixtures of stereoisomers.

  When the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is used as a therapeutic or prophylactic agent for the above diseases, the compound represented by the general formula (I) Or a pharmacologically acceptable salt or ester thereof is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, etc., and tablets, capsules, granules, powders or syrups, etc. Or can be administered parenterally in dosage forms such as injections, suppositories, patches or external preparations.

  These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and diluents.

  The excipient can be, for example, an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, pregelatinized starch and dextrin; cellulose derivatives such as crystalline cellulose; It can be rubber; dextran; or pullulan. Inorganic excipients include, for example, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium silicate derivatives; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or Or a sulfate such as calcium sulfate.

  Lubricants include, for example, stearic acid; metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate; or the above starch derivative obtain.

  The binder can be, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, or a derivative described in the above excipients.

  Disintegrants include, for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethyl cellulose; chemically modified starch / cellulose derivatives such as carboxymethyl starch and sodium carboxymethyl starch Or it may be cross-linked polyvinyl pyrrolidone.

  Emulsifiers include, for example, colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; benzalkonium chloride Or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester.

  Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; or sorbic acid.

  The corrigent can be, for example, commonly used sweeteners, acidulants, fragrances and the like.

The dose of the compound represented by formula (I) or a pharmacologically acceptable salt or ester thereof varies depending on the disease, the age of the patient, etc., but in the case of oral administration, the lower limit is 0.01 mg / dose per dose. kg (preferably 0.05 mg / kg), upper limit 500 mg / kg (preferably 100 mg / kg), and for intravenous administration, lower limit 0.001 mg / kg (preferably 0.005 mg / kg) and an upper limit of 100 mg / kg (preferably 20 mg / kg) are preferably administered to adults 1 to 6 times per day depending on the disease and its symptoms.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof has an excellent binding activity to LXR, and has absorption, biodistribution, blood half-life and the like. In that respect, it has excellent pharmacokinetic properties and low toxicity to the kidneys, liver, and other organs. Accordingly, the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is useful as a pharmaceutical for warm-blooded animals, preferably for humans. The compound represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof is, in particular, arteriosclerosis; atherosclerosis; arteriosclerosis caused by diabetes; hyperlipidemia; Lipid-related diseases; rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, inflammatory diseases that are caused by inflammatory cytokines, such as systemic lupus erythematosus, ulcerative colitis, Autoimmune diseases such as Crohn's disease; ischemic heart disease, cardiovascular disease such as heart failure; cerebrovascular disease; kidney disease; diabetes; diabetic complications such as retinopathy, nephropathy, neurosis, coronary artery disease Obesity; nephritis; hepatitis; cancer; or Alzheimer's disease; preferably arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, high Cholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, or diabetes; most preferably, it is useful as a medicament for the treatment or prevention of arteriosclerosis.

  EXAMPLES Hereinafter, although an Example, a test example, and a formulation 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, Examples (1-4), (2-4), (4-2), (7-3), (12-3), (16-2), (44-4), N- (4-Hydroxyphenyl) -N-methylacetamide used in (45-5) or (72-3) and the like is described in the literature (Harvison, PJ et al., J. Med. Chem., 1986). , 29, p. 1737-1743).

Example 1 tert-Butyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl} -5-iodobenzoate (Exemplary Compound Number: 1-70)
(1-1) 5-amino-2-methylbenzoic acid synthesized according to the method described in the literature (Ashton, MJ et al., J. Med. Chem., 1996, Vol. 39, p. 3343-3356) The acid (20.5 g, 136 mmol) was suspended in water (500 ml), and concentrated sulfuric acid (50 ml) was added under ice cooling. Under ice cooling, an aqueous solution (40 ml) of sodium nitrite (12.6 g, 183 mmol) was added dropwise while maintaining the temperature of the reaction solution at 10 ° C. or lower, and the mixture was further stirred for 20 minutes under ice cooling. To this reaction solution, an aqueous solution (50 ml) of potassium iodide (38.3 g, 231 mmol) was added under ice cooling. The reaction solution was immediately heated to 80 ° C. and stirred for 1 hour, and then the reaction solution was poured into water and extracted with ethyl acetate (three times). The organic layer was washed successively with water, 10% aqueous sodium thiosulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-iodo-2-methylbenzoic acid (41.3 g) as a pale orange solid. The obtained compound was used in the next step without further purification.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.11 (1H, d, J = 2.2 Hz), 7.80 (1H, dd, J = 8.1, 2.2 Hz), 7.14 (1H, d, J = 8.1 Hz), 2.48 (3H, s).
(1-2) Toluene solution (230 ml) of 5-iodo-2-methylbenzoic acid (41.3 g) obtained in Example (1-1), oxalyl dichloride (23.7 ml, 272 mmol), and N, N-dimethylformamide (0.30 ml) was added at room temperature, followed by stirring at 60 ° C. for 90 minutes. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. Furthermore, the operation of adding toluene (200 ml) and evaporating the solvent under reduced pressure was repeated twice. To a solution of the obtained residue in tetrahydrofuran (400 ml), potassium tert-butoxide (15.2 g, 136 mmol) was gradually added over 5 minutes under ice cooling. The reaction solution was returned to room temperature and further stirred for 1 hour, poured into 15% ammonium chloride and extracted with ethyl acetate (three times). The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 1-35 / 1) to give tert-butyl 5 as a pale orange oil. -Iodo-2-methylbenzoate (33.9 g, 78% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.10 (1H, d, J = 1.5 Hz), 7.65 (1H, dd, J = 8.1, 1.5 Hz), 6.95 (1H, d, J = 8.1 Hz), 2.50 (3H, s), 1.59 (9H, s).
(1-3) N-bromosuccinimide (12) was added to a benzene solution (190 ml) of tert-butyl 5-iodo-2-methylbenzoate (20.7 g, 65.1 mmol) obtained in Example (1-2). 0.5 g, 70.3 mmol) and 2,2′-azobis (isobutyronitrile) (100 mg) were added, and the mixture was heated to reflux for 1 hour. The reaction solution was returned to room temperature, poured into 0.5N hydrochloric acid and extracted with ethyl acetate (three times). The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 1-30 / 1) and purified as a colorless solid tert-butyl 2- (Bromomethyl) -5-iodobenzoate (21.8 g, 84% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (1H, d, J = 1.5 Hz), 7.76 (1H, dd, J = 8.1, 1.5 Hz), 7.14 (1H, d, J = 8.1 Hz), 4.84 (2H, s), 1.62 (9H, s).
(1-4) [Coupling step of various benzyl bromides and phenol derivatives]
Tert-Butyl 2- (bromomethyl) -5-iodobenzoate (2.47 g, 6.22 mmol) obtained in Example (1-3) and N- (4-hydroxyphenyl) -N-methylacetamide ( To an N, N-dimethylformamide solution (8 ml) of 1.03 g, 6.24 mmol), cesium carbonate (2.64 g, 8.10 mmol) was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed successively with water (3 times) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1-1-1) to give the title compound (1.21 g, yield 41%) as a colorless powder. It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.25 (1H, d, J = 2.2 Hz), 7.85 (1H, dd, J = 8.1, 2.2 Hz), 7.45 (1H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.40 (2H, s), 3.23 (3H, s), 1.85 (3H, s), 1.59 (9H, s ).
MS (FAB) (m / z): 482 ([M + H] ⁺ ).

(Example 2) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-chlorobenzoate (Exemplary compound number: 1-69)
(2-1) 12-N hydrochloric acid (8 ml) was added to 5-amino-2-methylbenzoic acid (1.00 g, 6.62 mmol), cooled to 0 ° C., then sodium nitrite (457 mg, 6.62 mmol) was added. Aqueous solution (5 ml) was added. After stirring at 0 ° C. for 1.5 hours, the reaction solution was added dropwise to 12N hydrochloric acid (5 ml) containing copper (I) chloride (655 mg, 6.62 mmol) at room temperature. The reaction solution was heated to 80 ° C. and stirred for 1.5 hours, and then the reaction solution was poured into water and extracted with ethyl acetate (three times). The organic layer was washed successively with water (twice) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloro-2-methylbenzoic acid (0.88 g, Yield 78%) was obtained.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 7.78 (1H, d, J = 2.2 Hz), 7.50 (1H, dd, J = 8.1, 2.2 Hz), 7.33 (1H, d, J = 8.1 Hz), 2.50 (3H, s).
(2-2) In the same manner as in Example (1-2), tert-butyl 5-chloro-2-methylbenzoate was obtained from 5-chloro-2-methylbenzoic acid obtained in Example (2-1). (757 mg, 64% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.78 (1H, d, J = 2.2 Hz), 7.32 (1H, dd, J = 8.1, 2.2 Hz), 7.15 (1H, d, J = 8.1 Hz), 2.53 (3H, s), 1.59 (9H, s).
(2-3) To a carbon tetrachloride solution (10 ml) of tert-butyl 5-chloro-2-methylbenzoate (757 mg, 3.34 mmol) obtained in Example (2-2), N-bromosuccinimide (713 mg, 713 mg, 4.01 mmol) and 2,2′-azobis (isobutyronitrile) (55 mg, 0.33 mmol) were added, and the mixture was heated to reflux for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2-30 / 1), and tert-butyl 2- (bromomethyl). ) -5-chlorobenzoate (1.03 g, 100% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.84 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 7.8, 2.0 Hz), 7.36 (1H, d, J = 7.8 Hz), 4.87 (2H, s), 1.63 (9H, s).
(2-4) In the same manner as in Example (1-4), tert-butyl 2- (bromomethyl) -5-chlorobenzoate (809 mg, 2.65 mmol) obtained in Example (2-3), N The title compound (578 mg, yield 56%) as a colorless powder was obtained from-(4-hydroxyphenyl) -N-methylacetamide (460 mg, 2.78 mmol) and cesium carbonate (1.09 g, 3.35 mmol). .
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.92 (1H, d, J = 2.0 Hz), 7.66 (1H, dd, J = 8.8, 2.0 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.43 (2H, s), 3.23 (3H, s), 1.85 (3H, s), 1.59 (9H, s ).
MS (FAB) (m / z): 390 ([M + H] ⁺ ).

(Example 3) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -3-bromobenzoate (Exemplary compound number: 1-16)
In the same manner as in Examples (1-2), (2-3), and (1-4), the title compound (4.24 g, yield 70%) was obtained from 3-bromo-2-methylbenzoic acid as a colorless powder. )
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.73 (1H, dd, J = 8.1, 1.5 Hz), 7.70 (1H, dd, J = 8.1, 1.5 Hz), 7.28 (1H, t, J = 8.1 Hz ), 7.10 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.46 (2H, s), 3.23 (3H, s), 1.85 (3H, s), 1.50 (9H , s).

Example 4 tert-Butyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -6-aminobenzoate (Exemplary Compound Number: 1-158)
(4-1) N, N-dimethylformamide ditert-butyl acetal (17.7 ml, 74.0 mmol) in a toluene solution (20 ml) of 2-methyl-6-nitrobenzoic acid (3.35 g, 18.5 mmol) Was added at room temperature, followed by stirring at 110 ° C. for 3 hours. The reaction solution was returned to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain tert-butyl 2-methyl-6-nitrobenzoate (3.56 g). The obtained compound was used in the next step without further purification.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.94 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 7.4 Hz), 7.41 (1H, app.t, J = 7.8 Hz), 2.45 (3H, s), 1.63 (9H, s).
(4-2)
Tert-Butyl 2-methyl-6-nitrobenzoate obtained in Example (4-1) (3.56 g, 15.0 mmol) in the same manner as in Examples (1-3) and (46-2). ) To give crude tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -6-nitrobenzoate. To a solution of the obtained crude tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -6-nitrobenzoate in ethyl acetate (40 ml), 10% palladium hydroxide-carbon (200 mg) was added. In addition, the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1-1-1 / 1) to give the title compound (250 mg, yield 4%) as colorless crystals.
¹ H-NMR (500MHz, CDCl ₃ ): δ 7.18 (1H, app.t, J = 7.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 6.85 (1H, d, J = 7.3 Hz), 6.67 (1H, d, J = 8.3 Hz), 5.25 (2H, s), 5.20 (2H, br.s), 3.22 (3H, s), 1.85, ( 3H.s), 1.55 (9H, s).
MS (FAB) (m / z): 371 ([M + H] ⁺ ).

(Example 5) tert-butyl 4-({4- [acetyl (methyl) amino] phenoxy} methyl) -1,1'-biphenyl-3-carboxylate (Exemplified compound number: 1-71)
Tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (70 mg, 0.15 mmol) obtained in Example (1-4) and phenylboric acid (21 mg , 0.17 mol) in a toluene-ethanol (5: 1, 2.4 ml) mixed solution, tris (dibenzylideneacetone) dipalladium (0) (10.7 mg, 0.012 mmol), tri-o-tolylphosphine (7.1 mg, 0,023 mmol) and 2N-sodium carbonate aqueous solution (0.8 ml) were added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (49 mg, yield) as a colorless powder. 78%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.18 (1H, br.s), 7.75 (2H, br.s), 7.62 (2H, br.d, J = 7.7 Hz), 7.47 (2H, app. t, J = 7.7 Hz), 7.39 (1H, app.t, J = 7.7 Hz), 7.12 (2H, d, J = 9.2 Hz), 7.03 (2H, d, J = 9.2 Hz), 5.51 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.61 (9H, s).
MS (FAB) (m / z): 431 ([M + H] ⁺ ).

Example 6 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (methylthio) benzoate (Exemplary Compound Number: 1-60)
In the same manner as in Examples (1-2), (1-3), and (1-4), the literature [Gol'dfarb, YL et al., J. Org. Chem. USSR (Engl.Transl.) , 1973, Vol. 9, p. 2409-2415], the title compound (13 mg, 5% yield) was obtained as a colorless oil from 2-methyl-5- (methylthio) benzoic acid synthesized It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.82 (1H, d, J = 2.2 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.39 (1H, dd, J = 8.1, 2.2 Hz), 7.10 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.23 (3H, s), 2.52 (3H, s), 1.85 (3H, s ), 1.58 (9H, s).

Example 7 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-29)
(7-1) Potassium tert-butoxide (5.40 g, 48.1 mmol) was added to an ice-cooled tetrahydrofuran solution (180 ml) of 2-methyl-5-trifluoromethylbenzoyl chloride (10.5 g, 47.2 mmol). It was added in small portions and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 1-20 / 1) to give colorless oily tert-butyl 2 -Methyl-5- (trifluoromethyl) benzoate (9.90 g, 81% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.03 (1H, br s), 7.57 (1H, br d, J = 7.8 Hz), 7.31 (1H, d, J = 7.8 Hz), 2.62 (3H, s ), 1.61 (9H, s).
(7-2) N-bromo was added to a solution of tert-butyl 2-methyl-5- (trifluoromethyl) benzoate (1.57 g, 6.03 mmol) obtained in Example (7-1) in benzene (25 ml). Succinimide (1.18 g, 6.63 mmol) and 2,2′-azobis (isobutyronitrile) (20 mg) were added, and the mixture was heated to reflux for 60 minutes. The reaction solution is returned to room temperature, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 8 / 1-6 / 1) to be colorless. A powder of tert-butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate (1.08, 53% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.12 (1H, br s), 7.69 (1H, br d, J = 8.1 Hz), 7.56 (1H, d, J = 8.1 Hz), 4.92 (2H, s ), 1.65 (9H, s).
(7-3) In the same manner as in Example (1-4), tert-butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate (150 mg,. 442 mmol), N- (4-hydroxyphenyl) -N-methylacetamide (80 mg, 0.48 mmol), and cesium carbonate (187 mg, 0.574 mmol) to give the title compound as a colorless powder (181 mg, 97% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.21 (1H, s), 7.90 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 5.53 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.62 (9H, s).
MS (FAB) (m / z): 424 ([M + H] ⁺ ).

(Example 8) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (2-pyridinyl) benzoate (Exemplary compound number: 1-73)
(8-1) Dimethyl tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (500 mg, 1.04 mmol) obtained in Example (1-4) In a sulfoxide solution (6.0 ml), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (290 mg, 1. 14 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (25.5 mg, 31.2 μmol) and potassium acetate (153 mg, 1.56 mmol) were added. Then, it stirred at 80 degreeC for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3 / 1-1 / 1) to give tert-butyl 2 as a colorless oil. -({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (330 mg, yield 66 %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.32 (1H, s), 7.94 (1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.47 (2H, s), 3.22 (3H, s), 1.85 (3H, s), 1.60 (9H, s), 1.36 (12H, s ).
(8-2) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (4,4,5,5-tetramethyl) obtained in Example (8-1) -1,3,2-dioxaborolan-2-yl) benzoate (50 mg, 0.10 mmol) and 2-bromopyridine (10 μl, 0.11 mol) in toluene-ethanol (5: 1, 1.2 ml) 2N-sodium carbonate aqueous solution (0.4 ml) and tetrakis (triphenylphosphine) palladium (0) (13 mg, 0.011 mmol) were sequentially added to the solution, and the mixture was stirred at 80 ° C. for 9 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (29 mg, yield) as a colorless powder. 65%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.72 (1H, d, J = 5.1 Hz), 8.55 (1H, d, J = 1.5 Hz), 8.17 (1H, dd, J = 8.1, 1.5 Hz), 7.82-7.76 (2H, m), 7.79 (1H, d, J = 8.1 Hz), 7.28 (1H, m), 7.11 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz) ), 5.53 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.63 (9H, s).
MS (FAB) (m / z): 433 ([M + H] ⁺ ).

Example 9 tert-Butyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (1,3-thiazol-2-yl) benzoate (Exemplary Compound Number: 1-72)
In the same manner as in Example (8-2), tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (4, From 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (50 mg, 0.10 mmol) and 2-bromothiazole (15 μl, 0.17 mmol), the title compound (39 mg Yield 85%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.52 (1H, d, J = 2.2 Hz), 8.12 (1H, dd, J = 8.5, 2.2 Hz), 7.91 (1H, d, J = 3.3 Hz), 7.80 (1H, d, J = 8.5 Hz), 7.38 (1H, d, J = 3.3 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 5.51 ( 2H, s), 3.23 (3H, s), 1.86 (3H, s), 1.63 (9H, s).

Example 10 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-nitrobenzoate (Exemplary Compound Number: 1-68)
(10-1) To a tetrahydrofuran solution (15 ml) of 2-methyl-5-nitrobenzoic acid (3.00 g, 16.6 mmol), tert-butyl alcohol (8.0 ml, 83.6 mmol), 4- (N, N-dimethylamino) pyridine (550 mg, 4.50 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.81 g, 19.9 ml) were added and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 1-25 / 1), and tert-butyl 2-methyl- 5-Nitrobenzoate (1.92 g, 49% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.64 (1H, d, J = 2.2 Hz), 8.20 (1H, dd, J = 8.5, 2.2 Hz), 7.39 (1H, d, J = 8.5 Hz), 2.68 (3H, s), 1.63 (9H, s).
(10-2) tert-Butyl 2-methyl-5-nitrobenzoate obtained in Example (10-1) (1. 2) in the same manner as in Examples (2-3) and (1-4). 92 g, 8.09 mmol) gave the title compound (609 mg, 26% yield) as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.79 (1H, d, J = 2.2 Hz), 8.38 (1H, dd, J = 8.8, 2.2 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 5.57 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.64 (9H, s ).
MS (FAB) (m / z): 401 ([M + H] ⁺ ).

Example 11 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (dimethylamino) benzoate (Exemplary Compound Number: 1-65)
(11-1) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-nitro obtained in Example (10-2) in the same manner as in Example (18) A colorless solid of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-aminobenzoate (160 mg, 38% yield) was obtained from benzoate (458 mg, 1.14 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.38 (1H, d, J = 8.1 Hz), 7.24 (1H, d, J = 2.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.97 ( 2H, d, J = 8.8 Hz), 6.81 (1H, dd, J = 8.1, 2.5 Hz), 5.31 (2H, s), 3.22 (3H, s), 1.85 (3H, s), 1.54 (9H, s ).
(11-2) Acetonitrile of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-aminobenzoate (75 mg, 0.20 mmol) obtained in Example (11-1) -To a mixed solution of methylene chloride (5: 1, 1.2 ml) under ice cooling, formalin (250 µl), acetic acid (12 µl, 0.021 mmol), and sodium cyanoborohydride (28 mg, 0.045 mmol) ) Were added sequentially, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/3) to give the title compound as a colorless powder (48 mg, yield). 60%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.41 (1H, d, J = 8.8 Hz), 7.28 (1H, d, J = 2.9 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.97 ( 2H, d, J = 8.8 Hz), 6.83 (1H, dd, J = 8.8, 2.9 Hz), 5.30 (2H, s), 3.23 (3H, s), 2.99 (6H, s), 1.85 (3H, s ), 1.54 (9H, s).
MS (FAB) (m / z): 399 ([M + H] ⁺ ).

(Example 12) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-tert-butylbenzoate (Exemplified compound number: 1-26)
(12-1) 4-tert-butyl-2-synthesized according to the method described in the literature (Tashiro, M. et al, J. Org. Chem., 1979, Vol. 44, p. 3037-3041) Methanol (50 ml), triethylamine (2.78 ml, 19.9 mmol), palladium (II) acetate (639 mg) in a solution of iodo-1-methylbenzene (4.31 g, 19.0 mmol) in N, N-dimethylformamide (50 ml). , 2.85 mmol) and 1,3-bis (diphenylphosphino) propane (1.33 g, 3.22 mmol) were added, followed by stirring at 80 ° C. for 72 hours under a carbon monoxide atmosphere. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate, and then the organic layer was washed successively with water (3 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-30 / 1) to give methyl 5 as a pale yellow oil. -Tert-Butyl-2-methylbenzoate (1.91 g, 67% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.92 (1H, d, J = 2.2 Hz), 7.44 (1H, dd, J = 8.1, 2.2 Hz), 7.18 (1H, d, J = 8.1 Hz), 3.90 (3H, s), 2.55 (3H, s), 1.32 (9H, s).
(12-2) Methyl 5-tert-butyl-2- obtained in Example (12-1) in the same manner as in Examples (72-4), (1-2) and (1-3) A colorless oily tert-butyl 2- (bromomethyl) -5-tert-butylbenzoate (330 mg, 11% yield) was obtained from methyl benzoate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.91 (1H, d, J = 2.2 Hz), 7.46 (1H, dd, J = 8.1, 2.2 Hz), 7.34 (1H, d, J = 8.1 Hz), 4.88 (2H, s), 1.65 (9H, s), 1.32 (9H, s).
(12-3) tert-Butyl 2- (bromomethyl) -5-tert-butylbenzoate (130 mg, 0.397 mmol) obtained in Example (12-2) in the same manner as in Example (1-4) , N- (4-hydroxyphenyl) -N-methylacetamide (72 mg, 0.44 mmol) and cesium carbonate (168 mg, 0.515 mmol) gave the title compound (125 mg, 76% yield) as a colorless gum. Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.98 (1H, d, J = 2.2 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.55 (1H, dd, J = 8.1, 2.2 Hz), 7.10 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.23 (3H, s), 1.86 (3H, s), 1.58 (9H, s ), 1.35 (9H, s).
HRMS (ESI) (m / z): calcd. For C ₂₅ H ₃₄ O ₄ N ([M + H] ⁺ ): 412.2488; found: 412.2481.

Example 13 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-isopropylbenzoate (Exemplary Compound Number: 1-23)
To a solution of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (200 mg, 0.416 mmol) obtained in Example (1-4) in tetrahydrofuran (4 ml) , Copper (I) iodide (4.0 mg, 0.021 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (18 mg, 0.022 mmol), zinc chloride -1.0 M diethyl ether solution (1.25 ml, 1.25 mmol) and isopropylmagnesium chloride-2.0 M tetrahydrofuran solution (0.55 ml, 1.10 mmol) were sequentially added, and the mixture was heated to reflux for 6 hours. The reaction mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane / methylene chloride / ethyl acetate = 2/1/1) and silica gel thin layer chromatography (developing solvent). : N-hexane / methylene chloride / ethyl acetate = 1/1/1) to give the title compound (90 mg, yield 54%) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.81 (1H, d, J = 2.2 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.39 (1H, dd, J = 8.1, 2.2 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.23 (3H, s), 2.96 (1H, sp., J = 7.3 Hz) , 1.86 (3H, s), 1.58 (9H, s), 1.28 (6H, d, J = 7.3 Hz).
HRMS (ESI) (m / z): calcd. For C ₂₄ H ₃₂ O ₄ N ([M + H] ⁺ ): 398.2332; found: 398.2334.

(Example 14) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-methylbenzoate (Exemplified compound number: 1-17)
In the same manner as in Example (13), tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (200 mg, 0) obtained in Example (1-4) was used. .416 mmol), copper (I) iodide (4.0 mg, 0.021 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (18 mg, 0.022 mmol) , Zinc chloride-1.0 M diethyl ether solution (1.25 ml, 1.25 mmol) and methylmagnesium chloride-0.93 M tetrahydrofuran solution (1.20 ml, 1.12 mmol) were used to give the title compound as a colorless powder (121 mg, 79%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.75 (1H, br.s), 7.54 (1H, d, J = 7.7 Hz), 7.31 (1H, br.d, J = 7.7 Hz), 7.08 (2H , d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.42 (2H, s), 3.23 (3H, s), 2.39 (3H, s), 1.85 (3H, s), 1.59 (9H, s).
HRMS (ESI) (m / z): calcd. For C ₂₂ H ₂₈ O ₄ N ([M + H] ⁺ ): 370.2018; found: 370.2025.

Example 15 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (2,2,2-trifluoroethyl) benzoate (Exemplary Compound No. 1-46)
(15-1) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (1.50 g, 3.11 mmol) obtained in Example (1-4) To a solution of N, N-dimethylformamide (2 ml), palladium (II) acetate (70 mg, 0.312 mmol) and 1,3-bis (diphenylphosphino) propane (129 mg, 0.312 mmol) were added. The mixture was stirred at 70 ° C. for 20 minutes in a carbon oxide atmosphere. Triethylamine (1.10 ml, 7.89 mmol) and tri-n-octylsilane (2.80 ml, 6.23 mmol) were added to the reaction mixture, and the mixture was further stirred at 70 ° C. for 21 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5 / 1-1 / 1), and tert-butyl 2-({ 4- [acetyl (methyl) amino] phenoxy} methyl) -5-formylbenzoate (241 mg, yield 20%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.04 (1H, s), 8.42 (1H, d, J = 1.6 Hz), 8.02 (1H, dd, J = 7.8, 1.6 Hz), 7.93 (1H, d , J = 7.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 5.53 (2H, s), 3.23 (3H, s), 1.85 (3H, s ), 1.63 (9H, s).
(15-2) Tetrahydrofuran of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-formylbenzoate (225 mg, 0.586 mmol) obtained in Example (15-1) (4 ml) To the solution, add (trifluoromethyl) trimethylsilane (130 μl, 0.880 mmol) and tetra-n-butylammonium fluoride-1.0 M-tetrahydrofuran solution (700 μl, 0.700 mmol), and bring to room temperature. And stirred for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 20/1), and tert-butyl 2-({4- [acetyl ( Methyl) amino] phenoxy} methyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) benzoate (150 mg, 56% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.06 (1H, s), 7.78 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.48 (2H, s), 5.10 (1H, m), 3.23 (3H, s), 2.86 (1H, m), 1.85 (3H, s ), 1.60 (9H, s).
(15-3) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (2,2,2-trifluoro-1) obtained in Example (15-2) -Hydroxyethyl) benzoate (60 mg, 0.13 mmol) in tetrahydrofuran (2.0 ml) was added with sodium hydride (55% oily, 8.0 mg, 0.19 mmol) under ice cooling and stirred for 10 minutes. did. P-Toluenesulfonyl chloride (33 mg, 0.17 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / methanol = 30/1), and tert-butyl 2-({4- [acetyl ( Methyl) amino] phenoxy} methyl) -5- (2,2,2-trifluoro-1-{[(4-methylphenyl) sulfonyl] oxy} ethyl) benzoate (80 mg, 99% yield) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ): δ 7.85 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.53 (1H, br d, J = 7.8 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 5.71 (1H, q, J = 6.3 Hz), 5.42 (2H, s), 3.23 (3H, s), 2.40 (3H, s), 1.86 (3H, s), 1.59 (9H, s).
(15-4) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (2,2,2-trifluoro-1) obtained in Example (15-3) -{[(4-Methylphenyl) sulfonyl] oxy} ethyl) benzoate (80 mg, 0.13 mmol) in methanol (2 ml) was added with 10% palladium-carbon (25 mg) and then at room temperature under hydrogen atmosphere. Stir for 1.5 hours. The catalyst was removed by celite filtration, and the resulting filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (14 mg, yield 25%) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.88 (1H, d, J = 1.6 Hz), 7.71 (1H, d, J = 7.8 Hz), 7.48 (1H, br.d, J = 7.8 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.46 (2H, s), 3.43 (2H, q, J = 10.9 Hz), 3.23 (3H, s), 1.86 (3H, s), 1.60 (9H, s).
MS (FAB) (m / z): 438 ([M + H] ⁺ ).

Example 16 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-cyclopropylbenzoate (Exemplary Compound Number: 1-51)
(16-1) 9-borabicyclo [3,3,1] nonane according to the method described in the literature (Soderquist, JA et al., Tetrahedron. Lett., 2000, Vol. 41, p. 4251-4255). -0.5M tetrahydrofuran solution (3.0 ml, 1.5 mmol), propargyl bromide (75 μl, 0.84 mmol), 3M aqueous sodium hydroxide solution (0.75 ml, 2.25 mmol), obtained in Example (1-1) 5-iodo-2-methylbenzoic acid (200 mg, 0.628 mmol) and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmol) to tert-butyl 5-cyclopropyl-2-methyl Benzoate (22 mg, 15% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.54 (1H, d, J = 1.5 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.04 (1H, dd, J = 8.0, 1.5 Hz), 2.50 (3H, s), 1.89 (1H, m), 1.59 (9H, s), 0.94 (2H, m), 0.68 (2H, m).
(16-2) tert-Butyl 5-cyclopropyl-2-methylbenzoate (37 mg) obtained in Example (16-1) in the same manner as in Examples (2-3) and (1-4) , 0.16 mmol) and N- (4-hydroxyphenyl) -N-methylacetamide (14 mg, 0.085 mmol) gave the title compound (16 mg, 26% yield) as a colorless solid.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.66 (1H, d, J = 1.8 Hz), 7.52 (1H, d, J = 8.1 Hz), 7.20, (1H, dd, J = 8.1, 1.8 Hz) , 7.09 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.40 (2H, S), 3.23 (3H, s), 1.94 (1H, m), 1.85 (3H, s), 1.57 (9H, s), 1.00 (2H, m), 0.73 (2H, m).
MS (FAB) (m / z): 396 ([M + H] ⁺ ).

Example 17 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-ethynylbenzoate (Exemplary Compound Number: 1-55)
Tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (60 mg, 0.12 mmol) obtained in Example (1-4) (1.0 ml) ) Solution of copper (I) iodide (2.0 mg, 0.011 mmol), dichlorobis (triphenylphosphine) palladium (II) (8.3 mg, 0.012 mmol), and trimethylsilylacetylene (45 μl, 0.032 mmol). ) Were sequentially added, and the mixture was heated to reflux for 4 hours. The reaction solution was filtered through Celite to remove insoluble matters, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1.0 ml), and tetra-n-butylammonium fluoride-1.0 M-tetrahydrofuran solution (0.15 ml, 0.15 mmol) was added under ice cooling for 1 hour. Stir. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound (27 mg, yield) as a colorless powder. 50%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.07 (1H, d, J = 1.5 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.63, (1H, dd, J = 8.1, 1.5 Hz) , 7.11 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.47 (2H, S), 3.23 (3H, s), 3.13 (1H, s), 1.85 (3H, s), 1.60 (9H, s).
MS (FAB) (m / z): 380 ([M + H] ⁺ ).

Example 18 tert-Butyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5-ethylbenzoate (Exemplified compound number: 1-20)
Tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-ethynylbenzoate (80 mg, 0.13 mmol) obtained in Example (17) in tetrahydrofuran-methanol (1: 1, 5% rhodium-alumina (20 mg) was added to the mixed solution, and the mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. The catalyst was removed by celite filtration, and the resulting filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / methylene chloride / ethyl acetate = 1/1/1) to obtain the title compound (63 mg, yield 78%) as a colorless oil. It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.78 (1H, d, J = 1.5 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.35, (1H, dd, J = 8.1, 1.5 Hz) , 7.10 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.42 (2H, s), 3.23 (3H, s), 2.70 (2H, q, J = 7.7 Hz) , 1.85 (3H, s), 1.58 (9H, s), 1.26 (3H, t, J = 7.7 Hz).
HRMS (ESI) (m / z): calcd. For C ₂₃ H ₃₀ O ₄ N ([M + H] ⁺ ): 384.2175; found: 384.2188.

Example 19 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylthio) benzoate (Exemplary Compound Number: 1-61)
According to the method described in the literature (Schopfer, U. et al., Tetrahedron, 2001, Vol. 57, p. 3069-3073), tert-butyl 2-({ 4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (368 mg, 0.764 mmol) in toluene (4.0 ml) was added to (oxydi-2,1-phenylene) bis (diphenylphosphine) ( DPEphos (manufactured by Aldrich) (8.2 mg, 0.015 mmol), thiophenol (80 μl, 0.78 mmol), and potassium tert-butoxide (172 mg, 1.53 mmol) were sequentially added, followed by heating under reflux for 3 hours. . The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5 / 1-1 / 1) to give the colorless amorphous title compound (137 mg). Yield 39%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.88 (1H, d, J = 1.5 Hz), 7.61 (1H, d, J = 8.1 Hz), 7.43-7.24 (6H, m), 7.10 (2H, d , J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.42 (2H, s), 3.23 (3H, s), 1.85 (3H, s), 1.55 (9H, s).

(Example 20) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylsulfinyl) benzoate (Exemplified compound number: 1-62) and tert-butyl 2- ({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (phenylsulfonyl) benzoate (Exemplary Compound Number: 1-63)
Tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylthio) benzoate (130 mg, 0.280 mmol) obtained in Example (19) in methylene chloride (2.0 ml) ) M-chloroperbenzoic acid (70%, 104 mg, 0.422 mmol) was added to the solution under ice cooling, and the mixture was further stirred at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain colorless amorphous tert-butyl 2-({ 4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylsulfinyl) benzoate (43 mg, 32% yield) and colorless amorphous tert-butyl 2-({4- [acetyl (methyl) amino ] Phenoxy} methyl) -5- (phenylsulfonyl) benzoate (43 mg, 31% yield) was obtained.
tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylsulfinyl) benzoate:
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, d, J = 2.2 Hz), 7.85 (1H, d, J = 8.1 Hz), 7.78, (1H, dd, J = 8.1, 2.2 Hz) , 7.70-7.67 (2H, m), 7.51 (3H, m), 7.11 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.46 (2H, S), 3.23 ( 3H, s), 1.85 (3H, s), 1.59 (9H, s).
MS (FAB) (m / z): 480 ([M + H] ⁺ ).
tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (phenylsulfonyl) benzoate:
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.49 (1H, d, J = 1.5 Hz), 8.07 (1H, dd, J = 8.1, 1.5 Hz), 7.98, (2H, m), 7.92 (1H, d, J = 8.1 Hz), 7.60, (1H, m), 7.54, (2H, m), 7.11 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.48 ( 2H, S), 3.22 (3H, s), 1.85 (3H, s), 1.61 (9H, s).
MS (FAB) (m / z): 496 ([M + H] ⁺ ).

(Example 21) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-vinylbenzoate (Exemplary compound number: 1-54)
According to the method described in the literature (Lee, HM et al., Org. Lett., 2000, Vol. 2, p. 2053-2055), tert-butyl 2- To a solution of ({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (200 mg, 0.416 mmol) in 1,4-dioxane (3.0 ml), vinyltrimethoxysilane (130 μl,. 849 mmol), palladium (II) acetate (9.2 mg, 0.041 mmol), 1,3-bis (2,6-diisopropylphenyl) imidazolium chloride (Strem) (18 mg, 0.042 mmol), and tetra -N-Butylammonium fluoride-1.0M-tetrahydrofuran solution (850 μl, 0.850 mmol) was sequentially added, followed by stirring at 80 ° C. for 7.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / methylene chloride / ethyl acetate = 1/1/1) to give the title compound as a colorless powder. (83 mg, 52% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.97 (1H, d, J = 1.5 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.57 (1H, dd, J = 8.1, 1.5 Hz), 7.10 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz),), 6.75 (1H, dd, J = 17.6, 11.0 Hz), 5.82 (1H, d, J = 17.6 Hz ), 5.45 (2H, s), 5.33 (1H, d, J = 11.0 Hz), 3.23 (3H, s), 1.85 (3H, s), 1.60 (9H, s).
MS (FAB) (m / z): 382 ([M + H] ⁺ ).

(Example 22) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-cyanobenzoate (Exemplified compound number: 1-67)
Tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (100 mg, 0.207 mmol) obtained in Example (1-4) in acetonitrile (2.0 ml) To the solution, potassium cyanide (27 mg, 0.41 mmol), copper (I) iodide (4.0 mg, 0.021 mmol), and tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.010 mmol) were sequentially added. After that, the mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound as a colorless solid (56 mg, yield). 70%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.27 (1H, d, J = 1.8 Hz), 7.94 (1H, dd, J = 8.1, 1.8 Hz), 7.82 (1H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 5.53 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.62 (9H, s ).
MS (FAB) (m / z): 381 ([M + H] ⁺ ).

(Example 23) 3-tert-butyl 1-methyl 4-({4- [acetyl (methyl) amino] phenoxy} methyl) isophthalate (Exemplary compound number: 1-66)
N, N- of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-iodobenzoate (3.00 g, 6.23 mmol) obtained in Example (1-4) Methanol (25 ml), dichlorobis (triphenylphosphine) palladium (II) (219 mg, 0.312 mmol), and triethylamine (2.61 ml, 18.7 mmol) were sequentially added to the dimethylformamide (13 ml) solution, and carbon monoxide was added. The mixture was stirred at 70 ° C. for 10 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure to about half volume, poured into water and extracted with ethyl acetate (twice). The organic layer was washed successively with 0.5N hydrochloric acid, water (3 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / methylene chloride / ethyl acetate = 2/2 / 1-1 / 1/1), The title compound (1.88 g, yield 73%) was obtained as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.59 (1H, d, J = 2.2 Hz), 8.18 (1H, dd, J = 8.5, 2.2 Hz), 7.83 (1H, d, J = 8.5 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 5.52 (2H, s), 3.96 (3H, s), 3.23 (3H, s), 1.86 (3H, s ), 1.62 (9H, s).
MS (FAB) (m / z): 414 ([M + H] ⁺ ).

(Example 24) tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (methoxymethyl) benzoate (Exemplified compound number: 1-49)
(24-1) 3-tert-butyl 1-methyl 4-({4- [acetyl (methyl) amino] phenoxy} methyl) isophthalate (1.86 g, 4.50 mmol) obtained in Example (23) To a tetrahydrofuran (50 ml) solution of lithium borohydride (296 mg, 13.5 mmol) was added under ice cooling and stirred for 6 hours. The reaction mixture was poured into carefully cooled 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / methylene chloride / ethyl acetate = 25/25 / 1-15 / 15/1), Pale yellow oily tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (hydroxymethyl) benzoate (1.30 g, yield 75%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.94 (1H, br.s), 7.69 (1H, d, J = 8.1 Hz), 7.54 (1H, dd, J = 8.1, 1.5 Hz), 7.09 (2H , d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.45 (2H, s), 4.74 (2H, s), 3.22 (3H, s), 1.84 (3H, s), 1.59 (9H, s).
(24-2) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5 obtained in Example (24-1) in the same manner as in Example (41-4) The title compound (52 mg, yield 50%) as a colorless powder was obtained from-(hydroxymethyl) benzoate (100 mg, 0.259 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.91 (1H, s), 7.68 (1H, d, J = 7.3 Hz), 7.51 (1H, d, J = 7.3 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.46 (2H, s), 4.50 (2H, s), 3.42 (3H, s), 3.23 (3H, s), 1.85 (3H, s ), 1.59 (9H, s).
MS (ESI) (m / z): 400 ([M + H] ⁺ ).

Example 25 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-[(methylthio) methyl] benzoate (Exemplified Compound No .: 1-50)
(25-1) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (hydroxymethyl) benzoate (270 mg, 0.700 mmol) obtained in Example (24-1) ) In tetrahydrofuran (5 ml) under ice cooling, triphenylphosphine (220 mg, 0.839 mmol) and carbon tetrabromide (279 mg, 0.841 mmol) were added and stirred for 3 hours. The insoluble material was removed by celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / methylene chloride / ethyl acetate = 2/2 / 1-3 / 3/2) to give colorless solid tert-butyl 2-({4 -[Acetyl (methyl) amino] phenoxy} methyl) -5- (bromomethyl) benzoate (281 mg, yield 89%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.96 (1H, d, J = 2.2 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.56 (1H, dd, J = 8.1, 2.2 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.46 (2H, s), 4.52 (2H, s), 3.23 (3H, s), 1.86 (3H, s ), 1.60 (9H, s).
(25-2) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (bromomethyl) benzoate (153 mg, 0.341 mmol) obtained in Example (25-1) Sodium thiomethoxide (50 mg, 0.713 mmol) was added to an N, N-dimethylformamide solution (2 ml) and stirred at 120 ° C. for 7 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / n-hexane / methanol / = 15/15/2) to give the title of pale orange oil The compound (25 mg, yield 18%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.87 (1H, d, J = 2.2 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.48 (1H, dd, J = 8.1, 2.2 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.44 (2H, s), 3.71 (2H, s), 3.23 (3H, s), 2.02 (3H, s ), 1.86 (3H, s), 1.59 (9H, s).
MS (FAB) (m / z): 416 ([M + H] ⁺ ).

Example 26 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-methoxybenzoate (Exemplary Compound Number: 1-56)
(26-1) In the same manner as in Examples (1-1), (23), (72-4), (1-2), and (15-4), the literature (Troxler, F., et al , Helv. Chim. Acta, 1968, 51, p. 1203-1213) and tert-butyl 5-hydroxy-2-synthesized from 5- (benzyloxy) -2-methylaniline. Methyl benzoate (2.59 g, 43% yield) was obtained. However, in the step corresponding to Example (15-4), ethanol was used instead of methanol as the solvent.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.33 (1H, d, J = 2.5 Hz), 7.07 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 8.1, 2.5 Hz), 2.47 (3H, s), 1.59 (9H, s).
(26-2) To a solution of tert-butyl 5-hydroxy-2-methylbenzoate obtained in Example (26-1) in N, N-dimethylformamide (15 ml), sodium hydride (60% oil, 600 mg, 15.0 mmol) was added and stirred at room temperature for 20 minutes, then triisopropylchlorosilane (3.0 ml, 14.0 mmol) was added and stirred for 30 minutes under ice cooling. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain tert-butyl 2-methyl-5-[(triisopropylsilyl) oxy] benzoate (4.63 g, 95%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.36 (1H, d, J = 2.5 Hz), 7.04 (1H, d, J = 8.8 Hz), 6.88 (1H, dd, J = 8.8, 2.5 Hz), 2.48 (3H, s), 1.58 (9H, s), 1.25 (3H, m), 1.10 (18H, d, J = 6.6 Hz).
(26-3) tert-butyl 2-methyl-5 obtained in Example (26-2) in the same manner as in Examples (2-3), (1-4) and (42-2) Tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-hydroxybenzoate (274 mg, 18%) was obtained from-[(triisopropylsilyl) oxy] benzoate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.51 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 2.5 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.01 ( 1H, dd, J = 8.8, 2.5 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 3.24 (3H, s), 1.86 (3H, s), 1.56 (9H, s ).
MS (FAB) (m / z): 372 ([M + H] ⁺ ).
(26-4) N of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-hydroxybenzoate (90 mg, 0.242 mmol) obtained in Example (26-3) , N-dimethylformamide solution (4 ml) was added potassium carbonate (50 mg, 0.36 mmol) and methyl iodide (20 μl, 0.32 mmol), and the mixture was stirred at room temperature for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: methylene chloride / ethyl acetate = 5/1) to give the title compound as a colorless powder (31 mg, 33%). Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.55 (1H, d, J = 8.8 Hz), 7.48 (1H, d, J = 2.9 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.05 ( 1H, dd, J = 8.8, 2.9 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 3.35 (3H, s), 3.23 (3H, s), 1.85 (3H, s ), 1.56 (9H, s).
MS (FAB) (m / z): 385 ([M + H] ⁺ ).

Example 27 tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-tert-butoxybenzoate (Exemplified Compound No .: 1-59)
Methylene chloride suspension of tert-butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5-hydroxybenzoate (156 mg, 0.420 mmol) obtained in Example (26-3) ( 3 ml) was added 2-methyl-1-propene (3 ml) and sulfuric acid (1 drop) and stirred at room temperature overnight. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 4/1) to give the title compound (22 mg, 12) as a colorless oil. %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.57 (1H, br.d, J = 2.6 Hz), 7.56 (1H, br.d, J = 8.4 Hz), 7.15, (1H, dd, J = 8.4 , 2.6 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 5.39 (2H, S), 3.24 (3H, s), 1.86 (3H, s), 1.57 (9H, s), 1.38 (9H, s).
MS (FAB) (m / z): 428 ([M + H] ⁺ ).

Example 28 tert-Butyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -4-chloro-5- (trifluoromethyl) benzoate (Exemplified compound number: 1-45)
(28-1) In the same manner as in Examples (15-4), (1-1), (12-1), (72-4), and (1-2), the literature (Gray, M. et al. al., Tetrahedron Lett., 2000, 41, p. 6237-6240) and tert. from 1-chloro-5-methyl-4-nitro-2- (trifluoromethyl) benzene synthesized according to the method described in -Butyl 4-chloro-2-methyl-5- (trifluoromethyl) benzoate (yield 5%) was obtained. However, in the step corresponding to Example (15-4), ethyl acetate was used in place of methanol as a solvent. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.15 (1H, s), 7.38 (1H, s), 2.61 (3H, s), 1.61 (9H, s).
(28-2) tert-Butyl 4-chloro-2-methyl-5- (obtained in Example (28-1) in the same manner as in Examples (1-3) and (1-4) Trifluoromethyl) benzoate (235 mg, 0.799 mmol) gave the title compound (250 mg, 22% yield) as a yellow oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.28 (1H, s), 7.97 (1H, s), 7.15 (2H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 5.50 (2H, s), 3.25 (3H, s), 1.87, (3H.s), 1.62 (9H, s).
MS (FAB) (m / z): 458 ([M + H] ⁺ ).

Example 29 N- (4-{[2- (3,3-dimethylbutanoyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (Exemplary Compound No. 1-1) )
(29-1) It was described in the literature (Norman, MH, et al, J. Med. Chem., 1996, Vol. 39, p. 1172-1188) in the same manner as in Example (1-1). 2-Iodo-4- (trifluoromethyl) benzoic acid (19.0 g, yield 100%) was obtained from 2-amino-4- (trifluoromethyl) benzoic acid synthesized according to the method.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.26 (1H, s), 8.04 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 7.8 Hz).
(29-2) Borane-tetrahydrofuran was added to a tetrahydrofuran solution (100 ml) of 2-iodo-4- (trifluoromethyl) benzoic acid (19.0 g, 60.0 mmol) obtained in Example (29-1). Complex-1M-tetrohydrofuran solution (90 ml, 90 mmol) was added and heated to reflux for 9 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1), and [2-iodo-4- (trifluoro Methyl) phenyl] methanol (14.3 g, yield 79%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.03 (1H, s), 7.62 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 4.70 (2H, s).
(29-3) [2-Iodo-4- (trifluoromethyl) phenyl] obtained in Example (29-2) in the same manner as in Examples (25-1) and (1-4) From methanol, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (14.3 g, 67% yield) was obtained. However, in the step corresponding to Example (25-1), methylene chloride was used in place of tetrahydrofuran as the solvent.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.12 (1H, br.s), 7.65 (1H, d, J = 8.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.14 (2H, d , J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.08 (2H, s), 3.24 (3H, s), 1.87 (3H, s).
(29-4) Tetrahydrofuran (6 ml) was added to isopropylmagnesium bromide-1M-tetrahydrofuran solution (1.17 ml, 1.17 mmol), followed by n-butyllithium-1.6M-hexane solution (1.46 ml, 2.17). 34 mmol) was added and stirred at 0 ° C. for 10 minutes. The reaction solution was cooled to −78 ° C., and N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methyl obtained in Example (29-3) was obtained. A tetrahydrofuran solution (6 ml) of acetamide (437 mg, 0.973 mmol) was added dropwise and stirred for 30 minutes. While maintaining the reaction temperature at −78 ° C., 3,3-dimethylbutanal (0.487 ml, 3.89 mmol) was added dropwise to the reaction solution, and then the temperature was gradually raised to room temperature and stirred for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1: 1), and N- (4-{[2- ( L-Hydroxy-3,3-dimethylbutyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (120 mg, 29%) was obtained. Further, 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) was added to a methylene chloride solution (4 ml) of the present compound (120 mg, 0.283 mmol). -On (136 mg, 0.321 mmol) was added, and the mixture was stirred for 2 hours under ice cooling. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were poured into the reaction solution, and the mixture was extracted with ethyl acetate (three times). The organic layer was washed successively with water and saturated brine, and then washed with anhydrous sodium sulfate. Dried. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound as a colorless powder (78.6 mg, Yield 66%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.01 (1H, s), 7.95 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.24 (3H, s), 2.91 (2H, s), 1.86, (3H.s), 1.08 (9H, s).
The NMR spectrum of the intermediate N- (4-{[2- (1-hydroxy-3,3-dimethylbutyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide is shown below. .
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.89 (1H, s), 7.60-7.52 (2H, m), 7.12 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz ), 5.18 (2H, s), 5.18 [1H, overlaps with 5.18 (2H, s)], 3.21 (3H, s), 2.63 (1H, br.s), 1.82, (3H.s), 1.79 (1H , dd, J = 14.8, 9.4 Hz), 1.57 (1H, dd, J = 14.8, 2.2 Hz), 1.02 (9H, s).

Example 30 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -N- (tert-butyl) -N-methyl-5- (trifluoromethyl) benzamide (Exemplary compound number: 1- 195)
(30-1) tert-Butyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate obtained in Example (7-3) (2.33 g, Trifluoroacetic acid (10 ml) was added to a 5.51 mmol) methylene chloride solution (50 ml), and the mixture was stirred at room temperature for 7 hours. After distilling off the solvent under reduced pressure and further adding toluene and distilling off under reduced pressure (twice), the residue was subjected to silica gel column chromatography (elution solvent: methylene chloride / n-hexane / methanol = 5/5 / Purification at 1) gave 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoic acid (1.84 g, yield 91%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.42 (1H, s), 7.98 (1H, d, J = 8.5 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 5.59 (2H, s), 3.25 (3H, s), 1.87, (3H.s).
MS (FAB) (m / z): 368 ([M + H] ⁺ ).
(30-2) 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoic acid (152 mg, 0.416 mmol) obtained in Example (30-1) , N, N-dimethylaminopyridine (5.1 mg, 0.042 mmol) and tert-butyl (methyl) amine (0.110 ml, 0.915 mmol) in methylene chloride solution (6 ml) A solution of triisopropylbenzenesulfonyl chloride (188 mg, 0.624 mmol) in methylene chloride (2 ml) was added in 20 portions every 3 minutes and then stirred overnight. 1N-hydrochloric acid was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N-aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain the title compound (54.4 mg, yield 30%) as a colorless powder. .
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.66-7.63 (2H, m), 7.49 (1H, s), 7.11 (2H, d, J = 7.3 Hz), 6.96 (2H, d, J = 7.3 Hz ), 5.16 (2H, br.s), 3.22 (3H, s), 2.80 (3H, s), 1.84, (3H.s), 1.47 (9H, s).
MS (FAB) (m / z): 437 ([M + H] ⁺ ).

Example 31 2,2,2-trifluoro-1,1-dimethylethyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. : 1-189)
2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoic acid obtained in Example (30-1) in the same manner as in Example (10-1) (105 mg, 0.286 mmol) to N, N-dimethylaminopyridine (10 mg), 1,1,1-trifluoro-2-methyl-2-propanol (0.312 ml, 2.86 mmol), and 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (109 mg, 0.572 mmol) was used to give the title compound (55.4 mg, yield 41%) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, s), 7.94 (1H, d, J = 8.2 Hz), 7.82 (1H, d, J = 8.2 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 5.48 (2H, s), 3.23 (3H, s), 1.86, (3H.s), 1.84 (6H, s).
MS (FAB) (m / z): 478 ([M + H] ⁺ ).

Example 32 Neopentyl 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified Compound No. 1-159)
2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoic acid obtained in Example (30-1) in the same manner as in Example (10-1) (107 mg, 0.291 mmol) to N, N-dimethylaminopyridine (10 mg), 2,2-dimethylpropanol (256 mg, 2.91 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide The title compound (40.6 mg, 41% yield) as a colorless oil was obtained using the hydrochloride (78.0 mg, 0.407 mmol).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.31 (1H, s), 7.95 (1H, d, J = 8.2 Hz), 7.83 (1H, d, J = 8.2 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 5.58 (2H, s), 4.06 (2H, s), 3.23 (3H, s), 1.86, (3H.s), 1.04 (9H, s).
MS (FAB) (m / z): 438 ([M + H] ⁺ ).

Example 33 2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -N- (tert-butyl) -5- (trifluoromethyl) benzamide (Exemplified Compound No: 1-192)
2-({4- [Acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoic acid (101 mg, 0.274 mmol) obtained in Example (30-2), tert-butylamine ( After adding 2-chloro-1-methyl-pyridinium iodide (105 mg, 0.411 mmol) to a methylene chloride solution (5 ml) of 80.6 μl, 0.767 mmol) and triethylamine (114 μl, 0.822 mmol), The mixture was heated to reflux for 5 hours. After pouring 1N-hydrochloric acid into the reaction solution and extracting with ethyl acetate, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/2), and the title compound (34.1 mg, yield) was obtained as a colorless powder. 29%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.76 (1H, s), 7.71-7.69 (2H, m), 7.13 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz ), 6.11 (1H, br.s), 5.26 (2H, s), 3.23 (3H, s), 1.84, (3H.s), 1.41 (9H, s).
MS (FAB) (m / z): 423 ([M + H] ⁺ ).

(Example 34) 1,1-diethylpropyl 2-({4- [acetyl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. 1-176)
(34-1) n-Butyllithium-1.6M-hexane solution (0.931 ml, 1.49 mmol) was added to a tetrahydrofuran solution (4 ml) of 1,1-diethylpropanol (228 μl, 1.62 mmol) at room temperature. After stirring for 30 minutes, a tetrahydrofuran solution (2 ml) of 2-methyl-5- (trifluoromethyl) benzoyl chloride (300 mg, 1.35 mmol) was added, and the mixture was heated to reflux for 2 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 15/1) to give 1,1-diethylpropyl 2-methyl. -5- (Trifluoromethyl) benzoate (376 mg, 92% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.07 (1H, d, J = 1.7 Hz), 7.59 (1H, dd, J = 8.2, 1.7 Hz), 7.34 (1H, d, J = 8.2 Hz), 2.63 (3H, s), 1.99, (6H.q, J = 7.5 Hz), 0.90 (9H, t, J = 7.5 Hz).
(34-2) 1,1-Diethylpropyl 2-methyl-5- (tri) obtained in Example (34-1) in the same manner as in Examples (1-3) and (1-4). From the fluoromethyl) benzoate (376 mg, 1.26 mmol), the title compound (242 mg, 44% yield) was obtained as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.19 (1H, d, J = 1.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.2, 1.2 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.99 (2H, d, J = 9.0 Hz), 5.52 (2H, s), 3.22 (3H, s), 2.00 (6H, q, J = 7.4 Hz), 1.85, (3H.s), 0.91 (9H, t, J = 7.4 Hz).
MS (FAB) (m / z): 466 ([M + H] ⁺ ).

(Example 35) N-methyl-N- (4-{[5- (trifluoromethyl) -1,1'-biphenyl-2-yl] methoxy} phenyl) acetamide (Exemplary compound number: 1-198)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (94 mg) obtained in Example (29-3) , 0.21 mmol) and phenylboric acid (30 mg, 0.25 mol) gave the title compound (83 mg, 99% yield) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.77 (1H, d, J = 8.1 Hz), 7.67 (1H, br.d, J = 8.1 Hz), 7.60 (1H, br.s), 7.48-7.35 (5H, m), 7.06 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 5.00 (2H, S), 3.21 (3H, s), 1.83 (3H, s) .

Example 36 N- (4-{[2 ′, 6′-Dimethyl-5- (trifluoromethyl) -1,1′-biphenyl-2-yl] methoxy} phenyl) -N-methylacetamide (Exemplary) Compound number: 1-205)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (100 mg) obtained in Example (29-3) , 0.22 mmol) and 2,6-dimethylphenylboric acid (40 mg, 0.27 mol) gave the title compound (26 mg, 28% yield) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.80 (1H, d, J = 8.2 Hz), 7.69 (1H, br.d, J = 8.2 Hz), 7.40 (1H, br.s), 7.21 (1H , dd, J = 6.7, 8.2 Hz), 7.13 (2H, m), 7.04 (2H, d, J = 9.0 Hz), 6.81 (2H, d, J = 9.0 Hz), 4.70 (2H, S), 3.20 (3H, s), 1.98 (6H, s), 1.82 (3H, s).
MS (FAB) (m / z): 428 ([M + H] ⁺ ).

Example 37 N-methyl-N- (4-{[2′-methyl-5- (trifluoromethyl) -1,1′-biphenyl-2-yl] methoxy} phenyl) acetamide (Exemplary Compound Number: 1-199)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (50 mg) obtained in Example (29-3) , 0.11 mmol) and 2-methylphenylboric acid (18 mg, 0.13 mol) gave the title compound (45 mg, 98% yield) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.77 (1H, d, J = 8.2 Hz), 7.68 (1H, br.d, J = 8.2 Hz), 7.48 (1H, br. S), 7.35-7.28 (2H, m), 7.25 (1H, m), 7.15 (1H, d, J = 8.2 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 4.83 (1H, d, J = 12.5 Hz), 4.78 (1H, d, J = 12.5 Hz), 3.20 (3H, s), 2.10 (3H, s), 1.82 (3H, s).
MS (FAB) (m / z): 414 ([M + H] ⁺ ).

Example 38 N- (4-{[2′-Chloro-5- (trifluoromethyl) -1,1′-biphenyl-2-yl] methoxy} phenyl) -N-methylacetamide (Exemplary Compound Number: 1-202)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (50 mg) obtained in Example (29-3) , 0.11 mmol) and 2-chlorophenylboric acid (21 mg, 0.13 mol) gave the title compound (30 mg, 63% yield) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.74 (1H, d, J = 8.2 Hz), 7.68 (1H, br.d, J = 8.2 Hz), 7.50-7.48 (2H, m), 7.38-7.31 (2H, m), 7.27 (1H, m), 7.02 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 4.97 (1H, d, J = 12.9 Hz), 4.82 (1H, d, J = 12.9 Hz), 3.19 (3H, s), 1.81 (3H, s).
MS (FAB) (m / z): 434 ([M + H] ⁺ ).

(Example 39) N-methyl-N-({[2- (1-naphthyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) acetamide (Exemplary compound number: 1-210)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (100 mg) obtained in Example (29-3) , 0.22 mmol) and 1-naphthaleneboric acid (46 mg, 0.13 mol) gave the title compound (69 mg, 69% yield) as a yellow oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.94 (1H, app.d, J = 3.9 Hz), 7.92 (1H, br.d, J = 3.9 Hz), 7.85 (1H, d, J = 8.2 Hz ), 7.76 (1H, app.d, J = 8.2 Hz), 7.62 (1H, br.s), 7.56-7.51 (2H, m), 7.47-7.38 (3H, m) 6.95 (2H, d, J = 8.8 Hz), 6.67 (1H, d, J = 8.8), 4.78 (2H, s), 3.16 (3H, s), 1.78 (3H, s).
MS (FAB) (m / z): 450 ([M + H] ⁺ ).

(Example 40) N-methyl-N- (4-{[2- (8-quinolinyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) acetamide (Exemplary compound number: 1-211)
In the same manner as in Example 5, N- (4-{[2-iodo-4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (100 mg) obtained in Example (29-3) , 0.22 mmol) and 8-quinolinyl boric acid (46 mg, 0.13 mol) gave the title compound (86 mg, 86% yield) as a pale yellow powder.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.92 (1H, d, J = 2.0 Hz), 8.27 (1H, dd, J = 7.8, 2.0 Hz), 7.93 (1H, d, J = 7.8 Hz), 7.79 (1H, d, J = 8.8 Hz), 7.73-7.69 (2H, m), 7.66 (1H, J = 7.8 Hz), 7.64 (1H, s), 7.46 (1H, dd, J = 8.8, 3.9 Hz ), 6.96 (2H, d, J = 8.8 Hz), 6.73 (2H, d, J = 8.8 Hz), 5.05 (1H, d, J = 13.7 Hz), 4.72 (1H, d, J = 13.7 Hz), 3.16 (3H, s), 1.78 (3H, s).
MS (FAB) (m / z): 451 ([M + H] ⁺ ).

Example 41 tert-Butyl 2-[({5- [acetyl (methyl) amino] -2-pyridinyl} oxy) methyl] -5- (trifluoromethyl) benzoate (Exemplary Compound No: 2-1)
(41-1) N, N-dimethylformamide solution (5 ml) of [2-iodo-4- (trifluoromethyl) phenyl] methanol (1.00 g, 3.31 mmol) obtained in Example (29-2) ) Was added with sodium hydride (60% oily, 145 mg, 3.63 mmol), stirred for 30 minutes under ice-cooling, and then added with 2-bromo-5-nitropyridine (672 mg, 3.33 mmol) at room temperature. Stir for 7 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 30/1) to give 2-{[2-iodo-4- (Trifluoromethyl) benzyl] oxy} -5-nitropyridine (719 mg, 51%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.10 (1H, d, J = 2.9 Hz), 8.43 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, br.s), 7.63 (1H , br.d, J = 8.1 Hz), 7.57 (1H, d, J = 8.1 Hz), 6.97 (1H, d, J = 8.8 Hz), 5.53 (2H, s), 1.55 (9H, s).
(41-2) In the same manner as in Examples (23), (72-4), (10-1), and (15-4), 2-{[ From 2-iodo-4- (trifluoromethyl) benzyl] oxy} -5-nitropyridine, tert-butyl 2-{[(5-amino-2-pyridinyl) oxy] methyl} -5- (trifluoromethyl) Benzoate (231 mg, 39%) was obtained. However, in the step corresponding to Example (15-4), ethyl acetate was used in place of methanol as a solvent.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.15 (1H, br.s), 7.74 (1H, d, J = 8.8 Hz), 7.69 (1H, dd, J = 8.8, 1.5 Hz), 7.63 (1H , d, J = 3.0 Hz), 7.06 (1H, dd, J = 8.8, 3.0 Hz), 6.70 (1H, d, J = 8.8 Hz), 5.70 (2H, s), 1.60 (9H, s).
(41-3) tert-Butyl 2-{[(5-amino-2-pyridinyl) oxy] methyl} -5- (trifluoromethyl) benzoate (231 mg, 0. 1) obtained in Example (41-2) 58 mmol) in tetrahydrofuran (2 ml) were added pyridine (60 μl, 0.74 mmol) and acetic anhydride (60 μl, 0.63 mmol) and stirred at room temperature for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1), and tert-butyl 2-({[5 -(Acetylamino) -2-pyridinyl] oxy} methyl) -5- (trifluoromethyl) benzoate (128 mg, 54%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.16 (1H, br.s), 8.10 (1H, d, J = 2.5 Hz), 7.96 (1H, dt, J = 8.8, 2.5 Hz), 7.74 (1H , d, J = 8.8 Hz), 7.70 (1H, br.d, J = 8.8 Hz), 7.09 (1H, br.s), 6.84 (1H, d, J = 8.8 Hz), 5.77 (2H, s) , 2.18 (3H, s), 1.61 (9H, s).
(41-4) tert-Butyl 2-({[5- (acetylamino) -2-pyridinyl] oxy} methyl) -5- (trifluoromethyl) benzoate (85 mg) obtained in Example (41-3) , 0.21 mmol) in N, N-dimethylformamide (1 ml), sodium hydride (60% oil, 10 mg, 0.25 mmol) and methyl iodide (15 μl, 0.24 mmol) were added to ice. Stir for 40 minutes under cooling. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound (83 mg, 95) as colorless crystals. %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.15 (1H, br.s), 8.00 (1H, d, J = 2.7 Hz), 7.75 (1H, br. D, J = 8.2 Hz), 7.71 (1H , br. d, J = 8.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 6.89 (1H, d, J = 8.6 Hz), 5.81 (2H, S), 3.23 (3H, s) , 1.87 (3H, s), 1.61 (9H, s).
MS (FAB) (m / z): 425 ([M + H] ⁺ ).

(Example 42) tert-butyl 2-({4- [acetyl (methyl) amino] -2-fluorophenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified compound number: 2-7)
(42-1) Example (26-2), literature (Nose, A., et al., Chem. Pharm. Bull., 1981, Vol. 29, p. 1159-1161), Example (41- 3) and in the same manner as (41-4), from 2-fluoro-4-nitrophenol, N- {3-fluoro-4-[(triisopropylsilyl) oxy] phenyl} -N-methylacetamide ( 2.91 g, 45%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 6.97 (1H, app.t, J = 8.8 Hz), 6.91 (1H, dd, J = 11.0, 2.5 Hz), 6.82 (1H, m), 3.22 (3H , s), 1.87 (3H, s), 1.27 (3H, m), 1.11 (18H, J = 7.3 Hz).
(42-2) N- {3-Fluoro-4-[(triisopropylsilyl) oxy] phenyl} -N-methylacetamide (2.91 g, 8.58 mmol) obtained in Example (42-1) Tetra-n-butylammonium fluoride-1.0M-tetrahydrofuran solution (9.0 ml, 9.0 mmol) was added to the tetrahydrofuran solution (15 ml), and the mixture was stirred at room temperature for 10 minutes. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain N- (3-fluoro-4-hydroxy) phenyl-N-methylacetamide (1.06 g, 67%).
¹ H-NMR (400 MHz, CD ₃ OD): δ 7.05 (1H, br.dd, J = 11.0, 2.3 Hz), 6.94 (1H, app.q, J = 8.6 Hz), 6.91 (1H, dd, J = 8.6, 2.3 Hz), 3.19 (3H, s), 1.85 (3H, s).
(42-3) tert-butyl 2-bromomethyl-5- (trifluoromethyl) benzoate (70 mg, 0.21 mmol) obtained in Example (7-2) in the same manner as in Example (1-4) , N- (3-Fluoro-4-hydroxyphenyl) -N-methylacetamide (42 mg, 0.23 mmol) obtained in Example (42-2) and cesium carbonate (87 mg, 0.27 mmol) were used. To give the title compound as a colorless powder (55 mg, 59%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.22 (1H, br.s), 7.98 (1H, d, J = 7.8 Hz), 7.81 (1H, br. D, J = 7.8 Hz), 7.08-6.98 (2H, m), 6.92 (1H, br.d, J = 9.4 Hz), 5.60 (2H, s), 3.23 (3H, s), 1.88 (3H, s), 1.63 (9H, s).
MS (FAB) (m / z): 442 ([M + H] ⁺ ).

Example 43 tert-Butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3-isopropylbenzoate (Exemplary Compound No. 1-82)
(43-1) In the same manner as in Examples (4-1) and (47-2), from 6-hydroxy-5-isopropyl-2-methylbenzoic acid (532 mg, 2.74 mmol) to tert-butyl 2- (Acetoxy) -3-isopropyl-6-methylbenzoate (622 mg, 78%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.22 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 8.0 Hz), 2.92 (1H, sp., J = 7.0 Hz), 2.38 (3H, s), 2.30 (3H, d, J = 1.0 Hz), 1.58 (9H, d, J = 1.0 Hz), 1.19 (6H, d, J = 7.0 Hz).
(43-2) tert-Butyl 2- (acetoxy) -3-isopropyl-6 obtained in Example (43-1) in the same manner as in Examples (1-3) and (1-4) -The title compound (12.0 mg, 3% yield) was obtained as a milky white powder from methyl benzoate (235 mg, 0.799 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.75 (1H, br.s), 7.34 (1H, d, J = 7.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.05 (1H, d , J = 7.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 5.28 (2H, s), 3.37 (1H, sp., J = 7.0 Hz), 3.23 (3H, s), 1.86 (3H, s), 1.56 (9H, s), 1.23 (6H, d, J = 7.0 Hz).
MS (FAB) (m / z): 414 ([M + H] ⁺ ).

Example 44 tert-Butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -3-ethyl-2-hydroxybenzoate (Exemplary Compound Number: 1-78)
(44-1) Reference (Corey, EJ, et al., J. Am. Chem. Soc., 1972, Vol. 94, p. 6190-6191), Examples (17) and (18) Similarly, [4-iodo-3- (methoxymethoxy) synthesized by the method of literature (Winkle, MR, et al., J. Org. Chem., 1982, Vol. 47, p. 2101-2108) Phenyl] methanol gave tert-butyl {[4-ethyl-3- (methoxymethoxy) benzyl] oxy} dimethylsilane (9.30 g, 59%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.11 (1H, d, J = 7.8 Hz), 7.05 (1H, s), 6.90 (1H, d, J = 7.8 Hz), 5.19 (2H, s), 4.70 (2H, s), 3.48 (3H, s), 2.64 (2H, q, J = 7.8 Hz), 1.19 (3H, t, J = 7.8 Hz), 0.94 (9H, s), 0.10 (6H, s ).
(44-2) tert-butyl {[4-ethyl-3- (methoxymethoxy) benzyl] oxy} dimethylsilane (1.0 g, 3.3 mmol) obtained in Example (44-1), and N , N, N ′, N′-tetramethylethylenediamine (0.50 ml, 4.2 mmol) in diethyl ether solution (10 ml) at −78 ° C. with n-butyllithium-1.58 M-hexane solution (2.7 ml, 4.3 mmol) was added, and the mixture was stirred for 1 hour under ice cooling. Further, after cooling to −40 ° C., di-tert-butyl dicarbonate (930 mg, 4.2 mmol) was added, and the temperature was gradually raised to room temperature. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100/1), and tert-butyl 6-({[tert-butyl (Dimethyl) silyl] oxy} methyl) -3-ethyl-2- (methoxymethoxy) benzoate (443 mg, 33%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.26 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 8.2 Hz), 5.01 (2H, s), 4.73 (2H, s), 3.57 (3H, s), 2.71 (2H, q, J = 7.8 Hz), 1.59 (9H, s), 1.22 (3H, t, J = 7.8 Hz), 0.93 (9H, s), 0.07 (6H, s ).
(44-3) tert-butyl 6-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-2- (methoxymethoxy) benzoate (443 mg, 443 mg, obtained in Example (44-2)) 1.08 mmol) in tetrahydrofuran (10 ml) was added acetic acid (63 μl, 1.1 mmol) and tetra-n-butylammonium fluoride-1.0 M-tetrahydrofuran solution (1.1 ml, 1.1 mmol). Stir at room temperature for 3 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain tert-butyl 3-ethyl-6- (hydroxymethyl) -2- (methoxymethoxy) benzoate (320 mg, 99%).
¹ H-NMR (500MHz, CDCl ₃ ): δ 7.26 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 5.02 (2H, s), 4.56 (2H, s), 3.58 (3H, s), 2.74 (2H, q, J = 7.8 Hz), 1.62 (9H, s), 1.23 (3H, t, J = 7.8 Hz).
(44-4) tert-Butyl 3-ethyl-6- (hydroxymethyl) -2- (methoxymethoxy) benzoate (320 mg, 1.08 mmol) obtained in Example (44-3) and literature (Harvison , PJ et al., J. Med. Chem., 1986, 29, p. 1737-1743), N- (4-hydroxyphenyl) -N-methylacetamide (165 mg, 1.00 mmol) N, N, N ′, N′-tetramethylazodicarboxamide (220 mg, 1.27 mmol) and tri-n-butylphosphine (320 mg, 1.28 mmol) were added to a tetrahydrofuran solution (10 ml) at room temperature. Stir overnight. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1), and tert-butyl 6-({4- [acetyl ( Methyl) amino] phenoxy} methyl) -3-ethyl-2- (methoxymethoxy) benzoate (205 mg, 43%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.27 (1H, d, J = 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.08 (2H, d, J = 8.6 Hz), 6.95 ( 2H, d, J = 8.6 Hz), 5.07 (2H, s), 5.05 (2H, s), 3.60 (3H, s), 3.22 (3H, s), 2.75 (2H, q, J = 7.8 Hz), 1.84 (3H, s), 1.54 (9H, s), 1.24 (3H, t, J = 7.8 Hz).
(44-5) tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -3-ethyl-2- (methoxymethoxy) benzoate (147 mg) obtained in Example (44-4) , 0.331 mmol) in methylene chloride (3 ml) was added trimethylchlorosilane (63 μl, 0.50 mmol) and tetra-n-butylammonium bromide (160 mg, 0.50 mmol), and the mixture was heated to reflux for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound (107 mg, 81%) as a colorless powder. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.70 (1H, s), 7.29 (1H, d, J = 7.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 5.28 (2H, S), 3.23 (3H, s), 2.69 (2H, q, J = 7.4 Hz), 1.85 (3H, s), 1.57 (9H, s), 1.23 (3H, t, J = 7.4 Hz).
MS (FAB) (m / z): 400 ([M + H] ⁺ ).

Example 45 tert-Butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. 1-90)
(45-1) 2- [2- (trifluoro) synthesized according to the method described in the literature (Miller, JA et al., J. Org. Chem., 1993, Vol. 58, p. 2637-2639). Methyl) phenoxy] tetrahydro-2H-pyran (21.38 g, 86.8 mmol) and N, N, N ′, N′-tetramethylethylenediamine (15.7 ml, 104 mmol) in diethyl ether (230 ml) At −20 ° C., n-butyllithium-1.58M tetrahydrofuran solution (65.9 ml, 104 mmol) was added dropwise over 10 minutes. The reaction solution was stirred at −20 ° C. for 30 minutes, and further stirred at room temperature for 40 minutes. The reaction mixture was cooled to −30 ° C., N, N-dimethylformamide (13.5 ml, 174 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. The reaction solution was carefully poured into cold water and extracted with ethyl acetate (3 times), and then the organic layer was washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water (twice) and saturated brine, and anhydrous sulfuric acid. Dry with sodium. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 20 / 1-10 / 1). The obtained pale yellow oily 2- (tetrahydro-2H-pyran-2-yloxy) -3- (trifluoromethyl) benzaldehyde was allowed to stand at room temperature overnight to obtain a pale yellow solid 2-hydroxy-3- ( Trifluoromethyl) benzaldehyde (31.73 g, yield 96%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.70 (1H, s), 9.93 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.10 (1H, t, J = 7.8 Hz).
The NMR spectrum of the intermediate 2- (tetrahydro-2H-pyran-2-yloxy) -3- (trifluoromethyl) benzaldehyde is shown below.
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.33 (1H, s), 8.02 (1H, dd, J = 7.8, 1.5 Hz), 7.83 (1H, dd, J = 7.8, 1.5 Hz), 7.33 (1H , t, J = 7.8 Hz), 4.80 (1H, dd, J = 7.4, 2.7 Hz), 3.99 (1H, m), 3.43 (1H, m), 2.07 (1H, m), 1.96 (1H, m) , 1.86 (1H, m), 1.67-1.50 (3H, m).
(45-2) To a solution of 2-hydroxy-3- (trifluoromethyl) benzaldehyde (31.7 g, 167 mmol) obtained in Example (45-1) in methanol (50 ml), trimethyl orthoformate (130 ml, 1.19 mol) and camphorsulfonic acid (1.55 g, 6.67 mmol) were added, followed by stirring at 50 ° C. for 6 hours. The reaction solution was poured into 1% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (3 times), and then the organic layer was washed successively with water (2 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer was dissolved in methylene chloride (400 ml), and diisopropylethylamine (50.9 ml, 292 mmol) and chloromethyl methyl ether (15.4 ml, 203 mmol) were added under ice cooling. Stir overnight. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was washed successively with 0.5N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. did. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 14 / 1-10 / 1) to give 1- ( Dimethoxymethyl) -2- (methoxymethoxy) -3- (trifluoromethyl) benzene (42.2 g, yield 93%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.77 (1H, dd, J = 7.8, 1.6 Hz), 7.59 (1H, dd, J = 7.8, 1.6 Hz), 7.24 (1H, t, J = 7.8 Hz ), 5.67 (1H, s), 5.07 (2H, s), 3.65 (3H, s), 3.38 (6H, s).
(45-3) 1- (dimethoxymethyl) -2- (methoxymethoxy) -3- (trifluoromethyl) benzene (39.3 g, 140 mmol) obtained in Example (45-2), and N, To a solution of N, N ′, N′-tetramethylethylenediamine (46.9 ml, 311 mmol) in diethyl ether (410 ml) was added an n-butyllithium-1.59M tetrahydrofuran solution (196 ml, 312 mmol) at −25 ° C. for 20 minutes. And dripped. The reaction solution was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 1.5 hours. The reaction mixture was cooled to −30 ° C., N, N-dimethylformamide (41.9 ml, 541 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. The reaction solution was carefully poured into cold 0.1N hydrochloric acid and extracted with ethyl acetate (4 times), and then the organic layer was washed successively with 0.1N hydrochloric acid, water (3 times) and saturated brine, and anhydrous sulfuric acid. Dry with sodium. The solvent was distilled off under reduced pressure to obtain crude 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzaldehyde. This compound was used in Example (45-4) without further purification.
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.71 (1H, s), 7.81 (1H, d, J = 8.2 Hz), 7.70 (1H, d, J = 8.2 Hz), 5.79 (1H, s), 5.07 (2H, s), 3.67 (3H, s), 3.50 (6H, s).
MS (FAB) (+ 0.1N KIaq.) (M / z): 347 ([M + K] ⁺ ).
(45-4)
To the crude 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzaldehyde tetrahydrofuran-methanol (5: 1, 100 ml) mixed solution obtained in Example (45-3), Under ice cooling, sodium borohydride (5.11 g, 135 mmol) was added and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate (4 times), and then the organic layer was washed successively with water (2 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5 / 1-2 / 1) to give [2- ( Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (22.6 g, yield 52%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.59 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 5.81 (1H, s), 5.01 (2H, s), 4.85 (2H, d, J = 7.0 Hz), 3.65 (3H, s), 3.50 (6H, s), 3.36 (1H, t, J = 7.0 Hz).
MS (FAB) (m / z): 309 ([MH] ⁺ ).
(45-5) [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (45-4) in the same manner as in Example (44-4) A colorless oily N- (4-{[2- (dimethoxymethyl)] from phenyl] methanol (377 mg, 1.22 mmol) and N- (4-hydroxyphenyl) -N-methylacetamide (241 mg, 1.46 mmol) -3- (Methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl) -N-methylacetamide (282 mg, yield 51%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.58 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 8.6 Hz), 7.07 (2H, d, J = 8.6 Hz), 6.98 ( 2H, d, J = 8.6 Hz), 5.76 (1H, s), 5.50 (2H, s), 5.04 (2H, s), 3.67 (3H, s), 3.48 (6H, s), 3.21 (3H, s ), 1.85 (3H, s).
MS (FAB) (m / z): 458 ([M + H] ⁺ ).
(45-6) N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl) obtained in Example (45-5) To a solution of -N-methylacetamide (265 mg, 0.579 mmol) in tetrahydrofuran (4 ml) was added 4N-hydrochloric acid (0.8 ml), and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was obtained by distilling off the solvent under reduced pressure. To a mixed solution of the obtained residue tert-butyl alcohol (6.3 ml), 1,4-dioxane (1.5 ml), and 2-methyl-2-butene (1.5 ml), sodium chlorite (314 mg) was added. , 3.47 mmol) and an aqueous solution (3.0 ml) of sodium dihydrogen phosphate monohydrate (314 mg, 2.28 mmol) were added dropwise, followed by stirring at room temperature for 30 minutes. A 5% aqueous sodium thiosulfate solution was added to the reaction solution, poured into 0.5N hydrochloric acid, and extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was obtained by distilling off the solvent under reduced pressure. After the obtained residue was dissolved in toluene (4.5 ml) and 1,4-dioxane (3.0 ml), N, N-dimethylformamide ditert-butyl acetal (0.555 ml, 2.31 mmol) And heated to reflux for 1.5 hours. The reaction mixture was poured into 0.1N hydrochloric acid and extracted with ethyl acetate (3 times), and then the organic layer was washed successively with water (2 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 5/4) to give the title compound as a colorless solid (102 mg, yield 40). %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.20 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 5.33 (2H, s), 3.23 (3H, s), 1.85 (3H, s), 1.64 (9H, s).
HRMS (FAB) (m / z): calcd. For C ₂₂ H ₂₅ O ₅ NF ₃ ([M + H] ⁺ ): 440.1684; found: 440.1682.
Anal.calcd.for C ₂₂ H ₂₄ O ₅ NF ₃ : C, 60.13; H, 5.51; N, 3.19; found: C, 60.06; H, 5.49; N, 3.15.

Example 46 tert-Butyl 2-({4-[[(allyloxy) carbonyl] (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified compound number: 1-41)
(46-1) 4-Methylaminophenol sulfate (5.11 g, 29.7 mmol) and triethylamine (12.3 ml, 89.1 mmol) in methylene chloride solution (100 ml) allyl chloroformate (6.90 ml) 65.3 mmol) and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol (50 ml), potassium carbonate (5.00 g, 36.2 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3 / 1-1 / 1) to give allyl 4-hydroxyphenyl (methyl ) Carbamate (4.58 g, 74% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.04 (2H, d, J = 8.6 Hz), 6.73 (2H, br. S), 5.90 (1H, br. S), 5.18 (2H, br. S) , 4.61 (2H, br.s), 3.26 (3H, s).
(46-2) [Coupling step of various benzyl bromides and phenol derivatives]
Tert-Butyl 2-bromomethyl-5- (trifluoromethyl) benzoate obtained in Example (7-2) (1.46 g, 7.05 mmol) and allyl obtained in Example (46-1) To a solution of 4-hydroxyphenyl (methyl) carbamate (1.99 g, 5.87 mmol) in N, N-dimethylformamide (20 ml) was added potassium carbonate (1.21 g, 8.80 mmol), and the mixture was stirred at room temperature overnight. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to give the title compound (2.19 g, yield) as a colorless oil. 80%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.18 (1H, s), 7.88 (1H, d, J = 8.2 Hz), 7.73 (1H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.2 Hz), 6.94 (2H, d, J = 8.2 Hz), 5.88 (1H, br.s), 5.48 (2H, br.s), 5.15 (2H, br.s), 4.59 (2H, br. s), 3.27 (3H, s), 1.62 (9H, s).
MS (FAB) (m / z): 465 ([M] ⁺ ).

Example 47 tert-Butyl 2-({4- [Methyl (propionyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-30)
(47-1) tert-butyl 2-({4-[[(allyloxy) carbonyl] (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate obtained in Example (46-2) (2.19 g, 4.71 mmol) of 1,4-dioxane (60 ml) and water (2 ml) in a mixed solution of pyrrolidine (1.17 ml, 14.1 mmol), tetrakis (triphenylphosphine) palladium (0) (134 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-1 / 1), and tert-butyl 2-{[ 4- (Methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (1.51 g, 85% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (1H, d, J = 1.6 Hz), 7.91 (1H, d, J = 8.2 Hz), 7.74 (1H, dd, J = 8.2, 1.6 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.58 (2H, d, J = 9.0 Hz), 5.42 (2H, s), 2.81 (3H, s), 1.61 (9H, s).
(47-2) tert-Butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (100 mg, 0.262 mmol) obtained in Example (47-1), Propanoic anhydride (51 mg, 0.39 mmol) was added to a methylene chloride solution (4 ml) of triethylamine (73 μl, 0.52 mmol), and the mixture was stirred overnight at room temperature. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound (84.0 mg, 8 mg, Yield 73%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.19 (1H, s), 7.88 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 5.51 (2H, s), 3.23 (3H, s), 2.08 (2H, q, J = 7.4 Hz), 1.62 (9H, s), 1.05 (3H, t, J = 7.4 Hz)
MS (FAB) (m / z): 438 ([M + H] ⁺ ).

Example 48 tert-Butyl 2-({4- [Butyryl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-32)
In the same manner as in Example (47-2), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate obtained in Example (47-1) ( 100 mg, 0.262 mmol) to triethylamine (73 μl, 0.52 mmol) and butanoic anhydride (62 mg, 0.39 mmol) to give the title compound (87.1 mg, 74% yield) as a colorless oil Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.19 (1H, s), 7.89 (1H, d, J = 8.2 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.51 (2H, s), 3.23 (3H, s), 2.04 (2H, t, J = 7.4 Hz), 1.62 (9H, s), 1.62-1.53 (2H, m), 0.83 (3H, t, J = 7.2 Hz).
MS (FAB) (m / z): 452 ([M + H] ⁺ ).

Example 49 tert-Butyl 2-({4- [Methyl (trifluoroacetyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. 1-36)
In the same manner as in Example (47-2), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate obtained in Example (47-1) ( 100 mg, 0.262 mmol) to triethylamine (73 μl, 0.52 mmol) and trifluoroacetic anhydride (83 mg, 0.39 mmol) to give the title compound as a yellow powder (87.1 mg, 74% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, s), 7.89 (1H, d, J = 8.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.19 (2H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.0 Hz), 5.53 (2H, s), 3.34 (3H, s), 1.61 (9H, s).

Example 50 tert-Butyl 2-({4- [isobutyryl (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified Compound No. 1-33)
Tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (100 mg, 0.262 mmol) obtained in Example (47-1) in methylene chloride (4 ml) ) Were added triethylamine (73 μl, 0.52 mmol) and isobutyryl chloride (42 mg, 0.39 mmol), and the mixture was stirred at room temperature overnight. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound as a colorless oil (98.1 mg, Yield 83%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, s), 7.91 (1H, d, J = 8.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.02 (2H, d, J = 9.0 Hz), 5.53 (2H, s), 3.23 (3H, s), 2.51 (1H, sp., J = 6.6 Hz), 1.62 (9H, s) , 1.02 (6H, d, J = 6.6 Hz).
MS (FAB) (m / z): 452 ([M + H] ⁺ ).

Example 51 tert-Butyl 2-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. 1-38)
In the same manner as in Example (50), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (75. 0 mg, 0.197 mmol) to triethylamine (82 μl, 0.59 mmol) and cyclopropanecarbonyl chloride (83 mg, 0.39 mmol) to give the title compound (71.2 mg, 80% yield) as a colorless powder. Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, s), 7.91 (1H, d, J = 8.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 5.53 (2H, s), 3.27 (3H, s), 1.62 (9H, s), 1.39 (1H, m), 1.00 (2H, m ), 0.61 (2H, m).
MS (FAB) (m / z): 450 ([M + H] ⁺ ).

(Example 52) tert-butyl 2-({4-[(methoxycarbonyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified compound number: 1-40)
In the same manner as in Example (50), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate obtained in Example (47-1) (86. 2 mg, 0.226 mmol) to triethylamine (63 μl, 0.45 mmol) and methyl chloroformate (32 mg, 0.34 mmol) to give the title compound (73.5 mg, 74% yield) as a colorless oil. Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.18 (1H, d, J = 1.4 Hz), 7.87 (1H, d, J = 8.2 Hz), 7.74 (1H, dd, J = 8.2, 1.4 Hz), 7.14 (2H, d, J = 8.6 Hz), 6.94 (2H, d, J = 8.6 Hz), 5.49 (2H, s), 3.68 (3H, br. S), 3.26 (3H, s), 1.62 (9H , s).
MS (FAB) (m / z): 440 ([M + H] ⁺ ).

Example 53 tert-Butyl 2-({4-[[(dimethylamino) carbonyl] (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified Compound No. 1-42)
In the same manner as in Example (50), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate obtained in Example (47-1) (86. 2 mg, 0.226 mmol) to triethylamine (63 μl, 0.45 mmol) and N, N-dimethylcarbamoyl chloride (36 mg, 0.34 mmol) to give the title compound (39.5 mg, yield 39) as a colorless oil. %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.17 (1H, d, J = 1.2 Hz), 7.87 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 8.2, 1.2 Hz), 7.00 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 5.47 (2H, s), 3.16 (3H, s), 2.66 (6H, s), 1.61 (9H, s ).
MS (FAB) (m / z): 453 ([M + H] ⁺ ).

Example 54 tert-butyl 2-({4-[(N, N-dimethylglycyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplified compound number: 1-35 )
Tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (73.0 mg, 0.192 mmol) obtained in Example (47-1) and N , N-dimethylglycine (53 mg, 0.38 mmol) in methylene chloride (4 ml), 4- (N, N-dimethylamino) pyridine (10 mg) and 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide hydrochloride (73 mg, 0.38 mmol) was added and stirred at room temperature overnight. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound (18.0 mg, 18.0 mg, Yield 20%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.19 (1H, s), 7.88 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.52 (2H, s), 3.23 (3H, s), 2.85 (2H, s), 2.24 (6H, s), 1.62 (9H, s ).
MS (FAB) (m / z): 467 ([M + H] ⁺ ).

Example 55 tert-Butyl 2-[(4- {methyl [(methylsulfonyl) acetyl] amino} phenoxy) methyl] -5- (trifluoromethyl) benzoate (Exemplified Compound No. 1-34)
In the same manner as in Example (54), tert-butyl 2-{[4- (methylamino) phenoxy] methyl} -5- (trifluoromethyl) benzoate (93. 0 mg, 0.244 mmol) to (methylsulfonyl) acetic acid (67 mg, 0.49 mmol), N, N-dimethylaminopyridine (10 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (93 mg, 0.49 mmol) was used to obtain the colorless amorphous title compound (106 mg, yield 87%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.19 (1H, d, J = 1.2 Hz), 7.88 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.2, 1.2 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.02 (2H, d, J = 9.0 Hz), 5.51 (2H, s), 3.80 (2H, s), 3.29 (3H, s), 3.19 (3H, s ), 1.60 (9H, s).
MS (FAB) (m / z): 502 ([M + H] ⁺ ).

Example 56 tert-Butyl 6-({4-[(Cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. 1-114) )
(56-1) [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1.42 g, 4.58 mmol) obtained in Example (45-4) A solution of allyl 4-hydroxyphenyl (methyl) carbamate (1.04 g, 5.04 mmol) obtained in Example (46-1) and triphenylphosphine (1.44 g, 5.50 mmol) in tetrahydrofuran (20 ml) ) Was added diethyl azodicarboxylate (1.32 ml, 5.50 mmol) and stirred at room temperature for 2 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10 / 1-1 / 1), and allyl 4-{[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl (methyl) carbamate (1.45 g, yield 63%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.63-7.53 (2H, m), 7.12 (2H, d, J = 8.8 Hz), 6.99-6.94 (2H, d, J = 8.8 Hz), 5.88 (1H , br. s), 5.75 (1H, s), 5.48 (2H, s), 5.18 (2H, br. s), 5.03 (2H, br. s), 4.59 (2H, br. s), 3.66 (3H , s), 3.47 (6H, s), 3.26 (3H, s).
(56-2) Allyl obtained in Example (56-1) in the same manner as in Example (47-1)
4-{[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl (methyl) carbamate (3.86 g, 7.61 mmol) to pyrrolidine (1.90 ml) , 22.8 mmol) and tetrakis (triphenylphosphine) palladium (0) (439 mg, 0.38 mmol) to give N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy)- 4- (Trifluoromethyl) benzyl] oxy} phenyl) -N-methylamine (3.01 g, yield 95%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.59-7.54 (2H, m), 6.85 (2H, d, J = 9.0 Hz), 6.56 (2H, d, J = 9.0 Hz), 5.73 (1H, s ), 5.41 (2H, s), 5.03 (2H, s), 3.66 (3H, s), 3.45 (6H, s), 2.79 (3H, s).
(56-3) N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl) obtained in Example (56-2) To a solution of -N-methylamine (500 mg, 1.20 mmol) in methylene chloride (8 ml) under ice-cooling, triethylamine (0.420 ml, 3.01 mmol) and cyclopropanecarbonyl chloride (0.162 ml, 1 .80 mmol) was sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (twice), and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was obtained by distilling off the solvent under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (13 ml) was added 4N-hydrochloric acid (2.5 ml), and the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was obtained by distilling off the solvent under reduced pressure. To a mixed solution of the obtained residue tert-butyl alcohol (12.5 ml), 1,4-dioxane (3.0 ml) and 2-methyl-2-butene (3.5 ml), sodium chlorite (650 mg, 7.19 mmol) and an aqueous solution (5.0 ml) of sodium dihydrogen phosphate monohydrate (650 mg, 4.71 mmol) were added dropwise, followed by stirring at room temperature for 30 minutes. A 5% aqueous sodium thiosulfate solution was added to the reaction solution, poured into 0.5N hydrochloric acid, and extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was obtained by distilling off the solvent under reduced pressure. The obtained residue was dissolved in toluene (9.0 ml) and 1,4-dioxane (6.0 ml), and then N, N-dimethylformamide ditert-butyl acetal (1.15 ml, 4.80 mmol). And heated to reflux for 1.5 hours. The reaction mixture was poured into 0.1N hydrochloric acid and extracted with ethyl acetate (3 times), and then the organic layer was washed successively with water (2 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound as a colorless powder (245 mg, yield 44). %).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.6 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.35 (2H, s), 3.26 (3H, s), 1.65 (9H, s), 1.38 (1H, m), 1.00 (2H, m ), 0.61 (2H, m).
HRMS (FAB) (m / z): calcd. For C ₂₄ H ₂₇ O ₅ NF ₃ ([M + H] ⁺ ): 466.1841; found: 466.1839.
Anal.calcd.for C ₂₄ H ₂₆ O ₅ NF ₃ : C, 61.93; H, 5.63; N, 3.01; F, 12.24; found: C, 61.78; H, 5.52; N, 2.89; F, 12.43.

Example 57 tert-Butyl 2-hydroxy-6-({4- [isobutyryl (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplary Compound No: 1-96)
In the same manner as in Example (56-3), N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (56-2) was obtained. ) Benzyl] oxy} phenyl) -N-methylamine (500 mg, 1.20 mmol) and isobutyryl chloride (0.190 ml, 1.80 mmol) to give the title compound as a colorless gum (261 mg, 46% yield) ) However, isobutyryl chloride was used in place of cyclopropanecarbonyl chloride in Example (56-3).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, s), 7.72 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.13 (2H, d, J = 8.6 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.35 (2H, s), 3.22 (3H, s), 2.51 (1H, sp., J = 6.3 Hz), 1.65 (9H, s) , 1.03 (6H, d, J = 6.3 Hz).
HRMS (FAB) (m / z): calcd.for C ₂₄ H ₂₉ O ₅ NF ₃ ([M + H] ⁺ ): 468.1998; found: 468.1988.

Example 58 tert-Butyl 2-hydroxy-6-({4- [methyl (propionyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplified compound number: 1-93)
In the same manner as in Example (56-3), N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (56-2) was obtained. ) Benzyl] oxy} phenyl) -N-methylamine (511 mg, 1.23 mmol) gave the title compound (122.9 mg, 22% yield) as a colorless powder. However, propionic anhydride was used in place of cyclopropanecarbonyl chloride in Example (56-3).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, br.s), 7.71 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.12 (2H, d , J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 5.35 (2H, s), 3.24 (3H, s), 2.08 (2H, q, J = 7.5 Hz), 1.65 (9H, s ), 1.05 (3H, t, J = 7.5 Hz)
MS (FAB) (m / z): 454 ([M + H] ⁺ ).

Example 59 tert-Butyl 6-({4- [Butyryl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplified Compound No: 1-95)
In the same manner as in Example (56-3), N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (56-2) was obtained. )] Benzyl] oxy} phenyl) -N-methylamine (479 mg, 1.15 mmol) gave the title compound (98.6 mg, 18% yield) as a yellow oil. However, butanoic acid anhydride was used in place of cyclopropanecarbonyl chloride in Example (56-3).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, br.s), 7.72 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.12 (2H, d , J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz), 5.35 (2H, s), 3.23 (3H, s), 2.03 (2H, t, J = 7.6 Hz), 1.64 (9H, s ), 1.64-1.54 (2H, m), 0.83 (3H, t, J = 7.2 Hz).
MS (FAB) (m / z): 468 ([M + H] ⁺ ).

Example 60 tert-Butyl 2-hydroxy-6-({4- [methyl (3-methylbutanoyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplified compound number: 1-97 )
In the same manner as in Example (56-3), N- (4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (56-2) was obtained. ) Benzyl] oxy} phenyl) -N-methylamine (454 mg, 1.09 mmol) afforded the title compound (113.0 mg, 22% yield) as a yellow oil. However, isovaleric anhydride was used in place of cyclopropanecarbonyl chloride in Example (56-3).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, br.s), 7.72 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.10 (2H, d , J = 9.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 5.35 (2H, s), 3.24 (3H, s), 2.13 (1H, m), 1.95 (2H, d, J = 7.0 Hz ), 1.64 (9H, s), 0.84 (6H, d, J = 6.7 Hz).
MS (FAB) (m / z): 482 ([M + H] ⁺ ).

Example 61 tert-Butyl 2-hydroxy-6-({4-[(methoxyacetyl) (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-99)
(61-1) Allyl 4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} phenyl (methyl) obtained in Example (56-1) 4N-hydrochloric acid (5 ml) was added to a tetrahydrofuran solution (20 ml) of carbamate (4.00 g, 8.01 mmol), and the mixture was stirred at 55 ° C. for 4 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The N, N-dimethylformamide solution (10 ml) of the residue obtained by evaporating the solvent under reduced pressure was added to allyl bromide (831 μl, 9.61 mmol) and potassium carbonate (1.33 g, 9.61 mmol). And stirred at 50 ° C. for 3 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. 2-Methyl-2-butene (20 ml) was added to a mixed solution of the residue 1,4-dioxane (20 ml) and tert-butanol (75 ml) obtained by evaporating the solvent under reduced pressure. . To the reaction solution, an aqueous solution (30 ml) of sodium chlorite (4.33 g, 48.1 mmol) and sodium dihydrogen phosphate monohydrate (4.33 g, 31.4 mmol) was added dropwise at room temperature. Stir for hours. A 10% aqueous sodium thiosulfate solution was poured into the reaction solution, stirred, acidified with 1N-hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. did. N, N-dimethylformamide ditert-butyl acetal (7.67 ml, 32.0 mmol) was added to a toluene solution (50 ml) of the residue obtained by evaporating the solvent under reduced pressure, and the mixture was heated at 110 ° C. for 6 hours. Stir. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-7 / 3), and tert-butyl 2- ( Allyloxy) -6-({4-[[(allyloxy) carbonyl] (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (2.80 g, 67% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.64 (1H, d, J = 7.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.16 (2H, d, J = 9.0 Hz), 6.90 ( 2H, d, J = 9.0 Hz), 6.11-6.02 (1H, m), 5.89 (1H, br.s), 5.42 (1H, m), 5.27 (1H, m), 5.17 (2H, br.s) , 5.11 (2H, br.s), 4.65-4.55 (4H, m), 3.27 (3H, s), 1.57 (9H, s).
(61-2) tert-Butyl 2- (allyloxy) -6-({4-[[(allyloxy) carbonyl]] obtained in Example (61-1) in the same manner as in Example (47-1). (Methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (2.80 g, 5.37 mmol) to tert-butyl 2-hydroxy-6-{[4- (methylamino) phenoxy] methyl} -3- (Trifluoromethyl) benzoate (1.64 g, 77% yield) was obtained.
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.23 (1H, br.s), 7.67 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 8.3 Hz), 6.79 (2H, d , J = 8.8 Hz), 6.58 (2H, d, J = 8.8 Hz), 5.26 (2H, s), 2.80 (3H, s), 1.62 (9H, s).
(61-3) tert-butyl 2-hydroxy-6-{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) benzoate (74.5 mg) obtained in Example (61-2) , 0.188 mmol) in methylene chloride (4 ml) was added triethylamine (78 μl, 0.56 mmol), methoxyacetyl chloride (34 μl, 0.38 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1), and tert-butyl 6-({4- [ (Methoxyacetyl) (methyl) amino] phenoxy} methyl) -2-[(methoxyacetyl) oxy] -3- (trifluoromethyl) benzoate (60.5 mg, 59% yield) was obtained. To a methanol solution (5 ml) of this compound (60.5 mg, 0.112 mmol) was added potassium carbonate (100 mg), and the mixture was stirred at room temperature for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound (26.9 mg) as a colorless oil. Yield 51%).
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.23 (1H, br.s), 7.71 (1H, d, J = 8.3 Hz), 7.25 (1H, d, J = 8.3 Hz), 7.13 (2H, d , J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 5.35 (2H, s), 3.77 (2H, s), 3.35 (3H, s), 3.25 (3H, s), 1.64 (9H , s).
MS (FAB) (m / z): 470 ([M + H] ⁺ ).

Example 62 tert-butyl 6-({4- [acryloyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplified Compound No. 1-117)
(62-1) tert-butyl 2-hydroxy-6-{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) benzoate (2.46 g) obtained in Example (61-2) , 6.20 mmol) in N, N-dimethylformamide solution (20 ml), triethylamine (3.44 ml, 24.8 mmol) is added, and tert-butylchlorodimethylsilane (2.79 g, 18.6 mmol) is added at room temperature. For 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-1 / 1) to obtain tert-butyl 2- { [tert-Butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) benzoate (2.38 g, 97% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.56 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 6.79 (2H, d, J = 9.0 Hz), 6.55 ( 2H, d, J = 9.0 Hz), 5.06 (2H, s), 2.79 (3H, s), 1.58 (9H, s), 1.01 (9H, s), 0.20 (6H, s).
(62-2) tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] methyl} -3 obtained in Example (62-1) -To a solution of (trifluoromethyl) benzoate (91.8 mg, 0.231 mmol) in methylene chloride (4 ml) was added triethylamine (96 μl, 0.70 mmol), acryloyl chloride (37 μl, 0.46 mmol) was added at room temperature. Stir overnight. Further, a small amount of methanol and a tetra-n-butylammonium fluoride-1.0M-tetrahydrofuran solution (2.3 ml, 2.3 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound as a colorless powder (33.1 mg). Yield 32%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.72 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.12 (2H, d, J = 9.0 Hz), 6.94 ( 2H, d, J = 9.0 Hz), 6.36 (1H, dd, J = 16.8, 1.8 Hz), 6.07 (1H, dd, J = 16.8, 10.4 Hz), 5.51 (1H, dd, J = 10.4, 1.8 Hz) ), 5.35 (2H, s), 3.33 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z): 452 ([M + H] ⁺ ).

Example 63 tert-Butyl 2-hydroxy-6-({4-[(methoxycarbonyl) (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-119)
In the same manner as in Example (62-2), tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) obtained in Example (62-1) ) Phenoxy] methyl} -3- (trifluoromethyl) benzoate (84.4 mg, 0.165 mmol), triethylamine (68 μl, 0.50 mmol), methyl chloroformate (31 mg, 0.33 mmol), and tetra-n A colorless powder of the title compound (21.2 mg, yield 28%) was obtained from a -butylammonium fluoride-1.0 M-tetrahydrofuran solution (1.6 ml, 1.6 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, br.s), 7.70 (1H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.16 (2H, d , J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 5.34 (2H, s), 3.70 (3H, br.s), 3.27 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z): 455 ([M] ⁺ ).

(Example 64) tert-butyl 6-({4-[(ethylsulfonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary compound number: 1-123)
In the same manner as in Example (62-2), tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) obtained in Example (62-1) ) Phenoxy] methyl} -3- (trifluoromethyl) benzoate (85.9 mg, 0.168 mmol), triethylamine (70 μl, 0.50 mmol), ethanesulfonyl chloride (43 mg, 0.34 mmol), and tetra-n- From the butylammonium fluoride-1.0M-tetrahydrofuran solution (1.6 ml, 1.6 mmol), the title compound (32.1 mg, yield 39%) as a colorless oil was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.15 (1H, br.s), 7.67 (1H, d, J = 8.2 Hz), 7.30 (2H, d, J = 9.0 Hz), 7.22 (1H, d , J = 8.2 Hz), 6.89 (2H, d, J = 9.0 Hz), 5.32 (2H, s), 3.31 (3H, s), 3.02 (2H, q, J = 7.4 Hz), 1.64 (9H, s ), 1.38 (3H, t, J = 7.4 Hz).
MS (FAB) (m / z): 489 ([M] ⁺ ).

Example 65 tert-Butyl 2-hydroxy-6-({4- [methyl (methylsulfonyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplary Compound No. 1-122)
In the same manner as in Example (62-2), tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) obtained in Example (62-1) ) Phenoxy] methyl} -3- (trifluoromethyl) benzoate (98.0 mg, 0.192 mmol), triethylamine (53 μl, 0.50 mmol), methanesulfonyl chloride (22 μl, 0.29 mmol), and tetra-n- A colorless amorphous title compound (85.7 mg, 94% yield) was obtained from a 1.0 M tetrahydrofuran solution (1.9 ml, 1.9 mmol) of butylammonium fluoride.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, br.s), 7.68 (1H, d, J = 8.2 Hz), 7.31 (2H, d, J = 9.0 Hz), 7.24 (1H, d , J = 8.2 Hz), 6.91 (2H, d, J = 9.0 Hz), 5.34 (2H, s), 3.29 (3H, s), 2.84 (3H, s), 1.66 (9H, s).
MS (FAB) (m / z): 475 ([M] ⁺ ).

Example 66 tert-Butyl 2-hydroxy-6-[(4- {methyl [(methylthio) acetyl] amino} phenoxy) methyl] -3- (trifluoromethyl) benzoate (Exemplified compound number: 1-101)
Tert-Butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) obtained in Example (62-1) ) Benzoate (141 mg, 0.276 mmol) and methylthioacetic acid (44 mg, 0.38 mmol) in methylene chloride (4 ml) were mixed with N, N-dimethylaminopyridine (10 mg) and 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (105 mg, 0.55 mmol) was added and stirred at room temperature overnight. Furthermore, a small amount of water and a tetra-n-butylammonium fluoride-1.0M-tetrahydrofuran solution (2.8 ml, 2.8 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give the title compound as a colorless oil (87.3 mg). Yield 65%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.72 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.21 (2H, d, J = 9.0 Hz), 6.94 ( 2H, d, J = 9.0 Hz), 5.35 (2H, s), 3.26 (3H, s), 3.02 (2H, s), 2.21 (3H, s), 1.64 (9H, s).
MS (FAB) (m / z): 486 ([M + H] ⁺ ).

Example 67 tert-Butyl 6-({4- [Glycoroyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No: 1-98)
Tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6 obtained in Example (62-1) in the same manner as in Example (66) and Example (72-4) -{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) benzoate (83.5 mg, 0.163 mmol) to acetoxyacetic acid (29 mg, 0.25 mmol), N, N-dimethylaminopyridine (10 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (63 mg, 0.33 mmol), tetra-n-butylammonium fluoride 1.0 M-tetrahydrofuran solution (1.6 ml, 1.6 mmol) ), And 1N aqueous sodium hydroxide solution (0.5 ml), the title compound (29.6 mg, yield 4) as a colorless powder was obtained. 0%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, br.s), 7.72 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.13 (2H, d , J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz), 5.35 (2H, s), 3.80 (2H, s), 3.31 (3H, s), 1.64 (9H, s).
MS (FAB) (m / z): 456 ([M + H] ⁺ ).

Example 68 tert-butyl 2-hydroxy-6-[(4- {methyl [(trifluoromethyl) sulfonyl] amino} phenoxy) methyl] -3- (trifluoromethyl) benzoate (Exemplified compound number: 1- 124)
Tert-Butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] methyl} -3- (trifluoromethyl) obtained in Example (62-1) ) 4- (N, N-dimethylamino) pyridine (63 mg, 0.517 mmol) was added to a methylene chloride solution (4 ml) of benzoate (88.1 mg, 0.172 mmol), and trifluoromethanesulfonic anhydride (56 μl, 0.344 mmol) was added and stirred at room temperature overnight. Furthermore, a small amount of water and a tetra-n-butylammonium fluoride-1.0M-tetrahydrofuran solution (1.7 ml, 1.7 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 5/1) to give the title compound (16.4 mg) as a colorless oil. Yield 18%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.21 (1H, br.s), 7.68 (1H, d, J = 8.2 Hz), 7.28 (2H, d, J = 9.0 Hz), 7.20 (1H, d , J = 8.2 Hz), 6.91 (2H, d, J = 9.0 Hz), 5.33 (2H, s), 3.43 (3H, app.q, J = 1.0 Hz), 1.63 (9H, s).
MS (FAB) (m / z): 529 ([M] ⁺ ).

Example 69 tert-Butyl 2-({4- [acetyl (2,2,2-trifluoroethyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. 1-212 )
(69-1) Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (0.85 ml, 0.59 mmol) was added to a xylene solution (6 ml) of 4-benzyloxyaniline (2.30 g, 11.5 mmol). The mixture was heated to reflux for 3 hours. After returning the reaction solution to room temperature, insolubles were filtered off. Tetrahydrofuran (6 ml), pyridine (5.0 ml), acetic anhydride (5.0 ml) and N, N-dimethylaminopyridine (20 mg) were added to the residue obtained by concentrating the filtrate under reduced pressure at room temperature overnight. Stir. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3 / 1-3 / 2), and N- [4- (benzyloxy ) Phenyl] -N- (2,2,2-trifluoroethyl) acetamide (1.48 g, 77% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.47-7.33 (5H, m), 7.15 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 5.08 (2H, s ), 4.31 (2H, q, J = 8.8 Hz), 1.88 (3H, s).
(69-2) In the same manner as in Example (15-4), N- [4- (benzyloxy) phenyl] -N- (2,2,2-trimethyl compound) obtained in Example (69-1) was used. Fluoroethyl) acetamide (1.45 g, 4.48 mmol) gave N- (4-hydroxyphenyl) -N- (2,2,2-trifluoroethyl) acetamide (1.04 g, 100% yield). . However, methanol-ethyl acetate (1: 2) was used as a solvent in place of methanol in Example (15-4).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.10 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.15-6.07 (1H, br.), 4.32 (2H, q, J = 8.8 Hz), 1.90 (3H, s).
(69-3) In the same manner as in Example (1-4), tert-butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate obtained in Example (7-2) (65 mg,. 19 mmol), N- (4-hydroxyphenyl) -N- (2,2,2-trifluoroethyl) acetamide (63 mg, 0.27 mmol) obtained in Example (69-2), and cesium carbonate ( 81 mg, 0.25 mmol) gave the title compound (62 mg, 66% yield) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (1H, br.s), 7.90 (1H, d, J = 8.1 Hz), 7.79 (1H, br. D, J = 8.1 Hz), 7.18 (2H , d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 5.54 (2H, s), 4.33 (2H, q, J = 8.8 Hz), 1.89 (3H, s), 1.62 (9H , s).

Example 70 tert-Butyl 2-({4-[(Dimethylamino) carbonyl] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-44)
Tert-Butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate (70 mg, 0.21 mmol) obtained in Example (7-2) in the same manner as in Example (1-4), literature (Baker , BR et al., J. Med. Chem., 1972, 15, p. 945-947), 4-hydroxy-N, N-dimethylbenzamide (35 mg, 0.21 mmol) ) And cesium carbonate (100 mg, 0.31 mmol) gave the title compound (20 mg, 22% yield) as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.20 (1H, br.s), 7.87 (1H, d, J = 8.1 Hz), 7.76 (1H, br. D, J = 8.1 Hz), 7.42 (2H , d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.53 (2H, s), 3.12-2.98 (6H, br.), 1.62 (9H, s).

Example 71 tert-Butyl 2-({4- [Methyl (methylsulfonyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate (Exemplary Compound No. 1-43)
In the same manner as in Example (1-4), tert-butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate (70 mg, 0.21 mmol) obtained in Example (7-2), literature ( N- (4-hydroxyphenyl) -N-methylmethanesulfonamide (35 mg, 0) synthesized according to the method described in Kidd, DAA et al., J. Chem. Soc., 1962, p. 1420-1427). .21 mmol) and cesium carbonate (100 mg, 0.31 mmol) gave the title compound (39 mg, 40% yield) as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.20 (1H, br.s), 7.87 (1H, d, J = 8.1 Hz), 7.77 (1H, br. D, J = 8.1 Hz), 7.31 (2H , d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.51 (2H, s), 3.29 (3H, s), 2.84 (3H, s), 1.62 (9H, s).
MS (FAB) (m / z): 459 ([M] ⁺ ).
Anal.calcd.for C ₂₁ H ₂₄ O ₅ NSF ₃ : C, 54.89; H, 5.27; N, 3.05; S, 6.98; F, 12.40; found: C, 54.70; H, 5.09; N, 3.07; S, 7.03; F, 12.19.

(Example 72) tert-butyl 2- (1- {4- [acetyl (methyl) amino] phenoxy} ethyl) -5- (trifluoromethyl) benzoate (Exemplified compound number: 2-10)
(72-1) A solution of [2-iodo-4- (trifluoromethyl) phenyl] methanol (8.00 g, 26.5 mmol) obtained in Example (29-2) in methylene chloride (200 ml) was activated. Manganese dioxide (16 g, 92 mmol) was added and stirred at room temperature for 7 hours. Insolubles were removed by Celite filtration, and the resulting filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 1-5 / 1) to give 2-iodo-4- (trifluoromethyl) benzaldehyde (5.34 g, Yield 67%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.08 (1H, s), 8.18 (1H, br.s), 7.95 (1H, d, J = 7.8 Hz), 7.71 (1H, br. D, J = 7.8 Hz).
(72-2) To a solution of 2-iodo-4- (trifluoromethyl) benzaldehyde (500 mg, 1.67 mmol) obtained in Example (72-1) in tetrahydrofuran (5 ml) was added odor under ice-cooling. A methylmagnesium chloride-3.0M tetrahydrofuran solution (0.830 ml, 2.49 mmol) was added dropwise, followed by stirring for 5 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- [2-iodo-4- (trifluoromethyl) phenyl] ethanol (526 mg, yield 100%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.01 (1H, br.s), 7.68 (1H, d, J = 8.6 Hz), 7.62 (1H, br. D, J = 8.6 Hz), 5.09 (1H , m), 2.03 (1H, m), 1.47 (3H, d, J = 6.3 Hz).
(72-3) 1- [2-Iodo-4- (trifluoromethyl) obtained in Example (72-2) in the same manner as in Example (56-1) and Example (23). From phenyl] ethanol (463 mg, 1.46 mmol) and N- (4-hydroxyphenyl) -N-methylacetamide (240 mg, 1.45 mmol), methyl 2- (1- {4- [acetyl (methyl) amino] ] Phenoxy} ethyl) -5- (trifluoromethyl) benzoate (420 mg, 73% yield) was obtained. However, in the step corresponding to Example (56-1), instead of [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol, 1- [2-iodo- 4- (Trifluoromethyl) phenyl] ethanol was used.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.23 (1H, br.s), 7.82 (1H, d, J = 8.2 Hz), 7.73 (1H, br. D, J = 8.2 Hz), 6.98 (2H , d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 6.35 (1H, q, J = 6.3 Hz), 3.99 (3H, s), 3.16 (3H, s), 1.80 (3H , s), 1.64 (3H, d, J = 6.3 Hz).
(72-4) Methyl 2- (1- {4- [acetyl (methyl) amino] phenoxy} ethyl) -5- (trifluoromethyl) benzoate (420 mg, 1.2) obtained in Example (72-3). (06 mmol) in tetrahydrofuran (3 ml) was added 1N aqueous sodium hydroxide solution (1.0 ml, 1.0 mmol), and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to give 2- (1- {4- [acetyl (methyl) amino] phenoxy} ethyl). -5- (Trifluoromethyl) benzoic acid (294 mg, yield 72%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.34 (1H, br.s), 7.84 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 8.1 Hz), 6.99 (2H, d , J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 6.45 (1H, q, J = 6.3 Hz), 3.20 (3H, s), 1.85 (3H, s), 1.65 (3H, d , J = 6.3 Hz).
(72-5) In the same manner as in Example (10-1), 2- (1- {4- [acetyl (methyl) amino] phenoxy} ethyl) -5- obtained in Example (72-4) (Trifluoromethyl) benzoic acid (294 mg, 0.771 mmol), tert-butyl alcohol (1.0 ml, 10 mmol), 4- (N, N-dimethylamino) pyridine (30 mg, 0.25 mmol), and 1- The title compound (132 mg, yield 39%) as a colorless oil was obtained from ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (200 mg, 1.04 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.06 (1H, br.s), 7.75 (1H, d, J = 8.6 Hz), 7.67 (1H, dd, J = 8.6, 1.6 Hz), 6.98 (2H , d, J = 8.9 Hz), 6.80 (2H, d, J = 8.9 Hz), 6.26 (1H, q, J = 6.3 Hz), 3.16 (3H, s), 1.80 (3H, s), 1.65 (9H , s), 1.63 (3H, d, J = 6.3 Hz).

Example 73 tert-Butyl 2-[({4- [Acetyl (methyl) amino] benzyl} oxy) methyl] -5- (trifluoromethyl) benzoate (Exemplified compound number: 2-4)
(73-1) Methyl 4- [acetyl (methyl) amino synthesized according to the method described in the literature (Jingjun, Y. et al., Org. Lett., 2000, Vol. 2, p. 1101-1104) Lithium borohydride (2.50 g, 115 mmol) was added to a tetrahydrofuran-methanol (5: 1, 240 ml) mixed solution of benzoate (11.6 g, 56.0 mmol) under ice cooling, And stirred for 2 hours. The reaction solution was cooled to 0 ° C., slowly poured into 0.5N hydrochloric acid, and extracted with ethyl acetate (three times). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 1-2 / 3) and purified as N- [4- (Hydroxymethyl) phenyl] -N-methylacetamide (2.76 g, yield 28%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.40 (2H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.2 Hz), 4.72 (2H, d, J = 5.5 Hz), 3.25 ( 3H, s), 1.90 (1H, m), 1.86 (3H, s).
(73-2) To a solution of N- [4- (hydroxymethyl) phenyl] -N-methylacetamide (81 mg, 0.45 mmol) obtained in Example (73-1) in tetrahydrofuran (5 ml) was added sodium hydride ( 55% oily, 27 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, tert-butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate obtained in Example (7-2) ( 230 mg, 0.68 mmol) was added, and the mixture was heated to reflux for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound (141 mg, yield) as a yellow oil. 71%) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.13 (1H, s), 7.90 (1H, d, J = 8.3 Hz), 7.76 (1H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz), 5.03 (2H, s), 4.69 (2H, s), 3.27 (3H, s), 1.88 (3H, s), 1.59 (9H, s )
MS (FAB) (m / z): 438 ([M + H] ⁺ ).

Example 74 tert-Butyl 6-({4-[(Cyclopropylacetyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. 1-112) )
In the same manner as in Example 66, tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] obtained in Example (62-1) was obtained. Methyl} -3- (trifluoromethyl) benzoate (486 mg, 0.950 mmol) and cyclopropylacetic acid (142 mg, 1.42 mmol) gave the title compound (299 mg, 66% yield) as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.19 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.23 (1H, d, J = 8.2 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.91 (2H, d, J = 8.8 Hz), 5.32 (2H, s), 3.24 (3H, s), 1.99 (2H, d, J = 7.0 Hz), 1.63 (9H, s), 1.06-0.95 (1H, m), 0.51-0.41 (2H, m), 0.00--0.05 (2H, m).
MS (FAB) (m / z): 480 ([M + H] ⁺ ).

Example 75 tert-Butyl 2-hydroxy-6-({4- [methyl (2-thienylacetyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplified Compound No: 1-213)
In the same manner as in Example 66, tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] obtained in Example (62-1) was obtained. Methyl} -3- (trifluoromethyl) benzoate (70.7 mg, 0.158 mmol) and 2-thienylacetic acid (29.3 mg, 0.207 mmol) gave the title compound as a colorless oil (44.6 mg, yield) 62%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.72 (1H, d, J = 7.8 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.15 (1H, d, J = 5.1 Hz), 7.12 ( 2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 6.88 (1H, app.dd, J = 5.1, 3.5 Hz), 6.73-6.70 (1H, m), 5.36 (2H , s), 3.63 (2H, s), 3.26 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z): 522 ([M + H] ⁺ ).

Example 76 tert-Butyl 2-hydroxy-6-[(4- {methyl [(1-methyl-1H-pyrrol-2-yl) carbonyl] amino} phenoxy) methyl] -3- (trifluoromethyl) Benzoate (Exemplary compound number: 1-214)
In the same manner as in Example 66, tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) phenoxy] obtained in Example (62-1) was obtained. Methyl} -3- (trifluoromethyl) benzoate (70.4 mg, 0.138 mmol) and 1-methyl-1H-pyrrole-2-carboxylic acid (26 mg, 0.21 mmol) gave the title compound as a colorless oil ( 32.4 mg, 47% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.70 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.10 (2H, d, J = 8.8 Hz), 6.88 ( 2H, d, J = 8.8 Hz), 6.59-6.57 (1H, m), 5.78 (1H, dd, J = 3.9, 2.7 Hz), 5.52 (1H, dd, J = 3.9, 1.6 Hz), 5.31 (2H , s), 3.90 (3H, s), 3.40 (3H, s), 1.62 (9H, s).
MS (FAB) (m / z): 505 ([M + H] ⁺ ).

Example 77 tert-Butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -2-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. : 2-46)
(77-1) In the same manner as in Examples (15-4) and (46-1), from 2-fluoro-4-nitrophenol (2.63 g, 16.8 mmol), N- (3-fluoro -4-Hydroxyphenyl) cyclopropanecarboxamide (1.36 g, 34% yield) was obtained. However, in the same process as Example (46-1), cyclopropanecarbonyl chloride was used as an acylating reagent instead of allyl chloroformate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.60-7.56 (1H, m), 6.97-6.88 (2H, m), 5.06 (1H, s), 1.49-1.40 (1H, m), 1.11-1.04 ( 2H, m), 0.88-0.81 (2H, m).
(77-2) N- (3-fluoro-4-hydroxyphenyl) cyclopropane obtained in Example (77-1) in the same manner as in Examples (82-1) and (82-2) Carboxamide (1.36 g, 6.97 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol obtained in Example (45-4) (1.80 g, 5.81 mmol) from tert-butyl 2- (allyloxy) -6-({4-[(cyclopropylcarbonyl) amino] -2-fluorophenoxy} methyl) -3- (trifluoromethyl) Benzoate (1.37 g, 47% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.62 (1H, d, J = 8.3 Hz), 7.50 (1H, app.d, J = 12.7 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.06-7.01 (1H, m), 6.90-6.83 (1H, m), 6.10-6.00 (1H, m), 5.45-5.38 (1H, m), 5.30-5.24 (1H, m), 5.15 (2H, br s), 4.57-4.53 (2H, m), 1.57 (9H, s), 1.28-1.23 (1H, m), 1.09-1.03 (2H, m), 0.86-0.80 (2H, m).
(77-3) tert-Butyl 2- (allyloxy) -6-({4) obtained in Example (77-2) in the same manner as in Examples (41-4) and (47-1) -[(Cyclopropylcarbonyl) amino] -2-fluorophenoxy} methyl) -3- (trifluoromethyl) benzoate (1.29 g, 2.53 mmol) to the title compound as a colorless powder (851 mg, 69% yield) Got.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.73 (1H, d, J = 8.2 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.10 (1H, dd, J = 11.3, 2.4 Hz), 7.03-6.98 (1H, m), 6.94-6.88 (1H, m), 5.44 (2H, s), 3.26 (3H, s), 1.66 (9H, s), 1.43-1.34 ( 1H, m), 1.06-0.98 (2H, m), 0.68-0.61 (2H, m).
MS (FAB) (m / z): 484 ([M + H] ⁺ ).

Example 78 tert-Butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. : 2-47)
(78-1) In the same manner as in Examples (15-4) and (46-1), from 3-fluoro-4-nitrophenol (2.58 g, 16.4 mmol), N- (2-fluoro -4-Hydroxyphenyl) cyclopropanecarboxamide (1.40 g, 34% yield) was obtained. However, in the same process as Example (46-1), cyclopropanecarbonyl chloride was used as an acylating reagent instead of allyl chloroformate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.04-7.91 (1H, m), 7.41-7.18 (1H, m), 6.69-6.49 (1H, m), 5.20 (1H, s), 1.63-1.47 ( 1H, m), 1.12-1.00 (2H, m), 0.93-0.76 (2H, m).
(78-2) N- (2-Fluoro-4-hydroxyphenyl) cyclo obtained in Example (78-1) in the same manner as in Examples (82-1) and (82-2) Propanecarboxamide (1.40 g, 7.17 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] obtained in Example (45-4) From methanol (1.85 g, 5.98 mmol), tert-butyl 2- (allyloxy) -6-({4-[(cyclopropylcarbonyl) amino] -3-fluorophenoxy} methyl) -3- (trifluoromethyl ) Benzoate (899 mg, 30% yield) was obtained.
¹ H-NMR (500MHz, CDCl ₃ ): δ 8.20-8.10 (1H, m), 7.63 (1H, d, J = 8.1 Hz), 7.33 (1H, d, J = 8.1 Hz), 6.77-6.61 (2H , m), 6.14-5.98 (1H, m), 5.52-5.36 (1H, m), 5.34-5.21 (1H, m), 5.08 (2H, br.s), 4.63-4.51 (2H, m), 1.56 (9H, s), 1.43-1.36 (1H, m), 1.15-1.03 (2H, m), 0.92-0.80 (2H, m).
(78-3) tert-Butyl 2- (allyloxy) -6-({obtained in Example (78-2) in the same manner as in Examples (41-4) and (47-1) 4-[(Cyclopropylcarbonyl) amino] -3-fluorophenoxy} methyl) -3- (trifluoromethyl) benzoate (716 mg, 1.41 mmol) to give the title compound as a yellow gum (271 mg, 40% yield). Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.70 (1H, d, J = 8.2 Hz), 7.29-7.17 (1H, m), 7.22 (1H, d, J = 8.2 Hz ), 6.80-6.70 (2H, m), 5.33 (2H, s), 3.20 (3H, s), 1.64 (9H, s), 1.35-1.27 (1H, m), 1.12-1.06 (2H, m), 0.90-0.82 (2H, m).
MS (FAB) (m / z): 484 ([M + H] ⁺ ).

Example 79 tert-Butyl 6-({4-[(cyclopropylcarbonothioyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. 1 -215)
Tert-Butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (105 mg) obtained in Example (56-3) , 0.226 mmol) in tetrahydrofuran (4 ml) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide (Lawesson reagent) (137 mg, 0.339 mmol) was added and the mixture was heated to reflux for 5 hours. The residue obtained by concentrating the reaction solution was purified by preparative thin layer silica gel chromatography (developing solvent: n-hexane / ethyl acetate = 3/1) to give the title compound as a colorless powder (65 mg, yield 60%). )
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 5.36 (2H, s), 3.73 (3H, s), 1.75-1.66 (1H, m), 1.64 (9H, s), 1.32-1.27 (2H, m), 0.78-0.72 (2H, m).
MS (FAB) (m / z): 482 ([M + H] ⁺ ).

Example 80 tert-Butyl 6-({3-amino-4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. : 2-61)
(80-1) In the same manner as in Examples (46-1), (82-1), (41-4), (82-2), and (47-1), 4-amino-3-nitro Phenol (2.22 g, 14.4 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (Example (45-4)) 3.31 g, 10.7 mmol) from tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3-nitrophenoxy} methyl) -3- (trifluoromethyl) benzoate (528 mg, Yield 10%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.28 (1H, s), 7.75 (1H, d, J = 8.6 Hz), 7.60 (1H, d, J = 3.1 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.33-7.23 (2H, m), 5.44 (2H, s), 3.26 (3H, s), 1.69 (9H, s), 1.15-1.18 (1H, m), 1.07-0.86 (2H, m), 0.65-0.57 (2H, m).
(80-2) In the same manner as in Example (18), tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3-nitro obtained in Example (80-1) The title compound (358 mg, 72% yield) was obtained as a colorless powder from phenoxy} methyl) -3- (trifluoromethyl) benzoate (528 mg, 1.04 mmol).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 8.3 Hz), 7.01 (1H, d, J = 8.3 Hz), 6.35 (1H, d, J = 2.5 Hz), 6.32 (1H, dd, J = 8.3, 2.5 Hz), 5.31 (2H, s), 3.18 (3H, s), 1.65 (9H, s ), 1.47-1.38 (1H, m), 1.04-0.90 (2H, m), 0.65-0.57 (2H, m).
MS (FAB) (m / z): 481 ([M + H] ⁺ ).

Example 81 tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3- (dimethylamino) phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate ( Exemplified compound number: 2-62)
Tert-butyl 6-({3-amino-4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl obtained in Example (80-2) in the same manner as in Example (11-2) ) -2-Hydroxy-3- (trifluoromethyl) benzoate (60 mg, 0.13 mmol) gave the title compound (45 mg, 71% yield) as a colorless powdery oil.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.03 (1H, d, J = 8.2 Hz), 6.57 (1H, d, J = 2.2 Hz), 6.41 (1H, dd, J = 8.2, 2.2 Hz), 5.31 (2H, s), 3.17 (3H, s), 2.78 (6H, s ), 1.65 (9H, s), 1.59-1.47 (1H, m), 1.03-0.96 (2H, m), 0.67-0.55 (2H, m).
MS ESI (ES-) (m / z): 507 ([MH] ⁺ ).

Example 82 tert-Butyl 6-({4-[(dimethylamino) carbonyl] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplified compound number: 1-125)
(82-1) Allyl 4-hydroxybenzoate (4) synthesized according to the method described in the literature (Stephen, C. et al., J. Med. Chem., 2002, Vol. 45, p.1348-1362) .04 g, 22.7 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (6.38 g) obtained in Example (45-4). , 20.6 mmol) in tetrahydrofuran solution (350 ml), 1,1 ′-(azodicarbonyl) dipiperidine (6.24 g, 24.7 mmol) and tri-n-butylphosphine (5.00 g, 24.7 mmol). ) And stirred at room temperature for 5 hours. The reaction solution was poured into a 0.1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7 / 1-3 / 1) to give allyl 4-{[ 2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} benzoate (6.24 g, 73% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.99 (2H, d, J = 9.0 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.49 (1H, d, J = 8.2 Hz), 7.00 ( 2H, d, J = 9.0 Hz), 6.08-5.96 (1H, m), 5.76 (1H, s), 5.55 (2H, s), 5.39 (1H, d, J = 17.2 Hz), 5.26 (1H, d , J = 10.2 Hz), 5.04 (2H, s), 4.79 (2H, d, J = 5.5 Hz), 3.66 (3H, s), 3.48 (6H, s).
MS (FAB) (m / z): 469 ([MH] ⁺ ).
(82-2) Allyl 4-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} benzoate obtained in Example (82-1) (7. P-Toluenesulfonic acid monohydrate (3.72 g, 19.6 mmol) was added to an acetone solution (40 ml) of 09 g, 15.1 mmol) and stirred at room temperature for 24 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was added to an N, N-dimethylformamide solution (20 ml), allyl bromide (1.56 ml, 18.1 mmol) and potassium carbonate (2.5 g, 18 mmol). And stirred at 50 ° C. for 6 hours. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. 2-Methyl-2-butene (21 ml) was added to a mixed solution of the residue 1,4-dioxane (21 ml) and tert-butanol (70 ml) obtained by evaporating the solvent under reduced pressure. . An aqueous solution (48 ml) of sodium chlorite (6.80 g, 75.5 mmol) and sodium dihydrogen phosphate monohydrate (6.80 g, 49.6 mmol) was added dropwise to the reaction solution at room temperature. Stir for hours. A 10% aqueous sodium thiosulfate solution was poured into the reaction solution and the mixture was stirred, acidified with 1N hydrochloric acid, and further extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. N, N-dimethylformamide ditert-butyl acetal (14.5 ml, 60.4 mmol) was added to a toluene solution (100 ml) of the residue obtained by evaporating the solvent under reduced pressure, and the mixture was heated at 110 ° C. for 6 hours. Stir. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-7 / 3), and tert-butyl 2- ( Allyloxy) -6-({4-[(allyloxy) carbonyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (4.17 g, 56% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.03 (2H, d, J = 8.8 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.36 (1H, d, J = 8.1 Hz), 6.96 ( 2H, d, J = 8.8 Hz), 6.12-5.95 (2H, m), 5.45-5.38 (2H, m), 5.30-5.26 (2H, m), 5.17 (2H, s), 4.80 (2H, app. dt, J = 5.4, 1.5 Hz), 4.57 (2H, app.dt, J = 5.4, 1.5 Hz), 1.56 (9H, s).
(82-3) tert-Butyl 2- (allyloxy) -6-({4-[(allyloxy) carbonyl] phenoxy obtained in Example (82-2) in the same manner as in Example (47-1) } Methyl) -3- (trifluoromethyl) benzoate (4.17 g, 8.48 mmol) to 4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy } Benzoic acid (3.08 g, yield 88%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, s), 8.07 (1H, d, J = 9.0 Hz), 7.76-7.64 (2H, m), 7.46-7.34 (2H, m), 6.98 (1H, d, J = 9.0 Hz), 5.40 (2H, s), 1.64 (9H, s).
(82-4) In the same manner as in Example 54, 4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] obtained in Example (82-3) From oxy} benzoic acid (100 mg, 0.243 mmol), the title compound (68 mg, yield 64%) was obtained as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.23 (1H, d, J = 8.2 Hz), 6.93 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 3.06 (6H, br.s), 1.63 (9H, s).
MS ESI (ES-) (m / z): 438 ([MH] ⁺ ).

Example 83 tert-butyl 2-hydroxy-6-({4-[(methylamino) carbonyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplified Compound No .: 1-216)
In the same manner as in Example 54, 4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} benzoic acid obtained in Example (82-3) ( 100 mg, 0.243 mmol) and methylamine 2.0M tetrahydrofuran solution (0.364 ml, 0.728 mmol) gave the title compound (38 mg, 37% yield) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.24 (1H, s), 7.76 (2H, d, J = 8.8 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 6.94 (2H, d, J = 8.8 Hz), 6.23-6.11 (1H, m), 5.36 (2H, s), 3.00 (3H, d, J = 4.7 Hz), 1.62 (9H, s ).
MS ESI (ES-) (m / z): 424 ([MH] ⁺ ).

Example 84 tert-Butyl 2-hydroxy-6-{[4- (1-pyrrolidinylcarbonyl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (Exemplified compound number: 1-217)
In the same manner as in Example 54, 4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} benzoic acid obtained in Example (82-3) ( From 100 mg, 0.243 mmol) and pyrrolidine (63 μl, 0.75 mmol), the colorless amorphous title compound (20 mg, 18% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.67 (1H, d, J = 8.0 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 5.34 (2H, s), 3.63 (2H, t, J = 6.9 Hz), 3.47 (2H, t, J = 6.5 Hz), 1.99- 1.84 (4H, m), 1.62 (9H, s).
MS ESI (ES-) (m / z): 464 ([MH] ⁺ ).

(Example 85) tert-butyl 3-tert-butyl-6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxybenzoate (Exemplified compound number: 1-89)
To a solution of (85-1) 3-tert-butyl-2-hydroxybenzaldehyde (28.8 g, 162 mmol) in methanol (20 ml), trimethyl orthoformate (100 ml, 972 mmol) and camphorsulfonic acid (751 mg, 3.24 mmol) ) And then stirred at 50 ° C. for 6 hours. The reaction mixture was poured into 1% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (3 times). The organic layer was washed with water (2 times) and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer was dissolved in N, N-dimethylformamide (100 ml), and sodium hydride (7.77 g, 162 mmol) and chloromethyl methyl ether (13.5 ml) were cooled with ice. 178 mmol) and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was washed with 0.5N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. . The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 14 / 1-10 / 1) to give 1-tert-butyl-3. -(Dimethoxymethyl) -2- (methoxymethoxy) benzene (10.4 g, yield 24%) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.44 (1H, dd, J = 7.6, 1.6 Hz), 7.33 (1H, dd, J = 7.8, 1.6 Hz), 7.08 (1H, app.t, J = 7.7 Hz), 5.64 (1H, s), 5.06 (2H, s), 3.66 (3H, s), 3.38 (6H, s), 1.41 (9H, s).
(85-2) In the same manner as in Examples (45-3) and (45-4), 1-tert-butyl-3- (dimethoxymethyl) -2- (methoxymethoxy) benzene (4.00 g, 14.9 mmol), [4-tert-butyl-2- (dimethoxymethyl) -3- (methoxymethoxy) phenyl] methanol (350 mg, yield 8%) was obtained. However, in the same step as Example (45-3), sec-butyllithium was used as a base instead of n-butyllithium.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.27 (1H, d, J = 7.8 Hz), 7.06 (1H, d, J = 7.8 Hz), 5.74 (1H, s), 4.95 (2H, s), 4.75 (2H, d, J = 6.8 Hz), 3.64 (3H, s), 3.52 (1H, t, J = 6.8 Hz), 3.46 (6H, s), 1.39 (9H, s).
(85-3) 4-Methylaminophenol sulfate (16.5 g, 95.7 mmol) and a solution of triethylamine (66.5 ml, 479 mmol) in methylene chloride (192 ml) under ice cooling with cyclopropanecarbonyl chloride ( 25.0 g, 239 mmol) was added dropwise. N, N-dimethylaminopyridine (585 mg, 4.79 mmol) was added to the reaction solution, and the mixture was returned to room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, and insoluble material was filtered off using celite. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol (96 ml), potassium carbonate (26.5 g, 191 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Insoluble material was filtered off using Celite, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and poured into 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated powder was collected by filtration to obtain N- (4-hydroxyphenyl) -N-methylcyclopropanecarboxamide (16.6 g, yield 90%) as a brown powder. .
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.12 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.29 (1H, s), 3.25 (3H, s), 1.43-1.37 (1H, m), 1.02-0.99 (2H, m), 0.64-0.60 (2H, m).
(85-4) [4-tert-Butyl-2] obtained in Example (85-2) in the same manner as in Examples (82-1), (82-2), and (47-1). -(Dimethoxymethyl) -3- (methoxymethoxy) phenyl] methanol (161 mg, 0.540 mmol) and N- (4-hydroxyphenyl) -N-methylcyclopropane obtained in Example (85-3) The title compound (85.7 mg, 35% yield) was obtained as a colorless oil from carboxamide (113 mg, 0.594 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.08 (1H, s), 7.40 (1H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.02 (1H, d, J = 8.2 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.28 (2H, s), 3.26 (3H, s), 1.59 (9H, s), 1.42 (9H, s), 1.42-1.35 (1H , m), 1.04-0.96 (2H, m), 0.67-0.56 (2H, m).
MS ESI (ES-) (m / z): 452 ([MH] ⁺ ).

Example 86 tert-Butyl 6-({4- [Ethyl (methylsulfonyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplified Compound No: 1-218)
(86-1) In the same manner as in Example (47-2), the literature (Northrop, Jr, RC, et al., J. Org. Chem., 1977, Vol. 42, p. 4148-4150) From N- [4- (benzyloxy) phenyl] -N-ethylamine (4.91 g, 21.6 mmol) and methanesulfonyl chloride (2.18 ml, 28.2 mmol) synthesized according to the described method, a white powder N- [4- (benzyloxy) phenyl] -N-ethylmethanesulfonamide (5,83 g, yield 88%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.46-7.31 (5H, m), 7.25 (2H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz), 5.06 (2H, s ), 3.68 (2H, q, J = 7.0 Hz), 2.87 (3H, s), 1.13 (3H, t, J = 7.0 Hz).
(86-2) In the same manner as in Example (15-4), N- [4- (benzyloxy) phenyl] -N-ethylmethanesulfonamide (5.83 g) obtained in Example (86-1) was obtained. , 19.1 mmol) gave colorless crystals of N-ethyl-N- (4-hydroxyphenyl) methanesulfonamide (3.83 g, yield 93%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.16 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6 Hz), 3.66 (2H, q, J = 7.0 Hz), 2.88 ( 3H, s), 1.13 (3H, t, J = 7.0 Hz).
(86-3) N-ethyl-N- (4) obtained in Example (86-2) in the same manner as in Examples (82-1), (82-2), and (47-1). -Hydroxyphenyl) methanesulfonamide (621 mg, 2.89 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (45-4) Phenyl] methanol (813 mg, 2.62 mmol) gave the title compound (225 mg, 16% yield) as colorless crystals.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.30-7.23 (3H, m), 6.94 (2H, d, J = 8.6 Hz ), 5.34 (2H, s), 3.69 (2H, q, J = 7.0 Hz), 2.88 (3H, s), 1.65 (9H, s), 1.14 (3H, t, J = 7.0 Hz).
MS ESI (ES-) (m / z): 488 ([MH] ⁺ ).

Example 87 tert-Butyl 6-[(4-{[ethyl (methyl) amino] carbonyl} phenoxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplified Compound No: 1-219)
In the same manner as in Example 33, 4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} benzoic acid obtained in Example (82-3) ( 100 mg, 0.243 mmol) and N-ethylmethylamine (84 μl, 0.97 mmol) gave the colorless amorphous title compound (14 mg, 13% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.21 (1H, s), 7.67 (1H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 8.2 Hz), 6.90 (2H, d, J = 8.8 Hz), 5.34 (2H, s), 3.64-2.88 (5H, m), 1.63 (9H, s), 1.27-1.11 (3H, m).
MS ESI (AP-) (m / z): 452 ([MH] ⁺ ).

Example 88 tert-Butyl 6-({3-chloro-4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. : 2-63)
(88-1) In the same manner as in Example (46-1), from 4-amino-3-chlorophenol hydrochloride (2.48 g, 13.8 mmol) to N- (2-chloro-4-hydroxyphenyl) Cyclopropanecarboxamide (2.15 g, 89% yield) was obtained. However, in this step, cyclopropanecarbonyl chloride was used as an acylating reagent instead of allyl chloroformate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.94-7.75 (1H, m), 6.90-6.80 (1H, m), 6.73-6.62 (1H, m), 1.65-1.54 (1H, m), 1.15- 1.03 (2H, m), 0.94-0.80 (2H, m).

(88-2) N-- obtained in Example (88-1) in the same manner as in Examples (82-1), (82-2), (41-4), and (47-1) (2-Chloro-4-hydroxyphenyl) cyclopropanecarboxamide (2.69 g, 15.2 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) obtained in Example (45-4) ) -4- (Trifluoromethyl) phenyl] methanol (3.62 g, 11.7 mmol) gave the title compound (1.06 g, 14% yield) as a yellow amorphous.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.21 (1H, s), 7.70 (1H, d, J = 8.0 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 2.8 Hz), 6.86 (1H, dd, J = 8.6, 2.8 Hz), 5.33 (2H, s), 3.19 (3H, s), 1.66 (9H, s ), 1.22-1.15 (1H, m), 1.09-0.90 (2H, m), 0.69-0.51 (2H, m).
MS ESI (ES-) (m / z): 498 ([MH] ⁺ ).

Example 89 tert-Butyl 6-({4-[(cyclopropylsulfonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound No. 1-220) )
In the same manner as in Example (62-2), tert-butyl 2-{[tert-butyl (dimethyl) silyl] oxy} -6-{[4- (methylamino) obtained in Example (62-1) ) Phenoxy] methyl} -3- (trifluoromethyl) benzoate (98 mg, 0.192 mmol) and cyclopropanesulfonyl chloride (26 mg, 0.21 mmol) to give the title compound as a colorless oil (35 mg, 36% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.68 (1H, d, J = 8.2 Hz), 7.33 (2H, d, J = 9.0 Hz), 7.22 (1H, d, J = 8.2 Hz), 6.88 ( 2H, d, J = 9.0 Hz), 5.32 (2H, s), 3.31 (3H, s), 2.41-2.30 (1H, m), 1.63 (9H, s), 1.12-1.03 (2H, m), 0.98 -0.87 (2H, m).
MS ESI (ES-) (m / z): 501 ([M] ⁺ ).

(Test Example 1) Co-transfection assay
The activation or inhibition of the transcriptional activity of LXR by a test compound can be measured by a cotransfection assay, which is a cell-based assay. LXR has been shown to function by forming a heterodimer with RXR. In the cotransfection assay, LXR and RXR expression plasmids and a luciferase reporter expression plasmid containing 3 copies of the LXR-RXR heterodimer responsive DNA sequence are first introduced into mammalian cells by transient transfection. Next, when this transfected cell is treated with a test compound having LXR agonist activity, the transcriptional activation effect of LXR is enhanced, and the LXR agonist activity of the test compound can be measured as an increase in luciferase activity. Similarly, the LXR antagonist activity of a test compound can be measured by determining the strength with which the test compound competitively inhibits transcriptional activation by an LXR agonist.
[1] Substances used (1) CV-1 African green monkey kidney cells (ATCC CCL-70)
(2) Cotransfection expression plasmid, pCDNA-hLXRα or pCDNA-hLXRβ, reporter (LXREx3-pTAL-Luc Vector)
(3) Lipofect AMINE, Plus Reagent (INVITROGEN) transfection reagent (4) Cell lysis buffer [Paasive Lysis Buffer, 5 × (PROMEGA CORPORATION) diluted with DW]
(5) Luciferase Assay Reagent (PROMEGA CORPORATION)
(6) Medium [Dulbecco's Modified Eagle Medium (GIBCO) 500ml, Gentamicin Reagent Solution (GIBCO) 2.5ml, 2mM L-Gluta Max I Suprement (GIBCO) 5.0ml, MEM Sodium Pyruvate Solution (GIBCO) 5.0ml, Penicillin-Streptomycin ( GIBCO) 5.0ml, Charcoal / Dextran Treated FBS (HyClone) 50ml]
(7) OPTI-MEM I Reduced-Serum Medium (GIBCO)
[2] Preparation of screening reagent The CV-1 cells were seeded in a 96 well assay plate (Costar 3610) at 2 × 10 ⁴ cells / 100 μM / well and incubated overnight at 37 ° C.

DNA transfection was performed as follows according to the instructions attached to the transfection reagent. 10 μl of OPTI-MEM I Reduced-Serum Medium (GIBCO) and 0.5 μl of Lipofect AMINE (INVITROGEN) were added to two 50 ml tubes, and the mixed solution was stirred to obtain a solution A. The substance (1) below was added to each tube, and the mixed solution was stirred and allowed to stand for 15 minutes to obtain a solution B. Moreover, the solution C was obtained by performing the same operation using the substance of the following (2);
(1) 10 μl OPTI-MEM I Reduced-Serum Medium, 1 μl Plus Reagent (INVITROGEN), and 0.1 μg DNA [PCMX-LXRα (33 ng) and LXRE (66 ng)];
(2) 10 μl of OPTI-MEM I Reduced-Serum Medium, 1 μl of Plus Reagent (INVITROGEN), and 0.1 μg of DNA [PCMX-LXRβ (33 ng) and LXRE (66 ng)].
The total amount of the above solution A was added to each of the above solutions B, and the mixture was stirred and allowed to stand for 15 minutes to obtain an LXRα solution. The same operation was performed using the above solution C and solution A to obtain an LXRβ solution.

  The medium was removed from the 96-well assay plate in which CV-1 cells were incubated as described above by decantation to remove water well, and 50 μl / well of OPTI-MEM I Reduced-Serum Medium was added to each well. Furthermore, 20 μl / well of the above LXRα solution or LXRβ solution was added to each well and incubated at 37 ° C. for 3 hours.

Three hours later, 70 μl / well of 20% Charcoal FBS-DMEM was added to each well. The medium FBS-DMEM was prepared by mixing Charcoal and Dextran Treated FBS in a ratio of 9: 1. Next, 1.4 μl / well of a test compound adjusted with DMSO to a concentration of 1 mM, 0.3 mM, 0.1 mM, 30 μM, 10 μM, 3 μM, 1 μM, or 0 μM was added to each well. At this time, the concentration of the test compound in the actual well is 1/100 of the above. CV-1 cells in each well prepared as described above were incubated overnight at 37 ° C.
[3] Measurement procedure After the incubation, CV-1 cells were microscopically examined. After removing the culture medium by decantation and removing water well, a white seal was applied to the bottom of each well. Passive Lysys Buffer (5 ×) (PROMEGA CORPORATION) diluted 5-fold with distilled water was added to each well at 20 μl / well, and CV-1 cells were lysed using a plate shaker for 15 minutes. 100 μl / well Luciferase Assay Reagent (PROMEGA CORPORATION) was added to each well, and luciferase activity was measured using Wallac ARVO HTS 1429 Multilabel Counter (registered trademark; Perkin Elmer) or Analyst HT (registered trademark; Bio Systems).

The LXR / LXRE cotransfection assay can determine the EC ₅₀ value, which indicates the strength of action of the test compound, and the Efficacy, which indicates the% activation ability of the test compound. Efficacy is expressed as a relative ability to activate relative to a control compound having LXR agonist activity or a control not having LXR agonist activity (DMSO / solvent). In this assay, as a control compound having LXR agonist activity, N- (2,2,2-trifluoroethyl) -N- {4- [2,2,2-trifluoro-1-hydroxy-1- (tri Fluoromethyl) ethyl] phenyl} benzenesulfonamide (Compound 12 described on page 55 of International Publication WO2000 / 054759; hereinafter referred to as Compound D) was used.

A concentration-response curve was prepared from the measured values at a concentration of a dilution series of a total of 8 points in (1/2) LOG units. The measured value at each concentration was calculated as an average value of 4 well values in a 96 well plate for each concentration. The data for this assay can be fitted to the following equation to calculate EC ₅₀ values:
Y = Bottom + (Top-Bottom) / (1 + 10 ^Z )
Z = (logEC ₅₀ −X) * HillSlope
EC ₅₀ values are defined as the concentration at which the test compound gives an intermediate value between the maximum response (Top) and baseline (Bottom) [“Fitting to Sigmoidal dose-response (variable slope)” (Graph Pad PRISM version See 3.02). The relative efficacy or% control value for the LXR agonist as the control compound was determined by comparison with the maximum response value shown by Compound D used as the control compound.

When tested in this assay, the compounds of Examples 1, 2, 5 to 10, 12 to 19, 21, 23 to 32, 34 to 71, and 74 to 89 have EC ₅₀ values of 3 μM or less for LXRα. showed that. In addition, the compounds of Examples 1, 3, 6, 7, 12 to 23, 26, 28, 31, 32, 35 to 40, 42 to 68, 70, 71, and 74 to 89 were 3 μM against LXRβ. The following EC ₅₀ values were shown. As described above, the compound of the present invention has an excellent binding activity to LXRα and LXRβ, and arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, hypercholesterolemia It is useful as a medicament for the treatment or prevention of lipid-related diseases, inflammatory diseases caused by inflammatory cytokines, or diabetes.

(Test Example 2) Anti-inflammatory action The animals and reagents used in this test example are as follows, except as noted.

  CD1 mice (6 to 10 weeks old, male and female) are purchased from Charles River, Japan, raised under the control of temperature and humidity, and optionally fed with food and drinking water. One group of 5 animals is used for experiments after 5 days of acclimatization.

  Phorbol 12-myristate-13-acetate (TPA) causes irritating contact dermatitis. Apply 10 μl of 0.03% (w / v) TPA / acetone solution to each of the inner and outer surfaces of the left ear of the test mouse (total 20 μl). Apply only acetone to the right ear. 45 minutes and 4 hours after TPA application, 20 μl of test compound (10 mM acetone solution) is applied to both ears. The control group animals are treated with only acetone used as a solvent.

  For allergic contact dermatitis, 20% of a 15% (w / v) 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) / acetone solution once a day on the shaved back of a CD1 female mouse Apply for 2 days to allow sensitization, and on the 7th day, apply 10 μl of 2% oxazolone / acetone solution on both sides of the left ear to induce. Apply only acetone to the right ear. 45 minutes and 4 hours after application of oxazolone to the ear, 20 μl of test compound (10 mM acetone solution) or acetone is applied as described above.

The degree of inflammation was determined by the percentage increase in ear thickness and / or ear weight between the left ear treated with the test compound and the right ear treated with the solvent 18 hours after the inflammation was induced by TPA or oxazolone. Measure and evaluate. Ear thickness is measured with a digital caliper, and tissue is collected using a 6 mm punch to measure changes in ear weight. The degree of inflammation is quantified according to the following formula:
Ear growth rate (%) = 100 x [(a)-(b) / (b)]
[Wherein (a) is the thickness or weight of the left ear treated with the test compound, and (b) is the thickness or weight of the control right ear].

The compounds of the present invention exhibit excellent anti-inflammatory effects when tested by this method and are useful as pharmaceuticals for inflammatory diseases.

Test Example 3 Hypoglycemic Action The hypoglycemic action of the compound of the present invention is measured as follows.

Blood is collected from the tail vein of KK mice (4 to 5 months old) purchased from CLEA Japan. After centrifugation, the plasma glucose concentration is measured with a glucose analyzer (Glucoloader-GXT, A & T). These diabetic mice are divided into groups (3 to 4 animals per group) and fed with powdered food (F-2, Funabashi Farm) containing 0.1 to 0.001% (w / w) test compound for 7 days. A group of mice administered with the test compound is defined as a test compound-administered group, and a group of mice administered with powdered food not containing the test compound is defined as a control group. Seven days later, blood is collected from the tail vein of each mouse and the plasma glucose concentration is measured. Plasma glucose reduction rate is calculated from the following formula:
Plasma glucose reduction rate (%) = (average plasma glucose concentration in control group−average plasma glucose concentration in test compound administration group) × 100 / plasma glucose concentration in control group.

  The compound of the present invention exhibits an excellent hypoglycemic action when tested by this method, and is useful as a pharmaceutical for diabetes.

(Formulation Example 1) Hard Capsule In a standard binary hard gelatin capsule, powdered compound of Example 1 (100 mg), lactose (150 mg), cellulose (50 mg) and magnesium stearate ( 6 mg) is filled to produce hard capsules, washed and dried.

Formulation Example 2 Soft Capsules A mixture of digestible oils such as soybean oil, olive oil and the compound of Example 2 is injected into gelatin so as to contain 100 mg of the active ingredient, Soft capsules are manufactured, washed and dried.

(Formulation Example 3) Tablets The compound of Example 3 (100 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (275 mg), starch (11 mg) and lactose ( 98.8 mg) is used to produce tablets according to conventional methods. The obtained tablets can be coated as necessary.

(Formulation Example 4) Suspension In 5 ml of the suspension, the compound of Example 4 (100 mg), sodium carboxymethylcellulose (100 mg), sodium benzoate (5 mg), sorbitol solution (Japan) A suspension is prepared to contain the pharmacopoeia, 1.0 g), and vanillin (0.025 ml).

(Formulation example 5) Cream white petrolatum (40% by weight), microcrystalline wax (3% by weight), lanolin (10% by weight), sorbitan monolaurate (5% by weight), 0.3% polyoxyethylene ( 20) A cream is prepared by mixing finely divided compound of Example 5 (100 mg) in 5 g of a cream consisting of sorbitan monolaurate (0.3 wt%) and water (41.7 wt%). .

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof has an excellent binding activity to LXR, and has absorption, biodistribution, blood half-life and the like. In that respect, it has excellent pharmacokinetic properties and low toxicity to the kidneys, liver, and other organs. Accordingly, the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is useful as a pharmaceutical for warm-blooded animals, preferably for humans. The compound represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof is, in particular, arteriosclerosis; atherosclerosis; arteriosclerosis caused by diabetes; hyperlipidemia; Lipid-related diseases; rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, inflammatory diseases that are caused by inflammatory cytokines, such as systemic lupus erythematosus, ulcerative colitis, Autoimmune diseases such as Crohn's disease; ischemic heart disease, cardiovascular disease such as heart failure; cerebrovascular disease; kidney disease; diabetes; diabetic complications such as retinopathy, nephropathy, neurosis, coronary artery disease Obesity; nephritis; hepatitis; cancer; or Alzheimer's disease; preferably arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, high Cholesterolemia, lipid-related diseases, inflammatory diseases that are caused by inflammatory cytokines, or diabetes; most preferably, it is useful as a medicament for the treatment or prevention of arteriosclerosis.

Claims (30)

Formula (I)

[Wherein R ¹ represents a formula —COR ⁹ , wherein R ⁹ represents a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, (C ₃ -C ₆ cycloalkyl)-(C _1- C ₄ alkyl) oxy group, halogeno C ₁ -C ₁₀ alkoxy group (the halogeno C ₁ -C ₁₀ alkoxy group represents a C ₁ -C ₁₀ alkoxy group substituted with 1 to 7 halogeno groups), phenyl - (C ₁ -C ₁₀ alkoxy) group, C ₃ -C ₆ cycloalkyl group, (C ₁ -C ₄ alkyl) - (C ₃ -C ₆ cycloalkyl) oxy groups, C ₁ -C ₁₀ alkyl amino group , Di (C ₁ -C ₁₀ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group consist of a nitrogen atom, an oxygen atom and a sulfur atom) 5- to 7-membered saturated heterocycles containing 1 to 3 atoms selected from the group May form a Le group), a phenyl group or a substituted phenyl group (said substituents may be the same or different, represents 1 to a 3 radicals) selected from the substituent group beta. A group having
C ₆ -C ₁₀ aryl group, substituted C ₆ -C ₁₀ aryl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α), 5 to 10-membered aromatic A heterocyclyl group or a substituted 5- to 10-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
R ² represents a hydrogen atom, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group represents a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups), hydroxyl group group, C ₁ -C ₄ alkoxy group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (wherein the alkyl groups are the same or different), or represents a halogeno group;
R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group (the halogeno C ₁ -C ₆ alkyl group is a C ₁ -C substituted with 1 to 7 halogeno groups) ₆ alkyl group), (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group, (C _1- C ₄ alkylthio)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylsulfinyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylsulfonyl)-(C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkylamino)-(C ₁ -C ₄ alkyl) group, [di (C ₁ -C ₄ alkyl) amino]-(C ₁ -C ₄ alkyl) group (the alkyl groups are the same or different), C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, hydroxyl group, C ₁ -C ₆ alkoxy group A halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), a phenyloxy group, C _1- C ₆ alkylthio group, a phenylthio group, C ₁ -C ₆ alkylsulfinyl group, phenylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, phenylsulfonyl group, an amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl groups, taken with together with the nitrogen atom of the amino group, selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed), (C ₁ -C ₆ alkoxy) carbonyl group, cyano group, nitro group, halogeno group , A phenyl group, or a 5- to 6-membered aromatic heterocyclyl group;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is 1 to 5 halogeno groups). showing a substituted C ₁ -C ₄ alkyl group), C ₃ -C ₆ cycloalkyl group, a hydroxyl group, C ₁ -C ₄ alkoxy groups, halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ An alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), or a halogeno group;
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ⁶ and R ⁷ may together form an ethylene group or a trimethylene group;
R ⁸ has the formula —N (R ¹⁰ ) ZR ¹¹ , —ZN (R ¹⁰ ) R ¹² , —ZR ¹² , —X ² N (R ¹⁰ ) ZR ¹¹ , —X ² ZN (R ¹⁰ ) R ¹² , or , -X ² ZR ¹²
[Wherein, R ¹⁰ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different, and 1 to 3 selected from the substituent group β) a group), (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₂ alkyl) group, C ₃ -C ₆ cycloalkyl group or a substituted C ₃ -C ₆ cycloalkyl group (the substituent, the Are the same or different and are 1 to 3 groups selected from the substituent group β),
R ¹¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a substituted C ₁ -C ₆ alkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group γ) , (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, substituted (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group (the substituents may be the same or different 1 to 3 groups selected from the substituent group γ), a phenyl- (C ₁ -C ₄ alkyl) group, a substituted phenyl- (C ₁ -C ₄ alkyl) group (substituent of the phenyl group) Are the same or different and are 1 to 3 groups selected from the substituent group β, and the substituents of the alkyl group are the same or different and are 1 to 3 groups selected from the substituent group γ present), (4-10 membered heterocyclyl) - (C ₁ -C ₄ alkyl) group, a substituted (4 to 10 membered heterocyclyl) - (C ₁ C ₄ alkyl) group (the substituent of the heterocyclyl group may be the same or different and are 1 to 3 groups selected from Substituent group beta, substituents of the alkyl groups may be the same or different, substituent group 1 to 3 groups selected from γ), a C ₃ -C ₆ cycloalkyl group, a substituted C ₃ -C ₆ cycloalkyl group (the substituents may be the same or different and selected from the substituent group γ). 1 to 3 groups), a C ₂ -C ₆ alkenyl group, a substituted C ₂ -C ₆ alkenyl group (the substituents are the same or different and are selected from 1 to 3 groups selected from the substituent group γ) A C ₁ -C ₆ alkoxy group, a substituted C ₁ -C ₆ alkoxy group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group γ), ( C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₃ -C ₆ A cycloalkyloxy group, a C ₃ -C ₆ alkenyloxy group, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed together with the nitrogen atom of the amino group. ), (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) amino group, C ₃ -C ₆ cycloalkylamino group, C ₃ -C ₆ alkenylamino group, N- (C ₁ -C ₆₎ Alkyl) -N-[(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, N- (C ₁ -C ₆ alkyl) -N- (C ₃ -C ₆ cycloalkyl) amino, N- (C ₁ -C ₆ alkyl) -N- (C ₃ -C ₆ alkenyl) amino group, off Nyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group β), 4 to 10 membered heterocyclyl group, or substituted (4 to 10 membered heterocyclyl) ) Groups (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), provided that the formulas —N (R ¹⁰ ) ZR ¹¹ and —X ² N (R ¹⁰ ) When Z is —SO ₂ — in ZR ¹¹ , R ¹¹ is not a hydrogen atom,
R ¹² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a substituted C ₁ -C ₆ alkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β) , (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, substituted (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group (the substituents may be the same or different 1 to 3 groups selected from substituent group β), phenyl- (C ₁ -C ₄ alkyl) group, substituted phenyl- (C ₁ -C ₄ alkyl) group (the substituents are the same) Or, it is 1 to 3 groups selected from the substituent group β), (5- to 7-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group, substituted (5- to 7-membered heterocyclyl)-(C ₁ -C ₄ alkyl) group (said substituents may be the same or different and are 1 to 3 groups selected from substituent group beta), C ₃ -C _{A 6} cycloalkyl group, a substituted C ₃ -C ₆ cycloalkyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a C ₂ -C ₆ alkenyl group, A substituted C ₂ -C ₆ alkenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a phenyl group, a substituted phenyl group (the substituents are the same or 5 to 7-membered heterocyclyl group or substituted (5- to 7-membered heterocyclyl) group (the substituents may be the same or different, Wherein R ¹² is not a hydrogen atom when Z is —SO ₂ — in the formulas —ZR ¹² and —X ² ZR ¹² ;
X ² represents a C ₁ -C ₂ alkylene group,
Z represents a group having the formula —CO—, —CS— or —SO ₂ —. A group having the formula:
X ¹ represents a single bond, a methylene group, or a substituted methylene group (the substituents are the same or different 1 to 2 C ₁ -C ₃ alkyl groups, and the two substituents are An ethylene group or a trimethylene group may be formed);
Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α), a 5- to 6-membered aromatic heterocyclyl group, or a substituted 5 group. To a 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
Substituent group α is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is a C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different), a formyl group, (C ₁ - A group consisting of a C ₄ alkyl) carbonyl group and a halogeno group;
Substituent group β is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), and show the group consisting of halogeno groups;
Substituent group γ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is C ₁ -C ₄ substituted with 1 to 5 halogeno groups). An alkyl group), a hydroxyl group, a C ₁ -C ₄ alkoxy group, a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group is C ₁ substituted with 1 to 5 halogeno groups) -C ₄ shows an alkoxy group), C ₁ -C ₄ alkylthio groups, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different), a carboxyl group, (C ₁ -C ₄ alkoxy) carbonyl group, a cyano group, and shows a group consisting of halogeno group. ]
Or a pharmacologically acceptable salt or ester thereof.
R ¹ is a formula —COR ^9a [wherein R ^9a is a C ₁ -C ₆ alkyl group, a C ₁ -C ₈ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) An oxy group, a halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₃ -C ₅ A cycloalkyloxy group, a (C ₁ -C ₂ alkyl)-(C ₃ -C ₅ cycloalkyl) oxy group, a C ₁ -C ₆ alkylamino group, or a di (C ₁ -C ₆ alkyl) amino group The alkyl group is the same or different, and the two alkyl groups together with the nitrogen atom of the amino group contain 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom A 5- to 7-membered saturated heterocyclyl group may be formed). A group having
Phenyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α1), 5 to 6-membered aromatic heterocyclyl group, or substituted 5 to 6-membered An aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α1);
Substituent group α1 is a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, an amino group, The compound or pharmacologically acceptable compound thereof according to claim 1, which represents a group consisting of a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a formyl group, an acetyl group, a fluoro group, a chloro group, and a bromo group. Salt or ester.
R ¹ represents a formula —COR ^9b [wherein R ^9b represents a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents 1 to 5 halogeno groups). A C ₁ -C ₄ alkoxy group substituted with a group). A group having
A phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α2);
The substituent group α2 represents a group consisting of a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a fluoro group, and a chloro group, or a compound according to claim 1 Pharmacologically acceptable salt or ester.
The compound according to claim 1, wherein R ¹ is a group having the formula -COR ^9c (wherein R ^9c represents a C ₂ -C ₆ alkoxy group), or a pharmacologically acceptable salt or ester thereof. .
R ¹ is a group having the formula -COR ^9d (wherein R ^9d represents a 2-methyl-2-propoxy group). The compound according to claim 1, or a pharmacologically acceptable salt thereof, ester.
6. R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group. Or a pharmacologically acceptable salt or ester thereof.
6. The compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt or ester thereof, wherein R ² is a hydrogen atom or a hydroxyl group.
The compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt or ester thereof, wherein R ² is a hydroxyl group.
R ³ is, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, one to five C ₁ -C ₄ alkyl group substituted with halogeno group shown), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group, C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, hydroxyl Group, C ₁ -C ₄ alkoxy group, halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups) ), C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino Groups (the alkyl groups are the same or different, Together with the nitrogen atom of the amino group to form a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom And a pharmacologically acceptable salt or ester thereof. 9. The compound according to any one of claims 1 to 8, which is a fluoro group, a chloro group, or a bromo group.
R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups) shown), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or, according to any of claims 1 to 8 chloro group A compound or a pharmacologically acceptable salt or ester thereof.
R ³ is methyl group, ethyl group, 2-propyl group, 1-butyl group, 2-methyl-2-propyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 8, which is a cyclopropyl group or a vinyl group.
12. R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group. Or a pharmacologically acceptable salt or ester thereof.
The compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt or ester thereof, wherein R ⁴ and R ⁵ are hydrogen atoms.
The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 13, wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group.
R ⁶ and R ⁷ are hydrogen atoms, The compound according to any one of claims 1 to 13, or a pharmacologically acceptable salt or ester thereof.
R ⁸ is represented by the formula -N (R ^10a ) ZR ^11a , -ZN (R ^10a ) R ^12a , -ZR ^12a , -X ² N (R ^10a ) ZR ^11a , -X ^2a ZN (R ^10a ) R ^12a , or , -X ^2a ZR ^12a
[Wherein, R ^10a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₃ alkyl group (the substituent is one group selected from the substituent group β1), ( C ₃ -C ₄ cycloalkyl) methyl group, C ₃ -C ₄ cycloalkyl group, or substituted C ₃ -C ₄ cycloalkyl group (the substituent is one group selected from substituent group β1) Is)
R ^11a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group γ1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different Or a phenyl- (C ₁ -C ₂ alkyl) group, a substituted phenyl- (C ₁ -C ₂ alkyl) group (substituent of the phenyl group). Are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different and are 1 to 2 groups selected from the substituent group γ1. A) (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, substituted (5- to 7-membered heterocyclyl)-( C ₁ -C ₂ alkyl) group (the substituents of the heterocyclyl group are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different, 1 or 2 groups selected from the substituent group γ1), a C ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (the substituents may be the same or different, and the substituent group γ1 A C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (the substituents are the same or different and are selected from the substituent group γ1). 2 groups), a C ₁ -C ₄ alkoxy group, a substituted C ₁ -C ₄ alkoxy group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ1) ), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) Oki Group, C ₃ -C ₄ alkenyloxy group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group is the amino group Together with the nitrogen atom, a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed), C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) amino group, C ₃ -C ₄ alkenyl group, a phenyl group or represents a 5 to 7-membered heterocyclyl group, provided that the formula -N (R ^10a) ZR ^11a and -X ^2a N (R ^10a) in ZR ^11a Z is -SO ₂ - when is, R ^11a is not hydrogen atom,
R ^12a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group β1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different A phenyl- (C ₁ -C ₂ alkyl) group, a (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, a C 1 -2 group selected from the substituent group β 1 ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (said substituents may be the same or different, from 1 to 2 groups selected from substituent group β1), C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (said substituents may be the same or different, 1乃selected from substituent group β1 A two group), a phenyl group or represents a 5 to 7-membered heterocyclyl group, however, Z in formula -ZR ^12a and -X ^2a ZR ^12a is -SO ₂ - when is, R ^12a is a hydrogen atom not,
X ^2a represents a methylene group. And a group having
Substituent group β1 is methyl group, ethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, hydroxyl group, methoxy group, ethoxy group, trifluoromethoxy group, fluoro group, A group consisting of a chloro group and a bromo group,
Substituent group γ1 includes methyl group, ethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, hydroxy group, methoxy group, ethoxy group, trifluoromethoxy group, methylthio group, , Ethylthio group, methylsulfinyl group, ethylsulfinyl group, methanesulfonyl group, ethanesulfonyl group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, cyano The compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 15, which represents a group consisting of a group, a fluoro group, a chloro group, and a bromo group.
R ⁸ is of the formula —N (R ^10b ) ZR ^11b or —ZN (R ^10b ) R ^12b
[Wherein, R ^10b represents a C ₁ -C ₄ alkyl group, a methoxymethyl group, a 2,2,2-trifluoroethyl group, a cyclopropylmethyl group, or a cyclopropyl group;
R ^11b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ2), (C ₃ -C ₄ cycloalkyl) ) Methyl group, substituted (C ₃ -C ₄ cycloalkyl) methyl group (the substituent is one group selected from substituent group γ2), C ₃ -C ₄ cycloalkyl group, C _2- C ₄ alkenyl group, C ₁ -C ₄ alkoxy group, (C ₃ -C ₄ cycloalkyl) methyloxy group, or C ₁ -C ₄ alkylamino group,
R ^12b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group β2), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or shows a C ₂ -C ₃ alkenyl group. And a group having
The substituent group β2 represents a group consisting of a methyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, a trifluoromethoxy group, a fluoro group, and a chloro group,
Substituent group γ2 is composed of methyl group, trifluoromethyl group, hydroxyl group, methoxy group, methylthio group, methylsulfinyl group, methanesulfonyl group, amino group, methylamino group, dimethylamino group, fluoro group, and chloro group. The compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt or ester thereof, wherein
R ⁸ is of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
The compound group according to any one of claims 1 to 15, or a pharmacologically acceptable salt or ester thereof, wherein the substituent group γ3 represents a group consisting of a methoxy group, a methylthio group, a methylamino group, and a dimethylamino group.
R ⁸ is of the formula —N (R ^10d ) COR ^11d , —N (R ^10d ) CSR ^11d , or —N (R ^10d ) SO ₂ R ^11d
[Wherein R ^10d represents a methyl group or an ethyl group,
R ^11d represents a methyl group, an ethyl group, a 2-propyl group, a methoxymethyl group, a methylthiomethyl group, a cyclopropylmethyl group, or a cyclopropyl group. 16. The compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt or ester thereof.
X ¹ is The compound or a pharmacologically acceptable salt or ester as claimed in any of claims 1 to 19 is a single bond or a methylene group.
The compound according to any one of claims 1 to 19, or a pharmacologically acceptable salt or ester thereof, wherein X ¹ is a single bond.
Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from the substituent group α1), a pyridyl group, or a substituted pyridyl group (the substituent is Or a pharmacologically acceptable salt or ester thereof. The compound according to any one of claims 1 to 21, which is the same or different and is one or two groups selected from the substituent group α1.
Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from the substituent group α3), or a pyridyl group;
The substituent group α3 represents a group consisting of a methoxy group, a methylamino group, a dimethylamino group, a fluoro group, and a chloro group, or a pharmacologically acceptable salt thereof. Or ester.
The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 21, wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group).
R ¹ is a formula —COR ^9a [wherein R ^9a is a C ₁ -C ₆ alkyl group, a C ₁ -C ₈ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₃ alkyl) An oxy group, a halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₃ -C ₅ A cycloalkyloxy group, a (C ₁ -C ₂ alkyl)-(C ₃ -C ₅ cycloalkyl) oxy group, a C ₁ -C ₆ alkylamino group, or a di (C ₁ -C ₆ alkyl) amino group The alkyl group is the same or different, and the two alkyl groups together with the nitrogen atom of the amino group contain 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom A 5- to 7-membered saturated heterocyclyl group may be formed). A group having
Phenyl group, substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group α1), 5 to 6-membered aromatic heterocyclyl group, or substituted 5 to 6-membered An aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α1);
R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group,
R ³ is, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, one to five C ₁ -C ₄ alkyl group substituted with halogeno group shown), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group, C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, hydroxyl Group, C ₁ -C ₄ alkoxy group, halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups) ), C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino Groups (the alkyl groups are the same or different, Together with the nitrogen atom of the amino group to form a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom Good), a fluoro group, a chloro group, or a bromo group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group,
R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group,
R ⁸ is represented by the formula -N (R ^10a ) ZR ^11a , -ZN (R ^10a ) R ^12a , -ZR ^12a , -X ² N (R ^10a ) ZR ^11a , -X ^2a ZN (R ^10a ) R ^12a , or , -X ^2a ZR ^12a
[Wherein, R ^10a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₃ alkyl group (the substituent is one group selected from the substituent group β1), ( C ₃ -C ₄ cycloalkyl) methyl group, C ₃ -C ₄ cycloalkyl group, or substituted C ₃ -C ₄ cycloalkyl group (the substituent is one group selected from substituent group β1) Is)
R ^11a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group γ1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different Or a phenyl- (C ₁ -C ₂ alkyl) group, a substituted phenyl- (C ₁ -C ₂ alkyl) group (substituent of the phenyl group). Are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different and are 1 to 2 groups selected from the substituent group γ1. A) (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, substituted (5- to 7-membered heterocyclyl)-( C ₁ -C ₂ alkyl) group (the substituents of the heterocyclyl group are the same or different and are 1 to 2 groups selected from the substituent group β1, and the substituents of the alkyl group are the same or different, 1 or 2 groups selected from the substituent group γ1), a C ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (the substituents may be the same or different, and the substituent group γ1 A C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (the substituents are the same or different and are selected from the substituent group γ1). 2 groups), a C ₁ -C ₄ alkoxy group, a substituted C ₁ -C ₄ alkoxy group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ1) ), (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) Oki Group, C ₃ -C ₄ alkenyloxy group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group is the amino group Together with the nitrogen atom, a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed), C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) amino group, C ₃ -C ₄ alkenyl group, a phenyl group or represents a 5 to 7-membered heterocyclyl group, provided that the formula -N (R ^10a) ZR ^11a and -X ^2a N (R ^10a) in ZR ^11a Z is -SO ₂ - when is, R ^11a is not hydrogen atom,
R ^12a represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a substituted C ₁ -C ₄ alkyl group (the substituents are the same or different and are one or two groups selected from the substituent group β1). , (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, substituted (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group (the substituents may be the same or different A phenyl- (C ₁ -C ₂ alkyl) group, a (5- to 7-membered heterocyclyl)-(C ₁ -C ₂ alkyl) group, a C 1 -2 group selected from the substituent group β 1 ₃ -C ₅ cycloalkyl group, a substituted C ₃ -C ₅ cycloalkyl group (said substituents may be the same or different, from 1 to 2 groups selected from substituent group β1), C ₂ -C ₄ alkenyl group, a substituted C ₂ -C ₄ alkenyl group (said substituents may be the same or different, 1乃selected from substituent group β1 A two group), a phenyl group or represents a 5 to 7-membered heterocyclyl group, however, Z in formula -ZR ^12a and -X ^2a ZR ^12a is -SO ₂ - when is, R ^12a is a hydrogen atom not,
X ^2a represents a methylene group. And a group having
X ¹ is a single bond or a methylene group,
Y is a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from the substituent group α1), a pyridyl group, or a substituted pyridyl group (the substituent is Or a pharmacologically acceptable salt or ester thereof. 2. The compound according to claim 1, wherein the compound is the same or different and is one or two groups selected from the substituent group α1.
R ¹ represents a formula —COR ^9b [wherein R ^9b represents a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents 1 to 5 halogeno groups). A C ₁ -C ₄ alkoxy group substituted with a group). A group having
A phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α2);
R ² is a hydrogen atom or a hydroxyl group,
R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups) the illustrated), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or a chloro group,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10b ) ZR ^11b or —ZN (R ^10b ) R ^12b
[Wherein, R ^10b represents a C ₁ -C ₄ alkyl group, a methoxymethyl group, a 2,2,2-trifluoroethyl group, a cyclopropylmethyl group, or a cyclopropyl group;
R ^11b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ2), (C ₃ -C ₄ cycloalkyl) ) Methyl group, substituted (C ₃ -C ₄ cycloalkyl) methyl group (the substituent is one group selected from substituent group γ2), C ₃ -C ₄ cycloalkyl group, C _2- C ₄ alkenyl group, C ₁ -C ₄ alkoxy group, (C ₃ -C ₄ cycloalkyl) methyloxy group, or C ₁ -C ₄ alkylamino group,
R ^12b is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group β2), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or shows a C ₂ -C ₃ alkenyl group. And a group having
X ¹ is a single bond,
2. The compound according to claim 1, wherein Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from the substituent group α3), or a pyridyl group. Salt or ester.
R ¹ is a group having the formula —COR ^9c (wherein R ^9c represents a C ₂ -C ₆ alkoxy group);
R ² is a hydrogen atom or a hydroxyl group,
R ³ is a methyl group, an ethyl group, a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, or a vinyl group. ,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
X ¹ is a single bond,
The compound or pharmacologically acceptable salt or ester thereof according to claim 1, wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group).
R ¹ is (wherein, R ^9d is. Showing a 2-methyl-2-propoxy) formula -COR ^9d is a group having the
R ² is a hydroxyl group,
R ³ is a methyl group, an ethyl group, a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, or a vinyl group. ,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10d ) COR ^11d , —N (R ^10d ) CSR ^11d , or —N (R ^10d ) SO ₂ R ^11d
[Wherein R ^10d represents a methyl group or an ethyl group,
R ^11d represents a methyl group, an ethyl group, a 2-propyl group, a methoxymethyl group, a methylthiomethyl group, a cyclopropylmethyl group, or a cyclopropyl group. And a group having
The compound or pharmacologically acceptable salt or ester thereof according to claim 1, wherein Y is a phenyl group or a substituted phenyl group (the substituent is one fluoro group).
tert-butyl 2-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -5- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3-isopropylbenzoate,
tert-butyl 3-tert-butyl-6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxybenzoate,
tert-butyl 6-({4- [acetyl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [methyl (propionyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [butyryl (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [isobutyryl (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4-[(methoxyacetyl) (methyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-[(4- {methyl [(methylthio) acetyl] amino} phenoxy) methyl] -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylacetyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 2-hydroxy-6-({4- [methyl (methylsulfonyl) amino] phenoxy} methyl) -3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonothioyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4- [ethyl (methylsulfonyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylsulfonyl) (methyl) amino] phenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate,
tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -2-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate, and
tert-butyl 6-({4-[(cyclopropylcarbonyl) (methyl) amino] -3-fluorophenoxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate 1 or a pharmacologically acceptable salt or ester thereof.
R ¹ represents a formula —COR ^9b [wherein R ^9b represents a C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (the halogeno C ₁ -C ₄ alkoxy group represents 1 to 5 halogeno groups). A C ₁ -C ₄ alkoxy group substituted with a group). And a group having
R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a hydroxyl group, a fluoro group, or a chloro group,
R ³ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group (the halogeno C ₁ -C ₄ alkyl group is a C ₁ -C ₄ alkyl group substituted with 1 to 5 halogeno groups) the illustrated), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or a chloro group,
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are a hydrogen atom,
R ⁸ is of the formula —N (R ^10c ) ZR ^11c
[Wherein R ^10c represents a methyl group, an ethyl group, a 1-propyl group, or a 2-propyl group;
R ^11c is a C ₁ -C ₄ alkyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is one group selected from the substituent group γ3), (C ₃ -C ₄ cycloalkyl) ) methyl, C ₃ -C ₄ cycloalkyl group, or show a vinyl group. And a group having
X ¹ is a single bond,
2. The compound according to claim 1, wherein Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from the substituent group α3), or a pyridyl group. Salt or ester.