JP2007039425A - Benzene compound having two or more substituents - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a benzene compound having two or more substituents, or its pharmacologically permissible salt or ester exhibiting excellent antiarteriosclerotic action and anti-inflammatory action by controlling the action of Liver X receptors (LXR) to ameliorate abnormal lipid metabolism or controlling the formation of an inflammation mediator. <P>SOLUTION: The invention provides a compound, etc., expressed by general formula (I) [R<SP>1</SP>is -COR<SP>9</SP>(R<SP>9</SP>is an alkyl, a (substituted)alkoxy or a (substituted)amino); R<SP>2</SP>is H, OH, an alkoxy, a (substituted)amino or the like; R<SP>3</SP>is H, a (substituted)alkyl, a cycloalkyl, a (substituted)alkoxy, a (substituted)amino, a halogeno or the like; R<SP>4</SP>and R<SP>5</SP>are each H, a (substituted)alkyl, a halogeno or the like; R<SP>6</SP>and R<SP>7</SP>are each H or an alkyl; R<SP>8</SP>is -X<SP>2</SP>R<SP>10</SP>[R<SP>10</SP>is -COR<SP>11</SP>(R<SP>11</SP>is OH, a (substituted)alkoxy, a (substituted)amino or the like), -SO<SB>2</SB>R<SP>12</SP>(R<SP>12</SP>is a (substituted)alkyl, a (substituted)amino or the like), tetrazol-5-yl or the like; X<SP>2</SP>is single bond, a (substituted)alkylene or the like]; X<SP>1</SP>is -NH-, -O-, -S- or the like; Y<SP>1</SP>is a (substituted)phenyl or a (substituted)5 to 6-membered aromatic heterocyclyl; and Y<SP>2</SP>is a (substituted)aryl, a (substituted)heterocyclyl or the like]. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention regulates the action of Liver X receptors (LXR) to improve lipid metabolism abnormality or control the production of inflammatory mediators, thereby exhibiting excellent anti-atherosclerotic and anti-inflammatory effects. The present invention relates to a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof.

  Furthermore, the present invention provides an LXR modulator, LXR agonist, or LXR antagonist, preferably an LXR modulator or LXR agonist, containing a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof. Relates to an LXR modulator.

  Furthermore, the present invention provides a pharmaceutical composition containing a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably for arteriosclerosis, atherosclerosis and diabetes. Caused arteriosclerosis, hyperlipidemia, hypercholesterolemia, lipid-related disease, inflammatory disease, autoimmune disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, cerebrovascular disease, renal disease Pharmaceutical composition for the treatment or prevention of diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, or Alzheimer's disease; more preferably arteriosclerosis, atherosclerosis, arteries resulting from diabetes To treat or prevent sclerosis, hyperlipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases, arteriosclerotic heart diseases, cardiovascular diseases, coronary artery diseases, or diabetes More preferably, for the treatment or prevention of arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, arteriosclerotic heart disease, cardiovascular disease, or coronary artery disease A pharmaceutical composition for treating or preventing arteriosclerosis, atherosclerosis, or arteriosclerotic heart disease; most preferably, treating or preventing arteriosclerosis or It relates to a pharmaceutical composition for prevention. The present invention also relates to a pharmaceutical composition for inducing ABCA1 expression or promoting reverse cholesterol transfer, which contains a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof as an active ingredient.

  Furthermore, the present invention relates to a pharmaceutical composition, preferably a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof for the production of a pharmaceutical composition for the treatment or prevention of the above-mentioned diseases. Regarding use.

  Furthermore, the present invention relates to a disease caused by administering a pharmacologically effective amount of a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human), preferably And a method for the treatment or prevention of the above diseases.

The present invention further relates to a method for producing a benzene compound having two or more substituents 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 cholesterol metabolism, drugs that regulate LXR are arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, lipid-related diseases, arteriosclerosis It is expected to be useful in the treatment or prevention of congenital heart disease, cardiovascular disease, or coronary artery disease.

  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.

So far, benzene compounds having two or more substituents having LXR regulating action (that is, acting on ABCA1 expression) are known, but the structure is different from the compound of the present invention (see Patent Documents 1 and 2). .
International Publication No. 2004/026816 Pamphlet International Publication No. 2002/024632 Pamphlet

The inventors have conducted extensive studies on the synthesis and pharmacological activity of benzene compounds having two or more substituents in order to find compounds having excellent binding activity to LXR. As a result, specific two or more substituents have been obtained. The present inventors have found that a benzene compound having an excellent binding activity to LXR has been completed.

  The present invention regulates the action of LXR to improve abnormal lipid metabolism or to control the production of inflammatory mediators, thereby exhibiting an excellent anti-atherosclerotic action and anti-inflammatory action. Or a pharmacologically acceptable salt or ester thereof.

  Furthermore, the present invention provides an LXR modulator, LXR agonist, or LXR antagonist, preferably an LXR modulator or LXR agonist, containing a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof. Provides an LXR modulator.

  Furthermore, the present invention provides a pharmaceutical composition containing a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably for arteriosclerosis, atherosclerosis and diabetes. Caused arteriosclerosis, hyperlipidemia, hypercholesterolemia, lipid-related disease, inflammatory disease, autoimmune disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, cerebrovascular disease, renal disease Pharmaceutical composition for the treatment or prevention of diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, or Alzheimer's disease; more preferably arteriosclerosis, atherosclerosis, arteries resulting from diabetes To treat or prevent sclerosis, hyperlipidemia, hypercholesterolemia, lipid-related diseases, inflammatory diseases, arteriosclerotic heart diseases, cardiovascular diseases, coronary artery diseases, or diabetes More preferably, for the treatment or prevention of arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, arteriosclerotic heart disease, cardiovascular disease, or coronary artery disease A pharmaceutical composition for treating or preventing arteriosclerosis, atherosclerosis, or arteriosclerotic heart disease; most preferably, treating or preventing arteriosclerosis or A pharmaceutical composition for prevention is provided. The present invention also provides a pharmaceutical composition for inducing ABCA1 expression or promoting reverse cholesterol transfer, which contains a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof as an active ingredient. .

  Furthermore, the present invention relates to a pharmaceutical composition, preferably a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof for the production of a pharmaceutical composition for the treatment or prevention of the above-mentioned diseases. Provide use.

  Furthermore, the present invention relates to a disease caused by administering a pharmacologically effective amount of a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human), preferably A method for the treatment or prevention of the above diseases is provided.

  Furthermore, the present invention provides a method for producing a benzene compound having two or more substituents, 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, a 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 ₁ -C ₁₀ alkylamino group, or, , 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) A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group may be formed);
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 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, 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 ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are the nitrogen atom of the amino group) And 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), (C _1- C ₆ alkoxy) represents a carbonyl group, a cyano group, a nitro group, or a halogeno 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;
R ⁸ has the formula —X ² R ¹⁰
[Wherein R ¹⁰ is a formula —COR ^{11 wherein} R ¹¹ is a C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cycloalkyl)-( C ₁ -C ₆ alkyl) group, C ₃ -C ₈ cycloalkyl group, an amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl )] Amino group, C ₃ -C ₈ cycloalkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups may be the same or different, and the two alkyl groups 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 a nitrogen atom, an oxygen atom and a sulfur atom), di [(C _3- C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] amino group, di (C ₃ -C ₈ cycloalkyl) Amino _{group, N - [(C 3 -C} 8 cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 1 -C} 6 alkyl) amino group, N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, N-[(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)]-N- (C ₃ -C ₈ cycloalkyl) amino group A hydroxylamino group or a hydroxyl (C ₁ -C ₆ alkyl) amino group]
Formula —SO ₂ R ^{12 wherein} R ¹² is a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or a C ₃ -C ₈ cycloalkyl group. , Amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group, C ₃ -C ₈ cycloalkylamino 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), a di [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group, a di (C ₃ -C ₈ cycloalkyl) amino group, N - [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] - N- (C ₁ -C ₆ alkyl) amino group, N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, or N-[(C ₃ -C ₈ cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 3 -C} 8 cycloalkyl) group having an amino group show a]
Formula -N (R ¹³ ) COR ¹⁴ wherein R ¹³ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or A C ₃ -C ₈ cycloalkyl group, wherein R ¹⁴ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or a C ₃ A group having a —C ₈ cycloalkyl group],
Wherein _{^{-N (R 13) SO 2 R}} 15 [ wherein, R ¹³ represents the same meaning as above, R ¹⁵ is, C ₁ -C ₆ alkyl, (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl) group or a group having a shows a C ₃ -C ₈ cycloalkyl group or, represents the tetrazol-5-yl group,
X ² represents a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents may be the same or different, and may be one or two groups selected from the substituent group γ). And the two substituents together may form a methylene group, an ethylene group, or a trimethylene group);
X ¹ represents a formula —NH—, —NR ¹⁶ — (wherein R ¹⁶ represents a C ₁ -C ₄ alkyl group), —O—, —S—, —SO—, or —SO ₂ —. A group having
Y ¹ 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 group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
Y ² is a 6 to 10-membered aryl group, a substituted 6 to 10-membered aryl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), 9 to 10 members An unsaturated cyclic hydrocarbon group (wherein Y ¹ is bonded to the benzene ring portion of the unsaturated cyclic hydrocarbon group), a substituted 9 to 10-membered unsaturated cyclic hydrocarbon group (where Y ¹ is the unsaturated group) Bonded to the benzene ring portion of the cyclic hydrocarbon group, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a 5- to 10-membered aromatic 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 β), a 9- to 10-membered unsaturated heterocyclyl group (provided that Y ¹ The unsaturated hete Bound to the aromatic ring moiety in cyclyl group), or a substituted 9 to 10 membered unsaturated heterocyclyl group (provided that, Y ¹ is bonded to the aromatic ring moiety in said unsaturated heterocyclyl group, the substituents may be the same or different And 1 to 3 groups selected from substituent group β);
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, C ₁ -C ₄ alkoxy group, and represents a group consisting of halogeno groups;
Substituent group β includes C ₁ -C ₆ alkyl group, hydroxy (C ₁ -C ₆ alkyl) group, carboxy (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkoxy) carbonyl- (C _1- C ₆ alkyl) group, halogeno C ₁ -C ₆ alkyl group (the halogeno C ₁ -C ₆ alkyl group represents a C ₁ -C ₆ alkyl group substituted with 1 to 7 halogeno groups), (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl) group, C ₂ -C ₇ alkenyl group, C ₂ -C ₇ alkynyl group, C ₃ -C ₈ cycloalkyl group, a hydroxyl groups, C ₁ -C ₆ alkoxy group, a halogeno C ₁ -C ₆ alkoxy group (said halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl , Amino group, C ₁ -C ₆ alkylamino group, C ₃ -C ₈ cycloalkyl group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group may be the same or different, are two of the alkyl group 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. ), di (C ₃ -C ₈ cycloalkyl) amino group, N-(C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, formylamino group, (C ₁ -C ₆ alkyl) carbonylamino group, (C ₃ -C ₈ cycloalkyl) carbonylamino _{group, N - [(C 1 -C} 6 alkyl) carbonyl] -N- (C ₁ -C ₆ alkyl) amino group, N - [( C ₃ -C ₈ cycloalkyl) carbonyl] -N- (C ₁ -C ₆ alkyl ) Amino group, C ₁ -C ₆ alkylsulfonylamino group, N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₁ -C ₆ alkyl) amino group, N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₃ -C ₈ cycloalkyl) amino group, a formyl group, (C ₁ -C ₆ alkyl) carbonyl group, a carboxyl group, (C ₁ -C ₆ alkoxy) carbonyl group, a carbamoyl group, (C ₁ - C ₆ alkylamino) carbonyl group, (C ₃ -C ₈ cycloalkylamino) carbonyl group, di (C ₁ -C ₆ alkyl) aminocarbonyl group (the alkyl groups are the same or different, and the two alkyl groups are And together with the nitrogen atom of the amino group, 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) , N- (C ₃ -C ₈ Black alkyl) -N- (C ₁ -C ₆ alkyl) aminocarbonyl group, a cyano group, a nitro group, and represents a group consisting of halogeno groups;
Substituent group γ includes a C ₁ -C ₆ alkyl group, a hydroxy (C ₁ -C ₆ alkyl) group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a mercapto (C ₁ -C ₆ ). ₆ alkyl) group, (C ₁ -C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkylsulfinyl)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ (Alkylsulfonyl)-(C ₁ -C ₆ alkyl) group, amino (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkylamino)-(C ₁ -C ₆ alkyl) group, (C ₃ -C ₈ cycloalkylamino)-(C ₁ -C ₆ alkyl) group, di (C ₁ -C ₆ alkyl) amino- (C ₁ -C ₆ alkyl) group (the alkyl groups may be the same or different, and di (C ₁ The two alkyl groups of the —C ₆ alkyl) amino moiety together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed), a di (C ₃ -C ₈ cycloalkyl) amino- (C ₁ -C ₆ alkyl) group, [N - (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino] - (C ₁ -C ₆ alkyl) group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cycloalkyloxy group, a mercapto group, C ₁ -C ₆ alkylthio group, C ₃ -C ₈ cycloalkyl thio groups, C ₁ -C ₆ alkylsulfinyl group, C ₃ -C ₈ cycloalkyl-sulfinyl group, C ₁ -C ₆ alkyl sulfonyl group, C ₃ -C ₈ cycloalkyl sulfonyl group, an amino group, C ₁ -C ₆ alkylamino group, C ₃ -C ₈ cycloalkyl group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group 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. ), di (C ₃ -C ₈ cycloalkyl) amino group, N-(C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, and shows a group consisting of halogeno group. ]
Or a pharmacologically acceptable salt or ester thereof.

  The present invention also relates to an LXR modulator, LXR agonist, or LXR antagonist, preferably an LXR modulator or LXR agonist, containing a benzene compound having two or more substituents or a pharmacologically acceptable salt or ester thereof. Preferably, an LXR modulator is provided.

  The present invention also provides a pharmaceutical composition comprising an effective amount of the 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. . In particular, the present invention provides the above pharmaceutical composition for the treatment or prevention of a disease in a warm-blooded animal, and the warm-blooded animal suffered from a disease that can be treated or prevented by regulating LXR function in the warm-blooded animal. It can be human. The disease may be a disease that can be treated or prevented by modulation of LXR function, preferably arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, hypercholesterolemia , Lipid-related disease, inflammatory disease, autoimmune disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, cerebrovascular disease, kidney disease, diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, And a disease selected from the group consisting of Alzheimer's disease; more preferably, arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, hypercholesterolemia, lipid-related disease, A disease selected from the group consisting of inflammatory disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, and diabetes; more preferably arteriosclerosis, atherosclerosis, diabetes Disease selected from the group consisting of arteriosclerosis, arteriosclerotic heart disease, cardiovascular disease and coronary artery disease; even more preferably, arteriosclerosis, atherosclerosis and arteries It may be a disease selected from the group consisting of sclerosing heart disease; most suitably arteriosclerosis. The present invention also provides a pharmaceutical composition for inducing ABCA1 expression or promoting reverse cholesterol transfer comprising the compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof as an active ingredient. To do.

  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 the 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 the treatment or prevention of diseases in warm-blooded animals. However, the warm-blooded animal can be a human suffering from a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal. The disease can be similar to that shown above.

  The present invention also provides treatment or prevention of diseases for warm-blooded animals by administering to the warm-blooded animals an effective amount of the compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof. The warm-blooded animal can be a human suffering from a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal. The disease can be similar to that shown above.

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, and diuretics There is provided a pharmaceutical composition comprising one or more medicaments selected from the group consisting of: and 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, 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 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 The compound described in (1), which may form a 5- to 7-membered saturated heterocyclyl group
(3) R ¹ is wherein -COR ^9b [wherein, R ^9b is C ₁ -C ₆ alkoxy group or a halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ alkoxy group, 1 to 5 the compounds described in a group having a indicating the number indicating the C ₁ -C ₄ alkoxy group substituted with halogeno groups)] (1),
(4) The compound described in (1), wherein R ¹ is a group having the formula —COR ^9c (wherein R ^9c represents a C ₃ -C ₅ alkoxy group),
(5) The compound described in (1), wherein R ¹ is a group having the formula —COR ^9d (wherein R ^9d represents a 2-methyl-2-propoxy group),
(6) R ² is a hydrogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, pentafluoroethyl group, a hydroxyl group, fluoro group, or a chloro group (1) to (5) A compound described in any of the above,
(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 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 a C substituted with 1 to 5 halogeno groups) ₁ -C shows a ₄ 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 - A 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), a C ₁ -C ₄ alkylthio group, a 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, two of the An alkyl group together with the nitrogen atom of the amino group 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), a fluoro group, a chloro group, or A compound described in any one of (1) to (8), which is a bromo group,
(10) R ³ is 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 a C substituted with 1 to 5 halogeno groups) shows the ₁ -C ₄ alkyl group), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or a chloro group (1) to (8 ) A compound described in any one of
(11) 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 methoxy group, a fluoro group, or A compound described in any one of (1) to (8), which is a chloro group,
(12) The compound according to any one of (1) to (8), wherein R ³ is a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, or a chloro group,
(13) The compound according to any one of (1) to (8), wherein R ³ is a trifluoromethyl group,
(14) 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 cyclopropyl group, a hydroxyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group. (1) to the compound described in any one of (13),
(15) The compound according to any one of (1) to (13), wherein R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom or a hydroxyl group,
(16) The compound according to any one of (1) to (13), wherein R ⁴ and R ⁵ are a hydrogen atom,
(17) The compound according to any one of (1) to (16), wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group,
(18) R ⁶ and R ^7, compounds described in any one of a hydrogen atom (1) to (16),
(19) R ⁸ is the formula -X ^2a R ^10a
[Wherein R ^10a represents the formula —COR ^11a [wherein R ^11a represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy] Group, C ₃ -C ₆ cycloalkyloxy group, amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C _3- C ₆ cycloalkylamino group, di (C ₁ -C ₄ 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, A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of an atom and a sulfur atom), a hydroxylamino group, or a hydroxyl (C ₁ -C ₄ alkyl) ) Represents an amino group],
Wherein -SO ₂ R ^12a [wherein, R ^12a is, C ₁ -C ₄ alkyl group, (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₃ -C ₆ cycloalkyl group , Amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C ₃ -C ₆ cycloalkylamino group, or di ( C ₁ -C ₄ 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 are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) Which may form a 5 to 7-membered saturated heterocyclyl group containing 1 to 3 atoms of
Formula —N (R ^13a ) COR ^14a [wherein R ^13a is a hydrogen atom, a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or shows the C ₃ -C ₅ cycloalkyl group, R ^14a represents a hydrogen atom, C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or,, C ₃ A group having a —C ₅ cycloalkyl group],
Wherein _{^{-N (R 13a) SO 2 R}} 15a [ wherein, R ^13a have the same meanings as above, R ^15a is C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or a group having a shows a C ₃ -C ₅ cycloalkyl group or, represents the tetrazol-5-yl group,
X ^2a represents a single bond, a C ₁ -C ₂ alkylene group, or a substituted C ₁ -C ₂ alkylene group (the substituents may be the same or different, and may be one or two groups selected from the substituent group γ1). And the two substituents together may form a methylene group, an ethylene group, or a trimethylene group). A group having
Substituent group γ1 is methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group, methylthiomethyl group, methylthioethyl group, aminomethyl group, aminoethyl group, methylaminomethyl group, ethyl Aminomethyl group, methylaminoethyl group, cyclopropylaminomethyl group, cyclopropylaminoethyl group, dimethylaminomethyl group, dimethylaminoethyl group, (N-methyl-N-ethylamino) methyl group, dicyclopropylaminomethyl group , Hydroxyl group, methoxy group, ethoxy group, cyclopropyloxy group, methylthio group, ethylthio group, cyclopropylthio group, amino group, methylamino group, ethylamino group, cyclopropylamino group, cyclobutylamino group, dimethylamino group , Diethylamino group, The compound described in any one of (1) to (18), which is a group consisting of a dicyclopropylamino group, an N-cyclopropyl-N-methylamino group, a fluoro group, and a chloro group;
(20) R ⁸ is a compound of the formula -X ^2b R ^10b
[Wherein, R ^10b represents a formula —COR ^11b [wherein R ^11b represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy] group, C ₃ -C ₅ cycloalkyl group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, a group having a methyl ethylamino group, or shows a hydroxylamino group],
Formula —SO ₂ R ^12b [wherein R ^12b represents a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or a C ₃ -C ₅ cyclo A group having an alkyl group] or a tetrazol-5-yl group,
X ^2b is a single bond, a methylene group, an ethylene group, or a substituted methylene group or a substituted ethylene group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ2, Two substituents may combine to form an ethylene or trimethylene group)];
Substituent group γ2 includes methyl group, ethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, (N-methyl-N-ethylamino) methyl group, methoxy group, A compound described in any one of (1) to (18), which is a group consisting of an ethoxy group, a methylamino group, a dimethylamino group, a fluoro group, and a chloro group;
(21) R ⁸ is represented by the formula -X ^2c R ^10c
[Wherein R ^10c represents a group having the formula —COR ^11c (wherein R ^11c represents a hydroxyl group or a methoxy group), or
Represents a group having the formula —SO ₂ R ^12c (wherein R ^12c represents a methyl group),
X ^2c is a single bond, a methylene group, or a substituted methylene group (the substituent is one group selected from the substituent group γ3, or the two substituents are combined together) An ethylene group may be formed). A group having
The substituent group γ3 is a compound described in any one of (1) to (18), which is a group consisting of a methyl group, an ethyl group, a hydroxymethyl group, a dimethylaminomethyl group, a methoxy group, and an ethoxy group,
(22) R ⁸ is a compound represented by the formula -X ^2d R ^10d
[Wherein R ^10d represents a group having the formula —COR ^11d (wherein R ^11d represents a hydroxyl group)
X ^2d represents a methylene group or a substituted methylene group (the substituent is one group selected from the substituent group γ4, or the two substituents together form an ethylene group; Which may be formed)
The substituent group γ4 is a compound described in any one of (1) to (18), which is a group consisting of a methyl group, an ethyl group, and a hydroxymethyl group,
(23) R ⁸ is a compound of the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a compound described in any one of (1) to (18), which is a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
(24) R ⁸ represents the formula -X ^2f R ^10f
[Wherein R ^10f represents a group having the formula —SO ₂ R ^12f (wherein R ^12f represents a methyl group),
X ^2f represents a single bond], or a compound according to any one of (1) to (18),
(25) The compound according to any one of (1) to (24), wherein X ¹ is a group having the formula —NH—, —O— or —S—,
(26) The compound according to any one of (1) to (24), wherein X ¹ is a group having the formula —O—,
(27) Y ¹ is a phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group α1), a 5- to 6-membered aromatic heterocyclyl group ( The heterocyclyl group represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyridazinyl group), or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is , A pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyridazinyl group, the substituents being the same or different, and one or two selected from the substituent group α1 Which is the basis of
The substituent group α1 is a compound described in any one of (1) to (26), which is a group consisting of a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a fluoro group, and a chloro group ,
(28) Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituent is A substituent selected from the substituent group α2, and the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), a thienyl group (substitution position of X ¹ and Y ² are bonded to said thienyl group are respectively 2 and 5 positions), a substituted thienyl group (the substituent is one group selected from substituent group [alpha] 2, The substitution positions of X ¹ and Y ² bonded to the thienyl group are the 2 and 5 positions, respectively, and the pyridyl group (the substitution positions of X ¹ and Y ² bonded to the pyridyl group are the 2 and 5 positions, respectively) Or 5th and 2nd) Is a substituted pyridyl group (said substituent is one group selected from Substituent group [alpha] 2, the substitution position of X ¹ and Y ² are bonded to said pyridyl group are each 2 and 5, or, 5th and 2nd)
The substituent group α2 is a compound described in any one of (1) to (26), which is a group consisting of a methyl group, a fluoro group, and a chloro group,
(29) Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are 1 and 4 positions, respectively) or a pyridyl group (X ¹ and Y bonded to the pyridyl group) The substitution positions of ² are respectively the 5 and 2 positions), and the compound according to any one of (1) to (26),
(30) The compound described in any one of (1) to (26), wherein Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions) ,
(31) Y ² is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group β1), an indanyl group or a tetrahydronaphthyl group (provided that Y ¹ binds to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group), substituted indanyl group or substituted tetrahydronaphthyl group (provided that Y ¹ binds to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group, The substituents are the same or different and are 1 to 3 groups selected from the substituent group β1) 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group, a furyl group, a thienyl group, An imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group; A substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group, and the substituent is 9 to 10-membered unsaturated heterocyclyl group (wherein Y ¹ is bonded to an aromatic ring moiety in the unsaturated heterocyclyl group, which are the same or different and are 1 to 3 groups selected from substituent group β1). The unsaturated heterocyclyl group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group), or a substituted 9 to 10-membered unsaturated heterocyclyl group (Y ¹ Is bonded to the aromatic ring moiety in the unsaturated heterocyclyl group, and the unsaturated heterocyclyl The ru group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group, and the substituents are the same or different and are 1 to 3 selected from the substituent group β1. Which is a group of
Substituent group β1 includes a C ₁ -C ₆ alkyl group, a hydroxy (C ₁ -C ₄ alkyl) group, a carboxy (C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkoxy) carbonyl- (C _1- (C ₄ alkyl) group, 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), (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₆ cycloalkyl group, a hydroxyl groups, 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 alkyl sulfonyl Group, amino group, C ₁ -C ₄ alkylamino group, C ₃ -C ₆ cycloalkyl group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group 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), formylamino group, (C ₁ -C ₄ alkyl) carbonylamino group, (C ₃ -C ₆ cycloalkyl) _{group, N - [(C 1 -C} 4 alkyl) carbonyl]-N-(C ₁ -C ₄ alkyl) amino _{group, N - [(C 3 -C} 6 cycloalkyl) carbonyl]-N-(C ₁ -C ₄ alkyl) amino group, C ₁ -C ₄ alkylsulfonylamino group, N- ( C ₁ -C ₄ alkylsulfonyl)-N-(C ₁ -C ₄ Alkyl) amino group, a formyl group, (C ₁ -C ₄ alkyl) carbonyl group, a carboxyl group, (C ₁ -C ₄ alkoxy) carbonyl group, a carbamoyl group, (C ₁ -C ₄ alkylamino) carbonyl group, di ( C ₁ -C ₄ alkyl) aminocarbonyl 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, 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 selected), a cyano group, a nitro group, a fluoro group, a chloro group, and a bromo group ( 1) to the compound described in any one of (30),
(32) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituent is Are the same or different and are 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, or the 1 and 4 positions, respectively. ), A thienyl group (substituent positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively), a substituted thienyl group (the substituents are the same or different, and from the substituent group β2) 1 or 2 groups selected, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively, and a thiazolyl group (Y ¹ and R bonded to the thiazolyl group) the substitution position of ^8, its Respectively are the 2 and 5 positions), a substituted thiazolyl group (said substituents may be the same or different and are 1 or 2 groups selected from Substituent group .beta.2, Y ¹ and R are bonded to said thiazolyl group ⁸ is substituted at the 2 and 5 positions, respectively, and a pyridyl group (the substituted positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, or the 3 and 5 positions, respectively), Or a substituted pyridyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are each 2 And 5th position, or 3rd and 5th position);
Substituent group β2 is, C ₁ -C ₄ alkyl group, hydroxymethyl group, 1-hydroxyethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, pentafluoroethyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₄ cycloalkyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methanesulfonyl group, an ethanesulfonyl group, an amino group, methylamino group, ethylamino group, dimethylamino A compound according to any one of (1) to (30), which is a group consisting of a group, a diethylamino group, a formyl group, a methylcarbonyl group, an ethylcarbonyl group, a cyano group, a nitro group, a fluoro group, and a chloro group,
(33) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, 1 or 2 groups selected from group β3, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively, and a thienyl group (Y bonded to the thienyl group) ¹ and R ⁸ are substituted at positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β3. The substitution positions of Y ¹ and R ⁸ bonded to the group are the 2 and 5 positions, respectively, and the pyridyl group (the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, respectively) Or substituted pyridyl (The substituents may be the same or different and are 1 or 2 groups selected from Substituent group .beta.3, the substitution position of Y ¹ and R ⁸ are bonded to said pyridyl group are respectively 2 and 5 positions );
Substituent group β3 is methyl, ethyl, 2-propyl, hydroxymethyl, trifluoromethyl, cyclopropyl, methoxy, methanesulfonyl, amino, methylamino, dimethylamino, methylcarbonyl A compound according to any one of (1) to (30), which is a group consisting of a group, an ethylcarbonyl group, a cyano group, a nitro group, a fluoro group, and a chloro group,
(34) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, One group selected from group β3 or two groups selected from substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively. there), the substitution position of Y ¹ and R ⁸ bind to a thienyl group (said thienyl group are respectively 2 and 5 positions), or a substituted thienyl group (wherein said substituents may be the same or different, substituent group β3 1 group selected from the above, or two groups selected from the substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively) Is;
The substituent group β4 is a compound described in any one of (1) to (30), which is a group consisting of a methyl group, an ethyl group, and a fluoro group,
(35) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively) or a substituted phenyl group (the substituent is a substituent group β5 A selected group, two methyl groups, or two fluoro groups, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively) Yes;
The substituent group β5 is described in any one of (1) to (30), which is a group consisting of a methyl group, an ethyl group, a 2-propyl group, a trifluoromethyl group, a nitro group, a fluoro group, and a chloro group. Compound,
(36) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively), a substituted phenyl group (the substituent is selected from substituent group β6) Y ¹ , R ⁸ bonded to the phenyl group and the substitution positions of the substituents are the 1, 3 and 2 positions, respectively, and a pyridyl group (Y ¹ bonded to the pyridyl group). and the substitution position of R ⁸ are each a 3 and 5 positions), or a substituted pyridyl group (said substituent is one group selected from substituent group .beta.6, Y is bonded to said pyridyl group ¹ , R ⁸ and the substitution positions of the substituents are 3, 5 and 4 positions respectively);
The substituent group β6 is a compound described in any one of (1) to (30), which is a group consisting of a C ₁ -C ₄ alkyl group, a methoxy group, a fluoro group, and a chloro group, or
(37) Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively) or a substituted phenyl group (the substituent is a substituent group β7 A group selected from the group consisting of Y ¹ , R ⁸ and the substitution position of the substituent bonded to the phenyl group are the ¹ , 3 and 2 positions, respectively);
The substituent group β7 is a compound described in any one of (1) to (30), which is a group consisting of a methyl group, an ethyl group, a methoxy group, or a fluoro group.

R ¹ selected from (2) to (5), (6) to (8) in the compound represented by the general formula (I) of the above (1) or a pharmacologically acceptable salt or ester thereof according to the present invention. R ² selected from), R ³ selected from (9) to (13), R ⁴ and R ⁵ selected from (14) to (16), and selected from (17) to (18) R ⁶ and R ⁷ , R ⁸ selected from (19) to (24), X ¹ selected from (25) to (26), Y ¹ selected from (27) to (30), and A compound obtained by arbitrarily combining Y ² selected from (31) to (37) is preferable. Moreover, the compound obtained by the following combinations is more preferable;
(I) R ⁸ selected from (22) to (23) and Y ² selected from (33) to (35);
(Ii) R ⁸ shown in (23) and Y ² selected from (36) to (37); and
(Iii) R ⁸ shown in (24) and Y ² selected from (36) to (37).

  Such suitable compounds are, for example,
  (38) R¹Is the formula -COR^9a[Wherein R^9aIs C₁-C₆Alkyl group, C₁-C₈Alkoxy group, halogeno C₁-C₆An alkoxy group (halogeno C)₁-C₆An alkoxy group is a C substituted with 1 to 7 halogeno groups₁-C₆Represents an alkoxy group), C₁-C₆An alkylamino group or di (C₁-C₆Alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) A 5- to 7-membered saturated heterocyclyl group containing 1 atom may be formed);
  R²Is 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^ThreeIs a hydrogen atom, C₁-C_FourAlkyl group, halogeno C₁-C_FourAlkyl group (halogeno C)₁-C_FourThe alkyl group is a C substituted with 1 to 5 halogeno groups.₁-C_FourRepresents an alkyl group), C_Three-C_FiveA cycloalkyl group, C₂-C_FourAlkenyl group, C₂-C_FourAlkynyl group, hydroxyl group, C₁-C_FourAlkoxy group, halogeno C₁-C_FourAn alkoxy group (halogeno C)₁-C_FourAn alkoxy group is a C substituted with 1 to 5 halogeno groups₁-C_FourRepresents an alkoxy group), C₁-C_FourAlkylthio group, C₁-C_FourAlkylsulfinyl group, C₁-C_FourAlkylsulfonyl group, amino group, C₁-C_FourAlkylamino group, di (C₁-C_FourAlkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) A 5- to 7-membered saturated heterocyclyl group containing 1 atom), a fluoro group, a chloro group, or a bromo group;
  R^FourAnd R^FiveAre the same or different and are a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a cyclopropyl group, a hydroxyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group;
  R⁶And R⁷Are the same or different and are a hydrogen atom or a methyl group;
  R⁸Is the formula -X^2aR^10a
[Wherein R^10aIs the formula -COR^11a[Wherein R^11aIs a hydroxyl group, C₁-C_FourAn alkoxy group, (C_Three-C₆Cycloalkyl)-(C₁-C_FourAlkyl) oxy group, C_Three-C₆Cycloalkyloxy group, amino group, C₁-C_FourAlkylamino group, [(C_Three-C₆Cycloalkyl)-(C₁-C_FourAlkyl)] amino group, C_Three-C₆A cycloalkylamino group, di (C₁-C_FourAlkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) A 5- to 7-membered saturated heterocyclyl group containing 1 atom), a hydroxylamino group, or a hydroxyl (C₁-C_FourAn alkyl) amino group]
  Formula -SO₂R^12a[Wherein R^12aIs C₁-C_FourAlkyl group, (C_Three-C₆Cycloalkyl)-(C₁-C_FourAlkyl) group, C_Three-C₆Cycloalkyl group, amino group, C₁-C_FourAlkylamino group, [(C_Three-C₆Cycloalkyl)-(C₁-C_FourAlkyl)] amino group, C_Three-C₆A cycloalkylamino group or di (C₁-C_FourAlkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) A 5- to 7-membered saturated heterocyclyl group containing 1 atom)
  Formula -N (R^13aCOR^14a[Wherein R^13aIs a hydrogen atom, C₁-C_FourAlkyl group, (C_Three-C_FiveCycloalkyl)-(C₁-C₂Alkyl) group or C_Three-C_FiveA cycloalkyl group, R^14aIs a hydrogen atom, C₁-C_FourAlkyl group, (C_Three-C_FiveCycloalkyl)-(C₁-C₂Alkyl) group or C_Three-C_FiveA group having a cycloalkyl group],
  Formula -N (R^13a) SO₂R^15a[Wherein R^13aIs as defined above and R^15aIs C₁-C_FourAlkyl group, (C_Three-C_FiveCycloalkyl)-(C₁-C₂Alkyl) group or C_Three-C_FiveA cycloalkyl group] or a tetrazol-5-yl group,
  X^2aIs a single bond, C₁-C₂Alkylene group or substituted C₁-C₂An alkylene group (the substituents are the same or different and are one to two groups selected from the substituent group γ1, and the two substituents together form a methylene group, an ethylene group, or a trimethylene group) May be formed). A group having
  X¹Is a group having the formula -NH-, -O- or -S-;
  Y¹Is a phenyl group or a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group α1), a 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is A pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group or a pyridazinyl group) or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group, a furyl group) Group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group or pyridazinyl group, and the substituents are the same or different and are one or two groups selected from substituent group α1) Is;
  Y²Are 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 β1), an indanyl group or a tetrahydronaphthyl group (provided that Y¹Is bonded to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group), substituted indanyl group or substituted tetrahydronaphthyl group (provided that Y¹Is bonded to the benzene ring part of the indanyl group or tetrahydronaphthyl group, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group β1). A heterocyclyl group (the heterocyclyl group represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group), a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group) Represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group, and the substituents are the same or different and are selected from the substituent group β1 1 to 3 9 to 10-membered unsaturated heterocyclyl group (provided that Y is¹Is bonded to an aromatic ring moiety in the unsaturated heterocyclyl group, and the unsaturated heterocyclyl group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group), or Substituted 9- to 10-membered unsaturated heterocyclyl group (provided that Y¹Is bonded to an aromatic ring moiety in the unsaturated heterocyclyl group, and the unsaturated heterocyclyl group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group, and the substituent Are the same or different and are 1 to 3 groups selected from substituent group β1),
  (39) R¹Is the formula -COR^9b[Wherein R^9bIs C₁-C₆Alkoxy group or halogeno C₁-C_FourAn alkoxy group (halogeno C)₁-C_FourAn alkoxy group is a C substituted with 1 to 5 halogeno groups₁-C_FourWhich represents an alkoxy group)];
  R²Is a hydrogen atom or a hydroxyl group;
  R^ThreeIs a hydrogen atom, C₁-C_FourAlkyl group, halogeno C₁-C_FourAlkyl group (halogeno C)₁-C_FourThe alkyl group is a C substituted with 1 to 5 halogeno groups.₁-C_FourRepresents an alkyl group), C_Three-C_FiveA cycloalkyl group, C₂-C_FourAlkenyl group, C₁-C_FourAn alkoxy group, a fluoro group, or a chloro group;
  R^FourIs a hydrogen atom and R^FiveIs a hydrogen atom or a hydroxyl group;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2bR^10b
[Wherein R^10bIs the formula -COR^11b[Wherein R^11bIs a hydroxyl group, C₁-C_FourAn alkoxy group, (C_Three-C_FiveCycloalkyl)-(C₁-C₂Alkyl) oxy group, C_Three-C_FiveA cycloalkyloxy group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group, or a hydroxylamino group]
  Formula -SO₂R^12b[Wherein R^12bIs C₁-C_FourAlkyl group, (C_Three-C_FiveCycloalkyl)-(C₁-C₂Alkyl) group or C_Three-C_FiveA cycloalkyl group] or a tetrazol-5-yl group,
  X^2bIs a single bond, a methylene group, an ethylene group, or a substituted methylene group or a substituted ethylene group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ2, The substituents together may form an ethylene group or a trimethylene group)];
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are substituted positions 1 and 3 or 1 and 4, respectively, and a substituted phenyl group (the substituent is a group selected from substituent group α2 and is bonded to the phenyl group) X to do¹And Y²Are substituted at the 1 and 3 positions or the 1 and 4 positions, respectively, and a thienyl group (X bonded to the thienyl group).¹And Y²Are substituted positions 2 and 5, respectively, and a substituted thienyl group (the substituent is one group selected from the substituent group α2 and is bonded to the thienyl group)¹And Y²Are substituted at positions 2 and 5, respectively, and a pyridyl group (X bonded to the pyridyl group)¹And Y²Are substituted positions 2 and 5 or 5 and 2, respectively, or a substituted pyridyl group (the substituent is one group selected from substituent group α2 and the pyridyl group X binding to¹And Y²Are the 2 and 5 positions, or the 5 and 2 positions, respectively);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3 or 1 and 4, respectively, and a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from substituent group β2). , Y bonded to the phenyl group¹And R⁸Are substituted at the 1- and 3-positions or the 1- and 4-positions, respectively, and a thienyl group (Y bonded to the thienyl group).¹And R⁸Are substituted positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2 and are bonded to the thienyl group) Y¹And R⁸Are substituted at the 2- and 5-positions, respectively), a thiazolyl group (Y bonded to the thiazolyl group)¹And R⁸Are substituted at the 2 and 5 positions, respectively, and a substituted thiazolyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2 and bonded to the thiazolyl group) Y¹And R⁸Are substituted at positions 2 and 5, respectively, and a pyridyl group (Y bonded to the pyridyl group).¹And R⁸Are substituted positions 2 and 5 or 3 and 5 respectively, or substituted pyridyl groups (the substituents are the same or different, and are 1 to 2 groups selected from substituent group β2) Y which binds to the pyridyl group¹And R⁸The substitution positions of are the 2 and 5 positions, or the 3 and 5 positions, respectively),
  (40) R¹Is the formula -COR^9c(Wherein R^9cIs C_Three-C_FiveA group having an alkoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs methyl, ethyl, 2-propyl, 2-methyl-2-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, fluoro, or chloro ;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2cR^10c
[Wherein R^10cIs the formula -COR^11c(Wherein R^11cRepresents a hydroxyl group or a methoxy group), or
  Formula -SO₂R^12c(Wherein R^12cRepresents a methyl group),
  X^2cIs a single bond, a methylene group, or a substituted methylene group (the substituent is one group selected from the substituent group γ3, or the two substituents together form an ethylene group May be formed). A group having
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are substituted at positions 1 and 4, respectively, or a pyridyl group (X bonded to the pyridyl group)¹And Y²Are the 5 and 2 positions, respectively);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3 or 1 and 4, respectively, and a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from substituent group β2). , Y bonded to the phenyl group¹And R⁸Are substituted at the 1- and 3-positions or the 1- and 4-positions, respectively, and a thienyl group (Y bonded to the thienyl group).¹And R⁸Are substituted positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2 and are bonded to the thienyl group) Y¹And R⁸Are substituted at the 2- and 5-positions, respectively), a thiazolyl group (Y bonded to the thiazolyl group)¹And R⁸Are substituted at the 2 and 5 positions, respectively, and a substituted thiazolyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2 and bonded to the thiazolyl group) Y¹And R⁸Are substituted at positions 2 and 5, respectively, and a pyridyl group (Y bonded to the pyridyl group).¹And R⁸Are substituted positions 2 and 5 or 3 and 5 respectively, or substituted pyridyl groups (the substituents are the same or different, and are 1 to 2 groups selected from substituent group β2) Y which binds to the pyridyl group¹And R⁸The substitution positions of are the 2 and 5 positions, or the 3 and 5 positions, respectively),
  (41) R¹Is the formula -COR^9d(Wherein R^9dIs a group having 2-methyl-2-propoxy group;
  R²Is a hydroxyl group;
  R^ThreeIs a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, or a chloro group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2dR^10d
[Wherein R^10dIs the formula -COR^11d(Wherein R^11dRepresents a hydroxyl group)
  X^2dIs a methylene group or a substituted methylene group (the substituent is one group selected from the substituent group γ4, or the two substituents together form an ethylene group). A group having
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are substituted at positions 1 and 4, respectively, or a pyridyl group (X bonded to the pyridyl group)¹And Y²Are the 5 and 2 positions, respectively);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 4, respectively, and a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β3, and are bonded to the phenyl group) Y¹And R⁸Are substituted at positions 1 and 4, respectively, and a thienyl group (Y bonded to the thienyl group)¹And R⁸Are substituted positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β3, and are bonded to the thienyl group) Y¹And R⁸Are substituted at positions 2 and 5, respectively, and a pyridyl group (Y bonded to the pyridyl group).¹And R⁸Or the substituted pyridyl group (the substituents are the same or different, and are 1 to 2 groups selected from the substituent group β3). Y to join¹And R⁸The substitution positions of are the 2 and 5 positions, respectively)
  (42) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2eR^10e
[Wherein R^10eIs the formula -COR^11e(Wherein R^11eRepresents a hydroxyl group)
  X^2eIs a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted at the 1 and 4 positions, respectively, and a substituted phenyl group (the substituents are the same or different and are selected from one group selected from the substituent group β3 or from the substituent group β4) Two groups, Y bound to the phenyl group¹And R⁸Are substituted at positions 1 and 4, respectively, and a thienyl group (Y bonded to the thienyl group)¹And R⁸Or the substituted thienyl group (the substituents are the same or different and are selected from one group selected from the substituent group β3, or selected from the substituent group β4). Y groups bonded to the thienyl group.¹And R⁸The substitution positions of are the 2 and 5 positions, respectively)
  (43) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2eR^10e
[Wherein R^10eIs the formula -COR^11e(Wherein R^11eRepresents a hydroxyl group)
  X^2eIs a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted at positions 1 and 4, respectively, or a substituted phenyl group (the substituent is one group selected from substituent group β5, two methyl groups, or two fluoro groups) Y which binds to the phenyl group¹And R⁸The substitution positions of are the 1 and 4 positions, respectively),
  (44) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2eR^10e
[Wherein R^10eIs the formula -COR^11e(Wherein R^11eRepresents a hydroxyl group)
  X^2eIs a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3, respectively, and a substituted phenyl group (the substituent is one group selected from the substituent group β6, and Y is bonded to the phenyl group)¹, R⁸And the substitution positions of the substituents are 1, 3 and 2 positions, respectively, and a pyridyl group (Y bonded to the pyridyl group)¹And R⁸Or the substituted pyridyl group (the substituent is one group selected from substituent group β6, and Y is bonded to the pyridyl group).¹, R⁸And the substitution positions of the substituents are the 3, 5 and 4 positions, respectively),
  (45) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2eR^10e
[Wherein R^10eIs the formula -COR^11e(Wherein R^11eRepresents a hydroxyl group)
  X^2eIs a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3, respectively, or a substituted phenyl group (the substituent is one group selected from substituent group β7, and Y is bonded to the phenyl group)¹, R⁸And the substitution positions of the substituents are the 1, 3 and 2 positions, respectively),
  (46) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2fR^10f
[Wherein R^10fIs the formula -SO₂R^12f(Wherein R^12fRepresents a methyl group),
  X^2fIs a group having a single bond];
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3, respectively, and a substituted phenyl group (the substituent is one group selected from the substituent group β6, and Y is bonded to the phenyl group)¹, R⁸And the substitution positions of the substituents are 1, 3 and 2 positions, respectively, and a pyridyl group (Y bonded to the pyridyl group)¹And R⁸Or the substituted pyridyl group (the substituent is one group selected from substituent group β6, and Y is bonded to the pyridyl group).¹, R⁸And the substitution positions of the substituents are the 3, 5 and 4 positions, respectively),
  (47) R¹Is the formula -COR^9d(Wherein R^9dRepresents a 2-methyl-2-propoxy group);
  R²Is a hydroxyl group;
  R^ThreeIs a trifluoromethyl group;
  R^FourAnd R^FiveIs a hydrogen atom;
  R⁶And R⁷Is a hydrogen atom;
  R⁸Is the formula -X^2fR^10f
[Wherein R^10fIs the formula -SO₂R^12f(Wherein R^12fRepresents a methyl group),
  X^2fIs a group having a single bond];
  X¹Is a group having the formula -O-;
  Y¹Is a phenyl group (X bonded to the phenyl group)¹And Y²Are the 1 and 4 positions);
  Y²Is a phenyl group (Y bonded to the phenyl group)¹And R⁸Are substituted positions 1 and 3, respectively, or a substituted phenyl group (the substituent is one group selected from substituent group β7, and Y is bonded to the phenyl group)¹, R⁸And the substitution positions of the substituents are 1, 3 and 2 positions, respectively), or
  (48) (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) acetic acid,
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) propanoic acid,
1- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) cyclopropanecarboxylic acid,
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) -3-hydroxypropanoic acid ,
2- [4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl] butanoic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1'-biphenyl-3-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-chloro-1,1'-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1'-biphenyl-4-yl) acetic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1′-biphenyl-3-yl) propanoic acid ,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) propanoic acid ,
1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) cyclopropane carboxylic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-methoxy-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-trifluoromethyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1'-biphenyl-4-yl) acetic acid,
tert-butyl 6-[({2'-ethyl-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl ) Benzoate,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1'-biphenyl-4-yl) acetic acid,
(2-amino-4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-formyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (hydroxymethyl) -1,1'-biphenyl-4-yl) acetic acid ,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyano-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-ethyl-1,1'-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1'-biphenyl-3-yl) acetic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) -3 -(Dimethylamino) propanoic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) propanoic acid ,
[5- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -4-methyl-2-thienyl] acetic acid,
2- (4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4-yl) propanoic acid ,
2- [4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -3-methylphenyl] propanoic acid,
2- (4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1'-biphenyl-4-yl) propanoic acid ,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1′-biphenyl-4-yl) Propanoic acid and
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) propane It is a compound described in (1) selected from the group consisting of acids.

The present invention also provides:
(49) R ¹¹ in group having the formula -COR ^11, shown in R ¹⁰ of the group having the formula -X ² R ¹⁰ in R ⁸ is a hydroxyl group, C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) oxy group, C ₃ -C ₈ cycloalkyloxy group, amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl)-( C ₁ -C ₆ alkyl)] amino group, C ₃ -C ₈ cycloalkylamino group, 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 group), di [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] amino group Di (C ₃ -C ₈ cycloalkyl) amino group, N - [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 1 -C} 6 alkyl) amino group, N - (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino _{group, N - [(C 3 -C} 8 cycloalkyl) - (C ₁ -C ₆ alkyl)] - N-( C ₃ -C ₈ cycloalkyl) amino group, a hydroxyl amino group or a hydroxyl (C ₁ -C ₆ alkyl) amino group,
X ^{2 of the} group having the formula —X ² R ¹⁰ in R ⁸ is a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents may be the same or different, The compound described in (1), which is 1 to 2 groups selected from the group γ, and the two substituents may be combined to form an ethylene group or a trimethylene group) Or a pharmacologically acceptable salt or ester thereof, and
(50) R ⁸ is the formula -X ^2g R ^10g
[Wherein R ^10g represents a formula —COR ^11g [wherein R ^11g represents a hydroxyl group, a C ₁ -C ₆ alkoxy group, an amino group, a C ₁ -C ₆ alkylamino group, or a di (C _1- C ₆ 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 are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom 1 Or a tetrazol-5-yl group, which may form a 5 to 7-membered saturated heterocyclyl group containing 3 to 3 atoms),
X ^2g is a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents are the same or different and are selected from the group consisting of a C ₁ -C ₄ alkyl group and a halogeno group) 1 to 2 groups, and the two substituents together may form an ethylene group or a trimethylene group);
Y ¹ 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 δ), a 5- to 6-membered aromatic heterocyclyl group, or a substituted group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group δ);
Y ² 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 δ), a 5- to 6-membered aromatic heterocyclyl group, or a substituted group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group δ);
Substituent group δ 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 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 (said alkyl group may be the same or different), a carboxyl group, according to (C ₁ -C ₄ alkoxy) carbonyl group, a cyano group, and a group consisting of halogeno group (1) Compound or its pharmacology Also provided are acceptable salts or esters.

Furthermore, the present invention provides
(51) The compound represented by the general formula (I) described in any one of (1) to (50) or a pharmacologically acceptable salt or ester thereof; and an HMG-CoA reductase inhibitor, CETP inhibition One or more medicines selected from the group consisting of a drug, an ACAT inhibitor, a cholesterol absorption inhibitor, a bile acid-adsorbing ion exchange resin, a fibrate, a nicotinic acid derivative, an angiotensin II inhibitor, and a diuretic as an active ingredient Containing pharmaceutical composition,
(52) The compound represented by the general formula (I) described in any one of (1) to (50) or a pharmacologically acceptable salt or ester thereof; and an HMG-CoA reductase inhibitor, CETP inhibition A pharmaceutical composition comprising as an active ingredient one or more medicaments selected from the group consisting of an agent and a cholesterol absorption inhibitor,
(53) A compound represented by the general formula (I) described in any one of (1) to (50) or a pharmacologically acceptable salt or ester thereof, and an HMG-CoA reductase inhibitor as an active ingredient A pharmaceutical composition containing as
(54) The pharmaceutical composition according to (53), wherein the HMG-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, or rosuvastatin, and
(55) The pharmaceutical composition according to (53), wherein the HMG-CoA reductase inhibitor is pravastatin, atorvastatin or rosuvastatin.

In the compound represented by the general formula (I) of the present invention, each substituent is defined as follows.

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 can be a 5-nonyloxy group, 4-ethyl-4-heptyloxy group, 4-decyloxy group, 5-decyloxy group, or 4- (1-propyl) -4-heptyloxy group, preferably C ₁ A —C ₈ alkoxy group, more preferably a C ₁ -C ₆ alkoxy group, even more preferably a C ₂ -C ₆ alkoxy group, and even more preferably a C ₃ -C ₆ alkoxy group. a group, particularly preferably, C ₃ -C ₅ alkoxy group (in particular, 2-propoxy, 2-methyl-2-propoxy or 2-methyl-2-butoxy group), most preferably, 2-methyl Ru-2-propoxy group.

The “C ₁ -C ₄ alkyl group” in R ⁴ , R ⁵ , R ¹⁶ and the substituent group α in the general formula (I) is a linear or branched alkyl having 1 to 4 carbon atoms. For example, methyl group, ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-1-propyl group, or 2-methyl-2-propyl group. it is a group, preferably a C ₁ -C ₃ alkyl group, more preferably a methyl group or an ethyl group, and most preferably a methyl group.

“C ₁ -C ₄ alkoxy group” in R ² , R ⁴ , R ⁵ and the substituent group α in the general formula (I) is a hydroxyl group substituted with _one C ₁ -C ₄ alkyl group. For example, a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-butoxy group, or a 2-methyl-2-propoxy group, and preferably a C an ₁ -C ₃ alkoxy group, more preferably a methoxy group or an ethoxy group, most preferably a methoxy 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 phenylmethoxy group or a 1-phenylethoxy group.

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-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, 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-heptylamino group, 3-heptylamino group, 4-heptylamino group, 3-methyl-3-hexylamino group, 3-ethyl-3-pentylamino group, 3-octylamino group, 4-octyl group Amino 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- be a propyl) -4-heptylamino 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, even more preferably, C ₃ -C ₅ alkylamino group (particularly, 2-propylamino group, 2-methyl-2-propylamino group or a 2-methyl-butyronitrile An amino group), 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 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. Is a group.

The “halogeno C ₁ -C ₄ alkyl group” in R ² , R ⁴ , R ⁵ and the substituent group α in the general formula (I) is the above C _1- substituted with 1 to 5 of the following halogeno groups C ₄ alkyl 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-fluoro butyl group, or, may be a 4,4,4-trifluoro-butyl group, preferably a halogeno C ₁ -C ₂ alkyl group ( The halogeno C ₁ -C ₂ alkyl group is 1 to indicate the five C ₁ -C ₂ alkyl group substituted with halogeno group), more preferably a trifluoromethyl group, 2,2,2 -A trifluoroethyl group or a pentafluoroethyl group, and most preferably a trifluoromethyl group.

The “C ₁ -C ₄ alkylamino group” in R ² of the general formula (I) is an amino group substituted with _one C ₁ -C ₄ alkyl group, for example, a methylamino group, an ethylamino group Propylamino group (for example, 1-propylamino group, 2-propylamino group), 1-butylamino group, 2-butylamino group, 2-methyl-1-propylamino group, or 2-methyl-2- it is a propylamino group, preferably a C ₁ -C ₃ alkylamino group, more preferably a methylamino group or an ethylamino group, and most preferably a methylamino group.

The “di (C ₁ -C ₄ alkyl) amino group” in R ² of the general formula (I) is an amino group substituted with the same or different two C ₁ -C ₄ alkyl groups described above. 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], 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 and the like], di (1-butyl) amino group, di (2-butyl) amino group, di (2-methyl-1-propyl) amino group, or di (2-methyl-2-propyl) obtained an amino group, preferably a di (C ₁ -C ₃ a A dimethyl) amino group (the alkyl groups are the same or different), more preferably a dimethylamino group, a methylethylamino group, a methylpropylamino group, a diethylamino group, an ethylpropylamino group, or a dipropylamino group. More preferably a dimethylamino group or a diethylamino group, and most preferably a 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.

“C ₁ -C ₆ alkyl group” in R ³ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , substituent group β, and substituent group γ in the general formula (I) is 1 to 6 Straight chain or branched chain alkyl groups having one carbon atom, for example, 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 It is a 2,3-dimethyl-1-butyl group, preferably a C ₁ -C ₄ alkyl group, More preferred is a C ₁ -C ₃ alkyl group (particularly a methyl group, ethyl group or propyl group), further preferred is a methyl group or ethyl group, and most preferred is a methyl group.

“Halogeno C ₁ -C ₆ alkyl group” in R ³ of general formula (I) and substituent group β is the above C ₁ -C ₆ alkyl group substituted with 1 to 7 of the above halogeno groups, 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, 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, Others, 6,6,6 be a trifluoromethyl hexyl, preferably halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, substituted by 1 to 5 halogeno groups a is showing a C ₁ -C ₄ alkyl group was), and more preferably a halogeno C ₁ -C ₄ alkyl group (said halogeno C ₁ -C ₄ alkyl groups, 1 to 5 fluoro, chloro or bromo A C ₁ -C ₄ alkyl group substituted with a group, and even more preferably a trifluoromethyl group, a 2,2,2-trifluoroethyl group, or a pentafluoroethyl group, especially A trifluoromethyl group or a 2,2,2-trifluoroethyl group is preferable, and a trifluoromethyl group is most preferable.

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.

R ³ in the general formula (I) - C ₁ -C ₄ alkylthio moiety of the "(C ₁ -C ₄ alkylthio) (C ₁ -C ₄ -alkyl) group", one of the C ₁ -C ₄ group A mercapto group substituted with, 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.

R ³ in the general formula (I) - C ₁ -C ₄ alkylsulfinyl moiety of the "(C ₁ -C ₄ alkylsulfinyl) (C ₁ -C ₄ alkyl) group", one of the C ₁ -C ₄ A sulfinyl group (—SO—) substituted with an alkyl group, for example, a methylsulfinyl group, an ethylsulfinyl group, a 1-propylsulfinyl group, a 2-propylsulfinyl group, a 1-butylsulfinyl group, a 2-butylsulfinyl group, or it may be a 2-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, A methylsulfinyl group;

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. .

R ³ in the general formula (I) "(C ₁ -C ₄ alkylsulfonyl) - (C ₁ -C ₄ alkyl) group" C ₁ -C ₄ alkylsulfonyl moieties of, one of the C ₁ -C ₄ A sulfonyl group (—SO ₂ —) substituted with an alkyl group, for example, a methanesulfonyl group, an ethanesulfonyl group, a 1-propanesulfonyl group, a 2-propanesulfonyl group, a 1-butanesulfonyl group, a 2-butanesulfonyl group; or it can be a 2-methyl-2-propanesulfonyl group, preferably a C ₁ -C ₃ alkylsulfonyl group, more preferably a methanesulfonyl group or an ethanesulfonyl group, and most preferably , A methanesulfonyl group.

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 ₃ -C ₆ cycloalkyl group” in R ³ , R ⁴ and R ⁵ in the general formula (I) is a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group or a cyclobutyl group. , cyclopentyl group or may be a cyclohexyl group, preferably a C ₃ -C ₅ cycloalkyl group, more preferably a C ₃ -C ₄ cycloalkyl group, and most preferably, cyclopropyl It is a group.

The “C ₂ -C ₆ alkenyl group” in R ³ of the general formula (I) is an alkenyl group having 1 to 2 carbon-carbon double bonds and 2 to 6 carbon atoms, such as a 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 2-hexenyl be a group, preferably, it is a C ₂ -C ₄ alkenyl group, more preferably a C ₂ -C ₃ alkenyl group, 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 preferably a C ₂ -C ₃ alkynyl group, and most preferably an ethynyl group.

The “C ₁ -C ₆ alkoxy group” in R ³ , R ¹¹ , substituent group β, and substituent group γ of general formula (I) was substituted with one of the above C ₁ -C ₆ alkyl groups. A hydroxyl group, 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-pentyloxy group, 3-methyl-1-pentyloxy group, 2-ethyl-1-butoxy group, 2,2-dimethyl-1-butoxy group, or 2,3 -Dimethyl-1-butoxy It is a group, preferably a C ₁ -C ₄ alkoxy group, more preferably, C ₁ -C ₃ alkoxy groups (particularly, methoxy, ethoxy or propoxy group), further preferably , A methoxy group or an ethoxy group, and most preferably a methoxy group.

"Halogeno C ₁ -C ₆ alkoxy group" in R ³ and Substituent group of the general formula (I) beta is 1 to 7 of the aforementioned halogeno group substituted the C ₁ -C ₆ alkyl group, for example, , 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-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoro-1-propoxy group, 1,1-trifluoro-2-propoxy group, 1,1,1-trichloro-2-propoxy group, 4,4,4-trifluoro-1-butoxy group, 4,4,4-tri Fluoro-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-tri Fluoro-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-trif Oro-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 _{The 1} -C ₄ alkoxy group is a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups, and more preferably a halogeno C ₁ -C ₂ alkoxy group (the halogeno C ₁ -C ₂ alkoxy group represents a C ₁ -C ₂ alkoxy group substituted with 1 to 5 fluoro, chloro or bromo groups, and even more preferably a trifluoromethoxy group, 2, 2, It is a 2-trifluoroethoxy group or a pentafluoroethoxy group, and most preferably a trifluoromethoxy group.

The “C ₁ -C ₆ alkylthio group” in R ³ , the substituent group β, and the substituent group γ in the general formula (I) is a mercapto group substituted with _one C ₁ -C ₆ alkyl group. Yes, 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, 2-ethyl-1-butylthio group, 2,2-dimethyl-1-butylthio group, or 2,3-dimethyl-1-buty It is a thio group, preferably a C ₁ -C ₄ alkylthio group, more preferably a C ₁ -C ₃ alkylthio group (in particular, methylthio group, ethylthio group or propylthio group), further preferably Is a methylthio group or an ethylthio group, and most preferably a methylthio group.

“C ₁ -C ₆ alkylsulfinyl group” in R ³ , substituent group β, and substituent group γ of general formula (I) is a sulfinyl group substituted with _one C ₁ -C ₆ alkyl group. (-SO-), 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 In 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 a C ₁ -C ₄ alkylsulfinyl group, more preferably a C ₁ -C ₃ alkylsulfinyl group (especially a methylsulfinyl group, an ethylsulfinyl group or a propylsulfinyl group), Preferred is a methylsulfinyl group or ethylsulfinyl group, and most preferred is a methylsulfinyl group.

The “C ₁ -C ₆ alkylsulfonyl group” in R ³ , substituent group β, and substituent group γ of the general formula (I) is a sulfonyl group substituted with _one C ₁ -C ₆ alkyl group. (-SO ₂ -) a and, for example, methanesulfonyl group, ethanesulfonyl group, 1-propanesulfonyl group, a 2-propanesulfonyl group, a 1-butanesulfonyl group, a 2-butanesulfonyl group, 2-methyl-1-propane Sulfonyl 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-pentane sulfonyl group, 2-ethyl-1-butanesulfonyl group, 2,2-dimethyl-1-butanesulfonyl group, or, can be a 2,3-dimethyl-1-butanesulfonyl group, preferably, C ₁ -C is ₄ alkylsulfonyl group, and more preferably, C ₁ -C ₃ alkylsulfonyl group (particularly a methanesulfonyl group, an ethanesulfonyl group or a propanesulfonyl group), and more preferably, methanesulfonyl group, or An ethanesulfonyl group, most preferably a methanesulfonyl group.

The “C ₁ -C ₆ alkylamino group” in R ³ , R ¹¹ , R ¹² , substituent group β, and substituent group γ in the general formula (I) is one C ₁ -C ₆ alkyl group. For example, methylamino group, ethylamino group, 1-propylamino group, 2-propylamino group, 1-butylamino group, 2-butylamino group, 2-methyl-1-propyl Amino 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 it may be a 2,3-dimethyl-1-butylamino group, preferably a C ₁ -C ₄ alkylamino group, more preferably, C ₁ -C ₃ alkylamino group ( In particular, a methylamino group, an ethylamino group, or a propylamino group), more preferably a methylamino group or an ethylamino group, and most preferably a methylamino group.

“Di (C ₁ -C ₆ alkyl) amino group” in R ³ , R ¹¹ , R ¹² , substituent group β, and substituent group γ in formula (I) is the same or different two C an amino group substituted with ₁ -C ₆ alkyl group, for example, dimethylamino group, methylethylamino group, methylpropylamino group [for example, N-(1-propyl) -N- methylamino group, etc.], methyl Butylamino group [eg N- (1-butyl) -N-methylamino group etc.], diethylamino group, ethylpropylamino group [eg N- (1-propyl) -N-ethylamino group etc.], dipropyl Amino 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, di Nylamino group [eg, di (1-pentyl) 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, etc.], preferably a di (C ₁ -C ₄ alkyl) amino group, more preferably di (C an ₁ -C ₃ alkyl) amino group, more preferably a dimethylamino group or diethylamino group, 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 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. Nyl group.

The “(C ₁ -C ₆ alkoxy) carbonyl group” in R ³ of the general formula (I) and substituent group β is a carbonyl group (—CO—) substituted with one of the above C ₁ -C ₆ alkoxy groups. 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, 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 Til-1-pentyloxycarbonyl group, 3-methyl-1-pentyloxycarbonyl group, 2-ethyl-1-butoxycarbonyl group, 2,2-dimethyl-1-butoxycarbonyl group, or 2,3-dimethyl- It can be a 1-butoxycarbonyl group, preferably a (C ₁ -C ₄ alkoxy) carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, most preferably a methoxycarbonyl group. is there.

The “halogeno C ₁ -C ₄ alkoxy group” in R ⁴ and R ⁵ of the general formula (I) is the above C ₁ -C ₄ alkoxy group substituted with 1 to 5 of the above halogeno groups, for example, fluoro Methoxy 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-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoro-1-propoxy group, 1,1, 1-trifluoro-2-propoxy group, 1,1,1-trichloro-2-propoxy group, 4,4,4-trifluoro-1-butoxy group, 4,4,4-trifluoro B-2-butoxy group, 2-trifluoromethyl-1-propoxy group or, can be a 2-trifluoromethyl-2-propoxy group, preferably a halogeno C ₁ -C ₂ alkoxy group (said 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, 2,2,2-trifluoro group. An ethoxy 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 ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) oxy group” in R ¹¹ of the general formula (I) is the above substituted with one C ₃ -C ₈ cycloalkyl group below. C ₁ -C ₆ alkoxy group, for example, cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group, cyclohexylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxy group, 2- Cyclobutylethoxy group, 2-cyclopentylethoxy group, 2-cyclohexylethoxy group, 2-cycloheptylethoxy group, 3-cyclopropyl-1-propoxy group, 2-cyclopropyl-1-propoxy group, 2-cyclopropyl-2 -Propoxy group, 3-cyclobutyl-1-propoxy group, 3-cyclopentyl-1-propoxy group 3-cyclohexyl-1-propoxy group, 4-cyclopropyl-1-butoxy group, 4-cyclopropyl-2-butoxy group, 3-cyclopropyl-2-methyl-1-propoxy group, 3-cyclopropyl-2 -Methyl-2-propoxy group, 4-cyclobutyl-1-butoxy group, 5-cyclopropyl-1-pentyloxy group, 5-cyclopropyl-2-pentyloxy group, 5-cyclopropyl-3-pentyloxy group, 4-cyclopropyl-2-methyl-2-butoxy group, 4-cyclopropyl-3-methyl-2-butoxy group, 6-cyclopropyl-1-hexyloxy group, 6-cyclopropyl-2-hexyloxy group, 6-cyclopropyl-3-hexyloxy group, 5-cyclopropyl-2-methyl-1-pentyloxy group, 5-cyclopropyl 3-methyl-1-pentyloxy group, 4-cyclopropyl-2-ethyl-1-butoxy group, 4-cyclopropyl-2,2-dimethyl-1-butoxy group, or 4-cyclopropyl-2,3 -Dimethyl-1-butoxy group, preferably a (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy group, more preferably (C ₃ -C ₅ cycloalkyl). Alkyl)-(C ₁ -C ₂ alkyl) oxy group, more preferably (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy group, most preferably cyclo A propylmethyloxy group;

“C ₃ -C ₈ cycloalkyloxy group” in R ¹¹ of the general formula (I) and substituent group γ is a hydroxyl group substituted with one C ₃ -C ₈ cycloalkyl group shown below, for example, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyl group or, can be a cyclooctyl group, preferably is C ₃ -C ₆ cycloalkyl group, and more preferably a C ₃ -C ₄ cycloalkyl group, and most preferably a cyclopropyl group.

The “[(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group” in R ¹¹ and R ¹² of the general formula (I) represents one of the following C ₃ -C ₈ cycloalkyl groups: The C ₁ -C ₆ alkylamino group substituted with, for example, cyclopropylmethylamino group, cyclobutylmethylamino group, cyclopentylmethylamino group, cyclohexylmethylamino group, cyclohexylmethylamino group, 1-cyclopropylethyl Amino group, 2-cyclopropylethylamino group, 2-cyclobutylethylamino group, 2-cyclopentylethylamino group, 2-cyclohexylethylamino group, 2-cycloheptylethylamino group, 3-cyclopropyl-1-propylamino Group, 2-cyclopropyl-1-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-butyl Amino group, 3-cyclopropyl-2-methyl-1-propylamino group, 3-cyclopropyl-2-methyl-2-propylamino group, 4-cyclobutyl-1-butylamino group, 5-cyclopropyl-1- Pentylamino group, 5-cyclopropyl-2-pentylamino group, 5-cyclopropyl-3-pentylamino group, 4-cyclopropyl-2-methyl-2-butylamino group, 4-cyclopropyl-3-methyl- 2-butylamino group, 6-cyclopropyl-1-hexylamino group, 6-cyclopropyl-2-hexylamino group, -Cyclopropyl-3-hexylamino group, 5-cyclopropyl-2-methyl-1-pentylamino group, 5-cyclopropyl-3-methyl-1-pentylamino group, 4-cyclopropyl-2-ethyl-1 -Butylamino group, 4-cyclopropyl-2,2-dimethyl-1-butylamino group, or 4-cyclopropyl-2,3-dimethyl-1-butylamino group, preferably (C _3- C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) amino group, more preferably (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) amino group, A (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) amino group is preferred, and a cyclopropylmethylamino group is most preferred.

“C ₃ -C ₈ cycloalkylamino group” in R ¹¹ , R ¹² , substituent group β, and substituent group γ of general formula (I) is one of the following C ₃ -C ₈ cycloalkyl groups: A substituted amino group, for example, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, or a cyclooctylamino group, and preferably a C _3- A C ₆ cycloalkylamino group, more preferably a C ₃ -C ₄ cycloalkylamino group, and most preferably a cyclopropylamino group.

The “di [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group” in R ¹¹ and R ¹² of the general formula (I) is the same or different two (C ₃ — C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl) amino group substituted with a group, for example, di (cyclopropylmethyl) amino group, N- cyclopropylmethyl -N- cyclobutylmethyl amino group, N -Cyclopropylmethyl-N-cyclopentylmethylamino group, N-cyclopropylmethyl-N-cyclohexylmethylamino group, N-cyclopropylmethyl-N-cycloheptylmethylamino group, N-cyclopropylmethyl-N-cyclooctylmethyl Amino group, N-cyclopropylmethyl-N-cyclopropylethylamino group, N-cyclopropylmethyl-N- (3-cyclopropyl-1-propyl) It may be a mino group, a di (cyclobutylmethyl) amino group, a di (cyclopentylmethyl) amino group, a di (cyclohexylmethyl) amino group, a di (cycloheptylmethyl) amino group, or a di (cyclooctylmethyl) amino group. , Preferably a di [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, more preferably a di [(C ₃ -C ₅ cycloalkyl)-(C _1- C ₂ alkyl)] amino group, more preferably a di [(C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl)] amino group, most preferably di ( Cyclopropylmethyl) amino group.

The “di (C ₃ -C ₈ cycloalkyl) amino group” in R ¹¹ , R ¹² , substituent group β, and substituent group γ of the general formula (I) is the same or different two C ₃ — An amino group substituted with a C ₈ cycloalkyl group, such as a dicyclopropylamino group, an N-cyclopropyl-N-cyclobutylamino group, an N-cyclopropyl-N-cyclopentylamino group, an N-cyclopropyl- group; N-cyclohexylamino group, N-cyclopropyl-N-cycloheptylamino group, N-cyclopropyl-N-cyclooctylamino group, dicyclobutylamino group, dicyclopentylamino group, dicyclohexylamino group, dicycloheptylamino group or can be a di-cyclooctyl group, preferably a di (C ₃ -C ₆ cycloalkyl) amino group, more preferably a A di (C ₃ -C ₄ cycloalkyl) amino group, and most preferably a dicyclopropylamino group.

Formula in R ¹¹ and R ¹² of (I) "N - [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 1 -C} 6 alkyl) amino group" One amino group substituted with the following (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group and one above-mentioned C ₁ -C ₆ alkyl group, such as N -Cyclopropylmethyl-N-methylamino group, N-cyclopropylmethyl-N-ethylamino group, N-cyclopropylmethyl-N-propylamino group, N-cyclopropylmethyl-N-butylamino group, N-cyclo Propylmethyl-N-pentylamino group, N-cyclopropylmethyl-N-hexylamino group, N-cyclopropylethyl-N-methylamino group, N- (3-cyclopropyl-1-propyl) -N-methylamino Group, N-cyclobutylmethyl -N-methylamino group, N-cyclopentylmethyl-N-methylamino group, N-cyclohexylmethyl-N-methylamino group, N-cycloheptylmethyl-N-methylamino group, or N-cyclooctylmethyl-N - it can be a methylamino group, preferably _{a, N - [(C 3 -C} 6 cycloalkyl) - (C ₁ -C ₄ alkyl)] - N-a (C ₁ -C ₄ alkyl) amino group, N-[(C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl)]-N- (C ₁ -C ₂ alkyl) amino group is more preferable, and N-[(C ₁ -C ₂ alkyl) amino group is more preferable. a [(C ₃ -C ₄ cycloalkyl) methyl] -N- methylamino group, and most preferably a N- cyclopropylmethyl -N- methylamino group.

“N— (C ₃ -C ₈ cycloalkyl) -N— (C ₁ -C ₆ alkyl) amino group” in R ¹¹ , R ¹² , substituent group β, and substituent group γ of formula (I) Is an amino group substituted with one of the following C ₃ -C ₈ cycloalkyl groups and one of the above C ₁ -C ₆ alkyl groups, for example, an N-cyclopropyl-N-methylamino group, N-cyclopropyl-N-ethylamino group, N-cyclopropyl-N-propylamino group, N-cyclopropyl-N-butylamino group, N-cyclopropyl-N-pentylamino group, N-cyclopropyl-N -Hexylamino group, N-cyclobutyl-N-methylamino group, N-cyclopentyl-N-methylamino group, N-cyclohexyl-N-methylamino group, N-cycloheptyl-N-methylamino group, or N- Cycloot It may be a octyl-N-methylamino group, preferably N- (C ₃ -C ₆ cycloalkyl) -N- (C ₁ -C ₄ alkyl) amino group, more preferably N- ( a C ₃ -C ₄ cycloalkyl) -N- (C ₁ -C ₂ alkyl) amino group, more preferably a N- (C ₃ -C ₄ cycloalkyl) -N- methylamino group, most N-cyclopropyl-N-methylamino group is preferable.

“N — [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)]-N— (C ₃ -C ₈ cycloalkyl) amino group” in R ¹¹ and R ¹² of formula (I) Is an amino group substituted with one (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group and one C ₃ -C ₈ cycloalkyl group, for example, N-cyclopropylmethyl-N-cyclopropylamino group, N-cyclobutylmethyl-N-cyclopropylamino group, N-cyclopentylmethyl-N-cyclopropylamino group, N-cyclohexylmethyl-N-cyclopropylamino group N-cycloheptylmethyl-N-cyclopropylamino group, N-cyclooctylmethyl-N-cyclopropylamino group, N-cyclopropylethyl-N-cyclopropylamino group, N- (3-cyclopropyl 1-propyl) -N-cyclopropylamino group, N-cyclopropylmethyl-N-cyclobutylamino group, or N-cyclopropylmethyl-N-cyclopentylamino group, preferably N- [(C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl)] - N-a (C ₃ -C ₆ cycloalkyl) amino group, more preferably, N - [(C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl)]-N- (C ₃ -C ₄ cycloalkyl) amino group, more preferably N-[(C ₃ -C ₄ cycloalkyl) methyl] a -N- (C ₃ -C ₄ cycloalkyl) amino group, most preferably a N- cyclopropylmethyl -N- cyclopropylamino group.

The “hydroxyl (C ₁ -C ₆ alkyl) amino group” in R ¹¹ of the general formula (I) is an amino group substituted with one of the above C ₁ -C ₆ alkyl groups and one hydroxyl group, For example, hydroxyl (methyl) amino group, hydroxyl (ethyl) amino group, hydroxyl (1-propyl) amino group, hydroxyl (2-propyl) amino group, hydroxyl (1-butyl) amino group, hydroxyl (2-butyl) amino Group, hydroxyl (2-methyl-1-propyl) amino group, hydroxyl (2-methyl-2-propyl) amino group, hydroxyl (1-pentyl) amino group, hydroxyl (2-pentyl) amino group, hydroxyl (3- Pentyl) amino group, hydroxyl (2-methyl-2-butyl) amino group, hydroxyl (3-methyl-2-butyl) amino group, hydroxyl (2- Methyl-2-butyl) amino group, hydroxyl (1-hexyl) amino group, hydroxyl (2-hexyl) amino group, hydroxyl (3-hexyl) amino group, hydroxyl (2-methyl-1-pentyl) amino group, hydroxyl (3-methyl-3-pentyl) amino group, hydroxyl (2-ethyl-1-butyl) amino group, hydroxyl (2,3-dimethyl-1-butyl) amino group, hydroxyl (1-heptyl) amino group, hydroxyl (3-heptyl) amino group, hydroxyl (4-heptyl) amino group, hydroxyl (3-methyl-3-hexyl) amino group, hydroxyl (3-ethyl-3-pentyl) amino group, hydroxyl (3-octyl) amino Group, hydroxyl (4-octyl) amino group, hydroxyl (3-ethyl-3-hexyl) amino group, hydroxyl (4-nonyl) Amino group, hydroxyl (5-nonyl) amino group, hydroxyl (4-ethyl-4-heptyl) amino group, hydroxyl (4-decyl) amino group, hydroxyl (5-decyl) amino group, or hydroxyl [4- ( 1-propyl) -4-heptyl] amino group, preferably a hydroxyl (C ₁ -C ₄ alkyl) amino group, more preferably a hydroxyl (methyl) amino group or a hydroxyl (ethyl) amino group And most preferably a hydroxylmethylamino group.

“(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group” in R ¹² , R ¹³ , R ¹⁴ , R ^{15 in} the general formula (I) and substituent group β is one The C ₁ -C ₆ alkyl group substituted by the following C ₃ -C ₈ cycloalkyl group, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclohexane Octylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2-cyclobutylethyl group, 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2-cycloheptylethyl group, 3-cyclopropyl-1 -Propyl group, 2-cyclopropyl-1-propyl group, 2-cyclopropyl-2-propyl group, 3-cyclobutyl-1-propyl group, 3-cyclope N-yl-1-propyl group, 3-cyclohexyl-1-propyl group, 4-cyclopropyl-1-butyl group, 4-cyclopropyl-2-butyl group, 3-cyclopropyl-2-methyl-1-propyl group, 3-cyclopropyl-2-methyl-2-propyl group, 4-cyclobutyl-1-butyl group, 5-cyclopropyl-1-pentyl group, 5-cyclopropyl-2-pentyl group, 5-cyclopropyl-3- Pentyl group, 4-cyclopropyl-2-methyl-2-butyl group, 4-cyclopropyl-3-methyl-2-butyl group, 6-cyclopropyl-1-hexyl group, 6-cyclopropyl-2-hexyl group 6-cyclopropyl-3-hexyl group, 5-cyclopropyl-2-methyl-1-pentyl group, 5-cyclopropyl-3-methyl-1-pentyl group, 4-silane It may be a ropropyl-2-ethyl-1-butyl group, a 4-cyclopropyl-2,2-dimethyl-1-butyl group, or a 4-cyclopropyl-2,3-dimethyl-1-butyl group, and preferably Is a (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) group, more preferably a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group. More preferably a (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl) group, even more preferably a cyclopropylmethyl group or a cyclopropylethyl group, most preferably a cyclopropyl group. Propylmethyl group.

R ¹² , R ¹³ , R ¹⁴ , R ^{15 in} the general formula (I) and the “C ₃ -C ₈ cycloalkyl group” in the substituent group β are cyclic alkyl groups having 3 to 8 carbon atoms. There, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or be a cyclooctyl group, preferably a C ₃ -C ₆ cycloalkyl group, more preferably, a C ₃ -C ₅ cycloalkyl group, more preferably a C ₃ -C ₄ cycloalkyl group (cyclopropyl group or a cyclobutyl group), and most preferably a cyclopropyl group.

The “C ₁ -C ₄ alkylene group” in X ² of the general formula (I) is an alkylene group having 1 to 4 carbon atoms, such as a methylene group, an ethylene group [— (CH ₂ ) ₂ —]. , Methylmethylene group [—CH (Me) —], trimethylene group [— (CH ₂ ) ₃ —], methylethylene group [—CH (Me) CH ₂ — or —CH ₂ CH (Me) —], tetramethylene Group [— (CH ₂ ) ₄ —], methyltrimethylene group [—CH (Me) CH ₂ CH ₂ —, —CH ₂ CH (Me) CH ₂ — or —CH ₂ CH ₂ CH (Me) —] There resulting, preferably, a C ₁ -C ₃ alkylene group, more preferably a methylene group or an ethylene group, and most preferably a methylene group.

The “5- to 6-membered aromatic heterocyclyl group” in Y ¹ of the general formula (I) is a 5- to 6-membered aromatic containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Heterocyclic groups such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl , A pyranyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, or a pyrazinyl group, preferably a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, or a pyridyl group, More preferably, it is a thienyl group or a pyridyl group, and most preferably It is a lysyl group.

The “6- to 10-membered aryl group” in Y ² of the general formula (I) is a 6- to 10-membered aromatic hydrocarbon group, for example, a phenyl group or a naphthyl group, preferably a phenyl group. .

The “9 to 10-membered unsaturated cyclic hydrocarbon group” in Y ² of the general formula (I) is a group in which a 9 to 10-membered aromatic hydrocarbon group is partially reduced and is not a saturated hydrocarbon group. , Y ¹ represents a group in which the cyclic group bonded to Y ¹ is a phenyl group. The 9 to 10-membered unsaturated cyclic hydrocarbon group can be, for example, an indanyl group or a tetrahydronaphthyl group, and is preferably an indanyl group.

The “5- to 10-membered aromatic heterocyclyl group” in Y ² 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. A heterocyclic group, for example, furyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, tetrazolyl group, pyridyl group, Pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl, azosinyl, azosinyl, indolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazo Ryl, quinolyl, isoquino Group, quinoxalinyl group or quinazolinyl group, preferably a 5- to 6-membered aromatic heterocyclyl group, more preferably a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group Group, pyridyl group or pyrimidinyl group, more preferably thienyl group, thiazolyl group or pyridyl group, and most preferably pyridyl group.

"9 to 10 membered unsaturated heterocyclyl group" for Y ² in the general formula (I), 9 to 10 membered aromatic heterocyclyl group is a partially reduced group, rather than a saturated heterocyclyl group, the Y ¹ A cyclic group to be bonded is an aromatic ring group. The 9 to 10-membered unsaturated heterocyclyl group may be, for example, an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group, and preferably an indolinyl group, a dihydrobenzofuryl group, Or, it is a dihydrobenzothienyl group.

The “hydroxy (C ₁ -C ₆ alkyl) group” in the substituent group β and the substituent group γ of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted by one hydroxyl group, For example, hydroxymethyl group, hydroxyethyl group, hydroxy (1-propyl) group, hydroxy (2-propyl) group, hydroxy (1-butyl) group, hydroxy (2-butyl) group, hydroxy (2-methyl-1- propyl) group, hydroxy (2-methyl-2-propyl) group, a hydroxy (1-pentyl) group or may be a hydroxy (1-hexyl) group, preferably a hydroxy (C ₁ -C ₄ alkyl) a group, more preferably a hydroxy (C ₁ -C ₃ alkyl) group (particularly hydroxymethyl group, hydroxyethyl group or hydroxypropyl group), more preferably, hydroxymethyl group or A Dorokishiechiru group, most preferably a hydroxymethyl group.

The “carboxy (C ₁ -C ₆ alkyl) group” in the substituent group β of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted with one carboxyl group, such as a carboxymethyl group Carboxyethyl group, carboxy (1-propyl) group, carboxy (2-propyl) group, carboxy (1-butyl) group, carboxy (2-butyl) group, carboxy (2-methyl-1-propyl) group, carboxy It can be a (2-methyl-2-propyl) group, a carboxy (1-pentyl) group, or a carboxy (1-hexyl) group, preferably a carboxy (C ₁ -C ₄ alkyl) group, and more preferably, carboxy (C ₁ -C ₃ alkyl) group (particularly a carboxymethyl group, a carboxyethyl group or carboxypropyl group), more preferably, a carboxymethyl group or a carboxyethyl In it, and most preferably a carboxymethyl group.

The “(C ₁ -C ₆ alkoxy) carbonyl- (C ₁ -C ₆ alkyl) group” in the substituent group β of the general formula (I) is substituted with one (C ₁ -C ₆ alkoxy) carbonyl group described below. is the C ₁ -C ₆ alkyl group, for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, butoxycarbonylmethyl group, pentyloxycarbonyl methyl group, hexyloxy carbonyl methyl group, a methoxycarbonylethyl group, methoxycarbonyl propyl, methoxycarbonyl butyl group, a methoxycarbonyl pentyl group, or, can be a methoxycarbonyl hexyl, preferably, (C ₁ -C ₄ alkoxy) carbonyl - (C ₁ -C ₄ alkyl) group And more preferably (C ₁ -C ₂ alkoxy) carbonyl- (C ₁ -C ₂ alkyl) group, more preferably a methoxycarbonylmethyl group or a methoxycarbonylethyl group, and most preferably a methoxycarbonylmethyl group.

The “C ₂ -C ₇ alkenyl group” in the substituent group β of the general formula (I) is a linear or branched alkenyl group having 2 to 7 carbon atoms (one or more carbon-carbon double bonds) For example, vinyl group, 2-propenyl group (allyl group), 2-butenyl group, 2-pentenyl group, 3-methyl-2-butenyl group, 2-hexenyl group, 3 -Methyl-2-pentenyl group, 2-heptenyl group, or 3-ethyl-2-pentenyl group, preferably a C ₂ -C ₅ alkenyl group, more preferably C ₂ -C _{A 4-} alkenyl group, and most preferably a vinyl group or a 2-propenyl group.

The “C ₂ -C ₇ alkynyl group” in the substituent group β of the general formula (I) is a linear or branched alkynyl group having 2 to 7 carbon atoms (including one or more carbon-carbon triple bonds). For example, an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 2-pentynyl group, a 2-hexynyl group, or a 2-heptynyl group. a ₂ -C ₅ alkynyl group, and more preferably is C ₂ -C ₄ alkynyl group, most preferably, an ethynyl group or a 2-propynyl group.

The “(C ₁ -C ₆ alkyl) carbonylamino group” in the substituent group β of the general formula (I) is the above C ₁ -C ₆ alkyl group having one carbon atom of the carbonylamino group (—CONH—). Substituted groups, for example, methylcarbonylamino group, ethylcarbonylamino group, (1-propyl) carbonylamino group, (2-propyl) carbonylamino group, (1-butyl) carbonylamino group, (2-butyl) ) Carbonylamino group, (2-methyl-1-propyl) carbonylamino group, (2-methyl-2-propyl) carbonylamino group, (1-pentyl) carbonylamino group, or (1-hexyl) carbonylamino group And is preferably a (C ₁ -C ₄ alkyl) carbonylamino group, more preferably a (C ₁ -C ₃ alkyl) carbonylamino group, and even more preferably a methyl group. A carbonylamino group or an ethylcarbonylamino group, most preferably a methylcarbonylamino group.

The “(C ₃ -C ₈ cycloalkyl) carbonylamino group” in the substituent group β of the general formula (I) is the above C ₃ -C ₈ cycloalkyl having one carbon atom of the carbonylamino group (—CONH—). A group substituted with a group, for example, a cyclopropylcarbonylamino group, a cyclobutylcarbonylamino group, a cyclopentylcarbonylamino group, a cyclohexylcarbonylamino group, a cycloheptylcarbonylamino group, or a cyclooctylcarbonylamino group, A (C ₃ -C ₆ cycloalkyl) carbonylamino group is preferable, a (C ₃ -C ₅ cycloalkyl) carbonylamino group is more preferable, and a (C ₃ -C ₄ ) is more preferable. Cycloalkyl) carbonylamino group (cyclopropylcarbonylamino group or cyclobutylcarbonylamino group) And most preferably a cyclopropylcarbonylamino group.

The “N-[(C ₁ -C ₆ alkyl) carbonyl] -N— (C ₁ -C ₆ alkyl) amino group” in the substituent group β of the general formula (I) is the above (C ₁ -C ₆ alkyl). A group in which the nitrogen atom of the carbonylamino group is substituted with _one C ₁ -C ₆ alkyl group, for example, an N-methylcarbonyl-N-methylamino group, an N-ethylcarbonyl-N-methylamino group, N-propylcarbonyl-N-methylamino group, N-butylcarbonyl-N-methylamino group, N-pentylcarbonyl-N-methylamino group, N-hexylcarbonyl-N-methylamino group, N-methylcarbonyl-N -Ethylamino group, N-methylcarbonyl-N-propylamino group, N-methylcarbonyl-N-butylamino group, N-methylcarbonyl-N-pentylamino group, or N-methylcarbonyl It may be a rubonyl-N-hexylamino group, preferably N-[(C ₁ -C ₄ alkyl) carbonyl] -N— (C ₁ -C ₄ alkyl) amino group, more preferably N -[(C ₁ -C ₂ alkyl) carbonyl] -N- (C ₁ -C ₂ alkyl) amino group, more preferably N-methylcarbonyl-N-methylamino group or N-ethylcarbonyl-N A methylamino group, most preferably an N-methylcarbonyl-N-methylamino group.

The “N-[(C ₃ -C ₈ cycloalkyl) carbonyl] -N— (C ₁ -C ₆ alkyl) amino group” in the substituent group β of the general formula (I) is the above [(C ₃ -C ₈ A cycloalkyl) carbonylamino group in which the nitrogen atom is substituted with _one C ₁ -C ₆ alkyl group, such as N-cyclopropylcarbonyl-N-methylamino group, N-cyclobutylcarbonyl-N -Methylamino group, N-cyclopentylcarbonyl-N-methylamino group, N-cyclohexylcarbonyl-N-methylamino group, N-cycloheptylcarbonyl-N-methylamino group, N-cyclooctylcarbonyl-N-methylamino group N-cyclopropylcarbonyl-N-ethylamino group, N-cyclopropylcarbonyl-N-propylamino group, N-cyclopropylcarbonyl-N-butyl Arylamino group, N- cyclopropylcarbonyl -N- pentylamino group or can be a N- cyclopropylcarbonyl -N- hexylamino group, _{preferably, N - [(C 3 -C} 6 cycloalkyl) carbonyl] -N- (C ₁ -C ₄ alkyl) amino group, more preferably N-[(C ₃ -C ₅ cycloalkyl) carbonyl] -N- (C ₁ -C ₂ alkyl) amino group. More preferably N-[(C ₃ -C ₄ cycloalkyl) carbonyl] -N- (C ₁ -C ₂ alkyl) amino, most preferably N-cyclopropylcarbonyl-N-methyl. An amino group.

The “C ₁ -C ₆ alkylsulfonylamino group” in the substituent group β of the general formula (I) is an amino group substituted with _one C ₁ -C ₆ alkylsulfonyl group, for example, methanesulfonylamino Group, ethanesulfonylamino group, 1-propanesulfonylamino group, 2-propanesulfonylamino group, 1-butanesulfonylamino group, 2-butanesulfonylamino group, 2-methyl-1-propanesulfonylamino group, 2-methyl- 2-propanesulfonylamino group, 1-pentanesulfonylamino group, 2-pentanesulfonylamino group, 3-pentanesulfonylamino group, 2-methyl-2-butanesulfonylamino group, 3-methyl-2-butanesulfonylamino group, 1-hexanesulfonylamino group, 2-hexanesulfonylamino group, 3-hexa Sulfonylamino group, 2-methyl-1-pentanesulfonylamino group, 3-methyl-1-pentanesulfonylamino group, 2-ethyl-1-butanesulfonylamino group, 2,2-dimethyl-1-butanesulfonylamino group Or a 2,3-dimethyl-1-butanesulfonylamino group, preferably a C ₁ -C ₄ alkylsulfonylamino group, more preferably a methanesulfonylamino group or an ethanesulfonylamino group. And most preferably a methanesulfonylamino group.

The “N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₁ -C ₆ alkyl) amino group” in the substituent group β of the general formula (I) represents one of the above C ₁ -C ₆ alkylsulfonyl. Group and an amino group substituted by one C ₁ -C ₆ alkyl group, for example, N-methanesulfonyl-N-methylamino group, N-methanesulfonyl-N-ethylamino group, N-methanesulfonyl- N-propylamino group, N-methanesulfonyl-N-butylamino group, N-methanesulfonyl-N-pentylamino group, N-methanesulfonyl-N-hexylamino group, N-ethanesulfonyl-N-methylamino group, N-propanesulfonyl-N-methylamino group, N-butanesulfonyl-N-methylamino group, N-pentanesulfonyl-N-methylamino group, or N-hexanesulfo It is a Le -N- methylamino group, preferably a N- (C ₁ -C ₄ alkylsulfonyl) -N- (C ₁ -C ₄ alkyl) amino group, more preferably, N- ( C ₁ -C ₂ alkylsulfonyl) -N- (C ₁ -C ₂ alkyl) amino group, more preferably N-methanesulfonyl-N-methylamino group or N-ethanesulfonyl-N-methylamino group And most preferably an N-methanesulfonyl-N-methylamino group.

The “N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₃ -C ₈ cycloalkyl) amino group” in the substituent group β of the general formula (I) represents one of the above C ₁ -C ₆ alkyl. An amino group substituted with a sulfonyl group and one C ₃ -C ₈ cycloalkyl group, such as an N-methanesulfonyl-N-cyclopropylamino group, an N-methanesulfonyl-N-cyclobutylamino group, an N group; -Methanesulfonyl-N-cyclopentylamino group, N-methanesulfonyl-N-cyclohexylamino group, N-ethanesulfonyl-N-cyclopropylamino group, N-propanesulfonyl-N-cyclopropylamino group, N-butanesulfonyl- N-cyclopropylamino group, N-pentanesulfonyl-N-cyclopropylamino group, or N-hexanesulfonyl-N-cyclo It is a Ropiruamino group, preferably a N- (C ₁ -C ₄ alkylsulfonyl) -N- (C ₃ -C ₆ cycloalkyl) amino group, more preferably, N- (C ₁ -C ₂ alkylsulfonyl) -N- (C ₃ -C ₄ cycloalkyl) amino group, more preferably N-methanesulfonyl-N-cyclopropylamino group or N-ethanesulfonyl-N-cyclopropylamino group. And most preferred is an N-methanesulfonyl-N-cyclopropylamino group.

The “(C ₁ -C ₆ alkyl) carbonyl group” in the substituent group β of the general formula (I) is a carbonyl group (—CO—) substituted with _one C ₁ -C ₆ alkyl group, For example, methylcarbonyl group (acetyl group), ethylcarbonyl group, (1-propyl) carbonyl group, (2-propyl) carbonyl group, (1-butyl) carbonyl group, (2-butyl) carbonyl group, (2-methyl) -1-propyl) carbonyl group, (2-methyl-2-propyl) carbonyl group, (1-pentyl) carbonyl group, or (1-hexyl) carbonyl group, preferably (C ₁ -C ₄ alkyl) carbonyl group, more preferably a (C ₁ -C ₃ alkyl) carbonyl group, still more preferably a methylcarbonyl group or an ethylcarbonyl group, most preferably a methylcarbonyl group. is there.

The “(C ₁ -C ₆ alkylamino) carbonyl group” in the substituent group β of the general formula (I) is a carbonyl group (—CO—) substituted with _one C ₁ -C ₆ alkylamino group. Yes, for example, methylaminocarbonyl group, ethylaminocarbonyl group, (1-propylamino) carbonyl group, (2-propylamino) carbonyl group, (1-butylamino) carbonyl group, (2-butylamino) carbonyl group, It can be a (2-methyl-1-propylamino) carbonyl group, a (2-methyl-2-propylamino) carbonyl group, a (1-pentylamino) carbonyl group, or a (1-hexylamino) carbonyl group. the a (C ₁ -C ₄ alkylamino) carbonyl group, more preferably a (C ₁ -C ₃ alkylamino) carbonyl group, more preferably a methylaminocarbonyl Or an ethylaminocarbonyl group, and most preferably a methylaminocarbonyl group.

The “(C ₃ -C ₈ cycloalkylamino) carbonyl group” in the substituent group β of the general formula (I) is a carbonyl group (—CO—) substituted with one C ₃ -C ₈ cycloalkylamino group. For example, a cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, a cyclopentylaminocarbonyl group, a cyclohexylaminocarbonyl group, a cycloheptylaminocarbonyl group, or a cyclooctylaminocarbonyl group. a ₃ -C ₆ cycloalkylamino group, more preferably a C ₃ -C ₄ cycloalkyl aminocarbonyl group, and most preferably a cyclopropylamino group.

The “di (C ₁ -C ₆ alkyl) aminocarbonyl group” in the substituent group β of the general formula (I) is a carbonyl group substituted with _one di (C ₁ -C ₆ alkyl) amino group (— CO-), for example, dimethylaminocarbonyl group, (N-methyl-N-ethylamino) carbonyl group, (N-methyl-N-propylamino) carbonyl group [for example, [N- (1-propyl)- N-methylamino] carbonyl group etc.], (N-methyl-N-butylamino) carbonyl group [e.g. [N- (1-butyl) -N-methylamino] carbonyl group etc.], (N-methyl-N -Pentylamino) carbonyl group, (N-methyl-N-hexylamino) carbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group [for example, di (1-propyl) aminocarbonyl group, di (2-propyl) aminocarbonyl Such cycloalkenyl group, dibutyl amino group, dipentylamino group, or, can be a dihexylamino group, preferably a di (C ₁ -C ₄ alkyl) aminocarbonyl group (said alkyl group may be the same or different More preferably a di (C ₁ -C ₂ alkyl) aminocarbonyl group (the alkyl groups are the same or different), more preferably a dimethylaminocarbonyl group or a diethylaminocarbonyl group, Most preferred is a dimethylaminocarbonyl group. In the di (C ₁ -C ₆ alkyl) aminocarbonyl group, the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed, in which case the di (C ₁ -C ₆ alkyl) aminocarbonyl group is, for example, pyrrolidinylcarbonyl group, piperidylcarbonyl Group, a piperazinylcarbonyl group, a morpholinylcarbonyl group, or a thiomorpholinylcarbonyl group, preferably a pyrrolidinylcarbonyl group, a piperidylcarbonyl group, or a morpholinylcarbonyl group.

The “N- (C ₃ -C ₈ cycloalkyl) -N— (C ₁ -C ₆ alkyl) aminocarbonyl group” in the substituent group β of the general formula (I) represents one N- (C ₃ — C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group-substituted carbonyl group (—CO—), for example, N-cyclopropyl-N-methylaminocarbonyl group, N-cyclopropyl -N-ethylaminocarbonyl group, N-cyclopropyl-N-propylaminocarbonyl group, N-cyclopropyl-N-butylaminocarbonyl group, N-cyclopropyl-N-pentylaminocarbonyl group, N-cyclopropyl-N -Hexylaminocarbonyl group, N-cyclobutyl-N-methylaminocarbonyl group, N-cyclopentyl-N-methylaminocarbonyl group, N-cyclohexyl-N-methyla Bruno carbonyl group, N- cycloheptyl -N- methylaminocarbonyl group or may be a N- cyclooctyl -N- methylaminocarbonyl group, preferably, N- (C ₃ -C ₆ cycloalkyl) -N -(C ₁ -C ₄ alkyl) aminocarbonyl group, more preferably N- (C ₃ -C ₄ cycloalkyl) -N- (C ₁ -C ₂ alkyl) aminocarbonyl group, and more preferably Is an N- (C ₃ -C ₄ cycloalkyl) -N-methylaminocarbonyl group, and most preferably an N-cyclopropyl-N-methylaminocarbonyl group.

The “(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is the above C substituted with _one C ₁ -C ₆ alkoxy group. a ₁ -C ₆ alkyl group, e.g., methoxymethyl group, ethoxymethyl group, propoxymethyl group, butoxymethyl group, pentyloxymethyl group, hexyloxy group, a methoxyethyl group, methoxypropyl group, methoxybutyl group, methoxy It may be a pentyl group or a methoxyhexyl group, preferably a (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group, more preferably (C ₁ -C ₂ alkoxy). A — (C ₁ -C ₂ alkyl) group, more preferably a methoxymethyl group or a methoxyethyl group, and most preferably a methoxymethyl group.

The “mercapto (C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted with one mercapto group, for example, a mercaptomethyl group , Mercaptoethyl group, mercapto (1-propyl) group, mercapto (2-propyl) group, mercapto (1-butyl) group, mercapto (2-butyl) group, mercapto (2-methyl-1-propyl) group, mercapto (2-methyl-2-propyl) group, a mercapto (1-pentyl) group or can be a mercapto (1-hexyl) group, preferably a mercapto (C ₁ -C ₄ alkyl) group, more preferably, mercapto (C ₁ -C ₃ alkyl) group (particularly, mercaptomethyl group, mercaptoethyl group or mercaptopropyl group), more preferably, mercaptomethyl group or mercaptoethyl group There, most preferably a mercaptomethyl group.

The “(C ₁ -C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is the above C substituted with _one C ₁ -C ₆ alkylthio group. a ₁ -C ₆ alkyl group, for example, methylthiomethyl group, ethylthiomethyl group, propyl thio methyl group, butylthiomethyl group, pentylthio -thieno group, hexyl thiomethyl group, methylthioethyl group, methylthiopropyl group, methylthio butyl group, methylthio pentyl group or, can be a methyl thio hexyl group, preferably a, (C ₁ -C ₄ alkylthio) - a (C ₁ -C ₄ alkyl) group, more preferably, (C ₁ - A C ₂ alkylthio)-(C ₁ -C ₂ alkyl) group, more preferably a methylthiomethyl group or a methylthioethyl group, and most preferably a methylthiomethyl group.

The “(C ₁ -C ₆ alkylsulfinyl)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) was substituted with one of the above C ₁ -C ₆ alkylsulfinyl groups. the C ₁ -C ₆ alkyl group, for example, methylsulfinyl methyl, ethyl sulfinyl methyl, propyl sulfinyl methyl, butyl sulfinyl methyl, pentylsulfamoyl Fini Resid methyl, hexyl sulfinyl methyl group, methylsulfinyl ethyl group, methyl sulfinyl propyl, methylsulfinylbutyl group, methylsulfinyl point pen butyl group, or be a methylsulfinyl hexyl group, preferably a, (C ₁ -C ₄ alkylsulfinyl) - a (C ₁ -C ₄ alkyl) group, More preferably, (C ₁ -C ₂ alkylsulfinyl)-(C ₁ -C ₂ alkyl) More preferably a methylsulfinylmethyl group or a methylsulfinylethyl group, and most preferably a methylsulfinylmethyl group.

The “(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) was substituted with one of the above C ₁ -C ₆ alkylsulfonyl groups. The C ₁ -C ₆ alkyl group, for example, methanesulfonylmethyl group, ethanesulfonylmethyl group, propanesulfonylmethyl group, butanesulfonylmethyl group, pentanesulfonylcymethyl group, hexanesulfonylmethyl group, methanesulfonylethyl group, methane sulfonyl propyl group, methanesulfonyl butyl group, methanesulfonyl pentyl group or, it can be a methane sulfonyl hexyl group, preferably a, (C ₁ -C ₄ alkylsulfonyl) - a (C ₁ -C ₄ alkyl) group, More preferred is a (C ₁ -C ₂ alkylsulfonyl)-(C ₁ -C ₂ alkyl) group, and even more preferred is a meta A sulfonylsulfonyl group or a methanesulfonylethyl group, and most preferably a methanesulfonylmethyl group.

The “amino (C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is the above C ₁ -C ₆ alkyl group substituted with one amino group, such as an aminomethyl group Aminoethyl group, amino (1-propyl) group, amino (2-propyl) group, amino (1-butyl) group, amino (2-butyl) group, amino (2-methyl-1-propyl) group, amino It can be a (2-methyl-2-propyl) group, an amino (1-pentyl) group, or an amino (1-hexyl) group, preferably an amino (C ₁ -C ₄ alkyl) group, and more Preferred is an amino (C ₁ -C ₃ alkyl) group (particularly an aminomethyl group, aminoethyl group or aminopropyl group), more preferred is an aminomethyl group or aminoethyl group, and most preferred Is an aminomethyl group.

The “(C ₁ -C ₆ alkylamino)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) was substituted with one of the above C ₁ -C ₆ alkylamino groups. The C ₁ -C ₆ 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-butylamino)-(1-propyl) group, methylamino (1-butyl) group, ethylamino (1-butyl) group, (1-propylamino)-(1-butyl) group, (1-butyl It may be an amino)-(1-butyl) group, a methylamino (1-pentyl) group, or a methylamino (1-hexyl) group, preferably (C ₁ -C ₄ alkylamino)-(C ₁ -C ₄ alkyl) group, more preferably, (C ₁ -C ₂ alkylamino) - (a C ₁ -C ₂ alkyl) group, more preferably a methylaminomethyl group, ethylamino methyl Or a methylaminoethyl group, and most preferably a methylaminomethyl group.

The “(C ₃ -C ₈ cycloalkylamino)-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is substituted with one of the above C ₃ -C ₈ cycloalkylamino groups. is one of the aforementioned C ₁ -C ₆ alkyl group, for example, cyclopropylamino methyl, cyclobutylmethyl aminomethyl group, cyclopentylamino methyl group, a cyclohexyl aminomethyl group, cycloheptyl amino methyl group, cyclooctyl aminomethyl group, cyclopropylamino ethyl group, a cyclopropyl amino propyl, cyclopropylamino butyl group, a cyclopropyl amino pentyl group or, can be a cyclopropyl aminohexyl group, preferably, (C ₃ -C ₆ cycloalkylamino )-(C ₁ -C ₄ alkyl) group, more preferably (C ₃ -C ₄ cycloalkylamino)-(C ₁ -C ₂ alkyl) group, more preferably a cyclopropylaminomethyl group or a cyclopropylaminoethyl group, and most preferably a cyclopropylaminomethyl group.

The “di (C ₁ -C ₆ alkyl) amino- (C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is one di (C ₁ -C ₆ alkyl) amino group A C ₁ -C ₆ alkyl group substituted with, for example, a dimethylaminomethyl group, (N-methyl-N-ethylamino) methyl group, (N-methyl-N-propylamino) methyl group, (N- Methyl-N-butylamino) methyl group, (N-methyl-N-pentylamino) methyl group, (N-methyl-N-hexylamino) methyl group, diethylaminomethyl group, dimethylaminoethyl group, dimethylaminopropyl group, It can be a dimethylaminobutyl group, a dimethylaminopentyl group, or a dimethylaminohexyl group, and preferably a di (C ₁ -C ₄ alkyl) amino- (C ₁ -C ₄ alkyl) group (the alkyl group is Same or different) Ri, more preferably di (C ₁ -C ₂ alkyl) amino - (C ₁ -C ₂ alkyl) group (said alkyl group may be the same or different), and more preferably, a dimethylaminomethyl group, A dimethylaminoethyl group or (N-methyl-N-ethylamino) methyl group, even more preferably a dimethylaminomethyl group or (N-methyl-N-ethylamino) methyl group, most preferably Is a dimethylaminomethyl group. In the di (C ₁ -C ₆ alkyl) amino- (C ₁ -C ₆ alkyl) group, the two alkyl groups in the di (C ₁ -C ₆ alkyl) amino moiety 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 a nitrogen atom, an oxygen atom and a sulfur atom. In this case, di (C ₁ The (C ₆ alkyl) aminocarbonyl group can be, for example, a pyrrolidinylmethyl group, a piperidylmethyl group, a piperazinylmethyl group, a morpholinylmethyl group, or a thiomorpholinylmethyl group, A pyrrolidinylmethyl group, a piperidylmethyl group, or a morpholinylmethyl group.

Formula "di (C ₃ -C ₈ cycloalkyl) amino - (C ₁ -C ₆ alkyl) group" in Substituent group γ of (I) is one of the di- (C ₃ -C ₈ cycloalkyl) C ₁ -C ₆ alkyl groups substituted with amino groups, such as dicyclopropylaminomethyl group, (N-cyclopropyl-N-cyclobutylamino) methyl group, (N-cyclopropyl-N-cyclopentylamino) ) Methyl group, (N-cyclopropyl-N-cyclohexylamino) methyl group, (N-cyclopropyl-N-cycloheptylamino) methyl group, (N-cyclopropyl-N-cyclooctylamino) methyl group, dicyclo Butylaminomethyl group, dicyclopentylaminomethyl group, dicyclohexylaminomethyl group, dicycloheptylaminomethyl group, dicyclooctylaminomethyl group, dicyclopropyl Minoechiru group, di-cyclopropylamino-propyl, di-cyclopropylamino-butyl group, dicyclopropylamino pentyl group or can be a di-cyclopropylamino hexyl group, preferably a di (C ₃ -C ₆ cycloalkyl) An amino- (C ₁ -C ₄ alkyl) group, more preferably a di (C ₃ -C ₄ cycloalkyl) amino- (C ₁ -C ₂ alkyl) group, most preferably a dicyclo A propylaminomethyl group;

The “[N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino]-(C ₁ -C ₆ alkyl) group” in the substituent group γ of the general formula (I) is: It is one of the aforementioned N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl group substituted with an amino group, e.g., (N-cyclopropyl - (N-methylamino) methyl group, (N-cyclopropyl-N-ethylamino) methyl group, (N-cyclopropyl-N-propylamino) methyl group, (N-cyclopropyl-N-butylamino) methyl group, (N-cyclopropyl-N-pentylamino) methyl group, (N-cyclopropyl-N-hexylamino) methyl group, (N-cyclobutyl-N-methylamino) methyl group, (N-cyclopentyl-N-methylamino) ) Methyl group, (N-cyclohexyl-N-methylamino) methyl , (N-cycloheptyl-N-methylamino) methyl group, (N-cyclooctyl-N-methylamino) methyl group, (N-cyclopropyl-N-methylamino) ethyl group, (N-cyclopropyl-N -Methylamino) propyl group, (N-cyclopropyl-N-methylamino) butyl group, (N-cyclopropyl-N-methylamino) pentyl group, or (N-cyclopropyl-N-methylamino) hexyl group And is preferably a [N- (C ₃ -C ₆ cycloalkyl) -N- (C ₁ -C ₄ alkyl) amino]-(C ₁ -C ₄ alkyl) group, more preferably , [N- (C ₃ -C ₄ cycloalkyl) -N- (C ₁ -C ₂ alkyl) amino]-(C ₁ -C ₂ alkyl) groups, most preferably (N-cyclopropyl- N-methylamino) methyl group.

The “C ₃ -C ₈ cycloalkylthio group” in the substituent group γ of the general formula (I) is a mercapto group substituted with one C ₃ -C ₈ cycloalkyl group, for example, a cyclopropylthio group , A cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, or a cyclooctylthio group, preferably a C ₃ -C ₆ cycloalkylthio group, more preferably a C 3 a ₃ -C ₅ cycloalkylthio group, more preferably a C ₃ -C ₄ cycloalkylthio group (cyclopropylthio group or a cyclobutylthio group), and most preferably a cyclopropylthio group.

The “C ₃ -C ₈ cycloalkylsulfinyl group” in the substituent group γ of the general formula (I) is a sulfinyl group (—SO—) substituted with one C ₃ -C ₈ cycloalkyl group, For example, cyclopropyl sulfinyl group, cyclobutyl sulfinyl group, a cycloalkyl pentylsulfamoyl sulfinyl group, cyclohexyl sulfinyl group, cycloheptyl sulfinyl group or be a cyclooctyl sulfinyl group, preferably, be a C ₃ -C ₆ cycloalkylsulfinyl group , more preferably a C ₃ -C ₅ cycloalkylsulfinyl group, more preferably a C ₃ -C ₄ cycloalkyl alkylsulfinyl group (cyclopropyl sulfinyl group or a cycloalkyl butylsulfinyl group), most preferably , A cyclopropylsulfinyl group.

The “C ₃ -C ₈ cycloalkylsulfonyl group” in the substituent group γ of the general formula (I) is a sulfonyl group (—SO ₂ —) substituted with one C ₃ -C ₈ cycloalkyl group. , for example, cyclopropane sulfonyl group, cyclobutane sulfonyl group, cyclopentanesulfonyl group, cyclohexanesulfonyl group, cycloheptane sulfonyl group, or can be a cyclooctane sulfonyl group, preferably, in the C ₃ -C ₆ cycloalkylsulfonyl group, More preferably a C ₃ -C ₅ cycloalkylsulfonyl group, still more preferably a C ₃ -C ₄ cycloalkylsulfonyl group (cyclopropanesulfonyl group or cyclobutanesulfonyl group), most preferably , A cyclopropanesulfonyl group.

  Each substituent in the substituent group δ of the general formula (I) has the same objection as described above.

In the general formula (I), X ¹ is preferably a group having the formula —NH—, —O— or —S—, and more preferably a group having the formula —O—.

In the general formula (I), when Y ¹ is a phenyl group or a substituted phenyl group, the substitution positions of X ¹ and Y ² bonded to Y ¹ are preferably 1 and 3 positions (represented by Y ^1a below), respectively. Or 1 and 4 positions (indicated by Y ^1b below), and more preferably 1 and 4 positions, respectively. When Y ¹ is a thienyl group or a substituted thienyl group, the substituted positions of X ¹ and Y ² are preferably the 2 and 4 positions, respectively, or the 2 and 5 positions (indicated by Y ^1c below), More preferred are the 2 and 5 positions respectively. When Y ¹ is a pyridyl group or a substituted pyridyl group, the substitution positions of X ¹ and Y ² are preferably 2 and 4 positions, 2 and 5 positions (indicated by Y ^1d below), 3 and 5 positions, respectively. Or 5 and 2 positions (indicated by Y ^1e below), more preferably 2 and 5 positions, respectively, and 5 and 2 positions, most preferably 5 and 2 positions respectively. .

In the general formula (I), when Y ² is a phenyl group or a substituted phenyl group, the substitution positions of Y ¹ and R ⁸ bonded to Y ² are preferably 1 and 3 positions (represented by Y ^2a below). Or 1 and 4 positions (indicated by Y ^2b below), more preferably 1 and 4 positions respectively. When Y ² is a thienyl group or a substituted thienyl group, the substitution positions of Y ¹ and R ⁸ are preferably 2 and 4 positions (indicated by Y ^2c below), 2 and 5 positions (by Y ^2d below), respectively. Or 4 and 2 positions (indicated by Y ^2e below), more preferably the 2 and 5 positions, respectively. When Y ² is a thiazolyl group or a substituted thiazolyl group, the substitution positions of Y ¹ and R ⁸ are preferably 2 and 4 positions (indicated by Y ^2f below), 2 and 5 positions (in accordance with Y ^2g below), respectively. Or 5 and 2 positions (indicated by Y ^2h below), more preferably 2 and 5 positions, respectively. When Y ² is a pyridyl group or a substituted pyridyl group, the substitution positions of Y ¹ and R ⁸ are preferably 2 and 4 positions (indicated by Y ²ⁱ below), 2 and 5 positions (in accordance with Y ^2j below), respectively. Or 3 and 5 positions (denoted by Y ^2k below), more preferably 2 and 5 positions, respectively, and 3 and 5 positions, most preferably 3 and 5 respectively. It is rank.

In general formula (I),
(I) Y ² is a substituted phenyl group, and the substitution positions of Y ¹ and R ⁸ bonded to Y ² are the 1 and 4 positions, respectively;
(Ii) Y ² is a substituted thienyl group, when the substitution position of Y ¹ and R ⁸ bind to Y ² is a 2 and 5 positions, respectively; or,
(Iii) Y ² is a substituted pyridyl group, when the substitution position of Y ¹ and R ⁸ bind to Y ² is a 2 and 5 positions, respectively, the substituents of Y ² are preferably substituent group 1 to 3 groups selected from β1, more preferably 1 to 2 groups selected from substituent group β2, and more preferably 1 selected from substituent group β3. Or more preferably, one group selected from the substituent group β3 or two groups selected from the substituent group β4, and most preferably a substituted group. One group selected from the group β5, two methyl groups, or two fluoro groups. The substitution position of the substituent of Y ² in the case of (i) is preferably the 2-position, the 3-position, the 2-position and the 3-position, or the 2-position and 5-position, more preferably the 2-position, 3-position. Or the 2nd and 3rd positions, most preferably the 2nd or 3rd position.

In general formula (I),
(Iv) Y ² is a substituted phenyl group, and the substitution positions of Y ¹ and R ⁸ bonded to Y ² are the 1 and 3 positions, respectively; or
(V) When Y ² is a substituted pyridyl group and the substitution positions of Y ¹ and R ⁸ bonded to Y ² are the 3 and 5 positions, respectively, the substituent of Y ² is preferably a substituent group 1 to 3 groups selected from β1, more preferably 1 to 2 groups selected from substituent group β2, more preferably 1 selected from substituent group β6. And most preferably one group selected from the substituent group β7. The substitution position of the substituent of Y ² is preferably the 2-position in the case of (iv) and the 4-position in the case of (v).

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 salt such as maleate; or glycine, lysine, arginine, ornithine, glutamic acid Ami, such as salt and aspartate It can be a no 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, Like organic amine salts such as perazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, choline salt, tromethamine salt [2-amino-2- (hydroxymethyl) propane-1,3-diol salt] An amine salt; or an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate salt, and an aspartate salt, and 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 forms a hydrate by leaving it in the air or by adsorbing water during recrystallization. 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 encompassed by 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 the general 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 diseases, it must be pharmacologically acceptable. For example, this protecting group is metabolized when the compound is administered to a mammal in vivo. 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 other than for 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 (eg, 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) 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 by a metabolic process (for example, hydrolysis) when administered into a living body of 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 carbonyloxyalkyl groups such as those selected from the group consisting of ₆ aryl or aryl groups optionally substituted with halogeno;
(Iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ optionally substituted by alkoxy phthalidyl group;
(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 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) in which the hydroxyl group is modified, an aliphatic acyl group (particularly, , C ₁ -C ₂₅ alkyl group) and a substituted carbonyloxy group is preferred.

In the compound represented by the general formula (I), a suitable compound may be a compound shown in the following Table 1 or 2. However, the compound of the present invention is not limited to these compounds.

In Tables 1, 2 and 3 below, the following abbreviations are used:
cBu: Cyclobutyl
cbx-cBu: 1-carboxy-1-cyclobutyl
cbx-cPr: 1-carboxy-1-cyclopropyl
cPr: Cyclopropyl
Dmbu: 2,3-dimethyl-2-butyl
Et: ethyl
Ety: Ethinyl
iPr: 2-propyl
Mbu: 2-methyl-2-butyl
Me: methyl
Mpe: 3-methyl-3-pentyl
nPr: 1-propyl
tBu: 2-methyl-2-propyl
Tet: Tetrazolyl
Tfe: 2,2,2-trifluoroethyl
Vin: Vinyl.

[Table 1]

_____________________________________________________
Exemplary compound R ¹ R ² R ³ R ⁴ R ⁵ R ⁸
Item number ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
1-1 COCH ₂ CMe ₃ OH CF ₃ HH CH ₂ COOH
1-2 COCH ₂ CMe ₃ OH CF ₃ HH cbx-cPr
1-3 COOiPr OH iPr HH CH ₂ COOH
1-4 COOiPr OH tBu HH CH ₂ COOH
1-5 COOiPr OH CF ₃ HH CH ₂ COOH
1-6 COOiPr OH CF ₃ HH cbx-cPr
1-7 COOiPr OH CF ₃ HH CH ₂ COOMe
1-8 COOtBu H Me HH CH ₂ COOH
1-9 COOtBu H Me HH cbx-cPr
1-10 COOtBu H Et HH CH ₂ COOH
1-11 COOtBu H Et HH cbx-cPr
1-12 COOtBu H iPr HH CH ₂ COOH
1-13 COOtBu H iPr HH cbx-cPr
1-14 COOtBu H tBu HH CH ₂ COOH
1-15 COOtBu H tBu HH cbx-cPr
1-16 COOtBu H CF ₃ HH CH ₂ COOH
1-17 COOtBu H CF ₃ HH CH ₂ COOMe
1-18 COOtBu H CF ₃ HH CH (Me) COOH
1-19 COOtBu H CF ₃ HHC (Me) ₂ COOH
1-20 COOtBu H CF ₃ HH cbx-cPr
1-21 COOtBu H Tfe HH CH ₂ COOH
1-22 COOtBu H Tfe HH cbx-cPr
1-23 COOtBu H cPr HH CH ₂ COOH
1-24 COOtBu H cPr HH cbx-cPr
1-25 COOtBu H Vin HH CH ₂ COOH
1-26 COOtBu H Vin HH cbx-cPr
1-27 COOtBu H Ety HH CH ₂ COOH
1-28 COOtBu H Ety HH cbx-cPr
1-29 COOtBu H OMe HH CH ₂ COOH
1-30 COOtBu H OMe HH cbx-cPr
1-31 COOtBu H SMe HH CH ₂ COOH
1-32 COOtBu H SMe HH cbx-cPr
1-33 COOtBu H SOMe HH CH ₂ COOH
1-34 COOtBu H SOMe HH cbx-cPr
1-35 COOtBu H SO ₂ Me HH CH ₂ COOH
1-36 COOtBu H SO ₂ Me HH cbx-cPr
1-37 COOtBu HFHH CH ₂ COOH
1-38 COOtBu HFHH cbx-cPr
1-39 COOtBu H Cl HH CH ₂ COOH
1-40 COOtBu H Cl HH cbx-cPr
1-41 COOtBu OH HHH CH ₂ COOH
1-42 COOtBu OH HHH cbx-cPr
1-43 COOtBu OH Me HH CH ₂ COOH
1-44 COOtBu OH Me HH cbx-cPr
1-45 COOtBu OH Et HH CH ₂ COOH
1-46 COOtBu OH Et HH cbx-cPr
1-47 COOtBu OH iPr HH CH ₂ COOH
1-48 COOtBu OH iPr HH cbx-cPr
1-49 COOtBu OH tBu HH CH ₂ COOH
1-50 COOtBu OH tBu HH CH ₂ COOMe
1-51 COOtBu OH tBu HH CH (Me) COOH
1-52 COOtBu OH tBu HHC (Me) ₂ COOH
1-53 COOtBu OH tBu HH cbx-cPr
1-54 COOtBu OH CF ₃ HH COOH
1-55 COOtBu OH CF ₃ HH CH ₂ COOH
1-56 COOtBu OH CF ₃ HH CH ₂ COOMe
1-57 COOtBu OH CF ₃ HH CH ₂ COOEt
1-58 COOtBu OH CF ₃ HH CH ₂ COOnPr
1-59 COOtBu OH CF ₃ HH CH ₂ CONH ₂
1-60 COOtBu OH CF ₃ HH CH ₂ CONHMe
1-61 COOtBu OH CF ₃ HH CH ₂ CONMe ₂
1-62 COOtBu OH CF ₃ HH CH (Me) COOH
1-63 COOtBu OH CF ₃ HHC (Me) ₂ COOH
1-64 COOtBu OH CF ₃ HH cbx-cPr
1-65 COOtBu OH CF ₃ HH cbx-cBu
1-66 COOtBu OH CF ₃ HH CF ₂ COOH
1-67 COOtBu OH CF ₃ HH (CH ₂ ) ₂ COOH
1-68 COOtBu OH CF ₃ HH 5-Tet
1-69 COOtBu OH CF ₃ FH CH ₂ COOH
1-70 COOtBu OH CF ₃ FH cbx-cPr
1-71 COOtBu OH CF ₃ Cl H CH ₂ COOH
1-72 COOtBu OH CF ₃ Cl H cbx-cPr
1-73 COOtBu OH Tfe HH CH ₂ COOH
1-74 COOtBu OH Tfe HH cbx-cPr
1-75 COOtBu OH CH ₂ OMe HH CH ₂ COOH
1-76 COOtBu OH CH ₂ OMe HH cbx-cPr
1-77 COOtBu OH CH ₂ SMe HH CH ₂ COOH
1-78 COOtBu OH CH ₂ SMe HH cbx-cPr
1-79 COOtBu OH cPr HH CH ₂ COOH
1-80 COOtBu OH cPr HH cbx-cPr
1-81 COOtBu OH Vin HH CH ₂ COOH
1-82 COOtBu OH Vin HH cbx-cPr
1-83 COOtBu OH Ety HH CH ₂ COOH
1-84 COOtBu OH Ety HH cbx-cPr
1-85 COOtBu OH OMe HH CH ₂ COOH
1-86 COOtBu OH OMe HH cbx-cPr
1-87 COOtBu OH SMe HH CH ₂ COOH
1-88 COOtBu OH SMe HH cbx-cPr
1-89 COOtBu OH SOMe HH CH ₂ COOH
1-90 COOtBu OH SOMe HH cbx-cPr
1-91 COOtBu OH SO ₂ Me HH CH ₂ COOH
1-92 COOtBu OH SO ₂ Me HH cbx-cPr
1-93 COOtBu OH FHH CH ₂ COOH
1-94 COOtBu OH FHH cbx-cPr
1-95 COOtBu OH Cl HH CH ₂ COOH
1-96 COOtBu OH Cl HH cbx-cPr
1-97 COOCH ₂ CMe ₃ OH CF ₃ HH CH ₂ COOH
1-98 COOCH ₂ CMe ₃ OH CF ₃ HH cbx-cPr
1-99 COOMbu OH CF ₃ HH CH ₂ COOH
1-100 COOMbu OH CF ₃ HH cbx-cPr
1-101 COOMpe OH CF ₃ HH CH ₂ COOH
1-102 COOMpe OH CF ₃ HH cbx-cPr
1-103 COODmbu OH CF ₃ HH CH ₂ COOH
1-104 COODmbu OH CF ₃ HH cbx-cPr
1-105 COOC (Et) ₃ OH CF ₃ HH CH ₂ COOH
1-106 COOC (Et) ₃ OH CF ₃ HH cbx-cPr
1-107 COOC (CF ₃ ) Me ₂ OH CF ₃ HH CH ₂ COOH
1-108 COOC (CF ₃ ) Me ₂ OH CF ₃ HH cbx-cPr
1-109 CONHtBu OH CF ₃ HH CH ₂ COOH
1-110 CONHtBu OH CF ₃ HH cbx-cPr
1-111 CON (Me) tBu OH CF ₃ HH CH ₂ COOH
1-112 CON (Me) tBu OH CF ₃ HH cbx-cPr
1-113 COOtBu OH CF ₃ HH CH ₂ SO ₂ NHMe
1-114 COOtBu OH CF ₃ HH CH (CH ₂ OH) COOH
1-115 COOtBu OH CF ₃ HH CH (OH) COOH
1-116 COOtBu OH CF ₃ HH CH (OEt) COOH
1-117 COOtBu OH CF ₃ HH CH ₂ CH (OH) COOH
1-118 COOtBu OH CF ₃ HH CH ₂ CON (Me) Et
1-119 COOtBu OH CF ₃ HH CH ₂ CONH (iPr)
1-120 COOtBu OH CF ₃ HH CH ₂ SO ₂ NMe ₂
1-121 COOtBu OH CF ₃ HH CH ₂ CONHEt
1-122 COOtBu OH CF ₃ HH CH ₂ CON (Me) iPr
1-123 COOtBu OH CF ₃ HH CH ₂ SO ₂ Me
1-124 COOtBu OH CF ₃ HHC (COOH) = CH ₂
1-125 COOtBu OH CF ₃ HHC (CH ₂ OH) ₂ COOH
1-126 COOCH (Me) CF ₃ OH CF ₃ HH CH ₂ COOH
1-127 COOtBu OH CF ₃ HH CH (CH ₂ OMe) COOH
1-128 COOtBu OH CF ₃ HH CH (CH ₂ OEt) COOH
1-129 COOtBu OH CF ₃ H OH CH ₂ COOH
1-130 COOtBu OH CF ₃ HH CH (OMe) COOH
1-131 COOtBu OH CF ₃ HH CH ₂ (5-Tet)
1-132 COOtBu OH CF ₃ HH CH (Et) COOH
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

[Table 2]

_____________________________________________________
Exemplary compound R ² R ³ R ⁶ R ⁷ R ⁸ X ¹ Y ¹ Y ² R ¹³ R ¹⁴
Item number ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
2-1 H CF ₃ HH 3-COOH O Y ^a Y ^f HH
2-2 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f HH
2-3 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-Me
2-4 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-F
2-5 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-Cl
2-6 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-Me
2-7 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-F
2-8 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-Cl
2-9 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-Me
2-10 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-F
2-11 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-Cl
2-12 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-Me
2-13 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-F
2-14 H CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-Cl
2-15 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-Me
2-16 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-OMe
2-17 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-Me
2-18 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-F
2-19 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-Cl
2-20 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-FH
2-21 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 2-Me
2-22 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-Me
2-24 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-F
2-25 H CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-Cl
2-26 H CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-27 H CF ₃ HH CH ₂ COOH O Y ^a Y ^l HH
2-28 OH CF ₃ HH 3-COOH O Y ^a Y ^f HH
2-29 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f HH
2-30 OH CF ₃ HH 3-CH ₂ COOMe O Y ^a Y ^f HH
2-31 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-Me
2-32 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-F
2-33 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-Cl
2-34 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-Me
2-35 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-F
2-36 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 4-Cl
2-37 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-Me
2-38 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-F
2-39 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 5-Cl
2-40 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-Me
2-41 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-F
2-42 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 6-Cl
2-43 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-Me
2-44 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-OMe
2-45 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-F
2-46 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-Cl
2-47 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-Me
2-48 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-F
2-49 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-Cl
2-50 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 2-Me H
2-51 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 2-FH
2-52 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 2-Cl H
2-53 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-Me H
2-54 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-FH
2-55 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 2-Me
2-56 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 2-Cl
2-57 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-Me
2-58 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-F
2-59 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-F 3-Cl
2-60 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f 3-Cl H
2-61 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-Me
2-62 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-Cl
2-63 OH CF ₃ HH 3-CH (Me) COOH O Y ^a Y ^f H 2-OMe
2-64 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 3-F
2-65 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 3-Cl
2-66 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f 3-FH
2-67 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f H 2-Me
2-68 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f H 2-Cl
2-69 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f H 3-Me
2-70 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f H 3-F
2-71 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f H 3-Cl
2-72 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f 3-FH
2-73 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f 3-F 2-Me
2-74 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f 3-F 3-Me
2-75 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f 3-F 3-F
2-76 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^f 3-F 3-Cl
2-77 OH CF ₃ HH 4-CH ₂ COOH NH Y ^a Y ^f HH
2-78 OH CF ₃ HH 4-CH ₂ COOH NMe Y ^a Y ^f HH
2-79 OH CF ₃ HH 4-CH ₂ COOH S Y ^a Y ^f HH
2-80 OH CF ₃ HH 4-CH ₂ COOH SO Y ^a Y ^f HH
2-81 OH CF ₃ HH 4-CH ₂ COOH SO ₂ Y ^a Y ^f HH
2-82 OH CF ₃ Me H 4-CH ₂ COOH O Y ^a Y ^f HH
2-83 OH CF ₃ Me Me 4-CH ₂ COOH O Y ^a Y ^f HH
2-84 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g HH
2-85 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g H 2-Me
2-86 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g H 3-Me
2-87 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g H 3-F
2-88 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g H 3-Cl
2-89 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^g 3-FH
2-90 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^g HH
2-91 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^g H 2-Me
2-92 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^g H 3-Me
2-93 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^g H 3-F
2-94 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^g H 3-Cl
2-95 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^h HH
2-96 OH CF ₃ HH 3-cbx-cPr O Y ^a Y ^h HH
2-97 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ⁱ HH
2-98 OH CF ₃ HH 3-cbx-cPr O Y ^a Y ⁱ HH
2-99 OH HHH 5-CH ₂ COOH O Y ^a Y ^j HH
2-100 OH HHH 5-cbx-cPr O Y ^a Y ^j HH
2-101 OH Me HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-102 OH Me HH 5-cbx-cPr O Y ^a Y ^j HH
2-103 OH Et HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-104 OH Et HH 5-cbx-cPr O Y ^a Y ^j HH
2-105 OH iPr HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-106 OH iPr HH 5-cbx-cPr O Y ^a Y ^j HH
2-107 OH tBu HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-108 OH tBu HH 5-cbx-cPr O Y ^a Y ^j HH
2-109 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^j HH
2-110 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^j 3-FH
2-111 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^j HH
2-112 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^j 3-FH
2-113 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-114 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^j 3-FH
2-115 OH CF ₃ HH 5-CH ₂ COOMe O Y ^a Y ^j HH
2-116 OH CF ₃ HH 5-CH ₂ COOEt O Y ^a Y ^j HH
2-117 OH CF ₃ HH 5-CH ₂ COOnPr O Y ^a Y ^j HH
2-118 OH CF ₃ HH 5-CH ₂ CONH ₂ O Y ^a Y ^j HH
2-119 OH CF ₃ HH 5-CH ₂ CONHMe O Y ^a Y ^j HH
2-120 OH CF ₃ HH 5-CH ₂ CONMe ₂ O Y ^a Y ^j HH
2-121 OH CF ₃ HH 5-CH (Me) COOH O Y ^a Y ^j HH
2-122 OH CF ₃ HH 5-CH (Me) COOH O Y ^a Y ^j 3-FH
2-123 OH CF ₃ HH 5-cbx-cPr O Y ^a Y ^j HH
2-124 OH CF ₃ HH 5-cbx-cPr O Y ^a Y ^j 3-FH
2-125 OH Tfe HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-126 OH Tfe HH 5-cbx-cPr O Y ^a Y ^j HH
2-127 OH cPr HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-128 OH cPr HH 5-cbx-cPr O Y ^a Y ^j HH
2-129 OH Vin HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-130 OH Vin HH 5-cbx-cPr O Y ^a Y ^j HH
2-131 OH OMe HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-132 OH OMe HH 5-cbx-cPr O Y ^a Y ^j HH
2-133 OH SMe HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-134 OH SMe HH 5-cbx-cPr O Y ^a Y ^j HH
2-135 OH SOMe HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-136 OH SOMe HH 5-cbx-cPr O Y ^a Y ^j HH
2-137 OH SO ₂ Me HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-138 OH SO ₂ Me HH 5-cbx-cPr O Y ^a Y ^j HH
2-139 OH FHH 5-CH ₂ COOH O Y ^a Y ^j HH
2-140 OH FHH 5-cbx-cPr O Y ^a Y ^j HH
2-141 OH Cl HH 5-CH ₂ COOH O Y ^a Y ^j HH
2-142 OH Cl HH 5-cbx-cPr O Y ^a Y ^j HH
2-143 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^k HH
2-144 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^k 3-FH
2-145 OH CF ₃ HH 5-cbx-cPr O Y ^a Y ^k HH
2-146 OH CF ₃ HH 5-cbx-cPr O Y ^a Y ^k 3-FH
2-147 OH CF ₃ HH CH ₂ COOH O Y ^a Y ^l HH
2-148 OH CF ₃ HH CH ₂ COOH O Y ^a Y ^l 3-FH
2-149 OH CF ₃ HH cbx-cPr O Y ^a Y ^l HH
2-150 OH CF ₃ HH cbx-cPr O Y ^a Y ^l 3-FH
2-151 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^m HH
2-152 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^m 3-FH
2-153 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^m HH
2-154 OH CF ₃ HH 4-cbx-cPr O Y ^a Y ^m 3-FH
2-155 OH CF ₃ HH 3-CH ₂ COOH O Y ^b Y ^f HH
2-156 OH CF ₃ HH 3-cbx-cPr O Y ^b Y ^f HH
2-157 OH CF ₃ HH 4-CH ₂ COOH O Y ^b Y ^f HH
2-158 OH CF ₃ HH 4-cbx-cPr O Y ^b Y ^f HH
2-159 OH CF ₃ HH 4-CH ₂ COOH O Y ^c Y ^f HH
2-160 OH CF ₃ HH 4-CH ₂ COOH O Y ^c Y ^f H 2-Me
2-161 OH CF ₃ HH 4-CH ₂ COOH O Y ^c Y ^f H 3-Me
2-162 OH CF ₃ HH 4-CH ₂ COOH O Y ^c Y ^f H 3-F
2-163 OH CF ₃ HH 4-CH ₂ COOH O Y ^c Y ^f H 3-Cl
2-164 OH CF ₃ HH 4-CH ₂ COOH O Y ^d Y ^f HH
2-165 OH CF ₃ HH 4-CH ₂ COOH O Y ^d Y ^f H 2-Me
2-166 OH CF ₃ HH 4-CH ₂ COOH O Y ^d Y ^f H 3-Me
2-167 OH CF ₃ HH 4-CH ₂ COOH O Y ^d Y ^f H 3-F
2-168 OH CF ₃ HH 4-CH ₂ COOH O Y ^d Y ^f H 3-Cl
2-169 OH CF ₃ HH 4-CH ₂ COOH O Y ^e Y ^f HH
2-170 OH CF ₃ HH 4-CH ₂ COOH O Y ^e Y ^f H 2-Me
2-171 OH CF ₃ HH 4-CH ₂ COOH O Y ^e Y ^f H 3-Me
2-172 OH CF ₃ HH 4-CH ₂ COOH O Y ^e Y ^f H 3-F
2-173 OH CF ₃ HH 4-CH ₂ COOH O Y ^e Y ^f H 3-Cl
2-174 OH CF ₃ HH 4-CH (Me) COOH O Y ^e Y ^f HH
2-175 OH CF ₃ HH 4-CH (Me) COOH O Y ^e Y ^f H 2-Me
2-176 OH CF ₃ HH 4-CH (Me) COOH O Y ^e Y ^f H 3-Me
2-177 OH CF ₃ HH 4-CH (Me) COOH O Y ^e Y ^f H 3-F
2-178 OH CF ₃ HH 4-CH (Me) COOH O Y ^e Y ^f H 3-Cl
2-179 OH CF ₃ HH 4-cbx-cPr O Y ^e Y ^f HH
2-180 OH CF ₃ HH 4-cbx-cPr O Y ^e Y ^f H 2-Me
2-181 OH CF ₃ HH 4-cbx-cPr O Y ^e Y ^f H 3-Me
2-182 OH CF ₃ HH 4-cbx-cPr O Y ^e Y ^f H 3-F
2-183 OH CF ₃ HH 4-cbx-cPr O Y ^e Y ^f H 3-Cl
2-184 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-OMe
2-185 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CF ₃
2-186 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-Et
2-187 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ⁿ HH
2-188 OH CF ₃ HH 3-SO ₂ Me O Y ^a Y ^f HH
2-189 OH CF ₃ HH 4-CH ₂ COOMe O Y ^a Y ^f H 2-Et
2-190 OH CF ₃ HH 3-NHSO ₂ Me O Y ^a Y ^f HH
2-191 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-NO ₂
2-192 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-NH ₂
2-193 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-NMe ₂
2-194 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-COCH ₃
2-195 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-iPr
2-196 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-CF ₃
2-197 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CHO
2-198 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CH ₂ OH
2-199 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CN
2-200 OH CF ₃ HH 3- (CH ₂ ) ₂ COOH O Y ^a Y ^f HH
2-201 OH CF ₃ HH 3-CH ₂ NHSO ₂ Me O Y ^a Y ^f HH
2-202 OH CF ₃ HH COOH O Y ^a Y ^p HH
2-203 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-SO ₂ Me
2-204 OH CF ₃ HH 3-N (Me) SO ₂ Me O Y ^a Y ^f HH
2-205 OH CF ₃ HH 3-CH ₂ N (Me) SO ₂ Me O Y ^a Y ^f HH
2-206 OH CF ₃ HH 4-COOH O Y ^a Y ^g HH
2-207 OH CF ₃ HH 4- (CH ₂ ) ₂ COOH O Y ^a Y ^g HH
2-208 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-nPr
2-209 OH CF ₃ HH 3-COMe O Y ^a Y ^f HH
2-210 OH CF ₃ HH 5-COMe O Y ^a Y ^g HH
2-211 OH CF ₃ HH 4-CH ₂ COOMe O Y ^a Y ^f H 3-Cl
2-212 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-COEt
2-213 OH CF ₃ HH COOH O Y ^a Y ^o HH
2-214 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-OH
2-215 OH CF ₃ HH 3-SO ₂ Me O Y ^a Y ^h HH
2-216 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^h H 2-Me
2-217 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CONMe ₂
2-218 OH CF ₃ HH 4-CH (CH ₂ OH) COOH O Y ^a Y ^f H 2-Et
2-219 OH CF ₃ HH 4-CH (CH ₂ OH) COOH O Y ^a Y ^f H 3-F
2-220 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-OH
2-221 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-cPr
2-222 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-NO ₂
2-223 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-Et
2-224 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-CN
2-225 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2-CH (OH) CH ₃
2-226 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 3-CONMe ₂
2-227 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-Et
2-228 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2,3-di-F
2-229 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2,3-di-Me
2-230 OH CF ₃ HH 4-CH (CH ₂ NMe ₂ ) COOH O Y ^a Y ^f H 3-F
2-231 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-Et
2-232 OH CF ₃ HH 5-CH ₂ COOH O Y ^a Y ^j H 3-Me
2-233 OH CF ₃ HH 3-CH (Me) COOH O Y ^a Y ^f H 2-Me
2-234 OH CF ₃ HH 3-CH (Me) COOH O Y ^a Y ^f H 2-Et
2-235 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-NO ₂
2-236 OH CF ₃ HH 4-CH (Me) COOH O Y ^d Y ^f H 2-Me
2-237 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 3-Et
2-238 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2,5-di-Me
2-239 OH CF ₃ HH 4-CH ₂ COOH O Y ^a Y ^f H 2,5-di-Me
2-240 OH CF ₃ HH COOH O Y ^a Y ^q HH
2-241 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-CF ₃
2-242 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-iPr
2-243 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2,3-di-F
2-244 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2,3-di-Me
2-245 OH CF ₃ HH 4-CH (Me) COOH O Y ^a Y ^f H 2-cPr
2-246 OH CF ₃ HH 3-CH ₂ COOH O Y ^a Y ^f H 2-OMe
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

[Table 3]

_____________________________________________________
Illustrative compound R ³ R ⁸ R ¹⁵ R ¹⁶
Item number ￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
3-1 iPr 4-CH ₂ COOH 2-Me H
3-2 iPr 4-CH ₂ COOH 2-Me 3-Me
3-3 iPr 4-CH ₂ COOH 2-Me 5-Me
3-4 iPr 4-CH ₂ COOH 3-Me H
3-5 iPr 4-CH ₂ COOH 2-Et H
3-6 iPr 4-CH ₂ COOH 3-Et H
3-7 iPr 4-CH ₂ COOH 2-iPr H
3-8 iPr 4-CH ₂ COOH 3-iPr H
3-9 iPr 4-CH ₂ COOH 2-CH ₂ OH H
3-10 iPr 4-CH ₂ COOH 2-CF ₃ H
3-11 iPr 4-CH ₂ COOH 3-CF ₃ H
3-12 iPr 4-CH ₂ COOH 2-cPr H
3-13 iPr 4-CH ₂ COOH 3-cPr H
3-14 iPr 4-CH ₂ COOH 2-OMe H
3-15 iPr 4-CH ₂ COOH 3-OMe H
3-16 iPr 4-CH ₂ COOH 2-SO ₂ Me H
3-17 iPr 4-CH ₂ COOH 3-SO ₂ Me H
3-18 iPr 4-CH ₂ COOH 2-NH ₂ H
3-19 iPr 4-CH ₂ COOH 2-NHMe H
3-20 iPr 4-CH ₂ COOH 2-NMe ₂ H
3-21 iPr 4-CH ₂ COOH 2-COMe H
3-22 iPr 4-CH ₂ COOH 2-COEt H
3-23 iPr 4-CH ₂ COOH 2-CN H
3-24 iPr 4-CH ₂ COOH 3-CN H
3-25 iPr 4-CH ₂ COOH 2-NO ₂ H
3-26 iPr 4-CH ₂ COOH 3-NO ₂ H
3-27 iPr 4-CH ₂ COOH 2-FH
3-28 iPr 4-CH ₂ COOH 2-F 3-F
3-29 iPr 4-CH ₂ COOH 2-F 5-F
3-30 iPr 4-CH ₂ COOH 3-FH
3-31 iPr 4-CH ₂ COOH 2-Cl H
3-32 iPr 4-CH ₂ COOH 3-Cl H
3-33 iPr 3-CH ₂ COOH 2-Me H
3-34 iPr 3-CH ₂ COOH 2-Et H
3-35 iPr 3-CH ₂ COOH 2-OMe H
3-36 iPr 3-CH ₂ COOH 2-FH
3-37 iPr 3-CH (Me) COOH 2-Me H
3-38 iPr 3-CH (Me) COOH 2-Et H
3-39 iPr 3-CH (Me) COOH 2-OMe H
3-40 iPr 3-CH (Me) COOH 2-FH
3-41 tBu 4-CH ₂ COOH 2-Me H
3-42 tBu 4-CH ₂ COOH 2-Me 3-Me
3-43 tBu 4-CH ₂ COOH 2-Me 5-Me
3-44 tBu 4-CH ₂ COOH 3-Me H
3-45 tBu 4-CH ₂ COOH 2-Et H
3-46 tBu 4-CH ₂ COOH 3-Et H
3-47 tBu 4-CH ₂ COOH 2-iPr H
3-48 tBu 4-CH ₂ COOH 3-iPr H
3-49 tBu 4-CH ₂ COOH 2-CH ₂ OH H
3-50 tBu 4-CH ₂ COOH 2-CF ₃ H
3-51 tBu 4-CH ₂ COOH 3-CF ₃ H
3-52 tBu 4-CH ₂ COOH 2-cPr H
3-53 tBu 4-CH ₂ COOH 3-cPr H
3-54 tBu 4-CH ₂ COOH 2-OMe H
3-55 tBu 4-CH ₂ COOH 3-OMe H
3-56 tBu 4-CH ₂ COOH 2-SO ₂ Me H
3-57 tBu 4-CH ₂ COOH 3-SO ₂ Me H
3-58 tBu 4-CH ₂ COOH 2-NH ₂ H
3-59 tBu 4-CH ₂ COOH 2-NHMe H
3-60 tBu 4-CH ₂ COOH 2-NMe ₂ H
3-61 tBu 4-CH ₂ COOH 2-COMe H
3-62 tBu 4-CH ₂ COOH 2-COEt H
3-63 tBu 4-CH ₂ COOH 2-CN H
3-64 tBu 4-CH ₂ COOH 3-CN H
3-65 tBu 4-CH ₂ COOH 2-NO ₂ H
3-66 tBu 4-CH ₂ COOH 3-NO ₂ H
3-67 tBu 4-CH ₂ COOH 2-FH
3-68 tBu 4-CH ₂ COOH 2-F 3-F
3-69 tBu 4-CH ₂ COOH 2-F 5-F
3-70 tBu 4-CH ₂ COOH 3-FH
3-71 tBu 4-CH ₂ COOH 2-Cl H
3-72 tBu 4-CH ₂ COOH 3-Cl H
3-73 tBu 3-CH ₂ COOH 2-Me H
3-74 tBu 3-CH ₂ COOH 2-Et H
3-75 tBu 3-CH ₂ COOH 2-OMe H
3-76 tBu 3-CH ₂ COOH 2-FH
3-77 tBu 3-CH (Me) COOH 2-Me H
3-78 tBu 3-CH (Me) COOH 2-Et H
3-79 tBu 3-CH (Me) COOH 2-OMe H
3-80 tBu 3-CH (Me) COOH 2-FH
3-81 CF ₃ 4-CH ₂ COOH 3-iPr H
3-82 CF ₃ 4-CH ₂ COOH 3-cPr H
3-83 CF ₃ 4-CH ₂ COOH 2-SO ₂ Me H
3-84 CF ₃ 4-CH ₂ COOH 2-NHMe H
3-85 CF ₃ 4-CH ₂ COOH 2-F 5-F
3-86 CF ₃ 3-CH (Me) COOH 2-FH
3-87 Cl 4-CH ₂ COOH 2-Me H
3-88 Cl 4-CH ₂ COOH 2-Me 3-Me
3-89 Cl 4-CH ₂ COOH 2-Me 5-Me
3-90 Cl 4-CH ₂ COOH 3-Me H
3-91 Cl 4-CH ₂ COOH 2-Et H
3-92 Cl 4-CH ₂ COOH 3-Et H
3-93 Cl 4-CH ₂ COOH 2-iPr H
3-94 Cl 4-CH ₂ COOH 3-iPr H
3-95 Cl 4-CH ₂ COOH 2-CH ₂ OH H
3-96 Cl 4-CH ₂ COOH 2-CF ₃ H
3-97 Cl 4-CH ₂ COOH 3-CF ₃ H
3-98 Cl 4-CH ₂ COOH 2-cPr H
3-99 Cl 4-CH ₂ COOH 3-cPr H
3-100 Cl 4-CH ₂ COOH 2-OMe H
3-101 Cl 4-CH ₂ COOH 3-OMe H
3-102 Cl 4-CH ₂ COOH 2-SO ₂ Me H
3-103 Cl 4-CH ₂ COOH 3-SO ₂ Me H
3-104 Cl 4-CH ₂ COOH 2-NH ₂ H
3-105 Cl 4-CH ₂ COOH 2-NHMe H
3-106 Cl 4-CH ₂ COOH 2-NMe ₂ H
3-107 Cl 4-CH ₂ COOH 2-COMe H
3-108 Cl 4-CH ₂ COOH 2-COEt H
3-109 Cl 4-CH ₂ COOH 2-CN H
3-110 Cl 4-CH ₂ COOH 3-CN H
3-111 Cl 4-CH ₂ COOH 2-NO ₂ H
3-112 Cl 4-CH ₂ COOH 3-NO ₂ H
3-113 Cl 4-CH ₂ COOH 2-FH
3-114 Cl 4-CH ₂ COOH 2-F 3-F
3-115 Cl 4-CH ₂ COOH 2-F 5-F
3-116 Cl 4-CH ₂ COOH 3-FH
3-117 Cl 4-CH ₂ COOH 2-Cl H
3-118 Cl 4-CH ₂ COOH 3-Cl H
3-119 Cl 3-CH ₂ COOH 2-Me H
3-120 Cl 3-CH ₂ COOH 2-Et H
3-121 Cl 3-CH ₂ COOH 2-OMe H
3-121 Cl 3-CH ₂ COOH 2-FH
3-122 Cl 3-CH (Me) COOH 2-Me H
3-123 Cl 3-CH (Me) COOH 2-Et H
3-124 Cl 3-CH (Me) COOH 2-OMe H
3-125 Cl 3-CH (Me) COOH 2-FH
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

In the above exemplified compounds, suitable compounds are exemplified compound numbers 1-16, 1-55, 1-62, 1-64, 1-114, 1-132, 2-29, 2-31, 2-43, 2 -46, 2-47, 2-48, 2-49, 2-54, 2-61, 2-62, 2-63, 2-64, 2-65, 2-70, 2-113, 2-165 , 2-184, 2-185, 2-186, 2-188, 2-189, 2-191, 2-192, 2-193, 2-194, 2-195, 2-196, 2-197, 2 -198, 2-199, 2-213, 2-216, 2-218, 2-219, 2-221, 2-222, 2-223, 2-227, 2-228, 2-229, 2-230 , 2-231, 2-232, 2-233, 2-234, 2-235, 2-236, 2-238, 2-239, 2-241, 2-242, 2-243, 2-244, or , 2-245 compounds, and more preferred compounds are:
Illustrative compound number 1-55: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid ,
Exemplary Compound No. 1-62: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl ) Propanoic acid,
Exemplified compound number 1-64: 1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl ) Cyclopropanecarboxylic acid,
Exemplified compound number 1-114: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl ) -3-hydroxypropanoic acid,
Illustrative compound number 1-132: 2- [4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl ] Butanoic acid,
Illustrative compound number 2-31: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-3 -Yl) acetic acid,
Illustrative compound number 2-43: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-46: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-chloro-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-48: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-49: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-63: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1′-biphenyl -3-yl) propanoic acid,
Illustrative compound number 2-64: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl -4-yl) propanoic acid,
Illustrative compound number 2-70: 1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl -4-yl) cyclopropanecarboxylic acid,
Illustrative compound number 2-184: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-methoxy-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-185: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-trifluoromethyl-1,1′-biphenyl -4-yl) acetic acid,
Illustrative compound number 2-186: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-189: tert-butyl 6-[({2′-ethyl-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-hydroxy -3- (trifluoromethyl) benzoate,
Illustrative compound number 2-191: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-192: (2-amino-4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-195: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-197: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-formyl-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-198: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (hydroxymethyl) -1,1′- Biphenyl-4-yl) acetic acid,
Illustrative compound number 2-199: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyano-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-221: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl- 4-yl) acetic acid,
Illustrative compound number 2-223: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-ethyl-1,1′-biphenyl-4 -Yl) acetic acid,
Illustrative compound number 2-227: (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-3 -Yl) acetic acid,
Illustrative compound number 2-230: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl -4-yl) -3- (dimethylamino) propanoic acid,
Illustrative compound number 2-231: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl -4-yl) propanoic acid,
Illustrative compound number 2-232: [5- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -4-methyl-2-thienyl] Acetic acid,
Illustrative compound number 2-235: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl -4-yl) propanoic acid,
Illustrative compound number 2-236: 2- [4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -3-methyl Phenyl] propanoic acid,
Illustrative compound number 2-242: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1′-biphenyl -4-yl) propanoic acid,
Illustrative compound number 2-244: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1 ′ -Biphenyl-4-yl) propanoic acid, or
Illustrative compound number 2-245: 2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′- Biphenyl-4-yl) propanoic acid compound.

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

In the structural formulas of the compounds of the methods A to P, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , X ² , Y ¹ , and Y ² are as defined above R ^a is a C ₁ -C ₁₀ alkoxy group, a halogeno C ₁ -C ₁₀ alkoxy group, a phenyl- (C ₁ -C ₁₀ alkoxy) group, a C ₁ -C ₁₀ alkylamino group in R ⁹ . Or a di (C ₁ -C ₁₀ alkyl) amino group, R ^b represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and two R ^b together represent an ethylene group or a trimethylene group ( The ethylene group or trimethylene group may be substituted with 1 to 4 methyl groups), R ^c represents a tetrahydrofuranyl group, a tetrahydropyranyl group or a methoxymethyl group, and R ^d represents a C ₁ -C ₆ alkyl group or an allyl group, R ^e is C ₁ -C ₆ represents an alkyl group, R ^f represents C ₁ -C ₆ alkoxy group in R ^11, amino group, C ₁ -C ₆ alkylamino group, or a di (C ₁ -C ₆ alkyl) amino group , R ^g represents an allyl group, and R ^h represents a silyl group (preferably tert-butyldimethyl) substituted with three groups selected from the group consisting of a C ₁ -C ₆ alkyl group and a phenyl group. Silyl group, tert-butyldiphenylsilyl group or triilopropylsilyl group), R ⁱ represents a hydroxyl-protecting group, preferably selected from the group consisting of C ₁ -C ₆ alkyl groups and phenyl groups Silyl groups substituted with three groups (particularly tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group or triilopropylsilyl group), tetrahydrofuranyl group, tetrahydropyranyl group, methoxy Butyl group, or an allyl group, R ^j and R ^k represents a C ₁ -C ₄ alkyl groups may form ethylene or trimethylene become together, X ^a and X ^c are Represents a chloro group, a bromo group or an iodo group, X ^b represents a group having the formula —NH—, —NR ¹² —, —O— or —S—, and X ^d represents a chloro group, a bromo group, An iodo group or a trifluoromethanesulfonyloxy group, Allyl represents an allyl group, Boc represents a tert-butoxycarbonyl group, t-Bu represents a tert-butyl group, MOM represents a methoxymethyl group Indicates.

  In the reaction of each step of the following methods A to P, 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 P 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 method A to method P 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 of each step of the following method A to method P 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 method A to method P, 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 P, 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 matter such as a catalyst is 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 drying agent 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 a compound (Ia) in which R ¹ is —COR ^a , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is X ^b in formula (I).
(Step A-1)
In step A-1, compound (1), which is known or easily obtained from a known compound, is reacted with compound (2) in the presence or absence of a base to produce compound (3). It is a process to do.

In the step A-1, when R ^a of the compound (2) is ^a C ₁ -C ₁₀ alkoxy group, a halogeno C ₁ -C ₁₀ alkoxy group or a phenyl- (C ₁ -C ₁₀ alkoxy) group, In the absence, compound (2a) R ^a X ^e (where X ^e represents an alkali metal, preferably sodium or potassium) can be used instead of compound (2). .

  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 in an esterification reaction or an amidation reaction, and is preferably an organic amine, more preferably triethylamine. It is.

  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 50 ° C.

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

A-1 process can also be performed according to the method similar to D-2 process, using a carboxylic acid compound instead of a compound (1).
(Step A-2)
Step A-2 is a step of producing compound (4) by halogenating compound (3) obtained in step A-1 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-2 can be carried out in the presence of a radical reaction initiator such as azoisobutyronitrile (preferably azoisobutyronitrile or benzoyl peroxide) as 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 30 minutes to 6 hours.
(Step A-3)
In step A-3, compound (4) obtained in step A-2 is reacted with compound (5) which is known or easily obtained from a known compound in the presence of a base to give compound (6 ).

  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.
(Step A-4)
Step A-4 is a step for producing compound (Ia) by reacting compound (6) obtained in step A-3 with compound (7) in the presence of a palladium catalyst and a base. Compound (7) is known, can be easily obtained from a known compound, or can be produced by Method I.

The palladium catalyst used is not particularly limited as long as it is usually used for the carbon-carbon bond formation reaction. J. Tsuji, Palladium Reagents and Catalysis: New Perspectives for the 21 ^st Centuty, 2004, John Wiley & It may be a palladium catalyst described in Sons, Inc. et al. The palladium catalyst used is, for example, tetrakis (triphenylphosphine) palladium (0), bis [1,2-bis (diphenylphosphino) ethane] palladium (0), tris (dibenzylideneacetone) dipalladium (0) Bis (tri-t-butylphosphine) palladium (0), bis (tricyclohexylphosphine) 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 (benzonitrile) paradi (II) chloride, bis (acetate) bis (triphenylphosphine) palladium (II), bis (acetonitrile) dichloropalladium (II), bis (benzonitrile) dichloropalladium (II), trans-benzyl (chloro) bis ( Triphenylphosphine) palladium (II), palladium-carbon, palladium hydroxide, or palladium hydroxide-carbon, preferably tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, tris (Dibenzylideneacetone) dipalladium (0) or [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct.

In step A-4, a phosphorus ligand capable of coordinating with the palladium catalyst may be used as necessary. The phosphorus ligands used can be those described in J. Tsuji, Palladium Reagents and Catalysis: New Perspectives for the 21 ^st Centuty, 2004, John Wiley & Sons, Inc. 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 (di Phenylphosphino) pentane, 1,6-bis (diphenylphosphino) hexane, 1,2-bis (dimethylphosphino) ethane, 1,1′-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphino) Ethyl) phenylphosphine, 2- (dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (S-PHOS), 2- (dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-) It can be iso-propyl-1,1′-biphenyl (X-PHOS) or bis (2-diphenylphosphinophenyl) ether (DPEphos), preferably triphenylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane, 2- (dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl, or bis (2-diphenylphosphinov Yl) ethers.

  The base used can be a base selected from the above base group or an alkali metal phosphate, preferably an alkali metal carbonate or alkali metal phosphate, more preferably sodium carbonate, carbonate. Potassium or potassium phosphate.

  The solvent to be used is selected from the above solvent group, preferably hydrocarbons, ethers, alcohols, amides, water, or a mixture thereof, more preferably toluene, tetrahydrofuran, ethanol. Dimethylacetamide, water, or a mixture thereof, most preferably a mixture of toluene and ethanol, a mixture of tetrahydrofuran and water, 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.

(Method B)
Method B is a method for producing a compound (Ia) in which R ¹ is —COR ^a , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is X ^b in formula (I).
(Step B-1)
In step B-1, compound (6) obtained in step A-3 is reacted with compound (8) that 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 (9).

  The palladium catalyst used may be similar to that shown in step A-4, preferably with [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct. is there. Moreover, a phosphorus ligand can be used suitably as needed like the A-4 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, preferably ethers, sulfoxides or mixtures thereof, more preferably tetrahydrofuran, dioxane, dimethyl sulfoxide, or mixtures thereof, Preferable is dimethyl sulfoxide or dioxane.

  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 B-2)
In the step B-2, the compound (9) obtained in the step B-1 is reacted with a compound (10) that is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, This is a process for producing compound (Ia).

B-2 process can be performed according to the method similar to A-4 process.

(Method C)
Method C is a method for producing a compound (Ib) in which R ⁶ and R ⁷ are hydrogen atoms and X ¹ is X ^b in formula (I).
(Step C-1)
Step C-1 is a step of producing compound (12) by halogenating compound (11) which is known or easily obtained from a known compound with a halogenating agent.

Step C-1 can be performed according to the same method as step A-2.
(Step C-2)
Step C-2 is a step for producing compound (Ib) by reacting compound (12) obtained in step C-1 with compound (13) in the presence of a base. Compound (13) is publicly known, can be easily obtained from a publicly known compound, or can be obtained by Method J, Method L or Method M.

  Step C-2 can be performed according to the same method as step A-3.

Step C-2 can also be performed using compound (12a) in which X ^a is a methanesulfonyloxy group, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group in compound (12).

In compound (Ib) obtained in step C-2, compound (Ib-1) in which ^Xb is a group having the formula -S- is mixed with 1 or 2 mol of metachloro in a solvent (preferably methylene chloride or the like). Oxidation with perbenzoic acid produces compound (Ib-2) in which R ⁶ and R ⁷ in formula (I) are hydrogen atoms and X ¹ is a group having the formula —SO— or —SO ₂ —. I can do it.

(Method D)
Method D is a method for producing compound (Ia) in which R ¹ is —COR ^a , R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is X ^b in formula (I).
(Process D-1)
Step D-1 is a step for producing compound (15) by treating compound (14) obtained by Method A, Method B or Method C 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 1 hour to 24 hours.
(Step D-2)
In the step D-2, the compound (15) obtained in the step D-1 is reacted with a compound (2) that is known or easily obtained from a known compound in the presence of a condensing agent. This is a process for producing Ia).

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 the 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 the compound (12) is an amine in the step D-2, an excessive amount of the compound (12) 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 D-2, compound (15) is converted into acid chloride with oxalyl chloride, thionyl chloride, etc. in a solvent (preferably methylene chloride, etc.), and then a base (preferably, triethylamine, etc.) is present. It can also carry out by making it react with a compound (2) or said compound (2a) below.

(E method)
In the method E, in formula (I), R ¹ is —COO (t-Bu), R ² is a hydroxyl group, R ⁶ and R ⁷ are hydrogen atoms, and X ¹ represents the formula —O—. And a compound (Ic) in which R ⁸ is —X ² COOH.
(Step E-1)
Step E-1 is a step of producing compound (17) by reacting compound (16) that is known or easily obtained from a known compound with dimethylformamide in the presence of alkyl lithium 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 E-1, depending on the type of compound (16), a compound having a hydroxyl group of —OR ^c in compound (17) may be obtained. In this case, compound (17) can be obtained by treating the resulting compound with an acid (preferably an inorganic acid, more preferably hydrochloric acid) and carrying out R ^c removal reaction.
(Step E-2)
Step E-2
(Step E-2a): a step of reacting compound (17) obtained in Step E-1 with methyl orthoformate in the presence of an acid; and
(Step E-2b): The step comprises the step of producing the compound (18) by reacting the compound obtained in the step E-2a with chloromethyl methyl ether in the presence of a base.
(E-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 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 1 to 24 hours, preferably 2 to 12 hours.
(E-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 E-3)
Step E-3
(Step E-3a): a step of reacting compound (18) obtained in Step E-2 with dimethylformamide in the presence of alkyllithium and a base; and
(Step E-3b): The step comprises the step of producing the compound (19) by reducing the compound obtained in the step E-3a with a reducing agent.
(E-3a process)
The alkyllithium used is selected from the alkyllithiums shown in the above base group and is preferably n-butyllithium. In the step E-3a, the ratio of the number of moles of the compound (18) and n-butyllithium is preferably 1: 1 to 1: 3, and more preferably 1: 1.5 to 1: 2. .5.

  The base used can have the property of taking care of lithium ions, and is preferably tetramethylethylenediamine. In the step E-3a, the ratio of the number of moles of the compound (18) and tetramethylethylenediamine is preferably 1: 1 to 1: 3, more preferably 1: 1 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 or tetrahydrofuran.

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

The reaction time is usually 30 minutes to 10 hours, preferably 30 minutes to 6 hours.
(E-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, preferably sodium borohydride.

  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 E-4)
Step E-4 is a step of producing compound (21) by reacting compound (19) obtained in step E-3 with compound (20) in the presence of an azodicarboxylate reagent and a phosphine reagent. is there. Compound (20) is publicly known, can be easily obtained from a publicly known compound, or can be obtained by Method J, Method L or Method M.

  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 or 1,1 ′ -(Azodicarbonyl) dipiperidine, more preferably diethylazodicarb Boxylate or 1,1 '-(azodicarbonyl) dipiperidine. 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 E-5)
Step E-5
(Step E-5a): In the compound (21) obtained in Step E-4, a step of converting a dimethoxymethyl group into a formyl group in the presence of an acid to remove the methoxymethyl group;
(Step E-5b): a step of reacting the hydroxyl group of the compound obtained in Step E-5a with allyl bromide in the presence of a base;
(Step E-5c): A step of oxidizing the compound obtained in Step E-5b with sodium hypochlorite (NaClO ₂ ) in the presence of sodium dihydrogen phosphate and 2-methyl-2-butene; and,
(Step E-5d): The compound obtained in Step E-5c is reacted with N, N-dimethylformamide ditert-butyl acetal [Me ₂ NC [O (t-Bu)] ₂ ] to give compound (22) It consists of the process of manufacturing.
(Step E-5a)
The acid used is selected from the above acid group and is preferably an organic sulfonic acid or an inorganic acid, more preferably p-toluenesulfonic acid or hydrochloric acid.

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

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

The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(E-5b process)
The base used is selected from the above group of bases and is preferably an alkali metal carbonate, more preferably potassium carbonate.

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

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

The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step E-5c)
The solvent used is selected from the above solvent group, preferably ethers, alcohols, water, or a mixture thereof, more preferably a mixture of 1,4-dioxane and water, 2- A mixture of methyl-2-propanol and water, or a mixture of 1,4-dioxane / 2-methyl-2-propanol / 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.
(E-5d process)
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.
(Step E-6)
Step E-6
(Step E-6a): A step of removing the allyl group in the presence of a palladium reagent in the allyloxy group of the compound (22) obtained in Step E-5; and
(Step E-6b): It comprises a step of producing compound (Ic) by a hydrolysis reaction in the presence of a base of the compound obtained in step E-6a.

In step E-6, when R ^d of compound (22) is an allyl group, R ^d is simultaneously removed in step E-6a, and therefore step E-6b is not necessary.
(Step E-6a)
The palladium reagent to be used is not particularly limited as long as it is usually used for the allyl group elimination reaction. For example, it can be the same as that shown in step A-4, and preferably tetrakis. (Triphenylphosphine) palladium (0).

  In the step E-6a, 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 or morpholine.

  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 12 hours, preferably 30 minutes to 6 hours.
(Step E-6b)
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 and is preferably an ether, an alcohol or a mixture thereof, more preferably tetrahydrofuran, methanol or a mixture thereof. In the step E-6b, water is always used, and only water can be used as a solvent.

  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.

(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 X ¹ represents the formula —O—. This is a method for producing a compound (Id) in which R ⁸ is —X ² COR ^f .
(Step F-1)
F-1 step, the compound obtained in E-5 step (23), by performing the removal reaction of R ^e, is a step for preparing a compound (24).

F-1 process can be performed in accordance with the method similar to E-6b process.
(Step F-2)
In the step F-2, the compound (24) obtained in the step F-1 is reacted with a compound (25) which is known or easily obtained from a known compound in the presence of a condensing agent. 26).

F-2 process can be performed according to the method similar to D-2 process.
(Step F-3)
Step F-3 is a step for producing compound (Id) by removing the allyl group in the presence of a palladium reagent in the allyloxy group of compound (26) obtained in step F-2.

F-3 process can be performed in accordance with the method similar to E-6a process.

(G method)
In the method G, in formula (I), R ¹ is —COR ^a , R ⁷ is a hydrogen atom, X ¹ is a group having the formula —O—, and R ⁸ is —X ² COOH or —X ^This is a method for producing compound (Ie) or compound (If) which is ² COR ^f .
(Step G-1)
Step G-1 is a step of producing compound (28) by reacting compound (27) which is known or easily obtained from a known compound with dimethylformamide in the presence of alkyl lithium and a base. It is.

G-1 process can be performed according to the method similar to E-3a process.
(Step G-2)
Step G-2 is a step of producing compound (30) by reacting compound (28) obtained in step G-1 with compound (29).

  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 30 minutes to 24 hours, preferably 1 hour to 12 hours.

In step G-2, compound R ⁶ MgCl can be used instead of compound (29).
(Step G-3)
Step G-3 is a step of producing compound (32) by reacting compound (30) obtained in step G-2 with compound (31) in the presence of an azodicarboxylate reagent and a phosphine reagent. is there. Compound (31) is publicly known, can be easily obtained from a publicly known compound, or can be obtained by Method J, Method L or Method M.

G-3 process can be performed according to the method similar to E-4 process.
(Step G-4)
G-4 process
(Step G-4a): In the compound (32) obtained in Step G-3, a step of converting a dimethoxymethyl group into a formyl group in the presence of an acid;
(Step G-4b): a step of oxidizing the compound obtained in Step G-4a with sodium hypochlorite (NaClO ₂ ) in the presence of sodium dihydrogen phosphate and 2-methyl-2-butene;
(Step G-4c): a step of reacting the compound obtained in Step G-4b with the above compound (2) known in the presence of a condensing agent or easily obtained from a known compound; and
(Step G-4d): The step includes the step of producing the compound (Ie) by removing the R ^g group in the presence of a palladium reagent in the —COOR ^g group of the compound obtained in the step G-4c.

Steps G-4a, G-4b, G-4c, and G-4d follow the same methods as steps E-5a, E-5c, D-2, and E-6a, respectively. ,It can be carried out.
(Step G-5)
In step G-5, compound (Ie) obtained in step G-4 is reacted with compound (25) which is known in the presence of a condensing agent or is easily obtained from a known compound, to give compound ( If).

G-5 process can be performed according to the method similar to D-2 process.

(Method H)
In the method H, in formula (I), R ¹ is —COO (t-Bu), R ² is a hydroxyl group, R ⁶ and R ⁷ are hydrogen atoms, and X ¹ is a formula —O—. And a compound (Ic) in which R ⁸ is —X ² COOH.
(Process H-1)
In the H-1 step, a compound (33) which is known or easily obtained from a known compound is converted into di-tert-butyl dicarbonate [(t-BuOCO) ₂ O in the presence of alkyllithium and a base. ] To produce a compound (34).

  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.
(Process H-2)
Step H-2 is a step of producing compound (35) by carrying out a silyl group (R ^h ) removal reaction in compound (34) obtained in step H-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. A mixture of acetic acid, tetrahydrofuran and water is also suitable as a combination of the reagent and solvent used in Step H-2.

  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 H-3)
Step H-3 is a step of producing compound (36) by reacting compound (35) obtained in step H-2 with compound (20) in the presence of an azodicarboxylate reagent and a phosphine reagent. is there. Compound (20) is publicly known, can be easily obtained from a publicly known compound, or can be obtained by Method J, Method L or Method M.

The H-3 step can be performed according to the same method as the E-4 step.
(Process H-4)
Step H-4 is a step for producing compound (37) by carrying out a methoxymethyl group removal reaction in compound (36) obtained in step H-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 (step H-5).
Step H-5 is a step of producing compound (Ic) by carrying out R ^d group removal reaction in compound (37) obtained in step H-4.

The H-5 step can be performed according to the same method as the E-6b step. Further, when R ^d of compound (37) is allyl group, H-5 step can also be carried out according to the same method as E-6a step.

(Method I)
Method I is a method for producing compound (7) used in step A-4.
(Step I-1)
In the step I-1, a compound (10) which is known or easily obtained from a known compound is converted to a compound (10) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base ( In this step, compound (7) is produced by reacting with 8).

Step I-1 can be performed according to the same method as in Step B-1.

(J method)
Method J is a method for producing compound (20) used in step E-4 or step H-3.
(Step J-1)
In step J-1, compound (38) which is known or easily obtained from a known compound is converted to compound (38) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base ( In this step, compound (39) is produced by reacting with 8).

J-1 process can be performed according to the method similar to B-1 process.
(Step J-2)
In step J-2, compound (39) obtained in step J-1 is reacted with compound (40) which is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, In this step, compound (41) is produced.

J-2 process can be performed according to the method similar to A-4 process.
(Step J-3)
Step J-3 is a step of producing compound (20) by removing the R ⁱ group from compound (41) obtained in step J-2.

The J-3 process depends on the type of R ⁱ group, and is a conventional method (for example, TH Greene, PG Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc., etc. ).

(K method)
Method K is a method for producing compound (41) used in Step J-3.
(Step K-1)
In step K-1, compound (40) which is known or easily obtained from a known compound is converted to compound (40) which is known or easily obtained from a known compound in the presence of a palladium reagent and a base ( In this step, compound (42) is produced by reacting with 8).

K-1 process can be performed according to the method similar to B-1 process.
(Step K-2)
In the step K-2, the compound (42) obtained in the step K-1 is reacted with a compound (38) which is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, In this step, compound (41) is produced.

K-2 process can be performed according to the method similar to A-4 process.

(L method)
Method L is a method for producing compound (47) wherein X ² is a methylene group in compound (20) used in step E-4 or step H-3.
(L-1 process)
Step L-1 is a step of producing compound (44) by reacting compound (43) that is known or easily obtained from a known compound with a cyanating reagent.

  The cyanating reagent to be used is not particularly limited as long as it is usually used in the cyanation reaction of alkyl halide, and may be, for example, an alkali metal cyanide, preferably sodium cyanide or potassium cyanide. .

  The solvent used is selected from the above solvent group, preferably an alcohol, water or a mixture thereof, more preferably ethanol, water or a mixture thereof, and more preferably ethanol and It is a mixture of water.

  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.
(Step L-2)
In the step L-2, the compound (44) obtained in the step L-1 is reacted with a compound (45) which is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, In this step, compound (46) is produced.

L-2 process can be performed according to the method similar to A-4 process.
(L-3 process)
L-3 process is
(Step L-3a): Step of hydrolyzing the compound (46) obtained in Step L-2 in the presence of an acid; and
(Step L-3b): The step comprises reacting the compound obtained in Step L-3a with compound R ^d OH in the presence of an acid to produce compound (47).
(L-3a process)
The acid used is an acid selected from the above acid group or a mixture thereof, preferably hydrochloric acid or a mixture of hydrochloric acid and acetic acid, more preferably a mixture of hydrochloric acid and acetic acid.

  The solvent used is selected from the above solvent group and is preferably acetic acid, water or a mixture thereof, and more preferably water. In the L-3a step, water is always used, and only water can be used as a solvent.

  The reaction temperature is usually 20 to 180 ° C, preferably 50 to 150 ° C.

  The reaction time is usually 1 hour to 72 hours, preferably 2 hours to 48 hours.

The L-3a step can also be performed according to the same method as the M-1a step.
(L-3b process)
The acid used is selected from the above acid group and is preferably hydrochloric acid or sulfuric acid, more preferably sulfuric acid.

The solvent used is selected from the above solvent group and is preferably an alcohol. In the step L-3b, it is preferable to use the compound R ^d OH as a solvent.

  The reaction temperature is usually 20 to 180 ° C, preferably 50 to 150 ° C.

  The reaction time is usually 1 hour to 36 hours, preferably 2 hours to 24 hours.

L-3b process can also be performed according to the method similar to M-1b process.

(M method)
Method M is a method for producing compound (47) in which X ² is a methylene group in compound (20) used in step E-4 or step H-3.
(Step M-1)
Step M-1
(Step M-1a): Step of hydrolyzing the compound (44) obtained in Step L-1 in the presence of a base; and
(Step M-1b): The step comprises reacting the compound obtained in Step M-1a with compound R ^d X ^{d in the} presence of a base to produce compound (48).
(M-1a process)
The base used can be an alkali metal hydroxide or alkaline earth metal hydroxide of the above base group, preferably sodium hydroxide or potassium hydroxide.

  The solvent used is selected from the above solvent group, preferably alcohols, water or a mixture thereof, more preferably a mixture of alcohols and water, more preferably ethylene glycol and It is a mixture of water. In the step M-1a, water is always used, and only water can be used as a solvent.

  The reaction temperature is usually 50 to 200 ° C, preferably 80 to 160 ° C.

  The reaction time is usually 1 hour to 72 hours, preferably 2 hours to 48 hours.

M-1a process can also be performed according to the method similar to L-3a process.
(M-1b process)
The base used is selected from the above group of bases, preferably an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydride, more preferably an alkali metal carbonate, and even more preferably. Is sodium carbonate or potassium carbonate.

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

  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.

M-1b process can also be performed according to the method similar to L-3b process.
(Step M-2)
In the step M-2, the compound (48) obtained in the step M-1 is reacted with a compound (45) which is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, In this step, compound (47) is produced.

M-2 process can be performed according to the method similar to A-4 process.

(N method)
Method N is a method for producing compound (53) wherein X ² is a methylene group substituted with R ^j and R ^k in compound (20) used in step E-4 or step H-3.
(N-1 process)
In step N-1, compound (49), which is known or easily obtained from a known compound, is sequentially reacted with compound (50) and compound (51) in the presence of a base to produce compound (52). It is a process to do. Step N-1 can also be performed using compound X ^c -R ¹ -X ^c (wherein R ¹ represents an ethylene group or trimethylene group) instead of compound (50) and compound (51). .

  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 0 to 150 ° C., preferably 20 to 100 ° C.

The reaction time is usually 30 minutes to 12 hours, preferably 1 to 6 hours.
(N-2 process)
In the N-2 step, the compound (52) obtained in the N-1 step is reacted with a compound (45) that is known or easily obtained from a known compound in the presence of a palladium catalyst and a base, In this step, the compound (53) is produced.

N-2 process can be performed according to the method similar to A-4 process.

(O method)
In the method O, in the compound (6) used in the step A-4 or the step B-1, R ^a is a t-butoxy group, R ² is a hydroxyl group, and X ^b has the formula —O—. This is a method for producing the compound (57) as a group.
(O-1 process)
Step O-1 is a step of producing compound (55) by reacting compound (19) obtained in step E-3 with compound (54) in the presence of an azodicarboxylate reagent and a phosphine reagent. is there. Compound (54) is known or can be easily obtained from a known compound.

O-1 process can be performed according to the method similar to E-4 process.
(Step O-2)
O-2 process is
(Step O-2a): In the compound (55) obtained in Step O-1, in the presence of an acid, a step of converting a dimethoxymethyl group into a formyl group and removing the methoxymethyl group; and
(O-2b step): From the step of oxidizing the compound obtained in the O-2a step with sodium hypochlorite (NaClO ₂ ) in the presence of sodium dihydrogen phosphate and 2-methyl-2-butene. Become.

  The O-2a step can be performed according to the same method as the E-5a step.

The O-2b step can be performed according to the same method as the E-5c step.
(O-3 process)
The O-3 process is
(Step O-3a): a step of reacting the compound (56) obtained in Step O-2 with di-tert-butyl dicarbonate [(tBuOCO) ₂ O] in the presence of a base; and
(O-3b step): The step comprises removing the Boc group on the hydroxyl group of the compound obtained in the O-3a step in the presence of a base.
(O-3a process)
The base used is selected from the above base group, preferably an organic amine, and more preferably 4- (N, N-dimethylamino) pyridine.

  The solvent used is selected from the above solvent group, preferably ethers, alcohols, or mixtures thereof, more preferably tetrahydrofuran, 2-methyl-2-propanol, or these It is a mixture.

  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 1 hour to 12 hours.
(O-3b process)
The base used is preferably pyrrolidine or piperidine, more preferably pyrrolidine.

  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 10 minutes to 12 hours, preferably 30 minutes to 6 hours.

(P method)
In the method P, in formula (I), R ¹ is —COO (t-Bu), R ² is a hydroxyl group, R ⁶ and R ⁷ are hydrogen atoms, and X ¹ represents the formula —O—. This is a method for producing a compound (Ic) in which R ⁸ is —X ² COOH.
(Step P-1)
Step P-1 is a step of reacting compound (18) obtained in Step E-2 with methyl iodide in the presence of alkyllithium and a base.

The P-1 step can be performed according to the same method as the E-3a step.
(Step P-2)
P-2 process is
(Step P-2a): In the compound (58) obtained in Step P-1, in the presence of an acid, a step of converting a dimethoxymethyl group into a formyl group and removing the methoxymethyl group; and
(Step P-2b): From the step of oxidizing the compound obtained in Step P-2a with sodium hypochlorite (NaClO ₂ ) in the presence of sodium dihydrogen phosphate and 2-methyl-2-butene. Become.

  P-2a process can be performed according to the method similar to E-5a process.

P-2b process can be performed in accordance with the method similar to E-5c process.
(Step P-3)
P-3 process is
(Step P-3a): a step of reacting compound (59) obtained in Step P-2 with di-tert-butyl dicarbonate [(tBuOCO) ₂ O] in the presence of a base; and
(Step P-3b): It comprises a step of producing a compound (60) by halogenating the compound obtained in the step P-3a with a halogenating agent.

  P-3a process can be performed according to the method similar to O-3a process.

P-3b process can be performed according to the method similar to A-2 process.
(Step P-4)
Step P-4 is a step of producing compound (61) by reacting compound (60) obtained in step P-3 with compound (20) in the presence of a base. Compound (20) is publicly known, can be easily obtained from a publicly known compound, or can be obtained by Method J, Method L or Method M.

  P-4 process can be performed according to the method similar to A-3 process.

P-4 process can also be carried out using X ^a in the compound (60) is a methanesulfonyloxy group, benzenesulfonyloxy group or compound is p- toluenesulfonyloxy group of (60a).

(Step P-5)
Step P-5 is a step of removing the Boc group on the hydroxyl group of compound (61) obtained in Step P-4 in the presence of a base.

P-5 process can be performed according to the method similar to O-3b process.
(Step P-6)
Step P-6 is a step of producing compound (Ic) by hydrolysis reaction of compound (62) obtained in step P-5 in the presence of a base.

P-5 process can be performed in accordance with the method similar to E-6b process.

In addition, a substituent introduction reaction under the following reaction conditions can be appropriately applied to the above-mentioned methods A to P as necessary.
(A) Bromination of the 2-position of the thiophene ring: N-bromosuccinimide, acetic acid (Jackson, PM, J. Chem. Soc., Perkin Trans. 1, 1990, Vol. 11, p. 2909-2918);
(B) Introduction of a methoxycarbonylmethyl group onto the pyrazole ring nitrogen: methyl bromoacetate, potassium carbonate;
(C) Introduction of a hydroxymethyl group at the benzyl position: paraformaldehyde, sodium bicarbonate;
(D) Introduction of an alkyl group at the benzylic position of phenylacetic acid ester:
(D-1) tetra-n-butylammonium hydrogen sulfate, lithium bis (trimethylsilyl) amide, or lithium diisopropylamide, and
(D-2) alkyl halide;
(E) Introduction of an alkyl group at the benzylic position of phenylacetic acid ester:
(E-1) lithium bis (trimethylsilyl) amide or lithium diisopropylamide,
(E-2) an aliphatic aldehyde, and
(E-3) sodium cyanoborohydride, acetic acid;
(F) Introduction of a dimethylaminomethyl group at the benzylic position of phenylacetic acid ester:
(F-1) N, N-dimethylformamide ditert-butyl acetal, and
(F-2) Sodium cyanoborohydride, acetic acid.

In the present invention, “arteriosclerosis” refers to (i) arteriosclerosis caused by various factors (including complex factors) such as smoking and heredity; and (ii) hyperlipidemia, high cholesterol Including arteriosclerosis resulting from diseases that can cause arteriosclerosis such as diabetes, lipid-related diseases, inflammatory diseases, diabetes, obesity, hypertension, such as atherosclerosis, arteriosclerosis, And obstructive arteriosclerosis. “Arteriosclerotic heart disease” refers to cardiovascular disease resulting from atherosclerosis, and “cardiovascular disease” includes, for example, ischemic heart disease, heart failure, angina pectoris, and myocardial infarction .

  In the present invention, “inflammatory disease” refers to a disease caused by inflammatory cytokines, and includes, for example, rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, and osteoporosis. “Autoimmune diseases” include systemic lupus erythematosus, ulcerative colitis, and Crohn's disease. “Diabetic complications” include retinopathy, nephropathy, neurosis, and coronary artery disease.

  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, the compound represented by the general formula (I) or the pharmacologically acceptable salt thereof Pharmaceutical compositions containing salts or esters and the following other pharmaceuticals as active ingredients can be formed and such pharmaceutical compositions are encompassed by the present invention. In the above-mentioned pharmaceutical composition, the active ingredients can be “administered simultaneously” as needed, or can be “administered separately at intervals”.

  When each active ingredient of the pharmaceutical composition is “administered simultaneously”, the dosage form is not particularly limited as long as it can be administered at approximately the same time. A preparation containing a compound or a pharmacologically acceptable salt or ester thereof, and a preparation containing the following other medicine (one or two or more preparations when the other medicine is 2 or more) Can be administered together, i.e. in the form of a combination of different different formulations, or the compound of general formula (I) of the invention or a pharmacologically acceptable salt or ester thereof and the following other medicaments: It can be administered in the form of a single preparation, ie, a combination preparation, which is contained simultaneously, and is preferably administered in the form of a combination of different and different preparations.

  When each active ingredient of the pharmaceutical composition is "administered separately at intervals", the dosage form is not particularly limited as long as it can be administered separately at different times. A compound represented by formula (I) or a pharmacologically acceptable salt or ester thereof is administered, and after a certain period of time, the following other medicament is administered, or first, the following other medicament is initially administered. After a certain period of time after administration, the compound represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof can be administered. The time from administration of one active ingredient to administration of the other active ingredient is not particularly limited, and the other active ingredient is administered within a time period during which the action of the first active ingredient administered lasts. It is preferable.

The “other medicine” is not particularly limited as long as it satisfies 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 resins, fibrates, nicotinic acid derivatives, niacinamide, LDL receptor inducers, vitamin B _6, vitamin B _12, anti-oxidant vitamins, angiotensin II inhibitor, angiotensin converting enzyme inhibitors, beta-blockers, fibrinogen inhibitor One or more medicaments selected from the group consisting of aspirin, aspirin, and a diuretic Preferably, from HMG-CoA reductase inhibitor, CETP inhibitor, ACAT inhibitor, cholesterol absorption inhibitor, bile acid adsorption ion exchange resin, fibrate, nicotinic acid derivative, angiotensin II inhibitor, and diuretic One or more pharmaceuticals selected from the group consisting of, more preferably one or more pharmaceuticals selected from the group consisting of HMG-CoA reductase inhibitors, CETP inhibitors and cholesterol absorption inhibitors; Is a combination of HMG-CoA reductase inhibitor, HMG-CoA reductase inhibitor and CETP inhibitor, or a combination of HMG-CoA reductase inhibitor and cholesterol absorption inhibitor, most preferably HMG-CoA reductase inhibitor.

  A pharmaceutical composition comprising 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 as active ingredients (the pharmaceutical composition is CETP inhibitor or cholesterol absorption inhibitor) may have excellent lipid metabolism-improving effects, such as arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, Hypercholesterolemia, lipid-related disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, or cerebrovascular disease; preferably arteriosclerosis, atherosclerosis, artery caused by diabetes Sclerosis, arteriosclerotic heart disease, cardiovascular disease or coronary artery disease; more preferably arteriosclerosis, atherosclerosis or arteriosclerotic heart disease; most preferably arteriosclerosis Disease It is useful as a pharmaceutical composition for the treatment or prevention. 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 (platosartan), 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 ′], as described in US Pat. -Biphenyl] -4-yl] methyl] -1H-imidazole-5-methanol monopotassium salt (potassium losartan) 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 thereof.

  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 medicament for the treatment or prevention of the above-mentioned diseases, the compound itself (as is) Or can be administered as a formulation such as tablets, capsules, granules, powders or syrups prepared by mixing with appropriate pharmacologically acceptable excipients, diluents, etc. Alternatively, it can be administered parenterally (preferably orally) as a preparation such as an injection, a suppository, a patch, or an external preparation produced in the same manner.

  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. Examples of the organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, pregelatinized starch, and dextrin; cellulose derivatives such as crystalline cellulose; It can be gum arabic; dextran; or pullulan. Inorganic excipients include, for example, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium silicate derivatives such as magnesium aluminate; 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 acids such as anhydrous silicic acid and silicic acid hydrate; It can be the starch derivative described.

  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 flavoring agent can be, for example, a sweetener such as sodium saccharin or aspartame; an acidulant such as citric acid, malic acid or tartaric acid; or a flavor such as menthol, lemon extract or orange extract.

  The diluent may be a compound that is usually used as a diluent, such as lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, Glycerol, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate, or a mixture thereof.

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, a 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. Therefore, 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) of the present invention or a pharmacologically acceptable salt or ester thereof is an LXR modulator, LXR agonist, or LXR antagonist, preferably LXR modulator or LXR agonist, more preferably , Useful as an LXR modulator. The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is useful as a medicament for inducing ABCA1 expression or promoting reverse cholesterol transfer.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is preferably used for arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia. Disease, hypercholesterolemia, lipid-related disease, inflammatory disease, autoimmune disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, cerebrovascular disease, kidney disease, diabetes, diabetic complications, obesity, Nephritis, hepatitis, cancer, or Alzheimer's disease; more preferably arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, hypercholesterolemia, lipid-related disease, inflammatory Disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, or diabetes; more preferably arteriosclerosis, atherosclerosis, arteriosclerosis resulting from diabetes, arteriosclerotic heart disease, Heart blood Tubular disease or coronary artery disease; even more preferably, arteriosclerosis, atherosclerosis or arteriosclerotic heart disease; most preferably a medicament for the treatment or prevention of arteriosclerosis Useful as.

  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 each of the following examples, the obtained compound can be purified by recrystallization, reprecipitation, silica gel column chromatography, or a combination thereof as necessary.

Example 1
(4 ′-{[2- (tert-butoxycarbonyl) -4-fluoro-3-hydroxybenzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound No .: 1-93)
(1-1)
To a solution of 2-fluoro-5-methylphenol (4.19 g, 33.3 mmol) in acetonitrile (100 ml), paraformaldehyde (3.86 g, 133 mmol), magnesium chloride (6.32 g, 66.5 mmol), and triethylamine (11.6 ml, 83.3 mmol) was added and stirred vigorously at 90 ° C. for 10 days. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to obtain crude 3-fluoro-2-hydroxy-6-methylbenzaldehyde. From the obtained crude product, in the same manner as in Example (28-3) and Example (28-4), tert-butyl 2-[(tert-butoxycarbonyl) oxy] -3-fluoro-6- Methylbenzoic acid (624 mg, total yield of 3 steps 6%) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.11-6.96 (2H, m), 2.33 (3H, s), 1.58 (9H, s), 1.54 (9H, s).
(1-2)
Tert-Butyl obtained in Example (1-1) in the same manner as in Example (28-5), Example (40-2), Example (33-5), and Example (7) 2-[(tert-Butoxycarbonyl) oxy] -3-fluoro-6-methylbenzoic acid (624 mg, 1.91 mmol) gave the title compound as a colorless powder (93 mg, total yield of 4 steps 34%).
In the step corresponding to Example (40-2) above, methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate obtained in Example (6-2) was used as a phenol derivative. It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.59-7.46 (4H, m), 7.33 (2H, d, J = 7.8 Hz), 7.24-7.19 (1H, app t J = 9.2 Hz), 7.08 (1H , dd, J = 8.4, 4.5 Hz), 6.98 (2H, d, J = 8.2 Hz), 5.28 (2H, s), 3.68 (2H, s), 1.60 (9H, s).
MS (ESI) (m / z): 451 ([MH] ⁺ ).

(Example 2)
(4 ′-{[2- (tert-butoxycarbonyl) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) acetic acid (Exemplary Compound Number: 2-2)
(2-1)
Potassium tert-butoxide (5.40 g, 48.1 mmol) was added to a tetrahydrofuran solution (180 ml) of ice-cooled 2-methyl-5-trifluoromethylbenzoyl chloride (10.5 g, 47.2 mmol) (Apollo Scientific). After adding little by little, it stirred for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate, and then 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).
(2-2)
N-bromosuccinimide (1.18 g) was added to a solution of tert-butyl 2-methyl-5- (trifluoromethyl) benzoate (1.57 g, 6.03 mmol) obtained in Example (2-1) in benzene (25 ml). , 6.63 mmol) and 2,2′-azobis (isobutyronitrile) (20 mg) were added, followed by heating 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). White 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).
(2-3)
Tert-Butyl 2- (bromomethyl) -5- (trifluoromethyl) benzoate (2.00 g, 5.90 mmol) obtained in Example (2-2) and 4-iodophenol (1.30 g, 5 .91 mmol) in N, N-dimethylformamide (20 ml) was added with potassium carbonate (1.30 g, 9.41 mmol) under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 times). 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 (elution solvent: n-hexane / ethyl acetate = 100 / 1-50 / 1), and colorless solid tert-butyl 2-[(4-iodophenoxy) methyl] -5- (Trifluoromethyl) benzoate (2.65 g, 94% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.20 (1H, s), 7.85 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz), 7.58 (2H, d, J = 9.4 Hz), 6.77 (2H, d, J = 9.4 Hz), 5.47 (2H, s), 1.61 (9H, s).
(2-4)
Dimethyl sulfoxide solution (15 ml) of tert-butyl 2-[(4-iodophenoxy) methyl] -5- (trifluoromethyl) benzoate (1.71 g, 3.59 mmol) obtained in Example (2-3) 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane [also known as bis (pinacolato) diboron] (1. 00 g, 3.94 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (146 mg, 0.179 mmol), and potassium acetate (530 mg, 5.40 mmol). After the addition, the mixture was stirred at 80 ° C. for 4 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 = 20 / 1-8 / 1), and tert-butyl 2-{[ 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate (1.14 g, 66% yield). Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.20 (1H, br s), 7.88 (1H, d, J = 8.8 Hz), 7.79-7.73 (3H, m), 6.98 (2H, d, J = 8.8 Hz), 5.52 (2H, s), 1.61 (9H, s), 1.34 (12H, s).
(2-5)
In the same manner as in Example (8-1), tert-butyl 2-{[4- (4,4,5,5-tetramethyl-1,3,2-) obtained in Example (2-4) was used. From dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate (88 mg, 0.18 mmol) and 3-bromophenylacetic acid (50 mg, 0.23 mmol), the title compound as a pale yellow powder ( 4.5 mg, 29% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.18 (1H, br s), 7.89 (1H, d, J = 7.8 Hz), 7.75 (1H, br d, J = 7.8 Hz), 7.50 (2H, d , J = 8.6 Hz), 7.47-7.42 (2H, m), 7.36 (1H, t, J = 7.8 Hz), 7.22 (1H, br d, J = 7.8 Hz), 7.02 (2H, d, J = 8.6 Hz), 5.53 (2H, s), 3.70 (2H, s), 1.62 (9H, s).

(Example 3)
(4 ′-{[2- (tert-Butoxycarbonyl) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-16)
(3-1)
Concentrated sulfuric acid (30 ml) was added to a methanol solution (1000 ml) of (4-bromophenyl) acetic acid (101 g, 468 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed successively with water, saturated aqueous sodium hydrogen carbonate, 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), and methyl (4-bromophenyl) acetate (107 g, Yield 100%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.43 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 3.69 (3H, s), 3.57 (2H, s).
(3-2)
In the same manner as in Example (8-1), tert-butyl 2-{[4- (4,4,5,5-tetramethyl-1,3,2-) obtained in Example (2-4) was used. Dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate (100 mg, 0.21 mmol) and methyl (4-bromophenyl) acetate (62 mg) obtained in Example (3-1) , 0.27 mmol) from tert-butyl 2-[({{4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -5- (trifluoromethyl) benzoate (54 mg, 52% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.21 (1H, d, J = 2.0 Hz), 7.92 (1H, d, J = 7.8 Hz), 7.78 (1H, dd, J = 7.8, 2.0 Hz), 7.54-7.49 (4H, m), 7.33 (2H, d, J = 7.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 5.55 (2H, s), 3.71 (3H, s), 3.66 (2H , s), 1.63 (9H, s).
(3-3)
In the same manner as in Example (7), tert-butyl 2-[({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl obtained in Example (3-2) was used. } Oxy) methyl] -5- (trifluoromethyl) benzoate (52 mg, 0.10 mmol) gave the title compound as a white powder (41 mg, 82% yield).
¹ H-NMR (500MHz, CDCl ₃ ): δ 8.21 (1H, br s), 7.92 (1H, d, J = 7.8 Hz), 7.78 (1H, app d, J = 7.8 Hz), 7.53 (4H, app d, J = 7.8 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 5.55 (2H, s), 3.70 (2H, s), 1.63 (9H, s).
MS (FAB) (m / z): 486 (M ⁺ ).

Example 4
[5- (4-{[2- (tert-butoxycarbonyl) -4- (trifluoromethyl) benzyl] oxy} phenyl) -2-thienyl] acetic acid (Exemplary compound number: 2-26)
(4-1)
Methyl synthesized from methyl 2-thienyl acetate according to the method described in the literature (Jackson, PM et al., J. Chem. Soc. Perkin Trans.1., 1990, Vol. 11, p. 2909-2918) (5-Bromo-2-thienyl) acetate and tert-butyl 2-{[4- (4,4,5,5-tetramethyl-1,3,2) obtained in Example (2-4) -Dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate according to the same method as in Example (8-1), tert-butyl 2- [4-({5-[(methoxy Carbonyl) methyl] -2-thienyl} phenoxy) methyl] -5- (trifluoromethyl) benzoate (53 mg, 13% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.20 (1H, br s), 7.89 (1H, d, J = 7.8 Hz), 7.77 (1H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.05 (1H, d, J = 3.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 6.87 (1H, d, J = 3.4 Hz), 5.52 (2H, s), 3.83 (2H, s), 3.75 (3H, s), 1.62 (9H, s).
(4-2)
In the same manner as in Example 7, tert-butyl 2- [4-({5-[(methoxycarbonyl) methyl] -2-thienyl} phenoxy) methyl] -5- obtained in Example (4-1) was used. From (trifluoromethyl) benzoate (300 mg, 0.62 mmol), the title compound (53 mg, 17% yield) was obtained as a pale yellow powder.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.20 (1H, br s), 7.89 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 8.3 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.06 (1H, br d, J = 2.9 Hz), 6.98 (2H, d, J = 8.8 Hz), 6.91 (1H, br d, J = 2.9 Hz), 5.52 (2H, s) , 3.88 (2H, s), 1.62 (9H, s).
MS (FAB) (m / z): 492 (M ⁺ ).

(Example 5)
(4 ′-{[2- (tert-Butoxycarbonyl) -4-chloro-3-hydroxybenzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-95)
(5-1)
To a solution of 2-chloro-5-methylphenol (5.80 g, 40.8 mmol) in acetonitrile (100 ml), paraformaldehyde (4.73 g, 163 mmol), magnesium chloride (7.76 g, 81.7 mmol), and triethylamine (14.2 ml, 102 mmol) was added and stirred vigorously at 90 ° C. for 10 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to obtain crude 3-chloro-2-hydroxy-6-methylbenzaldehyde. From the obtained crude product, in the same manner as in Example (28-3) and Example (28-4), tert-butyl 2-[(tert-butoxycarbonyl) oxy] -3-chloro-6- Methylbenzoic acid (1.82 g, total yield of 3 steps 13%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.34-7.31 (1H, m), 7.04-7.01 (1H, m), 2.35 (3H, s), 1.59 (9H, s), 1.56 (9H, s) .
(5-2)
Tert-Butyl obtained in Example (5-1) in the same manner as in Example (28-5), Example (40-2), Example (33-5), and Example (7) 2-[(tert-butoxycarbonyl) oxy] -3-chloro-6-methylbenzoic acid (1.82 g, 5.32 mmol) gave the title compound as a white powder (30 mg, 1% total yield over 4 steps). It was.
In the step corresponding to Example (40-2) above, methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate obtained in Example (6-2) was used as a phenol derivative. It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.52-7.46 (5H, m), 7.33 (2H, d, J = 8.6 Hz), 7.10 (1H, d, J = 8.6 Hz), 6.95 (2H, d , J = 8.6 Hz), 5.30 (2H, s), 3.68 (2H, s), 1.61 (9H, s).
MS (ESI) (m / z): 467 ([MH] ⁺ ).

(Example 6)
tert-butyl 2-hydroxy-6-[({4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-56)
(6-1)
Methyl (4-bromophenyl) acetate (573 mg, 2.50 mmol) obtained in Example (3-1) and 4-methoxyphenyl boric acid (380 mg, 2.50 mmol) in toluene-ethanol (6: 1, 6M) was added with 1M-sodium carbonate aqueous solution (2.8ml) and tetrakis (triphenylphosphine) palladium (0) (116mg, 0.10mmol), and then heated to reflux with stirring for 4 hours. . The reaction solution was returned to room temperature, poured into water, and extracted three times with ethyl acetate. The organic layer was washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a yellow solid. Purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-80 / 20), methyl (4′-methoxy-1,1′-biphenyl-4-yl) as pale yellow powder Acetate (617 mg, yield 96%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.52 (4H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.4 Hz), 3.85 ( 3H, s), 3.71 (3H, s), 3.66 (2H, s).
(6-2)
Methyl (4′-methoxy-1,1′-biphenyl-4-yl) acetate (210 mg, 0.82 mmol) obtained in Example (6-1) and tetra-n-butylammonium iodide (393 mg) , 1.1 mmol) in methylene chloride solution (5 ml) was added boron trichloride (1.0 N methylene chloride solution, 2.0 ml, 2.0 mmol) at −78 ° C. Stir for hours. Ice was added to the reaction mixture, 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 obtain methyl (4′-hydroxy-1,1 ′). -Biphenyl-4-yl) acetate (155 mg, 78% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.45 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.2 Hz), 6.83 ( 2H, d, J = 8.6 Hz), 5.25 (1H, s), 3.71 (3H, s), 3.66 (2H, s).

(6-3)
2- [2- (Trifluoromethyl) phenoxy] tetrahydro synthesized according to the method described in the literature (Miller, JA et al., J. Org. Chem., 1993, Vol. 58, p. 2637-2639) 2H-pyran (21.4 g, 86.8 mmol) and N, N, N ′, N′-tetramethylethylenediamine (15.7 ml, 104 mmol) in diethyl ether (230 ml) at −20 ° C. -Butyllithium-1.58M n-hexane 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 (2 times) and saturated brine, and anhydrous. Dried over 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 = 20 / 1-10 / 1). The obtained pale yellow oily substance 2- (tetrahydro-2H-pyran-2-yloxy) -3- (trifluoromethyl) benzaldehyde was allowed to stand at room temperature overnight, whereby a pale yellow solid 2-hydroxy-3- (Trifluoromethyl) benzaldehyde (31.7 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 ¹ H-NMR spectrum of 2- (tetrahydro-2H-pyran-2-yloxy) -3- (trifluoromethyl) benzaldehyde which is an intermediate 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), 4.03-3.96 (1H, m), 3.47-3.39 (1H, m), 2.11-2.03 (1H, m), 2.01-1.80 (2H, m), 1.67-1.50 (3H, m).

(6-4)
To a solution of 2-hydroxy-3- (trifluoromethyl) benzaldehyde (31.7 g, 167 mmol) obtained in Example (6-3) in methanol (50 ml), trimethyl orthoformate (130 ml, 1.19 mol), Then, camphorsulfonic acid (1.55 g, 6.67 mmol) was 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 successively added under ice cooling. The mixture was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed successively with 0.5N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and anhydrous sodium sulfate. Dried. 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- (dimethoxy) as a pale yellow oil. Methyl) -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).

(6-5)
1- (Dimethoxymethyl) -2- (methoxymethoxy) -3- (trifluoromethyl) benzene (39.3 g, 140 mmol) obtained in Example (6-4), and N, N, N ′, To a solution of N′-tetramethylethylenediamine (46.9 ml, 311 mmol) in diethyl ether (410 ml), an n-butyllithium-1.59M n-hexane solution (196 ml, 312 mmol) was added dropwise over 20 minutes at −25 ° C. . 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 is carefully poured into cold 0.1N hydrochloric acid and extracted with ethyl acetate (4 times), and then the organic layer is washed successively with 0.1N hydrochloric acid, water (3 times) and saturated brine, and anhydrous. Dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzaldehyde. This compound was used in Example (6-6) 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] ⁺ ).

(6-6)
To the mixed solution of crude 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzaldehyde obtained in Example (6-5) in tetrahydrofuran-methanol (5: 1, 100 ml), 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- (dimethoxy Methyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (22.6 g, total yield of 2 steps 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] ⁺ ).

(6-7)
[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (3.20 g, 10.3 mmol) obtained in Example (6-6) and Example To a tetrahydrofuran solution (40 ml) of methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate (2.50 g, 10.3 mmol) obtained in (6-2), 1,1′- (Azodicarbonyl) dipiperidine (3.10 g, 12.3 mmol) and tri-n-butylphosphine (3.10 ml, 12.4 mmol) were sequentially added, and the mixture was stirred at room temperature for 5 hours. The produced white precipitate was filtered off, and the precipitate was washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate (three times), and then the organic layer was washed successively with 3N-aqueous sodium hydroxide solution, 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 (elution solvent: n-hexane / ethyl acetate = 4/1) to obtain methyl (4 ′-{[2- (dimethoxymethyl)). -3- (Methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetate (3.16 g, yield 58%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.56-7.54 (2H, br s), 7.47 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.29 (2H, d, J = 7.8 Hz), 7.01 (2H, d, J = 9.0 Hz), 5.75 (1H, s), 5.51 (2H, s), 5.03 (2H, s), 3.70 (3H, s), 3.66 ( 3H, s), 3.64 (2H, s), 3.48 (6H, s)

(6-8)
Methyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl obtained in Example (6-7) P-Toluenesulfonic acid monohydrate (1.01 g, 5.31 mmol) was added to a solution of -4-yl) acetate (2.38 g, 4.45 mmol) in acetone (14 ml), and then at room temperature. Stir for hours. The reaction mixture was 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 residue was obtained by distilling off the solvent under reduced pressure. To a solution of the obtained residue in N, N-dimethylformamide (4 ml), potassium carbonate (738 mg, 5.34 mmol) and allyl bromide (0.462 ml, 5.34 mmol) were sequentially added, and the mixture was stirred at 50 ° C. for 2 hours. Stir. The reaction solution 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 = 50 / 1-2 / 1), and methyl (4 ′-{[ 3- (Allyloxy) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetate (1.81 g, yield 84%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.52 (1H, br s), 7.86 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.04 (2H, d, J = 8.4 Hz), 6.16-6.04 (1H, m) , 5.52-5.44 (3H, m), 5.39-5.34 (1H, m), 4.58 (2H, m), 3.70 (3H, s), 3.66 (2H, s).

(6-9)
Methyl (4 ′-{[3- (allyloxy) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl obtained in Example (6-8) ) A mixed solution of acetate (1.71 g, 3.53 mmol) in tert-butyl alcohol (15 ml), 1,4-dioxane (3.5 ml) and 2-methyl-2-butene (4.5 ml) An aqueous solution (7.5 ml) of sodium chlorate (1.28 g, 14.2 mmol) and sodium dihydrogen phosphate monohydrate (1.28 g, 9.28 mmol) was added dropwise, and then at room temperature for 4 hours. Stir. A 5% aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was 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 (12 ml), N, N-dimethylformamide ditert-butyl acetal (3.39 ml, 14.1 mmol) was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was poured into water 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. To a mixed solution of 1,4-dioxane-water (30: 1, 12 ml) of the residue obtained by distilling off the solvent under reduced pressure, pyrrolidine (0.500 ml, 5.99 mmol) and tetrakis (triphenyl) Phosphine) palladium (81.6 mg, 70.6 mmol) was added and stirred at room temperature for 4 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. Purification by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2-85 / 15) gave the title compound as a pale yellow powder (1.08 g, yield 59%).
^{1 H-NMR (400MHz, CDCl} 3): δ 12.23 (1H, s), 7.68 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2 Hz), 6.95 (2H, d, J = 9.0 Hz), 5.35 (2H, s), 3.70 ( 3H, s), 3.65 (2H, s), 1.63 (9H, s).

(Example 7)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1- 55)
Tert-Butyl 2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl]-obtained in Example (6-9) To a solution of 3- (trifluoromethyl) benzoate (467 mg, 0.90 mmol) in tetrahydrofuran (8 ml) was added 3N aqueous sodium hydroxide solution (0.33 ml, 0.33 mmol), and the mixture was stirred at room temperature for 10 hours. The reaction solution was poured into 1N-hydrochloric acid and extracted with ethyl acetate (three times), and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent under reduced pressure was reprecipitated using n-hexane-ethyl acetate to obtain the title compound (372 mg, yield 82%) as a white powder.
¹ H-NMR (400 MHz, acetone-d ₆ ): δ 12.26 (1H, br), 7.82 (1H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.56 (2H, d , J = 8.2 Hz), 7.41-7.33 (3H, m), 7.09 (2H, d, J = 8.6 Hz), 5.52 (2H, s), 3.66 (2H, s), 1.71 (9H, s).
MS (FAB) (m / z): 502 ([M] ⁺ ).

(Example 8)
tert-butyl 2-hydroxy-6-[({3 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 2-30)
(8-1)
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (3.84 g, 17.5 mmol) and literature (Muller, RN et al., Eur. J. Org. Chem., 2002, Vol. 23, p. 3966-3973), methyl (3-bromophenyl) acetate (4.00 g, 17.5 mmol) N, N- To a mixed solution of dimethylacetamide-water (10: 1, 66 ml), tetrakis (triphenylphosphine) palladium (0) (1.00 g, 0.88 mmol) and potassium carbonate (4.80 g, 37.0 mmol) were added. The mixture was further stirred at 110 ° C. for 6 hours. The reaction mixture was poured into 0.2N hydrochloric acid 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 = 2/1) to obtain methyl (4′-hydroxy-1,1 ′). -Biphenyl-3-yl) acetate (2.83 g, 67% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.50-7.43 (4H, m), 7.40-7.35 (1H, m), 7.25-7.20 (1H, m), 6.89 (2H, app d, J = 8.6 Hz ), 3.71 (3H, s), 3.69 (2H, s).
(8-2)
[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1) obtained in Example (6-6) in the same manner as in Example (6-7). .96 g, 6.32 mmol) and methyl (4′-hydroxy-1,1′-biphenyl-3-yl) acetate (1.68 g, 6.95 mmol) obtained in Example (8-1). , Methyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) acetate (1.83 g Yield 54%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.62-7.56 (2H, m), 7.53-7.43 (4H, m), 7.38-7.34 (1H, m), 7.24-7.19 (1H, m), 7.03 ( 2H, br d, J = 8.3 Hz), 5.77 (1H, s), 5.53 (2H, s), 5.04 (2H, s), 3.73-3.66 (8H, m), 3.49 (6H, s).
(8-3)
Methyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl obtained in Example (8-2) P-Toluenesulfonic acid monohydrate (0.716 g, 3.77 mmol) was added to a solution of -3-yl) acetate (1.83 g, 3.43 mmol) in acetone (20 ml), and then at room temperature. Stir for hours. The reaction solution was poured into water and extracted with ethyl acetate (twice), 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. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-70 / 30), and methyl (4 ′-{[2-formyl-3-hydroxy-4- (Trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) acetate (1.26 g, yield 83%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.66 (1H, s), 10.38 (1H, s), 7.82 (1H, br d, J = 7.8 Hz), 7.57-7.53 (2H, m), 7.47- 7.38 (2H, m), 7.42-7.36 (1H, m), 7.28-7.23 (1H, m), 7.11 (1H, br d, J = 7.8 Hz), 7.08-7.03 (2H, m), 5.37 (2H , s), 3.71 (3H, s), 3.69 (2H, s).

(8-4)
In the same manner as in Example (12-5) and Example (6-9), methyl (4 ′-{[2-formyl-3-hydroxy-4-) obtained in Example (8-3) was used. (Trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) acetate (1.26 g, 2.84 mmol) gave the title compound (609 mg, total yield of 2 steps 42%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.30 (1H, br s), 7.72 (1H, br d, J = 8.3 Hz), 7.56 (2H, br d, J = 8.3 Hz), 7.51-7.46 ( 2H, m), 7.43-7.46 (1H, m), 7.30 (1H, br d, J = 8.3 Hz), 7.28-7.23 (1H, m), 7.04-6.97 (2H, m), 5.39 (2H, s ), 3.72 (3H, s), 3.70 (2H, s), 1.67 (9H, s).

Example 9
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) acetic acid (Exemplary compound number: 2- 29)
In the same manner as in Example 7, tert-butyl 2-hydroxy-6-[({3 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-3) obtained in Example (8-4) was used. -Il} oxy) methyl] -3- (trifluoromethyl) benzoate (609 mg, 1.18 mmol) gave the colorless amorphous title compound (469 mg, 79% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.28 (1H, br s), 7.69 (1H, br d, J = 8.2 Hz), 7.52 (2H, br d, J = 8.8 Hz), 7.49-7.45 ( 2H, m), 7.41-7.35 (1H, m), 7.29-7.21 (2H, m), 6.98 (2H, br d, J = 8.8 Hz), 5.36 (2H, s), 3.70 (2H, s) 1.65 (9H, s).
MS (FAB) (m / z): 502 ([M] ⁺ ).

(Example 10)
(4 ′-{[2- (tert-Butoxycarbonyl) -4-tert-butyl-3-hydroxybenzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-49)
(10-1)
3-tert-butyl-2-hydroxybenzaldehyde (28.8 g) synthesized according to the method described in the literature (Hofslφkken, NU et al., Acta Chem. Scand., 1999, Vol. 53, p. 258-262) , 162 mmol) in methanol (20 ml) were added trimethyl orthoformate (106 ml, 0.972 mol) and camphorsulfonic acid (0.751 g, 3.24 mmol), and then stirred 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 N, N-dimethylformamide (100 ml). To this solution, sodium hydride (55% oily, 7.77 g, 178 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes, and then chloromethyl methyl ether (13.5 ml, 178 mmol) was added for 2 hours at room temperature. Stir. The reaction mixture was poured into water and extracted with ethyl acetate (twice), and then the organic layer was washed successively with 0.5N hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and anhydrous sodium sulfate. Dried. 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-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 = 7.8 Hz), 5.64 (1H, s), 5.06 (2H, s), 3.66 (3H, s), 3.38 (6H, s), 1.41 (9H, s).
(10-2)
1-tert-butyl-3- (dimethoxymethyl) -2- (methoxymethoxy) benzene (4.00 g, 14.9 mmol) obtained in Example (10-1), and N, N, N ′, To a solution of N′-tetramethylethylenediamine (4.72 ml, 31.3 mmol) in diethyl ether (100 ml) at −40 ° C., a mixed solution of sec-butyllithium-1.00M cyclohexane-n-hexane (29.8 ml, 29.29 ml). 8 mmol) was added dropwise over 20 minutes. The reaction solution was stirred at room temperature for 1 hour, cooled to −20 ° C., and N, N-dimethylformamide (2.30 ml, 31.3 mmol) was added. The reaction solution was returned to room temperature and further stirred for 1 hour, and then the reaction solution was carefully poured into cold 0.1N hydrochloric acid and extracted with ethyl acetate (three times). The combined organic layers were washed successively with 0.1N hydrochloric acid, water (3 times) 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 methanol (10 ml), sodium borohydride (111 mg, 3.00 mmol) was added under ice cooling, and the mixture was stirred at room temperature 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 = 10 / 1-3 / 1), and [4-tert-butyl- 2- (Dimethoxymethyl) -3- (methoxymethoxy) phenyl] methanol (350 mg, yield 8%) was obtained.
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), 3.52 (1H, t, J = 6.8 Hz), 3.64 (3H, s), 3.46 (6H, s), 1.39 (9H, s).

(10-3)
[4-tert-Butyl-2- (dimethoxymethyl) -3- (methoxymethoxy) phenyl] methanol (161 mg, 0.540 mmol) obtained in Example (10-2) and Example (6-2) The methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate (144 mg, 0.594 mmol) obtained in (1) was used as a starting material, and Examples (6-7) and (6- 8) and tert-butyl 3-tert-butyl-2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -1,1 ′ by the same method as in Example (6-9) -Biphenyl-4-yl} oxy) methyl] benzoate (52 mg, total yield of 3 steps 19%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.05 (1H, s), 7.51-7.47 (4H, m), 7.37 (1H, d, J = 7.8 Hz), 7.31 (2H, d, J = 8.2 Hz ), 7.01 (1H, d, J = 7.8 Hz), 6.96 (2H, d, J = 8.6 Hz), 5.29 (2H, s), 3.70 (3H, s), 3.65 (2H, s), 1.58 (9H , s), 1.42 (9H, s).
(10-4)
In the same manner as in Example 7, tert-butyl 3-tert-butyl-2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -1, obtained in Example (10-3), 1′-biphenyl-4-yl} oxy) methyl] benzoate (52 mg, 0.103 mmol) gave the title compound as a white powder (44 mg, 87% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.08 (1H, br s), 7.55-7.47 (4H, m), 7.39 (1H, br d, J = 8.2 Hz), 7.33 (2H, br d, J = 7.8 Hz), 7.03 (1H, br d, J = 8.2 Hz), 6.98 (2H, br d, J = 8.6 Hz), 5.30 (2H, s), 3.68 (2H, s), 1.58 (9H, s ), 1.41 (9H, s).
MS (ESI) (m / z ): 489 ([MH] +).

(Example 11)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-48)
(11-1)
To a mixed solution of 4-bromo-2-fluorobenzyl bromide (5.00 g, 18.7 mmol) in ethanol-water (3: 1, 40 ml) was added potassium cyanide (1.3 g, 20 mmol), and the mixture was at 60 ° C. for 2 hours. Stir. The reaction mixture was poured into water and 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 column chromatography (elution solvent: n-hexane / ethyl acetate) to give (4-bromo-2-fluorophenyl) acetonitrile (3 .75 g, 94% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.35-7.26 (3H, m), 3.72 (2H, s).
(11-2)
In the same manner as in Example (8-1), (4-bromo-2-fluorophenyl) acetonitrile (3.0 g, 14 mmol) obtained in Example (11-1) and 4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (3.45 g, 14 mmol) to (3-fluoro-4′-hydroxy-1,1′-biphenyl- 4-yl) acetonitrile (2.9 g, 91% yield) was obtained.
¹ H-NMR (400 MHz, MeOH-d ₄ ): δ 7.50-7.34 (5H, m), 6.87 (2H, d, J = 8.8 Hz), 3.92 (2H, s).

(11-3)
Acetic acid (10 ml) and (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetonitrile (2.4 g, 11 mmol) obtained in Example (11-2) and concentrated hydrochloric acid (10 ml) was added, followed by stirring at 110 ° C. for 1 hour. The reaction mixture was 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. Allyl alcohol (20 ml) and concentrated sulfuric acid (1.5 ml) were sequentially added to the residue obtained by concentration under reduced pressure, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 5 / 1-2 / 1) to give colorless solid allyl (3-fluoro -4′-hydroxy-1,1′-biphenyl-4-yl) acetate (2.0 g, total yield of 2 steps 66%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.42 (2H, d, J = 8.4 Hz), 7.31-7.21 (3H, m), 6.86 (2H, d, J = 8.4 Hz), 5.97-5.88 (1H , m), 5.32 (1H, app d, J = 16.4 Hz), 5.24 (1H, app d, J = 10.4 Hz), 4.96 (1H, br s), 4.64 (2H, app d, J = 6.0 Hz) , 3.73 (2H, s).

(11-4)
In the same manner as in Example (6-7), allyl (3-fluoro-4'-hydroxy-1,1'-biphenyl-4-yl) acetate (3.10 g) obtained in Example (11-3) , 10.9 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (3.70 g, 12) obtained in Example (6-6). 0.0 mmol) to light yellow oily allyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1-1 ′ -Biphenyl-4-yl) acetate (3.89 g, 61% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.57-7.56 (2H, m), 7.47 (2H, d, J = 8.4 Hz), 7.29-7.22 (3H, m), 7.03 (2H, d, J = 8.4 Hz), 5.97-5.87 (1H, m), 5.77 (1H, s), 5.53 (2H, s), 5.30 (1H, app d, J = 17.2 Hz), 5.23 (1H, app d, J = 10.4 Hz), 5.04 (2H, s), 4.63 (2H, app d, J = 5.6 Hz), 3.72 (2H, s), 3.67 (3H, s), 3.49 (6H, s).
(11-5)
In the same manner as in Example (12-4) and Example (12-5), allyl (4 ′-{[2- (dimethoxymethyl) -3- ( From methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -3-fluoro-l-1'-biphenyl-4-yl) acetate (3.89 g, 6.7 mmol), allyl (4 '-{[3- (allyloxy) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1'-biphenyl-4-yl) acetate (2.52 g, total of 2 steps Yield 71%).
^{1 H-NMR (500MHz, CDCl} 3): δ 10.55 (1H, s), 7.88 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.33-7.25 (3H, m), 7.06 (2H, d, J = 8.5 Hz), 6.16-6.08 (1H, m), 5.96-5.89 (1H, m), 5.52 (2H, s) , 5.49 (1H, dd, J = 17.5, 1.5 Hz), 5.38 (1H, dd, J = 10.0, 1.0 Hz), 5.31 (1H, dd, J = 17.0, 1.5 Hz), 5.24 (1H, dd, J = 10.0, 1.0 Hz), 4.64 (2H, app d, J = 5.5 Hz), 4.60 (2H, app d, J = 5.5 Hz), 3.73 (2H, s).
(11-6)
Allyl (4 ′-{[3- (allyloxy) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl obtained in Example (11-5) -4-yl) acetate (2.52 g, 4.8 mmol) in tert-butyl alcohol (51 ml), 1,4-dioxane (17 ml), and 2-methyl-2-butene (17 ml) An aqueous solution (22 ml) of sodium phosphate (2.6 g, 29 mmol) and sodium dihydrogen phosphate monohydrate (2.6 g, 19 mmol) was added dropwise, and the mixture was stirred at room temperature for 90 minutes. A 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture 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 was obtained by distilling off the solvent under reduced pressure. Methylene chloride (50 ml), 2-methyl-1-propene (150 ml) and sulfuric acid (1 ml) were sequentially added to the resulting residue, 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 obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10 / 1-3 / 1) to give tert-butyl 2 as colorless powder. -(Allyloxy) -6-{[(4 '-{[(allyloxy) carbonyl] methyl} -3'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl ) Benzoate (2.38 g, 83% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.64 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.31- 7.23 (3H, m), 7.00 (2H, d, J = 8.5 Hz), 6.11-6.03 (1H, m), 5.96-5.88 (1H, m), 5.43 (1H, dd, J = 17.5, 1.5 Hz) , 5.31 (1H, app d, J = 17.0 Hz), 5.28 (1H, app d, J = 10.0 Hz), 5.24 (1H, app d, J = 10.0 Hz), 5.16 (2H, s), 4.64 (2H , app d, J = 6.0 Hz), 4.58 (2H, app d, J = 5.5 Hz), 3.73 (2H, s), 1.58 (9H, s).
(11-7)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -3′-fluoro-1,1′-biphenyl-) obtained in Example (11-6) To a solution of 4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (790 mg, 1.32 mmol) in tetrahydrofuran (8 ml), morpholine (0.27 ml, 3.3 mmol) and tetrakis (triphenyl Phosphine) palladium (0) (57 mg, 0.049 mmol) was sequentially added, and the mixture was 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 3 / 1-0 / 1), and then mixed with methylene chloride-ethyl acetate. Crystallization from a solvent gave the title compound as a colorless powder (323 mg, 47% yield).
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.32-7.26 (4H, m ), 6.98 (2H, d, J = 8.5 Hz), 5.38 (2H, s), 3.76 (2H, s), 1.65 (9H, s).
MS (ESI) (m / z): 519 ([MH] ⁺ ).

(Example 12)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3′-fluoro-1,1′-biphenyl-4-yl) acetic acid (illustrated Compound number: 2-51)
(12-1)
To a 1,4-dioxane solution (300 ml) of methyl 4-bromophenylacetate (17.4 g, 76.0 mmol) obtained in Example (3-1), 4,4,4 ′, 4 ′, 5, 5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane [bis (pinacolato) diboron, 21.2 g, 83.6 mmol], [1,1′-bis (diphenylphos Fino) ferrocene] dichloropalladium (II) -dichloromethane adduct (3.1 g, 3.8 mmol) and potassium acetate (22.4 g, 228 mmol) were added, followed by stirring at 90 ° C. for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through celite. The filtrate 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 = 20 / 1-9 / 1) to give oily methyl [4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (21.0 g, yield 100%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.77 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 3.68 (3H, s), 3.64 (2H, s), 1.35-1.32 (12H, m).

(12-2)
Methyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (1.38 g, 5.0 mmol) obtained in Example (12-1) ) And 4-bromo-2-fluoro-phenol (1.15 g, 6.0 mmol) as a starting material, and the same procedure as in Examples (13-1) and (13-2) was performed to prepare allyl as white powder. (3′-Fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (430 mg, yield 33%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.50-7.45 (2H, m), 7.37-7.23 (4H, m), 7.08-7.02 (1H, m), 5.98-5.86 (1H, m), 5.34- 5.21 (3H, m), 4.65-4.59 (2H, m), 3.69 (2H, s).
(12-3)
In the same manner as in Example (6-7), allyl (3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate obtained in Example (12-2) (300 mg, 1.05 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (500 mg, 1.61 mmol) obtained in Example (6-6) From allyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -3′-fluoro-1,1′-biphenyl-4-yl ) Acetate (618 mg, 93% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.60 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.34- 7.29 (3H, m), 7.21-7.17 (1H, m), 7.03 (1H, app t, J = 8.6 Hz), 5.95-5.84 (1H, m), 5.74 (1H, s), 5.57 (2H, s ), 5.31-5.19 (2H, m), 5.03 (2H, s), 4.62-4.68 (2H, m), 3.67 (2H, s), 3.66 (3H, s), 3.47 (6H, s).
(12-4)
Allyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -3′-fluoro-1 obtained in Example (12-3) , 1′-biphenyl-4-yl) acetate (618 mg, 1.06 mmol) in acetone solution (10 ml) was added p-toluenesulfonic acid monohydrate (223 mg, 1.18 mmol), and 1 at 50 ° C. Stir for hours. The residue obtained by concentrating the reaction solution was diluted with ethyl acetate. The obtained solution was washed successively with saturated aqueous sodium hydrogen carbonate, 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) to give allyl (3′-fluoro-4 ′-{[ 2-Formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetate (476 mg, 91% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.68 (1H, s), 10.44 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.49 (2H, d, J = 7.8 Hz), 7.39-7.27 (4H, m), 7.13-7.06 (2H, m), 5.98-5.86 (1H, m), 5.43 (2H, s), 5.34-5.21 (2H, m), 4.64-4.60 (2H, m ), 3.69 (2H, s).

(12-5)
Allyl (3′-fluoro-4 ′-{[2-formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl- obtained in Example (12-4) 4-Nyl) acetate (476 mg, 0.975 mmol) in N, N-dimethylformamide (5 ml), potassium carbonate (148 mg, 1.07 mmol), and allyl bromide (0.091 ml, 1.1 mmol) sequentially In addition, the mixture was stirred at 50 ° C for 1.5 hours. The reaction solution 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 = 3/1) to give allyl (4 ′-{[3- (allyloxy). ) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -3′-fluoro-1,1′-biphenyl-4-yl) acetate (122 mg, 24% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.54 (1H, s), 7.92 (1H, d, J = 8.4 Hz), 7.87 (1H, d, J = 8.4 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.40-7.25 (4H, m), 7.09 (1H, app t, J = 8.6 Hz), 6.18-6.05 (1H, m), 5.97-5.86 (1H, m), 5.56 (2H, s ), 5.53-5.19 (4H, m), 4.67-4.56 (4H, m), 3.69 (2H, s).
(12-6)
Allyl (4 ′-{[3- (allyloxy) -2-formyl-4- (trifluoromethyl) benzyl] oxy} -3′-fluoro-1,1′- obtained in Example (12-5) To a mixed solution of biphenyl-4-yl) acetate in tert-butyl alcohol (2.4 ml), 1,4-dioxane (0.8 ml), and 2-methyl-2-butene (0.8 ml), chlorous acid An aqueous solution (1.1 ml) of sodium (125 mg, 1.38 mmol) and sodium dihydrogen phosphate monohydrate (125 mg, 0.91 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. A 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture 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 was obtained by distilling off the solvent under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -3-fluoro-1 ′. , 1-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoic acid (135 mg, 100% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.74 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.34- 7.19 (4H, m), 7.00 (1H, app t, J = 8.4 Hz), 6.12-6.00 (1H, m), 5.96-5.84 (1H, m), 5.47-5.18 (6H, m), 4.62-4.58 (4H, m), 3.67 (2H, s).

(12-7)
2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -3-fluoro-1 ′, 1-biphenyl-4-yl) obtained in Example (12-6) To a solution of oxy] methyl} -3- (trifluoromethyl) benzoic acid (135 mg, 0.248 mmol) in tert-butyl alcohol (2 ml), N, N-dimethylaminopyridine (9.5 mg, 0.077 mmol), and , Di-tert-butyl dicarbonate [(tBuOCO) ₂ O] (156 mg, 0.715 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 19 / 1-4 / 1) to give tert-butyl 2- (allyloxy) -6-{[ (4 ′-{[(Allyloxy) carbonyl] methyl} -3-fluoro-1′1-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (65 mg, 44% yield). Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.63 (1H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.35- 7.29 (3H, m), 7.25-7.21 (1H, m), 6.97 (1H, app t, J = 8.6 Hz), 6.10-5.99 (1H, m), 5.95-5.85 (1H, m), 5.45-5.38 (1H, m), 5.31-5.19 (5H, m), 4.62-4.59 (2H, m), 4.58-4.54 (2H, m), 3.68 (2H, s), 1.59 (9H, s).
(12-8)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl}-) obtained in Example (12-7) 3-Fluoro-1′1-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (65 mg, 0.108 mmol) to the title compound as a pale yellow powder (45 mg, 80% yield) Got.
^{1 H-NMR (400MHz, CDCl} 3): δ 12.23 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.37-7.29 (4H, m ), 7.26-7.22 (1H, m), 6.92 (1H, app t, J = 8.6 Hz), 5.43 (2H, s), 3.70 (2H, s), 1.66 (9H, s).
MS (ESI) (m / z): 519 ([MH] ⁺ ).

(Example 13)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2′-chloro-1,1′-biphenyl-4-yl) acetic acid (illustrated Compound number: 2-60)
(13-1)
Methyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (2.41 g, 8.73 mmol) obtained in Example (12-1) ) And 4-bromo-3-chlorophenol (2.17 g, 10.5 mmol) in a mixed solution of toluene-ethanol (5: 1, 36 ml), 2N-sodium carbonate aqueous solution (12 ml), and tetrakis ( Triphenylphosphine) palladium (0) (504 mg, 0.436 mmol) was added, followed by stirring at 110 ° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, ethanol (12 ml) and 1N aqueous sodium hydroxide solution (15 ml, 15 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction solution was 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 = 85 / 15-50 / 50) to give (2 ′ -Chloro-4'-hydroxy-1,1'-biphenyl-4-yl) acetic acid (1.95 g, yield 85%) was obtained.
¹ H-NMR (400MHz, CD ₃ OD): δ 7.35-7.28 (4H, m), 7.15 (1H, d, J = 7.8 Hz), 6.90 (1H, d, J = 2.3 Hz), 6.77 (1H, dd, J = 7.8, 2.3 Hz), 3.64 (2H, s).
MS (FAB) (m / z): 262 ([M] ⁺ ).
(13-2)
To a solution of (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetic acid (1.93 g, 7.35 mmol) obtained in Example (13-1) in benzene (30 ml) , Allyl alcohol (7.0 ml, 103 mmol), and concentrated sulfuric acid (0.1 ml) were sequentially added, and the mixture was heated to reflux for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (twice). 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 = 90 / 10-65 / 35) to give allyl (2 ′ -Chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (1.97 g, yield 89%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.33 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 7.09 (1H, d, J = 7.8 Hz), 6.92 ( 1H, d, J = 2.3 Hz), 6.66 (1H, dd, J = 7.8, 2.3 Hz), 5.97-5.85 (1H, m), 5.70 (1H, s), 5.29 (1H, dd, J = 17.2, 1.6 Hz), 5.23 (1H, br d, J = 10.2 Hz), 4.63 (2H, app d, J = 5.5 Hz), 3.71 (2H, s).
MS (EI) (m / z): 302 ([M] ⁺ ).

(13-3)
[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1) obtained in Example (6-6) in the same manner as in Example (6-7). .04 g, 3.35 mmol) and allyl (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (1.17 g, obtained in Example (13-2)) 3.86 mmol) to allyl (2′-chloro-4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1, 1'-biphenyl-4-yl) acetate (1.88 g, 94% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.59 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.33 ( 2H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 2.3 Hz), 6.93 (1H, dd, J = 8.6, 2.3 Hz), 5.98- 5.87 (1H, m), 5.77 (1H, s), 5.51 (2H, br s), 5.29 (1H, dd, J = 17.2, 1.6 Hz), 5.23 (1H, br d, J = 10.9 Hz), 5.04 (2H, s), 4.62 (2H, d, J = 6.3 Hz), 3.69 (2H, s), 3.67 (3H, s), 3.50 (6H, s).
MS (FAB) (m / z): 594 ([M] ⁺ ).
(13-4)
Allyl (2′-chloro-4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -1 obtained in Example (13-3) , 1′-biphenyl-4-yl) acetate (1.83 g, 3.08 mmol) in tetrahydrofuran (35 ml) was added 4N-hydrochloric acid (3.5 ml) and stirred at 45 ° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. A crude aldehyde was obtained by distilling off the solvent under reduced pressure. Using the obtained crude aldehyde as a starting material, tert-butyl 2 was obtained as a pale yellow oil in the same manner as in Example (12-5), Example (12-6), and Example (12-7). -(Allyloxy) -6-{[(4 '-{[(allyloxy) carbonyl] methyl} -2-chloro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) Benzoate (967 mg, total yield of 4 steps 51%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.65 (1H, d, J = 7.8 Hz), 7.40-7.32 (1H, overlapped with δ 7.38 or 7.34), 7.38 (2H, d, J = 7.8 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.24 (1H, d, J = 8.6 Hz), 7.06 (1H, d, J = 2.3 Hz), 6.89 (1H, dd, J = 8.6, 2.3 Hz), 6.14-6.01 (1H, m), 5.99-5.87 (1H, m), 5.43 (1H, d, J = 17.2 Hz), 5.33-5.20 (3H, m), 5.15 (2H, s), 4.62 (2H, app d, J = 6.3 Hz), 4.58 (2H, br d, J = 5.4 Hz), 3.70 (2H, s), 1.59 (9H, s).
MS (FAB) (m / z): 616 ([M] ⁺ ).
The crude aldehyde obtained as an intermediate below, allyl (2′-chloro-4 ′-{[2-formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′- ¹ shows the ¹ H-NMR spectrum of biphenyl-4-yl) acetate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.61 (1H, br s), 10.31 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.36 (2H, d, J = 8.6 Hz) , 7.32 (2H, d, J = 8.6 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.10-7.05 (2H, m), 6.90 (1H, dd, J = 7.8, 2.3 Hz), 5.97- 5.85 (1H, m), 5.34 (2H, s), 5.28 (1H, dd, J = 17.2, 1.6 Hz), 5.22 (1H, br d, J = 10.2 Hz), 4.61 (2H, app d, J = 5.5 Hz), 3.70 (2H, s).
(13-5)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -2-chloro-1,1′-biphenyl-4 obtained in Example (13-4) To a mixed solution of -yl) oxy] methyl} -3- (trifluoromethyl) benzoate (960 mg, 1.56 mmol) in 1,4-dioxane (9.5 ml) and water (0.5 ml), pyrrolidine (0 .525 ml, 6.29 mmol) and tetrakis (triphenylphosphine) palladium (0) (41 mg, 0.035 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction solution, followed by extraction with ethyl acetate (three times), 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 = 75 / 25-40 / 60) to give the title compound (446 mg) as a white powder. Yield 74%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, br s), 7.73 (1H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.28-7.24 (2H, m), 7.06 (1H, d, J = 2.7 Hz), 6.88 (1H, dd, J = 8.6, 2.7 Hz), 5.36 (2H, s), 3.71 ( 2H, s), 1.67 (9H, s).
MS (FAB) (m / z): 536 ([M] ⁺ ).

(Example 14)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2′-fluoro-1,1′-biphenyl-4-yl) acetic acid (illustrated Compound number: 2-54)
(14-1)
Methyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (2.04 g, 7.39 mmol) obtained in Example (12-1) ) And 4-bromo-3-fluorophenol (1.69 g, 8.87 mol) in N, N-dimethylformamide (50 ml), palladium (II) acetate (50 mg, 0.22 mmol), and tri -O-Tolylphosphine (135 mg, 0.44 mmol) and 2N-sodium carbonate aqueous solution (15 ml) were added, followed by stirring at 80 ° C for 3 hours. The reaction solution was 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 = 80 / 20-50 / 50), and methyl (2′-fluoro- 4′-hydroxy-1,1′-biphenyl-4-yl) acetate (1.13 g, yield 59%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.43 (2H, br d, J = 8.0 Hz), 7.31 (2H, br d, J = 8.0 Hz), 7.26-7.21 (1H, m), 6.66-6.60 (2H, m), 5.25 (1H, br s), 3.71 (3H, s), 3.66 (2H, s).

(14-2)
In the same manner as in Example (6-7), methyl (2′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (1. 02 g, 3.94 mmol) and [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1.71 g, obtained in Example (6-6)) 5.52 mmol) from methyl (4 ′-{[2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -2′-fluoro-1,1′-biphenyl -4-yl) acetate (2.01 g, 92% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.58-7.51 (2H, m), 7.45-7.42 (2H, m), 7.33-7.23 (4H, m), 6.83-6.73 (1H, m), 5.75 ( 1H, s), 5.49 (2H, s), 5.03 (2H, s), 3.70 (3H, s), 3.66 (3H, s), 3.65 (2H, s), 3.48 (6H, s).
(14-3)
In the same manner as in Example (6-8) and Example (6-9), methyl (4 ′-{[2- (dimethoxymethyl) -3- ( Methoxymethoxy) -4- (trifluoromethyl) benzyl] oxy} -2′-fluoro-1,1′-biphenyl-4-yl) acetate (2.01 g, 3.64 mmol) from tert-butyl 6- [ ({2-Fluoro-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (568 mg, 2 steps The overall yield was 29%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.27 (1H, br s), 7.71 (1H, br d, J = 8.3 Hz), 7.48 (2H, br d, J = 7.8 Hz), 7.40-7.32 ( 3H, m), 7.24 (1H, br d, J = 8.3 Hz), 6.78 (1H, app dd, J = 8.6, 2.4 Hz), 6.73 (1H, app dd, J = 12.2, 2.4 Hz), 5.35 ( 2H, s), 3.71 (3H, s), 3.66 (2H, s), 1.65 (9H, s).
(14-4)
In the same manner as in Example 7, tert-butyl 6-[({2-fluoro-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4) obtained in Example (14-3) was used. -Il} oxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (568 mg, 1.06 mmol) gave the title compound as a white powder (404 mg, 73% yield).
¹ H-NMR (500 MHz, CD ₃ OD): δ 7.65 (1H, br d, J = 8.3 Hz), 7.34 (2H, br d, J = 8.3 Hz), 7.31 (1H, br d, J = 8.3 Hz) ), 7.23 (2H, br d, J = 8.3 Hz), 7.20 (1H, br d, J = 8.3 Hz), 6.77 (1H, app dd, J = 8.3, 2.4 Hz), 6.74 (1H, app dd, J = 12.7, 2.4 Hz), 5.30 (2H, s), 3.52 (2H, s), 1.53 (9H, s).
MS (ESI) (m / z): 519 ([MH] ⁺ ).

(Example 15)
1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) cyclopropanecarboxylic acid (exemplified) Compound number: 1-64)
(15-1)
To a solution of methyl (4-bromophenyl) acetate (5.73 g, 25.0 mmol) obtained in Example (3-1) in N, N-dimethylformamide (50 ml) at 0 ° C., sodium hydride (55 % Oily) (2.40 g, 55.0 mmol) was added, followed by stirring at room temperature for 10 minutes. The reaction solution was cooled to 0 ° C., 1,2-dibromoethane (2.37 ml, 27.5 mmol) was added, and the mixture was further stirred at room temperature for 15 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1) to give oily methyl 1- (4-bromophenyl) Cyclopropanecarboxylate (2.97 g, 47% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.43 (2H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.2 Hz), 3.63 (3H, s), 1.63-1.59 (2H, m ), 1.18-1.14 (2H, m).
(15-2)
In the same manner as in Example (8-1), methyl 1- (4-bromophenyl) cyclopropanecarboxylate (2.96 g, 11.6 mmol) obtained in Example (15-1) and 4- From (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (2.55 g, 11.6 mmol), white powdered methyl 1- (4′-hydroxy-1, 1′-biphenyl-4-yl) cyclopropanecarboxylate (2.49 g, yield 80%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.46 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.2 Hz), 6.86 ( 2H, d, J = 8.6 Hz), 4.95 (1H, s), 3.64 (3H, s), 1.65-1.61 (2H, m), 1.24-1.20 (2H, m).

(15-3)
In the same manner as in Example 7 and Example (13-2), methyl 1- (4′-hydroxy-1,1′-biphenyl-4-yl) cyclo obtained in Example (15-2) From propanecarboxylate (2.49 g, 9.28 mmol), white powdered allyl 1- (4′-hydroxy-1,1′-biphenyl-4-yl) cyclopropanecarboxylate (2.1 g, 2 step yield) 77%).
In this step, the hydrolysis step corresponding to Example (7) was performed at a reaction temperature of 60 ° C.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.47-7.41 (4H, m), 7.37 (2H, d, J = 8.2 Hz), 6.85 (2H, d, J = 8.6 Hz), 5.88-5.77 (1H , m), 5.20-5.12 (2H, m), 5.09 (1H, s), 4.57-4.54 (2H, m), 1.67-1.63 (2H, m), 1.27-1.22 (2H, m).
(15-4)
Allyl 1- (4′-hydroxy-1,1′-biphenyl-4-yl) cyclopropanecarboxylate (479 mg, 1.63 mmol) obtained in Example (15-3) and Example (6- Using [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (505 mg, 1.63 mmol) obtained in 6) as a starting material, Example (6-7) ), Example (12-4), Example (12-5), and Example (12-6) by the same method, 2- (allyloxy) -6-{[(4 ′-{1- [(Allyloxy) carbonyl] cyclopropyl} -1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoic acid (175 mg, total yield of 4 steps 19%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.72 (1H, d, J = 8.2 Hz), 7.51-7.45 (3H, m), 7.43 (2H, d, J = 8.2 Hz), 7.36 (2H, d , J = 8.2 Hz), 6.98 (2H, d, J = 8.6 Hz), 6.11-6.00 (1H, m), 5.87-5.76 (1H, m), 5.45-5.38 (1H, m), 5.30-5.23 ( 3H, m), 5.19-5.10 (2H, m), 4.61-4.58 (2H, m), 4.56-4.53 (2H, m), 1.66-1.62 (2H, m), 1.25-1.21 (2H, m).

(15-5)
2- (Allyloxy) -6-{[(4 ′-{1-[(allyloxy) carbonyl] cyclopropyl} -1,1′-biphenyl-4-yl) oxy obtained in Example (15-4) ] Methyl} -3- (trifluoromethyl) benzoic acid (175 mg, 0.317 mmol) and N, N-dimethylformamide ditert-butyl acetal (0.300 ml, 1.27 mmol) dissolved in toluene (2 ml) And heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1) to give tert-butyl 2- (allyloxy) -6- { [(4 ′-{1-[(allyloxy) carbonyl] cyclopropyl} -1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (122 mg, 63% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.62 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.40- 7.36 (3H, m), 6.97 (2H, d, J = 8.6 Hz), 6.11-6.00 (1H, m), 5.88-5.76 (1H, m), 5.45-5.38 (1H, m), 5.29-5.24 ( 1H, m), 5.19-5.11 (4H, m), 4.58-4.53 (4H, m), 1.67-1.63 (2H, m), 1.58 (9H, s), 1.26-1.21 (2H, m).
(15-6)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{1-[(allyloxy) carbonyl) cyclo] obtained in Example (15-5) was used. Propyl} -1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (122 mg, 0.2 mmol) to give the title compound as a pale yellow powder (63 mg, 59% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.68 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.25 (1H, d, J = 8.2 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 1.72- 1.68 (2H, m), 1.64 (9H, s), 1.33-1.28 (2H, m).
MS (ESI) (m / z): 527 ([MH] ⁺ ).

(Example 16)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-fluoro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-45)
(16-1)
Performed from (4-bromo-3-fluorophenyl) methanol synthesized according to the method described in the literature (deSolms. Et al., J. Med. Chem., 2003, 46, p. 2973-2984) In the same manner as in Example (17-1), colorless oily (4-bromo-3-fluorophenyl) acetonitrile (1.60 g, yield 75%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.31-7.24 (2H, m), 7.04 (1H, app d, J = 8.8 Hz), 3.75 (2H, s).
(16-2)
(4-Bromo-3-fluorophenyl) acetonitrile (1.6 g, 7.5 mmol) obtained in Example (16-1) and 4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) phenol (1.65 g, 7.5 mmol) was used as a starting material and was colorless in the same manner as in Example (8-1) and Example (11-3). Solid allyl (2-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (0.78 g, total yield of 3 steps 36%) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.45 (2H, d, J = 9.0 Hz), 7.24 (1H, app s), 7.14 (1H, app d, J = 9.0 Hz), 6.96 (1H, app d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 5.94-5.89 (1H, m), 5.30 (1H, dd, J = 17.5, 1.5 Hz), 5.24 (1H, dd, J = 10.0, 1.5 Hz), 4.89 (1H, br s), 4.62 (2H, app d, J = 5.5 Hz), 3.69 (2H, s).
MS (ESI) (m / z): 285 ([MH] ⁺ ).
(16-3)
Allyl (2-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (650 mg, 2.27 mmol) obtained in Example (16-2) and Example (6-6) [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (987 mg, 3.18 mmol) obtained in (1)) was used as a starting material. Example (6-7) In the same manner as in Example (12-4), Example (12-5), Example (12-6), and Example (12-7), tert-butyl 2- ( Allyloxy) -6-{[(4 '-{[(allyloxy) carbonyl] methyl} -2'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoe -G (360 g, 5 step overall yield 26%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.65 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.24 ( 1H, app s), 7.15 (1H, app d, J = 9.5 Hz), 7.00 (2H, d, J = 9.0 Hz), 6.96 (1H, app d, J = 9.5 Hz), 6.11-6.03 (1H, m), 5.95-5.88 (1H, m), 5.43 (1H, dd, J = 17.0, 1.5 Hz), 5.32-5.27 (2H, m), 5.24 (1H, dd, J = 10.0, 1.0 Hz), 5.16 (2H, s), 4.62 (2H, app d, J = 5.5 Hz), 4.58 (2H, app d, J = 5.5 Hz), 3.69 (2H, s), 1.58 (9H, s).

(16-4)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl}-) obtained in Example (16-3) was used. From 2′-fluoro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (360 mg, 0.59 mmol), the title compound as a colorless powder (144 mg, yield) 47%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22, (1H, s), 7.68 (1H, d, J = 8.4 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.25-7.23 (2H, m), 7.15 (1H, app d, J = 9.6 Hz), 6.97-6.94 (3H, m), 5.36 (2H, s), 3.70 (2H, s), 1.64 (9H, s).
MS (FAB) (m / z): 543 ([M + Na] ⁺ ).

(Example 17)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-methyl-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-47)
(17-1)
(4-Bromo-2-methylphenyl) methanol synthesized according to the method described in the literature (Dawson, MI, et al., J. Med. Chem., 1984, Vol. 27, p. 1516-1531) After adding carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) to a tetrahydrofuran solution (50 ml) of 3.7 g, 18.4 mmol) under ice cooling. And stirred at room temperature for 1 hour. Hexane was added to the reaction solution and the insoluble material was filtered off. The obtained filtrate 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 = 10 / 0-10 / 1) to give 4-bromo-1- ( A crude product of bromomethyl) -2-methylbenzene was obtained. To the obtained crude 4-bromo-1- (bromomethyl) -2-methylbenzene in ethanol-water (3: 1, 40 ml) mixed solution was added potassium cyanide (1.3 g, 20 mmol), and 1. Stir for 5 hours. The reaction mixture was poured into water and 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 6 / 1-3 / 1) to give (4-bromo -2-methylphenyl) acetonitrile (2.4 g, total yield of 2 steps 63%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.38-7.36 (2H, m), 7.23 (1H, app d, J = 8.0 Hz), 3.61 (2H, s), 2.33 (3H, s).

(17-2)
Potassium hydroxide (0.60 g, 11 mmol) was added to an ethylene glycol solution (5 ml) of (4-bromo-2-methylphenyl) acetonitrile (1.0 g, 4.8 mmol) obtained in Example (17-1). In addition, the mixture was stirred at 130 ° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was acidified with concentrated 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 washed with water and then dried under reduced pressure to obtain a solid. To the obtained solid N, N-dimethylformamide solution (6 ml) were added potassium carbonate (0.97 g, 7.0 mmol) and methyl iodide (0.37 ml, 5.9 mmol), and the mixture was stirred at room temperature for 2 hours. . The reaction solution was diluted with ethyl acetate, and 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 = 99 / 1-10 / 1) to give oily methyl (4-bromo A crude product of -2-methylphenyl) acetate was obtained. The resulting crude methyl (4-bromo-2-methylphenyl) acetate and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (814 mg, 3.7 mmol), colorless solid methyl (4′-hydroxy-3-methyl-1,1′-biphenyl-4-yl) acetate (0.70 g, 3 steps) as in Example (8-1) The overall yield was 56%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.42 (2H, d, J = 8.0 Hz), 7.34 (1H, s), 7.31 (1H, app d, J = 8.0 Hz), 7.23 (1H, app d , J = 8.0 Hz), 6.84 (2H, d, J = 8.0 Hz), 5.10 (1H, br s), 3.72 (3H, s), 3.68 (2H, s), 2.36 (3H, s).
(17-3)
Methyl (4′-hydroxy-3-methyl-1,1′-biphenyl-4-yl) acetate (0.60 g, 2.3 mmol) obtained in Example (17-2) and Example (6) [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1.0 g, 3.3 mmol) obtained in 6) was used as a starting material. 6-7), Example (12-4), Example (12-5), and Example (6-9) in the same manner as described above, colorless solid tert-butyl 2-hydroxy-6-[( {4 ′-[(methoxycarbonyl) methyl] -3′-methyl-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (667 mg, total yield over 4 steps) 53%).
In this step, morpholine was used instead of pyrrolidine in the deprotection step corresponding to Example (6-9). Further, tetrahydrofuran was used as a reaction solvent in place of dioxane-water.
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.52 (2H, d, J = 9.0 Hz), 7.37 (1H, s), 7.35 (1H, d, J = 8.0 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 6.97 (2H, d, J = 9.0 Hz), 5.37 (2H, s), 3.71 (3H, s), 3.68 (2H, s), 2.37 (3H, s), 1.65 (9H, s).

(17-4)
Tert-Butyl 2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -3′-methyl-1,1′-biphenyl-4-yl} obtained in Example (17-3)} (Oxy) methyl] -3- (trifluoromethyl) benzoate (667 mg, 1.26 mmol) in tetrahydrofuran (8.5 ml) was added to a 1N aqueous sodium hydroxide solution (3.0 ml, 3.0 mmol) and methanol (0 ml). 0.5 ml) and stirred at room temperature for 6 hours. The reaction solution was 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 crystallized from a mixed solvent of ethanol-ethyl acetate to obtain the title compound (552 mg, yield 84%) as a colorless powder.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26, (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 9.0 Hz), 7.39 (1H, br s ), 7.36 (1H, d, J = 8.5 Hz), 7.29-7.26 (2H, m), 6.97 (2H, d, J = 9.0 Hz), 5.37 (2H, s), 3.72 (2H, s), 2.39 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z): 516 ([M] ⁺ ).

(Example 18)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-49)
(18-1)
To a solution of 4-bromo-2-chlorobenzoic acid (2.0 g, 8.5 mmol) in N, N-dimethylformamide (8 ml) was added potassium carbonate (1.38 g, 10 mmol) and methyl iodide (0.623 ml, 10 mmol). ) Was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was 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. Distilled diisobutylaluminum hydride-1.0M toluene solution (24 ml, 24 mmol) in toluene solution (30 ml) of the oily residue obtained by distilling off the solvent under reduced pressure was added dropwise at −78 ° C. for 3 hours. The temperature was raised to room temperature. Sodium sulfate decahydrate (12 g) was added to the reaction mixture, and the mixture was stirred for 30 min at room temperature. Celite (12 g) and anhydrous magnesium sulfate (12 g) were added, and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off, and then the solvent was distilled off from the obtained filtrate under reduced pressure to obtain a crude crude product of (4-bromo-2-chlorophenyl) methanol. From the obtained crude (4-bromo-2-chlorophenyl) methanol, in the same manner as in Example (17-1), (4-bromo-2-chlorophenyl) acetonitrile (1.4 g, yield) 71%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.61 (1H, d, J = 1.6 Hz), 7.47 (1H, app d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 3.79 (2H, s).

(18-2)
(4-Bromo-2-chlorophenyl) acetonitrile (1.37 g, 5.9 mmol) obtained in Example (18-1) and 4- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) phenol (1.3 g, 5.9 mmol) as a starting material, light yellow according to the same method as in Example (8-1) and Example (11-3) Solid allyl (3-chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (698 mg, total yield of 2 steps 39%) was obtained.
In this step, the reaction corresponding to Example (8-1) was performed at a reaction temperature of 85 ° C.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.56 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.39 (1H, app d, J = 8.0 Hz), 7.33 (1H, d, J = 8.0 Hz), 6.89 (2H, d, J = 8.8 Hz), 5.98-5.90 (1H, m), 5.32 (1H, app d, J = 16.4 Hz), 5.24 (1H, app d, J = 10.8 Hz), 4.88 (1H, br s), 4.65 (2H, app d, J = 6.0 Hz), 3.83 (2H, s).
(18-3)
Allyl (3-chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (560 mg, 1.85 mmol) obtained in Example (18-2) and Example (6-6) [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (807 mg, 2.6 mmol) obtained in (1) was used as a starting material. Example (6-7) In the same manner as in Example (12-4), Example (12-5), Example (12-6), and Example (12-7), colorless solid tert-butyl 2- (allyloxy) ) -6-{[(4 '-{[(allyloxy) carbonyl] methyl} -3'-chloro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoe- (622 mg, 5 To obtain a degree overall yield 54%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.65 (1H, d, J = 8.4 Hz), 7.57 (1H, d, J = 1.6 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.42- 7.38 (2H, m), 7.33 (1H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.4 Hz), 6.12-6.02 (1H, m), 5.98-5.88 (1H, m), 5.43 (1H, dd, J = 17.2, 1.6 Hz), 5.34-5.27 (2H, m), 5.24 (1H, dd, J = 11.2, 1.2 Hz), 5.16 (2H, s), 4.64 (2H, app d, J = 6.0 Hz), 4.58 (2H, app d, J = 5.6 Hz), 3.83 (2H, s), 1.58 (9H, s).

(18-4)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl}-) obtained in Example (18-3) was used. From 3′-chloro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (622 mg, 1.01 mmol), the title compound as a colorless powder (337 mg, yield) 62%) was obtained.
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.26, (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.60 (1H, d, 2.0 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.43 (1H, dd, J = 8.0, 2.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.28-7.26 (1H, m), 6.99 (2H, d, J = 8.5 Hz) , 5.38 (2H, s), 3.86 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 536 ([M] ⁺ ).
Anal.calcd.for C ₂₇ H ₂₄ ClF ₃ O ₆ : C, 60.40; H, 4.51; F, 10.62; Cl, 6.60; found: C, 60.20; H, 4.39; F, 10.72; Cl, 6.69.

Example 19
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 2-43)
(19-1)
1-bromo-4- (bromomethyl) -2-synthesized according to the method described in the literature (Hanessian, S. et al., J. Org. Chem., 2003, Vol. 68, p. 7204-7218) Using methylbenzene as a starting material, (4′-hydroxy-2-methyl-1,1′-) of a pale yellow solid was prepared in the same manner as in Example (11-1) and Example (8-1). Biphenyl-4-yl) acetonitrile (969 mg, yield 76%) was obtained.
In this step, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol is used as a borate ester reagent in the reaction corresponding to Example (8-1). It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.23-7.16 (5H, m), 6.89 (2H, d, J = 8.4 Hz), 4.86 (1H, br s), 3.75 (2H, s), 2.28 ( 3H, s).
(19-2)
In the same manner as in Example (11-3), (4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl) acetonitrile (969 mg, 4) obtained in Example (19-1) was obtained. .35 mmol) gave pale yellow oily allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl) acetate (1.19 g, yield 97%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.20-7.13 (5H, m), 6.86 (2H, d, J = 8.8 Hz), 5.98-5.89 (1H, m), 5.32 (1H, app dd, J = 17.2, 1.6 Hz), 5.24 (1H, app dd, J = 10.4, 1.6 Hz), 4.84 (1H, br s), 4.63 (2H, app d, J = 5.6 Hz), 3.65 (2H, s), 2.25 (3H, s).
(19-3)
Allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl) acetate (1.20 g, 4.3 mmol) obtained in Example (19-2) and Example (6) [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (1.84 g, 6.0 mmol) obtained in 6) was used as a starting material. 6-7), Example (12-4), Example (12-5), Example (12-6), and tert-butyl colorless oil by the same method as Example (12-7) 2- (allyloxy) -6-{[(4 '-{[(allyloxy) carbonyl] methyl} -2'-methyl-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoro Methyl) benzoate (1.26 g, 5 works) The total yield was about 46%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.66 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.18- 7.13 (3H, m), 6.97 (2H, d, J = 8.4 Hz), 6.12-6.02 (1H, m), 5.98-5.89 (1H, m), 5.43 (1H, dd, J = 16.8, 1.2 Hz) , 5.34-5.23 (3H, m), 5.16 (2H, s), 4.63 (2H, app d, J = 5.6 Hz), 4.58 (2H, app d, J = 5.6 Hz), 3.65 (2H, s), 2.25 (3H, s), 1.58 (9H, s).

(19-4)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl}-) obtained in Example (19-3) was used. From 2′-methyl-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (1.26 g, 2.1 mmol), the title compound (652 mg, Yield 60%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.27, (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.26-7.23 (2H, m), 7.20-7.15 (3H, m), 6.95 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 3.68 (2H, s), 2.27 (3H, s), 1.65 (9H, s ).
MS (FAB) (m / z): 516 ([M] ⁺ ).

(Example 20)
1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) cyclopropane Carboxylic acid (Exemplary compound number: 2-70)
(20-1)
In the same manner as in Example (11-1) and Example (11-3), 4-bromo-2-fluorobenzyl bromide (6.0 g, 22 mmol) was converted to methyl (4-bromo-2-fluorophenyl). ) Acetate (3.41 g, 3-step yield 62%) was obtained.
Then, in the esterification step included in the reaction corresponding to Example (11-3), methanol was used instead of allyl alcohol, and the reaction was performed at a reaction temperature of 50 ° C.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.29-7.23 (2H, m), 7.15 (1H, app t, J = 8.2 Hz), 3.72 (3H, s), 3.64 (2H, s).
(20-2)
In the same manner as in Example (15-1), Example (15-2), Example 7, and Example (13-2), methyl (4-bromo) obtained in Example (20-1) was used. 2-fluorophenyl) acetate (1.24 g, 5.02 mmol) from allyl 1- (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) cyclopropanecarboxylate ( 1.00 g, yield 64%) was obtained.
In this step, the hydrolysis step corresponding to Example 7 was performed at a reaction temperature of 60 ° C.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.39 (2H, d, J = 8.6 Hz), 7.29-7.15 (3H, m), 6.84 (2H, d, J = 8.6 Hz), 5.88-5.76 (1H , m), 5.28 (1H, br s), 5.21-5.11 (2H, m), 4.58-4.55 (2H, m), 1.73-1.69 (2H, m), 1.26-1.22 (2H, m).
(20-3)
Allyl 1- (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl) cyclopropanecarboxylate (303 mg, 0.97 mmol) obtained in Example (20-2) and [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (421 mg, 1.36 mmol) obtained in Example (6-6) was used as a starting material. In the same manner as in (6-7), Example (12-4), Example (12-5), Example (12-6), and Example (12-7), tert-butyl 2- (Allyloxy) -6-{[(4 '-{1-[(allyloxy) carbonyl] cyclopropyl} -3'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (tri Fluoromethyl L) benzoate (219 mg, total yield of 5 steps 36%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.62 (1H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.30- 7.18 (3H, m), 6.98 (2H, d, J = 8.6 Hz), 6.10-6.00 (1H, m), 5.86-5.76 (1H, m), 5.45-5.38 (1H, m), 5.29-5.24 ( 1H, m), 5.19-5.10 (4H, m), 4.58-4.54 (4H, m), 1.72-1.68 (2H, m), 1.57 (9H, s), 1.26-1.21 (2H, m).
(20-4)
In the same manner as in Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4 ′-{1-[(allyloxy) carbonyl) cyclo] obtained in Example (20-3) was used. Propyl} -3′-fluoro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (219 mg, 0.35 mmol) to white amorphous solid (amorphous) The compound (121 mg, yield 63%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.32-7.18 (4H, m ), 6.96 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 1.77-1.72 (2H, m), 1.64 (9H, s), 1.31-1.26 (2H, m).
MS (ESI) (m / z): 545 ([MH] ⁺ ).

(Example 21)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4-isopropylbenzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-47)
(21-1)
3-Isopropyl-2- (methoxymethoxy) benzaldehyde synthesized according to the method described in the literature (James, R. et al., J. Med. Chem., 1980, Vol. 23, p. 1350-1357.) To a methanol solution (65 ml) of (4.06 g, 19.5 mmol), trimethyl orthoformate (2.35 ml, 21.4 mmol) and ammonium chloride (52 mg, 0.98 mmol) were added, and the mixture was stirred with heating under reflux for 1 hour. did. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 12 / 0-12 / 1) to give colorless oily 1- (dimethoxy Methyl) -3-isopropyl-2- (methoxymethoxy) benzene (4.49 g, yield 91%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.39 (1H, dd, J = 7.8, 1.5 Hz), 7.28 (1H, dd, J = 7.8, 1.5 Hz), 7.15 (1H, t, J = 7.8 Hz ), 5.64 (1H, s), 4.99 (2H, s), 3.63 (3H, s), 3.40 (1H, sp, J = 6.8 Hz), 3.37 (6H, s), 1.23 (6H, d, J = (6.8 Hz).

(21-2)
In the same manner as in Example (6-5), Example (6-6), Example (6-7), Example (6-8), and Example (6-9), Example (21) -1) obtained from 1- (dimethoxymethyl) -3-isopropyl-2- (methoxymethoxy) benzene (4.49 g, 17.7 mmol) obtained as yellow oily tert-butyl 2-hydroxy-3-isopropyl- 6-[({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] benzoate (432 mg, total yield of 5 steps 5%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.78 (1H, s), 7.52 (4H, d, J = 8.2 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.08 (1H, d, J = 8.2 Hz), 6.99 (2H, d, J = 8.2 Hz), 5.31 (2H, s), 3.71 (2H, s), 3.55 (3H, s), 3.38 (1H, sp, J = 7.0 Hz), 1.58 (9H, s), 1.24 (6H, d, J = 7.0 Hz).
(21-3)
In the same manner as in Example (7), tert-butyl 2-hydroxy-3-isopropyl-6-[({4 ′-[(methoxycarbonyl) methyl] -1, obtained in Example (21-2), 1′-biphenyl-4-yl} oxy) methyl] benzoate (432 mg, 0.880 mmol) gave the title compound (176 mg, 42% yield) as a white powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.80 (1H, s), 7.54 (2H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.08 (1H, d, J = 8.2 Hz), 6.99 (2H, d, J = 8.2 Hz), 5.31 (2H, s), 3.71 ( 2H, s), 3.38 (1H, sp, J = 6.7 Hz), 1.58 (9H, s), 1.24 (6H, d, J = 6.7 Hz).
MS (FAB) (m / z): 476 ([M] ⁺ ).

(Example 22)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-44)
(22-1)
[2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (3) obtained in Example (6-6) in the same manner as in Example (6-7). 0.000 g, 9.66 mmol) and 4-bromophenol (2.00 g, 11.6 mmol) from 1-[(4-bromophenoxy) methyl] -2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (Trifluoromethyl) benzene (3.46 g, yield 77%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.56 (1H, d, J = 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.35 (2H, d, J = 9.0 Hz), 6.86 ( 2H, d, J = 9.0 Hz), 5.75 (1H, s), 5.46 (2H, s), 5.03 (2H, s), 3.66 (3H, s), 3.47 (6H, s).
(22-2)
1-[(4-bromophenoxy) methyl] -2- (dimethoxymethyl) obtained in Example (22-1) in the same manner as in Example (8-3) and Example (28-3) ) -3- (methoxymethoxy) -4- (trifluoromethyl) benzene (17.6 g, 56.0 mmol) to 6-[(4-bromophenoxy) methyl] -2-hydroxyl-3- (trifluoromethyl) ) Benzoic acid (12.0 g, total yield of 2 steps 55%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, S), 7.77 (1H, d, J = 8.0 Hz), 7.40 (2H, d, J = 9.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 6.80 (2H, d, J = 9.0 Hz), 5.38 (2H, s).

(22-3)
6-[(4-Bromophenoxy) methyl] -2-hydroxyl-3 obtained in Example (22-2) in the same manner as in Example (28-4) and Example (33-5) From-(trifluoromethyl) benzoic acid (3.22 g, 8.23 mmol) to tert-butyl 6-[(4-bromophenoxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (2.26 g , 2 step total yield 61%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.40 (2H, d, J = 9.0 Hz), 7.21 (1H, d, J = 8.2 Hz), 6.80 (2H, d, J = 9.0 Hz), 5.30 (2H, s), 1.62 (9H, s).
(22-4)
Tert-Butyl 6-[(4-bromophenoxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate obtained in Example (22-3) in the same manner as in Example (2-4) (10.2 g, 22.8 mmol) from tert-butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl } -3- (trifluoromethyl) benzoate (11.3 g, yield 99%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.77 (2H, d, J = 8.8 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.34 (2H, s), 1.33 (9H, s), 1.26 (12H, s).
(22-5)
To a methylene chloride solution (20 ml) of methyl (4-hydroxy-3-methoxyphenyl) acetate (1.70 g, 8.66 mmol), pyridine (2.10 ml, 25.9 mmol), trifluoromethanesulfonic anhydride (1.61 ml). , 9.53 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) were added and stirred for 10 minutes under ice-cooling, followed by stirring for 20 minutes at room temperature. 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 = 2/1) to give methyl (3-methoxy-4-{[( Trifluoromethyl) sulfonyl] oxy} phenyl) acetate (2.84 g, 99% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.14 (1H, d, J = 8.2 Hz), 6.96 (1H, s), 6.86 (1H, d, J = 8.2 Hz), 3.90 (3H, s), 3.71 (3H, s), 3.62 (2H, s).

(22-6)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} obtained in Example (22-4) -3- (Trifluoromethyl) benzoate (100 mg, 0.20 mmol) and methyl (3-methoxy-4-{[(trifluoromethyl) sulfonyl] oxy} phenyl obtained in Example (22-5) ) A mixed solution of acetate (79 mg, 0.24 mmol) in toluene-ethanol (6: 1, 3.5 ml) was added with 2M aqueous sodium carbonate (0.5 ml), tris (dibenzylideneacetone) dipalladium (0) 18 mg, 0.02 mmol) and bis (2-diphenylphosphinophenyl) ether (DPEphos) (22 mg, 0.04 mmol) After addition, the mixture was stirred for 5 hours at 100 ° C.. The reaction solution was returned to room temperature, poured into water, 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 compound obtained by distilling off the solvent under reduced pressure was treated in the same manner as in Example (17-4) to obtain the title compound (43 mg, yield 40%) as a pale yellow powder.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.78 (1H, s), 7.79 (1H, d, J = 8.4 Hz), 7.39 (2H, d, J = 7.2 Hz), 7.27 (1H, d , J = 8.4 Hz), 7.17 (1H, d, J = 8.0 Hz), 6.99-6.96 (3H, m), 6.86 (1H, dd, J = 8.0, 1.2 Hz), 5.34 (2H, s), 3.72 (3H, s), 3.57 (2H, s), 1.55 (9H, s).
MS (ESI) (m / z): 531 ([MH] ⁺ ).

(Example 23)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-chloro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-46)
(23-1)
Sulfuric acid (1 ml) was added dropwise at 0 ° C. to a methanol solution of 3-chloro-4-hydroxyphenylacetic acid (3.7 g, 20 mmol). The reaction solution was returned to room temperature and stirred for 4 hours. The solvent was distilled off under reduced pressure, poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate 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: ethyl acetate) to obtain crude methyl (3-chloro-4-hydroxyphenyl) acetate. To a methylene chloride solution (30 ml) of the obtained crude product, pyridine (8 ml, 99 mmol) and trifluoromethanesulfonic anhydride (3.4 ml, 20 mmol) were added dropwise under ice cooling and stirred for 1 hour. The reaction solution was poured into 1N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed successively with water, dilute hydrochloric acid 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) to give methyl (3-chloro-4- { [(Trifluoromethyl) sulfonyl] oxy} phenyl) acetate (6.3 g, yield 95%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.48 (1H, d, J = 2.0 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.8, 2.0 Hz), 3.73 (3H, s), 3.64 (2H, s).
(23-2)
Methyl (3-chloro-4-{[(trifluoromethyl) sulfonyl] oxy} phenyl) acetate (317 mg, 1.0 mmol) and 4-methoxyphenyl boric acid (152 mg) obtained in Example (23-1) , 1.0 mmol) in toluene-ethanol (5: 1, 9 ml) mixed solution of 2M aqueous sodium carbonate (1.5 ml), tris (dibenzylideneacetone) dipalladium (0) (23 mg, 25 μmol), and Bis (2-diphenylphosphinophenyl) ether (DPEphos) (28 mg, 52 μmol) was added, and the mixture was stirred at 100 ° C. for 5 hours with stirring. The reaction solution was returned to room temperature, poured into water, 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 solvent was distilled off under reduced pressure to obtain solid methyl (2-chloro-4′-methoxy-1,1′-biphenyl-4-yl) acetate (192 mg, yield 66%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.39-7.36 (3H, m), 7.30-7.28 (1H, m), 7.21 (1H, dd, J = 7.6, 1.6 Hz), 6.96 (2H, d, J = 8.4 Hz), 3.86 (3H, s), 3.73 (3H, s), 3.64 (2H, s).

(23-3)
Methyl (2-chloro-4′-methoxy-1,1′-biphenyl-4-yl) acetate (228 mg, 0.73 mmol) obtained in Example (23-2) and tetra-n-iodide To a solution of butylammonium (325 mg, 0.88 mmol) in methylene chloride (4 ml) was added boron trichloride (1.0 N methylene chloride solution, 1.8 ml, 1.8 mmol) at −78 ° C., and the mixture was warmed to room temperature. Warmed and stirred for 2 hours. Ice was added to the reaction mixture, 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 / 1-2 / 1) to give colorless solid methyl (2- Chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (144 mg, 71% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.39 (1H, s), 7.32 (2H, d, J = 8.0 Hz), 7.29-7.26 (1H, m), 7.21 (1H, d, J = 7.2 Hz ), 6.89 (2H, d, J = 8.0 Hz), 4.90 (1H, br s), 3.74 (3H, s), 3.64 (2H, s).
(23-4)
In the same manner as in Example (2-3), Example (33-5) and Example (17-4), methyl (2-chloro-4 ′) obtained in Example (23-3) -Hydroxy-1,1′-biphenyl-4-yl) acetate (150 mg, 0.54 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butyl) obtained in Example (28-5) Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (455 mg, 1.0 mmol) gave the colorless title compound (46 mg, 15% yield over 3 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.28 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.32-7.28 (2H, m), 7.24 (1H, dd, J = 8.0, 2.0 Hz), 6.97 (2H, d, J = 8.4 Hz), 5.39 (2H, s), 3.69 (2H , s), 1.65 (9H, s).
MS (FAB) (m / z): 536 ([M] ⁺ ).

(Example 24)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-methoxy-1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 2-184)
(24-1)
(4-Chloro-2-methoxyphenyl) methanol (2.00 g, 11.6 mmol) was used as a starting material, and crude (4-chloro-2-methoxyphenyl) was prepared in the same manner as in Example (17-1). Acetonitrile was obtained. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained crude product, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was 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 crude (4-chloro-2-methoxyphenyl) acetic acid. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the resulting crude product and stirred at 50 ° C. for 1 hour. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding ethyl acetate, the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate 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 methyl (4-chloro-2-methoxyphenyl) acetate. (1.37 g, yield 55%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.07 (1H, d, J = 8.0 Hz), 6.88 (1H, dd, J = 8.0, 2.0 Hz), 6.83 (1H, d, J = 2.0 Hz), 3.79 (3H, s), 3.67 (3H, s), 3.57 (2H, s).

(24-2)
Methyl (4-chloro-2-methoxyphenyl) acetate (43 mg, 0.2 mmol) obtained in Example (24-1) and tert-butyl 2-hydroxy obtained in Example (22-4) Of {[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (100 mg, 0.2 mmol) To a toluene (2.0 ml) solution was added tripotassium phosphate (127 mg, 0.60 mmol), palladium acetate (8 mg, 0.04 mmol), and 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1. , 1′-biphenyl (S-PHOS) (16 mg, 0.04 mmol) was added, followed by stirring at 70 ° C. for 4 hours. The reaction solution was returned to room temperature, poured into water, 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 = 2/1), and tert-butyl 2-hydroxy-6-[({ 4 ′-[(Methoxycarbonyl) methyl] -3′-methoxy-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (100 mg, 60% yield) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.23 (1H, d, J = 7.6 Hz), 7.10 (1H, dd, J = 7.6, 1.6 Hz), 7.03 (1H, d, J = 1.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.88 (3H, s), 3.71 (3H, s), 3.67 (2H, s), 1.65 (9H, s).
(24-3)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -3′-methoxy obtained in Example (24-2) was used. -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (100 mg, 0.18 mmol) gave the title compound as a white powder (75 mg, 78% yield). Obtained.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.14 (1H, br), 11.45 (1H, br), 7.81 (1H, d, J = 8.0 Hz), 7.66 (2H, d, J = 8.4 Hz ), 7.30 (1H, d, J = 8.0 Hz), 7.21 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 7.6 Hz), 7.07 (2H, d , J = 8.4 Hz), 5.36 (2H, s), 3.84 (3H, s), 3.51 (2H, s), 1.57 (9H, s).
MS (ESI) (m / z): 531 ([MH] ⁺ ).

(Example 25)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-trifluoromethyl-1,1′-biphenyl-4-yl) acetic acid ( Exemplified compound number: 2-185)
(25-1)
[4-Chloro-3- (trifluoromethyl) phenyl] methanol (2.00 g, 5.59 mmol) was used as a starting material in the same manner as in Example (17-1). Fluoromethyl) phenyl] acetonitrile was obtained. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained [4-chloro-3- (trifluoromethyl) phenyl] acetonitrile, and the mixture was stirred at 100 ° C. for 2 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 crude [4-chloro-3- (trifluoromethyl) phenyl] acetic acid. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the resulting crude product and stirred at 50 ° C. for 1 hour. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding ethyl acetate, the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate 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 methyl [4-chloro-3- (trifluoromethyl). ) Phenyl] acetate (1.08 g, 45% yield over 2 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.58 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.37 (1H, dd, J = 8.0, 2.0 Hz), 3.70 (3H, s), 3.64 (2H, s).
(25-2)
In the same manner as in Example (24-2) and Example (17-4), methyl [4-chloro-3- (trifluoromethyl) phenyl] acetate obtained in Example (25-1) ( 51 mg, 0.20 mmol) and tert-butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) obtained in Example (22-4) The title compound (24 mg, 44% yield over 2 steps) was obtained as a pale yellow powder from -yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (100 mg, 0.20 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.65 (1H, s), 7.48 (1H, d, J = 7.6 Hz), 7.31-7.24 (4H, m), 6.94 (2H, d, J = 8.4 Hz), 5.36 (2H, s), 3.75 (2H, s), 1.62 (9H, s).
MS (ESI) (m / z): 569 ([MH] ⁺ ).

(Example 26)
tert-butyl 6-[({2'-ethyl-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl ) Benzoate (Exemplary compound number: 2-189)
(26-1)
3-bromo-4-methoxybenzylcyanide (9.0 g, 40 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (400 mg, 0.49 mmol), and N, N-dimethylformamide (75 ml) was added to potassium carbonate (24.0 g, 174 mmol) at room temperature. Further, triethylborane (1M-n-hexane solution 50 ml, 50 mmol) was added dropwise, and the reaction solution was stirred at 70 ° C. for 5 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 residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 8 / 1-5 / 1) to give oily (3-ethyl- 4-Methoxyphenyl) acetonitrile (2.6 g, 38% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.11 (1H, d, J = 8.4 Hz), 7.08 (1H, s), 6.81 (1H, d, J = 8.4 Hz), 3.83 (3H, s), 3.67 (2H, s), 2.63 (2H, q, J = 7.6 Hz), 1.19 (3H, t, J = 7.6 Hz).
(26-2)
(3-ethyl-4-methoxyphenyl) acetonitrile (6.10 g, 34) obtained in Example (26-1) in the same manner as in Example (6-2) and Example (22-5). 0.8 mmol), oily 4- (cyanomethyl) -2-ethylphenyl trifluoromethanesulfonate (8.1 g, total yield of 78 steps) was obtained.
¹ H-NMR (500MHz, CDCl ₃ ): δ 7.32 (1H, d, J = 2.0 Hz), 7.28-7.23 (2H, m), 3.77 (2H, s), 2.76 (2H, q, J = 7.5 Hz ), 1.28 (3H, t, J = 7.5 Hz).
(26-3)
4- (cyanomethyl) -2-ethylphenyl trifluoromethanesulfonate (9.7 g, 33 mmol), 4-methoxyphenyl boric acid (5.3 g, 35 mmol) obtained in Example (26-2), [1 , 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (2.7 g, 3.3 mmol) and sodium carbonate (10.0 g, 94 mmol) in toluene (150 ml), ethanol ( 30 ml) and distilled water (30 ml) were added, followed by stirring at 80 ° C. for 4 hours. After the reaction solution was cooled to room temperature, insoluble matters were filtered off. The obtained filtrate was 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 residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7 / 1-6 / 1) to give oily (2-ethyl- 4′-methoxy-1,1′-biphenyl-4-yl) acetonitrile (5.5 g, 66% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.25-7.17 (5H, m), 6.95 (2H, d, J = 8.8 Hz), 3.86 (3H, s), 3.77 (2H, s), 2.61 (2H , q, J = 7.6 Hz), 1.10 (3H, t, J = 7.6 Hz).

(26-4)
To (2-ethyl-4′-methoxy-1,1′-biphenyl-4-yl) acetonitrile (5.5 g, 22 mmol) obtained in Example (26-3), acetic acid (55 ml) and odor Hydrochloric acid (55 ml) was added, and the mixture was stirred at 100 ° C. for 10 hr. The reaction mixture was cooled to room temperature, ethyl acetate was added, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Methanol (150 ml) was added to the residue obtained by distilling off the solvent under reduced pressure, and sulfuric acid (3 ml) was added under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue, 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 5 / 1-2 / 1) to give colorless solid methyl (2- Ethyl-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (5.0 g, yield 85%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.20-7.13 (5H, m), 6.86 (2H, d, J = 8.0 Hz), 4.76 (1H, br s), 3.73 (3H, s), 3.65 ( 2H, s), 2.58 (2H, q, J = 7.2 Hz), 1.09 (3H, t, J = 7.2 Hz).
(26-5)
Ethyl acetate (50 ml) of [2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (5.09 g, 16.4 mmol) obtained in Example (6-6) ) To the solution was added triethylamine (2.74 ml, 19.7 mmol). After dropwise addition of methanesulfonyl chloride (1.33 ml, 17.2 mmol) under ice cooling, the reaction solution was stirred at the same temperature for 30 minutes. The reaction was filtered through celite. The filtrate was washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. N-Hexane was added to the residue obtained by distilling off the solvent under reduced pressure. The precipitated crystals were collected by filtration to obtain pale yellow 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl methanesulfonate (5.37 g, yield 84%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.64 (1H, d, J = 8.2 Hz), 7.49 (1H, d, J = 8.2 Hz), 5.72 (1H, s), 5.65 (2H, s), 5.01 (2H, s), 3.65 (3H, s), 3.45 (6H, s), 3.06 (3H, s).
(26-6)
Methyl (2-ethyl-4′-hydroxy-1,1′-) obtained in Example (26-4) in the same manner as in Example (40-2) and Example (8-3). Biphenyl-4-yl) acetate (4.90 g, 18.1 mmol) and 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) obtained in Example (26-5) ) From benzyl methanesulfonate (8.35 g, 21.5 mmol), methyl (2-ethyl-4 ′-{[2-formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1) as a colorless solid , 1′-biphenyl-4-yl) acetate (6.77 g, total yield of the two steps 79%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.66 (1H, s), 10.40 (1H, s), 7.83 (1H, d, J = 8.0 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.21 (1H, s), 7.14 (2H, br s), 7.11 (1H, d, J = 8.0 Hz), 7.00 (2H, d, J = 8.0 Hz), 3.73 (3H, s), 3.66 (2H, s), 2.58 (2H, q, J = 7.6 Hz), 1.10 (3H, t, J = 7.6 Hz).
(26-7)
In the same manner as in Example (28-3), Example (28-4), and Example (33-5), methyl (2-ethyl-4′-) obtained in Example (26-6) was used. From {[2-formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetate (6.77 g, 14.3 mmol), the title compound as a colorless solid (5.87 g, total yield of 3 steps 76%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.69 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.18 (1H, s), 7.12 (2H, br s), 6.92 (2H, d, J = 8.4 Hz), 5.36 (2H, s), 3.72 (3H, s), 3.64 (2H, s), 2.58 (2H, q, J = 7.6 Hz), 1.64 (9H, s), 1.09 (3H, t, J = 7.6 Hz).
ESI (ES-) (m / z): 543 ([MH] ⁺ ).

(Example 27)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-fluoro-1,1′-biphenyl-3-yl) acetic acid (exemplary compound Number: 2-32)
Tert-butyl 2-{[4- (4,4,5,5-tetra) obtained in Example (22-4) in the same manner as in Example (24-2) and Example (7). Methyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate (450 mg, 0.910 mmol) and methyl (3-chloro-2-fluorophenyl) acetate ( From 184 mg, 0.910 mmol), the title compound (25 mg, total yield of 2 steps, 5%) was obtained as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.36 (1H, td, J = 7.4, 1.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.26-7.22 (1H, m), 7.17 (1H, t, J = 7.4 Hz), 6.99 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.79 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 520 ([M] ⁺ ).

(Example 28)
[5- (4-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -2-thienyl] acetic acid (Exemplary compound number: 2-113)
(28-1)
1- (Dimethoxymethyl) -2- (methoxymethoxy) -3- (trifluoromethyl) benzene (12.0 g, 42.9 mmol) obtained in Example (6-4) and N, N, N To a solution of ', N'-tetramethylethylenediamine (9.70 ml, 64.4 mmol) in tetrahydrofuran (100 ml), n-butyllithium-1.59M n-hexane solution (40.0 ml, 64.4 mmol) at -40 ° C Was added dropwise over 5 minutes. The reaction was stirred at 0 ° C. for 15 minutes. The reaction solution was cooled to −40 ° C., methyl iodide (5.3 ml, 85.85 mmol) was added, and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1) to give oily 2- (dimethoxymethyl) -3- (Methoxymethoxy) -1-methyl-4- (trifluoromethyl) benzene (7.19 g, 57% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.44 (1H, d, J = 8.2 Hz), 7.04 (1H, d, J = 8.2 Hz), 5.70 (1H, s), 4.99 (2H, s), 3.64 (3H, s), 3.43 (6H, s), 2.55 (3H, s).
(28-2)
In the same manner as in Example (8-3), 2- (dimethoxymethyl) -3- (methoxymethoxy) -1-methyl-4- (trifluoromethyl) benzene obtained in Example (28-1) ( 7.19 g, 24.4 mmol) gave 2-hydroxy-6-methyl-3- (trifluoromethyl) benzaldehyde (4.65 g, 93% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.58 (1H, s), 10.32 (1H, s), 7.65 (1H, d, J = 7.8 Hz), 6.79 (1H, d, J = 7.8 Hz), 2.67 (3H, s).
(28-3)
2-hydroxy-6-methyl-3- (trifluoromethyl) benzaldehyde (4.65 g, 22.8 mmol) obtained in Example (28-2) in tert-butyl alcohol (90 ml), 1,4-dioxane (30 ml) and a mixed solution of 2-methyl-2-butene (30 ml) with sodium chlorite (6.0 g, 66.3 mmol) and sodium dihydrogen phosphate monohydrate (6.0 g, 43.5 mmol) of an aqueous solution (40 ml) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled, 5% aqueous sodium thiosulfate solution was added, 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 obtained by distilling off the solvent under reduced pressure was crystallized from ethyl acetate and n-hexane to give colorless 2-hydroxy-6-methyl-3- (trifluoromethyl) benzoic acid (4 .21 g, 84% yield).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.73 (1H, s), 7.63 (1H, d, J = 7.8 Hz), 6.84 (1H, d, J = 7.8 Hz), 2.67 (3H, s).

(28-4)
2-hydroxy-6-methyl-3- (trifluoromethyl) benzoic acid (4.21 g, 19.1 mmol) obtained in Example (28-3) in tert-butyl alcohol-tetrahydrofuran (2: 1, 60 ml) ) N, N-dimethylaminopyridine (0.7 g, 5.7 mmol) and di-tert-butyl dicarbonate [(tBuOCO) ₂ O] (16.7 g, 76.5 mmol) were added to the mixed solution, Stir at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1) to give tert-butyl 2-[(tert-butoxycarbonyl) oxy]- 6-methyl-3- (trifluoromethyl) benzoate (6.27 g, yield 87%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.53 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 2.43 (3H, s), 1.59 (9H, s), 1.53 (9H, s).
(28-5)
Tetrachloride of tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-methyl-3- (trifluoromethyl) benzoate (18.6 g, 49.6 mmol) obtained in Example (28-4) N-bromosuccinimide (9.70 g, 54.5 mmol) and benzoyl peroxide (0.7 g) were added to a carbon (400 ml) solution, and the mixture was heated to reflux for 5 hours. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding n-hexane to the obtained residue and filtering, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene), and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (11 .66 g, 52% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.64 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 8.2 Hz), 4.60 (2H, s), 1.63 (9H, s), 1.52 (9H, s).
(28-6)
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (0.8 g, 3.65 mmol) and literature (Jackson, PM et al., J. Chem Soc. Perkin Trans.1., 1990, 11, p. 2909-2918) synthesized by the method described in ethyl (5-bromo-2-thienyl) acetate (1.00 g, 4.01 mmol) In a toluene-ethanol (5: 1, 24 ml) mixed solution of tris (dibenzylideneacetone) dipalladium (0) (110 mg, 0.12 mmol), tri-o-tolylphosphine (61 mg, 0.2 mmol), and 2N-sodium carbonate aqueous solution (4 ml) was added, and the mixture was stirred at 80 ° C. for 3 hr. Water was poured into the reaction mixture, 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) to give ethyl [5- (4-hydroxyphenyl)- 2-Thienyl] acetate (0.73 g, 77% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.41 (2H, d, J = 8.6 Hz), 7.00 (1H, d, J = 3.5 Hz), 6.85 (1H, d, J = 3.5 Hz), 6.80 ( 2H, d, J = 8.6 Hz), 4.89 (1H, s), 4.19 (2H, q, J = 7.0 Hz), 3.80 (2H, s), 1.29 (3H, t, J = 7.0 Hz).
(28-7)
Tert-butyl 6- (bromomethyl)-obtained in Example (28-5) in the same manner as in Example (2-3), Example (33-5) and Example (17-4) 2-[(tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (366 mg, 0.8 mmol) and the ethyl [5- (4-hydroxyphenyl) obtained in Example (28-6) ) -2-thienyl] acetate (211 mg, 0.8 mmol) to give the title compound as a colorless powder (56 mg, 14% yield over 3 steps).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.58 (1H, s), 11.44 (1H, s), 7.82 (1H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz ), 7.29 (1H, d, J = 7.8 Hz), 7.23 (1H, d, J = 3.5 Hz), 7.02 (2H, d, J = 7.8 Hz), 6.91 (1H, d, J = 3.5 Hz), 5.35 (2H, s), 3.81 (2H, s), 1.56 (9H, s).
MS (ESI) (m / z): 507 ([MH] ⁺ ).

(Example 29)
tert-Butyl 2-hydroxy-6-{[(4 '-{[(methylamino) sulfonyl] methyl} -1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (Exemplary compound number: 1-113)
(29-1)
An aqueous solution (40 ml) of sodium sulfite (2.52 g, 20.0 mmol) was added to an acetone solution (40 ml) of 4-bromobenzyl bromide (5.00 g, 20.0 mmol), and the mixture was heated to reflux for 48 hours. The reaction mixture was concentrated and the precipitated crystals were collected by filtration and washed with a small amount of acetone to obtain white crystals. The obtained crystals were suspended in methylene chloride (36 ml), oxalyl chloride (0.742 ml, 8.65 mmol) and N, N-dimethylformamide (0.1 ml) were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to obtain a reaction mixture (1.94 g). A part (150 mg) of the obtained reaction mixture was dissolved in tetrahydrofuran (3 ml) and tert-butanol (1.5 ml), 40% -methylamine aqueous solution (130 μl) was added, and the mixture was stirred at room temperature for 2 hours. . The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution 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 solvent was distilled off under reduced pressure to obtain 1- (4-bromophenyl) -N-methylmethanesulfonamide (80 mg) as a yellow solid.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.53 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 4.21 (2H, s), 4.03-3.99 (1H, m ), 2.73 (3H, d, J = 4.7 Hz).
(29-2)
1- (4-Bromophenyl) -N-methylmethanesulfonamide (80 mg, 0.30 mmol) obtained in Example (29-1) and tert-butyl obtained in Example (22-4) 2-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate (147 mg, 0.30 mmol) Tetrakis (triphenylphosphine) palladium (0) (10 mg, 8.9 μmol) and a 2N aqueous sodium carbonate solution (0.33 ml) were added to a toluene-ethanol mixed solution (6: 1, 1.2 ml) of The mixture was stirred for 8 hours while heating under reflux. Ethyl acetate and water were added to the reaction mixture, and the insoluble material was filtered off through celite. The obtained filtrate was 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 preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 50/1) to give the title compound as a pale yellow powder (7 mg, yield). 4%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.54 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.39 (2H, s), 4.30 ( 2H, s), 4.01 (1H, q, J = 5.1 Hz), 2.77 (3H, d, J = 5.1 Hz), 1.65 (9H, s).
MS (FAB) (m / z): 551 ([M] ⁺ ).

(Example 30)
[2- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -1,3-thiazol-5-yl] acetic acid (Exemplary Compound No. : 2-187)
(30-1)
4-methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), Heated to reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution 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 = 2/1) to give ethyl [2- (4-methoxyphenyl)- 1,3-thiazol-5-yl] acetate (1.79 g, 67% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.83 (2H, d, J = 8.6 Hz), 7.56 (1H, s), 6.93 (2H, d, J = 8.6 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.85-3.83 (5H, m), 1.29 (3H, t, J = 7.0 Hz).
(30-2)
In the same manner as in Example (26-4), ethyl [2- (4-methoxyphenyl) -1,3-thiazol-5-yl] acetate obtained in Example (30-1) (303 mg, 1. 1 mmol), allyl [2- (4-hydroxyphenyl) -1,3-thiazol-5-yl] acetate (195 mg, yield 65%) was obtained.
In this step, allyl alcohol was used instead of methanol in the esterification step.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.00 (1H, br s), 7.69 (2H, d, J = 8.6 Hz), 7.57 (1H, s), 6.79 (2H, d, J = 8.6 Hz) , 5.96-5.86 (1H, m), 5.36-5.23 (2H, m), 4.66-4.63 (2H, m), 3.88 (2H, s).
(30-3)
Tert-butyl 6- (bromomethyl)-obtained in Example (28-5) in the same manner as in Example (2-3), Example (33-5) and Example (11-7) 2-[(tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (314 mg, 0.69 mmol) and allyl obtained in Example (30-2) [2- (4-hydroxyphenyl ) -1,3-thiazol-5-yl] acetate (190 mg, 0.69 mmol) gave the title compound as a colorless powder (33 mg, total yield of 3 steps 9%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.69 (1H, s), 11.40 (1H, s), 7.85 (2H, d, J = 9.0 Hz), 7.80 (1H, d, J = 8.2 Hz ), 7.62 (1H, s), 7.27 (1H, d, J = 8.2 Hz), 7.08 (2H, d, J = 9.0 Hz), 5.37 (2H, s), 3.91 (2H, s), 1.54 (9H , s).
MS (ESI) (m / z): 508 ([MH] ⁺ ).

(Example 31)
tert-Butyl 2-hydroxy-6-({[3 ′-(methylsulfonyl) -1,1′-biphenyl-4-yl] oxy} methyl) -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 2 -188)
3-Bromophenylmethylsulfone (235 mg, 1.0 mmol) and tert-butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1) obtained in Example (22-4) , 3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (494 mg, 1.0 mmol) in dioxane (5.0 ml) and 2M aqueous sodium carbonate solution (1.0 ml). ) And [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (81 mg, 0.1 mmol), and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was returned to room temperature, poured into water 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 solvent was distilled off under reduced pressure to obtain solid tert-butyl 2-hydroxy-6-{[3 '-(methylsulfonyl) -1,1'-biphenyl-4-yl] oxy} methyl) -3- (Trifluoromethyl) benzoate (80 mg, 15% yield) was obtained.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 11.44 (1H, s), 8.12 (1H, s), 8.00 (1H, d, J = 8.0 Hz), 7.86 (1H, d, J = 8.0 Hz ), 7.82 (1H, d, J = 8.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 7.71 (1H, t, J = 8.0 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.0 Hz), 5.39 (2H, s), 3.29 (3H, s), 1.56 (9H, s).
MS (ESI) (m / z): 521 ([MH] ⁺ ).

(Example 32)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 2-186)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-[({2′-ethyl-4 ′-[(methoxycarbonyl) methyl]) obtained in Example (26-7) was used. -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (5.0 g, 9.2 mmol) to give the title compound as a colorless solid (4.79 g, 97% yield). )
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.26-7.22 (3H, m ), 7.16 (2H, br s), 6.95 (2H, d, J = 8.0 Hz), 5.38 (2H, s), 3.70 (2H, s), 2.60 (2H, q, J = 7.6 Hz), 1.65 ( 9H, s), 1.10 (3H, t, J = 7.6 Hz).
ESI (ES-) (m / z): 529 ([MH] ⁺ ).
Anal.calcd.for C ₂₉ H ₂₉ F ₃ O ₆ : C, 65.65; H, 5.51; F, 10.74; found: C, 65.63; H, 5.53; F, 10.78.

(Example 33)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-3-yl) acetic acid (exemplary compound Number: 2-31)
(33-1)
(3-Amino-2-methylphenyl) acetic acid (1.) synthesized according to the method described in the literature (Askam, V. et al., J. Chem. Soc. C; 1969, p. 1935-1936.). To a 10% sulfuric acid solution (72 ml) of 20 g, 17.2 mmol), an aqueous solution (2 ml) of sodium nitrite (1.92 g, 11.6 mmol) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was added dropwise to an aqueous solution (11 ml) of potassium iodide (3.66 g, 22.0 mmol). The reaction was warmed to 90 ° C. and stirred for 2.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with 10% aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. From the reaction mixture obtained by distilling off the solvent under reduced pressure, methyl (3-iodo-2-methylphenyl) acetate (2.23 g, yield 66%) was obtained in the same manner as in Example (3-1). )
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.02 (1H, t, J = 7.8 Hz), 6.80 (1H, d, J = 7.8 Hz), 6.70 (1H, d, J = 7.8 Hz), 3.70 ( 2H, s), 3.65 (3H, s), 2.19 (3H, s).
(33-2)
Methyl (3-iodo-2-methylphenyl) acetate (950 mg, 3.27 mmol) obtained in Example (33-1) and 4-methoxyphenylboric acid (498 mg, 3.27 mmol) N, N- To a dimethylformamide (8 ml) solution was added palladium (II) acetate (37 mg, 0.16 mmol), tri-o-tolylphosphine (100 mg, 0.327 mmol), and 2N aqueous sodium carbonate (2.5 ml). Then, it stirred at 80 degreeC for 5 hours. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained filtrate was 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 = 9/1) to give methyl (4′-methoxy-2) as yellow powder. -Methyl-1,1'-biphenyl-3-yl) acetate (59 mg, yield 7%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.23-7.12 (5H, m), 6.92 (2H, d, J = 8.6 Hz), 3.84 (3H, s), 3.71 (2H, s), 3.70 (3H , s), 2.18 (3H, s).

(33-3)
In the same manner as in Example (6-2), methyl (4′-methoxy-2-methyl-1,1′-biphenyl-3-yl) acetate (59 mg, 0) obtained in Example (33-2) was obtained. .22 mmol) gave methyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl) acetate (28 mg, 50% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.45-7.39 (1H, m), 7.18-7.12 (4H, m), 6.84 (2H, d, J = 8.6 Hz), 4.90 (1H, s), 3.71 (5H, s), 2.18 (3H, s).
(33-4)
In the same manner as in Example (40-2), methyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl) acetate (28 mg, 0) obtained in Example (33-3) was obtained. .11 mmol) from colorless oil tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({3 ′-[(methoxycarbonyl) methyl] -2′-methyl-1,1′-biphenyl -4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (19 mg, 28% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.73 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.24- 7.12 (5H, m), 6.97 (2H, d, J = 8.6 Hz), 5.27 (2H, s), 3.72 (2H, s), 3.71 (3H, s), 2.17 (3H, s), 1.58 (9H , s), 1.54 (9H, s).
(33-5)
Tert-Butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({3 '-[(methoxycarbonyl) methyl] -2'-methyl-1,1 obtained in Example (33-4) Pyrrolidine (3 μl, 0.036 mmol) was added to a tetrahydrofuran solution (1 ml) of '-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (19 mg, 0.030 mmol) at 40 ° C. Stir for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 3/1) to give tert-butyl 2- Hydroxy-6-[({3 ′-[(methoxycarbonyl) methyl] -2′-methyl-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (16 mg, Yield 100%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.25-7.13 (5H, m), 6.95 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.72 (5H, s), 2.19 (3H, s), 1.65 (9H , s).
(33-6)
In the same manner as in Example (7), tert-butyl 2-hydroxy-6-[({3 ′-[(methoxycarbonyl) methyl] -2′-methyl-1) obtained in Example (33-5) was used. , 1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (16 mg, 0.030 mmol) gave the title compound as a brown powder (12 mg, 77% yield).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.25-7.15 (5H, m), 6.96 (2H, d, J = 8.3 Hz), 5.38 (2H, s), 3.76 (2H, s), 2.21 (3H, s), 1.65 (9H , s).
MS (FAB) (m / z): 516 ([M] ⁺ ).

(Example 34)
[2- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -5-pyrimidinyl] acetic acid (Exemplary compound number: 2-151)
(34-1)
Tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) obtained in Example (28-5) in the same manner as in Example (2-3) and Example (33-5) ) Oxy] -3- (trifluoromethyl) benzoate (412 mg, 0.92 mmol) and allyl [2- (4-hydroxyphenyl) -5-pyrimidinyl] acetate (250 mg, 0.92 mmol) to tert-butyl 6 -{[4- (5-{[(allyloxy) carbonyl] methyl} -2-pyrimidinyl) phenoxy] methyl} -2-hydroxy-3- (trifluoromethyl) benzoate (140 mg, 28% yield over 2 steps) Got.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.24 (1H, s), 8.67 (2H, s), 8.38 (2H, d, J = 9.0 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.01 (2H, d, J = 9.0 Hz), 5.96-5.85 (1H, m), 5.38 (2H, s), 5.34-5.23 (2H, m), 4.64 -4.61 (2H, m), 3.66 (2H, s), 1.63 (9H, s).
(34-2)
In the same manner as in Example (11-7), tert-butyl 6-{[4- (5-{[(allyloxy) carbonyl] methyl} -2-pyrimidinyl) phenoxy obtained in Example (34-1) was obtained. The title compound (94 mg, 72% yield) as a colorless powder was obtained from methyl} -2-hydroxy-3- (trifluoromethyl) benzoate (140 mg, 0.26 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.62 (1H, s), 11.42 (1H, s), 8.72 (2H, s), 8.34 (2H, d, J = 9.0 Hz), 7.80 (1H , d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.11 (2H, d, J = 9.0 Hz), 5.39 (2H, s), 3.70 (2H, s), 1.54 (9H , s).
MS (ESI) (m / z): 505 ([M + H] ⁺ ).

(Example 35)
tert-butyl 2-hydroxy-6-[({3 '-[(methylsulfonyl) amino] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 2-190)
(35-1)
In the same manner as in Example (26-5), light yellow solid N- (3-iodophenyl) methanesulfonamide (490 mg, yield 72%) was obtained from 3-iodoaniline (500 mg, 2.28 mmol). It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.56 (1H, s), 7.53 (1H, d, J = 7.8 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.08 (1H, t, J = 7.8 Hz), 3.04 (3H, s).
(35-2)
In the same manner as in Example (31), N- (3-iodophenyl) methanesulfonamide (134 mg, 0.45 mmol) obtained in Example (35-1) and Example (22-4) The resulting tert-butyl 2-hydroxy-6-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoro From the methyl) benzoate (250 mg, 0.51 mmol), the title compound (20 mg, 8% yield) was obtained as a pale purple powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.40 (1H, s), 9.76 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz) ), 7.40-7.26 (4H, m), 7.14 (1H, d, J = 7.0 Hz), 7.07 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 3.01 (3H, s), 1.56 (9H, s).
MS (FAB +) (m / z): 537 (M ^{+ ・} ).

(Example 36)
[4- (5-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) phenyl] acetic acid (Exemplary compound number: 2-164)
(36-1)
Methyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (1.07 g, 3.86 mmol) obtained in Example (12-1) ) And 2-chloro-5-hydroxypyridine (500 mg, 3.86 mmol) in dimethoxyethane (20 ml), tetrakis (triphenylphosphine) palladium (0) (220 mg, 0.193 mmol), and 2N- An aqueous sodium carbonate solution (4.63 ml) was added, and the mixture was stirred overnight with heating under reflux. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained filtrate was extracted with ethyl acetate, and 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 2 / 1-1 / 1) to obtain methyl [4- (5- Hydroxy-2-pyridinyl) phenyl] acetate (230 mg, 24% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.30 (1H, s), 7.85 (2H, d, J = 8.3 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.21 (1H, d, J = 8.3 Hz), 3.71 (3H, s), 3.67 (2H, s).
(36-2)
In the same manner as in Example (40-2), Example (33-5), and Example (7), the methyl [4- (5-hydroxy-2-phenyl) obtained in Example (36-1) was obtained. Pyridinyl) phenyl] acetate (64 mg, 0.26 mmol) gave the title compound as a white powder (74 mg, total yield of 3 steps 67%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26 (1H, s), 8.44 (1H, d, J = 7.8 Hz), 7.87 (2H, d, J = 7.8 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.39 (2H, d, J = 7.8 Hz), 7.31-7.25 (2H, m), 5.43 (2H, s), 3.71 (2H, s ), 1.66 (9H, s).
MS (FAB) (m / z): 504 ([M + H] ⁺ ).

(Example 37)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-191)
(37-1)
In the same manner as in Example (29-2), Example (2-2), Example (11-1), and Example (26-4), 4-methoxyphenylboric acid (17.0 g, 112 mmol) And 4-bromo-2-nitrotoluene (22.1 g, 102 mmol) to methyl (4′-hydroxy-2-nitro-1,1′-biphenyl-4-yl) acetate (3.53 g, total of 4 steps) Yield 12%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.73-7.69 (1H, m), 7.52-7.47 (1H, m), 7.41-7.36 (1H, m), 7.18-7.10 (2H, m), 6.94- 6.86 (2H, m), 3.80-3.67 (5H, m).
(37-2)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl (4′-hydroxy-2-methyl) obtained in Example (37-1) was used. Nitro-1,1′-biphenyl-4-yl) acetate (1.71 g, 3.76 mmol) and tert-butyl 6- (bromomethyl) -2-[() obtained in Example (28-5) tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (1.08 g, 3.76 mmol) gave the title compound as a yellow oil (138 mg, 7% yield over 3 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.75 (1H, d, J = 1.2 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.50 (1H, dd, J = 8.0, 1.2 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.26-7.19 (3H, m), 6.94 (2H, d, J = 8.0 Hz), 5.35 (2H, s), 3.76 (2H, s), 1.63 (9H , s).
MS (FAB) (m / z): 547 ([M] ⁺ ).

(Example 38)
(2-Amino-4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-192)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1 obtained in Example (37-2) Rhodium-alumina (Rh5%) (100 mg) was added to a methanol solution (4 ml) of '-biphenyl-4-yl) acetic acid (130 mg, 0.237 mmol), and the mixture was stirred at room temperature for 2 days in a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 20/1) to obtain the title compound (63 mg, yield 51%) as a yellow amorphous substance.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.69 (1H, d, J = 8.0 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.0 Hz), 7.04 ( 1H, d, J = 8.0 Hz), 6.96 (2H, d, J = 8.6 Hz), 6.71 (1H, d, J = 8.0 Hz), 6.69 (1H, br s), 5.36 (2H, s), 3.58 (2H, s), 1.65 (9H, s).
MS (ESI) (m / z): 516 ([MH] ⁺ ).

(Example 39)
[4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (dimethylamino) -1,1′-biphenyl-4-yl] acetic acid (Exemplary compound number: 2-193)
(2-Amino-4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl- obtained in Example 38 4-yl) acetic acid (50 mg, 0.096 mmol) in acetonitrile (4 ml), 36% formalin aqueous solution (0.5 ml), acetic acid (100 μl), and sodium cyanoborohydride (36 mg, 0.59 mmol) sequentially In addition, the mixture was stirred overnight at room temperature. 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 preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 20/1) to give the title compound as a yellow oil (48 mg, yield). 92%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.68 (1H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.12 ( 1H, d, J = 8.2 Hz), 6.93-6.87 (4H, m), 5.34 (2H, s), 3.63 (2H, s), 2.53 (6H, s), 1.63 (9H, s).
MS (ESI) (m / z): 544 ([MH] ⁺ ).

(Example 40)
(2-acetyl-4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-194)
(40-1)
The literature (Watanabe, T. et al., Chem. Pharm. Bull., 1998, Vol. 46, p. 53-68) was used in the same manner as in Examples (22-5) and (26-3). To methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4) from methyl (3-acetyl-4-hydroxyphenyl) acetate (1.02 g, 4.90 mmol) synthesized according to the method described in 1). -Yl) acetate (644 mg, total yield of 2 steps 51%) was obtained.
In this step, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol is used as a borate ester reagent in the reaction corresponding to Example (26-3). It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.45-7.39 (2H, m), 7.36-7.30 (1H, m), 7.19-7.12 (2H, m), 6.90-6.83 (2H, m), 3.74 ( 3H, s), 3.70 (2H, s), 2.01 (3H, s).
(40-2)
Methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (122 mg, 0.429 mmol) obtained in Example (40-1) and Example (28-5) ) Solution of tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (181 mg, 0.429 mmol) obtained in 4 ml) was added cesium carbonate (209 mg, 0.644 mmol) and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (3 times). 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 preparative thin layer chromatography (developing solvent: hexane / ethyl acetate = 3/1), and tert-butyl 6-[({2′-acetyl-4 ′-[(methoxycarbonyl ) Methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (93 mg, 34% yield). It was.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.70 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.43-7.37 (2H, m), 7.31 (1H, d , J = 8.2 Hz), 7.26-7.21 (2H, m), 6.97 (2H, d, J = 8.6 Hz), 5.24 (2H, s), 3.71 (3H, s), 3.68 (2H, s), 1.99 (3H, s), 1.56 (9H, s), 1.53 (9H, s).
(40-3)
In the same manner as in Example (33-5) and Example (17-4), tert-butyl 6-[({2′-acetyl-4 ′-[) obtained in Example (40-2) was used. (Methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (93 mg, 0.14 mmol) To give the title compound as a yellow oil (48 mg, 61% yield over 2 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.70 (1H, d, J = 8.0 Hz), 7.46-7.38 (2H, m), 7.32 (1H, d, J = 8.0 Hz), 7.29-7.19 (3H , m), 6.97 (2H, d, J = 9.0 Hz), 5.36 (2H, s), 3.68 (2H, s), 2.00 (3H, s), 1.63 (9H, s).
MS (ESI) (m / z): 543 ([MH] ⁺ ).

(Example 41)
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) -3-hydroxypropanoic acid (Exemplary compound number: 1-114)
(41-1)
Tert-Butyl 2-hydroxy-6-[({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl]-obtained in Example (6-9) To 3- (trifluoromethyl) benzoate (400 mg, 0.77 mmol) was added dimethyl sulfoxide (3 ml), paraformaldehyde (purity 90%, 300 mg), and sodium hydrogen carbonate (300 mg, 3.57 mmol). For 3 hours. The reaction mixture was cooled to room temperature and diluted 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- 1/3) to give colorless solid tert-butyl 2 -Hydroxy-6-[({4 '-[2-hydroxy-1- (methoxycarbonyl) ethyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoe- (246 mg, yield 58%), tert-butyl 2-hydroxy-6-[({4 ′-[1- (methoxycarbonyl) vinyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (37 mg, 9% yield) and tert-butyl 2-hydroxy-6-[({4 '-[2-hydroxy-1-hydroxymethyl-1- ( Meto Aryloxycarbonyl) ethyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate - was obtained bets (112 mg, 25% yield).
The ¹ H-NMR spectrum of the obtained compound is shown below.
tert-butyl 2-hydroxy-6-[({4 '-[2-hydroxy-1- (methoxycarbonyl) ethyl] -1,1'-biphenyl-4-yl} oxy} methyl) -3- (trifluoro Methyl) benzoate
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 9.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.28-7.26 (1H, m), 6.98 (2H, d, J = 9.0 Hz), 5.38 (2H, s), 4.18-4.14 (1H , m), 3.91-3.84 (2H, m), 3.74 (3H, s), 2.26-2.23 (1H, m), 1.65 (9H, s).
tert-butyl 2-hydroxy-6-[({4 '-[1- (methoxycarbonyl) vinyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoe- G
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz), 7.55 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.28 (1H, d, J = 8.5 Hz), 6.99 (2H, d, J = 8.5 Hz), 6.38 (1H, s), 5.95 ( 1H, s), 5.38 (2H, s), 3.85 (3H, s), 1.65 (9H, s).
tert-butyl 2-hydroxy-6-[({4 '-[2-hydroxy-1-hydroxymethyl-1- (methoxycarbonyl) ethyl] -1,1'-biphenyl-4-yl} oxy) methyl]- 3- (Trifluoromethyl) benzoate
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.53 (2H, d, J = 9.0 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.28-7.23 (3H, m), 6.98 (2H, d, J = 9.0 Hz), 5.38 (2H, s), 4.39-4.35 (2H, m), 4.21-4.17 (2H, m) , 3.83 (3H, s), 2.89-2.86 (2H, m), 1.64 (9H, s).
(41-2)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-[({4 ′-[2-hydroxy-1- (methoxycarbonyl) ethyl] obtained in Example (41-1) was used. ] -1,1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate, 2- (4 ′-{[2- (tert-butoxycarbonyl)- 3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) -3-hydroxypropanoic acid (65 mg) was obtained.
In this step, 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.55 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.29-7.26 (1H, m), 6.98 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 4.21-4.17 (1H , m), 3.97-3.91 (2H, m), 1.65 (9H, s).
ESI (ES-) (m / z): 531 ([MH] ⁺ ).

(Example 42)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-195)
(42-1)
To a solution of zinc bromide (473 mg, 2.1 mmol) in tetrahydrofuran (2 ml), isopropylmagnesium bromide-0.63 M tetrahydrofuran solution (3.2 ml, 2.0 mmol) was added dropwise under ice cooling. After stirring for 15 minutes, the reaction solution was cooled to -78 ° C. 3-Bromo-4-methoxybenzylcyanide (226 mg, 1.0 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (32 mg, 0.04 mmol) Was added at -78 ° C, and then the reaction solution was warmed to room temperature and further stirred for 5 hours. 1N-hydrochloric acid was added to the reaction mixture, 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 subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 8 / 1-6 / 1) to give crude (3-isopropyl-4 -Methoxyphenyl) acetonitrile (158 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.12-7.11 (2H, m), 6.83 (1H, d, J = 9.2 Hz), 3.83 (3H, s), 3.69 (2H, s), 3.34-3.27 (1H, m), 1.21 (3H, d, J = 6.8 Hz), 1.20 (3H, d, J = 6.8 Hz).
(42-2)
In the same manner as in Example (26-4), from the crude product (158 mg) of (3-isopropyl-4-methoxyphenyl) acetonitrile obtained in Example (42-1), crude methyl (4-hydroxy -3-Isopropylphenyl) acetate (163 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.08 (1H, s), 6.98 (1H, d, J = 8.0 Hz), 6.70 (1H, d, J = 8.0 Hz), 4.64 (1H, br s) , 3.69 (3H, s), 3.55 (2H, s), 3.21-3.15 (1H, m), 1.25 (6H, d, J = 6.8 Hz).
(42-3)
In the same manner as in Example (22-5), Example (29-2), and Example (26-4), crude methyl (4-hydroxy-3) obtained in Example (42-2) was used. -Isopropylphenyl) acetate (163 mg) gave crude methyl (4'-hydroxy-2-isopropyl-1,1'-biphenyl-4-yl) acetate (147 mg).
In this step, in the step of Suzuki coupling corresponding to Example (29-2), tert-butyl 2-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 4-Methoxyphenyl boric acid was used in place of 2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.26-7.12 (5H, m), 6.87-6.82 (2H, m), 3.74 (3H, s), 3.67 (2H, s), 3.09-3.02 (1H, m), 1.15 (6H, d, J = 6.8 Hz).

(42-4)
Methyl (4′-hydroxy-2-isopropyl-1,1′-biphenyl) obtained in Example (42-3) in the same manner as in Example (40-2) and Example (8-3) -4-yl) acetate crude product (147 mg) and 2- (dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) benzyl methane obtained in Example (26-5) From sulfonate (252 mg, 0.65 mmol), crude methyl (4 ′-{[2-formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1-1′-biphenyl- 4-yl) acetate (169 mg) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.66 (1H, s), 10.39 (1H, s), 7.83 (1H, d, J = 8.0 Hz), 7.26-7.23 (3H, m), 7.12-7.10 (3H, m), 7.00 (2H, d, J = 8.5 Hz), 5.37 (2H, s), 3.73 (3H, s), 3.67 (2H, s), 3.05-3.02 (1H, m), 1.16 ( 6H, d, J = 6.5 Hz).
(42-5)
In the same manner as in Example (28-3), Example (28-4), and Example (33-5), methyl (4 ′-{[2- From a crude product (169 mg) of formyl-3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1-1′-biphenyl-4-yl) acetate, tert-butyl 2-hydroxy- 6-[({2′-Isopropyl-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (91 mg, 0. 16 mmol) was obtained.
In this step, in the step corresponding to Example (33-5), the compound was purified by silica gel column chromatography followed by high performance liquid chromatography (column: GL Science, Intosyl ODS-3; eluent: acetonitrile. : Water = 93 / 7-98 / 2).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.32-7.26 (2H, m), 7.21 (2H, d, J = 8.5 Hz ), 7.12 (2H, br s), 6.94 (2H, d, J = 8.5 Hz), 5.38 (2H, s), 3.73 (3H, s), 3.67 (2H, s), 3.09-3.04 (1H, m ), 1.65 (9H, s), 1.15 (6H, d, J = 6.5 Hz).
(42-6)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-[({2′-isopropyl-4 ′-[(methoxycarbonyl) methyl]) obtained in Example (42-5) -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (91 mg, 0.16 mmol) gave the title compound as a colorless solid (84 g, 94% yield). .
In this step, 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.25-7.24 (1H, m ), 7.19 (2H, d, J = 8.8 Hz), 7.12 (2H, br s), 6.92 (2H, d, J = 8.8 Hz), 5.36 (2H, s), 3.69 (2H, s), 3.07- 3.04 (1H, m), 1.65 (9H, s), 1.15 (6H, d, J = 6.8 Hz).
ESI (ES-) (m / z): 543 ([MH] ⁺ ).

(Example 43)
4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-carboxylic acid (Exemplary compound number: 1-54)
(43-1)
In the same manner as in Example (13-2), from 4′-hydroxy-1,1′-biphenyl-4-carboxylic acid (820 mg, 3.82 mmol), allyl 4′-hydroxy-1,1 ′ as an off-white solid was obtained. -Biphenyl-4-carboxylate (582 mg, yield 60%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.08 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.50 (2H, d, J = 8.6 Hz), 6.91 ( 2H, d, J = 8.6 Hz), 6.10-5.99 (1H, m), 5.44-5.20 (1H, m), 5.31-5.26 (1H, m), 5.01 (1H, s), 4.83 (2H, d, J = 5.5 Hz).
(43-2)
Allyl 4′-hydroxy-1,1′-biphenyl-4-carboxylate (190 mg, 0.75 mmol) obtained in Example (43-1) and tert obtained in Example (28-5) -Butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (400 mg, 0.88 mmol) was used, and Example (40-2) and Example (33 -5) and in the same manner as in Example (13-5), the title compound (293 mg, total yield of 3 steps 80%) was obtained as a colorless powder.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 12.9 (1H, br s), 11.4 (1H, br s), 7.98 (2H, d, J = 8.8 Hz), 7.82 (1H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz) ), 5.39 (2H, s), 1.57 (9H, s).
MS (FAB +) (m / z): 489 ([M + H] ⁺ ).

(Example 44)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-trifluoromethyl-1,1′-biphenyl-4-yl) acetic acid ( Exemplified compound number: 2-196)
(44-1)
To a solution of 4-bromo-1-methyl-2- (trifluoromethyl) benzene (2.0 g, 8.4 mmol) in carbon tetrachloride (20 ml), N-bromosuccinimide (1.49 g, 6.63 mmol), and 2,2′-Azobis (isobutyronitrile) (20 mg) was added, and the mixture was heated to reflux for 5 hours. The reaction solution is returned to room temperature, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (elution solvent: n-hexane) to give crude 4-bromo-1-bromomethyl-2- (Trifluoromethyl) benzene was obtained. To the obtained crude 4-bromo-1-bromomethyl-2- (trifluoromethyl) benzene in ethanol-water (3: 1, 12 ml) mixed solution was added potassium cyanide (365 mg, 5.6 mmol) at 70 ° C. Stir for 3 hours. The reaction mixture was poured into water and 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 10 / 1-5 / 1) to obtain solid [4-bromo- 2- (Trifluoromethyl) phenyl] acetonitrile (1.14 g, overall yield 52%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.80 (1H, d, J = 2.0 Hz), 7.65 (1H, dd, J = 8.0, 2.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 3.78 (2H, s), 3.70 (3H, s).
(44-2)
In the same manner as in Example (24-2) and Example (17-4), methyl [4-chloro-3- (trifluoromethyl) phenyl] acetate obtained in Example (44-1) ( 51 mg, 0.20 mmol) and tert-butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) obtained in Example (22-4) The title compound (24 mg, total yield of 2 steps 44%) was obtained as a pale yellow powder from -yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (100 mg, 0.20 mmol).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.50 (1H, s), 11.44 (1H, s), 7.90-7.86 (2H, m), 7.82 (1H, d, J = 8.4 Hz), 7.73 (2H, d, J = 7.2 Hz), 7.56 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.11 (2H, d, J = 7.2 Hz), 5.38 (2H , s), 3.81 (2H, s), 1.57 (9H, s).

(Example 45)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-formyl-1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 2-197)
(45-1)
In the same manner as in Example (1-1), Example (22-5), and Example (26-3), methyl 4-hydroxyphenylacetate (15.6 g, 110 mmol) was converted to methyl (2-formyl). -4′-hydroxy-1,1′-biphenyl-4-yl) acetate (6.32 g, total yield of 3 steps 21%) was obtained.
In this step, the reaction time in the reaction corresponding to Example (1-1) was 12 hours. In the reaction corresponding to Example (26-3), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol was used as the borate reagent.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 9.96 (1H, s), 7.88 (1H, s), 7.55 (1H, app d, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz) , 7.20 (2H, d, J = 8.3 Hz), 6.92 (2H, d, J = 8.3 Hz), 3.75-3.71 (5H, m).
(45-2)
In the same manner as in Example (2-3), tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) obtained in Example (28-5) was used. ) Benzoate (3.60 g, 8.56 mmol) and methyl (2-formyl-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (2) obtained in Example (45-1) .10 g, 7.78 mmol) from tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2′-formyl-4 ′-[(methoxycarbonyl) methyl] -1,1′- Biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (3.06 g, 61% yield) was obtained.
In this step, acetone was used as a reaction solvent instead of N, N-dimethylformamide.
¹ H-NMR (400MHz, CDCl ₃ ): δ 9.93 (1H, s), 7.87 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.01 (2H, d, J = 8.2 Hz), 5.27 ( 2H, s), 3.75-3.70 (5H, m), 1.58 (9H, s), 1.54 (9H, s).
(45-3)
Tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6- obtained in Example (45-2) in the same manner as in Example (33-5) and Example (17-4) [({2′-formyl-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (88 mg, 0.14 mmol) From the above, the title compound (28 mg, 38% yield over 2 steps) was obtained as a white powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 9.94 (1H, s), 7.89 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.2 Hz), 7.55 (1H, dd, J = 7.8, 2.0 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.76 (2H, s), 1.65 (9H, s).
ESI (ES-) (m / z): 529 ([MH] ⁺ ).

(Example 46)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (hydroxymethyl) -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 2-198)
In the same manner as in Example (6-6), Example (33-5), and Example (17-4), tert-butyl 2-[(tert- Butoxycarbonyl) oxy] -6-[({2′-formyl-4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) From the benzoate (200 mg, 0.371 mmol), the title compound (62 mg, total yield of 3 steps 31%) was obtained as a white powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.68 (1H, d, J = 8.2 Hz), 7.44 (1H, s), 7.30-7.18 (5H, m), 6.93 (2H , d, J = 8.2 Hz), 5.35 (2H, s), 4.59 (2H, s), 3.70 (2H, s), 1.64 (9H, s).
ESI (ES-) (m / z): 531 ([MH] ⁺ ).

(Example 47)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyano-1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 2-199)
(47-1)
Tert-Butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2′-formyl-4 ′-[(methoxycarbonyl) methyl] -1,1 obtained in Example (45-2) '-Biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (198 mg, 0.307 mmol) in ethanol solution (4 ml) was added pyridine (49 μl, 0.62 mmol) and hydroxylamine hydrochloride ( 42 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, 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 subjected to silica gel preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give crude tert-butyl 2-[( tert-butoxycarbonyl) oxy] -6-[({2 '-[(hydroxyimino) methyl] -4'-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (Trifluoromethyl) benzoate (170 mg) was obtained.
Crude tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2 '-[(hydroxyimino) methyl] -4'-[(methoxycarbonyl) methyl] -1,1 '-Biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (170 mg) in dichloromethane (4 ml), triethylamine (71 μl, 0.51 mmol), and methanesulfonyl chloride (23 μl,. 31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Triethylamine (71 μl, 0.51 mmol) was added to an ethanol solution (4 ml) of the obtained residue, and the mixture was heated to reflux for 14 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give crude tert-butyl 2-[( tert-butoxycarbonyl) oxy] -6-[({2'-cyano-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoro Methyl) benzoate (125 mg) was obtained.
The resulting crude tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2'-cyano-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4- Pyrrolidine (33 μl, 0.39 mmol) was added to a 1,4-dioxane solution (4 ml) of (yl} oxy) methyl] -3- (trifluoromethyl) benzoate (125 mg), and the mixture was stirred at 50 ° C. for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer chromatography on silica gel (developing solvent: n-hexane / ethyl acetate = 5/1) to give tert-butyl 6-[({2 '-Cyano-4'-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (100 mg, 60%). Obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.30 (1H, s), 7.71 (1H, d, J = 8.6 Hz), 7.67 (1H, d, J = 1.8 Hz), 7.55 (1H, dd, J = 8.6, 1.8 Hz), 7.51 (2H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6 Hz), 5.40 (2H, s), 3.74 (3H, s), 3.70 (2H, s), 1.65 (9H, s).

(47-2)
In the same manner as in Example (17-4), tert-butyl 6-[({2′-cyano-4 ′-[(methoxycarbonyl) methyl] -1,1 obtained in Example (47-1) was used. White amorphous title compound (80 mg, 82%) was obtained from '-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (100 mg, 0.184 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.29 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.68 (1H, d, J = 1.6 Hz), 7.55 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (2H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 7.02 (2H, d, J = 8.6 Hz), 5.40 (2H, s), 3.74 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 528 ([M + H] ⁺ ).

(Example 48)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2′-methyl-1,1′-biphenyl-4-yl) acetic acid (illustrated Compound number: 2-53)
In the same manner as in Example (6-7), Example (6-8), Example (6-9), and Example (7), it was obtained in Example (6-6) [2- (Dimethoxymethyl) -3- (methoxymethoxy) -4- (trifluoromethyl) phenyl] methanol (985 mg, 3.18 mmol) and methyl (4′-hydroxy-2′-methyl-1,1′-biphenyl) From -4-yl) acetate (626 mg, 2.44 mmol), the title compound (198 mg, total yield of 4 steps 16%) was obtained as colorless crystals.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.27-7.24 (3H, m ), 7.13 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 2.7 Hz), 6.98 (1H, dd, J = 8.2, 2.7 Hz), 5.35 (2H, s), 3.70 (2H , s), 2.26 (3H, s), 1.66 (9H, s).
MS (FAB) (m / z): 516 ([M] ⁺ ).

(Example 49)
tert-butyl 6-[({4 ′-[2- (dimethylamino) -2-oxoethyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl ) Benzoate (Exemplary compound number: 1-61)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl obtained in Example (7) To a solution of acetic acid (168 mg, 0.334 mmol) in acetonitrile (10 ml), dimethylamine hydrochloride (41 mg, 0.502 mmol), N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (96 mg) at room temperature. , 0.50 mmol), hydroxybenzotriazole (77 mg, 0.50 mmol), and triethylamine (0.10 ml) were added, and after stirring for 10 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate under reduced pressure. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3 / 1-methylene chloride / methanol = 15/1) to give the title compound as pale yellow crystals ( 303 mg, 34% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 7.68 (1H, d, J = 8.6 Hz), 7.51-7.47 (4H, m), 7.29-7.24 (3H, m), 6.96 (2H, d, J = 8.6 Hz), 5.35 (2H, s), 3.74 (2H, s), 3.03 (3H, s), 2.98 (3H, s), 1.64 (9H, s).
MS (530) (m / z): 530 ([M + H] ⁺ ).

(Example 50)
tert-Butyl 2-hydroxy-6-[({4 '-[2- (methylamino) -2-oxoethyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3-trifluoromethylbenzoate (Exemplary compound number: 1-60)
In the same manner as in Example (49), (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy}-obtained in Example (7) was obtained. From 1,1′-biphenyl-4-ylacetic acid (216 mg, 0.431 mmol) and methylamine hydrochloride (50 mg, 0.74 mmol), the title compound (160 mg, yield 72%) as colorless crystals was obtained. .
1H-NMR (400MHz, CDCl3): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.56-7.53 (4H, m), 7.32-7.27 (3H, m), 7.00 (2H , d, J = 7.0 Hz), 5.38 (2H, s), 3.61 (2H, s), 2.79 (3H, d, J = 5.0 Hz), 1.65 (9H, s).
MS (516) (m / z): 516 ([M + H] ⁺ ).

(Example 51)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4-methoxybenzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-85)
(51-1)
In the same manner as in Example (40-2), tert-butyl 6- (bromomethyl) -3-methoxy-2- (methoxymethyl) benzoate (1.20 g, 2.33 mmol) and Example (6-2) ) From methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate (619 mg, 2.56 mmol) obtained in tert-butyl 3-methoxy-2- (methoxymethoxy) -6- [ ({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] benzoate (306 mg, 25% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.55-7.46 (4H, m), 7.32 (2H, d, J = 8.2 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.00 (2H, d , J = 8.6 Hz), 6.92 (1H, d, J = 8.4 Hz), 5.17 (2H, s), 5.06 (2H, s), 3.85 (3H, s), 3.71 (3H, s), 3.66 (2H , s), 3.59 (3H, s), 1.54 (9H, s).
(51-2)
Tert-Butyl 3-methoxy-2- (methoxymethoxy) -6-[({4 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-] obtained in Example (51-1) (Il} oxy) methyl] benzoate (180 mg, 0.344 mmol) in dichloromethane (4.0 ml) was added with trimethylsilyl bromide (55 μl, 0.414 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into an aqueous sodium bicarbonate solution 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 preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 2/1), and tert-butyl 2-hydroxy-3. -Methoxy-6-[({4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] benzoate (146 mg, 89% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.61 (1H, s), 7.55-7.43 (5H, m), 7.35-7.30 (2H, m), 7.06-6.95 (3H, m), 5.27 (2H, s), 3.91 (3H, s), 3.71 (3H, s), 3.66 (2H, s), 1.57 (9H, s).
(51-3)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-3-methoxy-6-[({4 ′-[(methoxycarbonyl) methyl]-) obtained in Example (51-2) was used. 1,1′-biphenyl-4-yl} oxy) methyl] benzoate (146 mg, 0.305 mmol) gave the colorless amorphous title compound (110 mg, 78% yield).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.56-7.46 (4H, m), 7.36-7.31 (2H, m), 7.11-6.91 (4H, m), 5.27 (2H, s), 3.91 (3H, s), 3.69 (2H, s), 1.57 (9H, s).
ESI (ES-) (m / z): 463 ([MH] ⁺ ).

(Example 52)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -6-fluoro-1,1′-biphenyl-3-yl) acetic acid (Exemplary Compound Number: 2-41)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5) obtained in Example (22-4) in the same manner as in Example (6-1) and Example (7). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (424 mg, 0.858 mmol) and methyl (3-bromo-4-fluorophenyl) From the acetate (200 mg, 0.858 mmol), the title compound (220 mg, total yield of 2 steps 38%) was obtained as a white powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.33 (1H, d, J = 7.4 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.23-7.19 (1H, m), 7.11 (1H, dd, J = 10.2, 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz) ), 5.38 (2H, s), 3.68 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 520 ([M] ⁺ ).

(Example 53)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) (hydroxy) acetic acid (Exemplary Compound No. : 1-115)
In the same manner as in Example (31) and Example (17-4), methyl (4-bromophenyl) (hydroxy) acetate (100 mg, 0.41 mmol) and obtained in Example (22-4) Tert-butyl 2-hydroxy-6-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl ) The title compound (14 mg, 8% yield) as an off-white powder was obtained from benzoate (170 mg, 0.34 mmol).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.57 (1H, br), 11.40 (1H, br, s), 7.79 (1H, d, J = 8.6 Hz), 7.60 (2H, d, J = 9.4 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.6 Hz), 7.05 (2H, d, J = 9.4 Hz) ), 5.85 (1H, br), 5.35 (2H, s), 5.04 (1H, s), 1.56 (9H, s).
MS (FAB +) (m / z): 518 (M ^{+ ・} ).

(Example 54)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) (ethoxy) acetic acid (Exemplary Compound No. : 1-116)
In the same manner as in Example (31) and Example (17-4), methyl (4-bromophenyl) (ethoxy) acetate (110 mg, 0.4 mmol) and obtained in Example (22-4) Tert-butyl 2-hydroxy-6-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl ) The title compound (35 mg, 19% yield) as an off-white powder was obtained from benzoate (170 mg, 0.34 mmol).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.76 (1H, br, s), 11.41 (1H, br, s), 7.79 (1H, d, J = 8.6 Hz), 7.62-7.58 (4H, m), 7.42 (2H, d, J = 8.6 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.05 (2H, d, J = 9.4 Hz), 5.36 (2H, s), 4.87 (1H, s), 3.61-3.52 (1H, m), 3.46-3.38 (1H, m), 1.56 (9H, s), 1.16 (3H, t, J = 7.0 Hz).
MS (FAB +) (m / z): 546 (M ^{+ ・} ).

(Example 55)
3- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-3-yl) propanoic acid (Exemplary Compound No. : 2-200)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5) obtained in Example (22-4) in the same manner as in Example (6-1) and Example (7). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (300 mg, 0.607 mmol) and methyl 3- (3-bromophenyl) propanoate ( 148 mg, 0.607 mmol) gave the title compound as a white powder (111 mg, 35% yield over 2 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.53 (2H, d, J = 9.0 Hz), 7.41 (1H, d, J = 7.4 Hz), 7.40 (1H, s), 7.35 (1H, t, J = 7.4 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.17 (1H, d, J = 7.4 Hz), 6.99 ( 2H, d, J = 9.0 Hz), 5.38 (2H, s), 3.03 (2H, t, J = 7.8 Hz), 2.74 (2H, t, J = 7.8 Hz), 1.65 (9H, s).
MS (FAB) (m / z): 516 ([M] ⁺ ).

(Example 56)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -5-fluoro-1,1′-biphenyl-3-yl) acetic acid (exemplary compound Number: 2-38)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5) obtained in Example (22-4) in the same manner as in Example (24-2) and Example (7). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (400 mg, 0.809 mmol) and methyl (3-chloro-5-fluorophenyl) From the acetate (164 mg, 0.809 mmol), the title compound as a white powder (59 mg, 14% yield over 2 steps) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.28-7.20 (2H, m ), 7.18 (1H, ddd, J = 10.2, 2.0, 1.6 Hz), 7.00-6.96 (1H, m), 6.99 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.71 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 520 ([M] ⁺ ).

(Example 57)
tert-Butyl 6-{[(4 '-{[(dimethylamino) sulfonyl] methyl} -1,1'-biphenyl-4-yl) oxy] methyl} -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary compound number: 1-120)
In the same manner as in Example (29-1) and Example (29-2), the title compound (6 mg) was obtained as a white powder from 4-bromobenzyl bromide.
In this step, dimethylamine was used in place of the 40% -methylamine aqueous solution in the step corresponding to Example (29-1).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.00 (2H, d, J = 8.6 Hz), 5.39 (2H, s), 4.25 ( 2H, s), 2.78 (6H, s), 1.65 (9H, s).
MS (FAB) (m / z): 565 ([M] ⁺ ).

(Example 58)
tert-Butyl 2-hydroxy-6-{[(3 '-{[(methylsulfonyl) amino] methyl} -1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (Exemplary compound number: 2-201)
In the same manner as in Example (31), N- (3-bromobenzyl) methanesulfonamide (119 mg, 0.45 mmol) and tert-butyl 2-hydroxy-6 obtained in Example (22-4) were used. From {[4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (250 mg, 0.51 mmol) The title compound (49 mg, 20% yield) was obtained as a light brown powder.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 11.31 (1H, br s), 7.79 (1H, d, J = 7.8 Hz), 7.62-7.49 (5H, m), 7.39 (1H, t, J = 7.8 Hz), 7.32-7.25 (2H, m), 7.06 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 4.20 (2H, d, J = 6.3 Hz), 3.31 (3H, s ), 1.56 (9H, s).
MS (FAB +) (m / z): 551 (M ^{+ ・} ).

(Example 59)
tert-butyl 6-[({4 '-[2- (ethylamino) 2-oxoethyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl) Benzoate (Exemplary compound number: 1-121)
In the same manner as in Example (49), (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy}-obtained in Example (7) was obtained. From 1,1′-biphenyl-4-ylacetic acid (187 mg, 0.374 mmol) and ethylamine hydrochloride (61 mg, 0.75 mmol), the title compound (129 mg, 65% yield) was obtained as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.68 (1H, d, J = 7.8 Hz), 7.54-7.50 (4H, m), 7.29 (2H, d, J = 8.2 Hz ), 7.25 (1H, d, J = 7.8Hz), 6.97 (2H, d, J = 8.2 Hz), 5.37 (2H, s), 3.58 (2H, s), 3.30-3.22 (2H, m), 1.65 (9H, s), 1.08 (3H, t, J = 7.4 Hz).
MS (530) (m / z): 530 ([M + H] ⁺ ).

(Example 60)
tert-butyl 2-hydroxy-6-[({4 ′-[(methylsulfonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (Exemplary Compound Number: 1-123)
In the same manner as in Experimental Example (24-3), 1-chloro-4-[(methylsulfonyl) methyl] benzene (204 mg, 1.0 mmol) and tert-butyl obtained in Example (22-4) 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (494 mg, 1. 0 mmol) gave the title compound (62 mg, 12% yield).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 11.41 (1H, s), 7.79 (1H, d, J = 8.2 Hz), 7.65-7.63 (4H, m), 7.44 (2H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.06 (2H, d, J = 8.2 Hz), 5.36 (2H, s), 4.50 (2H, s), 2.92 (3H, s), 2.08 (9H, s).
MS (EI) (m / z): 535 ([MH] ^- ).

(Example 61)
[4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3- (methylsulfonyl) -1,1′-biphenyl-4-yl] acetic acid (Exemplary compound number: 2-203)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5) obtained in Example (22-4) in the same manner as in Example (6-1) and Example (7). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (150 mg, 0.30 mmol) and methyl [4-bromo-2- (methylsulfonyl) ) Phenyl] acetate (93 mg, 0.30 mmol) gave the title compound (93 mg, 53% yield over 2 steps) as yellow crystals.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 8.25 (1H, d, J = 2.0 Hz), 7.79 (1H, dd, J = 7.8, 2.0 Hz), 7.72 (1H, d , J = 8.2 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.46 (1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.03 (2H, d, J = 8.6 Hz), 5.39 (2H, s), 4.27 (2H, s), 3.17 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z ): 580 ([M] +).

(Example 62)
tert-Butyl 2-hydroxy-6-[({3 '-[methyl (methylsulfonyl) amino] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (illustrated Compound number: 2-204)
N- (3-iodophenyl) -N-methylmethanesulfonamide (310 mg, 1 mmol and tert-butyl 2-hydroxy-6-{[4- (4,4) obtained in Example (22-4)] , 5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (494 mg, 1 mmol) in 1,4-dioxane (5 ml) [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (82 mg, 0.1 mmol), 1,1′-bis (diphenylphosphino) ferrocene (166 mg, 0.3 mmol) And cesium carbonate (460 mg, 3 mmol) was added, and the mixture was stirred with heating at 60 ° C. for 4 hours, and then allowed to stand overnight at room temperature. N, N-dimethylformamide (5 ml) was added to the mixture, and the mixture was heated and stirred at 70 ° C. for 9 hours and allowed to stand at room temperature for 1 week. The extract was washed successively with water and saturated brine (twice), dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: n-hexane). After purification with / ethyl acetate = 3/1), recrystallization was performed using tetrahydrofuran and diisopropyl ether to obtain the title compound (115 mg, yield 21%) as off-white crystals.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 11.43 (1H, br s), 7.81 (1H, d, J = 7.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.57 (1H, d, J = 7.8 Hz), 7.46 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.30 (1H, d, J = 7.8 Hz) , 7.09 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 3.29 (3H, s), 2.97 (3H, s), 1.57 (9H, s).
MS (FAB +) (m / z): 551 (M ^{+ ・} ).

(Example 63)
6- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) nicotinic acid (exemplary compound number: 2-206)
In the same manner as in Example (8-1), Example (40-2), Example (33-5), and Example (17-4), methyl 6-chloronicotinate (177 mg, 1.02 mmol) ) To give the title compound as a colorless powder (220 mg, 44% yield over 4 steps).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 13.25 (1H, s), 11.41 (1H, s), 9.07 (1H, dd, J = 2.0, 0.8 Hz), 8.25 (1H, dd, J = 8.6, 2.0 Hz), 8.14 (2H, d, J = 9.0 Hz), 8.03 (1H, dd, J = 8.6, 0.8 Hz), 7.80 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.12 (2H, d, J = 9.0 Hz), 5.39 (2H, s), 1.55 (9H.s).
ESI (ES-) (m / z): 488 ([MH] ⁺ ).

(Example 64)
[5- (4-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -3-pyridinyl] acetic acid (Exemplary compound number: 2-95)
In the same manner as in Example (8-1), Example (40-2), Example (33-5), and Example (17-4), methyl (5-bromo-3-pyridinyl) acetate ( 397 mg, 1.72 mmol) gave the title compound as a colorless powder (86 mg, total yield of 4 steps 10%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.48 (1H, s), 11.41 (1H, s), 8.71 (1H, d, J = 2.0 Hz), 8.38 (1H, d, J = 2.0 Hz ), 7.91 (1H, t, J = 2.0 Hz), 7.80 (1H, d, J = 8.2 Hz), 7.67 (2H, d, J = 9.0 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.10 (2H, d, J = 9.0 Hz), 5.37 (2H, s), 3.69 (2H, s), 1.56 (9H, s).
ESI (ES-) (m / z): 502 ([MH] ⁺ ).

(Example 65)
3- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) propanoic acid (Exemplary Compound No. : 1-67)
In the same manner as in Example (31) and Example (17-4), methyl 3- (4-bromophenyl) propionate (131 mg, 0.51 mmol) and obtained in Example (22-4) Tert-butyl 2-hydroxy-6-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) The title compound (26 mg, yield 10%) as a colorless powder was obtained from benzoate (250 mg, 0.51 mmol).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.09 (1H, br), 11.40 (1H, br), 7.79 (1H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.6 Hz) ), 7.50 (2H, d, J = 8.6 Hz), 7.28-7.24 (3H, m), 7.03 (2H, d, J = 8.6 Hz), 5.35 (2H, s), 2.83 (2H, t, J = 7.8 Hz), 2.55 (2H, t, J = 7.8 Hz), 1.56 (9H, s).
MS (FAB +) (m / z): 516 (M ^{+ ・} ).

Example 66
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-propyl-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-208)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl (4′-hydroxy-2-propyl-1,1′-biphenyl-4-) Yl) acetate (140 mg, 0.493 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoro) obtained in Example (28-5) The title compound (128 mg, 48% yield) as a yellow amorphous was obtained from (methyl) benzoate (228 mg, 0.542 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.69 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.24-7.10 (5H, m), 6.93 (2H, d , J = 8.6 Hz), 5.36 (2H, s), 3.66 (2H, s), 2.57-2.50 (2H, m), 1.64 (9H, s), 1.53-1.43 (2H, m), 0.81 (3H, t, J = 7.2 Hz).
MS (ESI) (m / z): 543 ([MH] ⁺ ).

(Example 67)
tert-Butyl 6-{[(3′-acetyl-1,1′-biphenyl-4-yl) oxy] methyl} -2-hydroxy-3- (trifluoromethyl) benzoate (Exemplary Compound Number: 2-209)
In the same manner as in Example (8-1), Example (40-2), and Example (33-5), 1- (3-bromophenyl) ethanone (231 mg, 1.16 mmol) was used as a colorless powder. Of the title compound (205 mg, total yield of 3 steps 36%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 8.14-8.12 (1H, m), 7.89-7.85 (1H, m), 7.75-7.71 (1H, m), 7.69 (1H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.50 1H, dd, J = 7.8, 7.4 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.00 (2H, d , J = 8.6 Hz), 5.37 (2H, s), 2.65 (3H, s), 1.65 (9H, s).
ESI (ES-) (m / z): 485 ([MH] ⁺ ).

(Example 68)
tert-butyl 6-[({3'-chloro-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl ) Benzoate (Exemplified compound number: 2-211)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1 ′ obtained in Example (18-4) -Biphenyl-4-yl) acetic acid (60 mg, 0.11 mmol) in a mixed solution of benzene-methanol (4: 1, 2.5 ml), trimethylsilyldiazomethane-0.6 M hexane solution (0.20 ml, 0.12 mmol) was added and stirred for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane / methylene chloride / ethyl acetate = 9/1/1) to give the title compound (45 mg, Yield 73%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.71 (1H, d, J = 8.1 Hz), 7.58 (1H, d, J = 1.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.1, 1.8 Hz), 7.33 (1H, d, J = 8.1 Hz), 7.27 (1H, d, J = 8.1 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 3.81 (2H, s), 3.74 (3H, s), 1.65 (9H, s).
ESI (ES-) (m / z): 549 ([MH] ⁺ ).

(Example 69)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-propionyl-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-212)
Tert-butyl 6- (bromomethyl)-obtained in Example (28-5) in the same manner as in Example (40-2), Example (33-5) and Example (17-4) 2-[(tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (289 mg, 0.688 mmol) and methyl (4′-hydroxy-2-propionyl-1,1′-biphenyl-4-) Yl) acetate (174 mg, 0.626 mmol) gave the colorless amorphous title compound (194 mg, 53% yield).
^{1 H-NMR (400MHz, CDCl} 3): δ 7.68 (2H, d, J = 8.2 Hz), 7.35-7.30 (2H, m), 7.28-7.20 (3H, m), 6.94 (2H, d, J = 8.2 Hz), 5.34 (2H, s), 3.69 (2H, s), 2.27 (2H, q, J = 7.3 Hz), 1.63 (9H, s) 0.90 (3H, t, J = 7.3 Hz).
ESI (ES-) (m / z): 557 ([MH] ⁺ ).

(Example 70)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acrylic acid (Exemplary Compound No. : 1-124)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-[({4 ′-[1- (methoxycarbonyl) vinyl] -1, obtained in Example (41-1) 1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (29 mg, 0.055 mmol) gave the title compound as a colorless solid (7.3 mg, 25% yield). It was.
In this step, 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.4 Hz), 7.58-7.50 (6H, m), 7.28 (1H, d, J = 8.4 Hz) ), 6.99 (2H, d, J = 9.2 Hz), 6.53 (1H, s), 6.08 (1H, s), 5.39 (2H, s), 1.65 (9H, s)
ESI (ES-) (m / z): 513 ([MH] +).

(Example 71)
[6- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -5-methyl-3-pyridinyl] acetic acid (Exemplary Compound No .: 2 -85)
(71-1)
In the same manner as in Example (76-1), Example (76-2), Example (6-6), Example (26-5), and Example (11-1), 2,5- [6- (4-Methoxyphenyl) -5-methyl-3-pyridinyl] acetonitrile (320 mg, total yield of 5 steps 13%) was obtained from dibromo-3-methylpyridine (2.64 g, 10.5 mmol). .
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.44 (1H, d, J = 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 7.48 (2H, d, J = 8.6 Hz), 6.99 ( 2H, d, J = 8.6 Hz), 3.87 (3H, s), 3.77 (2H, s), 2.41 (3H, s).

(71-2)
[6- (4-Methoxyphenyl) -5-methyl-3-pyridinyl] acetonitrile (314 mg, 1.32 mmol) obtained in Example (71-1) was added to 47% hydrobromic acid (5 ml), Stir at 120 ° C. for 8 hours. The solvent was distilled off under reduced pressure and azeotroped with methanol (twice). It was again dissolved in methanol (5 ml) and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 1-1 / 4), and methyl [6- (4- Hydroxyphenyl) -5-methyl-3-pyridinyl] acetate (240 mg, 71% yield) was obtained.
^{1 H-NMR (400MHz, CDCl} 3): δ 8.97 (1H, br), 8.38 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 2.0 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.66 (2H, d, J = 8.6 Hz), 3.74 (3H, s), 3.64 (2H, s), 2.34 (3H, s).
(71-3)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), the methyl [6- (4-hydroxyphenyl) obtained in Example (71-2) was obtained. ) -5-Methyl-3-pyridinyl] acetate (330 mg, 1.28 mmol) gave the title compound as a colorless powder (240 mg, 37% yield over 3 steps).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.50 (1H, s), 11.45 (1H, s), 8.33 (1H, d, J = 2.0 Hz), 7.83 (1H, d, J = 8.2 Hz ), 7.58 (1H, d, J = 2.0 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.07 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.68 (2H, s), 2.32 (3H, s), 1.56 (9H, s).
ESI (ES-) (m / z): 516 ([MH] ⁺ ).

(Example 72)
(4 ′-{[3-Hydroxy-2- (isopropoxycarbonyl) -4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary compound number: 1-5 )
(72-1)
2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoic acid ( 150 mg, 0.29 mmol), 2-propanol (26 μl, 0.34 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in tetrahydrofuran (3 ml) at room temperature with diethyl azodicarboxylate (108 μl, 0.68 mmol) was added. After stirring at room temperature for 1 hour, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 4/1), and isopropyl 2- (allyloxy) -6-{[(4 ′-{[( Allyloxy) carbonyl] methyl} -1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (141 mg, 87% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.67 (1H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.40 ( 1H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 6.99 (2H, d, J = 8.2 Hz), 6.10-6.00 (1H, m), 5.97-5.87 (1H, m ), 5.32-5.22 (5H, m), 5.16 (2H, s), 4.62 (2H, d, J = 5.9 Hz), 4.57 (2H, d, J = 5.9 Hz), 3.68 (2H, s), 1.34 (6H, d, J = 6.3 Hz).
(72-2)
In the same manner as in Example (13-5), isopropyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -1, obtained in Example (72-1) 1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (141 mg, 0.248 mmol) gave the title compound (111 mg, 92% yield) as yellow crystals.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.74 (1H, d, J = 8.2 Hz), 7.53 (4H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 6.99 (2H, d, J = 8.6 Hz), 5.40 (2H, s), 5.39 (1H, sp, J = 6.3 Hz), 3.71 ( 2H, s), 1.41 (6H, d, J = 6.3 Hz).
MS (FAB) (m / z): 488 ([M] ⁺ ).

(Example 73)
[4 ′-({3-hydroxy-4- (trifluoromethyl) -2-[(2,2,2-trifluoro-1-methylethoxy) carbonyl] benzyl} oxy) -1,1′-biphenyl- 4-yl] acetic acid (Exemplified compound number: 1-126)
In the same manner as in Example (72-1) and Example (13-5), 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl] -1,1 ′ -Biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoic acid (150 mg, 0.29 mmol) and 1,1,1-trifluoro-2-propanol (31 μl, 0.34 mmol) From this, the title compound (68 mg, total yield of 43% for 2 steps) was obtained as yellow crystals.
¹ H-NMR (400MHz, CDCl ₃ ): δ 11.66 (1H, s), 7.82 (1H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 7.8 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.36 (2H, d, J = 7.8 Hz), 7.01 (2H, d, J = 8.6 Hz), 5.65 (1H, qq, J = 6.6 , 6.3 Hz), 5.44 (1H, d, J = 15.3 Hz), 5.32 (1H, d, J = 15.3 Hz), 3.71 (2H, s), 1.58 (6H, d, J = 6.6 Hz).
MS (FAB) (m / z): 542 ([M] ⁺ ).

(Example 74)
6- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -2,3-dihydro-1-benzofuran-3-carboxylic acid (illustrated Compound number: 2-213)
(74-1)
1- (4-Chloro-2-methoxyphenyl) -2-methoxy-2-oxoethanediazonium methyl (4-chloro-2-methoxyphenyl) acetate (410 mg, 1.91 mmol) and 1,8-diazabicyclo [ 5.4.0] -7-Undecene (871 mg, 5.73 mmol) in acetonitrile (6 ml) was added 4- (acetylamino) benzenesulfonyl azide (580 mg, 2.4 mmol) in acetonitrile (3 ml) at room temperature. Dropped and stirred for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was washed with saturated brine and dried over anhydrous magnesium 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 = 2/1) to give the title compound as a yellow solid (400 mg, yield 87). %).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.49 (1H, d, J = 7.8 Hz), 7.00 (1H, dd, J = 7.8 Hz, 2.0 Hz), 6.78 (1H, d, J = 2.0 Hz) , 3.83 (3H, s), 3.85 (3H, s).
(74-2)
Methyl 6-chloro-2,3-dihydro-1-benzofuran-3-carboxylate 1- (4-Chloro-2-methoxyphenyl) -2-methoxy-2-oxo obtained in Example (74-1) Nitrogen gas was blown into a toluene (5 ml) solution of ethanediazonium (200 mg, 0.83 mmol) at room temperature for 5 minutes. The reaction solution was heated to 80 ° C. while blowing nitrogen gas, tetrakis (triphenylacetate) dirhodium (II) (1 mg) was added, and the mixture was stirred for 15 minutes. The residue obtained by cooling to room temperature and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1) to give the title compound as a pale yellow oil. (127 mg, 72% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.27 (1H, d, J = 7.8 Hz), 6.87 (1H, dd, J = 7.8 Hz, 2.0 Hz), 6.82 (1H, d, J = 2.0 Hz) , 4.97 (1H, dd, J = 9.8 Hz, 5.8 Hz), 4.70 (1H, t, J = 9.8 Hz), 4.29 (1H, dd, J = 9.8 Hz, 5.8 Hz), 3.78 (3H, s).

(74-3)
6- (4-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -2,3-dihydro-1-benzofuran-3-carboxylic acid (24-2) and methyl 6-chloro-2,3-dihydro-1-benzofuran-3-carboxylate obtained in Example (74-2) in the same manner as in Example (17-4). (125 mg, 0.59 mmol) and tert-butyl 2-hydroxy-6-{[4- (4,4,5,5-tetramethyl-1,3, obtained in Example (22-4)] 2-Dioxoborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (350 mg, 0.71 mmol) to the title compound as an off-white powder (22 mg, 8% yield) Obtained.
In this step, 1,4-dioxane was used as a reaction solvent instead of toluene in the step corresponding to Example (24-2).
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 12.89 (1H, br, s), 11.43 (1H, br, s), 7.81 (1H, d, J = 7.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 7.8 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.06-7.03 (3H, m) , 5.37 (2H, s), 4.79 (1H, dd, J = 9.8 Hz, 5.8 Hz), 4.67 (1H, t, J = 9.8 Hz), 4.38 (1H, dd, J = 9.8 Hz, 5.8 Hz), 1.57 (9H, s).
MS (FAB +) (m / z): 530 (M ^{+ ・} ).

(Example 75)
tert-Butyl 2-hydroxy-6-({4- [5- (methylsulfonyl) -3-pyridinyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (Exemplified compound number: 2-215)
(75-1)
4- [5- (Methylthio) -3-pyridinyl] phenol (200 mg, 0.92 mmol) was used as a starting material, and tert-butyl 2-[(tert-butoxy) obtained in the same manner as in Example (40-2) was used. Carbonyl) oxy] -6-({4- [5- (methylthio) -3-pyridinyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (410 mg, 0.69 mmol) was added to methylene chloride-methanol (1: 1, 10 ml). To this solution, magnesium monoperoxyphthalate hexahydrate (860 mg, 1.39 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, 5% aqueous sodium thiosulfate solution was added, and the mixture was 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 7 / 3-0 / 10), and tert-butyl 2- [ (Tert-Butoxycarbonyl) oxy] -6-({4- [5- (methylsulfonyl) -3-pyridinyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (350 mg, 61% yield over 2 steps) )
¹ H-NMR (400MHz, CDCl ₃ ): δ 9.05 (1H, d, J = 2.3 Hz), 9.04 (1H, d, J = 2.3 Hz), 8.32 (1H, t, J = 2.3 Hz), 7.71 ( 1H, d, J = 8.2 Hz), 7.58-7.53 (3H, m), 7.07 (2H, d, J = 9.0 Hz), 5.28 (2H, s), 3.15 (3H, s), 1.58 (9H, s ), 1.54 (9H, s).
ESI (ES +) (m / z): 624 ([M + H] ⁺ ).
(75-2)
In the same manner as in Example (33-5), tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-({4- [5- (methylsulfonyl) obtained in Example (75-1)] ) -3-Pyridinyl] phenoxy} methyl) -3- (trifluoromethyl) benzoate (350 mg, 0.56 mmol) gave the title compound as a colorless powder (215 mg, 73% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.21 (1H, s), 9.06-9.04 (2H, m), 8.33 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 8.2 Hz ), 7.58 (2H, d, J = 9.0 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.05 (2H, d, J = 9.0 Hz), 5.39 (2H, s), 3.15 (3H, s ), 1.65 (9H, s).
ESI (ES-) (m / z): 522 ([MH] ⁺ ).

(Example 76)
[5- (4-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -4-methyl-3-pyridinyl] acetic acid (Exemplary compound number: 2 -216)
(76-1)
3,5-dibromo-4-methylpyridine (7.46 g) synthesized according to the method described in the literature (Gu, YG and Bayburt, EK, Tetrahedron Lett., Vol. 37, 1996, p. 2565-2568.) , 29.73 mmol) and 4-methoxyphenyl boric acid (4.52 g, 29.73 mmol) in a mixed solution of N, N-dimethylacetamide-water (20: 1, 100 ml), tetrakis (triphenylphosphine) palladium ( 0) (1.03 g, 0.89 mmol) and potassium carbonate (8.22 g, 59.5 mmol) were added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was brought to room temperature, ethyl acetate was added, and insoluble matters were removed by filtration. The obtained filtrate 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 = 4/1) to give 3-bromo-5- (4-methoxyphenyl). -4-Methylpyridine (3.83 g, yield 46%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.63 (1H, s), 8.32 (1H, s), 7.22 (2H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz), 3.87 (3H, s), 2.35 (3H, s).
(76-2)
To a solution of 3-bromo-5- (4-methoxyphenyl) -4-methylpyridine (1.55 g, 5.57 mmol) obtained in Example (76-1) in tetrahydrofuran (20 ml) at -78 ° C. n-Butyllithium-1.58M n-hexane solution (3.9 ml, 6.13 mmol) was added dropwise and stirred for 5 minutes. N, N-dimethylformamide (0.87 ml, 11.2 mmol) was added dropwise at the same temperature and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was raised to room temperature, 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 / 1-2 / 3) to give 5- (4-methoxyphenyl). ) -4-methylnicotinaldehyde (0.56 g, yield 44%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.34 (1H, s), 8.88 (1H, s), 8.58 (1H, s), 7.21 (2H, d, J = 9.0 Hz), 7.00 (2H, d , J = 9.0 Hz), 3.87 (3H, s), 2.58 (3H, s).
(76-3)
5- (4-methoxyphenyl)-obtained in Example (76-2) in the same manner as in Example (6-6), Example (90-4), and Example (11-1). From 4-methylnicotinaldehyde (406 mg, 1.79 mmol), [5- (4-methoxyphenyl) -4-methyl-3-pyridinyl] acetonitrile (227 mg, total yield of 3 steps 53%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.46 (1H, s), 8.42 (1H, s), 7.20 (2H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 3.86 (3H, s), 3.73 (2H, s), 2.30 (3H, s).

(76-4)
In the same manner as in Example (71-2), from [5- (4-methoxyphenyl) -4-methyl-3-pyridinyl] acetonitrile (300 mg, 1.26 mmol) obtained in Example (76-3). , Methyl [5- (4-methoxyphenyl) -4-methyl-3-pyridinyl] acetate (0.31 g, yield 96%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.34 (2H, s), 7.94 (1H, br), 7.14 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 3.73 (5H, s), 2.24 (3H, s).
(76-5)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), the methyl [5- (4-methoxyphenyl) obtained in Example (76-4) was obtained. ) -4-Methyl-3-pyridinyl] acetate (150 mg, 0.58 mmol) gave the title compound as a colorless powder (95 mg, total yield of 3 steps 44%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.49 (1H, s), 11.42 (1H, s), 8.30 (1H, s), 8.22 (1H, s), 7.81 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.07 (2H, d, J = 8.6 Hz), 5.37 (2H, s), 3.72 (2H , s), 2.13 (3H, s), 1.56 (9H, s).
ESI (ES-) (m / z): 516 ([MH] ⁺ ).

(Example 77)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) -3-methoxypropanoic acid (Exemplary compound number: 1-127)
tert-butyl 2- (allyloxy) -6-{[(4 '-{1-[(allyloxy) carbonyl] -2- (hydroxyethyl)}-1,1'-biphenyl-4-yl) oxy] methyl} To a toluene solution (1 ml) of -3- (trifluoromethyl) benzoate (61 mg, 0.1 mmol) was added silver oxide (120 mg, 0.52 mmol) and methyl iodide (180 μl, 2.9 mmol), and at 70 ° C. Stir for 17 hours. After cooling to room temperature, the reaction solution was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1-3 / 1) to give crude tert-butyl 2- (allyloxy) -6- { [(4 ′-{1-[(allyloxy) carbonyl] -2- (methoxyethyl)}-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate was obtained. . From the obtained compound, in the same manner as in Example (11-7), the title compound as a colorless solid (39 mg, total yield of 2 steps 71%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.28-7.25 (1H, m), 6.98 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 4.02-3.95 (2H , m), 3.72-3.69 (1H, m), 3.43 (3H, s), 1.65 (9H, s).
ESI (ES-) (m / z): 545 ([MH] +).

(Example 78)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) -3 -Hydroxypropanoic acid (Exemplary compound number: 2-218)
Tert-butyl 6-[({2′-ethyl-4 ′-[) obtained in Example (26-7) in the same manner as in Example (41-1) and Example (17-4). From (methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl) benzoate (200 mg, 0.36 mmol), the title compound as a colorless solid ( 110 mg, 54% yield over 2 steps).
In this step, 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran in the hydrolysis step corresponding to Example (17-4).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.24-7.14 (5H, m ), 6.95 (2H, d, J = 8.4 Hz), 5.38 (2H, s), 4.22-4.16 (1H, m), 3.95-3.89 (2H, m), 2.60 (2H, q, J = 7.6 Hz) , 1.65 (9H, s), 1.09 (3H, t, J = 7.6 Hz).
ESI (ES-) (m / z): 559 ([MH] +).

(Example 79)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) -3 -Hydroxypropanoic acid (Exemplified compound number: 2-219)
In the same manner as in Example (41-1) and Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4'-) obtained in Example (11-6) was obtained. From {[(allyloxy) carbonyl] methyl} -3′-fluoro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (200 mg, 0.33 mmol), The title compound (107 mg, total yield 53%) was obtained as a colorless solid.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.70 (1H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.37-7.26 (4H, m ), 6.98 (2H, d, J = 8.4 Hz), 5.37 (2H, s), 4.19-4.15 (2H, m), 3.91-3.90 (1H, m), 1.64 (9H, s).
ESI (ES-) (m / z): 549 ([MH] +).

(Example 80)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-hydroxy-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-220)
Tert obtained in Example (28-5) in the same manner as in Example (40-2), Example (51-2), Example (33-5), and Example (17-4) -Butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (1.66 g, 3.93 mmol) and methyl [4′-hydroxy-2- ( Methoxymethoxy) -1,1′-biphenyl-4-yl] acetate (990 mg, 3.28 mmol) gave the colorless amorphous title compound (111 mg, 7% yield).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.71 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.32 (1H, d, J = 8.3 Hz), 7.21 ( 1H, d, J = 7.3 Hz), 7.00-6.95 (2H, m), 6.90-6.80 (2H, m), 5.39 (2H, s), 3.57 (2H, s), 1.67 (9H, s).
ESI (ES-) (m / z): 517 ([MH] ⁺ ).

(Example 81)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) propanoic acid (Exemplary Compound No. : 1-62)
In the same manner as in Example (24-2) and Example (17-4), methyl 2- (4-chlorophenyl) propanoate (119 mg, 0.6 mmol) and Example (22-4) Tert-butyl 2-hydroxy-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) ) Benzoate (250 mg, 0.5 mmol) gave the title compound as a colorless solid (65 mg, 25% yield over 2 steps).
In this step, toluene / methanol / water (25/1/1) was used as a solvent in place of toluene in the Suzuki-Miyaura coupling reaction corresponding to Example (24-2). In the hydrolysis reaction corresponding to Example (17-4), 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.28 (1H, d, J = 8.5 Hz), 6.98 (2H, d, J = 8.5 Hz), 5.38 (2H, s), 3.81 ( 1H, q, J = 7.5 Hz), 1.65 (9H, s), 1.56 (3H, d, J = 7.5 Hz).
ESI (ES-) (m / z): 515 ([MH] +).

(Example 82)
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) acetic acid (exemplified) Compound number: 2-221)
(82-1)
Methyl (3-cyclopropyl-4-{[(trifluoromethyl) sulfonyl] oxy} phenyl) acetate Example (42-1), Example (6-2), and Example (22-5) In a similar manner to methyl (3-bromo-4-methoxyphenyl) acetate (1.2 g, 4.7 mmol), the oily methyl (3-cyclopropyl-4-{[(trifluoromethyl) sulfonyl] Oxy} phenyl) acetate (288 mg, total yield of 3 steps 18%) was obtained.
In this step, a cyclopropylmagnesium bromide-0.5M tetrahydrofuran solution was used as a Grignard reagent in the step corresponding to Example (42-1).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.18 (1H, d, J = 8.4 Hz), 7.14 (1H, dd, J = 8.4, 1.6 Hz), 6.92 (1H, d, J = 1.6 Hz), 3.70 (3H, s), 3.59 (2H, s), 2.11-2.05 (1H, m), 1.09-1.04 (2H, m), 0.78-0.73 (2H, m).
(82-2)
Methyl (2-cyclopropyl-4'-hydroxy-1,1'-biphenyl-4-yl) acetate Example (26-3) and Example (6-2) From (3-cyclopropyl-4-{[(trifluoromethyl) sulfonyl] oxy} phenyl) acetate (288 mg, 0.85 mmol) obtained in (82-1), oily methyl (2-cyclopropyl -4'-hydroxy-1,1'-biphenyl-4-yl) acetate (120 mg, 49% yield over 2 steps) was obtained.
In this step, in the Suzuki-Miyaura coupling reaction corresponding to Example (26-3), instead of [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct, tetrakis ( Triphenylphosphine) palladium (0) was used as a catalyst.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.23 (2H, d, J = 8.6 Hz), 7.15 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 6.91 ( 1H, s), 6.83 (2H, d, J = 8.6 Hz), 4.78 (1H, s), 3.70 (3H, s), 3.59 (2H, s), 2.11-2.05 (1H, m), 1.09-1.04 (2H, m), 0.77-0.73 (2H, m).
(82-3)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) acetic acid Examples (2-3), tert-butyl 6- (bromomethyl) -2- obtained in Example (28-5) in the same manner as in Example (33-5) and Example (17-4) [(Tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (256 mg, 0.55 mmol) and (methyl (2-cyclopropyl-4′-) obtained in Example (82-2) From the hydroxy-1,1′-biphenyl-4-yl) acetate (120 mg, 0.43 mmol), the title compound (91 mg, total yield of 3 steps 38%) was obtained as a colorless solid.
In this step, piperidine was used instead of morpholine in the step corresponding to Example (33-5). In the step corresponding to Example (17-4), 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.14 (1H, d, J = 8.0 Hz), 6.96 (2H, d, J = 8.4 Hz), 6.85 (1H, s), 5.38 ( 2H, s), 3.66 (2H, s), 1.91-1.85 (1H, m), 1.65 (9H, s), 0.87-0.82 (2H, m), 0.71-0.67 (2H, m).

(Example 83)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-nitro-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-222)
Tert-Butyl 2-hydroxy-{[4- (4,4,5,5) obtained in Example (22-4) in the same manner as in Examples (24-2) and (17-4). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -3- (trifluoromethyl) benzoate (313 mg, 0.634 mmol) and methyl (4-bromo-2-nitrophenyl) The title compound (33 mg, 9% yield) was obtained as a pale yellow powder from acetate (173 mg, 0.634 mmol).
¹ H-NMR (400MHz, CD ₃ OD): δ 8.26 (1H, d, J = 2.0 Hz), 7.85 (1H, dd, J = 7.8, 2.0 Hz), 7.72 (1H, d, J = 8.2 Hz) , 7.64 (2H, d, J = 8.7 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.08 (2H, d, J = 8.7 Hz), 5.41 (2H, s), 4.02 (2H, s), 1.63 (9H, s).
MS (FAB) (m / z): 547 ([M] ⁺ )

(Example 84)
[4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -3-methylphenyl] acetic acid (Exemplary Compound Number: 2 -165)
(84-1)
Tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) obtained in Example (28-5) in the same manner as in Example (2-3) and Example (33-5) From oxy] -3- (trifluoromethyl) benzoate (6.22 g, 13.7 mmol) and 6-chloro-3-pyridinol (1.77 g, 13.7 mmol), tert-butyl 6-{[(6- Chloro-3-pyridinyl) oxy] methyl} -2-hydroxy-3- (trifluoromethyl) benzoate (4.61 g, total yield of 2 steps 84%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.23 (1H, s), 8.11 (1H, dd, J = 3.1, 0.8 Hz), 7.72 (1H, d, J = 8.2 Hz), 7.29-7.20 (3H m), 5.37 (2H, s), 1.64 (9H, s).
(84-2)
1-bromo-4- (bromomethyl) -2-synthesized according to the method described in the literature (Hanessian, S. et al., J. Org. Chem., 2003, Vol. 68, p. 7204-7218) (4-Bromo-3-methylphenyl) acetonitrile (2.59 g, 12.3 mmol) obtained from methylbenzene in the same manner as in Example (11-1) was dissolved in acetic acid (10 ml). To this solution was added 6N-hydrochloric acid (10 ml), and the mixture was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure and azeotroped with toluene (twice). The residue was dissolved in methanol (10 ml), concentrated sulfuric acid (2 ml) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution 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 = 9/1) to obtain methyl (4-bromo-3-methylphenyl). Acetate (2.45 g, 82% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.45 (1H, d, J = 8.2 Hz), 7.13 (1H, d, J = 2.0 Hz), 6.94 (1H, dd, J = 8.2, 2.0 Hz), 3.68 (3H, s), 3.54 (2H, s), 2.37 (3H, s).
(84-3)
Into a dioxane solution (20 ml) of methyl (4-bromo-3-methylphenyl) acetate (1.0 g, 4.11 mmol) obtained in Example (84-2), 4, 4, 4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane [other name: bis (pinacolato) diboron] (1.15 g, 4.52 mmol), [1,1 ′ -Bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (168 mg, 0.21 mmol) and potassium acetate (1.21 mg, 12.34 mmol) were added, and then at 90 ° C. for 3 hours. Stir. The reaction solution was returned to room temperature, ethyl acetate was added, and the mixture was filtered through celite. The filtrate 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 = 9/1), and methyl [3-methyl-4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate (0.9 g, yield 75%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.73 (1H, d, J = 7.8 Hz), 7.10-7.06 (2H, m), 3.67 (3H, s), 3.59 (2H, s), 2.52 (3H , s), 1.33 (12H, s).
(84-4)
In the same manner as in Example (76-1), tert-butyl 6-{[(6-chloro-3-pyridinyl) oxy] methyl} -2-hydroxy-3- obtained in Example (84-1) was obtained. (Trifluoromethyl) benzoate (240 mg, 0.59 mmol) and methyl [3-methyl-4- (4,4,5,5-tetramethyl-1,3) obtained in Example (84-3) , 2-Dioxaborolan-2-yl) phenyl] acetate (224 mg, 0.77 mmol) from tert-butyl 2-hydroxy-6-{[(6- {4-[(methoxycarbonyl) methyl] -2-methylphenyl } -3-pyridinyl) oxy] methyl} -3- (trifluoromethyl) benzoate (157 mg, 50% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 8.41 (1H, d, J = 2.4 Hz), 7.72 (1H, d, J = 8.2 Hz), 7.34-7.23 (4H, m ), 7.18-7.14 (2H, m), 5.42 (2H, s), 3.69 (3H, s), 3.63 (2H, s), 2.35 (3H, s), 1.65 (9H, s).
(84-5)
In the same manner as in Example (17-4), tert-butyl 2-hydroxy-6-{[(6- {4-[(methoxycarbonyl) methyl] -2-] obtained in Example (84-4) was used. Methylphenyl} -3-pyridinyl) oxy] methyl} -3- (trifluoromethyl) benzoate (157 mg, 0.30 mmol) gave the title compound (110 mg, 72% yield) as a colorless powder.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.34 (1H, s), 11.49 (1H, s), 8.45-8.42 (1H, m), 7.84 (1H, d, J = 8.2 Hz), 7.50 -7.48 (2H, m), 7.33 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 7.4 Hz), 7.18-7.13 (2H, m), 5.45 (2H, s), 3.57 ( 2H, s), 2.30 (3H, s), 1.56 (9H, s).
ESI (ES-) (m / z): 516 ([MH] ⁺ ).

(Example 85)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-ethyl-1,1′-biphenyl-4-yl) acetic acid (exemplary compound Number: 2-223)
(85-1)
In the same manner as in Example (11-1) and Example (26-4), the literature (Nishide, H. et al., Bull. Chem. Soc. Jpn., Vol. 69, 1996, p. 499-508) from 4-bromo-2-iodobenzyl bromide (2.01 g, 6.24 mmol) synthesized according to the method described in 499-508), methyl (4-bromo-2-iodophenyl) acetate (1.90 g, The total yield of two steps was 86%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.94 (1H, d, J = 2.4 Hz), 7.43 (1H, dd, J = 8.6, 2.4 Hz), 7.13 (1H, d, J = 8.6 Hz), 3.76 (2H, s), 3.69 (3H, s).
(85-2)
Trimethylsilylacetylene (0.319 ml, 2.25 mmol) and acetic acid were added to a tetrahydrofuran solution (6 ml) of methyl (4-bromo-2-iodophenyl) acetate (400 mg, 1.13 mmol) obtained in Example (85-1). Palladium (12 mg, 56.3 μmol), triphenylphosphine (30 mg, 0.113 mmol), n-butylamine (0.334 ml, 3.38 mmol), and copper iodide (43 mg, 0.225 mmol) were added and brought to room temperature. And stirred for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 15/1) to obtain crude methyl (4-bromo-2-trimethylsilanyl). Ethynylphenyl) acetate (434 mg) was obtained.
Potassium carbonate (368 mg, 2.67 mmol) was added to a methanol solution (9 ml) of the obtained crude product, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to obtain methyl (4-bromo-2-ethynylphenyl) acetate. (177 mg, total yield of 2 steps 62%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.65 (1H, d, J = 2.4 Hz), 7.45 (1H, dd, J = 8.6, 2.4 Hz), 7.17 (1H, d, J = 8.6 Hz), 3.80 (2H, s), 3.71 (3H, s), 3.32 (1H, s).
(85-3)
To a solution of methyl (4-bromo-2-ethynylphenyl) acetate (177 mg, 0.699 mmol) obtained in Example (85-2) in methanol (6 ml), chlorotris (triphenylphosphine) rhodium (65 mg, 69.9 μmol). ) And stirred at room temperature under a hydrogen atmosphere for 16 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 15/1) to give methyl (4-bromo-2-ethylphenyl) acetate. (138 mg, 77% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.35 (1H, d, J = 2.4 Hz), 7.29 (1H, dd, J = 8.6, 2.4 Hz), 7.07 (1H, d, J = 8.6 Hz), 3.68 (2H, s), 3.61 (3H, s), 2.62 (2H, q, J = 7.4 Hz), 1.20 (3H, t, J = 7.4 Hz).

(85-4)
In the same manner as in Example (26-3), methyl (4-bromo-2-ethylphenyl) acetate (138 mg, 0.537 mmol) synthesized in Example (85-3) and 4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (142 mg, 0.644 mmol) to methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl-4-) Yl) acetate (122 mg, 84% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.46 (2H, d, J = 8.8 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.33 (1H, dd, J = 8.8, 2.0 Hz), 7.25 (1H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.95 (1H, s), 3.71 (2H, s), 3.70 (3H, s), 2.71 (2H, q , J = 7.8 Hz), 1.25 (3H, t, J = 7.8 Hz).
(85-5)
Methyl (3-ethyl-4′-hydroxy) synthesized in Example (85-4) in the same manner as in Example (40-2), Example (33-5), and Example (17-4) -1,1′-biphenyl-4-yl) acetate (122 mg, 0.45 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxy) obtained in Example (28-5) Carbonyl) oxy] -3- (trifluoromethyl) benzoate (226 mg, 0.50 mmol) gave the title compound (107 mg, total yield of 3 steps 46%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.3 (1H, s), 7.71 (1H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.41 (1H, d, J = 1.6 Hz), 7.28 (2H, dd, J = 8.8, 1.6 Hz), 6.98 (2H, d, J = 8.6Hz), 5.38 (2H, s), 3.74 (2H, s), 2.72 (2H, q , J = 7.8 Hz), 1.65 (9H, s), 1.23 (3H, t, J = 7.8 Hz).
MS (FAB) (m / z): 569 ([M + K] ⁺ ).

(Example 86)
[4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -2-chlorophenyl] acetic acid (Exemplary compound number: 2- 168)
(4-Bromo-2-chlorophenyl) acetonitrile (205 mg, 0.89 mmol) obtained in Example (18-1) in the same manner as in Example (84-2) and Example (84-3) From methyl [2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetate.
This compound obtained and tert-butyl 6-{[(6-chloro-3-pyridinyl) oxy] methyl} -2-hydroxy-3- (trifluoromethyl) obtained in Example (84-1) ) The title compound as a colorless powder (192 mg, total yield of 4 steps 40%) was obtained from benzoate in the same manner as in Example (76-1) and Example (17-4).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.46 (1H, s), 11.45 (1H, s), 8.42 (1H, s), 8.06 (1H, s), 8.00 (1H, d, J = 9.0 Hz), 7.92 (1H, d, J = 9.0 Hz), 7.81 (1H, d, J = 8.2 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 8.2 Hz) ), 7.29 (1H, d, J = 8.2 Hz), 5.45 (2H, s), 3.74 (2H, s), 1.56 (9H, s).
ESI (ES-) (m / z): 537 ([MH] ⁺ ).

(Example 87)
(4 ′-{[2- (tert-butoxycarbonyl) -3,6-dihydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid (Exemplary Compound Number: 1-129)
(87-1)
In the same manner as in Example (28-5), from tert-butyl 2,5-bis (methoxymethoxy) -6-methyl-3- (trifluoromethyl) benzoate (225 mg, 0.70 mmol), tert-butyl 2 -(Bromomethyl) -3,6-bis (methoxymethoxy) -5- (trifluoromethyl) benzoate (164 mg, yield 51%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.38 (1H, s), 5.28 (2H, s), 5.07 (2H, s), 4.53 (2H, s), 3.57 (3H, s), 3.52 (3H , s), 1.66 (9H, s).
(87-2)
Tert-Butyl 2- (bromomethyl)-obtained in Example (87-1) in the same manner as in Example (40-2), Example (8-3), and Example (17-4) 3,6-bis (methoxymethoxy) -5- (trifluoromethyl) benzoate (154 mg, 0.34 mmol) and methyl (4′-hydroxy-1,1 ′) obtained in Example (6-2) The title compound (25 mg, total yield of 3 steps 17%) was obtained from -biphenyl-4-yl) acetate (80 mg, 0.33 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 10.98 (1H, s), 7.55-7.51 (4H, m), 7.35 (2H, d, J = 8.2 Hz), 7.33 (1H, s), 7.03 (2H , d, J = 8.2 Hz), 5.57 (2H, s), 3.70 (2H, s), (1.59 (9H, s).
MS (EI) (m / z): 517 ([MH] ^- )

(Example 88)
(4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (1-hydroxyethyl) -1,1'-biphenyl-4-yl ) Acetic acid (Exemplary compound number: 2-225)
(88-1)
In the same manner as in Example (6-6), methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (170 mg, 0) obtained in Example (40-1) was used. 599 mmol), methyl [4′-hydroxy-2- (1-hydroxyethyl) -1,1′-biphenyl-4-yl] acetate (93 mg, 54% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.53 (1H, d, J = 1.6 Hz), 7.19 (1H, dd, J = 7.8, 1.6 HZ), 7.12 (1H, d, J = 7.8 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.77 (2H, d, J = 8.6 Hz), 4.98 (1H, q, J = 6.7 Hz), 3.72 (3H, s), 3.68 (2H, s), 1.37 (3H, d, J = 6.7 Hz).
(88-2)
Tert-butyl 6- (bromomethyl)-obtained in Example (28-5) in the same manner as in Example (40-2), Example (33-5) and Example (17-4) 2-[(tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (137 mg, 0.325 mmol) and the methyl [4′-hydroxy-2-yl] obtained in Example (88-1) (1-Hydroxyethyl) -1,1′-biphenyl-4-yl] acetate (93 mg, 0.325 mmol) gave the title compound as a pale yellow oil (60 mg, 34% yield).
¹ H-NMR (500MHz, CDCl ₃ ): δ 7.71 (1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 1.5 Hz), 7.29 (1H, d, J = 7.8 Hz), 7.25- 7.20 (3H, m), 7.15 (1H, d, J = 7.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 4.99 (1H, q, J = 6.4 Hz), 3.70 (2H, s), 1.65 (9H, s), 1.39 (3H, d, J = 6.4 Hz).
ESI (ES-) (m / z): 545 ([MH] ⁺ ).

Example 89
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-[(dimethylamino) carbonyl] -1,1′-biphenyl-4- Yl) Acetic acid (Exemplary compound number: 2-226)
(89-1)
In the same manner as in Example (26-3) and Example (68), methyl {4-bromo-2-[(dimethylamino) carbonyl] phenyl} acetate (102 mg, 0.340 mmol) and 4- From (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (90 mg, 0.408 mol), methyl {3-[(dimethylamino) carbonyl] -4′-hydroxy -1,1'-biphenyl-4-yl} acetate (82 mg, total yield of 2 steps 77%) was obtained.
¹ H-NMR (500MHz, CDCl ₃ ): δ 7.49 (1H, d, J = 7.8Hz), 7.39-7.32 (3H, m), 6.87-6.79 (3H, m), 4.95 (1H, s), 3.75 (2H, s), 3.70 (3H, s), 3.15 (3H, s), 2.93 (3H, s).
(89-2)
Methyl {3-[(dimethylamino) obtained in Example (89-1) in the same manner as in Example (2-3), Example (33-5), and Example (17-4) Carbonyl] -4′-hydroxy-1,1′-biphenyl-4-yl} acetate (82 mg, 0.262 mmol) and tert-butyl 6- (bromomethyl)-obtained in Example (28-5) The title compound (100 mg, total yield 67%) was obtained from 2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (131 mg, 0.288 mmol).
In this step, methyl ethyl ketone was used as a reaction solvent in place of N, N-dimethylformamide in the step corresponding to Example (2-3).
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.2 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 7.61 (1H, dd, J = 7.8, 2.0 Hz), 7.56-7.48 (3H , m), 7.45, (1H, d, J = 2.0 Hz), 7.27-7.25 (1H, m), 7.02-6.98 (2H, m), 5.39 (2H, s), 3.66 (2H, s), 3.24 (3H, s), 3.11 (3H, s), 1.65 (9H, s).

(Example 90)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-3-yl) acetic acid (Exemplary Compound Number: 2-227)
(90-1)
Under ice cooling, n-butyllithium-1.58M n-hexane solution (36.2 ml, 57.2 mmol) was added dropwise to a tetrahydrofuran solution (114 ml) of diisopropylamine (8.02 ml, 57.2 mmol). Stir for 30 minutes. The reaction solution was cooled to −50 ° C., and a tetrahydrofuran solution (38 ml) of 3-iodo-2-methylbenzoic acid (5.00 g, 19.1 mmol) was added. After stirring for 1 hour, iodomethane (9.51 ml, 153 mmol) was added, and the temperature was raised from −50 ° C. to −20 ° C. over 1 hour. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-iodo-2-ethylbenzoic acid (5.48 g, yield 100%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.05 (1H, d, J = 7.8 Hz), 7.93 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 7.8 Hz), 3.17 ( 2H, q, J = 7.4 Hz), 1.23 (3H, t, J = 7.4 Hz).
(90-2)
To a solution of 3-iodo-2-ethylbenzoic acid (5.48 g, 19.1 mmol) obtained in Example (90-1) in N, N-dimethylformamide (38 ml), potassium carbonate (3.17 g, 22. 9 mmol) and methyl iodide (1.43 ml, 22.9 mmol) were added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. From the obtained residue and 4-methoxyphenylboronic acid (2.90 g, 19.1 mmol), methyl 2-ethyl-4′-methoxy-1,1 ′ was obtained in the same manner as in Example (14-1). -Biphenyl-3-carboxylate (4.83 g, 94% yield, total yield over 2 steps) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.72 (1H, d, J = 7.4 Hz), 7.28 (1H, d, J = 7.4 Hz), 7.21 (1H, t, J = 7.4 Hz), 7.17 ( 2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 3.90 (3H, s), 3.85 (3H, s), 2.86 (2H, q, J = 7.4 Hz), 1.00 ( (3H, t, J = 7.4 Hz).
(90-3)
Methyl 2-ethyl-4′-methoxy-1,1′-biphenyl obtained in Example (90-2) was added to a tetrahydrofuran suspension (90 ml) of lithium aluminum hydride (1.02 g, 26.8 mmol). -3-Carboxylate (4.83 g, 17.9 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and water (1 ml) was added dropwise. After stirring for 5 minutes, 3N-aqueous sodium hydroxide solution (1 ml) was added at room temperature and stirred for 5 minutes. Further water (3 ml) was added and stirred for 20 minutes. The insoluble material was filtered off using celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4 / 1-3 / 1) to give (2-ethyl-4′-methoxy-1,1′-biphenyl- 3-yl) methanol (4.39 g, 100% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.41 (1H, d, J = 7.4 Hz), 7.23 (1H, t, J = 7.4 Hz), 7.21 (2H, d, J = 8.2 Hz), 7.14 ( 1H, d, J = 7.4 Hz), 6.92 (2H, d, J = 8.2 Hz), 4.81 (2H, s), 3.86 (3H, s), 2.66 (2H, q, J = 7.4 Hz), 0.99 ( (3H, t, J = 7.4 Hz).

(90-4)
To the methylene chloride solution (18 ml) of (2-ethyl-4′-methoxy-1,1′-biphenyl-3-yl) methanol (4.39 g, 17.9 mmol) obtained in Example (90-3) Thionyl chloride (4 ml) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3 ′-(chloromethyl) -2′-ethyl-1,1′-biphenyl-4-yl methyl ether (3.32 g, yield 71%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.36 (1H, dd, J = 7.8, 1.6 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.21 (1H, t, J = 7.8 Hz), 7.15 (1H, dd, J = 7.8, 1.6 Hz), 6.94 (2H, d, J = 9.0 Hz), 3.86 (3H, s), 2.71 (2H, q, J = 7.4 Hz), 1.03 (3H, t , J = 7.4 Hz).
(90-5)
3 ′-(Chloromethyl) -2′-ethyl-1,1′-biphenyl-4-yl methyl ether (3.32 g, 12.7 mmol) obtained in Example (90-4), N, N— An aqueous solution (7 ml) of potassium cyanide (829 mg, 12.7 mmol) was added dropwise to the dimethyl sulfoxide solution (7 ml) at 80 ° C., and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and 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 = 9 / 1-3 / 1), and (2-ethyl-4 ′ -Methoxy-1,1'-biphenyl-3-yl) acetonitrile (2.65 g, yield 83%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.40 (1H, d, J = 7.4 Hz), 7.24 (1H, t, J = 7.4 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.17 ( 1H, d, J = 7.4 Hz), 6.95 (2H, d, J = 8.6 Hz), 3.86 (3H, s), 3.80 (2H, s), 2.60 (2H, q, J = 7.4 Hz), 1.00 ( (3H, t, J = 7.4 Hz).
(90-6)
(2-Ethyl-4′-methoxy-1,1′-biphenyl-3-yl) acetonitrile (2.65 g, obtained in Example (90-5) was prepared in the same manner as in Example (26-4). 10.5 mmol) gave allyl (2-ethyl-4′-hydroxy-1,1′-biphenyl-3-yl) acetate (2.57 g, yield 83%).
In the esterification reaction, allyl alcohol was used instead of methanol.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.24 (1H, dd, J = 7.8, 1.6 Hz), 7.17 (1H, t, J = 7.8 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 7.8, 1.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 5.97-5.87 (1H, m), 5.82-5.21 (2H, m), 4.86 (1H, s) , 4.64-4.61 (2H, m), 3.76 (2H, s), 2.60 (2H, q, J = 7.4 Hz), 0.95 (3H, t, J = 7.4 Hz).
(90-7)
In the same manner as in Example (40-2), Example (33-5), and Example (13-5), allyl (2-ethyl-4′-) obtained in Example (90-6) was used. From the hydroxy-1,1′-biphenyl-3-yl) acetate (200 mg, 0.675 mmol), the title compound (222 mg, total yield of 3 steps 62%) was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.70 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.24-7.20 (1H, m ), 7.21 (2H, d, J = 8.6 Hz), 7.17 (1H, t, J = 7.4 Hz), 7.09 (1H, d, J = 7.4 Hz), 6.92 (2H, d, J = 8.6 Hz), 5.36 (2H, s), 3.77 (2H, s), 2.60 (2H, q, J = 7.8 Hz), 1.64 (9H, s), 0.96 (3H, t, J = 7.8 Hz).
MS (FAB) (m / z): 530 ([M] ⁺ ).

(Example 91)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-difluoro-1,1′-biphenyl-4-yl) acetic acid ( Illustrative compound number: 2-228)
(91-1)
In the same manner as in Example (22-5), Example (26-3), Example (2-2), Example (90-5), and Example (26-4), 2,3- From difluoro-4-methylphenol (2.50 g, 17.3 mmol) to brown powdered methyl (2,3-difluoro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (654 mg, 5 steps). The total yield was 14%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.42 (2H, d, J = 8.3 Hz), 7.12 (1H, dd, J = 8.0, 6.8 Hz), 7.05 (1H, dd, J = 8.0, 6.8 Hz) ), 6.91 (2H, d, J = 8.3 Hz), 4.91 (1H, s), 3.75 (3H, s), 3.73 (2H, s).
(91-2)
Methyl (2,3-difluoro-4) obtained in Example (91-1) in the same manner as in Example (40-2), Example (33-5), and Example (17-4). '-Hydroxy-1,1'-biphenyl-4-yl) acetate (200 mg, 0.72 mmol) gave the title compound as a white powder (16 mg, total yield over 3 steps 4%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.22 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.13 (1H, dd, J = 8.0, 6.7 Hz), 7.05 (1H, dd, J = 8.0, 6.7 Hz), 6.97 (2H, d, J = 8.6 Hz), 5.37 (2H, s ), 3.77 (2H, s), 1.65 (9H, s).
MS (FAB) (m / z): 538 ([M] ⁺ ).

(Example 92)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1′-biphenyl-4-yl) acetic acid ( Exemplified compound number: 2-229)
(92-1)
In the same manner as in Example (26-4), from 2,3-dimethyl-4-methoxyphenylacetonitrile (800 mg, 4.57 mmol), methyl (4-methoxy-2,3-dimethylphenyl) acetate (857 mg, 85 .3%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.01 (1H, d, J = 7.8 Hz), 6.69 (1H, dd, J = 7.8 Hz), 3.80 (3H, s), 3.68 (3H, s), 3.62 (2H, s), 2.20 (3H, s), 2.17 (3H, s).
(92-2)
In the same manner as in Example (6-2), methyl (4-methoxy-2,3-dimethylphenyl) acetate (857 mg, 4.12 mmol) obtained in Example (92-1) was converted into methyl (4- Hydroxy-2,3-dimethylphenyl) acetate (477 mg, 59.7%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.90 (1H, d, J = 7.8 Hz), 6.59 (1H, d, J = 7.8 Hz), 4.75-4.70 (1H, br s), 3.68 (3H, s), 3.60 (2H, s), 2.19 (3H, s), 2.18 (3H, s).
(92-3)
In the same manner as in Example (22-5) and Example (26-3), methyl (4-hydroxy-2,3-dimethylphenyl) acetate obtained in Example (92-2) (477 mg, 2.46 mmol) gave methyl (4′-hydroxy-2,3-dimethyl-1,1′-biphenyl-4-yl) acetate (282 mg, total yield of 2 steps 42.5%).
In this step, in the step of Suzuki coupling corresponding to Example (26-3), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 4-methoxyphenylboric acid. -2-yl) phenol was used.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.14 (2H, d, J = 8.6 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 6.84 ( 2H, d, J = 8.6 Hz), 4.99-4.95 (1H, br s), 3.72 (3H, s), 3.71 (2H, s), 2.26 (3H, s), 2.16 (3H, s).
(92-4)
Methyl (4′-hydroxy-2,3) synthesized in Example (92-3) in the same manner as in Example (40-2), Example (33-5), and Example (17-4) -Dimethyl-1,1'-biphenyl-4-yl) acetate (282 mg, 1.04 mmol) gave the title compound (256 mg, total yield of 3 steps 46.3%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.72 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.23-7.17 (2H, m ), 7.09 (1H, d, J = 7.8 Hz), 7.04 (1H, d, J = 7.8 Hz), 6.96-6.90 (2H, m), 5.30 (2H, s), 3.76 (2H, s), 2.28 (3H, s), 2.18 (3H, s), 1.65 (9H, s).
MS (FAB) (m / z): 530 ([M] ⁺ ).

(Example 93)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) -3 -(Dimethylamino) propanoic acid (Exemplary compound number: 2-230)
(93-1)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -3′-fluoro-1,1′-biphenyl-) obtained in Example (11-6) 4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (200 mg, 0.33 mmol) was dissolved in toluene (3 ml) and N, N-dimethylformamide ditert-butyl acetal (0.4 ml , 1.7 mmol) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was poured into water 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 column chromatography (elution solvent: n-hexane / ethyl acetate = 10 / 1-1 / 1), and tert-butyl 2- (allyloxy). ) -6-{[(4 '-{1-[(allyloxy) carbonyl] -2- (dimethylamino) vinyl} -3'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl}- 3- (Trifluoromethyl) benzoate (141 mg, 65% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.69 (1H, s), 7.64 (1H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.29-7.20 (3H, m), 7.00 (2H, d, J = 8.8 Hz), 6.11-6.08 (1H, m), 5.93-5.85 (1H, m), 5.43 (1H, d, J = 15.6 Hz), 5.28 (1H, d, J = 10.4 Hz), 5.21-5.10 (2H, m), 5.17 (2H, s), 4.59-4.58 (4H, m), 2.78 (6H, s), 1.58 (9H, s).
(93-2)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{1-[(allyloxy) carbonyl] -2- (dimethylamino) vinyl} -3′- obtained in Example (93-1) To a solution of fluoro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (67 mg, 0.10 mmol) in tetrahydrofuran (1 ml), morpholine (0.02 ml, 0 .23 mmol) and tetrakis (triphenylphosphine) palladium (0) (6 mg, 0.005 mmol) were sequentially added, and the mixture was 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 subjected to silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10 / 1-1 /> 99) to give crude tert-butyl 2- Hydroxy-6-{[(4 '-{1-[(allyloxy) carbonyl] -2- (dimethylamino) vinyl} -3'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl}- 3- (Trifluoromethyl) benzoate (42 mg) was obtained.
A neutral phosphate pH standard solution (pH 6.86, 0.2 ml) and sodium cyanoborohydride (15 mg, 0.24 mmol) were sequentially added to a solution of the obtained compound in acetonitrile (1 ml) at room temperature. After stirring for 1.5 hours, sodium cyanoborohydride (15 mg, 0.24 mmol) and a small amount of acetic acid were sequentially added and stirred at room temperature for 3 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate 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: ethyl acetate / methanol => 99 / 1-5 / 1) to give crude tert-butyl 6-{[ (4 ′-{1-[(allyloxy) carbonyl] -2- (dimethylamino) ethyl} -3′-fluoro-1,1′-biphenyl-4-yl) oxy] methyl} -2-hydroxy-3- (Trifluoromethyl) benzoate was obtained.
To a solution of the obtained compound in tetrahydrofuran (1 ml), morpholine (0.012 ml, 0.13 mmol) and tetrakis (triphenylphosphine) palladium (0) (6 mg, 0.005 mmol) were sequentially added, and then at room temperature for 1 hour. Stir. The solvent was distilled off under reduced pressure and diluted with ethyl acetate. A neutral phosphate pH standard solution (pH 6.86) and saturated saline were added to this 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 subjected to high performance liquid chromatography (column: GL Science, Inatosil ODS-3; elution solvent: acetonitrile: water = 85 / 15-98 / 2). Purification gave the title compound as a colorless solid (12 mg, total yield of 3 steps 20%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.39-7.23 (4H, m ), 6.98 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 4.08-4.05 (1H, m), 3.36 (1H, t, J = 12.4 Hz), 2.74-2.71 (1H, m) , 2.68 (3H, s), 2.68 (3H, s), 1.65 (9H, s).
MS (ESI) (m / z): 576 ([MH] ⁺ ).

(Example 94)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-231)
(94-1)
tert-Butyl 2- (allyloxy) -6-[({2'-ethyl-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3- (tri A solution of (fluoromethyl) benzoate (105 mg, 0.19 mmol) in tetrahydrofuran (2 ml) at −78 ° C. in a nitrogen atmosphere at −78 ° C. 32 mmol) was added and stirred for 0.5 hour, and then methyl iodide (30 μl, 0.48 mmol) was added and stirred for 1 hour. Saturated brine was added to the reaction mixture, 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 preparative thin layer chromatography (developing solvent: hexane / ethyl acetate = 5/1) to give oily tert-butyl 2- (allyloxy). ) -6-[({2′-ethyl-4 ′-[1- (methoxycarbonyl) ethyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoe- (30 mg, 27% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.66 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J = 8.0 Hz), 7.26-7.20 (3H, m), 7.14-7.13 (2H , m), 6.96 (2H, d, J = 8.5 Hz), 6.11-6.03 (1H, m), 5.43 (1H, dd, J = 17.0, 1.5 Hz), 5.28 (1H, dd, J = 10.5, 1.5 Hz), 5.16 (2H, s), 4.58 (2H, d, J = 5.5 Hz), 3.75 (1H, q, J = 7.0 Hz), 3.69 (3H, s), 2.58 (2H, q, J = 7.5 Hz), 1.57 (9H, s), 1.53 (3H, d, J = 7.0 Hz), 1.08 (3H, t, J = 7.5 Hz).
(94-2)
In the same manner as in Example (11-7) and Example (17-4), tert-butyl 2- (allyloxy) -6-[({2'-) obtained in Example (94-1) was obtained. From ethyl-4 ′-[1- (methoxycarbonyl) ethyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (64 mg, 0.11 mmol), The title compound was obtained as a colorless solid (31 mg, total yield of 2 steps 52%).
¹ H-NMR (500 MHz, CD ₃ OD): δ 7.77 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.23-7.22 (3H, m), 7.16 (1H, dd, J = 8.0, 2.0 Hz), 7.08 (1H, d, J = 8.0 Hz), 7.02 (2H, d, J = 9.0 Hz), 5.41 (2H, s), 3.70 (1H, q, J = 7.5 Hz), 2.58 (2H, q, J = 7.5 Hz), 1.63 (9H, s), 1.46 (3H, d, J = 7.5 Hz), 1.04 (3H, t, J = 7.5 Hz).
MS (ESI) (m / z): 543 ([MH] ⁺ ).

(Example 95)
tert-butyl 2-hydroxy-6-({[4 ′-(1H-tetrazol-5-yl) -1,1′-biphenyl-4-yl] oxy} methyl) -3- (trifluoromethyl) benzoate ( Exemplified compound number: 1-68)
(95-1)
To a solution of 4′-hydroxy-1,1′-biphenyl-4-carbonitrile (1.07 g, 5.49 mmol) in methylene chloride (10 ml) was added chloromethyl methyl ether (0.5 ml, 6.59 mmol) and diisopropyl Ethylamine (1.44 ml, 8.24 mmol) was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, 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 column chromatography (developing solvent: hexane / ethyl acetate = 5/1), and 4′-methoxymethoxy-1,1′-biphenyl- 4-carbonitrile (1.03 g, yield 78%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.70 (2H, d, J = 7.8 Hz), 7.64 (2H, d, J = 7.8 Hz), 7.56-7.51 (2H, m), 7.17-7.12 (2H m), 5.23 (2H, s), 3.51 (3H, s).
(95-2)
Sodium azide was added to a solution of 4′-methoxymethoxy-1,1′-biphenyl-4-carbonitrile (500 mg, 2.09 mmol) obtained in Example (95-1) in N, N-dimethylformamide (10 ml). (531 mg, 8.16 mmol) and ammonium chloride (435 mg, 8.16 mmol) were added, and the mixture was stirred at 120 ° C. for 1 week. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 5- (4′-methoxymethoxy-1,1′-biphenyl-4-yl) -1H-tetrazole (600 mg).
Allyl bromide (0.27 ml, 3.13 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to a solution of the obtained compound in N, N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction mixture, 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 column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give 1-allyl-5- (4′-methoxymethoxy-). 1,1′-biphenyl-4-yl) -1H-tetrazole and a mixture of 2-allyl-5- (4′-methoxymethoxy-1,1′-biphenyl-4-yl) -2H-tetrazole (504 mg) , 2 step total yield 71%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 8.20 (2H, d, J = 7.8 Hz), 7.68 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.14 ( 2H, d, J = 8.6 Hz), 6.21-6.09 (1H, m), 5.44 (1H, s), 5.41 (1H, d, J = 5.9 Hz), 5.28 (2H, d, J = 5.9 Hz), 5.23 (2H, s), 3.51 (3H, s).

(95-3)
1-allyl-5- (4′-methoxymethoxy-1,1′-biphenyl-4-yl) -1H-tetrazole and 2-allyl-5- (4′-) obtained in Example (95-2) To a methanol (5 ml) solution of a mixture of methoxymethoxy-1,1′-biphenyl-4-yl) -2H-tetrazole (504 mg, 1.50 mmol) was added 4N hydrochloric acid-dioxane solution (0.75 ml, 3.00 mmol). The mixture was stirred at 50 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 1-allyl-5- (4′-hydroxy-1,1′-biphenyl-4-yl) -1H-tetrazole and 2-allyl-5- ( A mixture (463 mg) of 4′-hydroxy-1,1′-biphenyl-4-yl) -2H-tetrazole was obtained.
The obtained crude mixture (463 mg, 1.50 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- obtained in Example (28-5) From (trifluoromethyl) benzoate (900 mg, 1.80 mmol), in the same manner as in Example (40-2) and Example (33-5), tert-butyl 6-({[4 ′-(1 -Allyl-1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl] oxy} methyl) -2-hydroxy-3- (trifluoromethyl) benzoate and tert-butyl 6-({ [4 ′-(2-Allyl-2H-tetrazol-5-yl) -1,1′-biphenyl-4-yl] oxy} methyl) -2-hydroxy-3- (trifluoromethyl (1) A mixture of benzoate (712 mg, total yield of 3 steps 86%) was obtained.
^{1 H-NMR (400MHz, CDCl} 6): δ 12.28-12.24 (1H, s), 8.22-8.18 (2H, m), 7.80-7.65 (3H, m), 7.63-7.59 (2H, m), 7.32- 7.27 (1H, m), 7.05-7.00 (2H, m), 6.25-6.20 (1H, m), 5.46-5.38 (4H, m), 5.29-5.26 (2H, m), 1.66 (9H, s).
(95-4)
Tetrakis (triphenylphosphine) palladium (0) (74 mg, 64.4 μmol) in a methylene chloride (6 ml) solution of the mixture (712 mg, 1.29 mmol) obtained in Example (95-3) under a nitrogen atmosphere. , Acetic acid (0.4 ml, 6.44 mmol) and phenylsilane (0.397 ml, 3.22 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The produced solid was filtered off and washed with methylene chloride to obtain the title compound (469 mg, yield 71%).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 11.45 (1H, s), 8.10 (2H, d, J = 7.8 Hz), 7.89 (2H, d, J = 8.3 Hz), 7.82 (1H, d , J = 8.8 Hz), 7.76 (2H, d, J = 8.3 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 5.40 (2H, s), 1.57 (9H, s).

Example 96
[5- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -4-methyl-2-thienyl] acetic acid (Exemplary Compound Number: 2 -232)
(96-1)
Phosphoryl chloride (5.3 ml, 0.57 mmol) was added dropwise to N, N-dimethylformamide (8.8 ml, 0.11 mmol) under ice cooling, followed by stirring at room temperature for 30 minutes. Under cooling with ice, 2-bromo-3-methylthiophene (5.00 g, 28.2 mmol) was added dropwise, and the mixture was stirred at 50 ° C. for 6 hours. The reaction solution was neutralized with 2N aqueous sodium hydroxide solution under ice cooling. The reaction solution was extracted with diethyl ether, and the organic layer was 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) to give 5-bromo-4-methyl-2-thiophene. Carbaldehyde (1.41 g, 24% yield) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.74 (1H, s), 7.44 (1H, s), 2.25 (3H, s).

(96-2)
In the same manner as in Example (6-6), Example (26-5), and Example (11-1), 5-bromo-4-methyl-2-methyl ester obtained in Example (96-1) was used. From 5-thiophenecarbaldehyde (1.41 g, 6.88 mmol), (5-bromo-4-methyl-2-thienyl) acetonitrile (0.19 g, total yield of 3 steps 13%) was obtained.
In this step, acetone was used in place of ethanol in the cyanation step corresponding to Example (11-1).
¹ H-NMR (400MHz, CDCl ₃ ): δ 6.76 (1H, s), 3.79 (2H, s), 2.16 (3H, s).
(96-3)
In the same manner as in Example (28-6), from (5-bromo-4-methyl-2-thienyl) acetonitrile (280 mg, 1.3 mmol) obtained in Example (96-2), [5- ( 4-Hydroxyphenyl) -4-methyl-2-thienyl] acetonitrile (131 mg, 44% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.30 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 6.87 (1H, s), 4.99 (1H, s), 3.86 (2H, s), 2.24 (3H, s).
(96-4)
In the same manner as in Example (84-2), from [5- (4-hydroxyphenyl) -4-methyl-2-thienyl] acetonitrile (131 mg, 0.57 mmol) obtained in Example (96-3). , Methyl [5- (4-hydroxyphenyl) -4-methyl-2-thienyl] acetate (133 mg, yield 87%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.29 (2H, d, J = 8.2 Hz), 6.85 (2H, d, J = 8.2 Hz), 6.74 (1H, s), 5.18 (1H, s), 3.78 (2H, s), 3.75 (3H, s), 2.22 (3H, s).
(96-5)
In the same manner as in Example (2-3), Example (33-5), and Example (17-4), the methyl [5- (4-hydroxyphenyl) obtained in Example (96-4) was obtained. ) -4-Methyl-2-thienyl] acetate (133 mg, 0.51 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) obtained in Example (28-5) From oxy] -3- (trifluoromethyl) benzoate (254 mg, 0.56 mmol), the title compound (35 mg, total yield 13% yield) was obtained as pale yellow crystals.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.37 (2H, d, J = 9.0 Hz), 7.27 (1H, d, J = 8.2 Hz), 6.94 (2H, d, J = 9.0 Hz), 6.78 (1H, s), 5.36 (2H, s), 3.83 (2H, s), 2.25 (3H, s), 1.64 (9H, s ).
ESI (ES-) (m / z): 521 ([MH] ⁺ ).

(Example 97)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-65)
(97-1)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{[(allyloxy) carbonyl] methyl} -3′-chloro-1,1′-biphenyl-) obtained in Example (18-3) To a solution of 4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (19 mg, 0.03 mmol) in dichloromethane (0.4 ml) was added tetra-n-butylammonium hydrogensulfate (21 mg, .0. (062 mmol), 2N-aqueous sodium hydroxide solution (0.06 ml, 0.12 mmol) and methyl iodide (10 μl, 0.16 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. 2N-aqueous sodium hydroxide solution (0.03 ml, 0.06 mmol) and methyl iodide (7 μl, 0.11 mmol) were added to the reaction solution, and the mixture was further stirred for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane / ethyl acetate = 5/1), and tert-butyl 2- (allyloxy) -6. -{[(4 '-{1-[(allyloxy) carbonyl] ethyl} -3'-chloro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate (8 mg, 42% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.64 (1H, d, J = 8.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.42 ( 1H, dd, J = 8.0, 2.0 Hz), 7.39 (1H, d, J = 8.0 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.00 (2H, d, J = 8.5 Hz), 6.11- 6.03 (1H, m), 5.92-5.84 (1H, m), 5.43 (1H, dd, J = 17.0, 1.5 Hz), 5.29-5.18 (3H, m), 5.16 (2H, s), 4.61 (2H, dd, J = 5.5, 1.5 Hz), 4.58 (2H, d, J = 5.5 Hz), 4.27 (1H, q, J = 7.0 Hz), 1.58 (9H, s), 1.54 (3H, d, J = 7.0 Hz).
(97-2)
Tert-Butyl 2- (allyloxy) -6-{[(4 ′-{1-[(allyloxy) carbonyl) ethyl] obtained in Example (97-1) in the same manner as in Example (11-7). } -3′-Chloro-1,1′-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate gave the title compound as a colorless solid.
¹ H-NMR (400MHz, CD ₃ OD): δ 7.76 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 1.2 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.53 -7.50 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.06 (2H, d, J = 8.4 Hz), 5.42 (2H, s) , 4.18 (1H, q, J = 7.2 Hz), 1.64 (9H, s), 1.48 (3H, d, J = 7.2 Hz).
MS (ESI) (m / z): 549 ([MH] ⁺ ).

(Example 98)
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1'-biphenyl-3-yl) propanoic acid (Exemplary compound number: 2-233)
(98-1)
In the same manner as in Example (26-4), methyl (4′-methoxy-2-methyl-1,1′-biphenyl-3-yl) acetate (780 mg, 2) obtained in Example (33-2) was obtained. (88 mmol) gave allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl) acetate (830 mg, yield 86%) as a brown oil.
In this step, allyl alcohol was used in place of methanol in the esterification reaction.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.19-7.12 (3H, m), 7.16 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 5.96-5.87 (1H , m), 5.31-5.21 (2H, m), 4.81 (1H, s), 4.62 (2H, d, J = 5.9 Hz), 3.74 (2H, s), 2.18 (3H, s).
(98-2)
Allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl) acetate (830 mg, 2.48 mmol) obtained in Example (98-1) and imidazole (170 mg, 2. To a solution of 48 mmol) in N, N-dimethylformamide (12 ml) was added tert-butyl (dimethyl) silyl chloride (370 mg, 2.48 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, 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 = 95 / 5-90 / 10) to give allyl (4 ′-{[ tert-Butyl (dimethyl) silyl] oxy} -2-methyl-1,1′-biphenyl-3-yl) acetate (675 mg, 69% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.19-7.12 (3H, m), 7.13 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 5.96-5.86 (1H , m), 5.30-5.20 (2H, m), 4.62 (2H, d, J = 5.9 Hz), 3.73 (2H, s), 2.18 (3H, s), 1.01 (9H, s), 0.24 (6H, s).
(98-3)
Allyl (4 ′-{[tert-butyl (dimethyl) silyl] oxy} -2-methyl-1,1′-biphenyl-3-yl) acetate (675 mg, 1. g) obtained in Example (98-2). 70 mmol) in tetrahydrofuran (6 ml) was added dropwise bis (trimethylsilyl) amidolithium-1.0M tetrahydrofuran solution (2.47 ml, 2.47 mmol) at -78 ° C. After stirring for 30 minutes, methyl iodide (512 μl, 8.22 mmol) was added and stirred at −78 ° C. for 1 hour. Water was added to the reaction mixture, 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 dissolved in tetrahydrofuran (5 ml). Tetra-n-butylammonium fluoride-1.0 M tetrahydrofuran solution (2.04 ml, 2.04 mmol) was added to this solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and 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 preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 3/1) to give allyl 2- (4′-hydroxy). -2-Methyl-1,1′-biphenyl-3-yl) propanoate (457 mg, 91% yield) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.27 (1H, dd, J = 7.4, 1.6 Hz), 7.20 (1H, t, J = 7.4 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.11 (1H, dd, J = 7.4, 1.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.93-5.83 (1H, m), 5.25-5.16 (2H, m), 4.84 (1H, s) , 4.65-4.55 (2H, m), 4.08 (1H, q, J = 7.4 Hz), 2.24 (3H, s), 1.53 (3H, d, J = 7.4 Hz).

(98-4)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), allyl 2- (4′-hydroxy-) obtained in Example (98-3) was used. From 2-methyl-1,1′-biphenyl-3-yl) propanoate (150 mg, 0.506 mmol), the title compound as a white powder (107 mg, total yield of 3 steps 40%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.14 (1H, d, J = 7.8 Hz), 6.96 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 4.10 (1H, q, J = 7.0 Hz), 2.26 (3H, s), 1.65 (9H, s), 1.55 (3H, d, J = 7.0 Hz).
MS (FAB) (m / z): 530 ([M] ⁺ ).

Example 99
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1'-biphenyl-3-yl) propanoic acid (Exemplary compound number: 2-234)
(99-1)
Allyl (2-ethyl-4'-hydroxy-1,1'-biphenyl) obtained in Example (90-6) in the same manner as in Example (98-2) and Example (98-3) -3-yl) acetate (400 mg, 1.35 mmol) to pale yellow powder of allyl 2- (2-ethyl-4′-hydroxy-1,1′-biphenyl-3-yl) propanoate (434 mg, total of 2 steps) Yield 100%).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.31 (1H, dd, J = 7.8, 1.2 Hz), 7.18 (1H, t, J = 7.8 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 7.8, 1.2 Hz), 6.86 (2H, d, J = 8.6 Hz), 5.92-5.82 (1H, m), 5.24-5.15 (2H, m), 4.80 (1H, s) , 4.65-4.52 (2H, m), 4.09 (1H, q, J = 7.0 Hz), 2.75-2.65 (1H, m), 2.62-2.53 (1H, m), 1.53 (3H, d, J = 7.0 Hz ), 1.05 (3H, t, J = 7.4 Hz).
(99-2)
Allyl 2- (2-ethyl-4) obtained in Example (99-1) in the same manner as in Example (40-2), Example (33-5), and Example (17-4). The title compound (97 mg, total yield of 43% in 3 steps) was obtained from light brown powder from '-hydroxy-1,1'-biphenyl-3-yl) propanoate (150 mg, 0.48 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.73 (1H, d, J = 8.2 Hz), 7.34 (1H, dd, J = 7.8, 1.2 Hz), 7.31 (1H, d , J = 8.2 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.21 (1H, t, J = 7.8 Hz), 7.08 (1H, dd, J = 7.8, 1.2 Hz), 6.95 (2H, d , J = 8.6 Hz), 5.38 (2H, s), 4.10 (1H, q, J = 7.0 Hz), 2.75-2.66 (1H, m), 2.63-2.54 (1H, m), 1.54 (3H, d, J = 7.0 Hz), 1.06 (3H, t, J = 7.4 Hz).
MS (FAB) (m / z): 544 ([M] ⁺ ).

(Example 100)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-64)
In the same manner as in Example (97-1) and Example (11-7), tert-butyl 2- (allyloxy) -6-{[(4'-) obtained in Example (11-6) was obtained. {[(Allyloxy) carbonyl] methyl} -3'-fluoro-1,1'-biphenyl-4-yl) oxy] methyl} -3- (trifluoromethyl) benzoate gives the title compound as a colorless solid. It was.
¹ H-NMR (500MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.38-7.22 (4H, m ), 6.98 (2H, d, J = 8.5 Hz), 5.38 (2H, s), 4.10 (1H, q, J = 7.0 Hz), 1.65 (9H, s), 1.57 (3H, d, J = 7.0 Hz) ).
MS (ESI) (m / z): 533 ([MH] ⁺ ).

(Example 101)
2- (4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-235)
(101-1)
Methyl (4′-hydroxy-2-nitro-1,1′-biphenyl-4-yl) acetate (203 mg, 0.71 mmol) obtained in Example (37-1) and Example (28-5) To a solution of tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (330 mg, 0.781 mmol) obtained in 1) in acetone (15 ml). Potassium (147 mg, 1.06 mmol) was added, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was 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 residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give crude tert-butyl 2-[(tert-butoxycarbonyl). Oxy] -6-[({4 ′-[(methoxycarbonyl) methyl] -2′-nitro-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate It was.
To a tetrahydrofuran solution (4 ml) of this compound was added lithium diisopropylamide-2.0 M heptane / tetrahydrofuran / ethylbenzene solution (192 μl, 0.386 mmol) at −78 ° C., and then methyl iodide (24 μl, 0.386 mmol). Was added dropwise and stirred for 1 hour. The reaction mixture was warmed 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 residue obtained by distilling off the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane / ethyl acetate = 4/1), and tert-butyl 2-[(tert-butoxy). Carbonyl) oxy] -6-[({4 ′-[1- (methoxycarbonyl) ethyl] -2′-nitro-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl ) Benzoate (84 mg, 17%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.76 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.53 ( 1H, dd, J = 7.9, 1.6 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.23 (2H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 5.25 ( 2H, s), 3.83 (1H, q, J = 7.3 Hz), 3.71 (3H, s), 1.57 (3H, d, J = 7.3 Hz), 1.57 (9H, s), 1.54 (9H, s).

(101-2)
In the same manner as in Example (33-5) and Example (17-4), tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6- obtained in Example (101-1) was obtained. [({4 ′-[1- (methoxycarbonyl) ethyl] -2′-nitro-1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (84 mg, 0. 146 mmol) afforded the title compound (47 mg, 64%) as a yellow oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.28 (1H, s), 7.79 (1H, d, J = 1.6 Hz), 7.71 (1H, d, J = 8.3 Hz), 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.28-7.23 (3H, m), 6.96 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 3.87 (1H , q, J = 7.3 Hz), 1.64 (9H, s), 1.61 (3H, d, J = 7.3 Hz).
MS (FAB) (m / z): 561 ([M] ⁺ ).

(Example 102)
2- [4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -3-methylphenyl] propanoic acid (exemplary compound Number: 2-236)
(102-1)
In the same manner as in Example (104-1), methyl [3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane] obtained in Example (84-3) was obtained. 2-yl) phenyl] acetate (640 mg, 2.21 mmol) from methyl 2- [3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Phenyl] propanoate (223 mg, 33% yield).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.73 (1H, d, J = 8.2 Hz), 7.11-7.06 (2H, m), 3.68 (1H, q, J = 7.0 Hz), 3.64 (3H, s ), 2.53 (3H, s), 1.47 (3H, d, J = 7.0 Hz), 1.32 (12H, s).
(102-2)
In the same manner as in Example (76-1) and Example (17-4), methyl 2- [3-methyl-4- (4,4,5,5) obtained in Example (102-1) was obtained. 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] propanoate (223 mg, 0.73 mmol) gave the amorphous title compound (63 mg, 17% yield over 2 steps). In this step, tert-butyl 6-{[(6-chloro-3-pyridinyl) oxy] obtained in Example (84-1) in the step of Suzuki coupling corresponding to Example (76-1)] Methyl} -2-hydroxy-3- (trifluoromethyl) benzoate was used as the halide.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.30 (1H, s), 8.50 (1H, d, J = 2.7 Hz), 7.75 (1H, d, J = 8.2 Hz), 7.38-7.27 (4H, m ), 7.17-7.13 (2H, m), 5.45 (2H, s), 3.70 (1H, q, J = 7.0 Hz), 2.29 (3H, s), 1.67 (9H, s), 1.51 (3H, d, J = 7.0 Hz).
ESI (ES-) (m / z): 530 ([MH] ⁺ ).

(Example 103)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-ethyl-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-237)
(103-1)
Methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl) obtained in Example (85-4) in the same manner as in Example (98-2) and Example (104-1) -4-yl) acetate (100 mg, 0.370 mmol) to methyl 2- (4 ′-{[tert-butyl (dimethyl) silyl] oxy} -3-ethyl-1,1′-biphenyl-4-yl) Propionate (104 mg, 71% yield over 2 steps) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.46-7.42 (2H, m), 7.38-7.35 (2H, m), 7.33-7.30 (1H, m), 6.90-6.86 (2H, m), 4.01 ( 1H, q, J = 7.0 Hz), 3.67 (3H, s), 2.84-2.70 (2H, m), 1.50 (3H, d, J = 7.0 Hz), 1.28 (3H, t, J = 7.8 Hz), 1.00 (9H, s), 0.22 (6H, s).
(103-2)
Methyl 2- (4 ′-{[tert-butyl (dimethyl) silyl] oxy} -3-ethyl-1,1′-biphenyl-4-yl) propionate obtained in Example (103-1) (104 mg, To a solution of 283 mmol) in tetrahydrofuran (5 ml) was added tetra-n-butylammonium fluoride-1.0 M tetrahydrofuran solution (0.39 ml, 0.391 mmol), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, 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 column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to give methyl 2- (3-ethyl-4′-hydroxy- 1,1′-biphenyl-4-yl) propionate (76 mg, 100%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.49-7.42 (2H, m), 7.37-7.33 (1H, m), 7.33-7.29 (1H, m), 7.26-7.21 (1H, m), 6.91- 6.86 (2H, m), 4.78 (1H, br s), 4.01 (1H, q, J = 7.0 Hz), 3.67 (3H, s), 2.82-2.69 (2H, m), 1.50 (3H, d, J = 7.0 Hz), 1.26 (3H, t, J = 7.8 Hz).
(103-3)
Methyl 2- (3-ethyl-4) obtained in Example (103-2) in the same manner as in Example (40-2), Example (33-5) and Example (17-4). The title compound (57.5 mg, total yield of 3 steps 39%) was obtained from '-hydroxy-1,1'-biphenyl-4-yl) propionate (76 mg, 0.269 mmol).
In this step, the step corresponding to Example (17-4) was performed at a reaction temperature of 40 ° C.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.2 (1H, s), 7.79 (1H, d, J = 8.0 Hz), 7.56-7.50 (2H, m), 7.41-7.35 (2H, m) , 7.30-7.25 (2H, m), 7.07-7.03 (2H, m), 5.35 (2H, s), 3.90 (1H, q, J = 7.1Hz), 2.79-2.65 (2H, m), 1.56 (9H , s), 1.36 (3H, d, J = 7.1 Hz), 1.21 (3H, t, J = 7.5 Hz).

(Example 104)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,5-dimethyl-1,1′-biphenyl-4-yl) Propanoic acid (Exemplary compound number: 2-238)
(104-1)
To a solution of methyl (4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl) acetate (730 mg, 2.57 mmol) obtained in Example (105-1) in tetrahydrofuran (6 ml) After adding lithium bis (trimethylsilyl) amide 1.0M-tetrahydrofuran solution (3.86 ml, 3.86 mmol) at −78 ° C., methyl iodide (800 μl, 12.9 mmol) was added dropwise and stirred for 1 hour. . A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was 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 column chromatography (eluent: hexane / ethyl acetate = 95 / 5-15 / 1) to give colorless oily methyl 2- (4 ′ -Methoxy-2,5-dimethyl-1,1'-biphenyl-4-yl) propanoate (620 mg, 81%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.24 (2H, d, J = 8.6 Hz), 7.12 (1H, s), 7.02 (1H, s), 6.94 (2H, d, J = 8.6 Hz), 3.95 (1H, q, J = 7.0 Hz), 3.85 (3H, s), 3.69 (3H, s), 2.34 (3H, s), 2.23 (3H, s), 1.50 (3H, d, J = 7.0 Hz ).
(104-2)
Methyl 2- (4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl) propanoate obtained in Example (104-1) in the same manner as in Example (6-2) From (617 mg, 2.07 mmol), methyl 2- (4′-hydroxy-2,5-dimethyl-1,1′-biphenyl-4-yl) propanoate (400 mg, yield 68%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.20-7.10 (3H, m), 7.00 (1H, s), 6.84 (2H, d, J = 7.8 Hz), 3.97 (1H, q, J = 7.0 Hz ), 3.70 (3H, s), 2.33 (3H, s), 2.20 (3H, s), 1.51 (3H, d, J = 7.0 Hz).
(104-3)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl 2- (4′-hydroxy-) obtained in Example (104-2) was used. From 2,5-dimethyl-1,1′-biphenyl-4-yl) propanoate (400 mg, 1.40 mmol), the title compound (308 mg, 40% yield) was obtained as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.17 (1H, s), 7.03 (1H, s), 6.94 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 3.99 (1H, q, J = 7.0 Hz), 2.36 (3H, s), 2.24 (3H, s), 1.65 (9H, s), 1.53 (3H, d, J = 7.0 Hz).
MS (ESI) (m / z): 543 ([MH] ⁺ ).

(Example 105)
(4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,5-dimethyl-1,1'-biphenyl-4-yl) acetic acid ( Exemplified compound number: 2-239)
(105-1)
In the same manner as in Example (26-4), Example (22-5) and Example (26-3), (4-hydroxy-2,5-dimethylphenyl) acetonitrile (1.52 g, 8 .68 mmol), methyl (4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl) acetate (1.79 g, total yield of 73 steps) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.24 (2H, d, J = 8.6 Hz), 7.08 (1H, s), 7.04 (1H, s), 6.94 (2H, d, J = 8.6 Hz), 3.85 (3H, s), 3.72 (3H, s), 3.64 (2H, s), 2.29 (3H, s), 2.23 (3H, s).
(105-2)
In the same manner as in Example (26-4), methyl (4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl) acetate (652 mg) obtained in Example (105-1) was obtained. , 2.29 mmol), methyl (4′-hydroxy-2,5-dimethyl-1,1′-biphenyl-4-yl) acetate (556 mg, yield 90%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.17 (2H, d, J = 8.6 Hz), 7.08 (1H, s), 7.03 (1H, s), 6.84 (2H, d, J = 8.6 Hz), 5.05 (1H, br s), 3.73 (3H, s), 3.65 (2H, s), 2.29 (3H, s), 2.21 (3H, s).
(105-3)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl (4′-hydroxy-2, The title compound (370 mg, yield 59%) as a colorless powder was obtained from 5-dimethyl-1,1′-biphenyl-4-yl) acetate (320 mg, 1.18 mmol).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.70 (1H, d, J = 8.2 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.09 (1H, s), 7.05 (1H, s), 6.94 (2H, d, J = 8.6 Hz), 5.37 (2H, s), 3.67 (2H, s), 2.31 (3H, s ), 2.23 (3H, s), 1.65 (9H, s).
MS (ESI) (m / z): 529 ([MH] ⁺ ).

(Example 106)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-chloro-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-62)
To a solution of methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl) acetate (650 mg, 2.68 mmol) obtained in Example (23-3) in methylene chloride (10 ml), Under ice cooling, diisopropylethylamine (936 μl, 5.37 mmol) and chloromethyl methyl ether (303 μl, 4.02 mmol) were sequentially added and stirred for 3 hours. The reaction mixture was 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 crude methyl [2-chloro-4 ′-(methoxymethoxy) -1,1′-biphenyl-4-yl] acetate. From the obtained compound, it carried out similarly to Example (104-1), Example (12-4), Example (40-2), Example (33-5), and Example (17-4). The title compound (260 mg, total yield of 18 steps, 18%) was obtained as a colorless powder.
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 1.6 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.32-7.23 (3H, m), 6.96 (2H, d, J = 8.6 Hz), 5.38 (2H, s), 3.76 (1H, q, J = 7.0 Hz), 1.65 (9H, s ), 1.56 (3H, d, J = 7.0 Hz).
MS (ESI) (m / z): 549 ([MH] ⁺ ).

(Example 107)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-61)
(107-1)
In the same manner as in Example (104-1) and Example (76-1), methyl (4-bromo-3-methylphenyl) acetate (0.64 g, 2) obtained in Example (84-2) was obtained. .63 mmol) gave methyl 2- (4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl) propanoate (337 mg, total yield of 2 steps 53%).
In this step, in the step of Suzuki coupling corresponding to Example (76-1), tert-butyl 2-{[4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -5- (trifluoromethyl) benzoate was used.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.20-7.14 (5H, m), 6.86 (2H, d, J = 8.6 Hz), 4.93 (1H, s), 3.74 (1H, q, J = 7.0 Hz ), 3.70 (3H, s), 2.26 (3H, s), 1.53 (3H, d, J = 7.0 Hz).
(107-2)
In the same manner as in Example (2-3), Example (33-5), and Example (17-4), methyl 2- (4′-hydroxy-) obtained in Example (107-1) was used. 2-Methyl-1,1′-biphenyl-4-yl) propanoate (224 mg, 0.83 mmol) and tert-butyl 6- (bromomethyl) -2-[() obtained in Example (28-5) Tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (415 mg, 0.91 mmol) gave the title compound as a colorless powder (235 mg, 53% yield over 3 steps).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.29 (1H, s), 11.45 (1H, s), 7.83 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz ), 7.28 (2H, d, J = 8.6 Hz), 7.20-7.12 (3H, m), 7.04 (2H, d, J = 8.6 Hz), 5.37 (2H, s), 3.66 (1H, q, J = 7.0 Hz), 2.21 (3H, s), 1.56 (9H, s), 1.38 (3H, d, J = 7.0 Hz).
ESI (ES-) (m / z): 529 ([MH] ⁺ ).

(Example 108)
2- [4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (trifluoromethyl) -1,1′-biphenyl-4- Yl] propanoic acid (Exemplified compound number: 2-241)
In the same manner as in Example (97-1) and Example (11-7), tert-butyl 2- (allyloxy) -6-({[4 ′-{[(allyloxy) carbonyl] methyl} -2 From '-(trifluoromethyl) -1,1'-biphenyl-4-yl] oxy} methyl) -3- (trifluoromethyl) benzoate (75 mg, 0.12 mmol), crude tert-butyl 2- Hydroxy-6-[({4 '-[1- (methoxycarbonyl) ethyl] -2'-(trifluoromethyl) -1,1'-biphenyl-4-yl} oxy) methyl] -3- (trifluoro Methyl) benzoate was obtained. The title compound (6.7 mg, total yield of 3 steps 10%) was obtained from the obtained compound in the same manner as in Example (17-4).
¹ H-NMR (400MHz, CD ₃ OD): δ 7.77 (1H, d, J = 8.0 Hz), 7.70 (1H, s), 7.58 (1H, d, J = 8.0 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.86 (1H, q, J = 6.8 Hz), 1.62 (9H, s), 1.52 (3H, d, J = 6.8 Hz)
MS (ESI) (m / z ): 583 ([MH] +).

(Example 109)
2- (4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1'-biphenyl-4-yl) propanoic acid (Exemplary compound number: 2-242)
(109-1)
In the same manner as in Example (42-1), from 3-bromo-4-methoxybenzylcyanide (8.7 g, 38.5 mmol) and isopropenylmagnesium bromide-0.5 M tetrahydrofuran solution (100 ml, 50 mmol). , (3-isopropenyl-4-methoxyphenyl) acetonitrile (4.42 g, yield 61%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.20 (1H, dd, J = 8.6, 2.3 Hz), 7.12 (1H, d, J = 2.3 Hz), 6.86 (1H, d, J = 8.6 Hz), 5.18-5.16 (1H, m), 5.06-5.04 (1H, m), 3.84 (3H, s), 3.68 (2H, s), 2.10 (3H, t, J = 1.2 Hz).
(109-2)
(3-Isopropenyl-4-methoxyphenyl) acetonitrile (4.42 g, 23.61 mmol) obtained in Example (109-1) was dissolved in ethanol (50 ml), and 10% palladium-carbon (1 g) was dissolved. In addition, the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1), and (3-isopropyl-4- Methoxyphenyl) acetonitrile (4.08 g, 91% yield) was obtained.
^{1 H-NMR (400MHz, CDCl} 3): δ 7.11-7.07 (2H, m), 6.80 (1H, d, J = 9.0 Hz), 3.82 (3H, s), 3.67 (2H, s), 3.35-3.24 (1H, m), 1.20 (6H, d, J = 6.7 Hz).
(109-3)
In the same manner as in Example (26-4), Example (22-5), Example (76-1), Example (98-2), and Example (98-3), Example (109) -2) from (3-isopropyl-4-methoxyphenyl) acetonitrile (900 mg, 4.76 mmol) obtained in methyl 2- (4′-hydroxy-2-isopropyl-1,1′-biphenyl-4-yl) ) Propanoate (290 mg, total yield of 5 steps 20%) was obtained.
In this step, in the step of Suzuki coupling corresponding to Example (76-1), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 4-methoxyphenylboric acid. -2-yl) phenol was used.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.26 (1H, s), 7.17-7.09 (4H, m), 6.85 (2H, d, J = 8.6 Hz), 4.88 (1H, br), 3.76 (1H , q, J = 7.0 Hz), 3.70 (3H, s), 3.12-3.01 (1H, m), 1.54 (3H, d, J = 7.0 Hz), 1.15 (3H, d, J = 6.6 Hz), 1.14 (3H, d, J = 6.6 Hz).
(109-4)
In the same manner as in Example (2-3), Example (33-5), and Example (17-4), methyl 2- (4′-hydroxy-) obtained in Example (107-1) was used. 2-Isopropyl-1,1′-biphenyl-4-yl) propanoate (290 mg, 0.97 mmol) and tert-butyl 6- (bromomethyl) -2-[() obtained in Example (28-5) tert-Butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (487 mg, 1.07 mmol) gave the title compound as a colorless powder (246 mg, 45% yield over 3 steps).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.30 (1H, s), 11.46 (1H, s), 7.83 (1H, d, J = 8.2 Hz), 7.32 (1H, d, J = 8.2 Hz ), 7.30 (1H, d, J = 2.0 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.12 (1H, dd, J = 7.8, 2.0 Hz), 7.06 (1H, d, J = 7.8 Hz) ), 7.04 (2H, d, J = 9.0 Hz), 5.37 (2H, s), 3.70 (1H, q, J = 7.0 Hz), 3.02-2.94 (1H, m), 1.56 (9H, s), 1.38 (3H, d, J = 7.0 Hz), 1.11 (3H, d, J = 6.7 Hz), 1.10 (3H, d, J = 6.7 Hz).
ESI (ES-) (m / z): 557 ([MH] ⁺ ).

(Example 110)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-difluoro-1,1′-biphenyl-4-yl) Propanoic acid (Exemplary compound number: 2-243)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl 2- (2,3-difluoro-4′-hydroxy-1,1′- Biphenyl-4-yl) propanoate (193 mg, 0.661 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3 obtained in Example (28-5) -(Trifluoromethyl) benzoate (306 mg, 0.726 mmol) gave the title compound as a white powder (45 mg, 12% yield).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.71 (1H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.18-7.08 (2H, m), 6.99 (2H, d, J = 8.8 Hz), 5.39 (2H, s), 3.78-3.73 (1H, m), 1.65 (9H, s), 1.58 (3H, d, J = 7.3 Hz).
MS (ESI) (m / z): 551 ([MH] ⁺ ).

(Example 111)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1′-biphenyl-4-yl) Propanoic acid (Exemplary compound number: 2-244)
Example (92-4) was obtained in the same manner as in Example (12-5), Example (104-1), Example (13-5), and Example (17-4) ( 4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1′-biphenyl-4-yl) acetic acid (105 mg , 0.198 mmol) gave the title compound (8.0 mg, 7% yield) as a colorless oil.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 12.27 (1H, s), 7.72 (1H, d, J = 8.3 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 5.38 (2H, s), 3.78- 3.70 (1H, m), 2.34 (3H, s), 2.19 (3H, s), 1.65 (9H, s), 1.55 (3H, d, J = 7.3 Hz).

(Example 112)
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) propane Acid (Exemplary compound number: 2-245)
(112-1)
Similar to Example (84-2), Example (104-1), Example (42-1), Example (6-2), Example (22-5), and Example (76-1) From 3-bromo-4-methoxybenzylcyanide (2.4 g, 10.62 mmol) to methyl 2- (2-cyclopropyl-4′-hydroxy-1,1′-biphenyl-4-yl) propanoate (135 mg, total yield of 6 steps 4%) was obtained.
In this step, a cyclopropylmagnesium bromide-0.5M tetrahydrofuran solution was used as a Grignard reagent in the step corresponding to Example (42-1). In the Suzuki coupling step corresponding to Example (76-1), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 was used instead of 4-methoxyphenylboric acid. -Yl) phenol was used.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.31 (2H, d, J = 8.6 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.13 (1H, dd, J = 7.8, 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.83 (1H, d, J = 2.0 Hz), 4.84 (1H, s), 3.71 (1H, q, J = 7.0 Hz), 3.68 (3H, s), 1.93-1.84 (1H, m), 1.51 (3H, d, J = 7.0 Hz), 0.86-0.81 (2H, m), 0.71-0.65 (2H, m).
(112-2)
In the same manner as in Example (2-3), Example (33-5), and Example (17-4), methyl 2- (2-cyclopropyl-) obtained in Example (112-1) was used. 4′-hydroxy-1,1′-biphenyl-4-yl) propanoate (135 mg, 0.46 mmol) and tert-butyl 6- (bromomethyl) -2- [obtained in Example (28-5) From the (tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (249 mg, 0.55 mmol), the title compound (115 mg, total yield of 45 steps, 45%) was obtained as a colorless powder.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ 12.28 (1H, s), 11.45 (1H, s), 7.83 (1H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.6 Hz) ), 7.31 (1H, d, J = 8.2 Hz), 7.14-7.09 (2H, m), 7.05 (2H, d, J = 8.6 Hz), 6.86 (1H, s), 5.37 (2H, s), 3.66 (1H, q, J = 7.0 Hz), 1.87-1.79 (1H, m), 1.56 (9H, s), 1.35 (3H, d, J = 7.0 Hz), 0.85-0.79 (2H, m), 0.64- 0.59 (2H, m).
ESI (ES-) (m / z): 555 ([MH] ⁺ ).

(Example 113)
2- [4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl] butanoic acid (Exemplary Compound No. : 1-132)
(113-1)
Methyl 2- (4′-hydroxy-1,1′-biphenyl-4-yl) butanoate Example (98-2) and Example (6-2) in the same manner as Example (98-3) From methyl (4′-hydroxy-1,1′-biphenyl-4-yl) acetate (266 mg, 1.1 mmol) obtained in 1 above, methyl 2- (4′-hydroxy-1,1′-biphenyl-4-) Yl) butanoate (94 mg, total yield of 2 steps 32%) was obtained.
In this step, ethyl iodide was used instead of methyl iodide in the step corresponding to Example (98-3).
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.49 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 6.89 ( 2H, d, J = 8.4 Hz), 4.86 (1H, bs), 3.67 (3H, s), 3.49 (1H, t, 7.6 Hz), 2.17-2.05 (1H, m), 1.86-1.79 (1H, m ), 0.92 (3H, t, J = 7.2 Hz).
(113-2)
In the same manner as in Example (40-2), Example (33-5), and Example (17-4), methyl 2- (4′-hydroxy-) obtained in Example (113-1) was used. From 1,1′-biphenyl-4-yl) butanoate (94 mg, 0.347 mmol), the title compound (99 mg, total yield of 3 steps, 53%) was obtained as a white powder.
In this step, 1,4-dioxane was used as a reaction solvent instead of tetrahydrofuran in the step corresponding to Example (17-4).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.25 (1H, s), 7.71 (1H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.29-7.25 (1H, m), 6.98 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 3.53 (1H, t , J = 7.6 Hz), 2.21-2.10 (1H, m), 1.91-1.80 (1H, m), 1.64 (9H, s), 0.95 (3H, t, J = 7.2 Hz).
MS (ESI) (m / z): 529 ([MH] ⁺ ).

(Example 114)
(4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1′-biphenyl-3-yl) acetic acid (Exemplary Compound Number: 2-246)
(114-1)
To a methanol solution (164 ml) of 2-hydroxy-3-nitrobenzoic acid (6.00 g, 32.8 mmol) was added 10% palladium-carbon (300 mg), and the mixture was stirred at room temperature for 5.5 hours under a hydrogen atmosphere. The insoluble material was filtered off using celite, and the filtrate was concentrated.
To a 10% sulfuric acid solution (164 ml) of the obtained residue, an aqueous solution (49 ml) of sodium nitrite (3.40 g, 49.2 mmol) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, an aqueous solution (31 ml) of potassium iodide (10.4 g, 62.3 mmol) was added dropwise to the reaction solution. The reaction was warmed to 90 ° C. and stirred for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with 10% aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and potassium carbonate (10.1 g, 78.7 mmol) and methyl iodide (4.90 ml, 78.7 mmol) were added to an N, N-dimethylformamide solution (60 ml) of the obtained residue. Was added under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, 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.
After distilling off the solvent under reduced pressure, a diisobutylaluminum hydride-1.0 M toluene solution (49.0 ml, 48.6 mmol) was added dropwise at −78 ° C. to a toluene solution (100 ml) of the resulting residue. The temperature was raised to -20 ° C over time. 2N-hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution 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 subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give crude (3-iodo-2-methoxyphenyl) methanol. Obtained.
From the obtained compound, in the same manner as in Example (90-4), Example (90-5), Example (84-2), and Example (14-1), methyl (4) '-Hydroxy-2-methoxy-1,1'-biphenyl-3-yl) acetate (792 mg, total yield of 7 steps 9%) was obtained.
In this step, methyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl in the step of Suzuki coupling corresponding to Example (14-1) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol was used in place of acetate.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.46 (2H, d, J = 8.3 Hz), 7.25 (1H, dd, J = 7.3, 1.5 Hz), 7.20 (1H, dd, J = 7.3, 1.5 Hz) ), 7.11 (1H, t, J = 7.3 Hz), 6.89 (2H, d, J = 8.3 Hz), 5.06 (1H, s), 3.73 (2H, s), 3.72 (3H, s), 3.34 (3H , s).
(114-2)
In the same manner as in Example (2-3), methyl (4′-hydroxy-2-methoxy-1,1′-biphenyl-3-yl) acetate (792 mg, 2) obtained in Example (114-1) was obtained. .91 mmol) and tert-butyl 6- (bromomethyl) -2-[(tert-butoxycarbonyl) oxy] -3- (trifluoromethyl) benzoate (1.32 g) obtained in Example (28-5) , 2.91 mmol) from tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2'-methoxy-3 '-[(methoxycarbonyl) methyl] -1,1' -Biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (1.20 g, yield 64%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): δ 7.73 (1H, d, J = 7.8 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.24 ( 1H, dd, J = 7.4, 1.2 Hz), 7.20 (1H, dd, J = 7.4, 1.2 Hz), 7.11 (1H, t, J = 7.4 Hz), 6.99 (2H, d, J = 8.0 Hz), 5.26 (2H, s), 3.72 (5H, s), 3.33 (3H, s), 1.57 (9H, s), 1.54 (9H, s).
(114-3)
Tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6- obtained in Example (114-2) in the same manner as in Example (33-5) and Example (17-4) [({2′-methoxy-3 ′-[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (150 mg, 0.23 mmol) To give the title compound as a yellow oil (58 mg, total yield of 2 steps 47%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.72 (1H, d, J = 8.2 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.27 (1H, dd, J = 7.4, 1.6 Hz), 7.22 (1H, dd, J = 7.4, 1.6 Hz), 7.14 (1H, t, J = 7.4 Hz), 6.98 (2H, d , J = 8.6 Hz), 5.37 (2H, s), 3.77 (2H, s), 3.38 (3H, s), 1.64 (9H, s).
MS (FAB) (m / z): 532 ([M] ⁺ ).

(Example 115)
2- (4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1'-biphenyl-3-yl) propanoic acid (Exemplary compound number: 2-63)
(115-1)
In the same manner as in Example (94-1), tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-[({2′-methoxy-3 ′) obtained in Example (115-1) was obtained. From [[(methoxycarbonyl) methyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (300 mg, 0.46 mmol), white amorphous tert-butyl 2- [(Tert-butoxycarbonyl) oxy] -6-[({2'-methoxy-3 '-[1- (methoxycarbonyl) ethyl] -1,1'-biphenyl-4-yl} oxy) methyl] -3 -(Trifluoromethyl) benzoate (212 mg, 69% yield) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.73 (1H, d, J = 7.8 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.24 ( 1H, dd, J = 7.8, 1.5 Hz), 7.22 (1H, dd, J = 7.8, 1.5 Hz), 7.14 (1H, t, J = 7.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 5.27 (2H, s), 4.19 (1H, q, J = 7.3 Hz), 3.69 (3H, s), 3.34 (3H, s), 1.57 (9H, s), 1.54 (9H, s), 1.51 (3H , d, J = 7.3 Hz).
(115-2)
Tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6- obtained in Example (115-1) in the same manner as in Example (33-5) and Example (17-4) [({2′-methoxy-3 ′-[1- (methoxycarbonyl) ethyl] -1,1′-biphenyl-4-yl} oxy) methyl] -3- (trifluoromethyl) benzoate (212 mg, 0. 32 mmol) gave the white amorphous title compound (70 mg, 40% yield over 2 steps).
¹ H-NMR (400MHz, CDCl ₃ ): δ 12.26 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.27 (1H, dd, J = 7.4, 1.6 Hz), 7.25 (1H, dd, J = 7.4, 1.6 Hz), 7.16 (1H, t, J = 7.4 Hz), 6.98 (2H, d , J = 8.6 Hz), 5.37 (2H, s), 4.20 (1H, q, J = 7.0 Hz), 3.38 (3H, s), 1.64 (9H, s), 1.55 (3H, d, J = 7.0 Hz ).
MS (FAB) (m / z): 546 ([M] ⁺ ).

(Test Example 1) Co-transfection assay
The effect of activating or inhibiting 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 co-transfection 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) Transfection reagent for Lipofect AMINE and Plus Reagent (INVITROGEN) (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 at 37 ° C. overnight.

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.
[4] Results When tested in this assay, Examples 1 to 5, 7 to 12, 14, 15, 17 to 29, and 31 to 47, 49, 50, 52, 54 to 67, 69 to 72, Compounds 74 to 79, 81 to 102, and 104 to 115 showed EC ₅₀ values of 5 μM or less for LXRα. In addition, the compounds of Examples 1 to 115 exhibited an EC ₅₀ value of 3 μM or less with respect to LXRβ.

As described above, the compound of the present invention has excellent binding activity to LXRα and LXRβ, and transcriptional activity of LXR, and arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, inflammatory disease, It is useful as a medicament for the treatment or prevention of diseases such as arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, and cerebrovascular disease.

(Test Example 2) Anti-inflammatory action The animals and reagents used in this test example are as follows except for those specifically described.

  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 the experiment 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 the. 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].

When tested by this method, the compounds of the present invention exhibit excellent anti-inflammatory activity 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. The group of mice administered with the test compound is defined as the test compound-administered group, and the group of mice administered with the powdered food not containing the test compound is defined as the 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.

When tested by this method, the compounds of the present invention exhibit excellent hypoglycemic activity and are useful as pharmaceuticals for diabetes.

Formulation Example 1 Hard Capsule In a standard bisected hard gelatin capsule, powdered compound of Example 1 (100 mg), lactose (150 mg), cellulose (50 mg), and stearic acid Hard capsules are prepared by filling with magnesium (6 mg), 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 active ingredient, Soft capsules are manufactured, washed and dried.

(Formulation Example 3) Tablet 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 lacto- A tablet is manufactured according to a conventional method using 98.8 mg. 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 wt%), microcrystalline wax (3 wt%), lanolin (10 wt%), sorbitan monolaurate (5 wt%), 0.3% polyoxyethylene ( 20) A cream was prepared by mixing the 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%). To do.

  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. Therefore, 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) of the present invention or a pharmacologically acceptable salt or ester thereof is an LXR modulator, LXR agonist, or LXR antagonist, preferably LXR modulator or LXR agonist, more preferably , Useful as an LXR modulator. The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is useful as a medicament for inducing ABCA1 expression or promoting reverse cholesterol transfer.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is preferably used for arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia. Disease, hypercholesterolemia, lipid-related disease, inflammatory disease, autoimmune disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, cerebrovascular disease, kidney disease, diabetes, diabetic complications, obesity, Nephritis, hepatitis, cancer, or Alzheimer's disease; more preferably arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia, hypercholesterolemia, lipid-related disease, inflammatory Disease, arteriosclerotic heart disease, cardiovascular disease, coronary artery disease, or diabetes; more preferably arteriosclerosis, atherosclerosis, arteriosclerosis resulting from diabetes, arteriosclerotic heart disease, Heart blood Tubular disease or coronary artery disease; even more preferably, arteriosclerosis, atherosclerosis or arteriosclerotic heart disease; most preferably a medicament for the treatment or prevention of arteriosclerosis Useful as.

Claims (50)

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, a 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 ₁ -C ₁₀ alkylamino group, or, , 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) A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group may be formed);
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 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, 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 ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are the nitrogen atom of the amino group) And 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), (C _1- C ₆ alkoxy) represents a carbonyl group, a cyano group, a nitro group, or a halogeno 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;
R ⁸ has the formula —X ² R ¹⁰
[Wherein R ¹⁰ is a formula —COR ^{11 wherein} R ¹¹ is a C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cycloalkyl)-( C ₁ -C ₆ alkyl) group, C ₃ -C ₈ cycloalkyl group, an amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl )] Amino group, C ₃ -C ₈ cycloalkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups may be the same or different, and the two alkyl groups 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 a nitrogen atom, an oxygen atom and a sulfur atom), di [(C _3- C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] amino group, di (C ₃ -C ₈ cycloalkyl) Amino _{group, N - [(C 3 -C} 8 cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 1 -C} 6 alkyl) amino group, N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, N-[(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)]-N- (C ₃ -C ₈ cycloalkyl) amino group A hydroxylamino group or a hydroxyl (C ₁ -C ₆ alkyl) amino group]
Formula —SO ₂ R ^{12 wherein} R ¹² is a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or a C ₃ -C ₈ cycloalkyl group. , Amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group, C ₃ -C ₈ cycloalkylamino 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), a di [(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)] amino group, a di (C ₃ -C ₈ cycloalkyl) amino group, N - [(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] - N- (C ₁ -C ₆ alkyl) amino group, N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, or N-[(C ₃ -C ₈ cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 3 -C} 8 cycloalkyl) group having an amino group show a]
Formula -N (R ¹³ ) COR ¹⁴ wherein R ¹³ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or A C ₃ -C ₈ cycloalkyl group, wherein R ¹⁴ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, or a C ₃ A group having a —C ₈ cycloalkyl group],
Wherein _{^{-N (R 13) SO 2 R}} 15 [ wherein, R ¹³ represents the same meaning as above, R ¹⁵ is, C ₁ -C ₆ alkyl, (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl) group or a group having a shows a C ₃ -C ₈ cycloalkyl group or, represents the tetrazol-5-yl group,
X ² represents a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents may be the same or different, and may be one or two groups selected from the substituent group γ). And the two substituents together may form a methylene group, an ethylene group, or a trimethylene group);
X ¹ represents a formula —NH—, —NR ¹⁶ — (wherein R ¹⁶ represents a C ₁ -C ₄ alkyl group), —O—, —S—, —SO—, or —SO ₂ —. A group having
Y ¹ 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 group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group α);
Y ² is a 6 to 10-membered aryl group, a substituted 6 to 10-membered aryl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), 9 to 10 members An unsaturated cyclic hydrocarbon group (wherein Y ¹ is bonded to the benzene ring portion of the unsaturated cyclic hydrocarbon group), a substituted 9 to 10-membered unsaturated cyclic hydrocarbon group (where Y ¹ is the unsaturated group) Bonded to the benzene ring portion of the cyclic hydrocarbon group, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group β), a 5- to 10-membered aromatic 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 β), a 9- to 10-membered unsaturated heterocyclyl group (provided that Y ¹ The unsaturated hete Bound to the aromatic ring moiety in cyclyl group), or a substituted 9 to 10 membered unsaturated heterocyclyl group (provided that, Y ¹ is bonded to the aromatic ring moiety in said unsaturated heterocyclyl group, the substituents may be the same or different And 1 to 3 groups selected from substituent group β);
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, C ₁ -C ₄ alkoxy group, and represents a group consisting of halogeno groups;
Substituent group β includes C ₁ -C ₆ alkyl group, hydroxy (C ₁ -C ₆ alkyl) group, carboxy (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkoxy) carbonyl- (C _1- C ₆ alkyl) group, halogeno C ₁ -C ₆ alkyl group (the halogeno C ₁ -C ₆ alkyl group represents a C ₁ -C ₆ alkyl group substituted with 1 to 7 halogeno groups), (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl) group, C ₂ -C ₇ alkenyl group, C ₂ -C ₇ alkynyl group, C ₃ -C ₈ cycloalkyl group, a hydroxyl groups, C ₁ -C ₆ alkoxy group, a halogeno C ₁ -C ₆ alkoxy group (said halogeno C ₁ -C ₆ alkoxy group represents a C ₁ -C ₆ alkoxy group substituted with 1 to 7 halogeno groups), C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl , Amino group, C ₁ -C ₆ alkylamino group, C ₃ -C ₈ cycloalkyl group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group may be the same or different, are two of the alkyl group 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. ), di (C ₃ -C ₈ cycloalkyl) amino group, N-(C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino group, formylamino group, (C ₁ -C ₆ alkyl) carbonylamino group, (C ₃ -C ₈ cycloalkyl) carbonylamino _{group, N - [(C 1 -C} 6 alkyl) carbonyl] -N- (C ₁ -C ₆ alkyl) amino group, N - [( C ₃ -C ₈ cycloalkyl) carbonyl] -N- (C ₁ -C ₆ alkyl ) Amino group, C ₁ -C ₆ alkylsulfonylamino group, N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₁ -C ₆ alkyl) amino group, N- (C ₁ -C ₆ alkylsulfonyl) -N- (C ₃ -C ₈ cycloalkyl) amino group, a formyl group, (C ₁ -C ₆ alkyl) carbonyl group, a carboxyl group, (C ₁ -C ₆ alkoxy) carbonyl group, a carbamoyl group, (C ₁ - C ₆ alkylamino) carbonyl group, (C ₃ -C ₈ cycloalkylamino) carbonyl group, di (C ₁ -C ₆ alkyl) aminocarbonyl group (the alkyl groups are the same or different, and the two alkyl groups are And together with the nitrogen atom of the amino group, 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) , N- (C ₃ -C ₈ Black alkyl) -N- (C ₁ -C ₆ alkyl) aminocarbonyl group, a cyano group, a nitro group, and represents a group consisting of halogeno groups;
Substituent group γ includes a C ₁ -C ₆ alkyl group, a hydroxy (C ₁ -C ₆ alkyl) group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a mercapto (C ₁ -C ₆ ). ₆ alkyl) group, (C ₁ -C ₆ alkylthio)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkylsulfinyl)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ (Alkylsulfonyl)-(C ₁ -C ₆ alkyl) group, amino (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkylamino)-(C ₁ -C ₆ alkyl) group, (C ₃ -C ₈ cycloalkylamino)-(C ₁ -C ₆ alkyl) group, di (C ₁ -C ₆ alkyl) amino- (C ₁ -C ₆ alkyl) group (the alkyl groups may be the same or different, and di (C ₁ The two alkyl groups of the —C ₆ alkyl) amino moiety together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms may be formed), a di (C ₃ -C ₈ cycloalkyl) amino- (C ₁ -C ₆ alkyl) group, [N - (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino] - (C ₁ -C ₆ alkyl) group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cycloalkyloxy group, a mercapto group, C ₁ -C ₆ alkylthio group, C ₃ -C ₈ cycloalkyl thio groups, C ₁ -C ₆ alkylsulfinyl group, C ₃ -C ₈ cycloalkyl-sulfinyl group, C ₁ -C ₆ alkyl sulfonyl group, C ₃ -C ₈ cycloalkyl sulfonyl group, an amino group, C ₁ -C ₆ alkylamino group, C ₃ -C ₈ cycloalkyl group, di (C ₁ -C ₆ alkyl) amino group (said alkyl group 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. ), di (C ₃ -C ₈ cycloalkyl) amino group, N-(C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino 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, a halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group) represents 1 to 7 of C ₁ -C ₆ alkoxy group substituted with halogeno group), C ₁ -C ₆ alkylamino group or a di (C ₁ -C ₆ alkyl) amino group (said alkyl group Are the same or different and each of the two alkyl groups together with the nitrogen atom of the amino group contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Or a pharmacologically acceptable salt or ester thereof. 2. The compound according to claim 1, which is a group having a) which may form a 7-membered saturated heterocyclyl group.
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). compound or a pharmacologically acceptable salt or ester as claimed in claim 1 is a group having been showing a C ₁ -C shows a ₄ alkoxy group) it was' substituted with a group.
The compound or a pharmacologically acceptable salt or ester thereof according to claim 1, wherein R ¹ is a group having the formula -COR ^9c (wherein R ^9c represents a C ₃ -C ₅ alkoxy group).
The compound or pharmacologically acceptable salt or ester thereof according to claim 1, wherein R ¹ is a group having the formula -COR ^9d (wherein R ^9d represents a 2-methyl-2-propoxy group). .
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.
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 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 a C ₁ -C substituted with 1 to 5 halogeno groups) ₄ represents an 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 A group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group; Group, C ₁ -C ₄ alkylsulfonyl group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are Together with the nitrogen atom of the amino group 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), a fluoro group, a chloro group or a bromo group The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt or ester thereof.
R ³ is 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 a C ₁ -C substituted with 1 to 5 halogeno groups) shows a ₄ alkyl group), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy groups, fluoro group, or, in any one of claims 1 to 8 chloro group The described compound or a pharmacologically acceptable salt or ester thereof.
R ³ is methyl group, ethyl group, 2-propyl group, 2-methyl-2-propyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, methoxy group, fluoro group, or chloro group The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt or ester thereof.
R ³ is a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, or a chloro group, or a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 8. Or ester.
The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt or ester thereof, wherein R ³ is a trifluoromethyl group.
2. 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 cyclopropyl group, a hydroxyl group, a methoxy group, a fluoro group, a chloro group, or a bromo group. The compound as described in any one of thru | or 13, or its pharmacologically acceptable salt or ester.
R ⁴ is hydrogen atom, R ⁵ is A compound or a pharmacologically acceptable salt or ester as claimed in any of claims 1 to 13 is a hydrogen atom or a hydroxyl group.
The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 13, 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 16, wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a methyl group.
The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 16, wherein R ⁶ and R ⁷ are hydrogen atoms.
R ⁸ represents the formula -X ^2a R ^10a
[Wherein R ^10a represents the formula —COR ^11a [wherein R ^11a represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy] Group, C ₃ -C ₆ cycloalkyloxy group, amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C _3- C ₆ cycloalkylamino group, di (C ₁ -C ₄ 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, A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of an atom and a sulfur atom), a hydroxylamino group, or a hydroxyl (C ₁ -C ₄ alkyl) ) Represents an amino group],
Wherein -SO ₂ R ^12a [wherein, R ^12a is, C ₁ -C ₄ alkyl group, (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₃ -C ₆ cycloalkyl group , Amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C ₃ -C ₆ cycloalkylamino group, or di ( C ₁ -C ₄ 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 are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) Which may form a 5 to 7-membered saturated heterocyclyl group containing 1 to 3 atoms of
Formula —N (R ^13a ) COR ^14a [wherein R ^13a is a hydrogen atom, a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or shows the C ₃ -C ₅ cycloalkyl group, R ^14a represents a hydrogen atom, C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or,, C ₃ A group having a —C ₅ cycloalkyl group],
Wherein _{^{-N (R 13a) SO 2 R}} 15a [ wherein, R ^13a have the same meanings as above, R ^15a is C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or a group having a shows a C ₃ -C ₅ cycloalkyl group or, represents the tetrazol-5-yl group,
X ^2a represents a single bond, a C ₁ -C ₂ alkylene group, or a substituted C ₁ -C ₂ alkylene group (the substituents may be the same or different, and may be one or two groups selected from the substituent group γ1). And the two substituents together may form a methylene group, an ethylene group, or a trimethylene group). A group having
Substituent group γ1 is methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group, methylthiomethyl group, methylthioethyl group, aminomethyl group, aminoethyl group, methylaminomethyl group, ethyl Aminomethyl group, methylaminoethyl group, cyclopropylaminomethyl group, cyclopropylaminoethyl group, dimethylaminomethyl group, dimethylaminoethyl group, (N-methyl-N-ethylamino) methyl group, dicyclopropylaminomethyl group , Hydroxyl group, methoxy group, ethoxy group, cyclopropyloxy group, methylthio group, ethylthio group, cyclopropylthio group, amino group, methylamino group, ethylamino group, cyclopropylamino group, cyclobutylamino group, dimethylamino group , Diethylamino group, The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 18, which is a group consisting of a dicyclopropylamino group, an N-cyclopropyl-N-methylamino group, a fluoro group, and a chloro group. Or ester.
R ⁸ represents the formula -X ^2b R ^10b
[Wherein, R ^10b represents a formula —COR ^11b [wherein R ^11b represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy] group, C ₃ -C ₅ cycloalkyl group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, a group having a methyl ethylamino group, or shows a hydroxylamino group],
Formula —SO ₂ R ^12b [wherein R ^12b represents a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or a C ₃ -C ₅ cyclo A group having an alkyl group] or a tetrazol-5-yl group,
X ^2b is a single bond, a methylene group, an ethylene group, or a substituted methylene group or a substituted ethylene group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ2, Two substituents may combine to form an ethylene or trimethylene group)];
Substituent group γ2 includes methyl group, ethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, (N-methyl-N-ethylamino) methyl group, methoxy group, The compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 18, which is a group consisting of an ethoxy group, a methylamino group, a dimethylamino group, a fluoro group, and a chloro group.
R ⁸ represents the formula -X ^2c R ^10c
[Wherein R ^10c represents a group having the formula —COR ^11c (wherein R ^11c represents a hydroxyl group or a methoxy group), or
Represents a group having the formula —SO ₂ R ^12c (wherein R ^12c represents a methyl group),
X ^2c is a single bond, a methylene group, or a substituted methylene group (the substituent is one group selected from the substituent group γ3, or the two substituents are combined together) An ethylene group may be formed). A group having
The substituent group γ3 is a group consisting of a methyl group, an ethyl group, a hydroxymethyl group, a dimethylaminomethyl group, a methoxy group, and an ethoxy group. Acceptable salt or ester.
R ⁸ represents the formula —X ^2d R ^10d
[Wherein R ^10d represents a group having the formula —COR ^11d (wherein R ^11d represents a hydroxyl group)
X ^2d represents a methylene group or a substituted methylene group (the substituent is one group selected from the substituent group γ4, or the two substituents together form an ethylene group; Which may be formed)
The substituent group γ4 is a group consisting of a methyl group, an ethyl group, and a hydroxymethyl group, or a compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 18.
R ⁸ represents the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a group having a methylene group or a substituted methylene group (the substituent is one methyl group), or a compound or pharmacological thereof according to any one of claims 1 to 18 Top acceptable salts or esters.
R ⁸ represents the formula -X ^2f R ^10f
[Wherein R ^10f represents a group having the formula —SO ₂ R ^12f (wherein R ^12f represents a methyl group),
The compound according to any one of claims 1 to 18, or a pharmacologically acceptable salt or ester thereof, wherein X ^2f represents a group having a single bond.
The compound or pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 24, wherein X ¹ is a group having the formula -NH-, -O- or -S-.
X ¹ is The compound or a pharmacologically acceptable salt or ester as claimed in any of claims 1 to 24 is a group having the formula -O-.
Y ¹ is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group α1), a 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group Represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group or a pyridazinyl group), or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group) , Furyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group, or pyridazinyl group, and the substituents are the same or different and are one or two groups selected from the substituent group α1 Is)
27. The substituent group α1 is a group consisting of a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a fluoro group, and a chloro group, or a compound according to any one of claims 1 to 26 Pharmacologically acceptable salt or ester.
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituent is a substituent) One group selected from group α2, and the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively, and a thienyl group (the thienyl group) And the substituted positions of X ¹ and Y ² bonded to the group are the 2 and 5 positions, respectively, and the substituted thienyl group (the substituent is one group selected from the substituent group α2), and the thienyl group X ¹ and Y ² are bonded at positions 2 and 5 respectively, and a pyridyl group (X ¹ and Y ² bonded to the pyridyl group are respectively substituted at positions 2 and 5 or 5 respectively. And 2nd place) or Pyridyl group (said substituent is one group selected from Substituent group [alpha] 2, the substitution position of X ¹ and Y ² are bonded to said pyridyl group are each 2 and 5 positions, or the 5 and 2 Is)
27. The substituent group α2 is a group consisting of a methyl group, a fluoro group, and a chloro group, or a compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 26.
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions, respectively) or a pyridyl group (the substitution of X ¹ and Y ² bonded to the pyridyl group) 27. The compound according to any one of claims 1 to 26, or a pharmacologically acceptable salt or ester thereof, wherein the positions are 5 and 2, respectively.
27. The compound according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof, wherein Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1- and 4-positions). Salt or ester.
Y ² is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group β1), an indanyl group or a tetrahydronaphthyl group (where Y ¹ is , Bonded to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group), substituted indanyl group or substituted tetrahydronaphthyl group (where Y ¹ is bonded to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group, and the substituent Are the same or different and are 1 to 3 groups selected from the substituent group β1), a 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, Oxazolyl group, thiazolyl group, pyridyl group or pyrimidinyl group) A substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group, and the substituents are the same or Unlike the above, it is 1 to 3 groups selected from the substituent group β1), a 9 to 10-membered unsaturated heterocyclyl group (wherein Y ¹ is bonded to the aromatic ring moiety in the unsaturated heterocyclyl group, The saturated heterocyclyl group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group), or a substituted 9 to 10-membered unsaturated heterocyclyl group (provided that Y ¹ is Bonded to the aromatic ring moiety in the unsaturated heterocyclyl group, the unsaturated heterocyclyl group is An indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group β1 );
Substituent group β1 includes a C ₁ -C ₆ alkyl group, a hydroxy (C ₁ -C ₄ alkyl) group, a carboxy (C ₁ -C ₄ alkyl) group, (C ₁ -C ₄ alkoxy) carbonyl- (C _1- (C ₄ alkyl) group, 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), (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₆ cycloalkyl group, a hydroxyl groups, 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 alkyl sulfonyl Group, amino group, C ₁ -C ₄ alkylamino group, C ₃ -C ₆ cycloalkyl group, di (C ₁ -C ₄ alkyl) amino group (said alkyl group may be the same or different, two of the alkyl group 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), formylamino group, (C ₁ -C ₄ alkyl) carbonylamino group, (C ₃ -C ₆ cycloalkyl) _{group, N - [(C 1 -C} 4 alkyl) carbonyl]-N-(C ₁ -C ₄ alkyl) amino _{group, N - [(C 3 -C} 6 cycloalkyl) carbonyl]-N-(C ₁ -C ₄ alkyl) amino group, C ₁ -C ₄ alkylsulfonylamino group, N- ( C ₁ -C ₄ alkylsulfonyl)-N-(C ₁ -C ₄ Alkyl) amino group, a formyl group, (C ₁ -C ₄ alkyl) carbonyl group, a carboxyl group, (C ₁ -C ₄ alkoxy) carbonyl group, a carbamoyl group, (C ₁ -C ₄ alkylamino) carbonyl group, di ( C ₁ -C ₄ alkyl) aminocarbonyl group (the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected), a cyano group, a nitro group, a fluoro group, a chloro group, and a bromo group, Item 31. The pharmacologically acceptable salt or ester thereof according to any one of Items 1 to 30.
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituents are the same or Differently, it is 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively) , A thienyl group (the positions of substitution of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively), a substituted thienyl group (the substituents are the same or different and are selected from the substituent group β2) 1 or 2 groups, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively, and the thiazolyl group (the substitution of Y ¹ and R ⁸ bonded to the thiazolyl group) Each position is 2 Preliminary 5-position is a) substituted thiazolyl group (said substituents may be the same or different and are 1 or 2 groups selected from Substituent group .beta.2, substitution of Y ¹ and R ⁸ are bonded to said thiazolyl group The positions are 2 and 5 positions, respectively), pyridyl group (the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, or the 3 and 5 positions, respectively) or the substitution A pyridyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, respectively; Or the 3rd and 5th positions);
Substituent group β2 is, C ₁ -C ₄ alkyl group, hydroxymethyl group, 1-hydroxyethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, pentafluoroethyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₄ cycloalkyl group, a hydroxyl group, a methoxy group, an ethoxy group, a methanesulfonyl group, an ethanesulfonyl group, an amino group, methylamino group, ethylamino group, dimethylamino The compound according to any one of claims 1 to 30, which is a group consisting of a group, a diethylamino group, a formyl group, a methylcarbonyl group, an ethylcarbonyl group, a cyano group, a nitro group, a fluoro group, and a chloro group Top acceptable salts or esters.
Y ² represents a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, and the substituent group β3 1 or 2 groups selected, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively, and a thienyl group (Y ¹ and R bonded to the thienyl group) ⁸ is substituted at positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β3, and are bonded to the thienyl group) Y ¹ and R ⁸ are substituted at positions 2 and 5 respectively), a pyridyl group (the positions of Y ¹ and R ⁸ bonded to the pyridyl group are substituted at positions 2 and 5 respectively), or Substituted pyridyl group Substituent is the same or different and are 1 or 2 groups selected from Substituent group .beta.3, in the substitution position of Y ¹ and R ⁸ are attached to the pyridyl group, respectively 2 and 5 positions) Yes;
Substituent group β3 is methyl, ethyl, 2-propyl, hydroxymethyl, trifluoromethyl, cyclopropyl, methoxy, methanesulfonyl, amino, methylamino, dimethylamino, methylcarbonyl The compound according to any one of claims 1 to 30, or a pharmacologically acceptable salt or ester thereof, which is a group consisting of a group, an ethylcarbonyl group, a cyano group, a nitro group, a fluoro group, and a chloro group.
Y ² represents a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, and the substituent group β3 1 group selected or 2 groups selected from the substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively) A thienyl group (the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively) or a substituted thienyl group (the substituents are the same or different and are selected from the substituent group β3) Or two groups selected from the substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively);
The substituent group β4 is a group consisting of a methyl group, an ethyl group, and a fluoro group, or a compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 30.
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively) or a substituted phenyl group (the substituent is selected from the substituent group β5) 1 group, 2 methyl groups, or 2 fluoro groups, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1- and 4-positions, respectively);
31. The compound according to claim 1, wherein the substituent group β5 is a group consisting of a methyl group, an ethyl group, a 2-propyl group, a trifluoromethyl group, a nitro group, a fluoro group, and a chloro group. Or a pharmacologically acceptable salt or ester thereof.
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively), a substituted phenyl group (the substituent is selected from the substituent group β6) And Y ¹ , R ⁸ bonded to the phenyl group and the substituents are substituted at positions 1, 3 and 2, respectively, and a pyridyl group (Y ¹ and R ⁸ bonded to the pyridyl group). Or the substituted pyridyl group (the substituent is one group selected from substituent group β6, and Y ¹ , R bonded to the pyridyl group are substituted positions of 3 and 5 respectively) ⁸ and the substitution positions of the substituents are the 3, 5, and 4 positions, respectively);
The substituent group β6 is a group consisting of a C ₁ -C ₄ alkyl group, a methoxy group, a fluoro group, and a chloro group, or a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30. Or ester.
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively) or a substituted phenyl group (the substituent is selected from the substituent group β7) And the substitution positions of Y ¹ , R ⁸ and the substituent bonded to the phenyl group are the ¹ , 3 and 2 positions, respectively);
The substituent group β7 is a group consisting of a methyl group, an ethyl group, a methoxy group, or a fluoro group, or a compound or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 30.
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, a halogeno C ₁ -C ₆ alkoxy group (the halogeno C ₁ -C ₆ alkoxy group) represents 1 to 7 of C ₁ -C ₆ alkoxy group substituted with halogeno group), C ₁ -C ₆ alkylamino group or a di (C ₁ -C ₆ alkyl) amino group (said alkyl group Are the same or different and each of the two alkyl groups together with the nitrogen atom of the amino group contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A 7-membered saturated heterocyclyl group may be formed);
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 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 a C ₁ -C substituted with 1 to 5 halogeno groups) ₄ represents an 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 A group (the halogeno C ₁ -C ₄ alkoxy group represents a C ₁ -C ₄ alkoxy group substituted with 1 to 5 halogeno groups), a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group; Group, C ₁ -C ₄ alkylsulfonyl group, amino group, C ₁ -C ₄ alkylamino group, di (C ₁ -C ₄ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are Together with the nitrogen atom of the amino group 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), a fluoro group, a chloro group or a bromo group Is;
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 cyclopropyl group, a hydroxyl 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 represents the formula -X ^2a R ^10a
[Wherein R ^10a represents the formula —COR ^11a [wherein R ^11a represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl) oxy] Group, C ₃ -C ₆ cycloalkyloxy group, amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C _3- C ₆ cycloalkylamino group, di (C ₁ -C ₄ 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, A 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of an atom and a sulfur atom), a hydroxylamino group, or a hydroxyl (C ₁ -C ₄ alkyl) ) Represents an amino group],
Wherein -SO ₂ R ^12a [wherein, R ^12a is, C ₁ -C ₄ alkyl group, (C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₄ alkyl) group, C ₃ -C ₆ cycloalkyl group , Amino group, C ₁ -C ₄ alkylamino group, [(C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl)] amino group, C ₃ -C ₆ cycloalkylamino group, or di ( C ₁ -C ₄ 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 are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) Which may form a 5 to 7-membered saturated heterocyclyl group containing 1 to 3 atoms of
Formula —N (R ^13a ) COR ^14a [wherein R ^13a is a hydrogen atom, a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or shows the C ₃ -C ₅ cycloalkyl group, R ^14a represents a hydrogen atom, C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or,, C ₃ A group having a —C ₅ cycloalkyl group],
Wherein _{^{-N (R 13a) SO 2 R}} 15a [ wherein, R ^13a have the same meanings as above, R ^15a is C ₁ -C ₄ alkyl group, (C ₃ -C ₅ cycloalkyl) - (C ₁ -C ₂ alkyl) group or a group having a shows a C ₃ -C ₅ cycloalkyl group or, represents the tetrazol-5-yl group,
X ^2a represents a single bond, a C ₁ -C ₂ alkylene group, or a substituted C ₁ -C ₂ alkylene group (the substituents may be the same or different, and may be one or two groups selected from the substituent group γ1). And the two substituents together may form a methylene group, an ethylene group, or a trimethylene group). A group having
X ¹ is a group having the formula —NH—, —O— or —S—;
Y ¹ is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group α1), a 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group Represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group or a pyridazinyl group), or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group) , A furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyridazinyl group, the substituents being the same or different and one or two groups selected from the substituent group α1 Is);
Y ² is a phenyl group, a substituted phenyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group β1), an indanyl group or a tetrahydronaphthyl group (where Y ¹ is , Bonded to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group), substituted indanyl group or substituted tetrahydronaphthyl group (where Y ¹ is bonded to the benzene ring moiety in the indanyl group or tetrahydronaphthyl group, and the substituent Are the same or different and are 1 to 3 groups selected from the substituent group β1), a 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, Oxazolyl group, thiazolyl group, pyridyl group or pyrimidinyl group) A substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group represents a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, or a pyrimidinyl group, and the substituents are the same or Unlike the above, it is 1 to 3 groups selected from the substituent group β1), a 9 to 10-membered unsaturated heterocyclyl group (wherein Y ¹ is bonded to the aromatic ring moiety in the unsaturated heterocyclyl group, The saturated heterocyclyl group represents an indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group), or a substituted 9 to 10-membered unsaturated heterocyclyl group (provided that Y ¹ is Bonded to the aromatic ring moiety in the unsaturated heterocyclyl group, the unsaturated heterocyclyl group is An indolinyl group, a dihydrobenzofuryl group, a dihydrobenzothienyl group, a tetrahydroquinolyl group, or a chromanyl group, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group β1 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)];
R ² is a hydrogen atom or a hydroxyl group;
R ³ is 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 a C ₁ -C substituted with 1 to 5 halogeno groups) ₄ represents an alkyl group), C ₃ -C ₅ cycloalkyl group, C ₂ -C ₄ alkenyl group, C ₁ -C ₄ alkoxy, fluoro, or chloro group;
R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom or a hydroxyl group;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2b R ^10b
[Wherein, R ^10b represents a formula —COR ^11b [wherein R ^11b represents a hydroxyl group, a C ₁ -C ₄ alkoxy group, (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) oxy] group, C ₃ -C ₅ cycloalkyl group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, a group having a methyl ethylamino group, or shows a hydroxylamino group],
Formula —SO ₂ R ^12b [wherein R ^12b represents a C ₁ -C ₄ alkyl group, a (C ₃ -C ₅ cycloalkyl)-(C ₁ -C ₂ alkyl) group, or a C ₃ -C ₅ cyclo A group having an alkyl group] or a tetrazol-5-yl group,
X ^2b is a single bond, a methylene group, an ethylene group, or a substituted methylene group or a substituted ethylene group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group γ2, Two substituents may combine to form an ethylene or trimethylene group)];
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituent is a substituent) One group selected from group α2, and the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively, and a thienyl group (the thienyl group) And the substituted positions of X ¹ and Y ² bonded to the group are the 2 and 5 positions, respectively, and the substituted thienyl group (the substituent is one group selected from the substituent group α2), and the thienyl group X ¹ and Y ² are bonded at positions 2 and 5 respectively, and a pyridyl group (X ¹ and Y ² bonded to the pyridyl group are respectively substituted at positions 2 and 5 or 5 respectively. And 2nd place) or Pyridyl group (said substituent is one group selected from Substituent group [alpha] 2, the substitution position of X ¹ and Y ² are bonded to said pyridyl group are each 2 and 5 positions, or the 5 and 2 Is)
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituents are the same or Differently, it is 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively) , A thienyl group (the positions of substitution of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively), a substituted thienyl group (the substituents are the same or different and are selected from the substituent group β2) 1 or 2 groups, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively, and the thiazolyl group (the substitution of Y ¹ and R ⁸ bonded to the thiazolyl group) Each position is 2 Preliminary 5-position is a) substituted thiazolyl group (said substituents may be the same or different and are 1 or 2 groups selected from Substituent group .beta.2, substitution of Y ¹ and R ⁸ are bonded to said thiazolyl group The positions are 2 and 5 positions, respectively), pyridyl group (the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, or the 3 and 5 positions, respectively) or the substitution A pyridyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, respectively; Or the 3 and 5 positions) or a pharmacologically acceptable salt or ester thereof.
R ¹ is a group having the formula —COR ^9c (wherein R ^9c represents a C ₃ -C ₅ alkoxy group);
R ² is a hydroxyl group;
R ³ is methyl group, ethyl group, 2-propyl group, 2-methyl-2-propyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, methoxy group, fluoro group, or chloro group Is;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2c R ^10c
[Wherein R ^10c represents a group having the formula —COR ^11c (wherein R ^11c represents a hydroxyl group or a methoxy group), or
Represents a group having the formula —SO ₂ R ^12c (wherein R ^12c represents a methyl group),
X ^2c is a single bond, a methylene group, or a substituted methylene group (the substituent is one group selected from the substituent group γ3, or the two substituents are combined together) An ethylene group may be formed). A group having
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are 1 and 4 positions, respectively) or a pyridyl group (the substitution of X ¹ and Y ² bonded to the pyridyl group) The positions are 5 and 2 respectively);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively), the substituted phenyl group (the substituents are the same or Differently, it is 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions or the 1 and 4 positions, respectively) , A thienyl group (the positions of substitution of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively), a substituted thienyl group (the substituents are the same or different and are selected from the substituent group β2) 1 or 2 groups, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively, and the thiazolyl group (the substitution of Y ¹ and R ⁸ bonded to the thiazolyl group) Each position is 2 Preliminary 5-position is a) substituted thiazolyl group (said substituents may be the same or different and are 1 or 2 groups selected from Substituent group .beta.2, substitution of Y ¹ and R ⁸ are bonded to said thiazolyl group The positions are 2 and 5 positions, respectively), pyridyl group (the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, or the 3 and 5 positions, respectively) or the substitution A pyridyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β2, and the substitution positions of Y ¹ and R ⁸ bonded to the pyridyl group are the 2 and 5 positions, respectively; Or the 3 and 5 positions) 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);
R ² is a hydroxyl group;
R ³ is a 2-propyl group, a 2-methyl-2-propyl group, a trifluoromethyl group, or a chloro group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula —X ^2d R ^10d
[Wherein R ^10d represents a group having the formula —COR ^11d (wherein R ^11d represents a hydroxyl group)
X ^2d represents a methylene group or a substituted methylene group (the substituent is one group selected from the substituent group γ4, or the two substituents together form an ethylene group; Which may be formed)
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are 1 and 4 positions, respectively) or a pyridyl group (the substitution of X ¹ and Y ² bonded to the pyridyl group) The positions are 5 and 2 respectively);
Y ² represents a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, and the substituent group β3 1 or 2 groups selected, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively, and a thienyl group (Y ¹ and R bonded to the thienyl group) ⁸ is substituted at positions 2 and 5, respectively, and a substituted thienyl group (the substituents are the same or different and are 1 to 2 groups selected from the substituent group β3, and are bonded to the thienyl group) Y ¹ and R ⁸ are substituted at positions 2 and 5 respectively), a pyridyl group (the positions of Y ¹ and R ⁸ bonded to the pyridyl group are substituted at positions 2 and 5 respectively), or Substituted pyridyl group Substituent is the same or different and are 1 or 2 groups selected from Substituent group .beta.3, in the substitution position of Y ¹ and R ⁸ are attached to the pyridyl group, respectively 2 and 5 positions) A compound according to claim 1 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);
R ² is a hydroxyl group;
R ³ is a trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² represents a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively), a substituted phenyl group (the substituents are the same or different, and the substituent group β3 1 group selected or 2 groups selected from the substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 4 positions, respectively) A thienyl group (the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively) or a substituted thienyl group (the substituents are the same or different and are selected from the substituent group β3) 1 or 2 groups selected from the substituent group β4, and the substitution positions of Y ¹ and R ⁸ bonded to the thienyl group are the 2 and 5 positions, respectively. Item 1 or a compound thereof Pharmacologically acceptable salt or ester.
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 trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are 1 and 4 positions, respectively) or a substituted phenyl group (the substituent is selected from substituent group β5) 1 group, 2 methyl groups, or 2 fluoro groups, and the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1- and 4-positions, respectively. 1 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);
R ² is a hydroxyl group;
R ³ is a trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively), a substituted phenyl group (the substituent is selected from the substituent group β6) And Y ¹ , R ⁸ bonded to the phenyl group and the substituents are substituted at positions 1, 3 and 2, respectively, and a pyridyl group (Y ¹ and R ⁸ bonded to the pyridyl group). Or the substituted pyridyl group (the substituent is one group selected from substituent group β6, and Y ¹ , R bonded to the pyridyl group are substituted positions of 3 and 5 respectively) ^The compound according to claim 1, or a pharmacologically acceptable salt or ester thereof, wherein ⁸ and the substituents are substituted at positions 3, 5, and 4, respectively.
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 trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2e R ^10e
[Wherein R ^10e represents a group having the formula —COR ^11e (wherein R ^11e represents a hydroxyl group)
X ^2e is a group having a methylene group or a substituted methylene group (the substituent is one methyl group);
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively) or a substituted phenyl group (the substituent is selected from the substituent group β7) The compound according to claim 1 or the pharmacology thereof, wherein Y ¹ , R ⁸ and the substitution position of the substituent bonded to the phenyl group are the ¹ , 3 and 2 positions, respectively. Top acceptable salts or esters.
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 trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2f R ^10f
[Wherein R ^10f represents a group having the formula —SO ₂ R ^12f (wherein R ^12f represents a methyl group),
X ^2f represents a single bond];
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively), a substituted phenyl group (the substituent is selected from the substituent group β6) And Y ¹ , R ⁸ bonded to the phenyl group and the substituents are substituted at positions 1, 3 and 2, respectively, and a pyridyl group (Y ¹ and R ⁸ bonded to the pyridyl group). Or the substituted pyridyl group (the substituent is one group selected from substituent group β6, and Y ¹ , R bonded to the pyridyl group are substituted positions of 3 and 5 respectively) ^The compound according to claim 1, or a pharmacologically acceptable salt or ester thereof, wherein ⁸ and the substituents are substituted at positions 3, 5, and 4, respectively.
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 trifluoromethyl group;
R ⁴ and R ⁵ are hydrogen atoms;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ represents the formula -X ^2f R ^10f
[Wherein R ^10f represents a group having the formula —SO ₂ R ^12f (wherein R ^12f represents a methyl group),
X ^2f represents a single bond];
X ¹ is a group having the formula —O—;
Y ¹ is a phenyl group (the substitution positions of X ¹ and Y ² bonded to the phenyl group are the 1 and 4 positions);
Y ² is a phenyl group (the substitution positions of Y ¹ and R ⁸ bonded to the phenyl group are the 1 and 3 positions, respectively) or a substituted phenyl group (the substituent is selected from the substituent group β7) The compound according to claim 1 or the pharmacology thereof, wherein Y ¹ , R ⁸ and the substitution position of the substituent bonded to the phenyl group are the ¹ , 3 and 2 positions, respectively. Top acceptable salts or esters.
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) propanoic acid,
1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) cyclopropanecarboxylic acid,
2- (4 '-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1'-biphenyl-4-yl) -3-hydroxypropanoic acid ,
2- [4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl] butanoic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-3-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methyl-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-chloro-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-chloro-1,1′-biphenyl-4-yl) acetic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-methoxy-1,1′-biphenyl-3-yl) propanoic acid ,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) propanoic acid ,
1- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) cyclopropane carboxylic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-methoxy-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-trifluoromethyl-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) acetic acid,
tert-butyl 6-[({2'-ethyl-4 '-[(methoxycarbonyl) methyl] -1,1'-biphenyl-4-yl} oxy) methyl] -2-hydroxy-3- (trifluoromethyl ) Benzoate,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4-yl) acetic acid,
(2-amino-4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-formyl-1,1′-biphenyl-4-yl) acetic acid,
(4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2- (hydroxymethyl) -1,1'-biphenyl-4-yl) acetic acid ,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyano-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-ethyl-1,1′-biphenyl-4-yl) acetic acid,
(4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-3-yl) acetic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -3-fluoro-1,1′-biphenyl-4-yl) -3 -(Dimethylamino) propanoic acid,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-ethyl-1,1′-biphenyl-4-yl) propanoic acid ,
[5- (4-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} phenyl) -4-methyl-2-thienyl] acetic acid,
2- (4 ′-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-nitro-1,1′-biphenyl-4-yl) propanoic acid ,
2- [4- (5-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-pyridinyl) -3-methylphenyl] propanoic acid,
2- (4 '-{[2- (tert-Butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-isopropyl-1,1'-biphenyl-4-yl) propanoic acid ,
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2,3-dimethyl-1,1′-biphenyl-4-yl) Propanoic acid and
2- (4 ′-{[2- (tert-butoxycarbonyl) -3-hydroxy-4- (trifluoromethyl) benzyl] oxy} -2-cyclopropyl-1,1′-biphenyl-4-yl) propane The compound according to claim 1 or a pharmacologically acceptable salt or ester thereof selected from the group consisting of acids.
R ¹¹ in group having the formula -COR ^11, shown in R ¹⁰ of the group having the formula -X ² R ¹⁰ in R ⁸ is a hydroxyl group, C ₁ -C ₆ alkoxy group, (C ₃ -C ₈ cycloalkyl )-(C ₁ -C ₆ alkyl) oxy group, C ₃ -C ₈ cycloalkyloxy group, amino group, C ₁ -C ₆ alkylamino group, [(C ₃ -C ₈ cycloalkyl)-(C _1- C ₆ alkyl)] amino group, C ₃ -C ₈ cycloalkylamino group, di (C ₁ -C ₆ alkyl) amino group (the alkyl groups are the same or different, and the two alkyl groups are the nitrogen of the amino group) Together with the atom, it may form a 5- to 7-membered saturated heterocyclyl group containing 1 to 3 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms), di [( C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₆ alkyl)] amino group, di (C ₃ -C ₈ cycloalkyl) amino _{group, N - [(C 3 -C} 8 cycloalkyl) - (C ₁ -C _{6 alkyl)] - N- (C 1 -C} 6 alkyl) amino group, N- (C ₃ -C ₈ cycloalkyl) -N- (C ₁ -C ₆ alkyl) amino _{group, N - [(C 3 -C} 8 cycloalkyl) - (C ₁ -C ₆ alkyl)] - N- (C ₃ -C ₈ cycloalkyl) amino group, hydroxylamino group, or hydroxyl (C ₁ -C ₆ alkyl) amino group,
X ^{2 of the} group having the formula —X ² R ¹⁰ in R ⁸ is a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents may be the same or different, The compound according to claim 1, wherein the compound is 1 to 2 groups selected from the group γ, and the two substituents may be combined to form an ethylene group or a trimethylene group). Or a pharmacologically acceptable salt or ester thereof.
R ⁸ is the formula -X ^2g R ^10g
[Wherein R ^10g represents a formula —COR ^11g [wherein R ^11g represents a hydroxyl group, a C ₁ -C ₆ alkoxy group, an amino group, a C ₁ -C ₆ alkylamino group, or a di (C _1- C ₆ 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 are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom 1 Or a tetrazol-5-yl group, which may form a 5 to 7-membered saturated heterocyclyl group containing 3 to 3 atoms),
X ^2g is a single bond, a C ₁ -C ₄ alkylene group, or a substituted C ₁ -C ₄ alkylene group (the substituents are the same or different and are selected from the group consisting of a C ₁ -C ₄ alkyl group and a halogeno group) 1 to 2 groups, and the two substituents together may form an ethylene group or a trimethylene group);
Y ¹ 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 δ), a 5- to 6-membered aromatic heterocyclyl group, or a substituted group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group δ);
Y ² 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 δ), a 5- to 6-membered aromatic heterocyclyl group, or a substituted group A 5- to 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from the substituent group δ);
Substituent group δ 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, C ₁ -C ₄ alkoxy groups, halogeno C ₁ -C ₄ alkoxy group (said halogeno C ₁ -C ₄ alkoxy groups, C ₁ substituted with 1 to 5 halogeno groups -C ₄ shows an alkoxy 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 (said alkyl group may be the same or different), a carboxyl group, (C ₁ -C ₄ alkoxy) carbonyl group, a cyano group, and, according to claim 1 is a group consisting of halogeno groups Compound or its pharmacology Top acceptable salts or esters.