TWI454473B - Fused ring compounds and use thereof - Google Patents

Description

Fused ring compound and its use

The present invention relates to a fused ring compound having glucokinase activation and which is useful as a therapeutic agent for diabetes or the like.

Glucose kinase (sometimes referred to as GK in this specification) (EC 2.7.1 1. 1) is one of the four hexokinases found in mammals, also known as hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate, the first step in glycolytic action. GK is mainly located in pancreatic β cells and liver, and acts as a receptor for extracellular glucose concentration in pancreatic β cells to control glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes a rate determining factor and regulates glycogen synthesis and glycolytic effects. The three hexokinases (I, II, III) other than GK achieve the highest enzyme activity at a glucose concentration of 1 mM or less. Conversely, GK has low affinity for glucose and a Km value of 8 to 15 mM, which is close to physiological blood glucose concentration. Therefore, GK media promotes intracellular glucose metabolism, which is equivalent to changing blood glucose from normal concentration (5 mM) to postprandial hyperglycemia concentration (10 to 15 mM).

Matschinsky et al. in 1984 proposed that the hypothesis that GK acts as a glucose receptor in pancreatic beta cells and hepatocytes has been confirmed in recent years by glucokinase transgenic mouse assays (see J. Biol. Chem., 1995). , vol. 270, p. 30253-30256; J. Biol. Chem., 1997, vol. 272, p. 22564-22569; J. Biol. Chem., 1997, vol. 272, p. 22570-22575; NIPPON RINSHO, 2002, vol. 60, p. 523-534; and Cell, 1995, vol. 83, p. 69-78). That is, a GK heterozygous-deficient mouse develops a hyperglycemic disorder, and an abnormal glucose-stimulated insulin secretion reaction further occurs. GK homozygous-deficient mice die shortly after birth due to significant hyperglycemia and symptoms of diabetes. On the other hand, mice overexpressing GK (heterozygous type) may have a decrease in blood glucose concentration, an increase in blood glucose clearance, and an increase in liver glycogen content. As a result of this, it is apparent that GK plays an important role in systemic glucose homeostasis. In other words, a decrease in GK activity leads to a decline in insulin secretion and a decrease in hepatic glucose metabolism, which leads to impaired glucose tolerance and diabetes. Conversely, an increase in GK activation or GK activity due to excessive performance promotes insulin secretion and promotes hepatic glucose metabolism, thereby increasing systemic glucose utilization and improving glucose tolerance.

In addition, the analysis of GK gene abnormalities mainly in the family of MODY2 (Maturity Onset Diabetes of the Young) shows that GK is also used as a glucose receptor in human body and is in the role of glucose stabilization. Play a key role (see Nature, 1992, vol. 356, p. 721-722). In the GK gene abnormality, since the affinity of GK for glucose is lowered (Km value is increased) and Vmax is decreased, the glucose threshold of blood in the insulin secretion action is increased, and the insulin secretion ability is decreased. In the liver, glucose absorption is reduced due to a decrease in GK activity, and thus a phenomenon of promoting glucose production, reducing hepatic sugar synthesis, and hepatic insulin resistance occurs. On the other hand, a family having a mutation phenomenon in which GK activity is increased has also been found. In these families, fasting hypoglycemia that occurs with an increase in insulin concentration in plasma is observed (see New England Journal Medicine, 1998, vol. 338, p. 226-230).

As mentioned above, GK acts as a glucose receptor in mammals, including humans, and plays an important role in glucose regulation in the blood. On the other hand, the use of the GK glucose receptor system to control blood glucose has opened a new way to treat diabetes in many patients with type 2 diabetes. In particular, since the GK activating substance is expected to exhibit an insulin secretion-promoting action in pancreatic β cells and exhibit an effect of promoting glucose absorption and inhibiting glucose release in the liver, it is suitable as a prophylactic or therapeutic agent for type 2 diabetes. In recent years, it has been known that pancreatic β-cell type glucokinase is locally expressed in the rat brain feeding center (lower ventral aspect: VMH). A small group of nerve cells present in VMH are called glucose-reactive neurons and play an important role in weight control. In electrophysiological tests, neurons are activated with physiological changes in glucose concentration (5 to 20 mM). However, since it is assumed that the glucose concentration sensor system of VMH has the same function as the insulin secretion of pancreatic β cells, it is different from pancreatic β cells and liver, and the agent that can activate VHM glucokinase should be It not only provides the effect of correcting blood glucose, but also improves obesity.

As described above, the GK-activating drug is suitable for the prevention or treatment of diabetes, diabetic complications, and obesity.

The following compounds have been proposed as ruthenium compounds.

(1) A compound has been proposed to express a compound of the following formula:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a nitro group, -CN, -OH, -COOH, -CF ₃ , -NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ each independently a hydrogen atom, C _1-6 alkyl, -CO-C _1-6 alkyl, -C _1-6 alkyl carboxy, -CC _1-6 alkyl -COOH, -SO ₂ CH ₃ , aryl, etc.), C _1-6 alkyl group, C _3-8 cycloalkyl group, heteroaryl group, etc.; R ⁵ is C _1-6 alkyl group; and A is a thiazolyl group which may be optionally substituted It is a glucokinase activator and is suitable for the treatment of diabetes and the like (WO 2005/049019 (PTL 1)).

(2) A compound has been proposed to express a compound of the following formula:

Wherein ring A is a 6-membered ring which may be substituted, W is O, S(O) _m (where m is 0, 1 or 2), CR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are each independently a hydrogen atom) Or C _1-6 alkyl), or NR ⁷ (wherein R ⁷ is a hydrogen atom or R ³ '-Y'-, wherein R ³ 'is a hydrocarbyl group which may be optionally substituted, a hydroxyl group which may be optionally substituted, optionally Substituted thiol group, optionally substituted amino group or optionally substituted heterocyclic group, and Y' is a bond, CO, S(O) _q (where q is 0, 1 or 2) or CR ⁸ 'R ⁹ ' (wherein R ⁸ 'and R ⁹ ' are independently hydrogen or C _1-6 alkyl), Y is a bond, CO, S(O) _p (where p is 0, 1 or 2) Or CR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are each independently a hydrogen atom or a C _1-6 alkyl group), and R ³ is a hydrocarbon group which may be optionally substituted, a hydroxyl group which may be optionally substituted, and a hydrogen which may be optionally substituted Thio group, optionally substituted amino group or optionally substituted heterocyclic group, Z is a bond, CO, O, S(O) _n (where n is 0, 1 or 2), or NR ¹⁰ (wherein R ¹⁰ is a hydrogen atom or a C _1-6 alkyl group), and R ¹ is a hydrogen atom, a halogen atom, a hydrocarbon group which may be optionally substituted, and a hydroxy group which may be optionally substituted Or a hydrogenthio group which may be substituted, R ² is a hydrogen atom, a hydrocarbyl group which may be substituted, a hydroxyl group which may be optionally substituted, a hydrogenthio group which may be substituted as needed, an amine group which may be optionally substituted or may be optionally required The substituted heterocyclic group, or R ¹ and R ^{2 ,} are bonded to each other to form a ring which may optionally be substituted, which is a glucokinase activator (WO 2006/112549 (PTL 2)).

(3) A compound has been proposed to express a compound as follows:

Wherein R ¹ is an aryl group which may be optionally substituted or a heteroaryl group which may be optionally substituted; R ¹¹ is an optionally substituted aryl group, a 5- to 7-membered aliphatic heterocyclic group, or may be optionally substituted. 5- or 6-membered heteroaryl; R ² is indolyl, OH, C _1-6 alkyl, -CH _3-a F _a , -OCH _3-a F _a (where a is 1 to 3), Amino, cyano, halogen atom or -(CH ₂ ) _1-4 -OH; R ³ is C _1-6 alkyl, -(CH ₂ ) _1-6 -OH, -C(O)-OC _{1- 6} alkyl, -(CH ₂ ) _1-6 -OC _1-6 alkyl, -(CH ₂ ) _1-6 -NH ₂ , cyano, -C(O)-C _1-6 alkyl, halogen atom , C _2-6 alkenyl, -OC _1-6 alkyl, -COOH or OH; R ⁴ is a hydrogen atom or a C _1-6 alkyl group; Y is a carbon atom or a nitrogen atom; Z ₁ is -O-, - S-, -S(O)- or S(O) ₂ -; Z ₂ is -O-, -S-, -S(O)-, S(O) ₂ - or -CH ₂ -, as needed Substituted by a halogen atom, a C _1-6 alkyl group or the like, or a single bond; at least two of Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently a carbon atom, and the remainder are carbon atoms or nitrogen atoms; Ring A is a heteroaryl group; X is a carbon atom or a nitrogen atom; m is 0 to 2; and q is 0 to 2, which is a glucokinase activator suitable for treating diabetes, obesity Symptoms, etc. (WO 2007/037534 (PTL 3)).

However, none of the above prior art articles discloses the following formula (I).

Excerpt from the list of patent documents

PTL 1: WO 2005/049019

PTL 2: WO 2006/112549

PTL 3: WO 2007/037534

An object of the present invention is to provide a glucokinase activator or the like suitable for use as a medicament, which is, for example, a medicament for preventing or treating diabetes, obesity or the like.

The inventors have conducted intensive studies and found a compound represented by the formula (I) or a salt thereof (hereinafter referred to simply as the compound (I)]:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be replaced as needed; W ¹ and W ² are independently O, S, SO, SO ₂ Or NR ⁴ , wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group; R ¹ is a substituted methyl group, optionally substituted C _2-6 alkyl group, optionally substituted C _3-10 naphthenic ring a C _6-14 aryl group which may be substituted or a heterocyclic group which may be optionally substituted; R ² is a C _1-6 alkyl group which may be optionally substituted or a C _3-10 cycloalkyl group which may be optionally substituted And R ³ is a hydrogen atom or a halogen atom, but the limitation is that N-methyl-4-[(1-methyl-1H-tetrazol-5-yl)thio]-2-(1, 3-thiazol-2-yl)-1H-indole-7-amine, which has surprisingly superior glucokinase activation and has excellent properties as a drug, such as stability, etc., and is safe and suitable. The medicament thus completes the invention.

Therefore, the present invention is related

[1] A compound represented by the formula (I) or a salt thereof:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be replaced as needed; W ¹ and W ² are independently O, S, SO, SO ₂ Or NR ⁴ , wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group; R ¹ is a substituted methyl group, optionally substituted C _2-6 alkyl group, optionally substituted C _3-10 naphthenic ring a C _6-14 aryl group which may be substituted or a heterocyclic group which may be optionally substituted; R ² is a C _1-6 alkyl group which may be optionally substituted or a C _3-10 cycloalkyl group which may be optionally substituted And R ³ is a hydrogen atom or a halogen atom, but the limitation is that N-methyl-4-[(1-methyl-1H-tetrazol-5-yl)thio]-2-(1, 3-thiazol-2-yl)-1H-indole-7-amine;

[2] A compound represented by the formula (I) or a salt thereof:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be replaced as needed; W ¹ and W ² are independently O, S, SO, SO ₂ Or NR ⁴ , wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group; R ¹ is a C _3-10 cycloalkyl group which may be optionally substituted, optionally substituted C _6-14 aryl or may be optionally substituted a heterocyclic group; R ² is a C _1-6 alkyl group which may be optionally substituted or a C _3-10 cycloalkyl group which may be optionally substituted; and R ³ is a hydrogen atom or a halogen atom, but the limitation is not including N-methyl-4-[(1-methyl-1H-tetrazol-5-yl)thio]-2-(1,3-thiazol-2-yl)-1H-indole-7-amine;

[3] A compound represented by the formula (I) or a salt thereof:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be replaced as needed; W ¹ and W ² are independently O, S, SO, SO ₂ Or NR ⁴ , wherein R ⁴ is C _1-6 alkyl; R ¹ is C _3-10 cycloalkyl which may be substituted, _optionally substituted C _6-14 aryl or optionally substituted heterocyclic ring And R ² is a C _1-6 alkyl group which may be optionally substituted or a C _3-10 cycloalkyl group which may be optionally substituted; and R ³ is a hydrogen atom or a halogen atom;

[4] A compound represented by the formula (I) or a salt thereof:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be substituted as needed; W ¹ and W ² are independently O, S, SO or SO ₂ And R ¹ is a C _3-10 cycloalkyl group which may be optionally substituted, a C _6-14 aryl group which may be substituted or a heterocyclic group which may be optionally substituted; and R ² is a C _{1-6 which} may be optionally substituted. An alkyl group or a C _3-10 cycloalkyl group which may be substituted; and R ³ is a hydrogen atom or a halogen atom;

[5] The compound of the above [1], wherein the ring A is benzene;

[6] The compound of the above [1], wherein the B ring is a 5-membered nitrogen-containing hetero ring which may be optionally substituted;

[7] The compound of the above [1], wherein W ¹ and W ² are both O;

[8] The compound of the above [1], wherein R ¹ is a C _6-14 aryl group which may be optionally substituted or a heterocyclic group which may be optionally substituted;

[9] The compound of the above [1], wherein R ² is a C _1-6 alkyl group which may be optionally substituted;

[10] The compound of the above [1], wherein R ³ is a hydrogen atom;

[11] The compound of the above [1], wherein the ring A is benzene, and the ring B is a 5-membered nitrogen-containing hetero ring which may be optionally substituted, and W ¹ and W ² are both O, and R ^{1 may} be optionally substituted. a C _6-14 aryl group or a heterocyclic group which may be optionally substituted, R ² is a C _1-6 alkyl group which may be optionally substituted, and R ³ is a hydrogen atom;

[12] A compound represented by formula (II) or a salt thereof (hereinafter referred to as compound (II)]:

The ring A is a 6-membered ring which can be replaced by a visible one; the ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which can be substituted as needed; W ¹ and W ² are independently O, S, SO or SO ₂ And R ¹ is a C _3-10 cycloalkyl group which may be optionally substituted, a C _6-14 aryl group which may be substituted or a heterocyclic group which may be optionally substituted; and R ² is a C _{1-6 which} may be optionally substituted. An alkyl group or a C _3-10 cycloalkyl group which may be substituted; and R ³ is a hydrogen atom or a halogen atom;

[13] 2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4, 5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide or a salt thereof;

[14] 2-(2-{7-(2-Methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2 -yl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol or a salt thereof;

[15] 2-Methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H -Indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol or a salt thereof;

[16] N-(2-Hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy }}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide or a salt thereof;

[17] 2-[2-(7-Ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4, 5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide or a salt thereof;

[18] N-[2-Hydroxypropyl]-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-IH- Ind-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide or a salt thereof;

[19] A prodrug of the compound of the above [I];

[20] A glucokinase activator comprising the compound of the above [I] or a prodrug thereof;

[21] An agent comprising the compound of the above [I] or a prodrug thereof;

[22] The agent according to the above [21], which is an agent for preventing or treating diabetes or obesity;

[23] A method for preventing or treating diabetes or obesity in a mammal, comprising administering to the mammal a compound of the above [I] or a prodrug thereof;

[24] Use of a compound of the above [I] or a prodrug thereof for the manufacture of a medicament for preventing or treating diabetes or obesity;

The utility of the invention

Since the compound (I) has an excellent glucokinase activation action, the compound (I) is suitably used as a pharmaceutical agent, for example, a medicament for preventing or treating diabetes, obesity, or the like.

Unless otherwise stated herein, "halogen atom" in the specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Unless otherwise stated herein, "C _1-3 alkylenedioxy" as used herein means methylenedioxy, ethylenedioxy, and the like.

Unless otherwise stated herein, "C _1-6 alkyl" as used in the specification means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third Butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- Dimethyl butyl, 2-ethyl butyl and the like.

Unless otherwise stated herein, "C _2-6 alkyl" as used in the specification means ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, Pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethyl Butyl, 2-ethylbutyl and the like.

Unless otherwise stated herein, "C _1-6 alkoxy" in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Dibutoxy, tert-butoxy, and the like.

Unless otherwise stated herein, " _C1-6 alkoxy-carbonyl" in the specification means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a third butoxycarbonyl group or the like.

Unless otherwise stated herein, "C _1-6 alkyl-carbonyl" as used in the specification means ethyl, propyl, butyl, isobutyl, pentylene, isoamyl, hexyl. Wait.

The codes in the chemical formula are described in detail below.

R ¹ is a substituted methyl group, optionally substituted C _2-6 alkyl, optionally substituted C _3-10 cycloalkyl, optionally substituted C _6-14 aryl or optionally substituted Heterocyclic group.

The R ¹ "of the optionally substituted C _2-6 alkyl" of the "C _2-6 alkyl" and "the substituted methyl" in the "group" may optionally have at position 1 of the substituted Up to 3 substituents.

Examples of substituents include

(1) C _3-10 cycloalkyl (for example: cyclopropyl, cyclohexyl);

(2) C _6-14 aryl (for example: phenyl, naphthyl) which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed.

(b) hydroxyl,

(c) a C _1-6 alkoxy group, and

(d) a halogen atom;

(3) An aromatic heterocyclic group (for example, thienyl, furyl, pyridyl, pyrimidinyl, anthracene) base, Azyl, thiazolyl, tetrazolyl, Diazolyl, pyridyl a group, a quinolyl group, a fluorenyl group, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed.

(b) hydroxyl,

(c) a C _1-6 alkoxy group, and

(d) a halogen atom;

(4) Non-aromatic heterocyclic groups (for example, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperidine) Base, two Moki, two Alkanoalkyl, 1,3-dihydro-2-benzofuranyl, thiazolidinyl, thiazolinyl), which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of:

(a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed.

(b) hydroxyl,

(c) C _1-6 alkoxy,

(d) C _1-6 alkyl-carbonyl,

(e) C _1-6 alkylsulfonyl,

(f) a pendant oxy group, and

(g) a halogen atom;

(5) an amine group which may be mono- or disubstituted by a substituent selected from the following: if necessary:

(a) a C _1-6 alkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a C _1-6 alkylsulfonyl group (for example, methylsulfonyl),

(b) C _1-6 alkyl-carbonyl,

(c) a C _1-6 alkoxy-carbonyl group which may be optionally substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group),

(d) a C _6-14 aryl-carbonyl group (eg, benzamidine),

(e) C _7-13 aralkyl-carbonyl (eg benzylcarbonyl, phenylethylcarbonyl),

(f) an aminemethanyl group which may be mono- or disubstituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a C _6-14 aryl group (for example, a phenyl group) and a C _7-13 aralkyl group, as necessary. Base (eg benzyl),

(g) C _1-6 alkylsulfonyl (for example: methylsulfonyl, ethylsulfonyl, isopropylsulfonyl),

(h) C _6-14 arylsulfonyl (for example: phenylsulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl), which may be substituted with 1 to 3 C _1-6 alkyl groups as needed ,

(i) a C _7-13 aralkylsulfonyl group (eg, benzylsulfonyl),

(j) a C _3-10 cycloalkyl group (for example, cyclohexyl) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a C _1-6 alkyl group,

(k) an aromatic heterocyclic group (for example, a triazolyl group), and

(1) a non-aromatic heterocyclic group (for example, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxyindolizidine); Note: oxido has a condition called oxygen anion group]

(6) formazan;

(7) C _1-6 alkyl-carbonyl, which may optionally be substituted with 1 to 3 halogen atoms;

(8) a C _1-6 alkoxy-carbonyl group which may be optionally substituted with 1 to 3 halogen atoms;

(9) an aromatic heterocyclic group-carbonyl group (for example, thienylcarbonyl group, mercaptocarbonyl group), which may be substituted with 1 to 3 amine groups as needed [the amine group may be optionally substituted with a substituent selected from the following Substituted or disubstituted: C _1-6 alkyl and aromatic heterocyclic-sulfonyl (eg, thienylsulfonyl)];

(10) Non-aromatic heterocyclic-carbonyl (for example: piperidinylcarbonyl, piperidine Alkylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxo-oxythiomorpholinylcarbonyl, 1,1-dioxainylthiomorpholinylcarbonyl, pyrrolidinylcarbonyl, nitrogen heterocycle Butanylcarbonyl) which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) a C _1-6 alkyl group which may be substituted with from 1 to 3 hydroxy groups as desired.

(c) a halogen atom,

(d) carboxyl group,

(e) C _1-6 alkoxy-carbonyl,

(f) an amine group, and

(g) C _1-6 alkylsulfonyl;

(11) C _1-6 alkylsulfonyl (for example: methylsulfonyl, ethylsulfonyl), which may be substituted with 1 to 3 halogen atoms as needed;

(12) an amine carbaryl group which may be mono- or disubstituted by a substituent selected from the following: if necessary:

(a) a C _1-6 alkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a C _1-6 alkoxy group, a C _1-6 alkylsulfonyl group (for example, a methyl group). Sulfhydryl) and an aromatic heterocyclic group (eg, furyl),

(b) a C _6-14 aryl group (eg phenyl),

(c) a C _7-13 aralkyl group (eg benzyl),

(d) C _1-6 alkoxy,

(e) a C _3-10 cycloalkyl group (eg, cyclopropyl),

(f) a C _1-6 alkylsulfonyl group (for example: methylsulfonyl),

(g) an aromatic heterocyclic group (for example, a triazolyl group or a tetrazolyl group), and

(h) a non-aromatic heterocyclic group (for example, tetrahydropyranyl);

(13) an thiocarbamoyl group which may be mono- or disubstituted by the following groups as needed: a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;

(14) an amine sulfonyl group which may be mono- or disubstituted by the following groups as needed: a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;

(15) a carboxyl group;

(16) a hydroxyl group;

(17) C _1-6 alkoxy, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom,

(b) carboxyl group,

(c) a C _1-6 alkoxy group, and

(d) C _1-6 alkoxy-carbonyl;

(18) a C _2-6 alkenyloxy group (for example, a vinyloxy group) which may be optionally substituted with 1 to 3 halogen atoms;

(19) C _3-10 cycloalkyloxy (for example: cyclohexyloxy);

(20) a C _7-13 aralkyloxy group (for example, a benzyloxy group) which may be optionally substituted with 1 to 3 halogen atoms;

(21) C _6-14 aryloxy (eg phenyloxy, naphthyloxy);

(22) C _1-6 alkyl-carbonyloxy (eg, ethoxycarbonyl, tert-butylcarbonyloxy);

(23) a hydrogenthio group;

(24) C _1-6 alkylthio (for example: methylthio, ethylthio), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom,

(b) C _6-14 aryl, and

(c) a carboxyl group;

(25) C _6-14 arylthio (for example, phenylthio, naphthylthio);

(26) an aromatic heterocyclic group-thio group (for example, tetrazolylthio group) which may be optionally substituted with 1 to 3 C _1-6 alkyl groups;

(27) a sulfo group;

(28) cyano group;

(29) an azide group;

(30) nitro;

(31) nitroso;

(32) a halogen atom;

(33) C _1-6 alkylsulfinyl (for example: methylsulfinyl);

(34) C _3-10 cycloalkyl-C _1-6 alkyloxy (for example: cyclopropylmethyloxy);

(35) C _1-3 alkyl dioxy;

(36) an aromatic heterocyclic group-carbonylthio group (for example, a mercaptocarbonylthio group) which may be optionally substituted with 1 to 3 amine groups [the amine group may be optionally substituted by a substituent selected from the following: Or disubstituted: C _1-6 alkyl and aromatic heterocyclic-sulfonyl (for example: thienylsulfonyl)];

(37) formazan;

(38) An aromatic heterocyclic group-oxy group (for example, pyrimidinyloxy group, pyridyl) Baseoxy);

(39) C _1-6 alkylsulfonyloxy (for example: methylsulfonyloxy);

(40) C _2-6 alkenyl-carbonyl (for example: vinylcarbonyl);

(41) a non-aromatic heterocyclic group-carbonyloxy group (for example, morpholinylcarbonyloxy group) which may be optionally substituted with 1 to 3 C _1-6 alkyl groups;

(42) di-t-butylphenyl decyloxy; and the like. When two or more substituents are used, the substituents may be the same or different.

Examples of the "C _3-10 cycloalkyl group" of "C _3-10 cycloalkyl group which may be substituted as needed" of R ¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a ring. Xinji et al.

The above C _3-10 cycloalkyl group may be condensed with a benzene ring as needed to form a fused ring group. Examples of the fused ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, anthryl and the like. Further, the above C _3-10 cycloalkyl group includes a crosslinked hydrocarbon group such as a bicyclo[2.2.1]heptyl group, a bicyclo[2.2.2]octyl group, a bicyclo[3.2.1]octyl group, a bicyclo[3.2.2] Mercapto, bicyclo [3.3.1] fluorenyl, bicyclo [4.2.1] fluorenyl, bicyclo [4.3.1] fluorenyl, adamantyl, norbornyl, etc., etc.

R "of the optionally substituted C _3-10 cycloalkyl group" of ¹ of the "C _3-10 cycloalkyl group" in the optionally may have 1 to 3 substituents of the substituted position.

Examples of substituents include

(1) "C _2-6 alkyl group" in the "C _2-6 alkyl group which may be optionally substituted" of R ¹ may _optionally have a substituent example;

(2) C _1-6 alkyl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom,

(b) carboxyl group,

(c) hydroxyl group,

(d) a C _1-6 alkoxy group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and a C _1-6 alkoxy-carbonyl group,

(e) C _1-6 alkyl-carbonyl,

(f) C _1-6 alkoxy-carbonyl,

(g) a C _1-6 alkyl-carbonyloxy group (e.g., an etecyloxy group, a tert-butylcarbonyloxy group),

(h) an amine carbenyl group which may be mono- or disubstituted by a substituent selected from the following: if necessary:

(i) a C _1-6 alkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group, a hydroxyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy group, a carbonyl group, and an amine group. With C _1-6 alkylsulfonyl,

(ii) a C _3-10 cycloalkyl group which may optionally be substituted with 1 to 3 substituents selected from C _1-6 alkyl, carboxy, hydroxy, C _1-6 alkoxy-carbonyl, amine With C _1-6 alkylsulfonyl,

(iii) a C _1-6 alkylsulfonyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl, carboxyl, hydroxy, C _1-6 alkoxy-carbonyl and Amine group, and

(iv) an amine group which may be mono- or disubstituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a carboxyl group, a hydroxyl group, a C _1-6 alkoxy group-carbonyl group and a C _1-6 alkyl group.醯基,

(i) an aromatic heterocyclic group (for example, thienyl, tetrazolyl, imidazolyl, furyl, pyridyl) which may be substituted with 1 to 3 C _1-6 alkyl groups as needed,

(j) non-aromatic heterocyclic groups (eg, tetrahydrofuranyl, N-piperidinyl, piperidine) Base, morpholinyl, dihydrogen Diazolyl, hexahydropyridyl and Base (eg hexahydropyridyl) And [2,1-c][1,4] a thiomorpholinyl group, a 1-oxooxythiomorpholinyl group, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl-carbonyl and pendant oxy group,

(k) an amine group which may be mono- or disubstituted by a substituent selected from the following:

(i) a C _1-6 alkyl group which may optionally be substituted with 1 to 3 substituents selected from the group consisting of non-aromatic heterocyclic groups (for example: morpholinyl), C _1-6 alkoxy groups and C _{1 -6} alkylsulfonyl, and

(ii) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl),

(l) a C _1-6 alkylsulfonyl group which may be substituted with 1 to 3 carboxyl groups as needed.

(m) a C _1-6 alkylthio group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group, a C _1-6 alkoxy-carbonyl group, a hydroxyl group and an amine mercapto group,

(n) a phosphono group, which may be mono- or di-substituted with a C _1-6 alkyl group as desired.

(o) a non-aromatic heterocyclic group-carbonyl group (for example, morpholinylcarbonyl),

(p) an aromatic heterocyclic group-carbonyl group (for example, thienylcarbonyl, fluorenylcarbonyl);

(q) cyano group, and

(r) a C _6-14 aryloxy group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and a C _1-6 alkoxy-carbonyl group;

(3) a C _2-6 alkenyl group (for example, a vinyl group, a 1-propenyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom,

(b) carboxyl group,

(c) C _1-6 alkoxy-carbonyl, and

(d) an amine methyl sulfhydryl group;

(4) C _7-13 aralkyl (for example: benzyl) which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed.

(b) hydroxyl,

(c) a C _1-6 alkoxy group, and

(d) a halogen atom; When two or more substituents are used, the substituents may be the same or different.

Examples of the "C _6-14 aryl group" in the "C _6-14 aryl group which may be _optionally substituted" of R ¹ include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, an anthracenyl group, a biphenyl group and the like. Among them, a phenyl group, a 1-naphthyl group or a 2-naphthyl group is preferred.

The "C _6-14 aryl group" in the "C _6-14 aryl group which may be optionally substituted" of R ¹ may optionally have 1 to 3 substituents at a position which may be substituted. Examples of the substituent include those which may be optionally substituted with "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

Examples of the "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

Examples of the aromatic heterocyclic group include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (which contains 1 to 4 in addition to a carbon atom as a ring constituent atom) One is selected from the group consisting of an oxygen atom, a sulfur atom (which may be oxidized as needed) and a hetero atom of a nitrogen atom, and a fused aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a group derived from a fused ring or the like, which is composed of a ring corresponding to a 4- to 7-membered monocyclic aromatic heterocyclic group and 1 or 2 selected ones. 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms (eg pyrrole, imidazole, pyrazole, pyridinium) , pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing a sulfur atom (for example, thiophene) is condensed with a ring of a benzene ring.

Preferable examples of the aromatic heterocyclic group include a monocyclic aromatic heterocyclic group such as a furyl group (e.g., 2-furyl group, 3-furyl group), a thienyl group (e.g., 2-thienyl group, 3-thiophene group). , pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridine (eg 2-pyridinyl, 4-pyrimidinyl, 5-pyrimidinyl), hydrazine Base (for example: 3-嗒 Base, 4-嗒 Base Base (for example: 2-pyridyl a pyrrolyl group (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), Pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl ( For example: 4-isothiazolyl), Azolyl (eg 2- Azolyl, 4- Azolyl, 5- Zozolyl) Azolyl, Diazolyl (eg 1,2,4- Diazol-3-yl, 1,2,4- Diazol-5-yl, 1,3,4- Diazol-2-yl), thiadiazolyl (eg: 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiazide Diazol-5-yl), triazolyl (eg: 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazole-1 -yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl) ,three Base (for example: 1, 2, 4-three -1-base, 1,2,4-three -3-yl) and the like; a fused heterocyclic group such as a quinolyl group (for example, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolinyl), isoquinoline a group (for example, 3-isoquinolinyl), a quinazolinyl group (for example, 2-quinazolinyl, 4-quinazolinyl), quinolin Lolinyl (eg 2-quinoline Lolinyl, 6-quinoline Phenyl), benzofuranyl (eg 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg 2-benzothienyl, 3-benzothienyl), benzo Azolyl (eg 2-benzo) Zozolyl) Azolyl (eg 7-benziso) Zizozolyl), benzothiazolyl (eg 2-benzothiazolyl), benzimidazolyl (eg benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl) , benzotriazolyl (for example: 1H-1,2,3-benzotriazol-5-yl), fluorenyl (for example: ind-1-yl, ind-2-yl, anthracene) 3-yl, indol-5-yl), carbazolyl (eg 1H-carbazol-3-yl), pyrrolopypene Base (for example: 1H-pyrrolo[2,3-b]pyridyl -2-yl, 1H-pyrrolo[2,3-b]pyridyl -6-yl), imidazopyridyl (for example: 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazole And [1,2-a]pyridin-3-yl), imidazopyridine Base (for example: 1H-imidazo[4,5-b]pyridinyl 2-yl), imidazothiazolyl (eg imidazo[2,1-b]thiazol-5-yl), pyrazolopyridyl (eg 1H-pyrazolo[4,3-c]pyridine- 3-yl), pyrazolo-thienyl (for example: 2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolo Base (for example: pyrazolo[5,1-c][1,2,4] -3-yl) et al;

Examples of the non-aromatic heterocyclic group include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group (which contains 1 in addition to a carbon atom as a ring constituent atom) Up to 4 hetero atoms selected from oxygen atoms, sulfur atoms (which may be oxidized as needed) and nitrogen atoms, and fused non-aromatic heterocyclic groups. Examples of the condensed non-aromatic heterocyclic group include a group derived from a fused ring derived from a ring corresponding to a 4- to 7-membered monocyclic non-aromatic heterocyclic group and 1 or 2 A 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing one or two nitrogen atoms (eg, pyrrole, imidazole, pyrazole, pyridinium) , pyridine, pyrimidine, pyrrolidine, imidazolium, pyrazole, piperidine, piperidine a 5-membered aromatic or non-aromatic heterocyclic ring containing a sulfur atom (for example, thiophene, tetrahydrothiophene) condensed with a ring of a benzene ring, and a portion in which the above group is saturated, and the like.

Preferable examples of the non-aromatic heterocyclic group include a monocyclic non-aromatic heterocyclic group such as a tetrahydrofuranyl group (e.g., 2-tetrahydrofuranyl group), a pyrrolidinyl group (e.g., 1-pyrrolidinyl group), and a piperidinyl group. (eg N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (eg N-morpholinyl), thiomorpholinyl (eg N - thiomorpholinyl), 1-oxo-ionic thiomorpholinyl (for example: 1-oxo-oxathiomorpholin-4-yl), 1,1-dioxo-ionic thiomorpholinyl ( For example: 1,1-dioxy-ionic thiomorpholin-4-yl), piperazine Base (eg 1-piper Base, 2-pipeper Base, 3-piperider a hexamethyleneimine group (for example, hexamethyleneimine-1-yl), Azolidinyl (eg: Zoxadin-2-yl), thiazolidinyl (eg thiazolidin-2-yl), imidazolidinyl (eg imidazolidin-2-yl, imidazolidin-3-yl), Oxazolinyl (eg: Oxazolin-2-yl), thiazolinyl (eg thiazolin-2-yl), imidazolinyl (eg imidazolin-2-yl, imidazolin-3-yl), Moki (for example: 1,3-two Mole-4-yl), two Alkyl groups (for example: 1,3-two Methane-4-yl), dihydrogen Diazolyl (eg 4,5-dihydro-1,2,4- Diazol-3-yl), thioketo Azolidinyl (for example: 2-thioketo-1,3- Zoxazin-5-yl), piperidyl (eg 4-chloropyranyl), tetrahydropyranyl (eg 4-tetrahydropyranyl), thiopyranyl (eg 4-thiopyranyl) , tetrahydrothiopyranyl (for example: 4-tetrahydrothiopyranyl), 1-oxoionic tetrahydrothiopyranyl (for example: 1-oxo-yltetrahydrothiopyran-4-yl), 1,1- Dioxy ion-tetrahydrothiopyranyl (for example: 1,1-dioxainyltetrahydrothiopyran-4-yl), pyrazolyl (for example: pyrazolidine-1-yl), tetrahydropyrimidinyl ,two Alkyl (eg 1,3-di) Alkan-2-yl, 1,3-two Alk-4-yl, 1,3-two Alkan-5-yl, 1,4-two Alkan-2-yl), dioxolyl (for example: 4H-1,3-dioxen-2-yl, 4H-1,3-dioxen-4-yl) 4H-1,3-dioxet-5-yl, 4H-1,3-dioxen-6-yl, 2,3-dihydro-1,4-dioxe Hexen-2-yl, 2,3-dihydro-1,4-dioxol-5-yl), etc.; a fused non-aromatic heterocyclic group such as a dihydroindenyl group (for example : 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuran Base (for example: 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxanyl (for example: 2,3-dihydro-1,4-benzoic) Oxecyclohexenyl), dihydrobenzodioxenyl (for example: 3,4-dihydro-2H-1,5-benzodioxenyl), tetrahydrobenzo Furanyl (for example: 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (chromenyl is called " In the case of an alkenyl group (for example, 4H-chromen-2-yl, 2H-chromen-3-yl), dihydroquinolyl (for example, 1,2-dihydroquinolin-4-yl), Tetrahydroquinolyl (for example: 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (for example: 1,2-dihydroisoquinolin-4-yl), Tetrahydroisoquinolinyl (for example: 1,2,3,4-tetrahydroisoquinolin-4-yl), indoline Base (eg 1,4-dihydroanthracene) -4-yl), hexahydropyridyl and Base (eg hexahydropyridyl) And [2,1-c][1,4] Base) etc; etc.

The "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ may optionally have 1 to 3 substituents at a position which may be substituted. Examples of the substituent include those which may be optionally substituted with "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

R ^{1 is} preferably a C _6-14 aryl group (preferably a phenyl group) which may be optionally substituted or a heterocyclic group which may be optionally substituted (preferably an aromatic heterocyclic group (preferably a pyridyl group)).

Preferred examples of the substituent of the C _6-14 aryl or heterocyclic group include

(1) C _1-6 alkylsulfonyl (preferably methylsulfonyl),

(2) C _1-6 alkyl (preferably methyl), which may optionally be substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy groups), etc., particularly preferably C _{1- 6} alkylsulfonyl (preferably methylsulfonyl).

R ^{1 is more} preferably a C _6-14 aryl group (preferably a phenyl group) which may be optionally substituted with 1 to 3 C _1-6 alkylsulfonyl groups (preferably methylsulfonyl).

In another specific embodiment, R ^{1 is more} preferably a C _6-14 aryl group (preferably a phenyl group) or a heterocyclic group (preferably an aromatic heterocyclic group (preferably a pyridyl group)). It may be substituted with 1 to 3 substituents selected from the following:

(1) C _1-6 alkylsulfonyl (preferably methylsulfonyl), and

(2) C _1-6 alkyl group (preferably methyl) which may be optionally substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy groups).

In a specific embodiment, R ^{1 is} particularly preferably a C _6-14 aryl group (preferably a phenyl group) or a heterocyclic group (preferably an aromatic heterocyclic group (preferably a pyridyl group)), respectively It may be substituted with 1 to 3 C _1-6 alkylsulfonyl groups (preferably methylsulfonyl).

R ² is a C _1-6 alkyl group which may be optionally substituted or a C _3-10 cycloalkyl group which may be optionally substituted.

The "C _1-6 alkyl group" in the "C _1-6 alkyl group which may be optionally substituted" of R ² may optionally have 1 to 3 substituents at a position which may be substituted. Examples of the substituent include those which may be optionally substituted with "C _2-6 alkyl group" in the "C _2-6 alkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

Examples of the "C _3-10 cycloalkyl group which may be optionally substituted" of R ² include those similar to the "C _3-10 cycloalkyl group which may be optionally substituted" of R ¹ .

R ^{2 is} preferably a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl) which may be optionally substituted. Preferred examples of the substituent of the C _1-6 alkyl group include

(1) a C _6-14 aryl group (preferably a phenyl group),

(2) an aromatic heterocyclic group (preferably a pyridyl group, an imidazolyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom (preferably a chlorine atom), and

(b) C _1-6 alkyl (preferably methyl),

(3) a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(4) hydroxyl,

(5) C _1-6 alkoxy group (preferably methoxy group),

(6) Di-t-butylphenyl decyloxy group, and the like.

More preferably, R ² is a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(1) a C _6-14 aryl group (preferably a phenyl group),

(2) an aromatic heterocyclic group (preferably a pyridyl group, an imidazolyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom (preferably a chlorine atom), and

(b) C _1-6 alkyl (preferably methyl),

(3) a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(4) hydroxyl,

(5) a C _1-6 alkoxy group (preferably a methoxy group), and

(6) Di(tert-butyl)phenyl fluorenyloxy.

R ³ is a hydrogen atom or a halogen atom.

R ^{3 is} preferably a hydrogen atom.

The A ring is a 6-member ring that can be replaced by a visual need.

Examples of the "6-membered ring" in the "6-member ring which can be replaced by the need for a ring" of the ring A include benzene, cyclohexene, cyclohexadiene, 6-membered aromatic heterocyclic ring and 6-membered non-aromatic Family heterocycle.

Examples of the 6-membered aromatic heterocyclic ring include a 6-membered ring selected from the group consisting of an aromatic heterocyclic group exemplified as the "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ . Ring, specifically, pyridine, hydrazine Pyrimidine, pyridyl ,three Wait.

Examples of the 6-membered non-aromatic heterocyclic ring include a 6-membered ring selected from non-aromatic impurities exemplified as "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ . Ring of the ring, specifically, piperidine, piperidine , morpholine, thiomorpholine, piperazine, tetrahydropyran, thiopyran, tetrahydrothiopyran, 1-oxoyltetrahydrothiopyran, 1,1-dioxyindolizine, tetrahydrogen Pyrimidine, two Alkane, etc.

The "6-membered ring" of the "6-member ring which can be replaced by the need to be visually recognized" of the A ring is preferably benzene.

In addition to having -W ¹ -R ¹ and -W ² -R ² , the "6-membered ring" of the "ring-replaced 6-member ring" of the A ring is required to have a position at the replaceable position. 1 or 2 substituents. Examples of the substituent include those which may be optionally substituted with "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

Preferable examples of the substituent of the "6-membered ring" include a halogen atom (preferably a fluorine atom) and the like.

The A ring is preferably a 6-membered ring (preferably benzene), wherein in addition to -W ¹ -R ¹ and -W ² -R ² , it is also possible to pass 1 to 3 halogen atoms (preferably fluorine atoms). Replace.

The A ring is more preferably a 6-membered ring (preferably benzene) which has no other substituents other than -W ¹ -R ¹ and -W ² -R ² .

The B ring is a 5- to 7-membered nitrogen-containing heterocyclic ring that is optionally substituted.

Examples of the "5- to 7-membered nitrogen-containing heterocyclic ring" in the "5- to 7-membered nitrogen-containing heterocyclic ring which may be optionally substituted" of the ring B include a 5- to 7-membered ring containing at least one nitrogen atom. , which is selected from the group consisting of a "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ , and specifically, is a pyridine, a pyrimidine or a pyrene. Pyr , pyrroline, imidazole, pyrazole, thiazole, isothiazole, Azole Azole, Diazole, thiadiazole, triazole, tetrazole, three , pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine , hexamethyleneimine, Azole, thiazole, imidazolium, Oxazoline, thiazoline, imidazoline, dihydrogen Diazoline, pyrazole, tetrahydropyrimidine, and the like.

The "5- to 7-membered nitrogen-containing heterocyclic ring" in the "5- to 7-membered nitrogen-containing heterocyclic ring which may be optionally substituted" of the ring B is preferably a 5-membered nitrogen-containing heterocyclic ring (preferably a thiazoline). Further, a thiazole or a thiadiazole) is more preferably a 5-membered nitrogen-containing non-aromatic heterocyclic ring (preferably a thiazoline).

The "5- to 7-membered nitrogen-containing heterocyclic ring" of the "ring-replaceable 5- to 7-membered nitrogen-containing heterocyclic ring" of the ring B may optionally have 1 to 5 at a position which can be substituted (preferably) 1 to 3 substituents. Examples of the substituent include those which may be optionally substituted with "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

When two or more substituents are used, the two substituents are bonded on a single atom or on adjacent atoms, combining to form a "ring that may be substituted".

Examples of the "ring" which may be regarded as a ring which is required to be substituted include C _3-10 cycloalkane, C _3-10 cycloalkenene, C _4-10 cycloalkadiene, C _6-14 aryl group, heterocyclic ring and the like.

Examples of the C _3-10 cycloalkane include a ring corresponding to "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" of R ¹ .

Examples of the C _6-14 aromatic hydrocarbon include a ring corresponding to "C _6-14 aryl group" in the "C _6-14 aryl group which may be _optionally substituted" of R ¹ .

Examples of the heterocyclic ring include a ring of an aromatic heterocyclic group and a non-aromatic heterocyclic group exemplified as "heterocyclic group" in the "heterocyclic group which may be optionally substituted" of R ¹ .

Examples of the C _3-10 cycloolefin include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, and the like.

Examples of the C _4-10 cycloalkene include 1,3-cyclopentadiene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,3-cycloheptadiene and the like.

The "ring" in the "ring which may be substituted" may optionally have 1 to 3 substituents at positions which may be substituted. Examples of the substituent include those which may be optionally substituted with "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl group which may be optionally substituted" similar to R ¹ . When two or more substituents are used, the substituents may be the same or different.

Preferred examples of the substituent include:

(1) C _1-6 alkyl (preferably methyl, ethyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine methyl sulfhydryl group,

(c) carboxyl group,

(d) a C _1-6 alkoxy-carbonyl group (preferably an ethoxycarbonyl group), and

(e) a non-aromatic heterocyclic group (preferably a thiomorpholinyl group, a 1-oxoylthiomorpholinyl group),

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl), and the like.

In another specific embodiment, preferred examples of the substituent include

(1) C _1-6 alkyl (preferably methyl, ethyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine carbenyl group which may be mono- or disubstituted by a substituent selected from the following:

(i) C _1-6 alkyl (preferably methyl, ethyl, propyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of hydroxy and C _1-6 alkane An oxy group (preferably a methoxy group), and

(ii) a C _3-10 cycloalkyl group (preferably a cyclopropyl group),

(c) a C _1-6 alkoxy group (preferably a methoxy group),

(d) carboxyl group,

(e) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl),

(f) a non-aromatic heterocyclic group (preferably thiomorpholino, 1-oxothiothiomorpholinyl), and

(g) a non-aromatic heterocyclic group-carbonyl group (preferably morpholinocarbonyl group),

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl), and the like.

The B ring is preferably a 5- to 7-membered nitrogen-containing heterocyclic ring (preferably a 5-membered nitrogen-containing heterocyclic ring (preferably thiazoline, thiazole, thiadiazole), more preferably a 5-membered nitrogen-containing non-aromatic A heterocyclic ring (preferably a thiazoline) which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of:

(1) C _1-6 alkyl (preferably methyl, ethyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine methyl sulfhydryl group,

(c) carboxyl group,

(d) a C _1-6 alkoxy-carbonyl group (preferably an ethoxycarbonyl group), and

(e) a non-aromatic heterocyclic group (preferably a thiomorpholino group, a 1-oxoylthiomorpholinyl group), and

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl).

In another embodiment, the B ring is preferably a 5- to 7-membered nitrogen-containing heterocyclic ring (preferably a 5-membered nitrogen-containing heterocyclic ring (preferably a thiazoline, a thiazole, a thiadiazole), Preferably, the 5-membered nitrogen-containing non-aromatic heterocyclic ring (preferably thiazoline) is substituted with 1 to 3 substituents selected from the group consisting of:

(1) C _1-6 alkyl (preferably methyl, ethyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine carbenyl group which may be mono- or disubstituted by a substituent selected from the following:

(i) C _1-6 alkyl (preferably methyl, ethyl, propyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of hydroxy and C _1-6 alkane An oxy group (preferably a methoxy group), and

(ii) a C _3-10 cycloalkyl group (preferably a cyclopropyl group),

(c) a C _1-6 alkoxy group (preferably a methoxy group),

(d) carboxyl group,

(e) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl),

(f) a non-aromatic heterocyclic group (preferably thiomorpholino, 1-oxothiothiomorpholinyl), and

(g) a non-aromatic heterocyclic-carbonyl group (preferably morpholinocarbonyl), and

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl).

In the formula (I), the following structural formula

It refers to a group derived from a bicyclic ring formed by a ring A and a pyrrole ring having a common bond (ie, condensation). The bond multiplicity involving the formation of the bicyclic A ring is the same as the bond multiplicity of the pyrrole ring. For example: when the structure is expressed as follows

When the structural formula is expressed as follows

Ring A is "benzene".

W ¹ and W ² are each independently O, S, SO, SO ₂ or NR ⁴ , wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group.

W ¹ and W ^{2 are} preferably independently O, S, SO or SO _{2 , respectively} .

More preferably, both W ¹ and W ² are O.

Compound (I) does not include N-methyl-4-[(1-methyl-1H-tetrazol-5-yl)thio]-2-(1,3-thiazol-2-yl)-1H-indole哚-7-amine.

The compound (I) is preferably the following compound.

[Compound (A'-I)]

Compound (I) wherein ring A is benzene; ring B is a 5-membered nitrogen-containing heterocyclic ring which may be optionally substituted; W ¹ and W ² are both 0; and R ¹ is a C _6-14 aryl group which may be _optionally substituted. Or a heterocyclic group which may be optionally substituted; R ² is a C _1-6 alkyl group which may be optionally substituted; and R ³ is a hydrogen atom.

[Compound (A-I)]

Compound (I) wherein ring A is a 6-membered ring (preferably benzene) having no other substituents other than -W ¹ -R ¹ and -W ² -R ² ; B ring is 5- to 7-member a nitrogen-containing heterocyclic ring (preferably a 5-membered nitrogen-containing heterocyclic ring (preferably a thiazoline, a thiazole, a thiadiazole), more preferably a 5-membered nitrogen-containing non-aromatic heterocyclic ring (preferably a thiazoline)) It may be substituted by 1 to 3 substituents selected from the following:

(1) C _1-6 alkyl (preferably methyl, ethyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine methyl sulfhydryl group,

(c) carboxyl group,

(d) a C _1-6 alkoxy-carbonyl group (preferably an ethoxycarbonyl group), and

(e) a non-aromatic heterocyclic group (preferably a thiomorpholino group, a 1-oxoylthiomorpholinyl group), and

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl); W ¹ and W ² are both 0; R ¹ is a C _6-14 aryl group (preferably a phenyl group), which is visible It is required to be substituted with 1 to 3 C _1-6 alkylsulfonyl groups (preferably methylsulfonyl); R ² is a C _1-6 alkyl group (preferably methyl, isopropyl), which is visible It needs to be substituted with 1 to 3 substituents selected from the following:

(1) a C _6-14 aryl group (preferably a phenyl group),

(2) an aromatic heterocyclic group (preferably a pyridyl group, an imidazolyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom (preferably a chlorine atom), and

(b) C _1-6 alkyl (preferably methyl),

(3) a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(4) hydroxyl,

(5) a C _1-6 alkoxy group (preferably a methoxy group), and

(6) bis-tert-butylphenyl fluorenyloxy; and R ³ is a hydrogen atom.

[Compound (B-I)]

Compound (I) wherein ring A is a 6-membered ring (preferably benzene), which may optionally have 1 to 3 halogen atoms in addition to -W ¹ -R ¹ and -W ² -R ² (preferably Substituted for a fluorine atom; B ring is a 5- to 7-membered nitrogen-containing heterocyclic ring (preferably a 5-membered nitrogen-containing heterocyclic ring (preferably thiazoline, thiazole, thiadiazole), more preferably 5-membered a nitrogen-containing non-aromatic heterocyclic ring (preferably a thiazoline) which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of:

(1) C _1-6 alkyl (preferably methyl, ethyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of:

(a) hydroxyl,

(b) an amine carbenyl group which may be mono- or disubstituted by a substituent selected from the following:

(i) C _1-6 alkyl (preferably methyl, ethyl, propyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of hydroxy and C _1-6 alkane An oxy group (preferably a methoxy group), and

(ii) a C _3-10 cycloalkyl group (preferably a cyclopropyl group),

(c) a C _1-6 alkoxy group (preferably a methoxy group),

(d) carboxyl group,

(e) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl),

(f) a non-aromatic heterocyclic group (preferably thiomorpholino, 1-oxothiothiomorpholinyl), and

(g) a non-aromatic heterocyclic-carbonyl group (preferably morpholinocarbonyl), and

(2) C _1-6 alkoxy-carbonyl (preferably ethoxycarbonyl); W ¹ and W ² are both 0; R ¹ is C _6-14 aryl (preferably phenyl) or heterocyclic ring a group (preferably an aromatic heterocyclic group (preferably pyridyl)) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(1) C _1-6 alkylsulfonyl (preferably methylsulfonyl), and

(2) C _1-6 alkyl (preferably methyl) which may optionally be substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy groups); R ² is a C _1-6 alkane a group (preferably methyl, ethyl, isopropyl) which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of:

(1) a C _6-14 aryl group (preferably a phenyl group),

(2) an aromatic heterocyclic group (preferably a pyridyl group, an imidazolyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom (preferably a chlorine atom), and

(b) C _1-6 alkyl (preferably methyl),

(3) a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(4) hydroxyl,

(5) a C _1-6 alkoxy group (preferably a methoxy group), and

(6) bis-tert-butylphenyl fluorenyloxy; and R ³ is a hydrogen atom.

Among the compounds (I), the compound (II) is preferred, and the following compounds are more preferred.

[Compound (A-II)]

Compound (II) wherein ring A is benzene; ring B is a 5-membered nitrogen-containing heterocyclic ring which may be optionally substituted; W ¹ and W ² are both 0; and R ¹ is a C _6-14 aryl group which may be _optionally substituted. Or a heterocyclic group which may be optionally substituted; R ² is a C _1-6 alkyl group which may be optionally substituted; and R ³ is a hydrogen atom.

[Compound (B-II)]

Compound (II) wherein ring A is a 6-membered ring (preferably benzene), which may optionally have 1 to 3 halogen atoms in addition to -W ¹ -R ¹ and -W ² -R ² (preferably Substituted for a fluorine atom; B ring is a 5- to 7-membered nitrogen-containing heterocyclic ring (preferably a 5-membered nitrogen-containing heterocyclic ring (preferably thiazoline, thiazole, thiadiazole), more preferably 5-membered a nitrogen-containing non-aromatic heterocyclic ring (preferably a thiazoline) which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (1) C _1-6 alkyl (preferably methyl, ethyl) , isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (a) a hydroxy group, (b) an amine mercapto group, which may optionally be substituted or disubstituted with a substituent selected from the group consisting of: : (i) C _1-6 alkyl (preferably methyl, ethyl, propyl, isobutyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of hydroxy and C _1-6 Alkoxy (preferably methoxy), and (ii) C _3-10 cycloalkyl (preferably cyclopropyl), (c) C _1-6 alkoxy (preferably methoxy) , (d) a carboxyl group, (e) a C _1-6 alkoxy-carbonyl group (preferably an ethoxycarbonyl group), (f) a non-aromatic heterocyclic group (preferably a thiomorpholino group, a 1-oxygen group) Ionic thiomorpholinyl), and (g) Aromatic heterocyclic - carbonyl group (preferably morpholinyl carbonyl), and (2) C _1-6 alkoxy - carbonyl group (preferably ethoxycarbonyl); W ¹ and W ² are both 0; R ¹ is a C _6-14 aryl group (preferably a phenyl group) or a heterocyclic group (preferably an aromatic heterocyclic group (preferably a pyridyl group)), which may optionally be one to three selected from the following Substituent substitution: (1) C _1-6 alkylsulfonyl (preferably methylsulfonyl), and (2) C _1-6 alkyl (preferably methyl), which may be subjected to 1 Up to 3 C _1-6 alkoxy groups (preferably methoxy); R ² is C _1-6 alkyl (preferably methyl, ethyl, isopropyl), which may be 1 through 3 substituents selected from the group consisting of (1) a C _6-14 aryl group (preferably a phenyl group), and (2) an aromatic heterocyclic group (preferably a pyridyl group, an imidazolyl group), which may optionally be subjected to 1 to 3 substituents selected from the group consisting of (a) a halogen atom (preferably a chlorine atom), and (b) a C _1-6 alkyl group (preferably a methyl group), and (3) a non-aromatic hybrid. a cyclic group (preferably tetrahydropyranyl), (4) a hydroxyl group, a (5) C _1-6 alkoxy group (preferably a methoxy group), and (6) a di-tert-butylphenyl decane. a oxy group; and R ³ is a hydrogen atom.

When the compound (I) or the compound (II) [hereinafter collectively referred to as the compound (I)] is in the form of a salt, such salts may be mentioned, for example, a salt formed with an inorganic base, a salt formed with an organic base, and a mineral acid. a salt formed, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like.

Preferable examples of the salt formed with the inorganic base include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts and the like.

Preferable examples of the salt formed with the organic base include with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-diphenylmethylethylene a salt formed by an amine or the like.

Preferable examples of the salt formed with the inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Preferred examples of the salt formed with an organic acid include with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and a salt formed by toluenesulfonic acid or the like.

Preferable examples of the salt formed with the basic amino acid include salts formed with arginine, lysine, ornithine, and the like.

Preferable examples of the salt formed with the acidic amino acid include salts formed with aspartic acid, glutamic acid and the like.

The compound (I) is a compound which can be converted into the compound (I) by an enzyme, a stomach acid or the like under physiological conditions in vivo: it can also be converted into a compound by an enzyme oxidation, reduction, hydrolysis or the like ( The compound of I), and a compound which can be converted into the compound (I) by a reaction such as hydrolysis by gastric acid or the like. The compound (I) may be a compound obtained by deuteration, alkylation or phosphorylation of the amine group in the compound (I) (for example, the amine group in the compound (I) is thiolated, propylamine-based. , pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethyl a compound obtained by deuteration, alkylation, phosphorylation or boration of a hydroxyl group in the compound (I); a compound obtained by deuteration, alkylation, phosphorylation or boration (for example, a compound) The hydroxyl group in (I) is acetylated, palmitoylated, propylated, trimethyl acetylated, amber thiolated, methacrylylated, propyl amidated or dimethylamino a compound obtained by methylcarbonylation; a compound obtained by esterification or guanidation of a carboxyl group in the compound (I) (for example, a carboxyl group in the compound (I) is esterified with ethyl ester, phenyl esterified, carboxymethyl group Esterification, dimethylaminomethyl esterification, trimethylacetoxymethyl esterification, ethoxycarbonyloxyethyl esterification, mercaptoesterification, (5-methyl-2- Oxo-1,3-oxe-4-yl a compound obtained by methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation). These compounds can be prepared from the compound (I) by a method known per se.

The compound (I) may also be a compound which is converted to the compound (I) under physiological conditions, such as IYAKUHIN NO KAIHATSU (Development of Pharmaceuticals), vol. 7, Design of Molecules, p. 163-198, published by HIROKAWA SHOTEN. (1990) stated.

Preferred clear examples of the prodrug of the compound (I) include a compound in which the amino group of the pyrrole moiety in the structural formula represented by the formula (I) is deuterated, alkylated, sulfonated or phosphorylated.

The compound (I) can be labeled with an isotope (for example, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like.

Further, the compound (I) may be a non-hydrate or a hydrate.

The deuterated compound in which ¹ H has been converted to ² H (D) is also included in the range of the compound (I).

The compound (I) or a prodrug thereof (hereinafter sometimes referred to as a compound of the present invention) has low toxicity and can be used for preventing or treating various mammals (for example, human, mouse, rat, rabbit, dog) described below. An agent for diseases of cats, cows, horses, pigs, monkeys, which may be used in its own form or may be mixed with a pharmaceutically acceptable carrier or the like into a pharmaceutical composition.

In this case, a plurality of organic or inorganic carriers which are commonly used as materials for pharmaceutical preparations can be used as pharmaceutically acceptable carriers, which can be added as excipients, lubricants, binders and disintegrants for solid preparations; As a solvent, a dissolution aid, a suspending agent, an isotonic agent, a buffering agent and a soothing agent of a liquid preparation; If necessary, additives for pharmaceutical preparations such as preservatives, antioxidants, colorants, sweeteners, and the like can be used.

Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose. Sodium, acacia gum, pullulan, light anhydrous citric acid, synthetic aluminum citrate, aluminum magnesium metasilicate.

Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal vermiculite and the like.

Preferred examples of the binder include α-starch, saccharose, gelatin, acacia gum, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D - mannitol, trehalose, dextrin, polytriglucose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.

Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous citric acid, and low substitution. Hydroxypropyl cellulose and the like.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferable examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, ginsyl methane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, water. Sodium salicylate, sodium acetate, and the like.

Preferred examples of suspending agents include surfactants such as: stearyl triethanolamine, sodium lauryl sulfate, lauryl alanine propionate, lecithin, benzalkonium chloride, benzethon chloride Ammonium (benzethonium chloride), glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyl Ethyl cellulose, hydroxypropyl cellulose, etc.; polysorbate, polyoxyethylene hydrogenated castor oil;

Preferred examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and the like.

Preferred examples of the buffer include a phosphate buffer, an acetate buffer, a carbonate buffer, a citrate buffer, and the like.

Preferred examples of the mitigating agent include benzyl alcohol and the like.

Preferable examples of the preservative include p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

Preferred examples of the antioxidant include sulfite, ascorbate and the like.

Preferred examples of the coloring agent include water-soluble edible tar pigments (for example, food colorings such as food coloring red 2 and 3, food coloring yellow 4 and 5, food coloring blue 1 and 2, etc.), water insoluble. A lake pigment (for example, an aluminum salt of the above-mentioned water-soluble edible tar pigment), a natural pigment (for example, β-carotene, chlorophyll, and red iron oxide).

Preferable examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The dosage form of the above pharmaceutical composition is, for example, an oral preparation such as a tablet (including a sugar-coated tablet, a film-coated tablet, a sublingual tablet and a disintegrating tablet in the mouth), a capsule (including a soft capsule and a microcapsule), a granule, a powder, and a tablet. Agent, syrup, emulsion, suspension, film (for example: disintegrating film in the mouth), etc.; or parenteral agent, such as: injection (for example: subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip Infusion), external preparations (for example, skin-wearing preparations, ointments), suppositories (for example, rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalation), ophthalmic preparations, etc.; Such dosage forms can be safely administered by oral or parenteral (e.g., topical, rectal, intravenous, etc.) routes.

Such formulations may be controlled release formulations, such as rapid release formulations and sustained release formulations (eg, sustained release microcapsules).

The pharmaceutical composition can be prepared according to a method commonly used in the field of pharmaceutical preparations, such as the method described in the Japanese Pharmacopoeia. The clear preparation method of the preparation is described in detail below.

Although the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention or the like is, for example, about 0.1 to 100% by weight.

The compound of the present invention has excellent GK activation, and thus can be used as an agent for preventing or treating a plurality of different diseases of a mammal (for example, human, cow, horse, dog, cat, monkey, mouse, rat, specifically human). . Furthermore, since the compounds of the present invention have selective GK activation, they exhibit low toxicity (for example, acute toxicity, chronic toxicity, cardiotoxicity, carcinogenicity, genotoxicity), so that side effects are low.

The compound of the present invention can be used as an agent for preventing or treating diabetes (for example, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity diabetes, etc.); an agent for preventing or treating obesity; and an agent for preventing or treating hyperlipemia (for example: High blood triglyceride, hypercholesterolemia, hypoxemia HDL, postprandial hyperlipidemia, etc.; agents for preventing or treating arteriosclerosis; agents for preventing or treating impaired glucose tolerance [IGT]; and preventing glucose tolerance An abnormal drug that develops into diabetes.

Diagnostic criteria for diabetes can be found in the latest diagnostic criteria reported by the Japanese Diabetes Association in 1999.

According to this report, diabetes is a condition in which any of the following symptoms occurs: fasting blood glucose concentration (intravenous plasma glucose concentration) not less than 126 mg / dl, 75 g oral glucose tolerance test (75 g OGTT) 2 hours blood glucose The concentration (intravenous plasma glucose concentration) is not less than 200 mg/dl, and the non-fasting blood glucose concentration (intravenous plasma glucose concentration) is not less than 200 mg/dl. The above symptoms of diabetes did not appear, but different from "glucose concentration in fasting blood (intravenous plasma glucose concentration) below 110 mg / dl or 75 g oral glucose tolerance test (75 g OGTT) 2 hours blood glucose concentration (intravenous plasma The symptom of glucose concentration below 140 mg/dl" (normal type) is called "edge type".

In addition, the ADA (American Diabetes Association) and WHO also proposed the latest diagnostic criteria for diabetes.

According to these reports, diabetes is a condition in which the glucose concentration in the fasting blood (intravenous plasma glucose concentration) is not less than 126 mg/dl or 75 g oral glucose tolerance test for 2 hours of blood glucose concentration (intravenous plasma) The medium glucose concentration is not less than 200 mg/dl.

According to the above report of ADA and WHO, abnormal glucose tolerance is a condition with the following symptoms: 75 g oral glucose tolerance test 2 hours blood glucose concentration (intravenous plasma glucose concentration) is not less than 140 mg / dl, but less than 200 mg /dl. According to the ADA report, the symptom of fasting blood glucose concentration (intravenous plasma glucose concentration) of not less than 100 mg/dl but less than 126 mg/dl is called IFG (fasting glucose abnormality). According to the WHO report, in the IFG (fasting glucose abnormality), there is a 75-gram oral glucose tolerance test for 2 hours. The blood glucose concentration (intravenous plasma glucose concentration) is not less than 110 mg/dl, but less than 126 mg/dl. The condition is called IFG (fasting blood glucose abnormality).

The compound of the present invention can also be used for the prevention or treatment of diabetes, marginal type, impaired glucose tolerance, IFG (fasting glucose abnormality) and IFG (fasting blood glucose abnormality) determined according to the above-mentioned latest diagnostic criteria. Furthermore, the compounds of the present invention prevent the development of marginal type, impaired glucose tolerance, IFG (fasting glucose abnormality) or IFG (fasting blood glucose abnormality) into diabetes.

The compounds of the invention may also be used for the prevention or treatment of, for example, diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disease, osteopenia, hyperosmolar diabetic coma, infectious diseases (eg, respiratory tract) Infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic foot injury (eg gangrene, ulcer), dry mouth, hearing loss, cerebrovascular disease, peripheral blood circulation disease, diabetic diarrhea], Obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological malignant disease, endocrine disease cachexia, infectious disease cachexia or cachexia caused by acquired immunodeficiency syndrome), fatty liver, high Blood pressure, polycystic ovarian syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerular sclerosis, renal syndrome, hypertensive nephrosclerosis, end stage renal disease, pyelonephritis, hydronephrosis), muscle nutrition Poor, myocardial infarction, angina, cerebrovascular accident : cerebral infarction, stroke, abnormal glucose metabolism, abnormal lipid metabolism, insulin resistance syndrome, X syndrome, metabolic syndrome (in accordance with the WHO report above, refers to at least one of type 2 diabetes, impaired glucose tolerance and insulin resistance) And obesity, abnormal lipid metabolism, at least two of hypertension and microalbuminuria, Cushing's syndrome, hyperinsulinemia, hyperinsulinemia-induced sensory lesions, tumors (eg leukemia) , breast cancer, prostate cancer, skin cancer), irritating intestinal syndrome, acute or chronic diarrhea, inflammation (eg chronic rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, postoperative or Traumatic inflammation, swelling, neuralgia, pharyngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, gastric mucosal injury (including Inas Gastric Mucosal Injury Caused by Pilling), Visceral Fat Syndrome, Alzheimer's Disease, Cerebrovascular Dementia, Depression Pharmacy such as illness.

The compound of the present invention can also be used for improving insulin resistance, promoting or increasing insulin secretion, reducing visceral fat, suppressing visceral fat accumulation, improving glucose metabolism, improving lipid metabolism (including inhibiting oxidative LDL production, improving lipoprotein metabolism, and reducing blood residue), Improve coronary metabolism, prevent or treat cardiovascular complications, prevent or treat complications of heart failure, prevent or treat anovulation, prevent or treat hirsutism, prevent and treat hyperandremia in the blood, and improve pancreas (β cells) Function, regeneration of pancreas (β-cell), promotion of pancreas (β-cell) regeneration, etc.

The compounds of the present invention are also useful for the subsequent prevention and prevention of the development of various diseases mentioned above (for example, cardiovascular problems such as myocardial infarction, etc.).

The compounds of the present invention are particularly useful as agents for the prevention or treatment of type 2 diabetes, obesity diabetes, and the like.

Although the dose of the compound of the present invention will depend on the subject to be administered, the route of administration, the target disease, the condition, and the like, if administered to a diabetic adult patient, for example, orally, the compound of the present invention is usually administered in a single dose in an amount of about 0.01 to 100 mg. / kg body weight, preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight. This dose is administered 1 to 3 times a day as needed.

The compound of the present invention can be used in combination with the following drugs, for example, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipemia, an antihypertensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, and an antithrombotic agent. A therapeutic agent for osteoporosis, an anti-dementia agent, an improvement agent for erectile dysfunction, a therapeutic agent for frequent urination or urinary incontinence, a therapeutic agent for dysuria, and the like (hereinafter referred to as a combination drug). In this case, there is no limitation on the administration time of the compound of the present invention and the combination drug. They may be administered to the subject at the same time or in a staggered manner. Further, the compound of the present invention and the combination drug may be administered in two formulations each containing the active ingredient, or may be administered as a single preparation containing both active ingredients.

The dose of the combination drug can be appropriately determined depending on the dose used in clinical practice. The ratio of the compound of the present invention to the combination drug can be appropriately determined depending on the administration target, the administration route, the target disease, the condition, the combination, and the like. When, for example, the administration target is a human, the combination drug is used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.

Examples of therapeutic agents for diabetes include: insulin preparations (for example, animal insulin preparations extracted from the pancreas of cattle or pigs; human insulin preparations synthesized using Escherichia coli or yeast genes; zinc insulin; protamine zinc) Insulin; a fragment or derivative of insulin (eg, INS-1), an oral insulin preparation), an insulin sensitizer (eg, pioglitazone or a salt thereof (preferably hydrochloride), Logta Rosiglitazone or its salts (preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Mehta Metaglidasen, Naveglitazar, AMG-131, THR-0921), α-glucosidase inhibitors (eg voglibose, acarbose, MiG) Migitol, emiglitate, biguanides (eg metformin, buformin or its salts (eg hydrochloride, fumarate, succinate) ), insulin-promoting agent [sulfonylurea (for example: tolbutam) Ide), glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclocyramide, Glimepiride, glipizide, glybuzole, repaglinide, nateglide, mitiglinide or its calcium salt hydrate a dipeptidyl peptidase IV inhibitor (eg, Alogliptin or a salt thereof (preferably benzoate), Vildagliptin, Sitagliptin, Sagagliptin ), T-6666, TS-021), β3 agonist (eg AJ-9677), glucose-dependent insulin secretagogue (eg TAK-875), GPR40 agonist (eg: described in WO2006083781A1 and US) Compound of 2007/0265332A1), GPR119 agonist (for example: MBX-2982, PSN-821, APD-668), GLP-1 receptor agonist [eg GLP-1, GLP-1MR agent, NN-2211 , AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131], amyloid (amylin) An agonist (eg pluripeptide (pra) Mlintide)), phosphotyrosine phosphatase inhibitor (eg sodium vanadate), inhibitor of glucose production (eg glycophosphorylase inhibitor, glucose-6-phosphatase inhibitor, glycosidic antagonist) ), SGLT (sodium-glucose co-transporter) inhibitor (eg T-1095), 11β-hydroxysteroid dehydrogenase inhibitor (eg BVT-3498, dapagliflozin, Limoliffe) Remogliflozin), adiponectin or its agonist, IKK inhibitor (eg AS-2868), drug for improving leptin resistance, growth hormone releasing inhibitor receptor agonist, glucokinase Activator (for example: Ro-28-1675), GIP (glucose-dependent insulinotropic peptide), and the like.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Minarrestat, Fidarestat, CT-112, ranirestat (AS-3201), neurotrophic factors and their promoting drugs (eg NGF, NT-3, BDNF) , a neurotrophin production-secretion promoter, which is described in WO01/14372 (for example: 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2- Methylphenoxy)propyl] Oxazole)), a nerve regeneration promoter (eg, Y-128), a PKC inhibitor (eg, ruboxistaurin mesylate), an AGE inhibitor (eg, ALT-946, pimagedine) ), N-benzhydrylmethylthiazolium bromide (ALT-766), ALT-711, EXO-226, Pyridorin, Pyridoxamine, active oxygen scavenger (eg sulfur Citrate), cerebral vasodilators (eg, tiapride, mexiletine), ghrelin receptor agonist (BIM23190), apoptotic signal-regulated kinase-1 (ASK-1) ) inhibitors and the like.

Examples of therapeutic agents for hyperlipemia include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin). , fluvastatin, pitavastatin, rosuvastatin and its salts (eg sodium salt, calcium salt), squalene synthetase inhibitors (lapaquistat Or a salt thereof (preferably acetate), a fibrate compound (for example, bezafibrate, clofibrate, simfibrate) ), clinofibrate, ACAT inhibitors (eg, Avasimibe, Eflucimibe), anion exchange resins (eg, colestyramine), Pro Probucol, nicotinic acid drugs (eg nicomol, niceritrol), ethyl eicosapentaenoate, phytosterols (eg, soy sterol, gamma-valley) Wei Su) and so on.

Examples of antihypertensive agents include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, deLapril), angiotensin II antagonists (e.g., Ganda) Candesartan cilexetil, losartan, eprosartan, valsartah, telmisartan, irbesartan, tasosartan ), 1-[[2'-(2,5-dihydro-5-o-oxy-4H-1,2,4- (oxazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid), calcium ion antagonist (eg, manidipine, Nifedipine, amlodipine, efenidipine, nicardipine, potassium channel openers (eg levcromakalim, L-27152, AL 0671) , NIP-121), clonidine, and the like.

Examples of anti-obesity agents include anti-obesity agents acting on the central nervous system (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, Ampmont) (amfepramone), dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (eg SB-568849; SNAP-7941; illustrated in WO01 /82925 and compounds of WO01/87834); neuropeptide Y antagonists (for example: CP-422935); cannabinoid receptor antagonists (for example: SR-141716, SR-147778); ghrelin antagonists; Pancreatic lipase inhibitors (eg, orlistat, ATL-962), β3 agonists (eg, AJ-9677), peptides or anorectic agents (eg, leptin, CNTF (ciliary neurotrophy) Factor)), cholecystokinin agonist (eg, lintitript, FPL-15849), ingestion inhibitor (eg, P-57), and the like.

Examples of diuretics include xanthine derivatives (e.g., sodium salicylate and sodium theobromine, calcium salicylate and theobromine), thidium Thiazide preparation (eg: ethyl thiazide) (ethiazide), cyclopentathia (cyclopenthiazide), trichloromethylthiazide (trichloromethiazide), hydrochlorothiazide (hydrochlorothiazide), hydrofluorothiazide (hydroflumethiazide), benzyl hydrochlorothiazide (benzylhydrochlorothiazide), pentofluorothiazide (penflutizide), polythiazide (polythiazide), methyl chlorothiazide (methyclothiazide)), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonate dehydratase inhibitors (eg, acetazolamide), chlorobenzene Sulfonamide preparations (eg, chlortalidone, mefruside, indapamide), azosemide, isosorbide, etacrynic acid , pittanide, bumetanide, furosemide, and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), metabolic antagonists (eg, methotrexate, 5-fluorouracil or derivatives thereof) , anti-tumor antibiotics (eg mitomycin, adriamycin), plant-derived anti-tumor agents (eg, vincristine, vindesine, paclitaxel) (Taxol)), cisplatin, carboplatin, etoposide, and the like. Among them, Furtulon or NeoFurtulon, which is a 5-fluorouracil derivative, is preferable.

Examples of immunotherapeutic agents include microbial or bacterial components (e.g., muramyl dipeptide derivatives, Picibanil), polysaccharides having enhanced immunological activity (e.g., lentinan, Citrosaccharine (schizophyllan), yuncin (krestin), cytokines obtained by genetic engineering techniques (eg, interferon, interleukin (IL)), community stimulating factors (eg, granulocyte community stimulating factor, promoting Erythropoietin), etc., preferably interleukin, such as: IL-1, IL-2, IL-12, and the like.

Examples of antithrombotic agents include heparin (eg, sodium heparin, calcium heparin, sodium dalteparin), warfarin (eg, acetone benzyl hydroxycoumarin potassium), antithrombin Drugs (eg, aragatroban), thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monp kinase) (monteplase), pemiteplase, platelet aggregation inhibitor (eg ticlopidine hydrochloride, cilostazol, ethyl eicosapentaenoate, Brass sodium) (beraprost sodium), saprogrelate hydrochloride, and the like.

Examples of therapeutic agents for osteoporosis include alpha-calciferol, calcitriol, elcatonin, calcitonin salmon, estriol, and estriol. Ipriflavone, risedronate disodium, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.

Examples of anti-dementia agents include tacrine, donepezil, rivastigmine, galanthamine, and the like.

Examples of the improvement agent for erectile dysfunction include apomorphine, sildenafil citrate, and the like.

Examples of therapeutic agents for frequent urinary or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, and the like.

Examples of the therapeutic agent for dysuria include an acetylcholinesterase inhibitor (for example, distigmine) and the like.

In addition, drugs which have been determined in animal models and clinically to have a cachectic effect can be mentioned, for example, a cyclooxygenase inhibitor (for example, indometacin), a progesterone derivative (for example, megestrol acetate). (megesterol) acetate, glucosteroid (eg dexamethasone), metoclopramide, tetrahydrocannabinol, fat metabolism improving agent (eg: twenty Carbaenoic acid), growth hormone, IGF-1 or an antibody against a cachexia factor, such as: TNF-α, LIF, IL-6, oncostatin M, etc., which can be used in combination with the compound of the present invention .

The combination drug is preferably an insulin preparation, an insulin sensitizer, an α-glucosidase inhibitor, a biguanide, an insulinotropic secretion agent (preferably sulfonylurea) or the like.

The above two or more combination drugs may be used in an appropriate combination.

When the compound of the present invention is used in combination with a combination drug, the counterbalance of these drugs can be considered, and the amount thereof can be reduced to a safe range. In particular, the insulin sensitizer, insulin secretagogue (preferably sulfonylurea) and biguanide may be administered at a lower dose than the normal dose. Therefore, it is safe to avoid the side effects that these agents may cause. In addition, the dose of a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, and an antihypertensive agent can also be reduced, thereby effectively avoiding side effects which may be caused by such agents.

The compound (I) can be produced according to, for example, the method shown in the following reaction schemes 1, 2, 3 or 4.

Wherein R ⁶ , R ^{6 '} and R ^6" are each independently a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted C _6-14 aryl; R ⁷ , R ⁸ , R ⁹ and R ^{10 is} independently a hydrogen atom or a "substituent" of the above B ring; and the other symbols are as defined above.

Examples of the "C _1-6 alkyl group which may be optionally substituted ^" of R ⁶ , R ^6' or R ^6" include those similar to the "C _1-6 alkyl group which may be optionally substituted" of R ² , and Preferably, a methyl group and an ethyl group are used.

Examples of the "C _6-14 aryl group which may be optionally substituted ^" of R ⁶ , R ^{6 '} or R ^6" include those similar to the "C _6-14 aryl group which may be _optionally substituted" of R ¹ , and Phenyl and 4-methoxyphenyl are preferred.

The compound (I-B) can be produced from the compound (2) according to the method described in Angew. Chem., Int. Ed., 2003, vol. 42, p. 83; Tetrahedron, 1999, vol. 55, p. 10271.

This reaction is carried out by reacting the compound (2) with triphenylphosphine oxide, trifluoromethanesulfonic anhydride or phosphorus pentachloride.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; nitriles such as: acetonitrile, propionitrile, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, etc.; These solvents can be used in a mixture in an appropriate ratio.

The triphenylphosphine oxide is usually used in an amount of from 1 to 10 moles, preferably from 1 to 6 moles per 1 mole of the compound (2).

The amount of trifluoromethanesulfonic anhydride or phosphorus pentachloride is usually from 1 to 10 moles, preferably from 1 to 6 moles per 1 mole of the compound (2).

The reaction temperature is usually -70 ° C to 100 ° C, preferably -30 ° C to 60 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 0.5 to 6 hours.

The compound (2) used as a starting material of this reaction can be produced, for example, according to the method shown in the following Reaction Scheme 5 or the like.

Wherein G is a nitro group, an amine group which may be protected or a hydroxyl group which may be protected as needed; X ¹ is a halogen atom; R ²² is any of the above R ¹ and R ² ; when R ²² is R ¹ , W ²² is W ¹ , or when R ²² is R ² , W ²² is W ² ; when R ²² is R ¹ , W ²³ is W ² , or when R ²² is R ² , W ²³ is W ¹ ; E is a hydroxyl group or a leaving group; and other codes are as defined above.

Examples of the "debonding group" of E include a halogen atom; a C _1-6 alkylsulfonyloxy group which may be halogenated as required (for example, a methylsulfonyloxy group, an ethylsulfonyloxy group, a trichloromethanesulfonyl group) Oxy, trifluoromethanesulfonyloxy); C _6-10 arylsulfonyloxy, which may optionally have from 1 to 3 substituents selected from C _1-6 alkyl, C _{1- 6} alkoxy and nitro (for example: phenylsulfonyloxy, m-nitrophenylsulfonyloxy, p-toluenesulfonyloxy); C _1-6 alkoxysulfonyloxy ; C _6-10 aryloxysulfonyloxy and the like.

Examples of the protecting group of the amine group in "the amine group which may be protected by protection" of G include those as described below.

Examples of the protecting group of the hydroxyl group in "the hydroxyl group which is required to be protected" of G include those as described below.

The compound (3) can be produced by using a halogenating agent from the compound (1) according to a method known per se (for example, as described in "Jikken Kagaku Koza (Experimental Chemistry Course)", 4th edition, vol. 19, p The method of 424 to 467) or the like is carried out by halogenation.

Examples of the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, iodine, benzyltrimethylammonium dichloroiodate, and the like.

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, butanol, etc.; organic acids such as acetic acid, formic acid, and the like; Ethers such as: 1,4-two Alkane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane, etc.; esters such as ethyl formate, ethyl acetate, n-butyl acetate, acetic acid a third butyl ester or the like; a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, trichloroethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; Amidoximes, such as: formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.; nitriles, such as: acetonitrile, propionitrile, etc.; Dimethyl hydrazine, etc.; cyclobutyl hydrazine; hexamethylphosphoramide; water; These solvents can be used in a mixture in an appropriate ratio.

The halogenating agent is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (1).

The reaction temperature is usually -30 ° C to 120 ° C, preferably -10 ° C to 100 ° C.

The reaction time is usually from 0.5 to 24 hours, preferably from 1 to 20 hours.

The compound (3-2) can be produced by the compound (3) and the compound (3-1) in the presence of a metal reagent according to a method known per se (for example, as described in Synthesis, 2005, p. 1706; Organic Letters, 2003, p. 3843 et al.) or a similar method of reaction.

Examples of the metal reagent used in the reaction include a palladium reagent such as palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), ruthenium (triphenylphosphine)palladium(0), etc.; copper reagent For example, copper (I) iodide, (1,10-phenanthroline) bis(triphenylphosphine) copper (I) nitrate, etc.; It can be mixed in an appropriate ratio.

The yield of this reaction can be improved by carrying out in the coexistence of a base. Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as carbonic acid Sodium, potassium carbonate, cesium carbonate, etc.; alkali metal hydrogencarbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal phosphates, such as: potassium phosphate, sodium phosphate, etc.; alkali metal C _1-6 alkoxide, Such as: sodium methoxide, sodium ethoxide, potassium butoxide, etc.; organic bases, such as: trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrole Pyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diaza Heterobicyclo[5.4.0]-7-undecene, etc.;

This reaction is preferably carried out in a solvent inert to the reaction. Examples of the solvent include those exemplified in the production method of the above compound (3). Further, as the solvent, the above organic bases such as triethylamine, pyridine or the like can be used.

The compound (3-1) is usually used in an amount of from 1 to 5 moles, preferably from 1 to 3 moles per 1 mole of the compound (3).

The metal reagent is usually used in an amount of 0.05 to 3 moles, preferably 0.1 to 1 mole per 1 mole of the compound (3).

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (3).

The reaction temperature is usually from -30 ° C to 140 ° C, preferably from -10 ° C to 100 ° C.

Although the reaction time depends on the kind and amount of the metal reagent to be used, it is usually from 0.5 to 24 hours, preferably from 1 to 20 hours.

When G is a protected amino group or a protected hydroxyl group, if necessary, the compound (3-3) can be produced by the compound (3-2) by a general peptide chemical or the like by a deprotection method (for example, an acid treatment method) , alkali treatment, catalytic reduction, etc.).

When G is a nitro group, the compound (3-3) can be produced by reducing the compound (3-2) with a reducing agent.

Examples of the reducing agent include metals such as iron, zinc, tin, etc.; sulfides such as sodium dithonite; and the like.

The amount of reducing agent is preferably determined by the type of reducing agent. For example, the amount of the metal is usually 1 to 20 moles, preferably 1 to 5 moles per 1 mole of the compound (3-2), and the amount of the sulfide is usually used per 1 mole of the compound (3-2). 1 to 20 moles, preferably 1 to 5 moles.

This reduction reaction can also be carried out by a hydrogenation reaction. At this time, for example, a catalyst such as palladium carbon, palladium black, platinum dioxide, Raney-nickel, ruthenium cobalt, ferric chloride or the like can be used.

The amount of the catalyst is usually 5 to 1000% by weight (wt%) based on the compound (3-2), preferably about 10 to 300% by weight.

The hydrogenation reaction can also be carried out using hydrogen or a variety of different hydrogen sources. Examples of the hydrogen source include formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine, and the like.

The hydrogen source is usually used in an amount of from 1 to 100 moles, preferably from 1 to 5 moles per 1 mole of the compound (3-2).

The reduction reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.; ethers such as diethyl ether and diisopropyl. Ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; These solvents can be used in a mixture in an appropriate ratio.

Although the reaction time varies depending on the kind and amount of the reducing agent and the catalyst to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours.

The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

The compound (I) can be produced by reacting the compound (3-3) with the compound (19) or the compound (20).

When E is a hydroxyl group, the reaction is carried out according to a method known per se, for example, the method described in Synthesis, 1981, p. 1, or the like. Specifically, the reaction is usually carried out in the presence of an organophosphorus compound and an electrophile in a solvent which does not adversely affect the reaction.

Examples of the organophosphorus compound include triphenylphosphine, tributylphosphine, and the like.

Examples of electrophiles include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldiperidine. Wait.

The preferred amount of the organophosphorus compound and the electrophile is 1 to 5 moles per 1 mole of the compound (3-3), respectively.

The compound (19) or the compound (20) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (3-3).

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, and Halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; guanamines such as N,N-dimethylformamide; Classes, such as: dimethyl hydrazine, etc.; These solvents can be used in a mixture in an appropriate ratio.

The reaction temperature is usually -50 to 150 ° C, preferably -10 to 100 ° C.

The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

When E is a leaving group, the reaction is carried out in the presence of a base according to a conventional method.

Examples of the base include inorganic bases such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, etc.; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride, sodium hydride, etc.; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, Potassium tert-butoxide or the like; alkyl lithiums such as n-butyllithium, t-butyllithium, methyllithium, etc.;

The base is preferably used in an amount of from 1 to 5 moles per 1 mole of the compound (3-3).

The compound (19) or the compound (20) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (3-3).

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as tetrahydrofuran, Alkane, ether, etc.; ketones, such as: acetone, 2-butanone, etc.; halogenated hydrocarbons, such as: chloroform, dichloromethane, etc.; guanamines, such as: N, N-dimethylformamide, etc.; Anthraquinones, such as: dimethyl hydrazine, etc.; These solvents can be used in a mixture in an appropriate ratio.

The reaction temperature is usually -50 to 150 ° C, preferably -10 to 100 ° C.

The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

Compound (I) can also be produced by reacting compound (3-3) with an alkylating agent.

Examples of the alkylating agent include diazomethane analogs such as diazomethane, trimethylsulfonyldiazomethane, and the like; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and the like;

The alkylating agent is preferably used in an amount of from 1 to 5 moles per 1 mole of the compound (3-3).

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as tetrahydrofuran, Alkane, ether, etc.; ketones, such as: acetone, 2-butanone, etc.; nitriles, such as: acetonitrile, propionitrile, etc.; halogenated hydrocarbons, such as: chloroform, dichloromethane, etc.; guanamines, such as: N, N-dimethylformamide, etc.; anthraquinones, such as: dimethyl hydrazine, etc.; water; These solvents can be used in a mixture in an appropriate ratio.

When a dialkyl sulfate or the like is used, the reaction can be carried out in the presence of a base. Examples of the base include inorganic bases such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, etc.; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride, sodium hydride, etc.; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, Potassium tert-butoxide, etc.; alkyl lithium, such as: n-butyl lithium, t-butyl lithium, methyl lithium, etc.;

The base is preferably used in an amount of from 1 to 5 moles per 1 mole of the compound (3-3).

The reaction temperature is usually -50 to 150 ° C, preferably -10 to 120 ° C.

The reaction time is usually from 0.5 to 100 hours, preferably from 1 to 60 hours.

The compound (1) used as a starting material of this reaction can be produced according to the method shown in the following reaction scheme 8, the method known per se or the like.

The compound (3-1), the compound (19) and the compound (20) which are used as starting materials for this reaction can be produced according to a method known per se or a method analogous thereto.

Wherein R ¹¹ , R ^{11 '} , R ¹³ and R ¹⁴ are each independently a hydrogen atom or a "substituent" of the above-mentioned B ring; R ¹² is a C _1-6 alkyl group which may be optionally substituted or may be optionally substituted C _3-10 cycloalkyl; R ¹⁵ is a C _1-6 alkyl group which may be optionally substituted or an aryl group which may be optionally substituted; R ¹⁶ and R ¹⁷ are each independently a hydrogen atom; C _1-6 alkyl group; It may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group, a hydroxyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-carbonyl group, an amine group and a C _1-6 alkylsulfonyl group; C _3-10 cycloalkyl, which may optionally be substituted with 1 to 3 substituents selected from C _1-6 alkyl, carboxy, hydroxy, C _1-6 alkoxy, C _1-6 alkoxy a carbonyl group, an amine group and a C _1-6 alkylsulfonyl group; a C _1-6 alkylsulfonyl group, which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a C _1-6 alkyl group and a carboxyl group; a hydroxy group, a C _1-6 alkoxy-carbonyl group and an amine group; or an amine group which may be mono- or disubstituted with a substituent selected from the group consisting of C _1-6 alkyl, carboxyl group, hydroxyl group, C _{1- 6} alkoxy - carbonyl group and the C _1-6 alkylsulfonyl group, or R ¹⁶ and R ¹⁷ optionally form a nitrogen-containing composition (Example: morpholine), which may be optionally substituted with 1 to 3 substituents selected from the following: C _1-6 alkyl, carboxy, hydroxy, C _1-6 alkoxy - carbonyl group, with the group C _{1- 6} alkylsulfonyl; and other codes are as defined above.

Examples of the "C _1-6 alkyl group which may be optionally substituted" of R ¹² or R ¹⁵ include those which are similar to the "C _1-6 alkyl group which may be optionally substituted" of R ² .

Examples of the "C _3-10 cycloalkyl group which may be optionally substituted" of R ¹² include those similar to the "C _3-10 cycloalkyl group which may be optionally substituted" of R ¹ .

Examples of the "C _6-14 aryl group which may be optionally substituted" of R ¹⁵ include those similar to the "C _6-14 aryl group which may be _optionally substituted" of R ¹ .

The compound (I-B') can be produced in three steps using the compound (4).

In the first step, the oximation reaction can be carried out from the compound (4) to give the compound (5).

This reaction is carried out according to a method known per se, for example, the method (A), the condensation of the compound (4) or a salt thereof with ammonia or a salt thereof directly using a condensing agent (for example, dicyclohexylcarbodiimide); or a method ( B), a reactive derivative of a carboxyl group of the compound (4) or a salt thereof is appropriately reacted with ammonia or a salt thereof;

Examples of the reactive derivative of the carboxyl group of the compound (4) include 1) an acid halide; 2) an acid azide; 3) a mixed acid anhydride formed with an acid (for example, a substituted phosphate such as a dialkyl group; Phosphate ester, phenyl phosphate, diphenyl phosphate, diphenylmethyl phosphate, halogenated phosphate, etc.; dialkyl phosphite; sulfurous acid; thiosulfuric acid; sulfuric acid; sulfonic acid, such as: methanesulfonic acid, etc. ; aliphatic carboxylic acids, such as: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.; aromatic carboxylic acids, such as: benzoic acid, etc.; 4) symmetrical anhydride; 5) activated guanamine formed with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; 6) activated esters such as cyanomethyl ester, A Oxymethyl methyl ester, dimethyl iminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methylsulfonyl phenyl Ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl ester, p-cresolyl thioester, carboxymethyl thioester, piperidyl ester, pyridyl ester, piperidine a base ester, an 8-quinolylthio ester or the like; 7) an ester formed with an N-hydroxy compound (for example, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N - hydroxy amber imine, N-hydroxy quinone, 1-hydroxy-1H-benzotriazole); These reactive derivatives are preferably determined depending on the type of the compound (4) to be used.

Examples of the salt of the reactive derivative of the compound (4) or its carboxyl group include salts formed with a base such as an alkali metal salt (for example, a sodium salt, a potassium salt, etc.), an alkaline earth metal salt (for example, a calcium salt, Magnesium salt, etc., ammonium salts, organic alkali salts (for example: trimethylamine salt, triethylamine salt, pyridinium salt, methylpyridine salt, dicyclohexylamine salt, N,N-diphenylmethyl Ethylenediamine salt, etc.);

Examples of ammonia or a salt thereof include ammonia water, ammonium acetate, ammonium chloride, 1-hydroxybenzotriazole ammonia complex, and the like.

When an acid halide is used as the reactive derivative of the carboxyl group, the reaction is carried out in the presence of a base in a solvent which does not adversely affect the reaction.

Examples of the base include alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate and carbonic acid. Potassium and the like; alkali metal hydrogencarbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal C _1-6 alkoxide, such as: sodium methoxide, sodium ethoxide, potassium butoxide, etc.; organic bases, such as : trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4. 3. 0]-5-pinene, 1,4-diazabicyclo[2. 2. 2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, etc. Lithium amide, such as: methyl lithium, n-butyl lithium, second butyl lithium, t-butyl lithium, etc.;

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

Examples of the solvent which does not adversely affect the reaction include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, 1,4-two Alkane, diethyl ether, etc.; ethyl acetate; water; These solvents can be used in a mixture in an appropriate ratio.

The amount of ammonia or its salt is usually from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (4).

The reaction temperature is usually -30 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

When a mixed acid anhydride is used as the reactive derivative of the carboxyl group, the reaction is carried out from the compound (4) with a chlorocarbonate (for example, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) in a base (for example: In the presence of triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate, etc., the reaction is carried out in a solvent which does not adversely affect the reaction, and then The resulting compound is reacted with ammonia or a salt thereof.

The chlorocarbonate is usually used in an amount of from 1 to 5 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

The amount of ammonia or its salt is usually from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (4).

Examples of the solvent which does not adversely affect the reaction include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, 1,4-two Alkane, diethyl ether, etc.; ethyl acetate; water; These solvents can be used in a mixture in an appropriate ratio.

The reaction temperature is usually from -30 ° C to 100 ° C.

The reaction time is usually from 0.5 to 20 hours.

When the compound (4) is used in the form of a free acid or a salt thereof, the reaction is carried out in a solvent inert to the reaction in the presence of a conventional condensing agent such as a carbodiimide (for example, N, N). '-Dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinylethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide Amine, N, N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) carbonization Imine, etc.), N,N'-carbonylbis(2-methylimidazole), trialkyl phosphate, polyphosphate (for example: polyethyl phosphate, isopropyl polyphosphate, etc.), phosphonium chloride, two Phenylphosphonium azide, sulfinium chloride, oxalic acid chloride, lower alkyl ester of haloformic acid (for example: ethyl chloroformate, isopropyl chloroformate, etc.), triphenylphosphine, N-hydroxyl Benzotriazole, 1-(p-chlorophenylsulfonyloxy)-6-chloro-1H-benzotriazole, Vilsmeier-reagent (by N,N'-dimethylformamidine) The amine is prepared by reacting with sulfinium chloride, carbon ruthenium chloride, trichloromethyl chloroformate, phosphonium chloride, etc.).

The condensing agent is usually used in an amount of from 1 to 5 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

The amount of ammonia or its salt is usually from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (4).

This reaction can be carried out in the presence of a base, if necessary. Examples of the base include triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like.

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

Examples of the solvent which does not adversely affect the reaction include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, 1,4-two Alkane, diethyl ether, etc.; ethyl acetate; water; These solvents can be used in a mixture in an appropriate ratio.

The reaction temperature is usually -30 ° C to 100 ° C, preferably 0 ° C to 60 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

When an acid azide, a symmetric acid anhydride, an activated guanamine, an activated ester, an ester formed with an N-hydroxy compound, or the like is used as a reactive derivative of a carboxyl group, the reaction can be carried out by a method known per se.

The compound (4) used as a starting material of this reaction can be produced by the method shown in the following reaction scheme 6 or the like.

In the second step, the compound (6) can be obtained by reacting the compound (5) with a dehydrating agent.

Examples of the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, phosphorus pentoxide, phosphorus pentachloride, phosphonium chloride, sulfoxide chloride, grass chloroform, 1,3-dicyclohexylcarbodiimide, cyanuric acid Cyanuric chloride and the like.

This reaction can be carried out in the presence of a base, if necessary. Examples of the base include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and the like; inorganic bases such as sodium carbonate, potassium carbonate and the like; and the like.

This reaction can be carried out without using a solvent or in a solvent inert to the reaction. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, Alkane, ether, etc.; esters, such as: methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate, etc.; guanamines, such as: N, N-dimethylformamide, N, N - dimethylacetamide, etc.; anthraquinones, such as: dimethyl hydrazine, etc.; These solvents can be used in a mixture in an appropriate ratio.

The dehydrating agent and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (5).

The reaction temperature is usually -30 ° C to 120 ° C, preferably -10 ° C to 100 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

In the third step, the compound (I-B') can be produced from the compound (6).

This reaction is carried out by reacting the compound (6) with the compound (7) according to the method described in Eur. J. Med. Chem., 1993, vol. 28, p.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.; ethers such as 1,4-di Alkane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane, etc.; esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc.; halogenation Hydrocarbons such as: dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; nitriles such as acetonitrile, propionitrile, etc.; These solvents can be used in a mixture in an appropriate ratio.

This reaction can be carried out in the presence of an acid if necessary. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, etc.; Lewis acids such as boron trihalide (for example, boron trichloride, boron trifluoride), titanium tetrahalide (for example, tetrachlorinated) Titanium, titanium tetrabromide), aluminum halide (for example: aluminum chloride, aluminum bromide), etc.; organic acids such as acetic acid, formic acid, trifluoroacetic acid, etc.;

The compound (7) and the acid are usually used in an amount of 0.1 to 10 moles, preferably 1 to 3 moles per 1 mole of the compound (6).

The reaction temperature is usually from -30 ° C to 120 ° C, preferably from 0 ° C to 100 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compound (7) used as a starting material of this reaction can be produced according to a method known per se or a method analogous thereto.

Compound (I-C) can be produced in two steps using Compound (5).

In the first step, the compound (8) can be produced by reacting the compound (5) with phosphorus pentasulfide or Lawesson's reagent.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform , carbon tetrachloride, trichloroethylene, etc.; alkalis, such as: pyridine, N, N-dimethylaniline, etc.; These solvents can be used in a mixture in an appropriate ratio.

The phosphorus pentasulfide or the Lawson's agent is usually used in an amount of from 0.5 to 10 moles, preferably from 0.5 to 3 moles per 1 mole of the compound (5).

The reaction temperature is usually -30 ° C to 140 ° C, preferably -10 ° C to 120 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

In the second step, the compound (I-C) can be produced by reacting the compound (8) with the compound (9) in the presence of the compound (10). This reaction was carried out in accordance with the method described in J. Org. Chem., 2002, vol. 67, p. 4595.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform , carbon tetrachloride, trichloroethylene, etc.; These solvents can be used in a mixture in an appropriate ratio.

The compound (9) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 4 moles per 1 mole of the compound (8).

The compound (10) is usually used in an amount of 0.1 to 10 moles, preferably 0.1 to 4 moles per 1 mole of the compound (8).

The reaction temperature is usually -30 ° C to 140 ° C, preferably -10 ° C to 120 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compounds (9) and (10) which are used as starting materials for this reaction can be produced by a method known per se or a method analogous thereto.

The compound (I-D) can be produced by subjecting the compound (I-C) to a reduction reaction.

Examples of the reducing agent used in this reaction include metal hydrides such as aluminum hydride, diisobutylaluminum hydride, tributyltin hydride, and the like; metal hydrogen complex compounds such as lithium aluminum hydride, sodium borohydride, Lithium borohydride, calcium borohydride, etc.; borane complex, such as: borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, etc.; alkylboranes, such as: third hexylborane ( Thexylborane), di(second isoamyl)borane (disiamylborane), etc.; diborane;

The amount of reducing agent is preferably determined by the type of reducing agent. For example, the metal hydride or metal hydrogen complex is used in an amount of from 0.25 to 10 moles, preferably from 0.5 to 5 moles per 1 mole of compound (IC); and a borane complex, an alkylborane or The diborane is used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (IC).

The reduction reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.; ethers such as diethyl ether and diisopropyl. Ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; These solvents can be used in a mixture in an appropriate ratio.

Although the reaction time varies depending on the kind and amount of the reducing agent to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

The compound (I-E) can be produced by subjecting the compound (I-C) to a hydrolysis reaction. The hydrolysis reaction is carried out according to a conventional method using an acid or a base.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, etc.; Lewis acids such as boron trichloride, boron tribromide, aluminum trichloride, aluminum tribromide, etc.; organic acids such as trifluoroacetic acid; P-toluenesulfonic acid, etc.; Lewis acid can be used in combination with a mercaptan (for example: ethanethiol) or a sulfide (for example, dimethyl sulfide).

Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkali metal C _1-6 alkane Alkoxides, such as: sodium methoxide, sodium ethoxide, potassium butoxide, etc.; organic bases, such as: triethylamine, imidazole, formazan, etc.;

The acid or base is usually used in an amount of about 0.5 to 10 moles, preferably about 0.5 to 6 moles per 1 mole of the compound (I-C).

The hydrolysis reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, propanol, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane and Alkanes, etc.; organic acids, such as: formic acid, acetic acid, etc.; ethers, such as: tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; guanamines, such as: N,N-dimethylformamide, N,N-dimethylacetamide, etc.; halogenated hydrocarbons, such as: Methyl chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ketones such as acetone, methyl ethyl ketone, etc.; : dimethyl hydrazine, etc.; water; These solvents can be used in a mixture in an appropriate ratio.

The reaction time is usually from 10 minutes to 60 hours, preferably from 10 minutes to 12 hours. The reaction temperature is usually -10 to 200 ° C, preferably 0 to 120 ° C.

The compound (I-F) can be produced by reacting the compound (I-E) or a reactive derivative thereof with a carboxyl group or a salt thereof with the compound (11).

Examples of the reactive derivative of the carboxyl group of the compound (I-E) include those exemplified as the reaction for preparing the compound (5) from the compound (4) in the reaction of Fig. 3.

This reaction is carried out in the same reaction manner as in the preparation of the compound (5) from the compound (4) in the reaction scheme 3.

The compound (11) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (I-E).

The reaction temperature is usually -30 ° C to 100 ° C, preferably 0 ° C to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compound (11) used as a starting material of this reaction can be produced according to a method known per se or a method analogous thereto.

Wherein R ¹⁸ is a C _1-6 alkyl group which may be optionally substituted or a C _1-6 alkoxy group which may be optionally substituted; R ¹⁹ is a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed. ; L ¹ is a leaving group; and other codes are as defined above.

Examples of "dissociation groups" of L ¹ include those as exemplified in the above E.

The compound (I-G) can be produced by reacting the compound (8) with the compound (12).

If desired, the reaction can be carried out in the presence of an acid or a base.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, etc.; Lewis acids such as boron trihalide (for example, boron trichloride, boron trifluoride), titanium tetrahalide (for example, titanium tetrachloride, tetrabromide) Titanium), aluminum halide (for example: aluminum chloride, aluminum bromide), etc.; organic acids such as acetic acid, formic acid, trifluoroacetic acid, etc.;

Examples of the base include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, etc.;

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; These solvents can be used in a mixture in an appropriate ratio.

When an acid is used, the compound (12) and the acid are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (8).

Although the reaction time varies depending on the kind (8), the compound (12) and the kind and amount of the acid to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

When a base is used, the compound (12) and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (8).

Although the reaction time varies depending on the kind and amount of the compound (8), the compound (12) and the base to be used, it is usually from 1 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 ° C to 120 ° C, preferably 0 ° C to 80 ° C.

The compound (12) can be produced according to a method known per se or a method analogous thereto.

The compound (14) can be produced by reacting the compound (4) or a reactive derivative thereof with a carboxyl group or a salt thereof with the compound (13).

The reactive derivative of the carboxyl group of the compound (4) or a salt thereof includes those exemplified as the reaction for preparing the compound (5) from the compound (4) in the reaction of Fig. 3.

This reaction can be carried out in the same reaction manner as in the preparation of the compound (5) from the compound (4) in the reaction of Figure 3.

The compound (14) can also be produced in two steps using the compound (4) or a reactive derivative thereof or a salt thereof.

In the first step, the compound (15) can be produced by reacting the compound (4) or a reactive derivative thereof with a carboxyl group or a salt thereof with hydrazine or a salt thereof.

Examples of the reactive derivative of the carboxy compound (4) or a salt thereof include those exemplified as the reaction for preparing the compound (5) from the compound (4) in the reaction of Fig. 3.

Examples of hydrazine or a salt thereof include hydrazine hydrate, hydrazine hydrochloride, hydrazine sulfate, and the like.

The amount of hydrazine or a salt thereof is usually from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (4).

This reaction is carried out in the same reaction manner as in the preparation of the compound (5) from the compound (4) in the reaction scheme 3.

In the second step, the compound (14) can be obtained by reacting the compound (15) with the compound (16).

This reaction is carried out in a solvent which does not adversely affect the reaction. Examples of the solvent which does not adversely affect the reaction include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, Alkane, diethyl ether, etc.; ethyl acetate; water; These solvents can be used in a mixture in an appropriate ratio.

This reaction can be carried out in the presence of a base, if necessary. Examples of the base include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, etc.;

The compound (16) and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (15).

The reaction temperature is usually -30 ° C to 100 ° C, preferably -10 ° C to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compounds (13) and (16) can be produced according to a method known per se or a method analogous thereto.

The compound (I-H) can be produced by reacting the compound (14) with phosphorus pentasulfide or Lawesson's reagent.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform , carbon tetrachloride, 1,2-dichloroethane, etc.; bases, such as: pyridine, N, N-dimethylaniline, etc.; These solvents can be used in a mixture in an appropriate ratio.

The phosphorus pentasulfide or Lawson's reagent is usually used in an amount of from 0.5 to 10 moles, preferably from 0.5 to 3 moles per 1 mole of the compound (14).

The reaction temperature is usually -30 ° C to 100 ° C, preferably -10 to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compound (2) can be produced, for example, by the following method.

Reaction Figure 5

The codes are as defined above.

The compound (2) can be produced by reacting the compound (4) or a reactive derivative thereof with a carboxyl group or a salt thereof with the compound (17).

The reactive derivative of the carboxy compound (4) or a salt thereof includes those exemplified as the reaction for producing the compound (5) from the compound (4) in Fig. 3.

This reaction is carried out in the same reaction manner as in the production of the compound (5) from the compound (4) in the reaction of Fig. 3. This reaction can be carried out in the presence of a base, if necessary.

The compound (17) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (4).

The reaction temperature is usually -30 ° C to 100 ° C, preferably 0 ° C to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

The compound (17) used as a starting material of this reaction can be produced according to a method known per se or a method analogous thereto.

The compound (4) can be produced, for example, by the following method.

Wherein R ²¹ is a C _1-6 alkyl group which may be optionally substituted; and the other symbols are as defined above.

Examples of the "C _1-6 alkyl group which may be optionally substituted" of R ²¹ include those similar to the "C _1-6 alkyl group which may be optionally substituted" of R ² .

Compound (4) can be produced in two steps using Compound (18-A) or Compound (18-B) as a starting material.

In the first step, the compound (21) can be produced by reacting the compound (18-A) with the compound (19). Alternatively, the compound (21) can also be produced by reacting the compound (18-B) with the compound (20). Alternatively, the compound (21) can also be produced by reacting the compound (18-A) or the compound (18-B) with an alkylating agent. This reaction is carried out in the same reaction manner as in the preparation of the compound (1) from the compound (3-3) in the reaction of Fig. 2.

In the second step, the compound (4) can be produced by subjecting the compound (21) to a hydrolysis reaction.

This reaction is carried out in the same manner as in the reaction of Figure 3 from the preparation of the compound (I-E) of the compound (I-C).

The compounds (19) and (20) which are the starting materials of this reaction can be produced by a method known per se or a method analogous thereto.

The compound (18-A) or the compound (18-B) which is the starting material of this reaction can be produced, for example, by the following method.

Wherein H-X is a mineral acid such as hydrochloric acid, sulfuric acid or the like, or an organic acid such as acetic acid, formic acid, trifluoroacetic acid, etc., and each code is as defined above.

Compound (25) can be produced by reacting Compound (26) with Compound (27).

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; These solvents can be used in a mixture in an appropriate ratio.

The acid catalyst can be used to promote the reaction. Examples of the acid catalyst include mineral acids such as hydrochloric acid, sulfuric acid, etc.; Lewis acids such as boron trihalide (for example, boron trichloride, boron trifluoride), titanium tetrahalide (for example, titanium tetrachloride, Titanium tetrabromide), aluminum halide (for example: aluminum chloride, aluminum bromide), etc.; organic acids such as acetic acid, formic acid, trifluoroacetic acid, etc.;

The compound (27) and the acid catalyst are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (26).

Although the reaction time varies depending on the kind and amount of the compound (26), the compound (27) and the acid catalyst to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

Compound (25) can also be prepared from compound (1) by Japp-Klingemann reaction [Org. Reactions, 1959, vol. 10, p. 143; J. Chem. Soc., 1927, page 1 ].

This reaction is carried out by reacting the compound (23), which is prepared by reacting the compound (1) with an acid (H-X) and sodium nitrite according to a method known per se, with the compound (24) in the presence of a base.

Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as carbonic acid Sodium, potassium carbonate, etc.; alkali metal hydrogencarbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; organic bases, such as: trimethylamine, triethylamine, diisopropylethylamine, pyridine, A Pyridine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2] octyl Alkane, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.;

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, butanol, etc.; ethers such as 1,4-di Alkanes, tetrahydrofuran, diethyl ether, diphenyl ether, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane, etc.; halogenated hydrocarbons such as: dichloromethane, chloroform, tetrachlorination Carbon, trichloroethylene, chlorobenzene, 1,2-dichlorobenzene, etc.; hydrocarbons such as: n-hexane, benzene, toluene, xylene, etc.; guanamines such as: formazan, N, N-dimethyl Mercaptoamine, N,N-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; water; These solvents can be used in a mixture in an appropriate ratio.

The compound (24) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (23).

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (23).

The acid (H-X) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (1).

The amount of sodium nitrite is usually 1 to 5 moles, preferably 1 to 3 moles per 1 mole of the compound (1).

The reaction time is usually from 1 hour to about 100 hours, preferably from 1 hour to 50 hours. The reaction temperature is usually -20 ° C to 120 ° C, preferably 0 ° C to 80 ° C.

Compound (18-C) can be obtained from compound (25) by Fischer method [Berichte, 1883, vol. 16, p. 2241].

This reaction is carried out by heating the compound (25) with an acid.

Examples of the acid include zinc chloride, hydrochloric acid, sulfuric acid, acetic acid, boron fluoride, polyphosphoric acid, phosphorus pentoxide, methanesulfonic acid, toluenesulfonic acid and the like. These acids can be used in a mixture in an appropriate ratio.

The amount of the acid is usually 0.1 to 10 moles, preferably 0.5 to 3 moles per 1 mole of the compound (25).

This reaction is preferably carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include those exemplified in the production method of the compound (25).

Although the reaction time varies depending on the kind and amount of the acid to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 50 ° C to 190 ° C.

Compound (18-C) can also be obtained from the compound (28) Reissert method [Berichte, 1897, vol. 30, p. 1030] in two steps.

In the first step, compound (28) is reacted with compound (29) in the presence of a base to give compound (30). In the second step, a reduction reaction is carried out from the compound (30) to give a compound (18-C).

Examples of the base used in the first step include alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like;

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include those exemplified in the production method of the compound (25).

The compound (29) and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (28).

The reaction temperature is usually -30 ° C to 140 ° C, preferably -10 ° C to 110 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 to 15 hours.

In the second step, the reduction reaction is carried out using a reducing agent.

Examples of the reducing agent include metals such as iron, zinc, tin, etc.; sulfides such as sodium disulfinate, and the like; and the like.

The amount of reducing agent is preferably determined by the type of reducing agent. For example, the amount of metal is usually 1 to 20 moles, preferably 1 to 5 moles per 1 mole of compound (30), and the amount of sulfide is usually 1 to 20 moles per 1 mole of compound (30). The ear is preferably 1 to 5 moles.

This reduction reaction can also be carried out by a hydrogenation reaction. At this time, for example, a catalyst such as palladium carbon, palladium black, platinum dioxide, ruthenium nickel, ruthenium cobalt, ferric chloride or the like can be used.

The amount of the catalyst is usually from 5 to 1,000% by weight, preferably from about 10 to 300% by weight based on the compound (30).

The hydrogenation reaction can also be carried out using hydrogen or a variety of different hydrogen sources. Examples of the hydrogen source include formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine, and the like.

The hydrogen source is usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 5 moles per 1 mole of the compound (30).

The reduction reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.; ethers such as diethyl ether and diisopropyl. Ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; These solvents can be used in a mixture in an appropriate ratio.

Although the reaction time varies depending on the kind and amount of the reducing agent and the catalyst to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 ° C to 120 ° C, preferably 0 ° C to 80 ° C.

The compound (18-A) or the compound (18-B) can be produced, if necessary, by the compound (18-C) wherein G is a protected amine group, a protected thio group or a protected hydroxy group. Peptide chemistry and other commonly used methods for removing the protecting group, such as acid treatment, alkali treatment, catalytic reduction, and the like.

The compounds (24), (26), (27), (28) and (29) can be produced according to a method known per se or a method analogous thereto.

Compound (1) can also be produced, for example, according to the method shown in the following reaction scheme.

Wherein Y is a halogen atom; and other codes are as defined above.

Compound (1) can be produced in two steps using Compound (31) as a starting material.

In the first step, the compound (33) can be obtained by reacting the compound (31) with the compound (32).

This reaction can be carried out in the presence of a base, if necessary.

Examples of the base include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, sodium hydride, etc.;

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; These solvents can be used in a mixture in an appropriate ratio.

When a base is used, the compound (32) and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (31).

Although the reaction time varies depending on the kind and amount of the compound (31), the compound (32) and the base to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 ° C to 120 ° C, preferably 0 ° C to 80 ° C.

In the second step, the compound (1) can be obtained by subjecting the compound (33) to a reduction reaction.

This reduction reaction is carried out in the same reaction manner as in the reaction of the compound (30) to prepare the compound (18-C) in Fig. 7.

The compounds (31) and (32) which are the starting materials of this reaction can be produced by a method known per se or a method analogous thereto.

Compound (17) can also be produced, for example, according to the following method.

Wherein L ² is a leaving group, and other codes are as defined above.

Examples of "dissociation groups" of L ² include those as exemplified in the above E.

Compound (36) can be produced from Compound (34) according to a known method [J. Org. Chem. Soc., 1963, vol. 28, 1240page; Tetrahedron, 2003, vol. 59, page 4979].

This reaction is carried out by reacting the compound (34) with the compound (35) and nitromethane in the presence of a base.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamine, etc.; nitriles such as acetonitrile, propionitrile, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-Dichloroethane, carbon tetrachloride, trichloroethylene, and the like. These solvents can be used in a mixture in an appropriate ratio.

Examples of the base include amines such as pyrrolidine and piperidine. , morpholine, ethylenediamine, etc.;

The base is usually used in an amount of from 0.01 to 10 moles, preferably from 0.05 to 2 moles per 1 mole of the compound (34).

The compound (35) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (34).

The amount of nitromethane is usually from 1 to 50 moles, preferably from 1 to 10 moles per 1 mole of compound (34).

Although the reaction time varies depending on the kind and amount of the compound (34), the compound (35), the nitromethane and the base to be used, it is usually from about 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 25 ° C to 100 ° C.

Compound (36) can also be obtained from compound (34) in three steps.

In the first step, a Henry reaction is carried out from the compound (34) and nitromethane in the presence of a base [J. Org. Chem., 1963, vol. 28, page 1240; Synthesis, 1994, page 190; J. Am. Chem. Soc., 2003, vol. 125, page 3700] Compound (37) was obtained.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, butanol, etc.; ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamine, etc.; nitriles such as acetonitrile, propionitrile, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-Dichloroethane, carbon tetrachloride, trichloroethylene, and the like. These solvents can be used in a mixture in an appropriate ratio.

Examples of the base include alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like;

The base is usually used in an amount of from 0.01 to 10 moles, preferably from 0.05 to 2 moles per 1 mole of the compound (34).

The amount of nitromethane is usually from 1 to 50 moles, preferably from 1 to 10 moles per 1 mole of compound (34).

Although the reaction time varies depending on the kind (34), the kind and amount of the nitromethane and the base to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 25 ° C to 100 ° C.

In the second step, the compound (37) is subjected to a dehydration reaction to obtain a compound (38).

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamine, etc.; nitriles such as acetonitrile, propionitrile, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-Dichloroethane, carbon tetrachloride, trichloroethylene, etc.; pyridine, and the like. These solvents can be used in a mixture in an appropriate ratio.

This dehydration reaction is usually carried out using a dehydrating agent. Examples of the dehydrating agent include chlorinating agents such as sulfinium chloride, phosphonium chloride, etc.; sulfonating agents such as: methanesulfonyl chloride, methanesulfonic anhydride, etc.; deuterating agents such as ethyl chloroform, acetic anhydride , trifluoroacetic anhydride, etc.;

The dehydrating agent is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (37).

This reaction can be carried out in the presence of a base, if necessary. Examples of the base include alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate and carbonic acid. Potassium and the like; alkali metal hydrogencarbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal C _1-6 alkoxide, such as: sodium methoxide, sodium ethoxide, potassium butoxide, etc.; organic bases, such as : trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3. 0]-5-pinene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.; lithium amide, such as : methyllithium, n-butyllithium, t-butyllithium, t-butyllithium, etc.;

The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (37).

The reaction temperature is usually -30 ° C to 200 ° C, preferably -10 ° C to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 hour to 15 hours.

In the third step, compound (36) is obtained by reacting compound (38) with compound (35) in the presence of a base.

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, butanol, etc.; ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamine, etc.; nitriles such as acetonitrile, propionitrile, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-Dichloroethane, carbon tetrachloride, trichloroethylene, and the like. These solvents can be used in a mixture in an appropriate ratio.

Examples of bases include those exemplified in the second step above.

The compound (35) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 2 moles per 1 mole of the compound (38).

The base is usually used in an amount of from 0.05 to 10 moles, preferably from 0.1 to 3 moles per 1 mole of the compound (38).

The reaction temperature is usually -30 ° C to 100 ° C, preferably -10 ° C to 80 ° C. The reaction time is usually from 0.5 to 20 hours, preferably from 1 hour to 15 hours.

The compound (17-A) can be produced by subjecting the compound (36) to a reduction reaction.

This reduction reaction is carried out, for example, using a reducing agent. Examples of the reducing agent include metal hydrides such as aluminum hydride, diisobutylaluminum hydride, tributyltin hydride, etc.; metal hydride complexes such as lithium aluminum hydride, sodium borohydride, etc.; borane mismatch , such as: borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, etc.; alkylboranes, such as: trimethylpropylborane, two second isoamylborane, etc.; Borane; metal, such as: zinc, aluminum, tin, iron, etc.;

The amount of the reducing agent is preferably determined depending on the type of the reducing agent. For example, the amount of metal hydride or metal hydride complex is usually from 0.25 to 10 moles, preferably from 0.5 to 5 moles per 1 mole of compound (36); borane complex, alkyl borane Or diborane is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles per 1 mole of the compound (36); the amount of the metal is usually from 1 to 20 moles per 1 mole of the compound (36). The ear is preferably 1 to 5 moles.

The reduction reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.; ethers such as diethyl ether and diisopropyl. Ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N, N-di Methylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; These solvents can be used in a mixture in an appropriate ratio.

Although the reaction time varies depending on the kind and amount of the reducing agent to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

The compounds (34) and (35) which are the starting materials of this reaction can be produced by a method known per se or a method analogous thereto.

The compound (17) can be produced by reacting the compound (40) with the compound (41), if necessary, in the presence of an acid or a base.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, etc.; organic acids such as acetic acid, formic acid, trifluoroacetic acid, and the like;

Examples of the base include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, etc.;

This reaction is carried out without using a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; esters, such as: ethyl formate, ethyl acetate, n-butyl acetate, etc.; aromatic hydrocarbons, such as: benzene, toluene, etc.; saturated hydrocarbons, such as : cyclohexane, hexane, etc.; guanamines, such as: N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, etc.; These solvents can be used in a mixture in an appropriate ratio.

When an acid is used, the compound (41) and the acid are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (40).

Although the reaction time varies depending on the kind (40), the compound (41) and the kind and amount of the acid to be used, it is usually from 0.5 to 100 hours, preferably from 1 to 50 hours. The reaction temperature is usually -20 ° C to 120 ° C, preferably 0 ° C to 80 ° C.

When a base is used, the compound (41) and the base are usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per 1 mole of the compound (40).

Although the reaction time varies depending on the kind and amount of the compound (40), the compound (41) and the base to be used, it is usually from 1 hour to 100 hours, preferably from 1 hour to 50 hours. The reaction temperature is usually -20 to 120 ° C, preferably 0 to 80 ° C.

The compound (41) which is the starting material of this reaction can be produced by a method known per se or a method analogous thereto.

Compound (33) can also be produced, for example, according to the method shown in Figure 10 below.

The codes are as defined above.

The compound (33) can be produced from the compound (41) in the same manner as in the reaction of the compound (3) prepared in the compound (3-3) in Fig. 2 or the like.

The compound (41) which is the starting material of this reaction can be produced according to a method known per se or a method analogous thereto.

The compound (I-I) can be produced, for example, according to the method shown in the reaction scheme of Fig. 11.

Wherein M is a metal or a metal halide, and each R ²³ is a C _1-6 alkyl group which may be optionally substituted, a C _3-10 cycloalkyl group which may be optionally substituted, a C _6-14 aryl group which may be _optionally substituted or a visible The substituted heterocyclic group is required, and other codes are as defined above.

The compound (I-I) can be obtained by reacting the compound (I-C) with the compound (43). Preferable examples of the compound (43) include organolithium such as methyllithium, n-butyllithium, phenyllithium, etc.; Grignard reagents such as methylmagnesium bromide, methylmagnesium chloride, chlorine Ethyl magnesium, phenyl magnesium bromide, and the like.

This reaction is preferably carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and examples thereof include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform , carbon tetrachloride, 1,2-dichloroethane, etc.; These solvents can be used in a mixture in an appropriate ratio.

Although the reaction time varies depending on the kind and amount of the reagent and solvent to be used, it is usually from 10 minutes to 100 hours, preferably from 30 minutes to 50 hours. The reaction temperature is usually -70 to 100 ° C, preferably 0 to 80 ° C.

The compound (43) is used in an amount of from about 0.5 to about 20 moles, preferably from about 1 to about 10 moles per 1 mole of the compound (I-C).

In the above reaction, the obtained product and the functional group in the molecule of the compound (I) can be converted into a desired functional group by a chemical reaction known per se. Examples of the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, a hydrolysis reaction, an amination reaction, a guanidine reaction, an esterification reaction, an aryl coupling reaction, a deprotection reaction, and the like.

In the above methods, when the starting compound has an amine group, a carboxyl group, a hydroxyl group, a carbonyl group or a thiol group as a substituent, a commonly used protecting group such as a peptide chemistry can be introduced into the groups, and if necessary, The protecting group is removed after the reaction to give the subject compound.

Examples of the amino-protecting group include a fluorenyl group; a C _1-6 alkyl-carbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group), a C _1-6 alkoxy group-carbonyl group (e.g., a methoxycarbonyl group, a Oxycarbonyl, tert-butoxycarbonyl), benzhydryl, C _7-13 aralkyl-carbonyl (eg benzylcarbonyl), C _7-13 aralkyloxy-carbonyl (eg benzene) Methyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl, fluorenyl, N,N-dimethylaminomethylene, substituted decyl (eg trimethyl decane) , triethyl decyl, dimethylphenyl decyl, tert-butyldimethyl decyl, tert- _butyldiethyl decyl, C _2-6 alkenyl (eg 1-alkenyl) Base) and so on. These groups may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the carboxy-protecting group include a C _1-6 alkyl group, a C _7-20 aralkyl group (e.g., benzyl group), a phenyl group, a trityl group, a substituted decyl group (e.g., trimethyl decyl group). , triethyl decyl, dimethylphenyl decyl, tert-butyldimethyl decyl, tert- _butyldiethyl decyl, C _2-6 alkenyl (eg 1-allyl) )Wait. These groups may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the hydroxy-protecting group include a C _1-6 alkyl group, a trityl group, a C _7-13 aralkyl group (e.g., benzyl group), a decyl group, a C _1-6 alkyl-carbonyl group, and a benzamidine group. a C _7-13 aralkyl-carbonyl group (for example: benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted alkylene (for example: trimethyldecyl, triethyl)矽alkyl, dimethylphenyldecyl, tert-butyldimethylalkyl, tert- _{butyldiethylalkyl} ), C _2-6 alkenyl (eg 1-allyl), C _{1 -6} alkylsulfonyl (for example: methylsulfonyl, ethylsulfonyl), C _6-10 arylsulfonyl, the C _6-10 arylsulfonyl group may be subjected to 1 to 3 Substituted by a substituent selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and nitro (eg phenylsulfonyl, m-nitrophenylsulfonyl, p-toluenesulfonyl), etc. . These groups may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a nitro group.

Examples of the carbonyl protecting group include a cyclic acetal (for example, 1,3-two) Alkane), acyclic acetal (for example: di C _1-6 alkyl acetal), and the like.

Examples of the thiol-protecting group include a C _1-6 alkyl group, a trityl group, a C _7-10 aralkyl group (e.g., benzyl group), a C _1-6 alkyl-carbonyl group, a benzylidene group, and C. _7-10Aralkyl -carbonyl (for example: benzylcarbonyl), _C1-6 alkoxy-carbonyl, C _6-14 aryloxy-carbonyl (for example: phenyloxycarbonyl), C _{7- 14} aralkyloxy-carbonyl (for example: benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl, C _1-6 alkylamino-carbonyl (for example: A Aminocarbonyl, ethylaminocarbonyl, and the like. These groups may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a nitro group.

The compound (I) obtained by the above production method can be isolated and purified in a known manner, for example, a concentration method, a reduced pressure concentration method, a solvent extraction method, a crystallization method, a recrystallization method, a phase transfer method, a chromatography method and the like. In addition, the various starting compounds used in each of the above processes can be isolated and purified in a known manner, such as those described above. Alternatively, the starting compound can be used directly in the form of a reaction mixture which does not require isolation as a starting material for the next step.

For the production of the compound (I), when the starting compound can form a salt, the compound can also be used in the form of a salt. Examples of the salt include those similar to the salt of the compound (I).

When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer or a rotamer, these isomers are all included in the compound (I), and can be synthesized according to a synthesis method known per se. A single product is obtained by a separation method. For example, optical isomers and optical isomers resolved from this compound are also included in the compound (I).

Compound (I) may be in a crystalline form.

The crystal of the compound (I) (hereinafter sometimes referred to as the crystal of the present invention) can be obtained by crystallizing the compound (I) according to a crystallization method known per se.

In the present specification, the melting point means a value measured by, for example, a minute melting point measuring device (Yanako, MP-500D or Buchi, B-545) or a DSC (differential scanning thermal analysis) device (SEIKO, EXSTAR 6000).

Generally, the melting point varies depending on the measuring equipment, the measurement conditions, and the like. In the present specification, the crystal may have a melting point different from that described in the specification as long as it is within the general error range.

The crystal of the invention has excellent physicochemical properties (for example: melting point, solubility, stability) and biological properties (for example: pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy performance), and is highly suitable as a medicament .

Example

The present invention is explained in detail by the following reference examples, examples, experimental examples, and examples, but the embodiments are not limited. Further, the invention can be modified without departing from the scope of the invention.

The term "room temperature" in the following Reference Examples and Examples means a temperature range generally ranging from about 10 ° C to about 35 ° C. "%" is used in the yield to mean mol/mol %, used in the solvent of column chromatography to refer to % by volume, and the other "%" is % by weight. The OH protons, NH protons, etc. on the proton NMR spectrum cannot be confirmed because the data does not include a broad peak.

The other codes used in this paper are defined as follows:

s: single peak

d: double peak

t: three peaks

q: four peaks

Spt: seven peaks

m: multi-peak

Br: wide peak

Brs: wide single peak

J: coupling constant

Hz: Hertz

CDCl ₃ : deuterated chloroform

DMSO-d ₆ : dimethyl hydrazine-d ₆

¹ H-NMR: proton nuclear magnetic resonance

Mp: melting point

TFA: trifluoroacetic acid

MgSO ₄ : magnesium sulfate

CO ₂ : carbon dioxide

In the following Reference Examples and Examples, nuclear magnetic resonance spectroscopy (NMR) was measured under the following conditions.

NMR assay tools: Varian Inc. Varian Gemini 200 (200 MHz), Varian Gemini 300 (300 MHz), Bruker BioSpin Corp. AVANCE 300.

In the following examples, high performance liquid chromatography (HPLC)-mass spectrometry (LC-MS) was carried out under the following conditions.

Measuring tool: Micromass Ltd., Quattro Micro and Agilent Technologies, Inc. HP1100, or Waters Corporation, MUX system (Micromass Ltd., ZQ)

Column: Shiseido Co., Ltd., Capcelpak C18 UG-120, 1.5 × 35 mm (mm)

Solvent: solution A; 5 mM ammonium acetate/2% acetonitrile / water, solution B; 5 mM ammonium acetate / 95% acetonitrile / water

Gradient cycle: 0.00 minutes (solution A 100%), 2.00 minutes (solution B 100%), 3.00 minutes (solution B 100%), 3.01 minutes (solution A 100%), 3.80 minutes (solution A 100%)

Flow rate: 0.5 ml/min (ml/min), detection: UV 220 nm (nm)

Ionization: Electrospray ionization: ESI

In the following Reference Examples and Examples, preparative high performance liquid chromatography (HPLC) purification was carried out under the following conditions. However, if the compound has a basic functional group, when it is operated using trifluoroacetic acid, a neutralization reaction or the like may be required to obtain a free compound.

Tools: GilSon, Inc., High Throughput Purification System

Column: Shiseido Co., Ltd., Capcelpak C18 UG-120, S-5μM, 20×50mm

Solvent: solution A; water containing 0.1% trifluoroacetic acid, solution B; acetonitrile containing 0.1% trifluoroacetic acid

Gradient cycle: 0.00 minutes (solution A / solution B = 95/5), 1.10 minutes (solution A / solution B = 95/5), 5.00 minutes (solution A / solution B = 0 / 100), 6.40 minutes (solution A /solution B = 0/100), 6.50 minutes (solution A / solution B = 95/5).

Flow rate: 20ml/min, detection: UV 220nm or,

Tool: Waters Mass Preparation System (UV Purification System)

Column: Develosil ODS-UG-10

Solvent: solution A; water containing 0.1% trifluoroacetic acid, solution B; acetonitrile containing 0.1% trifluoroacetic acid

Gradient cycle: 0.00 minutes (solution A / solution B = 95/5), 1.00 minute (solution A / solution B = 95 / 5), 2.00 minutes (solution A / solution B = 80 / 20), 5.00 minutes (solution A / solution B = 5 / 95), 5.10 minutes (solution A / solution B = 0 / 100), 7.00 minutes (solution A / solution B = 100 / 0)

Flow rate: 150ml/min, detection: UV 220nm

In the following Reference Examples and Examples, preparative high performance liquid chromatography (HPLC) was carried out using K-Prep manufactured by YMC Co., Ltd. to carry out palmar analysis, and MultiGram manufactured by METTLER-TOLEDO KK was used. II for preparative supercritical fluid chromatography (SFC)

Reference example 1

2-(benzyloxy)-4-fluoro-1-nitrobenzene

Benzyl bromide was added to a mixture of 5-fluoro-2-nitrophenol (50.0 g), potassium carbonate (44.0 g) and N,N-dimethylformamide (150 mL) under ice cooling. 59.9 g), the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced vacuo. The organic layer was washed with brine, dried over magnesium sulfate The obtained solid was washed with hexane toield of pale crystals of

¹ H NMR (CDCl ₃ ) δ 5.23 (2H, s), 6.64-6.79 (1H, m), 6.83 (1H, dd, J = 10.2, 2.5 Hz), 7.28-7.57 (5H, m), 7.97 ( 1H, dd, J = 9.0, 6.0 Hz).

Reference example 2

2-(Benzyloxy)-4-[4-(methylthio)phenoxy]-1-nitrobenzene

2-(Benzyloxy)-4-fluoro-1-nitrobenzene (16.8g), 4-methylthiophenol (10.0g), potassium carbonate (14.1g) and N,N-di A mixture of methylformamide (150 mL) was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced vacuo. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained solid was washed with diethyl ether toiel The pale yellow solid was recrystallized from ethanol to give a pale yellow crystal. Melting point 81 to 82 ° C.

Reference example 3

2-(Benzyloxy)-4-[4-(methylsulfonyl)phenoxy]-1-nitrobenzene

2-(Benzyloxy)-4-[4-(methylthio)phenoxy]-1-nitrobenzene (10.3 g) was dissolved in tetrahydrofuran (200 mL)-methanol (100 mL)-water ( In 50 mL of a mixed solvent, OXONE (42.0 g) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered to give a white solid. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained solid was washed with diethyl ether-hexane-hexane toiel 142 to 143 ° C melting point.

Reference example 4

2-(Benzyloxy)-4-[4-(methylsulfonyl)phenoxy]aniline

Take 2-(benzyloxy)-4-[4-(methylsulfonyl)phenoxy]-1-nitrobenzene (11.0g), iron powder (7.6g), calcium chloride ( A mixture of 0.3 g), water (30 mL) and ethanol (120 mL) was stirred at 80 ° C for 2 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained crude product was crystallized from EtOAc (EtOAc:EtOAc) MS 370 (MH ⁺ ).

Reference example 5

2-({2-(Benzyloxy)-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propionic acid ethyl ester

2-(Benzyloxy)-4-[4-(methylsulfonyl)phenoxy]phenylamine (43.8 g) was suspended in a mixed solvent of acetonitrile (50 mL)-ethanol (400 mL) at 10 ° C Concentrated hydrochloric acid (25 mL) was added below. Then ethanol (100 mL) was added. An aqueous solution (16 mL) of sodium nitrite (9.8 g) was added dropwise at -5 to 0 ° C, and the mixture was stirred at -5 ° C for 30 min. Water (100 mL) was added to the reaction mixture, and the mixture was added dropwise to 2-methyl-3-oxoethoxybutyrate (18.8 mL) at -13 ° C to -11 ° C over 2 hours. A mixture of potassium hydroxide (85%, 23 g), water (100 mL) and ethanol (100 mL). The reaction mixture was stirred at -11 ° C for 40 min and a precipitated orange solid was collected by filtration. The obtained solid was washed with ethyl acetate and diethyl ether toiel

¹ H NMR (CDCL ₃ ) δ 1.38 (3H, t, J = 7.0 Hz), 2.06 (3H, s), 3.05 (3H, s), 4.32 (2H, q, J = 6.9 Hz), 5.11 (2H) , s), 6.67-6.77 (2H, m), 7.00 (2H, d, J = 8.7 Hz), 7.33 - 7.42 (5H, m), 7.62 (1H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.7 Hz), 8.10 (1H, s).

Reference example 6

Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

P-Toluenesulfonic acid monohydrate (16.1 g) was refluxed in toluene for 1.5 hours, and water was removed by azeotropic dehydration. The solution was cooled to 80 ° C and ethyl 2-({2-(benzyloxy)-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propionate was added ( 37.2 g), the mixture was stirred at 80 ° C for 10 minutes. The reaction solution was washed with water, aq. The obtained crude product was subjected to EtOAc EtOAc EtOAc (EtOAc (EtOAc) Light yellow solid. The pale yellow solid was recrystallized from ethyl acetate-hexane to yield pale yellow crystals. The temperature of 148 to 149 ° C.

Reference example 7

7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.9 g) was dissolved in tetrahydrofuran (10 mL) - A 1 M aqueous sodium hydroxide solution (10 mL) was added to a mixed solvent of ethanol (10 mL), and the mixture was stirred at 50 ° C for 45 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The obtained crystals were collected by chromatography,jjjjjjjjjj The pale orange solid was recrystallized from ethanol-hexane to yield pale orange crystals. The temperature of 232 to 233 ° C.

Reference Example 8

7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

Taking 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.59 g), 1-[3-(two Methylamino)propyl-3-ethylcarbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole ammonium salt (1.1 g) and N,N-dimethylformamide (40 mL) The mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitated solid was collected,jjjjjjjjjjjjjjj The pale yellow solid recrystallized from N,N-dimethylformamide-water to yield pale yellow crystals. Mp 251 to 252 ° C.

Reference Example 9

Ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (0.40 g) was dissolved in tetrahydrofuran (5 mL) - To a mixed solvent of ethanol (5 mL), 10% palladium-carbon (containing 50% water, 0.80 g) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was evaporated evaporated. The residue was crystallized from diethyl ether. The pale yellow solid was recrystallized from ethanol-hexane to yield pale yellow crystals. Melting point 197 to 198 ° C.

Reference example 10

7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbonitrile

Under ice cooling, containing 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (840 mg), pyridine ( 0.23 mL) and a mixture of N,N-dimethylformamide (20 mL) were added dropwise with dichloromethane (0.25 mL), and the mixture was stirred for 2 hr. Pyridine (0.23 mL) and grass chloroform (0.25 mL) were added sequentially, and the mixture was stirred for further 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc. The obtained solid was washed with diethyl ether-hexane (hexane) toield The resulting yellow crystals were recrystallized from ethanol-hexane to yield yellow crystals. Mp 209 to 210 ° C.

Reference example 11

Ethyl 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.39 g), 2-(bromomethyl)-6-chloro A mixture of pyridine (840 mg), potassium carbonate (1.02 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to EtOAc EtOAc EtOAcjjjjjjj %) of white crystals. MS 501 (MH ⁺ ).

Reference example 12

7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Take 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid ethyl ester (1.0 g The mixture was dissolved in tetrahydrofuran (10 mL)-ethanol (10 mL), and 1M aqueous sodium hydroxide (5 mL) was added, and the mixture was stirred at 50 ° C for 50 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The obtained crystals were collected by EtOAcjjjjjjjjj The resulting crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. Melting point 249 to 250 ° C (decomposition).

Reference example 13

7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

Taking 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (780 mg), 1-[3-(Dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (632 mg), 1-hydroxybenzotriazole ammonium salt (502 mg) and N,N-dimethyl A mixture of formamide (30 mL) was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitated solid was collected,jjjjjjjjjjjjjj The resulting crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. Melting point 259 to 260 ° C.

Reference example 14

Ethyl 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (100 mg), 2-(chloromethyl)-1-methyl A mixture of -1H-imidazole hydrochloride (50 mg), potassium carbonate (83 mg) and N,N-dimethylformamide (20 mL) was stirred at 50 ° C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to EtOAc EtOAcjjjjjjjjj The white solid was recrystallized from ethyl acetate-hexane to yield colorless crystals. 91.92 ° C melting point.

Reference example 15

7-[(1-Methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Taking 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid B The ester (100 mg) was dissolved in tetrahydrofuran (2 mL)-ethanol (2 mL), and 1M aqueous sodium hydroxide (2 mL) was added and the mixture was stirred at 50 ° C for 50 min. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The obtained crystals were collected by chromatography,jjjjjjjjjjj The white solid was recrystallized from N,N-dimethylformamide-water to give colorless crystals. Mp 209 to 210 ° C (decomposition).

Reference example 16

7-[(1-Methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

Containing 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (940 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (817 mg), 1-hydroxybenzotriazole ammonium salt (648 mg) and N,N A mixture of dimethylformamide (20 mL) was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained solid was washed with ethyl acetate-diethyl ether. MS 441 (MH ⁺ ).

Reference example 17

Ethyl 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperazin-4-ylmethoxy)-1H-indole-2-carboxylate

Ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (400 mg), tetrahydro-2H-pyran-4-ylmethanol A mixture of (250 mg), 1,1'-(azodicarbonyl)dipiperidine (540 mg), tributylphosphine (0.5 mL) and tetrahydrofuran (10 mL) was stirred at 50 ° C for 13 hours. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The filtrate was concentrated under reduced pressure. EtOAc m. . MS 474 (MH ⁺ ).

Reference Example 18

5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carboxylic acid

Take 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester (3.5 g) In a mixed solvent of tetrahydrofuran (30 mL)-ethanol (30 mL), 1M aqueous sodium hydroxide (15 mL) was added, and the mixture was stirred at 50 ° C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained crude product was crystallized from a mixed solvent of ethanol-hexane-diethyl ether. The obtained colorless crystals were recrystallized from acetone-hexane to give the title compound (1.1 g). Melting point 256 to 258 ° C (decomposition).

Reference example 19

5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carboxamide

5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carboxylic acid (1.0 g) , 1-[3-(Dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.9 g), 1-hydroxybenzotriazole (0.6 g) and N,N-di A mixture of methylformamide (15 mL) was stirred at room temperature for 15 minutes. A 28% aqueous ammonia solution (0.8 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained crude product was crystallized from ethyl acetate-diethyl ether. MS 445 (MH ⁺ ).

Reference example 20

5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carbonitrile

5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indole-2-carboxamide (250 mg) The mixture was dissolved in N,N-dimethylformamide (5 mL). Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained crude product was subjected to methylene chloride chromatography (ethyl acetate: hexane = 10:90 to 60:40) to give the title compound (240 mg, yield 100%) as white solid. MS 445 (MH ⁺ ).

Reference example 21

7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H -indole-2-carboxylic acid ethyl ester

Ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.3 g), 1-{[di-t-butyl (benzene)矽)alkyl]oxy}propan-2-ol (3.9 g), 1,1'-(azodicarbonyl)dipiperidine (3.1 g), tributylphosphine (3.1 mL) and tetrahydrofuran (20 mL) The mixture was stirred at 50 ° C for 18 hours. The reaction solution was cooled to room temperature, and a white solid precipitate was filtered. The filtrate was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjj Things. MS 672 (MH ⁺ ).

Reference example 22

7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H -indole-2-carboxylic acid

Taking 7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]- Ethyl 1H-indole-2-carboxylate (2.4 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), and 1M aqueous sodium hydroxide (5 mL) was added, and the mixture was stirred at 50 ° C for 1 hour. A 1 M aqueous sodium hydroxide solution (1 mL) was added to the reaction solution, and the mixture was stirred at 50 ° C for 40 minutes. A 1 M aqueous sodium hydroxide solution (1 mL) was again added, and the mixture was further stirred at 50 ° C for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid and ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 644 (MH ⁺ ).

Reference example 23

7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H -吲哚-2-carboxyguanamine

Taking 7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy] -1H-indole-2-carboxylic acid (2.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.19 g), 1-hydroxybenzene A mixture of triazolium ammonium salt (943 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 9 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid, water and saturated brine, dried over magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to EtOAc EtOAcjjjjjjjj MS 643 (MH ⁺ ).

Reference example 24

[2-({7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}carbonyl)indolyl](sideoxy Ethyl acetate

A solution of hydrazine monohydrate (0.1 mL) in ethanol (2 mL) was added dropwise to a solution containing diethyl oxalate (0.3 mL) in ethanol (2 mL). The reaction mixture was concentrated under reduced pressure to give a white solid. Take 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (450 mg), 1-[3-(dimethyl Mixture of propylamino)propyl-3-ethylcarbodiimide hydrochloride (403 mg), 1-hydroxybenzotriazole (284 mg) and N,N-dimethylformamide (20 mL) in a chamber After stirring for 30 minutes at room temperature, the previously obtained white solid was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained crude product was subjected to EtOAc EtOAc (EtOAc:EtOAc: MS 552 (MH ⁺ ).

Reference example 25

Ethyl 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Taking ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g), tributylphosphine (2.6 mL), 1, A mixture of 1'-(azodicarbonyl)dipiperidine (2.69 g), 2-propanol (0.81 mL) and tetrahydrofuran (50 mL) was stirred at 70 ° C for 5.5 hours. Further, tributylphosphine (0.7 mL) and 1,1'-(azodicarbonyl)dipiperidine (0.7 g) were added to the mixture. After stirring at 70 ° C for 2 hours, the mixture was cooled to 0 ° C and filtered to remove a precipitate. The filtrate was concentrated, and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc 1/99 to 35/65, by volume) gave the title compound (1.87 g, 84%) as white white solid. MS 418 (MH ⁺ ).

Reference example 26

7-(1-Methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Ethyl 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.87 g) was dissolved in tetrahydrofuran (20 mL) A mixture of 1 M aqueous sodium hydroxide (9 mL) was added to a mixture with ethanol (20 mL). After stirring at 60 ° C for 1 hour, the mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was cooled to 0 ° C and 1M hydrochloric acid (10 mL) was then evaporated. The resulting white suspension was filtered and a white precipitate was collected. The precipitate was dissolved in ethyl acetate. EtOAc (EtOAc m. MS 390 (MH ⁺ ).

Reference example 27

7-(1-Methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

Taking 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.8 g), N-ethyl- N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.77 g), 1-hydroxybenzotriazole (1.24 g) and N,N-dimethylformamide (45 mL) The mixture was stirred at 50 ° C for 25 minutes. The mixture was cooled to room temperature, and a 28% aqueous ammonium hydroxide solution (1.3 mL) was added to the mixture at room temperature. Stir at room temperature for 16 hours and add water to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAcjjjjjjjj MS 389 (MH ⁺ ).

Reference example 28

7-(1-Methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-thiocarboxamide

A solution of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (700 mg) in tetrahydrofuran (40 mL) Lawson's reagent (729 mg) was added, and the mixture was stirred at 60 ° C for 40 minutes. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 405 (MH ⁺ ).

Reference example 29

4-fluoro-2-(1-methylethoxy)-1-nitrobenzene

A mixture of 5-fluoro-2-nitrophenol (91.0 g), 2-iodopropane (103.4 g), potassium carbonate (146 g) and N,N-dimethylformamide (600 mL) was taken at 50 ° C Stir for 3.5 hours. The mixture was concentrated under reduced pressure and water was added to residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified with EtOAc EtOAc m.

¹ H NMR (CDCl ₃ ) δ 1.42 (6H, d, J = 6.0 Hz), 4.63 (1H, spt, J = 6.1 Hz), 6.64 - 6.73 (1H, m), 6.76 (1H, dd, J = 10.6, 2.5 Hz), 7.88 (1H, dd, J = 9.0, 6.0 Hz).

Reference example 30

3-(1-methylethoxy)-4-nitrophenol

A 20% aqueous sodium hydroxide solution was added to a solution of 4-fluoro-2-(1-methylethoxy)-1-nitrobenzene (20.34 g) in dimethyl hydrazine (150 mL) at room temperature ( 68 mL), the mixture was stirred at 60 ° C for 3 hours. The mixture was cooled to room temperature and 6M hydrochloric acid (50 mL) was then added to mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual oil was crystallised from EtOAc EtOAcjjjjj

¹ H NMR (CDCl ₃ ) δ 1.41 (6H, d, J = 6.1 Hz), 4.61 (1H, spt, J = 6.1 Hz), 5.54 (1H, brs), 6.40 (1H, dd, J = 8.9, 2.5 Hz), 6.51 (1H, d, J = 2.7 Hz), 7.87 (1H, d, J = 9.1 Hz).

Reference example 31

2-[3-(1-methylethoxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine

3-(1-methylethoxy)-4-nitrophenol (27.3 g), cesium carbonate (90.4 g), 2-bromo-5-(methylsulfonyl)pyridine (32.7 g) and A mixture of N,N-dimethylformamide (250 mL) was stirred at 100 ° C for 4 hours. The mixture was concentrated under reduced pressure and water was added to residue. The resulting brown suspension was filtered and a brown solid was collected. The title compound (38.82 g, 79%) MS 353 (MH ⁺ ).

Reference example 32

2-(1-methylethoxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}aniline

Take 2-[3-(1-methylethoxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (39.89g), iron powder (31g), calcium chloride (1.3 g), a mixture of ethanol (400 mL) and water (100 mL) was stirred at 80 ° C for 3 hours. The mixture was filtered through EtOAc (EtOAc)EtOAc. Add water and brine to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with EtOAcqqqqqqq MS 323 (MH ⁺ ).

Reference example 33

2-{[2-(1-methylethoxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl]indenyl}ethyl propionate

Acetonitrile (50 mL) containing 2-(1-methylethoxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenylamine (32 g) at 0 ° C Concentrated hydrochloric acid (30 mL) was added to a stirred suspension of a mixture of ethanol (100 mL). After cooling to -5 ° C, an aqueous solution (25 mL) containing sodium nitrite (8.2 g) was added dropwise to the mixture while maintaining the temperature below 0 °C. The mixture was stirred at -10 to -5 °C for 30 minutes. The mixture was added to 2-methyl-3-oxoethoxybutyrate (15.7 mL), potassium hydroxide (85%, 26 g), ethanol (140 mL) at -40 to -30 °C over 30 minutes. ) in a mixture with water (140 mL). After stirring for 1 h at -38 °C, MS 434 (MH ⁺ ).

Reference example 34

Ethyl 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate

The orange solid obtained in Reference Example 33 was dissolved in toluene (180 mL), and the solution was refluxed for 2 hours and azeotroped to remove water. p-Toluenesulfonic acid monohydrate (37 g) was refluxed in toluene (200 mL) for 2 hours and azeotroped to remove water, and the mixture was cooled to 90 °C. The toluene solution prepared above was added to the mixture. The mixture was stirred at 90 ° C for 1 hour. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Crystal form solid. MS 419 (MH ⁺ ).

Reference example 35

5-[3-(Benzyloxy)-4-nitrophenoxy]-2-(methylsulfonyl)pyridine

2-(Benzyloxy)-4-fluoro-1-nitrobenzene (21.0 g), 6-(methylsulfonyl)pyridin-3-ol (14.7 g) and potassium carbonate (12.2 g) The mixture of N,N-dimethylformamide (130 mL) was stirred at 90 ° C for 5 hours and then at 60 ° C for 15 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous EtOAc. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated to give pale yellow crystals from ethyl acetate - washed with hexane, to give the title compound (28.0g, 82%) of pale yellow crystals. MS 401 (MH ⁺ ).

Reference example 36

2-(Benzyloxy)-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline

5-[3-(Benzyloxy)-4-nitrophenoxy]-2-(methylsulfonyl)pyridine (28.0 g), calcium chloride (0.78 g), iron (powder) A mixture of 19.0 g), ethanol (500 mL) and water (110 mL) was refluxed for 5 hours. The mixture was cooled to 40 ° C and filtered through a pad of celite pad. The filtrate was concentrated in vacuo to remove ethanol. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) MS 371 (MH ⁺ ).

Reference example 37

2-amino-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenol

a mixed solution of tetrahydrofuran (200 mL) and methanol (50 mL) containing 2-(benzyloxy)-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenylamine (26 g) Palladium on carbon (5 g, 10 wt%, wet) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 5 hours. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residual oil was taken from EtOAc EtOAcjjjjjjj MS 281 (MH ⁺ ).

Reference example 38

2-[(2-Hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ethyl ester

Adding a concentrated suspension of ethanol containing 2-amino-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenol (17.28 g) (150 mL) at 0 ° C Hydrochloric acid (13.6 mL). After cooling to -5 ° C, an aqueous solution (20 mL) containing sodium nitrite (5.1 g) was added dropwise, and the mixture was kept at a temperature below -5 °C. The mixture was stirred at -10 °C for 20 minutes. Add this mixture to 2-methyl-3-oxoethoxybutyrate (9.8 mL), potassium hydroxide (85%, 14.2 g), ethanol (150 mL) and water at -30 to -25 °C In a mixture of (150 mL). After stirring at -30 ° C for 30 minutes, 1 M hydrochloric acid (110 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAc (EtOAc) MS 394 (MH ⁺ ).

Reference example 39

2-[(2-[(methylsulfonyl)oxy]-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ester

Ethyl 2-((2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl)oxy}phenyl)indolyl]propanoate (21.1) at 0 ° C To a solution of pyridine (220 mL) was added methanesulfonium chloride (5.0 mL). The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 16 hours. The mixture was cooled to 0 ° C and additional methanesulfonium chloride (5.0 mL) was added to the mixture. After stirring at room temperature for 2 hours, water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with aq. EtOAc EtOAc. The residue was taken from EtOAc EtOAc EtOAc. MS 472 (MH ⁺ ).

Reference example 40

Ethyl 7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

Methanesulfonic acid (13 mL) was added to an Eaton's reagent (19 g) at 80 °C. After stirring at 80 ° C for 20 minutes, toluene (200 mL) was added. 2-[(2-[(Methylsulfonyl)oxy]-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid Ethyl ester (19 g) was added to the mixture in 3 portions. The mixture was stirred at 80 ° C for 40 minutes and cooled to room temperature. Water and sodium hydrogencarbonate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 455 (MH ⁺ ).

Reference example 41

7-Hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

Taking 7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid ethyl ester ( 1.56 g) was dissolved in a mixture of tetrahydrofuran (10 mL) and ethanol (15 mL). An aqueous solution (10 mL) containing potassium hydroxide (85%, 0.8 g) was added to the mixture at 0 °C. The mixture was allowed to warm to room temperature and stirred for 13 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (14 mL) was added to mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAcqqqqqqq MS 349 (MH ⁺ ).

Reference example 42

Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

7-Hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (4.7 g) in methanol (30 mL) at 0 ° A 2 M solution of trimethylsulfonyldiazomethane in diethyl ether (7.4 mL) was added dropwise to a mixture of toluene (90 mL). The mixture was stirred at 0 ° C for 30 minutes, and a 2M solution of trimethylsulfanyl diazomethane (3.7 mL) was added dropwise to the mixture. After stirring at 0 ° C for 30 minutes, 1 M hydrochloric acid (2 mL) was added to the mixture to terminate the reaction. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual yellow oil was solidified with ethyl acetate-diethyl ether. The resulting solid was washed with EtOAcqqqqqq MS 363 (MH ⁺ ).

Reference example 43

Methyl 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.1 g) was dissolved in ethyl acetate (20 mL) ) in a mixture with methanol (5 mL). The mixture was cooled to 0 ° C, and a 2M solution of trimethylsulfanyl diazomethane (2 mL) was added dropwise to the mixture. The mixture was stirred at 0 ° C for 30 minutes, and then a 2M solution of trimethylsulfanyl diazomethane (0.5 mL) was added dropwise to the mixture. After stirring at 0 ° C for 30 minutes, 1 M hydrochloric acid (1 mL) was added to the mixture to terminate the reaction. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, dried over magnesium sulfate, The residue was crystallized from EtOAcqqqqqq MS 377 (MH ⁺ ).

Reference example 44

7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

Methyl 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.99 g) was dissolved in tetrahydrofuran (10 mL) ) in a mixture with methanol (10 mL). A 1 M aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at 50 ° C for 45 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1 M hydrochloric acid was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual amorphous solid was purified with EtOAc (EtOAc) MS 363 (MH ⁺ ).

Reference example 45

7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide

Taking 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (0.9 g), N-ethyl- N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.95 g), 1-hydroxybenzotriazole (0.67 g) and N,N-dimethylformamide (15 mL) The mixture was stirred at 50 ° C for 20 minutes. The mixture was cooled to room temperature and a 10% aqueous ammonium hydroxide solution (2 mL) was added to the mixture. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. Water was added to the residue. EtOAc m. MS 362 (MH ⁺ ).

Reference example 46

7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarboxamide

In tetrahydrofuran (150 mL) containing 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.66 g) Lawessen reagent (0.89 g) was added to the solution, and the mixture was stirred at 50 ° C for 1 hour. Tetrahydrofuran (100 mL) and Lawson's reagent (0.42 g) were added to the mixture. After stirring at 50 ° C for 13 hours, the mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS 378 (MH ⁺ ).

Reference example 47

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Methyl 2-carboxylate

Take methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g), tributylphosphine ( a mixture of 1.6 mL), 1,1'-(azodicarbonyl)dipiperidine (1.7 g), 1,3-dimethoxypropan-2-ol (0.8 g) and tetrahydrofuran (20 mL) at 50 ° C Stir under 13 hours. Additional tributylphosphine (0.82 mL), 1,1'-(azodicarbonyl)dipiperidine (0.83 g) and 1,3-dimethoxypropan-2-ol (0.4 g) were added to the mixture. The mixture was stirred at 70 ° C for 5 hours. Additional tributylphosphine (1.64 mL), 1,1'-(azodicarbonyl)dipiperidine (1.66 g) and 1,3-dimethoxypropan-2-ol (0.8 g) were added to the mixture. . After stirring at 70 ° C for 3 hours, the mixture was cooled to 0 ° C and filtered to remove insoluble material. The filtrate was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjj Things. MS 463 (MH ^- ).

Reference example 48

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole 2-carboxylic acid

In the presence of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H- To a mixed solution of methyl hydrazine-2-carboxylate (1.79 g) in THF (15 mL) and methanol (15 mL) was added 1M aqueous sodium hydroxide (15 mL), and the mixture was stirred at 50 ° C for 30 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed 3 times with diethyl ether. The ether layers were combined and extracted with water. The aqueous layers were combined and 1M hydrochloric acid (15 mL) was then added to mixture. The resulting white suspension was filtered to give crystal crystal crystal crystal crystal crystal MS 451 (MH ⁺ ).

Reference example 49

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole -2-carboxyguanamine

Take 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H- Indole-2-carboxylic acid (1.02 g), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (868 mg), 1-hydroxybenzotriazole ( A mixture of 612 mg) and N,N-dimethylformamide (20 mL) was stirred at 50 ° C for 25 min. The mixture was cooled to room temperature and a 10% aqueous ammonium hydroxide solution (3 mL) was added to the mixture. After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 450 (MH ⁺ ).

Reference example 50

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole -2-thioformamide

In the presence of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H- A solution of indole-2-carboxamide (1.0 g) in tetrahydrofuran (15 mL) was added with a Lawson reagent (1.0 g), and the mixture was stirred at 50 ° C for 45 minutes. The mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjj . MS 466 (MH ⁺ ).

Reference example 51

2-[3-(Benzyloxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine

3-(Benzyloxy)-4-nitrophenol (31.4g), 2-bromo-5-(methylsulfonyl)pyridine (30.3g), cesium carbonate (83.6g) and N, A mixture of N-dimethylformamide (300 mL) was stirred at 100 ° C for 3 hours. The mixture was concentrated under reduced pressure. Water was added to the residue. EtOAc m.

¹ H NMR (CDCl ₃ ) δ 3.11 (3H, s), 5.22 (2H, s), 6.84 (1H, dd, J = 8.9, 2.5 Hz), 6.96 (1H, d, J = 2.3 Hz), 7.14 (1H, d, J = 8.0 Hz), 7.33 - 7.48 (5H, m), 8.02 (1H, d, J = 9.1 Hz), 8.24 (1H, dd, J = 8.5, 2.5 Hz), 8.68 (1H, d, J = 2.7 Hz).

Reference example 52

2-(Benzyloxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}aniline

Take 2-[3-(benzyloxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (45.56g), iron powder (31.7g), calcium chloride ( 1.26 g), a mixture of ethanol (400 mL) and water (100 mL) was stirred at 80 ° C for 3.5 hours. The mixture was filtered through hydrazine salt and the filtrate was concentrated. The residual solid was washed with EtOAc (EtOAc m. MS 371 (MH ⁺ ).

Reference example 53

2-amino-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenol

a solution of a mixture of tetrahydrofuran (400 mL) and methanol (150 mL) containing 2-(benzyloxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenylamine (46 g) Palladium on carbon (7 g, 10% by weight, wet) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 15 hours. The mixture was filtered to remove the catalyst and the filtrate was concentrated. The residual solid was washed with EtOAc EtOAc (EtOAc) MS 281 (MH ⁺ ).

Reference example 54

2-[(2-Hydroxy-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)indenyl]propionic acid ethyl ester

a mixture of ethanol (150 mL) and acetonitrile (20 mL) containing 2-amino-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenol (27.68 g) at 0 °C Concentrated hydrochloric acid (21.8 mL) was added to the stirred suspension. After cooling to -5 ° C, an aqueous solution (20 mL) containing sodium nitrite (8.18 g) was added dropwise to the mixture while maintaining the temperature below -5 °C. The mixture was stirred at -10 ° C for 30 minutes. The mixture was added at -30 to -20 ° C to ethyl 2-methyl-3-oxobutanoate (15.7 mL), potassium hydroxide (85%, 22.8 g), ethanol (50 mL) and water ( In a mixture of 150 mL). After stirring at -30 ° C for 1 hour, 1 M hydrochloric acid (150 mL) was added to the mixture. Water and ethyl acetate were added. The resulting brown solid was filtered to give crystal crystal crystal crystal crystal crystal The filtrate was extracted again with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAc (EtOAc) Further, the filtrate was concentrated, EtOAcjjjjjjjjj MS 394 (MH ⁺ ).

Reference example 55

2-[(2-[(methylsulfonyl)oxy]-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)indenyl]propionic acid ester

Ethyl 2-[(2-hydroxy-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-indenyl]propanoate (at ethyl acetate) at 0 ° C To a solution of 37.7 g of pyridine (450 mL) was added methanesulfonium chloride (8.9 mL), and the mixture was stirred at room temperature for 1 hour. Methanesulfonium chloride (8.9 mL) was again added to the mixture at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Methanesulfonium chloride (8.9 mL) was added to the mixture at 0 ° C, and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure. After the addition of water to a residue, the mixture was evaporated. The residual solid was washed with EtOAc (EtOAc) MS 472 (MH ⁺ ).

Reference example 56

Ethyl 7-[(methylsulfonyl)oxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate

Methanesulfonic acid (24 mL) was added to an Eaton's reagent (36 g) at 90 °C. After stirring at 90 ° C for 1 hour, toluene (200 mL) was added to the mixture. 2-[(2-[(Methylsulfonyl)oxy]-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)indenyl]propionic acid Ethyl ester (36.1 g) was added to the mixture in 3 portions. The mixture was stirred at 90 ° C for 50 minutes and then cooled to room temperature. Water and sodium hydrogencarbonate were added and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified twice by hydrazine column chromatography (ethyl acetate /hexane = 20 / 80 to 75 / 25, volume ratio) to yield a yellow solid. The title compound (8.57 g, 25%) MS 455 (MH ⁺ ).

Reference example 57

7-Hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid

Taking ethyl 7-[(methylsulfonyl)oxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate ( 11.74 g) was suspended in a mixture of tetrahydrofuran (300 mL) and ethanol (150 mL). An aqueous solution (100 mL) of potassium hydroxide (85%, 6.8 g) was added to the mixture at 0 °C. The mixture was allowed to warm to room temperature and stirred for 12 hours. The mixture was concentrated and 1M aqueous HCl (130 mL) was then evaporated. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAc EtOAcqqqq MS 349 (MH ⁺ ).

Reference example 58

Methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate

Methanol containing 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (8.71 g) at 0 °C A 2 M solution of trimethylsulfonyldiazomethane in diethyl ether (12.5 mL) was added dropwise to a suspension of a mixture of 300 mL and toluene (300 mL), and the mixture was stirred at 0 ° C for 1.5 hours. A 2 M solution of trimethylsulfonyldiazomethane in diethyl ether (10 mL) was added to the mixture, and the mixture was stirred at 0 ° C for 1 hour and repeated three times. Then a 2M solution of trimethylsulfonyldiazomethane in diethyl ether (5 mL) was added and the mixture was stirred at 0 ° C for 30 min and then twice. 1 M hydrochloric acid (80 mL) was added to the mixture to quench the reaction. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAc (EtOAc) MS 363 (MH ⁺ ).

Reference example 59

Methyl 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate

Methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (3.12 g) at 0 ° C A 2 M solution of trimethylsulfonyl diazomethane (4.3 mL) was added dropwise to a mixture of tetrahydrofuran (30 mL) and methanol (5 mL). The mixture was stirred at 0<0>C for 1 h, then a solution of <RTI ID=0.0>> A 2 M solution of trimethylsulfonyldiazomethane (4.0 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. 6M Hydrochloric acid (9 mL) was added to the mixture to quench the reaction. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate and brine, dried over magnesium sulfate, The residual solid was washed with EtOAc EtOAcqqqq MS 377 (MH ⁺ ).

Reference example 60

7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid

In tetrahydrofuran (25 mL) containing methyl 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.78 g) A 1 M aqueous sodium hydroxide solution (11 mL) was added to a mixed solution of ethanol (20 mL), and the mixture was stirred at 50 ° C for 40 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (11 mL) was added to mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was crystallized from EtOAcqqqqqq MS 363 (MH ⁺ ).

Reference example 61

7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide

Taking 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (2.18 g), N-ethyl- N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.3g), 1-hydroxybenzotriazole (1.6g) and N,N-dimethylformamide (20mL) The mixture was stirred at 50 ° C for 25 minutes. The mixture was cooled to room temperature and a 10% aqueous ammonium hydroxide solution (3 mL) was added to the mixture. After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 362 (MH ⁺ ).

Reference example 62

7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-thiocarboxamide

In tetrahydrofuran (400 mL) containing 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (2.1 g) Lawson's reagent (2.3 g) was added to the solution, and the mixture was stirred at 60 ° C for 50 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate The residue was triturated with EtOAc (EtOAc) MS 378 (MH ⁺ ).

Reference example 63

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole Methyl 2-carboxylate

Take methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.75 g), tributylphosphine ( a mixture of 3.7 mL), 1,1'-(azodicarbonyl)dipiperidine (3.8 g), 1,3-dimethoxypropan-2-ol (1.8 g) and tetrahydrofuran (50 mL) at 50 ° C Stir under 8 hours. Additional tributylphosphine (1.9 mL), 1,1'-(azodicarbonyl)dipiperidine (1.9 g) and 1,3-dimethoxypropan-2-ol (0.9 g) were added to the mixture. The mixture was stirred at 50 ° C for 8 hours. Further adding tributylphosphine (3.7 mL), 1,1'-(azodicarbonyl)dipiperidine (3.8 g) and 1,3-dimethoxypropan-2-ol (1.8 g) to the mixture . After stirring at 50 ° C for 24 hours, the mixture was cooled to 0 ° C and filtered to remove a precipitate. The filtrate was concentrated, and the residue was purified by hydrazine column chromatography (ethyl acetate/hexane = 10/90 to 80/20, volume ratio) for 2 times, and then purified by basic column chromatography (acetic acid B) Ester/hexane 20/80 to 85/15) gave the title compound (3. MS 465 (MH ⁺ ).

Reference example 64

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole 2-carboxylic acid

In the presence of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H- A mixed solution of methyl hydrazine-2-carboxylate (3.42 g) in tetrahydrofuran (20 mL) and ethanol (15 mL) was added 1M aqueous sodium hydroxide (18 mL), and the mixture was stirred at 50 ° C for 50 min. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed with diethyl ether. 1M Hydrochloric acid (18.5 mL) was added to the aqueous layer, and the mixture was evaporated. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual amorphous solid was crystallised from diethyl ether to afford titled compound (1. MS 553 (MH ⁺ ).

Reference example 65

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-carboxyguanamine

Containing 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H- Indole-2-carboxylic acid (1.66 g), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole A mixture of (1.0 g) and N,N-dimethylformamide (15 mL) was stirred at 50 ° C for 30 min. The mixture was cooled to room temperature and a 25% ammonium hydroxide solution (1.5 mL) was added to the mixture. After stirring at room temperature for 14 hours, the mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Amorphous solid. MS 450 (MH ⁺ ).

Reference example 66

7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-thioformamide

In the presence of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H- A solution of hydrazine-2-carboxyguanamine (1.66 g) in tetrahydrofuran (40 mL) was added with a Lawson reagent (1.5 g), and the mixture was stirred at 50 ° C for 2 hours. Lawson's reagent (0.5 g) was again added to the mixture. After stirring at 50 ° C for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Amorphous solid. MS 466 (MH ⁺ ).

Reference example 67

Ethyl 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

P-Toluenesulfonic acid monohydrate (11.8 g) was refluxed in toluene (200 mL) for 2 hours and azeotropically removed water. The mixture was cooled to 110 ° C and added with 2-[(2-methoxy-4-{[6-(methoxymethyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid A solution of the ester (11.58 g) in toluene (50 mL). The mixture was stirred at 110 ° C for 5.5 hours. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by column chromatography (ethyl acetate / hexane = 10 / 90 to 75 / 25) and then purified by basic column chromatography (ethyl acetate /hexane = 10 / 90) To 50/50, by volume), a yellow solid was produced. The title compound (2.32 g, 21%) MS 357 (MH ⁺ ).

Reference example 68

7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

In tetrahydrofuran (15 mL) containing ethyl 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.39 g) A 1 M aqueous sodium hydroxide solution (10 mL) was added to a mixed solution of ethanol (10 mL), and the mixture was stirred at 50 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (10 mL) was then added to mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 329 (MH ⁺ ).

Reference example 69

7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide

Taking 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (2.28 g), N-ethyl- N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.66 g), 1-hydroxybenzotriazole (2.13 g) and N,N-dimethylformamide (30 mL) The mixture was stirred at room temperature for 20 minutes. A 25% ammonium hydroxide solution (3 mL) was added to the mixture. After stirring at room temperature for 15.5 hours, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was crystallized from EtOAcqqqqqqq MS 328 (MH ⁺ ).

Reference example 70

7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarboxamide

In tetrahydrofuran (40 mL) containing 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (1.86 g) Lawson's reagent (2.3 g) was added to the solution, and the mixture was stirred at 50 ° C for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 344 (MH ⁺ ).

Reference example 71

Ethyl 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Add to a solution of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g) in tetrahydrofuran (80 mL) at room temperature 1-methoxypropan-2-ol (1.04 mL), tributylphosphine (2.46 mL) and 1,1'-(azodicarbonyl)dipiperidine (2.69 g). The mixture was stirred at 50 ° C for 1 hour. Then add 1-methoxypropan-2-ol (0.5 mL), tributylphosphine (1.2 mL) and 1,1'-(azodicarbonyl)dipiperidine (1.34 g) to the mixture, the mixture Stir at 50 ° C overnight. The mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 448 (MH ⁺ ).

Reference example 72

7-(2-Methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Ethyl 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.36 g), a mixture of tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1M aqueous sodium hydroxide (7.9 mL). The mixture was stirred at 50 ° C for 2 hours and at room temperature overnight. A 1 M aqueous sodium hydroxide solution (10.5 mL) was added to the mixture. All were further stirred at 50 ° C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was acidified with 1M hydrochloric acid. Ethyl acetate and water were added to the mixture, and the organic layer was separated. Organic layer was washed with water, dehydrated (MgSO _4), filtered, and concentrated in vacuo. The residue was triturated with EtOAc (EtOAc) The solid was recrystallized from ethyl acetate-hexanes to yield white crystals. Mp 135.9 to 137.4 °C.

Reference example 73

7-(2-Methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

Containing 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate at room temperature Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.98 g) to a solution of the acid (1.072 g) in N,N-dimethylformamide (15 mL) And 1-hydroxybenzotriazole ammonium salt (0.788 g). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. Water and ethyl acetate were added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed sequentially with brine and water, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 419 (MH ⁺ ).

Reference example 74

7-(1-Methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid

Take ethyl 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (10.7 g) A mixture of 1 M aqueous sodium hydroxide (50 mL), ethanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 50 ° C for 2 hr. 1M Hydrochloric acid (50 mL) was added to the mixture, and the mixture was adjusted to pH = 6 using 1M aqueous sodium hydroxide and water. All were extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo to give the title compound (6.35g, 64%) of a tan amorphous solid. MS 391 (MH ⁺ ).

Reference example 75

7-(1-Methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide

Taking 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (4.0 g) , 1-hydroxybenzotriazole (2.07g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.93g) and N,N-dimethyl A mixture of formamide (50 mL) was stirred at 50 ° C for 30 minutes and then cooled to room temperature. Aqueous ammonium hydroxide (10%, 10 mL) was added to the mixture. All were stirred at room temperature for 12 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was crystallized from EtOAc (EtOAc:EtOAc) MS 390 (MH ⁺ ).

Reference example 76

2-(methoxymethyl)-5-[3-(1-methylethoxy)-4-nitrophenoxy]pyridine

A mixture containing 6-(bromomethyl)pyridin-3-yl benzenesulfonate (60.0 g), sodium methoxide (49.4 g) and methanol (800 mL) was refluxed for 20 hours and then cooled to 0 °C. A solution of hydrochloric acid in methanol (10%, 400 mL) was added to the mixture at 0 °C. After stirring at 0 ° C for 15 minutes, the mixture was concentrated in vacuo. Toluene was added to the residue and the mixture was concentrated in vacuo to remove methanol. Containing the residue, 4-fluoro-2-(1-methylethoxy)-1-nitrobenzene (36.4 g), potassium carbonate (75.9 g) and N,N-dimethylformamide ( A mixture of 300 mL) was stirred at 60 ° C for 15 h then concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc MS 319 (MH ⁺ ).

Reference example 77

4-{[6-(methoxymethyl)pyridin-3-yl]oxy}-2-(1-methylethoxy)aniline

2-(Methoxymethyl)-5-[3-(1-methylethoxy)-4-nitrophenoxy]pyridine (20.5g), iron (powder, 17.9g), chlorine A mixture of calcium (710 mg), ethanol (400 mL) and water (100 mL) was refluxed for 5 hours. The mixture was filtered through yttrium salt. The filtrate was concentrated in vacuo to remove ethanol. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 289 (MH ⁺ ).

Reference example 78

Ethyl 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylate

4-{[6-(Methoxymethyl)pyridin-3-yl]oxy}-2-(1-methylethoxy)aniline (13.7 g), ethanol (200 mL) at 0 °C Concentrated hydrochloric acid (8.7 mL) was added to a mixture with acetonitrile (20 mL). An aqueous solution (10 mL) of sodium nitrite (3.93 g) was added dropwise to the mixture at 0 to 5 °C. All were stirred at 5 ° C for 30 minutes to produce a diazonium mixture. Add 2-methyl-3-oxoethoxybutyrate (7.53 g) to a cooled (-20 ° C) solution of potassium hydroxide (85%, 9.4 g) in ethanol (40 mL) and water (40 mL) . The diazonium mixture prepared as described above was added to the solution at -30 to -20 ° C over a period of 15 minutes. All were stirred at -20 ° C for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc

A mixture containing p-toluenesulfonic acid monohydrate (8.9 g) and toluene (50 mL) was refluxed for 2 hours and azeotropically removed water, then cooled to 90 °C. A solution of the above yellow oil (9.45 g) in toluene (50 mL) was added to the mixture at 90 °C. All were stirred at 90 ° C for 1 hour and then cooled to room temperature. An aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc

A mixture containing p-toluenesulfonic acid monohydrate (3.80 g) and toluene (50 mL) was refluxed for 2 hours and azeotroped to remove water, then cooled to 90 °C. A solution of toluene (15 mL) containing a yellow oil (4.0 g) as above was added at 90 °C. All were refluxed for 24 hours and then cooled to room temperature. An aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) MS 385 (MH ⁺ ).

Reference example 79

5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylic acid

Take ethyl 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylate (1.65 g) A mixture of 1 M aqueous sodium hydroxide (10 mL), THF (10 mL) Water and 1 M hydrochloric acid (10 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo to give the title compound (1.43g, 93%) of a tan amorphous solid. MS 357 (MH ⁺ ).

Reference example 80

5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxamide

5-{[6-(Methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylic acid (1.43 g) , 1-hydroxybenzotriazole (810 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g) and N,N-dimethylmethyl A mixture of decylamine (50 mL) was stirred at room temperature for 30 min. Aqueous ammonium hydroxide (25%, 5 mL) was added to the mixture. All were stirred at room temperature for 4.5 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was washed with EtOAc (EtOAc)EtOAc. MS 356 (MH ⁺ ).

Reference example 81

2-(methoxymethyl)-5-(3-methoxy-4-nitrophenoxy)pyridine

A mixture containing 6-(bromomethyl)pyridin-3-ylbenzenesulfonate (40.7 g), sodium methoxide (33.5 g) and methanol (600 mL) was refluxed for 15 hr then cooled to 0 °C. A solution of hydrochloric acid in methanol (2M, 500 mL) was added to the mixture at 0 °C. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. Toluene was added to the residue and the mixture was concentrated in vacuo to remove methanol. A mixture containing residual, 4-fluoro-2-methoxy-1-nitrobenzene (21.2 g), potassium carbonate (120 g) and N,N-dimethylformamide (800 mL) at 90 ° C Stir for 20 hours then concentrate in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was crystallized from ethyl acetate-hexanes. The mother liquor was concentrated in vacuo and the residue was purified eluting elut elut elut elut elut elut elut A total of 27.15 g (75%) was produced. The crystals were recrystallized from ethyl acetate-hexane to give yellow prisms. MS 291 (MH ⁺ ).

Reference example 82

2-methoxy-4-{[6-(methoxymethyl)pyridin-3-yl]oxy}aniline

2-(Methoxymethyl)-5-(3-methoxy-4-nitrophenoxy)pyridine (27.0 g), iron (powder, 25.9 g), calcium chloride (1.03 g) A mixture of ethanol (400 mL) and water (100 mL) was refluxed for 6 hours. Iron (powder, 12.9 g) and calcium chloride (1.03 g) were then added to the mixture, and all were refluxed for another 2 hours. The mixture was cooled to room temperature and filtered through EtOAc. The filtrate was concentrated in vacuo to remove ethanol. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc MS 261 (MH ⁺ ).

Reference example 83

2-[(2-Methoxy-4-{[6-(methoxymethyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ethyl ester

2-methoxy-4-{[6-(methoxymethyl)pyridin-3-yl]oxy}phenylamine (20.1 g), ethanol (300 mL) and acetonitrile (30 mL) at 5 °C Concentrated hydrochloric acid (14.2 mL) was added to the mixture. An aqueous solution (20 mL) containing sodium nitrite (6.39 g) was added dropwise to the mixture at 5 °C. All were stirred at room temperature for 30 minutes. The mixture was added over 15 minutes at -20 to -10 ° C to potassium hydroxide (85%, 15.2 g), ethyl 2-methyl-3-oxobutanoate (12.2 g), ethanol ( 60 mL) in a mixture with water (60 mL). All were stirred at -20 ° C for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 374 (MH ⁺ ).

Reference example 84

Ethyl 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

A mixture containing p-toluenesulfonic acid hydrate (1.03 g) and toluene (15 mL) was refluxed for 2 hours and azeotroped to remove water, then cooled to 90 °C. Adding 2-[(2-methoxy-4-{[6-(methoxymethyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ethyl ester at 90 ° C A solution of (1.0 g) in toluene (10 mL) was added to the mixture. All were stirred at 90 ° C for 1 hour and then refluxed for 2 hours. An aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by basic gel chromatography (ethyl acetate:hexane = 1:4 to 2:1, volume ratio), and then purified by silica gel chromatography (ethyl acetate:hexane = 1:9) 2:1, by volume) gave the title compound (140 mg, 15%) as pale yellow crystal. MS 357 (MH ⁺ ).

Reference example 85

7-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.5 g) at 60 ° C, To a solution of tributylphosphine (2.79 g) and 1-methoxypropan-2-ol (1.24 g) in tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (3.48 g). All were stirred at 60 ° C for 1.5 hours and then concentrated in vacuo. Diisopropyl ether was added to the residue and filtered to remove insolubles. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:2 to 2:1, volume ratio), and then purified by basic gel chromatography (ethyl acetate:hexane = 1:2) 2:1, by volume), resulting in a colorless oil. A mixture of the oil, 1M aqueous sodium hydroxide (15 mL), THF (15 mL) and methanol (15 mL) was stirred at room temperature for 20 hr. The mixture was washed with diethyl ether. The organic layer was extracted with 1M aqueous sodium hydroxide. The combined aqueous layers were acidified with 1M HCI andEtOAc. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was washed with EtOAc (EtOAc m. MS 421 (MH ⁺ ).

Reference example 86

7-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxyindole amine

Containing 7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2- Carboxylic acid (1.40 g), 1-hydroxybenzotriazole (670 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.95 g) and N, A mixture of N-dimethylformamide (50 mL) was stirred at room temperature for 30 min. Aqueous ammonium hydroxide (25%, 5 mL) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-hexane toiel MS 420 (MH ⁺ ).

Reference example 87

Ethyl 2-((2-hydroxy-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propionate

Ethyl alcohol (40 mL) containing 2-amino-5-[4-(methylsulfonyl)phenoxy]phenol (4.3 g) and concentrated hydrochloric acid (2.8 mL) at -5 to -10 °C Aqueous solution of sodium nitrite (1.27 g) (5 mL) was added to EtOAc (10 mL) EtOAc. After stirring at -5 to -10 ° C for 30 minutes, the resulting clear brown solution was added dropwise at -10 to -20 ° C to potassium hydroxide (85%, 3.05 g) and 2-methyl-3-oxooxy. Ethyl butyrate (2.44 mL) in ethanol (30 mL) and water (30 mL) in ice-cooled. After stirring at -10 to -20 ° C for 20 minutes, the mixture was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual light brown solid was purified eluting elut elut elut elut elut elut elut MS 391 (MH ⁺ ).

Reference example 88

Ethyl 2-({2-[(methylsulfonyl)oxy]-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propionate

Icing and stirring of pyridine (60 mL) containing ethyl 2-({2-hydroxy-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propanoate (5.8 g) Methanesulfonium chloride (1.4 mL) was added to the solution, and the mixture was stirred at 4 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous EtOAc. The organic layer was successively washed with aqueous citric acid and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) MS 471 (MH ⁺ ).

Reference example 89

Ethyl 7-[(methylsulfonyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

A mixture containing p-toluenesulfonic acid hydrate (0.63 g) and toluene (40 mL) was refluxed for 2 hours and azeotroped to remove water, then cooled to 50 °C. Add 2-({2-[(methylsulfonyl)oxy)-4-[4-(methylsulfonyl)phenoxy]phenyl}indenyl)propanoic acid B at 50 °C The ester (0.52 g) was added to the mixture. After stirring at 50 ° C for 30 minutes, the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 452 (MH ⁺ ).

Reference example 90

7-Hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

Ethyl 7-[(methylsulfonyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.81 g), tetrahydrofuran An aqueous solution (20 mL) of potassium hydroxide (85%, 1.8 g) was added to a mixture of (30 mL) and methanol (20 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light brown solid, ethyl acetate - washed with hexane, to give the title compound (2.12g, 98%) of a pale orange solid.

¹ H NMR (DMSO-d ₆ ) δ 3.17 (3H, s), 6.40 (1H, d, J = 1.8 Hz), 6.87 (1H, d, J = 1.8 Hz), 7.04 (1H, d, J = 2.4 Hz), 7.10 (2H, dd, J = 1.8, 6.9 Hz), 7.86 (2H, dd, J = 1.8, 6.9 Hz), 9.91 (1H, s).

Reference example 91

N-[2-(Benzylthio)-3,3-dimethoxypropyl]-7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole -2-carboxyguanamine

In the presence of 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (2.1 g) and 2-(benzylthio)-3,3 Add 1-hydroxybenzotriazole (1.1 g) and 1-B to an ice-cooled and stirred mixture of dimethoxypropan-1-amine (2.9 g) in N,N-dimethylformamide (50 mL) Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was concentrated in vacuo, and the residue was purified by chromatography (ethyl acetate:hexane = 35:65 to 60:40, volume ratio) to give pale yellow crystals. The title compound (1.73 g, 50%) elute MS 569 (MH ⁺ ).

Reference example 92

N-[2-(Benzylthio)-3,3-dimethoxypropyl]-7-(2-methoxy-1-methylethoxy)-5-[4-(A Sulfosyl)phenoxy]-1H-indole-2-carboxamide

Containing N-[2-(benzylsulfanyl)-3,3-dimethoxypropyl]-7-hydroxy-5-[4-(methylsulfonate) at room temperature and under argon atmosphere Benzyl)phenoxy]-1H-indole-2-carboxamide (1.73 g), tributylphosphine (1.4 mL) and 1-methoxypropan-2-ol (0.59 mL) in tetrahydrofuran (50 mL) To the stirred solution was added 1,1'-(azodicarbonyl)dipiperidine (1.53 g). The whole mixture was stirred at 50 ° C for 4 hours, and tributylphosphine (1.4 mL), 1-methoxypropan-2-ol (0.59 mL) and 1,1'-(azodicarbonyl)dipiperidine ( 1.53g). After stirring at 50 ° C for 3 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ether and filtered to remove insoluble material and washed with diethyl ether. The combined filtrate and washings were concentrated in vacuo. EtOAc (EtOAc:EtOAc:EtOAc The oil was taken up between ethyl acetate and water. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated to give a yellow oil which was purified by silica gel chromatography (ethyl acetate: hexane = 35: 65 to 70:30, volume The title compound (1.6 g, 82%) was obtained as pale yellow oil. MS 641 (MH ⁺ ).

Reference example 93

2-(benzyloxy)-3,4-difluoro-1-nitrobenzene

A mixture of 2,3-difluoro-6-nitrophenol (15.1 g), benzyl bromide (10.8 mL) and potassium carbonate (11.9 g) in N,N-dimethylformamide (60 mL) was taken. Stir at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated to give the title compound (22.1g, 97%) of a pale yellow solid. MS 264 (MH ⁺ ).

Reference example 94

5-[3-(Benzyloxy)-2-fluoro-4-nitrophenoxy]-2-(methylsulfonyl)pyridine

Taking 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (7.65g), 6-(methylsulfonyl)pyridin-3-ol (5.0g) and potassium carbonate A mixture of (4.4 g) of N,N-dimethylformamide (40 mL) was stirred at 90 ° C for 5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc %) of pale yellow crystals.

¹ H NMR (CDCl ₃ ) δ 3.25 (3H, s), 5.31 (2H, s), 6.94 (1H, dd, J = 5.1, 9.6 Hz), 7.32-7.48 (6H, m), 7.72 (1H, Dd, J = 2.1, 9.6 Hz), 8.09 (1H, d, J = 9.6 Hz), 8.46 (1H, d, J = 2.7 Hz).

Reference example 95

2-(Benzyloxy)-3-fluoro-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline

5-[3-(Benzyloxy)-2-fluoro-4-nitrophenoxy]-2-(methylsulfonyl)pyridine (8.4 g), iron (powder, 5.5 g) A mixture of calcium chloride (0.24 g), ethanol (200 mL) and water (40 mL) was refluxed for 4 hours. The mixture was cooled to room temperature and filtered through a pad of salt. The filtrate was concentrated in vacuo to remove ethanol. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 389 (MH ⁺ ).

Reference example 96

6-Amino-2-fluoro-3-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenol

Containing 2-(benzyloxy)-3-fluoro-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenylamine (5.5 g), 10% palladium/carbon ( A mixture containing 50% water, 1.6 g), tetrahydrofuran (100 mL) and methanol (80 mL) was hydrogenated at room temperature under balloon pressure for 20 hours. The catalyst was removed by filtration and washed with tetrahydrofuran-methanol. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was concentrated in vacuo to give title compound (d. MS 299 (MH ⁺ ).

Reference example 97

2-[(3-Fluoro-2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ethyl ester

6-Amino-2-fluoro-3-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenol (4.2 g) and concentrated hydrochloric acid (2.6 mL) at -10 °C An aqueous solution (20 mL) of sodium nitrite (1.16 g) was added portionwise over ice-cooled and stirred mixture of ethanol (40 mL) and water (10 mL). After stirring at -10 ° C for 10 minutes, the solution was added dropwise at -5 ° C to potassium hydroxide (85%, 2.8 g) and ethyl 2-methyl-3-oxetoxybutyrate (2.2 mL). Ethanol (25 mL) was cooled with water (25 mL). After stirring at -5 to -10 ° C for 30 minutes, the mixture was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual brown oil was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 412 (MH ⁺ ).

Reference example 98

2-[(3-Fluoro-2-[(methylsulfonyl)oxy]-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenylene Ethyl propionate

Containing 2-[(3-fluoro-2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)indenyl]propionic acid ethyl ester (4.95g To the chilled and stirred solution of pyridine (50 mL) was added methanesulfonium chloride (1.1 mL), and the mixture was stirred at 4 ° C to room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous EtOAc. The organic layer was successively washed with aqueous citric acid and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual light brown solid was washed with EtOAc EtOAcjjjjj MS 490 (MH ⁺ ).

Reference example 99

6-Fluoro-7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid Ethyl ester

A mixture containing p-toluenesulfonic acid monohydrate (6.2 g) and toluene (180 mL) was refluxed for 1 hour and azeotropically removed, then cooled to 60 °C. Add 2-[(3-fluoro-2-[(methylsulfonyl)oxy]-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy} at 60 °C Phenyl)indenyl]ethyl propionate (5.4 g) was added to the mixture. Stir at 60 ° C for 1 hour. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo to give a pale yellow solid.

Methanesulfonic acid (3.6 mL) was added to an Eaton's reagent (5.3 g) at 90 ° C, and the mixture was stirred at 90 ° C for 30 minutes, then toluene (30 mL) was added. After the mixture was stirred at 90 ° C for 10 minutes, a suspension of toluene (50 mL) containing the above pale yellow solid was added portionwise to the mixture. The mixture was stirred at 90 ° C for 2 hours and then cooled to room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. Residual brown oil was purified by EtOAc (EtOAc:EtOAc:HHHHHHHHH 3.1 g, 62%) of colorless crystals. MS4 73 (MH ⁺ ).

Reference example 100

6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

In the presence of 6-fluoro-7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2- An aqueous solution (15 mL) of potassium hydroxide (85%, 1.9 g) was added to a mixture of ethyl acetate (3.1 g), tetrahydrofuran (25 mL) and methanol (25 mL). The mixture was stirred at room temperature for 15 hours then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to produce pale pink solid, from ethyl acetate - washed with hexane, to give the title compound (2.52g, 100%) of a pale pink solid. MS 365 (MH ⁺ ).

Reference example 101

6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide

N, N containing 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (2.5 g) Addition of 1-hydroxybenzotriazole ammonium salt (1.25 g) to 1-ethyl-3-(3-dimethylaminopropyl) carbonization with ice-cooled and stirred mixture of dimethylformamide (30 mL) Diimine hydrochloride (1.57 g). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to yield a beige solid from tetrahydrofuran - ethyl acetate and washed, to give the title compound (0.55g, 22%) of a pale pink Color solid. MS 366 (MH ⁺ ).

Reference example 102

6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide

Take 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.98 g), 2- Mixture of methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1'-(azodicarbonyl)dipiperidine (1.35 g) in tetrahydrofuran (130 mL) at 50 ° C with argon Stir under 6 hours. 2-Methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1'-(azodicarbonyl)dipiperidine (1.35 g) were added to the mixture, and the mixture was mixed with argon at 50 ° C. Stir under the atmosphere for 15 hours. Further, 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1'-(azodicarbonyl)dipiperidine (1.35 g) were added to the mixture. After stirring at 0<0>C for 18 h under argon, the mixture was concentrated in vacuo. The insoluble matter produced was filtered off and the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 424 (MH ⁺ ).

Reference example 103

6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarbamate Guanamine

Take 6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate A mixture of decylamine (0.61 g) and Lawson's reagent (0.61 g) in tetrahydrofuran (25 mL) was stirred at 55 ° C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ) pale yellow crystals. MS 440 (MH ⁺ ).

Reference example 104

Methyl 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

Methyl 7-hydroxy-5-([6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g) and potassium carbonate (0.50 g) Ethyl iodide (0.28 mL) was added to an ice-cooled and stirred solution of N,N-dimethylformamide (10 mL)-tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 18 hours and then stirred at 55 ° C. for 15 hours. the reaction mixture was concentrated in vacuo. the residue was partitioned between ethyl acetate and aqueous citric acid solution. the organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated in vacuo. the residue by silica gel layer The title compound (0.65 g, 50%), ^m .

Reference example 105

7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

Methyl 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.65 g), tetrahydrofuran (10 mL) An aqueous solution (5 mL) of potassium hydroxide (85%, 0.33 g) was added to a mixture with methanol (10 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow oil from ethyl acetate - hexane to give the title compound (548mg, 88%) of pale yellow crystals. MS 377 (MH ⁺ ).

Reference example 106

7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide

N,N-di in 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (0.54 g) 1-Chlorobenzotriazole ammonium salt (0.33 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added to the ice-cooled and stirred mixture of methylformamide (20 mL). Amine hydrochloride (0.42 g). After 15 hours at 4 ° C to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow oil from ethyl acetate - hexane to give the title compound (441mg, 82%) Light yellow crystals. MS 376 (MH ⁺ ).

Reference example 107

7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarboxamide

Taking 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.43 g) and Lawson's reagent ( A mixture of 0.28 g of tetrahydrofuran (30 mL) was stirred at 55 ° C for 2 hours. The reaction mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal MS 392 (MH ⁺ ).

Reference example 108

Ethyl 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate

Ethyl acetate (30 mL)-methanol (8 mL) containing ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.08 g) 2M trimethylsulfonyl diazomethane (diethyl ether solution, 2.8 mL) was added to the ice-cooled and stirred solution, and the mixture was stirred at 4 ° C for 2 hours, then 2M trimethyldecyl diazomethane (diethyl ether solution, 2.8 mL) was added. ). After stirring at 4 ° C for 1 hour, the reaction mixture was quenched with EtOAc EtOAc. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow oil from ethyl acetate - hexane to give the title compound (933mg, 83%) Light yellow crystals. Mp 161 to 162 °C.

Reference example 109

7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid

In tetrahydrofuran (15 mL) and methanol (15 mL) containing ethyl 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (0.93 g) An aqueous solution (10 mL) of potassium hydroxide (85%, 0.50 g) was added to the stirred solution. The mixture was stirred at room temperature for 15 hours then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow amorphous solid from ethyl acetate - hexane to give the title compound (783mg, 91%) of pale yellow crystals. MS 362 (MH ⁺ ).

Reference example 110

7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide

N,N-dimethylformamide containing 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (0.78 g) Add 20-mL of ice-cold and stirred solution to 1-hydroxybenzotriazole ammonium salt (0.66 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.83) g). After stirring at room temperature for 7 hours, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to give a pale yellow non- The title compound (733 mg, 94%) was obtained as crystals. MS 361 (MH ⁺ ).

Reference example 111

7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-thiocarboxamide

Taking 4-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (0.73 g) and Lawson's reagent (0.49 g) in tetrahydrofuran ( The 30 mL) mixture was stirred at 55 ° C for 3 hours. The reaction mixture was concentrated to give crystal crystal crystal crystal crystal crystal crystal crystal crystal MS 375 (MH ⁺ ).

Example 1

(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1, 3-thiazol-5-yl)ethyl acetate

7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (640 mg) was dissolved in tetrahydrofuran (20 mL). Sen reagent (593 mg), and the mixture was stirred at 50 ° C for 50 minutes. The reaction solution was concentrated under reduced pressure, and the residue was crystallized from a solvent mixture of tetrahydrofuran-hexane. The resulting yellow crystals were washed with diisopropyl ether and dried. The obtained yellow crystals were dissolved in tetrahydrofuran (12 mL)-toluene (20 mL), and ethyl 2-butynoate (0.49mL) and tributylphosphine (0.42mL) were added, and the mixture was stirred at 50 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc: Crystal form solid. MS 565 (MH ⁺ ).

Example 2

2-(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro- 1,3-thiazol-5-yl)ethanol

(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1 Ethyl acetate (3- thiazol-5-yl)acetate (470 mg) was dissolved in tetrahydrofuran (8 mL). 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane = 30:70 to 100:0, volume ratio), and the obtained yellow oil was crystallized from ethanol. The crystals obtained were recrystallized from ethanol to give the title compound (52 mg, yield 12%) as colorless crystal. Melting point 97 to 98 ° C. MS 523 (MH ⁺ ).

Example 3

(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1, 3-thiazol-5-yl)acetic acid

(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1 Ethyl acetate (3- thiazol-5-yl)acetate (1.0 g) was dissolved in tetrahydrofuran (6 mL)-ethanol (6 mL). . The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid and filtered. The obtained solid was washed with EtOAc EtOAcjjjjjjj The resulting solid was recrystallized from ethanol-hexane to yield colorless crystals. The temperature of 218 to 219 ° C. MS 537 (MH ⁺ ).

Example 4

2-(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro- 1,3-thiazole-5-yl)acetamide

Containing (2-(7-(benzyl)oxy-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl}-4,5-dihydro- 1,3-thiazol-5-yl)acetic acid (500 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (356 mg), 1-hydroxybenzo A mixture of triazolium ammonium salt (283 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, followed by water, ethanol and diethyl ether. washing the resulting brown solid was recrystallized from ethanol to give the title compound (300 mg of, 60% yield) of colorless crystals. temperature of 134 to ^{135 ℃ .MS 536 (MH +)} .

Example 5

(2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4 ,5-dihydro-1,3-thiazol-5-yl)ethyl acetate

Take 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (630 mg) Lawson's reagent (537 mg) was added to tetrahydrofuran (30 mL), and the mixture was stirred at 50 ° C for 50 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to EtOAc (EtOAc: hexane = hexane = 10:90 to 50:50). The obtained yellow solid (680 mg) was dissolved in tetrahydrofuran (10 mL)-toluene (20 mL), and ethyl 2-butynoate (0.34 mL) and tributylphosphine (0.49 mL) were added, and the mixture was stirred at 50 ° C. hour. The reaction solution was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj Shape. MS 600 (MH ⁺ ).

Example 6

2-(2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)ethanol

Take (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}- Ethyl 4,5-dihydro-1,3-thiazol-5-yl)acetate (400 mg) was dissolved in tetrahydrofuran (8 mL). . 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to methylene chloride chromatography (ethyl acetate: hexane = 40:60 to 100:0) to give the title compound (75 mg, yield: 20%). The amorphous solid crystallized from diethyl ether to give a pale yellow crystal. Melting point 93 to 94 ° C. MS 558 (MH ⁺ ).

Example 7

(2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4 ,5-dihydro-1,3-thiazol-5-yl)acetic acid

Take (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}- Ethyl 4,5-dihydro-1,3-thiazol-5-yl)acetate (250 mg) was dissolved in tetrahydrofuran (6 mL)-ethanol (8 mL). The mixture was stirred for 30 minutes and then stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The reaction mixture was filtered. The resulting yellow solid was recrystallized from ethanol to yield pale yellow crystals. Melting point 175 to 176 ° C. MS 572 (MH ⁺ ).

Example 8

2-(2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)acetamide

Containing (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)acetic acid (180 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride ( A mixture of 161 mg), 1-hydroxybenzotriazole ammonium salt (128 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15.5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed sequentially with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from EtOAc (EtOAc) The temperature of 147 to 148 ° C. MS 571 (MH ⁺ ).

Example 9

(2-{7-[(1-Methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- Ethyl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl acetate

Take 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (940 mg) was dissolved in tetrahydrofuran (30 mL), and Lawson reagent (1.36 g) was added, and the mixture was stirred at 50 ° C for 13 hours. The white solid in the mixture was collected by filtration and suspended in tetrahydrofuran (30 mL). Ethyl 2-butynoate (0.5 mL) and tributylphosphine (0.7 mL) were added, and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc The crude product is orange oily. On the other hand, the filtrate obtained above was concentrated under reduced pressure, and the residue was suspended in a mixed solvent of tetrahydrofuran (20 mL) and toluene (15 mL). Ethyl 2-butynoate (0.5 mL) and tributylphosphine (0.7 mL) were added, and the mixture was stirred at 60 ° C for 30 min. Further, ethyl 2-butynoate (1.4 mL) and tributylphosphine (2.0 mL) were added to the reaction solution, and the mixture was further stirred at 60 ° C for 1 hour. Further, ethyl 2-butynoate (1.0 mL) and tributylphosphine (1.5 mL) were added, and the mixture was further stirred at 60 ° C for 1 hour. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc: Oily crude product. MS 569 (MH ⁺ ). The crude product obtained was used in the next reaction without further purification.

Example 10

(2-{7-[(1-Methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- }}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid

Take (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2 Ethyl- 4,5-dihydro-1,3-thiazol-5-yl)acetate (1 g) was dissolved in tetrahydrofuran (10 mL)-ethanol (10 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The mixture was washed with ethyl acetate and brine evaporated. Ethanol was added to the residue, and the insoluble matter was filtered off. The filtrate was concentrated and the title compound was crystalljjjjjjjjj MS 541 (MH ⁺ ).

Example 11

2-(2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole- 2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide

Containing (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole- 2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (210 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide A mixture of the hydrochloride (150 mg), 1-hydroxybenzotriazole ammonium salt (118 mg) and N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to residue, and the mixture was washed with diisopropyl ether. Sodium chloride was added to the aqueous layer to give a saturated solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The obtained crude product was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Colorless crystal. The temperature of 130 to 131 ° C. MS 540 (MH ⁺ ).

Example 12

(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy Ethyl]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl acetate

Taking 7-(2-{[di-t-butyl(phenyl)decyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]- 1H-indole-2-carboxamide (1.37 g) was dissolved in tetrahydrofuran (40 mL), and the Lawson reagent (1.05 g) was added, and the mixture was stirred at 50 ° C for 50 minutes. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc) The yellow oil was dissolved in a mixed solvent of tetrahydrofuran (20 mL)-toluene (20 mL), ethyl 2-butynoate (0.6 mL) and tributylphosphine (0.7 mL), and the mixture was stirred at 50 ° C for 50 min. . The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc: Oily. MS 771 (MH ⁺ ).

Example 13

2-(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl) Phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol

Take (2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)benzene Ethyl oxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (500 mg) was dissolved in tetrahydrofuran (20 mL). Lithium borohydride (21 mg) was stirred and the mixture was stirred for 1 hour. Lithium borohydride (28 mg) was again added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour, and then stirred at 50 ° C for 7 hours. 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 729 (MH ⁺ ).

Example 14

(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy -1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid

Take (2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)benzene Ethyl oxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (480 mg) dissolved in tetrahydrofuran (10 mL)-ethanol (10 mL) A 1 M aqueous sodium hydroxide solution (7 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid. The precipitated solid was collected to give the title compound (320 mg, yield 70%) MS 743 (MH ⁺ ).

Example 15

2-(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl) Phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide

Containing (2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl) Phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (320 mg), 1-[3-(dimethylamino)propyl Mixture of benzyl-3-ethylcarbodiimide hydrochloride (165 mg), 1-hydroxybenzotriazole ammonium salt (131 mg) and N,N-dimethylformamide (8 mL) at room temperature 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The obtained crude product was subjected to EtOAc EtOAc EtOAcjjjjjjj MS 742 (MH ⁺ ).

Example 16

2-({2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenoxy ]-1H-吲哚-7-yl}oxy)propan-1-ol

Take 2-(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl) Phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol (270 mg) was dissolved in tetrahydrofuran (2 mL), and tetrabutyl fluoride was added. The solution was stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to EtOAc EtOAc (EtOAc:EtOAc:EtOAc:EtOAc solid. The resulting white solid was recrystallized from ethyl acetate-diethyl ether to yield colourless crystals. 165 to 169 ° C melting point. MS 491 (MH ⁺ ).

Example 17

2-(2-{7-(2-hydroxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4 ,5-dihydro-1,3-thiazol-5-yl)acetamide

Take 2-(2-{7-(2-{[di-t-butyl(phenyl)decyl)oxy}-1-methylethoxy)-5-[4-(methylsulfonyl) Phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamidamine (262 mg) was dissolved in tetrahydrofuran (2 mL) with fluorination Tetrabutylammonium (0.5 mL), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to EtOAc EtOAcjjjjjjjj The resulting white solid was recrystallized from ethyl acetate-hexane to yield colorless crystals. The temperature of 137 to 142 ° C. MS 504 (MH ⁺ ).

Example 18

(2-{5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indol-2-yl}- 4,5-dihydro-1,3-thiazol-5-yl)ethyl acetate

5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperazin-4-ylmethoxy)-1H-indole-2-carboxamide (500 mg) Dissolved in tetrahydrofuran (20 mL), Lawson's reagent (455 mg) was added, and the mixture was stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was applied to mjjjjjjjjjjj The obtained yellow oil was dissolved in tetrahydrofuran (10 mL)-toluene (15 mL), and ethyl 2-butynoate (0.26 mL) and tributylphosphine (0.30 mL) were added, and the mixture was stirred at 50 ° C for 2.5 hours. . The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc Oily. MS 573 (MH ⁺ ).

Example 19

2-(2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indol-2-yl }-4,5-dihydro-1,3-thiazol-5-yl)ethanol

(2-{5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-piperidin-4-ylmethoxy)-1H-indol-2-yl} -4,5-Dihydro-1,3-thiazol-5-yl)acetate (310 mg) was dissolved in tetrahydrofuran (15 mL), EtOAc (EtOAc) Stir for 2.5 hours and then stir at 50 ° C for 2.5 hours. Lithium borohydride (24 mg) was added to the reaction mixture, and the mixture was stirred at 50 ° C for 30 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate The crude product was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) Light yellow solid. The temperature of 104 to 105 ° C. MS 531 (MH ⁺ ).

Example 20

5-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3,4-thiadiazole- Ethyl 2-carboxylate

[2-({7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}carbonyl)indenyl](lateral oxygen Ethyl acetate (420 mg) was dissolved in tetrahydrofuran (15 mL), and Lawson reagent (308 mg) was added, and the mixture was stirred at 50 ° C for 5 hours. Lawson's reagent (300 mg) was again added to the reaction solution, and the mixture was further stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) %) of pale yellow crystals. The crystals obtained were recrystallized from ethyl acetate-diethyl ether to give pale yellow crystals. Melting point 194 to 195 ° C. MS 550 (MH ⁺ ).

Example 21

(5-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3,4-thiadiazole -2-yl)methanol

Take 5-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3,4-thiadiazole Ethyl-2-carboxylate (230 mg) was dissolved in tetrahydrofuran (8 mL)-methanol (2 mL). Water and 1 M hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. The obtained crude product was subjected to EtOAc EtOAcjjjjjjjj The resulting pale yellow solid was recrystallized from ethyl acetate-diethyl ether to yield pale yellow crystals. 159 to 160 ° C melting point. MS 508 (MH ⁺ ).

Example 22

2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3-thiazole-5-carboxylic acid Ethyl ester

Taking 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-thioformamide (280 mg), 2-chloro-3 A mixture of potassium ethyl oxypropionate (234 mg), acetic acid (0.5 mL) and N,N-dimethylacetamide (5 mL) was stirred at 100 ° C for 4 hours. Further, ethyl 2-chloro-3-oxopropionate (234 mg) and acetic acid (0.5 mL) were added, and the mixture was stirred at 100 ° C for 3 hours. Further, potassium 2-chloro-3-oxopropionate (234 mg) and acetic acid (0.5 mL) were added, and the mixture was stirred at 100 ° C for 7 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, dried over magnesium sulfate, The residue was purified by EtOAc EtOAcjjjjjjjjj MS 549 (MH ⁺ ).

Example 23

(2-{7-(Benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3-thiazol-5-yl Methanol

Containing 2-{7-(benzylsulfanyl)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3 at 0 °C To a solution of ethyl thiazole-5-carboxylate (242 mg) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (50 mg). The mixture was stirred at 0 ° C for 30 minutes, and ethanol was added dropwise until hydrogen gas was no longer released. A saturated aqueous solution of ammonium chloride was added to the mixture, and the resulting yellow suspension was filtered over EtOAc. The filtrate was concentrated, and the residue was purified by EtOAc EtOAc (EtOAc/hexane = 20/80 to 100/0). The crystals were recrystallized from ethanol-ethyl acetate to yield yellow crystals. The crystals were purified by hydrazine column chromatography (ethyl acetate /hexane = 20 / 80 to 90/10, by volume) to yield yellow crystals. The crystals were recrystallized from ethanol-hexane to yield crystals of crystals of the title compound (52mg, 23%). MS 507 (MH ⁺ ). Mp 125 to 126 °C.

Example 24

(2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro- Ethyl 1,3-thiazole-5-yl)acetate

Take 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-thiocarboxamide (857 mg), 2-butyl A mixture of ethyl acetylate (0.6 mL), tributylphosphine (0.6 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was stirred at 60 ° C for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS 517 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 1.38 (6H, d, J = 6.0 Hz), 2.69-2.76 (2H, m), 3.04 (3H, s), 4.19 (2H, q, J = 7.1 Hz), 4.24 - 4.49 (3H, m), 4.63 (1H, spt, J = 6.0 Hz), 6.44 (1H, d, J = 1.9 Hz), 6.84 (1H, d, J = 2.3 Hz), 6.91 (1H, d, J = 1.5 Hz), 7.01 - 7.11 (2H, m), 7.81 - 7.90 (2H, m), 9.22 (1H, brs).

Example 25

2-(2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-di Hydrogen-1,3-thiazol-5-yl)ethanol

Taking (2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro Ethyl acetate - 1,3-thiazol-5-yl) (330 mg) was dissolved in a mixture of THF (15 mL) and methanol (3 mL). Lithium borohydride (30 mg) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, dried over magnesium sulfate, The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 475 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.37-1.41 (7H, m), 1.82-2.10 (2H, m), 3.04 (3H, s), 3.74-3.86 (2H, m), 4.13-4.34 (2H, m ), 4.36-4.49 (1H, m), 4.59-4.67 (1H, m), 6.44 (1H, d, J = 1.9 Hz), 6.85 (1H, d, J = 1.9 Hz), 6.91 (1H, d, J = 1.5 Hz), 7.02-7.11 (2H, m), 7.81-7.90 (2H, m), 9.23 (1H, brs).

Example 26

2-methyl-1-(2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}- 4,5-dihydro-1,3-thiazol-5-yl)propan-2-ol

Containing (2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl}- at 0 ° C To a solution of ethyl 4,5-dihydro-1,3-thiazol-5-yl)acetate (490 mg) in tetrahydrofuran (10 mL). After the mixture was stirred at room temperature for 1.5 hours, a 1 M solution of methylmagnesium bromide in tetrahydrofuran (3.4 mL) was added to the mixture. The mixture was stirred at room temperature for 2 hours. Further, a 1 M solution of methylmagnesium bromide in tetrahydrofuran (3.4 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1M aqueous HCl. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc (EtOAc/hexane = EtOAc/EtOAc) The oil was crystallized from ethyl acetate-diethyl ether-hexane to yield pale yellow crystals. The crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (50 mg, 10%) MS 503 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.30 (3H, s), 1.32 (3H, s), 1.38 (6H, d, J = 6.1 Hz), 1.93-2.11 (2H, m), 3.04 (3H, s) , 4.03-4.14(1H,m),4.14-4.28(1H,m),4.47-4.71(2H,m),6.44(1H,dd,J=1.9Hz),6.84(1H,d,J=1.9Hz ), 6.91 (1H, d, J = 1.9 Hz), 7.06 (2H, d, J = 9.1 Hz), 7.85 (2H, d, J = 9.1 Hz), 9.23 (1H, brs).

Example 27

[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- Ethyl 1,3-thiazole-5-yl]

Taking 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarboxamide (10.7 g), 2- A mixture of ethyl butyrate (8.2 mL), tributylphosphine (7.0 mL) and tetrahydrofuran (400 mL) was stirred at 60 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 490 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.73 (2H, d, J = 6.1 Hz), 3.21 (3H, s), 3.93 (3H, s), 4.19 (2H) , q, J = 7.2 Hz), 4.27-4.48 (3H, m), 6.45 (1H, d, J = 1.9 Hz), 6.85 (1H, d, J = 2.3 Hz), 6.96 (1H, d, J = 1.9 Hz), 7.34 (1H, dd, J = 8.7, 3.0 Hz), 8.00 (1H, d, J = 8.7 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.27 (1H, brs).

Example 28

[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- 1,3-thiazol-5-yl]acetic acid

[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro Ethyl acetate of -1,3-thiazol-5-yl] (11.06 g) was dissolved in a mixture of tetrahydrofuran (100 mL) and ethanol (100 mL). A 1 M aqueous sodium hydroxide solution (37 mL) was added and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (37 mL) was added to mixture. The resulting yellow suspension was filtered and a yellow solid was collected. The solid was dissolved in ethyl acetate-tetrahydrofuran. The solution was dehydrated over magnesium sulfate, filtered and concentrated. The residual solid was washed with EtOAcqqqqqq MS 462 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 2.54-2.64 (1H, m), 2.71-2.85 (1H, m), 3.24 (3H, s), 3.88 (3H, s), 4.17-4.30 (2H, m ), 4.32-4.48 (1H, m), 6.69 (1H, d, J = 1.9 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.02 (1H, d, J = 1.9 Hz), 7.48 (1H) , dd, J = 8.7, 3.0 Hz), 8.00 (1H, d, J = 9.0 Hz), 8.54 (1H, d, J = 2.6 Hz), 11.88 (1H, s), 12.48 (1H, brs).

Example 29

2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (90 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg), 1-hydroxyl A mixture of benzotriazole ammonium salt (59 mg) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofurane. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual oil was crystallized from acetonitrile and crystals washed with EtOAc-EtOAc. The crystals were recrystallized from ethanol to give the title compound (58 mg, 64%) as pale white crystals. MS 461 (MH ⁺ ). Mp 225 to 227 ° C.

Example 30

2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (800 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg), 1-hydroxybenzene A mixture of triazole (350 mg) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 30 min. Triethylamine (440 mg) and methylamine hydrochloride (230 mg) were then added to the mixture. All were stirred at room temperature for 20 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were washed with ethyl acetate-hexane toiel The crystals were recrystallized from acetone-hexane to give colorless columnar crystals. MS 475 (MH ⁺ ). Mp 201 to 202 °C.

Example 31

2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Take 2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5 a solution of dihydro-1,3-thiazol-5-yl]-N-methylacetamide (425 mg) in methanol (425 mL) using preparative supercritical fluid chromatography (SFC) using CHIRALPAK AS ( 2 cm id × 25 cm, Daicel Chemical Industries, Ltd.), using supercritical carbon dioxide/methanol (60/40) as a mobile phase, and parsing at 10 MPa and 35 ° C according to a flow rate of 50 mL/min. The fractions containing the single-mirror isomers with a retention time of 4.8 minutes were collected and concentrated to give the title compound (198 mg) as white crystal. Recrystallization from acetone-hexane gave colorless crystals (181 mg). MS 475 (MH ⁺ ). Mp 196 to 197 °C.

Example 32

2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Take 2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5 a solution of dihydro-1,3-thiazol-5-yl]-N-methylacetamide (425 mg) in methanol (425 mL) using preparative supercritical fluid chromatography (SFC) using CHIRALPAK AS ( 2 cm id × 25 cm, Daicel Chemical Industries, Ltd.), using supercritical carbon dioxide/methanol (60/40) as a mobile phase, and parsing at 10 MPa and 35 ° C according to a flow rate of 50 mL/min. The fractions containing the single-mirror isomers with a residence time of 6.0 min were collected and concentrated to give the title compound (196 mg) as white crystal. Recrystallization from acetone-hexane gave colorless crystals (173 mg). MS 475 (MH ⁺ ). Mp 195 to 197 °C.

Example 33

[2-(7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]ethyl acetate

Take 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H- a mixture of hydrazine-2-thiocarbamide (940 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.5 mL), tetrahydrofuran (15 mL) and toluene (20 mL) at 60 ° C Stir for 50 minutes. The mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj Yellow amorphous solid. MS 578 (MH ⁺ ).

¹ H NMR (CDCL ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.69-2.76 (2H, m), 3.21 (3H, s), 3.45 (3H, s), 3.46 (3H, s) , 3.61-3.74 (4H, m), 4.19 (2H, q, J = 7.2 Hz), 4.25-4.53 (4H, m), 6.68 (1H, d, J = 1.9 Hz), 6.85 (1H, d, J = 1.9 Hz), 7.06 (1H, d, J = 1.9 Hz), 7.33 (1H, dd, J = 8.7, 2.7 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.45 (1H, d, J) =2.7 Hz), 10.53 (1H, s).

Example 34

[2-(7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid

Taking [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy} Ethyl acetate -1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl] (390 mg) was dissolved in a mixture of THF (5 mL) and methanol (5 mL). A 1 M aqueous sodium hydroxide solution (2 mL) was added and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M aqueous hydrochloric acid (2 mL) was added to mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 550 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 2.80 (2H, d, J = 7.2 Hz), 3.21 (3H, s), 3.45 (3H, s), 3.46 (3H, s), 3.60-3.78 (4H, m) , 4.25-4.56 (4H, m), 6.67 (1H, d, J = 1.9 Hz), 6.85 (1H, d, J = 1.9 Hz), 7.05 (1H, d, J = 1.9 Hz), 7.33 (1H, Dd, J = 8.7, 2.7 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.45 (1H, dd, J = 2.7 Hz), 1054 (1H, s).

Example 35

2-[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy) }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (190 mg), N-ethyl-N'-(3-dimethylamino group A mixture of propyl)carbodiimide hydrochloride (133 mg), 1-hydroxybenzotriazole (93 mg) and N,N-dimethylformamide (5 mL) was stirred at 50 ° C for 20 min. After cooling to room temperature, a 10% aqueous ammonium hydroxide solution (0.5 mL) was added to the mixture, and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual oil was recrystallized from ethyl acetate. The crystals obtained were washed with diethyl ether. The crystals were recrystallized from acetonitrile to give the title compound ( 139 g, 74%). MS 549 (MH ⁺ ). Mp 172 to 173 ° C.

Example 36

2-[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide

Containing [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy) }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (180 mg), N-ethyl-N'-(3-dimethylamino group Propyl)carbodiimide hydrochloride (126 mg), 1-hydroxybenzotriazole (88 mg), methylammonium chloride (44 mg), triethylamine (0.09 mL) and N,N-dimethyl A mixture of formamide (5 mL) was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by basic EtOAc EtOAc (EtOAc/EtOAc/EtOAc/EtOAc The solid was recrystallized from EtOAc (EtOAc:EtOAc) MS 563 (MH ⁺ ). Mp 149 to 151 ° C.

Example 372-[2-(7-[2-Methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl] Oxy}}H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]ethanol

Taking [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy} Ethyl acetate -1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl] (220 mg) was dissolved in THF (2 mL). Lithium borohydride (41 mg) was added to the mixture at 0 ° C, and the mixture was stirred at room temperature for 6.5 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc (EtOAc/EtOAc/EtOAc/EtOAc) The oil was taken up from acetonitrile. The crystals were recrystallized from EtOAc (EtOAc:EtOAc) MS 536 (MH ⁺ ). Mp 69 to 71 ° C.

Example 38

[2-(7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- Ethyl 1,3-thiazole-5-yl]

Taking 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-thioformamide (2.06 g), 2- A mixture of ethyl butyrate (0.95 mL), tributylphosphine (1.35 mL), tetrahydrofuran (50 mL) and toluene (100 mL) was stirred at 50 ° C for 2 hr. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 490 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.69-2.76 (2H, m), 3.09 (3H, s), 3.93 (3H, s), 4.19 (2H, q, J = 7.2 Hz), 4.24 - 4.47 (3H, m), 6.50 (1H, d, J = 1.9 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.99 - 7.06 (2H, m), 8.15 ( 1H, dd, J = 8.7, 2.6 Hz), 8.74 (1H, d, J = 1.9 Hz), 9.24 (1H, s).

Example 39

1-[2-(7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-2-methylpropan-2-ol

Containing [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)- at 0 ° C To a solution of 4,5-dihydro-1,3-thiazol-5-yl]acetate (600 mg) in tetrahydrofuran (20 mL). 30 minutes. Further, a 1 M solution of methylmagnesium bromide in tetrahydrofuran (5 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1M aqueous HCl. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by hydrazine column chromatography (ethyl acetate / hexane = 50 / 50 to 85 / 15, volume ratio), and then purified by basic column chromatography (ethyl acetate /hexane = 50/50 to 100/0, by volume) gave the title compound (1.36 g, 51%) as a pale yellow amorphous solid. The amorphous solid crystallized from ethyl acetate-diethyl ether. The crystals were recrystallized from ethyl acetate-diethyl ether. MS 490 (MH ⁺ ). Mp 171 to 173 ° C.

Example 40

2-[2-(7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]ethanol

Taking [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro Ethyl acetate - 1,3-thiazol-5-yl] (270 mg) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (1.5 mL). Lithium borohydride (62 mg) was added to the mixture at 0 ° C, and the mixture was stirred at room temperature for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by hydrazine column chromatography (ethyl acetate / hexane = 20 / 80 to 100 / 0, volume ratio), and then purified by basic column chromatography (methanol / ethyl acetate / hexane Alkane = 0/20/80 to 10/90/0) gave the title compound (110 mg, 43%) as white white solid. MS 448 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.40 (1H, t, J = 4.9 Hz), 1.82-2.03 (2H, m), 3.09 (3H, s), 3.73-3.85 (2H, m), 3.93 (3H, s), 4.09-4.32 (2H, m), 4.36-4.49 (1H, m), 6.50 (1H, d, J = 1.9 Hz), 6.87 (1H, d, J = 2.3 Hz), 6.98-7.05 (2H m), 8.15 (1H, dd, J = 8.9, 2.5 Hz), 8.74 (1H, d, J = 2.7 Hz), 9.24 (1H, brs).

Example 41

[2-(7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- 1,3-thiazol-5-yl]acetic acid

Taking [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro Ethyl acetate - 1,3-thiazol-5-yl] (500 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL). A 1 M aqueous sodium hydroxide solution (3 mL) was added and the mixture was stirred at room temperature for 50 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1M aqueous HCl (3 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residual solid was washed with EtOAc (EtOAc) MS 462 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 2.55-2.88 (2H, m), 3.27 (3H, s), 3.87 (3H, s), 4.14 - 4.32 (2H, m), 4.40 (1H, d, J = 7.9 Hz), 6.65 (1H, dd, J = 1.9 Hz), 6.84 (1H, d, J = 1.9 Hz), 7.00 (1H, d, J = 1.9 Hz), 7.15 (1H, d, J = 8.7) Hz), 8.28 (1H, dd, J = 8.7, 2.6 Hz), 8.64 (1H, d, J = 2.6 Hz), 11.77 (1H, s).

Example 42

2-[2-(7-Methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Containing [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (280 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (233 mg), 1-hydroxyl A mixture of benzotriazole (164 mg), methylammonium chloride (82 mg), triethylamine (0.2 mL) and N,N-dimethylformamide (12 mL) was stirred at room temperature for 5 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-THF. The organic layer was washed with aq. EtOAc EtOAc. The residue was purified by basic EtOAc EtOAc (EtOAc/EtOAc/EtOAc/EtOAc/EtOAc The amorphous solid crystallized from ethyl acetate-diethyl ether to yield white crystals. The crystals were washed with EtOAc EtOAc (EtOAc) MS 475 (MH ⁺ ). Mp 207 to 209 °C.

Example 43

[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]ethyl acetate

Containing 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H- Mixture of 吲哚-2-thiocarbamamine (1.69g), ethyl 2-butynoate (0.84mL), tributylphosphine (0.9mL), tetrahydrofuran (20mL) and toluene (30mL) at 50°C Stir under 13 hours. The mixture was concentrated under reduced pressure, and the residue was purified by hexane column chromatography (methanol / ethyl acetate / hexane = 0 / 20 / 80 to 5 / 95 / 0 / vol. The title compound (1.14 g, 55%) was obtained as a brown solid. MS 578 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.69-2.76 (2H, m), 3.09 (3H, s), 3.45 (3H, s), 3.46 (3H, s) , 3.64 - 3.74 (4H, m), 4.19 (2H, q, J = 7.2 Hz), 4.25 - 4.54 (4H, m), 6.71 (1H, d, J = 1.9 Hz), 6.86 (1H, d, J =2.3 Hz), 7.01 (1H, d, J = 8.7 Hz), 7.12 (1H, d, J = 1.9 Hz), 8.14 (1H, dd, J = 8.9, 2.5 Hz), 8.73 (1H, d, J) =2.6 Hz), 1047 (1H, s).

Example 44

1-[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]-2-methylpropan-2-ol

Containing [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridine-2 at 0 °C Addition of 1M Bromine to a solution of ethyl-oxy]-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (600 mg) in tetrahydrofuran (15 mL) A solution of methylmagnesium in tetrahydrofuran (4 mL) was stirred at room temperature for 30 min. Further, a 1 M solution of methylmagnesium bromide in tetrahydrofuran (4 mL) was added to the mixture at room temperature, and the mixture was stirred for 1 hour. The mixture was acidified with 1 M hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by hydrazine column chromatography (methanol / ethyl acetate / hexanes / hexanes / 50 / 50 to 15 / 85 / 0 / volume ratio), and then purified by basic column chromatography (acetic acid) Ethyl acetate/hexane = 40/60 to 0/100, mp. MS 564 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.30 (3H, s), 1.32 (3H, s), 1.94-2.10 (2H, m), 3.09 (3H, s), 3.45 (6H, s), 3.64-3.74 ( 4H, m), 4.02-4.27 (2H, m), 4.43-4.61 (2H, m), 6.70 (1H, d, J = 1.9 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.00 (1H) , d, J = 8.7 Hz), 7.11 (1H, d, J = 1.9 Hz), 8.14 (1H, dd, J = 8.7, 2.3 Hz), 8.73 (1H, d, J = 2.3 Hz), 10.04 (1H , brs).

Example 45

[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid

Taking [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy} Ethyl acetate -1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl] (540 mg) was dissolved in a mixture of tetrahydrofuran (10 mL) and ethanol (10 mL). A 1 M aqueous sodium hydroxide solution (3 mL) was added to the mixture, and the mixture was stirred at room temperature for 50 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was acidified with 1M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 550 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 2.78 (2H, d, J = 7.2 Hz), 3.09 (3H, s), 3.45 (3H, s), 3.46 (3H, s), 3.63-3.78 (4H, m) , 4.22-4.59 (4H, m), 6.70 (1H, d, J = 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.02 (1H, d, J = 9.5 Hz), 7.11 (1H, d, J = 1.9 Hz), 8.14 (1H, dd, J = 8.9, 2.5 Hz), 8.73 (1H, d, J = 1.9 Hz), 10.47 (1H, s).

Example 46

2-[2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide

Containing [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy) }-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (280 mg), N-ethyl-N'-(3-dimethylamino group Propyl)carbodiimide hydrochloride (195 mg), 1-hydroxybenzotriazole (138 mg), methylammonium chloride (69 mg), triethylamine (0.14 mL) and N,N-dimethyl A mixture of formamide (15 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-THF. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by basic EtOAc (methanol / ethyl acetate = 0/100 to 5/95, vol. The amorphous solid crystallized from acetonitrile-diethyl ether to yield white crystals. The crystals were recrystallized from ethyl acetate-EtOAc toiel MS 563 (MH ⁺ ). Mp 123 to 125 ° C.

Example 47

[2-(7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- Ethyl 1,3-thiazole-5-yl]

Taking 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarboxamide (2.04 g), 2- A mixture of ethyl butyrate (1.8 mL), tributylphosphine (1.5 mL), tetrahydrofuran (25 mL) and toluene (30 mL) was stirred at 50 ° C for one hour. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS 578 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.72 (2H, d, J = 6.4 Hz), 3.47 (3H, s), 3.91 (3H, s), 4.19 (2H) , q, J = 7.2 Hz), 4.23-4.46 (3H, m), 4.55 (2H, s), 6.48 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J = 2.3 Hz), 6.85 (1H, d, J = 1.9 Hz), 7.22-7.29 (1H, m), 7.31-7.37 (1H, m), 8.36 (1H, d, J = 2.3 Hz), 9.20 (1H, brs).

Example 48

[2-(7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- 1,3-thiazol-5-yl]acetic acid

[2-(7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro Ethyl acetate -1,3-1,3-thiazol-5-yl] (1.36 g) was dissolved in a mixture of tetrahydrofuran (15 mL) and ethanol (15 mL). A 1 M aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was neutralized with 1M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. MS 428 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 2.78 (2H, d, J = 7.2 Hz), 3.48 (3H, s), 3.92 (3H, s), 4.25-4.47 (3H, m), 4.56 (2H, m) , 6.48 (1H, d, J = 1.9 Hz), 6.83 (1H, d, J = 1.9 Hz), 6.85 (1H, d, J = 1.9 Hz), 7.24 - 7.39 (2H, m), 8.33 (1H, d, J = 2.6 Hz), 9.51 (1H, s).

Example 49

2-[2-(7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (160 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg), 1-hydroxyl A mixture of benzotriazole monohydrate (115 mg), 25% aqueous ammonium hydroxide (1 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by basic column chromatography (methanol / ethyl acetate = / / / / / / / / / / / / / / The amorphous solid crystallized from ethyl acetate-diethyl ether to yield white crystals. The crystals were recrystallized from ethyl acetate-hexane toiel MS 427 (MH ⁺ ). Mp 135 to 136 °C.

Example 50

2-[2-(7-Methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Containing [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (300 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg), 1-hydroxyl A mixture of benzotriazole monohydrate (216 mg), methylammonium chloride (95 mg), triethylamine (0.2 mL) and N,N-dimethylformamide (13 mL) was stirred at room temperature 2 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by basic ruthenium column chromatography (methanol / ethyl acetate = 0/100 to 5 / 95, volume ratio), and then purified by column chromatography (methanol / ethyl acetate = 0 / 100 to 8/92, by volume), yielding a yellow oil. The oil was crystallized from acetonitrile-diethyl ether to yield white crystals. The crystals were recrystallized from EtOAc (EtOAc:EtOAc) MS 441 (MH ⁺ ). Mp 102 to 104 °C.

Example 51

N-ethyl-2-[2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)- 4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (300 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg), 1-hydroxyl A mixture of benzotriazole monohydrate (214 mg), 2M ethylamine in tetrahydrofuran (0.7 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate The residue was purified by basic EtOAc (methanol /EtOAc /EtOAc /EtOAc /EtOAc The amorphous solid crystallizes from acetonitrile to yield white crystals. The crystals were recrystallized from acetonitrile to give the title compound ( 222 mg, 70% MS 455 (MH ⁺ ). Mp 130 to 132 °C.

Example 52

(2-{7-(2-Methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4 ,5-dihydro-1,3-thiazol-5-yl)ethyl acetate

Containing 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate at room temperature Lawen's reagent (845 mg) was added to a solution of decylamine (874 mg) in tetrahydrofuran (20 mL). The mixture was stirred at 50 ° C for 45 minutes and then cooled to room temperature. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 50:50 to 100:0). Ethyl 2-butynoate (0.507 mL) and tributylphosphine (0.652 mL) were added to a solution of this solid in tetrahydrofuran (20 mL). All were stirred at 50 ° C for 45 minutes. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 547 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 1.13-1.23 (6H, m), 2.59-2.75 (1H, m), 2.81-2.93 (1H, m), 3.17 (3H, s), 3.30 (3H, s ), 3.45-3.53 (1H, m), 3.55-3.65 (1H, m), 4.04-4.16 (2H, m), 4.20-4.47 (3H, m), 4.58-4.74 (1H, m), 6.69 (1H) , d, J = 1.89 Hz), 6.84 (1H, d, J = 1.89 Hz), 6.96 (1H, d, J = 1.89 Hz), 7.06-7.14 (2H, m), 7.79-7.92 (2H, m) , 11.66 (1H, s).

Example 53

(2-{7-(2-Methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4 ,5-dihydro-1,3-thiazol-5-yl)acetic acid

In the presence of (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} A mixture of -4,5-dihydro-1,3-thiazol-5-yl)acetate (134 mg), tetrahydrofuran (1 mL) and ethanol (1 mL) All were stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was acidified with 1M hydrochloric acid and then ethyl acetate-THF. The organic layer was successively washed with water and brine, dried (MgSO _4), filtered, and concentrated in vacuo to give the title compound (57mg, 43%) of a yellow amorphous solid. MS 519 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 1.25 (3H, d, J = 6.06 Hz), 2.52-2.63 (1H, m), 2.66-2.83 (1H, m), 3.17 (3H, s), 3.31 ( 3H, s), 3.44 - 3.54 (1H, m), 3.57-3.66 (1H, m), 4.14 - 4.34 (2H, m), 4.34 - 4.50 (1H, m), 4.62-4.74 (1H, m), 6.68 (1H, d, J = 1.89 Hz), 6.83 (1H, d, J = 1.89 Hz), 6.96 (1H, d, J = 1.89 Hz), 7.04-7.18 (2H, m), 7.78-7.94 (2H , m), 11.63 (1H, s).

Example 54

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)acetamide

Containing (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole at room temperature 1-ethyl-3 was added to a solution of 2-methyl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (48 mg) in N,N-dimethylformamide (2 mL) -(3-Dimethylaminopropyl)carbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole ammonium salt (28 mg). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the resulting mixture was washed with water, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:MeOH:MeOH:MeOH: The title compound (11 mg, 23%) elute Mp 107 to 112 °C.

¹ H NMR (CDCl ₃ ) δ 1.20-1.42 (3H, m), 2.49-2.74 (2H, m), 3.04 (3H, s), 3.37-3.58 (4H, m), 3.57-3.77 (1H, m ), 4.22-4.46 (3H, m), 4.44 - 4.64 (1H, m), 5.24 - 5.56 (2H, m), 6.58 (1H, s), 6.85 (1H, s), 6.96-7.12 (3H, m ), 7.85 (2H, d, J = 8.71 Hz), 9.96 (1H, brs).

Example 55

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)ethanol

Containing (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole at 0 °C To a solution of ethyl-2-ethyl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (277 mg) in tetrahydrofuran (5 mL) After stirring at 0 ° C for 1.5 hours, lithium borohydride (22 mg) was added to the mixture. All were stirred at 0 ° C for 2 hours, at room temperature for 2.5 hours, and then at 50 ° C overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Organic layer was washed with water, dehydrated (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 505 (MH ⁺ ).

^l H NMR (DMSO-d ₆ ) δ 1.25 (3H, d, J = 6.40 Hz), 1.60-1.78 (1H, m), 1.79-1.94 (1H, m), 3.17 (3H, s), 3.30 ( 3H, s), 3.43-3.54 (3H, m), 3.55-3.66 (1H, m), 4.07-4.27 (2H, m), 4.35-4.47 (1H, m), 4.60-4.74 (2H, m), 6.68(1H,d,J=2.07Hz), 6.84(1H,d,J=2.0Hz), 6.97(1H,d,J=1.88Hz),7.07-7.14(2H,m),7.82-7.91(2H , m), 11.63 (1H, s).

Example 56

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1 H -indol-2-yl }-4,5-dihydro-1,3-thiazol-5-yl)ethanol

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- A solution of ethyl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol (40 mg) in ethanol (10 mL) using preparative high performance liquid chromatography (HPLC) using CHIRALPAK AD (50mm Id x 50 mmL, Daicel Chemical Industries, Ltd.), using ethanol (100%) as the mobile phase, and parsing at 30 ° C at a flow rate of 60 mL/min. The fractions containing the single-image isomer were collected for 29 minutes and concentrated to give the title compound (10 mg) as white powder. The compound was dissolved in methanol and the solution was filtered. The filtrate was concentrated to give the title compound (1. MS 505 (MH ⁺ ).

Example 57

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)ethanol

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- A solution of ethyl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol (40 mg) in ethanol (10 mL) using preparative high performance liquid chromatography (HPLC) using CHIRALPAK AD (50mm Id x 50 mmL, Daicel Chemical Industries, Ltd.), using ethanol (100%) as the mobile phase, and parsing at 30 ° C at a flow rate of 60 mL/min. The fractions containing the single-image isomer were collected for 35 minutes and concentrated to give the title compound (11 mg) as a white powder. The compound was dissolved in methanol and the solution was filtered. The filtrate was concentrated to give the title compound (1. MS 505 (MH ⁺ ).

Example 58

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)ethanol

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- A solution of ethyl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol (40 mg) in ethanol (10 mL) using preparative high performance liquid chromatography (HPLC) using CHIRALPAK AD (50mm Id x 50 mmL, Daicel Chemical Industries, Ltd.), using ethanol (100%) as the mobile phase, and parsing at 30 ° C at a flow rate of 60 mL/min. The title compound (10 mg) was obtained as a white powder. The compound was dissolved in methanol and the solution was filtered. The filtrate was concentrated to give the title compound (1. MS 505 (MH ⁺ ).

Example 59

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)ethanol

2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2- A solution of ethyl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol (40 mg) in ethanol (10 mL) using preparative high performance liquid chromatography (HPLC) using CHIRALPAK AD (50mm Id x 50 mm L, Daicel Chemical Industries, Ltd.), using ethanol (100%) as the mobile phase, and parsing at 30 ° C at a flow rate of 60 mL/min. The fractions which were collected for a period of 52 minutes and which actually contained only the pure single-mirror isomers and concentrated to give the title compound (12 mg) as a white powder. The compound was dissolved in methanol and the mixture was filtered. The filtrate was concentrated to give the title compound (1. MS 505 (MH ⁺ ).

Example 60

1-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-inden-2-yl} -4,5-dihydro-1,3-thiazol-5-yl)-2-methylpropan-2-ol

Containing (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole at 0 °C Add methylmagnesium bromide (1M tetrahydrofuran solution, 5.4 mL) to a solution of ethyl-2-ethyl-5,5-dihydro-1,3-thiazol-5-yl)acetate (490 mg) in tetrahydrofuran (20 mL) . After stirring at room temperature for 1 hour, methylmagnesium bromide (1 M tetrahydrofuran solution, 5.4 mL) was added to the mixture. Then all was stirred at room temperature for 1 hour. Methylmagnesium bromide (1 M tetrahydrofuran solution, 5.4 mL) was again added to the mixture, and the mixture was further stirred at room temperature for 1 hour. Water and 1 M hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1:1 to 1:9). The oil was crystallized from EtOAc (EtOAc:EtOAc) The crystals were recrystallized from ethyl acetate-diethyl ether to give colorless column crystals. MS 533 (MH ⁺ ). Mp 112 to 113 °C.

Example 61

{2-[7-(1-Methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4 , 5-dihydro-1,3-thiazol-5-yl}ethyl acetate

Containing 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (2.0 g A mixture of Lawson's reagent (2.27 g) and tetrahydrofuran (70 mL) was stirred at 65 ° C for 1 hour. The mixture was concentrated in vacuo. Toluene and diisopropyl ether were added to the residue to produce crystals. The crystals were collected by filtration and washed with toluene-diisopropyl ether to yield yellow crystals. A mixture containing the crystal, ethyl 2-butynoate (1.44 g), tributylphosphine (1.03 g) and tetrahydrofuran (100 mL) was stirred at 70 ° C for 2 hr then concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 518 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.19 Hz), 1.39 (6H, d, J = 6.06 Hz), 2.73 (2H, d, J = 6.44 Hz), 3.09 (3H, s ), 4.05-4.48 (5H, m), 4.55-4.73 (1H, m), 6.49 (1H, d, J = 1.89 Hz), 6, 85 (1H, d, J = 2.27 Hz), 6.97 (1H, d, J = 1.51 Hz), 7.01 (1H, d, J = 9.47 Hz), 8.14 (1H, dd, J = 8.71, 2.65 Hz), 8.73 (1H, d, J = 1.89 Hz), 9.25 (1H, Brs).

Example 62

2-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}ethanol

Containing {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole at 0 °C To a mixture of ethyl-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (500 mg), tetrahydrofuran (20 mL) and methanol (5 mL), lithium borohydride (110 mg). All were stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexanes = 1:2 to 9:1) to give a pale yellow amorphous solid. The title compound (210 mg, 46% The crystals were recrystallized from ethyl acetate-diethyl ether to give pale yellow column crystals. MS 476 (MH ⁺ ). Mp 172 to 173 ° C.

Example 63

2-methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol

{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole at room temperature Add methylmagnesium bromide (1M tetrahydrofuran solution, 5.2 mL) to a solution of ethyl-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (680 mg) in tetrahydrofuran (30 mL) . After stirring at room temperature for 2 hours, a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2:1 to 1:9, volume ratio) to yield a yellow amorphous solid. The solid was crystallized from EtOAc (EtOAc:EtOAc) The crystals were recrystallized from ethyl acetate-diethyl ether to give pale yellow column crystals. MS 504 (MH ⁺ ). Mp 151 to 153 ° C.

Example 64

2-methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol

2-Methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole a solution of indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol (150 mg) in methanol (7.5 mL) by preparative supercritical fluid chromatography Using CHIRALPAK IA (2cm id × 25cm, Daicel Chemical Industries, Ltd.) with supercritical carbon dioxide / ethanol / acetonitrile (620 / 304 / 76) as the mobile phase, at 10 MPa and 35 ° C according to the flow rate of 50 ‧ mL / min Under the analysis. The fractions containing the single-mirror isomers with a residence time of 5.0 minutes were collected and concentrated to give the title compound (54 mg) as white crystal. Recrystallization from acetonitrile gave colorless crystals (45 mg). MS 504 (MH ⁺ ). Mp 145 to 146 °C.

Example 65

2-methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol

Taking 2-methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H- a solution of indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol (150 mg) in methanol (7.5 mL) by preparative supercritical fluid chromatography Method (SFC), using CHIRALPAK IA (2 cm id × 25 cm, Daicel Chemical Industries, Ltd.), with supercritical carbon dioxide / ethanol / acetonitrile (620 / 304 / 76) as the mobile phase, at a flow rate of 50 mL / min at 10 MPa Analyzed at 35 ° C. The fractions containing the single-image isomer were stored for 5.8 minutes and concentrated to give the title compound (60 mg) as white crystal. Recrystallization from acetonitrile gave colorless crystals (50 mg). MS 504 (MH ⁺ ). Mp 145 to 146 °C.

Example 66

{2-[7-(1-Methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4 ,5-dihydro-1,3-thiazol-5-yl}acetic acid

Containing {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl] a mixture of -4,5-dihydro-1,3-thiazol-5-yl}acetate (980 mg), tetrahydrofuran (10 mL), ethanol (10 mL) and 1M aqueous sodium hydroxide (10 mL) 3 hours. Water and 1 M hydrochloric acid (10 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual crystals were washed with EtOAc (EtOAc) MS 490 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 1.32 (6H, d, J = 6.06 Hz), 2.53-2.66 (1H, m), 2.75-2.86 (1H, m), 3.27 (3H, s), 4.19- 4.33(2H,m),4.34-4.50(1H,m),4.68(1H,dt,J=11.83,6.01Hz), 6.65(1H,d,J=1.89Hz),6.83(1H,d,J= 1.89 Hz), 6.97 (1H, d, J = 1.89 Hz), 7.14 (1H, d, J = 8.71 Hz), 8.27 (1H, dd, J = 8.71, 2.65 Hz), 8.64 (1H, d, J = 2.27 Hz), 11.63 (1H, d, J = 1.51 Hz), 12.49 (1H, brs).

Example 67

2-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}acetamide

Containing {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl] -4,5-Dihydro-1,3-thiazol-5-yl}acetic acid (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg A mixture of 1-hydroxybenzotriazole (100 mg) and N,N-dimethylformamide (5 mL) was stirred at 50 ° C for 30 minutes and then cooled to 0 °C. Aqueous ammonium hydroxide (10%, 1 mL) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 90:10, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (90 mg, 39%) MS 489 (MH ⁺ ). Mp 212 to 213 ° C.

Example 68

N-methyl-2-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetamide

Containing {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg) a mixture of 1-hydroxybenzotriazole (80 mg), methylamine hydrochloride (60 mg), triethylamine (70 mg) and N,N-dimethylformamide (3 mL) at room temperature Stir for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give crystals of crystals of crystals MS 503 (MH ⁺ ). Mp 190 to 192 °C.

Example 69

{2-[5-{[6-(Methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4 , 5-dihydro-1,3-thiazol-5-yl}ethyl acetate

5-{[6-(Methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxamide (1.0 g) A mixture of Lawson's reagent (1.25 g) and tetrahydrofuran (100 mL) was stirred at 70 ° C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to yield a yellow amorphous solid. A mixture containing the solid, ethyl 2-butynoate (0.78g), tributylphosphine (565mg) and tetrahydrofuran (50mL) was refluxed for 15 hours, then ethyl 2-butynoate (0.78g) and three were added. Butylphosphine (565. mg) was added to the mixture. All was refluxed for a further 30 minutes and then concentrated in vacuo. The residue was purified by basic gel chromatography (ethyl acetate:hexane = 1:9 to 1:1, volume ratio), and then purified by silica gel chromatography (ethyl acetate:hexane = 1:9) 2:1) The title compound (0.68 g, 50%) MS 484 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.25 - 1.32 (3H, m), 1.37 (6H, d, J = 6.06 Hz), 2.72 (2H, d, J = 6.44 Hz), 3.47 (3H, s), 4.04 -4.48 (5H, m), 4.55 (2H, s), 4.56-4.69 (1H, m), 6.47 (1H, d, J = 1.89 Hz), 6.81 (2H, dd, J = 7.00, 2.08 Hz), 7.16-7.28 (1H, m), 7.29-7.37 (1H, m), 8.36 (1H, d, J = 2.65 Hz), 9.20 (1H, brs).

Example 70

{2-[5-{[6-(Methoxymethyl)pyridin-3-yl]oxy)-7-(1-methylethoxy)-1H-indol-2-yl]-4 ,5-dihydro-1,3-thiazol-5-yl}acetic acid

Containing {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl] Mixture of -4,5-dihydro-1,3-thiazol-5-yl}acetate (680 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and 1M aqueous sodium hydroxide (5 mL) For 30 minutes, then cool to room temperature. Water and 1 M hydrochloric acid (5 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo to give the title compound (600mg, 94%) of a yellow amorphous solid. MS 456 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.39 (6H, d, J = 5.68 Hz), 2.70-2.84 (2H, m), 3.47 (3H, s), 4.25 - 4.47 (3H, m), 4.57 (2H, s), 4.58-4.68 (1H, m), 6.48 (1H, d, J = 1.89 Hz), 6.80-6.88 (2H, m), 7.27-7.40 (2H, m), 8.33 (1H, d, J = 2.27 Hz), 9.70 (1H, brs).

Example 71

2-{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}-N-methylacetamide

Containing {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg) a mixture of 1-hydroxybenzotriazole (130 mg), methylamine hydrochloride (90 mg), triethylamine (150 mg) and N,N-dimethylformamide (5 mL) at room temperature Stir for 13 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS 469 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.37 (6H, d, J = 6.06 Hz), 2.39-2.68 (2H, m), 2.84 (3H, d, J = 4.92 Hz), 3.47 (3H, s), 4.23 -4.47(3H,m),4.55(2H,s),4.57-4.71(1H,m),5.39-5.58(1H,m),6.47(1H,d,J=1.89Hz),6.81(2H,dd , J = 6.63, 2.08 Hz), 7.22-7.29 (1H, m), 7.29-7.37 (1H, m), 8.35 (1H, d, J = 2.65 Hz), 9.16 (1H, brs).

Example 72 N-cyclopropyl-2-{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetamide

Containing {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg) A mixture of 1-hydroxybenzotriazole (130 mg), cyclopropylamine (75 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to afford crystals of pale yellow crystals of the title compound (170 mg, 52%). MS 495 (MH ⁺ ). Mp 100 to 101 °C.

Example 73 N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzene A mixture of triazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min. A solution of 1-amino-2-methylpropan-2-ol (77 mg) in N,N-dimethylformamide (1 mL) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (150 mg, 65%). MS 533 (MH ⁺ ). Mp 200 to 201 ° C.

Example 74 N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy a solution of -1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide (420 mg) in methanol (182 mL) by preparative supercritical fluid layer Analytical method (SFC), using CHIRALCELOJ-H (2cm id × 25cm, Daicel Chemical Industries, Ltd.), with supercritical CO ₂ /methanol (65/35) as the mobile phase, at a flow rate of 50mL/min at 10MPa and 35 Analyzed at °C. The fractions containing the single-mirror isomers with a retention time of 8.8 minutes were collected and concentrated to give the title compound (210 mg) as white crystals. The crystals were recrystallized from acetone-hexane to give the title compound (165 mg). MS 533 (MH ⁺ ). Mp 173 to 174 °C.

Example 75 N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}- 1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy a solution of -1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide (420 mg) in methanol (182 mL) by preparative supercritical fluid layer Analytical method (SFC) using CHIRALCELOJ-H (LA001) (2 cm id × 25 cm, Daicel Chemical Industries, Ltd.) with supercritical CO ₂ /methanol (65/35) as the mobile phase at a flow rate of 50 mL/min Analyzed at 10 MPa and 35 °C. The fractions containing the single-mirror isomers with a residence time of 10.4 minutes were collected and concentrated to give the title compound (203 mg) as white crystal. The crystals were recrystallized from acetone-hexane to give the title compound (157 mg). MS 533 (MH ⁺ ). Mp 173 to 174 °C.

Example 76 N-cyclopropyl-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl) -4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzene A mixture of triazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 minutes, then cyclopropylamine (50 mg) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to yield pale crystals. The crystals were recrystallized from acetone-methanol to give the title compound (150 mg, 68%). MS 501 (MH ⁺ ). Mp 248 to 249 °C.

Example 77 N-ethyl-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)- 4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzene A mixture of triazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, then ethylamine (2M tetrahydrofuran solution, 0.43 mL) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to yield pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (130 mg, 62%). MS 489 (MH ⁺ ). Mp 236 to 237 °C.

Example 78 N-(2-methoxyethyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Ind-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzene A mixture of triazole (130 mg), 2-methoxyethylamine (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 20 hr. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (200 mg, 59%) as pale yellow column crystal. MS 519 (MH ⁺ ). Mp 175 to 176 °C.

Example 79 2-[2-(7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N,N-dimethylacetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzene A mixture of triazole (230 mg), dimethylamine (2M tetrahydrofuran solution, 1.1 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (370 mg, 69%) as pale yellow column crystal. MS 489 (MH ⁺ ). Mp 206 to 207 ° C.

Example 80 N-[(2S)-2-hydroxypropyl]-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H -吲哚-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzene A mixture of triazole (130 mg), (2S)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 40 hr. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (230 mg, 68%). MS 519 (MH ⁺ ). Mp 185 to 186 °C.

Example 81 N-[(2R)-2-hydroxypropyl]-2-[2-(7-methoxy-5-{[6((methylsulfonyl)pyridin-3-yl)oxy}-1H -吲哚-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzene A mixture of triazole (130 mg), (2R)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (220 mg, 65%). MS 519 (MH ⁺ ). Mp 185 to 186 °C.

Example 82 7-Methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-2-{5-[2-(morpholin-4-yl)-2-oxanoxy Ethylethyl]-4,5-dihydro-1,3-thiazol-2-yl}-1H-indole

Containing [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzene A mixture of triazole (230 mg), morpholine (190 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from acetone-hexanes and then crystallised from acetone-methanol to give the title compound (250 mg, 43%) MS 531 (MH ⁺ ). Mp 148 to 149 ° C.

Example 83 {2-[7-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole- 2-ethyl]-4,5-dihydro-1,3-thiazol-5-yl}ethyl acetate

Containing 7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2- A mixture of carboxyguanamine (1.28 g), Lawson's reagent (1.38 g) and tetrahydrofuran (100 mL) was stirred at 70 ° C for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was applied to a pad of EtOAc (EtOAc). The ethyl acetate solution was concentrated in vacuo. A mixture containing the residue, ethyl 2-butynoate (0.87 g), tributylphosphine (0.63 g) and tetrahydrofuran (50 mL) was stirred at 70 ° C under argon for 30 min then concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS 548 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 1.20 (3H, d, J = 7.20 Hz), 1.25 (3H, d, J = 6.44 Hz), 2.59-2.73 (1H, m), 2.80-2.97 (1H, m), 3.24 (3H, s), 3.32 (3H, s), 3.43-3.68 (2H, m), 4.10 (2H, q, J = 6.94 Hz), 4.19-4.48 (3H, m), 4.62-4.78 (1H, m), 6.77 (1H, d, J = 1.89 Hz), 6.85 (1H, d, J = 1.89 Hz), 7.02 (1H, d, J = 1.51 Hz), 7.47 (1H, dd, J = 8.90, 2.84 Hz), 8.00 (1H, d, J = 8.71 Hz), 8.53 (1H, d, J = 2.65 Hz), 11.71 (1H, s).

Example 84 2-{2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}ethanol

Containing {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy at 0 °C Addition of boron to a mixture of ethyl acetate (660 mg), tetrahydrofuran (30 mL) and methanol (5 mL) Lithium hydride (130 mg). All were stirred together at room temperature for 5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:1 to 1:0, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexanesiel MS 506 (MH ⁺ ). Mp 138 to 139 ° C.

Example 85 {2-[7-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole- 2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid

Containing {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Ethyl-2-(4-yl)-4,5-dihydro-1,3-thiazol-5-yl}acetate (580 mg), tetrahydrofuran (3 mL), ethanol (3 mL) and 1M aqueous sodium hydroxide (3 mL) The mixture was stirred at room temperature for 4 hours. Water and 1 M hydrochloric acid (3 mL) were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo to give the title compound (510mg, 93%) of a tan amorphous solid. MS 520 (MH ⁺ ).

¹ H NMR (DMSO-d ₆ ) δ 1.25 (3H, d, J = 6.44 Hz), 2.53-2.88 (2H, m), 3.24 (3H, s), 3.30 (3H, s), 3.45-3.68 ( 2H,m), 4.17-4.50(3H,m),4.62-4.78(1H,m),6.77(1H,d,J=1.89Hz), 6.85(1H,d,J=2.27Hz),7.02(1H , d, J = 1.89 Hz), 7.47 (1H, dd, J = 8.71, 2.65 Hz), 8.00 (1H, d, J = 8.71 Hz), 8.53 (1H, d, J = 2.65 Hz), 11.72 (1H , d, J = 1.51 Hz), 12.42 (1H, brs).

Example 86 2-{2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetamide

Containing {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide A mixture of the amine hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min. Aqueous ammonium hydroxide solution (25%, 1 mL) was added to the mixture. All were stirred at room temperature for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to afford crystals of pale crystals of the title compound (150 mg, 60%). MS 519 (MH ⁺ ). Mp 131 to 132 °C.

Example 87

2-{2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}-N-methylacetamide

Containing {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Indole-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg), methylamine hydrochloride (100 mg), triethylamine (120 mg) and N,N-dimethylformamide (3 mL) The mixture was stirred at room temperature for 15 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5, volume ratio) to yield pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to afford crystals of pale yellow crystals of the title compound (160 mg, 62%). MS 533 (MH ⁺ ). Mp 107 to 109 °C.

Example 88 2-[5-(Dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-(2-methoxy-1-methylethoxy)- 5-[4-(methylsulfonyl)phenoxy]-1H-indole

Trifluoromethanesulfonic anhydride (0.13 mL) was added to an ice-cooled and stirred solution of triphenylphosphine oxide (0.43 g) in acetonitrile (8 mL), and the mixture was stirred at 4 ° C for 30 minutes, then added N-[2 -(benzylthio)-3,3-dimethoxypropyl]-7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl) A solution of phenoxy]-1H-indole-2-carboxamide (0.25 g) and thioanisole (0.093 mL) in acetonitrile (5 mL). After stirring at 4 ℃ 30 minutes, the reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate, the organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated. The resulting precipitate was removed by filtration and washed with ethyl acetate-hexane. The filtrate and the washing liquid were combined, and concentrated, and the residue was purified by basic gel chromatography (ethyl acetate:hexane = 25:75 to 35:65, volume ratio), and then purified by gelatin chromatography (acetic acid B) Ethyl ester: hexane = 25:75 to 80:20). MS 535 (MH ⁺ ). Mp 109 to 112 °C.

Example 89 {2-[6-Fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2 -yl]-4,5-dihydro-1,3-thiazol-5-yl}ethyl acetate

6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy} at room temperature and argon atmosphere Add 1-butylphosphine (0.40) to a stirred solution of -1H-indole-2-thiocarbamide (0.58 g), ethyl 2-butynoate (0.31 mL), tetrahydrofuran (10 mL) and toluene (15 mL) mL). After stirring at 40 ° C for 3 hours, the title compound was obtained (jjjjjjj 525 mg, 72%) of pale yellow oil. MS 552 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.72 (2H, d, J = 7.2 Hz), 3.20 (3H, s), 3.59 (3H, s), 3.76-3.82 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 4.24 - 4.48 (5H, m), 6.83 (1H, d, J = 2.1 Hz), 7.17 (1H, d, J = 6.6 Hz) , 7.31 (1H, dd, J = 2.7, 8.7 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.69 (1H, brs).

Example 90 2-{2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}ethanol

In the presence of {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Ethyl borohydride (ethyl acetate) (200 mg) in tetrahydrofuran (8 mL)-methanol (6 mL) 40 mg), the mixture was stirred at room temperature for 2.5 hours, then lithium borohydride (40 mg) was added. After the mixture was stirred at room temperature for 2 hours, lithium borohydride (40 mg) was further added. After stirring at room temperature for 2 hours, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by EtOAc (EtOAc: EtOAc (EtOAc:EtOAc) , 41%) of colorless crystals. MS 510 (MH ⁺ ). Mp 160 to 161 °C.

Example 91 {2-[6-Fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2 -yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid

In the presence of {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Add potassium hydroxide (85%) to a mixture of ethyl-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (0.30 g), tetrahydrofuran (12 mL) and methanol (12 mL) , 0.18 g) of an aqueous solution (10 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow oil from ethyl acetate - hexane to give the title compound (267mg, 94%) of pale yellow crystals. MS 524 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 2.80 (2H, d, J = 6.9 Hz), 3.21 (3H, s), 3.57 (3H, s), 3.78-3.84 (2H, m), 4.30-4.50 (5H, m), 6.85 (1H, d, J = 1.8 Hz), 7.17 (1H, d, J = 6.6 Hz), 7.31 (1H, dd, J = 2.7, 8.7 Hz), 8.00 (1H, d, J = 8.7) Hz), 8.46 (1H, d, J = 2.7 Hz), 10.77 (1H, brs).

Example 92 2-{2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}-N-methylacetamide

Add {2-[6-fluoro-7) to an ice-cold and stirred mixture of methylamine hydrochloride (35 mg) and triethylamine (0.072 mL) in N,N-dimethylformamide (7 mL) -(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-di Hydrogen-1,3-thiazol-5-yl}acetic acid (135 mg), 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (100 mg). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to give colorless crystals from tetrahydrofuran - ethyl acetate and recrystallized to give the title compound (109mg, 79%) as colorless crystals of . MS 537 (MH ⁺ ). Mp 151 to 152 °C.

Example 93 2-{2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole -2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetamide

In the presence of {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole Addition of 2-ethyl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg) to N,N-dimethylformamide (7 mL) in ice-cooled and stirred mixture Hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was cooled in an ice bath, and a 10% aqueous ammonia solution (1.0 mL) was added. The mixture was stirred at room temperature for 5 hours and partitioned between ethyl acetate and water. Washed with aqueous sodium bicarbonate and brine and the organic layer was dehydrated (MgSO _4), filtered, and concentrated to give pale yellow crystals, from tetrahydrofuran - ethyl acetate and recrystallized to give the title compound (84mg) of pale yellow crystals. MS 523 (MH ⁺ ). Mp 143 to 144 °C.

Example 94 [2-(7-Ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- Ethyl 1,3-thiazole-5-yl]

Containing 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-thiocarb at room temperature and argon Tributylphosphine (0.31 mL) was added to a stirred solution of decylamine (0.41 g), ethyl 2-butynoate (0.25 mL), tetrahydrofuran (10 mL) and toluene (15 mL). After stirring at 40 ° C for 3 hours, the title compound was obtained (jjjjjjjj 350 mg, 66%) of light yellow oil. MS 504 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 1.47 (3H, t, J = 7.2 Hz), 2.70-2.80 (2H, m), 3.20 (3H, s), 4.08 -4.48 (7H, m), 6.42 (1H, d, J = 1.8 Hz), 6.84 (1H, d, J = 2.1 Hz), 6.93 (1H, d, J = 1.8 Hz), 7.32 (1H, dd, J = 2.7, 8.7 Hz), 7.98 (1H, d, J = 8.7 Hz), 8.44 (1H, d, J = 2.7 Hz), 9.36 (1H, brs).

Example 95 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]ethanol

In the presence of [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-1,3-thiazol-5-yl]acetate (110 mg) in tetrahydrofuran (8 mL)-methanol (2 mL) EtOAc. Then, lithium borohydride (25 mg) was added. After stirring at room temperature for 3 hours, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 54%) of colorless crystals. MS 462 (MH ⁺ ). Mp 147 to 148 °C.

Example 96 [2-(7-Ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro- 1,3-thiazol-5-yl]acetic acid

In the presence of [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di An aqueous solution (5 mL) of potassium hydroxide (85%, 0.10 g) was added to a mixture of ethyl acetate (0.22 g), THF (l.sub.2), and THF (10 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light yellow amorphous solid from ethyl acetate - hexane to give the title compound (186mg, 90%) of pale yellow crystals. MS 476 (MH ⁺ ). Mp 208 to 210 °C.

Example 97 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Add [2-(7-ethoxyl) to an ice-cold and stirred mixture of methylamine hydrochloride (26mg) and triethylamine (0.053mL) in N,N-dimethylformamide (5mL) -5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl Acetic acid (90 mg), 1-hydroxybenzotriazole (52 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 mg). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to a light yellow amorphous solid from ethyl acetate - hexane to give the title compound (91mg, 99%) Light yellow crystals. MS 489 (MH ⁺ ). Mp 233 to 235 ° C.

Example 98 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Take 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5 -Dihydro-1,3-thiazol-5-yl]-N-methylacetamide (360 mg) in methanol-acetonitrile (500:500, 360 mL) by preparative supercritical fluid chromatography (SFC) Using CHIRALPAK AS-H (2 cm id × 25 cm, Daicel Chemical Industries, Ltd.) with supercritical CO ₂ /methanol/acetonitrile (70/15/15) as the mobile phase, at a flow rate of 50 mL/min at 10 MPa and 30 Analyzed at °C. The fractions containing the single-image isomer were stored for 7.4 min and concentrated to give the title compound (155 mg). Recrystallization from ethyl acetate-hexane gave the title compound (140 mg). MS 501 (MH ⁺ ). Mp 224 to 225 °C.

Example 99 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]-N-methylacetamide

Take 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5 -Dihydro-1,3-thiazol-5-yl]-N-methylacetamide (360 mg) in methanol-acetonitrile (500:500, 360 mL) by preparative supercritical fluid chromatography (SFC) Using CHIRALPAK AS-H (2 cm id × 25 cm, Daicel Chemical Industries, Ltd.) with supercritical CO ₂ /methanol/acetonitrile (70/15/15) as the mobile phase, at a flow rate of 50 mL/min at 10 MPa and 30 Analyzed at °C. The fractions containing a single spectromer were retained for 9.0 min and concentrated to give the title compound (150 mg). Recrystallization from ethyl acetate-hexane gave the title compound (137 mg). MS 501 (MH ⁺ ). Mp 225 to 226 °C.

Example 100 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Hydrogen-1,3-thiazol-5-yl]acetamide

In the presence of [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-di Add 1-hydroxybenzotriazole ammonium salt (61 mg) to an ice-cooled and stirred mixture of hydrogen-1,3-1,3-thiazol-5-yl]acetic acid (95 mg) in N,N-dimethylformamide (5 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to a light yellow amorphous solid from ethyl acetate - hexane to give the title compound (84mg) as colorless crystals of . Recrystallization from ethyl acetate-hexane gave the title compound (71 mg, 76%). MS 475 (MH ⁺ ). Mp 195 to 196 °C.

Example 101 (2-{7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole- 5-base ethyl acetate

Containing 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-thioformamide (0.69 g) at room temperature under argon atmosphere Tributylphosphine (0.54 mL) was added to a stirred solution of ethyl 2-butynoate (0.43 mL), tetrahydrofuran (15 mL) and toluene (25 mL). After the mixture was stirred at 40 ° C for 4 hours, ethyl 2-butynoate (0.22 mL) and tributylphosphine (0.27 mL) were added. After stirring at 40 ° C for 2 hours, the title compound was obtained (jjjjjjj 684 mg, 72%) of light yellow oil. MS 489 (MH ⁺ ).

¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.2 Hz), 2.74 - 2.84 (2H, m), 3.04 (3H, s), 3.91 (3H, s), 4.18 (2H, q, J = 7.2 Hz), 4.24 - 4.46 (3H, m), 6.45 (1H, d, J = 2.1 Hz), 6.83 (1H, d, J = 2.1 Hz), 6.93 (1H, d, J = 2.1 Hz) , 7.05 (2H, d, J = 9.0 Hz), 7.84 (2H, d, J = 9.0 Hz), 9.27 (1H, brs).

Example 102 (2-{7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole- 5-based) acetic acid

Containing (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3- An aqueous solution (5 mL) of potassium hydroxide (85%, 0.25 g) was added to a mixture of thiazol-5-yl)acetate (0.42 g), tetrahydrofuran (8 mL) and methanol (8 mL). The mixture was stirred at room temperature for 15 hours and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated to yield a light-colored amorphous solid, from ethyl acetate - hexane to give the title compound (340mg, 86%) of pale yellow crystals. MS 461 (MH ⁺ ). Mp 144 to 145 °C.

Example 103 2-(2-{7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3- Thiazol-5-yl)-N-methylacetamide

Add (2-{7-methoxyl) to an ice-cold and stirred mixture of methylamine hydrochloride (48 mg) and triethylamine (0.10 mL) in N,N-dimethylformamide (10 mL) -5-[4-(Methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.16 g) 1-Hydroxybenzotriazole (94 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg). After stirring at 4 ° C to room temperature for 7 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to a light yellow oil which was purified by silica gel chromatography (ethyl acetate: methanol = 100: 0 to 90: 10, by volume), resulting in a colorless oil. The oil was crystallized from EtOAc (EtOAc) elute MS 474 (MH ⁺ ). Mp 125 to 126 °C.

Example 104 2-(2-{7-Methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3- Thiazol-5-yl)acetamide

Containing (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3- 1-Hydroxybenzotriazole ammonium salt (53 mg) and 1-ethyl-3 were added to the ice-cooled and stirred mixture of thiazol-5-yl)acetic acid (80 mg) in N,N-dimethylformamide (10 mL). -(3-Dimethylaminopropyl)carbodiimide hydrochloride (67 mg). After stirring at 4 ° C to room temperature for 15 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with aqueous sodium bicarbonate and brine, dried (MgSO _4), filtered, and concentrated to a light yellow oil from ethyl acetate - hexane to give the title compound (72mg, 91%) Colorless crystal. MS 460 (MH ⁺ ). Mp 169 to 170 ° C.

Reference Example 1A Glucose Kinase (GK) Expression Vector Construction Method

In Escherichia coli, plastid DNA for expressing a protein containing GST (glutathione S-transferase) (GST-hLGK1) is added to the amino terminal of human liver GK, and the preparation method is as follows.

First, human liver cDNA (Marathon Ready cDNA, Clontech Laboratories, Inc.) was used as a template, and two synthetic DNAs (5'-CAGCTCTCCATCCAAGCAGCCGTTGCT-3' (SEQ ID NO: 1) and 5'-GGCGGCCTGGGTCCTGACAAG-3' were used. (SEQ ID NO: 2)) PCR was carried out, and the obtained DNA fragment was selected using a TOPO TA selection kit (Invitrogen Corporation). The resulting plastid DNA was used as a template, and synthetic DNA (5'-GGATCCATGCCCAGACCAAGATCCCAACTCCCACAACCCAACTCCCAGGTAGAGCAGATCCTGGCAGAG-3' (SEQ ID NO: 3), which is preceded by a BamHI cleavage) and synthetic DNA (5) was used. '-GAATTCCTGGCCCAGCATACAGGC-3' (SEQ ID NO: 4), which is followed by a Stopping codon followed by an EcoRI cleavage) for PCR. The resulting DNA fragment was subcultured into pGEX6P-2 (Amersham Biosciences K.K.) lysed by BamHI and EcoRI to produce a plastid (pGEX6P-2/hLGK1) expressing human liver GK.

Reference Example 2A GST-hLGK1 Expression and Purification Method

The pGEX6P-2/hLGK1 transfected BL21 strain (Stratagene) obtained in Reference Example 1A was shaken and cultured in a 200 ml Erlenmeyer flask containing 50 ml of LB medium containing 100 μg/ml of ampicillin for 14 hours at 37 °C. The medium (25 ml) was diluted with 225 ml of LB medium containing 100 μg/ml ampicillin, and cultured in a 1 L Erlenmeyer flask at 37 ° C for 1 hour with shaking. After the incubation, the Erlenmeyer flask was cooled on ice, and 125 μL of 100 mM isopropyl-thio-β-D-galactofuranoside (IPTG) (final concentration: 50 μM) was added thereto, followed by incubation at 17 ° C for 20 hours. The medium was centrifuged and the resulting fungus was broken up by ultrasonic waves. The desired protein (GST-hLGK1) was purified from the supernatant using Glutathione Sepharose 4B (Amersham Biosciences K.K.).

Experimental Example 1 GK activation value measurement method

The GK enzyme reaction is carried out at 50 mmol/L HEPES pH 7.4, ₂₀₀ mmol/L KCl, 5 mmol/L MgCl ₂ , ₂ mmol/L DTT (containing 50 μmol/L 2'-(or-3')-O-(N-methylortho Aminoglycanyl) adenosine 5'-triphosphate (Mant-ATP) (Jena Bioscience GmbH), 5 mmol/L D-glucose, 5% DMSO and 6 μg/mL GST-hLGK1 from Reference Example 2A) Carry out, the total volume is 50 μL. The reaction was carried out in a 384-well black disk (Nalge Nunc International KK). Prior to the reaction, the enzyme and the test compound were incubated at 37 ° C for 10 minutes, and a 25 mM D-glucose solution (10 μL) was added to start the reaction.

After incubation at 37 ° C for 60 minutes, 25 μL of the suspension reaction solution (containing 200 mM HEPES (pH 7.4), 20 mM MgCl ₂ , 200 mM EDTA, 0.03% Triton-X 100, 0.3% Coating 3 reagent (Caliper) was added. Life Sciences, Inc.)) to stop the reaction.

After the reaction, Mant-ATP (substrate, 2'-(or-3')-O-(N-methyl-orthoamine) was separated from each well by a microchip type capillary electrophoresis apparatus 250 HTS (Caliper Life Sciences, Inc.). Indomethacin) adenosine 5'-triphosphate) and Mant-ADP (reaction product obtained). The reaction rate ((the peak height of the obtained reaction product) / (the peak height of the obtained reaction product + the peak of the reaction product) was calculated from the ratio of the peak height of the received peak obtained by fluorescence detection (excitation wavelength 355 nm, measurement wavelength 460 nm) to the peak height of the obtained reaction product Height) × 100 (%)], and used as an indicator of GK activity.

The reaction rate calculated in the same manner without using the test compound was used as a control group.

The reaction rate of the wells to which various concentrations of the test compound were added (the test compound group was added) was divided by the reaction rate of the control group to obtain a percentage, and as the GK activity value, the highest activity value of the test compound group was added to the activity value of the control group. The concentration of the test compound at the intermediate point was determined as the EC ₅₀ value. The results are shown in Table 1.

As can be seen from Table 1, the compounds of the present invention have excellent glucokinase activation.

Formulation example 1 (capsule method) 1) Compound of Example 1 30 mg

Take 1), 2) and 3) and 30 g of 4), mix with water, vacuum dry and sieve. The sieved powder was mixed with 14 g of 4) and 1 g of 5), and the mixture was pressed using a tablet press. In this manner, 1000 tablets were prepared in which 30 mg of the compound of Example 1 was contained per ingot.

Industrial utilization

The compound of the present invention has excellent glucokinase activation and is suitable for use as an agent such as a medicament for preventing or treating diabetes, obesity or the like.

<110> Takeda Pharmaceutical Industry Co., Ltd.

<120> fused ring compounds and uses thereof

<130> 2114

<150> PCT/JP2009/057625

<151> 2009-04-09

<160> 4

<170> Patent In version 3.3

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<223> Introduction to glucokinase

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<223> Introduction to glucokinase

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<223> Introduction to glucokinase

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Claims (10)

A compound or a salt thereof, which is 2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2 -yl)-4,5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide. A compound or a salt thereof, which is 2-(2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]- 1H-Indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethanol. A compound or a salt thereof, which is 2-methyl-1-{2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl ]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}propan-2-ol. A compound or a salt thereof, which is N-(2-hydroxy-2-methylpropyl)-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridine) -3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide. A compound or a salt thereof, which is 2-[2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2 -yl)-4,5-dihydro-1,3-thiazol-5-yl]-N-methylacetamide. A compound or a salt thereof, which is N-[2-hydroxypropyl]-2-[2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl] Oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetamide. A glucokinase activator comprising a compound of any one of claims 1 to 6 or a salt thereof. An agent comprising a compound of any one of claims 1 to 6 or a salt thereof. An agent according to claim 8 which is an agent for preventing or treating type 2 diabetes. The use of a compound of any one of claims 1 to 6 or a salt thereof for the manufacture of a medicament for preventing or treating type 2 diabetes.