JP2003055345A - Biphenylcarboxamide isoindoline derivative, a method of producing the same and synthetic intermediate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel biphenylcarboxamide isoindoline derivative that is useful as a medicine because it has excellent apolipoprotein B secretion inhibitory action and the serum lipid-lowering action, and provide a method of producing the derivative and the synthetic intermediate. SOLUTION: The novel biphenylcarboxamide isoindoline derivative is represented by general formula [I] (wherein the ring A is a benzene ring which may be substituted; the ring B is a benzene ring which may be substituted; Q is -CO- or -CH2 -; R is a lower alkyl which may be substituted, a lower alkenyl which may be substituted, a carbamoyl which may be substituted, a heterocyclic ring which may be substituted or an aryl group which may be substituted) and contains their pharmacologically acceptable salts.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel biphenylcarboxamidoisoindoline derivative which has an excellent apolipoprotein B (ApoB) secretion inhibitory action and a serum lipid lowering action and is useful as a medicine, a process for producing the same, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art International Patent Publication WO 96/40640 discloses 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (thiophen-2-yl-acetyl)-
1,2,3,4-Tetrahydroisoquinolin-6-yl] -amide, 4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (pyridin-2-yl-acetyl) -1,2,3,3 4-tetrahydroisoquinoline-6
-Yl] -amide and the like are also disclosed in WO98 /
No. 23593 includes 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2- (pyridin-2-yl) ethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl]-. It has been suggested that amide and the like have an ApoB secretion inhibitory action and can be used as a serum lipid lowering agent.

However, all of the amide compounds described therein are compounds having a tetrahydroisoquinoline ring, and compounds such as the compound of the present invention having an isoindoline ring are not described.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel biphenylcarboxamide isoindoline derivative having excellent apolipoprotein B secretion inhibitory action and serum lipid lowering action. Further, the present invention also provides a method for producing such a novel compound and a synthetic intermediate thereof.

[0005]

[Means for Solving the Problems] In order to solve the problems, the present inventors have conducted diligent research and found a novel biphenylcarboxamide isoindoline derivative having an apolipoprotein B secretion inhibitory effect and a serum lipid lowering effect. Completed the invention.

That is, the present invention has the general formula [I]:

[0007]

[Chemical 32]

(In the formula, ring A may be substituted benzene ring, ring B may be substituted benzene ring, Q may be --CO-- or --CH _2- , and R may be substituted. A lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group) The present invention relates to a carboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent on ring A in the object compound [I] of the present invention is selected from, for example, (1) trifluoromethyl group, (2) hydroxyl group, oxo group and hydroxyimino group. Substituted with 1 to 3 same or different groups selected from lower alkyl group which may be substituted with 1 to 3 same or different groups, (3) lower alkoxy group, hydroxyl group, and lower alkylamino group Optionally lower alkoxy group, (4) hydroxyl group, (5) nitro group, (6) cyano group, (7) lower alkyl group, lower alkoxy lower alkyl group, halogeno lower alkyl group, and aryl lower alkyl group A group selected from a carbamoyl group which may be substituted with a group, (8) a protecting group for an amino group, a lower alkyl group, and a lower alkylsulfonyl group. Which may be an amino group,
(9) a lower alkanoyloxy group which may be substituted with an aryl group, (10) a lower alkoxycarbonyl group,
Etc.

Ring A may be substituted with 1 to 3 same or different groups selected from the above (1) to (10).

The substituent on ring B in the object compound [I] of the present invention includes, for example, (1) nitro group, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group, aryl group,
(Lower alkylamino) aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group, piperazinyl group, And a lower alkoxy group which may be substituted with a group selected from a lower alkylpiperazinyl group, (4) lower alkoxycarbonyl group, (5) (i) lower alkoxy group, amino group, lower alkyl group amino group, and It may be substituted with a lower alkanoyl group substituted with 1 to 3 groups which are the same or different and selected from a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) a pyridyl group or a lower alkylamino group. Good lower alkyl group, and (iv) pyridylca Carbonyl group, an amino group optionally substituted with a group selected from the group consisting of, (6) lower alkyl group, a lower alkoxy lower alkyl group, and a carbamoyl group optionally substituted with a lower alkylamino lower alkyl group , (7) morpholinocarbonyl group,
(8) cyano group, (9) lower alkylaminocarbonyloxy group and the like.

Ring B may be substituted with 1 to 3 same or different groups selected from the above (1) to (9).

When R in the object compound [I] of the present invention is an optionally substituted lower alkyl group, the substituent on the lower alkyl group is (i) a lower alkyl group;
Hydroxy lower alkyl group; lower alkanoyl group; lower alkoxy group; nitro group; lower alkoxycarbonyl group; carboxyl group; oxo group; trifluoromethyl group; carbamoyl group (wherein the carbamoyl group is a lower alkyl group, halogeno lower alkyl group, and hydroxy An amino group (which may be substituted with a group selected from a lower alkyl group); the amino group is a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and a lower alkyl group. Optionally substituted with a group selected from aminoalkylidene group); cyano group; optionally protected hydroxyl group; halogen atom; and substituted with 1 to 3 same or different groups selected from formyl group A good heterocyclic group, (ii Lower alkyl group; amino group (wherein the amino group is a lower alkanoyl group, lower alkoxycarbonyl group, lower alkyl group, pyridyl lower alkyl group, lower alkylaminocarbonyl group, halogeno lower alkylaminocarbonyl group, lower alkanoyl group, or halogeno lower alkanoyl group) A lower alkoxy group; an aryl lower alkoxy group; a benzyloxy lower alkoxy group; a lower alkylamino lower alkoxy group; a nitro group; an optionally protected hydroxyl group; a lower alkylcarbamoyl group; a halogeno lower An alkylcarbamoyl group; and an aryl group or a fluorenyl group, which may be substituted with 1 to 3 same or different groups selected from a morpholinyl group, (iii) an optionally protected hydroxyl group, and (iv) lower alkyl , Halogeno-lower alkyl group, and a carbamoyl group which may be substituted by a group selected from benzothiazolyl group, (v) Formula:

[0014]

[Chemical 33]

(Wherein n represents an integer of 0 to 4), (vi) a lower alkoxycarbonyl group, (v
ii) Amino group-protecting group, lower alkyl group, pyridyl group, or amino group which may be substituted with pyrimidinyl group, (viii) halogen atom, and (ix) oxo group.

The lower alkyl group for R is the above (i).
It may be substituted with 1 to 3 groups that are the same or different and are selected from to (ix).

When R in the object compound [I] of the present invention is an optionally substituted lower alkenyl group, examples of the substituent on the lower alkenyl group include an aryl group and the like.

When R in the object compound [I] of the present invention is an optionally substituted carbamoyl group, examples of the substituent on the carbamoyl group include a lower alkyl group, a halogeno lower alkyl group and a benzothiazolyl group. . Further, the carbamoyl group which may be substituted has a formula:

[0019]

[Chemical 34]

(In the formula, m represents an integer of 0 to 4), and the like.

When R in the object compound [I] of the present invention is an optionally substituted heterocyclic group, the substituent on the heterocyclic group is a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group. Group, amino group, lower alkylamino group, optionally protected hydroxyl group, optionally protected amino group and the like.

The heterocyclic group for R may be substituted with 1 to 3 same or different groups selected from the above substituents.

When R in the object compound [I] of the present invention is an optionally substituted heterocyclic group, the heterocyclic group is, for example, at least one selected from nitrogen, oxygen and sulfur. Mention may be made of monocyclic, bicyclic or tricyclic heterocyclic groups containing heteroatoms. Specifically, pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b]
Furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11
-Dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl group, dihydropyrazolyl group, tetrazolyl group and the like.

When R in the object compound [I] of the present invention is an optionally substituted aryl group, the substituent on the aryl group is a lower alkyl group, a lower alkoxy group, a lower alkylcarbamoyl group or a halogeno lower group. Examples thereof include an alkylcarbamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group.

The aryl group in R may be substituted with 1 to 3 same or different groups selected from the above substituents.

When R in the object compound [I] of the present invention is an optionally substituted aryl group, specific examples of the aryl group include phenyl group, naphthyl group, anthranyl group, phenanthryl group and the like. Can be mentioned.

When the above-mentioned object compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include a lower alkoxycarbonyl group which may be substituted and a lower alkenyloxycarbonyl group. , An acyl group, an optionally substituted aryl group, a substituted lower alkyl group, a lower alkenyl group, and the like, specifically, an ethoxycarbonyl group, a methoxycarbonyl group,
Lower alkoxycarbonyl group which may be substituted with a halogen atom such as tert-butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, etc., lower alkoxy group such as benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, etc. And an aryl group which may be substituted with a lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group such as an allyloxycarbonyl group, an acyl group such as a formyl group, an acetyl group, a propionyl group and a butyryl group. Furthermore, an aryl group-substituted lower alkyl group which may be substituted with a lower alkoxy group such as a benzyl group and a 4-methoxybenzyl group, a lower alkenyl group such as an allyl group, a 9-fluorenylmethoxycarbonyl group and the like can be mentioned. Of these, a lower alkoxycarbonyl group which may be substituted is preferred, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. The protected amino group also includes, for example, the case where a phthalimido group is formed together with the protected amino group.

When the object compound [I] of the present invention has a protected hydroxyl group, the protective group for the hydroxyl group may be an optionally substituted aryl lower alkyl group, an acyl group or an optionally substituted aryl lower alkyl group. There may be mentioned conventional protecting groups such as a good lower alkoxycarbonyl group and a trialkylsilyl group. Among them, the preferable one is
For example, unsubstituted aryl lower alkyl group such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, acyl group such as benzoyl group, lower alkoxy such as methoxycarbonyl group, ethoxycarbonyl group, etc. Examples thereof include tri-lower alkylsilyl groups such as carbonyl group, trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group. Furthermore, a triphenylmethyl group, a 2-cyanoethyl group and the like can also be mentioned.

Among the desired compounds [I] of the present invention, a preferred compound is ring A having the formula:

[0030]

[Chemical 35]

R ¹ is substituted with a group selected from (1) trifluoromethyl group, (2) lower alkyl group, (3) lower alkyl group, and phenyl lower alkyl group. A carbamoyl group, (4) phenyl lower alkanoyloxy group, or (5) lower alkoxycarbonyl group, ring B having the formula:

[0032]

[Chemical 36]

R ² is a group represented by: (1) hydrogen atom, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group, phenyl group, (lower alkylamino) phenyl group,
Lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, lower alkylamino group,
Lower alkylcarbamoyl group, cyano group, pyridyl group,
A lower alkoxy group optionally substituted with a group selected from a pyrrolidinyl group, a morpholinyl group, and a lower alkylpiperazinyl group, (4) a lower alkoxycarbonyl group, (5) a lower alkyl group, a pyridyl lower alkyl group,
Lower alkylamino lower alkyl group, and amino group optionally substituted with a group selected from pyridylcarbonyl group, (6) lower alkylcarbamoyl group, (7) morpholinocarbonyl group, (8) lower alkylaminocarbonyloxy group, Alternatively, (9) a cyano group and R has the formula:

[0034]

[Chemical 37]

Wherein p is 1 or 2, ring C is a pyridine ring, a pyrrole ring, a thiazole ring, a pyrimidine ring, a pyrazole ring, a triazole ring, or a tetrazole ring, and R ³ and R ⁴ are the same or different. Hydrogen atom, lower alkyl group, hydroxy lower alkyl group, nitro group, lower alkoxycarbonyl group, carboxyl group,
Examples thereof include a compound which is a cyano group or a group selected from an amino group.

Among the desired compounds [I] of the present invention, as other preferred compounds, ring A has the formula:

[0037]

[Chemical 38]

R ¹ is substituted with a group selected from (1) trifluoromethyl group, (2) lower alkyl group, (3) lower alkyl group, and phenyl lower alkyl group. A carbamoyl group, (4) phenyl lower alkanoyloxy group, or (5) lower alkoxycarbonyl group, ring B having the formula:

[0039]

[Chemical Formula 39]

R ² is a group represented by: (1) hydrogen atom, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group, phenyl group, (lower alkylamino) phenyl group,
Lower alkoxy optionally substituted with a lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyrrolidinyl group, morpholinyl group, and lower alkylpiperazinyl group. Group, (4) lower alkoxycarbonyl group, (5) lower alkyl group, pyridyl lower alkyl group, lower alkylamino lower alkyl group, and amino group which may be substituted with a group selected from pyridylcarbonyl group, (6) Morpholinocarbonyl group, (7) lower alkylaminocarbonyloxy group,
Alternatively, (8) a cyano group, Q is —CO—, and R is a formula:

[0041]

[Chemical 40]

And a compound represented by the formula ( ³⁾ , wherein R ³ and R ⁴ are the same or different and are selected from a hydrogen atom, a lower alkyl group, a cyano group or an amino group.

Among the desired compounds [I] of the present invention, as other preferred compounds, ring A is represented by the formula:

[0044]

[Chemical 41]

A ring represented by (1), wherein R ¹ is a carbamoyl group optionally substituted with a group selected from (1) trifluoromethyl group, (2) lower alkyl group, and phenyl lower alkyl group; ) A phenyl lower alkanoyloxy group, or (4) a lower alkoxycarbonyl group, and ring B has the formula:

[0046]

[Chemical 42]

R ² is a group represented by (1) hydrogen atom, (2) hydroxyl group, (3) lower alkoxy group, phenyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, and cyano group. A lower alkoxy group which may be substituted with a selected group, (4) a lower alkoxycarbonyl group, or (5) a lower alkylaminocarbonyloxy group, (6) a cyano group, and Q is -CO.
-, R is the formula:

[0048]

[Chemical 43]

And a compound represented by the formula ( ³⁾ , wherein R ³ and R ⁴ are the same or different and are selected from a hydrogen atom, a cyano group or an amino group.

Among the desired compounds [I] of the present invention, as other preferred compounds, ring A is represented by the formula:

[0051]

[Chemical 44]

A ring represented by the formula: wherein ring B is of the formula:

[0053]

[Chemical formula 45]

R ² is a hydrogen atom, a lower alkoxy group, a lower alkylamino lower alkoxy group, a pyridyl lower alkoxy group, a (lower alkylamino) phenyl lower alkoxy group, a pyrrolidino lower alkoxy group, a hydroxy lower alkoxy. Group, a lower alkoxy lower alkoxy group, a lower alkylcarbamoyl lower alkoxy group, a lower alkylamino lower alkanoylamino group, a pyridylcarbonylamino group, a lower alkylamino lower alkylamino group, or a lower alkoxycarbonyl group, wherein R is the following (1) to Lower alkyl group substituted with group selected from (3): (1) Lower alkyl group, and pyrazolyl group optionally substituted with group selected from nitro group, (2) Pyridyl group, and (3) A compound that is a triazolyl group And the like.

Among the preferred compounds [I] of the present invention, as other preferred compounds, ring A has the formula:

[0056]

[Chemical formula 46]

R ¹ is a trifluoromethyl group or a lower alkanoyl group, Ring B is a lower alkoxy group, (lower alkylamino) lower alkanoylamino group, lower alkylamino lower alkoxy group, lower alkylcarbamoyl group. , And a benzene ring which may be substituted with a group selected from a lower alkoxycarbonyl group,
R is a lower alkyl group substituted with a group selected from the following (1) to (5): (1) selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a cyano group, an amino group and a hydroxy lower alkyl group. An optionally substituted pyrazolyl group, (2) pyridyl group, (3) triazolyl group,
(4) a tetrazolyl group and (5) a thiazolyl group optionally substituted with an amino group.

Among the preferred compounds [I] of the present invention, as other preferred compounds, ring A has the formula:

[0059]

[Chemical 47]

Is a ring represented by, wherein ring B is a benzene ring,
Examples thereof include a compound in which Q is —CO—, R is a pyrazolylmethyl group which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a cyano group, an amino group, and a hydroxy lower alkyl group. To be

Among the object compounds [I] of the present invention, particularly preferred compounds include, for example, 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino. ] -Isoindoline, 2- [2- (1H-pyrazol-1-yl) ethyl] -5- [2- (4-trifluoromethylphenyl)
Benzoylamino] -isoindoline, 2- (3-amino-4-cyano-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline, 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4- (N,
N-dimethylcarbamoyl) phenyl) -3-methoxybenzoylamino] -isoindoline, 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-phenylacetoxyphenyl) benzoylamino] -isoindoline, 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl)-
3- (1-ethoxycarbonyl-1-methylethoxy)
Benzoylamino] -isoindoline, 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-
(N, N-dimethylcarbamoyl) phenyl) benzoylamino] -isoindoline or a pharmacologically acceptable salt thereof.

When the substituent on ring A, the substituent on ring B and / or R has an asymmetric atom, the object compound [I] of the present invention exists as an optical isomer based on the asymmetric atom. However, the present invention includes any of these optical isomers and mixtures thereof.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof has an apolipoprotein B secretion inhibitory action and exhibits an excellent serum lipid lowering action.

Therefore, the object compound [I] of the present invention or a pharmaceutically acceptable salt thereof is hyperlipidemia, ischemic heart disease, atherosclerosis, coronary arteriosclerosis, hypercholesterolemia, hypertriglyceridemia. Disease, familial hyperlipidemia, hyperlipoproteinemia, arteriosclerosis, coronary arteriosclerosis, coronary heart disease, ischemic brain disease, stroke, circulatory / microcirculatory disturbance, thrombosis, hyperglycemia, diabetes, acute bleeding It is expected to be applied to the prevention and treatment of pancreatitis, obesity, steatosis, constipation, etc. Furthermore, the object compound [I] of the present invention has low toxicity and is highly safe as a medicine.

The object compound [I] of the present invention can be used in medicinal use either in a free form or in the form of a pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt of the compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citric acid. Examples thereof include salts, methanesulfonates, benzenesulfonates, organic acid salts such as tosylate salts and maleate salts, and the like. When it has a substituent such as a carboxyl group, a salt with a base (for example, sodium salt,
Alkali metal salts such as potassium salts or alkaline earth metal salts such as calcium salts).

The object compound [I] or a salt thereof of the present invention includes any of its inner salt, adduct, solvate or hydrate thereof.

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used as tablets, granules, capsules, powders and injections. , Can be used as a conventional pharmaceutical preparation such as an inhalant.

The dose of the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is determined by the administration method, the age of the patient,
Although it depends on the body weight and condition, it is usually about 0.01 to 5 mg / kg per day, especially about 0.1 to 3 mg / kg per day for an injection, and usually 1 for an oral preparation.
About 0.1-100 mg / kg per day, especially about 0.1
It is preferably about 50 mg / kg.

According to the present invention, the object compound [I] can be produced by the following [Method A] to [Method H].
It is not limited to these. [Method A] The biphenylcarboxamide isoindoline derivative represented by the target compound [I] of the present invention has the general formula [5]:

[0070]

[Chemical 48]

(However, the symbols have the same meanings as above)
And a salt thereof and a compound represented by the general formula [6]:

[0072]

[Chemical 49]

(However, the symbols have the same meaning as above)
It can be produced by reacting with a carboxylic acid compound represented by or its salt.

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, and in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone and the like. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide / hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI),
Diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP), 2,4,6
-Trichlorobenzoyl chloride and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOS).
u), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH) and the like. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU) and the like.

The amount of the condensing agent used is 1 to 10 equivalents, preferably 1 to 2 relative to the compound [5] or the compound [6].
An equivalent amount can be used. The activator can be used in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [5] or compound [6]. This reaction can be carried out, for example, at 0 to 100 ° C, preferably 0 to 50 ° C.

Further, the compound [6] is converted into a reactive derivative such as an acid chloride or a mixed acid anhydride, and then reacted with the compound [5] in the presence of a base to give the compound [I].
You can also get [Method B] The biphenylcarboxamidoisoindoline derivative represented by the object compound [I] of the present invention can also be produced by the reaction of the general formula [15]

[0077]

[Chemical 50]

(Wherein X ¹ represents a leaving group, and other symbols have the same meanings as described above), or a salt thereof; and a general formula [16]:

[0079]

[Chemical 51]

(In the formula, M is the same or different selected from a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group, an aryloxy group, an arylenedioxy group and an arylthio group. It can also be produced by reacting with a compound represented by the formula (3), which represents a metal which may be coordinated with a group, and other symbols have the same meanings as described above.

This reaction can be carried out in a solvent, in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of an additive. The solvent may be any solvent that does not adversely influence the reaction, for example, methylene chloride,
Chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, xylene,
Examples thereof include water, 1-methylpyrrolidinone, dimethoxyethane, dioxane, diethylamine, triethylamine and the like. Examples of the metal of M include boron, tin, silicon, zinc, magnesium, aluminum, lithium and nickel. Examples of the catalyst include palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, bis (dibenzylideneacetone) palladium, bisbenzonitrile palladium dichloride and the like. Examples of the base include sodium carbonate, potassium carbonate, potassium phosphate, triethylamine, diisopropylethylamine and the like. Examples of the additive include triphenylphosphine, tri-o-toluylphosphine, tri-n-butylphosphine, copper (I) bromide, copper (I) iodide, triphenylarsine, tri (2-furyl) phosphine. , Diphenylphosphinoferrocene (d
ppf), diphenylphosphinobutane (dppb),
2,6-di-tert-butyl-4-cresol and the like can be mentioned.

The amount of the compound [16] used is the same as that of the compound [1].
5] can be used in an amount of 1 to 5 equivalents, preferably 1 to 1.5 equivalents. The amount of the catalyst used is compound [15]
With respect to 0.001 to 0.5 equivalent, preferably 0.0
5 to 0.2 equivalents can be used. The amount of base used is
1 to 20 equivalents relative to compound [15], preferably 1
~ 5 equivalents can be used. The additive is used in an amount of 1-10 equivalents, preferably 1-5, relative to compound [15].
An equivalent amount can be used. This reaction is, for example, 0 to 15
It can be carried out at 0 ° C, preferably 30 to 120 ° C.

As the leaving group X ¹ , a fluorine atom,
Examples thereof include halogen atoms such as chlorine atom, bromine atom and iodine atom, and trifluoromethanesulfonyloxy group. [Method C] Of the object compound [I] of the present invention, a compound of the general formula [I] in which Q is —CO—, that is,
General formula [Ia]:

[0084]

[Chemical 52]

(However, the symbols have the same meaning as above)
The biphenylcarboxamidoisoindoline derivative represented by is represented by the general formula [13]:

[0086]

[Chemical 53]

(However, the symbols have the same meanings as above)
And a salt thereof represented by the formula [2]: R-COOH [2] (where the symbols have the same meaning as described above), or a carboxylic acid compound represented by the formula or a salt thereof. You can also

This reaction can be carried out in a solvent, in the presence of a condensing agent, in the presence or absence of an activator, and in the presence or absence of a base. The solvent may be any solvent that does not adversely affect the reaction, and for example, the above-mentioned [A
The solvent exemplified in the reaction of [Method] can be appropriately used. Also, as the base or activator, for example, those exemplified in the reaction of the above-mentioned [Method A] can be appropriately used.

Further, after converting the compound [2] into a reactive derivative such as an acid chloride or a mixed acid anhydride, the compound [I] is reacted with the compound [13] in the presence of a base.
-A] can also be obtained. [Method D] Of the object compounds of the present invention, in the general formula [I], Q is —CH ₂ —, that is, the general formula [Ib]:

[0090]

[Chemical 54]

(However, the symbols have the same meanings as above)
The biphenylcarboxamidoisoindoline derivative represented by can be produced by subjecting the compound represented by the general formula [Ia] or a salt thereof to a reduction reaction.

The reduction reaction can be carried out in a solvent in the presence of a suitable reducing agent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane and the like. Suitable reducing agents include, for example:
Examples thereof include sodium borohydride-boron trifluoride diethyl ether complex, lithium aluminum hydride, aluminum hydride, lithium borohydride, diborane-dimethyl sulfide complex, diborane-tetrahydrofuran complex and the like.

The reducing agent can be used in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [Ia]. This reaction can be carried out, for example, at -30 to 100 ° C, preferably 0 to 50 ° C. [Method E] Of the target compound [I] of the present invention, the compound of the general formula [I]
The biphenylcarboxamidoisoindoline derivative represented by the formula -b] is also a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [17]: R-CHO [17] It can also be produced by subjecting an aldehyde compound represented by the formula (1) having) or a salt thereof to a condensation reaction and then subjecting it to a reduction reaction.

The above condensation reaction can be carried out in a solvent in the presence or absence of a base, and the subsequent reduction reaction can be carried out in the presence of a reducing agent. The solvent used in the condensation reaction or the reduction reaction may be any solvent that does not adversely affect the reaction, for example, methylene chloride, tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, isopropyl alcohol, 1,2-dichloroethane, water and the like. Is mentioned. Examples of the base include triethylamine, diisopropylethylamine,
4-methylmorpholine and the like can be mentioned. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, hydrogen-palladium carbon, sodium borohydride-acetic acid and the like.

The amount of the compound [17] used is the same as that of the compound [1].
3] can be used in an amount of 1 to 5 equivalents, preferably 1 to 1.5 equivalents. The amount of the base used is the same as that of the compound [13].
With respect to 1 to 20 equivalents, preferably 1 to 5 equivalents can be used. The reducing agent can be used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at -30 to 100 ° C, preferably 0 to 50 ° C.

The above condensation reaction and reduction reaction can also be carried out in one pot as a reductive amination reaction. [Method F] Of the target compound [I] of the present invention, the compound of the general formula [I]
The biphenylcarboxamide isoindoline derivative represented by general formula [b] is also a compound represented by the general formula [13] or a salt thereof, and a compound represented by the general formula [18]: R—CH ₂ —X ² [18] (wherein, X ² Represents a leaving group, and other symbols have the same meaning as described above), and can also be produced by reacting with a compound represented by the above.

This reaction can be carried out in a solvent in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction,
For example, tetrahydrofuran, dimethylformamide,
Examples thereof include dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, acetonitrile and the like. As the base, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine,
Pyridine, sodium hydroxide, potassium hydroxide and the like can be mentioned, and as the additive, sodium iodide, copper (I) iodide, copper (II) iodide, copper powder, potassium iodide, tetrabutylammonium chloride, tetraethyl Tetra lower alkyl ammonium halides such as ammonium chloride and the like can be mentioned.

The amount of the compound [18] used is the same as that of the compound [1].
3] can be used in an amount of 1 to 5 equivalents, preferably 1 to 1.5 equivalents. The amount of the base used is the same as that of the compound [13].
With respect to 1 to 20 equivalents, preferably 1 to 5 equivalents can be used. The additive may be used in an amount of 1-10 equivalents, preferably 1-5 equivalents, relative to compound [13]. This reaction can be carried out, for example, at -30 to 150 ° C, preferably 0 to 80 ° C.

As the leaving group X ² , for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethanesulfonyloxy group, p
-Toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, hydroxyl group and the like.

When the leaving group X ² is a hydroxyl group, Mitsunobu reagents such as triphenylphosphine-diethylazodicarboxylate and triphenylphosphine-diisopropylazodicarboxylate can also be used. [Method G] Of the object compound [I] of the present invention, a compound represented by the general formula [I]
-C]:

[0101]

[Chemical 55]

The biphenylcarboxamidoisoindoline derivative represented by the formula (wherein P represents a hydroxyl-protecting group and the other symbols have the same meanings as described above) is represented by the general formula [1
[3] or a salt thereof, and a compound of the general formula [1
9]:

[0103]

[Chemical 56]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting with a compound represented by

This reaction can be carried out in a solvent in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction,
For example, methanol, ethanol, isopropyl alcohol, dimethylformamide, acetonylyl and the like can be mentioned. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine and the like. Examples of the additive include ammonium chloride and tin (II) iodide. [Method H] Of the object compound [I] of the present invention, a compound represented by the general formula [I]
-D]:

[0106]

[Chemical 57]

(In the formula, R ⁵ represents an optionally substituted heterocyclic group or an optionally substituted aryl group, and other symbols have the same meanings as described above). The indoline derivative is a compound represented by the general formula [13] or a salt thereof, and a general formula [20]:

[0108]

[Chemical 58]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting with a compound represented by

This reaction can be carried out in a solvent in the presence or absence of a base or an acid. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, ethanol and propanol. Examples of the base include triethylamine, diisopropyrylamine and the like. Examples of the acid include acetic acid, formic acid, p-toluenesulfonic acid and the like.

The object compound [I] of the present invention is obtained by substituting the substituents on ring A, the substituents on ring B and / or the group R of the compound obtained as described above with other desired substituents. It can also be produced by converting into Such a method for converting a substituent may be appropriately selected according to the kind of the desired substituent, and for example, (method a) to (method k)
Can be implemented as follows.

(Method a: Alkylation of amino group (reductive amination reaction)) Substitution containing an optionally substituted lower alkylamino group (for example, dimethylamino group) in the group R in the general formula [I]. The target compound [I] which is a group is
The corresponding compound [I] in which the group R is a substituent containing an unprotected primary or secondary amino group and the corresponding aldehyde compound (for example, formaldehyde),
Method] and can be manufactured.

(Method b: Oximeation of carbonyl group) In the target compound [I] in which the substituent on ring A in the general formula [I] is a substituent containing an oxime, the substituent on ring A is a carbonyl group. It can be produced by reacting the corresponding compound [I], which is a substituent containing, with hydroxylamine.

(Method c: amidation) In the general formula [I], the substituent on ring A, the substituent on ring B, and / or the group R
The target compound [I], which is a substituent containing an optionally substituted carbamoyl group, is a substituent on ring A, a substituent on ring B, and / or a substituent in which group R contains a carboxyl group. The corresponding compound [I] and a corresponding primary or secondary amine compound can be produced in the same manner as in the above [Method A].

(Method d: N-Acylation) In the general formula [I], the substituent on ring A, the substituent on ring B, and / or the target compound wherein the group R is a substituent containing an acylamino group [ [I] is a substituent on ring A, a substituent on ring B, and / or a group R is a substituent containing an amino group, and the corresponding compound [I] and the corresponding acylating agent (eg, picolinic acid, Dimethylaminoglycine) and the same treatment as in the above [Method A].

(Method e: Alkyl halide substitution reaction)
The group R in the general formula [I] is an optionally substituted nitrogen-containing heterocyclic group substituted lower alkyl group (eg, 1-pyrazolylmethyl group) or lower alkylamino lower alkyl group (eg, dimethylaminomethyl group) A compound [I] includes a corresponding compound [I] in which the group R is a lower alkyl group substituted with a halogen atom (for example, a chloromethyl group) and a corresponding optionally substituted nitrogen-containing heterocycle (for example, Pyrazole) or a primary or secondary lower alkylamine (eg, dimethylamine) in the presence of a base. Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride and sodium hydrogen carbonate.

(Method f: Reduction Reaction of Nitro Group) A target compound in which the substituent on ring A, the substituent on ring B, and / or the group R in the general formula [I] is a substituent containing an amino group. [I] is a corresponding compound [I] in which the substituent on ring A, the substituent on ring B and / or the group R is a substituent containing a nitro group.
It can be produced by reacting in the presence of (carbon).

(Method g: Palladium Coupling and Hydrolysis) The object compound [I] in which the group R in the general formula [I] is a substituent containing an acetyl group, the group R is a substituent containing a halogen atom. After reacting a corresponding compound [I] with tri-lower alkyl (1-lower alkoxyvinyl) tin in the presence of a catalyst (eg, bistriphenylphosphine palladium dichloride, palladium acetate, etc.),
It can be produced by hydrolysis.

(Method h: Reduction of Carbonyl Group) The target compound [I] in which the substituent on ring A in the general formula [I] and / or the group R is a substituent containing a hydroxyl group is ring A
The corresponding compound [I] in which the above substituent and / or the group R is a substituent containing a carbonyl group is treated with a conventional reducing agent (eg, sodium borohydride, lithium aluminum hydride, lithium borohydride, etc.). It can be produced by processing.

(Method i: azidation and reduction reaction) The group R in the general formula [I] is an amino lower alkyl group (for example,
Aminomethyl group-containing substituent [I]
Is obtained by reacting the corresponding compound [I] in which the group R is a substituent containing a lower alkyl group (for example, a chloromethyl group) substituted with a halogen atom with an azidating agent, and then subjecting the compound to a reduction reaction. It can be manufactured. Examples of the azidating agent include sodium azide, trimethylsilane azide, tributyltin azide and the like.
Examples of the reducing agent include hydrogen / palladium-carbon, triphenylphosphine-water, zinc-acetic acid, sodium hydrosulfite, and the like.

(Method j: O-acylation or O-alkylation reaction) The substituent on ring A and / or the substituent on ring B in the general formula [I] may be an acyloxy group or a substituent. The target compound [I], which is a substituent containing a good lower alkoxy group, includes the corresponding compound [I] in which the substituent on ring A and / or the substituent on ring B is a substituent containing a hydroxyl group, and an acyl compound. Prepared by reacting an agent (eg, phenylacetyl chloride) or an optionally substituted lower alkyl halide (eg, 2-methoxyethyl chloride) in the presence of a base (eg, potassium carbonate, cesium carbonate). be able to.

(Method k: Reduction Reaction of Amide) General Formula [I]
The target compound [I] in which the substituent on ring A in and / or the substituent on ring B is a substituent containing an optionally substituted lower alkylamino group is a substituent on ring A, And / or the corresponding compound [I], which is a substituent containing an optionally substituted lower alkanoylamino group, is reacted in the presence of a reducing agent (for example, borane-dimethyl sulfide complex). It can be manufactured.

[A method] to [H method] or (a
The object compound [I] of the present invention obtained by the methods (1) to (k) can be converted to a pharmacologically acceptable salt, if desired. Conversion to a pharmaceutically acceptable salt is
It may be performed according to a method known to those skilled in the art.

Next, a method for adjusting the raw material compounds used in the above method will be described below.

Starting compound [5] ([5-a] and [5]
-B]) can be produced, for example, according to the following method.

[0126]

[Chemical 59]

(However, the symbols have the same meanings as described above.) The reaction for producing the compound [3] from the isoindoline [1] and the carboxylic acid compound [2] can be carried out in the same manner as in the above-mentioned [Method A]. it can.

The reaction for producing the compound [3] from the dichloro compound [7] and the compound [8] can be carried out in the presence of a base, in the presence or absence of an additive. Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide and the like. Examples of the additive include tetra-lower alkylammonium halides such as tetrabutylammonium chloride and tetraethylammonium chloride.

As an example of this step, for example,

[0130]

[Chemical 60]

And the like.

The reaction for producing the compound [4] from the compound [3] can be carried out in the presence of a suitable nitrating agent. Suitable nitrating agents include, for example, concentrated nitric acid / concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, potassium nitrate / trifluoroacetic acid and the like.

The reaction for producing the compound [9] from the compound [1] can be carried out in the same manner as the reaction for producing the compound [4] from the compound [3].

The reaction for producing the compound [4] from the compound [9] and the carboxylic acid compound [2] can be carried out in the same manner as in the above-mentioned [Method A].

The reaction for producing compound [5-a] from compound [4] can be carried out in the presence of a suitable reducing agent. Examples of the reducing agent include hydrogen / palladium-carbon, lithium aluminum hydride, zinc-acetic acid, iron (II) chloride-hydrochloric acid, tin (II) chloride-hydrochloric acid, iron-hydrochloric acid,
Iron-ammonium chloride, ammonium formate / palladium-carbon and the like can be mentioned.

The reaction for producing the compound [5-b] from the compound [5-a] can be carried out in the same manner as in the above-mentioned [Method D].

In the reaction for producing the compound [5-b] from the compound [9], the same treatment (N-alkylation) as in the above-mentioned [Method F] is performed, and then the compound [5-a] is converted from the compound [4]. It can be carried out by treatment (reduction of nitro group) in the same manner as in the production reaction.

When R is a lower alkyl group having a halogen atom, a substituent can be introduced on the alkyl group by reacting with various nucleophiles in the presence or absence of a base. Examples of the halogen atom include halogen atoms such as chlorine atom, bromine atom and iodine atom. Examples of the nucleophile include nitrogen-containing heterocyclic groups such as imidazole, pyrazole, pyrrole, indole and triazole, and primary or secondary lower alkylamino such as dimethylamine, diethylamine, ethylamine, morpholine, piperidine and pyrrolidine. Groups and the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, cesium fluoride, sodium hydroxide, potassium hydroxide and the like.

As an example of this step, for example,

[0140]

[Chemical formula 61]

And the like.

The starting compound [6] can be produced, for example, according to the following method.

[0143]

[Chemical formula 62]

(In the formula, X ⁰ is a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group, Y is a lower alkoxycarbonyl group or (mono- or di-))
Lower alkylamino group, X ³ represents a leaving group, X ⁴ represents a leaving group, and other symbols have the same meanings as described above.) The reaction for producing compound [24] from compound [23] is
It can be carried out as follows.

When X ⁰ is a hydrogen atom or a halogen atom, a compound represented by the formula: M—X ³ or M—M is reacted in a solvent in the presence of a base and in the presence or absence of an additive, If necessary, it can be carried out by treating with an acid. Examples of the solvent include tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane and the like. Examples of the base include n-butyllithium, sec-butyllithium and the like.
Examples of the additive include tetramethylethylenediamine, hexamethylphosphoric triamide, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, ammonium chloride and the like.

When X ⁰ is a halogen atom or a trifluoromethanesulfonyloxy group, it is represented by the formula: M—X ^{3 in} a solvent, in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of an additive. Alternatively, it can be carried out by reacting a compound represented by MM and, if necessary, treating with an acid. Examples of the solvent include dimethoxyethane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, or a mixed solvent thereof. Examples of the catalyst include palladium acetate, tetrakistriphenylphosphine palladium, bis (diphenylphosphinoferrocene) dichloropalladium and the like. Examples of the base include potassium acetate, potassium carbonate, sodium carbonate and the like. Examples of the additive include triphenylphosphine, tri-o-toluylphosphine, tri-n-butylphosphine, diphenylphosphinoferrocene (dppf), diphenylphosphinobutane (dppb), and 2,6-di-tert-butyl. -4-
Examples include cresol and the like. Examples of the acid include hydrochloric acid, sulfuric acid, ammonium chloride and the like.

The reaction for producing compound [28] from compound [24] and compound [25] is carried out in a solvent in the presence of a catalyst.
It can be carried out in the presence or absence of a base, or in the presence or absence of an additive. As the solvent, for example,
Examples thereof include dimethoxyethane, water, ethanol, toluene, dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, and mixed solvents thereof.
Examples of the catalyst include palladium acetate, bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, bis (dibenzylideneacetone) palladium, bisbenzonitrile palladium dichloride and the like. Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like. Examples of the additive include triphenylphosphine, tri-n-butylphosphine, tri-o-
Toluylphosphine, diphenylphosphinoferrocene (dppf), diphenylphosphinobutane (dpp)
b), 2,6-di-tert-butyl-4-cresol and the like.

Specific examples of the leaving group X ³ include a halogen atom such as chlorine, bromine and iodine, a lower alkoxy group, a cyano group and a trifluoromethanesulfonyloxy group.

Specific examples of the compound represented by the formula: MX ³ include tri-n-butyltin chloride and tri-n-.
Butyltin trifluoromethanesulfonate, tri-lower alkoxyborane and the like can be mentioned.

Specific examples of the compound represented by the formula: MM include bispinacolate diborone, biscatecholate diborone, bistrin-butyltin and the like.

Specific examples of the leaving group X ⁴ in the compound [25] or the compound [27] include halogen atom such as chlorine, bromine and iodine, trifluoromethanesulfonyloxy group and the like.

The reaction for producing the compound [16] from the compound [26] can be carried out in the same manner as the reaction for producing the compound [24] from the compound [23].

The reaction for producing compound [28] from compound [16] and compound [27] can be carried out in the same manner as the reaction for producing compound [28] from compound [24]. The reaction for producing the compound [6] from the compound [28] can be carried out by treating with an acid or a base. Examples of the acid include concentrated hydrochloric acid, sulfuric acid and the like. Examples of the base include sodium hydroxide,
Examples thereof include potassium hydroxide, lithium hydroxide, lithium hydroxide-hydrogen peroxide and the like.

The starting compound [13] can be produced, for example, according to the following method.

[0155]

[Chemical formula 63]

(However, the symbols have the same meanings as above.) The reaction for producing the compound [10] from the compound [9] is carried out by di-tert-butyl dicarbonate (Boc _{2) in} a solvent.
O), in the presence or absence of a base. Examples of the solvent include tetrahydrofuran, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and the like. Examples of the base include triethylamine, potassium carbonate, sodium carbonate, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.

The reaction for producing compound [11] from compound [10] can be carried out in the same manner as the reaction for producing compound [5-a] from compound [4].

The reaction for producing the compound [12] from the compound [11] and the compound [6] can be carried out in the same manner as in the above-mentioned [Method A].

The reaction for producing the compound [13] from the compound [12] can be carried out in the presence of a Boc group deprotecting agent. Examples of the Boc group deprotecting agent include hydrochloric acid-dioxane, hydrochloric acid-ethyl acetate, trifluoroacetic acid,
Examples thereof include iodotrimethylsilane.

The starting compound [15] can be produced, for example, according to the following method.

[0161]

[Chemical 64]

(However, symbols have the same meanings as described above.) The reaction for producing the compound [15] from the compound [5] and the compound [14] can be carried out in the same manner as in the above-mentioned [Method A].

Compounds [I], [Ia] and [I-
b], [I-c], or [I-d], each intermediate compound is not limited to the one shown in the above chemical reaction formula, and its salt or its salt if it does not adversely affect the reaction. Reactive derivatives can also be used as appropriate. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium, pyridine,
Salts with organic bases such as triethylamine and diisopropylethylamine, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid , Citric acid, formic acid,
Examples thereof include salts with organic acids such as fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.

Further, in the production of the object compound and starting compound of the present invention, when the starting compound or each intermediate has a functional group, appropriate protection for each functional group is carried out by a conventional synthetic chemistry method other than the above. A group may be introduced, and if necessary, those protecting groups may be appropriately removed.

In the present invention, the alkyl includes straight-chain or branched-chain alkyl having 1 to 16 carbon atoms, and particularly alkyl having 1 to 8 carbon atoms. Examples of lower alkyl or lower alkoxy include linear or branched ones having 1 to 6 carbon atoms, and particularly ones having 1 to 4 carbon atoms. Further, the lower alkanoyl includes a straight or branched one having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms, and the cycloalkyl means
Examples thereof include those having 3 to 20 carbon atoms, and particularly those having 3 to 12 carbon atoms. Examples of cyclo lower alkyl include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. The alkenyl includes those having 2 to 16 carbon atoms, especially those having 2 to 10 carbon atoms, and the lower alkenyl includes those having 2 to 8 carbon atoms, especially those having 2 to 4 carbon atoms. Can be mentioned. Examples of the alkylene include linear or branched ones having 1 to 16 carbon atoms, and particularly 1 to 10 carbon atoms, and lower alkylene refers to linear ones having 1 to 8 carbon atoms, especially 1 to 6 carbon atoms. And branched chains.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Heterocyclic groups include, for example, nitrogen,
Examples thereof include monocyclic, bicyclic or tricyclic heterocyclic groups containing at least one heteroatom selected from oxygen and sulfur. Specifically, a pyridyl group, an indolyl group, a thiazolyl group, an imidazolyl group, a pyrrolyl group, a pyrimidinyl group,
Thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group, quinolyl group,
Isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11-dihydro-dibenzo [b,
e] [1,4] Oxazepin-5-yl group, dihydropyrazolyl group, tetrazolyl group and the like. Examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, a phenanthryl group, and the like.

[0166]

[Examples] Specific examples (Examples) of the target compound [I] of the present invention synthesized by the above-mentioned methods are shown below, but the present invention is not limited thereto.

Example 1 (1) 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) under an argon atmosphere.
8 g, 2-pyridyl acetic acid / hydrochloride 896 mg, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / hydrochloride 1.07 g, 4-dimethylaminopyridine 630 mg and triethylamine 478 mg in methylene chloride (36 ml), Stir overnight at room temperature. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is a saturated aqueous sodium hydrogen carbonate solution,
After washing with water and saturated saline solution in that order, it is dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol =
40: 1) to give 2- (2-pyridyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline 2.12
g as a foam. (2) The compound obtained in (1) above was added with 40 m of methanol.
Dissolve in 1 l and under ice cooling 10% hydrochloric acid-methanol solution 4 ml
Add. The solvent was distilled off, and the residue was recrystallized with a mixed solution of acetone-diethyl ether to give 2- (2-
Pyridyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline.
1.91 g of the hydrochloride are obtained as colorless needles. M. p. Two
11.0-212.0 ° C

Example 2-31 The corresponding starting material compound was prepared as Example 1 (1) or Example 1
By treating in the same manner as (1) and (2), the compounds shown in Table 1 are obtained. (The unit of MS or IR measurement value in the table is "m / z" or "cm ^-1 ", respectively. The same shall apply hereinafter.)

[0169]

[Table 1]

[0170]

[Table 2]

[0171]

[Table 3]

[0172]

[Table 4]

[0173]

[Table 5]

Example 32 5- [2- (4-trifluoromethylphenyl) -benzoylamino] -isoindoline hydrochloride (Reference Example 40)
(Compound obtained in (5)) 100 mg of methylene chloride (5 ml) -saturated sodium hydrogen carbonate aqueous solution (1.5 m
l) mixed solution of 2-thenoyl chloride 36.5 mg
And stir at room temperature for 2 hours. The reaction solution is extracted with chloroform, the organic layer is washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate =
After purification with 2: 1), the residue was washed with diethyl ether-ethyl acetate to give 2- (2-thenoyl) -5.
96 mg of-[2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 148-151 ° C

Example 33 2- (2-Nitrophenyl) acetyl-5- [2- (4
-Trifluoromethylphenyl) benzoylamino]-
Isoindoline (compound obtained in Example 9) 422 m
g and 10% palladium-carbon (42 mg) were suspended in a mixed solution of methanol (8.4 ml) -tetrahydrofuran (4.2 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 4 hours. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 50: 1 → 30: 1).
Recrystallization from a mixed solution of methanol-diisopropyl ether gives 380 mg of 2- (2-aminophenyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline as colorless prism crystals. . M. p. 235.0-237.0 ° C

Example 34 Under an argon atmosphere, 150 mg of 2- (2-aminophenyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 33) and Tetrahydrofuran (9 ml) of 36% aqueous formaldehyde solution (0.5 ml)
Sodium triacetoxyborohydride 136
Add mg and stir at room temperature for 24 hours. Further, 173 mg of sodium triacetoxyborohydride is added, and the mixture is stirred at room temperature for 48 hours. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 20: 1). Dissolve the crude product in methanol, and under ice cooling 1
Add 0% hydrochloric acid-methanol solution. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-diethyl ether to give 2- (2-dimethylaminophenyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino]-. Isoindoline / hydrochloride 12
0 mg are obtained as colorless needles. M. p. 179.0-
181.0 ° C

Example 35 150 mg of 2- (2-aminophenyl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 33) under an argon atmosphere, A solution of 57 mg of 2- (chloromethyl) pyridine hydrochloride, 98 mg of sodium hydrogen carbonate and 48 mg of sodium iodide in hexamethylphosphoric triamide (HMPA) (3 ml) was added at 80 ° C. for 8 hours.
Stir for hours. After cooling to room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by preparative chromatography (developing solvent; n-hexane: ethyl acetate = 1: 10). The crude product is dissolved in methanol, and 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-diethyl ether to give 2- [2- (2-pyridylmethylamino) phenyl] acetyl-5- [2- (4-trifluoromethylphenyl). ) Benzoylamino] -isoindoline hydrochloride 1
28 mg are obtained as colorless needles. M. p. 182.0-184.0 ° C

Example 36 2- (2-Benzyloxycarbonylamino-2-phenylacetyl) -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (Compound obtained in Example 12) A mixed suspension of 676 mg and 10% palladium-carbon 67 mg in ethanol (6 ml) -tetrahydrofuran (6 ml) is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 18 hours. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 20: 1 → 9 :).
Purify in 1). The crude product is dissolved in methanol, and 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethanol-diethyl ether to give 2- (2-amino-2-phenylacetyl) -5- [2- (4-trifluoromethylphenyl) benzoylamino. ] -Isoindoline hydrochloride 459 mg is obtained as colorless needles. M. p. 215.0-217.0 ° C

Example 37 2- (2-chloro-2-phenylacetyl) -5- [2
-(4-Trifluoromethylphenyl) benzoylamino] -isoindoline (compound obtained in Example 13)
150 mg, 50% dimethylamine aqueous solution (1 ml) and sodium iodide 46 mg ethanol (6 ml)
The solution is heated and stirred at 50 ° C. for 3 hours. After cooling to room temperature,
The reaction solution is concentrated. Dilute aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 90: 7). The crude product is dissolved in methanol, and 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-diethyl ether to give 2- (2-dimethylamino-2-phenylacetyl) -5- [2- (4-trifluoromethylphenyl) benzoyl. Amino] -isoindoline hydrochloride 14
5 mg are obtained as colorless needles. M. p. 212.5-215.0 ° C

Example 38 2- [4- [2- (tert-Butoxycarbonyl) amino] thiazolyl] acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (in Example 16) A 4M hydrochloric acid-dioxane solution (0.63 ml) was added dropwise to a solution of the obtained compound (157 mg) in dioxane (2 ml), and the mixture was stirred at room temperature for 2 days. The reaction solution is concentrated, water is added, concentrated ammonia water is added to make the solution basic, and then the solution is extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform-methanol = 50:
2- [4- (2-amino) thiazolyl] acetyl-5 by purification in 1) and trituration with diethyl ether.
107 mg of-[2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as a light brown powder. M. p. 146 ° C (decomposition)

Example 39 2- [2- (4-benzyloxyphenyl) acetyl]-
5 [% of a solution of 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 18) 1.36 g in ethanol (5 ml) 5%
Palladium-carbon (300 mg) is added, and the mixture is stirred under a hydrogen atmosphere at room temperature for 1 day. The catalyst was removed by filtration, the filtrate was concentrated, a diethyl ether-n-hexane mixed solution was added to the residue, and the precipitated powder was collected by filtration to give 2- [2- (4-
1.02 g of hydroxyphenyl) acetyl] -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless powder. M. p. 155-160 ° C

Example 40 2- [2- (4-hydroxyphenyl) acetyl] -5-
To a solution of [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 39) (180 mg) in dimethylformamide (1 ml), 2- (dimethylamino) ethyl chloride.hydrochloride 5 was added.
Add 7 mg and 70 mg potassium carbonate and add 1 at 50 ° C.
Heat and stir for 2 hours. Further, 70 mg of potassium carbonate is added, and the mixture is heated with stirring at 60 ° C. for 24 hours. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. After the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate), a solution of the crude product in ethyl acetate was mixed with 4M hydrochloric acid-dioxane solution, and the precipitate was collected by filtration to give 2- [4
-[(2-Dimethylaminoethyl) oxy] phenyl] acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride 44
mg is obtained as a colorless powder. M. p. 130-160 ℃ (decomposition)

Example 41 2- (3-Nitropyridin-2-yl) acetyl-5-
By treating [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 23) in the same manner as in Example 33, 2-
(3-Aminopyridin-2-yl) acetyl-5- [2
-(4-Trifluoromethylphenyl) benzoylamino] -isoindoline is obtained. M. p. 223.5-225 ° C

Example 42 2- (3-Aminopyridin-2-yl) acetyl-5-
A solution of [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 41) (100 mg) and triethylamine (39 mg) in methylene chloride (5 ml) was cooled with ice and 23 mg of methoxyacetyl chloride in methylene chloride was added. (2 ml) solution is added and stirred at room temperature for 2 hours. The reaction solution is poured into water and extracted with chloroform. The organic layer is a saturated aqueous sodium hydrogen carbonate solution,
After washing with water and saturated saline, it is dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative chromatography (developing solvent; chloroform: methanol = 12:
Purify in 1). The crude product is dissolved in methanol, and 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-diethyl ether to give 2- (3-methoxyacetylaminopyridin-2-yl) acetyl-5- [2- (4-trifluoromethylphenyl). ) Benzoylamino] -isoindoline hydrochloride 114 mg is obtained as colorless needles. M. p. 216.0-219.0 ° C (decomposition)

Example 43 2- (3-Aminopyridin-2-yl) acetyl-5-
A suspension of [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 41) 108 mg, methanesulfonyl chloride 24 mg and potassium carbonate 40 mg in dimethylformamide (2 ml) was stirred overnight at room temperature. To do. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 15: 1). The obtained powder is dissolved in methanol, and a 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of methanol-diethyl ether to give 2- (3-dimethylaminomethylideneaminopyridin-2-yl) acetyl-5- [2- (4-trifluoro). Methylphenyl) benzoylamino] -isoindoline dihydrochloride 4
3 mg are obtained as colorless needles. M. p. 187.0-189.0 ° C

Example 44 2-[(5-bromo-thiophene-
2-yl) acetyl] -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 25) 148 mg, tributyl (1-ethoxyvinyl) tin 191 mg and bistriphenylphosphine 18 mg of palladium dichloride
A solution of the above in dioxane (2.5 ml) is heated under reflux for 8 hours. After cooling to room temperature, the reaction solution is diluted with ethyl acetate, 10% potassium fluoride aqueous solution is further added, and the mixture is stirred at room temperature for 1 hour. The insoluble matter is filtered off, the organic layer of the filtrate is separated,
After washing with water and saturated saline, it is dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (Fuji Silysia) (developing solvent: chloroform), and further silica gel column chromatography (developing solvent: chloroform-methanol = 97:
After purification in 3), 2-[(5-acetyl-thiophen-2-yl) acetyl] -5- [2- (4-trifluoromethylphenyl) benzoyl was obtained by powdering with ethyl acetate-diisopropyl ether. 21 mg of amino] -isoindoline are obtained as a light brown powder. M. p. 161-165 ° C (decomposition)

Example 45 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (Reference Example 40)
By treating the compound obtained in (5) in the same manner as in Example 32, 2-phenylacetyl-5- [2- (4
-Trifluoromethylphenyl) benzoylamino]-
Isoindoline is obtained as colorless crystals. M. p. 145-147 ° C

Example 46 (1) 5- [2- (4-trifluoromethylphenyl)
To a mixed solution of 4.19 g of benzoylamino] -isoindoline hydrochloride (the compound obtained in Reference Example 40 (5)) and 4.19 g of potassium carbonate in 40 ml of ethyl acetate-40 ml of water, 1.2 ml of 2-chloroacetyl chloride was added. Tetrahydrofuran solution (2 ml) was added dropwise with stirring,
Stir at room temperature for 1 hour. After separating the reaction solution, the organic layer is water,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 100:
Purified in 1), dissolved in ethyl acetate, and treated with activated carbon to give 4.50 g of 2-chloroacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline as an amorphous powder. obtain. MS (APCI) m / z; 459 (M + H), IR (N
ujol) cm ⁻¹ : 1652, 1603. (2) To a solution of 183 mg of the compound obtained in (1) above in dimethylformamide (2 ml), 68 mg of pyrazole
And 138 mg of potassium carbonate are added, and the mixture is heated with stirring at 54 ° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. By purifying the residue by silica gel column chromatography (developing solvent; ethyl acetate), 2-
(1H-pyrazol-1-yl) acetyl-5- [2-
(4-Trifluoromethylphenyl) benzoylamino] -isoindoline is obtained. (3) By adding 4M hydrochloric acid-dioxane solution to the compound obtained in the above (2) and distilling off the solvent under reduced pressure, 2
-(1H-pyrazol-1-yl) acetyl-5- [2
123 mg of-(4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride is obtained as a colorless powder. M. p. 130-133 ° C (decomposition)

Examples 47-66 The corresponding starting compounds were treated in the same manner as in Example 46 (1) (2) to give the compounds shown in Table 2.

[0190]

[Table 6]

[0191]

[Table 7]

[0192]

[Table 8]

[0193]

[Table 9]

In Example 53 and Example 54, after treating the corresponding starting material compound in the same manner as in Example 46 (2),
Obtained by separating the resulting mixture by silica gel column chromatography.

Example 67 (1) 2- (4-Ethoxycarbonyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (Example 51 Compound obtained in 1.), 690 mg, 1M aqueous sodium hydroxide solution (3.6 ml) in methanol (1
4 ml) -tetrahydrofuran (7 ml) mixed solution is stirred at room temperature for 2 days. After concentrating the reaction solution, water is added to the residue to make the solution acidic with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was triturated with a mixed solution of ethyl acetate-diisopropyl ether to give 2- (4-hydroxycarbonyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-tri- 518 mg of fluoromethylphenyl) benzoylamino] -isoindoline are obtained as a colorless powder. MS (ESI) m / z; 533 (MH), IR (Nu
jol) cm ⁻¹ : 1677, 1645. (2) 140 mg of the compound obtained in the above (1), 2,
78 mg of 2,2-trifluoroethylamine, 42 mg of 1-hydroxybenzotriazole and 65 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride dimethylformamide (2.8 m
l) Stir the solution at room temperature overnight. The reaction solution is poured into a dilute aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 15: 1), and recrystallized with a mixed solution of methanol-diisopropyl ether to give 2- [4- ( 2,2,2-
93 mg of trifluoroethylaminocarbonyl) -1H-pyrazol-1-yl] acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 231.0-232.5 ° C

Example 68 Under an argon atmosphere, 2- (4-hydroxycarbonyl-
1H-pyrazol-1-yl) acetyl-5- [2-
To a solution of (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 67 (1)) 140 mg and diethylamine 57 mg in dimethylformamide (2.8 ml) was added diethyl cyanophosphonate 47 mg at room temperature, Stir overnight at same temperature. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (developing solvent; ethyl acetate), and recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 2- [4-diethylaminocarbonyl-1H- Pyrazol-1-yl]
86 mg of acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 251.0-253.0 ° C

Example 69 2- (4-Nitro-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl)
To a solution of 170 mg of benzoylamino] -isoindoline (the compound obtained in Example 50) in acetic acid (2 ml), 680 mg of zinc dust was added, and the mixture was heated with stirring at 100 ° C. for 3 hours. The reaction solution is filtered through Celite, and the solvent is distilled off from the filtrate under reduced pressure. Chloroform and saturated aqueous sodium hydrogen carbonate solution are added and the mixture is stirred at room temperature. The organic layer is separated, water,
After washing with saturated saline, it is dried over anhydrous sodium sulfate and the solvent is distilled off. Silica gel column chromatography of the residue (developing solvent; chloroform: methanol = 20: 1)
After being purified by the method described above, it was recrystallized from a mixed solution of n-hexane-ethyl acetate to give 2- (4-acetylamino-1).
H-pyrazol-1-yl) acetyl-5- [2- (4
-Trifluoromethylphenyl) benzoylamino]-
30 mg of isoindoline are obtained as colorless crystals. M. p. 250-252 ° C

Example 70 The corresponding starting material compound (the compound obtained in Example 58) was treated in the same manner as in Example 69 to give the compounds shown in Table 3.

[0199]

[Table 10]

Example 71 (1) 686 mg of 2-chloroacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 46 (1))
To a dimethylformamide (15 ml) solution of was added 3-dimethoxymethyl-1H-pyrazole (424 mg) and potassium carbonate (412 mg), and the mixture was heated with stirring at 50 ° C. for 19 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol =
2- (3-dimethoxymethyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline and 2 by crude purification with 200: 1). 474 mg of-(5-dimethoxymethyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as a mixture. (2) To a solution of 441 mg of the mixture obtained in (1) above in tetrahydrofuran (8 ml) is added 0.43 ml of 2M hydrochloric acid, and the mixture is stirred at room temperature for 1 day. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. Distill off the solvent to give 2-
(3-Formyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline and 2- (5-formyl) -1H-pyrazol-1-yl ) Acetyl-5
A mixture of-[2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline is obtained. (3) By separating and purifying the mixture obtained in (2) above by silica gel column chromatography (developing solvent; chloroform: methanol = 200: 1), 2-
(3-Formyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl)
200 mg of benzoylamino] -isoindoline are obtained as a colorless powder. MS (APCI) m / z; 519 (M + H), IR (n
ujol) cm ⁻¹ ; 1694, 1660, 1602.

Example 72 (1) To a solution of 152 mg of the mixture obtained in Example 71 (2) in methanol (3 ml), 18 mg of sodium borohydride was added little by little under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative chromatography (developing solvent; chloroform: methanol = 50:
By purifying in 1), 2- (3-hydroxymethyl-1H-pyrazol-1-yl) acetyl-5- [2
-(4-Trifluoromethylphenyl) benzoylamino] -isoindoline 80 mg (72 (a)) and 2
-(5-Hydroxymethyl-1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (72
(B)) 60 mg is obtained as a colorless powder. Furthermore, by recrystallizing the colorless powder of compound 72 (a) in a mixed solvent of ethyl acetate-diisopropyl ether,
40 mg of colorless needles are obtained. M. p. 180-185 ° C (72 (a)) MS (APCI) m / z; 521 (M + H), IR (N
ujol) cm ⁻¹ : 1652, 1601. (72
(B))

Example 73 (1) 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) 30 under argon atmosphere
To a solution of 0 mg and 182 mg of triethylamine in methylene chloride (6 ml) was added 2-bromopropionyl bromide 17
Add 0 mg under ice cooling and stir at room temperature for 2 hours. The reaction solution is poured into water and extracted with chloroform. The organic layer is washed successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 15: 1) to give 2- (2-bromo-1-oxopropyl) -5- [2- (4 -Trifluoromethylphenyl)
349 mg of benzoylamino] -isoindoline are obtained as a colorless powder. MS (APCI) m / z; 518 (M + H), IR (N
ujol) cm ⁻¹ : 1647, 1618, 1603. (2) In an argon atmosphere, 325 mg of the compound obtained in (1) above, 86 mg of pyrazole, and potassium carbonate 1
A 74 mg suspension of dimethylacetamide (6.4 ml) is heated with stirring at 60 ° C. for 2 hours. After cooling to room temperature, the reaction solution is poured into ice water, the deposited precipitate is filtered off, washed with water and dried. The resulting crude product was subjected to preparative chromatography (developing solvent; chloroform: methanol = 90:
After purification in 7), it was recrystallized with a mixed solution of ethyl acetate-diisopropyl ether to give 2- [2-
235 mg of (1H-pyrazol-1-yl) -1-oxopropyl] -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 132.5-133.5 ° C

Example 74 The corresponding starting material compound was treated in the same manner as in Example 73 to obtain the compounds shown in Table 4.

[0204]

[Table 11]

Example 75 (1) 4-nitropyrazole 2.5 under an argon atmosphere
g, 3.88 g of methyl 2-bromopropionate and 4.59 g of potassium carbonate in a dimethylformamide suspension (20 ml) are stirred at room temperature for 2 hours. The reaction solution is concentrated, ethyl acetate is added to the residue, and the insoluble material is filtered off. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: ethyl acetate = 30: 1) to give methyl 2- (4-nitro-1H-pyrazol-1-yl) propionate 3 .90 g are obtained as a colorless oil. MS (APCI) m / z; 200 (M + H), IR (N
ujol) cm ⁻¹ : 1749. (2) Under an argon atmosphere, a solution of 505 mg of the compound obtained in (1) above and 540 mg of methyl iodide in tetrahydrofuran (5 ml) under ice cooling was added with 111 mg of 60% sodium hydride washed with n-pentane, Stir at room temperature for 2 hours. After concentrating the reaction solution, chloroform is added to the residue and the insoluble matter is removed by filtration. After concentrating the filtrate,
The residue is preparative chromatography (developing solvent;
Purification with chloroform: ethyl acetate = 20: 1) gives 270 mg of methyl 2-methyl- (4-nitro-1H-pyrazol-1-yl) propionate as a colorless oil. MS (APCI) m / z; 214 (M + H), IR (N
ujol) cm ⁻¹ : 1746. (3) 117 mg and 1 of the compound obtained in (2) above
A solution of M aqueous sodium hydroxide solution (0.55 ml) in methanol (5 ml) is stirred at room temperature overnight. After concentrating the reaction solution, the residue is triturated with acetone to obtain 120 mg of 2-methyl- (4-nitro-1H-pyrazol-1-yl) propionic acid sodium salt as a colorless powder. MS (ESI) m / z; 198 (M-Na), IR (N
ujol) cm ⁻¹ : 1612. (4) 114 mg of the compound obtained in (3) above and dimethylformamide (1 drop) in methylene chloride (3 ml)
To the suspension, 184 mg of thionyl chloride was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and the residue was converted to 5- [2
216 mg of-(4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) and triethylamine 16
Add to a solution of 4 mg methylene chloride (6 ml) and add 1 at room temperature.
Stir for hours. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative chromatography (developing solvent; chloroform:
After purification with methanol = 90: 7), the crystals were recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 2- [2-methyl-2- (4-nitro-1H-pyrazol-1-yl) -1. -Oxopropyl] -5- [2-
203 mg of (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 164.5-166.5 ° C

Example 76 (1) To a solution of 6.03 g of 2-pyridylacetonitrile and 13.22 g of 1,4-dibromobutane in dimethyl sulfoxide (150 ml) was added sodium amide 4.2.
Add 9 g under ice cooling and stir at room temperature for 5 hours. The reaction solution is poured into ice water and extracted with diethyl ether. Water organic layer,
It is washed successively with saturated saline and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography (developing solvent; chloroform) to obtain 5.79 g of 1- (2-pyridyl) -1-cyclopentanecarbonitrile as a yellow liquid. MS (APCI) m / z; 173 (M + H), IR (N
eat) cm ⁻¹ : 2235. (2) 47% of 2.08 g of the compound obtained in (1) above
A solution of hydrobromic acid (10 ml) is heated to reflux for 3 hours.
After cooling to room temperature, the reaction solution is concentrated under reduced pressure. Toluene is added to the residue and concentrated again. By crystallizing the residue with acetone, 2.80 g of 1- (2-pyridyl) -1-cyclopentanecarboxylic acid / hydrobromide is obtained as colorless needle crystals. M. p. 227.0-229.0 ° C. (3) The compound (195 mg) obtained in (2) above is treated in the same manner as in Example 75 (4), and the resulting crude product is dissolved in methanol and cooled to 10% under ice-cooling. Add hydrochloric acid-methanol solution. After the solvent was distilled off, the residue was recrystallized with a mixed solution of acetone-diethyl ether to give 2-[(2-
Pyridyl) cyclopentyl] carbonyl-5- [2- (4
-Trifluoromethylphenyl) benzoylamino]-
174 mg of isoindoline hydrochloride are obtained as colorless needles. M. p. 185.0-187.0 ° C

Example 77 3-Benzyloxy-2,2-dimethylpropionic acid 2
To a solution of 10 mg of methylene chloride (2 ml), 105 μl of oxalyl chloride was added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, this solution was chlorinated with 432 mg of 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (the compound obtained in Reference Example 40 (5)) and 0.7 ml of triethylamine. Methylene (4m
l) Add dropwise to the solution. After stirring at the same temperature for 4 hours, the organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate, and the solvent is distilled off. Silica gel column chromatography of the residue (developing solvent; n-hexane: ethyl acetate =
After purification by 1: 1), it was powdered with a mixed solution of n-hexane-ethyl acetate to give 2- (3-benzyloxy-2,2-dimethylpropanoyl) -5- [2-
399 mg of (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as a colorless powder. M. p. 124-126 ° C

Example 78 The compound obtained in Example 77 was treated in the same manner as in Example 39 to give 2- (3-hydroxy-2,2-dimethylpropanoyl) -5- [2- (4-tri- Fluoromethylphenyl) benzoylamino] -isoindoline is obtained as colorless crystals. M. p. 180-183 ° C

Example 79 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (Reference Example 40)
(Compound obtained in (5)) and cinnamoyl chloride are treated in the same manner as in Example 32 to give 432 mg of 2-cinnamoyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline as colorless. Obtained as crystals. M. p. 184-195 ° C (decomposition)

Example 80 2-Cinnamoyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (compound obtained in Example 79) 147 mg of tetrahydrofuran (10 ml) -methanol (10 ml) 5% Palladium-carbon (50 mg) is added to the mixed solution, and the mixture is stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was recrystallized from a mixed solution of n-hexane-ethyl acetate to give 2- (3-phenylpropanoyl).
102 mg of -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 188-190 ° C

Example 81 5-Amino-2-[(1H-pyrazol-1-yl) acetyl] -isoindoline (Compound obtained in Reference Example 44 (3)) 438 mg, 2- (4-trifluoromethylphenyl) ) -3-Nitrobenzoic acid (compound obtained in Reference Example 6 (2)) 675 mg and 1-hydroxybenzotriazole 245 mg of dimethylformamide (12
ml) solution under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / hydrochloride 414 m
g and stir at 50 ° C. for 2 hours. Dilute aqueous ammonia was added to the reaction solution, the mixture was stirred for 1 hour, the precipitated crystals were collected by filtration, dried, and recrystallized from ethyl acetate to give 2-
[(1H-pyrazol-1-yl) acetyl] -5- [2
688 mg of-(4-trifluoromethylphenyl) -3-nitrobenzoylamino] -isoindoline are obtained as pale yellow crystals. M. p. 225.5-227.0 ° C

Examples 82 to 112 The corresponding starting materials are treated in the same manner as in Example 81 to give compounds as shown in Table 5.

[0213]

[Table 12]

[0214]

[Table 13]

[0215]

[Table 14]

[0216]

[Table 15]

[0217]

[Table 16]

[0218]

[Table 17]

Example 113 2-[(1H-pyrazol-1-yl) acetyl] -5-
To a solution of [2- (4-methoxymethoxyphenyl) -benzoylamino] -isoindoline (the compound obtained in Example 82) 1.54 g in dioxane (40 ml), 4M.
Hydrochloric acid-dioxane solution (40 ml) was added, and the mixture was stirred at room temperature for 12 hours.
Stir for hours. Diethyl ether is poured into the reaction solution, and the precipitated powder is collected by filtration and dried. The powder is dissolved in water, aqueous ammonia is added, and the mixture is stirred at room temperature for 1 hour. After acetic acid is added (pH is set to 3 to 4), the precipitate is filtered and dried. By recrystallizing the obtained powder with ethanol, 2-
[(1H-pyrazol-1-yl) acetyl] -5- [2
1.26 g of-(4-hydroxyphenyl) benzoylamino] -isoindoline are obtained as pale red crystals. M. p. 229.0-230.5 ° C

Example 114 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-hydroxyphenyl) benzoylamino]
Isoindoline (compound obtained in example 113) 1
To a solution of 20 mg of dimethylformamide (3 ml), 69 mg of potassium carbonate and 0.024 ml of methyl iodide are added, and the mixture is stirred at room temperature for 3.5 hours. Water is poured into the reaction solution, and the precipitated powder is collected by filtration and dried. The powder was dissolved in ethanol by heating, treated with activated carbon, and recrystallized from ethanol to give 2-[(1H-pyrazol-1-yl) acetyl] -5- [2- (4-methoxyphenyl) -benzoylamino]. -46 mg of isoindoline are obtained as colorless crystals. M. p. 143-145 ° C

Example 115 The corresponding starting material compound was treated in the same manner as in Example 114 to obtain the compounds shown in Table 6.

[0222]

[Table 18]

Example 116 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-hydroxyphenyl) benzoylamino]
Isoindoline (compound obtained in example 113) 1
To a solution of 37 mg of dimethylformamide (3 ml), 86 mg of potassium carbonate and 98 mg of 2-bromoethyltetrahydropyranyl ether were added, and the mixture was allowed to stand at room temperature for 50 hours for 50 hours.
Stir for 10 hours. The reaction solution is cooled to room temperature, water is poured, and the precipitated powder is collected by filtration and dried. Preparative chromatography of the powder (developing solvent; chloroform:
Purify with methanol = 20: 1), dissolve the resulting foamy substance in methanol (3 ml), add 5 mg of p-toluenesulfonic acid monohydrate, and stir at room temperature for 2.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 20: 1) and recrystallized from ethyl acetate to give 2-[(1H
-Pyrazol-1-yl) acetyl] -5- [2- (4-
46 mg of (2-hydroxyethoxy) phenyl) -benzoylamino] -isoindoline are obtained as colorless crystals. M. p. ~ 113 ° C

Example 117 2- (1H-pyrazol-1-yl) acetyl-5-
[2- (4-hydroxyphenyl) -benzoylamino]
Isoindoline (compound obtained in example 113)
To a suspension of 4.84 g and 4.91 ml of triethylamine in methylene chloride (100 ml), a solution of 4.1 g of phenylacetyl chloride in methylene chloride (50 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hours. Pour the reaction solution into water,
Extract with chloroform. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 25: 1), and recrystallized from ethyl acetate to give 2- (1H-pyrazol-1-yl) acetyl-. 5- [2- (4-phenylacetoxyphenyl)
4.34 g of -benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 169.5-171.5 ° C

Example 118 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-Trifluoromethylphenyl) -3-nitrobenzoylamino] -isoindoline (compound obtained in Example 81) 600 mg and 10% palladium-
A suspension of 300 mg of carbon in acetic acid (30 ml) is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 8 hours. After removing the catalyst by filtration and concentrating the filtrate, the residue is dissolved in dimethylformamide.
Dilute aqueous ammonia is added, the precipitated powder is collected by filtration, dissolved by heating in a mixed solvent of chloroform-ethanol, and treated with activated carbon. Then, by recrystallizing with a mixed solvent of chloroform-ethanol, 2-[(1H-pyrazole-
427 mg of 1-yl) acetyl] -5- [2- (4-trifluoromethylphenyl) -3-aminobenzoylamino] -isoindoline are obtained as colorless crystals. M. p. 238.0-240.0 ° C

Example 119 2-[(1H-pyrazol-1-yl) acetyl] -5-
[2- (4-Trifluoromethylphenyl) -3-aminobenzoylamino] -isoindoline (Example 118
170 mg, the compound obtained in 1.), N, N-dimethylglycine / hydrochloride 58 mg, 1-hydroxybenzotriazole 45 mg and 4-dimethylaminopyridine 5 mg
78 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / hydrochloride was added to a dimethylformamide (5 ml) solution of 8:
Stir for hours. Dilute aqueous ammonia is poured, and the precipitated powder is collected by filtration and dried. The resulting powder was purified by preparative chromatography (developing solvent; chloroform: methanol = 20: 1) and then recrystallized from a mixed solution of chloroform-ethanol to give 2-[(1H-pyrazol-1-yl) acetyl. ] -5- [2- (4-Trifluoromethylphenyl) -3- (dimethylaminoacetylamino) -benzoylamino] -isoindoline 9
2 mg are obtained as colorless crystals. M. p. 263-265 ° C

Examples 120-121 The corresponding starting materials were treated in the same manner as in Example 119 to give compounds shown in Table 7.

[0228]

[Table 19]

Example 122 (1) Under an argon atmosphere, 2- (1H-pyrazole-1)
-Yl) acetyl-5- [3-methoxycarbonyl-2
-(4-Trifluoromethylphenyl) benzoylamino] -isoindoline (compound obtained in Example 90)
137 mg and 1 M aqueous sodium hydroxide solution 1.25
A solution of ml of methanol (6 ml) is heated under reflux for 10 hours. After cooling to room temperature, the reaction solution is concentrated. Water is added to the residue, the liquid is made acidic with a 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 2- (1H-pyrazol-1-yl) acetyl-5- [3-hydroxycarbonyl-2- (4-
82 mg of trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 178.0-182.0 ° C. (2) 80 mg of the compound obtained in (1) above, 25 mg of dimethylamine hydrochloride, 24 mg of 1-hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide. A solution of 36 mg of the hydrochloride salt and 3 mg of 4-dimethylaminopyridine in dimethylformamide (6 ml) is stirred at room temperature overnight. The reaction solution is poured into a dilute aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 12: 1), and recrystallized with a mixed solution of ethyl acetate-diisopropyl ether to give 2- (1H-pyrazole). 84 mg of -1-yl) acetyl-5- [3-dimethylaminocarbonyl-2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless needles. M. p. 172.0-174.0 ° C

Example 123 The compound shown in Table 8 is obtained by treating the compound obtained in Example 122 (1) and morpholine in the same manner as in Example 122 (2).

[0231]

[Table 20]

Example 124 2- (1H-pyrazol-1-yl) acetyl-5-
A solution of 243 mg of [2- (4-trifluoromethylphenyl) -3-benzyloxybenzoylamino] -isoindoline (the compound obtained in Example 105) in methanol (8 ml) -ethyl acetate (4 ml) was charged with 10% palladium- 82 mg of carbon is suspended, and under a hydrogen atmosphere, room temperature,
Stir at atmospheric pressure for 3 days. After removing the catalyst by filtration and concentrating the filtrate,
The residue was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give 2- (1H-pyrazole-1).
192 mg of -yl) acetyl-5- [2- (4-trifluoromethylphenyl) -3-hydroxybenzoylamino] -isoindoline are obtained as colorless needles. M. p. 191.0-192.5 ° C

Example 125 By treating the compound obtained in Example 106 in the same manner as in Example 124, the compounds shown in Table 9 are obtained.

[0234]

[Table 21]

Example 126 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) -3-hydroxybenzoylamino] -isoindoline (Example 124) under an argon atmosphere. To a solution of 80 mg of the compound obtained in 1.) in dimethylformamide (2 ml), 66 mg of potassium carbonate and 19 mg of dimethylcarbamoyl chloride were added,
Stir for 30 minutes at 50 ° C. Cool the reaction to room temperature,
Pour into ice water and extract with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl).
-3-Dimethylcarbamoyloxybenzoylamino]
-84 mg of isoindoline are obtained as colorless needles. M. p. 232.0-233.0 ° C

Example 127 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) -3-hydroxybenzoylamino] -isoindoline (Example 124) under an argon atmosphere. Compound obtained in 1.) 1.27 g
In dimethylacetamide (10 ml) of 1.38 g of potassium carbonate, ethyl bromoisobutyrate 1.9.
Add 5 g and stir at 60 ° C. for 6 hours. The reaction solution is cooled to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: ethyl acetate = 1: 1).
2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-trifluoromethylphenyl) -3- (by recrystallizing with a mixed solvent of n-hexane-ethyl acetate. 1-Ethoxycarbonyl-1-methylethoxy) benzoylamino]]-isoindoline 839
mg is obtained as colorless needles. M. p. 179.0-181.0 ° C

Examples 128 to 133 The corresponding starting materials were treated in the same manner as in Example 127 to give compounds shown in Table 10.

[0238]

[Table 22]

Example 134 2- (1H-pyrazol-1-yl) acetyl-5-
[2- (4-trifluoromethylphenyl) -3- (1
-Methoxycarbonyl-1-methylethoxy) benzoylamino]]-isoindoline (compound obtained in Example 128) 31 mg ethanol (0.5 ml) -tetrahydrofuran (1 ml) mixed solution at room temperature, 1M sodium hydroxide. Aqueous solution (55 μl) is added, and the mixture is stirred at the same temperature for 3 days. Adjust to pH 2 with 10% hydrochloric acid and extract with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to column chromatography (Yamazen Co., Ltd. Ultrapack TM diol,
The developing solvent was purified with chloroform: methanol = 95: 5), and the residue was lyophilized with tert-butyl alcohol to give 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-tri 27 mg of fluoromethylphenyl) -3- (1-carboxy-1-methylethoxy) benzoylamino]]-isoindoline are obtained as a colorless powder. MS (ESI) m / z; 591 (M-H), IR (Nu
jol) cm ⁻¹ : 1729.

Examples 135 to 136 By treating the compound obtained in Example 134 and the corresponding starting material compound in the same manner as in Example 122, the compounds shown in Table 11 are obtained.

[0241]

[Table 23]

Example 137 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (compound obtained in Reference Example 44 (3)) 242 mg, 2- (4-trifluoromethylphenyl) benzoic acid Acid 293mg, triethylamine 167μ
A solution of 1 and 195 mg of diethyl cyanophosphonate in dimethylformamide (10 ml) is stirred at room temperature for 23 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline,
Dry over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 100: 1) to give 2- (1H-pyrazol-1-yl) acetyl-.
412 mg of 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 46 (2)) are obtained.

Examples 138-141 The corresponding starting compounds were treated in the same manner as in Example 137 to obtain the compounds shown in Table 12.

[0244]

[Table 24]

Example 142 (1) To a solution of 1.59 g of 2- (4-trifluoromethylphenyl) benzoic acid in methylene chloride (30 ml) was added oxalyl chloride (1.05 ml) and dimethylformamide (4 drops), and the mixture was stirred at room temperature for 1 hour. Stir for hours. The reaction solution is concentrated,
Toluene is added to the residue, the insoluble matter is removed by decantation, and the procedure of concentration is repeated twice. 2- (4-trifluoromethylphenyl) benzoic acid chloride 1.7
3 g are obtained as a pale yellow oil. (2) 5-Amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (compound obtained in Reference Example 44 (3)) 1.21 g of methylene chloride (40 ml)
To the suspension, 1.05 ml of triethylamine was added, and a solution of 1.73 g of 2- (4-trifluoromethylphenyl) benzoyl chloride obtained in (1) above in methylene chloride (10 ml) was added dropwise under ice cooling. . The reaction is stirred at room temperature for 1.5 hours. Ethyl acetate is added to the reaction solution to dilute it, and the organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 100: 1).
And purified by recrystallization from ethyl acetate.
(1H-pyrazol-1-yl) acetyl-5- [2-
(4-Trifluoromethylphenyl) benzylamino]
2.30 g of isoindoline (compound obtained in Example 46 (2)) are obtained. M. p. 207-209 ° C

Example 143 (1) 2- (1H-pyrazol-1-yl) acetyl-
5- [2- (4-nitrophenyl) benzoylamino]-
Isoindoline (compound obtained in Example 138) 26
3 mg, 10% palladium-carbon 136 mg acetic acid (5
ml) -tetrahydrofuran (5 ml) suspension is stirred under hydrogen atmosphere at room temperature and atmospheric pressure for 2 hours. The catalyst was filtered off,
The filtrate is concentrated, the residue is dissolved in ethyl acetate, the organic layer is washed with aqueous potassium carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent, 2
-(1H-pyrazol-1-yl) acetyl-5- [2
229 mg of-(4-aminophenyl) benzoylamino] -isoindoline are obtained. M. p. Decomposition gradually from 135 ° C. (2) A solution of 89 mg of the compound obtained in (1) above, 23 μl of acetic anhydride and 34 μl of triethylamine in methylene chloride (4 ml) was stirred at room temperature for 6.5 hours. The reaction solution is diluted with chloroform, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, and dried over anhydrous sodium sulfate. The residue is subjected to preparative chromatography (developing solvent; chloroform: methanol = 20: 1).
After being purified by 10: 1), it is washed with ethyl acetate-diisopropyl ether to give 2- (1H-pyrazol-1-yl) acetyl-5- [2- (4-acetylaminophenyl) benzoylamino]-. 60 mg of isoindoline are obtained. M. p. Decomposes gradually from 182 ℃

Example 144 2- (1H-pyrazol-1-yl) acetyl-5-
[2- (4-Aminophenyl) benzoylamino] -isoindoline (Compound obtained in Example 143 (1)) 8
A solution of 9 mg, 19 μl methanesulfonyl chloride and 82 μl pyridine in methylene chloride (4 ml) is stirred at room temperature for 7 hours. The reaction solution is diluted with chloroform, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, and dried over anhydrous sodium sulfate. The residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 10: 1) and then washed with ethyl acetate-diisopropyl ether to give 2- (1H
-Pyrazol-1-yl) acetyl-5- [2- (4-
Methanesulfonylaminophenyl) benzoylamino]
-58 mg of isoindoline are obtained. M. p. Decomposes gradually from 130 ℃

Example 145 2- (1H-pyrazol-1-yl) acetyl-5-
[2- (4-propionylphenyl) benzoylamino]
-Isoindoline (compound obtained in Example 139) 1
2 mg of an ethanol (5 ml) -water (0.25 ml) mixture of 22 mg and 90 mg of hydroxylamine hydrochloride was added.
Heat to reflux for 3 hours. The solvent is evaporated, ethyl acetate is added to the residue, the organic layer is washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue is preparative chromatography (developing solvent; chloroform: methanol =
After being purified by 15: 1), it was recrystallized from methanol to give 2- (1H-pyrazol-1-yl) acetyl-5- {2- [4- (1-hydroxyiminopropyl).
Phenyl] benzoylamino} -isoindoline 74m
get g. M. p. 225-228 ° C

Example 146 2- (1H-pyrazol-1-yl) acetyl-5-
[2- (4-propionylphenyl) benzoylamino]
-Isoindoline (compound obtained in Example 139) 1
29 mg of ethanol (5 ml) -tetrahydrofuran (5 ml) solution was added with sodium borohydride 1 under ice cooling.
Add 8 mg, and stir under ice cooling for 1 hour and at room temperature for 5.5 hours. The reaction solution is diluted with ethyl acetate, the organic layer is washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by preparative chromatography (developing solvent; chloroform: methanol = 15: 1), and recrystallized from methanol to give 2-
(1H-pyrazol-1-yl) acetyl-5- {2-
74 mg of [4- (1-hydroxypropyl) phenyl] benzoylamino} -isoindoline are obtained. M. p. 179-182 ° C

Example 147 (1) 2-chloroacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (the compound obtained in Example 46 (1)) 1000 m
g of 1,3-dimethyl-2-imidazolidinone (5 m
l) Sodium azide (284 mg) is added to the solution under ice cooling, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is dissolved in tetrahydrofuran (20 ml) -ethanol (20 ml), 10% palladium-carbon (300 mg) is added, and the mixture is catalytically reduced under a hydrogen atmosphere and normal pressure for 1 hour. Palladium-carbon was filtered off,
The residue obtained by concentrating the filtrate is used as a hydrochloride to obtain 812 mg of 2-aminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride as colorless crystals. M. p. 188-190 ° C (2) 10% of 176 mg of the compound obtained in the above (1)
Aqueous potassium carbonate solution (10 ml) -ethyl acetate (10 m
l) A mixed solution of acetyl chloride (200 μm) under ice cooling.
1) is added, and the mixture is stirred at the same temperature for 30 minutes. The organic layer is separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was crystallized from a mixed solution of ethyl acetate-n-hexane to give 2-acetylaminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline 118m.
g are obtained as colorless crystals. M. p. 208-210 ° C

Example 148 2-Aminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline.
Hydrochloride (Compound obtained in Example 147 (1)) 151
To a mixed solution of 10% aqueous potassium carbonate solution (10 ml) -ethyl acetate (10 ml) was added 40 μl of methyl chlorocarbonate under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The organic layer is separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is crystallized from ethyl acetate-diisopropyl ether to give 2-methoxycarbonylaminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline (98 mg) as colorless crystals. M. p. 221-222 ° C

Example 149 2-Aminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline.
Hydrochloride (Compound obtained in Example 147 (1)) 205
A solution of mg, 2-bromopyrimidine 205 mg and triethylamine (400 mg) in ethanol (3 ml) is heated under reflux for 18 hours. The reaction mixture is concentrated, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform-methanol = 100: 1 to 50: 1), and recrystallized with a mixed solution of ethyl acetate-diisopropyl ether to give 2- (Pyrimidin-2-yl) aminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline 9
5 mg are obtained as colorless crystals. M. p. 196-198 ° C

Example 150 (1) 2-Aminoacetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (Compound obtained in Example 147 (1))
A solution of 205 mg, 2,5-dibromopyridine 306 mg and diisopropylethylamine 400 mg in ethanol (3 ml) is heated at 150 ° C. for 5 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform-methanol = 100: 1 to 50:
After purification in 1), it was recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 2- (5-bromopyridin-2-yl) aminoacetyl-5- [2-
60 mg of (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless crystals. (2) Dissolve 60 mg of the compound obtained in (1) above in 3 ml of tetrahydrofuran-3 ml of ethanol to obtain 10%.
Palladium-carbon 20 mg, triethylamine 0.1 m
1 is added, and the mixture is subjected to catalytic reduction under hydrogen atmosphere and normal pressure for 4 hours. Palladium-carbon is filtered off, the filtrate is made alkaline with 10% aqueous potassium carbonate solution, and then extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate-diisopropyl ether to give 2- (pyridin-2-yl) aminoacetyl-5-.
31 mg of [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 201-204 ° C

Example 151 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (Reference Example 40)
209 mg of the compound obtained in (5) is suspended in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, the organic layer is separated, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is dissolved in ethanol (5 ml), 30 mg of acetic acid and 105 mg of 2-vinylpyridine are added, and the mixture is heated under reflux for 1 day. The solvent is distilled off under reduced pressure, the residue is dissolved in chloroform, washed with water and saturated saline and then dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 20: 1) and then recrystallized from ethyl acetate to give 2- [2- (2-pyridyl) ethyl] -5- [2-. (4-trifluoromethylphenyl)
132 mg of benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 195-200 ° C

Example 152 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) 200 m under argon atmosphere
g, 2-phenylethyl bromide 106 mg and potassium carbonate 165 mg in dimethylformamide (2 m
1) is heated and stirred at 60 ° C. for 5 hours. After cooling to room temperature,
The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 5).
After purification with 0: 1), recrystallization with a mixed solution of ethyl acetate-diisopropyl ether gave 2- (2-
Phenylethyl) -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline 12
3 mg are obtained as colorless needles. M. p. 231.5-
232.5 ° C

Examples 153 to 168 The corresponding starting materials were treated in the same manner as in Example 152 or Example 152 and Example 2 (2) to give the first compound.
The compounds listed in Table 3 are obtained.

[0257]

[Table 25]

[0258]

[Table 26]

[0259]

[Table 27]

Example 169 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) 199 m under an argon atmosphere.
g, 126 mg of 3-chloromethylpyridine and 0.23 ml of triethylamine in ethanol (4 ml)
Is heated and stirred at 50 ° C. for 19 hours. After cooling to room temperature, the reaction solution is concentrated, the residue is dissolved in chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 40: 1), and recrystallized with a mixed solution of methanol-diisopropyl ether to give 2-[(pyridine-3
-Yl) methyl] -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline 91m
g are obtained as colorless needles. M. p. 212.5-214 ° C

Example 170 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline.hydrochloride (compound obtained in Reference Example 40 (5)) 200 m under argon atmosphere
g, 2-thiazolecarboxaldehyde 59 mg and triethylamine 51 mg methylene chloride (4 ml)
To the solution is added sodium triacetoxyborohydride (212 mg) at room temperature, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into dilute aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by preparative chromatography (developing solvent; chloroform: methanol = 90: 7). The crude product is dissolved in methanol, and 10% hydrochloric acid-methanol solution is added under ice cooling. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethanol-diethyl ether to give 2- (thiazol-2-yl) methyl-5- [2- (4-trifluoromethylphenyl) benzoylamino]-. 232 mg of isoindoline hydrochloride are obtained as colorless needles. M. p. 182.0-185.0 ° C

Examples 171-174 The corresponding starting materials are treated in the same manner as in Example 170, to give compounds as shown in Table 14.

[0263]

[Table 28]

Example 175 200 mg of 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (compound obtained in Reference Example 40 (5)) under argon atmosphere
And triethylamine 53 mg ethanol (5 m
l) 117 mg of benzyl glycidyl ether is added to the solution at room temperature, and the mixture is heated with stirring at 50 ° C. for 8 hours. After cooling to room temperature, the reaction solution is concentrated. Dilute aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. Water organic layer,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to preparative chromatography (developing solvent; chloroform: methanol = 90: 7).
Purify with. Dissolve the crude product in methanol, and under ice cooling 1
Add 0% hydrochloric acid-methanol solution. The solvent was distilled off, and the residue was recrystallized from a mixed solution of acetone-diethyl ether to give 2- (3-benzyloxy-2-hydroxypropyl) -5- [2- (4-trifluoromethylphenyl) benzoyl. 161 mg of amino] -isoindoline hydrochloride is obtained as colorless needles. M. p. 182.0-186.0 ° C

Example 176 2- (3-benzyloxy-2-hydroxypropyl)
-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride (Example 17
111 mg of the compound obtained in 5) and 10 mg of palladium-carbon (50 mg) in methanol (4 ml) are stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 7 hours. The catalyst was filtered off, the filtrate was concentrated, and the residue was recrystallized from a mixed solution of ethanol-diethyl ether to give 2- (2,3-
92 mg of dihydroxypropyl) -5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride are obtained as colorless needles. M. p. 215.0-218.0 ° C

Example 177 (1) 2-[(1H-pyrazole-
1-yl) acetyl] -5- [2-bromobenzoylamino] -isoindoline (compound obtained in Reference Example 44 (4)) 650 mg and 4-carboxyphenylboronic acid 266 mg in dimethoxyethane (60 ml) suspension. , Palladium acetate 9 mg, triphenylphosphine 4
0 mg and potassium carbonate 740 mg water (20 ml)
The solution is added and the reaction is heated to reflux for 2 hours. The precipitate is filtered off and the filtrate is concentrated. Water is added to the residue, and the solution is made acidic with a 10% aqueous citric acid solution and stirred at room temperature for 1 hour. The powder precipitated during stirring is collected by filtration and dried, whereby 2-
[(1H-pyrazol-1-yl) acetyl] -5- [2
-(4-Carboxyphenyl) benzoylamino] -isoindoline is obtained as a powder. (2) To a suspension of the compound obtained in (1) above in dimethylformamide (10 ml), under ice cooling, potassium carbonate 28
5 mg and 0.165 ml of ethyl iodide are added, and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction solution, the mixture is stirred at room temperature for 1 hour, and the precipitated powder is collected by filtration and dried. The powder was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 25: 1) to give 2-[(1H-pyrazol-1-yl) acetyl]-.
66 mg of 5- [2- (4-ethoxycarbonylphenyl) benzoylamino] -isoindoline are obtained as a colorless powder. MS (APCI) m / z; 495 (M + H), IR (N
ujol) cm ⁻¹ ; 1710, 1660.

Example 178 2- (4-trifluoromethylphenyl) benzoic acid and 5-amino-2- (1H-pyrazol-1-yl) ethyl-isoindoline (compound obtained in Reference Example 51).
In the same manner as in Example 67 (2),
[2- (1H-pyrazol-1-yl) ethyl] -5-
[2- (4-Trifluoromethylphenyl) benzoylamino] -isoindoline (the compound described in Example 168) is obtained as colorless needle crystals.

Example 179 5-Amino-2- (1H-pyrazol-1-yl) ethyl-isoindoline (compound obtained in Reference Example 51) and 2- (4-trifluoromethylphenyl) benzoic acid chloride (Example) By treating the compound obtained in Example 142 (1)) in the same manner as in Example 142 (2),
[2- (1H-pyrazol-1-yl) ethyl] -5-
[2- (4-Trifluoromethylphenyl) benzoylamino] -isoindoline (the compound described in Example 168) is obtained as colorless needle crystals.

Reference Example 1 (1) Under an argon atmosphere, to a solution of methyl 2-iodobenzoate (1.01 g) and 4-methoxymethoxyphenyltributyltin (2.00 g) in dimethylformamide (10 ml) was added bistriphenylphosphine palladium dichloride (138 mg). Stir at 100 ° C. for 3 hours. The reaction solution is cooled to room temperature, diluted with ethyl acetate, added with 10% aqueous potassium fluoride solution, and stirred at room temperature for 1 hour. The reaction solution is filtered through Celite, and the organic layer is separated from the filtrate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 30 to 1:10), and 776 mg of methyl 2- (4-methoxymethoxyphenyl) benzoate was obtained. Obtained as a yellow oil. (2) To a solution of 757 mg of the compound obtained in (1) above in methanol (15 ml) is added 3.3 ml of a 1M aqueous sodium hydroxide solution, and the mixture is stirred at 50 ° C. for 12 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. The residue is dissolved in water and washed with ether. Cool the water layer with an ice bath and
Hydrochloric acid is added dropwise to neutralize and then extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is distilled off to obtain 644 mg of 2- (4-methoxymethoxyphenyl) benzoic acid as a colorless powder. MS (ESI) m / z; 257 (MH), IR (Nu
jol) cm ⁻¹ : 1695, 1610.

Reference Example 2-7 (1) The corresponding starting materials are treated in the same manner as in Reference Example 1 (1) to obtain the following compound. Reference Example 2 (1): Methyl 2- (4-trifluoromethylphenyl) -5-methoxybenzoate (colorless oil) MS (EI) m / z; 310 (M), IR (Neat)
cm ⁻¹ : 1730, 1615, 1605. Reference Example 3 (1): Methyl 2- (4-trifluoromethylphenyl) -4,5-dimethoxybenzoate (colorless solid) MS (APCI) m / z; 341 (M + H), IR (N)
ujol) cm ⁻¹ : 1700. Reference Example 4 (1): Methyl 2- (4-trifluoromethylphenyl) -3-methoxybenzoate (colorless solid) MS (APCI) m / z; 311 (M + H), IR (N)
ujol) cm ⁻¹ : 1730, 1680. Reference Example 5 (1): Methyl 2- (4-trifluoromethylphenyl) -3-methoxycarbonylbenzoate (colorless solid) MS (EI) m / z; 338 (M), IR (Nujo)
1) cm < ^-1 >: 1736, 1726. Reference Example 6 (1): Methyl 2- (4-trifluoromethylphenyl) -3-nitrobenzoate MS (EI) m / z; 325 (M), IR (Neat)
cm ⁻¹ : 1725. Reference Example 7 (1): Methyl 2- (4-isopropylphenyl) benzoate (colorless oil) MS (APCI) m / z; 255 (M + H), IR (N)
eat) cm ⁻¹ : 1723. (2) The compounds shown in Table 15 are obtained by treating the compounds obtained in (1) above in the same manner as in Reference Example 1 (2).

[0271]

[Table 29]

Reference Example 8 Under an argon atmosphere, a solution of 4.1 g of methyl 2-iodo-3-methoxybenzoate and 3.74 g of 4-trifluoromethylphenylboric acid in dimethoxyethane (50 ml) was added with 79 mg of palladium acetate and triethyl acetate. An aqueous solution of 369 mg of phenylphosphine and 4.86 g of potassium carbonate (1
7.5 ml) is added and the mixture is heated under reflux for 4 hours. The reaction solution is diluted with ethyl acetate, and the insoluble matter is filtered through Celite when hot. The filtrate is concentrated, the residue is dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 40: 1) to give methyl 2- (4-trifluoromethylphenyl) -3-methoxybenzoate. (Compound described in Reference Example 4 (1)) 4.26 g is obtained as a colorless solid.

Reference Example 9 By treating the corresponding starting material compound in the same manner as in Reference Example 8, methyl 2- (4-trifluoromethylphenyl) -3-methoxycarbonylbenzoate (the compound described in Reference Example 5 (1)) As a colorless solid.

Reference Example 10 (1) Methyl 3-methoxy-2- (4-trifluoromethylphenyl) benzoate under an argon atmosphere (Reference Example 4
A mixture of 554 mg of the compound obtained in (1) and 8.26 g of pyridine / hydrochloride is heated and stirred at 190 ° C. for 2 hours. After cooling to room temperature, 10% hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with 10% hydrochloric acid and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixed solution of diisopropyl ether-n-hexane to give 3-hydroxy-2-
(4-Trifluoromethylphenyl) benzoic acid 499m
g are obtained as colorless needles. M. p. 169.0-170.0 ° C (2) 100 mg of the compound obtained in the above (1), 2-
(Dimethylamino) ethyl chloride / hydrochloride 112m
g and 245 mg of potassium carbonate 2-butanone (5 m
l) -dimethylformamide (2 ml) mixed suspension,
Heat and stir at 80 ° C. for 2 hours. After cooling to room temperature, the reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent, 3- (2-dimethylaminoethyl) oxy-2-
150 mg of (2-dimethylamino) ethyl (4-trifluoromethylphenyl) benzoate are obtained as a pale yellow oil. MS (APCI) m / z; 425 (M), IR (Nea
t) cm ⁻¹ : 1723, 1617. (3) Compounds of 328 mg and 1 obtained in the above (2)
A solution of M sodium hydroxide aqueous solution (0.77 ml) in methanol (3.8 ml) is heated under reflux for 2 hours. After cooling to room temperature, the reaction solution was concentrated, and the residue was triturated with diethyl ether to give 3- (2-dimethylaminoethyl) oxy-2- (4-trifluoromethylphenyl).
175 mg of benzoic acid sodium salt is obtained as a pale yellow powder. MS (ESI) m / z; 352 (M-Na), IR (N
ujol) cm ⁻¹ : 1600.

Reference Example 11-21 By treating the corresponding starting material compound in the same manner as in Reference Example 10 (2) (3), the compounds shown in Table 16 are obtained.

[0276]

[Table 30]

[0277]

[Table 31]

Reference Example 22 (1) 2- (4-trifluoromethylphenyl) -3-
A solution of 500 mg of methoxycarbonylbenzoic acid (the compound obtained in Reference Example 5 (2)) in thionyl chloride (2 ml) is heated under reflux for 1 hour. After cooling to room temperature, the reaction solution is concentrated. The residue was dissolved in methylene chloride (5 ml) and cooled with ice,
Concentrated aqueous ammonia (2 ml) is added dropwise over 5 minutes, and the mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was recrystallized from a mixed solution of diisopropyl ether-n-hexane to give 2- (4-trifluoromethylphenyl) -3.
-478 mg of methyl carbamoyl benzoate are obtained as colorless needles. M. p. 174.0-175.5 ° C. (2) A solution of 300 mg of the compound obtained in (1) above in phosphorus oxychloride (1 ml) is heated and stirred at 100 ° C. for 2 hours. After cooling to room temperature, the reaction solution is concentrated. The residue was dissolved in chloroform, water, saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off to give methyl 2- (4-trifluoromethylphenyl) -3-cyanobenzoate 279 mg.
As a colorless oil. MS (EI) m / z; 305 (M), 274 (M-OC)
^{_{H 3, B), IR (}} neat) cm -1; 2232,1
733, 1620. (3) In a mixed solution of 928 mg of the compound obtained in (1) above in dioxane (10 ml) -pyridine (0.58 ml), under ice cooling, trifluoroacetic anhydride (0.60 ml).
Is added dropwise over 5 minutes and stirred at room temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent, 2
867 mg of methyl-(4-trifluoromethylphenyl) -3-cyanobenzoate (the compound described in (2) above) is obtained as a colorless oil. (3) By treating the compound obtained in (2) above in the same manner as in Reference Example 1 (2), 2- (4-trifluoromethylphenyl) -3-cyanobenzoic acid is obtained. M. p. 165.0-167.0 ° C

Reference Example 23 (1) 2- (4-trifluoromethylphenyl) -3-
700 mg of 10% palladium-carbon was suspended in a solution of 2.0 g of methyl nitrobenzoate (the compound obtained in Reference Example 6 (1)) in tetrahydrofuran (50 ml), and under a hydrogen atmosphere, at room temperature and atmospheric pressure for 1.5 hours. Stir. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (developing solvent; n-hexane: chloroform = 4: 1) to give 2- (4-trifluoromethylphenyl)-. 1.46 g of methyl 3-aminobenzoate are obtained as a colorless solid. MS (APCI) m / z; 296 (M + H), IR (N
ujol) cm ⁻¹ : 3485, 3375, 1705,
1615. (2) 300 mg of the compound obtained in the above (1), N, N-dimethylglycine / hydrochloride 214 under an argon atmosphere
mg, 4-dimethylaminopyridine 125 mg, and triethylamine 464 mg tetrahydrofuran (2
(0 ml) suspension, while cooling with ice, a solution of 2,4,6-trichlorobenzoyl chloride in tetrahydrofuran (5 ml) was added to 5 ml.
The mixture is added dropwise over a period of 1 minute and stirred at the same temperature for 3 hours. The reaction mixture is poured into ice-cooled dilute aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is a saturated aqueous sodium hydrogen carbonate solution,
After washing with water and saturated saline, it is dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 3 :).
1 → 3: 2) to obtain 385 mg of methyl 2- (4-trifluoromethylphenyl) -3- (2-dimethylaminoacetyl) aminobenzoate as a colorless powder. MS (APCI) m / z; 381 (M + H), IR (N
ujol) cm ⁻¹ : 1729, 1619. (3) In a tetrahydrofuran (10 ml) solution of the compound (378 mg) obtained in (2) above under an argon atmosphere,
Under ice cooling, 113 mg of sodium borohydride and 564 mg of boron trifluoride / diethyl ether complex salt were added,
Stir at room temperature for 5 hours. The reaction solution is ice-cooled again, 10% hydrochloric acid is added, and the mixture is heated under reflux for 1 hour. The reaction solution is cooled to room temperature, made basic with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 100: 1 → 50: 1) to give 2- (4-trifluoromethylphenyl) -3-.
Methyl 3- (2-dimethylaminoethyl) aminobenzoate 3
04 mg are obtained as a colorless oil. MS (APCI) m / z; 367 (M + H), IR (N
eat) cm ⁻¹ : 3357, 1729, 1616. (4) The compound obtained in (3) above is used in Reference Example 10 (3).
2- (4-trifluoromethylphenyl) -3- (2-dimethylaminoethyl) by treating in the same manner as
Aminobenzoic acid sodium salt is obtained. MS (ESI) m / z; 351 (M-Na), IR (N
ujol) cm ⁻¹ ; 1620.

Reference Example 24 (1) 2- (4-trifluoromethylphenyl) -3-
By treating methyl aminobenzoate (the compound obtained in Reference Example 23 (1)) and picolinic acid in the same manner as in Reference Example 23 (2), 2- (4-trifluoromethylphenyl) -3- (2- Methyl pyridylcarbonylamino) benzoate is obtained as a colorless solid. MS (APCI) m / z; 401 (M + H), IR (N
ujol) cm ⁻¹ : 1730, 1690. (2) Under an argon atmosphere, a solution of 382 mg of the compound obtained in (1) above in tetrahydrofuran (10 ml) was cooled in a dry ice-acetone bath, and 2M-borane dimethyl sulfide complex tetrahydrofuran solution (2.86 ml) was added thereto. , Stir at room temperature for 5 hours. The reaction solution is cooled again in a dry ice-acetone bath, a solution of 2 g of oxalic acid in methanol (10 ml) is added, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Evaporate the solvent,
By purifying the residue by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1), 2- (4-trifluoromethylphenyl)-
Methyl 3- (2-pyridylmethylamino) benzoate 16
3 mg are obtained as a colorless foam. MS (APCI) m / z; 387 (M + H), IR (N
ujol) cm ⁻¹ : 1725. (3) By treating the compound obtained in (2) above in the same manner as in Reference Example 1 (2), 2- (4-trifluoromethylphenyl) -3- (2-pyridylmethylamino) benzoic acid is colorless. Obtained as a foam. MS (ESI) m / z; 371 (M-H), IR (Nu
jol) cm ⁻¹ : 3435, 1700.

Reference Example 25 (1) Under an argon atmosphere, 4-bromopropiophenone 426 mg, 2-methoxycarbonylphenyltributyltin 1024 mg, copper (I) bromide 57 mg, triphenylphosphine 106 mg, 2,6-di-tert.
A solution of one particle of -butyl-p-cresol and 141 mg of bistriphenylphosphine palladium dichloride in dioxane (10 ml) is heated under reflux for 2.5 hours.
The reaction mixture is cooled, ethyl acetate and 10% aqueous potassium fluoride solution are added, and the mixture is stirred. The insoluble matter is filtered through Celite, the organic layer is separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 20: 1) to obtain 461 mg of methyl 2- (4-propionylphenyl) benzoate as a colorless oily substance. MS (APCI) m / z; 269 (M + H), IR (N
eat) cm ⁻¹ : 1728, 1685, 1606. (2) By treating 441 mg of the compound obtained in (1) above in the same manner as in Reference Example 1 (2), 401 mg of 2- (4-propionylphenyl) benzoic acid is obtained. MS (ESI) m / z; 253 (MH), IR (Nu
jol) cm ⁻¹ : 1675, 1604.

Reference Examples 26-30 (1) The corresponding starting materials were treated in the same manner as in Reference Example 25 (1) to give the following compounds. Reference Example 26 (1): 2- (4-trifluoromethyl-2)
-Nitrophenyl) methyl benzoate IR (Nujol) cm < ^-1 >: 1715. Reference Example 27 (1): 2- [4-trifluoromethyl-2
-(2-Methoxyethylaminocarbonyl) phenyl]
Methyl benzoate MS (APCI) m / z; 382 (M + H), IR (N
eat) cm ⁻¹ : 1720, 1665. (In addition, N- (2-methoxyethyl) which is a raw material compound
2-Chloro-5- (trifluoromethyl) benzoic acid amide can be produced as follows. 2-
A solution of 1.25 g of chloro-5- (trifluoromethyl) benzoyl chloride in dichloromethane (15 ml) is cooled in an ice bath, a solution of 939 mg of 2-methoxyethylamine in dichloromethane (5 ml) is added dropwise, and the mixture is stirred for 2 hours.
The reaction solution is brought to room temperature, diluted with chloroform, and then washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.50 g of N- (2-methoxyethyl) -2-chloro-5- (trifluoromethyl) benzoic acid amide as a colorless solid. obtain. MS (AP
CI) m / z; 282 (M + H), IR (Nujol)
cm ^<-1> : 1655. ) Reference Example 28 (1): Methyl 2- (4-formylphenyl) benzoate MS (EI) m / z; 240 (M). Reference Example 29 (1): Methyl 2- (4-cyanophenyl) benzoate MS (EI) m / z; 310 (M), IR (Neat)
cm ⁻¹ : 1730, 1615, 1605. Reference Example 30 (1): Methyl 2- (4-nitrophenyl) benzoate MS (EI) m / z; 237 (M), IR (Neat).
cm ⁻¹ : 2228, 1727, 1609. (2) By treating the compound obtained in (1) above in the same manner as in Reference Example 1 (2), the compounds shown in Table 17 are obtained.

[0283]

[Table 32]

Reference Example 31 (1) Methyl 2- (4-formylphenyl) benzoate (compound obtained in Reference Example 28 (1)) 350 mg of acetone (15 ml) was added to potassium permanganate 34.
A 5 mg solution of water (10 ml) is added dropwise. After stirring at room temperature for 2 hours, the reaction solution is filtered through Celite. Acetone is distilled off from the filtrate, 10% hydrochloric acid is added to the obtained aqueous layer, and the mixture is extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off,
4- (2-methoxycarbonylphenyl) benzoic acid 30
1 mg is obtained as a colorless powder. MS (ESI) m / z; 255 (MH), IR (Ne
at) cm < ^-1 >: 1730, 1685. (2) To a solution of 290 mg of the compound obtained in (1) above, 138 mg of dimethylamine · hydrochloride, 156 mg of 1-hydroxybenzotriazole and 5 mg of 4-dimethylaminopyridine in dimethylformamide (5 ml), 0.4 ml of triethylamine and 1-ethyl ester. -3- (3-Dimethylaminopropyl) -carbodiimide / hydrochloride 43
Add 1 mg and stir at room temperature for 1 hour. The reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with 1% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
By purification with chloroform: methanol = 40: 1), 280 mg of methyl 2- (4-dimethylcarbamoylphenyl) benzoate is obtained as a pale yellow caramel-like substance. MS (APCI) m / z; 284 (M + H), IR (N
eat) cm ⁻¹ : 1725, 1615, 1635. (3) To a solution of 270 mg of the compound obtained in (2) above in methanol (10 ml) is added 2.9 ml of 1M sodium hydroxide aqueous solution, and the mixture is stirred at room temperature for 36 hours. The reaction solution is concentrated under reduced pressure, and the obtained aqueous layer is washed with diethyl ether. The aqueous layer is cooled in an ice bath, 10% hydrochloric acid is added dropwise, and the mixture is extracted with chloroform. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated to give 240 mg of 2- (4-dimethylcarbamoylphenyl) benzoic acid as a colorless amorphous powder. MS (ESI) m / z; 268 (MH), IR (Nu
jol) cm ⁻¹ : 1700.

Reference Example 32-34 4- (2-methoxycarbonylphenyl) benzoic acid (the compound obtained in Reference Example 31 (1)) and the corresponding starting compound were treated in the same manner as in Reference Example 31 (2) (3). By treating, the compounds shown in Table 18 are obtained.

[0286]

[Table 33]

Reference Example 35 (1) Under argon atmosphere, 1.50 g of methyl 2-phenylbenzoate and 1.44 g of acetic anhydride in methylene chloride (50
ml) solution, add 3.77 g of aluminum chloride, and add 3
Heat to reflux for days. The reaction solution was poured into ice water, the organic layer was washed with water,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 4).
2- (4-acetylphenyl)
444 mg of methyl benzoate are obtained as a colorless caramel-like substance. MS (APCI) m / z; 255 (M + H), IR (N
eat) cm ⁻¹ : 1725, 1685, 1605. (2) The compound obtained in the above (1) is used in Reference Example 1 (2).
2- (4-Acetylphenyl) benzoic acid is obtained as a colorless powder by the same treatment. MS (ESI) m / z; 239 (M-H), IR (Ne
at) cm ⁻¹ : 1695, 1675.

Reference Example 36 (1) Under argon atmosphere, 1144 mg of N, N-dimethyl-4-bromobenzoic acid amide and bis (pinacolato)
Diboron 1430 mg, potassium acetate 1480 mg,
[1,1'-bis (diphenylphosphino) ferrocene]
A mixture of 123 mg of dichloropalladium methylene chloride complex in 30 ml of dimethylformamide is stirred at 80 ° C. for 2.5 hours. Ethyl acetate and water are added to the reaction solution, and insoluble matter is removed by filtration using Celite. The organic layer is separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 2: 1) to give N, N-dimethyl- [4- (4,4.
4,5,5-Tetramethyl (1,3,2-dioxaborolan-2-yl)) phenyl] carboxamide 980m
get g. MS (APCI) m / z; 276 (M + H), IR (n
eat) cm ⁻¹ ; 1638. (2) 2-iodo-3-methoxy-under an argon atmosphere
Benzoic acid benzyl ester 266 mg, N, N-dimethyl- [4- (4,4,5,5-tetramethyl (1,3,3
2-Dioxaborolan-2-yl)) phenyl] carboxamide 303 mg, 2M aqueous sodium carbonate solution 2.5
ml, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium methylene chloride complex 24.2 m
A mixture of 5 g of dimethylformamide in g is stirred at 80 ° C. for 3 hours. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1) to give 276 mg of 2- (4-N, N-dimethylcarbamoylphenyl) -3-methoxy-benzoic acid benzyl ester. obtain. MS (APCI) m / z; 39
0 (M + H), IR (neat) cm ⁻¹ ; 1723,
1633. (3) 263 mg and 1 of the compound obtained in (2) above
A tetrahydrofuran (7 ml) -water (0.7 ml) mixed suspension of 0% palladium-carbon 84.4 mg is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 2 hours. The catalyst was filtered off,
By concentrating the filtrate, 2- (4-N, N-dimethylcarbamoylphenyl) -3-methoxy-benzoic acid 1
91 mg are obtained. MS (APCI) m / z; 300 (M + H), IR (n
eat) cm ⁻¹ ; 1703, 1613.

Reference Example 37 N, N-dimethyl-4-bromobenzoic acid amide 227 mg, bis (pinacolato) diboron 286 mg, potassium acetate 297 mg, [1,1′-bis (diphenylphosphino) ferrocene] dichloro under an argon atmosphere. A mixture of 24.3 mg of palladium methylene chloride complex in 5 ml of dimethylformamide is stirred at 80 ° C. for 2.5 hours. 2-iodo-3-methoxy-benzoic acid benzyl ester 224 mg in the reaction solution, 2M sodium carbonate aqueous solution 2.05
ml, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium methylene chloride complex 20.5 m
g and heat for an additional 2.5 hours. Ethyl acetate and water are added to the reaction solution, and the insoluble matter is removed by filtration using Celite. The organic layer is separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1 → 2: 1) to give 2
-(4-N, N-dimethylcarbamoylphenyl) -3
-Methoxy-benzoic acid benzyl ester (Reference Example 36
148 mg of the compound obtained in (2) is obtained.

Reference Example 38 (1) By treating N, N-dimethyl-4-bromobenzoic acid amide and 2-iodo-3-methoxy-benzoic acid methyl ester in the same manner as in Reference Example 37, 2- (4
-N, N-Dimethylcarbamoylphenyl) -3-methoxy-benzoic acid methyl ester is obtained as a yellow solid. MS (APCI) m / z; 314 (M + H), IR (N
ujol) cm ⁻¹ ; 1715, 1635. (2) By treating the compound obtained in (1) above in the same manner as in Reference Example 1 (2), 2- (4-N, N-dimethylcarbamoylphenyl) -3-methoxy-benzoic acid (Reference Example 36). The compound obtained in (3)) is obtained as a pale yellow solid. MS (ESI) m / z; 298 (MH), IR (Nu
jol) cm ⁻¹ ; 1715.

Reference Example 39 (1) By treating N, N-dimethyl-4-bromobenzoic acid amide and 2-iodo-3-benzyloxy-benzoic acid methyl ester in the same manner as in Reference Example 37, 2
-(4-N, N-dimethylcarbamoylphenyl) -3
-Benzyloxy-benzoic acid methyl ester is obtained. M. p. 115.0-117.5 ° C (2) By treating the compound obtained in (1) above in the same manner as in Reference Example 1 (2), 2- (4-N, N-dimethylcarbamoylphenyl) -3- Benzyloxy-benzoic acid is obtained. M. p. 222.5-223.5 ° C

Reference Example 40 (1) Isoindolin 22.43 g of methanol (10
The solution (0 ml) was cooled in a dry ice-acetone bath, 20.47 g of concentrated sulfuric acid was added dropwise thereto, diethyl ether was added, and the precipitated powder was collected by filtration. After drying under reduced pressure, the obtained powder is dissolved in 220 ml of concentrated sulfuric acid, and 15.8 ml of concentrated nitric acid is added dropwise under ice cooling. After stirring for 2.5 hours, the mixture is poured into ice water, sodium hydroxide (added as a solid) is added to make the mixture basic, and the mixture is extracted with ethyl acetate. Water organic layer,
After washing with saturated saline, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to give 5-nitroisoindoline 2
3.0 g are obtained as crude product. (2) Di-ter was added to a solution of 2.62 g of the compound obtained in (1) above in tetrahydrofuran (40 ml) under ice cooling.
A solution of 3.86 g of t-butyl dicarbonate in tetrahydrofuran (10 ml) is added dropwise, and the mixture is stirred for 1.5 hours.
The solvent is distilled off, ethyl acetate is added to the residue, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) and recrystallized from a mixed solution of n-hexane-ethyl acetate to give 5-nitro-2- (tert- 3.09 g of butoxycarbonyl) -isoindoline are obtained. M. p. 159-160 ° C. (3) 3.46 g and 1 of the compound obtained in the above (2)
A suspension of 0% palladium-carbon (340 mg) in tetrahydrofuran (50 ml) was stirred at room temperature under atmospheric pressure at room temperature for 1 hour.
Stir for hours. After removing the catalyst by filtration and concentrating the filtrate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1).
5-amino-2- (tert-butoxycarbonyl)-
3.05 g of isoindoline is obtained as a colorless oil. (4) 7.59 g of the compound obtained in the above (3), 2-
(4-Trifluoromethylphenyl) benzoic acid 8.99
g and 4-dimethylaminopyridine (4.21 g) in methylene chloride (100 ml), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride 7.19 g is added and stirred overnight at room temperature. 5% in the reaction solution
Add an aqueous citric acid solution and extract with chloroform. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue was dissolved in ethyl acetate with heating, treated with activated carbon, and recrystallized from a mixed solution of n-hexane-ethyl acetate to give 2- (tert-butoxycarbonyl)-.
10.8 g of 5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline are obtained as colorless crystals. M. p. 183-185 ° C. (5) To a solution of the compound (10.8 g) obtained in (4) above in dioxane (100 ml) was added 4M hydrochloric acid-dioxane solution (50 ml), and the mixture was stirred at room temperature overnight. Diethyl ether was added and the mixture was stirred at room temperature, and after 30 minutes, the deposited precipitate was collected by filtration and washed with diethyl ether to give 5-
[2- (4-Trifluoromethylphenyl) benzoylamino] -isoindoline hydrochloride 9.37 g is obtained as a crude product.

[0293]

Reference Examples 41-43 The corresponding starting materials were treated in the same manner as in Reference Examples 40 (4) (5) to give the compounds shown in Table 19.

[0295]

[Table 34]

However, the de-tert-butoxycarbonyl reaction in Reference Example 43 (reaction of Reference Example 40 (5)) was
Trifluoroacetic acid is used instead of 4M hydrochloric acid-dioxane.

Reference Example 44 (1) A suspension of 6.60 g of 5-nitro-2- (tert-butoxycarbonyl) -isoindoline (the compound obtained in Reference Example 40 (2)) in dioxane (25 ml) was added,
4M hydrochloric acid-dioxane solution (40 ml) is added, and the mixture is stirred at room temperature overnight. By adding diethyl ether and collecting the deposited precipitate by filtration, 5-nitro-isoindoline.
5.50 g of the hydrochloride salt are obtained as crude product. (2) 4.72 g of the compound obtained in the above (1), (1H
-Pyrazol-1-yl) acetic acid / hydrochloride 2.89 g, 4
1-ethyl-3- (3-dimethylaminopropyl) in a solution of 30 mg of dimethylaminopyridine and 9 ml of triethylamine in dimethylformamide (70 ml).
-Add 4.90 g of carbodiimide-hydrochloride and stir overnight at room temperature. The reaction solution was poured into ice water, and the precipitated powder was collected by filtration, dried and recrystallized from a mixed solution of chloroform-methanol to give 5-nitro-2- (1H-pyrazol-1-yl) acetyl-isoindoline. 5.31 g
Is obtained as colorless crystals. M. p. 247-248 ° C. (3) A suspension of 1.005 g of the compound obtained in (2) above and 98 mg of 10% palladium-carbon in acetic acid (15 ml) is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 1 hour.
The catalyst was removed by filtration, the filtrate was concentrated, and the residue was recrystallized with a mixed solution of chloroform-methanol to give 759 mg of 5-amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline as colorless crystals. Get as. M. p. 218-219 ° C. (4) By treating the compound obtained in (3) above and 2-bromobenzoic acid in the same manner as in Reference Example 31 (2), 2
-[(1H-pyrazol-1-yl) acetyl] -5-
[2-Bromobenzoylamino] -isoindoline is obtained as colorless crystals. M. p. 192.5-194.0 ° C

Reference Example 45 To a solution of tert-butyl bromoacetate (5.00 g) in dimethylformamide (20 ml), 2.09 g of pyrazole and 7.07 g of potassium carbonate were added. 1 hour at room temperature,
After stirring at 50 ° C. for 3.5 hours, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent;
By purification with ethyl acetate: n-hexane = 1: 3, (1H-pyrazol-1-yl) acetic acid tert-
4.23 g of butyl are obtained as a colorless oil. (2) 4M hydrochloric acid-dioxane solution 2 was added to a solution of 4.21 g of the compound obtained in (1) above in dioxane (10 ml).
Add 5 ml and stir at room temperature for 12 hours. Diethyl ether was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and the precipitated powder was collected by filtration and dried under reduced pressure to give (1H-pyrazol-1-yl) acetic acid hydrochloride (3.50 g) as a colorless powder. obtain.

Reference Example 46 (1) 170 g of pyrazole and 260 m of methyl bromoacetate
1 and 414 g of potassium carbonate in acetone were added to 2
Heat to reflux for 5 hours. After cooling to room temperature, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. By distilling the residue,
580 g of methyl (1H-pyrazol-1-yl) acetate are obtained. B. p. 105-120.0 ° C. (15 mmHg) (2) 219 g of the compound obtained in (1) above is dissolved in 2M aqueous hydrochloric acid solution (1.5 L) and heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure to 500 ml, pH is adjusted to 0.5-0.6 by adding potassium carbonate under ice cooling, and the formed precipitate is collected by filtration and dried under reduced pressure. By recrystallizing with 2 L of tetrahydrofuran, (1H-pyrazol-1-yl)
127.3 g of acetic acid are obtained. M. p. 171-172 ° C

Reference Example 47 (1) To a solution of 4-nitropyrazole (1.0 g) and potassium carbonate (1.82 g) in dimethylformamide (10 ml) was added tert-butyl bromoacetate (1.81 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To do. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent;
Purification with n-hexane: ethyl acetate = 4: 1) gives 1.88 g of tert-butyl (4-nitro-1H-pyrazol-1-yl) acetate as a pale yellow solid. MS (APCI) m / z; 228 (M + H), IR (N
ujol) cm ⁻¹ : 1749, 1705. (2) 1.87 g of the compound obtained in (1) above is dissolved in a 4M hydrochloric acid-dioxane (20 ml) solution, the mixture is stirred at room temperature for 3 days, and the reaction mixture is concentrated under reduced pressure. Toluene is added to the residue and concentrated again. The residue is diethyl ether-n
-By recrystallizing with a mixed solution of hexane, (4-
1.40 g of nitro-1H-pyrazol-1-yl) acetic acid
Is obtained as colorless prism crystals. M. p. 156.5-157.0 ° C

Reference Example 48 The corresponding starting material compound was treated in the same manner as in Reference Example 47 (1) (2) to give (3-amino-4-cyano-1H-pyrazol-1-yl) acetic acid · hydrochloride. . MS (ESI) m / z; 165 (MH), IR (Nu
jol) cm ⁻¹ ; 2241, 1749.

Reference Example 49 Pyrazole 6.8 g of dimethylformamide (10 m
l) To the solution, 4 g of 60% sodium hydride is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. 1,2-dibromoethane 9
Add 3.5 g under ice cooling and stir at room temperature overnight. Diethyl ether is added to the reaction solution, the insoluble matter is filtered off, and the mixture is concentrated under reduced pressure. By purifying the residue by silica gel column chromatography (developing solvent; ethyl acetate), 1- (2
2.0 g of -bromoethyl) pyrazole are obtained as a colorless oil. MS (APCI) m / z; 177,175 (M + H).

Reference Example 50 (1) 102 g of pyrazole and chloroacetamide 16
8 g of dimethylformamide (1 L) solution is cooled in a dry ice-acetone bath. 72 g of sodium hydroxide is added in several times, and the mixture is stirred at room temperature for 1.5 hours. 262 g of o-dichloroxylene dimethylformamide (50
(0 ml) solution, then cooled in a dry ice-acetone bath, and 132 g of sodium hydroxide is added in several portions. After stirring at room temperature for 2 hours, the reaction solution was mixed with ice water (ice 2 L,
Pour into 4 L of water), add 10% aqueous hydrochloric acid to adjust the pH to 6 to 7, and collect the precipitate by filtration. The precipitate is washed with diisopropyl ether and then dried. By recrystallizing with a tetrahydrofuran-methanol (1: 1) mixed solvent, 2
179 g of-(1H-pyrazol-1-yl) acetylisoindoline are obtained as colorless crystals. M. p. 214-215 ° C. (2) Isoindolin 699 mg, (1H-pyrazol-1-yl) acetic acid / hydrochloride (compound obtained in Reference Example 45 (2)) 900 mg, 1-hydroxybenzotriazole 785 mg and triethylamine 0.81 ml To the dimethylformamide (30 ml) solution, 1.10 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride is added, and the mixture is stirred at room temperature for 6 hours.
The reaction solution is poured into ice water, and the precipitated powder is collected by filtration and dried. By recrystallizing the obtained powder with methanol, 2- (1H-pyrazol-1-yl) acetyl-isoindoline (the compound obtained in the above (1)) 1.00
g are obtained as colorless crystals. (3) 2- (1H-pyrazol-1-yl) acetyl-
To a solution of 11.87 g of isoindoline (the compound obtained in (1) or (2) above) in concentrated sulfuric acid (60 ml), concentrated nitric acid (3.6 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. . The reaction solution is poured into ice water, the deposited precipitate is filtered, washed with water, and dried. By recrystallizing the obtained crude product with a mixed solvent of acetic acid-water, 5-nitro-2- (1H
-Pyrazol-1-yl) acetyl-isoindoline 1
0.62 g are obtained as colorless crystals. M. p. 247-248 ° C

Reference Example 51 5-Amino-2- (1H-pyrazol-1-yl) acetyl-isoindoline (Reference Example 44) under an argon atmosphere.
To a solution of 800 mg of the compound obtained in (3)) in anhydrous tetrahydrofuran (80 ml), 625 mg of sodium borohydride is added. To this mixture was added 3.04 g of boron trifluoride diethyl ether complex under ice cooling, and the mixture was heated under reflux for 1 hour while gradually raising the temperature. Cool to room temperature, 1
0% Hydrochloric acid water (10 ml) is added dropwise and the mixture is heated under reflux for 1 hr. Cool to room temperature, add potassium carbonate (add as solid) to make the reaction mixture basic, and extract with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is preparative chromatography (developing solvent; chloroform: methanol = 1)
After purification with 0: 1), recrystallized with a mixed solvent of ethyl acetate-diisopropyl ether to give 395 mg of 5-amino-2- (1H-pyrazol-1-yl) ethyl-isoindoline as colorless needle crystals. obtain.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 405/06 C07D 405/06 409/06 409/06 417/06 417/06 // A61K 31/4035 A61K 31/4035 31/4155 31/4155 31/4178 31/4178 31/4196 31/4196 31/427 31/427 31/4439 31/4439 31/4709 31/4709 31/506 31/506 31/5377 31 / 5377 31/553 31/553 A61P 3/06 A61P 3/06 43/00 111 43/00 111 (72) Inventor Koichi Nagata 1-18-5 Tajima, Saitama City Saitama Prefecture Land Heights Nishiurawa Room 202 (72) Inventor Mikiko Yasuhara 2-4-8 Nakamachi, Toda City, Saitama Seju Fuji B-203 F term (reference) 4C063 AA01 BB04 CC07 CC12 CC14 CC22 CC25 CC29 CC41 CC57 CC62 CC76 CC92 DD04 DD06 DD07 EE01 4C086 AA01 AA13 BC17 BC10 BC BC28 BC36 BC38 BC42 BC60 BC73 BC75 BC82 BC84 GA02 GA 04 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZC02 ZC33 4C204 AB01 BB01 CB04 DB01 EB01 FB20 GB32

Claims (20)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl Group, an optionally substituted heterocyclic group, or an optionally substituted aryl group)), or a pharmaceutically acceptable salt thereof. 2. A benzene ring in which ring A may be substituted with the same or different 1 to 3 groups selected from the following (1) to (10): (1) trifluoromethyl group, (2) A lower alkyl group which may be substituted with 1 to 3 same or different groups selected from a hydroxyl group, an oxo group and a hydroxyimino group, (3) the same selected from a lower alkoxy group, a hydroxyl group and a lower alkylamino group Or a lower alkoxy group which may be substituted with 1 to 3 different groups, (4)
A carbamoyl group which may be substituted with a group selected from a hydroxyl group, (5) nitro group, (6) cyano group, (7) lower alkyl group, lower alkoxy lower alkyl group, halogeno lower alkyl group, and aryl lower alkyl group. ,
(8) an amino group that may be substituted with a group selected from an amino group protecting group, a lower alkyl group, and a lower alkylsulfonyl group, (9) a lower alkanoyloxy group that may be substituted with an aryl group, and , (10) lower alkoxycarbonyl group, and ring B has the following (1) to (9)
A benzene ring which may be substituted with 1 to 3 same or different groups selected from: (1) nitro group, (2) hydroxyl group, (3) lower alkoxy group, hydroxyl group, aryl group, (lower alkylamino) Aryl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, carboxyl group, amino group, lower alkylamino group, lower alkylcarbamoyl group, cyano group, pyridyl group, pyrrolidinyl group, morpholinyl group,
Lower alkoxy group optionally substituted with a group selected from piperazinyl group and lower alkylpiperazinyl group, (4) lower alkoxycarbonyl group, (5) (i)
Lower alkoxy group, amino group, lower alkylamino group,
And a lower alkanoyl group substituted by the same or different 1 to 3 groups selected from the following, and a lower alkoxycarbonyl group, (ii) a protecting group for an amino group, (iii) a pyridyl group, or a lower alkylamino group. Optionally lower alkyl group, and (iv) pyridylcarbonyl group, optionally substituted amino group,
(6) A carbamoyl group which may be substituted with a group selected from a lower alkyl group, a lower alkoxy lower alkyl group, and a lower alkylamino lower alkyl group, (7)
Morpholino carbonyl group, (8) cyano group, and
(9) A lower alkylaminocarbonyloxy group, R is
(1) Lower alkyl group which may be substituted with 1 to 3 same or different groups selected from the following (i) to (ix): (i) lower alkyl group; hydroxy lower alkyl group; lower alkanoyl group Lower alkoxy group; nitro group; lower alkoxycarbonyl group; carboxyl group; oxo group;
Trifluoromethyl group; carbamoyl group (the carbamoyl group may be substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a hydroxy lower alkyl group); an amino group (the amino group is a lower alkanoyl group, A lower alkoxy lower alkanoyl group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylaminoalkylidene group may be substituted); a cyano group;
A hydroxyl group which may be protected; a halogen atom; and a heterocyclic group which may be substituted with 1 to 3 same or different groups selected from a formyl group, (ii) a lower alkyl group; an amino group (the amino group). The group may be substituted with a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group, a pyridyl lower alkyl group, a lower alkylaminocarbonyl group, a halogeno lower alkylaminocarbonyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group) Lower alkoxy group; aryl lower alkoxy group; benzyloxy lower alkoxy group; lower alkylamino lower alkoxy group; nitro group; optionally protected hydroxyl group; lower alkylcarbamoyl group; halogeno lower alkylcarbamoyl group; and morpholinyl group Same Others may be substituted with 1 to 3 groups different, aryl group, or fluorenyl group, (i
ii) an optionally protected hydroxyl group, (iv) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group, (v) formula: (In the formula, n represents an integer of 0 to 4), (v
i) a lower alkoxycarbonyl group, (vii) an amino group-protecting group, a lower alkyl group, a pyridyl group, or an amino group which may be substituted with a pyrimidinyl group, (vii
i) a halogen atom, and (ix) an oxo group, (2)
A lower alkenyl group which may be substituted with an aryl group,
(3) a carbamoyl group optionally substituted with a group selected from a lower alkyl group, a halogeno lower alkyl group, and a benzothiazolyl group, (4) formula: (In the formula, m represents an integer of 0 to 4),
(5) lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, amino group, lower alkylamino group,
A heterocyclic group which may be substituted with 1 to 3 same or different groups selected from an optionally protected hydroxyl group and an optionally protected amino group, or (6)
Selected from a lower alkyl group, a lower alkoxy group, a lower alkylcarbamoyl group, a halogeno lower alkylcarbamoyl group, a morpholinyl group, an amino group, a lower alkylamino group, an optionally protected hydroxyl group, and an optionally protected amino group. The compound according to claim 1, which is an aryl group which may be substituted with 1 to 3 groups which are the same or different. 3. A monocyclic ring wherein the heterocyclic group contains at least one hetero atom selected from nitrogen, oxygen and sulfur.
The compound according to claim 2, which is a cyclic or tricyclic heterocyclic group. 4. The heterocyclic group is a pyridyl group, indolyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrimidinyl group, thienyl group, benzo [b] furyl group, benzo [b] thienyl group, pyrazolyl group, triazolyl group. Base,
Quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, 5,11-dihydro-dibenzo [b, e] [1,4] oxazepin-5-yl group, dihydropyrazolyl group or tetrazolyl group, ring A
The compound according to claim 2, wherein the substituent above, the substituent on ring B or the aryl group in R is a phenyl group, a naphthyl group, an anthranyl group, or a phenanthryl group. 5. Ring A has the formula: R ¹ is a group represented by: (1) trifluoromethyl group, (2) lower alkyl group, (3) lower alkyl group,
And a carbamoyl group which may be substituted with a group selected from a phenyl lower alkyl group, (4) a phenyl lower alkanoyloxy group, or (5) a lower alkoxycarbonyl group, and ring B has the formula: Wherein R ² is (1) hydrogen atom, (2)
Hydroxyl group, (3) lower alkoxy group, hydroxyl group, phenyl group, (lower alkylamino) phenyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group,
A lower alkoxy group which may be substituted with a group selected from a carboxyl group, a lower alkylamino group, a lower alkylcarbamoyl group, a cyano group, a pyridyl group, a pyrrolidinyl group, a morpholinyl group, and a lower alkylpiperazinyl group, (4) Lower alkoxycarbonyl group, (5) lower alkyl group, pyridyl lower alkyl group, lower alkylamino lower alkyl group, and amino group optionally substituted with a group selected from pyridylcarbonyl group, (6) lower alkylcarbamoyl group, (7) morpholinocarbonyl group, (8) lower alkylaminocarbonyloxy group,
Alternatively, (9) a cyano group and R has the formula: And p is 1 or 2, ring C is a pyridine ring, a pyrrole ring, a thiazole ring, a pyrimidine ring, a pyrazole ring, a triazole ring, or a tetrazole ring, R ³
The compound according to claim 4, wherein R ⁴ is the same or different and is a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a carboxyl group, a cyano group, or an amino group. . 6. Ring A is of the formula: Wherein R ¹ is a trifluoromethyl group, (2) a lower alkyl group, (3) a lower alkyl group,
And a carbamoyl group which may be substituted with a group selected from a phenyl lower alkyl group, (4) a phenyl lower alkanoyloxy group, or (5) a lower alkoxycarbonyl group, and ring B has the formula: Wherein R ² is (1) a hydrogen atom, (2)
Hydroxyl group, (3) lower alkoxy group, hydroxyl group, phenyl group, (lower alkylamino) phenyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group,
Lower alkylamino group, lower alkylcarbamoyl group,
A lower alkoxy group which may be substituted with a group selected from a cyano group, a pyrrolidinyl group, a morpholinyl group, and a lower alkylpiperazinyl group, (4) a lower alkoxycarbonyl group, (5) a lower alkyl group, a pyridyl lower alkyl group An amino group which may be substituted with a group selected from a lower alkylamino lower alkyl group and a pyridylcarbonyl group, (6) morpholinocarbonyl group, (7)
A lower alkylaminocarbonyloxy group, or
(8) A cyano group, Q is —CO—, and R is of the formula: The compound according to claim 5, wherein R ³ and R ⁴ are the same or different and are selected from a hydrogen atom, a lower alkyl group, a cyano group, or an amino group. 7. R ¹ is (1) a trifluoromethyl group,
(2) a lower alkyl group and a carbamoyl group optionally substituted with a group selected from a phenyl lower alkyl group, (3) a phenyl lower alkanoyloxy group, or (4) a lower alkoxycarbonyl group, R ² is
(1) hydrogen atom, (2) hydroxyl group, (3) lower alkoxy group, phenyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, and lower alkoxy group optionally substituted with a group selected from cyano group,
(4) a lower alkoxycarbonyl group, or (5) a lower alkylaminocarbonyloxy group, (6) a cyano group, and R have the formula: 7. The compound according to claim 6, wherein R ³ and R ⁴ are the same or different and are selected from a hydrogen atom, a cyano group, or an amino group. 8. Ring A is of the formula: And a ring B is represented by the formula: In a ring represented, R ² is a hydrogen atom, a lower alkoxy group, a lower alkyl amino lower alkoxy group, a pyridyl lower alkoxy group, (lower alkylamino) phenyl lower alkoxy group, pyrrolidino-lower alkoxy, hydroxy lower alkoxy group, a lower Alkoxy lower alkoxy group, lower alkylcarbamoyl lower alkoxy group, lower alkylamino lower alkanoylamino group, pyridylcarbonylamino group, lower alkylamino lower alkylamino group, or lower alkoxycarbonyl group, and R is the following (1) to (3) A lower alkyl group substituted with a group selected from: (1) a lower alkyl group, and a pyrazolyl group optionally substituted with a group selected from a nitro group, (2) a pyridyl group, and (3) a triazolyl group, 5. The compound according to claim 4, wherein . 9. Ring A is of the formula: R ¹ is a trifluoromethyl group or a lower alkanoyl group, ring B is a lower alkoxy group, a (lower alkylamino) lower alkanoylamino group, a lower alkylamino lower alkoxy group, a lower alkylcarbamoyl group, and a lower ring. A benzene ring optionally substituted with a group selected from an alkoxycarbonyl group, a lower alkyl group in which R is substituted with a group selected from the following (1) to (5): (1) a lower alkyl group, a nitro group, A pyrazolyl group which may be substituted with a group selected from a lower alkoxycarbonyl group, a cyano group, an amino group and a hydroxy lower alkyl group, (2) a pyridyl group, (3) a triazolyl group,
The compound according to claim 4, which is (4) a tetrazolyl group and (5) a thiazolyl group optionally substituted with an amino group. 10. Ring A is of the formula: , A ring B is a benzene ring, and Q is -CO.
The compound according to claim 4, wherein-and R are pyrazolylmethyl groups which may be substituted with a group selected from a lower alkyl group, a nitro group, a lower alkoxycarbonyl group, a cyano group, an amino group, and a hydroxy lower alkyl group. 11. 2- (1H-pyrazol-1-yl)
Acetyl-5- [2- (4-trifluoromethylphenyl) benzoylamino] -isoindoline, 2- [2-
(1H-pyrazol-1-yl) ethyl] -5- [2-
(4-Trifluoromethylphenyl) benzoylamino] -isoindoline, 2- (3-amino-4-cyano-1H-pyrazol-1-yl) acetyl-5- [2-
(4-Trifluoromethylphenyl) benzoylamino] -isoindoline, 2- (1H-pyrazole-1-
Yl) acetyl-5- [2- (4- (N, N-dimethylcarbamoyl) phenyl) -3-methoxybenzoylamino] -isoindoline, 2- (1H-pyrazole-1
-Yl) acetyl-5- [2- (4-phenylacetoxyphenyl) benzoylamino] -isoindoline, 2
-(1H-pyrazol-1-yl) acetyl-5- [2
-(4-Trifluoromethylphenyl) -3- (1-ethoxycarbonyl-1-methylethoxy) benzoylamino] -isoindoline, 2- (1H-pyrazole-1
The compound according to claim 1, which is selected from -yl) acetyl-5- [2- (4- (N, N-dimethylcarbamoyl) phenyl) benzoylamino] -isoindoline or a pharmaceutically acceptable salt thereof. 12. A compound represented by the general formula [5]: (In the formula, Q is —CO— or —CH ₂ —, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted Which represents an optionally substituted heterocyclic group or an optionally substituted aryl group) or a salt thereof, and a compound of the general formula [6]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Represents a benzene ring which may be substituted) or a salt thereof to give a product as a pharmacologically acceptable salt, if desired. ]: [Chemical 17] (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 13. A compound represented by the general formula [15]: (In the formula, ring B is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, R is optionally substituted lower alkyl group, optionally substituted lower alkenyl group, substituted An optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group, X ¹ represents a leaving group) or a salt thereof; 16]: (In the formula, ring A is an optionally substituted benzene ring, M is a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an alkylenedioxy group,
An aryloxy group, an arylenedioxy group and an arylthio group, which represent a metal that may be coordinated with the same or different groups)),
If desired, the product may be a pharmacologically acceptable salt of the general formula [I]: (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 14. A compound represented by the general formula [13]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Represents a benzene ring which may be substituted) or a salt thereof, and a compound represented by the general formula [2]: R-COOH [2] (wherein R is a lower alkyl group which may be substituted, Represents a lower alkenyl group which may be substituted, a carbamoyl group which may be substituted, a heterocyclic group which may be substituted, or an aryl group which may be substituted) or a salt thereof. React with
A compound of the general formula [Ia], characterized in that the product is optionally a pharmaceutically acceptable salt: (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 15. The formula [Ia]: embedded image (In the formula, ring A is an optionally substituted benzene ring, ring B
Is an optionally substituted benzene ring, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group Group, or an optionally substituted aryl group) or a salt thereof is subjected to a reduction reaction to give a product as a pharmaceutically acceptable salt, if desired. [Ib]: (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 16. A compound represented by the general formula [13]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Is a benzene ring which may be substituted) or a salt thereof, and a compound of the general formula [17]: R-CHO [17] (wherein R is a lower alkyl group which may be substituted, Represents an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group) or a salt thereof. Is subjected to a condensation reaction and then subjected to a reduction reaction, and if desired, the product is converted into a pharmacologically acceptable salt.
b]: (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 17. The general formula [13]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Compound or a salt thereof represented by the representative) a benzene ring which may be substituted represented by the general formula [18]: R-CH 2 -X 2 [18] ( wherein, R may be substituted lower An alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group, X ² is a leaving group. The compound represented by the formula) or a salt thereof is reacted with the product to form a pharmaceutically acceptable salt, if desired, and the compound is represented by the general formula [Ib]: (However, the symbols have the same meanings as described above), and a method for producing a biphenylcarboxamide isoindoline derivative or a pharmaceutically acceptable salt thereof. 18. A compound represented by the general formula [13]: (In the formula, ring A is an optionally substituted benzene ring, ring B
Represents an optionally substituted benzene ring) or a salt thereof. 19. A compound represented by the general formula [5]: (In the formula, Q is —CO— or —CH ₂ —, R is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted carbamoyl group, an optionally substituted Which represents an optionally substituted heterocyclic group or an optionally substituted aryl group) or a salt thereof. 20. General formula [15]: embedded image (In the formula, ring B is an optionally substituted benzene ring, Q is —CO— or —CH ₂ —, R is optionally substituted lower alkyl group, optionally substituted lower alkenyl group, substituted An optionally substituted carbamoyl group, an optionally substituted heterocyclic group, or an optionally substituted aryl group, X ¹ represents a leaving group) or a salt thereof.