JP2000136182A - Indole derivative and mono- or di-azidoindole derivative having amino band - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having cyclooxygenase-2 which inhibits activity associated with the biosynthesis of prostaglandin E2 or the like, capable of exhibiting excellent antiinflammatory activity, improved water-solubility or the like, and useful as an antiinflammatory agent. SOLUTION: A compound of formula I (A1 and A2 are each CH= or N=; R1 is an alkyl or amine; R2 is aryl, a hetero cyclic group or the like; Q is O=, S= or the like; Y and Z are each H, an alkyl or the like), or its salt or hydrate, for example, (1-(4-fluorobenzyl)-5-methanesulfonylindol-2-yl)carbonylphrrolidine. In order to obtain a compound of formula I, for example, a new intermediate of formula III (R3 is an alkyl) is obtained by starting from a compound of formula II (RX is an alkyl; X is a halogen), and the obtained intermediate of formula III is treated, for example, with an amine having a group X and a group Z, or ammonia. The treatment with the amine or ammonia is preferably carried out at 20-40 deg.C by using methanol or the like as reaction solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel indole derivative and a mono- or diazaindole derivative which exhibit anti-inflammatory activity and the like and are useful as a medicine.

[0002]

2. Description of the Related Art At present, most of drugs widely used as anti-inflammatory agents are prostaglandin E2 (PGE).
Cyclooxygenase (CO) involved in the biosynthesis of 2)
X) Nonsteroidal anti-inflammatory drugs (NS)
AID). However, the synthetic activity of PGE2 is present in every tissue of the living body and controls the homeostasis of the living body, and when the NSAID is administered thereto, various side effects are caused. For example, in the stomach and kidney, PGE2
Has the effect of maintaining blood flow in those organs,
NSAID administration makes it difficult to maintain local blood flow, causing gastric and renal disorders.

[0003] Under such circumstances, the existence of COX isozymes was confirmed. Conventionally recognized C
To distinguish it from OX, the conventional type was called COX-1, and the newly discovered isozyme was called COX-2. In addition, it has been revealed that this COX-2 is induced during inflammation and is rarely expressed normally.
It was also revealed that SAID non-specifically inhibits both COX-1 and COX-2 enzymes. This raises the possibility that compounds having a COX-2 inhibitory action may be useful as new anti-inflammatory agents.

At present, COX-1 is not inhibited and COX-2
Some compounds are known to selectively inhibit inflammatory activity (Inflammation and immunity, 3 (1), 29-36, 1995, Bioorganic & Me
d. Chem. Lett. 5 (8), 867-872, 1995 etc.). However, none of these effects are satisfactory, and some of them have insufficient water-solubility or oral absorbability, and there is a need for a drug that exhibits a better COX-2 inhibitory effect.

[0005] Also, from JP-A-10-77266 (Japanese Patent Application No. 9-24567), an indole derivative which selectively inhibits COX-2 is known. However, these indole derivatives are metabolically unstable, and there is a need for a COX-2 inhibitor having better metabolic stability.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to reduce CO2
An object of the present invention is to provide an indole derivative and a mono- or diazaindole derivative having an X-2 inhibitory activity and useful as a drug such as an anti-inflammatory agent.

[0007]

Means for Solving the Problems The present inventors have proposed COX-
As a result of intensive studies for the purpose of developing a compound which selectively or non-selectively inhibits No. 2 and has an anti-inflammatory effect equal to or higher than existing NSAIDs such as indomethacin, the compound is represented by the general formula (I) The inventors have found that the compound has an excellent anti-inflammatory effect, has improved water solubility, and / or has excellent metabolic stability, and is useful as a medicament. Based on this finding, the present invention has been completed.

[0008]

That is, the present invention provides a compound represented by the general formula (I):

[0009]

Embedded image

Wherein A ¹ and A ² each independently represent -CH = or -N =; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent;
＝ O, ＳS, or ＮN-CN; Y and Z are the same or different and are a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent Represents a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent, or Forms a ring together with the nitrogen atom to which it is bonded (this ring may further have an oxygen atom, a nitrogen atom, and / or a sulfur atom as a ring atom, and further has a substituent at any position on the ring. Or a salt thereof with a pharmaceutically acceptable acid or base, or a hydrate thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of the compound represented by the general formula (1), A ¹ and A ² are each independently —C
Represents H = or -N =. Among them A ¹ is a -CH =, A ² is a compound which is an -CH =; A ¹ is -CH =
And A ² is -N =; and A ¹ is-
Is N =, A ² is -N =, compound may be mentioned.

R ¹ represents an alkyl group or an amino group. As the alkyl group, a linear or branched alkyl group having 1 to 3 carbon atoms, specifically, a methyl group, an ethyl group, an n- A propyl group, and an i-propyl group. R ¹ is particularly preferably a methyl group or an amino group.

R ² is an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent. the group, a hydroxyl group, a halogen atom, a cyano group, a carboxyl group, COOR ^a (where, R ^a is a straight chain or branched represents a chain alkyl group having 1 to 3 carbon atoms) or amino group (the amino group May be further mono- or di-substituted by a linear or branched alkyl group having 1 to 3 carbon atoms) and may be substituted by a linear or branched alkyl group having 1 to 4 carbon atoms. Group; hydroxyl group, halogen atom,
Cyano group, carboxyl group, COOR ^b (where R
^b represents a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms) or an amino group (this amino group is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms and is further mono- or di-alkyl). A straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms which may be substituted;
(Where, n represents an integer of 0 to 2, R ^c represents a linear or branched alkyl group having 1 to 3 carbon ^{_{atoms) -S (O) n -R c}} ; halogen atom; Amino group; nitro group; cyano group; carboxyl group; hydroxyl group; carbamoyl group; and COOR ^d (where R ^d represents a linear or branched alkyl group having 1 to 3 carbon atoms). Specifically, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a t-butyl group, a trifluoromethyl group, a methoxy group, an ethoxy group , Methylthio group, methanesulfonyl group, ethanesulfonyl group, amino group, nitro group, cyano group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
Carbamoyl group, hydroxymethyl group, 2-hydroxyethyl group, aminomethyl group, dimethylaminomethyl group,
2-aminoethyl group, 2-dimethylaminoethyl group, cyanomethyl group, 2-cyanoethyl group, 3-cyanopropyl group, carboxymethyl group, 2-carboxyethyl group,
Examples include a methoxycarbonylmethyl group and a 2-methoxycarbonylethyl group. Among them, a fluorine atom is preferred.

The optionally substituted aryl groups in R ² may be the same or different, and may have one or more, preferably mono, di, or tri-substituted carbon atoms, with the above substituents. 6 to 12 aryl groups, particularly a phenyl group and a naphthyl group. Among them, the same or different, the above-mentioned substituents are preferably a mono-, di- or tri-substituted phenyl group, preferably a 4-methylphenyl group, a 4-ethylphenyl group,
4-i-propylphenyl group, 4-t-butylphenyl group, 4-fluorophenyl group, 4-chlorophenyl group,
4-bromophenyl group, 4-methoxyphenyl group, 4-
Cyanophenyl group, 4-nitrophenyl group, 4-trifluoromethylphenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dimethylphenyl group, 3-chloro-4-methylphenyl group , 4-
A methoxycarbonylphenyl group, a 4-ethoxycarbonylphenyl group, a 4-propoxycarbonylphenyl group,
4-carbamoylphenyl group, 2-methoxycarbonyl-4-fluorophenyl group, 2-ethoxycarbonyl-
4-fluorophenyl group, 2-propoxycarbonyl-
4-fluorophenyl group and 2-carbamoyl-4-
Fluorophenyl groups are particularly preferred, and 4-fluorophenyl groups are even more particularly preferred.

The heterocyclic group which may have a substituent in R ² may be the same or different, and
3- to 8-membered aliphatic or aromatic containing one, two or three heteroatoms such as oxygen, nitrogen and sulfur, which may be mono-, di- or tri-substituted And a heterocyclic group (this heterocyclic group may be further condensed with a 3- to 8-membered aliphatic or aromatic heterocyclic ring, but is preferably not condensed). 6
A pyridyl group, a piperazinyl group, a piperidinyl group, a pyrimidinyl group, a pyrrolyl group, a pyranyl group, a furyl group, an oxazolyl group, a triazolyl group, a thioxazolyl group, and a thienyl group. Among them, a pyridyl group which may have a substituent, a furyl group which may have a substituent, and a thienyl group which may have a substituent (wherein the substituent is a halogen atom as well as/
Or a nitro group is preferred). Examples of the heterocyclic group which may have a substituent include a 3-pyridyl group, a 2-chlorothiophen-5-yl group, and a 2-nitrofuran-
A 5-yl group is particularly preferred.

The optionally substituted cycloalkyl groups in R ² may be the same or different and may be one or more, preferably mono-, di- or tri-substituted by the aforementioned substituents. Particularly, a cycloalkyl group having 3 to 6 carbon atoms is exemplified, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Among them, a cyclohexyl group which may have a substituent is preferable. Examples of the cycloalkyl group which may have a substituent include a cyclohexyl group,
A methoxycyclohexyl group is particularly preferred.

Typically, R ² represents a phenyl group which may have a substituent, a cyclohexyl group which may have a substituent, a pyridyl group which may have a substituent, a substituent The compound of the formula (I) which is a furyl group which may have a thienyl group which may have a substituent is preferable.

In the definition of the compound of the formula (I), Q
Represents = O, = S, or = N-CN.

The substituents in the definition of Y and Z include:
A halogen atom such as fluorine, chlorine, bromine or iodine; a hydroxyl group; a linear or branched alkoxy group having 1 to 5 carbon atoms;
A cyano group; a nitro group; an amino group (which may be further mono- or di-substituted by a linear or branched alkyl group having 1 to 5 carbon atoms); a carboxyl group; a thiol group; And a linear or branched alkylthio group.

The alkyl group which may have a substituent in the definition of Y and Z is the same or different and is one or more, preferably mono-, di- or tri-substituted by the aforementioned substituent. And particularly a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an i-propyl group, an n-propyl group and a 2-
Fluoroethyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 2-cyanoethyl group, 2
-Nitroethyl group, hydroxymethyl group, methoxymethyl group, cyanomethyl group, 1-ethylpropyl group, t-butyl group, bis (trifluoromethyl) methyl group and the like, and a methyl group, a hydroxymethyl group, a methoxymethyl group Group, cyanomethyl group, ethyl group, i-propyl group, n-propyl group, 2-fluoroethyl group, 2,2
2-trifluoroethyl group, 2-hydroxyethyl group,
A 2-cyanoethyl group and a 2-nitroethyl group are preferred. Further, as the alkoxy group which may have a substituent, the same or different, one or more of the above substituents,
Preferable examples include mono-, di- or tri-substituted, particularly straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms, and specific examples include methoxy, ethoxy and n.
-Propoxy group and the like, and a methoxy group is preferable. As the cycloalkyl group which may have a substituent, the same or different, one or more, preferably mono-, di- or tri-substituted by the above-mentioned substituent,
Particularly, a cycloalkyl group having 3 to 8 carbon atoms is mentioned, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a cyclopentyl group and a cyclohexyl group are preferable. The aryl group which may have a substituent is the same or different and is an aryl group having 6 to 12 carbon atoms, which may be substituted with one or more, preferably mono, di or tri-substituted substituents. Groups, specifically, phenyl group and naphthyl group,
A phenyl group is preferred. The heterocyclic group optionally having substituent (s) may be the same or different, and may be one or more, preferably mono-, di- or tri-substituted by the above-mentioned substituent, an oxygen atom, a nitrogen atom, Atom, and a 3- to 8-membered aliphatic or aromatic heterocyclic group containing 1, 2 or 3 heteroatoms such as a sulfur atom.
May be condensed with an 8-membered aliphatic or aromatic heterocyclic ring, but is preferably not condensed), and specifically, a 5- to 6-membered pyridyl group, oxazolyl group, and thioxazolyl group And a pyridyl group and a thioxazolyl group are preferred.

Typically, one of Y and Z is hydrogen, methyl, hydroxymethyl, methoxymethyl, cyanomethyl, ethyl, i-propyl, n-
A propyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxyethyl group, a 2-cyanoethyl group, a 2-nitroethyl group, a methoxy group, a cyclopentyl group, a cyclohexyl group, or a phenyl group And a compound of the formula (I) wherein the other is a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.

The combination of Y and Z is preferably a compound in which both Y and Z are hydrogen atoms; one of Y and Z is a hydrogen atom, and the other is an alkyl which may have a substituent. Groups (eg, methyl, ethyl,
n-propyl group, 2,2,2-trifluoroethyl group,
A compound which is a hydroxymethyl group, a methoxymethyl group, a cyanomethyl group or the like); a compound wherein both Y and Z are an alkyl group which may have a substituent (for example, a methyl group); A hydrogen atom, and the other is optionally substituted with an alkoxy group (for example,
Methoxy group); and one of Y and Z is an alkyl group which may have a substituent (eg, a methyl group), and the other is an alkoxy group which may have a substituent ( For example, a compound which is a methoxy group) can be mentioned.

Further, Y and Z together form a ring together with the nitrogen atom to which they are attached (this ring further has an oxygen atom, a nitrogen atom and / or a sulfur atom as a ring atom). In particular) to form a 3- to 8-membered ring, more preferably a 3- to 7-membered ring, particularly preferably a 5- or 6-membered ring. Of these, pyrrolidine and morpholine are preferred. Further, this ring may have the above substituent at any position on the ring. The number of the substituents is one or more, preferably one, two and three.

The compounds of the formula (I) specifically include the following compounds and hydrates thereof:
(1- (4-fluorobenzyl) -5-methanesulfonylindol-2-yl) carbonylpyrrolidine; (1
-(4-fluorobenzyl) -5-methanesulfonylindol-2-yl) carbonylmorpholine; 1- (4
-Fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-carboxamide; N, N-dimethyl-1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxamide; N-ethyl-1
-(4-fluorobenzyl) -5-methanesulfonylindole-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonylindole-Nn-
Propyl-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methoxy-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methoxy-N- Methyl-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-
Methyl-2-thioamide; 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methyl-
N'-cyano-2-carboxamidine; 1- (4-fluorobenzyl) -5-methanesulfonyl-N-methyl-
1H-pyrrolo [2,3-b] pyridine-2-carboxamide; N-ethyl-1- (4-fluorobenzyl) -5
-Methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-Nn-propyl-1H
-Pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-N, N-dimethyl-1H-pyrrolo [2,3-b]
Pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-N-methoxy-1H
-Pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-N-methoxy-N-methyl-1H-pyrrolo [2
3-b] pyridine-2-carboxamide; 1- (cyclohexylmethyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-
Carboxamide; 1- (4-fluorobenzyl) -5
Methanesulfonyl-N- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 5- (4-fluorobenzyl) -N-methyl-2-methanesulfonyl -5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide; N-ethyl-5-
(4-fluorobenzyl) -2-methanesulfonyl-5
H-pyrrolo [2,3-b] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; 5- (4 -Fluorobenzyl) -2-methanesulfonyl-N-methoxy-5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -2-methanesulfonyl-N-methoxy-
N-methyl-5H-pyrrolo [2,3-b] pyrazine-6
-Carboxamide; 5-cyclohexylmethyl-2-methanesulfonyl-N-methyl-5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide; N, N-dimethyl-5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; 5- (4-fluoro Benzyl) -N-methyl-2-sulfamoyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; and Nn-propyl-
5- (4-Fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide.

Among them, 1- (4-fluorobenzyl)-
5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide, N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3 -B] pyridine-2-carboxamide and 1- (4-fluorobenzyl) -5
-Methanesulfonyl-NN-propyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide is particularly preferred.

The compound of the present invention can also be obtained as a salt of the above-mentioned compound of the formula (I) with a pharmaceutically acceptable acid or base, or a hydrate thereof. Salts with pharmaceutically acceptable acids or bases include salts with alkali metals or alkaline earth metals (such as sodium, potassium and calcium salts) and salts with inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid) , Hydrobromic acid and the like), and salts with organic acids (salts with acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, malonic acid, trifluoroacetic acid and the like).

The present invention also provides compounds of formula (II) which are useful intermediates for preparing compounds of formula (I):

[0028]

Embedded image

Wherein A ¹ and A ² each independently represent —CH ＝ or —N ＝; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent;
³ represents an alkyl group], a salt thereof with a pharmaceutically acceptable acid or base, or a hydrate thereof.

In the compounds of formula (II), A ¹ and A
² represents -CH = or -N = each independently as in the above-mentioned compound of the formula (I). R ¹ is also of the formula (I)
As in the case of the compound of the formula (1), it represents an alkyl group or an amino group, and examples of the alkyl group include straight-chain or branched-chain alkyl groups having 1 to 3 carbon atoms. The groups specifically described for R ^{1 in} the definition of the compound can be mentioned. R ^{2 is} also an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic ring which may have a substituent, similarly to the compound of the formula (I). Represents a group. The aryl group which may have a substituent is the same or different as the substituent specifically described for R ^{2 in} the definition of the compound of the formula (I), and may be one or more, preferably mono, di or tri. -An aryl group which may be substituted and has 6 to 12 carbon atoms,
No. The cycloalkyl groups which may have a substituent may be the same or different and may be one or more, preferably mono-, di- or tri-substituted by the above-mentioned substituents, and particularly preferably have 3 to 6 carbon atoms. A cycloalkyl group. Further, the heterocyclic group which may have a substituent may be the same or different, and may be one or more, preferably mono-, di- or tri-substituted by the above-mentioned substituent.
Monocyclic or bicyclic, especially monocyclic, aliphatic or aromatic heterocyclic groups containing one, two or three heteroatoms such as oxygen, nitrogen and sulfur atoms. Each specific group includes R.sup.1 in the definition of the compound of the formula (I) above.
^The groups specifically described for ² can be mentioned. R ³ represents an alkyl group.
To 4 linear or branched alkyl groups. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, and a t-butyl group. Particularly preferred is a methyl group. It is.

The compound of the formula (II) of the present invention can also be obtained as a salt of the above-mentioned compound of the formula (II) with a pharmaceutically acceptable acid or base, or a hydrate thereof.
Salts with pharmaceutically acceptable acids or bases include salts with alkali metals or alkaline earth metals (such as sodium, potassium and calcium salts) and salts with inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid) , Hydrobromic acid and the like), and salts with organic acids (salts with acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, malonic acid, trifluoroacetic acid and the like).

The compounds of the formula (I) and the compound of the formula (II) according to the present invention can be prepared by the following reaction schemes 1, 3, 4, 5, 6, 7, 8,
And 9 by using a reagent having a desired group. Among the compounds of the formula (II) of the present invention, the compound wherein R ¹ is an alkyl group can be prepared by the following reaction formula 1 or 3. Reaction formula 1

[0033]

Embedded image

[Wherein, R ^x represents an alkyl group, particularly a linear or branched alkyl group having 1 to 3 carbon atoms; X ¹ and X each independently represent a halogen atom;
² represents -CH = or -N =; R ² represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a group which has a substituent. R ³ represents an alkyl group;

[0035] Compound 1 (R ^x represents an alkyl group, particularly a straight-chain or branched alkyl group having 1 to 3 carbon atoms, X ¹
Represents a halogen atom) and can be converted to compound 2 by cross-coupling compound 1 and trimethylsilylacetylene in the presence of a palladium catalyst, a base, and a copper reagent. As the base, triethylamine, tripropylamine, tributylamine,
Diisopropylethylamine, triisobutylamine,
Diethylamine, dipropylamine, dibutylamine,
Potassium carbonate, sodium carbonate, sodium bicarbonate,
Potassium hydrogen carbonate or the like is used, and preferably triethylamine is used. Copper (0), copper acetate (I
I), copper (I) bromide, copper (II) bromide, copper (I) chloride, copper (II) chloride, copper (I) iodide, copper (II) iodide, copper (I) oxide, oxidation Use copper (II), copper sulfate (II), etc.
Preferably, copper (I) iodide is used. As the palladium reagent, for example, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, or the like is used, and preferably, dichlorobis (triphenylphosphine) palladium is used. As a reaction solvent, dioxane, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, benzene, toluene, dimethylsulfoxide and the like are used.
Preferably, dioxane is used. Reaction is 20-150
C., preferably at 50-100.degree.

Conversion of compound 2 to compound 3 can be carried out by treating compound 2 with a fluorinated compound. As the fluorinated compound, tetrabutylammonium fluoride, a hydrogen fluoride-pyridine complex, hydrogen fluoride, or the like is used, and tetrabutylammonium fluoride is preferably used. As a reaction solvent, dioxane,
N, N-dimethylformamide, acetonitrile, N, N
N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, benzene, toluene, dimethylsulfoxide, dichloromethane, chloroform, water, methanol, ethanol, and the like are used, but tetrahydrofuran is preferably used. The reaction is carried out at -78 to 40C, preferably at -78 to 0C.

Conversion of compound 4 to compound 5 can be carried out by treating compound 4 with a base and then treating with carbon dioxide, dry ice or the like. The base is n-
Butyllithium, s-butyllithium, t-butyllithium, lithium isopropylamide, lithium bis (trimethylsilyl) amide, and the like are preferably used.
-Use butyllithium. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, or the like is used, and tetrahydrofuran is preferably used. The reaction is carried out at -78 to 60 ° C, preferably -7.
Perform at 8-30 ° C. In addition, in compound 4, A ² = C
Compounds in which H- and R ^x are methyl groups are disclosed in
This is described in Reference Example 10 of 77266.

Conversion of compound 5 to compound 6 (R ³ represents an alkyl group, particularly a linear or branched alkyl group having 1 to 4 carbon atoms) is performed by converting compound 5 to a desired group R ³ . It can be carried out by acid treatment in an alcohol (R ³ OH). As the alcohol, methanol, ethanol, isopropanol, or the like can be used depending on the desired group R ³ . As the acid, an inorganic acid such as sulfuric acid or hydrochloric acid, an organic acid such as p-toluenesulfonic acid or the like is used, and an inorganic acid such as sulfuric acid is preferably used. The reaction is 2
The reaction is carried out at 0 to 100 ° C, preferably at 50 to 90 ° C.

The conversion of compound 4 to compound 6 can also be carried out directly by treating compound 4 with a base and then treating with a carbonate having a desired group R ³ .
As the base, n-butyllithium, s-butyllithium, t-butyllithium, lithium isopropylamide, lithium bis (trimethylsilyl) amide and the like are used, and lithium diisopropylamide is preferably used. As the carbonate ester, dimethyl carbonate, diethyl carbonate, methyl chlorocarbonate, ethyl chlorocarbonate and the like can be used depending on the desired group R ³ . As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane,
Dioxane or the like is used, and tetrahydrofuran is preferably used. The reaction is carried out at -78 to 60C, preferably at -78 to -20C.

Conversion of compound 6 to compound 7 can be carried out by oxidizing compound 6. Oxone (registered trademark OXONE) and m-chloroperbenzoic acid are used as the oxidizing agent. Reaction solvents include tetrahydrofuran, ether, dimethoxyethane, dioxane, dichloromethane, chloroform, methanol, ethanol,
And water or the like are used alone or as a mixed solvent. Preferably, when oxone (registered trademark OXONE) is used, a mixed solvent of tetrahydrofuran-water is used, and when m-chloroperbenzoic acid is used, dichloromethane is used. The reaction is -20 to 4
The reaction is performed at 0 ° C., preferably at −20 to 20 ° C.

Conversion of compound 7 to compound 8 can be carried out by treating compound 7 with a base. As the base, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is used, but potassium hydroxide is preferably used. As the reaction solvent, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethoxyethane, water and the like are used alone or as a mixed solvent, but preferably, a mixed solvent of methanol and methanol-tetrahydrofuran is used. Reaction is -20 to 5
It is carried out at 0 ° C, preferably at -20 to 30 ° C.

Compound 8 is converted to compound 9 by subjecting compound 8 to a base treatment and then to compound R ² C having desired group R ^2.
It can be performed by treating with H ₂ X. As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and preferably, sodium hydride is used. As the reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, methanol, ethanol, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, benzene, toluene, dimethylsulfoxide and the like are used, and preferably, N, N- Use dimethylformamide. The reaction is -2
It is carried out at 0 to 70 ° C, preferably at 0 to 50 ° C.

The conversion of compound 6 to compound 7 is omitted, and compound 6 is treated with a base in the same manner as the conversion of compound 7 to compound 8, followed by conversion of compound 8 to compound 9, that is, the group R After subjecting to the reaction of introduction of ² CH ^2- ,
Compound 9 can also be obtained by performing an oxidation reaction of the group R _x S-.

Reaction formula 3

[0045]

Embedded image

[In the formula, R ^x represents an alkyl group, particularly a linear or branched alkyl group having 1 to 3 carbon atoms;
² and X ³ independently represent a halogen atom;
R ² represents an optionally substituted aryl group, which may have a substituent cycloalkyl group, or a heterocyclic group which may have a substituent; R ³ is alkyl Represents a group)

Conversion of compound 12 to compound 13 can be carried out by treating compound 12 with an alkylthiol sodium salt having a desired group R ^x (R ^x SNa) in the presence or absence of a palladium reagent. it can. R ^x
As the alkylthiol sodium salt having the following, methanethiol sodium salt, ethanethiol sodium salt, propanethiol sodium salt, and the like can be used depending on the desired group ^Rx . As the palladium reagent, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, or the like is used, and preferably, tetrakis (triphenylphosphine) palladium is used. As the reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, methanol, ethanol, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, benzene, toluene, dimethylsulfoxide and the like are used, and preferably, N, N- Use dimethylformamide. The reaction is carried out at 20 to 100 ° C.
Perform at 0-80 ° C.

Conversion of compound 13 to compound 14 can be carried out by reacting a halogen in the presence or absence (preferably in the presence) of an organic base such as pyridine. As the halogen, chlorine, bromine, iodine or the like is used, but bromine is preferably used. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, benzene, toluene, dichloromethane, chloroform and the like are used, but chloroform is preferably used. The reaction is carried out at 0-100 ° C, preferably 20-5 ° C.
Perform at 0 ° C.

Conversion of compound 14 to compound 15 can be carried out by subjecting compound 14 to cross-coupling with 2-propyn-1-ol in the presence of a palladium catalyst, a base, and a copper reagent. As the base, triethylamine, tripropylamine, tributylamine,
Diisopropylethylamine, triisobutylamine,
Diethylamine, dipropylamine, dibutylamine,
Potassium carbonate, sodium carbonate, sodium bicarbonate,
Potassium hydrogen carbonate or the like is used, and preferably triethylamine is used. Copper (0), copper acetate (I
I), copper (I) bromide, copper (II) bromide, copper (I) chloride, copper (II) chloride, copper (I) iodide, copper (II) iodide, copper (I) oxide, oxidation Use copper (II), copper sulfate (II), etc.
Preferably, copper (I) iodide is used. As the palladium reagent, for example, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, or the like is used, and preferably, dichlorobis (triphenylphosphine) palladium is used. As a reaction solvent, dioxane, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, benzene, toluene, dimethylsulfoxide and the like are used.
Preferably, dioxane is used. Reaction is 20-150
C., preferably at 50-100.degree.

Conversion of compound 15 to compound 16 can be carried out by treating compound 15 with copper iodide. As a reaction solvent, dioxane, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane,
Benzene, toluene, dimethyl sulfoxide and the like are used, but N, N-dimethylformamide is preferably used. The reaction is carried out at 50 to 200 ° C.
Perform at 0-170 ° C.

Conversion of compound 16 to compound 17 can be carried out by oxidizing compound 16. As the oxidizing agent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate and the like are used, and manganese dioxide is preferably used. As the reaction solvent,
Acetone, dioxane, acetonitrile, tetrahydrofuran, dimethoxyethane, benzene, toluene, dichloromethane, chloroform and the like are used, but acetone is preferably used. The reaction is carried out at 0-60 ° C, preferably at 20-40 ° C.

Conversion of compound 17 to compound 18 can be carried out by treating compound 17 with a base and then treating with compound R ² CH ₂ X having a desired group R ² . As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and preferably, sodium hydride is used. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane,
Methanol, ethanol, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide,
Benzene, toluene, dimethyl sulfoxide and the like are used, but N, N-dimethylformamide is preferably used. The reaction is carried out at -20 to 70 ° C, preferably 0 to 5 ° C.
Perform at 0 ° C.

Conversion of compound 18 to compound 19 '
This can be carried out by oxidizing compound 18 in an alcohol having the desired group R ³ (R ³ OH) in the presence of cyanide. Manganese dioxide is used as the oxidizing agent. As the cyanide, sodium cyanide, potassium cyanide, or the like is used, and sodium cyanide is preferably used. As the alcohol (R ³ OH) as a reaction solvent, methanol, ethanol, isopropanol, or the like can be used depending on a desired group R ³ . The reaction is carried out at 0-60 ° C, preferably at 0-40 ° C.

The conversion of compound 19 'to compound 20 is as follows:
It can be carried out by oxidizing compound 19 '.
Oxone (registered trademark OXONE), m
Using chloroperbenzoic acid; As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, dichloromethane, chloroform, methanol, ethanol, water and the like are used alone or as a mixed solvent, and preferably, when oxone (registered trademark OXONE) is used, a tetrahydrofuran-water mixed solvent is used. Or tetrahydrofuran-methanol-water mixed solvent, and dichloromethane when m-chloroperbenzoic acid is used. The reaction is -20 to 4
The reaction is performed at 0 ° C., preferably at −20 to 20 ° C.

Among the compounds of the formula (II) of the present invention, R
^The compound in which ¹ is an amino group can be prepared by the following reaction formula 4.

Reaction formula 4

[0057]

Embedded image

[In the formula, R ^x represents an alkyl group, particularly a linear or branched alkyl group having 1 to 3 carbon atoms; A ¹ and A ² each independently represent -CH = or -N R ² represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent; ³ represents an alkyl group)

Conversion of compound 19 to compound 21 can be carried out by oxidizing compound 19. Oxone (registered trademark OXONE) and m-chloroperbenzoic acid are used as the oxidizing agent. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, dichloromethane, chloroform, methanol, ethanol, water and the like are used alone or as a mixed solvent,
Preferably, a mixed solvent of tetrahydrofuran and water is used when oxone (registered trademark OXONE) is used, and dichloromethane is used when m-chloroperbenzoic acid is used. Reaction is -20 to 40
C., preferably at -20 to 20.degree.

The conversion of the compound 21 to the compound 22 is carried out by treating the compound 21 with an acid anhydride, followed by hydrolysis, followed by a Pummerer reaction, followed by treating the compound obtained by chlorination in the presence of an acid with aqueous ammonia. be able to. As the acid anhydride, trifluoroacetic anhydride, acetic anhydride, or the like is used, and trifluoroacetic anhydride is preferably used. As a reaction solvent, dichloromethane, chloroform, or the like is used, but dichloromethane is preferably used. The reaction is carried out at 20 to 80C, preferably at 20 to 40C. The hydrolysis is carried out at 0 to 10 ° C. using a dichloromethane-water mixed solvent as a reaction solvent. When treating with chlorine gas in the presence of an acid, acetic acid is used as the acid, and a dichloromethane-water mixed solvent is used as the reaction solvent.
Perform at 10 ° C. In the treatment with aqueous ammonia, tetrahydrofuran is used as a reaction solvent, and the reaction is carried out at 0 to 10 ° C.

Conversion of compound 22 to compound 23 can be carried out by reducing compound 22 using formic acid, triethylamine and palladium on carbon. As a reaction solvent, methanol, ethanol, or the like is used, and ethanol is preferably used. The reaction is carried out at 20 to 90 ° C, preferably at 40 to 80 ° C.

The compound of the formula (I) of the present invention can be prepared by reacting the compound represented by the formula (1)
Starting from compounds of formula (II) prepared in 3 and 4, they can be prepared according to the following Schemes 5-9.

Reaction formula 5

[0064]

Embedded image

[Wherein A ¹ and A ² each independently represent -CH = or -N =; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent;
³ represents an alkyl group; Y and Z are the same or different and are each a hydrogen atom, an alkyl group which may have a substituent,
An alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent Or together form a ring with the nitrogen atom to which they are attached (the ring may further have oxygen, nitrogen and / or sulfur atoms as ring atoms) , And may have a substituent at any position on the ring)]

Conversion of compound 9 or compound 20 to compound 24 can be accomplished by converting compound 9 or compound 20 to an amine having the desired groups Y and Z, or ammonia (a compound in which both Y and Z are hydrogen atoms). Case). As the amine, various amines including methylamine, ethylamine, propylamine, dimethylamine and the like can be used depending on the desired groups Y and Z. As the reaction solvent, methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, or the like is used alone or as a mixed solvent, and preferably, methanol or a mixed solvent of methanol and tetrahydrofuran is used. The reaction is carried out at 0 to 80 ° C, preferably at 20 to 40 ° C.

Reaction formula 6

[0068]

Embedded image

Wherein A ¹ and A ² each independently represent —CH ＝ or —N ＝; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent;
³ represents an alkyl group; Y and Z are the same or different and are each a hydrogen atom, an alkyl group which may have a substituent,
An alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent Or together form a ring with the nitrogen atom to which they are attached (the ring may further have oxygen, nitrogen and / or sulfur atoms as ring atoms) , And may have a substituent at any position on the ring)]

Conversion of compound 9 or compound 20 to compound 25 can be carried out by treating compound 9 or compound 20 with a base. As the base, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is used, but potassium hydroxide or sodium hydroxide is preferably used. As the reaction solvent, methanol, ethanol,
Isopropanol, tetrahydrofuran, dioxane,
Dimethoxyethane, water and the like are used alone or as a mixed solvent, but preferably a mixed solvent of dioxane-water or a mixed solvent of tetrahydrofuran-water-methanol is used.
The reaction is carried out at 0 to 120 ° C, preferably 20 to 100 ° C.
Perform at ° C.

The conversion of compound 25 to compound 24 can be carried out by converting compound 25 into an acid chloride and then treating with an amine having desired groups Y and Z in the presence or absence of a base. As a reagent for preparing the acid chloride, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, or the like is used, but thionyl chloride is preferably used. The reaction is carried out at 0 to 120 ° C., preferably,
Perform at 20-100 ° C. As a base used for the reaction with the amine, triethylamine, diisopropylethylamine, pyridine, or the like is used, and triethylamine is preferably used. As a reaction solvent used for the reaction with the amine, methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform, or the like is used alone or as a mixed solvent, and preferably, tetrahydrofuran is used. Reaction is -10 to 50
C., preferably at 0-30.degree.

The conversion of compound 25 into compound 24 can also be carried out by treating compound 25 with a condensing agent and then treating it with an amine having desired groups Y and Z. As the condensing agent, 1,1'-carbonyldiimidazole, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, dicyclohexylcarbodiimide, diethylphosphoric cyanide and the like are used, and preferably 1,1 '
-Carbonyldiimidazole or benzotriazole-
1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate is used. As a reaction solvent, methanol, ethanol, tetrahydrofuran,
Dioxane, dimethoxyethane, dichloromethane, chloroform and the like are used alone or as a mixed solvent, and preferably, tetrahydrofuran, dichloromethane, or a mixed solvent of methanol and dichloromethane is used. The reaction is -1
It is carried out at 0 to 50 ° C, preferably at 0 to 30 ° C.

Compound 25 can be converted to compound 24 by treating compound 25 with a chlorocarbonate and a base, followed by an amine having desired groups Y and Z or ammonia (both Y and Z are hydrogen atoms). (When a certain compound is desired). As chlorocarbonates, methyl chlorocarbonate,
Ethyl chlorocarbonate or the like is used, and ethyl chlorocarbonate is preferably used. As the base, triethylamine,
Diisopropylethylamine, pyridine and the like are used, and triethylamine is preferably used. As a reaction solvent, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform and the like are used alone or as a mixed solvent, but tetrahydrofuran is preferably used. The reaction is carried out at -10 to 50C, preferably at 0 to 30C.

Reaction formula 7

[0075]

Embedded image

[0076] wherein, A ² represents -CH = or -N =; R ^x is an alkyl group, particularly a straight-chain or branched alkyl group having 1 to 3 carbon atoms; R ² is Represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent; X represents a halogen atom; Y and Z are the same or different and are a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an aryl group which may have a substituent, or a heterocyclic group which may have a substituent, or together form a ring with the nitrogen atom to which they are attached (this ring is Further has an oxygen atom, a nitrogen atom and / or a sulfur atom as a ring atom Bets can be, may further have a substituent at any position on the ring)]

Conversion of compound 5 to compound 26 can be carried out by converting compound 5 into an acid chloride and then treating the compound with an amine having desired groups Y and Z in the presence or absence of a base. Reagents for preparing acid chloride include thionyl chloride, oxalyl chloride, phosphorus oxychloride,
Phosphorus pentachloride or the like is used, preferably thionyl chloride. The reaction is carried out at 0 to 120 ° C.
Perform at 0-100 ° C. As a base used for the reaction with the amine, triethylamine, diisopropylethylamine, pyridine, or the like is used, and triethylamine is preferably used. As a reaction solvent used for the reaction with the amine, methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform, or the like is used alone or as a mixed solvent, and preferably, tetrahydrofuran is used. Reaction is -10 to 50
C., preferably at 0-30.degree.

Conversion of compound 5 to compound 26 can also be carried out by treating compound 5 with a condensing agent and then treating it with an amine having desired groups Y and Z. As the condensing agent, 1,1'-carbonyldiimidazole, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, dicyclohexylcarbodiimide, diethylphosphoric cyanide, and the like are used.
Carbonyldiimidazole or benzotriazole-1
-Yloxy-tris (dimethylamino) phosphonium hexafluorophosphate is used. As a reaction solvent, methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform or the like is used alone or as a mixed solvent, and preferably, tetrahydrofuran or dichloromethane is used.
The reaction is carried out at -10 to 50C, preferably at 0 to 30C.
Do with.

Conversion of compound 5 to compound 26 can also be carried out by treating compound 5 with a chlorocarbonate and a base, and then treating with an amine having desired groups Y and Z. As the chlorocarbonate, methyl chlorocarbonate, ethyl chlorocarbonate and the like are used, and ethyl chlorocarbonate is preferably used. As the base, triethylamine, diisopropylethylamine, pyridine and the like are used, and preferably triethylamine is used. As a reaction solvent, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane,
Although chloroform or the like is used alone or as a mixed solvent,
Preferably, tetrahydrofuran is used. Reaction is -10
It is carried out at -50 ° C, preferably at 0-30 ° C.

Conversion of compound 26 to compound 27 can be carried out by oxidizing compound 26. Oxone (registered trademark OXONE) and m-chloroperbenzoic acid are used as the oxidizing agent. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, dichloromethane, chloroform, methanol, ethanol, water and the like are used alone or as a mixed solvent. Preferably, when oxone (registered trademark OXONE) is used, a tetrahydrofuran-water mixed solvent is used. When m-chloroperbenzoic acid is used, dichloromethane is used. Reaction is -20 to 40 ° C
, But preferably at -20 to 20 ° C.

Conversion of compound 27 to compound 28 can be carried out by treating compound 27 with a base.
As the base, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is used, but potassium hydroxide is preferably used. As the reaction solvent, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethoxyethane, water or the like is used alone or as a mixed solvent, but preferably, methanol or methanol-
A mixed solvent of tetrahydrofuran is used. Reaction is -20
-50 ° C, preferably at -20 to 30 ° C.

Compound 28 can be converted to compound 24 by treating compound 28 with a base and then treating with compound R ² CH ₂ X having desired group R ² .
As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and preferably, sodium hydride is used. As a reaction solvent, tetrahydrofuran, ether, dimethoxyethane, dioxane, methanol, ethanol, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, benzene, toluene, dimethylsulfoxide and the like are used.
Preferably, N, N-dimethylformamide is used. The reaction is carried out at -20 to 70C, preferably at 0 to 50C.

Reaction formula 8

[0084]

Embedded image

[Wherein A ¹ and A ² each independently represent -CH = or -N =; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent; Y and Z are the same or different and are a hydrogen atom, an alkyl group which may have a substituent, or a substituent An alkoxy group, a cycloalkyl group which may have a substituent,
Represents an aryl group which may have a substituent, or a heterocyclic group which may have a substituent, or together form a ring with the nitrogen atom to which they are attached (this ring is , And may have an oxygen atom, a nitrogen atom, and / or a sulfur atom as a ring atom, and may further have a substituent at any position on the ring.)

Conversion of compound 24 to compound 29 can be carried out by treating compound 24 with Lawesson's Reagent. As the reaction solvent,
Tetrahydrofuran, dimethoxyethane, dioxane,
Benzene, toluene, dichloromethane, chloroform and the like are used, but toluene is preferably used. The reaction is 2
The reaction is carried out at 0 to 140 ° C, preferably at 80 to 120 ° C.

Reaction formula 9

[0088]

Embedded image

Wherein A ¹ and A ² each independently represent —CH ＝ or —N ＝; R ¹ represents an alkyl group or an amino group; R ² has a substituent An aryl group which may be substituted, a cycloalkyl group which may have a substituent,
Or a heterocyclic group which may have a substituent; Y and Z are the same or different and are a hydrogen atom, an alkyl group which may have a substituent, or a substituent An alkoxy group, a cycloalkyl group which may have a substituent,
Represents an aryl group which may have a substituent, or a heterocyclic group which may have a substituent, provided that one of Y and Z is always a hydrogen atom]

Conversion of compound 29 to compound 30 can be carried out by treating compound 29 with ethyl iodide and sodium hydride and then treating with cyanamide and sodium hydride. As a reaction solvent for the treatment with ethyl iodide and sodium hydride, tetrahydrofuran, dimethoxyethane, dioxane, benzene, toluene, or the like is used, and tetrahydrofuran is preferably used. The reaction is carried out at −20 to 50 ° C., preferably,
Perform at 0-30 ° C. The subsequent reaction of treating with cyanamide and sodium hydride can be carried out without treating the compound 29 with ethyl iodide and sodium hydride and then performing isolation or the like. The reaction is carried out at 20-100 ° C,
Preferably, it is performed at 50 to 80 ° C.

The compounds of the present invention other than the above-mentioned compounds can also be produced by a method similar to the above-mentioned method or by a method which is partly changed according to the target compound to be produced.

The compounds of the present invention can also be produced by applying the specific production methods described in the examples.

The compounds of the present invention have a cyclooxygenase-2 (COX-2) inhibitory activity and are useful as anti-inflammatory agents. The compounds of the present invention can be administered orally or parenterally, such as orally, intravenously, by mucosal application, transdermal application. In this case, the dosage is 3 to 1 orally per day.
50 mg / kg, parenterally, 1 to 50 mg / kg.

When these compounds are administered as medicaments, they can be formulated using ordinary formulation techniques, tablets, capsules, powders, granules, suppositories, creams, ointments, aqueous solutions And solid or liquid dosage forms such as emulsions, oils and suspensions.

Furthermore, in this case, excipients, disintegrants, lubricants, binders, preservatives, stabilizers, osmotic pressure adjusting agents, bases and the like, which are the commonly used additive components in the formulation, are used. Can be used.

Examples of these additional components include glucose, lactose, starch, carboxymethylcellulose, magnesium stearate, talc, liquid paraffin, polyvinyl alcohol, vegetable oil, polyalkylene glycol and the like. In addition, it can also contain a pharmaceutical ingredient.

[0097]

The method for preparing the compound of the present invention will be described below in detail with reference to Examples.

In order to show the usefulness of the compounds of the present invention, the results of pharmacological tests on the COX-2 inhibitory activity of representative compounds of the compounds of the present invention are shown in Test Examples.

Example 1 (1- (4-Fluorobenzyl) -5-methanesulfonylindol-2-yl) carbonylpyrrolidine

[0100]

Embedded image

(1) Preparation of 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid Under a nitrogen atmosphere, a solution of 1-benzenesulfonyl-5-methylthioindole (4.31 g) in tetrahydrofuran (150 ml) was added at -78 ° C. And n-butyllithium (1.
59M, 10.7 ml) was added dropwise, and the mixture was stirred at the same temperature for 45 minutes, and then hexamethylphosphoric triamide (4.94 ml) was added.
Was added dropwise, and the mixture was stirred at the same temperature for 25 minutes. Carbon dioxide gas is bubbled through the stirred reaction mixture at the same temperature,
After stirring for an hour, the temperature was raised to 15 to 30 ° C. 2N hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized (hexane-ethyl acetate) to obtain 3.43 g of the target substance as white crystals. ¹ H-NMR (DMSO-d ₆ )
δ value: 2.49 (3H, s), 7.24 (1H, s), 7.38 (1H, dd, J =
1.7,8.6 Hz), 7.54 (1H, d, J = 1.7 Hz), 7.62 (2H, t,
J = 7.3 Hz), 7.72 (1H, t, J = 7.3 Hz), 7.95 (1H, d, J =
8.6 HZ), 8.00 (2H, d, J = 7.6 Hz).

(2) Preparation of (1-benzenesulfonyl-5-methylthioindol-2-yl) carbonylpyrrolidine To a mixture of the compound (0.5 g) obtained in Example 1 (1) and tetrahydrofuran (5 ml) was added At 0 ° C., triethylamine (0.3 ml) and ethyl chlorocarbonate (0.17)
ml) and stirred at the same temperature for 15 minutes. 0 ° C for the mixture
Then, pyrrolidine (0.36 ml) was added thereto, and the mixture was stirred at 15 to 30 ° C for 1 hour. Dilute the reaction mixture with ethyl acetate and add 1
The mixture was washed sequentially with normal hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1). Thus, 0.45 g of a white amorphous target product was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 1.98 (4H, m), 2.48 (3H, s),
3.45 (2H, t, J = 6.3 Hz), 3.71 (2H, t, J = 6.6 Hz), 6.6
3 (1H, s), 7.28 (1H, dd, J = 1.7, 8.9 Hz), 7.38 (1H,
d, J = 1.7 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.53 (1H,
t, J = 7.3 Hz), 7.95 (1H, d, J = 8.9 Hz), 8.11 (2H, d,
J = 7.3 Hz).

(3) (1- (4-fluorobenzyl)-
Preparation of 5-methanesulfonylindol-2-yl) carbonylpyrrolidine 0% was added to a mixture of the compound obtained in Example 1 (2) (0.44 g), tetrahydrofuran (10 ml) and water (5 ml).
Oxone (registered trademark OXONE) at 1.degree. C. (1.35 g)
Was added and stirred for 15 minutes, followed by stirring at 15 to 30 ° C. for 1 hour. The mixture was diluted with ethyl acetate, and the organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Obtained as crude product. A methanol solution of the obtained (1-benzenesulfonyl-5-methanesulfonylindol-2-yl) carbonylpyrrolidine (0.53 g) (1
2 ml) was added with a 1N aqueous potassium hydroxide solution (3 ml) at 15-30 ° C., and the mixture was stirred for 1 hour. The mixture was diluted with ethyl acetate, and the insolubles were filtered. The filtrate was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
0.3 g of methanesulfonylindol-2-yl) carbonylpyrrolidine was obtained as a crude product. (5
-Methanesulfonylindol-2-yl) carbonylpyrrolidine (0.1 g) and N, N-dimethylformamide (6 ml) were added at 0 ° C. with 60% sodium hydride (20 mg) and stirred at the same temperature for 30 minutes. did. The reaction mixture was added to 4-fluorobenzyl bromide (0.
09 ml) and stirred at 15-30 ° C for 2 hours. After dilution with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Then, 0.11 g of a white amorphous target product was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 1.7-2.0 (4H, m), 3.09 (3H,
s), 3.41 (2H, t, J = 6.6 Hz), 3.56 (2H, t, J = 6.9 H
z), 5.60 (2H, s), 6.87 (1H, s), 6.95 (2H, m), 7.08
(2H, m), 7.50 (1H, d, J = 8.9 Hz), 7.79 (1H, dd, J =
1.6, 8.9 Hz), 8.30 (1H, d, J = 1.6 Hz).

Example 2 (1- (4-Fluorobenzyl) -5-methanesulfonylindol-2-yl) carbonylmorpholine

[0105]

Embedded image

(1) Preparation of (1-benzenesulfonyl-5-methylthioindol-2-yl) carbonylmorpholine In the same manner as in Example 1 (2), pyrrolidine was replaced by morpholine to obtain the target compound as a colorless oil. Was. ¹ H-NMR (CDCl ₃ ) δ value: 2.48 (3H, s), 3.4-3.5 (2H,
m), 3.7-3.8 (2H, m), 3.8-3.9 (4H, m), 6.63 (1H,
s), 7.28 (1H, dd, J = 1.6, 8.6 Hz), 7.39 (1H, d, J =
1.6 Hz), 7.46 (2H, t, J = 7.3 Hz), 7.55 (1H, t, J = 7.
3 Hz), 7.92 (1H, d, J = 8.6 Hz), 8.10 (2H, d, J = 7.3
Hz).

(2) (1- (4-fluorobenzyl)-
Preparation of 5-methanesulfonylindol-2-yl) carbonylmorpholine (1-benzenesulfonyl-5-methylthioindol-2-yl) carbonylpyrrolidine was converted to (1-benzenesulfonyl-5) in the same manner as in Example 1 (3). Instead of -methylthioindol-2-yl) carbonylmorpholine, a white amorphous target product was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 3.09 (3H, s), 3.2-3.8 (8H,
m), 5.54 (2H, s), 6.75 (1H, s), 6.90-7.15 (4H, m),
7.55 (1H, d, J = 8.9 Hz), 7.82 (1H, dd, J = 1.7,8.9 H
z), 8.31 (1H, d, J = 1.7 Hz).

Example 3 1- (4-Fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-carboxamide

[0109]

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(1) Preparation of 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid methyl ester 1-benzenesulfonyl-5-methylthioindole-
A mixture of 2-carboxylic acid (3.5 g), sulfuric acid (10 ml) and methanol (10 ml) was heated at reflux for 12 hours. The reaction mixture was poured into ice water and extracted with dichloromethane.
The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane) to give 3.4 g of the desired product as white crystals.
I got ¹ H-NMR (CDCl ₃ ) δ value: 2.51 (3H, s), 3.93 (3H, s),
7.10 (1H, s), 7.37 (1H, dd, J = 2.0, 8.9 Hz), 7.44 (1
H, d, J = 2.0 Hz), 7.48 (2H, t, J = 7.9 Hz), 7.58 (1H,
t, J = 7.9 Hz), 8.01 (2H, d, J = 7.9 Hz), 8.05 (1H,
d, J = 8.9 Hz).

(2) 5-methanesulfonylindole
Preparation of 2-Carboxylic Acid Methyl Ester A mixture of the compound obtained in Example 3 (1) (3.4 g), tetrahydrofuran (90 ml) and water (45 ml) was added with 0%.
Oxone (OXONE) (8.7 g) was added at ℃, stirred for 20 minutes, and stirred at 15 to 30 ℃ for 1 hour. The mixture was diluted with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 3.5 g of 1-benzenesulfonyl-5-methanesulfonylindole-2-carboxylic acid methyl ester as a white amorphous substance. Obtained as product. 1-benzenesulfonyl-5 obtained
Potassium hydroxide (0.79 g) was added to a mixture of methanesulfonylindole-2-carboxylic acid methyl ester (3.5 g), tetrahydrofuran (45 ml) and methanol (90 ml) at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. did. 2N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.2 g of a white amorphous 5-methanesulfonylindole-2-carboxylic acid methyl ester as a crude product. ¹ H-NMR (CDCl ₃ ) δ value: 3.10 (3H, s), 3.99 (3H, s),
7.35 (1H, d, J = 1.7 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.8
6 (1H, dd, J = 1.7, 8.6 Hz), 8.38 (1H, s), 9.24 (1H,
brs).

(3) 1- (4-fluorobenzyl) -5
Preparation of -methanesulfonylindole-2-carboxylic acid methyl ester The compound (1.2 g) obtained in Example 3 (2) and N,
To a mixture of N-dimethylformamide (23 ml) was added 60% sodium hydride (204 mg) at 0 ° C., and the mixture was stirred at the same temperature for 20 minutes. 4-Fluorobenzyl bromide (0.65 ml) was added to the reaction mixture at 0 ° C.
Stirred at C for 2 hours. 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane) to obtain 1 g of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.09 (3H, s), 3.92 (3H, s),
5.86 (2H, s), 6.9-7.1 (4H, m), 7.50 (1H, s), 7.50
(1H, d, J = 8.6 Hz), 7.83 (1H, dd, J = 2.0, 8.6 Hz),
8.38 (1H, d, J = 2.0 Hz).

(4) 1- (4-fluorobenzyl) -5
Preparation of -methanesulfonylindole-N-methyl-2-carboxamide A mixture of the compound obtained in Example 3 (525 mg), a 40% solution of methylamine in methanol (5 ml) and tetrahydrofuran (5 ml) was prepared at 15 to 30 ° C. Stir for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to give 0.44 of the desired product as white crystals.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 3.00 (3H, d, J = 5.0 Hz), 3.08
(3H, s), 5.82 (2H, s), 6.30 (1H, m), 6.95 (2H, t, J
= 8.9 Hz), 7.00 (1H, s), 7.0-7.1 (2H, m), 7.47 (1H,
d, J = 8.9 Hz), 7.78 (1H, dd, J = 2.0, 8.9 Hz), 8.31
(1H, d, J = 2.0 Hz).

Example 4 N, N-dimethyl-1- (4-fluorobenzyl) -5
-Methanesulfonylindole-2-carboxamide

[0115]

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(1) 1- (4-fluorobenzyl) -5
Preparation of -methanesulfonylindole-2-carboxylic acid 1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxylic acid methyl ester (0.26
g), tetrahydrofuran (5 ml) and methanol (1
(0 ml) at 15 to 30 ° C., 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred for 2 hours. 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. Wash the organic layer with water,
The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain 0.25 g of the target substance as white crystals. ¹ H-NMR (CDCl ₃ ) δ value: 3.10 (3H, s), 5.86 (2H, s),
6.9-7.1 (4H, m), 7.52 (1H, d, J = 8.9 Hz), 7.64 (1H,
s), 7.86 (1H, dd, J = 1.6, 8.9 Hz), 8.41 (1H, d, J =
1.6 Hz).

(2) N, N-dimethyl-1- (4-fluorobenzyl) -5-methanesulfonylindole-2
-Preparation of carboxamide Compound (94 mg) obtained in Example 4 (1), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (150 mg),
A mixture of triethylamine (0.05 ml), a 2 mol / l dimethylamine methanol solution (0.2 ml) and dichloromethane (3 ml) was stirred at 15-30 ° C. for 8 hours. Water was added and extracted with dichloromethane. Wash the organic layer with water,
The residue obtained after drying over sodium sulfate and concentrating under reduced pressure was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain 77 mg of the target compound as a white amorphous substance. ¹ H-NMR (CDCl ₃ ) δ value: 2.95 (3H, brs), 3.05 (3H, br
s), 3.09 (3H, s), 5.51 (1H, s), 6.78 (1H, s), 6.96
(2H, t, J = 8.9 Hz), 7.05-7.15 (2H, m), 7.49 (1H, d,
J = 8.6 Hz), 7.78 (1H, dd, J = 1.7, 8.6 Hz), 8.30 (1
(H, d, J = 1.7 Hz).

Example 5 N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxamide

[0119]

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1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxylic acid (86 mg),
A mixture of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (150 mg), triethylamine (0.1 ml), ethylamine hydrochloride (30 mg) and dichloromethane (3 ml) was stirred at 15-30 ° C. for 9 hours. . Water was added and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was recrystallized (hexane-ethyl acetate) to obtain 36 mg of the target substance as white crystals. ¹ H-NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7.3 Hz), 3.08
(3H, s), 3.50 (2H, m), 5.81 (2H, s), 6.20 (1H, m),
6.9-7.2 (3H, m), 7.48 (1H, d, J = 8.9 Hz), 7.78 (1H,
dd, J = 1.7, 8.9 Hz), 8.31 (1H, d, J = 1.7 Hz).

Example 6 1- (4-Fluorobenzyl) -5-methanesulfonylindole-Nn-propyl-2-carboxamide

[0122]

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1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxylic acid (72 mg),
Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (150 mg), triethylamine (0.05 ml), n-
Propylamine (0.03 ml) and dichloromethane (3
ml) of the mixture was stirred at 15-30 ° C for 9 hours. Water was added and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was recrystallized (hexane-ethyl acetate) to obtain 30 mg of the desired product as white crystals. ¹ H-NMR (CDCl ₃ ) δ value: 0.96 (3H, t, J = 7.6 Hz), 1.63
(2H, m), 3.08 (3H, s), 3.40 (2H, q, J = 6.9 Hz), 5.80
(2H, s), 6.22 (1H, m), 6.94 (2H, t, J = 8.6Hz), 7.0
0 (1H, s), 7.0-7.2 (2H, m), 7.49 (1H, d, J = 8.9 H
z), 7.78 (1H, dd, J = 1.7, 8.9 Hz), 8.31 (1H, d, J =
1.7 Hz).

Example 7 1- (4-Fluorobenzyl) -5-methanesulfonylindole-N-methoxy-2-carboxamide

[0125]

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1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxylic acid (72 mg),
Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (110 mg), triethylamine (0.07 ml), O-
A mixture of methylhydroxylamine hydrochloride (21 mg) and dichloromethane (2 ml) was stirred at 15-30 <0> C for 48 hours. Water was added and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 5) to obtain 52 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.08 (3H, s), 3.80 (3H, s),
5.73 (2H, s), 6.92 (2H, t, J = 8.6 Hz), 7.01 (1H, s),
7.02-7.12 (2H, m), 7.46 (1H, d, J = 8.9 Hz), 7.75 (1
H, dd, J = 1.7, 8.9 Hz), 8.22 (1H, d, J = 1.7 Hz), 9.3
8 (1H, brs).

Example 8 1- (4-Fluorobenzyl) -5-methanesulfonylindole-N-methoxy-N-methyl-2-carboxamide

[0128]

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1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxylic acid (72 mg),
Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (110 mg), triethylamine (0.07 ml), O,
A mixture of N-dimethylhydroxylamine hydrochloride (24 mg) and dichloromethane (2 ml) was added at 15-30 ° C for 48 hours.
Stirred for hours. Water was added and extracted with dichloromethane.
The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 5) to obtain 50 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.09 (3H, s), 3.33 (3H, s),
3.50 (3H, s), 5.68 (2H, s), 6.94 (2H, t, J = 8.9 Hz),
7.26 (1H, s), 7.50 (1H, d, J = 8.6 Hz), 7.80 (1H, d
d, J = 1.3, 8.6 Hz), 8.35 (1H, d, J = 1.3 Hz).

Example 9 1- (4-Fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-thioamide

[0131]

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A mixture of 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-carboxamide (190 mg), Lawesson's reagent (150 mg) and toluene (10 ml) was heated under reflux for 2 hours. The residue obtained after concentrating the reaction mixture under reduced pressure was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
The resulting product was subjected to 1) to obtain 180 mg of a yellow amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.07 (3H, s), 3.31 (3H, d, J =
5.0 Hz), 5.91 (2H, s), 6.81 (1H, s), 6.94 (2H, t, J
= 8.6 Hz), 7.0-7.1 (2H, m), 7.40 (1H, d, J = 8.9 Hz),
7.73 (1H, brd, 8.9 Hz), 7.87 (1H, m), 8.25 (1H, b
rs).

Example 10 1- (4-Fluorobenzyl) -5-methanesulfonylindole-N-methyl-N'-cyano-2-carboxamidine

[0134]

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To a mixture of 1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-thioamide (135 mg) and tetrahydrofuran (4 ml) at 0 ° C. ethyl iodide (0.15 ml) and 60 % Sodium hydride (16 mg) was added, and the mixture was stirred at 15 to 30 ° C for 30 minutes. The reaction mixture was charged at 0 ° C. with cyanamide (160
mg) and 60% sodium hydride (130 mg),
The mixture was heated under reflux for 4 hours. Again at 0 ° C. the reaction mixture was charged with cyanamide (160 mg) and 60% sodium hydride (130 mg).
mg) and heated under reflux for 14 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2).
Then, 67 mg of a white amorphous target product was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 3.02 (3H, s), 3.04 (3H, d, J =
5.0 Hz), 5.47 (2H, s), 6.85 (1H, s), 6.85-7.00 (5H,
m), 7.32 (1H, d, J = 8.9 Hz), 7.58 (1H, brd, J = 8.9 H
z), 7.89 (1H, brs).

Example 11 1- (4-Fluorobenzyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-
2-carboxamide

[0137]

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(1) 1-benzenesulfonyl-2-trimethylsilyl-5-methylthio-1H-pyrrolo [2,3
-B] Preparation of pyridine Under a nitrogen atmosphere, trimethylsilylacetylene (0.41
g), 2-benzenesulfonylamino-3-iodo-5
-Methylthiopyridine (0.82 g), triethylamine (0.42 g), cuprous iodide (30 mg), dichlorobis (triphenylphosphine) palladium (75 mg)
And a mixture of dioxane (2 ml) was stirred at 70 ° C. for 16 hours. Next, water and ethyl acetate were added to the reaction solution, and insolubles were filtered off. After adding a saturated aqueous solution of sodium hydrogen carbonate to the filtrate, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
10: 1) to give 0.61 g of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 0.51 (9H, s), 2.46 (3H, s),
6.78 (1H, s), 7.42-7.58 (3H, m), 7.75 (1H, d, J = 2.0
Hz), 8.10-8.14 (2H, m), 8.33 (1H, d, J = 2.0Hz).

(2) Preparation of 1-benzenesulfonyl-5-methylthio-1H-pyrrolo [2,3-b] pyridine Under a nitrogen atmosphere, 1-benzenesulfonyl-2-trimethylsilyl-5-methylthio-1H-pyrrolo [2 , 3-
b] pyridine (0.60 g), tetrabutylammonium fluoride-tetrahydrofuran solution (1.0 M,
0.8 ml) and tetrahydrofuran (100 ml) was stirred at -25 ° C for 30 minutes. To the reaction solution was added a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane:
Ethyl acetate = 5: 1) to give 0.40 g of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 2.49 (3H, s), 6.54 (1H, d, J =
4.0Hz), 7.45-7.62 (3H, m), 7.71 (1H, d, J = 4.0Hz),
7.80 (1H, d, J = 2.0Hz), 8.15-8.20 (2H, m), 8.39 (1
(H, d, J = 2.0Hz).

(3) Preparation of 1-benzenesulfonyl-5-methylthio-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester Under a nitrogen atmosphere, 1-benzenesulfonyl-5-methylthio-1H- Pyrrolo [2,3-b] pyridine (0.80
g) and a mixture of tetrahydrofuran (30 ml) were added dropwise with a solution of lithium diisopropylamide tetrahydrofuran (5.81 mmol) at -78 ° C, and then at -30 ° C.
And stirred for 20 minutes. Then, a mixture of dimethyl carbonate (0.91 g) and tetrahydrofuran (2 ml) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 6 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 0.54 g of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 2.51 (3H, s), 3.99 (3H, s),
6.98 (1H, s), 7.52-7.68 (3H, m), 7.83 (1H, d, J = 2.3
Hz), 8.37-8.42 (2H, m), 8.53 (1H, d, J = 2.3Hz).

(4) 1-benzenesulfonyl-5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-
Preparation of 2-carboxylic acid methyl ester Under a nitrogen atmosphere, 1-benzenesulfonyl-5-methylthio-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester (0.18 g), m-chloroperbenzoic acid A mixture of the acid (0.24 g) and dichloromethane (10 ml) was stirred at 15-30 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 0.19 g of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 3.13 (3H, s), 4.04 (3H, s),
7.12 (1H, s), 7.57-7.73 (3H, m), 8.44-8.51 (3H, m),
9.09 (1H, d, J = 2.3Hz).

(5) 1- (4-fluorobenzyl) -5
Preparation of -Methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester Under a nitrogen atmosphere, 1-benzenesulfonyl-5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine- 2-
A mixture of carboxylic acid methyl ester (0.19 g), potassium hydroxide (90 mg) and methanol (20 ml) was added to 1
Stirred at 5-30 ° C for 1 hour. After adding water to the reaction solution and neutralizing with hydrochloric acid, the precipitated crystals were collected by filtration. Sodium hydride (16 mg), 4-fluorobenzyl bromide (80 mg) and N, N-dimethylformamide (5 ml) were added to the obtained crude crystals, and the mixture was stirred at 15 to 30 ° C for 1 hour. Next, water was added to the reaction solution, and the mixture was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration. 110 mg of the obtained crystals were obtained as the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 3.17 (3H, s), 3.93 (3H, s),
5.99 (2H, s), 6.90-6.98 (2H, m), 7.24-7.30 (2H, m),
7.41 (1H, s), 8.62 (1H, d, J = 2.0Hz), 9.02 (1H, d,
J = 2.0Hz).

(6) 1- (4-fluorobenzyl) -5
-Methanesulfonyl-N-methyl-1H-pyrrolo [2,
3-b] Preparation of pyridine-2-carboxamide Under a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester (55 mg) A mixture of 40% methylamine-methanol solution (1 ml) and tetrahydrofuran (1 ml) was stirred at 15 to 30 ° C. for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized (ethyl acetate-hexane) to obtain 35 mg of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 3.00 (3H, d, J = 5.3Hz), 3.15
(3H, s), 5.97 (2H, s), 6.10-6.22 (1H, m), 6.87-6.96
(3H, m), 7.27-7.35 (2H, m), 8.53 (1H, d, J = 2.0H
z), 8.97 (1H, d, J = 2.0Hz).

Example 12 N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-
2-carboxamide

[0145]

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(1) 1- (4-fluorobenzyl) -5
Preparation of -methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid Under a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] Pyridine-2-carboxylic acid methyl ester (0.18 g), 20
% Potassium hydroxide aqueous solution (5 ml) and dioxane (5 m
The mixture of l) was stirred at 90 ° C. for 20 minutes. After adding water to the reaction solution and neutralizing with hydrochloric acid, the precipitated crystals were collected by filtration.
The obtained crude crystals were recrystallized (ethyl acetate) to obtain 0.13 g of the desired product. ¹ H-NMR (DMSO-d ₆ ) δ value: 3.33 (3H, s), 5.93 (2H, s),
7.06-7.17 (4H, m), 7.53 (1H, s), 8.77 (1H, d, J =
2.3Hz), 8.95 (1H, d, J = 2.3Hz).

(2) N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,
3-b] Preparation of pyridine-2-carboxamide Under a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid (65 mg) and chloride Thionyl (1 ml)
Was heated to reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (1 ml), a 40% ethylamine-tetrahydrofuran solution (0.5 ml) was added, and the mixture was stirred at 15 to 30 ° C for 30 minutes. The reaction solution is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 3) to obtain 40 mg of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 1.23 (3H, t, J = 7.3Hz), 3.15
(3H, s), 3.47 (2H, dq, J = 5.6,7.3Hz), 5.95 (2H, s),
6.15-6.30 (1H, m), 6.88-6.96 (3H, m), 7.28-7.32 (2
H, m), 8.51 (1H, d, J = 2.0Hz), 8.96 (1H, d, J = 2.0H
z).

Example 13 1- (4-Fluorobenzyl) -5-methanesulfonyl-Nn-propyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide

[0149]

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In a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-
b] A mixture of pyridine-2-carboxylic acid (35 mg) and thionyl chloride (0.5 ml) was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (1 ml).
g) and tetrahydrofuran (0.5 ml) were added and stirred at 0 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure,
The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the desired product in 3
8 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 7.3Hz), 1.50-
1.65 (2H, m), 3.15 (3H, s), 3.47 (2H, dq, J = 5.6, 7.
3Hz), 5.96 (2H, s), 6.10-6.25 (1H, m), 6.87-6.97
(3H, m), 7.27-7.32 (2H, m), 8.53 (1H, d, J = 2.0Hz),
8.97 (1H, d, J = 2.0Hz).

Example 14 1- (4-Fluorobenzyl) -5-methanesulfonyl-N, N-dimethyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide

[0152]

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In a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide (46
mg), methyl iodide (0.2 ml), 60% sodium hydride (10 mg) and tetrahydrofuran (2 ml) was stirred at 15-30 ° C. for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 3) to obtain 40 mg of the desired product. ¹ H-NMR (DMSO-d ₆ ) δ value: 2.71 (3H, s), 3.01 (3H, s),
3.16 (3H, s), 5.70 (2H, s), 6.66 (1H, s), 6.92-6.
99 (3H, m), 7.16-7.26 (2H, m), 8.51 (1H, d, J = 2.3H
z), 8.95 (1H, d, J = 2.3Hz).

Example 15 1- (4-Fluorobenzyl) -5-methanesulfonyl-N-methoxy-1H-pyrrolo [2,3-b] pyridine-2-carboxamide

[0155]

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Under a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-
b] A mixture of pyridine-2-carboxylic acid (60 mg) and thionyl chloride (1 ml) was heated at reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in tetrahydrofuran (2 ml), and then O-methylhydroxylamine hydrochloride (0.10 g) and triethylamine (0.2 ml)
And a mixture of acetonitrile (2 ml) and 15-30
Stirred at ° C for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 3) to obtain 25 mg of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 3.16 (3H, s), 3.84 (3H, s),
5.93 (2H, s), 6.87-6.97 (3H, m), 7.29-7.35 (2H, m),
8.55 (1H, d, J = 2.3Hz), 8.65-8.75 (1H, m), 9.00 (1
(H, d, J = 2.3Hz).

Example 16 1- (4-Fluorobenzyl) -5-methanesulfonyl-N-methoxy-N-methyl-1H-pyrrolo [2,3-
b] pyridine-2-carboxamide

[0158]

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In a nitrogen atmosphere, 1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-
b] A mixture of pyridine-2-carboxylic acid (60 mg) and thionyl chloride (1 ml) was heated at reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (1 ml), and a mixture of N, O-dimethylhydroxylamine hydrochloride (0.10 g) and triethylamine (0.2 ml) was added to the solution. The mixture was stirred at 30 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 25 mg of the desired product. ¹ H-NMR (CDCl ₃ ) δ value: 3.16 (3H, s), 3.29 (3H, s),
3.33 (3H, s), 5.88 (2H, s), 6.89-6.96 (3H, m), 7.11
(1H, s), 7.16-7.22 (2H, m), 8.56 (1H, d, J = 2.3H
z), 8.98 (1H, d, J = 2.3Hz).

Example 17 1- (Cyclohexylmethyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-
2-carboxamide

[0161]

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(1) 1- (cyclohexylmethyl) -5
Preparation of -Methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester 5-Methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid methyl ester (130 mg) And a mixture of N, N-dimethylformamide (7 ml)
At 60 ° C., 60% sodium hydride (30 mg) was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added cyclohexylmethyl bromide (0.11 ml) at 0 ° C, and the mixture was stirred at 60 ° C for 2 hours. Add a saturated aqueous ammonium chloride solution,
Extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1) to obtain 64 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 1.0-1.3 (4H, m), 1.4-1.6 (2H,
m), 1.6-2.0 (5H, m), 3.16 (3H, s), 3.97 (3H, s),
4.65 (2H, d, J = 7.6 Hz), 7.38 (1H, s), 8.58 (1H, d,
J = 2.0 Hz), 8.96 (1H, d, J = 2.0 Hz).

(2) 1- (cyclohexylmethyl) -5
-Methanesulfonyl-N-methyl-1H-pyrrolo [2,
3-b] Preparation of pyridine-2-carboxamide A mixture of the compound (60 mg) obtained in Example 17 (1), a 40% methylamine methanol solution (0.5 ml) and tetrahydrofuran (0.5 ml) was heated at 15 to 30 ° C. For 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 60 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 1.0-1.3 (4H, m), 1.4-1.6 (2H,
m), 1.6-1.8 (4H, m), 1.8-2.0 (1H, m), 3.05 (3H, d,
J = 5.0 Hz), 3.15 (3H, s), 4.62 (2H, d, J = 7.3Hz),
6.52 (1H, m), 6.88 (1H, s), 8.46 (1H, d, J = 2.0 H
z), 8.88 (1H, d, J = 2.0 Hz).

Example 18 1- (4-Fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide

[0165]

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1- (4-Fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-
A mixture of 2-carboxylic acid methyl ester (90 mg), tetrahydrofuran (5 ml), methanol (5 ml) and concentrated aqueous ammonia (28%) (5 ml) was added at 15-30 ° C. for 48 hours.
Stirred for hours. Add 1N aqueous sodium hydroxide solution,
Extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 30 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.16 (3H, s), 5.80 (2H, m),
6.00 (2H, s), 6.93 (2H, t, J = 8.6 Hz), 7.03 (1H, s),
7.2-7.4 (2H, m), 8.57 (1H, d, J = 2.0 Hz), 9.00 (1
(H, d, J = 2.0 Hz).

Example 19 1- (4-Fluorobenzyl) -5-methanesulfonyl-N- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxamide

[0168]

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1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-
2-carboxylic acid (42 mg) and tetrahydrofuran (1
1,1'-carbonyldiimidazole (40 mg) was added to the mixture at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes.
To the reaction mixture was added 2,2,2-trifluoroethylamine (0.02 ml) at 0 ° C, and the mixture was stirred at 15 to 30 ° C for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane: methanol = 1).
00: 1) to obtain 36 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.16 (3H, s), 4.10 (2H, m),
5.96 (2H, s), 6.46 (1H, m), 6.93 (2H, t, J = 8.6 Hz),
7.04 (1H, s), 7.2-7.4 (2H, m), 8.56 (1H, d, J = 2.0
Hz), 9.01 (1H, d, J = 2.0 Hz).

Example 20 5- (4-Fluorobenzyl) -N-methyl-2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-
6-carboxamide

[0171]

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(1) Preparation of 2-amino-5-methylthiopyrazine 2-amino-5-bromopyrazine (100 mg), 95% methanethiol sodium salt (84.8 mg), tetrakis (triphenylphosphine) palladium (66. 4mg)
Of N, N-dimethylformamide suspension (2.9 ml) in 6
Stirred at 0 ° C. for 15 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with toluene, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2).
And 67.8 mg (84%) of the desired product as a white powder.
%). H-NMR (CDCl ₃ ) δ value: 2.52 (3H, s), 4.42 (2H, brs),
7.91 (1H, d, J = 1.2 Hz), 7.98 (1H, d, J = 1.2 Hz).

(2) Preparation of 2-amino-3-bromo-5-methylthiopyrazine Pyridine (56.0 mg) was added to a chloroform solution (18 ml) of the compound (100 mg) obtained in Example 20 (1). Then, a solution of bromine (113 mg) in chloroform (18
ml) was added dropwise over 1 hour at 15 to 30 ° C under light shielding, and the mixture was further stirred at the same temperature for 30 minutes. After the reaction,
The reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 112 g (72%) of a target product as a white powder. H-NMR (CDCl ₃ ) δ value: 2.52 (3H, s), 4.90 (2H, brs),
7.91 (1H, s).

(3) Preparation of 3- (2-amino-5-methylthiopyrazin-3-yl) -2-propyn-1-ol A solution of the compound (440 mg) obtained in Example 20 (2) in dioxane (10 ml). ) To 2-propyn-1-ol (168)
mg), bistriphenylphosphinepalladium dichloride (72 mg), copper (I) iodide (38 mg), and triethylamine (304 mg) were sequentially added, followed by stirring at 70 ° C. for 2 hours in a sealed tube. After cooling, the reaction solution was poured into water, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 347 mg (88.9) of the target substance as a brown oil.
%). ¹ H-NMR (CDCl ₃ ) δ value: 2.53 (3H, s), 4.57 (2H, s),
4.90 (2H, brs), 7.95 (1H, s).

(4) Preparation of (2-methylthio-5H-pyrrolo [2,3-b] pyrazin-6-yl) methanol The compound (381 mg) obtained in Example 20 (3) was treated with N,
Copper (I) iodide (111 mg) was added to a solution of N-dimethylformamide (10 ml), and the mixture was stirred at 150 ° C for 2 hours. The reaction solution was poured into water, extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated using silica gel preparative TLC (chloroform: methanol = 20: 1) to obtain 155 mg (40.7%) of the desired product as a yellow powder. ¹ H-NMR (CDCl ₃ ) δ value: 2.65 (3H, s), 4.93 (2H, s),
6.48 (1H, s), 8.12 (1H, s).

(5) Preparation of 2-methylthio-5H-pyrrolo [2,3-b] pyrazine-6-carbaldehyde To a solution of the compound (123 mg) obtained in Example 20 (4) in acetone (40 ml) was added: Manganese dioxide (1.86 g)
Was added and the mixture was stirred at 15 to 30 ° C for 1 hour. After the reaction solution was filtered through celite, it was concentrated under reduced pressure to obtain the target product 6 as a yellow powder.
0 mg (49.3%) were obtained. ¹ H-NMR (CDCl ₃ ) δ value: 2.67 (3H, s), 7.31 (1H, s),
8.37 (1H, s), 9.96 (1H, s).

(6) 5- (4-fluorobenzyl) -2
-Methylthio-5H-pyrrolo [2,3-b] pyrazine-
Preparation of 6-carbaldehyde N, N of the compound (10 mg) obtained in Example 20 (5)
To a dimethylformamide (0.5 ml) solution was added 60% sodium hydride (3 mg) at 0 ° C., and the mixture was stirred for 20 minutes. Then, 4-fluorobenzyl bromide (15 ml) was added.
g) was added dropwise, and the mixture was stirred at 15 to 30 ° C for 30 minutes. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with chloroform, washed with water, and dried over magnesium sulfate.
It was concentrated under reduced pressure. The obtained residue is subjected to silica gel preparative TLC.
(Hexane: ethyl acetate = 5: 1) to obtain 15 mg (99.6%) of the desired product as an orange powder. ¹ H-NMR (CDCl ₃ ) δ value: 2.66 (3H, s), 5.84 (2H, s),
6.93 (2H, t, J = 8.6Hz), 7.27-7.33 (3H, m), 8.36 (1H,
s), 9.96 (1H, s).

(7) 5- (4-fluorobenzyl) -2
-Methylthio-5H-pyrrolo [2,3-b] pyrazine-
Preparation of 6-carboxylic acid methyl ester To the compound (15 mg) obtained in Example 20 (6), methanol (2.8 ml), manganese dioxide (22 mg), and sodium cyanide (13 mg) were added at 0 ° C. Later, 15-
The mixture was stirred at 30 ° C. for 15 hours. Next, the reaction solution was filtered through celite, extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel preparative TLC (chloroform: methanol = 10
0: 1) and 11 mg (6 mg) of the desired product as a white powder.
6.4%). ¹ H-NMR (CDCl ₃ ) δ value: 2.66 (3H, s), 3.91 (3H, s),
5.88 (2H, s), 6.93 (2H, t, J = 8.9Hz), 7.20-7.25 (2H,
m), 7.32 (1H, s), 8.30 (1H, s)

(8) 5- (4-fluorobenzyl) -2
-Methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxylic acid methyl ester The compound (1.06 g) obtained in Example 20 (7) in tetrahydrofuran (40 ml), methanol (40 ml), water ( Oxone (registered trademark O) in a suspension at 0 ° C.
XONE) (2.16 g) was added and the mixture was stirred at 15 to 30 ° C for 4 hours. Furthermore, Oxone (registered trademark OXONE)
(1.08 g) was added, and the mixture was stirred at 15 to 30 ° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into saturated sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Next, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2, 2: 2).
The target product 852 was separated as pale yellow crystals by separation using 1).
mg (73%) was obtained. H-NMR (CDCl ₃ ) δ value: 3.32 (3H, s), 3.98 (3H, s), 5.9
8 (2H, s), 6.96 (2H, t, J = 8.5 Hz), 7.2-7.4 (2H, m),
7.52 (1H, s), 9.19 (1H, s)

(9) 5- (4-fluorobenzyl) -N
-Methyl-2-methanesulfonyl-5H-pyrrolo [2,
3-b] Preparation of pyrazine-6-carboxamide The compound (102 mg) obtained in Example 20 (8) was dissolved in a 40% methylamine methanol solution (10 ml),
Stirred at 30 ° C. for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated using silica gel preparative TLC (methanol: chloroform = 1: 20) to obtain 99.0 mg (97%) of a target product as white crystals. Was. ¹ H-NMR (CDCl ₃ ) δ value: 3.03 (3H, d,
J = 5.1), 3.29 (3H, s), 5.9
4 (2H, s), 6.31 (1H, br)
s), 6.94 (2H, t, J = 8.7 H)
z), 7.05 (1H, s), 7.3-7.4
(2H, m), 9.14 (1H, s).

Example 21 N-ethyl-5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-
6-carboxamide

[0182]

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(1) 5- (4-fluorobenzyl) -2
Preparation of -methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxylic acid 5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6 A 1 N aqueous solution of potassium hydroxide (3.30 ml) was added to a solution of carboxylic acid methyl ester (600 mg) in a 1,4-dioxane solution (17 ml), and the mixture was stirred at 15 to 30 ° C. for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in water, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and reduced pressure. It was concentrated below. Next, the obtained residue was recrystallized from chloroform-methanol-hexane to obtain 541 mg (94%) of the target substance as white needles. ¹ H-NMR (CDCl ₃ ) δ value: 3.33 (3H, s), 5.98 (2H, s),
6.96 (2H, t, J = 8.6 Hz), 7.2-7.4 (2H, m), 7.65 (1H,
s), 9.22 (1H, s).

(2) N-ethyl-5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,
3-b] Preparation of pyrazine-6-carboxamide To a solution of the compound obtained in Example 21 (1) (100 mg) in tetrahydrofuran (2.9 ml) was added 1,1'-carbonyldiimidazole (70 mg) and the mixture was heated at 0 ° C. After stirring for 1 hour at room temperature, a solution of ethylamine in tetrahydrofuran (2.
(0M solution) (0.22 ml) and stirred for an additional 2 hours. The reaction mixture was poured into water, extracted with chloroform, washed with water and an aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel preparative TLC (chloroform: methanol = 10:
1), 50 mg of the desired product as a white powder (45.
8%). ¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.3Hz), 3.29
(3H, s), 3.45-3.56 (2H, m), 5.93 (2H, s), 6.24 (2H,
brs), 6.94 (2H, t, J = 8.6 Hz), 7.03 (1H, s), 7.24-
7.36 (2H, m), 9.14 (1H, s).

Example 22 5- (4-Fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide

[0186]

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5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-
6-carboxylic acid (40 mg) in tetrahydrofuran (1.
1 ml) solution, triethylamine (19 mg) and ethyl chlorocarbonate (22 mg) were added at 0 ° C., and the mixture was stirred for 20 minutes. Next, ammonia gas was bubbled into the mixed solution, and the mixture was further stirred for 30 minutes. Pour the reaction mixture into water,
After extraction with chloroform, washing with water and an aqueous solution of sodium hydrogen carbonate, the mixture was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated using silica gel preparative TLC (chloroform: methanol = 10: 1) to obtain 38 mg (99.2%) of the desired product as a white powder. MS (m / z): 349 (M ⁺ ), 109 (base); ¹ H-NMR (CDCl ₃ ) δ value: 3.30 (3H, s), 5.98 (2H, s),
6.95 (2H, t, J = 8.6 Hz), 7.16 (1H, s), 7.29-7.38 (2
H, m), 9.17 (1H, s).

Example 23 5- (4-Fluorobenzyl) -2-methanesulfonyl-N-methoxy-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide

[0189]

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5- (4-Fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-
6-carboxylic acid (50 mg) and tetrahydrofuran (1
1,1′-carbonyldiimidazole (35 mg) was added to the mixture at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes.
O-Methylhydroxylamine hydrochloride (18 mg) and triethylamine (0.03 ml) were added to the reaction mixture at 0 ° C, and the mixture was stirred at 15 to 30 ° C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain 22 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.28 (3H, s), 3.87 (3H, s),
5.92 (2H, s), 6.95 (2H, t, J = 8.6 Hz), 7.17 (1H, s),
7.26-7.30 (2H, m), 9.15 (1H, s), 9.16 (1H, brs).

Example 24 5- (4-Fluorobenzyl) -2-methanesulfonyl-N-methoxy-N-methyl-5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide

[0192]

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In the same manner as in Example 23, O-methylhydroxylamine hydrochloride was replaced with O, N-dimethylhydroxylamine hydrochloride to obtain a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.32 (9H, s), 5.82 (2H, s),
6.95 (2H, t, J = 8.6 Hz), 7.15-7.25 (3H, m), 9.14 (1
H, s).

Example 25 5-Cyclohexylmethyl-2-methanesulfonyl-N
-Methyl-5H-pyrrolo [2,3-b] pyrazine-6
Carboxamide

[0195]

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(1) 5-cyclohexylmethyl-2-methylthio-5H-pyrrolo [2,3-b] pyrazine-6
Preparation of carbaldehyde 2-methylthio-5H-pyrrolo [2,3-b] pyrazine-6-carbaldehyde (1) obtained in Example 20 (5)
00 mg) of N, N-dimethylformamide (5.2 ml)
After adding 60% sodium hydride (31 mg) to the solution at 0 ° C and stirring for 30 minutes, cyclohexylmethyl bromide (138 mg) was then added dropwise, and the mixture was stirred at 15 to 30 ° C for 1 hour and at 65 ° C for 3 hours. . The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was separated using silica gel preparative TLC (hexane: ethyl acetate = 5: 1) to give the desired product 8 as an orange powder.
5 mg (56.5%) were obtained. MS (m / z): 289 (M ⁺ ), 260 (base); ¹ H-NMR (CDCl ₃ ) δ value: 0.98-1.95 (11H, m), 2.66 (3H,
s), 4.50 (2H, t, J = 7.6Hz), 7.28 (1H, s), 8.31 (1
H, s), 9.98 (1H, s).

(2) 5-cyclohexylmethyl-2-methylthio-5H-pyrrolo [2,3-b] pyrazine-6
Preparation of carboxylic acid methyl ester To the compound (85 mg) obtained in Example 25 (1), methanol (5.0 ml), manganese dioxide (126 mg), and sodium cyanide (71 mg) were added. And stirred for 3 hours. The reaction mixture was filtered through celite, the filtrate was poured into water, extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel preparative TLC (chloroform: methanol =
100: 1), 86 mg of the desired product as a yellow powder
(92.8%). ¹ H-NMR (CDCl ₃ ) δ value: 1.01-1.97 (11H, m), 2.66 (3H,
s), 3.95 (3H, s), 4.54 (2H, t, J = 7.6Hz), 7.30 (1
H, s), 8.26 (1H, s)

(3) Preparation of methyl 5-cyclohexylmethyl-2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxylate (86 mg) The compound obtained in Example 25 (2) Oxone (OXONE®) (664 mg) was added to a tetrahydrofuran-water mixed solution (2: 1, 8.1 ml) of
The mixture was stirred at 15 to 30 ° C for 3 hours. Then, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The obtained residue was separated using silica gel preparative TLC (hexane: chloroform: acetone = 6: 3: 1) to obtain 93 mg (98.0%) of the desired product as a yellow powder. ¹ H-NMR (CDCl ₃ ) δ value: 1.00-1.98 (11H, m), 3.31 (3H,
s), 4.02 (3H, s), 4.65 (2H, t, J = 7.3Hz), 7.50 (1
H, s), 9.13 (1H, s).

(4) 5-cyclohexylmethyl-2-methanesulfonyl-N-methyl-5H-pyrrolo [2,3-
b] Preparation of pyrazine-6-carboxamide To a compound (93 mg) obtained in Example 25 (3), a 40% methanol solution of methylamine (7.8 ml) was added, and the mixture was stirred at 15 to 30 ° C for 30 minutes. did. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel preparative TLC.
(Chloroform: methanol = 10: 1) to obtain 86 mg (94.4%) of the desired product as a yellow powder. ¹ H-NMR (CDCl ₃ ) δ value: 1.02-1.98 (11H, m), 3.09 (3H,
d, J = 4.9Hz), 3.29 (3H, s), 4.63 (2H, t, J = 7.3Hz),
6.36 (1H, brs), 7.02 (1H, s), 9.09 (1H, s).

Example 26 N, N-dimethyl- [5- (4-fluorobenzyl)-
2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine] -6-carboxamide

[0201]

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5- (4-Fluorobenzyl) -N-methyl-2-methanesulfonyl-5H-pyrrolo [2,3-
b] In a solution of pyrazine-6-carboxamide (99.0 mg) in tetrahydrofuran (3 ml) under a nitrogen atmosphere,
% Sodium hydride (13.1 mg) at 15 to 30 ° C
After stirring for 5 minutes, methyl iodide (46.6 mg) was added, and the mixture was stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction solution was poured into saturated saline, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Next, the obtained residue was separated using silica gel preparative TLC (methanol: chloroform = 1: 20), and the obtained target product was recrystallized from chloroform-methanol-hexane to obtain a white crystal. 91.0 mg (89%) of the product were obtained. ¹ H-NMR (CDCl ₃ ) δ value: 2.68 (3H, s), 3.03 (3H, s),
3.30 (3H, s), 5.66 (2H, s), 6.82 (1H, s), 6.98 (2H,
t, J = 8.5 Hz), 7.1-7.3 (2H, m), 9.12 (1H, s).

Example 27 5- (4-Fluorobenzyl) -N-methyl-2-sulfamoyl-5H-pyrrolo [2,3-b] pyrazine-6
-Carboxamide

[0204]

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(1) 5- (4-fluorobenzyl) -2
Preparation of -methanesulfinyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxylic acid methyl ester 5- (4-fluorobenzyl) -2-methylthio-5H
-Pyrrolo [2,3-b] pyrazine-6-carboxylic acid methyl ester (0.16 g), tetrahydrofuran (10
Oxone (registered trademark) (0.3 g) was added to a mixture of water (2.5 ml) and water (2.5 ml) at 0 ° C., followed by stirring at the same temperature for 2 hours. Water was added and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 150 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 2.98 (3H, s), 3.96 (3H, s),
5.97 (2H, s), 6.95 (2H, t, J = 8.9 Hz), 7.25-7.35 (2
H, m), 7.43 (1H, s), 9.06 (1H, s).

(2) 7-chloro-5- (4-fluorobenzyl) -2-sulfamoyl-5H-pyrrolo [2,3
-B] Preparation of methyl pyrazine-6-carboxylate To a mixture of the compound obtained in Example 27 (1) (0.15 g) and dichloromethane (4 ml) at 15 to 30 ° C was added trifluoroacetic anhydride (0.75 ml). ) And stirred at 40 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, toluene was further added, and the mixture was concentrated again under reduced pressure. The residue obtained was diluted with dichloromethane (4 ml) and water (0.8 ml) at 0 ° C under a nitrogen stream.
ml) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. Acetic acid (0.8 ml) was added to the reaction mixture at 0 ° C., followed by bubbling chlorine gas at the same temperature with stirring for 20 minutes. Ice water, a saturated aqueous solution of sodium hydrogen carbonate, and a 5% aqueous solution of sodium thiosulfate were added, and the mixture was extracted with dichloromethane.
The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was diluted with tetrahydrofuran (4 ml), and concentrated aqueous ammonia (28%) (0.8 ml) was added at 0 ° C. For 10 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane: methanol = 1).
00: 1), 145 mg of white amorphous target product
I got ¹ H-NMR (CDCl ₃ ) δ value: 4.01 (3H, s), 5.25 (2H, brs),
5.95 (2H, s), 6.96 (2H, t, J = 8.3 Hz), 7.15-7.25
(2H, m), 9.18 (1H, s).

(3) 5- (4-fluorobenzyl) -2
Preparation of -Sulfamoyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxylic acid methyl ester The compound obtained in Example 27 (2) (135 mg), triethylamine (0.24 ml), formic acid (0.05 ml) , 10%
A mixture of palladium on carbon (50 mg) and ethanol (10 ml) was heated at reflux for 3 hours. After filtration through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 108 mg of a white amorphous target product. ¹ H-NMR (CDCl ₃ ) δ value: 3.97 (3H, s), 5.17 (2H, s),
5.97 (2H, s), 6.95 (2H, t, J = 8.6 Hz), 7.2-7.4 (2H,
m), 7.49 (1H, s), 9.14 (1H, s).

(4) 5- (4-fluorobenzyl) -2
-Sulfamoyl-N-methyl-5H-pyrrolo [2,3
-B] Preparation of pyrazine-6-carboxamide A mixture of the compound obtained in Example 27 (3) (60 mg), a 40% methylamine methanol solution (1 ml) and tetrahydrofuran (1 ml) was stirred at 15 to 30 ° C for 2 hours. .
The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate to obtain 58 mg of a white amorphous target product. ¹ H-NMR (Acetone-d ₆ ) δ value: 2.92 (3H, d, J = 4.6 Hz),
6.00 (2H, s), 6.80 (2H, s), 7.03 (2H, t, J = 8.9 H
z), 7.29 (1H, s), 7.35-7.45 (2H, m), 8.13 (1H, m),
8.96 (1H, s).

Example 28 Nn-propyl-5- (4-fluorobenzyl) -2
-Methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide

[0210]

Embedded image

5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-
6-carboxylic acid (50 mg) in tetrahydrofuran (1.
To the solution (4 ml) was added 1,1'-carbonyldiimidazole (35 mg), and the mixture was stirred at 0 ° C. for 1 hour. Then, n-propylamine (0.02 ml) was added, and the mixture was further stirred for 2 hours. The reaction mixture was poured into water, extracted with chloroform, washed with water and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel preparative TLC (chloroform: methanol = 1).
0: 1) and 22 mg (4%) of the desired product as a white powder.
0.2%). ¹ H-NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 7.3 Hz), 1.55-
1.69 (2H, m), 3.28 (3H, s), 3.42 (2H, q, J = 6.9Hz),
5.93 (2H, s), 6.93 (2H, t, J = 8.6 Hz), 7.07 (1H,
s), 7.25-7.34 (2H, m), 9.12 (1H, s).

Test Example 1 Method for Measuring Inhibitory Activity on Human COX-1 and COX-2 Using Peripheral Blood To 500 μl of peripheral blood collected from a healthy person, 1 μl of a DMSO solution of the compound of the present invention was added. When measuring COX-1 activity, the calcium ionophore A23187 was incubated at 37 ° C. for 4.5 hours.
Was added to a final concentration of 500 μM, incubated at 37 ° C. for 30 minutes, and transferred to ice to stop the reaction. When measuring COX-2 activity, lipopolysaccharide (LPS) (E.
Escherichia coli 026: B6 (manufactured by Sigma) was added to a concentration of 10 μg / ml, and the mixture was incubated at 37 ° C. for 5 hours, and then transferred to ice to stop the reaction. Centrifugation operation (15
0 G x 10 minutes), and then thromboxane B contained in the supernatant.
The amount of 2 was measured with a thromboxane B2 EIA kit (manufactured by Cayman), and the value of the solvent control (prepared by the same operation as above without adding the compound) was 100%.
As it was indicated concentrations showing the 50% inhibition activity as IC _{5 0} value. Inhibitory activity against COX-1 and COX-2 in the resulting present compound (IC _{5 0} value), shown in Table 1.

[0213]

[Table 1]

[0214]

The compound of the present invention has an inhibitory effect on COX-2 and is useful as a drug such as an anti-inflammatory drug.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/44 A61K 31/44 31/4985 31/495 605 31/5377 31/535 606 C07D 403/06 207 C07D 403 / 06 207 471/04 104 471/04 104Z 487/04 140 487/04 140 (72) Inventor Noriaki Maruyama 1-135 Komamon, Gotemba-shi, Shizuoka Chugai Pharmaceutical Co., Ltd. (72) Inventor Takenobu Ishizawa Gotemba-shi, Shizuoka 1-135, Komamon, Chugai Pharmaceutical Co., Ltd. (72) Inventor Yasuharu Kato 1-1135, Komamon, Gotemba-shi, Shizuoka Prefecture F-term in Chugai Pharmaceutical Co., Ltd. AA04 BB04 CC01 DD02 EE02 HH01 JJ09 KK08 KK09 PP03 4C086 AA01 AA02 AA03 BC13 BC73 CB05 GA07 MA04 NA14 ZB11 ZC02 4C204 BB01 BB09 CB03 DB26 EB02 FB14 GB30

Claims (13)

[Claims] 1. A compound of the general formula (I): Wherein, A ¹ and A ² are each independently a -CH = or -N =; R ¹ represents an alkyl group or an amino group; R ² is
Represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent; Q is ＝ O, ＳS, Or = N-
Represents CN; Y and Z are the same or different and are each a hydrogen atom, an alkyl group optionally having a substituent, an alkoxy group optionally having a substituent, or an optionally substituted group; Represents a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, or together forms a ring with the nitrogen atom to which they are attached (This ring may further have an oxygen atom, a nitrogen atom, and / or a sulfur atom as a ring atom, and may further have a substituent at any position on the ring.) A compound of the formula or a salt thereof with a pharmaceutically acceptable acid or base, or a hydrate thereof. 2. A ¹ is -CH = and A ² is -CH
The compound according to claim 1, wherein =. Wherein A ¹ is a -CH =, A ² is -N =
The compound according to claim 1, which is 4. The compound of claim 1, wherein A ¹ is -N = and A ² is -N =. 5. R ¹ is a methyl group or an amino group,
A compound according to any one of claims 1 to 4. 6. R ² is a phenyl group which may have a substituent, a cyclohexyl group which may have a substituent,
The pyridyl group which may have a substituent, the furyl group which may have a substituent, or the thienyl group which may have a substituent, according to any one of claims 1 to 5. Compound. 7. One of Y and Z is a hydrogen atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, a cyanomethyl group, an ethyl group, an i-propyl group, an n-propyl group,
2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 2-cyanoethyl group,
2-nitroethyl group, methoxy group, cyclopentyl group,
The compound according to any one of claims 1 to 6, wherein the compound is a cyclohexyl group or a phenyl group, and the other is a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group. 8. Y and Z together form a 3 to 8 membered ring with the nitrogen atom to which they are attached (the ring may further comprise an oxygen, nitrogen, and / or sulfur atom). Which may be present as a ring atom and may further have a substituent at any position on the ring).
The compound according to any one of the above. 9. (1- (4-fluorobenzyl) -5
(Methanesulfonylindol-2-yl) carbonylpyrrolidine; (1- (4-fluorobenzyl) -5-methanesulfonylindol-2-yl) carbonylmorpholine; 1- (4-fluorobenzyl) -5-methanesulfonylindole-N -Methyl-2-carboxamide;
N, N-dimethyl-1- (4-fluorobenzyl) -5
-Methanesulfonylindole-2-carboxamide;
N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonylindole-2-carboxamide; 1-
(4-fluorobenzyl) -5-methanesulfonylindole-Nn-propyl-2-carboxamide; 1-
(4-fluorobenzyl) -5-methanesulfonylindole-N-methoxy-2-carboxamide; 1- (4
-Fluorobenzyl) -5-methanesulfonylindole-N-methoxy-N-methyl-2-carboxamide;
1- (4-fluorobenzyl) -5-methanesulfonylindole-N-methyl-2-thioamide; 1- (4-
(Fluorobenzyl) -5-methanesulfonylindole-N-methyl-N'-cyano-2-carboxamidine;
1- (4-fluorobenzyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-
2-carboxamide; N-ethyl-1- (4-fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1-
(4-fluorobenzyl) -5-methanesulfonyl-N
-N-propyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-fluorobenzyl)
-5-methanesulfonyl-N, N-dimethyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1
-(4-fluorobenzyl) -5-methanesulfonyl-
N-methoxy-1H-pyrrolo [2,3-b] pyridine-
2-carboxamide; 1- (4-fluorobenzyl)-
5-methanesulfonyl-N-methoxy-N-methyl-1
H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (cyclohexylmethyl) -5-methanesulfonyl-N-methyl-1H-pyrrolo [2,3-b] pyridine-2-carboxamide; 1- (4-Fluorobenzyl) -5-methanesulfonyl-1H-pyrrolo [2,3-
b] pyridine-2-carboxamide; 1- (4-fluorobenzyl) -5-methanesulfonyl-N- (2,2,
2-trifluoroethyl) -1H-pyrrolo [2,3-
b] pyridine-2-carboxamide; 5- (4-fluorobenzyl) -N-methyl-2-methanesulfonyl-5
H-pyrrolo [2,3-b] pyrazine-6-carboxamide; N-ethyl-5- (4-fluorobenzyl) -2-
Methanesulfonyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -2-methanesulfonyl-N-methoxy-
5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -2-methanesulfonyl-N-methoxy-N-methyl-5H-pyrrolo [2,3-b] pyrazine- 6-carboxamide; 5-cyclohexylmethyl-2-methanesulfonyl-N-methyl-5H-pyrrolo [2,3-b] pyrazine-6-carboxamide; N, N-dimethyl-5- (4-fluorobenzyl) -2 -Methanesulfonyl-5H-pyrrolo [2,3
-B] pyrazine-6-carboxamide; 5- (4-fluorobenzyl) -N-methyl-2-sulfamoyl-5
H-pyrrolo [2,3-b] pyrazine-6-carboxamide; or Nn-propyl-5- (4-fluorobenzyl) -2-methanesulfonyl-5H-pyrrolo [2,3-
b] pyrazine-6-carboxamide or a hydrate thereof. 10. A compound of the general formula (II): Wherein, A ¹ and A ² are each independently a -CH = or -N =; R ¹ represents an alkyl group or an amino group; R ² is
Represents an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent; R ³ represents an alkyl group] Or a salt thereof with a pharmaceutically acceptable acid or base, or a hydrate thereof. 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 as a main component together with additional components. A cyclooxygenase inhibitor comprising the compound according to any one of claims 1 to 9. 13. An anti-inflammatory agent comprising the compound according to any one of claims 1 to 9.