WO2017056338A1

WO2017056338A1 - Method for producing pyrazole derivative

Info

Publication number: WO2017056338A1
Application number: PCT/JP2015/080877
Authority: WO
Inventors: 佐藤　勉; ジーウェンリー; シャオゲンヤン; ヨウチュワン; センフェイマオ
Original assignee: 持田製薬株式会社
Priority date: 2015-09-30
Filing date: 2015-11-02
Publication date: 2017-04-06
Also published as: JPWO2017056338A1; CN106554351A; JP6592521B2

Abstract

The present invention provides a method for producing a compound represented by formula (I). Thereby provided is a 4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylic acid amide derivative.

Description

Method for producing pyrazole derivative

The present invention relates to 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5] represented by the formula (I) having an inhibitory action on phosphodiesterase 10 (hereinafter referred to as “PDE10”). -A] Pyridin-7-yl) -1H-pyrazole-5-carboxylic acid amide derivative.

4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1H-pyrazole-5-carboxylic acid represented by the formula (I) Amide derivatives have excellent PDE10 inhibitory action, and are used in various psychiatric disorders involving PDE10 (eg, delusional, dismantled, strained, indistinguishable, or residual schizophrenia). It is expected to be useful for the treatment and / or prevention of symptoms and / or prevention, and as a therapeutic agent with reduced side effects.

A method for producing N-([1,2,4] triazolo [1,5-a] pyridin-7-yl) -1H-pyrazole-5-carboxylic acid amide derivative (formula (i)) is disclosed in International Publication No. 2012. / 076430 pamphlet, p26, scheme 1 (Patent Document 1). According to Patent Document 1, the compound of formula (i) is produced by a condensation reaction of a carboxylic acid derivative (formula (ii)) and an amine derivative (formula (iii)).

The compound of formula (iii) is prepared using a 2-aminopyridine derivative (formula (iv)) and O- (mesitylsulfonyl) hydroxylamine (formula (E-1)).

In addition, International Publication No. 2014/133046 (Patent Document 2) also discloses 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl. ) -1H-pyrazole-5-carboxylic acid amide derivatives (formula (vi)) are disclosed. According to Patent Document 2, the compound of formula (vi) is produced by a condensation reaction of a carboxylic acid derivative (formula (CA)) and an amine derivative (formula (AM)).

One of the formulas (AM), 7-amino- [1,2,4] triazolo [1,5-a] pyridine derivative (AM-4) is a 2-aminopyridine derivative (B-1), and It is produced from O- (mesitylsulfonyl) hydroxylamine (E-1) (in Patent Document 1, <Production Method D> and <Production Method E>).

The derivative represented by the formula (I) in the present invention can be produced according to the method described in Patent Document 1 or Patent Document 2. The compound of formula (iii) or the compound of formula (AM-4) used for the production is produced using the compound of formula (E-1). However, it is pointed out that the compound of the formula (E-1) is not suitable for use in mass synthesis or industrial production due to the stability and safety of the compound (Non-patent Document 1). ing. Accordingly, when considering mass synthesis or industrial production of the derivative represented by the formula (I), it is required to find a new production method different from the production methods disclosed in Patent Document 1 and Patent Document 2. It has been.

On the other hand, 2-phenyl- [1,2,4] triazolo [1,5-a] pyridine derivative (TAP-1) can be produced by reacting an amidine derivative (AMD-1) with an oxidizing agent. [Sodium hypochlorite (Non-patent document 2), lead tetraacetate (Non-patent document 3), oxygen (air) in the presence of a copper reagent (Non-patent document 4), iodine (Non-patent document 5) Or [Bis (trifluoroacetoxy) iodo] benzene (PIFA) (Non-patent Document 6) and the like]. However, in each of the production methods, the production of formula (I) in the present invention is not disclosed, and in each of the production methods, the safety of the reaction reagent, the reaction conditions, the yield, or the reaction application There is a problem in any of the limitation of the range.

Therefore, it has been desired to establish an efficient production method suitable for mass synthesis or industrial production of the derivative represented by the formula (I) to overcome the above-mentioned problems.

International Publication No. 2012/076430 Pamphlet International Publication No. 2014/133046 Pamphlet

Without using the compounds of the formula (iii) and the formula (AM-4), an efficient production method suitable for mass synthesis of the derivative represented by the formula (I) or industrial production, particularly the formula (I It aims at providing the novel manufacturing method which manufactures the derivative | guide_body represented by this.

The present inventors have intensively studied to solve the above problems. As a result, a method for producing a derivative represented by the following formula (I) easily and safely in a short process with good yield and purity has been found, and the present invention has been completed based on this finding. In particular, in the oxidation reaction using PIFA, in order to obtain the target product with high yield, it is necessary to use hexafluoropropanol (HFIP) as a solvent, and as a result of extensive research, A synthetic method using a general-purpose solvent that is acceptable in production or industrial production is found, and a certain amount of water is added to the general-purpose solvent used to produce the derivative represented by the formula (I) with high purity. I also found a method.

(In formula (I), the definitions of p, q, R ¹ , R ² , R ³ , R ⁴ , and the ring A group will be described later in the embodiment [1].)

The present invention is a method for producing a derivative represented by the above formula (I) having a PDE10 inhibitory action. INDUSTRIAL APPLICABILITY The present invention can provide an industrially advantageous production method that is good in yield, high purity, easy and safe in a short process, and has high industrial utility. *

[Aspect of the Invention]
The present invention relates to 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl represented by the formula (I) shown in the following embodiment ) -1H-pyrazole-5-carboxylic acid amide derivative production method, which will be described below.

[1] A first aspect of the present invention is the following formula (I):

[In the formula (I), p represents an integer of 0 to 3; q represents an integer of 0 to 2; and R ¹ each independently represents a halogen atom, a cyano group, a C _1-6 alkyl group, C _{3 ~ 8} cycloalkyl group, a halogenated _{C 1 ~ 6} alkyl _{group, C 2 ~ 6} alkenyl _{group, C 1 ~ 6} alkoxy _{group, C 1 ~ 6} alkoxy _{C 1 ~ 6} alkyl group, hydroxy _{C 1 ~ 6} alkyl group , and C _{2 ~ 7} represents a group selected arbitrarily from alkanoyl group; R ² represents a C 1 _{~ 6} alkyl group; R ³ represents a hydrogen atom, and a group from the fluorine atoms optionally selected; R ⁴ are each independently a halogen _atom, a _{C 1 ~ 6} alkyl group, and _C 1 _{~ 6} group selected from alkoxy groups optionally; formula (II):

A ring A group represented by: a thiazol-2-yl group, a thiazol-4-yl group, a 1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, Arbitrarily selected from 2,4-thiadiazol-5-yl group, pyridin-2-yl group, pyridazin-3-yl group, pyrimidin-2-yl group, pyrimidin-4-yl group, and pyrazin-2-yl group Which represents a monocyclic 5- to 6-membered heteroaryl group], comprising the formula (AD-3):

[In formula (AD-3), p, q, R ¹ , R ² , R ³ , R ⁴ and the ring A group represented by formula (II) are the same as those in formula (I) in embodiment [1]. The same as defined above], and [bis (trifluoroacetoxy) iodo] benzene (PIFA) as the oxidizing agent, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, tripotassium phosphate, In the presence or absence of a base such as sodium acetate, DBU, triethylamine, cesium fluoride, pyridine, acetonitrile, methanol, 2-propanol, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, pyridine, etc. Using a solvent that does not participate in the reaction or a mixed solvent of these solvents that does not participate in the reaction, the cyclization reaction is performed at a temperature at which the solvent refluxes from room temperature. A production method including a step of obtaining a compound represented by formula (I).

[1-1] In a preferred form of the embodiment [1], the above formula (I) [wherein p, q, R ³ and the ring A group represented by the formula (II) in the formula (I) 1] The same definition as in [1]; R ¹ represents a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a difluoromethyl group, trifluoro Represents a group arbitrarily selected from a methyl group, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy group, and an ethoxyethyl group; R ² represents a methyl group; R ⁴ represents a fluorine atom, a methyl group, A process for producing a compound of the formula (I) [same as the step in the above embodiment [1]; Place of formula (AD-3) The definition of the group is the production method include aspects [1-1] defined as the same as the formula (I) in.

[1-1-1] As a more preferable embodiment of the embodiment [1], the ring represented by the above formula (I) [in the formula (I), p, R ¹ , R ² , R ⁴ and the formula (II) A group is the same as defined in the above embodiment [1-1]; q represents an integer of 0; R ³ represents a fluorine atom]. The step of obtaining a compound represented by formula [AD is the same as that in the embodiment [1]; the definition of the substituent in the formula (AD-3) of the starting material is as defined in the formula (1-1-1) It is the same as the definition of I)].

[1-1-2] As a more preferable embodiment of the embodiment [1], in the above formula (I) [in the formula (I), p, q, R ¹ , R ² , R ³ and R ⁴ are The same as defined in [1-1-1]; the ring A group represented by the formula (II) is a thiazol-2-yl group and a pyrimidin-4-yl group; the p, R ¹ , More specific groups combined with the definition of the ring A group represented by (II) are 4- (trifluoromethyl) thiazol-2-yl group, 5-fluoro-2-methoxypyrimidin-4-yl group, Which represents a group arbitrarily selected from 2,5-dimethylpyrimidin-4-yl group and 2-methylpyrimidin-4-yl group], which is a compound represented by the formula (I) [Same as the step in the above-mentioned embodiment [1]; Defining D-3) of the substituents is a method for manufacturing include aspects [1-1-2] defined to be the same in formula (I) in.

[1-2] In a preferred form of the embodiment [1], the equivalent amount of the oxidizing agent (PIFA) is 1.0 to 2.5 equivalents relative to the starting material.

[1-2-1] In a more preferred form of the embodiment [1], the equivalent amount of the oxidizing agent (PIFA) is 1.2 to 2.0 equivalents relative to the starting material.

[1-3] In a preferred form of embodiment [1], the base is present.

[1-3-1] In a preferred form of the embodiment [1-3], the base is cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, DBU, triethylamine, cesium fluoride, or pyridine.

[1-3-2] In a more preferred form of the embodiment [1-3], the base is sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, DBU, triethylamine, cesium fluoride, or pyridine.

[1-4] In a preferred form of the embodiment [1], the equivalent amount of the base is 1.0 to 2.5 equivalents relative to the starting material.

[1-4-1] In a more preferred form of the embodiment [1], the equivalent amount of the base is 1.2 to 2.0 equivalents relative to the starting material.

[1-5] In a preferred form of embodiment [1], the solvent is 2-propanol, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, water, or a solvent not involved in the reaction such as pyridine. Or a mixed solvent of solvents not involved in these reactions.

[1-5-1] In a more preferred form of the embodiment [1], the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water. It is a mixed solvent.

[1-5-2] In a more preferred form of the embodiment [1], the solvent is a mixed solvent of N, N-dimethylformamide and water.

[1-6] In a preferred form of the embodiment [1], the solvent is a mixed solvent of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water. The volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 20: 1 to 1: 1.

[1-6-1] In a more preferred form of the embodiment [1], the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water. A volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 10: 1 to 3: 1. It is.

[1-6-2] In a more preferred form of the embodiment [1], the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water. The volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 8: 1.

[1-7] In a preferred form of embodiment [1], the reaction temperature is between 0 ° C. and about 50 ° C.

[1-7-1] In a more preferred form of embodiment [1], the reaction temperature is between 0 ° C. and about 40 ° C.

[1-7-2] In a more preferred form of the embodiment [1], the reaction temperature is room temperature.

[2] A second embodiment of the present invention is the following (Scheme 1): [(Scheme 1) wherein p, q, R ¹ , R ² , R ³ , R ⁴ , and the ring A group represented by the formula (II) Is the same as defined in the above embodiment [1]].

The groups in the formulas of the above embodiments [1] to [2] will be specifically described below.
In the description of the compound of the present invention, for example, “C _1-6 ” indicates that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms.

In the present specification, unless otherwise specified, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Unless otherwise specified, in this specification, examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Examples include hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Unless otherwise specified, in this specification, “halogenated” means that 1 to 5 of the “halogen atoms” may be contained as a substituent. “Halogenated” is also referred to as “optionally halogenated” or “halogeno”.

In the present specification, unless otherwise specified, the “halogenated C _1-6 alkyl group” means a group in which the “C _1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.

Herein, unless otherwise specified, as the "C _{3 ~ 8} cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Herein, unless otherwise specified, as the "C _{2 ~ 6} alkenyl group", for example, vinyl, allyl, isopropenyl, butenyl, pentenyl, and hexenyl, and the like.

Unless otherwise specified, in this specification, examples of the “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclo Examples include butyloxy, cyclopentyloxy, and cyclohexyloxy.

In the present specification, unless otherwise specified, the “C _1-6 alkoxy C _1-6 alkyl group” refers to a group in which the “C _1-6 alkoxy group” is substituted with the “C _1-6 alkyl group”. Means. In the present specification, unless otherwise specified, examples of the “C _1-6 alkoxy C _1-6 alkyl group” include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

In the present specification, unless otherwise specified, the “hydroxy C _1-6 alkyl group” means a group in which the “C _1-6 alkyl group” is optionally substituted with 1 to 5 hydroxyl groups. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-ethyl and the like.

Herein, unless otherwise specified, as the "C _{2 ~ 7} alkanoyl group", for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl And cyclohexylcarbonyl.

Herein, unless otherwise specified, as the _{"C 7 ~ 20} aralkyl group", for example, benzyl, phenethyl, diphenylmethyl, trityl, biphenyl methyl, naphthylmethyl, indanyl methyl, 1,2,3,4 -Tetrahydronaphthalen-1-ylmethyl and the like.

In the present specification, unless otherwise specified, when a cyclic substituent is substituted with a variable substituent, the variable substituent is bonded to a specific carbon atom of the cyclic group or a specific NH group in the cyclic group. It means not. For example, the variable substituent R ^x in the following formula A can be substituted for any of the carbon atoms i, ii, iii, iv, or v in the formula A, and the variable substituent R ^y in the following formula B is represented by the formula A carbon atom vi in B or vii can be substituted, and a variable substituent R ^z in the following formula C can be substituted with any of the carbon atoms viii, ix, x, or xi in formula C. It means you can do it.

In all of the above embodiments, when the term “compound” is used, “the pharmaceutically acceptable salt” is also referred to. *

The compound in the present invention may form an acid addition salt or a salt with a base depending on the type of substituent. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned.

When the compound in the present invention is acidic, a salt may be formed from an inorganic or organic base. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and represents a salt prepared from a pharmaceutically acceptable non-toxic base including an inorganic or organic base. Salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts. , Barium salt, potassium salt, sodium salt, cesium salt and zinc salt, etc.

Examples of the salt obtained from the organic base include methylamine, ethylamine, t-butylamine, t-octylamine, cyclohexylamine, ethanolamine, ethylenediamine, diethylamine, dicyclohexylamine, dibenzylamine, diethanolamine, N, N′-di Salts with benzylethylenediamine, trimethylamine, triethylamine, triethanolamine, piperidine, morpholine, pyridine, picoline, 2,6-lutidine, lysine, arginine, ornithine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, etc. Is mentioned.

When the compound in the present invention is basic, a salt may be formed from an inorganic acid and an organic acid. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, mandelic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfone. Acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid, camphorsulfonic acid, citric acid, gluconic acid, isethionic acid, mucoic acid, pamoic acid, pantothenic acid, hydroiodic acid, formic acid, trifluoroacetic acid , Propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oxalic acid, malonic acid, phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, aspartic acid and the like. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

According to a conventional method, for example, the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then collected by filtration, or the mixed solvent is distilled. It can be obtained by leaving. In addition, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.

Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) are published as detailed reviews on salt, and are described in detail in this document. The salt can be produced with reference to the review article.

The compounds in the present invention can exist in unsolvated or solvated forms. As used herein, “solvate” means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is particularly called “hydrate”.

When the compounds in the present invention have isomers such as geometric isomers, configuration isomers, tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, any one isomerism And mixtures of isomers are also encompassed in the compounds of the present invention. Furthermore, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from the racemate is also encompassed in the compound of the present invention.

When the compound in the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist.

If the include "C _{2 ~ 6} alkenyl group" in the compounds of the present invention, geometrical isomers (cis / trans or Z / E,) may be present.

If structural isomers can be interconverted by a low energy barrier, tautomerism can occur. Examples of tautomerism include proton tautomerism in compounds having an imino group, a keto group, or an oxime group.

When the compound in the present invention contains geometric isomers, configuration isomers, stereoisomers, conformational isomers, and the like, each can be isolated by a known means.

When the compound in the present invention is an optically active substance, it can be separated from the corresponding racemate into the (+) form or the (−) form [D form or L form] by ordinary optical resolution means.

When the compound in the present invention includes optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is singly identified by a synthesis method or separation method known per se. It can obtain as a compound of. Examples of the separation method include optical resolution methods such as a fractional recrystallization method, a diastereomer method, and a chiral column method. Hereinafter, each division method will be described in detail.

Fractionation recrystallization method: An optical resolution agent is ion-bonded to the racemate to obtain a crystalline diastereomer, and then the crystalline diastereomer is separated by a fractional recrystallization method and optionally optically resolved. In this method, an optically pure compound is obtained through the agent removal step. Optical resolution agents include, for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine , (−)-Cinchonidine, brucine and the like.

Diastereomer method: An optical resolution agent is covalently bonded to a racemic mixture to obtain a mixture of diastereomers, and then by a conventional separation means (for example, fractional recrystallization, silica gel column chromatography, HPLC, etc.) In this reaction, an optically pure optical isomer is obtained through separation into an optically pure diastereomer, followed by a step of removing an optical resolution agent by a chemical reaction (hydrolysis reaction or the like).

For example, when the compound of the present invention has a hydroxyl group or an amino group (primary or secondary), the compound and an optically active organic acid (for example, α-methoxy-α- (trifluoromethyl) phenylacetic acid, and ( A diastereomer of an ester form or an amide form is obtained from each by a condensation reaction with-)-menthoxyacetic acid or the like). Moreover, when the compound of this invention has a carboxy group, the diastereomer of an amide body or an ester body is obtained from each by the condensation reaction of the said compound, an optically active amine, or an optically active alcohol. The diastereomers obtained by the condensation reaction are separated, and each diastereomer is subjected to a hydrolysis reaction with an acid or a base to be converted into an optically pure optical isomer of the original compound.

Chiral column method: A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting to a chromatography using a chiral column (optical isomer separation column).

For example, in the case of high performance liquid chromatography (HPLC), a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel Corporation), and an elution solvent (water, various buffer solutions (for example, phosphate buffer) is added. Liquid) and organic solvents (eg, single solvents such as ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, and diethylamine, or mixed solvents thereof) to develop optical isomers. Separation is possible. For example, in the case of gas chromatography, chiral isomers (for example, CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.)) can be used to separate optical isomers.

The compound in the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a crystal form mixture.

The compound in the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.

The compounds in the present invention include isotopes (eg, hydrogen isotopes, ² H and ³ H, carbon isotopes, ¹¹ C, ¹³ C, and ¹⁴ C, chlorine isotopes, ³⁶ Cl, etc. Fluorine isotopes, ¹⁸ F, iodine isotopes, ¹²³ I and ¹²⁵ I, nitrogen isotopes, ¹³ N and ¹⁵ N, oxygen isotopes, ¹⁵ O, ¹⁷ O, ¹⁸ O, phosphorus, etc. Isotopes, ³² P, etc., as well as sulfur isotopes, ³⁵ S, etc.).

Among the compounds in the present invention, compounds labeled or substituted with certain isotopes (for example, positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be obtained by, for example, positron emission tomography ( It can be used as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.

Of the compounds in the present invention, compounds labeled or substituted with certain isotopes are useful in drug and / or substrate tissue distribution studies. For example, ³ H and ¹⁴ C are useful for this research purpose because they are easy to label or displace with them and are easy to detect.

Among the compounds in the present invention, an isotope-labeled compound can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the examples described later. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

[Production Method of Formula (AD-3) in the Present Invention]
The method for producing the compounds of formula (AD-1), formula (AD-2), formula (AD-3), and formula (PY-1) in the following (Scheme 2) in the present invention will be described in detail. In the present invention, the compounds of formula (AD-1), formula (AD-2), formula (AD-3), and formula (PY-1), their salts and solvates thereof are commercially available compounds or commercially available compounds. Can be easily produced by combining known general chemical production methods using a compound easily obtained by a known production method from the literature as a starting material or a synthetic intermediate. It is possible to manufacture according to a manufacturing method. Further, the present invention is not limited to the manufacturing method described below.

Formula (A-1), Formula (A-2), Formula (A-3), Formula (ET-1), Formula (CA-1), Formula (AD-1), Formula ( PY-1), substituents p, q, R ¹ , R ² , R ³ , R ⁴ , and formulas in the formulas (AD-2), (IM-1), and (AD-3) The definition of ring A represented by (II) is the same as the definition of each of the embodiments [1] to [1-1-2] unless otherwise specified.

The definition of X in the production method is a halogen atom unless otherwise specified. The definition of W in the production method is boronic acid ester, boronic acid, trifluoroborate salt, or boronic acid N-methyliminodiacetic acid ester unless otherwise specified. Definition of ^{R A} in the manufacturing method, unless otherwise _specified, is a _{C 1 ~ 6} alkyl group, and _{C 7 ~ 20} aralkyl group. Definition of R ^B in the manufacturing process, unless otherwise specified, is a C 1 _{~ 6} alkyl group. Defining ^{R D} in the manufacturing process, unless otherwise _specified, is a _{C 1 ~ 6} alkyl _{group, C 6 ~ 14} aryl group, and _{C 7 ~ 20} groups selected arbitrarily from aralkyl groups.

Each formula in each step in the production method of the present invention may form a salt, and examples of the salt include the same salts as those of the formula (I) described above.

The raw material compound in each step in the production method of the present invention can be used in the next reaction as the reaction solution or as a crude product. It can also be isolated from the reaction mixture according to a conventional method, and easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, and chromatography. Is possible.

Solvents used in the above recrystallization are, for example, water, methanol, ethanol, 2-propanol, butanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, n-hexane, cyclohexane, heptane, benzene, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile, acetone, diphenyl ketone, methyl acetate, ethyl acetate, dimethyl sulfoxide , Acetic acid, trifluoroacetic acid, methanesulfonic acid, and the like. These solvents can be used alone, or two or more kinds of solvents can be mixed and used in an appropriate ratio, for example, a ratio of 1: 1 to 1:10. Moreover, when the compound in a formula is marketed, it can also use a commercial item as it is, It is also possible to use what was manufactured by the method known per se, or a method according to it.

Each expression of each step in the manufacturing method of the present invention, transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, C 1 _{~ 6} alkoxycarbonyl group, C 6 _{~ 14} aryloxy carbonyl group, C 7 _{~ 20} aralkyloxycarbonyl group, a sulfo group, in the case containing a halogen atom, etc.), to produce a variety of compounds by converting by methods analogous thereto, or a method known per se these functional groups Can do.

In the above conversion reaction, when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also.

These functional group transformations are described in, for example, Comprehensive Organic Transformations, 2nd edition, published in October 1999, by Richard C. Larock, et al. VCH) can be carried out according to the method described in the book.

When each formula in each step in the production method of the present invention has a reactive group such as a hydroxyl group, an amino group, a carboxy group, and a thiol group as a substituent, these groups are appropriately protected in each reaction step, The protecting group can be removed at an appropriate stage.

The method of introducing and removing the protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Green, et al., “Protective Groups in Organic Synthesis”. ) 4th edition, 2007, can be performed by the method described in the book of John Wiley & Sons.

The reaction temperature in each step in the production method of the present invention is not limited as long as it is in the range of the temperature at which the solvent is refluxed from −78 ° C. unless otherwise specified. The reaction time is not limited as long as the reaction is sufficiently advanced unless otherwise specified.

The term “range of the temperature at which the solvent is refluxed from −78 ° C.” in the reaction temperature means a temperature within the range from −78 ° C. to the temperature at which the solvent (or mixed solvent) used in the reaction is refluxed. . For example, when methanol is used as the solvent, “at a temperature at which the solvent is refluxed from −78 ° C.” means a temperature within a range from −78 ° C. to a temperature at which the methanol is refluxed. Similarly, “at a temperature at which the reaction solution is refluxed from −78 ° C.” means a temperature within a range from −78 ° C. to a temperature at which the reaction solution is refluxed.

In the production method of the present specification, unless otherwise specified, “room temperature” means a temperature in a laboratory, a laboratory, etc., and means a temperature in the range of 1 to 30 ° C.

The reaction in each step in the production method of the present invention can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.

Examples of the solvent not involved in the reaction include water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N, N-dimethylformamide ( DMF), N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1, 4-dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Emissions, triethylamine, N, N- diisopropylethylamine, pyridine, lutidine, acetic anhydride, formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and the like. These solvents can be used alone, or can be appropriately selected depending on the reaction conditions, and two or more solvents can be mixed and used at an appropriate ratio.

Unless otherwise specified, in the production method of the present specification, when “solvent not involved in the reaction” is described, the solvent to be used may be a single solvent, or may be appropriately selected depending on the reaction conditions and used in two types. It means that the above solvents may be mixed and used at an appropriate ratio.

The base (or deoxidizing agent) used in each step in the production method of the present invention is, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate. Calcium carbonate, sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N , N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] Octane, 1,8-diazabicyclo [5.4.0] -7 Undecene (DBU), imidazole, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, methyllithium, Examples thereof include n-butyllithium, sec-butyllithium, tert-butyllithium and the like. However, it is not necessarily limited to those described above.

Examples of the acid or acid catalyst used in each step in the production method of the present invention include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, Tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, Etc. However, it is not necessarily limited to those described above.

<Production method A>
Method for producing amide derivative (AD-1):

<Step 1>
<In the case of formula (A-2) where W = boronic acid ester>
Using a compound represented by the formula (A-1), it is described in literature known methods, for example, “The Journal of Organic Chemistry, 60, 7508-2665, 1995”. In the presence of diboron esters such as bis (pinacolato) diboron and bis (neopentylglycolate) diboron, palladium (II) acetate, tetrakistriphenylphosphine palladium, tri (dibenzylideneacetone) dipalladium, In the presence of a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex, G Phosphine reagents such as phenylphosphine, tri (tert-butyl) phosphine, tri (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, and triethylamine, N, N-diisopropylethylamine, carbonic acid In the presence or absence of an organic or inorganic base such as potassium or potassium acetate, or in the presence or absence of tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of a phosphine reagent, toluene, N, N-dimethylformamide, Using a solvent that does not participate in the reaction such as dimethyl sulfoxide and 1,4-dioxane, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce a boronic ester of the formula (A-2) can do.

<In the formula (A-2), when W = boronic acid>
In accordance with a method known in the literature using a compound represented by the formula (A-1), for example, a method described in “Chemiche Berichte, 42, 3090, 1909”, toluene, tetrahydrofuran, Using a solvent not involved in the reaction such as 1,4-dioxane, or a mixed solvent thereof, alkyllithium such as n-butyllithium and sec-butyllithium, Grignard reagent such as isopropylmagnesium chloride, or metallic magnesium In the presence of water, trialkylborate such as trimethylborate and triisopropylborate is added and reacted at −78 ° C. at room temperature, then acid such as hydrochloric acid and sulfuric acid is added, and the reaction is performed at 0 ° C. at a temperature at which the solvent is refluxed. To produce a boronic acid of formula (A-2) it can.

<In the case of formula (A-2) where W = trifluoroborate salt>
Using the boronic acid ester or boronic acid obtained by the above-mentioned method, difluoride according to a method known in the literature, for example, the method described in “Chemical Reviews, 108, 288-325, 2008”. In the presence of potassium hydride (KHF ₂ ), the reaction is carried out using a solvent that does not participate in the reaction, such as methanol, ethanol, water, or a mixed solvent thereof, at a temperature at which the solvent refluxes from 0 ° C. ) Trifluoroborate salt can be produced.

<In the formula (A-2), W = boronic acid N-methyliminodiacetic acid (MIDA) ester>
Using the boronic acid obtained by the above method, a method known in the literature, for example, a method described in “Journal of Organometallic Chemistry, 307 (1), p1-6, 1986”. Similarly, in the presence of N-methyliminodiacetic acid (MIDA), the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof To produce a boronic acid N-methyliminodiacetic acid (MIDA) ester of the formula (A-2).

<Process 2>
<Production method A> Using the compound of formula (A-2) obtained in <Step 1> and the halogenated heteroaryl derivative of formula (A-3), methods known in the literature, for example, “Experimental Chemistry Course No. 1” 5th edition 18 Synthesis of organic compounds VI-Organic synthesis using metals-327-352, Maruzen, 2004, and Journal of Medicinal Chemistry, 48 (20), p6326- 6339, 2005 ”, palladium (II) acetate (Pd (OAc) ₂ ), tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), tri (dibenzylideneacetone) dipalladium ( _(dba) 3 _Pd 2), bis (dibenzylideneacetone) palladium ((dba ₂ Pd), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl _2), etc. of a palladium catalyst, triphenylphosphine, tri (tert- butyl) phosphine, tri ( phosphine reagents such as o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, and triethylamine, N, In the presence of an organic or inorganic base such as N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, etc., toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, 1,2-dimethoxyethane, acetonitrile ( Acetonitrile / water), 1, 4 Using a solvent that does not participate in the reaction such as dioxane (1,4-dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compound of -1) can be produced. Or it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.

<Step 3>
<In the formula (ET-1), R ^D = C _1-6 alkyl group>
<Production Method A> Using the compound of formula (ET-1) obtained in <Step 2>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1- 43, 1992, Maruzen, etc., in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water, methanol, ethanol, Using a solvent inert to the reaction such as 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, or a mixed solvent thereof, the reaction is performed at a temperature from 0 ° C. to the reflux of the solvent. A compound of (CA-1) can be produced.

<When R ^D = tert-butyl group in Formula (ET-1)>
<Production Method A> Using a compound of formula (ET-1) obtained in <Step 2>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition” According to the deprotection method described in the fourth edition, 2007, John Wiley & Sons, Greene et al., Hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc. The compound of formula (CA-1) can be produced by carrying out the reaction with an acid at a temperature at which the solvent is refluxed from 0 ° C.

<In the formula (ET-1), R ^D = benzyl group>
<Production Method A> Using the compound of formula (ET-1) obtained in <Step 2>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / In accordance with the method described in Labeled Compound, 159-266, 1992, Maruzen, etc., palladium-carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide (PtO ₂ ), dichlorotri (tri In the presence of a catalyst such as phenylphosphine) ruthenium, in an atmosphere of hydrogen gas, an alcohol solvent such as methanol, ethanol, 2-propanol, ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane Using a solvent that does not participate in the reaction, such as a polar solvent such as a system solvent, ethyl acetate, or methyl acetate, or a mixed solvent thereof, The solvent is carried out at a temperature of refluxing, it is possible to produce a compound of formula (CA-1).

<Step 4>
<Production Method A> Using the compound represented by the formula (CA-1) obtained in <Step 3>, a method known in the literature, for example, Synthesis, (12), p954-955, 1979, In the presence of a base such as N, N-diisopropylethylamine, triethylamine, pyridine, etc., a compound of ClCOOR ^A or di-tert-butyl dicarbonate (Boc ₂ O) in the presence of a base such as N, N-diisopropylethylamine, triethylamine or pyridine Using an ether solvent such as 1,2-dimethoxyethane or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to form an active ester. Without isolating the active ester form, the method was subsequently published in a method known in the literature, for example, “Journal of the American Chemical Society, 75, p637-640, 1953”. According to the method described, a base such as N, N-diisopropylethylamine, triethylamine, pyridine, and ammonium carbonate were added to the above reaction solution, and the reaction was carried out at a temperature at which the solvent refluxed from 0 ° C. A compound represented by AD-1) can be produced.

<Step 5>
<Production Method A> Using the compound represented by the formula (ET-1) obtained in <Step 2>, a method known in the literature, for example, International Publication No. 2006/043145, P120, Example 43 (April 2006). The compound represented by the formula (AD-1) can be produced by carrying out the reaction at a temperature at which the reaction solution is refluxed from 0 ° C. using an aqueous ammonia solution in accordance with the method described in the publication on May 27. .

<Production method B>
Method for Producing Pyridine Acid Derivative (PY-1) [(PY-1-1): R ³ = Fluorine Atom]:

<Step 1>
Methods known in the literature, for example, “Bioorganic & Medicinal Chemistry Letters, 22 (10), p3431-3436, 2012”, “International Publication No. 2011-073845 (June 2011) Published on the 23rd), p116, Example 56, step (A) ”, etc., in a solvent inert to the reaction such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or a mixed solvent thereof. At a temperature of −78 ° C., a mixed solution of lithium diisopropylamide (LDA) prepared from N, N-diisopropylamine and n-butyllithium (n-hexane solution) was added to the formula (B-1 ) (For ^{R 3} = fluorine atom, the starting material, 2,5-difluoro-pyridine [CAS Number: 84476-99-3] in a) objects After 3 hours stirring added, further added iodine, from -78 ° C. The compound of formula (B-2) can be produced by carrying out the reaction at a temperature of 0 ° C.

<Process 2>
<Manufacturing method B> Using the compound of formula (B-2) obtained in <Step 1>, a method known in the literature, for example, Synthesis, 12, p905-908, 1989, etc. According to the method, a sealed tube reaction is carried out at 0 ° C. to 150 ° C. using a solvent inert to the reaction such as 1,4-dioxane in the presence of aqueous ammonia to produce the compound of formula (PY-1). be able to.

<Manufacturing method C>
Method for producing amidine acid derivative (AD-3):

<Step 1>
<Production method A> Using a compound of formula (AD-1) obtained in <Step 4> or <Step 5> and a compound of formula (PY-1) obtained in <Production method B><Step2> In the presence of N, N-dimethyl-1,2-ethanediamine, copper iodide (CuI), and inorganic bases such as potassium carbonate and potassium phosphate, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc. The compound of the formula (AD-2) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. in a solvent inert to the above reaction or a mixed solvent thereof.

<Process 2>
<Production method C> Compounds of formula (AD-2) and formula (IM-1) obtained in <Step 1> or salts thereof (formula (IM-1) and salts thereof are commercially available compounds or commercially available compounds. The reaction is carried out at a temperature at which the solvent refluxes from 0 ° C. in a solvent that does not participate in the reaction, such as dimethyl sulfoxide and pyridine. ) Can be produced.

Next, in order to describe the present invention in more detail, reference examples of examples will be given, but the present invention is not limited thereto.
For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-ECX400 (JEOL JNM-ECX400) FT-NMR (manufactured by JEOL Ltd.), Geol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (JEOL) (Made by Co., Ltd.) was used. LC-Mass was measured by one of the following methods. A Waters FractionLynx MS system (manufactured by Waters) was used, the column was manufactured by Waters, a SunFire column (4.6 mm × 5 cm, 5 μm), and the mobile phase was methanol: 0.05% aqueous acetic acid solution = 10: 90 (0 min). Gradient conditions of ˜100: 0 (2 minutes) to 100: 0 (3 minutes) were used.
In (physical property data) of (Example), LC-MS means LC-Mass, and in LC-MS, M is molecular weight, RT is retention time (retention time), [M + H] ⁺ , [M + 3H] ³⁺ , And [M + Na] ⁺ shall mean molecular ion peaks. ^{In the 1} H-NMR data, the NMR signal pattern is s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet.

Example 1 Synthesis of 5-fluoro-4-iodopyridin-2-amine <Step 1> Synthesis of 2,5-difluoro-4-iodopyridine Using 2,5-difluoropyridine, International Publication No. 20111 / The crude 2,5-difluoro-4-iodopyridine (96% crude yield) was obtained by a similar method described in pamphlet No. 073845 (published on June 23, 2011: p116, Example 56, step (A)). Obtained. The ¹ H NMR data of the obtained 2,5-difluoro-4-iodopyridine was consistent with the data described in WO 2011/073845.

<Step 2> Synthesis of 5-fluoro-4-iodopyridin-2-amine (Example 1) Crude 2,5-difluoro-4-iodopyridine (2.26 g, 9.4) obtained in <Step 1> Mmol), 28% aqueous ammonia (6.8 mL) and 1,4-dioxane (2.3 mL) were added to a sealed tube reactor and heated in an oil bath at 135 ° C. for 53 hours. Water was added to the reaction mixture, and the mixture was extracted with methyl-tert-butyl ether (MTBE). The obtained organic layer was washed with water and concentrated under reduced pressure. Crude 5-fluoro-4-iodopyridin-2-amine (1.90 g, 85%) was obtained as a moss green solid.

(Physical data) LC-MS: M = 238 , RT = 0.55 ( ^{min), [M + H] +} = 239 1 H NMR (400MHz, DMSO-d 6, δppm):. 7.82 (1H, s) , 6.92 (1H, d, J = 4 Hz), 6.00 (2H, s).

Example 2 Synthesis of N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide <Step 1> 4- (2,5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (also known as ethyl 4- (2,5-dimethylpyrimidin-4-yl) ) Synthesis of -1-methyl-1H-pyrazole-5-carboxylate) 4-Bromo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (CAS number: 1328640-39-6: 5 g, 21 mmol) , tri (dibenzylideneacetone) dipalladium _{_{(0) (Pd 2 (dba}} ) 3) (0.39g, 0.43 mmol), 2- Jishikurohekishi Phosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (0.35 g, 0.86 mmol) and triethylamine (9.0 mL, 64 mmol) were mixed with toluene (25 mL) to give 4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (3.1 mL, 21 mmol) was added at room temperature. After the resulting mixture was stirred at 90 ° C. for 45 minutes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 10.5 mmol) was added, and 45 ° C. at the same temperature. The reaction was performed for a minute. Potassium carbonate (8.9 g, 64 mmol) was dissolved in water (10 mL) and slowly added to the reaction mixture, and then 4-chloro-2,5-dimethylpyrimidine (3.1 g, 21 mmol) and ethanol (20 mL) were added. It was. The resulting mixture was refluxed for 2 hours, cooled to room temperature, filtered through celite, and washed with ethyl acetate and water. The filtrate was extracted with 3N hydrochloric acid. The aqueous layer was washed with methyl-tert-butyl ether (MTBE), basified with potassium carbonate, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and crude 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (4.1 g, 52% yield, 71% Purity) was obtained as a brown oil.

(Physical property data) LC-MS: M = 260, RT = 0.83 (min), [M + H] ⁺ = 261. ¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 8.50 (1H, s), 7.56 (1H, s), 4.22 (3H, s), 4.17 (2H, q, J = 7 Hz), 2.72 (3H, s), 2.16 (2H, s), 1 .05 (3H, t, J = 7 Hz).

<Step 2> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 2) Crude 4 synthesized in the same manner as in <Step 1> A mixture of-(2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (0.50 g, 1.9 mmol) and 25% aqueous ammonia (5 mL) at room temperature For 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. 4- (2,5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (0.13 g, 30%) was obtained as a pale yellow solid.

(Physical property data) LC-MS: M = 231, RT = 0.54 (min), [M + H] ⁺ = 232. ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 8.57 (1H, s ), 8.28 (1H, brs), 7.84 (1H, s), 7.79 (1H, brs), 3.98 (3H, s), 2.56 (3H, s), 2.30. (2H, s).

<Step 3> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (Example 2) Crude 4- (2 synthesized in <Step 1> , 5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (4.0 g, 16 mmol) in 1N aqueous sodium hydroxide solution (19 mL, 19 mmol) and toluene (20 mL) ) And stirred at room temperature for 5 hours. The aqueous layer was separated and concentrated hydrochloric acid was added to pH = 1. The precipitated solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (2.4 g, 65% ) Was obtained as a pale yellow solid.

(Physical data) LC-MS: M = 232 , RT = 0.65 ( ^{min), [M + H] +} = 233 1 H-NMR (400MHz, DMSO-d 6, δppm):. 8.49 (1H, s ), 7.61 (1H, s), 4.07 (3H, s), 2.55 (3H, s), 2.15 (3H, s).

<Step 4> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 2) 4- synthesized in the same manner as in <Step 3> (2,5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.5 g, 2.2 mmol) and diisopropylethylamine (0.4 mL, 2.4 mmol) were added to tetrahydrofuran. (5 mL) and ethyl chloroformate (0.23 mL, 2.4 mmol) was added dropwise under ice cooling. After stirring for 20 minutes under ice cooling, ammonium carbonate (0.41 g, 4.3 mmol) and diisopropylethylamine (0.75 mL, 4.3 mmol) were added, and the resulting mixture was stirred at room temperature for 45 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. 4- (2,5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (0.37 g, 73%) was obtained as a white solid. The obtained 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide data was synthesized in the above (Example 2) <Step 1>. , 5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide.

<Step 5> Synthesis of N- (2-amino-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide Crude 5-fluoro-4-iodopyridin-2-amine (104 mg, 0.44 mmol) synthesized in Example 1), (Example 2) 4- (2,5-dimethyl) obtained in <Step 4> Pyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (92 mg, 0.4 mmol), N, N′-dimethyl-1,2-ethanediamine (4.1 mg, 0.05 mmol) , Copper iodide (CuI) (9.1 mg, 0.05 mmol) and potassium carbonate (110 mg, 0.8 mmol) in 1,4-dioxane (1 mL) and mixed in an oil bath at 100 ° C. for 20 minutes. Heated for hours Crude 5-fluoro-4-iodopyridin-2-amine (16 mg, 0.07 mmol), N, N′-dimethyl-1,2-ethanediamine (2 mg, 0.02 mmol), copper iodide (CuI) (4 mg, 0.02 mmol) was added and heated in an oil bath at 100 ° C. for 6 hours, followed by additional crude 5-fluoro-4-iodopyridin-2-amine (16 mg, 0.07 mmol). And stirred for 15 hours. Water and dichloromethane were added to the reaction mixture, insoluble materials were removed by filtration, and then the organic layer was separated. The obtained organic layer was washed with water and concentrated under reduced pressure. To remove excess 5-fluoro-4-iodopyridin-2-amine, the resulting solid was washed with methyl-tert-butyl ether (MTBE) to give N- (2-amino-5-fluoropyridine-4- Yl) -4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (82 mg, 60%) was obtained as a brown solid.

(Physical property data) LC-MS: M = 341, RT = 0.67 (min), [M + H] ⁺ = 342. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 10.7 (1H, s ), 8.56 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J = 3 Hz), 7.29 (1H, brs), 5.95 (2H, s) , 4.00 (3H, s), 2.43 (3H, s), 2.36 (3H, s).

<Step 6> Synthesis of N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide Example 2) N- (2-amino-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1-methyl synthesized by the same method as in <Step 5> A mixture of -1H-pyrazole-5-carboxamide (100 mg, 0.29 mmol) and methylbenzimidothioate hydroiodide (106 mg, 0.38 mmol) in pyridine (0.5 mL) and dimethyl sulfoxide (0. 25 mL) was added. The resulting solution was stirred in an oil bath at 80 ° C. for 7 hours. Acetone (0.5 mL), saturated aqueous sodium hydrogen carbonate solution (0.5 mL) and water (2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The obtained solid was collected by filtration, washed with water, and dried to give N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 -Methyl-1H-pyrazole-5-carboxamide (112 mg, 86%) was obtained as a white yellow solid.

(Physical data) LC-MS: M = 444 , RT = 0.81 ( ^{min), [M + H] +} = 445 1 H-NMR (400MHz, DMSO-d 6, δppm):. 10.9 (1H, s ), 9.86 (1H, brs), 8.57 (1H, s), 8.31 (1H, d, J = 2 Hz), 8.03-8.01 (3H, m), 7.92 ( 1H, brs), 7.67-7.47 (3H, m), 4.02 (3H, s), 2.41 (3H, s), 2.37 (3H, s).

Example 3 Synthesis of N- (2-benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide <Step 1> Synthesis of methyl 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylate 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No .: 514816-42-3: 2.0 g, 9.1 mmol) and 4-chloro-2-methylpyrimidine (0.94 g), or a method similar to (Example 2) <Step 1> or In a similar manner, methyl 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylate (1.26 g) was converted into a yellow oily substance. Got as.

(Physical data) LC-MS: M = 232 , RT = 0.75 ( ^{min), [M + H] +} = 233 1 H-NMR (300MHz, CDCl 3, δppm):. 8.62 (1H, d, J = 5 Hz), 7.85 (1H, s), 7.29 (1H, d, J = 5 Hz), 4.15 (3H, s), 3.87 (3H, s), 2.74 (3H, s).

<Step 2> Synthesis of 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylic acid (Example 3) Methyl 1-methyl-obtained in <Step 1> Using 4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylate (1.26 g), the same method as in (Example 2) <Step 3> or a method analogous thereto The title compound (682 mg) was obtained as a colorless solid.

(Physical data) LC-MS: M = 218 , RT = 0.67 ( ^{min), [M + H] +} = 219 1 H-NMR (300MHz, CDCl 3, δppm):. 8.79 (1H, d, J = 6 Hz), 8.09 (1 H, s), 7.56 (1 H, d, J = 6 Hz), 4.36 (3 H, s), 2.81 (3 H, s).

<Step 3> Synthesis of 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (Example 3) 1-methyl synthesized by the same method as in <Step 2> -4- (2-Methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylic acid (2.0 g, 9.2 mmol) and diisopropylethylamine (1.8 mL, 10 mmol) in tetrahydrofuran (20 mL) And benzyl chloroformate (1.7 mL, 10 mmol) was added dropwise under ice cooling. After stirring for 30 minutes under ice cooling, ammonium carbonate (1.8 g, 18 mmol) and diisopropylethylamine (3.2 mL, 18 mmol) were added, and the resulting mixture was stirred at room temperature for 1.25 hours. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solid in the aqueous layer was collected by filtration, and the obtained aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid residue and the solid obtained from the aqueous layer were combined, triturated with methyl-tert-butyl ether (MTBE), collected by filtration, washed with MTBE, and dried to give 1-methyl-4- (2-methylpyrimidine- 4-yl) -1H-pyrazole-5-carboxamide (1.2 g, 59%) was obtained as a white solid.

(Physical data) LC-MS: M = 217 , RT = 0.57 ( ^{min), [M + H] +} = 218 1 H-NMR (400MHz, DMSO-d 6, δppm):. 9.17 (1H, s ), 8.66 (1H, d, J = 6 Hz), 8.12 (1H, s), 8.03 (1H, s), 7.54 (1H, d, J = 6 Hz), 3.96 ( 3H, s), 2.60 (3H, s).

<Step 4> Synthesis of N- (2-amino-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (Examples) 5-Fluoro-4-iodopyridin-2-amine (482 mg, 2.0 mmol) synthesized in the same manner as 1), and 1-methyl-4-synthesized in Example 3 <Step 3> (2-Methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (400 mg, 1.8 mmol) was used for the reaction according to the method according to (Example 6) <Step 2>. Aqueous ammonium solution (0.8 mL) was added, and the mixture was stirred at room temperature and diluted with water. The precipitated solid was collected by filtration, washed with water and dried, and the resulting crude product was triturated in ethyl acetate / ethanol / MTBE (1: 2: 10) to give N- (2-amino-5-fluoro Pyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (299 mg, 50%) was obtained as a white solid.

(Physical data) LC-MS: M = 327 , RT = 0.69 ( ^{min), [M + H] +} = 328 1 H-NMR (400MHz, DMSO-d 6, δppm):. 11.6 (1H, s ), 8.68 (1H, d, J = 5 Hz), 8.22 (1H, s), 7.87 (1H, d, J = 2 Hz), 7.66 (1H, d, J = 5 Hz), 7.30 (1H, s), 5.90 (2H, s), 4.00 (3H, s), 2.49 (3H, s).

<Step 5> Synthesis of N- (2-benzimidazolid-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (Examples) 3) N- (2-amino-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) -1H— synthesized by the same method as in <Step 4> With pyrazole-5-carboxamide (290 mg, 0.89 mmol) and methylbenzimidothioate hydroiodide (322 mg, 1.2 mmol, 74 mg, 0.27 mmol, 49 mg, 0.18 mmol), Example 2 N- (2-benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidi) was synthesized in the same manner as in <Step 5>. -4-yl)-1H-pyrazole-5-carboxamide (368mg, 97%) was obtained as a gray solid.

(Physical data) LC-MS: M = 430 , RT = 0.84 ( ^{min), [M + H] +} = 431 1 H-NMR (400MHz, DMSO-d 6, δppm):. 11.8 (1H, s ), 9.80 (1H, s), 8.70 (1H, d, J = 6 Hz), 8.35 (1H, d, J = 1 Hz), 8.27 (1H, s), 8.04 ( 2H, d, J = 7 Hz), 7.91 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 5 Hz), 7.53-7.46 (3H, m), 4. 03 (3H, s), 2.49 (3H, s).

Example 4 N- (2-Benzimidamide-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide <Step 1> Synthesis of methyl 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylate 4-bromo-1-methyl-1H-pyrazole- Using 5-carboxylic acid methyl ester (CAS number: 514816-42-3: 2.52 g, 11.5 mmol) and 4-chloro-5-fluoro-2-methoxypyrimidine (1.5 g) Example 2) Methyl 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-in the same manner as in <Step 1> or a method analogous thereto 1H-pyrazole-5-carboxylate (1.6 g) was obtained as a pale yellow liquid.

(Physical data) LC-MS: M = 266 , RT = 0.91 ( ^{min), [M + H] +} = 267 1 H-NMR (300MHz, CDCl 3, δppm):. 8.35 (1H, d, J = 2 Hz), 7.86 (1H, d, J = 1 Hz), 4.15 (3H, s), 4.00 (3H, s), 3.86 (3H, s).

<Step 2> Synthesis of 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (Example 4) Methyl obtained in <Step 1> Using 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylate (1.6 g), similar to (Example 2) <Step 3> By the method or a method analogous thereto, 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.65 g) was obtained as a colorless solid.

(Physical data) LC-MS: M = 252 , RT = 0.81 ( ^{min), [M + Na] +} = 275 1 H-NMR (300MHz, CDCl 3, δppm):. 8.54 (1H, d, J = 3 Hz), 8.28 (1H, d, J = 4 Hz), 4.36 (3H, s), 4.09 (3H, s).

<Step 3> Synthesis of 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 4) Synthesis was performed in the same manner as in <Step 2>. 4- (5-Fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.50 g, 2.0 mmol), and ethyl chloroformate (0.21 mL) (Example 2) 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5 by the same method as in <Step 4>. Carboxamide (0.40 g, 80%) was obtained as a white solid.

(Physical data) LC-MS: M = 251 , RT = 0.67 ( ^{min), [M + H] +} = 252 1 H-NMR (400MHz, DMSO-d 6, δppm):. 8.64 (1H, d , J = 3 Hz), 8.18 (1H, s), 7.97 (1H, s), 7.95 (1H, d, J = 3 Hz), 3.90 (3H, s), 3.89 ( 3H, s).

<Step 4> of N- (2-amino-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide Synthesis 5-Fluoro-4-iodopyridin-2-amine (104 mg, 0.44 mmol) synthesized in the same manner as in Example 1 (Example 4) 4- (5 synthesized in <Step 3> -Fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (100 mg, 0.4 mmol), trans-N, N′-dimethylcyclohexane-1,2-diamine (34 mg 0.24 mmol), copper iodide (CuI) (23 mg, 0.12 mmol) and potassium phosphate (169 mg, 0.8 mmol) in dimethyl sulfoxide (1 mL They were mixed in, and heated at 60 ° C. 3.7 hours. A 28% aqueous ammonium solution (0.2 mL) was added, and the mixture was stirred at room temperature and diluted with water. The reaction mixture was extracted with methylene chloride, and the obtained organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The obtained solid residue was triturated with methyl-tert-butyl ether (MTBE), collected by filtration, washed with methyl-tert-butyl ether, and dried to give N- (2-amino-5-fluoropyridin-4-yl). -4- (5-Fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (99 mg, 69%) was obtained as a gray solid.
(Physical property data) LC-MS: M = 361, RT = 0.71 (min), [M + H] ⁺ = 362.
¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 10.8 (1H, s), 8.65 (1H, d, J = 3 Hz), 8.02 (1H, d, J = 3 Hz), 7.84 (1H, s), 7.37 (1H, d, J = 5 Hz), 5.91 (2H, s), 3.92 (3H, s), 3.68 (3H, s).

<Step 5> of N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide Synthesis (Example 4) N- (2-amino-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl synthesized in <Step 4> A mixture of -1H-pyrazole-5-carboxamide (80 mg, 0.22 mmol) and methylbenzimide thioate hydroiodide (80 mg, 0.29 mmol) in pyridine (0.4 mL) and dimethyl sulfoxide (0. 2 mL) was added. The resulting solution was stirred at 80 ° C. for 35 minutes, methylbenzimide thioate hydroiodide (12 mg, 0.04 mmol) was added, and the mixture was further stirred for 40 minutes. Acetone (0.4 mL) and saturated aqueous sodium hydrogen carbonate solution (0.4 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Water (1.6 mL) was added, and the mixture was further stirred for 1 hr. The obtained solid was collected by filtration, washed with water, and dried to give N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl). -1-Methyl-1H-pyrazole-5-carboxamide (86 mg, 84%) was obtained as a gray solid.

(Physical property data) LC-MS: M = 464, RT = 0.82 (min), [M + H] ⁺ = 465. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 11.1 (1H, s ), 8.67 (1H, d, J = 3 Hz), 8.30 (1H, s), 8.07-8.01 (3H, m), 7.99-7.90 (1H, m), 7.54-7.45 (3H, m), 3.97 (3H, s), 3.68 (3H, s).

Example 5 N- (2-Benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide <Step 1> Synthesis of methyl-4- (5,5-dimethyl-1,3,2-dioxaborinan) -2-yl) -1 methyl-1H-pyrazole-5-carboxylate 4-bromo-1- Methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS number: 514816-42-3: 2.0 g, 9.1 mmol), 5,5,5 ′, 5′-tetramethyl-2,2′- To a solution of bi (1,3,2-dioxaborinane) (4.1 g, 18 mmol) in dimethyl sulfoxide (10 ml) was added 1,1′-bis (diphenylphosphino) ferrocene-palladium ( I) dichloride dichloromethane complex (0.37 g, 0.46 mmol) and potassium acetate (3.6 g, 37 mmol) was added, under a nitrogen atmosphere and stirred for 4 hours at 100 ° C.. The reaction solution was cooled, water (50 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (silica gel: eluent; heptane: ethyl acetate = 90: 10 to 40:60) to give the title compound (1.0 g) as brown Obtained as a solid.

(Physical data) LC-MS: M = 252 , RT = 0.67 ( min), ^{[M +} H] of the corresponding boronic acid ^{+ = 185 1 H-NMR (} 300MHz, CDCl 3, δppm):. 7.58 ( 1H, s), 4.11 (3H, s), 3.88 (3H, s), 3.74 (4H, s), 1.05 (6H, s).

<Step 2> Synthesis of methyl 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylate (Example 5) Methyl-synthesized in <Step 1> 4- (5,5-dimethyl-1,3,2-dioxaborinan) -2-yl) -1 methyl-1H-pyrazole-5-carboxylate (300 mg, 1.19 mmol), and 2-bromo-4- (Trifluoromethyl) thiazole (291 mg) was used in the same manner as in (Example 2) <Step 1> or a method analogous thereto, but methyl 1-methyl-4- (4- (trifluoromethyl) thiazole- 2-yl) -1H-pyrazole-5-carboxylate (259 mg) was obtained as a light brown solid.

(Physical property data) LC-MS: M = 291, RT = 1.05 (min), [M + H] ⁺ = 292. ¹ H-NMR (400 MHz, CDCl ₃ , δ ppm): 8.11 (1H, s), 7.77-7.76 (1H, m), 4.21 (3H, s), 3.98 (3H, s).

<Step 3> Synthesis of 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylic acid (Example 5) Methyl obtained in <Step 2> 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylate (210 mg) was used in the same manner as in (Example 2) <Step 3> or In a similar manner, 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylic acid (173 mg) was obtained as a brown white solid.

(Physical data) LC-MS: M = 277 , RT = 4.98 ( ^{min), [M + H] +} = 278 1 H-NMR (400MHz, CDCl 3, δppm):. 8.48-8.46 (1H , M), 8.08 (1H, s), 4.12 (3H, s).

<Step 4> Synthesis of 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide (Example 5) Synthesis was performed in the same manner as in <Step 3>. 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylic acid (0.15 g, 0.54 mmol), and ethyl chloroformate (0.057) 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole--by the same method as in Example 2, <Step 4> 5-carboxamide (66 mg, 44%) was obtained as a white solid.

(Physical data) LC-MS: M = 276 , RT = 0.90 ( ^{min), [M + H] +} = 277 1 H-NMR (400MHz, DMSO-d 6, δppm):. 8.65 (1H, s ), 8.44 (1H, q, J = 1 Hz), 8.12 (1H, s), 8.02 (1H, s), 3.96 (3H, s).

<Step 5> of N- (2-amino-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide Synthesis 5-Fluoro-4-iodopyridin-2-amine (38 mg, 0.16 mmol) synthesized in the same manner as in Example 1 and 1-methyl synthesized in Example 5 <Step 4> Using 4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide (40 mg, 0.14 mmol) according to the method according to (Example 4) <Step 4> After the reaction, 28% aqueous ammonium solution (0.08 mL) was added, and the mixture was stirred at room temperature, diluted with water, and extracted with methylene chloride. The obtained organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The resulting solid residue was triturated in MTBE to give N- (2-amino-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl)- 1H-pyrazole-5-carboxamide (33 mg, 59%) was obtained as a beige solid.

(Physical property data) LC-MS: M = 386, RT = 0.86 (min), [M + H] ⁺ = 387. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 11.2 (1H, s ), 8.46 (1H, s), 8.13 (1H, s), 7.87 (1H, s), 7.32 (1H, d, J = 4 Hz), 5.94 (2H, s) 4.02 (3H, s).

<Step 6> of N- (2-benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide Synthesis (Example 5) N- (2-amino-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) synthesized in <Step 5> -1H-pyrazole-5-carboxamide (25 mg, 0.06 mmol) and methylbenzimidothioate hydroiodide (23 mg, 0.08 mmol, 3.6 mg, 0.01 mmol) Example 4) N- (2-Benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiol was prepared in the same manner as in <Step 5>. It was obtained 2-yl)-1H-pyrazole-5-carboxamide (27mg, 85%) as a beige solid.

(Physical data) LC-MS: M = 489 , RT = 0.95 ( ^{min), [M + H] +} = 490 1 H-NMR (400MHz, DMSO-d 6, δppm):. 11.4 (1H, s ), 9.82 (1H, s), 8.46 (1H, s), 8.33 (1H, s), 8.16 (1H, s), 8.04 (2H, d, J = 6 Hz) , 7.89 (1H, s), 7.53-7.45 (3H, m), 4.06 (3H, s).

Example 6 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- Yl) -1-methyl-1H-pyrazole-5-carboxamide

(Method A) N- (2-benzimidamido-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 synthesized in the same manner as in Example 2 -Methyl-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol) and sodium bicarbonate (6.8 mg, 0.08 mmol) in a mixed solvent of DMF and water (0.5 mL, DMF: water = 8: 1), (bis (trifluoroacetoxy) iodo) benzene (35 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution (0.2 mL) was added under ice cooling, and the mixture was stirred for 1.5 hours. The resulting solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo. [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (15 mg, 75%) was obtained as a white solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 442, RT = 1.12 (min), [M + H] ⁺ = 443.

(Method B) N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 synthesized in the same manner as in Example 2 -Methyl-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol) and tripotassium phosphate (17.2 mg, 0.08 mmol) were mixed with DMF and water (0.5 mL, DMF: water = 8). 1), (bis (trifluoroacetoxy) iodo) benzene (35 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. A saturated aqueous sodium hydrogen carbonate solution (0.2 mL) was added under ice cooling, and the mixture was stirred for 1 hr. The resulting solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo. [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (16 mg, 80%) was obtained as a beige solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 442, RT = 1.12 (min), [M + H] ⁺ = 443.

(Method C) N- (2-benzimidamido-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 synthesized in the same manner as in Example 2 -Methyl-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol) and sodium acetate (6.6 mg, 0.08 mmol) in a mixed solvent of DMF and water (0.5 mL, DMF: water = 8: 1) ), (Bis (trifluoroacetoxy) iodo) benzene (35 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. A saturated aqueous sodium hydrogen carbonate solution (0.2 mL) was added under ice cooling, and the mixture was stirred for 1 hr. The resulting solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo. [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (12 mg, 60%) was obtained as a pale orange solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 442, RT = 1.12 (min), [M + H] ⁺ = 443.

(Method D) N- (2-benzimidamide-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 synthesized in the same manner as in Example 2 -Methyl-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol) and DBU (12 μL, 0.08 mmol) in a mixed solvent of DMF and water (0.5 mL, DMF: water = 8: 1). After mixing, (bis (trifluoroacetoxy) iodo) benzene (35 mg, 0.08 mmol) was added and stirred at room temperature for 18.5 hours. A saturated aqueous sodium hydrogen carbonate solution (0.2 mL) was added under ice cooling, and the mixture was stirred for 1 hr. The resulting solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo. [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (14 mg, 70%) was obtained as a beige solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 442, RT = 1.12 (min), [M + H] ⁺ = 443.

(Method E) N- (2-benzimidamido-5-fluoropyridin-4-yl) -4- (2,5-dimethylpyrimidin-4-yl) -1 synthesized in the same manner as in Example 2 -Methyl-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol) and triethylamine (11 μL, 0.08 mmol) in a mixed solvent of DMF and water (0.5 mL, DMF: water = 8: 1). After mixing, (bis (trifluoroacetoxy) iodo) benzene (35 mg, 0.08 mmol) was added and stirred at room temperature for 18.5 hours. A saturated aqueous sodium hydrogen carbonate solution (0.2 mL) was added under ice cooling, and the mixture was stirred for 1 hr. The resulting solid was collected by filtration, washed with water, and dried to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo. [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (15 mg, 75%) was obtained as a beige solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 442, RT = 1.12 (min), [M + H] ⁺ = 443.

Example 7 N- (6-Fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-4- (2-methylpyrimidine- Synthesis of 4-yl) -1H-pyrazole-5-carboxamide

(Method A) N- (2-benzimidamido-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) synthesized in the same manner as in Example 3 -1H-pyrazole-5-carboxamide (50 mg, 0.12 mmol) and sodium bicarbonate (17.6 mg, 0.21 mmol) in a mixed solvent of DMF and water (1.25 mL, DMF: water = 8: 1) (Bis (trifluoroacetoxy) iodo) benzene (90 mg, 0.21 mmol) was added and stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution (0.5 mL) was added under ice cooling, and the mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with water, and dried to give N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (48 mg, 97%) was obtained as a white solid. The product was identified by LC-MS data.
(Physical property data) LC-MS: M = 428, RT = 1.16 (min), [M + H] ⁺ = 429.

(Method B) N- (2-benzimidamido-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) synthesized in the same manner as in Example 3 -1H-pyrazole-5-carboxamide (250 mg, 0.58 mmol) and cesium fluoride (159 mg, 1.05 mmol) in a mixed solvent of DMF and water (6.25 mL, DMF: water = 8: 1) After mixing, (bis (trifluoroacetoxy) iodo) benzene (450 mg, 1.05 mmol) was added and stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution (2.5 mL) was added under ice cooling, and the mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with water, and dried to give N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (231 mg, 93%) was obtained as a white solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 428, RT = 1.16 (min), [M + H] ⁺ = 429.

(Method C) N- (2-benzimidamido-5-fluoropyridin-4-yl) -1-methyl-4- (2-methylpyrimidin-4-yl) synthesized in the same manner as in Example 3 -1H-pyrazole-5-carboxamide (250 mg, 0.58 mmol) and pyridine (85 μL, 1.05 mmol) were mixed in a mixed solvent of DMF and water (6.25 mL, DMF: water = 8: 1). , (Bis (trifluoroacetoxy) iodo) benzene (450 mg, 1.05 mmol) was added and stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution (2.5 mL) was added under ice cooling, and the mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with water, and dried to give N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (225 mg, 90%) was obtained as a white solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 428, RT = 1.16 (min), [M + H] ⁺ = 429.

Example 8 4- (5-Fluoro-2-methoxypyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine- Synthesis of 7-yl) -1-methyl-1H-pyrazole-5-carboxamide

N- (2-benzimidazolid-5-fluoropyridin-4-yl) -4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl synthesized in the same manner as in Example 4 -1H-pyrazole-5-carboxamide (13 mg, 0.03 mmol) and pyridine (4.1 μL, 0.05 mmol) in a mixed solvent of DMF and water (0.33 mL, DMF: water = 8: 1) After mixing, (bis (trifluoroacetoxy) iodo) benzene (22 mg, 0.05 mmol) was added and stirred at room temperature for 16.75 hours. A saturated aqueous sodium hydrogen carbonate solution (0.13 mL) was added under ice cooling, and the mixture was stirred for 1.5 hours. The resulting solid was collected by filtration, washed with water, and dried to give 4- (5-fluoro-2-methoxypyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4 Triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (9 mg, 70%) was obtained as a white solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 462, RT = 1.12 (min), [M + H] ⁺ = 463.

Example 9 N- (6-Fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-4- (4- (trifluoro Synthesis of methyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide

N- (2-benzimidamide-5-fluoropyridin-4-yl) -1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) synthesized in the same manner as in Example 5 -1H-pyrazole-5-carboxamide (5.9 mg, 0.01 mmol) and pyridine (1.8 μL, 0.02 mmol) in a mixed solvent of DMF and water (0.15 mL, DMF: water = 8: 1) (Bis (trifluoroacetoxy) iodo) benzene (9.3 mg, 0.02 mmol) was added and stirred at room temperature for 16.75 hours. A saturated aqueous sodium hydrogen carbonate solution (0.06 mL) was added under ice cooling, and the mixture was stirred for 1.5 hours. The resulting solid was collected by filtration, washed with water, and dried to give N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide (3 mg, 51%) was obtained as a white solid. The product was identified by LC-MS data.

(Physical property data) LC-MS: M = 487, RT = 1.26 (min), [M + H] ⁺ = 488.

According to the present invention, there is provided an industrially advantageous production method for the derivative represented by the formula (I) with good yield, high purity, easy and safe in a short process.

Claims

The following formula (I):

[In the formula (I), p represents an integer of 0 to 3; q represents an integer of 0 to 2; and R 1 each independently represents a halogen atom, a cyano group, a C 1-6 alkyl group, C 3 ~ 8 cycloalkyl group, a halogenated C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 1 ~ 6 alkoxy group, C 1 ~ 6 alkoxy C 1 ~ 6 alkyl group, hydroxy C 1 ~ 6 alkyl group , and C 2 ~ 7 represents a group selected arbitrarily from alkanoyl group; R 2 represents a C 1 ~ 6 alkyl group; R 3 represents a hydrogen atom, and a group from the fluorine atoms optionally selected; R 4 are each independently a halogen atom, a C 1 ~ 6 alkyl group, and C 1 ~ 6 group selected from alkoxy groups optionally; formula (II):

A ring A group represented by: a thiazol-2-yl group, a thiazol-4-yl group, a 1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, Arbitrarily selected from 2,4-thiadiazol-5-yl group, pyridin-2-yl group, pyridazin-3-yl group, pyrimidin-2-yl group, pyrimidin-4-yl group, and pyrazin-2-yl group Which represents a monocyclic 5- to 6-membered heteroaryl group], comprising the formula (AD-3):

[In formula (AD-3), p, q, R 1 , R 2 , R 3 , R 4 and the ring A group represented by formula (II) are defined in formula (I) in claim 1] And bis (trifluoroacetoxy) iodo] benzene, and cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, tripotassium phosphate, sodium acetate, DBU, triethylamine, In the presence or absence of a base selected from the group of cesium fluoride and pyridine, acetonitrile, methanol, 2-propanol, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) , Water, and a solvent selected from the group of pyridine, or a mixed solvent of solvents that do not participate in these reactions Performs cyclization reaction at a temperature solvent from room temperature to reflux, a manufacturing method including a step of obtaining a compound represented by the formula (I).