WO2023204629A1

WO2023204629A1 - Method for producing cftr activator compound and intermediate used therefor

Info

Publication number: WO2023204629A1
Application number: PCT/KR2023/005378
Authority: WO
Inventors: 유근철; 이건희; 권재욱
Original assignee: 일동제약(주)
Priority date: 2022-04-20
Filing date: 2023-04-20
Publication date: 2023-10-26
Also published as: TW202400166A

Abstract

The present invention relates to a method for producing a CFTR activator compound and an intermediate used therefor and, more specifically, to a method for producing a novel compound that enhances the activity of CFTR, and a novel intermediate used in the method.

Description

Method for preparing CFTR activator compounds and intermediates used therein

The present invention relates to a method of preparing a compound that modulates the activity of cystic fibrosis transmembrane conductance regulator (CFTR) and to intermediates used therein. More specifically, it relates to a novel compound that increases the activity of CFTR. It relates to a process for preparing a compound and novel intermediates used in the process.

Cystic fibrosis transmembrane conductance regulator (CFTR) refers to a membrane protein and chloride ion (Cl ^- ) channel encoded by the CFTR gene. Activating CFTR present in the cell membrane can treat a number of diseases mediated by loss or deterioration of CFTR function, for example, dry eye syndrome by activating chlorine ion (Cl ^- ) channels to increase tear volume. Abnormal tear film that appears can be corrected.

The present inventors have completed the present invention by not only providing a method for producing a new compound capable of controlling CFTR activity, but also by devising a new method that is more suitable for mass production and can obtain the target compound with high purity and high efficiency. did.

[Prior art literature]

[Patent Document]

Korean Patent Publication No. 10-2018-0102590

One aspect is to provide a method for preparing a compound represented by Formula 1 or Formula 1a.

Another aspect is to provide an intermediate that can be used in the above manufacturing method.

Another aspect is to provide a compound represented by Formula 1 or Formula 1a according to the above production method.

Another aspect is to provide a use of a CFTR activator compound represented by Formula 1 or Formula 1a.

Other objects and advantages of the present application will become clearer from the following detailed description together with the appended claims. Contents not described in this specification can be fully recognized and inferred by anyone with ordinary knowledge in the technical field of this application or a similar technical field, so description thereof is omitted.

One aspect provides a method for preparing a compound represented by Formula 1 or Formula 1a.

Another aspect provides an intermediate that can be used in the above manufacturing method.

Another aspect provides a compound represented by Formula 1 or Formula 1a according to the above production method.

Another aspect provides the use of a CFTR activator compound represented by Formula 1 or Formula 1a.

The present invention appropriately suppresses the production of unnecessary by-products in each process and obtains intermediate compounds as solids, so the reproducibility of the manufacturing process is excellent, manufacturing management is easy, and even on a scale-up scale for large-scale production. Since the target compound can be manufactured with high purity, it can be effectively used in the commercial manufacture of pharmaceuticals.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention.

One aspect provides a method for preparing a compound of Formula 1, comprising the step of preparing a compound of Formula 1 by benzoylating a compound of Formula 5 below or a pharmaceutically acceptable acid addition salt thereof.

[Formula 1]

[Formula 5]

In Formula 1,

R ₁ is C _1-3 alkoxy,

R ₂ is C _1-4 alkyl or C _3-4 cycloalkyl, and when R ₂ is C _1-4 alkyl, two adjacent R ₂ are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,

R ₃ is C _1-3 alkyl or halogen,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

a is an integer from 0 to 5,

In Formula 5 above,

R ₁ is C _1-3 alkoxy,

n is an integer from 0 to 2,

m is an integer from 0 to 2.

As used herein, the term “alkyl” refers to a straight-chain or branched hydrocarbon residue that may be substituted or unsubstituted. For example, alkyl having 1 to 4 carbon atoms may include without limitation all possible isomers thereof, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, and t-butyl.

As used herein, the term “alkoxy” refers to a straight-chain or branched hydrocarbon residue, which may be substituted or unsubstituted, connected to oxygen. For example, an alkoxy with 1 to 4 carbon atoms limits all possible isomers thereof, such as methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy. Can be included without.

As used herein, the term “halogen” refers to an element in group 17 of the periodic table as a chemical series. For example, halogens may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).

As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring having a ring carbon atom. For example, cycloalkyl having 3 to 6 carbon atoms may include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “spiro” refers to two rings sharing one atom, and refers to the case where the two rings are not connected by a bridge. As used herein, unless otherwise specified, the term “spirocycloalkyl” refers to a saturated carbocycle forming two rings, where both rings share only one carbon atom as part of the ring. For example, spirocycloalkyl having 3 to 4 carbon atoms may include spirocyclopropyl and spirocyclobutyl.

In one embodiment, R ₁ can be methoxy, ethoxy, propoxy, or isopropoxy. In one embodiment, R ₁ can be methoxy.

In one embodiment, R ₂ can be methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, spirocyclopropyl, or spirocyclobutyl. In one embodiment, R ₂ can be methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl.

In one embodiment, R ₃ can be methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, or iodine. In one embodiment, R ₃ can be methyl, fluoro, or chloro.

In one embodiment, the compound of Formula 5 may be in the form of a free base or an acid addition salt. The acid addition salt may be any pharmaceutically acceptable acid addition salt for the compound, and may be prepared by any suitable method available to those skilled in the art.

When using the acid addition salt of Formula 5, the compound can be solidified, making it suitable for mass production, and has the advantage of being able to obtain the target compound in high purity without undergoing a purification process such as column chromatography. Therefore, the acid addition salt can be included in the present invention regardless of its type as long as it can solidify the compound of Formula 5 in free base form.

In one embodiment, the acid addition salt of the compound of Formula 5 may be an acid addition salt formed by a free acid, and the free acid may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid; Organic acids such as L-aspartic acid, L-glutamic acid, maleic acid, fumaric acid, oxalic acid, and 4-aminosalicylic acid; Halogen acetic acids such as 2,2-dichloroacetic acid and trifluoroacetic acid; or organic sulfonic acids or derivatives thereof such as alkanesulfonic acids or derivatives thereof such as ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid; Naphthalenesulfonic acid or derivatives thereof such as naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid; It may be benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, (+)-1-(1S)-camphor-10-sulfonic acid, and 1-dodecanesulfonic acid.

In one embodiment, the acid addition salt may be an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, or sulfate; Organic acid salts such as L-aspartate, L-glutamate, maleate, fumarate, oxalate, and 4-aminosalicylate; Halogen acetate such as 2,2-dichloroacetate and trifluoroacetate; or organic sulfonates or derivatives thereof such as alkanesulfonates or derivatives thereof such as ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate; Naphthalenesulfonate or derivatives thereof such as naphthalene-1,5-disulfonate, naphthalene-2-sulfonate, di(tert-butyl)naphthalenedisulfonate, di(tert-butyl)naphthalenesulfonate; It may be benzenesulfonate, 4-toluenesulfonate, camphorsulfonate, (+)-1-(1S)-camphor-10-sulfonate, and 1-dodecanesulfonate.

For example, the pharmaceutically acceptable acid addition salt of the compound of Formula 5 is any one of trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonate, and 4-toluenesulfonate. It can be. In one embodiment, the compound of Formula 1 can be prepared by subjecting the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof to a benzoylation reaction.

As used herein, the term “benzoylation” or “benzoylation reaction” is a chemical reaction in which a benzoyl group is bonded to an organic compound.

In one embodiment, the benzoylation may be performed by reacting the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6 below.

[Formula 6]

In Formula 6 above,

R ₃ is C _1-3 alkyl or halogen,

R ₄ is halogen, hydroxy, or

ego,

a is an integer from 0 to 5.

In one embodiment, the compound of Formula 6 may be a compound of Formula 6a below.

[Formula 6a]

In Formula 6a,

R _4a is halogen, hydroxy, or

am.

In one embodiment, the reagent used in the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and any of these. It may be any one selected from the group consisting of combinations. For example, the reagent used in the benzoylation reaction may be benzoyl chloride, benzoic anhydride, or benzoic acid.

Additionally, the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof can be performed in the presence of a base. The type of the base is not particularly limited as long as it does not inhibit the benzoylation reaction. For example, it may be performed in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof.

Additionally, the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof can be performed with the base in the presence of an amide coupling agent. The amide coupling agent is propanephosphonic anhydride (T ₃ P), thionyl chloride (SOCl ₂ ), phosphorus trichloride (PCl- ₃ ), phosphorus pentachloride (PCl- ₅ ), phosphorus oxychloride (POCl ₃ ), and pivalo chloride. yl(PivCl), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), N,N,N,N '-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination thereof. . For example, the amide coupling agent used in the amidation reaction may be propanephosphonic acid anhydride (T ₃ P).

In one embodiment, the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is any one selected from benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and combinations thereof. reagent; and

It may be performed in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination thereof.

In one embodiment, the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is any one selected from benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and combinations thereof. reagent;

at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof;

Propanephosphonic acid anhydride (T ₃ P), thionyl chloride (SOCl ₂ ), phosphorus trichloride (PCl- ₃ ), phosphorus pentachloride (PCl- ₅ ), phosphorus oxychloride (POCl ₃ ), pivaloyl chloride (PivCl), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), N,N,N,N'-tetramethyl- Performed in the presence of an amide coupling agent selected from the group consisting of O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combinations thereof. It can be.

In one embodiment, the method may further include preparing a compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof by deprotecting the amine protecting group of the compound of Formula 4 below.

[Formula 4]

In Formula 4 above,

R ₁ is C _1-3 alkoxy,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It may be any one amine protecting group selected from among.

Alternatively, Pr may be another commercially available amine protecting group.

In one embodiment, the amine protecting group of the compound of Formula 4 is 2,2-dichloroacetic acid, trifluoroacetic acid, 4-aminosalicylic acid, naphthalene-1,5-disulfonic acid, L-aspartic acid, L-glutamic acid, Maleic acid, oxalic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, (+)-1- (1S)-camphor-10-sulfonic acid, naphthalene-2-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 1-dodecanesulfonic acid, hydrochloric acid, hydrobromic acid, iodide It may be deprotected by at least one member selected from the group consisting of hydrogen acid, nitric acid, phosphoric acid, sulfuric acid, metal catalyst, non-nucleophilic base, and any combination thereof. The metal catalyst may be selected from the group consisting of palladium, carbon, and combinations thereof, but is not limited thereto. The non-nucleophilic base may be selected from the group consisting of piperidine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and combinations thereof. , but is not limited to this.

The deprotection reaction of the amine protecting group Pr of Formula 4 can be controlled by varying the reagents used and reaction conditions depending on the type of protecting group Pr.

For example, when the amine protecting group Pr of Formula 4 is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), or tetrahydropyranyl (THP), the deprotection reaction can be performed under acid conditions. In one embodiment, the type of the acid is not particularly limited as long as it can effectively remove the amine protecting group, for example, 2,2-dichloroacetic acid, L-aspartic acid, benzenesulfonic acid, camphorsulfonic acid, (+ )-1-(1S)-camphor-10-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 1-dodecanesulfonic acid, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, L-glutamic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, maleic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nitric acid, oxalic acid. , phosphoric acid, 4-aminosalicylic acid, sulfuric acid, 4-toluenesulfonic acid, trifluoroacetic acid, and any combination thereof.

For example, when the amine protecting group Pr of Formula 4 is benzyloxycarbonyl (Cbz) or benzyl (Bn), the deprotection reaction can be performed under hydrogenation reaction conditions. In one specific example, the hydrogenation reaction may be performed by reacting the compound of Formula 4 under a metal catalyst (palladium/carbon).

For example, when the amine protecting group Pr of Formula 4 is fluorenylmethoxycarbonyl (Fmoc), the deprotection reaction can be performed under non-nucleophilic base conditions. In one embodiment, the type of the non-nucleophilic base is not particularly limited as long as it can effectively remove the amine protecting group, for example, piperidine, diisopropylethylamine, 1,8-diazabicyclo[5, 4,0]undec-7-ene (DBU) and any combination thereof.

In one embodiment, the pharmaceutically acceptable acid addition salt of the compound of Formula 5 is produced by evaporation without a post-treatment process after the deprotection reaction process of the compound of Formula 4, or by using another appropriate solvent. The acid addition salt can be obtained by adding or precipitating it as an acid addition salt, or by a general method of preparing a free base salt known to those skilled in the art.

For example, when the amine protecting group Pr of the compound represented by Formula 4 is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), or tetrahydropyranyl (THP), the deprotection reaction is carried out under acid conditions. Under these conditions, it can be obtained directly as an acid addition salt without a separate post-treatment process. Alternatively, the free base can be obtained through evaporation and precipitation, or an acid addition salt can be obtained by adding a free acid to the free base after a post-treatment process. Specific methods for performing the above-described evaporation, precipitation, acquisition of free base, addition of free acid, etc. can be performed according to conditions and methods commonly used in the art.

For example, the amine protecting group of the compound of Formula 4 is t-butoxycarbonyl (Boc), and it can be deprotected with hydrochloric acid to form the hydrochloride salt of Formula 5.

For example, when the amine protecting group Pr of the compound represented by Formula 4 is benzyloxycarbonyl (Cbz) or benzyl (Bn), the deprotection reaction can be performed under hydrogenation conditions, and the free base is formed through evaporation and precipitation. An acid addition salt can be obtained by a general method of adding a free acid to a free base after a post-treatment process.

For example, when the amine protecting group Pr of the compound represented by Formula 4 is fluorenylmethoxycarbonyl (Fmoc), the deprotection reaction can be carried out under non-nucleophilic base conditions, and the free base can be obtained through evaporation or precipitation, or An acid addition salt can be obtained by a general method of adding a free acid to a free base after a post-treatment process.

In one embodiment, the method may further include preparing the compound of Formula 4 through an amidation reaction between the compound of Formula 2 and the compound of Formula 3.

[Formula 2]

[Formula 3]

In Formula 2,

R ₁ is C _1-3 alkoxy,

n is an integer from 0 to 2,

In Formula 3 above,

m is an integer from 0 to 2,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It is any one amine protecting group selected from among.

As used herein, the term “amidation” or “amidation reaction” is a chemical reaction in which the carboxyl group of a compound of Formula 2 and the amine group of a compound of Formula 3 are combined.

In one embodiment, the amidation reaction between the compound of Formula 2 and the compound of Formula 3 may be performed in the presence of an amide coupling agent. The amide coupling agent is thionyl chloride (SOCl ₂ ), phosphorus trichloride (PCl- ₃ ), phosphorus pentachloride (PCl- ₅ ), phosphorus oxychloride (POCl ₃ ), pivaloyl chloride (PivCl), and propanephosphonic acid anhydride ( T ₃ P), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), N,N,N,N '-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination thereof. . For example, the amide coupling agent used in the amidation reaction is thionyl chloride (SOCl ₂ ), pivaloyl chloride (PivCl), propanephosphonic acid anhydride (T ₃ P), N,N,N,N'- It may be tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU).

Additionally, the amidation reaction between the compound of Formula 2 and the compound of Formula 3 can be performed in the presence of a base. The type of the base is not particularly limited as long as it does not inhibit the amide reaction, and for example, from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination thereof. It may be performed in the presence of at least one selected base.

In one embodiment, the amidation reaction of the compound of Formula 2 and the compound of Formula 3 includes thionyl chloride (SOCl ₂ ), phosphorus trichloride (PCl- ₃ ), phosphorus pentachloride (PCl- ₅ ), and phosphorus oxychloride (POCl ₃ ), pivaloyl chloride (PivCl), propanephosphonic anhydride (T ₃ P), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carboxylic acid Bodiimide hydrochloride (EDC), N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT) ) and at least one amide coupling agent selected from the group consisting of any combination thereof; and

It can all be performed in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof.

The preparation method according to one embodiment is carried out under an appropriate solvent. The solvent is an inorganic solvent or an organic solvent. The organic solvents include, for example, alcohols (methanol, ethanol, propanol, isopropanol, ethylene glycol, etc.), ethers (diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), dioxane, etc.), ketones. (methyl ethyl ketone, acetone, etc.), aliphatic hydrocarbons (hexane, heptane, octane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane (DCM), chloroform, chlorobenzene etc.), alkoxys (methoxyethane, dimethoxyethane (DME), methoxypropane, dimethoxypropane, etc.), nitriles (acetonitrile, benzonitrile, trinitrile, etc.), or amides. The inorganic solvent may be, for example, water, but is not limited thereto. In one embodiment, the production method may be performed in a non-polar organic solvent. The non-polar organic solvent may be 2-methyltetrahydrofuran (MeTHF), dichloromethane (DCM), tetrahydrofuran (THF), or acetonitrile, but is not limited thereto.

In one embodiment, the compound of Formula 1 may be any one compound selected from the group consisting of the compounds shown in Table 1 below.

[Table 1]

Another aspect provides one or more compounds selected from the compounds of Formula 4, the compounds of Formula 5, and pharmaceutically acceptable acid addition salts of Formula 5 as intermediates for preparing the compound represented by Formula 1.

(The definitions of Formula 1, Formula 4, and Formula 5 and their substituents R ₁ , R ₂ , R ₃ , n, m, a, Pr, and pharmaceutically acceptable acid addition salts are the same as described above.)

In the above compound according to one embodiment

R ₁ is C _1-3 alkoxy,

R ₂ is C _1-3 alkyl, C _3-4 cycloalkyl, or spirocyclopropyl,

R ₃ is C _1-3 alkyl or halogen,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

a is an integer from 0 to 5,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), or fluorenylmethoxycarbonyl (Fmoc) It can be.

In the above compound according to one embodiment

R ₁ is C _1-3 alkoxy,

R ₂ is C _1-3 alkyl, C _3-4 cycloalkyl, or spirocyclopropyl,

R ₃ is methyl, fluoro, or chloro,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

a is an integer from 0 to 5,

Pr may be t-butoxycarbonyl (Boc).

In the above compound according to one embodiment

R ₁ is methoxy,

R ₂ is methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl,

R ₃ is methyl, fluoro, or chloro,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

a is an integer from 0 to 5,

Pr may be t-butoxycarbonyl (Boc).

In the above compound according to one embodiment

R ₁ is methoxy,

R ₂ is methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl,

R ₃ is methyl, fluoro, or chloro,

n is an integer of 2,

m is an integer from 1 to 2,

a is an integer from 0 to 5,

Pr may be t-butoxycarbonyl (Boc).

In the above compound according to one embodiment

R ₁ is methoxy,

R ₂ is methyl,

n is 2,

m is 1,

a is 0,

Pr may be t-butoxycarbonyl (Boc).

The other aspect of work is

Preparing a compound of Formula 4a by amidating a compound of Formula 2a and a compound of Formula 3a;

Preparing a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof by deprotecting the amine protecting group of the compound of Formula 4a; and

A method for preparing a compound of Formula 1a is provided, comprising the step of preparing a compound of Formula 1a by benzoylating a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof.

[Formula 1a]

[Formula 2a]

[Formula 3a]

[Formula 4a]

[Formula 5a]

In one embodiment, the benzoylation may be performed by reacting the compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6a below.

[Formula 6a]

In Formula 6a,

R _4a is halogen, hydroxy, or

am.

In one embodiment, the pharmaceutically acceptable acid addition salt of Formula 5a may be any one compound selected from the following Formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag.

[Formula 5aa]

[Formula 5ab]

[Formula 5ac]

[Formula 5ad]

[Formula 5ae]

[Formula 5af]

[Formula 5ag]

The other aspect of work is

As an intermediate for preparing the compound represented by Formula 1a, one or more compounds selected from the compounds of Formula 4a, the compounds of Formula 5a, and pharmaceutically acceptable acid addition salts of Formula 5a are provided.

(The definitions of Chemical Formula 1a, Chemical Formula 4a, Chemical Formula 5a, and pharmaceutically acceptable acid addition salts are the same as described above.)

In another embodiment,

In Formula 5a, the pharmaceutically acceptable acid addition salt is any one selected from the group consisting of trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonate, and 4-toluenesulfonate. It can be.

In one embodiment,

As an intermediate for the preparation of the compound represented by Formula 1a, the pharmaceutically acceptable acid addition salt of Formula 5a is selected from the group consisting of compounds represented by the following formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag. It may be one or more types of compounds.

[Formula 5aa]

[Formula 5ab]

[Formula 5ac]

[Formula 5ad]

[Formula 5ae]

[Formula 5af]

[Formula 5ag]

The other aspect of work is

As an intermediate for preparing the compound represented by Formula 1a, any one compound selected from Formula 4a, a compound of Formula 5a, or a pharmaceutically acceptable acid addition salt of Formula 5a is provided.

(The definitions of Formula 1 or Formula 1a and their substituents R ₁ , R ₂ , R ₃ , n, m, a, and Pr are the same as described above.)

In one embodiment, the compound represented by Formula 1 or Formula 1a may be provided as a pharmaceutically acceptable salt.

In one embodiment, the compound represented by Formula 1 or Formula 1a may be provided as a CFTR-activating pharmaceutical composition containing its isomer, solvate, hydrate, polymorph, or pharmaceutically acceptable salt thereof.

Another aspect provides the use of the compound represented by Formula 1 or Formula 1a in regulating CFTR.

The manufacturing method according to one embodiment can be expressed as Scheme 1 below.

[Scheme 1]

(In the above formula, (HA) in Formula 5 indicates the presence or absence of an acid addition salt. In addition, the compounds of Formulas 1 to 6 and their respective substituents R ₁ , R ₂ , R ₃ , n, m, a, Pr The definition is the same as described above.)

The manufacturing method may include the following steps.

Step 1: Preparation of Compound of Formula 4

Step 2: Preparation of compound of formula 5 or acid addition salt thereof

Step 3: Preparation of Compound of Formula 1

In one embodiment, Step 1 is a step of preparing a compound of Formula 4a through an amidation reaction between a compound of Formula 2a and a compound of Formula 3a.

The amidation reaction in step 1 may be performed by adding an amide coupling agent and a base in an appropriate solvent.

For example, the amidation reaction can be performed by adding pivaloyl chloride (PivCl) and triethylamine (TEA) in a halogenated hydrocarbon solvent such as dichloromethane.

For example, the amidation reaction can be performed by adding propanephosphonic anhydride (T ₃ P) and triethylamine (TEA) in an ether-based solvent such as 2-methyltetrahydrofuran (MeTHF).

In one embodiment, step 2 is a step of preparing a compound of formula 5ac by deprotecting the amine protecting group of the compound of formula 4a.

In one embodiment, the deprotection may be performed by adding an acid in an appropriate solvent.

For example, the deprotection can be performed by adding hydrogen chloride (5-6N 2-propanol solution) under 2-propanol (IPA).

In one embodiment, step 3 is a step of preparing a compound of formula 1a by benzoylating a compound of formula 5ac.

In one embodiment, the benzoylation may be performed by adding a benzoylation reagent and a base in an appropriate solvent. In one embodiment, the benzoylation may be performed by additionally adding an amide coupling agent.

For example, the benzoylation can be performed by addition of benzoyl chloride and triethylamine (TEA) in a halogenated hydrocarbon solvent such as dichloromethane.

For example, the benzoylation can be carried out by addition of benzoic acid, an amide coupling agent (such as propanephosphophane anhydride (T ₃ P)), and TEA, in an etheric solvent such as 2-methyltetrahydrofuran (MeTHF). there is.

In the process of preparing a compound of Formula 1 according to one aspect of the present invention, intermediates prepared according to the method of the present invention (e.g., a compound of Formula 4, a compound of Formula 5, or a pharmaceutically acceptable acid addition salt) ) is obtained in a solid phase, so it is easier to separate intermediates, and impurities are well removed during this process, so the target compound (compound of Formula 1) can be produced with high purity without additional separation and purification processes such as column chromatography. In addition, since it has the advantage of being more suitable for scale up for large-scale production by avoiding column processes that are difficult to apply to mass production, the compound of Formula 1 can be produced on a scale that allows commercial manufacturing of pharmaceuticals. .

The manufacturing method according to one embodiment is as follows.

(In the above formula, (HA) in Formula 5 indicates the presence or presence of an acid addition salt, and HA is selected from trifluoroacetic acid, fumaric acid, hydrochloric acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid, and 4-toluenesulfonic acid. It is one of those things.

Additionally, in Formula 6a, the substituent R _4a is halogen, hydroxy, and

It is one selected from among.)

In the production method according to one embodiment, separation of the intermediate may be simpler because the intermediate is obtained in solid phase in steps 1 and 2, and impurities are well removed, so there is no need to perform column chromatography necessary for additional separation and purification. does not exist. In particular, in Step 2, pharmaceutically acceptable acid addition salts of Formula 5a (Formula 5aa, Formula 5ab, Formula 5ac, Formula 5ad, Formula 5ae, Formula 5ad, Formula 5af, and Formula 5ag) are obtained, and Step 3 is performed to obtain the target compound. The purity of Chemical Formula 1a can be improved from 99.6% to a maximum of 99.9%. In addition, it is possible to avoid column processes that are difficult to apply to mass production at all stages, so it has the advantage of being more suitable for scale up for large-scale production, and the compound of Formula 1a can be produced on a scale capable of commercial manufacturing of pharmaceuticals. You can.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above are illustrative in all respects and are not restrictive. All numbers used herein expressing amounts of components, properties such as molecular weight, reaction conditions, etc. are understood to be modified in all cases by the term “about”, unless otherwise specified. Accordingly, the numbers set forth herein are approximations that may vary depending on the desired properties to be achieved by the present invention.

As used herein, the term “about” means within 5% of a predetermined value or range, preferably within 1% to 2%. For example, “about 10%” means 9.5% to 10.5%, preferably 9.8% to 10.2%. For another example, “about 100°C means 95°C to 105°C, preferably 98°C to 102°C.

As used herein, terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features. For example, when one structure is shown, it is understood that all stereoisomeric and tautomeric forms are included, unless otherwise noted.

The term "protecting group" means that when covalently attached to a functional group, such as an amino or alcohol group, the functional group is prevented from undergoing an undesirable reaction, but the functional group can be regenerated (i.e., deprotected) after treatment with an appropriate reagent. It refers to the functional group that makes it possible.

The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example 1: tert -Butyl (S) -4- (7- (3,4-dimethoxyphenyl) pyrazolo [1,5- a ] pyrimidine-2-carbonyl) -2-methylpiperazine-1 -Preparation of carboxylate (Formula 4a)

A mixture of 5.0 g of 7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carboxylic acid (Formula 2a), 74.5 g of chloroform, and 0.12 g of N,N -dimethylformamide 2.98 g of thionyl chloride was added, the reaction mixture was stirred at reflux temperature for 20 hours, and then concentrated under reduced pressure. The residue was dissolved in 74.5 g of chloroform, 3.96 g of pyridine was added, cooled to 0 °C, and 3.68 g of tert- butyl (S) -2-methylpiperazine-1-carboxylate (Formula 3a) was slowly added. Stirred for 1 hour at room temperature. The reaction mixture was washed with 50 mL of 2N aqueous hydrochloric acid solution, 50 mL of saturated aqueous sodium bicarbonate solution, and 50 mL of 7% aqueous sodium chloride solution. 2.5 g of anhydrous magnesium sulfate was added to the organic layer, stirred for 1 hour, filtered, washed with chloroform, and the filtrate was concentrated. 16 mL of ethanol was added to the residue, refluxed and stirred for 1 hour, cooled to room temperature, and 40 mL of n-hexane was added. The resulting solid was stirred for 2 hours, filtered, and dried at 50°C to obtain 6.11 g (yield 76.0%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (dd, J _a = 4.4 Hz, J _b = 1.5 Hz, 1H), 7.73 - 7.58 (m, 2H), 7.15 (d, J = 7.8 Hz, 1H) ), 7.07 - 6.95 (m, 2H), 4.70 - 4.17 (m, 3H), 4.02 - 3.79 (m, 7H), 3.43 - 2.87 (m, 3H), 1.50 - 1.43 (m, 9H), 1.25 - 1.08 (m, 3H)

Example 2: tert -Butyl (S) -4- (7- (3,4-dimethoxyphenyl) pyrazolo [1,5- a ] pyrimidine-2-carbonyl) -2-methylpiperazine-1 -Preparation of carboxylate (Formula 4a)

A mixture of 170.0 g of 7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carboxylic acid (Formula 2a), 2,261 g of dichloromethane, and 63.2 g of triethylamine was heated at 0°C. After cooling, 71.9 g of pivaloyl chloride was slowly added and stirred at the same temperature for 1 hour. 125.1 g of tert- butyl (S) -2-methylpiperazine-1-carboxylate (Formula 3a) was slowly added to the mixture, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed with 1.7 L of 1N aqueous hydrochloric acid solution, 1.7 L of 1N aqueous sodium hydroxide solution, and 1.7 L of 9% aqueous sodium chloride solution. 119 g of anhydrous magnesium sulfate and 34.0 g of activated carbon were added to the organic layer, stirred for 2 hours, filtered, washed with dichloromethane, and the filtrate was concentrated. 680 mL of ethyl acetate was added to the residue, stirred under reflux for 1 hour, cooled to room temperature, and 680 mL of n-heptane was added. The resulting solid was stirred at room temperature for 3 hours, filtered, and dried at 50°C to obtain 235.0 g (yield 85.9%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (dd, J _a = 4.4 Hz, J _b = 1.2 Hz, 1H), 7.72 - 7.61 (m, 2H), 7.16 - 7.14 (d, J = 8.0 Hz, 1H), 7.06 - 6.98 (m, 2H), 4.68 - 4.17 (m, 3H), 4.00 - 3.79 (m, 7H), 3.41 - 2.87 (m, 3H), 1.48 - 1.47 (m, 9H) , 1.24 - 1.11 (m, 3H)

Example 3: tert -Butyl (S) -4- (7- (3,4-dimethoxyphenyl) pyrazolo [1,5- a ] pyrimidine-2-carbonyl) -2-methylpiperazine-1 -Preparation of carboxylate (Formula 4a)

7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carboxylic acid (Formula 2a) 1001.2 g, tert- Butyl (S) -2-methylpiperazine-1- Propanephosphonic anhydride (T ₃ P) (50 wt% in EtOAc, 2982.7 g) was added to a mixture of 736.2 g of carboxylate (Formula 3a), 1021.7 g of triethylamine and 10.0 L of 2-methyltetrahydrofuran (MeTHF). It was added slowly and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with 5 L of 1 M aqueous hydrochloric acid solution, 5 L of 1 M aqueous sodium hydroxide solution, and 2 L of 5% aqueous sodium chloride solution. The organic layer was concentrated, isopropyl acetate was added, stirred overnight, and n -heptane was slowly added dropwise to the resulting solid. The solid was stirred at room temperature for an additional 2 hours, filtered, and dried at 50°C to obtain 1409.3 g (yield 87.5%) of the title compound.

Example 4: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone ( Preparation of formula 5a)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 1, Chemical Formula 4a) 14.2 g of trifluoroacetic acid was added to a mixture of 6.0 g and 79.8 g of dichloromethane, and stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in 50 mL of water, and the pH was adjusted to 9 or higher with 150 mL of 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL The filtrate was concentrated. 5 mL of dichloromethane and 50 mL of n-heptane were added to the residue, and the slurry was stirred overnight, filtered, and dried at 40°C to obtain 4.51 g of the title compound (yield 95.0%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 - 8.54 (dd, J _a = 4.4 Hz, J _b = 2.4 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.09 (s, 1H), 7.04 - 6.98 (m, 2H), 4.67 - 4.64 (m, 1H), 4.53 - 4.48 (m, 1H), 3.99 - 3.95 (m, 6H), 3.24 - 2.50 (m, 5H), 1.16 - 0.98 (m, 3H)

Example 5: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone tri Preparation of fluoroacetate (Formula 5aa)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 4.15 g of concentrated hydrochloric acid was added to a mixture of 10.0 g and 63.4 g of methanol, and stirred at reflux temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in 100 mL of water, and the pH was adjusted to over 9 with 50 mL of 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL The filtrate was concentrated. The residue was dissolved in 40 mL of ethanol, 1.42 g of trifluoroacetic acid was slowly added, and then 20 mL of ethyl acetate was added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 50°C to obtain the title compound 8.75. g (85.0% yield) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.15 (s, 2H), 8.68 - 8.67 (d, J = 4.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.41 - 7.39 (dd, J _a = 6.6 Hz, J _b = 4.6 Hz, 1H), 7.21 - 7.16 (t, J = 8.4 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 4.71 - 4.63 (m, 1H), 4.54 - 4.49 (t, J = 10.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59 - 3.01 (m, 5H), 1.30 - 1.14 (m, 3H)

Example 6: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone fumaric acid Preparation of salt (Formula 5ab)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 4.15 g of concentrated hydrochloric acid was added to a mixture of 10.0 g and 78.9 g of ethanol, and stirred at reflux temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in 100 mL of water, and the pH was adjusted to over 9 with 50 mL of 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL The filtrate was concentrated. The residue was dissolved in 40 mL of methanol, 2.41 g of fumaric acid was slowly added, and then 20 mL of ethyl acetate was added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 50°C to give 8.93 g of the title compound (yield). 86.4%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 - 8.65 (d, J = 4.4 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.39 - 7.37 (t, J = 4.0 Hz, 1H) , 7.21 - 7.17 (t, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.54 - 6.52 (d, J = 8.0 Hz, 2H), 4.55 - 4.44 (m, 2H), 3.88 (s, 3H) ), 3.85 (s, 3H), 3.45 - 2.82 (m, 5H), 1.21 - 1.05 (m, 3H)

Example 7: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride Preparation of (Formula 5ac)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 10.0 mL of hydrogen chloride (5-6N 2-propanol solution) was added to a mixture of 10.0 g and 78.6 g of 2-propanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, 40 mL of ethyl acetate was added at room temperature, and the resulting crystals were stirred at room temperature for 2 hours, then filtered and dried at 50°C to obtain 8.26 g of the title compound (yield 95.2%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.17 (s, 2H), 8.60 - 8.59 (d, J = 3.6 Hz, 1H), 7.74 - 7.72 (d, J = 8.4 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.22 - 7.20 (d, J = 8.0 Hz, 1H), 7.07 - 7.02 (m, 2H), 5.01 - 4.98 (m, 1H), 4.79 - 4.73 (m, 1H), 4.03 - 3.50 (m, 9H), 3.39 - 3.27 (m, 2H), 3.12 - 3.03 (m, 1H), 1.61 - 1.40 (m, 3H)

Example 8: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride Preparation of (Formula 5ac)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 3, Chemical Formula 4a) 494.8 g of hydrogen chloride (6 N HCl solution in 2-propanol) was added to a mixture of 759.6 g and 15 L of 2-propanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, the mixture was stirred at room temperature overnight, and the resulting crystals were filtered and dried at 40°C to obtain 595.3 g (yield 90.3%) of the title compound.

Example 9: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone bromination Preparation of Hydrogenate (Formula 5ad)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 3.5 g of aqueous hydrobromic acid solution (48%) was added to a mixture of 10.0 g and 78.6 g of 2-propanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and 20 mL of ethanol was added to the residue and concentrated once more. 40 mL of ethanol and 60 mL of acetone were added to the residue, stirred at reflux temperature for 1 hour, and then cooled to room temperature. The resulting crystals were stirred at room temperature for 1 hour, filtered, and dried at 50°C to obtain 8.73 g of the title compound ( Yield 90.9%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.13 (s, 1H), 8.86 (s, 1H), 8.69 - 8.68 (d, J = 4.4 Hz, 1H), 7.82 - 7.74 (m, 2H) , 7.42 - 7.39 (dd, J _a = 7.2 Hz, J _b = 4.4 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.11 - 7.10 (d, J = 4.0 Hz, 1H), 4.71 - 4.63 (m , 1H), 4.54 - 4.49 (t, J = 10.6 Hz, 1H), 3.88 (s, 3H) 3.86 (s, 3H), 3.62 - 3.03 (m, 5H), 1.31 - 1.15 (m, 3H)

Example 10: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone benzene Preparation of sulfonate (Formula 5ae)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 12.5 mL of hydrogen chloride (4N 1,4-dioxane solution) was added to a mixture of 10.0 g and 55.3 g of ethanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in 100 mL of water, and the pH was adjusted to over 9 with 50 mL of 2N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL The filtrate was concentrated. The residue was dissolved in 30 mL of methanol and 50 mL of ethyl acetate, and 3.29 g of benzenesulfonic acid was slowly added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 50°C to obtain 9.86 g of the title compound (yield 88.0). %) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.08 (s, 1H), 8.76 - 8.74 (d, J = 7.6 Hz, 1H), 8.68 - 8.67 (d, J = 4.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.64 - 7.61 (m, 2H), 7.41 - 7.39 (dd, J _a = 6.8 Hz, J _b = 4.4 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.21 - 7.16 (m, 1H), 7.10 (d, J = 2.4 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.54 - 4.49 (t, J = 10.6 Hz, 1H), 3.88 (s, 3H), 3.85 ( s, 6H), 3.60 - 3.01 (m, 5H), 1.31 - 1.14 (m, 3H)

Example 11: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone camphor Preparation of sulfonate (Formula 5af)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 19.9 mL of hydrogen chloride (2.5N ethanol solution) was added to a mixture of 10.0 g and 55.3 g of ethanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in 100 mL of water, and the pH was adjusted to over 9 with 50 mL of 2N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL was concentrated. The residue was dissolved in 50 mL of methanol, and 4.82 g of camphorsulfonic acid was slowly added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 50°C to obtain 11.2 g of the title compound (yield 87.8%). .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.15 (s, 1H), 8.84 - 8.82 (d, J = 6.0 Hz, 1H), 8.68 - 8.67 (d, J = 4.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.42 - 7.39 (m, 1H), 7.21 - 7.17 (m, 1H), 7.10 - 7.09 (d, J = 2.4 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.54 - 4.49 (m, 1H), 3.88 (s, 3H), 3.86 (s, 6H), 3.63 - 3.04 (m, 5H), 2.93 - 2.90 (d, J = 14.8 Hz, 1H), 2.70 - 2.61 (m , 1H), 2.45 - 2.41 (d, J = 14.8 Hz, 1H), 2.28 - 2.21 (m, 1H), 1.96 - 1.93 (t, J = 4.4 Hz, 1H), 1.89 - 1.78 (m, 2H), 1.36 - 1.15 (m, 5H), 1.04 (s, 3H), 0.75 (s, 3H)

Example 12: (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone 4 -Manufacture of toluenesulfonate (Formula 5ag)

tert -Butyl (S) -4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Chemical Formula 4a) 10.0 mL of hydrogen chloride (5-6N 2-propanol solution) was added to a mixture of 10.0 g and 78.6 g of 2-propanol, and stirred at reflux temperature for 2 hours. After completion of the reaction, 50 mL of water was added, the reaction mixture was concentrated, the residue was dissolved in 100 mL of water, and the pH was adjusted to 9 or higher with 50 mL of 2N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (100 mL The residue was dissolved in 50 mL of methanol, and 3.58 g of 4-toluenesulfonic acid was slowly added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 50°C to give 10.35 g of the title compound (yield 90.0%). Obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.07 (s, 1H), 8.75 - 8.73 (d, J = 7.6 Hz, 1H), 8.68 - 8.67 (d, J = 4.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.51 - 7.49 (dd, J _a = 6.4 Hz, J _b = 1.6 Hz, 2H), 7.41 - 7.39 (dd, J _a = 7.2 Hz, J _b = 4.4 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.13 - 7.10 (m, 3H), 4.72 - 4.63 (m, 1H), 4.54 - 4.48 (t, J = 10.8 Hz, 1H), 3.88 (s, 3H), 3.85 ( s, 3H), 3.59 - 3.01 (m, 5H), 2.29 (s, 3H), 1.30 - 1.13 (m, 3H)

Example 13: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

(S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone (Example 4, A mixture of 4.0 g of Formula 5a), 53.2 g of dichloromethane, 1.27 g of triethylamine, and 0.06 g of 4-dimethylaminopyridine was cooled to 0°C, 1.4 g of benzoyl chloride was slowly added, and the reaction mixture was stirred at room temperature for 20 hours. did. After completion of the reaction, the reaction mixture was washed with 1N aqueous hydrochloric acid solution (40 mL After washing with dichloromethane, the filtrate was concentrated. 50 mL of isopropyl ether was added to the residue, and the slurry was stirred at room temperature overnight, filtered, and dried at 70 °C to obtain 4.26 g of the title compound (yield 83.7%, HPLC purity: 98.78 % [area %]). .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (m, 1H), 7.71 - 7.57 (m, 2H), 7.43 - 7.38 (m, 5H), 7.18 - 7.16 (d, J = 6.8 Hz, 1H), 7.03 - 6.97 (m, 2H), 4.75 - 4.59 (m, 3H), 4.17 - 3.75 (m, 7H), 3.38 - 2.90 (m, 3H), 1.34 - 1.23 (m, 3H)

Example 14: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

Dissolve 1.72 g of sodium carbonate in 80 g of water, cool to 0°C, and add (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)( 8.0 g of 3-methylpiperazin-1-yl)methanone trifluoroacetate (Example 5, Chemical Formula 5aa) was added and stirred at room temperature for 30 minutes. After confirming that the pH of the water layer was above 9, the water layer was extracted with dichloromethane (40 mL x 2). The organic layer was washed with 80 mL of 7% aqueous sodium chloride solution, then 4.0 g of anhydrous magnesium sulfate was added, stirred for 1 hour, filtered, and washed with dichloromethane. The filtrate was cooled to 0°C, 1.64 g of triethylamine and 2.16 g of benzoyl chloride were slowly added, and stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (100 mL and concentrated the filtrate. 80 mL of methyl tert -butyl ether was added to the residue, the slurry was stirred at room temperature overnight, filtered, and dried at 70°C to give 6.37 g of the title compound (yield 81.3%, HPLC purity: 99.93% [area %]). Obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (m, 1H), 7.71 - 7.57 (m, 2H), 7.43 - 7.38 (m, 5H), 7.18 - 7.16 (d, J = 6.8 Hz, 1H), 7.04 - 6.97 (m, 2H), 4.75 - 4.60 (m, 3H), 4.15 - 3.75 (m, 7H), 3.49 - 2.89 (m, 3H), 1.34 - 1.21 (m, 3H)

Example 15: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

Dissolve 1.72 g of sodium carbonate in 80 g of water, cool to 0°C, and add (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)( 8.0 g of 3-methylpiperazin-1-yl)methanone fumarate (Example 6, Formula 5ab) was added and stirred at room temperature for 30 minutes. 25 mL of 1N sodium carbonate aqueous solution was added, and after confirming that the pH of the aqueous layer was above 9, the aqueous layer was extracted with dichloromethane (50 mL x 2). The organic layer was washed with 100 mL of 7% aqueous sodium chloride solution, then 5.0 g of anhydrous magnesium sulfate was added, stirred for 1 hour, filtered, and washed with dichloromethane. The filtrate was cooled to 0°C, 1.79 g of triethylamine and 2.15 g of benzoyl chloride were slowly added, and stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (120 mL Washed with dichloromethane and concentrated the filtrate. 80 mL of n-heptane was added to the residue, and the slurry was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 6.65 g of the title compound (yield 85.1%, HPLC purity: 99.88% [area %]). .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (m, 1H), 7.71 - 7.57 (m, 2H), 7.43 - 7.38 (m, 5H), 7.18 - 7.16 (d, J = 6.8 Hz, 1H), 7.04 - 6.98 (m, 2H), 4.80 - 4.59 (m, 3H), 4.19 - 3.75 (m, 7H), 3.49 - 2.89 (m, 3H), 1.34 - 1.23 (m, 3H)

Example 16: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

(S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride (Example 7 A mixture of 8.0 g of Chemical Formula 5ac), 106.4 g of dichloromethane, and 4.26 g of triethylamine was cooled to 0°C, 2.56 g of benzoyl chloride was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (80 mL and concentrated the filtrate. 90 mL of diethyl ether was added to the residue, and the slurry was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 8.34 g of the title compound (yield 89.7%, HPLC purity: 99.87% [area %]). .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (m, 1H), 7.71 - 7.57 (m, 2H), 7.43 - 7.38 (m, 5H), 7.18 - 7.16 (d, J = 7.2 Hz, 1H), 7.03 - 6.98 (m, 2H), 4.75 - 4.60 (m, 3H), 4.17 - 3.75 (m, 7H), 3.49 - 2.90 (m, 3H), 1.35 - 1.19 (m, 3H)

Example 17: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

(S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride (Example 8 , Formula 5ac) 2510 g of propanephosphonic anhydride (T ₃ P) (50 wt% in EtOAc) was slowly added to a mixture of 1085 g, 514 g of benzoic acid, 799 g of triethylamine, and 10 L of 2-methyltetrahydrofuran (MeTHF). The reaction mixture was stirred below 25 °C. When the reaction is complete, the reaction mixture is washed with 1 M aqueous hydrochloric acid solution (5 L x 3), 5 L of 1 M aqueous sodium hydroxide solution, and 5 L of constant water. The organic layer was concentrated, isopropyl acetate was added, and the resulting solid was stirred overnight, then cooled to 0 ~ 5 ℃, stirred, filtered, and dried at 40 ℃ to obtain 854.3 g of the title compound (yield 69.0%, HPLC purity: 99.95 % [area %). ]) was obtained.

Example 18: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

(S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrobromide (practice Example 9, a mixture of 8.0 g of Chemical Formula 5ad), 106.4 g of dichloromethane, and 3.85 g of triethylamine was cooled to 0°C, 3.72 g of benzoic anhydride was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (80 mL and concentrated the filtrate. 80 mL of cyclohexane was added to the residue, and the slurry was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 6.69 g of the title compound (yield 79.6%, HPLC purity: 99.82% [area %]).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 - 8.56 (m, 1H), 7.71 - 7.57 (m, 2H), 7.43 - 7.38 (m, 5H), 7.17 - 7.16 (d, J = 6.8 Hz, 1H), 7.03 - 6.98 (m, 2H), 4.75 - 4.59 (m, 3H), 4.17 - 3.76 (m, 7H), 3.49 - 2.89 (m, 3H), 1.34 - 1.19 (m, 3H)

Example 19: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

Dissolve 2.05 g of potassium carbonate in 80 g of water, cool to 0°C, and add (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl) 8.0 g of (3-methylpiperazin-1-yl)methanone benzenesulfonate (Example 10, Chemical Formula 5ae) was added and stirred at room temperature for 30 minutes. After confirming that the pH of the water layer was above 9, the water layer was extracted with dichloromethane (40 mL x 2). The organic layer was washed with 80 mL of 7% aqueous sodium chloride solution, then 4.0 g of anhydrous magnesium sulfate was added, stirred for 1 hour, filtered, and washed with dichloromethane. The filtrate was cooled to 0°C, 1.65 g of triethylamine and 1.98 g of benzoyl chloride were slowly added, and stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (100 mL and concentrated the filtrate. 210 mL of ethanol was added to the residue, and the resulting solid was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 6.08 g of the title compound (yield 84.5%, HPLC purity: 99.80% [area %]). .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 - 8.55 (m, 1H), 7.70 - 7.56 (m, 2H), 7.43 - 7.37 (m, 5H), 7.17 - 7.15 (d, J = 6.8 Hz, 1H), 7.04 - 6.97 (m, 2H), 4.74 - 4.59 (m, 3H), 4.16 - 3.74 (m, 7H), 3.47 - 2.88 (m, 3H), 1.34 - 1.20 (m, 3H)

Example 20: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

Dissolve 1.8 g of potassium carbonate in 80 g of water, cool to 0°C, and add (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl) 8.0 g of (3-methylpiperazin-1-yl)methanone camphorsulfonate (Example 11, Chemical Formula 5af) was added and stirred at room temperature for 30 minutes. After confirming that the pH of the water layer was above 9, the water layer was extracted with dichloromethane (40 mL x 2). The organic layer was washed with 80 mL of 7% aqueous sodium chloride solution, then 4.0 g of anhydrous magnesium sulfate was added, stirred for 1 hour, filtered, and washed with dichloromethane. The filtrate was cooled to 0°C, 1.45 g of triethylamine and 1.74 g of benzoyl chloride were slowly added, and stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (100 mL Washed with methane and concentrated the filtrate. 140 mL of methanol was added to the residue, and the resulting solid was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 6.06 g of the title compound (yield 86.3%, HPLC purity: 99.82% [area %]). .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 - 8.55 (m, 1H), 7.70 - 7.56 (m, 2H), 7.43 - 7.37 (m, 5H), 7.17 - 7.15 (d, J = 6.8 Hz, 1H), 7.03 - 6.97 (m, 2H), 4.74 - 4.59 (m, 3H), 4.15 - 3.74 (m, 7H), 3.48 - 2.88 (m, 3H), 1.33 - 1.22 (m, 3H)

Example 21: (S) -(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl ) Method for producing methanone (Formula 1a)

Dissolve 2.0 g of potassium carbonate in 80 g of water, cool to 0°C, and add (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl) 8.0 g of (3-methylpiperazin-1-yl)methanone 4-toluenesulfonate (Example 12, Formula 5ag) was added and stirred at room temperature for 30 minutes. After confirming that the pH of the water layer was above 9, the water layer was extracted with dichloromethane (40 mL x 2). The organic layer was washed with 80 mL of 7% aqueous sodium chloride solution, then 4.0 g of anhydrous magnesium sulfate was added, stirred for 1 hour, filtered, and washed with dichloromethane. The filtrate was cooled to 0°C, 1.61 g of triethylamine and 1.93 g of benzoyl chloride were slowly added, and stirred at room temperature for 1 hour. The reaction mixture was washed with 1N aqueous hydrochloric acid solution (100 mL and concentrated the filtrate. The residue was dissolved by adding 130 mL of ethyl acetate, and 320 mL of n-heptane was slowly added. The resulting solid was stirred at room temperature overnight, filtered, and dried at 70°C to obtain 5.32 g of the title compound (84.1% yield, HPLC). purity: 99.69% [area %]) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 - 8.55 (m, 1H), 7.70 - 7.56 (m, 2H), 7.42 - 7.37 (m, 5H), 7.17 - 7.15 (d, J = 6.8 Hz, 1H), 7.02 - 6.97 (m, 2H), 4.74 - 4.58 (m, 3H), 4.16 - 3.75 (m, 7H), 3.49 - 2.89 (m, 3H), 1.33 - 1.18 (m, 3H)

A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims

A method for producing a compound of Formula 1, comprising the step of preparing a compound of Formula 1 by benzoylating a compound of Formula 5 below or a pharmaceutically acceptable acid addition salt thereof:

[Formula 1]

[Formula 5]

In each of Formula 1 or Formula 5,

R 1 is C 1-3 alkoxy,

R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed, n is an integer from 0 to 2,

m is an integer from 0 to 2,

In Formula 1,

R 3 is C 1-3 alkyl or halogen,

a is an integer from 0 to 5.
The method of claim 1, wherein the benzoylation is performed by reacting the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6 below:

[Formula 6]

In Formula 6 above,

R 3 is C 1-3 alkyl or halogen,

R 4 is halogen, hydroxy, or
ego,

a is an integer from 0 to 5.
The method according to claim 1, wherein the reagent used in the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, and benzoic acid, and any of these. A manufacturing method, which is any one selected from the group consisting of combinations.
The method according to claim 1, further comprising the step of preparing the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof by deprotecting the amine protecting group of the compound of Formula 4 below:

[Formula 4]

In Formula 4 above,

R 1 is C 1-3 alkoxy,

R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It is an amine protecting group selected from among.
The method of claim 4, wherein the amine protecting group of the compound of Formula 4 is 2,2-dichloroacetic acid, trifluoroacetic acid, 4-aminosalicylic acid, naphthalene-1,5-disulfonic acid, L-aspartic acid, L-glutamic acid, Maleic acid, oxalic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, (+)-1- (1S)-camphor-10-sulfonic acid, naphthalene-2-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 1-dodecanesulfonic acid, hydrochloric acid, hydrobromic acid, iodide Hydroxic acid, nitric acid, phosphoric acid, sulfuric acid, palladium, carbon, piperidine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and any combinations thereof. A production method, wherein the method is deprotected by at least one member selected from the group consisting of.
The method of claim 4, wherein the amine protecting group of the compound of Formula 4 is t-butoxycarbonyl (Boc), and is deprotected with hydrochloric acid to form the hydrochloride salt of Formula 5.
The method according to claim 4, further comprising the step of preparing the compound of Formula 4 by subjecting a compound of Formula 2 and a compound of Formula 3 to amidation reaction:

[Formula 2]

[Formula 3]

In Formula 2,

R 1 is C 1-3 alkoxy,

n is an integer from 0 to 2,

In Formula 3 above,

R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,

m is an integer from 0 to 2,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It is an amine protecting group selected from among.
The method of claim 7, wherein the amidation reaction of the compound of Formula 2 and the compound of Formula 3 includes thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl- 3 ), phosphorus pentachloride (PCl- 5 ), and phosphorus oxychloride (POCl). 3 ), pivaloyl chloride (PivCl), propanephosphonic anhydride (T 3 P), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)- Carbodiimide hydrochloride (EDC), N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride ( TCT) and any combination thereof.
The method according to claim 1, wherein the compound of Formula 1 is any one compound selected from the group consisting of the following compounds:

1) (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methane on;

2) (4-benzoylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone;

3) (4-benzoyl-3,3-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone;

4) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(perfluorobenzoyl)piperazine- 1-day) methanone;

5) (S)-(4-(2-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-day) methanone;

6) (S)-(4-(3-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-day) methanone;

7) (S)-(4-(4-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-day) methanone;

8) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(3-fluorobenzoyl)-3-methylpiperazine -1-day) methanone;

9) (R)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methane on;

10) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(4-fluorobenzoyl)-3-methylpiperazine -1-day) methanone;

11) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(4-methylbenzoyl)piperazine- 1-day) methanone;

12) (S)-(4-(2,5-difluorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a ]pyrimidin-2-yl)methanone;

13) ((3R,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2 -1) Methanone;

14) ((3S,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2 -1) Methanone;

15) ((2R,5S)-4-benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2 -1) Methanone;

16) ((2S,5S)-4-benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2 -1) Methanone;

17) (4-benzoyl-4,7-diazaspiro[2.5]octane-7-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl ) methanone;

18) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(2-fluorobenzoyl)-3-methylpiperazine -1-day) methanone;

19) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(3-methylbenzoyl)piperazine- 1-day) methanone;

20) (S)-(4-benzoyl-3-ethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methane on;

21) (S)-(4-benzoyl-3-isopropylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl) methanone;

22) (S)-(4-benzoyl-3-propylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methane on;

23) (S)-(4-benzoyl-3-cyclopropylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl) methanone; and

24) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(2-methylbenzoyl)piperazine- 1-day) Methanone.
An intermediate for the production of a compound represented by the following formula (1): at least one compound selected from the group consisting of a compound of the formula (4), a compound of the formula (5), and a pharmaceutically acceptable acid addition salt of the formula (5):

[Formula 1]

[Formula 4]

[Formula 5]

In each of Formula 1, Formula 4, or Formula 5,

R 1 is C 1-3 alkoxy,

R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

In Formula 1,

R 3 is C 1-3 alkyl or halogen,

a is an integer from 0 to 5,

In Formula 4 above,

Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It is an amine protecting group selected from among.
In claim 10,

R 1 is C 1-3 alkoxy,

R 2 is C 1-3 alkyl, C 3-4 cycloalkyl, or spirocyclopropyl,

R 3 is methyl, fluoro, or chloro,

n is an integer from 0 to 2,

m is an integer from 0 to 2,

a is an integer from 0 to 5,

Pr is t-butoxycarbonyl (Boc).
Preparing a compound of Formula 4a by amidating a compound of Formula 2a and a compound of Formula 3a;

Preparing a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof by deprotecting the amine protecting group of the compound of Formula 4a; and

A method for preparing a compound of Formula 1a, comprising the step of preparing a compound of Formula 1a by benzoylating a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof:

[Formula 1a]

[Formula 2a]

[Formula 3a]

[Formula 4a]

[Formula 5a]

.
The method of claim 12, wherein the benzoylation is performed by reacting the compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6a:

[Formula 6a]

In Formula 6a,

R 4a is halogen, hydroxy, or
am.
The method of claim 12, wherein the pharmaceutically acceptable acid addition salt of Chemical Formula 5a is any one compound selected from the following Chemical Formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag:

[Formula 5aa]

[Formula 5ab]

[Formula 5ac]

[Formula 5ad]

[Formula 5ae]

[Formula 5af]

[Formula 5ag]

.
An intermediate for the preparation of a compound represented by the following formula (1a), comprising at least one compound selected from the group consisting of a compound of the formula (4a), a compound of the formula (5a), and a pharmaceutically acceptable acid addition salt of the formula (5a):

[Formula 1a]

[Formula 4a]

[Formula 5a]

.
The method of claim 15, wherein the pharmaceutically acceptable acid addition salt of Formula 5a is one or more compounds selected from the group consisting of compounds represented by the following formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag:

[Formula 5aa]

[Formula 5ab]

[Formula 5ac]

[Formula 5ad]

[Formula 5ae]

[Formula 5af]

[Formula 5ag]

.