TW202400166A - Method of preparing compound for cftr activator and intermediate used therein - Google Patents

Abstract

Provided are a method of preparing a compound for a cystic fibrosis transmembrane conductance regulator (CFTR) activator and an intermediate used therein, and more particularly, to a preparation method for a novel compound that increases activity of a CFTR, and a novel intermediate used in the preparation method.

Description

Methods for preparing compounds for CFTR activators and intermediates used therein

The present invention relates to the preparation method of compounds used to regulate the activity of cystic fibrosis transmembrane conductance regulator (CFTR) and the intermediates thereof, and more specifically to the preparation method of new compounds that increase the activity of CFTR. , as well as novel intermediates used in the preparation methods.

CFTR refers to the membrane protein and chloride ion (Cl ^- ) channel encoded by the CFTR gene. When CFTR present in the cell membrane is activated, diseases mediated by loss and degeneration of CFTR function can be treated. For example, Cl ^- channels can be activated to increase tear production, thereby correcting the abnormal tear film associated with dry eye syndrome.

The present invention not only provides a method for preparing novel compounds that modulate CFTR activity, but also designs a novel method that is more suitable for high-efficiency mass production of high-purity target compounds.

Related patents Korean Patent Application No.10-2018-0102590

technical issues

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

Another embodiment provides intermediates for use in the preparation method.

Another embodiment provides a compound represented by Formula 1 or Formula 1a prepared according to a preparation method.

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

Other objects and advantages of the present disclosure can be more clearly explained from the following detailed content and patent scope. Those with ordinary knowledge in the technical field of the present invention or similar technical fields can fully understand and infer that content that is not explained here will be omitted here.

problem solving methods

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

Another embodiment provides intermediates for use in the preparation method.

Another embodiment provides a compound represented by Formula 1 or Formula 1a prepared according to a preparation method.

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

Advantageous effects of the present invention

Unnecessary by-products generated in each process are appropriately suppressed, and the intermediate compound can be obtained in solid form. In this regard, the manufacturing process has excellent reproducibility, easy manufacturing management, and can produce high-purity target compounds even in scaled-up mass production, so the compounds disclosed herein can be effectively used for commercial manufacturing of pharmaceuticals.

The invention is described in further detail below.

Unless otherwise defined, all technical terms used in this specification generally have the same meanings as understood by those with ordinary knowledge in the relevant fields. In addition, the instructions describe suitable methods or samples, but similar or identical methods and samples also fall within the scope of the instructions.

One embodiment provides a method for preparing the compound of Formula 1, including preparing the compound of Formula 1 via benzylation of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof:

Formula 1

Formula 5

In equation 1, where

R ₁ can be C _1-3 epoxy group,

R ₂ can be C _1-4 alkyl or C _3-4 cycloalkyl. When R ₂ is C _1-4 alkyl, two adjacent R ₂ can form a spiro-connected cyclopropyl or spiro ring. attached cyclobutyl,

R ₃ can be C _1-3 alkyl or halogen, and

n can be an integer from 0 to 2,

m can be an integer from 0 to 2, and

a can be an integer from 0 to 5, and

In equation 5, where

R ₁ can be C _1-3 alkoxy,

R ₂ can be C _1-4 alkyl or C _3-4 cycloalkyl. When R ₂ is C _1-4 alkyl, two adjacent R ₂ can form a spiro-connected cyclopropyl or spiro ring. attached cyclobutyl,

n can be an integer from 0 to 2, and

m can be an integer from 0 to 2.

The term "alkyl" used in the specification refers to a linear or branched hydrocarbon residue substituted or unsubstituted by a substituent. For example, C _1-4 alkyl may include all possible isomers such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, or tertiary butyl, but is not limited thereto.

The term "alkoxy" used in the specification refers to a linear or branched chain hydrocarbon residue connected with oxygen, wherein the hydrocarbon residue may be substituted or unsubstituted. For example, C _1-4 alkoxy may include all possible isomers such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or tert-butyl Oxygen group, but not limited to this.

The term "halogen" in the manual refers to chemical elements in Group 17 of the periodic table. For example, halogen may include fluorine, chlorine, bromine, or iodine.

The term "cycloalkyl" used in the specification refers to a saturated hydrocarbon ring having carbon atoms arranged in a cyclic manner. For example, C _3-6 cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "spirocycle" as used in the specification refers to two rings that share a single atom and are not bridged with each other. Unless otherwise stated, the term "spirocycloalkyl" as used in the specification refers to a saturated carbocyclic ring containing two rings in which a single carbon atom shared by the two rings serves as part of the ring. For example, C _3-4 spirocycloalkyl may include spirocyclopropyl or 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, tert-butyl, cyclopropyl, cyclobutyl, spirocyclopropyl, or spiro cyclobutyl. 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, fluorine, chlorine, bromine, or iodine. In one embodiment, R ₃ can be methyl, fluorine, or chlorine.

In one embodiment, the compound of Formula 5 may be in the form of a free base or an acid addition salt. The acid adduct may be a pharmaceutically acceptable acid addition salt of the compound, and its preparation may be any suitable method available to one of ordinary skill in the art.

When the acid addition salt of the compound of Formula 5 is used, the compound of Formula 5 can be solidified and is suitable for mass production. Under this consideration, high-purity target compounds can be obtained without purification processes such as column chromatography. Therefore, regardless of the type, as long as the base form of the compound of Formula 5 of the present disclosure can be cured, the acid addition salt can be used.

In one embodiment, the acid addition salt of the compound of Formula 5 can be an acid addition salt formed from a free acid, and the free acid can be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid, or Sulfuric acid; organic acids such as L-aspartic acid, L-glutamic acid, maleic acid, fumaric acid, oxalic acid, or 4-aminosalicylic acid; halogenated acetic acids such as 2,2-dichloroacetic acid or Trifluoroacetic acid; or organic sulfonic acid or its derivatives such as alkanesulfonic acid or its derivatives (such as ethane-1,2-sulfonic acid, methanesulfonic acid, ethanesulfonic acid, or 2-hydroxyethanesulfonic acid), Naphthalene sulfonic acid or its derivatives (such as naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, di(tert-butyl)naphthalene disulfonic acid, di(tert-butyl)naphthalene sulfonic acid), Benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, (+)-1-(1S)-camphor-10-sulfonic acid, or 1-dodecanesulfonic acid.

In one embodiment, the acid addition salt may be an inorganic salt such as hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, or sulfate; an organic salt such as L-aspartate, L-glutamate, maleate, fumarate, oxalate, or 4-aminosalicylate; haloacetates such as 2,2-dichloroacetate or trifluoroacetate Acetate; or organic sulfonate or its derivatives such as alkanesulfonate or its derivatives (such as ethane-1,2-sulfonate, methanesulfonate, ethanesulfonate, or 2-hydroxy ethanesulfonate), naphthalene sulfonate or its derivatives (such as naphthalene-1,5-disulfonate, naphthalene-2-sulfonate, di(tert-butyl)naphthalene disulfonate, di(tert-butyl)naphthalene disulfonate, tert-butyl)naphthalene sulfonate), benzenesulfonate, 4-toluenesulfonate, camphorsulfonate, (+)-1-(1S)-camphor-10-sulfonate, or 1-deca Dialkane sulfonate.

For example, pharmaceutically acceptable acid addition salts of the compound of Formula 5 can be trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonate , and any one of 4-toluenesulfonate. In one embodiment, the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof can be forminated to prepare the compound of Formula 1.

The term "benzoylation" or "benzoylation reaction" as used in this disclosure refers to the chemical reaction of joining a benzyl group to an organic compound.

In one embodiment, benzylation can be a reaction between a compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof and a compound of Formula 6:

Formula 6

In equation 6,

R ₃ can be C _1-3 alkyl or halogen, and

R ₄ can be halogen, hydroxyl, or ,as well as

a can be an integer from 0 to 5.

In one embodiment, the compound of Formula 6 can be a compound of Formula 6a:

Formula 6a

In equation 6a,

R _4a can be halogen, hydroxyl, or .

In one embodiment, the reagent used to benzoate the compound of Formula 5 or its pharmaceutically acceptable acid addition salt can be selected from benzoyl fluoride, benzoyl chloride, benzoyl bromide, and benzoyl bromide. Any one of the group consisting of iodine, benzoic anhydride, benzoic acid, and any combination of the above. For example, the reagent used for benzylation may be benzoyl chloride, benzoic anhydride, or benzoic acid.

In addition, the benzylation reaction of the compound of Formula 5 or its pharmaceutically acceptable acid addition salt can be carried out in the presence of a base. The type of base is not particularly limited as long as it does not inhibit the benzylation reaction. For example, benzene can be prepared in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination of the above. chelation reaction.

In addition, the benzylation reaction of the compound of Formula 5 or its pharmaceutically acceptable acid addition salt can be carried out in the presence of a amide coupling agent and at least one base. The amide coupling agent can be selected from propane phosphoric anhydride (T ₃ P), styrene chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride ( POCl ₃ ), pivalyl chloride (PivCl), 1,1-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride ( EDC), N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any of the above A group composed of combinations. For example, the amide coupling agent used in the amide reaction may be propanephosphonic anhydride (T ₃ P).

In one embodiment, the benzylation reaction of the compound of Formula 5 or its pharmaceutically acceptable acid addition salt can be selected from the group consisting of benzoyl fluoride, benzoyl chloride, benzoyl bromide, and benzoyl chloride. Iodine, benzoic anhydride, benzoic acid, any reagent in any combination of the above; and

It is carried out 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 benzylation reaction of the compound of Formula 5 or its pharmaceutically acceptable acid addition salt can be selected from the group consisting of benzoyl fluoride, benzoyl chloride, benzoyl bromide, and benzoyl chloride. Iodine, benzoic anhydride, benzoic acid, any reagent in any combination of the above;

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

Selected from propane phosphoric anhydride (T ₃ P), styrene chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxytrichloride (POCl ₃ ), pivalidyl Chlorine (PivCl), 1,1-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N, The group consisting of N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination of the above in the presence of amide coupling agent.

In one embodiment, the preparation method may further include deprotecting the amine protecting group of the compound of Formula 4 to prepare the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof:

Formula 4

Among them, in equation 4,

R ₁ can be C _1-3 alkoxy,

R ₂ can be C _1-4 alkyl or C _3-4 cycloalkyl, wherein when R ₂ is C _1-4 alkyl, two adjacent R ₂ can form a spiro-connected cyclopropyl or spiro ring. ring-linked cyclobutyl,

n can be an integer from 0 to 2,

m can be an integer from 0 to 2, and

Pr can be selected from the group consisting of tert-butoxycarbonyl (Boc), trityl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn) and fluorenylmethoxy Any amine protecting group from the group consisting of carbonyl (Fmoc).

In one embodiment, Pr can be other commercially available amine protecting groups.

In one embodiment, it can be selected from 2,2-dichloroacetic acid, trifluoroacetic acid, 4-aminosalicylic acid, naphthalene-1,5-disulfonic acid, L-aspartic acid, L-glutamine 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-dodecane At least one of the group consisting of sulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, metal catalysts, non-nucleophilic bases, and any combination of the above (but not limited to this) Amine protecting group protecting the compound of formula 4. The metal catalyst can be selected from the group consisting of palladium, carbon, and any combination of the above, but is not limited thereto. The non-nucleophilic base can be selected from piperidine, diisopropylethylamine, 1,8-diazabicyclo[1,8-diazabicyclo[5,4,0]undec-7-ene ( DBU), and any combination of the above, but is not limited to this.

The reagents and reaction conditions can be changed according to the type of protecting group Pr to control the deprotection reaction of the amine protecting group Pr of the compound of formula 4.

For example, when the amine protecting group Pr of the compound of Formula 4 is tert-butoxycarbonyl (Boc), trityl (Trt), or tetrahydropyranyl (THP), it can be carried out under acidic conditions deprotection response. In one embodiment, the type of acid is not particularly limited as long as it can effectively remove the amine protecting group. For example, the acid may be selected from 2,2-dichloroacetic acid, L-aspartic acid, benzenesulfonic acid, camphorsulfonic acid, (+)-1-(1S)-camphor-10-sulfonic acid, bis( tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenedisulfonic 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, phosphate, 4 - The group consisting of aminosalicylic acid, sulfuric acid, 4-toluenesulfonic acid, trifluoroacetic acid, and any combination of the above.

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

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

In one embodiment, the salts of the free base can be prepared by deprotection reaction of the compound of formula 4, evaporation without post-treatment process, addition of other suitable solvents for precipitation, or preparation of free base salts by those skilled in the art. Following the general procedure, a pharmaceutically acceptable acid addition salt of the compound of formula 5 is obtained.

For example, when the amine protecting group Pr of the compound of formula 4 is tert-butoxycarbonyl (Boc), trityl (Trt), or tetrahydropyranyl (THP), it can be carried out under acidic conditions Deprotection reaction to directly obtain acid addition salt without separate post-treatment process. The acid addition salt can be obtained from the free base obtained by evaporation or precipitation, or the acid addition salt can be obtained by adding the free acid to the free base after the post-treatment process. Details of evaporation, precipitation, obtaining free bases, adding free acids, or similar methods can be carried out according to methods and conditions commonly used in this technical field.

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

For example, when the amine protecting group Pr of the compound of Formula 4 is benzyloxycarbonyl (Cbz) or benzyl (Bn), the deprotection reaction can be performed under hydrogenation conditions. The acid addition salt can then be obtained from the free base obtained by evaporation or precipitation, or by the usual method of adding a free acid to a free base that has been subjected to a work-up process.

For example, when the amine protecting group Pr of the compound of Formula 4 is fluorenylmethoxycarbonyl (Fmoc), the deprotection reaction can be performed under non-nucleophilic base conditions. The acid addition salt can then be obtained from the free base obtained by evaporation or precipitation, or by the usual method of adding a free acid to a free base that has been subjected to a work-up process.

In one embodiment, the preparation method may further include preparing the compound of Formula 4 via a acylation reaction between the compound of Formula 2 and the compound of Formula 3:

Formula 2

Formula 3

Among them, in equation 2,

R ₁ can be C _1-3 alkoxy, and

n can be an integer from 0 to 2, and

In equation 3,

R ₂ can be C _1-4 alkyl or C _3-4 cycloalkyl, wherein when R ₂ is C _1-4 alkyl, two adjacent R ₂ can form a spiro-connected cyclopropyl or spiro ring. ring-linked cyclobutyl,

m can be an integer from 0 to 2, and

Pr can be selected from the group consisting of tert-butoxycarbonyl (Boc), trityl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn) and fluorenylmethoxy Any amine protecting group from the group consisting of carbonyl (Fmoc).

The term "amidation" or "amidation reaction" used in the present disclosure refers to a chemical reaction in which the carboxyl group of the compound of Formula 2 and the amine group of the compound of Formula 3 are bonded to each other.

In one embodiment, the amide reaction between the compound of Formula 2 and the compound of Formula 3 can be performed in the presence of a amide coupling agent. The amide coupling agent can be selected from the group consisting of styrene chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride (POCl ₃ ), and pivaloyl chloride , PivCl), propane phosphoric anhydride (T ₃ P), 1,1'-carbonyldiimidazole (1,1'-carbonyldiimidazole, CDI), 1-ethyl-3-(3'-dimethylaminopropyl) Carbodiimide hydrochloride (EDC), N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)hexafluorophosphate urea (HBTU), cyanuric chloride (TCT), and any combination of the above. For example, the amide coupling agent used in the amide reaction can be styrene chloride (SOCl ₂ ), pivalyl chloride (PivCl), propane phosphonic anhydride (T ₃ P), or N,N,N, N'-Tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU).

Furthermore, the amidation reaction between the compound of formula 2 and the compound of formula 3 can be carried out in the presence of a base. The type of base is not particularly limited as long as it does not inhibit the amide reaction. For example, it may be present in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination of the above. Next, the acylation reaction is carried out.

In one embodiment, the amidation reaction between the compound of formula 2 and the compound of formula 3 can be carried out in the presence of at least one amide coupling agent and at least one base, wherein the at least one amide coupling agent can be selected from chlorine. Phosphorus trichloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride (POCl ₃ ), pivalyl chloride (PivCl), propane phosphoric 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)urea hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination thereof; and

At least one base may be selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination thereof.

The preparation method of an embodiment can be performed in the presence of an appropriate solvent. The solvent can be an inorganic solvent or an organic solvent. For example, the organic solvent can be alcohol-based (such as methanol, ethanol, propanol, isopropyl alcohol, ethylene glycol, or the like), ether-based (such as diethyl ether, tetrahydrofuran (THF), 2-methyl Tetrahydrofuran (MeTHF), dioxane, or similar), mainly ketones (such as methyl ethyl ketone, acetone, or similar), mainly aliphatic hydrocarbons (such as hexane, heptane, octane, or similar) , mainly aromatic hydrocarbons (such as benzene, toluene, xylene, or similar), mainly halogenated hydrocarbons (such as dichloromethane (DCM), chloroform, chlorobenzene, or similar), alkoxy groups are Mainly (such as methoxyethane, dimethoxyethane (DME), methoxypropane, or the like), nitrile-based (such as acetonitrile, benzonitrile, trinitrile, or the like), or acyl Mainly amine. The inorganic solvent can be water, but is not limited to this. In one embodiment, the preparation method can be performed in the presence of a non-polar organic solvent. The non-polar organic solvent can be methyltetrahydrofuran (MeTHF), dichloromethane (DCM), tetrahydrofuran (THF), or acetonitrile, but not limited thereto.

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

Table 1 order Mode Structural formula Compound name 1) 1a (S)-(4-Benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-yl)methanone 2) 1aa (4-Benzoylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone 3) 1ab (4-Benzoyl-3,3-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2 -Methyl ketone 4) 1ac (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(perfluorobenzoyl) (yl)piperazin-1-yl)methanone 5) 1ad (S)-(4-(2-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 6) 1ae (S)-(4-(3-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 7) 1af (S)-(4-(4-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 8) 1ag (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(3-fluorobenzoyl)-3- Methylpiperazin-1-yl)methanone 9) 1ah (R)-(4-Benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-yl)methanone 10) 1ai (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(4-fluorobenzoyl)-3- Methylpiperazin-1-yl)methanone 11) 1aj (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(4-methylbenzyl) acyl)piperazin-1-yl)methanone 12) 1ak (S)-(4-(2,5-difluorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[ 1,5-a]pyrimidin-2-yl)methanone 13) 1al ((3R,5S)-4-Benzoyl-3,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 14) 1am ((3S,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 15) 1an ((2R,5S)-4-Benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 16) 1ao ((2S,5S)-4-benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone 17) 1ap (4-Benzoyl-4,7-diazaspiro[2.5]octane-7-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a ]pyrimidin-2-yl)methanone 18) 1aq (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(2-fluorobenzoyl)-3- Methylpiperazin-1-yl)methanone 19) 1ar (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(3-methylbenzyl) acyl)piperazin-1-yl)methanone 20) 1as (S)-(4-Benzoyl-3-ethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-yl)methanone twenty one) 1at (S)-(4-Benzoyl-3-isopropylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine -2-yl)methanone twenty two) 1au (S)-(4-Benzoyl-3-propylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-yl)methanone twenty three) 1av (S)-(4-Benzoyl-3-cyclopropylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine -2-yl)methanone twenty four) 1aw (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(2-methylbenzyl) acyl)piperazin-1-yl)methanone

Another embodiment provides a compound as an intermediate for preparing the compound represented by Formula 1, including at least one selected from the group consisting of a compound of Formula 4, a compound of Formula 5, and a pharmaceutically acceptable acid addition salt of a compound of Formula 5. One.

In formulas 1, 4, and 5, the definitions of substituents R ₁ , R ₂ , R ₃ , n, m, a, and Pr, as well as pharmaceutically acceptable acid addition salts are the same as above.

In one embodiment of the compound,

R ₁ can be C _1-3 alkoxy,

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

R ₃ can be C _1-3 alkyl or halogen,

n can be an integer from 0 to 2,

m can be an integer from 0 to 2,

a can be an integer from 0 to 5, and

Pr can be tert-butoxycarbonyl (Boc), trityl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn) or fluorenylmethoxycarbonyl (Fmoc).

In one embodiment of the compound,

R ₁ can be C _1-3 alkoxy,

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

R ₃ can be methyl, fluorine, or chlorine,

n can be an integer from 0 to 2,

m can be an integer from 0 to 2,

a can be an integer from 0 to 5, and

Pr may be tert-butoxycarbonyl (Boc).

In one embodiment of the compound,

R ₁ can be methoxy,

R ₂ can be methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl,

R ₃ can be methyl, fluorine, or chlorine,

n can be an integer from 0 to 2,

m can be an integer from 0 to 2,

a can be an integer from 0 to 5, and

Pr may be tert-butoxycarbonyl (Boc).

In one embodiment of the compound,

R ₁ can be methoxy,

R ₂ can be methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl,

R ₃ can be methyl, fluorine, or chlorine,

n can be 2,

m can be an integer from 1 to 2,

a can be an integer from 0 to 5, and

Pr may be tert-butoxycarbonyl (Boc).

In one embodiment of the compound,

R ₁ can be methoxy,

R ₂ can be methyl,

n can be 2,

m can be 1,

a can be 0, and

Pr may be tert-butoxycarbonyl (Boc).

Another embodiment provides a method for preparing the compound of formula 1a, comprising:

The compound of formula 4a is prepared by the amidation reaction between the compound of formula 2a and the compound of formula 3a;

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

The compound of formula 1a is prepared by benzoylation of the compound of formula 5a or its pharmaceutically acceptable acid addition salt.

Formula 1a

Formula 2a

Formula 3a

Formula 4a

Equation 5a

In one embodiment, benzylation can be a reaction between a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof and a compound of Formula 6a.

Formula 6a

In formula 6a, R _4a can be halogen, hydroxyl, or .

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

Formula 5aa

Formula 5ab

Formula 5ac

Formula 5ad

Formula 5ae

Formula 5af

Formula 5ag

Another embodiment provides a compound as an intermediate for preparing the compound represented by formula 1a, and the compound includes a compound selected from the group consisting of a compound of formula 4a, a compound of formula 5a, and a pharmaceutically acceptable acid addition salt of a compound of formula 5a. At least one of.

The definitions of formulas 1a, 4a, and 5a and pharmaceutically acceptable acid addition salts are the same as above.

In some embodiments of Formula 5a, the pharmaceutically acceptable acid addition salt may be selected from trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonic acid Any one of the group consisting of salt, and 4-toluenesulfonate.

In one embodiment, the intermediate used to prepare the compound represented by formula 1a can be a pharmaceutically acceptable acid addition salt of the compound represented by formula 5a, which can be selected from formulas 5aa, 5ab, 5ac, 5ad, 5ae, At least one compound of the group consisting of the compounds represented by 5af and 5ag.

Formula 5aa

Formula 5ab

Formula 5ac

Formula 5ad

Formula 5ae

Formula 5af

Formula 5ag

Another embodiment provides intermediates for preparing the compound represented by Formula 1a, such as any compound selected from the group consisting of the compound of Formula 4a, the compound of Formula 5a, and a pharmaceutically acceptable acid addition salt with the compound of Formula 5a.

Another embodiment provides a compound represented by Formula 1 or 1a prepared according to a preparation method.

The definitions of formula 1 or 1a and the substituents R ₁ , R ₂ , R ₃ , n, m, a, and Pr are the same as above.

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

In one embodiment, the form of the compound represented by Formula 1 or 1a can be a pharmaceutical composition used as a CFTR activator, which contains isomers, solvates, hydrates, and polymorphs of the compound represented by Formula 1 or 1a. substances, or pharmaceutically acceptable salts.

Another embodiment uses compounds shown in Figure 1 or 1a for modulating CFTR.

The preparation method of one embodiment is shown in reaction scheme 1:

Reaction scheme 1

In the above formula, HA in Formula 5 refers to the presence or absence of an acid addition salt. In addition, the definitions of the compounds of formulas 1 to 6 and the substituents R ₁ , R ₂ , R ₃ , n, m, and Pr are the same as above.

The preparation method may include the following steps:

Step 1: Prepare the compound of formula 4.

Step 2: Prepare the compound of formula 5 or its acid addition salt.

Step 3: Prepare the compound of formula 1.

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

The amide coupling agent and base B can be added in the presence of an appropriate solvent to perform the amide reaction in step 1.

For example, pivalyl chloride (PivCl) and triethylamine (TEA) can be added in the presence of a halogenated hydrocarbon-based solvent such as methylene chloride to perform the amidation reaction.

For example, propanephosphonic anhydride (T ₃ P) and triethylamine (TEA) can be added in the presence of an ether-based solvent such as methyltetrahydrofuran (MeTHF) to perform the amidation reaction.

In one embodiment, step 2 can remove the amide protecting group of the compound of formula 4a to prepare the compound of formula 5ac.

In one embodiment, acid can be added in the presence of an appropriate solvent for deprotection.

For example, hydrogen chloride can be added for deprotection in the presence of 2-propanol (IPA) (5N to 6N 2-propanol solution).

In one embodiment, step 3 may benzylation of the compound of formula 5ac to prepare the compound of formula 1a. In one embodiment, a benzylation reagent and a base can be added in the presence of an appropriate solvent to perform benzylation. In one embodiment, a amide coupling agent may be further added to perform benzylation.

For example, benzyl chloride and triethylamine (TEA) can be added in the presence of a solvent based on halogenated hydrocarbons, such as methylene chloride, to perform benzylation.

For example, benzoic acid and amide coupling agents (such as propanephosphonic acid anhydride (T ₃ P)) can be added in the presence of an ether-based solvent such as 2-methyltetrahydrofuran (MeTHF). ), and TEA for benzylation.

In a method for preparing a compound of Formula 1 according to an embodiment of the present invention, the intermediates prepared according to the method disclosed here (such as the compound of Formula 4 and the compound of Formula 5, or their pharmaceutically acceptable acid addition salts) can be prepared by It is obtained in solid phase form, so the intermediate can be easily isolated. Since this process can also remove impurities, high-purity target compounds (such as compounds of Formula 1) can be prepared without any additional separation-purification processes. In addition, avoiding the column process that is difficult to apply in large-scale production is beneficial to large-scale mass production of the compound of Formula 1. Therefore, the production scale of the compound of Formula 1 can realize commercial drug manufacturing.

The preparation method of one embodiment is as follows:

In the above formula, HA in Formula 5 refers to the presence or absence of acid addition salt, and can be selected from trifluoroacetic acid, fumaric acid, hydrochloric acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid, Either with 4-toluenesulfonic acid.

In addition, the substituent R _4a in formula 6a may be halogen, hydroxyl, and any of.

In the preparation method of one embodiment, a solid phase intermediate can be obtained in steps 1 and 2, so the intermediate can be easily separated. Therefore, impurities can also be removed without the need for column chromatography for additional separation and purification. Specifically, when the compounds of formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5ad, 5af, and 5ag are used in step 2 as a pharmaceutically acceptable acid addition salt of the compound of formula 5a and each is subjected to step 3, The purity of the target compound (ie, the compound of formula 1a) can be increased to 99.6% or higher, and as high as 99.9%. In addition, each step can avoid the column process that is difficult to mass-produce, thereby making the compound of formula 1a suitable for larger-scale mass production. The production scale of the compound of formula 1a can realize commercial drug manufacturing.

The above description is only for illustrating the present disclosure, and for those of ordinary skill in the art, the embodiments of the present disclosure can be easily adjusted to other specific forms without changing the spirit or basic characteristics of the technology. Accordingly, the embodiments described herein are in all respects illustrative and not restrictive. Unless otherwise stated, all numerical values expressing ingredients, properties such as molecular weight, reaction conditions, or the like are to be understood to be adjusted in all instances by the term "about." In summary, the numerical values stated herein are approximations and may vary depending on the desired characteristics sought by this disclosure.

The term "about" in the specification refers to a value within 5% of a given value or range, preferably within 1% to 2%. For example, "about 10%" refers to a value between 9.5% and 10.5%. A value between 9.8% and 10.2% is preferred. For example, "about 100˚C" refers to a temperature between 95˚C and 105˚C, preferably between 98˚C and 102˚C.

The expressions "have", "may have", "include" and "may include" in the specification refer to the existence of corresponding features (such as numerical values or components such as compositions or the like) and do not exclude the existence of additional features. For example, when a structure is stated, it is understood that it includes all optional stereoisomers and tautomeric forms unless otherwise stated.

The term "protecting group" as used in the specification refers to a functional group that, when covalently bonded to a functional group such as an amine or alcohol group, avoids unwanted reactions but is regenerable upon treatment with a suitable reagent (i.e. to protect).

All disclosures cited in the specification are incorporated herein by reference.

The present invention will be described in detail below with examples. However, these examples are for illustrative purposes only and do not limit the scope of the invention. [Example]

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

2.98 g of trisene chloride was added to 5.0 g of 7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (formula 2a), 74.5 g of chloroform, and a mixture of 0.12 g of N,N-dimethylformamide, and the reaction mixture was stirred at reflux temperature for 20 hours, and then concentrated under reduced pressure. The concentrate was dissolved in 74.5 g of chloroform, and then 3.96 g of pyridine was added to the solution. After cooling to 0˚C, 3.68 g of tert-butyl (S)-2-methylpiperazine-1-carboxylate (Formula 3a) was slowly added to the above mixture and stirred at room temperature for 1 hours. The reaction mixture was washed with 50 mL of 2N hydrochloric acid aqueous solution, 50 mL of saturated sodium bicarbonate solution, and 50 mL of 7% sodium chloride aqueous solution. 2.5 g of anhydrous magnesium sulfate can be added to the organic layer, stir for 1 hour and then filter. Rinse the filter cake with chloroform, collect the filtrate and concentrate. Add 16 mL of ethanol to the concentrate and stir and reflux for 1 hour. After cooling to room temperature, 40 mL of n-heptane was added to the cooled liquid to precipitate a solid. Stir at room temperature for 2 hours, filter and dry the solid at 50˚C to give 6.11 g of the title compound (yield 76.0%).

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

170.0 g of 7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (formula 2), 2261 g of dichloromethane, and 63.2 g of triethyl The amine mixture was cooled to 0˚C and 71.9 g of neopentyl chloride was slowly added. Then stir 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 above mixture and stirred at room temperature for 1 hour. After completing the reaction, the reacted mixture was extracted and washed with 1.7 L of 1N hydrochloric acid aqueous solution, 1.7 L of 1N sodium hydroxide aqueous solution, and 1.7 L of 9% sodium chloride aqueous solution. 119 g of anhydrous magnesium sulfate and 34.0 g of activated carbon can be added to the organic layer, stir for 2 hours and then filter. Rinse the filter cake with methylene chloride, collect the filtrate and concentrate. Add 680 mL of ethyl acetate to the concentrate, and stir and reflux for 1 hour. After cooling to room temperature, 680 mL of n-heptane was added to the cooled liquid to precipitate a solid. Stir at room temperature for 3 hours, filter and dry the solid at 50˚C to give 235.0 g of the title compound (yield 85.9%).

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: Preparation of tertiary butyl (S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-2-methyl Piperazine-1-carboxylate (Formula 4a)

Propane phosphonic anhydride (T ₃ P) (50 wt% in ethyl acetate, 2982.7 g) was slowly added 7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine- 2-carboxylic acid (formula 2a), 736.2 g of tert-butyl (S)-2-methylpiperazine-1-carboxylate (formula 3a), 1021.7 g of triethylamine, and 10.0 L of 2-methyl tetrahydrofuran (MeTHF) and stirred at room temperature for 2 hours. After the reaction was completed, the reacted mixture was extracted with 5 L of 1 M hydrochloric acid aqueous solution, 5 L of 1 M sodium hydroxide aqueous solution, and 2 L of 5% sodium chloride aqueous solution to obtain an organic layer. After concentrating the organic layer, isopropyl acetate was added to the concentrate to obtain a solution and stirred overnight, and then n-heptane was slowly added dropwise to precipitate the solid. This was followed by stirring at room temperature for an additional 2 hours, filtering and drying the filter cake at 50˚C to give 1409.3 g of the title compound (yield 87.5%).

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 4: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- base) methyl ketone (formula 5a)

14.2 g of trifluoroacetic acid was added to 6.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl )-2-methylpiperazine-1-carboxylate (Example 1, formula 4a) and a mixture of 79.8 g of methylene chloride, and stirred at room temperature for 20 hours. After completing the reaction, the reaction mixture was concentrated, and the concentrate was dissolved in 50 mL of water. Then adjust the pH value of the solution to greater than or equal to 9 with 150 mL of 1N sodium hydroxide aqueous solution. Extract the aqueous layer (100 mL x 2) with dichloromethane, and wash the organic layer with 200 mL of 7% sodium chloride aqueous solution. 10.0 g of anhydrous magnesium sulfate was added to the organic layer, and the reaction mixture was stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. Add 5 mL of methylene chloride and 50 mL of n-heptane to the concentrate, stir the slurry overnight and then filter. The filter cake was dried at 40˚C to afford 4.51 g of the title compound (95.0% yield).

¹ H NMR (400 MHz, CDCl3): 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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone trifluoroacetate (formula 5aa)

4.15 g of concentrated hydrochloric acid was added to 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl) A mixture of -2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 63.4 g of methanol was stirred under reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated and the concentrate was dissolved in 100 mL of water. Then adjust the pH value of the solution to greater than or equal to 9 with 50 mL of 1N sodium hydroxide aqueous solution. Extract the aqueous layer (100 mL x 2) with dichloromethane, and wash the organic layer with 200 mL of 7% sodium chloride aqueous solution. 10.0 g of anhydrous magnesium sulfate was added to the organic layer, and the reaction mixture was stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. The concentrate was dissolved in 40 mL of ethanol, and 1.42 g of trifluoroacetic acid was added to the solution, followed by 20 mL of ethyl acetate to obtain a solid. After stirring at room temperature overnight, it was filtered, and the filter cake was dried at 50˚C to obtain 8.75 g of the title compound (yield 85.0%).

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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone fumarate (formula 5ab)

4.15 g of concentrated hydrochloric acid was added to 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl) A mixture of -2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 78.9 g of ethanol was stirred under reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated and the concentrate was dissolved in 100 mL of water. Then adjust the pH value of the solution to greater than or equal to 9 with 50 mL of 1N sodium hydroxide aqueous solution. Extract the aqueous layer (100 mL x 2) with dichloromethane, and wash the organic layer with 200 mL of 7% sodium chloride aqueous solution. 10.0 g of anhydrous magnesium sulfate was added to the organic layer, and the reaction mixture was stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. The concentrate was dissolved with 40 mL of methanol, and 2.41 g of fumaric acid was added to the solution, followed by 20 mL of ethyl acetate to obtain a solid. After stirring at room temperature overnight, it was filtered, and the filter cake was dried at 50˚C to obtain 8.93 g of the title compound (yield 86.4%).

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

10.0 mL of hydrochloric acid (5N to 6N in isopropyl alcohol) was added with 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -A] mixture of pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 78.6 g of isopropanol, and stirred under reflux for 2 hours. After completing the reaction, 40 mL of ethyl acetate was added to the reaction product at room temperature to precipitate crystals, and stirred at room temperature for 2 hours. After filtration, the filter cake was 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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- base) methanone hydrochloride (formula 5ac)

494.8 g of hydrochloric acid (6N hydrochloric acid solution in isopropyl alcohol) was added to 759.6 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1 , 5-a]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, formula 4a) and 15 L of isopropyl alcohol, and stirred under reflux for 2 hours. After completing the reaction, the reaction mixture was stirred at room temperature overnight to obtain crystals, and the filter cake was filtered and dried at 40˚C to obtain 595.3 g of the title compound (yield 90.3%).

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 9: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone hydrobromide (formula 5ad)

3.5 g of hydrobromic acid solution (48%) was added with 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a] A mixture of pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 78.6 g of isopropanol was stirred under reflux for 2 hours. After completing the reaction, the reaction mixture was concentrated, and 20 mL of ethanol was added to the concentrate. The reaction mixture was then concentrated again. 40 mL of ethanol and 40 mL of acetone were added to the concentrate, stirred under reflux for 1 hour, and then cooled to room temperature to obtain crystallization. After stirring at room temperature for 1 hour, the filter cake was filtered and dried at 50˚C to obtain 8.73 g of the title compound (yield 90.9%).

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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone benzene sulfonate (formula 5ae)

12.5 mL of hydrochloric acid (4N solution in 1,4-dioxane) was added to 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, formula 4a) and a mixture of 55.3 g of ethanol, and stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated and the concentrate was dissolved in 100 mL of water. Then adjust the pH value of the aqueous solution to greater than or equal to 9 with 50 mL of 2N sodium hydroxide aqueous solution. Extract the aqueous layer with dichloromethane (100 mL x 2) to obtain an organic layer, and wash the organic layer with 200 mL of 7% sodium chloride aqueous solution. Add 10.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. Dissolve the concentrate with 30 mL of methanol and 50 mL of ethyl acetate, and slowly add 3.29 g of benzenesulfonic acid to the solution to form a solid. Stir at room temperature overnight, filter and dry the filter cake at 50˚C to obtain 9.86 g of the title compound (yield 88.0%).

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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- base) methanone camphorsulfonate (formula 5af)

Add 10.0 g of tert-butyl (S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a] to 19.9 mL of hydrochloric acid (2.5N ethanol solution) A mixture of pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 55.3 g of ethanol was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated and the concentrate was dissolved in 100 mL of water. Then adjust the pH value of the aqueous solution to greater than or equal to 9 with 50 mL of 2N sodium hydroxide aqueous solution. Extract the aqueous layer with dichloromethane (100 mL x 2) to obtain an organic layer, and wash the organic layer with 200 mL of 7% sodium chloride aqueous solution. Add 10.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. Dissolve the concentrate with 50 mL of methanol, and slowly add 4.82 g of camphorsulfonic acid to the solution to form a solid. Stir at room temperature overnight, filter and dry the filter cake 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: Preparation of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- Methanone-4-toluenesulfonate (formula 5ag)

10.0 mL of hydrochloric acid (5N to 6N in isopropyl alcohol) was added with 10.0 g of tert-butyl(S)-4-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -A] mixture of pyrimidine-2-carbonyl)-2-methylpiperazine-1-carboxylate (Example 2, Formula 4a) and 78.6 g of isopropanol, and stirred under reflux for 2 hours. After completing the reaction, 50 mL of water was added to the reaction mixture, and the reaction mixture was concentrated. Dissolve the concentrate in 100 mL of water, and adjust the pH value of the aqueous solution to greater than or equal to 9 with 50 mL of 2N sodium hydroxide aqueous solution. Extract the aqueous layer with dichloromethane (100 mL x 2) to obtain an organic layer, add 10.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. Dissolve the concentrate with 50 mL of methanol, and slowly add 3.58 g of 4-toluenesulfonic acid to the solution to form a solid. Stir at room temperature overnight, filter and dry the filter cake at 50˚C to obtain 10.35 g of the title compound (yield 90%).

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, Ja = 6.4 Hz, Jb = 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

4.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazin-1-yl) A mixture of methanone (Example 4, Formula 5a), 53.2 g of methylene chloride, 1.27 g of triethylamine, and 0.06 g of 4-dimethylaminopyridine was cooled to 0˚C, and then 1.4 g of Benzyl chloride was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 20 hours. After completing the reaction, the reaction mixture was extracted with 1 N hydrochloric acid aqueous solution (40 mL x 2), 40 mL of 1 N sodium carbonate aqueous solution, and 40 mL of 7% sodium chloride aqueous solution to obtain an organic layer. Add 2.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. 50 mL of isopropyl ether was added to the concentrate, and the resulting slurry was stirred at room temperature overnight. After filtration, the filter cake was dried at 70˚C to obtain 4.26 g of the title compound (yield: 83.7%, HPLC purity was 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

1.72 g of sodium carbonate are dissolved in 80 g of water and then cooled to 0˚C. Then, 8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone trifluoroacetate (Example 5, Formula 5aa) was added to the sodium carbonate solution and stirred at room temperature for 30 minutes. After confirming that the pH value of the aqueous solution is greater than or equal to 9, the aqueous layer is extracted with dichloromethane (40 mL x 2) to obtain an organic layer. Wash the organic layer with 80 mL of 7% sodium chloride aqueous solution, add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. Cool the filtrate to 0˚C, and slowly add 1.64 g of triethylamine and 2.16 g of benzyl chloride to the filtrate. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was washed with 1 N hydrochloric acid aqueous solution (100 mL x 2), 100 mL of 1 N sodium carbonate aqueous solution, and 100 mL of 7% sodium chloride aqueous solution to obtain an organic layer, and 5.0 g of Anhydrous magnesium sulfate was added to the organic layer and stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. 80 mL of methyl tert-butyl ether was added to the concentrate to obtain a slurry, and the slurry was stirred at room temperature overnight, then filtered, and the filter cake was dried at 70˚C to obtain 6.37 g of the title compound (product The rate is 81.3% and the HPLC purity is 99.93% [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 - 6.97 (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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

1.72 g of sodium carbonate are dissolved in 80 g of water and then cooled to 0˚C. Then, 8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone fumarate (Example 6, Formula 5ab) was added to the sodium carbonate solution and stirred at room temperature for 30 minutes. After adding 25 mL of 1N sodium carbonate aqueous solution and confirming that the pH value of the aqueous solution is greater than or equal to 9, the aqueous layer was extracted with dichloromethane (50 mL x 2) to obtain an organic layer. Wash the organic layer with 100 mL of 7% sodium chloride aqueous solution, add 5.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was cooled to 0˚C, and 1.79 g of triethylamine and 2.15 g of benzyl chloride were slowly added to the filtrate. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was extracted with 1 N hydrochloric acid aqueous solution (120 mL x 2), 120 mL of 1 N sodium bicarbonate aqueous solution, and 120 mL of 7% sodium chloride aqueous solution to obtain an organic layer, and 6.0 g Anhydrous magnesium sulfate was added to the organic layer and stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. 80 mL of n-heptane was added to the concentrate to obtain a slurry, and the slurry was stirred at room temperature overnight, then filtered, and the filter cake was dried at 70˚C to obtain 6.65 g of the title compound (yield 85.1% , HPLC purity is 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazin-1-yl) A mixture of methanone hydrochloride (Example 7, Formula 5ac), 106.4 g of methylene chloride, and 4.26 g of triethylamine was cooled to 0˚C, and then 2.56 g of benzoic anhydride was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was extracted with 1 N hydrochloric acid aqueous solution (80 mL x 2), 80 mL of 1 N sodium carbonate aqueous solution, and 80 mL of 7% sodium chloride aqueous solution to obtain an organic layer. Add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. 90 mL of diethyl ether was added to the concentrate, and the resulting slurry was stirred at room temperature overnight. After filtration, the filter cake was dried at 70˚C to obtain 8.34 g of the title compound (yield: 89.7%, HPLC purity is 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

2510 g of propanephosphonic anhydride (T ₃ P) (50 wt% in ethyl acetate) was slowly added 1085 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[ 1,5-a]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone hydrochloride (Example 8, formula 5ac), 514 g of benzoic acid, 799 g of triethylamine , with 10 L of 2-methyltetrahydrofuran (MeTHF) and stir at 25˚C or lower. After the reaction was completed, the reacted mixture was washed with 1 M hydrochloric acid aqueous solution (5 L x 3), 5 L of 1 M sodium hydroxide aqueous solution, and 5 L of water to obtain an organic layer. After the organic layer was concentrated, isopropyl acetate was added to the organic layer to precipitate a solid. After stirring overnight, it was cooled to about 0˚C to 5˚C and stirred again. After filtration, the solid was dried at 40˚C to obtain 854.3 g of the title compound (yield 69.0%, HPLC purity 99.95% [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 18: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazin-1-yl) The mixture of methanone hydrobromide (Example 9, Formula 5ad), 106.4 g of methylene chloride, and 3.85 g of triethylamine was cooled to 0˚C, and then 3.72 g of benzoic anhydride was slowly added to the mixture. . The reaction mixture was then stirred at room temperature for 2 hours. After completing the reaction, the reaction mixture was extracted with 1 N hydrochloric acid aqueous solution (80 mL x 2), 80 mL of 1 N sodium carbonate aqueous solution, and 80 mL of 7% sodium chloride aqueous solution to obtain an organic layer. Add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was then concentrated. 80 mL of cyclohexane was added to the concentrate, and the resulting 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 was 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

2.05 g of potassium carbonate are dissolved in 80 g of water and then cooled to 0˚C. Then, 8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone benzene sulfonate (Example 10, Formula 5ae) was added to the potassium carbonate solution and stirred at room temperature for 30 minutes. After confirming that the pH value of the aqueous solution is greater than or equal to 9, the aqueous layer is extracted with dichloromethane (40 mL x 2) to obtain the organic layer. Wash the organic layer with 80 mL of 7% sodium chloride aqueous solution, add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. Cool the filtrate to 0˚C, and slowly add 1.65 g of triethylamine and 1.98 g of benzyl chloride to the filtrate. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was washed with 1 N hydrochloric acid aqueous solution (100 mL x 2), 100 mL of 1 N potassium carbonate aqueous solution, and 100 mL of 7% sodium chloride aqueous solution to obtain an organic layer, and 5.0 g of Anhydrous magnesium sulfate was added to the organic layer and stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. Add 210 mL of ethanol to the concentrate to obtain a solid, stir at room temperature overnight, then filter, and dry the filter cake 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

1.8 g of potassium carbonate is dissolved in 80 g of water and then cooled to 0˚C. Then, 8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone camphorsulfonate (Example 11, Formula 5af) was added to the potassium carbonate solution and stirred at room temperature for 30 minutes. After confirming that the pH value of the aqueous solution is greater than or equal to 9, the aqueous layer is extracted with dichloromethane (40 mL x 2) to obtain an organic layer. Wash the organic layer with 80 mL of 7% sodium chloride aqueous solution, add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. Cool the filtrate to 0˚C, and slowly add 1.45 g of triethylamine and 1.74 g of benzyl chloride to the filtrate. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was washed with 1 N hydrochloric acid aqueous solution (100 mL x 2), 100 mL of 1 N potassium carbonate aqueous solution, and 100 mL of 7% sodium chloride aqueous solution to obtain an organic layer, and 5.0 g of Anhydrous magnesium sulfate was added to the organic layer and stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. 140 mL of methanol was added to the concentrate to obtain a solid, which was stirred at room temperature overnight and filtered, and the filter cake was 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: Preparation of (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5 -a]pyrimidin-2-yl)methanone (formula 1a)

2.0 g of potassium carbonate are dissolved in 80 g of water and then cooled to 0˚C. Then, 8.0 g of (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methylpiperazine-1- methyl ketone 4-toluenesulfonate (Example 12, formula 5ag) was added to the potassium carbonate solution and stirred at room temperature for 30 minutes. After confirming that the pH value of the aqueous solution is greater than or equal to 9, the aqueous layer is extracted with dichloromethane (40 mL x 2) to obtain an organic layer. Wash the organic layer with 80 mL of 7% sodium chloride aqueous solution, add 4.0 g of anhydrous magnesium sulfate to the organic layer, stir for 1 hour, filter, and rinse the filter cake with dichloromethane. The filtrate was cooled to 0˚C, and 1.61 g of triethylamine and 1.93 g of benzyl chloride were slowly added to the filtrate. The reaction mixture was then stirred at room temperature for 1 hour. After completing the reaction, the reaction mixture was washed with 1 N hydrochloric acid aqueous solution (100 mL x 2), 100 mL of 1 N potassium carbonate aqueous solution, and 100 mL of 7% sodium chloride aqueous solution to obtain an organic layer, and 5.0 g of Anhydrous magnesium sulfate was added to the organic layer and stirred for 1 hour. After filtration, rinse the filter cake with dichloromethane. The filtrate was then concentrated. The concentrate was dissolved in 130 mL of ethyl acetate, and 320 mL of n-heptane was slowly added to precipitate the solid. After stirring at room temperature overnight, it was filtered and the filter cake was dried at 70˚C to give 5.32 g of the title compound (84.1% yield, 99.69% HPLC purity [area %]).

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).

It will be understood by those of ordinary skill in the art that the present invention can be implemented in modified forms without departing from the essential characteristics of the invention. The disclosed embodiments should therefore be considered illustrative rather than limiting. The scope of the present invention should be defined by the patent application scope rather than the above description, and differences equivalent to the scope should be included in the present invention.

without

without.

without.

Claims (16)

A method for preparing a compound, including benzylation of a compound of formula 5 or a pharmaceutically acceptable acid addition salt thereof to prepare a compound of formula 1: Formula 1 Formula 5 Wherein in each of formulas 1 and 5, R ₁ is C _1-3 alkoxy, R ₂ is C _1-4 alkyl or C _3-4 cycloalkyl, wherein when R ₂ is C _1-4 alkyl , two adjacent R ₂ form a spiro-linked cyclopropyl group or a spiro-linked cyclobutyl group, and n is an integer from 0 to 2, m is an integer from 0 to 2, and in Formula 1, R ₃ is C _1-3 alkyl or halogen, and a is an integer from 0 to 5. Such as the preparation method of the compound of claim 1, wherein benzyl is chelated into the reaction between formula 5 or its pharmaceutically acceptable acid addition salt and the compound of formula 6: Formula 6 Wherein in formula 6, R ₃ is C _1-3 alkyl or halogen, R ₄ is halogen, hydroxyl, or , and a is an integer from 0 to 5. Such as the preparation method of the compound of claim 1, wherein the reagent used to benzoate the compound of formula 5 or its pharmaceutically acceptable acid addition salt is selected from benzoyl fluoride, benzoyl chloride, and benzoyl bromide. , benzoyl iodine, benzoic anhydride, benzoic acid, and any one of the group consisting of any combination of the above. The method for preparing the compound of claim 1 further includes deprotecting the amine protecting group of the compound of formula 4 to prepare the compound of formula 5 or its pharmaceutically acceptable acid addition salt: Formula 4 Wherein in formula 4, R ₁ is C _1-3 alkoxy, R ₂ is C _1-4 alkyl or C _3-4 cycloalkyl, where when R ₂ is C _1-4 alkyl, two Adjacent R ₂ forms a spiro-linked cyclopropyl or spiro-linked cyclobutyl, n is an integer from 0 to 2, m is an integer from 0 to 2, and Pr is selected from the group consisting of tertiary butoxycarbonyl ( Boc), trityl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and the group consisting of fluorenylmethoxycarbonyl (Fmoc) Any amine protecting group. Such as the preparation method of the compound of claim 4, wherein the step of removing the amine protecting group of the compound of formula 4 adopts 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, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, palladium, carbon, piperidine, diisopropylethylamine, 1 , 8-diazabicyclo[1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), at least one of the group consisting of any combination of the above. Such as the preparation method of the compound of claim 4, wherein the amine protecting group of the compound of formula 4 is tertiary butoxycarbonyl (Boc), and the amine protecting group is removed with hydrochloric acid to form the hydrochloride salt of the compound of formula 5. The method for preparing the compound of claim 4 further includes preparing the compound of formula 4 through amide reaction between the compound of formula 2 and the compound of formula 3: Formula 2 Formula 3 wherein in formula 2, R ₁ is C _1-3 alkoxy, and n is an integer from 0 to 2, and in formula 3, R ₂ is C _1-4 alkyl or C _3-4 epoxy, Wherein when R ₂ is a C _1-4 alkyl group, two adjacent R ₂ form a spiro-linked cyclopropyl group or a spiro-linked cyclobutyl group, m is an integer from 0 to 2, and Pr is selected from tert-butoxycarbonyl (Boc), trityl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc ) any amine protecting group from the group consisting of. The preparation method of the compound of claim 7, wherein the amide reaction between the compound of formula 2 and the compound of formula 3 is carried out in the presence of at least one amide coupling agent, and the amide coupling agent is selected from tyrene chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride (POCl ₃ ), pivalyl chloride (PivCl), propane phosphoric anhydride (T ₃ P), 1 , 1-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N,N,N'-tetrakis A group consisting of methyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination of the above. Such as the preparation method of the compound of claim 1, wherein the compound of formula 1 is selected from any one of 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)methanone; 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]pyrimidine -2-yl)methanone; 4) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(perfluorobenzene Formyl)piperazin-1-yl)methanone; 5) (S)-(4-(2-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 6) (S)-(4-(3-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 7) (S)-(4-(4-chlorobenzoyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 8) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl) (4-(3-fluorobenzoyl)- 3-methylpiperazin-1-yl)methanone; 9) (R)-(4-Benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a] Pyrimidin-2-yl)methanone; 10) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(4-(4-fluorobenzoyl)- 3-methylpiperazin-1-yl)methanone; 11) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(4-methyl Benzyl)piperazin-1-yl)methanone; 12) (S)-(4-(2,5-difluorobenzyl)-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazole And[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]pyrimidin-2-yl)methanone; 14) ((3S,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 15) ((2R,5S)-4-benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)methanone; 16) ((2S,5S)-4-benzoyl-2,5-dimethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl)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-methylpiperazin-1-yl)methanone; 19) (S)-(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(3-methyl-4-(3-methyl Benzyl)piperazin-1-yl)methanone; 20) (S)-(4-Benzoyl-3-ethylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[1,5-a] Pyrimidin-2-yl)methanone; 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)methanone; 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-methyl Benzyl)piperazin-1-yl)methanone. A compound, as an intermediate for preparing the compound of formula 1, including at least one selected from the group consisting of a compound of formula 4, a compound of formula 5, and a pharmaceutically acceptable acid addition salt of a compound of formula 5 By: Formula 1 Formula 4 Formula 5 Wherein in each of formulas 1, 4, and 5, R ₁ is C _1-3 alkoxy, R ₂ is C _1-4 alkyl or C _3-4 cycloalkyl, where R ₂ is C _1-4 When alkyl, two adjacent R ₂ form a spiro-linked cyclopropyl or spiro-linked cyclobutyl, n is an integer from 0 to 2, and m is an integer from 0 to 2, In formula 1, R ₃ is C _1-3 alkyl or halogen, and a is an integer from 0 to 5, and in formula 4, Pr is selected from the group consisting of tert-butoxycarbonyl (Boc), trityl (Trt), tetrakis Any amine protecting group from the group consisting of hydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). Such as the compound of claim 10, wherein R ₁ is C _1-3 alkoxy, R ₂ is C _1-3 alkyl, C _3-4 cycloalkyl, or spirocyclopropyl, R ₃ is methyl, fluorine , or chlorine, n is an integer from 0 to 2, m is an integer from 0 to 2, a is an integer from 0 to 5, and Pr is tert-butoxycarbonyl (Boc). A method for preparing a compound of formula 1a, including: preparing a compound of formula 4a through an amination reaction between a compound of formula 2a and a compound of formula 3a; removing the amine protecting group of the compound of formula 4a to prepare a compound of formula 5a A compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof; and benzylation of a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof to prepare a compound of Formula 1a: Formula 1a Formula 2a Formula 3a Formula 4a Equation 5a . Such as the preparation method of the compound of claim 12, wherein benzylation is a reaction between the compound of formula 5a or its pharmaceutically acceptable acid addition salt and the compound of formula 6a, formula 6a Wherein in formula 6a, R _4a is halogen, hydroxyl, or . Such as the preparation method of the compound of claim 12, wherein the pharmaceutically acceptable acid addition salt of the compound of formula 5a is selected from the group consisting of the compounds of formula 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag Either: Equation 5a Formula 5ab Formula 5ac Formula 5ad Formula 5ae Formula 5af Formula 5ag . A compound, as an intermediate for preparing the compound represented by formula 1a, including at least one selected from the group consisting of a compound of formula 4a, a compound of formula 5a, and a pharmaceutically acceptable acid addition salt of a compound of formula 5a: Formula 1a Formula 4a Equation 5a . The compound of claim 15, wherein the pharmaceutically acceptable acid addition salt of the compound of formula 5a includes at least one of the group of compounds represented by formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag. By: Formula 5aa Formula 5ab Formula 5ac Formula 5ad Formula 5ae Formula 5af Formula 5ag .