Pyrazolopyrimidines and pyrazolotriazines

专利摘要:
The present invention relates to the pyrazolopyrimidines and pyrazolotriazines of the formulas (1) and (2), or pharmaceutically acceptable salts thereof. Surprisingly, these compounds have selective affinity for the 5-HT 6 receptor. Thus, they are of central nervous system diseases such as psychosis, schizophrenia, mood swings, depression, neurological diseases, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea. Suitable for treatment and prevention
公开号:KR19990077741A
申请号:KR1019990007881
申请日:1999-03-10
公开日:1999-10-25
发明作者:뵈스미하엘；리에머클라우스；스타들러하인츠
申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Pyrazolopyrimidines and pyrazolotriazines}
The present invention relates to the pyrazolopyrimidines and pyrazolotriazines of the formulas (1) and (2) and their pharmaceutically acceptable salts.
Formula 1

Formula 2

Where
R ¹ is phenyl optionally substituted by one or more lower alkyl, halogen, lower alkoxy, tolyl, pyridyl, naphthyl or thiophenyl;
R ² is hydrogen, lower alkyl, lower thioalkyl or hydroxy-lower-alkoxy;
R ³ is amino; Lower alkylamino; Di-lower-alkyl-amino; Piperazinyl optionally substituted by one or more lower alkyl, benzyl, phenyl or hydroxy-lower-alkyl; Morpholinyl; Imidazolyl; (CH ₃ ) ₂ N (CH ₂ ) _n NH—; (CH ₃ ) ₂ N (CH ₂ ) _n O—; Or morpholinyl- (CH ₂ ) _n O—, where n is 2 or 3;
R ⁴ is hydrogen, lower alkyl or hydroxy-lower-alkyl;
R ⁵ is hydrogen; halogen; Lower alkyl; C ₃ -C ₆ -cycloalkyl; Lower alkyl-lower-alkoxy; Hydroxy-lower-alkyl-lower-alkoxy; (CH ₃ ) ₂ N (CH ₂ ) _n NH—; Piperazinyl optionally substituted by lower alkyl; Methyl-piperazinyl optionally substituted by lower alkyl, morpholinyl, methyl-morpholinyl, di-lower-alkylamino or di-lower-alkylamino-lower-alkyl;
R ⁴ and R ⁵ together are — (CH ₂ ) m — or —CH ₂ —S—CH ₂ —, where m is 3 or 4;
Surprisingly, these compounds are selectively friendly to the 5-HT ₆ receptor. Thus, they are central nervous system diseases such as psychosis, schizophrenia, manic depression (Bryan L. Roth et al., J. Pharmacol, Exp. Ther., 268, pages 1403-1410 (1994)), depression [oetry]. David R. Sibley et al., "Mol, Pharmacol., 43, pages 320-327 (1993)", nervous system diseases (Anne Bourson et al., J. Pharmacol. Exp. Ther., 274). , pages 173-180 (1995) "; RP Ward et al., "Neuroscience, 64, pages 1105-1110 (1995)", memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea (Andrew J. Sleight et al. [Neurotransmissons, 11, pages 1-5 (1995)]] is suitable for the treatment and prevention.
The present invention seeks to provide pyrazolopyrimidines and pyrazolotriazines which have selective affinity for 5-HT ₆ receptors and are active and have low toxicity against central nervous system diseases.
It is an object of the present invention to provide novel compounds of formulas (1) and (2) and their pharmaceutically acceptable salts, their use as therapeutically active substances, their preparation, optionally their pharmaceutically acceptable In the preparation of such medicaments, as well as medicaments containing one or more compounds which are one form of salt.
The following compounds are preferred for the types of use described above.
Particularly preferred are those compounds of formula (1), wherein R ³ is amino, examples of which are:
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidin-8-ylamine,
3-benzenesulfonyl-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-6-ylamine,
3-benzenesulfonyl-N5, N5-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine,
3-benzenesulfonyl-N5- (2-dimethylamino-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine,
3-benzenesulfonyl-5- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine and
3-benzenesulfonyl-5-dimethylaminomethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine.
Further preferred are compounds of formula (1), wherein R ³ is piperazinyl, examples of which are as follows:
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3- (4-tert-butyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-5,6-dimethyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-propyl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrimidine,
5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-ethyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine and
3-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine.
Further preferred are compounds of formula (1) and formula (2) wherein R ³ is methylpiperazinyl, examples of which are as follows:
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] Pyrimidine,
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrid Midine,
3-benzenesulfonyl-5-isopropyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and
2- [3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-5-yloxy] -ethanol.
Other preferred triazines of formula (2) are 8-benzenesulfonyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-ylamine and 8-benzenesulfur Phonyl-2-methyl-4- (4-methylpiperazin-1-yl) -7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazine.
The term "lower alkyl" as used herein refers to a moiety having from 1 to 7, preferably from 1 to 4 carbon atoms, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl and tert-butyl.
The term "lower alkoxy" refers to lower alkyl moieties as described above bonded via an oxygen atom, examples of which are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and Tert-butoxy.
The term "lower alkylamino" refers to a lower alkyl moiety as described above bonded through an NH group, examples of which are methylamino and ethylamino.
The term "di-lower-alkylamino" refers to a lower alkyl moiety that is the same or different as described above, bonded through a nitrogen atom, examples of which are dimethylamino, diethylamino or methyl-ethyl-amino.
The term "halogen" includes fluorine, chlorine, bromine and iodine.
The term "lower thioalkyl" refers to lower alkyl moieties as described above bonded via sulfur atoms.
The preparation of the novel compounds can be carried out in a manner known per se, the preparation of formula (1) is described in Examples 1 to 123 and the preparation of formula (2) is described in Examples 124 to 129. have. In addition, Schemes (1) to (3) provide general schemes available for the preparation of these novel compounds, while starting compounds of formula (III) in Scheme (1) are similar to methods known or described in the literature. It can be prepared by the method.
Compounds of formula (1) and formula (2) also include compounds in which hydrogen can be replaced by titanium.
Compounds of formula (1) and formula (2) can be prepared by reacting a compound of formula (3) or a compound of formula (4) with a compound of formula (5), and The compound optionally converts to a pharmaceutically acceptable salt:

HR ³
Where
R ¹ to R ⁵ are as described above.
The reaction of the compound of formula (3) or formula (4) with formula (5) is carried out according to methods known per se. Conveniently, the compound of formula (3) or formula (4) is dissolved in DMF and depends on the reaction partner, which can be dissolved in DMF or alcohol and can be reacted at room temperature or at the boiling point of the solvent used. Particularly preferred reaction partners of compounds of formula (3) or (4) are piperazine, 1-methyl-piperazine, NH ₃ , methylamine, dimethylamine, morpholine, imidazole, N-benzylpiperidine, 1 -(2-hydroxyethyl) -piperazine, 1-phenylpiperazine, 2-dimethylaminoethylamine or cis-2,6-dimethylpiperazine.
Subsequently, the compounds of formula (1) and formula (2) may be converted into pharmaceutically acceptable salts. Salts are considered to be organic acids as well as inorganic acids. Examples of many such salts are hydrochloride, hydrobromide, sulfate, nitrate, citrate, acetate, malate, succinate, methanesulfonate, p-toluenesulfonate and the like. These salts can be prepared according to methods known per se and will be familiar to those skilled in the art.
Where
R ¹ is as described above.
Where
R ¹ , R ² , R ³ and R ⁴ are as described above.
Where
R ¹ , R ² , R ³ and R ⁵ are as described above.
The compounds of formula (1) are prepared according to Examples 1-123:


The compounds of formula (2) are prepared according to Examples 122-127:
As mentioned above, the compounds of the formulas (1) and (2) are novel compounds. They have pharmacological properties and little toxicity. These are common features and show excellent affinity for them based on their activity at the 5-HT ₆ receptor and include central nervous system diseases such as psychosis, schizophrenia, manic depression, depression, nervous system disease, memory disorders, Parkinson's disease, muscular dystrophy It is suitable for the treatment and prevention of lateral sclerosis, Alzheimer's disease and Huntington's chorea.
The binding of the compounds of formulas (1) and (2) to the 5-HT ₆ receptor according to the invention was measured as follows.
Membranes from HEK 1293 cells transfected with the 5-HT ₆ receptor from rats were used.
The cells were purified by two-fold centrifugation (3000g for 10 minutes) in phosphate buffer-sodium chloride solution. The cell mass consists of 50 mm Tris-HCl buffer, 10 mm MgCl ₂ , 0.5 mm EDTA, and 0.1 mm phenylmethylsulfonyl fluoride and homogenized (polytron homogenizer, for 15 seconds at maximum speed) in an ice cold solution. Suspended. The cell mass was again suspended in the Tris buffer solution described above. The cell concentration obtained was 4 × 10 ⁻⁷ cells / mL. An aliquot of the homogenate was frozen at -80 ° C.
Alternative experiments were performed to determine the affinity of the test substance for the 5-HT ₆ receptor. In performing the test, the homogenate was suspended and dissolved in a buffer solution (pH 7.4) consisting of Tris -HCl buffer, 50mm, 5mm of MgCl _2, 10 ^-5 M ascorbic acid in a Parr Guilin and 0.1%. 100 μL of the membrane suspension, 50 μL of [ ³ H] -LSD (specific activity 85 Ci / m mol, final concentration 1 NM) and 50 μL of test substance solution were incubated at 37 ° C. for 1 hour. Each test substance was irradiated at 7 different concentrations of 10 ⁻¹⁰ M to 10 ⁻⁴ M. The binding reaction of the test material was inhibited by rapid filtration through Whatmann GF / B filters. The filter was washed twice with 2 mL of Tris-HCl buffer (50 mm, pH 7.4) and the radioactivity of the filter was measured by scintillation spectroscopy in 2 mL of scintillation solution. All tests were performed three times and three times. The pKi value (pKi = -log ₁₀ Ki) of the test substance was measured. Ki value is defined by the following equation (1):
Ki = {IC ₅₀ } / {1 + [(L) / (K _D )]}
Where
IC ₅₀ values represent the concentration of test compound in NM where 50% of the ligand bound to the receptor is replaced. (L) is the concentration of ligand, and K _D value is the dissociation constant of the ligand.
The compounds according to the invention have a selective affinity for the 5-HT ₆ receptors with pKi values of 6.5 to 9.5.
Specific experimental data demonstrating the pharmacological effects of the compounds according to the invention are shown in Table 3 below.
The compounds of formula (1) and formula (2) and their pharmaceutically acceptable salts can be used as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered in oral form (eg, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions and suspensions). However, it may also be administered rectally (eg in the form of suppositories) or parenterally (eg in the form of injectable solutions).
In the preparation of pharmaceutical preparations, the compounds of formula (1) and formula (2) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Examples of suitable carriers for soft gelatin capsules are vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active ingredient, there is usually no need for a carrier in the case of soft gelatin capsules. Examples of suitable carriers for the production of solutions and syrups are water, polyols, glycerol, vegetable oils and the like. Examples of suitable carriers for suppositories are natural or hardened oils, waxes, fats, semisolid or liquid polyols and the like.
In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other pharmaceutically possible substances.
Agents containing a compound of formula (1) or formula (2) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also objects of the present invention and in a manner known per se to formulas (1) and ( It is also an object of the present invention to prepare one or more of the pharmaceutically acceptable addition salts and / or one or more pharmaceutically acceptable substances, if necessary, in the form of a herbal dosage form.
According to the invention, pharmaceutically acceptable salts, in addition to the compounds of formulas (1) and (2), include central nervous system diseases such as psychosis, schizophrenia, manic depression, depression, nervous system disorders, memory disorders, Parkinson's disease, muscular atrophy It can be used for the treatment and prevention of lateral sclerosis, Alzheimer's disease and Huntington's chorea and in the preparation of corresponding medicaments. Dosages may vary widely and will, of course, be adjusted to suit the individual needs in each particular case. For oral administration, the upper limit of dosage may be greater than that given, but this is about 0.1 mg to about 1000 mg per day of the compound of formula (1) or formula (2) or the corresponding amount of pharmaceutically acceptable salt.
The following examples illustrate the invention in more detail. However, they are not intended to limit its scope in any way.
Example 1
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo- [1,5-a] pyrimidine
a) A solution of 6.30 g (21 mmol) of 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and 3.24 mL (25.8 mmol) of ethyl acetoacetate in 20 mL of acetic acid under reflux for 1.5 hours Heated. The reaction solution was cooled to 0 ° C. and stirred at this temperature for 30 minutes. The separated crystals were filtered off with suction and dried at 50 ° C./10 Torr. Thus, 6.10 g (87%) of 3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol was obtained as white crystals having a melting point of 220 DEG C or higher. .
b) refluxing a suspension of 3.0 g (8.94 mmol) of 3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 20 mL POCl ₃ for 45 minutes. Under heating. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / AcOEt 19: 1) to give 3-benzenesulfonyl-7-chloro-5-methyl-2-methyl as pale yellow crystals with melting points of 163 to 165 ° C. 3.0 g (94%) of sulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
c) 0.3 g (3.4 mmol) of piperazine in 10 mL of DMF and 0.6 g of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF. (1.7 mmol) and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 1) is carried out and crystallized from EtOH to give 3-benzenesulfonyl-5-methyl-2- as colorless crystals having a melting point of 201 to 202 ° C. 0.35 g (51%) of methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 2
3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo- [1,5-a] pyrimidine
0.15 g (1.5 mmol) of 1-methyl-piperazine in 10 mL of DMF was added to 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF. 0.45 g (1.275 mmol) was added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 15: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5-methyl-7- as colorless crystals having a melting point of 209 to 210 ° C. 0.40 g (75%) of (4-methyl-7-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 3
(3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -methyl-amine
10 mL of a 33% solution of methylamine in EtOH was added to 0.3 g of a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 5 mL of DMF. 0.85 mmol) and stirred at room temperature for 2 hours. The reaction solution was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 15: 1) is carried out and crystallized from EtOH to give (3-benzenesulfonyl-5-methyl-2-methyl as colorless crystals having a melting point of at least 230 ° C. 0.18 g (60%) of sulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -methyl-amine was obtained.
Example 4
(3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) amine
10 mL of a 50% solution of NH ₃ in MeOH was added to 0.40 g of a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF. 1.13 mmol) and stirred at room temperature for 2 hours. The reaction solution was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 7: 1) is carried out and crystallized from EtOH to give (3-benzenesulfonyl-5-methyl-2-methyl as colorless crystals having a melting point of at least 230 ° C. 0.25 g (66%) of sulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) amine was obtained.
Example 5
(3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) dimethyl-amine
(3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) amine was added to 3-benzenesulfonyl-7-chloro-5- in 10 mL of DMF. To 0.30 g (0.85 mmol) of a solution of methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was added and stirred at room temperature for 1 hour. The reaction solution was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 15: 1) is carried out and crystallized from EtOH to give (3-benzenesulfonyl-5-methyl-2-methyl as colorless crystals having a melting point of at least 230 ° C. 0.18 g (58%) of sulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) dimethyl-amine was obtained.
Example 6
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7-morpholin-4-yl-pyrazolo [1,5-a] pyrimidine
0.20 g (2.2 mmol) of morpholine 0.25 g (0.85 mmol) of a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 L of DMF ) And stirred at 60 ° C. for 1 h. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 25: 1) is performed and crystallized from EtOH to give 3-benzene-sulfonyl-5-methyl-2 as colorless crystals having a melting point of 206 to 208 ° C. 0.20 g (70%) of -methylsulfanyl-7-morpholin-4-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 7
3-benzenesulfonyl-7-imidazol-1-yl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
0.08 g (1.5 mmol) of sodium methanolate was added to 0.122 g (1.8 mmol) of a suspension of imidazole in 30 mL of DMF and stirred at 60 ° C. for 15 minutes. Subsequently, 0.53 g (1.5 mmol) of a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF was added to the suspension. Add and stir at 60 ° C. for 1 hour. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 15: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-7-imidazol-1-yl as colorless crystals having a melting point of at least 230 ° C. 0.30 g (51%) of -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 8
3-benzenesulfonyl-7- (4-benzyl-piperazin-1-yl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
0.35 g (2 mmol) N-benzyl-piperazine was added to a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 5 mL of DMF. Add to g (1 mmol) and stir at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) is carried out and crystallized from EtOH to give 3-benzene-sulfonyl-7- (4- as colorless crystals having a melting point of 156 to 158 ° C. 0.36 g (73%) of benzyl-piperazin-1-yl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 9
2- [4- (3-Benzenesulfonyl-5-methyl-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -piperazin-1-yl] -ethanol
0.26 g (2 mmol) of 1- (2-hydroxy) -piperazine was added to 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine. To 0.35 g (1 mmol) of solution was added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) is performed and crystallized from EtOH to give 2- [4- (3-benzenesulfonyl- as colorless crystals having a melting point of 189 to 190 ° C. 0.36 g (73%) of 5-methyl-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -piperazin-yl] -ethanol was obtained.
Example 10
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7- (4-phenyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
0.16 g (1 mmol) N-phenyl-piperazine was added to a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 3 mL of DMF. To g (0.5 mmol) was added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5-methyl-2-methylsulfa as colorless crystals having a melting point of at least 230 ° C. 0.16 g (67%) of nile-7- (4-phenyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine was obtained.
Example 11
N- (3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -N ', N'-dimethyl-ethane-1,2- Diamine
0.088 g (1 mmol) of 2-dimethylamineethylamine in a solution of 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 3 mL of DMF To g (0.5 mmol) was added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) was carried out and crystallized from EtOH to give N- (3-benzenesulfonyl-5-methyl as colorless crystals having a melting point of 190 to 191 ° C. 0.23 g (73%) of 2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl) -N ', N'-dimethyl-ethane-1,2-diamine was obtained.
Example 12
(3R, 5S) -3-benzenesulfonyl-7- (3,5-dimethyl-piperazin-1-yl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
0.28 g (2 mmol) cis-2,6-dimethylpiperazine was added to 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 5 mL of DMF. To 0.35 g (1 mmol) of a solution of was added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) was performed and crystallized from EtOH to give (3R, 5S) -3-benzenesulfonyl- as colorless crystals having a melting point of 220 to 221 ° C. 0.29 g (67%) of 7- (3,5-dimethyl-piperazin-1-yl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 13
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) A solution of 7.08 g (25 mmol) of 5-methylsulfanyl-4- (toluene-4-sulfonyl) -2H-pyrazol-3-ylamine and 4.0 mL (31.25 mmol) of ethyl acetoacetate in 30 L of acetic acid Heated under reflux for 1.5 hours. The reaction solution was cooled to 0 ° C. and stirred at this temperature for 30 minutes. The separated crystals were filtered off with suction and dried at 50 ° C./10 Torr. Thus, 7.20 g (82) of 5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ol as white crystals having a melting point of 230 DEG C or higher. %) Was obtained.
b) 3.8 g (10.8 mmol) of a suspension of 5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ol in 20 L of POCl ₃ ) Was heated to reflux for 1 hour. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with CH ₂ Cl ₂ and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 25: 1) to give 7-chloro-5-methyl-2-methylsulfanyl-3- (as pale yellow crystals having a melting point of 197 to 198 ° C. 3.8 g (95%) of toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine were obtained.
c) 0.3 g (3.4 mmol) of piperazine in 10 mL of DMF was dissolved in 7-chloro-5-methyl-2-methyl-sulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5- in 10 mL of DMF. a] was added to 0.62 g (1.7 mmol) of pyrimidine and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and evaporated under high vacuum. The residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 6: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-5-methyl-2- as colorless crystals having a melting point of 137 to 139 ° C. 0.30 g (42%) of methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 14
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine and 1- 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-4-sulfonyl) as colorless crystal having a melting point of 221 to 223 DEG C from methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 15
Methyl- [5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-yl] -amine
In a manner similar to that described in Example 3, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine and methylamine Methyl- [5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-as colorless crystal having a melting point of 230 ° C. or higher from An amine was obtained.
Example 16
5-Methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a similar manner as described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH and 5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is obtained as colorless crystals having a melting point of 230 ° C. or higher from NH ₃ . It was.
Example 17
Dimethyl- [5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-yl] amine
In a similar manner as described in Example 5, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidine in EtOH and Dimethyl- [5-methyl-2-methylsulfanyl-3- (toluene-4-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-yl as colorless crystals having a melting point of 230 ° C. or higher from dimethylamine. ] Amine was obtained.
Example 18
3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 1.8 g (44.6 mmol) of NaH (60% suspension in oil) were added dropwise to a solution of 5 g (22.3 mmol) of (4-isopropyl-benzenesulfonyl) -acetonitrile and 1.4 mL of CS _{2 in 14} mL of DMSO, 45 Heated at room temperature for minutes. Subsequently, 2.9 mL (47 mmol) methyl iodide was slowly added dropwise thereto and stirred for 2 hours. After addition of 30 mL of H ₂ O, the separated crystals were filtered off with suction and crystallized from EtOH ₂ / CH ₂ Cl ₂ . Thus, 4.9 g (67%) of 2- (4-isopropyl-benzenesulfonyl) -3,3-bis-methylsulfanyl-acrylonitrile were obtained as pale yellow crystals having a melting point of 87 占 폚.
b) Add 0.36 mL (7.3 mmol) of NH ₂ NH ₂ to 2.0 g (6.1 mmol) of 2- (4-isopropyl-benzenesulfonyl) -3,3-bis-methylsulfanyl-acrylonitrile in 11 mL of EtOH. And heated to reflux for 30 minutes. The light brown solution was evaporated and chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1). Thus, 1.82 g (69%) of 4-isopropyl-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine was obtained as a beige foam.
c) 1.80 g (5.8 mmol) of 4- (4-isopropyl-benzenesulfonyl) -5-methylsulfanyl-2H-pyrazol-3-ylamine and 1.13 mL (8.8 mmol) of ethyl acetoacetate in 10 mL of acetic acid. The solution was heated at reflux for 1.5 h. The reaction solution was cooled to 0 ° C. and stirred at this temperature for 30 minutes. The separated crystals were filtered off with suction and dried at 50 ° C./10 Torr. Thus, 1.82 g of 3- (4-isopropyl-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol as white crystals having a melting point of 230 DEG C or higher. 83%) was obtained.
d) 1.8 g (4.8 mmol) of a suspension of 3- (4-isopropyl-benzenesulfonyl) -5-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 30 mL POCl ₃ Heated under reflux for 45 minutes. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with CH ₂ Cl ₂ and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / AcOEt 19: 1) to give 3- (4-isopropyl-benzenesulfonyl) -5-methyl- as pale yellow crystals with a melting point of 183 to 184 ° C. 1.78 g (93%) of 2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
e) 7-chloro-3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] in a similar manner as described in Example 1c) 3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1 as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and piperazine. , 5-a] pyrimidine was obtained.
Example 19
3- (4-isopropyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 2, 7-chloro-3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 3- (4-isopropyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2 as colorless crystal having a melting point of 218 to 219 ° C from 1-methyl-piperazine -Methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 20
3- (4-isopropyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 4, 7-chloro-3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in MeOH 3- (4-isopropyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl as colorless crystals having a melting point of 230 ° C. or higher from midines and NH ₃ ; Pyrazolo [1,5-a] pyrimidine was obtained.
Example 21
[3- (4-Isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl] -diamine-amine
In a manner similar to that described in Example 5, 7-chloro-3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in EtOH [3- (4-Isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine as colorless crystals having a melting point of 222 to 224 ° C. from midines and dimethylamine. -7-yl] -dimethyl-amine was obtained.
Example 22
3- (4-tert-butyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 3- (4-tert-butyl-benzenesulfonyl as a beige foam from (4-tert-butyl-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) ) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) In a manner similar to that described in Example 1c), 3- (4-tert-butyl-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5- a] 3- (4-tert-butyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1- as colorless crystals having a melting point of 178 to 180 ° C. from pyrimidine and piperazine Il-pyrazolo [1,5-a] pyrimidine was obtained.
Example 23
3- (4-tert-butyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyri Midine
In a manner similar to that described in Example 2, 3- (4-tert-butyl-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyri 3- (4-tert-butyl-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazine-1- as colorless crystals having a melting point of 238 to 239 ° C. from midine and 1-methyl-piperazine. Il) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 24
3- (4-tert-butyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 3- (4-tert-butyl-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a in MeOH ] 3- (4-tert-butylbenzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and NH ₃ -7-ylamine was obtained.
Example 25
3- (4-Chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 7-chloro-3- (4-chloro-benzenesulfonyl) -5 in a similar manner as described in Examples 18a) to d) as colorless foam from (4-chloro-benzenesulfonyl) -acetonitrile -Methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyri in a similar manner as described in Example 1c) 3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1 as colorless crystals having a melting point of 214 to 217 ° C. from midine and piperazine. , 5-a] pyrimidine was obtained.
Example 26
3- (4-Chloro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 2, 7-chloro-3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 1 3- (4-chloro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methyl as colorless crystal having a melting point of 200 to 201 ° C. from -methyl-piperazine Sulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 27
3- (4-Chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in MeOH And 3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine as colorless crystal having a melting point of 230 ° C. or higher from NH ₃ . Obtained.
Example 28
[3- (4-Chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl] -dimethyl-amine
In a manner similar to that described in Example 5, 7-chloro-3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in EtOH And [3- (4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-7 as colorless crystals having a melting point of 221 to 223 DEG C from dimethylamine. -Yl] -dimethyl-amine was obtained.
Example 29
3- (2,4-Dichloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 7-chloro-3- (2,4-dichloro-benzenesulphur) as a colorless foam from (2,4-chloro-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) Ponyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-3- (2,4-dichloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a in a similar manner as described in Example 1c) ] 3- (2,4-dichloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and piperazine [1,5-a] pyrimidine was obtained.
Example 30
3- (2,4-Chloro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
7-Chloro-3- (2,4-dichloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in a manner similar to that described in Example 2 And 3- (2,4-chloro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2 as colorless crystal having a melting point of 230 ° C. or higher from 1-methyl-piperazine. -Methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 31
3- (2,4-Chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a similar manner to that described in Example 4, 7-chloro-3- (2,4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] in MeOH. 3- (2,4-chloro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine- as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and NH ₃ . 7-ylamine was obtained.
Example 32
3- (4-Bromo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 3- (4-bromo-benzenesulfonyl) -7-chloro as a colorless foam from (4-bromo-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) -5-Methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 3- (4-bromo-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] in a similar manner as described in Example 1c) 3- (4-bromo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo as colorless crystals having a melting point of 212 to 214 ° C. from pyrimidine and piperazine. [1,5-a] pyrimidine was obtained.
Example 33
3- (4-Bromo-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 3- (4-bromo-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 3- (4-bromo-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2 as colorless crystal having a melting point of 202 to 203 ° C. from 1-methyl-piperazine -Methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 34
3- (4-Bromo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 3- (4-bromo-benzenesulfonyl) -7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in MeOH 3- (4-bromo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-7- as colorless crystal having a melting point of 230 ° C. or higher from midine and NH ₃ Yield monoamine.
Example 35
3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 7-chloro-3- (4-methoxy-benzenesulfonyl) as a colorless foam from (4-methoxy-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) -5-Methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] in a similar manner as described in Example 1c) From pyrimidine and piperazine to 3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo as colorless crystals having a melting point of 176 to 177 ° C. [1,5-a] pyrimidine was obtained.
Example 36
3- (4-methoxy-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 2, 7-chloro-3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 3- (4-methoxy-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2 as colorless crystal having a melting point of 212 to 213 ° C from 1-methyl-piperazine -Methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 37
3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in MeOH 3- (4-methoxy-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-7- as colorless crystal having a melting point of 230 ° C. or higher from midine and NH ₃ ; Yield monoamine.
Example 38
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methylsulfanyl-3- (naphthalene) as a colorless foam from (naphthalene-2-sulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) -2-sulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 2) And 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (naphthalene-2-sulfonyl) as colorless crystal having a melting point of 230 ° C. or higher from 1-methyl-piperazine. ) -Pyrazolo [1,5-a] pyrimidine was obtained.
Example 39
Dimethyl- [5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-yl] -amine
In a similar manner as described in Example 6, 7-chloro-5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in EtOH and Dimethyl- [5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7- as colorless crystal having a melting point of 230 ° C. or higher from dimethyl-amine. Il] -amine was obtained.
Example 40
5-Methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a similar manner as described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH and 5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is obtained as colorless crystals having a melting point of 230 ° C. or higher from NH ₃ . It was.
Example 41
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (4-trifluoromethoxy-benzenesulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methylsulfanyl- as a colorless foam from (4-trifluoromethoxy-benzenesulfonyl) -acetonitrile in a manner similar to that described in Examples 18a) to d) 3- (4-Trifluoromethoxy-benzenesulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (4-trifluoromethoxy-benzenesulfonyl) -pyrazolo [1,5- in a similar manner as described in Example 1c) a] 5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (4-trifluoromethoxy-benzenesulfonyl as colorless crystals having a melting point of 203 to 204 DEG C from pyrimidine and piperazine ) -Pyrazolo [1,5-a] pyrimidine was obtained.
Example 42
5-Methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (4-trifluoromethoxy-benzenesulfonyl) -pyrazolo [1,5-a] pyri Midine
In a similar manner as described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (4-trifluoromethoxy-benzenesulfonyl) -pyrazolo [1,5-a] pyri 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (4-tri as colorless crystals having a melting point of 213 to 214 ° C from midine and 1-methyl-piperazine. Fluoromethoxy-benzenesulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
Example 43
3- (4-Fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 7-chloro-3- (4-fluoro-benzenesulfonyl) as a colorless foam from (4-fluoro-benzenesulfonyl) -acetonitrile in a manner similar to that described in Examples 18a) to d) -5-Methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] in a similar manner as described in Example 1c) 3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo as colorless crystals having a melting point of 180 to 181 ° C. from pyrimidine and piperazine. [1,5-a] pyrimidine was obtained.
Example 44
3- (4-Fluoro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 2, 7-chloro-3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 3- (4-fluoro-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -2 as colorless crystal having a melting point of 197 to 198 ° C. from 1-methyl-piperazine -Methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 45
3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in MeOH 3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-7- as colorless crystals having a melting point of 230 ° C. or higher from midines and NH ₃ ; Yield monoamine.
Example 46
3- (4-iodo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
a) 7-chloro-3- (4-iodo-benzenesulfonyl) as a colorless foam from (4-iodo-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) -5-Methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-3- (4-iodo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a in MeOH in a similar manner as described in Example 4 ] 3- (4-iodo-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine- as colorless crystal having a melting point of 230 ° C. or higher from pyrimidine and NH ₃ 7-ylamine was obtained.
Example 47
3-benzenesulfonyl-5,6-dimethyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) In a similar manner as described in Examples 1a) and b), 3 as colorless foam from 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and 2-methyl-acetoacetate -Benzenesulfonyl-7-chloro-5,6-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 3-benzenesulfonyl-7-chloro-5,6-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and piperazine in a manner similar to that described in Example 1c) 3-benzenesulfonyl-5,6-dimethyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine as colorless crystals having melting points of from 159 to 160 ° C. Obtained.
Example 48
3-benzenesulfonyl-5,6-dimethyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 1c), 3-benzenesulfonyl-7-chloro-5,6-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 1-methyl- 3-benzenesulfonyl-5,6-dimethyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1] as colorless crystals having a melting point of 183 to 185 ° C from piperazine. , 5-a] pyrimidine was obtained.
Example 49
3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-propyl-pyrazolo [1,5-a] pyrimidine
a) 3-benzene as a colorless foam from 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and ethyl butyrylacetate in a manner similar to that described in Examples 1a) and b) Sulfonyl-7-chloro-2-methylsulfanyl-5-propyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) melting point from 3-benzenesulfonyl-7-chloro-2-methylsulfanyl-5-propyl-pyrazolo [1,5-a] pyrimidine and piperazine in a similar manner as described in Example 1c) 3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-propyl-pyrazolo [1,5-a] pyrimidine was obtained as colorless crystals having 197 to 199 ° C.
Example 50
3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5-propyl-pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, from 3-benzenesulfonyl-7-chloro-2-methylsulfanyl-5-propyl-pyrazolo [1,5-a] pyrimidine and 1-methyl-piperazine 3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5-propyl-pyrazolo [1,5-a] as colorless crystals with a melting point of 207 to 209 ° C. Pyrimidine was obtained.
Example 51
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and ethyl 3-cyclopropyl-3-oxo-prop in a similar manner as described in Examples 1a) and b) 3-Benzenesulfonyl-7-chloro-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained as colorless foam from cypionate.
b) from 3-benzenesulfonyl-7-chloro-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and piperazine in a similar manner as described in Example 1c) 3-Benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained as colorless crystals having a melting point of 214 to 215 ° C. .
Example 52
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7 (4-methylpiperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, from 3-benzenesulfonyl-7-chloro-5-cyclo-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 1-methyl-piperazine 3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7 (4-methylpiperazin-1-yl) -pyrazolo [1,5-a] pyri as colorless crystals with melting points of 162 to 164 ° C. Midines were obtained.
Example 53
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, the melting point from 3-benzenesulfonyl-7-chloro-5-cyclo-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and NH _{3 in} MeOH 3-Benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained as colorless crystals of 230 占 폚 or higher.
Example 54
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine
a) colorless foam from 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and ethyl cyclopentane-2-carboxylate in a similar manner as described in Examples 1a) and b) 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine was obtained.
b) 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5 in a similar manner as described in Example 1c) -a] 3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclo as colorless crystals having a melting point of 221 to 222.5 ° C. from pyrimidine and piperazine Penta [d] pyrazolo [1,5-a] pyrimidine was obtained.
Example 55
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] Pyrimidine
In a manner similar to that described in Example 2, 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] 3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-6,7 as colorless crystals having a melting point of 228 to 229.5 ° C. from pyrimidine and 1-methyl-piperazine. -Dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine was obtained.
Example 56
3-benzenesulfonyl-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidin-8-ylamine
In a manner similar to that described in Example 4, 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5- in MeOH. a] 3-benzenesulfonyl-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and NH ₃ ; ] Pyrimidin-8-ylamine was obtained.
Example 57
3-benzenesulfonyl-2-methylsulfanyl-9-piperazin-1-yl-5,6,7,8-tetrahydro-pyrazolo [5,1-b] quinazoline
a) colorless from 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and ethyl cyclohexanone-2-carboxylate in a similar manner as described in Examples 1a) and b) As foam, 3-benzenesulfonyl-9-chloro-2-methylsulfanyl-5,6,7,8-tetrahydro-pyrazolo [5,1-b] pyrimidine was obtained.
b) 3-benzenesulfonyl-9-chloro-2-methylsulfanyl-5,6,7,8-tetrahydro-pyrazolo [5,1-b] in a similar manner as described in Example 1c) 3-benzenesulfonyl-2-methylsulfanyl-9-piperazin-1-yl-5,6,7,8-tetrahydro-pyrazolo as colorless crystals having a melting point of 121 to 123 ° C. from pyrimidine and piperazine. [5,1-b] quinazoline was obtained.
Example 58
3-benzenesulfonyl-9- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5,6,7,8-tetrahydro-pyrazolo [5,1-b] quinazoline
In a similar manner as described in Example 2, 3-benzenesulfonyl-9-chloro-2-methylsulfanyl-5,6,7,8-tetrahydro-pyrazolo [5,1-b] quinazoline and 3-benzenesulfonyl-9- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5,6,7, as colorless crystals having a melting point of 198 to 200 캜 from 1-methyl-piperazine 8-tetrahydro-pyrazolo [5,1-b] quinazoline was obtained.
Example 59
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrimidine
a) 4-benzenesulfonyl-5-methylsulfonyl-2H-pyrazol-3-ylamine and methyl 4-oxo-tetrahydro-thiophene- in a similar manner as described in Examples 1a) and b) 3-Benzenesulfonyl-8-chloro-2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrimidine as colorless foam from 3-carboxylate It was.
b) 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4- in a similar manner as described in Example 1c) d] 3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-5H, 7H-pyrazolo [1,5-a] as colorless crystals having a melting point of 230 ° C. or more from pyrimidine and piperazine. Thieno [3,4-d] pyrimidine was obtained.
Example 60
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrid Midine
In a manner similar to that described in Example 2, 3-benzenesulfonyl-8-chloro-2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrid 3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5H, 7H-pyrazolo as colorless crystals having a melting point of 230 ° C. or higher from midine and 1-methyl-piperazine. [1,5-a] thieno [3,4-d] pyrimidine was obtained.
Example 61
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methylsulfanyl-3- (thiophen-2) as a colorless solid from thien-2-ylsulfonylacetonitrile in a similar manner as described in Examples 18a) to d) -Sulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyri in a similar manner as described in Example 1c) 5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (thiophen-2-sulfonyl) -pyrazolo [1 as colorless crystals having a melting point of 229 to 230 ° C. from midines and piperazine. , 5-a] pyrimidine was obtained.
Example 62
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine and 1 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (thiophene-2-sulfonyl) as colorless crystal having a melting point of 230 ° C. or higher from -methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 63
5-Methyl-2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH And 5-methyl-2-methylsulfanyl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine as colorless crystals having a melting point of 230 ° C. or higher from NH ₃ . Obtained.
Example 64
3-benzenesulfonyl-5-isopropyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
a) in a similar manner as described in Examples 1a) and b), 3- as colorless foam from 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and ethyl isobutyrylacetate. Benzenesulfonyl-7-chloro-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 3-benzenesulfonyl-7-chloro-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and 1-methyl- in a similar manner as described in Example 2 3-benzenesulfonyl-5-isopropyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1, as colorless crystals having a melting point of 212 to 214 DEG C from piperazine. 5-a] pyrimidine was obtained.
Example 65
3-benzenesulfonyl-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
Melting point from 3-benzenesulfonyl-7-chloro-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and NH _{3 in} MeOH in a similar manner as described in Example 4 3-benzenesulfonyl-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained as colorless crystals having 210 to 211 ° C.
Example 66
3-benzenesulfonyl-5-tert-butyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 2 g (7.4 mmol) of 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and 2.91 mL (18.3 mmol) of ethyl pivaloyl acetate are added to 27 g of polyphosphoric acid, Heated at 120 ° C. for 5 hours. After cooling, 100 mL of water was slowly added thereto and the mixture was extracted three times with CH ₂ Cl ₂ . The organic phase was dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / EtOAc) was carried out to yield 3-benzenesulfonyl-5-tert-butyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine- as a colorless foam. 1.34 g (48%) of 7-ol were obtained.
b) 1.34 g (3.5 mmol) of 3-benzenesulfonyl-5-tert-butyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 20 mL POCl ₃ for 30 minutes Heated to reflux. The reaction solution was cooled down and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with CH ₂ Cl ₂ and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (silica gel, CH ₂ Cl ₂ / AcOEt 19: 1) to give 3-benzenesulfonyl-5-tert-butyl-7-chloro-2-methylsulfanyl-pyra as a pale yellow foam. 1.23 g (78%) of solo [1,5-a] pyrimidine was obtained.
c) 0.67 g (7.7 mmol) of piperazine in 10 mL of DMF was substituted with 3-benzenesulfonyl-5-tert-butyl-7-chloro-2-methylsulfanyl-pyrazolo [1,5-a] pyridine in 10 mL of DMF. To 1.23 g (3.1 mmol) of a solution of midine was added and stirred at room temperature for 2 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5-tert-butyl as colorless crystals having a melting point of 236 to 237 ° C. 0.25 g (18%) of 2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 67
3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidine
a) 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and ethyl 4,4,4-trifluoroacetate in a similar manner as described in Examples 66a) and b) 3-benzenesulfonyl-2-methylsulfanyl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ol was obtained as a colorless foam.
b) 3-benzenesulfonyl-2-methylsulfanyl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ol and pipepe in a similar manner as described in Example 1c) 3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidine as colorless crystals having a melting point of 230 ° C. or higher from raazine. Obtained.
Example 68
3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 3-benzenesulfonyl-2-methylsulfanyl-5-trifluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ol and 1-methyl- 3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfonyl-5-trifluoromethyl-pyrazolo [1,] as colorless crystals having a melting point of 230 ° C. or more from piperazine. 5-a] pyrimidine was obtained.
Example 69
3-benzenesulfonyl-2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 0.2 mL glacial acetic acid was added to 5.0 g (27.6 mmol) of a suspension of phenylsulfonylacetonitrile in 17.6 mL (88.6 mmol) triethyl orthopropionate, and subsequently heated to 140 ° C. The formed EtOH was continuously distilled off. After 1.5 hours, the mixture was cooled to room temperature and evaporated to dryness under high vacuum. Thus, a mixture of (E) -2-benzenesulfonyl-3-ethoxy-pent-2-enenitrile and (Z) -2-benzenesulfonyl-3-ethoxy-pent-2-enenitrile as colorless oil 7.3 g (100%) was obtained.
b) A solution of (E) -2-benzenesulfonyl-3-ethoxy-pent-2-enenitrile and (Z) -2-benzenesulfonyl-3-ethoxy-pent-2-enenitrile in 50 mL of EtOH. 5.2 g (19.6 mmol) were heated at reflux for 1 h. The brown reaction solution was cooled to room temperature, evaporated and chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1). Thus, 2.9 g (59%) of 4-benzenesulfonyl-5-ethyl-2H-pyrazol-3-ylamine was obtained as a beige oil.
c) A solution of 2.9 g (11.5 mmol) of 4-benzenesulfonyl-5-ethyl-2H-pyrazol-3-ylamine and 1.8 mL (13.8 mmol) of ethyl acetoacetate in 10 mL of acetic acid was heated under reflux for 3 hours. . The reaction solution was cooled to room temperature and evaporated. The residue was partitioned between CH ₂ Cl ₂ and H ₂ O and the aqueous phase was washed three times with 150 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Crystallization from ethyl acetate gave 2.6 g (71%) of 3-benzenesulfonyl-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidin-7-ol as colorless crystals.
d) 2.0 g (6.3 mmol) of a suspension of 3-benzenesulfonyl-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidin-7-ol in 30 mL POCl ₃ under reflux for 45 minutes. Heated. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 49: 1) to give 3-benzenesulfonyl-7-chloro-2-ethyl-5-methyl-pyrazolo [1,5- as colorless crystals. a] 2.0 g (94%) of pyrimidine was obtained.
e) 0.64 g (7.4 mmol) piperazine in 10 mL DMF 1.0 g of a solution of 3-benzenesulfonyl-7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine in 10 mL DMF (3 mmol) and stirred at 60 ° C. for 2 hours. DMF was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 50 mL of CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-2-ethyl-5- as colorless crystals having a melting point of 150 to 150.8 ° C. 0.32 g (27%) of methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 70
3-benzenesulfonyl-2-ethyl-5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, the melting point from 3-benzenesulfonyl-7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine and 1-methyl-piperazine 3-benzenesulfonyl-2-ethyl-5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine as colorless crystals at 171 to 172 ° C It was.
Example 71
N- (3-benzenesulfonyl-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl) -N ', N'-dimethyl-ethane-1,2-diamine
In a manner similar to that described in Example 11, N- from 3-benzenesulfonyl-7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine and 2-dimethylaminoethylamine (3-benzenesulfonyl-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl) -N ', N'-dimethyl-ethane-1,2-diamine was obtained. .
Example 72
3- (4-Bromo-benzenesulfonyl) -2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 3- (4-bromo-benzenesulfonyl) -7-chloro as colorless crystal from (4-bromo-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 64a) to d) -2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 3- (4-bromo-benzenesulfonyl) -7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 1c) And 3- (4-bromo-benzenesulfonyl) -2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5 as colorless crystals having a melting point of 196-197 ° C. from piperazine. -a] pyrimidine was obtained.
Example 73
3- (4-Bromo-benzenesulfonyl) -2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 3- (4-bromo-benzenesulfonyl) -7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine and 1- 3- (4-bromo-benzenesulfonyl) -2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo [1, as colorless crystals having a melting point of 215 to 216 ° C. from methyl-piperazine. 5-a] pyrimidine was obtained.
Example 74
N- [3- (4-Bromo-benzenesulfonyl) -2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl] -N ', N'-dimethyl-ethane -1,2-diamine
In a manner similar to that described in Example 11, 3- (4-bromo-benzenesulfonyl) -7-chloro-2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine and 2- N- [3- (4-bromo-benzenesulfonyl) -2-ethyl-5-methyl-pyrazolo [1,5-a] pyrimidine as colorless crystals having a melting point of 210 to 211 ° C. from dimethylaminoethylamine. -7-yl] -N ', N'-dimethyl-ethane-1,2-diamine was obtained.
Example 75
2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 7-chloro-2-ethyl-3- (4-methoxy- as colorless crystals from (4-methoxy-benzenesulfonyl) -acetonitrile in a similar manner as described in Examples 69a) to d) Benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 1c) And 2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-7-piperazin-1-yl-pyrazolo [1,5 as colorless crystals having a melting point of 196-197 ° C. from piperazine. -a] pyrimidine was obtained.
Example 76
2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 7-chloro-2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine and 1- 2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-7- (4-methyl-piperazin-1-yl) as colorless crystal with melting point of 178-188 ° C. from methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 77
2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine in MeOH and 2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine as colorless crystals having a melting point of 186 to 188 ° C. from NH ₃ ; Obtained.
Example 78
(3R, 5S) -7- (3,5-Dimethyl-piperazin-1-yl) -2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5 -a] pyrimidine
In a manner analogous to that described in Example 12, 7-chloro-2-ethyl-3- (4-methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine and cis- (3R, 5S) -7- (3,5-dimethyl-piperazin-1-yl) -2-ethyl-3- (4 as colorless crystals having a melting point of 151 to 152 占 폚 from 2,6-dimethyl-piperazine. -Methoxy-benzenesulfonyl) -5-methyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 79
3-benzenesulfonyl-2-ethyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine
a) in a similar manner as described in Examples 69c) and d), as colorless foam from 4-benzenesulfonyl-5-ethyl-2H-pyrazol-3-ylamine and ethyl cyclopentanone-2-carboxylate 3-Benzenesulfonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine was obtained.
b) 3-benzenesulfonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a in a similar manner as described in Example 1c) ] 3-benzenesulfonyl-2-ethyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] as colorless crystals having a melting point of 200 to 201 ° C. from pyrimidine and piperazine. Pyrazolo [1,5-a] pyrimidine was obtained.
Example 80
3-benzenesulfonyl-2-ethyl-8- (4-methyl-piperazin-1-yl) -6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine
In a manner analogous to that described in Example 2, 3-benzenesulfonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine And 3-benzenesulfonyl-2-ethyl-8- (4-methyl-piperazin-1-yl) -6,7-dihydro- as colorless crystal having a melting point of 235 to 236 ° C. from 1-methyl-piperazine. 5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine was obtained.
Example 81
3-benzenesulfonyl-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidin-8-ylamine
In a manner similar to that described in Example 4, 3-benzenesulfonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] in MeOH. 3-benzenesulfonyl-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine- as colorless crystals having a melting point of 230 ° C. or higher from pyrimidine and NH ₃ . 8-ylamine was obtained.
Example 82
(3R, 5S) -3-benzenesulfonyl-8- (3,5-dimethyl-piperazin-1-yl) -2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [ 1,5-a] pyrimidine
In a manner similar to that described in Example 12, 3-benzenesulfonyl-8-chloro-2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine And (3R, 5S) -3-benzenesulfonyl-8- (3,5-dimethyl-piperazin-1-yl) as colorless crystals having a melting point of 220 to 221 ° C from cis-2,6-dimethyl-piperazine. 2-ethyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine was obtained.
Example 83
3-benzenesulfonyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 6.88 mL of N, N-dimethylformamide diethyl acetal was added to 7.0 g (38.6 mmol) of a suspension of phenylsulfonylacetonitrile in 30 mL of hexane while cooling with ice and subsequently stirred at room temperature for 12 hours. The separated crystals were filtered to yield 9.08 g (99%) of 2-benzenesulfonyl-3-dimethylamino-acrylonitrile as beige crystals with a melting point of 108 to 110 ° C.
b) 2.05 mL (40.9 mmol) of NH ₂ NH ₂ was added to 9.08 g (38.3 mmol) of a solution of 2-benzenesulfonyl-3-dimethylamino-acrylonitrile in 60 mL of EtOH and stirred at 40 ° C. for 5 hours. . The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) was carried out to give 2.5 g (30%) of 4-benzenesulfonyl-1H-pyrazol-3-ylamine as a beige powder having a melting point of 159 to 161 ° C. ) Was obtained.
c) A solution of 1.0 g (4.47 mmol) of 4-benzenesulfonyl-1H-pyrazol-3-ylamine and 0.6 mL (5.37 mmol) of ethyl acetoacetate in 8 mL of acetic acid was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature and evaporated. The residue was partitioned between CH ₂ Cl ₂ and H ₂ O and the aqueous phase was washed three times with 150 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 20: 1) was carried out to give 0.91 g (70%) of 3-benzenesulfonyl-5-methyl-pyrazole [1,5-a] pyrimidine as beige crystals. Was obtained.
d) 0.91 g (3.14 mmol) of a suspension of 3-benzenesulfonyl-5-methyl-pyrazolo [1,5-a] pyrimidine in 15 mL POCl ₃ was heated at reflux for 1 h. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 30 mL ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 20 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 19: 1) to give 3-benzenesulfonyl-7-chloro-5-methyl-pyrazolo [1,5-a] pyri as a beige solid. 0.84 g (87%) of midine was obtained.
e) melting point 180-181 ° C. from 3-benzenesulfonyl-7-chloro-5-methyl-pyrazolo [1,5-a] pyrimidine and piperazine in a similar manner as described in Example 1c) 3-Benzenesulfonyl-5-methyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained as colorless crystals.
Example 84
3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, melting point of 230 ° C. or higher from 3-benzenesulfonyl-7-chloro-5-methyl-pyrazolo [1,5-a] pyrimidine and 1-methyl-piperazine 3-Benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine was obtained as colorless crystals.
Example 85
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methyl-sulfanyl-3- () as a colorless foam from (toluene-2-sulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) Toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 1c) And 5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1,2 as colorless crystals having a melting point of 215 to 215.5 ° C. from piperazine. 5-a] pyrimidine was obtained.
The (toluene-2-sulfonyl) -acetonitrile used was prepared as follows:
2.2 mL (34.5 mmol) of chloroacetonitrile were added to 4.5 g (28.8 mmol) of a suspension of toluene-2-sulfinic acid sodium salt in 100 mL of DMF and stirred at 100 ° C. for 1 hour. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ . The combined organic phases were washed once with H ₂ O, dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ ) was performed to yield 2.9 g (50%) of (toluene-2-sulfonyl) -acetonitrile as a colorless oil.
Example 86
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
In a manner similar to that described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine and 1- 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-2-sulfonyl) as colorless crystal having a melting point of 199 to 200 ° C. from methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 87
5-Methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a manner similar to that described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH and 5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is obtained as colorless crystals having a melting point of 250 ° C. or higher from NH ₃ . It was.
Example 88
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methyl-sulfanyl-3- () as a colorless foam from (toluene-3-sulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) Toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 1c) And 5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1, as colorless crystals having a melting point of 165 to 165.5 ° C. from piperazine. 5-a] pyrimidine was obtained.
The (toluene-3-sulfonyl) -acetonitrile used was prepared as follows:
2.65 mL (42 mmol) of chloroacetonitrile was added to 7.5 g (42 mmol) of a suspension of toluene-3-sulfinic acid sodium salt in 80 mL of DMF and stirred at 100 ° C. for 1 hour. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ . The combined organic phases were washed once with H ₂ O, dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ ) was performed to yield 2.06 g (25%) of (toluene-3-sulfonyl) -acetonitrile as colorless oil.
Example 89
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine
In a similar manner to that described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine and 1- 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (toluene-3-sulfonyl) as colorless crystal having a melting point of 183 to 184 ° C from methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 90
5-Methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a similar manner as described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH and 5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is obtained as colorless crystals having a melting point of 250 ° C. or higher from NH ₃ . It was.
Example 91
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine
a) 7-chloro-5-methyl-2-methyl-sulfanyl-3- () as a colorless foam from (pyridine-3-sulfonyl) -acetonitrile in a similar manner as described in Examples 18a) to d) Pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine was obtained.
b) 7-chloro-5-methyl-2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine in a similar manner as described in Example 1c) And 5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (pyridine-3-sulfonyl) -pyrazolo [1,2 as colorless crystals having a melting point of 222 to 223 DEG C from piperazine. 5-a] pyrimidine was obtained.
The (pyridine-3-sulfonyl) -acetonitrile used was prepared as follows:
2.1 mL (33.4 mmol) of chloroacetonitrile was added to 4.6 g (42 mmol) of a suspension of pyridine-3-sulfinic acid sodium salt in 50 mL of DMF and stirred at 90 ° C. for 1 hour. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ . The combined organic phases were washed once with H ₂ O, dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , AcOEt / hexane 2: 1) was performed to yield 4.1 g (80%) of (pyridine-3-sulfonyl) -acetonitrile as a beige solid.
Example 92
5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5 -a] pyrimidine
In a similar manner as described in Example 2, 7-chloro-5-methyl-2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine and 1- 5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-3- (pyridine-3-sulfonyl) as colorless crystals having a melting point of 188.4 to 189 ° C from methyl-piperazine Pyrazolo [1,5-a] pyrimidine was obtained.
Example 93
5-Methyl-2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
In a similar manner as described in Example 4, 7-chloro-5-methyl-2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidine in MeOH and 5-methyl-2-methylsulfanyl-3- (pyridine-3-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine as colorless crystals having a melting point of 226.8 to 227.5 ° C from NH ₃ Obtained.
Example 94
2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-6-yl] -ethanol
a) A solution of 2.69 g (10 mmol) of 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and 1.28 g (10 mmol) of 2-acetyl-butyrolactone in 10 mL of acetic acid was added. Heated under reflux for hours. After cooling to room temperature, the mixture was treated with 50 mL of H ₂ O and extracted three times with CH ₂ Cl ₂ . The organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 20: 1) to give 2- (3-benzenesulfonyl-7-hydroxy-5-methyl-2-methylsulfanyl-pyra as colorless foam. 1.5 g (36%) of zolo [1,5-a] pyrimidin-6-yl) -acetate was obtained.
b) ethyl 2- (3-benzenesulfonyl-7-hydroxy-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] -pyrimidin-6-yl) -acetate in 30 mL POCl ₃ 1.5 g (3.56 mmol) of a suspension of was heated under reflux for 4 hours. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 70 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ 20: 1) to give 2- (3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [as a pale yellow solid]. 1.0 g (94%) of 1,5-a] -pyrimidin-6-yl) -acetate was obtained.
c) 0.1 g (1 mmol) of 1-methyl-piperazine in 5 mL of DMF was added 2- (3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5] in 15 mL of DMF. To 0.35 g (0.8 mmol) of a solution of -a] -pyrimidin-6-yl) -acetate and stirred at 60 ° C. for 2 hours. DMF was evaporated under high vacuum, the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ , and the aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) was carried out to give 0.34 g of a yellow foam, which was 50 mL of a mixture of tetrahydrofuran / dioxane / H ₂ O 1: 1: 1. Dissolved in. After addition of 4 mL of 2N NaOH, the mixture was stirred for 12 h at 45 ° C., treated with 100 mL of H ₂ O and extracted three times with 60 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 1) was carried out to yield 2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl)-as a colorless foam. 0.18 g (48%) of 2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-6-yl] -ethanol was obtained.
Example 95
2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-2-yloxy] -ethanol
a) 0.88 g (22 mmol) of powdered NaOH was added to 2 g (11 mmol) of a solution of phenylsulfonylacetonitrile in 20 mL of acetonitrile and stirred at room temperature for 2 hours. Subsequently, 1.14 mL (11 mmol) of a solution of 2-chloroethyl chloroformate in 4 mL of acetonitrile were added dropwise at 5 ° C. and the mixture was heated at reflux for 1 h. After cooling to room temperature, the precipitate was filtered off and the filtrate was evaporated. The brown oil thus obtained was dissolved in 50 mL of EtOH, treated with 0.54 mL (11 mmol) of NH ₂ NH ₂ and heated at reflux for 1 h. After evaporation of the reaction solution, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / NH ₄ OH 110: 10: 1) was carried out to afford 2- (5-amino-4-benzenesulfonyl-1H- as a colorless solid. 1.4 g (45%) of pyrazol-3-yloxy) -ethanol was obtained.
b) 0.75 mL of ethyl acetate is added to 1.14 g (4.9 moles) of a solution of 2- (5-amino-4-benzenesulfonyl-1H-pyrazol-3-yloxy) -ethanol in 10 mL of acetic acid and for 3 hours. Heated to reflux. After cooling to room temperature, the mixture was treated with 50 mL of H ₂ O and extracted three times with CH ₂ Cl ₂ . The organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) to give 2- (3-benzenesulfonyl-7-hydroxy-5-methyl-pyrazolo [1,5- as colorless oil. a] pyrimidin-2-yl) -acetate 0.8 g (42%) was obtained.
c) 0.8 g (2) suspension of ethyl 2- (3-benzenesulfonyl-7-hydroxy-5-methyl-pyrazolo [1,5-a] pyrimidin-2-yloxy) -acetate in 20 mL POCl ₃ Mmol) was heated to reflux for 4 hours. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 80 mL ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 70 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 40: 1) to give 2- [3-benzenesulfonyl-5-methyl-7- [4-methyl-piperazine-1- as a colorless solid 0.56 g (68%) of 1) -pyrazolo [1,5-a] pyrimidin-2-yloxy] -acetate was obtained.
d) 0.38 mL (3.4 mmol) of 1-methyl-piperazine in 5 mL of DMF was converted to ethyl 2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl)-in 10 mL of DMF. To 0.56 g (1.4 mmol) of a solution of pyrazolo [1,5-a] pyrimidin-2-yloxy] -acetate, it was stirred for 1.5 hours at room temperature. DMF was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) was performed to yield ethyl-2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazine) as colorless foam. 0.61 g (92%) of 1-yl) -pyrazolo [1,5-a] pyrimidin-2-yloxy] -acetate was obtained.
e) 0.126 g of a solution of KOH in 5 mL of H ₂ O was converted to ethyl 2- [3-benzenesulfonyl-5-methyl-7- (4-methyl-piperazin-1-yl) in 20 mL of dioxane / THF 1: 1. -Prazolo [1,5-a] pyrimidin-2-yloxy] -acetate was added to a solution of 0.61 mg and stirred at room temperature for 2.5 hours. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was washed three times with 30 mL of CH ₂ Cl ₂ , and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1) and crystallized from EtOH to give 2- [3-benzenesulfonyl-5-methyl- as colorless crystals with a melting point of 177.5 to 178 ° C. 0.18 g (18%) of 7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-2-yloxy] -ethanol was obtained.
Example 96
3-benzenesulfonyl-5- (2-methoxy-ethyl) -2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) 2.69 g (10 mmol) of 4-benzylsulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine in 10 mL of acetic acid and 1.6 g (10 mmol) of methyl 5-methoxy-3-oxo-valerate ) Solution was stirred at reflux for 4 h. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 80 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 20: 1) was carried out to give 3-benzenesulfonyl-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1 as beige powder. 2.5-g (61%) of, 5-a] pyrimidin-7-ol was obtained.
b) of 3-benzenesulfonyl-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 40 mL POCl ₃ and 20 mL diethylaniline 2.3 g (6.0 mmol) of the suspension were heated at reflux for 1 h. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 200: 1) to give 3-benzenesulfonyl-7-chloro-5- (2-methoxy-ethyl) -2-methyl as a pale yellow powder. 1.8 g (75%) of sulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
c) 0.4 g (4.8 mmol) of piperazine in 3 mL of DMF was converted to 3-benzenesulfonyl-7-chloro-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1,5 in 10 mL of DMF. -a] was added to 0.35 g (0.8 mmol) of a solution of pyrimidine and stirred at room temperature for 2 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5- (2-methine as colorless crystals having a melting point of 155 to 156 ° C. 0.25 g (62%) of methoxy-ethyl) -2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 97
3-benzenesulfonyl-5- (2-methoxy-ethyl) -7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
0.5 g (5 mmol) of 1-methyl-piperazine in 3 mL of DMF was added to 3-benzenesulfonyl-7-chloro-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1 in 20 mL of DMF. , 5-a] pyrimidine solution was added to 0.45 g (1.13 mmol) and stirred for 3 hours at room temperature. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (silica gel, CH ₂ Cl ₂ / MeOH 12: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-5- (2-methine as colorless crystals having a melting point of 160 to 161 ° C. 0.255 g (67%) of oxy-ethyl) -7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 98
3-benzenesulfonyl-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
10 mL of a solution of 50% NH ₃ in MeOH was added to 3-benzenesulfonyl-7-chloro-5- (2-methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] in 10 mL of DMF. To 0.50 g (1.25 mmol) of a solution of pyrimidine was added and stirred at room temperature for 2 hours. The reaction solution was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) is carried out and crystallized from EtOH to give 3-benzenesulfonyl-5- (2-methine as colorless crystals having a melting point of 186 to 187 ° C. 0.30 g (63%) of methoxy-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 99
3-benzenesulfonyl-5- (2-methoxy-ethyl) -2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine
a) A solution of 2.69 g (10 mmol) of 4-benzylsulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and 1.46 g (10 mmol) of ethyl 4-methoxy-acetate in 10 mL of acetic acid Heated under reflux for hours. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 80 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 25: 1) was carried out to give 3-benzenesulfonyl-5-methoxymethyl-2-methylsulfanyl-pyrazol as a beige powder having a melting point of 175 to 155 ° C. 3.1 g (85%) of [1,5-a] pyrimidin-7-ol were obtained.
b) 2.5 g (6.8) of a suspension of 3-benzenesulfonyl-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 40 mL POCl ₃ and 20 mL diethylaniline Mmol) was heated to reflux for 1 hour. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 20: 1) was carried out to give 3-benzenesulfonyl-7-chloro-5-methoxymethyl-2-methylsulfa as a pale yellow powder having a melting point of 194 to 197 ° C. 2.1 g (79%) of nile-pyrazolo [1,5-a] pyrimidine were obtained.
c) 0.4 g (4.8 mmol) of piperazine in 3 mL of DMF was substituted with 3-benzenesulfonyl-7-chloro-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 15 mL of DMF. To 0.50 g (1.13 mmol) of a solution of was added and stirred at room temperature for 2 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-5- (2-methine as colorless crystals having a melting point of 170 to 171 ° C. 0.42 g (74%) of methoxy-ethyl) -2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 100
3-benzenesulfonyl-5-methoxymethyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5- a] pyrimidine
0.50 g (5 mmol) of 1-methyl-piperazine in 3 mL of DMF was added to 3-benzenesulfonyl-7-chloro-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] in 15 mL of DMF. To 0.50 g (1.3 mmol) of a solution of pyrimidine was added and stirred at room temperature for 2 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) was performed and crystallized from EtOH to give 3-benzenesulfonyl-5-methoxymethyl- as colorless crystals having a melting point of 207 to 208 ° C. 0.42 g (72%) of 7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 101
3-benzenesulfonyl-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
10 mL of a solution of 50% NH ₃ in MeOH is added to a solution of 3-benzenesulfonyl-7-chloro-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF. To g (1.3 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5-methoxymethyl-2- as colorless crystals having a melting point of at least 230 ° C. 0.38 g (80%) of methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 102
3-benzenesulfonyl-5-chloro-7- (4-methyl-piperazin-1-yl-)-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
a) 5.38 g (20 mmol) of 4-benzylsulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine and 9 mL (60 mmol) of diethyl malonate were subsequently prepared to prepare a freshly prepared sodium ethanolate in EtOH. The solution was added (prepared from 0.89 g (77 mmol) sodium in 100 mL of EtOH) and the mixture was heated at reflux for 48 h. After cooling to room temperature, the mixture was subsequently poured into 140 mL of ice water. The resulting precipitate was filtered off and dried at 50 ° C. under high vacuum. Thus, 6.5 g (96%) of 3-benzenesulfonyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diol was obtained as a beige powder having a melting point of 230 ° C. or higher.
b) 3.0 g (8.89 mmol) of a suspension of 3-benzenesulfonyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diol in 40 mL POCl ₃ were heated under reflux for 1 hour. It was. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 90 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 1.5: 1) to give 3-benzenesulfonyl-5,7-dichloro-2-methylsulfanyl- as colorless crystals having a melting point of 193 to 197 ° C. 1.8 g (54%) of pyrazolo [1,5-a] pyrimidine was obtained.
c) CH ₂ Cl ₂ in 3mL 1- methyl - piperazine 0.1mL (1 mmol) in a CH ₂ Cl ₂ 3- benzenesulfonyl-5,7-dichloro-2-methylsulfanyl-in 20mL - pyrazolo [1, 5-a] pyrimidine was added to 0.37 g (1 mmol) of solution and stirred for 1 hour at room temperature. The mixture was poured into ice water and the pH was adjusted to 8 with saturated NaHCO ₃ solution and extracted three times with 30 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 4: 1) was carried out to give 3-benzenesulfonyl-5-chloro-7- (4-methyl-piperazine as colorless crystals having a melting point of at least 230 ° C. 0.38 g (86%) of 1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 103
3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl-)-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine
0.15 g of Pd / C (10%) and 0.3 mL of NEt ₃ were added to 3-benzenesulfonyl-5-chloro-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyra in 30 mL of EtOH. To 0.189 g (0.4 mmol) of a solution of zolo [1,5-a] pyrimidine was added and hydrogenated at room temperature for 12 hours. The reaction mixture was filtered over Dicalite and the filtrate was evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 20: 1) to give 3-benzenesulfonyl-7- (4-methyl-piperazine-1- as colorless crystals with melting points of 107 to 109 ° C. Il) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine 0.08 g (49%) was obtained.
Example 104
2- [3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl-)-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-5-yloxy] -ethanol
0.115 g (5 mmol) of sodium is added to 20 mL of ethylene glycol, and this solution is added to 3-benzenesulfonyl-5-chloro-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyra. Treated with 0.22 g (0.5 mmol) of solo [1,5-a] pyrimidine and subsequently stirred at 80 ° C. for 1 hour. After cooling to room temperature, the reaction solution was poured into 70 mL of ice water and extracted three times with 50 mL of AcOEt. The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / NH ₄ OH 110/10: 1) and crystallized from EtOH to give 2- [3-benzenesulfur as colorless crystals having a melting point of 187 to 189 ° C. 0.16 g (69%) of ponyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-5-yloxy] -ethanol It was.
Example 105
3-benzenesulfonyl-5-chloro-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
10 mL of a solution of 50% NH ₃ in MeOH was mixed with 0.35 g (0.935 mmol) of a solution of 3-benzenesulfonyl-5,7-dichloro-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine in 10 mL of DMF. ) And stirred at room temperature for 12 hours. DMF was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 15: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5-chloro-2-methylsulfa as colorless crystals having a melting point of at least 230 ° C. 0.28 g (84%) of silyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 106
3-benzenesulfonyl-N5, N5-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine and 3-benzenesulfonyl-N5- (2-dimethylamino- Ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine
0.26 g (3 mmol) of 2-dimethylaminoethylamine in 5 mL of DMF was substituted with 3-benzenesulfonyl-5-chloro-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yl in 10 mL of DMF. To 0.4 g (1 mmol) solution of amine was added and stirred at 90 ° C. for 1 hour. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 50 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 1) was carried out to give 3-benzenesulfonyl-N5, N5-dimethyl-2-methylsulfanyl-pyra as colorless crystals having a melting point of 230 ° C. or higher. 0.20 g (48%) of zolo [1,5-a] pyrimidine-5,7-diamine and 3-benzenesulfonyl-N5- (2-dimethylamino-ethyl)-as colorless crystals having a melting point of 210 to 212 ° C. 0.08 g (17%) of 2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine was obtained.
Example 107
3-benzenesulfonyl-5- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
0.1 g (1 mmol) of 1-methyl-piperazine was added to a solution of 3-benzenesulfonyl-5-chloro-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine in 5 mL of DMF. 0.14 g (0.4 mmol) was added and stirred at 90 ° C. for 1 h. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 50 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl-5- (4-methyl-pipepe as colorless crystals having a melting point of at least 230 ° C. 0.1 g (59%) of razin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 108
3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
a) A newly prepared solution of sodium ethanolate in EtOH followed by 7.90 g (31.4 mmol) of 4-benzylsulfonyl-5-ethyl-2H-pyrazol-3-ylamine and 14.3 mL (94.3 mmol) of diethyl malonate. (Prepared from 2.7 g (119.5 mmol) sodium in 320 mL EtOH) and heated at reflux for 48 h. After cooling to room temperature, the mixture was subsequently poured into 140 mL of ice water. The resulting precipitate was filtered off and dried at 50 ° C. under high vacuum. Thus, 4.8 g (48%) of 3-benzenesulfonyl-2-ethyl-pyrazolo- [1,5-a] pyrimidine-5,7-diol having a melting point of at least 230 ° C was obtained.
b) 2.8 g (8.8 mmol) of a suspension of 3-benzenesulfonyl-2-ethyl-pyrazolo [1,5-a] pyrimidine-5,7-diol in 30 mL POCl ₃ were heated at reflux for 1 h. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ ) to give 1.1 g of 3-benzenesulfonyl-5,7-dichloro-2-ethyl-pyrazolo [1,5-a] pyrimidine as colorless crystals. 35%) was obtained.
c) CH ₂ Cl ₂ in 3mL 1- methyl - piperazine 0.86mL (7.7 mmol) CH ₂ Cl ₂ 3- benzenesulfonyl-5,7-dichloro-2-acetate in 20mL - pyrazolo [1,5- a] to 2.5 g (7 mmol) of a solution of pyrimidine and stirred at room temperature for 2 hours. The mixture was poured into ice water, the pH was adjusted to 8 with saturated NaHCO ₃ solution and extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (silica gel, CH ₂ Cl ₂ / MeOH 4: 1) is performed and crystallized to give 3-benzenesulfonyl-5,7-dichloro-2- as colorless crystals having a melting point of 166 to 167 ° C. 2.5 g (85%) of ethyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 109
3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
0.1 g of Pd / C (10%) was added to 3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a in 40 mL of EtOH. ] 0.267 g (0.63 mmol) of a solution of pyrimidine, and the mixture was hydrogenated at room temperature for 4 hours. The reaction mixture was filtered over decalite and the filtrate was evaporated. The residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 19: 1) and crystallized from EtOH to give 0.2 g (53%) as light beige crystals having a melting point of 206 to 207 ° C.
Example 110
3-benzenesulfonyl-2-ethyl-5,7-bis- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine
0.33 mL (3 mmol) of 1-methyl-piperazine in 5 mL of DMF was converted to 3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazol in 15 mL of DMF. To 0.50 g (1.2 mmol) of [1,5-a] pyrimidine was added and stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / NH ₄ OH 110: 10: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-2-ethyl- as colorless crystals having a melting point of 232 to 235 ° C. 0.04 g (69%) of 5,7-bis- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidine was obtained.
Example 111
3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl)-5-morpholin-4-yl-pyrazolo [1,5-a] pyrimidine
0.26 mL (3 mmol) of morpholine in 5 mL of DMF was converted to 3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5 in 15 mL of DMF. -a] was added to 0.50 g (1.2 mmol) of a solution of pyrimidine and stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 15: 1) is carried out and crystallized from EtOH to give 3-benzenesulfonyl-2-ethyl-7- (4 as colorless crystals having a melting point of at least 250 ° C. 0.45 g (80%) of -methyl-piperazin-1-yl) -5-morpholin-4-yl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 112
2- [3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yloxy] -ethanol
0.274 g (12 mmol) sodium is added to 40 mL of ethylene glycol, and this solution is added to 3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [ 1,5-a] pyrimidine was treated with 0.50 g (1.2 mmol) and subsequently stirred at 80 ° C. for 1 hour. After cooling to room temperature, the reaction solution was poured into 70 mL of ice water and extracted three times with 50 mL of AcOEt. The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1) to give 2- [3-benzenesulfonyl-2-ethyl-7- (4- as colorless crystals with melting points of 153 to 154 ° C. 0.24 g (44%) of methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yl-oxy) -ethanol was obtained.
Example 113
[3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yl] -dimethyl-amine and N- [ 3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yl] -N ', N'-dimethyl- Ethane-1,2-diamine
0.72 g (6.5 mmol) of 2-dimethylaminoethylamine in 5 mL of DMF was converted to 3-benzenesulfonyl-5-chloro-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazol in 20 mL of DMF. To 1.1 g (2.6 mmol) of a solution of [1,5-a] pyrimidine was added and stirred at 90 ° C. for 1 hour. After cooling to room temperature, the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 80 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (silica gel, CH ₂ Cl ₂ / MeOH / NH ₄ OH 65: 10: 1) was carried out to give [3-benzenesulfonyl-2-ethyl- as colorless crystals having a melting point of 211 to 212 ° C. Colorless with 0.20 g (13%) of 7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yl] -dimethyl-amine and a melting point of 163-164 ° C. N- [3-benzenesulfonyl-2-ethyl-7- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-5-yl] -N 'as a crystal, 0.30 g (24%) of N'-dimethyl-ethane-1,2-diamine was obtained.
Example 114
3-benzenesulfonyl-5-chloro-2-ethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
20 mL of a solution of 50% NH ₃ in MeOH was added to 1.1 g (3.1 mmol) of a solution of 3-benzenesulfonyl-2-ethyl-pyrazolo [1,5-a] pyrimidine-5,7-diol in 10 mL of DMF. Add and stir for 12 hours at room temperature. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. The residue was treated with 5 mL of EtOH and the crystals obtained were filtered. Thus, 0.80 g (77%) of 3-benzenesulfonyl-5-chloro-2-ethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained as colorless crystals having a melting point of 220 DEG C or higher. .
Example 115
3-benzenesulfonyl-2-ethyl-5- (4-methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine
0.33 g (3 mmol) of 1-methyl-piperazine was added to 0.4 g of a solution of 3-benzenesulfonyl-5-chloro-2-ethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine in 5 mL of DMF. (1.2 mmol) and stirred at 90 ° C. for 1 hour. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 50 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1) was carried out and crystallized from EtOH to give 3-benzenesulfonyl-2-ethyl-5- (4 as colorless crystals having a melting point of at least 250 ° C. 0.24 g (50%) of -methyl-piperazin-1-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 116
3-benzenesulfonyl-2-ethyl-N5, N5-dimethyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine and 3-benzenesulfonyl-N5- (2-dimethylamino-ethyl) 2-ethyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine
0.73 g (6.68 mmol) of 2-dimethylaminoethylamine in 5 mL of DMF was added to a solution of 3-benzenesulfonyl-5-chloro-2-ethyl-pyrazolo [1,5-a] pyrimidin7-ylamine in 10 mL of DMF. 0.45 g (1.3 mmol) was added and stirred at 90 ° C. for 1 h. The reaction solution was evaporated and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase was extracted three times with 80 mL of CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (silica gel, CH ₂ Cl ₂ / MeOH / NH ₄ OH 65: 10: 1) was carried out to give 3-benzenesulfonyl-2-ethyl-N5 as colorless crystals having a melting point of 228 to 230 ° C. , N5-dimethyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine 0.12 g (26%) and 3-benzenesulfonyl-N5- (2- as colorless crystals having a melting point of 149.5 to 150.5 ° C. 0.09 g (17%) of dimethylamino-ethyl) -2-ethyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine was obtained.
Example 117
3-benzenesulfonyl-5-dimethylaminoethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
a) 6.8 mL (50 mmol) of ethyl-4-chloro-acetoacetate are added to 13.5 mL (50 mmol) of 4-benzenesulfonyl-5-methylsulfanyl-2H-pyrazol-3-ylamine in 80 mL of acetic acid Heated at reflux for 1.5 h. After cooling to room temperature, the obtained crystals were filtered off, washed with EtOH and dried at 50 ° C. under high vacuum. Thus, 10.5 g (56%) of 3-benzenesulfonyl-5-chloromethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol as a colorless powder having a melting point of 215 to 217 ° C. Obtained.
b) 5 mL of a solution of 33% dimethylamine in EtOH with a solution of 3-benzenesulfonyl-5-chloromethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 20 mL DMF To 1.4 g (3.7 mmol) was added and stirred for 4 hours at room temperature. The reaction mixture was evaporated and the residue was partitioned between 0.5 N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 4: 1) was carried out to give 3-benzenesulfonyl-5-dimethylaminoethyl-2-methylsulfanyl-pyrazolo [1] as a beige powder having a melting point of 220 ° C. or higher. 1.3 g (92%) of, 5-a] pyrimidin-7-ol were obtained.
c) 1.3 g (3.43 mmol) of a suspension of 3-benzenesulfonyl-5-dimethylaminomethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 50 mL POCl ₃ for 3 hours. Heated under reflux. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 100 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was subjected to chromatography (SiO ₂ , CH ₂ Cl ₂ / AcOEt 1: 1) to give (3-benzenesulfonyl-7-chloro-2-methylsulfanyl-pyrazolo [1,5-a as colorless foam). ] 1.2 g (88%) of pyrimidin-5-ylmethyl) -dimethyl-amine was obtained.
d) 20 mL of a solution of 50% NH ₃ in MeOH (3-benzenesulfonyl-7-chloro-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-5-ylmethyl) in 30 mL DMF Add 1.20 g (3 mmol) of a solution of dimethyl-amine and stir at room temperature for 4 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 6: 1) was carried out to give 3-benzenesulfonyl-5-dimethylaminomethyl-2-methylsulfanyl as colorless crystals with melting points of 216 to 218 ° C. 0.90 g (78%) of pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 118
3-benzenesulfonyl-5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
a) 1.57 mL (15.70 mmol) of 1-methyl-piperazine was added to 3-benzenesulfonyl-5-chloromethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 20 mL of DMF. To 2.9 g (7.84 mmol) of a solution of was added and stirred for 4 hours at room temperature. The reaction mixture was evaporated and the residue was partitioned between 0.5 N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 4: 1) was carried out to give 3-benzenesulfonyl-5- (4-methyl-piperazin-1-ylmethyl)-as a beige powder having a melting point of 220 ° C. or higher. 1.85 g (53%) of 2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol were obtained.
b) of 3-benzenesulfonyl-5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 100 mL POCl ₃ 4.0 g (9 mmol) of the suspension were heated at reflux for 3 hours. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 150 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) to give 3-benzenesulfonyl-7-chloro-5- (4-methyl- as a light brown powder with a melting point of 113 to 116 ° C. 4.0 g (98%) of piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine was obtained.
c) 10 mL of a solution of 50% NH ₃ in MeOH with 3-benzenesulfonyl-7-chloro-5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo in 20 mL of DMF. To 0.8 g (1.77 mmol) of a solution of [1,5-a] pyrimidine was added and stirred at room temperature for 4 hours. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / Na ₄ OH 90: 10: 1) was carried out to give 3-benzenesulfonyl-5- (4- as colorless crystals having a melting point of 203 to 205 ° C. 0.59 g (77%) of methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 119
3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5- a] pyrimidine
0.4 g (4 mmol) of 1-methyl-piperazine was converted to 3-benzenesulfonyl-7-chloro-5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo in 20 mL of DMF. To 0.8 g (1.77 mmol) of a solution of [1,5-a] pyrimidine was added and stirred for 6 hours at room temperature. The reaction mixture was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / NH ₄ OH 80: 10: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl- as colorless crystals having a melting point of 193 to 195 ° C. 7- (4-methyl-piperazin-1-yl) -5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine 0.75 g (82%) was obtained.
Example 120
3-benzenesulfonyl-5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine
a) 2.0 g of a solution of 3-benzenesulfonyl-5-chloromethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ol in 1 mL (6 mmol) of morpholine in 20 mL of DMF ( 5.40 mmol) and stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue was partitioned between 0.5 N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) was carried out to give 3-benzenesulfonyl-2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,1] as a beige foam. 5-a] pyrimidin-7-ol 2.0g (88%) was obtained.
b) 2.0 g (4.75 mmol) of a suspension of 3-benzenesulfonyl-2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,5-a] pyrimidin-7-ol in 30 mL POCl ₃ ) Was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and evaporated. The residue was treated with 100 mL of ice water and the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The aqueous phase was extracted three times with 70 mL of CH ₂ Cl ₂ , and the organic phase was dried (MgSO ₄ ), filtered and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1) to give 3-benzenesulfonyl-7-chloro-2-methylsulfanyl-5 as a light brown powder with a melting point of 174 to 176 ° C. 1.8 g (86%) of morpholin-4-ylmethyl-pyrazolo [1,5-a] pyrimidine was obtained.
c) 10 mL of a solution of 50% NH ₃ in MeOH was added 3-benzenesulfonyl-7-chloro-2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,5-a in 20 mL DMF. ] Add 0.9 g (2 mmol) of a solution of pyrimidine and stir for 4 hours at room temperature. DMF was evaporated under high vacuum and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was washed three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (silica gel, CH ₂ Cl ₂ / MeOH / Na ₄ OH 80: 10: 1) is performed and crystallized from EtOH to give 3-benzenesulfonyl- as colorless crystals having a melting point of 224 to 226 ° C. 0.70 g (83%) of 5- (4-methyl-piperazin-1-ylmethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine was obtained.
Example 121
3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,5-a] pyrimidine
0.4 g (4 mmol) of 1-methyl-piperazine was added to 3-benzenesulfonyl-7-chloro-2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,5-a in 20 mL of DMF. ] Add 0.9 g (2 mmol) of a solution of pyrimidine and stir for 4 hours at room temperature. The reaction mixture was evaporated and the residue was partitioned between 2N NaOH and CH ₂ Cl ₂ . The aqueous phase was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / NH ₄ OH 80: 1: 1) was carried out to give 3-benzenesulfonyl-7- (4- as colorless crystals having a melting point of 199 to 201 ° C. 0.80 g (77%) of methyl-piperazin-1-yl) -2-methylsulfanyl-5-morpholin-4-ylmethyl-pyrazolo [1,5-a] pyrimidine was obtained.
Example 122
[2- (3-Benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-yloxy) -ethyl] -dimethyl-amine
0.28 mL (2.38 mmol) of 2-dimethylaminoethanol and 3.68 g of Cs ₂ CO _{3 were} added to 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5- in 40 mL of acetonitrile. a] to 0.8 g (2.26 mmol) of a solution of pyrimidine was added and stirred at room temperature for 12 hours. The reaction mixture was poured into semiconcentrated aqueous sodium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and evaporated. Subsequently, chromatography was carried out to give 2- (3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine as a pale yellow solid having a melting point of 176 to 178 ° C. 0.65 g (70%) of -7-yloxy) -ethyl] -dimethyl-amine was obtained.
Example 123
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7- (2-morpholin-4-yl-ethoxy) -pyrazolo [1,5-a] pyrimidine
In a similar manner as described in Example 122, 3-benzenesulfonyl-7-chloro-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and N- (2-hydroxy 3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7- (2-morpholin-4-yl-ethoxy) -pyrazolo [1,5- as light yellow solid from -ethyl) -morpholine a] pyrimidine was obtained.
Example 124
8-benzenesulfonyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-ylamine
0.10 g (0.37 mmol) of 5-amino-3-methylthio-4-phenylsulfonyl-pyrazole was mixed with 0.25 g (2.55 mmol) of N-cyano-methanimate and stirred at 100 ° C. for 16 hours. . The resulting light beige paste was dissolved in AcOEt / MeOH and treated in an ultrasonic bath. The suspension thus obtained was filtered. Chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 95: 5) was carried out to give 8-benzenesulfonyl-7-methylsulfanyl-pyrazolo [1,5-a] as light beige crystals having a melting point of 280 ° C. or higher. 0.052 g (44%) of [1,3,5] -triazin-4-ylamine was obtained.
Example 125
(8-benzenesulfonyl-2-methyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-yl) -methylamine
a) A solution of 0.54 (2 mol) of 5-amino-3-methylthio-4-phenylsulfonyl-pyrazole and 0.54 g (3.4 mmol) of ethyl 1-ethoxy-ethylidene-carbamate in acetic acid for 3 hours Stir at 100 ° C. After cooling to room temperature, the precipitate was filtered off, washed with a large amount of Et ₂ O and dried at 45 ° C. under high vacuum. 8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] -triazin-4-one 0.41 as white crystals having a melting point of at least 300 ° C. g (61%) was obtained.
b) 0.36 g of a suspension of 8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] triazin-4-one in 20 mL POCl ₃ (1 mmol) was treated with 0.12 mL (1.5 mmol) pyridine and heated at 110 ° C. for 3 hours. The reaction solution was cooled to room temperature and evaporated. The residue was azeotropically dried twice with 50 mL of toluene each. The residue thus obtained was added in 10 mL of 2 N methylamine in tetrahydrofuran and stirred at room temperature for 4 hours. The reaction solution was evaporated and partitioned between H ₂ O and AcOEt. The organic phase was washed with H ₂ O and saturated NaCl solution, dried (MgSO ₄ ), filtered and evaporated. Chromatography (SiO ₂ , AcOEt / hexane 1: 1) was carried out to give (8-benzenesulfonyl-2-methyl-7-methylsulfanyl-pyrazolo [1,5) as white crystals having a melting point of 285 ° C. (decomposition). -a] [1,3,5] triazin-4-yl) -methylamine 0.28 g (80%) was obtained.
Example 126
(8-benzenesulfonyl-2-methyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-yl) -dimethylamine
8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] triazine-4 in a similar manner as described in Example 123b) (8-benzenesulfonyl-2-methyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] as light pink crystals with melting points of 228 to 230 ° C. from -one and dimethylamine Triazin-4-yl) -dimethylamine was obtained.
Example 127
(8-benzenesulfonyl-2-methyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-yl) -N ', N'-dimethyl-propane -1,3-diamine
8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] triazine-4 in a similar manner as described in Example 123b) (8-benzenesulfonyl-2-methyl, having a melting point of 249 to 250 ° C., converted from -one and 3-dimethylamino-1-propylamine to the corresponding hydrogen chloride (1: 1.75) using HCl / diethyl ether -7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-yl) -N ', N'-dimethyl-propane-1,3-diamine was obtained.
Example 128
8-benzenesulfonyl-2-methyl-4- (4-methylpiperazin-1-yl) -7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazine
8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] triazine-4 in a similar manner as described in Example 123b) 8-benzenesulfonyl-2-methyl-4- (4-methyl-piperazin-1-yl) -7-methylsulfanyl- as yellow crystals having a melting point of 169 to 171 ° C. from -one and 1-methylpiperazine. Pyrazolo [1,5-a] [1,3,5] triazine was obtained.
Example 129
8-benzenesulfonyl-2-methyl-4- (4-benzylpiperazin-1-yl) -7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazine
8-benzenesulfonyl-2-methyl-7-methylsulfanyl-3H-pyrazolo [1,5-a] [1,3,5] triazine-4 in a similar manner as described in Example 123b) 8-benzenesulfonyl-2-methyl-4- (4-benzylpiperazin-1-yl) -7-methylsulfanyl- as beige crystals having a melting point of 190 to 192 ° C. from -one and 1-benzylpiperazine. Pyrazolo [1,5-a] [1,3,5] triazine was obtained.
Example A
The tablets of the composition of Table 4 below were prepared in a conventional manner.
Furtherancemg / tablet Active ingredient100 Powder lactose95 White corn starch35 Polyvinylpyrrolidone8 Na carboxymethyl starch10 Magnesium stearate2 Tablet weight250
The present invention has provided pyrazolopyrimidines and pyrazolotriazines with selective affinity for the 5-HT ₆ receptor, which is active and has low toxicity against central nervous system disease.

权利要求:
Claims (13)
[1" claim-type="Currently amended] A compound of formula (1) or formula (2), or a pharmaceutically acceptable salt thereof:
Formula 1

Formula 2

Where
R ¹ is phenyl optionally substituted by one or more lower alkyl, halogen, lower alkoxy, tolyl, pyridyl, naphthyl or thiophenyl;
R ² is hydrogen, lower alkyl, lower thioalkyl or hydroxy-lower-alkoxy;
R ³ is amino; Lower alkylamino; Di-lower-alkyl-amino; Piperazinyl optionally substituted by one or more lower alkyl, benzyl, phenyl or hydroxy-lower-alkyl; Morpholinyl; Imidazolyl; (CH ₃ ) ₂ N (CH ₂ ) _n NH—; (CH ₃ ) ₂ N (CH ₂ ) _n O—; Or morpholinyl- (CH ₂ ) _n O—, where n is 2 or 3;
R ⁴ is hydrogen, lower alkyl or hydroxy-lower-alkyl;
R ⁵ is hydrogen; halogen; Lower alkyl; C ₃ -C ₆ -cycloalkyl; Lower alkyl-lower-alkoxy; Hydroxy-lower-alkyl-lower-alkoxy; (CH ₃ ) ₂ N (CH ₂ ) _n NH—; Piperazinyl optionally substituted by lower alkyl; Methyl-piperazinyl optionally substituted by lower alkyl, morpholinyl, methyl-morpholinyl, di-lower-alkylamino or di-lower-alkylamino-lower-alkyl;
R ⁴ and R ⁵ together are — (CH ₂ ) m — or —CH ₂ —S—CH ₂ —, where m is 3 or 4;
[2" claim-type="Currently amended] The method of claim 1,
A compound of formula (1) wherein R ³ is amino.
[3" claim-type="Currently amended] The method of claim 2,
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3- (4-isopropyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (naphthalene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
3- (4-fluoro-benzenesulfonyl) -5-methyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidin-8-ylamine,
3-benzenesulfonyl-5-isopropyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
5-methyl-2-methylsulfanyl-3- (toluene-3-sulfonyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine,
3-benzenesulfonyl-5-methoxymethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-6-ylamine,
3-benzenesulfonyl-N5, N5-dimethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine,
3-benzenesulfonyl-N5- (2-dimethylamino-ethyl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine-5,7-diamine,
3-benzenesulfonyl-5- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine and
3-benzenesulfonyl-5-dimethylaminomethyl-2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-7-ylamine.
[4" claim-type="Currently amended] The method of claim 1,
A compound of formula (1) wherein R ³ is piperazine.
[5" claim-type="Currently amended] The method of claim 4, wherein
3-benzenesulfonyl-5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3- (4-tert-butyl-benzenesulfonyl) -5-methyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-5,6-dimethyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-7-piperazin-1-yl-5-propyl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7-piperazin-1-yl-pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-methylsulfanyl-8-piperazin-1-yl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrimidine,
5-methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (thiophen-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-2-ethyl-8-piperazin-1-yl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] pyrimidine and
5-Methyl-2-methylsulfanyl-7-piperazin-1-yl-3- (toluene-2-sulfonyl) -pyrazolo [1,5-a] pyrimidine.
[6" claim-type="Currently amended] The method of claim 1,
A compound of formula (1) wherein R ³ is methylpiperazinyl.
[7" claim-type="Currently amended] The method of claim 6,
3-benzenesulfonyl-5-cyclopropyl-2-methylsulfanyl-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a] pyrimidine,
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-6,7-dihydro-5H-cyclopenta [d] pyrazolo [1,5-a] Pyrimidine,
3-benzenesulfonyl-8- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-5H, 7H-pyrazolo [1,5-a] thieno [3,4-d] pyrid Midine,
3-benzenesulfonyl-5-isopropyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidine and
2- [3-benzenesulfonyl-7- (4-methyl-piperazin-1-yl) -2-methylsulfanyl-pyrazolo [1,5-a] pyrimidin-5-yloxy] -ethanol A compound selected from the group consisting of.
[8" claim-type="Currently amended] The method of claim 1,
A compound of formula (2) wherein R ³ is amino or methylpiperazinyl.
[9" claim-type="Currently amended] The method of claim 8,
8-benzenesulfonyl-7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazin-4-ylamine or 8-benzenesulfonyl-2-methyl-4- (4 -Methylpiperazin-1-yl) -7-methylsulfanyl-pyrazolo [1,5-a] [1,3,5] triazine.
[10" claim-type="Currently amended] Psychosis, schizophrenia, mood swings, depression, comprising a compound of formula (1) or formula (2) according to any one of claims 1 to 9 or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier material , Agents for treating or preventing central nervous system diseases such as neurological diseases, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.
[11" claim-type="Currently amended] Reacting a compound of formula (3) or a compound of formula (4) with a compound of formula (5) and, if necessary, converting a compound of formula (1) or formula (2) into a pharmaceutically acceptable salt Method for preparing a compound of formula (1) or formula (2) according to claim 1, comprising:
Formula 3

Formula 4

Formula 5
HR ³
Where
R ¹ to R ⁵ are as described above in claim 1.
[12" claim-type="Currently amended] A compound of formula (1) or formula (2) as defined in any one of claims 1 to 9, prepared according to the method as defined in claim 11 or a method equivalent thereto.
[13" claim-type="Currently amended] The method according to any one of claims 1 to 9,
Compounds for use as therapeutically active substances.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-03-11|Priority to EP98104346

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1998-03-11|Priority to EP98104346.6

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1999-03-10|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 아게

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1999-10-25|Publication of KR19990077741A

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2001-11-05|Application granted

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2001-11-05|Publication of KR100313181B1

优先权:

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申请号 | 申请日 | 专利标题

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EP98104346|1998-03-11|

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EP98104346.6|1998-03-11|