JP2006056882A - Pyrazolopyrimidine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having an excellent SK channel-blocking activity and useful as a medicine. <P>SOLUTION: This pyrazolo[3,4-d]pyrimidine-based compound expressed by general formula [I] or its pharmacologically acceptable salts is provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a novel pyrazolopyrimidine compound or a pharmacologically acceptable salt thereof which has an excellent small conductance type Ca ²⁺ -dependent potassium (SK) channel blocking action and is useful as a pharmaceutical.

Ca ²⁺ -dependent potassium channels are classified into at least three types: large (BK), medium (IK) and small (SK). These potassium channels are activated by increasing intracellular Ca ²⁺ concentration. BK and IK channels are sensitive to changes in membrane potential in addition to intracellular Ca ²⁺ , but SK channels are not characterized by significant membrane potential sensitivity. The SK channel is also characterized by its low single channel conductance (6-20 pS) and high sensitivity to apamin.

  SK channels are present not only in excitable cells such as nerves and muscles but also in a wide variety of cells such as liver and blood cells, and are involved in cell functions such as release of chemical mediators, muscle contraction, and secretion.

  Apamin is well known as a selective blocker for the SK channel, and its pharmacological action includes enhancement of the gastrointestinal motility transport function (Non-patent Documents 1 and 2) and improvement of learning and memory impairment (non-patented) References 3 and 4) and shortening of the immobility time in the forced swimming test (Non-Patent Document 5) have been reported. In patients with myotonic dystrophy, the presence of a specific binding site of apamin in skeletal muscle and symptom reduction by administration of apamin have been reported (Non-patent Documents 6 and 7). Furthermore, it has been reported that mice in which SK3, which is one of the SK channel subtypes, is forcibly expressed, develop respiratory dysfunction under low oxygen partial pressure (Non-patent Document 8).

  As a compound exhibiting a SK channel blocking action, Patent Document 1 discloses 1,1 ′-(α, α′-para-xylene) -3,3 ′-(α, α′-meta-xylene) -bis (benzimidazo). Bis (benzimidazole) derivatives such as Lithium) are disclosed in Patent Document 2 in 7,18-diaza-3,4 (1,4) -dibenzena-1,6 (1,4) -diquinolinacyclooctadecaphane. Cyclophane derivatives such as 3 trifluoroacetic acid hydrate are cross-linked to Patent Document 3, such as 1,4-bis- (2-methyl-quinolin-4-yl)-[1,4] -diazepane. Bisquinoline derivatives are disclosed. Patent Document 4 discloses a compound having a spirocyclohexane-1,1 ′ (2′H) -isoquinoline skeleton as a compound having an SK channel blocking action. Patent Document 5 discloses 2- [4- (5-amino-1H-benzimidazol-2-yl) -pyridin-3-yl] -benzimidazol-5-ylamine as a compound having an SK channel blocking action. Bisbenzimidazole compounds such as are disclosed.

Conventional technology

International Patent Publication WO00 / 01676

International Patent Publication No. WO97 / 48705 US Pat. No. 5,866,562 International Patent Publication No. WO02 / 79189 International Patent Publication WO03 / 094861 S. A. Waterman and M. Costa, J. Physiology 477, 459-468, 1994 N. Spencer et al., J. Physiology 517, 889-898, 1999 S. Ikonen et al., Eur. J. Pharmacol. 347, 13-21, 1998 C. Ghelardini et al., Br. J. Pharmacol. 123, 1079-1084, 1998 N. Galeotti et al., Br. J. Pharmacol. 126, 1653-1659, 1999 J.F.Renaud et al., Nature 319, 678-680, 1986 M.I.Behrens et al., Muscle & Nerve 17, 1264-1270, 1994 C. T. Bond et al., Science 289, 1942-1946, 2000

  An object of the present invention is to provide a novel pyrazolopyrimidine compound having an excellent SK channel blocking action and useful as a medicine.

  The present invention relates to general formula [I]:

[Wherein A represents formula (a):

Or a substituted cyclohexyl group represented by formula (b):

A substituted piperidyl group represented by:
R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkenoyl group, an amino lower alkyl group (of the group) The amino group moiety may be substituted with a lower alkyl group) or a cyclo-lower alkylcarbonyl group, or they may be bonded together at the ends to form a nitrogen-containing heterocyclic group with the adjacent nitrogen atom, R ¹³ and R ¹⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a lower alkenoyl group, a cyclo lower alkylcarbonyl group, an amino lower alkyl group (of the group) The amino group moiety may be substituted with a lower alkyl group), low A nitrogen-containing heterocyclic group optionally substituted with a secondary alkyl group or a nitrogen-containing heterocyclic group-substituted lower alkyl group, Q is a lower alkylene group, and R ² is a formula:

R ³⁰ is a halogen atom, R ³¹ is a lower alkyl group which may be substituted with a halogen atom, R ³² , R ³³ , R ³⁴ and R ³⁵ are a lower alkyl group, a lower alkoxy group, a halogen-substituted lower group An alkoxy group, a lower alkanoyl group or an amino group (the amino group may be substituted with a lower alkyl group), R ³⁶ , R ³⁷ and R ³⁸ are a lower alkyl group, a lower alkoxy group or a lower alkanoyl group, and n is 0 Or an integer of 1 (provided that when A is a group represented by the formula (a), R ³² , R ³³ and R ³⁴ do not become a lower alkyl group or a lower alkoxy group). ]
Or a pharmacologically acceptable salt thereof.

  Since the target compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits a superior antagonistic action against apamin in a competitive binding test with apamin known as an SK channel blocker, SK channel blocking Useful as a medicine. Therefore, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for the prevention / treatment of diseases associated with SK channels, such as constipation and irritable bowel syndrome, postoperative ileus, reflux esophagitis Gastrointestinal motility dysfunction, learning and memory impairment, emotional disorder, Alzheimer's dementia, depression, central diseases such as Parkinson's disease, myotonic dystrophy, and sleep apnea Conceivable.

  In addition, the target compound [I] of the present invention is characterized by low toxicity and high safety as a medicine.

Specific examples of the compound [I] of the present invention include, for example,
A is a substituted cyclohexyl group represented by the formula (a), R ¹¹ and R ¹² are a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, A di (C _1-6 alkyl) amino-C _1-6 alkyl group or a nitrogen-containing heterocyclic group-substituted C _1-6 alkyl group, the other being a C _1-6 alkyl group, a C _2-7 alkanoyl group or C _3-8 cycloalkyl-carbonyl groups, or both are bonded to each other at the end to form a nitrogen-containing heterocyclic group together with the adjacent nitrogen atom, Q is a C _1-6 alkylene group, and R ² is a formula:

R ³³ is a halogen-substituted C _1-6 alkoxy group, C _2-7 alkanoyl group or di (C _1-6 alkyl) amino group, R ³⁵ is a C _1-6 alkoxy group, and R ³⁶ is C _1. A compound having a _-6 alkyl group, R ³⁷ is a C _2-7 alkanoyl group, R ³⁸ is a C _1-6 alkoxy group, or A is a substituted piperidyl group represented by the formula (b), one of R ¹³ and R ¹⁴ is C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, C _1-6 alkoxy-C _1-6 alkyl group, di (C _1-6 alkyl) amino-C _1-6 alkyl group or nitrogen-containing heterocycle A formula group-substituted C _1-6 alkyl group, the other being a C _1-6 alkyl group, a C _1-6 alkyl-substituted nitrogen-containing heterocyclic group, a C _2-7 alkanoyl group or a C _3-8 cycloalkyl-carbonyl group And Q is A C _1-6 alkylene group, R ² is represented by the formula:

In which R ³² is a C _1-6 alkoxy group, R ³³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ³⁴ is a C _1-6 alkyl group.

In the compound [I] of the present invention, the nitrogen-containing heterocyclic group in R ¹¹ , R ¹² , R ¹³ or R ¹⁴ is, for example, a saturated or unsaturated nitrogen-containing 5-6 such as pyrrolidinyl group, piperidyl group and the like. A membered heterocyclic group.

  Of the compounds [I] of the present invention, preferred compounds include those in which Q is a methylene group.

  Moreover, as a more preferable compound among the above, for example, the general formula [IA]:

[In the formula, one of R ^11A and R ^12A is a lower alkyl group and the other is a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, or both are bonded to each other at the end and together with an adjacent nitrogen atom Forms a 5- to 6-membered nitrogen-containing heterocyclic group, and R ²¹ represents the formula:

R ^30A is a halogen atom, R ^31A is a halogen-substituted lower alkyl group, R ^33A is an amino group or lower alkanoyl group optionally substituted with a lower alkyl group, R ^36A is a lower alkyl group, and R ^37A is A lower alkanoyl group, R ^38A represents a lower alkoxy group, and n represents an integer of 0 or 1. ]
The compound shown by these is mention | raise | lifted.

  Moreover, as another more preferable compound, for example, the general formula [IB]:

[In the formula, one of R ^13A and R ^14A may be substituted with a lower alkyl group, an amino lower alkyl group (the amino group portion of the group may be substituted with a lower alkyl group), or a lower alkyl group. Preferred nitrogen-containing 5- to 6-membered heterocyclic group or nitrogen-containing 5- to 6-membered heterocyclic group-substituted lower alkyl group, the other being a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group Or a cyclo-lower alkylcarbonyl group, R ²³ represents the formula:

R ^32B represents a lower alkoxy group, R ^33B represents a lower alkyl group or a lower alkoxy group, and R ^34B represents a lower alkyl group]
The compound shown by these is mention | raise | lifted.

Among the compounds [I] of the present invention, more preferred compounds include, for example:
(1) In the general formula [IA],
One of R ^11A and R ^{12A is} a C _1-4 alkyl group such as an isopropyl group or a tert-butyl group and the other is a C such as a hydroxy-C _1-4 alkyl group such as a hydroxyethyl group or a methoxyethyl group. _{A 1-4} alkoxy-C _1-4 alkyl group, or they are bonded to each other to form a nitrogen-containing 6-membered heterocyclic group such as a piperidyl group together with the adjacent nitrogen atom, and R ^30A is a fluorine atom, R ^31A is a trifluoro C _1-4 alkyl group such as a trifluoromethyl group, and R ^33A is a di C _1-4 alkyl-amino group such as a dimethylamino group or a C _2-5 such as an acetyl group or a propionyl group. alkanoyl ^{group, R 36A} is a methyl group, an ethyl group, such as _{C 1-4} alkyl groups such as ^{propyl, R 37A} is an acetyl group, a propionyl group Compounds as _{C 2-5} alkanoyl ^{group, R 38A} is a methoxy group, an ethoxy group, such as _{C 1-4} alkoxy group and propyl group;
(2) In the general formula [IB],
i) One of R ^13A and R ^{14A is} a C _1-4 alkyl group such as a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or a C _1-4 alkyl substituted nitrogen-containing 6-membered complex such as a methyl piperidyl group. A cyclic group, the other being a C _1-4 alkyl group such as an isopropyl group or a tert-butyl group, a hydroxy-C _1-4 alkyl group such as a hydroxyethyl group, or a C _1-4 alkoxy such as a methoxyethyl group -C _1-4 alkyl group, R ^32B is a C _1-4 alkoxy group such as methoxy group, ethoxy group, propyloxy group, etc., and R ^33B is C such as methyl group, ethyl group, propyl group or tert-butyl group. _1-4 alkyl group or a methoxy group, such as _{C 1-4} alkoxy group such as ethoxy ^{group, R 34B} is a methyl group, an ethyl group, Pro Compounds which are such _{C 1-4} alkyl groups such as Le group or tert- butyl group; or ⁱⁱ⁾ such one of ^{R 13A} and ^{R 14A} are as dimethyl aminoethyl group or a diisopropylamino ethyl di _{(C 1-4} alkyl ) A nitrogen-containing 5-membered heterocyclic group-substituted C _1-4 alkyl group such as amino-C _1-4 alkyl group or pyrrolidinylethyl group, and the other is a C _2-5 alkanoyl group such as acetyl group or cyclo C _3-6 cycloalkyl-carbonyl group such as propylcarbonyl group, R ^32B is C _1-4 alkoxy group such as methoxy group, ethoxy group, propyloxy group, etc., and R ^33B is methyl group, ethyl group, propyl group or such _{C 1-4} alkyl group or a methoxy group such as a tert- butyl group, such as _{C 1,} such as an ethoxy group, a propyloxy group _-4 alkoxy group, a compound wherein R ^34B is a C _1-4 alkyl group such as a methyl group, an ethyl group, a propyl group or a tert-butyl group;
Etc.

Among the compounds [I] of the present invention, particularly preferred compounds are
4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1-[(6-propionylpyridin-2-yl) methyl] -1H-pyrazolo [3,4 -D] pyrimidine;
4- [4-[[trans-4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] cyclohexyl] carbonyl] piperazin-1-yl] -1- (1-propionyl Piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine 1-[(3-methoxycyclohexyl) methyl] -4- [4-[[trans-4-[[N- (2-methoxyethyl) ) -N- (tert-butyl) amino] methyl] cyclohexyl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine 1- (2-oxo-1-propyl-1,2-dihydropyridine -3-yl) -4- [4-[[trans-4-[[N-tert-butyl- (2-methoxyethyl) amino] methyl] cyclohexyl] carbonyl] pipe 1-yl]-1H-pyrazolo [3,4-d] pyrimidine;
1- (2-oxo-1-propyl-1,2-dihydropyridin-3-yl) -4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1H- Pyrazolo [3,4-d] pyrimidine;
1- [2-Fluoro-3- (trifluoromethyl) benzyl] -4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1H-pyrazolo [3 4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl] piperidin-1-yl] carbonyl] piperazine-1- Yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[[(2-Propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl ] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (cyclopropylcarbonyl) -N- [2- (dimethylamino) ethyl] amino] methyl] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (cyclopropylcarbonyl) -N- [2- (diisopropylamino) ethyl] amino] methyl] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl] piperidin-1-yl ] Carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] piperazine- 1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1- (3-Ethoxybenzyl) -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3 4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] piperazin-1-yl]- 1H-pyrazolo [3,4-d] pyrimidine;
1-[(2-propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(2-propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazine -1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-hydroxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-hydroxyethyl) -N-isopropylamino] methyl] piperidin-1-yl] carbonyl Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4- [N- (2-hydroxyethyl) -N-isopropylamino) methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
Or a pharmacologically acceptable salt thereof.

When the target compound [I] of the present invention has an asymmetric carbon atom on the substituent in A and / or R ² , a plurality of stereoisomers based on the asymmetric carbon atom (diastereoisomers, optical isomerism) The present invention includes any one of these stereoisomers or a mixture thereof.

  Since the target compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits a superior antagonistic action against apamin in a competitive binding test with apamin known as an SK channel blocker, SK channel blocking Useful as a medicine. Therefore, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for the prevention / treatment of diseases associated with SK channels, such as constipation and irritable bowel syndrome, postoperative ileus, reflux esophagitis Gastrointestinal motility dysfunction, learning and memory impairment, emotional disorder, Alzheimer's dementia, depression, central diseases such as Parkinson's disease, myotonic dystrophy, and sleep apnea Conceivable.

  In addition, the target compound [I] of the present invention is characterized by low toxicity and high safety as a medicine.

  The object compound [I] of the present invention can be used for pharmaceutical use either in a free form or in the form of a pharmacologically acceptable salt thereof. Examples of pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone. And organic acid salts such as acid salts, benzenesulfonate, tosylate and maleate. In addition, when it has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt) can be used.

  The object compound [I] or a salt thereof, or a synthetic intermediate [II] or a salt thereof of the present invention includes any of its internal salts and adducts, solvates or hydrates thereof, and the like.

  The object compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can also be administered into tablets, granules, capsules, powders, injections, inhalants. It can be used as a conventional pharmaceutical preparation such as

  The dose of the object compound [I] or a pharmaceutically acceptable salt thereof of the present invention varies depending on the administration method, patient age, body weight, and condition, but usually about 0 per day for an injection. 0.001 to 1 mg / kg, especially about 0.001 to 0.1 mg / kg, ordinarily about 0.001 to 100 mg / kg per day, especially about 0.01 to 10 mg / kg It is preferable to do this.

  According to the present invention, the pyrazolopyrimidine compound represented by the general formula [I] can be produced by the following method, but is not limited thereto.

(Method A)
Among the compounds [I] of the present invention, the general formula [Id]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the general formula [II]:

[Wherein the symbols have the same meaning as described above. ]
Or a salt thereof and a general formula [III]:

[Wherein R ³ represents a hydrogen atom, a lower alkyl group or a benzyl group, and other symbols have the same meaning as described above. ]
It can manufacture by making it react with the carboxylic acid compound or its salt shown by these.

When R ³ is a hydrogen atom, this reaction can be carried out in a solvent in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1, Examples include 2-dimethoxyethane. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), Diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbonylditriazole, N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (PS) -Carbodiimide), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), hexafluorophosphate 2- (7-azabenzo) Triazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), hexafluorophosphate 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetra Methyluronium (HBTU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate ( TBTU), chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (ACTU) and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), penta Examples include fluorophenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene (PS-HOBt), N- (methylpolystyrene) -4- (methylamino) pyridine (PS-DMAP), and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), and the like.

  In this reaction, the amount of compound [II] used can be 0.3 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to compound [III]. The amount of the condensing agent to be used can be 1 to 10 equivalents, preferably 1.5 to 4 equivalents, relative to compound [IIa] or [III]. The amount of the base to be used can be 1 to 10 equivalents, preferably 2 to 4 equivalents, relative to compound [II] or [III]. The amount of the activator to be used can be 1 to 10 equivalents, preferably 1.5 to 4 equivalents, relative to compound [II] or [III]. This reaction can be carried out at -20 to 80 ° C, preferably 0 to 30 ° C.

In the general formula [III], when R ³ is a hydrogen atom, the compound is converted to a reactive derivative such as a corresponding acid halide or mixed acid anhydride, and then the reactive derivative is converted in the presence of the base. Compound [I] can also be produced by reacting with compound [II] in a solvent or without solvent.

Further, in the general formula [III], when R ³ is a lower alkyl group or a benzyl group, this reaction is carried out by subjecting the ester compound [III] to conventional hydrolysis, acid decomposition with hydrochloric acid, formic acid, trifluoroacetic acid or the like. Alternatively, after conversion to the corresponding carboxylic acid compound by a reduction reaction, the carboxylic acid compound and compound [II] can be treated in the same manner as described above.

Furthermore, in the general formula [III], when R ³ is a lower alkyl group or a benzyl group, this reaction is carried out by directly reacting compound [II] and compound [III] in the presence of a base in a solvent or without solvent. It can be carried out by reacting. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, methanol, Examples thereof include ethanol and isopropanol. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), dimethylaminopyridine (DMAP), potassium carbonate, sodium carbonate, carbonate Examples thereof include sodium hydrogen.

  In this reaction, the amount of compound [III] used can be 0.3 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to compound [II]. The amount of the base to be used can be 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound [II] or [III]. This reaction can be carried out at 25 to 150 ° C, preferably 60 to 100 ° C.

(Method B)
Among the compounds [I] of the present invention, the general formula [Ia]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by general formula [IV]:

[Wherein W ¹ represents a reactive residue, and other symbols have the same meaning as described above. ]
And a compound represented by the general formula [V]:

[Wherein the symbols have the same meaning as described above. ]
Or the compound [II] and the general formula [VI]:

[Wherein the symbols have the same meaning as described above. ]
It can also manufacture by making the compound shown by react.

  The reaction for obtaining the compound [Ia] from the compounds [IV] and [V] or the compounds [II] and [VI] can be carried out in a solvent in the presence of a base. Any solvent may be used as long as it does not affect the reaction. For example, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and the like. The amount of compound [V] or [II] to be used may be 0.8 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound [IV] or [VI]. The usage-amount of a base should just be 1-4 equivalent with respect to compound [IV] or [V] or compound [II] or [VI], Preferably it is 2-3 equivalent. This reaction can be carried out at 25 to 150 ° C, preferably 60 to 120 ° C.

  Compound [IV] is compound [II] and general formula [VII]:

(Wherein, ^{W 2} is a reactive residue, ^{W 1} has the same meaning as defined)
The compound [VI] can be produced by reacting the compound [V] with the above compound [VII] (the phosgene, phosgene precursor or phosgene equivalent, etc.). Can be manufactured. In the compound [VII], examples of the reactive residue represented by W ¹ and W ² include a halogen atom, a phenoxy group, a p-nitrophenoxy group, a lower alkoxy group, or a nitrogen-containing aromatic heteromonocyclic group. Can be mentioned.

  The reaction for obtaining the compound [IV] or [VI] can be carried out in a solvent in the presence of a base. Any solvent may be used as long as it does not affect the reaction. For example, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and the like. Examples of the phosgene precursor include triphosgene and diphosgene (phosgene dimer). Examples of the phosgene equivalent include p-nitrophenyl chloroformate, 1,1′-carbonyldiimidazole, phenyl chloroformate, and diphenyl carbonate. Diethyl carbonate, N, N′-disuccinimidyl carbonate, dipyridin-2-yl carbonate and the like. The amount of compound [VII] to be used may be 0.2 to 4 equivalents, preferably 0.4 to 2 equivalents, relative to compound [II] or [V]. The usage-amount of a base should just be 3-6 equivalent with respect to compound [II] or [V], Preferably it is 3-4 equivalent. This reaction can be carried out at -4 to 60 ° C, preferably 0 to 30 ° C.

  In this method, compound [Ia] can also be produced by continuously carrying out each reaction in the same reaction vessel without isolating compound [IV] or [VI]. is there.

  The target compound [I] of the present invention can also be produced by converting the substituent on A of the compound obtained as described above into another target substituent. Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as in (Method a) to (Method d).

(Method a)
The target compound [I] of the present invention having a group containing a lower alkoxy group as a substituent on A includes, for example, (1) the compound of the present invention having a group containing a hydroxyl group as a substituent on A and the corresponding substituent. Or (2) a compound of the present invention having a group containing a hydroxyl group as a substituent on A, in the presence of a base (for example, sodium hydride, potassium carbonate), or It is obtained by reacting the corresponding lower alkanol in a suitable solvent in the presence of a condensing agent (eg, a trisubstituted phosphine such as triphenylphosphine and a dilower alkyl azodicarboxylate such as diisopropyl azodicarboxylate). be able to.

(Method b)
The compound [I] of the present invention having a group containing a lower alkylamino group as a substituent on A corresponds to the compound of the present invention having a group containing a primary or secondary amino group as a substituent on A. It can be obtained by reacting a lower alkyl halide with an appropriate solvent in the presence of a base, or reacting a corresponding lower aldehyde with an appropriate solvent in the presence of a reducing agent.

(Method c)
Compound [I] of the present invention having a group containing an acylamino group such as a lower alkanoylamino group as a substituent on A, that is, the general formula [Ib]:

[Wherein A ¹ represents formula (a1):

Or a group represented by formula (b1):

R ^a is a hydrogen atom, a di-lower alkylamino lower alkyl group or a nitrogen-containing heterocyclic group-substituted lower alkyl group, R ^b is a lower alkyl group, a cyclo lower alkyl group or a lower alkenyl group, and n is 0 or 1 is represented. ]
Is a compound [I] of the present invention having a group containing a primary or secondary amino group as a substituent on A, that is, the general formula [Ic]:

[Wherein A ² represents formula (a2):

Or a group represented by formula (b2):

R ^a represents a hydrogen atom, a di-lower alkylamino lower alkyl group or a nitrogen-containing heterocyclic group-substituted lower alkyl group, and n represents 0 or 1. ]
And a compound of the general formula [1]:
R ^b —COOH [1]
[Wherein the symbols have the same meaning as described above. ]
Or a reactive derivative thereof (for example, an acid halide such as acid chloride) can be obtained in the same manner as in the above-mentioned method A.

Examples of the nitrogen-containing heterocyclic group in R ^a include saturated or unsaturated nitrogen-containing 5- to 6-membered heterocyclic groups such as a pyrrolidinyl group and piperidyl group.

(Method d)
As a substituent on A:

(Wherein m represents an integer of 4, 5 or 6)
The object compound [I] of the present invention having a group containing a nitrogen-containing heterocyclic group represented by the formula [VIII] and a compound of the present invention having a group containing an amino group as a substituent on A:
_{^{X 1 - (CH 2) m}} -X 2 [VIII]
(Wherein, X ¹ and X ² are halogen atoms, and other symbols have the same meaning as described above.)
It can obtain by making it react with the compound shown by presence of a base in a suitable solvent.

  In carrying out the above methods A to B and a to d, when a raw material compound or each intermediate has a functional group such as an amino group, an appropriate protecting group is introduced into the functional group by a conventional method of synthetic chemistry, Accordingly, those protecting groups can be appropriately removed.

Compound [II], which is a synthetic intermediate of target compound [I] of the present invention, is shown in the following reaction process diagram, for example:
(1) Compound [IX] is directly reacted with compound [X], or compound [IX] is treated with a halogenating agent to convert to compound [IX-A], and then compound [IX-A] Compound [II-A] is produced by reacting the compound [X] with the compound [II-A], and then (2) Compound [II-B] is produced by reacting the compound [II-A] with the compound [XI]. Furthermore, (3) the compound [II-B] can be prepared by removing the amino-protecting group G by a conventional method.

(Wherein, G represents a protecting group of amino group, X ^a is a halogen atom, X ³ represents a hydroxyl group or a leaving group, and other symbols have the same meaning.)
The reaction of compound [IX] and compound [X] can be carried out in the presence or absence of an activator, in the presence or absence of an additive, in a solvent or without solvent. Any solvent may be used as long as it does not affect the reaction. Examples thereof include xylene and chloroform. Examples of the activator include hexamethyldisilazane, N, O-bistrimethylsilylacetamide, chlorotrimethylsilane, and the like. Examples of the additive include ammonium sulfate, chlorotrimethylsilane, triethylamine hydrochloride, pyridine hydrochloride, triethylamine and the like.

  The reaction for treating compound [IX] with a halogenating agent to obtain compound [IX-A] can be carried out in the presence of a base in the presence of a solvent or without solvent. Any solvent that does not affect the reaction may be used, and examples thereof include tetrahydrofuran, 1,4-dioxane, chloroform, dichloromethane, 1,2-dichloroethane, toluene, xylene and the like. The amount of the halogenating agent used can be 1 to 40 equivalents, preferably 2 to 20 equivalents, relative to compound [IX], and the amount of base (diisopropylethylamine, triethylamine, potassium carbonate, etc.) used can be The amount can be 1 to 10 equivalents, preferably 1 to 3 equivalents with respect to [IX]. This reaction can be carried out at 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.

  The reaction of compound [IX-A] and compound [X] can be carried out in the presence of a base in a solvent or without a solvent. As the solvent and base, those exemplified in the reaction for obtaining compound [IX-A] from compound [IX] can be appropriately selected and used.

  The reaction of compound [IX] with a halogenating agent, the reaction with compound [IX-A], and the reaction of compound [IX-A] with compound [X] isolates compound [IX-A]. It is also possible to carry out continuously in the same reaction vessel.

The reaction of compound [II-A] and compound [XII] can be carried out in a suitable solvent in the presence of a dehydrating agent or a base. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methylpyrrolidinone, tetrahydrofuran, Examples include 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene and the like. When X ³ is a hydroxyl group, examples of the dehydrating agent include a combination of a di-lower alkyl azodicarboxylate such as diisopropyl azodicarboxylate and a trisubstituted phosphine such as triphenylphosphine, or cyanomethylene tri-n-butylphosphorane. Phosphorane such as When X ³ is a leaving group such as a halogen group, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, the base may be an alkali metal hydroxide such as lithium hydroxide, an alkali metal hydride, or an alkali metal carbonate. , Alkali metal lower alkoxide, lithium diisopropylamide (LDA), and the like.

  Further, in the above compound [II-B], the amino-protecting group G includes, for example, an aryl lower alkyl group such as a benzyl group, a lower alkoxycarbonyl group such as an ethoxycarbonyl group, a tert-butoxycarbonyl group, and the like, benzyloxy An aryl lower alkyloxycarbonyl group such as a carbonyl group and the like can be mentioned, and removal of the protective group can be carried out by a conventional method.

  The raw material compound [III] in the present invention is a known compound per se, or can be produced using a conventional method of synthetic chemistry as follows. That is, the compound [III] has the general formula:

(In the formula, the symbols have the same meaning as described above.)
A compound represented by the general formula [XV]:
(R ¹¹ ) (R ¹² ) NH [XV]
(In the formula, the symbols have the same meaning as described above.)
Or a reductive amination reaction in the presence of a compound represented by the general formula [XVI]:

(In the formula, the symbols have the same meaning as described above.)
It can manufacture by reducing the amide group of the obtained product after making the carboxylic acid compound shown by and compound [XV] react.

In addition, the compound [V] is represented by, for example, the general formula [XVII]:

[Wherein, R represents a carboxyl group, a formyl group or an oxo group, and other symbols have the same meaning as described above. ]
Can be produced by subjecting the compound represented by the above formula to amidation and reduction reaction or reductive amination reaction in the presence of compound [XV].

It can also be produced by further converting the substituents (R ¹¹ and / or R ¹² ) of the compounds [III] and [V] obtained as described above into other desired substituents. it can. Such a substituent conversion method may be appropriately selected according to the type of the target substituent. For example, an N-alkylation reaction, an N-acylation reaction, an O-alkylation reaction, or the like is applied. Can do.

  The desired compound [I] of the present invention obtained by the above-mentioned methods [A] to [B] and [a] to [d] is converted to a pharmacologically acceptable salt, if desired. You can also. Conversion to a pharmacologically acceptable salt may be performed according to methods known to those skilled in the art.

  In the present invention, examples of lower alkyl or lower alkoxy include linear or branched alkoxy groups having 1 to 6 carbon atoms, preferably those having 1 to 4 carbon atoms. As a lower alkylene group, a C1-C6 linear or branched alkylene group is mention | raise | lifted, Preferably a C1-C4 thing is mention | raise | lifted. Examples of lower alkanoyl include linear or branched alkanoyl groups having 2 to 7 carbon atoms, preferably 2 to 5 carbon atoms, and examples of cyclo lower alkyl include cycloalkyl groups having 3 to 8 carbon atoms, preferably Includes those having 3 to 6 carbon atoms. Lower alkenyl includes alkenyl groups having 2 to 8 carbon atoms, preferably those having 2 to 4 carbon atoms. Furthermore, as a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom is mentioned. Examples of lower alkenoyl include linear or branched alkenoyl groups having 3 to 8 carbon atoms, preferably those having 3 to 6 carbon atoms.

  Specific examples (Examples) of the target compound of the present invention synthesized by each of the above exemplified methods are shown below, but the present invention is not limited thereby.

Example 1
(1) methyl trans-4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] cyclohexanecarboxylate (compound obtained in Reference Example 1 described later) 43 mg in 1 mL of ethanol To the mixture, 100 μL of 2N aqueous sodium hydroxide solution is added and stirred at 60 ° C. for 2 hours. The reaction mixture is cooled to room temperature, 50 μL of 5N hydrochloric acid is added, and the mixture is concentrated. To the residue was added 1 mL of chloroform, 34 mg of 1-[(6-dimethylaminopyridin-2-yl) methyl] -4-piperazin-1-yl-1H-pyrazolo [3,4-d] pyrimidine trihydrochloride, 1-hydroxy Add 0.5 mL of 0.5 M dimethylformamide solution of benzotriazole, 84 μL of triethylamine, and 0.4 mL of 0.5 M chloroform solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and stir at room temperature for 12 hours. To do. The reaction solution is diluted with 2 mL of chloroform, and 3 mL of saturated aqueous sodium hydrogen carbonate solution is added and stirred. The organic layer was separated and concentrated, and the resulting crude product was purified by high-performance liquid chromatography (Waters XTerra PrepMS C18 column, 10 mM ammonium carbonate / methanol = 1: 1 to 5:95). (6-Dimethylaminopyridin-2-yl) methyl] -4- [4- [trans-4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] cyclohexyl] Carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine is obtained.
(2) 1N hydrochloric acid is added to an ethanol (1 mL) solution of the compound obtained in (1) above, followed by concentration. The residue was dissolved in water and lyophilized to give 1-[(6-dimethylaminopyridin-2-yl) methyl] -4- [4- [trans-4-[[N- (2-methoxyethyl)]. -N- (tert-butyl) amino] methyl] cyclohexyl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (40 mg, 64% yield) as an amorphous solid Get as.
MS (APCI) m / z; 592 [M + H] ^< +>.

Example 2
(1) Trans-4- (piperidin-1-yl) cyclohexanecarboxylic acid / hydrochloride (compound obtained in Reference Example 2 described later) 30 mg, chloroform 1 mL, 1-[(6-dimethylaminopyridin-2-yl) methyl ] -4-piperazin-1-yl-1H-pyrazolo [3,4-d] pyrimidine trihydrochloride 34 mg, 1-hydroxybenzotriazole 0.5 M dimethylformamide solution 0.3 mL, triethylamine 84 μL, 1-ethyl- 0.4 mL of a 0.5M chloroform solution of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride is sequentially added and stirred at room temperature for 12 hours. The reaction solution is diluted with 2 mL of chloroform, and 1.5 mL of saturated aqueous sodium hydrogen carbonate solution and 1.5 mL of water are added and stirred. The organic layer was separated and concentrated, and the resulting crude product was purified by high performance liquid chromatography (XTerra PrepMS C18 column manufactured by Waters, 10 mM ammonium carbonate / methanol = 1: 1 to 5:95) to give 1-[( 6-dimethylaminopyridin-2-yl) methyl] -4- [4-[[trans-4- (piperidin-1-yl) cyclohexyl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3 4-d] pyrimidine is obtained.
(2) The compound obtained in (1) is treated in the same manner as in Example 1 (2) to give 1-[(6-dimethylaminopyridin-2-yl) methyl] -4- [4-[[[ Trans-4- (piperidin-1-yl) cyclohexyl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (43 mg, 76% yield) is obtained as an amorphous solid. .
MS (APCI) m / z; 532 [M + H] ^< +>.

Example 3
(1) 1- (3-Ethoxybenzyl) -4-piperazin-1-yl-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride 60 mg in methylene chloride 1.2 mL solution at 0 ° C. with N, N -Add 85 μL of diisopropylethylamine and 49 mg of p-nitrophenyl chloroformate and stir at room temperature for 2 hours 30 minutes. After diluting the reaction solution with 1 mL of chloroform, 1.5 mL of saturated aqueous sodium hydrogen carbonate solution is added and stirred. The organic layer is separated, the aqueous layer is extracted with chloroform, and the combined organic layer is dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel flash column chromatography (n-hexane / ethyl acetate = 9: 1 to 0:10) to give 1- (3-ethoxybenzyl) -4- [4- [(4-Nitrophenoxy) carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine (72 mg, 100% yield) is obtained as an amorphous solid.
MS (APCI) m / z; 504 (M + H) ^<+> .
(2) To a solution of 35 mg of the compound obtained in (1) above in 0.4 mL of N, N-dimethylacetamide at room temperature, 61 μL of N, N-diisopropylethylamine and 4-[[N- (2-methoxyethyl) -N- ( Add 0.42 mL of a 0.5 M dimethylacetamide solution of tert-butyl) amino] methyl] piperidine (a compound obtained in Reference Example 1 (4) described later), and stir at 85 ° C. for 2 days. The reaction solution is cooled to room temperature, diluted with 2 mL of chloroform, added with 1.5 mL of saturated aqueous sodium hydrogen carbonate solution and 1.5 mL of water, and stirred. The organic layer was separated and concentrated, and the resulting crude product was purified by high performance liquid chromatography (XTerra PrepMS C18 column manufactured by Waters, 10 mM ammonium carbonate / methanol = 1: 1 to 5:95). -Ethoxybenzyl) -4- [4-[[4- [N- (2-methoxyethyl) -N- (tert-butyl) aminomethyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H -Pyrazolo [3,4-d] pyrimidine is obtained.
(3) The compound obtained in (2) above is treated in the same manner as in Example 1 (2) to give 1- (3-ethoxybenzyl) -4- [4-[[4- [N- (2- Methoxyethyl) -N- (tert-butyl) aminomethyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (30 mg, 73% yield) Is obtained as an amorphous solid.
MS (APCI) m / z; 593 [M + H] ^< +>.

Examples 4-62
The corresponding raw material compounds are treated in the same manner as in any of Examples 1 to 3 to give the compounds listed in Tables 1 to 16 below.

Reference example 1
(1) 254 mL of thionyl chloride is added dropwise to 1500 mL of methanol over about 1 hour under cooling at −30 ° C., and the mixture is stirred at room temperature for 0.5 hour. Add 500.0 g of trans-cyclohexane-1,4-dicarboxylic acid to the mixture and stir at room temperature for 17 hours. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is separated, dried over sodium sulfate, and the solvent is concentrated under reduced pressure. The resulting residue is crystallized with hexane, and the crystals are collected by filtration and dried to obtain 545.0 g of dimethyl trans-cyclohexane-1,4-dicarboxylate.
MS (APCI) m / z: 201 [M + H] ^< +>.
(2) A mixed solution of 149 g of 28% sodium methoxide-methanol solution and 13.2 g of water was added to 1500 mL of tetrahydrofuran in 150.0 g of dimethyl trans-cyclohexane-1,4-dicarboxylate obtained in (1) above under ice-cooling. After dropping, the mixture is stirred at room temperature for 3.5 hours. Pour 1500 mL of hexane into the reaction solution, and collect the precipitate by filtration. The precipitate is added to a mixed solution of 50 mL of concentrated hydrochloric acid, 450 mL of water and 1000 mL of chloroform under ice cooling, and stirred at room temperature for 20 minutes. The organic layer is separated, the aqueous layer is extracted again with chloroform, and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is crystallized with hexane, and the precipitated crystals are collected by filtration and dried to obtain 106.0 g of monomethyl trans-cyclohexane-1,4-dicarboxylate.
MS (ESI) m / z: 185 [M-H] -.
(3) To a solution of 14.3 g of monomethyl trans-cyclohexane-1,4-dicarboxylate in 78 mL of tetrahydrofuran is added dropwise 100 mL of a 1.0 M borane / tetrahydrofuran complex tetrahydrofuran solution at −50 ° C. in an argon atmosphere over 1 hour. The mixture is stirred at −10 ° C. for 1 hour. Under ice-cooling, 160 mL of water and 160 mL of saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the mixture is extracted 4 times with 160 mL of ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column flash chromatography (chloroform / methanol = 20: 1) to give methyl trans-4- (hydroxymethyl) cyclohexanecarboxylate (13.25 g, yield 100%) as an oil. obtain.
MS (APCI) m / z; 173 [M + H] ^< +>.
(4) Under an argon atmosphere, dimethyl sulfoxide (4.55 g) in methylene chloride (5 mL) is dropped at −60 ° C. into 4.48 mL of methylene chloride (50 mL), and the mixture is stirred at the same temperature for 15 minutes. A solution of 5.9 g of the compound obtained in (3) above in 30 mL of methylene chloride is added dropwise to the solution over 30 minutes, and the mixture is stirred at the same temperature for 1 hour. After dropwise addition of 16.7 mL of triethylamine to the reaction solution at −60 ° C., the mixture is stirred at the same temperature for 30 minutes and further stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with chloroform, washed successively with water, 5% aqueous citric acid solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl trans-4-formylcyclohexanecarboxylate (5 .32 g, 91% yield) is obtained as an oil.
MS (APCI) m / z: 171 [M + H] ^< +>.
(5) To a mixed solution of 2.78 g of the compound obtained in the above (4) and 4 g of (2-methoxyethyl) (tert-butyl) amine in 30 mL of chloroform, 5.19 g of sodium triacetoxyborohydride and 1.1 of acetic acid were added under ice cooling. Add 87 mL sequentially and stir at room temperature for 2 days. The reaction solution is neutralized with 200 mL of saturated aqueous sodium hydrogen carbonate solution, and then stirred overnight at room temperature. The organic layer is separated and the aqueous layer is extracted twice with chloroform. The combined organic layers are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 40 g of a cation exchange resin (Amberlyst 15 dry, 4.7 meq / g) was added to a 50 mL chloroform solution of the resulting crude product and allowed to stand for 2 hours. The mixture was filtered through a glass filter, and the resin was methanol / methylene chloride = Wash 1: 1 (200 mL). The product is eluted from the resin with a 2N ammonia methanol solution, and the eluate is concentrated under reduced pressure. The obtained oil was purified by silica gel column flash chromatography (chloroform / ethyl acetate = 1: 1 to 1: 3) to give methyl trans-[(2-dimethylaminoethylamino) methyl] cyclohexanecarboxylate (1. 92 g, 42% yield) is obtained as a yellow oil.
MS (APCI) m / z: 286 [M + H] ^< +>.

Reference example 2
(1) 155 g of diphenyl phosphate azide and 78.6 mL of triethylamine were added to 1000 mL of tert-butanol in 100.0 g of monomethyl trans-cyclohexane-1,4-dicarboxylate (compound obtained in the above Reference Example 1 (2)), Heat at about 60 ° C. for 1 hour and heat at reflux for an additional 17 hours. The reaction mixture is cooled, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. 750 mL of water is added to a solution of the obtained residue in 250 mL of methanol, and the mixture is stirred for 0.5 hour under ice cooling. The precipitate is collected by filtration, washed successively with 1000 mL of water-methanol (3: 1) and hexane, and then dried to obtain 117.0 g of methyl trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylate.
MS (APCI) m / z: 275 [M + NH 4] +.
(2) To a solution of the compound 234.0 g obtained in (1) above in 500 mL of dioxane, 500 mL of 4N hydrochloric acid dioxane solution is added and stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure, the resulting residue is suspended in diethyl ether, and the precipitate is collected by filtration to obtain 121.9 g of trans-4-aminocyclohexanecarboxylic acid methyl hydrochloride.
MS (APCI) m / z: 158 [M + H] ^< +>.
(3) A suspension of 10.0 g of the compound obtained in the above (2), 20.1 g of 1,5-diiodopentane and 16.4 g of sodium carbonate in 300 mL of tetrahydrofuran / 60 mL of N-dimethylacetamide was added at 70 ° C. Stir for hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in ethyl acetate-water, and the organic layer is separated. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by NH silica gel flash column chromatography (elution solvent: ethyl acetate / n-hexane = 0: 10-5: 1), and 10.2 g of methyl trans-4- (1-piperidyl) cyclohexanecarboxylate. Get.
MS (APCI) m / z: 226 [M + H] ^< +>.
(4) 70 mL of 2N hydrochloric acid is added to a solution of 10.2 g of the compound obtained in (3) in 130 mL of dioxane, and the mixture is stirred at 105 ° C. for 3 hours while distilling off methanol. The reaction mixture was concentrated under reduced pressure, the resulting residue was suspended in diethyl ether, and the precipitate was collected by filtration to give trans-4- (1-piperidyl) cyclohexanecarboxylic acid / hydrochloride (11.8 g, yield 100). %) As a pale yellow solid.
MS (APCI) m / z: 212 [M + H] ^< +>.

Reference example 3
(1) 4- (carboxyl) -1- (tert-butoxycarbonyl) piperidine (2.0 g) in methylene chloride (26 mL), N, N-diisopropylethylamine (3.0 mL), hexafluorophosphate bromotrispyrrolidinophosphonium (PyBroP) 6 .1 g and (2-methoxyethyl) (tert-butyl) amine 1.6 g are sequentially added and stirred at room temperature for 4 days. After diluting the reaction solution with chloroform, a saturated aqueous sodium hydrogen carbonate solution is added and stirred, and the organic layer is separated. The aqueous layer is extracted again with chloroform, and the combined organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel flash column chromatography (n-hexane / ethyl acetate = 10: 0 to 70:30) to give 4- [tert-butyl (2-methoxyethyl). Carbamoyl] -1- (tert-butoxycarbonyl) piperidine (887 mg, 30% yield) is obtained as an amorphous solid.
MS (APCI) m / z; 343 [M + H] ^< +>.
(2) 6.7 mL of borane-tetrahydrofuran complex 1M tetrahydrofuran solution is added to 11 mL tetrahydrofuran solution of 1.2 g of the compound obtained in (1) above, and the mixture is heated to reflux for 7 hours. The reaction mixture is cooled to room temperature, 10% hydrochloric acid is added, and the mixture is stirred at 65 ° C. for 40 minutes and concentrated under reduced pressure. After treating the resulting residue with chloroform and water, potassium carbonate is added with stirring until the pH reaches 10 or more, and extracted twice with chloroform. The combined chloroform layers are dried over anhydrous sodium sulfate, filtered and concentrated. To the resulting residue, n-hexane / ethyl acetate = 8: 1 was added and stirred. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-[[N- (2-methoxyethyl) -N. -(Tert-Butyl) amino] methyl] piperidine (573 mg, 70% yield) is obtained as a yellow oil.
MS (APCI) m / z; 229 [M + H] ^< +>.

Reference example 4
(1) To a mixed solution of 1.0 g of 4-formyl-1- (tert-butoxycarbonyl) piperidine and 766 μL of 2-dimethylaminoethylamine in 12 mL of chloroform was sequentially added 2.0 g of sodium triacetoxyborohydride and 537 μL of acetic acid under ice cooling. Stir at room temperature for 1 day. The reaction solution is diluted with chloroform, neutralized (pH 10) by adding saturated aqueous sodium hydrogen carbonate solution and powdered potassium carbonate with stirring, and extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to give 4-[[[2- (dimethylamino) ethyl] amino] methyl] -1- (tert-butoxycarbonyl) piperidine (3 g) as a colorless oil. obtain.
(2) 6 g of N- (methylpolystyrene) -4- (methylamino) pyridine (PS-DMAP, 1.57 mmol / g), 10 ml of acetyl chloride in a 10 mL solution of the crude product obtained in (1) above in methylene chloride. Add 7 mL and shake at room temperature for 18 hours. After removing PS-DMAP and insoluble matter by filtration, the filtrate was concentrated under reduced pressure to give 4-[[N-acetyl-N- [2- (dimethylamino) ethyl] amino] methyl] -1- (tert-butoxy. Carbonyl) piperidine (1.3 g) is obtained as a colorless solid.
(3) To a solution of 1.3 g of the crude product obtained in (2) above in 5.8 mL of dioxane, add 5.8 mL of 4N dioxane solution in hydrochloric acid and stir at room temperature for 20 hours. The reaction mixture is diluted with dry ether to insolubilize the desired product as an oil. The supernatant is removed, and the residue is washed with dry ether and then dried under reduced pressure. The residue was dissolved in water and lyophilized to give 4-[[N-acetyl-N- [2- (dimethylamino) ethyl] amino] methyl] piperidine dihydrochloride (918 mg, 65% yield) as amorphous. Obtain as a solid.
MS (APCI) m / z; 228 [M + H] ^< +>.

Reference Example 5
(1) A suspension of 4- (4-tert-butoxycarbonylpiperazin-1-yl) -1H-pyrazolo [3,4-d] pyrimidine, 5 g of 4-ethoxybenzyl alcohol and 8.62 g of triphenylphosphine in 50 mL of tetrahydrofuran. Under cooling with ice, 6.98 g of diisopropyl azadicarboxylate is added dropwise to the liquid and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol / 100: 1) to give 1- (3-ethoxybenzyl) -4- (4-tert-butoxycarbonylpiperazine- 1-yl) -1H-pyrazolo [3,4-d] pyrimidine (12.95 g, quantitative) is obtained as an oil.
MS (APCI) m / z; 439 [M + H] ^< +>.
(2) To a solution of the compound (12.9 g) obtained in (1) above in 28 mL of methanol is added 28 mL of 4N hydrochloric acid dioxane solution, and the mixture is stirred at room temperature for 16 hours. After adding 56 mL of ethyl acetate to the reaction solution, the precipitate was collected by filtration and washed with ethyl acetate to give 1- (3-ethoxybenzyl) -4-piperazin-1-yl-1H-pyrazolo [3,4 -D] Pyrimidine dihydrochloride (4.19 g, 62% yield) is obtained as colorless crystals.
MS (APCI) m / z; 339 [M + H] ^< +>.

Reference Example 6
(1) 812 μL of methanesulfonyl chloride and 1.46 mL of triethylamine were added to a 10 mL chloroform solution of 1.17 g of 3-hydroxymethyl-1-propyl-1H-pyridin-2-one obtained in Reference Example 33 at room temperature. Stir overnight. The reaction solution was diluted with chloroform, washed with 10% aqueous citric acid solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methanesulfonic acid (2-oxo-1-propyl-1, 2-Dihydropyridin-3-ylmethyl) ester is obtained as a crude product.
(2) To the crude product obtained in (1) above and 4- (4-tert-butoxycarbonylpiperazin-1-yl) -1H-pyrazolo [3,4-d] pyrimidine (1.94 g) in 20 mL of dimethylacetamide Add 457 mg of lithium hydroxide at room temperature and stir overnight. The reaction mixture is poured into 200 mL of ice water, extracted twice with ethyl acetate, and the extract is concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column flash chromatography (chloroform / methanol = 50: 1) to give 1- (2-oxo-1-propyl-1,2-dihydropyridin-3-ylmethyl) -4 -(4-tert-Butoxycarbonylpiperazin-1-yl) -1H-pyrazolo [3,4-d] pyrimidine (2.92 g) is obtained as a solid.
(3) A solution of 2.92 g of the compound obtained in (2) above in 2 mL of chloroform and 2 mL of trifluoroacetic acid is stirred at room temperature for 1 day. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted 3 times with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel flash column flash chromatography (chloroform / methanol / aqueous ammonia = 19: 1: 0.2) to give 1- (2-oxo-1-propyl- 1,2-Dihydropyridin-3-ylmethyl) -4-piperazin-1-yl-1H-pyrazolo [3,4-d] pyrimidine (1.23 g, total yield of 2 steps, 50%) is obtained as a pale yellow solid.
MS (APCI) m / z; 354 [M + H] ^< +>.

Reference Examples 7-18
The corresponding starting material compounds are treated in the same manner as in Reference Example 5 or Reference Example 6 (2) to give the compounds described in Tables 17-18 below.

Reference Examples 19-23
The corresponding starting material compounds are treated in the same manner as in Reference Example 1 (5) to give the compounds shown in Table 19 below.

Reference Examples 24-32
The corresponding starting material compounds are treated in the same manner as in Reference Example 3 to obtain the compounds shown in Table 20 below.

Reference Example 33
(1) To a solution of 5.5 g of 2-hydroxynicotinic acid in 50 mL of methanol and 8.0 mL of water, 5.1 g of 86% potassium hydroxide is added and heated to reflux for 20 minutes. The reaction solution is cooled to room temperature, added with 10 mL of n-propyl iodide, and heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is dissolved in 2N hydrochloric acid and extracted with chloroform (twice). The combined extracts are washed successively with 10% sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by flash chromatography on silica gel (chloroform / methanol = 97: 3) and recrystallized from n-hexane / ethyl acetate to give 2-oxo-1-propyl-1,2-dihydropyridine. -3-carboxylic acid (3.8 g, 54% yield) is obtained as crystals.
MS (ESI) m / z; 180 [MH] ^- .
(2) To a suspension of 3.22 g of the compound obtained in (1) above in 15 mL of methylene chloride, 3.1 mL of oxalyl chloride and 1 drop of dimethylformamide are added and stirred at room temperature for 4.5 hours. The reaction mixture is concentrated under reduced pressure, and the residue is azeotroped with methylene chloride and dried under reduced pressure. The obtained acid chloride is dissolved in 15 mL of acetonitrile and 15 mL of tetrahydrofuran, 2.0 g of sodium borohydride is added, and the mixture is stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred at room temperature for 3 days. The reaction solution is extracted with chloroform (twice), the extract is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude product was purified by silica gel flash column flash chromatography (chloroform / methanol = 20: 1) to give 3-hydroxymethyl-1-propyl-1H-pyridin-2-one (1.85 g, yield). 62%) is obtained as a colorless oil.
MS (APCI) m / z; 168 [M + H] ^< +>.

Reference Example 34
(1) Under an argon atmosphere, ethyl bromide was added to a 1.5 mL tetrahydrofuran solution containing 1.5 g of 2-cyano-6-methylpyridine, 2.22 g of tert-butyldimethylsilane chloride and 55 mg of copper (I) bromide at -70 ° C. 23.6 mL of magnesium 0.86M tetrahydrofuran solution is added dropwise and stirred for 10 minutes. The reaction mixture is stirred at room temperature for 2.5 hours, water is added under ice cooling, and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel flash column flash chromatography (n-hexane / ethyl acetate = 20: 1) to give 1- (6-methylpyridin-2-yl) propan-1-one (1. 24 g, 66% yield) is obtained as a red oil.
MS (APCI) m / z; 150 [M + H] ^< +>.
(2) To a solution of 950 mg of the compound obtained in (1) above in 15 mL of toluene, 2.0 mL of ethylene glycol and 125 mg of p-toluenesulfonic acid monohydrate are added and heated under reflux for 1 day (2.0 mL of ethylene glycol during the reaction). And 125 mg of p-toluenesulfonic acid monohydrate are added twice). The reaction mixture is cooled to room temperature, basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2- (2-ethyl- [1,3] dioxolan-2-yl) -6-methylpyridine (1.23 g). ) As a yellow oil.
MS (APCI) m / z; 174 [M + H] ^< +>.
(3) 1.15 g of the crude product obtained in (2) above, 2.1 g of N-bromosuccinimide and 5 mg of 2,2′-azobis (isobutyronitrile) (AIBN) in 1.0 mL of carbon tetrachloride And stirred at 110 ° C. for 15 hours. Cool the reaction to room temperature, add water and extract with ethyl acetate. The extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column flash chromatography (n-hexane / ethyl acetate = 10: 1) to give 2-bromomethyl-6- (2-ethyl- [1,3] dioxolane-2- Yl) methylpyridine (155 mg, 10% yield) is obtained as a yellow oil.
MS (APCI) m / z; 272/274 [M + H] ^< +>.

Reference Example 35
Dissolve 1.0 g of 3-piperidinemethanol in 8 mL of 10% aqueous sodium hydroxide, add dropwise 760 μL of propionyl chloride in ether (10 mL) to the solution and stir vigorously at room temperature for 3 hours. The reaction solution was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1- (3-hydroxymethylpiperidin-1-yl) propan-1-one (1.3 g, yield 87). %) As a yellow oil.
MS (APCI) m / z; 172 [M + H] ^< +>.

Reference Example 36
To a mixed solution of 1.0 g of 3-piperidinemethanol and 1.2 mL of propionaldehyde in chloroform (10 mL) are sequentially added 3.54 g of sodium triacetoxyborohydride and 1.0 mL of acetic acid under ice cooling, and the mixture is stirred at room temperature for 21 hours. The reaction solution is diluted with chloroform, and adjusted to pH 10 with a saturated aqueous solution of sodium bicarbonate with stirring. Saturate the aqueous layer with powdered potassium carbonate and extract twice with chloroform. The extract is dried over anhydrous sodium sulfate and concentrated to give (1-propylpiperidin-3-yl) methanol (1.82 g) as a crude product.
MS (APCI) m / z; 158 [M + H] ^< +>.

Reference Example 37
Under an argon atmosphere, 10 mL of a borane-dimethylsulfide complex 2.0M tetrahydrofuran solution is added dropwise to a 10 mL tetrahydrofuran solution of 2.5 g of 3-methoxycyclohexanecarboxylic acid at −78 ° C. and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3-methoxycyclohexyl) methanol (2.64 g) as a crude product.
MS (APCI) m / z; 162 [M + H] ^< +>.

The target compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent SK channel blocking action, and is associated with SK channel-related diseases (constipation, irritable bowel syndrome, postoperative ileus, Prevention and prevention of gastrointestinal motor dysfunction such as reflux esophagitis, learning and memory impairment, emotional disorder, Alzheimer's dementia, depression, central diseases such as Parkinson's disease, myotonic dystrophy, and sleep apnea Useful for treatment.

Claims (11)

Formula [I]:

[Wherein A represents formula (a):

Or a substituted cyclohexyl group represented by formula (b):

A substituted piperidyl group represented by:
R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkenoyl group, an amino lower alkyl group (this group Or an amino group part thereof may be substituted with a lower alkyl group) or a cyclo-lower alkylcarbonyl group, or both are bonded to each other at the end to form a nitrogen-containing heterocyclic group together with the adjacent nitrogen atom, R ¹³ and R ¹⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a lower alkenoyl group, a cyclo lower alkylcarbonyl group, an amino lower alkyl group (this group In which the amino group moiety may be substituted with a lower alkyl group), A nitrogen-containing heterocyclic group optionally substituted with a lower alkyl group or a nitrogen-containing heterocyclic group-substituted lower alkyl group, Q is a lower alkylene group, R ² is a formula:

R ³⁰ is a halogen atom, R ³¹ is a lower alkyl group which may be substituted with a halogen atom, R ³² , R ³³ , R ³⁴ and R ³⁵ are a lower alkyl group, a lower alkoxy group, a halogen-substituted lower group An alkoxy group, a lower alkanoyl group or an amino group (the amino group may be substituted with a lower alkyl group), R ³⁶ , R ³⁷ and R ³⁸ are a lower alkyl group, a lower alkoxy group or a lower alkanoyl group, and n is 0 Or an integer of 1 (provided that when A is a group represented by the formula (a), R ³² , R ³³ and R ³⁴ do not become a lower alkyl group or a lower alkoxy group). ]
Or a pharmacologically acceptable salt thereof. A is a substituted cyclohexyl group represented by the formula (a), one of R ¹¹ and R ¹² is a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl A di (C _1-6 alkyl) amino-C _1-6 alkyl group or a nitrogen-containing heterocyclic group-substituted C _1-6 alkyl group, the other being a C _1-6 alkyl group, a C _2-7 alkanoyl group Or a C _3-8 cycloalkyl-carbonyl group, or they are bonded to each other at the end to form a nitrogen-containing heterocyclic group together with an adjacent nitrogen atom, Q is a C _1-6 alkylene group, and R ² is formula:

R ³³ is a halogen-substituted C _1-6 alkoxy group, C _2-7 alkanoyl group or di (C _1-6 alkyl) amino group, R ³⁵ is a C _1-6 alkoxy group, and R ³⁶ is C _1. The compound according to claim 1, wherein the _-6 alkyl group, R ³⁷ is a C _2-7 alkanoyl group, and R ³⁸ is a C _1-6 alkoxy group. A is a substituted piperidyl group represented by the formula (b), one of R ¹³ and R ¹⁴ is a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, A di (C _1-6 alkyl) amino-C _1-6 alkyl group or a nitrogen-containing heterocyclic group-substituted C _1-6 alkyl group, the other being a C _1-6 alkyl group, a C _1-6 alkyl-substituted nitrogen-containing group A heterocyclic group, a C _2-7 alkanoyl group or a C _3-8 cycloalkyl-carbonyl group, Q is a C _1-6 alkylene group, and R ² is a formula:

The compound according to claim 1, wherein R ³² is a C _1-6 alkoxy group, R ³³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ³⁴ is a C _1-6 alkyl group. The compound according to claim 1, 2 or 3, wherein the nitrogen-containing heterocyclic group is a saturated or unsaturated nitrogen-containing 5- to 6-membered heterocyclic group. The compound according to claim 4, wherein Q is a methylene group. General formula [IA]:

[In the formula, one of R ^11A and R ^12A is a lower alkyl group and the other is a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, or both are bonded to each other at the end and together with an adjacent nitrogen atom Forms a 5- to 6-membered nitrogen-containing heterocyclic group, and R ²¹ represents the formula:

R ^30A is a halogen atom, R ^31A is a halogen-substituted lower alkyl group, R ^33A is an amino group or lower alkanoyl group optionally substituted with a lower alkyl group, R ^36A is a lower alkyl group, and R ^37A is A lower alkanoyl group, R ^38A represents a lower alkoxy group, and n represents an integer of 0 or 1. ]
Or a pharmaceutically acceptable salt thereof. General formula [IB]:

[In the formula, one of R ^13A and R ^14A may be substituted with a lower alkyl group, an amino lower alkyl group (the amino group portion of the group may be substituted with a lower alkyl group), or a lower alkyl group. Preferred nitrogen-containing 5- to 6-membered heterocyclic group or nitrogen-containing 5- to 6-membered heterocyclic group-substituted lower alkyl group, the other being a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group Or a cyclo-lower alkylcarbonyl group, R ²² is represented by the formula:

R ^32B represents a lower alkoxy group, R ^33B represents a lower alkyl group or a lower alkoxy group, and R ^34B represents a lower alkyl group]
Or a pharmaceutically acceptable salt thereof. One of R ^11A and R ^12A is a C _1-4 alkyl group and the other is a hydroxy-C _1-4 alkyl group or a C _1-4 alkoxy-C _1-4 alkyl group, or both are bonded to each other Forms a nitrogen-containing 6-membered heterocyclic group together with the adjacent nitrogen atom, R ^30A is a fluorine atom, R ^31A is a trifluoro C _1-4 alkyl group, R ^{33A is a} diC _1-4 alkyl-amino group or C ₂ The compound according to claim 6, wherein the _-5 alkanoyl group, R ^36A is a C _1-4 alkyl group, R ^37A is a C _2-5 alkanoyl group, and R ^38A is a C _1-4 alkoxy group. One of R ^13A and R ^14A is a C _1-4 alkyl group or a C _1-4 alkyl-substituted nitrogen-containing 6-membered heterocyclic group, and the other is a C _1-4 alkyl group, a hydroxy-C _1-4 alkyl group or C _1-4 alkoxy-C _1-4 alkyl group, R ^32B is a C _1-4 alkoxy group, R ^33B is a C _1-4 alkyl group or a C _1-4 alkoxy group, and R ^34B is a C _1-4 alkyl group. 8. A compound according to claim 7. One of R ^13A and R ^14A is a di (C _1-4 alkyl) amino-C _1-4 alkyl group or a nitrogen-containing 5-membered heterocyclic group-substituted C _1-4 alkyl group, and the other is a C _2-5 alkanoyl group. Or a C _3-6 cycloalkyl-carbonyl group, R ^32B is a C _1-4 alkoxy group, R ^33B is a C _1-4 alkyl group or a C _1-4 alkoxy group, and R ^34B is a C _1-4 alkyl group. Item 8. The compound according to Item 7. 4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1-[(6-propionylpyridin-2-yl) methyl] -1H-pyrazolo [3,4 -D] pyrimidine;
4- [4-[[trans-4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] cyclohexyl] carbonyl] piperazin-1-yl] -1- (1-propionyl Piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine 1-[(3-methoxycyclohexyl) methyl] -4- [4-[[trans-4-[[N- (2-methoxyethyl) ) -N- (tert-butyl) amino] methyl] cyclohexyl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine 1- (2-oxo-1-propyl-1,2-dihydropyridine -3-yl) -4- [4-[[trans-4-[[N-tert-butyl- (2-methoxyethyl) amino] methyl] cyclohexyl] carbonyl] pipe 1-yl]-1H-pyrazolo [3,4-d] pyrimidine;
1- (2-oxo-1-propyl-1,2-dihydropyridin-3-yl) -4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1H- Pyrazolo [3,4-d] pyrimidine;
1- [2-Fluoro-3- (trifluoromethyl) benzyl] -4- [4-[(trans-4-piperidin-1-ylcyclohexyl) carbonyl] piperazin-1-yl] -1H-pyrazolo [3 4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl] piperidin-1-yl] carbonyl] piperazine-1- Yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[[(2-Propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl ] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (cyclopropylcarbonyl) -N- [2- (dimethylamino) ethyl] amino] methyl] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (cyclopropylcarbonyl) -N- [2- (diisopropylamino) ethyl] amino] methyl] Piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- [2- (diisopropylamino) ethyl] -N-pivaloylamino] methyl] piperidin-1-yl ] Carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] piperazine- 1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1- (3-Ethoxybenzyl) -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3 4-d] pyrimidine;
1- (3-ethoxybenzyl) -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] piperazin-1-yl]- 1H-pyrazolo [3,4-d] pyrimidine;
1-[(2-propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(2-propyl-1,3-thiazol-4-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazine -1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-hydroxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-Ethoxypyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-hydroxyethyl) -N-isopropylamino] methyl] piperidin-1-yl] carbonyl Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[[N- (2-methoxyethyl) -N- (tert-butyl) amino] methyl] piperidine-1 -Yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[(N, N-diisopropylamino) methyl] piperidin-1-yl] carbonyl] piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4-[[N-ethyl-N- (tert-butyl) amino] methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
1-[(6-propylpyridin-2-yl) methyl] -4- [4-[[4- [N- (2-hydroxyethyl) -N-isopropylamino) methyl] piperidin-1-yl] carbonyl] Piperazin-1-yl] -1H-pyrazolo [3,4-d] pyrimidine;
Or a pharmacologically acceptable salt thereof.