JP2003252871A - Spiroisoquinoline derivative, method of producing the same, and synthetic intermediate therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new spiroisoquinoline derivative that is useful as a medicine that has excellent SK channel inhibitory action, a method of producing the same and a synthetic intermediate. <P>SOLUTION: The spiroisoquinoline derivative is represented by general formula [I] (wherein ring A is a benzene ring which may be substituted; R<SP>10</SP>is H or -Z-R<SP>1</SP>where R<SP>1</SP>is H or a lower alkyl which may be substituted; a lower alkenyl which may be substituted; Z is -CH<SB>2</SB>- or -CO-; R<SP>2</SP>is H or a heterocyclic ring group which may be substituted; B is a tertiary N or a tertiary CH; R<SP>3</SP>is an amino group which may be substituted or a N-including aliphatic heterocyclic group which may be substituted and Y is -CH<SB>2</SB>- or -CO-) and includes pharmacologically acceptable salts thereof. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel spiroisoquinoline derivative having excellent small conductance type Ca ²⁺ -dependent potassium (SK) channel blocker activity and useful as a medicine, a process for producing the same, and a synthetic intermediate therefor.

[0002]

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. The BK and IK channels are sensitive to changes in the membrane potential in addition to intracellular Ca ²⁺ , but the SK channel is characterized by having no significant membrane potential sensitivity. SK channels are also characterized by their low single channel conductance (6-20 pS) and their high sensitivity to apamin.

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

Apamin is well known as a selective blocker for SK channels, and its pharmacological action is to enhance the motor transport function of the digestive tract (SA Waterman and
M. Costa, J. Physiology 477, 459-468, 1994; N. Spe
ncer et al., J. Physiology 517, 889-898, 1999)
And improvement of learning and memory impairment (S. Ikonen et al., Eur. JP
harmacol. 347, 13-21, 1998; C. Ghelardini et al.,
Br. J. Pharmacol. 123, 1079-1084, 1998) and reduction of immobility time in the forced swimming test (N. Galeotti et al.,
Br. J. Pharmacol. 126, 1653-1659, 1999) has been reported. Also, in patients with myotonic dystrophy,
The presence of specific apamin binding sites in skeletal muscle and apamin administration have been reported to reduce symptoms (JF
Renaudet al., Nature 319, 678-680, 1986; MI Beh
rens et al., Muscle & Nerve 17, 1264-1270, 199
Four). Furthermore, it has been reported that mice forcibly expressing SK3, which is one of the SK channel subtypes, develop respiratory dysfunction under hypoxia (C.
T. Bond et al., Science 289, 1942-1946, 2000).

As a compound having an SK channel blocker action, 1,1 'is disclosed in International Publication WO00 / 01676.
-(Α, α'-para-xylene) -3,3 '-(α,
A bis (benzimidazole) derivative such as α'-meta-xylene) -bis (benzimidazolium) is disclosed in WO 97/48705 as 7,18-diaza-.
Cyclophane derivatives such as 3,4 (1,4) -dibenzena-1,6 (1,4) -diquinolinacyclooctadecaphane-3 trifluoroacetic acid hydrate are described in US Pat.
No. 6562 discloses ring-bridged bisquinoline derivatives such as 1,4-bis- (2-methyl-quinolin-4-yl)-[1,4] -diazepan. However, none of these describes a compound having a structure containing a spiroisoquinoline ring.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel spiroisoquinoline derivative having an excellent SK channel blocking activity and useful as a medicine, a method for producing the same, and a synthetic intermediate thereof. Furthermore, the present invention provides a therapeutic and preventive agent for gastrointestinal motility dysfunction and central diseases, which comprises a compound having an SK channel blocker action as an active ingredient
In addition, the present invention also provides a therapeutic and prophylactic agent for gastrointestinal motility dysfunction and central diseases, which comprises a compound having an SK channel blocker action and an acetylcholinesterase inhibitory action as an active ingredient.

[0007]

The present invention has the general formula [I]:

[0008]

[Chemical formula 46]

[0009] (wherein ring A is benzene ring which may be substituted, R ¹⁰ is a group represented by hydrogen or -Z-R ^1, R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, Z is -CH ₂ - group represented by or -CO-, ^{R 2}
Is a hydrogen atom or an optionally substituted heterocyclic group, B
Is

[0010]

[Chemical 47]

R ³ is an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group, and Y is a group represented by --CH ₂ -or --CO--. Represents a spiroisoquinoline derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a synthetic intermediate thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent on ring A in the object compound [I] of the present invention is, for example, a lower alkyl group,
Examples thereof include a lower alkoxy group, an optionally protected hydroxyl group, a halogen atom, an amino group and a lower alkylenedioxy group.

Ring A may be substituted with 1 to 4 same or different groups selected from the above lower alkyl group, lower alkoxy group, optionally protected hydroxyl group, halogen atom and amino group, or 1 It may be substituted with ˜2 lower alkylenedioxy groups.

When R ¹ in the object compound [I] of the present invention is an optionally substituted lower alkyl group, the substituent on the lower alkyl group is (i) a halogen atom,
(Ii) optionally protected hydroxyl group, (iii) lower alkyl group; cyclo lower alkyl group; aryl lower alkyl group; lower alkoxycarbonyl group; acyl group; 1-
Amino-2-nitrovinyl group; 1- (mono- or di-) lower alkylamino-2-nitrovinyl group; 1-amino-2,2-dicyanovinyl group; 1- (mono- or di-) lower alkylamino- 2,2-dicyanovinyl group; 3-aminocyclobut-3-ene-1,2-dione-4-yl group; 3- (mono- or di-) lower alkylamino-cyclobut-3-ene-1, 2-dione-4-
An yl group; and an amino group which may be substituted with a group selected from a group capable of being enzymatically or chemically metabolized in vivo, (iv) a lower alkyl group, a cyclo lower alkyl group and a cyano group Selected from a guanidino group optionally substituted with a group, (v) a lower alkyl group and a cyclo lower alkyl group, an ureido group optionally substituted with a group, (vi) a lower alkyl group and a cyclo lower alkyl group And a thioureido group which may be substituted with a group.

The "group which can be removed by being metabolized enzymatically or chemically in vivo in R ¹ " is specifically a group which can be removed by hydrolysis, oxidation or reduction in vivo. And, more specifically, the formula:

[0016]

[Chemical 48]

(Wherein R ⁵ is the formula:

[0018]

[Chemical 49]

(In the formula, R ⁵¹ is a hydrogen atom or a lower alkyl group, R ⁵² is a lower alkyl group optionally substituted with a carboxyl group, a cyclo lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group or an aryl group, R
⁵³ is a lower alkyl group or an aryl group, R ⁵⁴ and R ⁵⁵ are the same or different and are a hydrogen atom, a lower alkanoyloxy group, an arylcarbonyloxy group, a lower alkoxycarbonyloxy group, a lower alkanoyloxymethyloxy group, a halogen atom and a lower alkyl. R ⁵⁶ is a hydrogen atom, a lower alkanoyloxy lower alkyl group or an arylcarbonyloxy lower alkyl group, m is 0 or 1, and R ⁵⁷ is an optionally protected amino group, lower alkoxy group, carbamoyloxy group. Group, (mono- or di-) lower alkylcarbamoyloxy group or acyl group, p is 1 or 2, R ⁵⁸ is a lower alkoxy group, acyl group, carbamoyloxy group or (mono- or di-) lower alkylcarbamoyloxy group , Q is 1 Include groups is represented by a group represented by represents a 2)).

The lower alkyl group for R ¹ may be substituted with 1 to 3 same or different groups selected from the above substituents.

When R ² in the object compound [I] of the present invention is an optionally substituted heterocyclic group, the substituent on the heterocyclic group is (i) a lower alkyl group, (i)
Examples thereof include i) lower alkoxy group, (iii) optionally protected hydroxyl group, (iv) halogen atom, (v) lower alkylenedioxy group, (vi) acyl group and the like.

The heterocyclic group for R ² may be substituted with 1 to 4 identical or different groups selected from the above substituents.

Examples of the heterocyclic group for R ² include a monocyclic or bicyclic nitrogen-containing heterocyclic group. Specific examples thereof include a 1,2,3,4-tetrahydroisoquinolyl group, a 3,4-dihydroisoquinolyl group and an isoquinolyl group.

A specific example of R ² is the formula:

[0025]

[Chemical 50]

(Wherein R ²¹ represents a hydrogen atom or a lower alkyl group, W represents a group represented by —CH ₂ — or —CO—, and other symbols have the same meanings as described above) Can be mentioned.

When R ³ in the object compound [I] of the present invention is an optionally substituted amino group, the substituent on the amino group is (i) an oxo group or an optionally protected amino group. , A (mono- or di-) lower alkylamino group, an aryl lower alkylimidazolylthio group, and a pyridylamino group (the pyridyl portion of the pyridylamino group may be substituted with a lower alkyl group). Optionally a lower alkyl group, (i
i) an acyl group, (iii) a nitrogen-containing heterocyclic group optionally substituted with a lower alkyl group, and an amino group optionally substituted with a group selected from a lower alkyl group, (iv)
Examples thereof include a lower alkyl group, a lower alkoxy group, an aryl lower alkyl group, a hydroxyl group which may be protected, and a nitrogen-containing heterocyclic group which may be substituted with a group selected from an amino group.

The amino group in R ³ may be substituted with 1 or 2 identical or different groups selected from the above substituents.

When R ³ in the object compound [I] of the present invention is an optionally substituted nitrogen-containing aliphatic heterocyclic group, the substituent on the nitrogen-containing aliphatic heterocyclic group is
(I) nitroso group, (ii) optionally protected amino group, (iii) oxo group, oxide group, lower alkyl group, cyano lower alkyl group, cyclo lower alkyl lower alkyl group (carbon on the cyclo lower alkyl group Atom may be substituted with a sulfur atom), pyrrolidinylcarbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl group, aryl lower alkyl group (the aryl portion of the aryl lower alkyl group is a lower alkyl group, Substituted with a lower alkoxy group, (mono- or di-) lower alkylamino group, lower alkoxy lower alkyl group, halogen atom, trihalogenomethyl group, trihalogenomethoxy group, nitro group, or cyano group ), A thienyl lower alkyl group (the thienyl lower alkyl The thienyl moiety of may be substituted with a group selected from a halogen atom and a lower alkoxy group), a furyl lower alkyl group (the furyl moiety of the furyl lower alkyl group is a lower alkyl group and a (mono- or di-) lower alkyl). Optionally substituted with a group selected from amino lower alkyl group), imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group is a lower alkyl group, hydroxy group, (mono- or di-) Optionally substituted with a group selected from a lower alkylamino group and a lower alkoxy lower alkyl group), a pyrazolyl lower alkyl group,
Pyrimidinyl lower alkyl group (pyrimidinyl part of the pyrimidinyl lower alkyl group may be substituted with lower alkyl group), pyridazinyl lower alkyl group, pyridyl lower alkyl group (pyridyl part of the pyridinyl lower alkyl group is lower alkyl group, halogen Atom, lower alkoxy group, lower alkoxy lower alkyl group, (mono- or di-) lower alkylamino group, lower alkoxycarbonyl group, (mono- or di-) lower alkylcarbamoyl group, (mono- or di-) lower alkyl An amino lower alkyl group, a hydroxy lower alkyl group, may be substituted with a group selected from an oxo group and an oxide group), a carboxyl group, a lower alkoxycarbonyl group,
Halogen atom, hydroxy lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, aryl lower alkoxy lower alkyl group (the aryl part of the aryl lower alkoxy lower alkyl group may be substituted with a halogen atom), amino Group protecting group, amino group optionally substituted with lower alkyl group, cyclo lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, lower alkenyl group, halogeno lower alkenyl group, and aryl group (the aryl group). Is a nitrogen-containing heterocyclic group which may be substituted with a group selected from a group selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group (forming an onium salt on nitrogen) May be present), (iv) oxo group, pyridyl group An imino group, a pyrazolyl group (the pyrazolyl group may be substituted with a group selected from a lower alkyl group and a benzyl group), a carbamoyl group (the carbamoyl group is substituted with a group selected from a pyridyl group and a lower alkyl group) ), A thiocarbamoyl group (the thiocarbamoyl group may be substituted with a group selected from a pyridyl group and a lower alkyl group),
An amino group (the amino group is an N-lower alkyl-N-pyridylcarbamoyl group, a lower alkylcarbamoyl group, a pyridylcarbamoyl group, a lower alkyl group, an amino group protecting group, a pyridylcarbonyl group, a pyridylthiocarbonyl group, a pyridyl group, and 1-cyanoimino-1-pyridylmethyl group, which may be substituted with a group selected from), a lower alkyl group which may be substituted with a group selected from
Etc.

The nitrogen-containing aliphatic heterocyclic group for R ³ is
It may be substituted with 1 to 4 identical or different groups selected from the above substituents.

Examples of the nitrogen-containing aliphatic heterocyclic group for R ³ include monocyclic 4- to 8-membered nitrogen-containing aliphatic heterocyclic groups. Specific examples thereof include an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group, an azepinyl group, a diazepinyl group, an azeosynyl group, and a diazeosynyl group.

The nitrogen-containing heterocyclic group for R ³ is
Examples thereof include monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic groups. Specifically, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, an imidazolinyl group, a pyrazolyl group, a pyridyl group, a dihydropyridyl group, a pyridazinyl group, a pyrimidinyl group,
Tetrahydropyrimidinyl group, pyrazinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidyl group, piperazinyl group, triazinyl group, morpholinyl group, indolyl group, quinolyl group, isoquinolyl group,
Purinyl group, 1H-indazolyl group, quinazolinyl group,
Cinnolinyl group, quinoxalinyl group, phthalazinyl group,
Examples thereof include a pteridinyl group, a pyrazolopyrimidinyl group, a triazolopyrimidinyl group, an imidazopyrimidinyl group, a pyrazolopyridyl group, a triazolopyridyl group, and an imidazopyridyl group.

Examples of the aryl group for R ¹ or R ³ include a phenyl group, a naphthyl group, an anthryl group,
Examples thereof include a phenanthryl group.

When the above-mentioned object compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include an optionally substituted lower alkoxycarbonyl group, an acyl group and the like. Specifically, ethoxycarbonyl group, methoxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2, 2,2-trichloroethyloxycarbonyl group, formyl group, acetyl group, propionyl group,
Examples include butyryl group. Furthermore, a benzyl group, 4-
A methoxybenzyl group, an allyl group, etc. are also mentioned. Of these, a lower alkoxycarbonyl group which may be substituted is preferred, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group. The protected amino group also includes, for example, the case where a phthalimido group is formed together with the protected amino group.

When the object compound [I] of the present invention has a protected hydroxyl group, the hydroxyl-protecting group may be an optionally substituted aryl lower alkyl group, an acyl group, a trialkylsilyl group or the like. Conventional protecting groups may be mentioned. Of these, preferred are, for example, unsubstituted aryl lower alkyl groups such as benzyl group and phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group and the like. Examples thereof include trialkylsilyl groups such as acyl group, trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group. Furthermore, a triphenylmethyl group, a 2-cyanoethyl group and the like can also be mentioned.

Further, when the object compound [I] of the present invention has a protected carboxyl group, the protecting group for the carboxyl group is a protecting group which can be eliminated by hydrolysis or hydrogenolysis, such as lower alkyl. Base,
Or a benzyl group which may be substituted with 1 to 2 groups selected from a halogen atom, a lower alkyl group and a lower alkoxy group, and the like, and specific examples include a methyl group, an ethyl group, a propyl group and a tert-group. Butyl group, benzyl group, 4-chlorobenzyl group, 4-fluorobenzyl group,
4-methylbenzyl group, 4-methoxybenzyl group and the like can be mentioned. Of these, preferably a methyl group, an ethyl group,
A benzyl group can be mentioned.

Among the target compounds of the present invention, a preferred compound is a group: R ¹ of the formula:

[0038]

[Chemical 51]

(Wherein R ⁴ is a hydrogen atom or a lower alkyl group, and n is an integer of 1 to 6) are compounds or prodrugs thereof.

Among the target compounds of the present invention, more preferred compounds are those in which R ¹ has the formula:

[0041]

[Chemical 52]

(However, the symbols have the same meanings as above)
A group of the compound represented by: A group capable of being enzymatically or chemically metabolized in vivo to remove the nitrogen atom bonded to R ⁴ , specifically, a hydrolysis reaction or an oxidation reaction in vivo. , Compounds further substituted with a group that can be removed by a reduction reaction or the like.

As a more specific example, the group: R ¹ is of the formula:

[0044]

[Chemical 53]

(However, the symbols have the same meanings as above)
In group compound is a group represented: nitrogen atom bonded to the R ⁴ has the formula:

[0046]

[Chemical 54]

(Wherein R ⁵ is the formula:

[0048]

[Chemical 55]

(In the formula, R ⁵¹ is a hydrogen atom or a lower alkyl group, R ⁵² is a lower alkyl group optionally substituted with a carboxyl group, a cyclo lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group or an aryl group, R
⁵³ is a lower alkyl group or an aryl group, R ⁵⁴ and R ⁵⁵ are the same or different and are a hydrogen atom, a lower alkanoyloxy group, an arylcarbonyloxy group, a lower alkoxycarbonyloxy group, a lower alkanoyloxymethyloxy group, a halogen atom and a lower alkyl. R ⁵⁶ is a hydrogen atom, a lower alkanoyloxy lower alkyl group or an arylcarbonyloxy lower alkyl group, m is 0 or 1, and R ⁵⁷ is an optionally protected amino group, lower alkoxy group, carbamoyloxy group. Group, (mono- or di-) lower alkylcarbamoyloxy group or acyl group, p is 1 or 2, R ⁵⁸ is a lower alkoxy group, acyl group, carbamoyloxy group or (mono- or di-) lower alkylcarbamoyloxy group , Q is 1 Include the compounds further substituted with a group represented by represents) a group represented by represents a 2).

Of these, among others, R ⁵ is of the formula:

[0051]

[Chemical 56]

(However, the symbols have the same meanings as described above.)
A compound which is a group represented by is preferable.

Among the object compounds [I] of the present invention, preferable compounds in view of their efficacy are [group a]: the same or different 2 selected from the lower alkoxy group of ring A and optionally protected hydroxyl group.
Benzene ring optionally substituted with a group, R ¹⁰ is-
A group represented by Z-R ^1, R ¹ is a hydrogen atom or a lower alkyl group, Z is -CH 2 _- and in a group represented by, R ² is a lower alkyl group, an acyl group, is a lower alkoxy group and a protected 1,2,3,4-tetrahydroisoquinolyl group which may be substituted with a group selected from a hydroxyl group which is optionally substituted, and a lower group in which R ³ is substituted with a (1) (mono- or di-) lower alkylamino group An alkylamino group or (2) a piperazinyl group optionally substituted with a group selected from the following,
(I) A monocyclic nitrogen-containing heterocyclic group which may be substituted with a group selected from a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, an oxo group, an oxide group and a hydroxy lower alkyl group (nitrogen An onium salt may be formed above), and (ii) N
-Pyridyl-N-lower alkylcarbamoyl group, oxo group, imino group, amino group and lower alkyl group optionally substituted with a group selected from pyridyl group, Y is -CO
A group represented by-.

Among the object compounds [I] of the present invention, other compounds which are preferable in terms of their pharmacological effects include [Group b ₁ ]: the same or different 2 selected from the lower alkoxy group of the ring A and the hydroxyl group which may be protected. A benzene ring optionally substituted with a group, R ¹⁰ is a group represented by —Z—R ¹ , and R ¹ is a lower alkyl group substituted with a (mono- or di-) lower alkylamino group, Z is a group represented by —CH ₂ — or —CO—, R ²
May be substituted with (1) a hydrogen atom, or (2) a group selected from a lower alkyl group, an acyl group, a lower alkoxy group and an optionally protected hydroxyl group, 1, 2,
3,4-tetrahydroisoquinolyl group, R ³ is amino group, lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, hydroxy lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, aryl lower Alkyl group (the aryl portion of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with an oxide group) ), A thienyl lower alkyl group, a lower alkylamino group, a halogenobenzyloxy lower alkyl group, a lower alkenyl group, a cyclo lower alkyl group, and an aryl group (the aryl group is selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group. Substitute with a group A compound selected from the group consisting of: a piperazinyl group substituted with a monocyclic or bicyclic nitrogen-containing heterocyclic group, and Y is a group represented by -CO-; Is mentioned.

Among the desired compounds [I] of the present invention, other preferred compounds in view of their pharmacological effects include [group b ₂ ]: ring A of the formula:

[0056]

[Chemical 57]

(In the formula, R ⁸ represents a lower alkoxy group)
A ring represented by, R ¹⁰ is a group represented by —Z—R ¹ , R ¹ is a lower alkyl group substituted with a (mono- or di-) lower alkylamino group, and Z is —CO—. The group shown, R ² is of the formula:

[0058]

[Chemical 58]

(In the formula, R ²¹ is a hydrogen atom or a lower alkyl group, W is a group represented by —CH ₂ — or —CO—,
R ²² represents a lower alkoxy group), R ³
Is a piperazinyl group substituted with a group selected from the following,
(1) a pyrazolopyrimidinyl group substituted with a lower alkyl group, a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), 2) an imidazopyridyl group substituted with a lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and
(3) Lower alkyl group or aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group)
A triazolopyrimidinyl group substituted with, Y is -CO-
A group represented by

Among the desired compounds [I] of the present invention, other compounds which are preferable in terms of efficacy include [group c]: ring A having the formula:

[0061]

[Chemical 59]

(In the formula, R ⁸ represents a lower alkoxy group)
Is a ring represented by, R ¹⁰ is a group represented by —Z—R ¹ , and R ¹ is an amino optionally substituted with a 1- (mono- or di-) lower alkylamino-2-nitrovinyl group. A lower alkyl group substituted with a group, Z is a group represented by —CH ₂ —, R ² is a hydrogen atom, R ³ is a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group is a nitro group , A piperazinyl group substituted with a pyrazolopyrimidinyl group substituted with a halogen atom or a lower alkyl group), and Y is a group represented by —CO—.

Among the object compounds [I] of the present invention, as the compounds more preferable from the viewpoint of efficacy, [group d ₁ ]: two same or different ring A selected from lower alkoxy group and optionally protected hydroxyl group A benzene ring optionally substituted with a group, R ¹⁰ is a group represented by —Z—R ¹ , and R ¹ is an amino group-substituted lower alkyl group (the amino group of the amino group-substituted lower alkyl group is Substituted with an alkyl group and a group capable of being enzymatically or chemically metabolized in vivo to be removed),
Z is a group represented by —CH ₂ — or —CO—; R ² is selected from (1) hydrogen atom, or (2) lower alkyl group, acyl group, lower alkoxy group and optionally protected hydroxyl group. 1, 2, optionally substituted with groups
3,4-tetrahydroisoquinolyl group, R ³ is amino group, lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, hydroxy lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, aryl lower Alkyl group (the aryl portion of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with an oxide group) ), A thienyl lower alkyl group, a lower alkylamino group, a halogenobenzyloxy lower alkyl group, a lower alkenyl group, a cyclo lower alkyl group, and an aryl group (the aryl group is selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group. Substitute with a group A compound selected from the group consisting of: a piperazinyl group substituted with a monocyclic or bicyclic nitrogen-containing heterocyclic group, and Y is a group represented by -CO-; Is mentioned.

Among the object compounds [I] of the present invention, as the other compounds more preferable in view of efficacy, [group d ₂ ]: ring A is represented by the formula:

[0065]

[Chemical 60]

(In the formula, R ⁸ represents a lower alkoxy group)
Wherein R ¹⁰ is a group represented by —Z—R ¹ , and R ¹ is an amino group-substituted lower alkyl group (the amino group of the amino group-substituted lower alkyl group is a lower alkyl group or in vivo). Substituted with a group capable of being enzymatically or chemically metabolized at), Z is a group represented by —CO—, and R ² is of the formula:

[0067]

[Chemical formula 61]

(In the formula, R ²¹ is a hydrogen atom or a lower alkyl group, W is a group represented by —CH ₂ — or —CO—,
R ²² represents a lower alkoxy group), R ³
Is a piperazinyl group substituted with a group selected from the following,
(1) a pyrazolopyrimidinyl group substituted with a lower alkyl group, a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), 2) an imidazopyridyl group substituted with a lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and
(3) Lower alkyl group or aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group)
A triazolopyrimidinyl group substituted with, Y is -CO-
A group represented by

Of the object compounds [I] of the present invention, compounds particularly preferable in terms of efficacy include those represented by the general formula [I-h]:

[0070]

[Chemical formula 62]

(In the formula, R ⁸¹ , R ⁸² and R ⁸³ are the same or different and are selected from a hydrogen atom, a lower alkoxy group, an optionally protected hydroxyl group and a halogen atom,
R ¹⁰ is a hydrogen atom or a group represented by —Z—R ¹ , Z is a group represented by —CH ₂ — or —CO—, R ¹
Is (1) a hydrogen atom, (2) a lower alkyl group optionally substituted with a group selected from the following, (i) a halogen atom,
(Ii) optionally protected hydroxyl group, (iii) lower alkyl group; cyclo lower alkyl group; aryl lower alkyl group; lower alkoxycarbonyl group; acyl group; 1-
Amino-2-nitrovinyl group; 1- (mono- or di-) lower alkylamino-2-nitrovinyl group; 1-amino-2,2-dicyanovinyl group; 1- (mono- or di-) lower alkylamino- 2,2-dicyanovinyl group; 3-aminocyclobut-3-ene-1,2-dione-4-yl group; 3- (mono- or di-) lower alkylamino-cyclobut-3-ene-1, 2-dione-4-
An yl group; and an amino group which may be substituted with a group selected from a group capable of being enzymatically or chemically metabolized in vivo, (iv) a lower alkyl group, a cyclo lower alkyl group and a cyano group A guanidino group optionally substituted with a group, (v) an ureido group optionally substituted with a group selected from a lower alkyl group and a cyclo lower alkyl group, and (vi) a lower alkyl group and a cyclo lower alkyl group A thioureido group optionally substituted with a group selected from (3) a lower alkenyl group, R ³⁰ represents an oxo group, an oxide group, a lower alkyl group,
Cyano lower alkyl group, cyclo lower alkyl lower alkyl group (the carbon atom on the cyclo lower alkyl group may be substituted with a sulfur atom), pyrrolidinylcarbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl group An aryl lower alkyl group (the aryl part of the aryl lower alkyl group is a lower alkyl group,
A lower alkoxy group, a halogen atom, a trihalogenomethyl group, a trihalogenomethoxy group, a nitro group, and a cyano group may be substituted), a thienyl lower alkyl group (the thienyl portion of the thienyl lower alkyl group is Optionally substituted with a halogen atom), furyl lower alkyl group, imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group may be substituted with lower alkyl group), pyrazolyl lower alkyl Group, pyrimidinyl lower alkyl group, pyridazinyl lower alkyl group, pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with lower alkyl group or oxide group), carboxyl group, lower alkoxycarbonyl group, halogen original A hydroxy lower alkyl group, a carboxyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an aryl lower alkoxy lower alkyl group (the aryl part of the aryl lower alkoxy lower alkyl group may be substituted with a halogen atom), an amino group Protecting group, amino group optionally substituted with lower alkyl group, cyclo lower alkyl group, N-pyridyl-N-
A group selected from a lower alkylcarbamoyl group, a lower alkenyl group, a halogeno lower alkenyl group, and an aryl group (the aryl group may be substituted with a group selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group) And a nitrogen-containing heterocyclic group which may be substituted with (representing an onium salt may be formed on nitrogen).

Among the object compounds [I] of the present invention, as other compounds particularly preferable in view of efficacy, R ³⁰ in the compound [Ih] is represented by the formula:

[0073]

[Chemical formula 63]

(In the formula, D ¹ and D ² are the same or different and are a group represented by —N═ or —CH═, E ¹ and E 2
² is a group in which one is represented by -N =, the other is represented by -N = or -CH =, R ³¹ is a hydrogen atom, an oxo group, an oxide group, a lower alkyl group, a cyano lower alkyl group, cyclo Lower alkyl lower alkyl group (the carbon atom on the cyclo lower alkyl group may be substituted with a sulfur atom), pyrrolidinylcarbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl group,
Aryl lower alkyl group (the aryl part of the aryl lower alkyl group is a lower alkyl group, a lower alkoxy group,
Halogen atom, trihalogenomethyl group, trihalogenomethoxy group, nitro group, and cyano group may be substituted), thienyl lower alkyl group (thienyl part of the thienyl lower alkyl group is substituted with halogen atom) Optionally)), a furyl lower alkyl group,
Imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group may be substituted with a lower alkyl group), pyrazolyl lower alkyl group, pyrimidinyl lower alkyl group, pyridazinyl lower alkyl group, pyridyl lower alkyl group (The pyridyl portion of the pyridyl lower alkyl group may be substituted with a lower alkyl group or an oxide group), a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a hydroxy lower alkyl group, a carboxyl lower alkyl group, a lower alkoxycarbonyl lower Alkyl group, aryl lower alkoxy lower alkyl group (the aryl part of the aryl lower alkoxy lower alkyl group may be substituted with a halogen atom), amino group protecting group, lower alkyl group Optionally substituted amino group, cyclo lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, lower alkenyl group, halogeno lower alkenyl group, and aryl group (the aryl group is a trifluoromethyl group, a lower alkoxy group, And a group which is represented by (which may be substituted with a group selected from a nitro group)).

Among the object compounds [I] of the present invention, as other compounds particularly preferable in view of efficacy, R ³⁰ in the compound [I-h] is represented by the formula:

[0076]

[Chemical 64]

R in the above formula, which is a group represented by
³¹ is a lower alkyl group, a pyridyl lower alkyl group (the pyridyl part of the pyridyl lower alkyl group may be substituted with a lower alkyl group), a thiazolyl lower alkyl group (the thiazolyl part of the thiazolyl lower alkyl group is a lower alkyl group) And a phenyl lower alkyl group (the phenyl portion of the phenyl lower alkyl group may be substituted with a lower alkyl group).

Among the object compounds [I] of the present invention, specific examples of preferable compounds include (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2 '
-[3- (1-Methylamino-2-nitrovinylamino) propyl] -4- [4- [1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-2 '-[3- (1-amino-2-nitrovinylamino) propyl] -4- [4- [1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4 -Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4β) -3', 4'-dihydro-
6 ', 7'-dimethoxy-2'-[3- (N-normal butylureido) propyl] -4- [4- [1- (2-
Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2'-[3- (N-ethylureido) propyl] -4- [4- [1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-2 '-[3- (3-dimethylamino-3-cyclobuten-1,2-dione-4-yl) aminopropyl] -4- [4- [1- (2-nitrobenzyl)- 1H-pyrazolo [3,4-d] pyrimidine-4-
Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-2 '-[3- (3-methylamino-3-cyclobuten-1,2-dione-4-yl) aminopropyl] -4- [4- [1- (2-nitrobenzyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (3-amino-3-cyclobutene-1,
2-dione-4-yl) aminopropyl] -4- [4-
[1- (2-nitrobenzyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline], (1α, 4β) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2'-[3
-(1-Amino-2,2-dicyanovinylamino) propyl] -4- [4- [1- (2-nitrobenzyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α,
4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (1,3-dimethyl-2-cyanoguanidino) propyl] -4- [4- [1- (2 -Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-2 '-[3- (N-isopropylamino) propyl] -4- [4- [1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4β) -3', 4'-dihydro-6 ',
7'-dimethoxy-2 '-(N, N-dimethylaminoacetyl) -4- [4- [1- (2-nitrobenzyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl]
Piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1
α, 4β) -3 ′, 4′-Dihydro-6 ′, 7′-dimethoxy-2′-ethyl-4- [4- [1- (3-methylbenzyl) -1H-pyrazolo [3,4-d ] Pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-2'-methyl-4- [4- [1-
(2-Fluorobenzyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -3 ′, 4′-
Dihydro-6 ', 7'-dimethoxy-2'-[3- (N
-Ethoxycarbonylamino) propyl] -4- [4-
[1- (2-bromobenzyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline], (1α, 4β) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2'-[3
-(N-Ethoxycarbonylamino) propyl] -4-
[4- [1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2 '
-[3- (N-ethoxycarbonylamino) propyl]
-4- [4- [1- (2-cyanobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-3 ', 4'-dihydro-6', 7'-diethoxy-
2'-Methyl-4- [4- [1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Diethoxy-2'-methyl-4- [4- [1- (3-chlorobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-
Examples include spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], or a pharmacologically acceptable salt thereof.

Among the desired compounds [I] of the present invention, other preferred specific examples of the preferred compounds include, for example, (1α, 4
β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (N, N-dimethylamino) propionyl] -4- [4- (1- (3-methylbenzyl)) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (N, N-dimethylamino) propionyl] -4- [4- (1- (3-methoxybenzyl)) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α,
4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[2- (N, N-dimethylamino) ethyl]-
4- [4- (1- (6-methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Diethoxy-2 '-[2- (N, N-dimethylamino) ethyl] -4- [4- (1- (6-methylpyridine-2-
Ilmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β)- 3 ', 4'-dihydro-
6 ', 7'-diethoxy-2'-(N, N-dimethylaminoacetyl) -4- [4- (1- (3-methylbenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-4- [4- (1- (3-ethoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6′-methoxy-4- [4- (1- (3-ethoxybenzyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -2 ′-(N-methylaminoacetyl) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-4- [4-
(1- (3-Ethoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) isoquinoline], (1α, 4β) -2'
-(N-methylaminoacetyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- (1- (3-
Trifluoromethoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) isoquinoline], (1α, 4β) -2'
-(N-methylaminoacetyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- (1- (6-
Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- (1- (6-n-propylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) isoquinoline], (1α, 4β) -2'-(N, N-dimethylaminoacetyl) -3 ', 4 '-Dihydro-6'-ethoxy-
4- [4- (1- (6-ethoxypyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) isoquinoline], or a pharmaceutically acceptable salt thereof.

Among the object compounds [I] of the present invention, other specific examples of preferable compounds include, for example, (1α, 4
β) -2′-methyl-3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4- [4- (3-methyl-3H-
1,2,3-triazolo [4,5-d] pyrimidine-7
-Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-Diethoxy-4- [4- (1- (3-ethoxyphenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -2′-methyl-3 ′, 4 ′
-Dihydro-6 ', 7'-diethoxy-4- [4- (1
-(6-Methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-2 '-(N, N-dimethylaminoacetyl) -3',
4'-dihydro-6'-methoxy-4- [4- (1-
(6-Methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-3 ', 4'-dihydro-6', 7'-dimethoxy-4
-[4- (1- (6-Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Diethoxy-4- [4- (1- (6-ethylpyridine-
2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β ) -2'-Methyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-4- [4-
(1- (6-ethylpyridin-2-ylmethyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -2′-methyl-3 ′, 4′-dihydro-6 ′,
7'-diethoxy-4- [4- (1- (6-ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -2′-ethyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4
-[4- (1- (6-Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -2′-dimethylaminoacetyl-
3 ', 4'-dihydro-6', 7'-diethoxy-4-
[4- (1- (6-ethylpyridin-2-ylmethyl)
-1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-4- [4- (1- (2-ethylthiazol-4-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1 , 1 ′ (2′H) -isoquinoline], (1α, 4β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6′-ethoxy-4
-[4- (1- (6-Methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -2′-dimethylaminoacetyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- (1- (2-Methylthiazol-4-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
Or the pharmacologically acceptable salt thereof is mentioned.

Among the object compounds [I] of the present invention, other specific examples of preferable compounds include, for example, 2 '-[3-
(Methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,2,3,
4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl]-
1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- (methylamino) propionyl] -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(2-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2′-
[3- (Methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1 -Isoquinolyl) -4-
[4- [1- (3-pyridylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-
Spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'-[3- (methylamino) propionyl] -3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (4-n-butyl-4H-imidazo [4
5-b] pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- (methylamino) propionyl]
-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl
-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (3-methyl-3H-1,2,3-
Triazolo [4,5-d] pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-[3- (methylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy
-2- (2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (1-n-propyl-1H-pyrazolo [3,4-d ] Pyrimidin-4-yl) -1-
Piperazinyl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline], 2 ′-[3- (methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,2 , 3,4-Tetrahydro-6,7-
Dimethoxy-1-isoquinolyl) -4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine
-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3-
(Methylamino) propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4--
[1- (3-methylphenylmethyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- (methylamino) propionyl] -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (1-n-butyl-1H-pyrazolo [3,4
-d] pyrimidin-4-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'-(3-aminopropyl) -3 ', 4'-dihydro -6 ', 7'-dimethoxy-4- [4- [1-
(2-Pyridylmethyl) -1H-pyrazolo [3,4-
d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)
-Isoquinoline], 2 '-(3-aminopropyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], 2'-[3-
(2-Cyano-3,3-dimethylguanidino) propyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1]
H-pyrazolo [3,4-d] pyrimidin-4-yl]-
1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3
-(1-Dimethylamino-2-nitro-vinylamino)
Propyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-4-[[4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl] -1-piperazinyl] carbonyl] -spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
2 '-(3-aminopropyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- [1- (2-bromophenylmethyl) -1H-pyrazolo [3,4- d]
Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- [N- (propionyloxymethyloxycarbonyl) -N-methyl Amino] propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4 −
[4- [1- (4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-[3- [N- (pivaloyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'-
[3- [N- (pivaloyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2 , 3,
4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4- [4- (3-Methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) -1-piperazinyl]
Carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'-[3- [N- (cyclopropylcarbonyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3 ', 4 '-Dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'
-[3- (Pivaloyloxymethyloxycarbonylamino) propyl] -3 ', 4'-dihydro-6', 7 '
-Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy- 4- [4- [1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- (3-methylbenzyl)- 1H-pyrazolo
[3,4-d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -2′-methyl-3 ′ , 4'-Dihydro-6 ', 7'-dimethoxy-4- [4- (3-methyl-
3H-1,2,3-triazolo [4,5-d] pyrimidine-7
-Yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β)
-2′-ethyl-3 ′, 4′-dihydro-6 ′, 7′-diethoxy-4- [4- [1- (2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4 -Yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline], or a pharmacologically acceptable salt thereof.

In particular, (1R ^* , 2R ^* (S ^* ), 4R ^* )-
2 '-[3- (methylamino) propionyl] -3', 4 '
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1
-Isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1
R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- [N- (propionyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1
α, 4β) -2'-methyl-3 ', 4'-dihydro-6',
7'-dimethoxy-4- [4- (3-methyl-3H-1,2,2
3-triazolo [4,5-d] pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1 ,,
1 ′ (2′H) -isoquinoline], or a pharmacologically acceptable salt thereof, is preferable.

In addition, a compound of the general formula [II-A], which is a synthetic intermediate of the object compound [I] of the present invention:

[0084]

[Chemical 65]

(Wherein ring A is an optionally substituted benzene
Zen ring, R¹⁰Is a hydrogen atom or -Z-R¹Indicated by
Group, R¹Is a hydrogen atom, optionally substituted lower
Alkyl group or optionally substituted lower alkenyl
Group, Z is -CH_TwoA group represented by -or -CO-, R^Two
Is a hydrogen atom or an optionally substituted heterocyclic group, R
⁶Represents a hydrogen atom, a lower alkyl group or a benzyl group.
Spiroisoquinoline derivative or salt thereof
Is also a novel compound.

In addition, a compound of the general formula [II-B], which is a synthetic intermediate of the object compound [I] of the present invention:

[0087]

[Chemical formula 66]

[0088] (wherein ring A is benzene ring which may be substituted, R ¹⁰ is a group represented by hydrogen or -Z-R ^1, R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, Z is -CH ₂ - group represented by or -CO-, ^{R 2}
Represents a hydrogen atom or an optionally substituted heterocyclic group) and a spiroisoquinoline derivative or a salt thereof is also a novel compound.

The object compound [I] of the present invention comprises R ¹ , R ²
And / or a substituent on R ³ and an asymmetric atom on the spiro skeleton, the compound may exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric atom. The invention includes any one of these stereoisomers or a mixture thereof.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits a predominant antagonism against ¹²⁵ I-apamine in a competitive binding test with apamin known as an SK channel blocker. Therefore, it is useful as a SK channel blocker, and is used for prevention and treatment of diseases related to SK channel, for example, constipation, irritable bowel syndrome, gastroesophageal reflux disease, gastrointestinal dysfunction such as postoperative ileus, Alzheimer's disease. It is expected to be applied to the prevention and treatment of learning and memory disorders including type dementia, emotional disorders, myotonic dystrophy, and sleep apnea.

Further, among the target compounds [I] of the present invention, there are also compounds having both an SK channel blocking action and an acetylcholinesterase (AChE) inhibitory action. These compounds are constipation, irritable bowel syndrome, gastroesophageal reflux disease, gastrointestinal motility dysfunction such as postoperative ileus, learning and memory disorders including Alzheimer-type dementia, emotional disorders,
It may be applied to the prevention and treatment of myotonic dystrophy and sleep apnea.

Examples of the compound having both SK channel blocking action and acetylcholinesterase (AChE) inhibitory action are described in the above [group b ₁ ], [group b ₂ ], [group d ₁ ] and [group d ₂ ]. Compounds of

Further, the object compound [I] of the present invention has low toxicity and is highly safe as a medicine.

The object compound [I] of the present invention can be used for medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate and methanesulfone. Examples thereof include acid salts, benzene sulfonates, organic acid salts such as tosylate salts and maleate salts, and the like. Further, 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, potassium salt or the like, or an alkaline earth metal salt such as calcium salt) is included.

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

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used as tablets, granules, capsules, powders, injections. , Can be used as a conventional pharmaceutical preparation such as an inhalant.

The dose of the object compound [I] of the present invention or a pharmaceutically acceptable salt thereof is determined by the administration method, the age of the patient,
Although it depends on the body weight and condition, it is usually about 0.0001 to 1 mg / kg per day, especially about 0.001 to 0.1 mg / kg per day for an injection, and usually per day for an oral preparation. About 0.001 to 100 mg / kg,
Particularly, it is preferably about 0.01 to 10 mg / kg. <Production Method of Spiroisoquinoline Derivative> According to the present invention,
The spiroisoquinoline derivative of the objective compound [I] can be produced by, but not limited to, the following [Method A] to [Method G].

[Method A] Among the target compounds [I] of the present invention, general formula [Ia]:

[0099]

[Chemical formula 67]

(However, the symbols have the same meanings as above)
The compound represented by the general formula [II-A]:

[0101]

[Chemical 68]

(However, the symbols have the same meanings as described above.)
Or a salt thereof, and a compound represented by the general formula [16]: R ³ —H [16] (where the symbols have the same meanings as described above) or a salt thereof. You can

When R ⁶ 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, and in the presence or absence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene and 1,2-
Dichloroethane, 1-methylpyrrolidinone, 1,2-dimethoxyethane and the like can be mentioned. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEP)
C), diisopropylcarbodiimide (DIPCI),
Benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBO
P), carbonylditriazole and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOS).
u), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH) and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-
Diazabicyclo [5,4,0] -7-undecene (DB
U) and the like.

When R ⁶ is a hydrogen atom, the compound [I
IA] into a reactive derivative such as the corresponding acid halide or mixed acid anhydride at its carboxyl group,
Compound [Ia] can also be obtained by reacting with compound [16] in the presence of the above base.

When R ⁶ is a lower alkyl group or a benzyl group, this reaction can be carried out by converting the ester to a carboxylic acid by a conventional hydrolysis method or reduction reaction, and then treating the same as above. it can.

When R ⁶ is a lower alkyl group or a benzyl group, this reaction can also be carried out by reacting directly with the compound [16] in the presence of a base or in the presence or absence of a solvent. . The solvent may be any solvent that does not adversely influence the reaction, for example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, methanol, Examples thereof include ethanol and isopropyl alcohol. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0]-
7-undecene (DBU), dimethylaminopyridine (DMAP) and the like can be mentioned.

[Method B] Among the target compounds [I] of the present invention, general formula [Ie]:

[0108]

[Chemical 69]

(However, the symbols have the same meanings as described above.)
The compound represented by the general formula [II-c]:

[0110]

[Chemical 70]

(However, the symbols have the same meanings as described above.)
Or a salt thereof and a general formula [9]: XZR ¹ [9] (wherein, X represents a leaving group, and other symbols have the same meanings as described above). The compound of the general formula [II-b]:

[0112]

[Chemical 71]

(However, the symbols have the same meanings as described above.)
Then, the product [II-
It can be produced by reacting b] with the compound [16] or a salt thereof.

From compound [II-c] to compound [II-
The reaction for producing b] can be carried out as follows.

When Z is a group represented by -CO-, this reaction can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone and the like. To be Examples of the base include pyridine, triethylamine,
Diisopropylethylamine, 4-methylmorpholine,
1,8-diazabicyclo [5,4,0] -7-undecene (DBU) and the like can be mentioned.

Of these, X is a hydroxyl group and Z is -C.
When it is O-, after converting the compound [9] into a reactive derivative such as an acid halide or a mixed acid anhydride at the carboxyl group, the compound [II-in the presence of the above base.
Compound [II-b] can also be obtained by reacting with c].

When X is a hydroxyl group, the compound [II-
The reaction for producing the compound [II-b] from [c] is [A
Method].

When Z is a group represented by --CH _2- , this reaction can be carried out in a solvent, in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone and the like. To be As the base, for example,
Triethylamine, diisopropylethylamine, 4-
Methylmorpholine, 1,8-diazabicyclo [5,4,4]
0] -7-undecene (DBU), potassium carbonate, sodium carbonate and the like. As the additive, for example,
Examples thereof include potassium iodide.

Of these, when X is a hydroxyl group, the hydroxyl group is converted to a halogen atom or a reactive residue such as a p-toluenesulfonyloxy group and then reacted with the compound [II-c] in the presence of the above base. [II-
b] can also be obtained.

From compound [II-b] to compound [Ie]
The reaction for producing can be carried out in the same manner as in [Method A].

[Method C] Of the object compound [I] of the present invention, compound [Ie]
Is represented by the general formula [If]:

[0122]

[Chemical 72]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting the compound represented by or a salt thereof with a compound [9] or a salt thereof.

This reaction is carried out by using the compound [II] in the [Method B].
The reaction can be carried out in the same manner as the reaction for producing compound [II-b] from [c].

[Method D] Of the object compound [I] of the present invention, the compound [Ie] is obtained by reacting the compound [II-c] or its salt with the compound [16] or its salt. [If], and then the product [If]
Can also be produced by reacting with the compound [9] or a salt thereof.

From compound [II-c] to compound [If]
The reaction for producing can be carried out in the same manner as in [Method A].

The reaction for producing compound [Ie] from compound [If] can be carried out in the same manner as in [Method C].

The group represented by —Z—R ¹ of the compound [Ie] is a protecting group for amino group (eg, formyl group,
In the case of an acetyl group, a propionyl group, etc.), compound [If] can also be produced by removing the protecting group from compound [Ie] by a conventional method.

[Method E] Among the target compounds [I] of the present invention, general formula [Ib]:

[0130]

[Chemical formula 73]

(However, the symbols have the same meanings as described above.)
The compound represented by can be produced by reducing the compound [Ie] or a salt thereof.

This reaction can be carried out in a solvent in the presence of a reducing agent. The solvent may be any solvent that does not adversely influence the reaction, for example, tetrahydrofuran,
Examples include dioxane, toluene, benzene and the like. Examples of the reducing agent include borane / tetrahydrofuran complex, borane / dimethyl sulfide complex, lithium aluminum hydride, aluminum hydride and the like.

[Method F] According to the present invention, among the target compound [I], the compound of the general formula [I]
-D]:

[0134]

[Chemical 74]

(However, the symbols have the same meanings as described above.)
The compound represented by can be produced as follows.

[0136]

[Chemical 75]

(However, the symbols have the same meanings as described above.) The reaction for producing the compound [I-d ₁ ] from the compound [Ic] can be carried out as follows.

When R ⁵² is a lower alkyl group which may be substituted with a carboxyl group, a cyclo lower alkyl group or an aryl group, it may be combined with compound [Ic] and general formula [17] in a solvent in the presence of a base. :

[0139]

[Chemical 76]

It can be carried out by reacting with a compound represented by the formula (wherein X ¹ represents a leaving group and other symbols have the same meanings as described above). As a solvent,
Any solvent that does not adversely affect the reaction may be used, for example,
Examples thereof include chloroform, methylene chloride, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like. Examples of the base include triethylamine, diisopropylethylamine, cesium carbonate, potassium carbonate, sodium hydrogen carbonate and the like. Examples of the leaving group X ¹ include a halogen atom such as a chlorine atom and a bromine atom, a 2-pyridyloxy group, a paranitrophenoxy group, and a succinimidooxy group.

Alternatively, the compound [I-d ₁ ] is the same as the compound of the general formula [18]:

[0142]

[Chemical 77]

[Wherein, X ² represents a halogen atom, and other symbols have the same meanings as described above] to react with a compound represented by the general formula [I-d ₇ ]:

[0144]

[Chemical 78]

(However, the symbols have the same meanings as described above.)
And then the product [I-
It can also be carried out by reacting d ₇ ] with a compound represented by the general formula [19]: R ⁵² —COOH [19] (where the symbols have the same meaning as described above) or a salt thereof.

The reaction for obtaining compound [Id ₇ ] from compound [Ic] and compound [18] can be carried out in a solvent in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include acetonitrile, dimethylformamide, dimethylacetamide and the like. Examples of the base include cesium carbonate, potassium carbonate, sodium hydrogen carbonate, silver nitrate, mercury acetate, and the like. Examples of the additive include molecular sieves and the like.

The reaction for obtaining the compound [I-d ₁ ] from the compound [I-d ₇ ] and the compound [19] is the same as the above-mentioned compound [I-d ₁ ].
It can be carried out in the same manner as the reaction for obtaining the compound [Id- ₇ ] from c].

The reaction of obtaining the compound [I-d ₁ ] from the compound [I-c] via the compound [I-d ₇ ] is an intermediate product (compound [I-d ₇ ]) in the same reaction vessel. Can also be carried out without isolation.

When R ⁵² is a lower alkoxy group or a cyclo lower alkoxy group, this reaction is carried out in a solvent in the presence of a base, the compound [18], the presence or absence of an additive, carbon dioxide gas. In the presence of lower alcohol or cyclo lower alcohol. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include chloroform, methylene chloride, acetonitrile, dimethylformamide and the like. Examples of the base include triethylamine, diisopropylethylamine, cesium carbonate and the like. Examples of the additive include tetrabutylammonium iodide,
Examples thereof include tetraethylammonium iodide.

From compound [Ic] to compound [I-
d _2], [reaction for producing _{I-d 3]} or _{[I-d 6]} is in a solvent in the presence of phosgene equivalent in the presence of a base, the general formula [20]:

[0151]

[Chemical 79]

(However, the symbols have the same meanings as described above.)
A compound represented by the following general formula [21]:

[0153]

[Chemical 80]

(However, the symbols have the same meanings as described above.)
Or a compound represented by the general formula [22]:

[0155]

[Chemical 81]

(However, the symbols have the same meanings as described above.)
It can be carried out by reacting the compound shown by with the compound [Ic]. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include chloroform and methylene chloride. Examples of the phosgene equivalent include phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), and the like. Examples of the base include triethylamine, diisopropylethylamine and pyridine.

From compound [I-c] to compound [I-d ₄ ]
Alternatively, the reaction for producing [I-d ₅ ] is carried out in the presence of a base in a solvent, represented by the general formula [23]:

[0158]

[Chemical formula 82]

(Wherein X ³ represents a leaving group and other symbols have the same meanings as described above), or a compound of the general formula [24]:

[0160]

[Chemical 83]

(However, the symbols have the same meanings as described above.)
It can be carried out by reacting the compound shown by with the compound [Ic]. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include chloroform and methylene chloride. As a base,
For example, triethylamine, diisopropylethylamine, pyridine and the like can be mentioned.

When X ³ is a hydroxyl group, the carboxyl group is converted to a reactive derivative such as an acid halide or a mixed acid anhydride, and then reacted in the presence of the above-mentioned base to give a compound [I-d ₄ ] or Compound [I-d ₅ ] can also be produced.

When X ³ is a hydroxyl group, a conventional condensing agent can be used.

[G method] Among the target compounds [I] of the present invention, general formula [Ig]:

[0165]

[Chemical 84]

(However, the symbols have the same meanings as described above.)
The compound represented by the general formula [II-B]:

[0167]

[Chemical 85]

(However, the symbols have the same meanings as described above.)
And a salt thereof and a compound of the general formula [16]: R ³ —H [16] (where the symbols have the same meanings as described above) or a salt thereof in the presence of a phosgene equivalent. It can be produced by reacting.

This reaction can be carried out in a solvent in the presence of a phosgene equivalent and in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, toluene and the like. Examples of the phosgene equivalent include phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), phenyl chlorocarbonate, diethyl carbonate and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.

<Production Method of Synthetic Intermediate> The compound [II-A] or [II-B] which is a synthetic intermediate of the object compound [I] of the present invention is a novel compound, and is produced, for example, as follows. can do.

That is, of the synthetic intermediate [II-A], the compound represented by the general formula [II-a] or [II-e] can be produced, for example, as follows.

[0172]

[Chemical 86]

(In the formula, R ⁶⁰ is a lower alkyl group, R ⁷ is a protecting group for a carboxyl group, R ²¹ is a hydrogen atom or a lower alkyl group, W is a group represented by —CH ₂ — or —CO—, Other symbols have the same meanings as described above.) The reaction for producing compound [3] from compound [1] and compound [2] can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran, tert-butyl alcohol, dioxane, toluene, benzene, and mixed solvents thereof. Examples of the base include potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine and the like.

The reaction for producing compound [4] from compound [3] can be carried out in the presence or absence of a solvent, and in the presence of a suitable deprotecting agent. The solvent may be any solvent which does not adversely influence the reaction, for example, methylene chloride, chloroform, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methanol, ethanol, benzene, toluene, ethyl acetate, water or a mixed solvent thereof. Etc. Examples of the deprotecting agent include sodium hydroxide, potassium hydroxide, formic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, palladium-carbon / hydrogen, palladium-carbon / formic acid, trifluoroacetic acid and the like. Can be mentioned.

The reaction for producing the compound [6] from the compound [4] and the compound [5] is carried out by converting the compound [4] into a reactive derivative (eg acid halide, mixed acid anhydride, etc.) and then in a solvent. , In the presence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dimethoxyethane, ethyl acetate, water, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, and a mixed solvent thereof. Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. This reaction can also be carried out directly from compound [4] and compound [5] in the presence of a conventional condensing agent. As the condensing agent,
For example, dicyclohexylcarbodiimide (DCC),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEP)
C), diisopropylcarbodiimide (DIPCI),
Benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBO
P), carbonylditriazole and the like.

The reaction for producing the compound [7] from the compound [6] can be carried out in a solvent in the presence of a suitable dehydrating agent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include acetonitrile, benzene, toluene, chlorobenzene, methylene chloride, chloroform, nitromethane, and mixed solvents thereof. Examples of the dehydrating agent include phosphorus oxychloride, polyphosphoric acid (PPA), polyphosphoric acid ester (PPE), phosphorus pentachloride and the like, or a mixture thereof.

The reaction for producing compound [7-b] from compound [7] and compound [7-a] is [method C] (where Z is --CO
In the case of a group represented by-), it can be carried out in the same manner.

The reaction for producing compound [8] from compound [7-b] can be carried out in a solvent in the presence of a reducing agent. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include ethanol, tetrahydrofuran, methanol, methyl cellosolve, dimethoxyethane, isopropanol, dioxane, methylene chloride, chloroform, acetic acid, or a mixed solvent thereof. Examples of the reducing agent include sodium borohydride, platinum oxide, palladium-carbon, lithium borohydride, calcium borohydride, zinc borohydride, borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, diisobutylaluminum hydride, bis. (2-Methoxyethoxy) aluminum hydride (Re
d-Al) and the like. In this reaction, a compound [8] in which W is a group represented by —CH ₂ — or a compound [8] that is a group represented by —CO— can be produced depending on the type of reducing agent and reaction conditions. it can.

The reaction for producing the compound [7-d] from the compound [7] and the compound [7-c] is [method C] (where Z is —CH).
_{2- (in} the case of the group represented by _2- ).

The reaction for producing the compound [8] (when W is a group represented by —CH ₂ —) from the compound [7-d] is the same as the reaction for producing the compound [8] from the compound [7-b]. It can be implemented similarly.

The reaction for producing compound [10] from compound [8] and compound [9] can be carried out in the same manner as in [Method A].

The reaction for producing compound [II-a] from compound [10] can be carried out by subjecting it to a decarboxylation reaction after the hydrolysis reaction. The hydrolysis reaction can be carried out in a solvent in the presence of a base or an acid. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, water, dioxane, and mixed solvents thereof. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Examples of the acid include trifluoroacetic acid, formic acid, p-toluenesulfonic acid and the like. The decarboxylation reaction can be carried out by heating in the presence or absence of a solvent, or in the presence or absence of a base. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, benzene, acetic acid, toluene and pyridine. Examples of the base include pyridine and dimethylaminopyridine. The heating temperature is preferably 40 ° C to 200 ° C, particularly preferably 50 ° C to 150 ° C.

The above hydrolysis reaction and decarboxylation reaction can also be carried out continuously in the same reaction vessel.

The carboxylic acid obtained by this reaction can be esterified by a conventional method, if necessary.

The compound [10] or [II-a] wherein Z is a group represented by -CH _2- is a compound [10] or [II-a] wherein Z is a group represented by -CO-.
Can be produced by subjecting the compound to a reduction reaction.
This reaction can be carried out in a solvent in the presence of a reducing agent. The solvent may be any solvent that does not adversely influence the reaction, for example, tetrahydrofuran, dioxane,
Examples thereof include dimethoxyethane and diethyl ether.
Examples of the reducing agent include borane-dimethyl sulfide complex, lithium aluminum hydride, borane-tetrahydrofuran complex, and the like.

The reaction for producing the compound [II-e] from the compound [8] is carried out from the compound [10] to the compound [II-a].
Can be carried out in the same manner as the reaction for producing.

Among the synthetic intermediates [II-A], the compounds represented by the general formulas [II-b], [II-c] and [II-d] are produced, for example, as follows. be able to.

[0188]

[Chemical 87]

(Where the symbols have the same meanings as described above) The reaction for producing compound [12] from compound [5] and compound [11] is carried out in the presence or absence of a solvent, in the presence of a dehydrating agent or It can be carried out in the absence. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include ethanol, methanol, isopropanol, toluene, xylene, chlorobenzene, dimethylformamide and the like. Examples of the dehydrating agent include polyphosphoric acid (PPA), polyphosphoric acid ester (PPE), phosphorus pentoxide, polyphosphoric acid silyl ester (PPSE), and the like.

The reaction for producing compound [13] from compound [12] and compound [9] is carried out in the same manner as the reaction for producing compound [II-b] from compound [II-c] in [Method B]. be able to.

When the group represented by -Z-R ¹ in compound [13] is a protecting group for amino group (eg, formyl group, acetyl group, propionyl group, etc.), compound [1
[3] is subjected to a conventional deprotection reaction to give compound [1
2] can also be manufactured.

The reaction for producing compound [II-b] from compound [13] is the same as compound [II-b].
It can be carried out in the same manner as the reaction for producing a].

When the group represented by -Z-R ¹ of compound [II-b] is a protecting group for amino group (eg, formyl group, acetyl group, propionyl group, etc.), compound [II-b] ] To a conventional deprotection reaction,
Compound [II-c] can also be produced.

Compound [14] can also be produced by subjecting compound [II-b] to a reduction reaction. This reaction can be carried out in a solvent in the presence of a reducing agent. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether and the like. Examples of the reducing agent include borane-dimethyl sulfide complex, lithium aluminum hydride, borane-tetrahydrofuran complex, and the like.

Compound [II-d] can also be produced by subjecting compound [14] to an oxidation reaction. This reaction can be carried out in a solvent in the presence of an oxidizing agent. The solvent may be any solvent that does not adversely influence the reaction, for example, methylene chloride, chloroform,
Water, tert-butyl alcohol, acetonitrile, acetone and the like can be mentioned. Examples of the oxidizing agent include chromic acid and pyridinium dichromate (PDC). The compound [II-d] is prepared by converting the compound [14] into the compound of the general formula [15]:

[0196]

[Chemical 88]

(However, the symbols have the same meanings as described above.)
It can be produced by subjecting the aldehyde compound represented by the formula (3) to an oxidation reaction. Examples of the oxidant for converting the compound [14] to the aldehyde derivative [15] include, for example,
Oxalyl chloride / dimethyl sulfoxide / triethylamine (Swan oxidizer), sulfatrioxide / pyridine complex, pyridinium chlorochromate (PC
C), pyridinium dichromate (PDC) and the like, and from aldehyde compound [15] to compound [II-
Examples of the oxidant for b] include sodium hypochlorite, silver nitrate, sodium chlorite, and the like. The obtained carboxylic acid can be converted into an ester by an ordinary esterification reaction if necessary.

Of the synthetic intermediates [II-B] of the object compound [I] of the present invention, the compounds of the general formula [II-f] or [II]
The compound represented by -g] can be produced, for example, as follows.

[0199]

[Chemical 89]

(However, the symbols have the same meanings as described above.) In the reaction for producing the compound [26] from the compound [5] and the compound [25], the compound [12] is obtained from the compound [5] and the compound [11]. It can be carried out in the same manner as the reaction to be produced.

The reaction for producing the compound [II-f] from the compound [26] can be carried out in a solvent in the presence of a base or an acid. The solvent may be any solvent that does not adversely affect the reaction, for example, ethylene glycol,
Examples thereof include ethanol, methanol, water, methylene chloride, chloroform and the like. Examples of the base include alkali hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Examples of the acid include formic acid,
Examples include trifluoroacetic acid and hydrochloric acid. The base or acid can be appropriately selected and used according to the group R ⁶⁰ of the compound [26] by a method known to those skilled in the art.

The reaction for producing compound [27] from compound [26] and compound [9] can be carried out in the same manner as in [method C].

The reaction for producing the compound [II-g] from the compound [27] is the same as the compound [II-g].
It can be carried out in the same manner as the reaction for producing f].

Of the synthetic intermediate [16] of the object compound [I] of the present invention, the compound represented by the general formula [III] can be produced, for example, as follows.

[0205]

[Chemical 90]

(In the formula, G represents an amino-protecting group, and other symbols have the same meanings as described above.) The reaction for producing compound [III] from compound [28] and compound [29] is
It can be carried out in the absence or presence of a solvent, in the presence of an activator, or in the presence of an additive. This reaction does not particularly require a solvent, but when a solvent is used, the solvent may be any solvent that does not adversely affect the reaction, and 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.

In particular, when hexamethyldisilazane is used as an activator and ammonium sulfate is used as an additive, the production of the compound [I
II] can be obtained.

The amount of compound [29] used is compound [28]
1 to 4 equivalents, preferably 2 to 3 equivalents can be used. This reaction can be carried out, for example, at 100 to 200 ° C, especially at 130 to 150 ° C.

A specific example of the amino-protecting group: G is:
Examples thereof include a benzyl group and a lower alkoxycarbonyl group.

From the racemic compound [II-A] obtained by the above method, an optically active compound [II-A] can be produced by using an optical resolving agent (however, the meso form is excluded). . That is, the optically active compound [II-A] is prepared by reacting a racemic compound [II-A] with an optical resolving agent to form a diastereomer mixture, and the mixture is prepared by a conventional method (for example, column chromatography). After separation, it can be produced by removing the optical resolving agent. Examples of the optical resolving agent include, for example, general formula [30]:

[0211]

[Chemical Formula 91]

(In the formula, R ⁹ is a lower alkyl group, an aryl lower alkyl group, a cyclo lower alkyl group or an aryl group, Q is an oxygen atom or a sulfur atom, and * is an asymmetric carbon atom).

Specifically, for example, the racemic compound [II-A] and the compound [30] are subjected to a condensation reaction to give a diastereomer mixture [II-A ']:

[0214]

[Chemical Formula 92]

(However, the symbols have the same meanings as described above.)
After separating the mixture [II-A ′] by column chromatography, an optical resolution agent is separated from each separated product by a conventional hydrolysis reaction (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, water). The optically active compound [II-A] can be produced by removing it with a mixture of lithium oxide and hydrogen peroxide).

The object compound [I] of the present invention, its synthetic intermediate [II] and / or its starting compound are the substituents on the ring A and the substituents on R ^{1 of the} compound obtained as described above, The substituent on R ² and / or the substituent on R ³ is
It can also be produced by converting it to another desired substituent. Such a method of converting a substituent may be appropriately selected according to the kind of the desired substituent, but can be carried out as in (method a) to (method t), for example.

(Method a: O-alkylation reaction) Compounds [I] and [II] in which the substituent on ring A is a lower alkoxy group.
Alternatively, the starting compound is a compound [I] or [II] corresponding to a substituent on the ring A being a hydroxyl group or a starting compound thereof and a lower alkyl halide (eg, methyl iodide, ethyl iodide, propyl iodide). Can be produced by reacting in the presence of a base (eg, sodium hydride, potassium carbonate).

(Method b: Halogenation reaction) Compounds [I], [II] or their starting compounds in which the substituent on ring A is a halogen atom are those in which the site corresponding to the halogen atom on ring A is unsubstituted. A corresponding compound [I], [II] or a starting compound thereof and a halogenating agent (for example, sulfuryl chloride,
N-chlorosuccinimide, N-bromosuccinimide)
It can be produced by reacting with.

(Method c: Michael addition reaction of amino group) The substituent —Z—R ¹ has the formula:

[0220]

[Chemical formula 93]

(In the formula, R ⁴¹ and R ⁴² are hydrogen atoms,
A compound [I] or [II] which is a group represented by the same or different groups selected from a lower alkyl group, a cyclo lower alkyl group and an aryl lower alkyl group.
Has the substituent —Z—R ¹ is of the formula:

[0222]

[Chemical 94]

The corresponding compound [I] or [II], which is a group represented by: and a compound of the general formula [31]: H—N (R ⁴¹ ) (R ⁴² ) [31] (where the symbols have the same meanings as described above). Compound) or a salt thereof having a base (for example, triethylamine, sodium hydroxide, potassium hydroxide) in the presence or absence thereof can be produced.

(Method d: Double bond reduction reaction) Substituent R ¹
[I] or [II] wherein is a lower alkyl group
Can be produced by reducing the corresponding compound [I] or [II] in which the substituent R ¹ is a lower alkenyl group by a conventional method (eg, palladium-carbon / hydrogen).

(Method e: Deprotection reaction of amino group) Substituent R
^The compound [I] or [II] in which ¹ is an amino lower alkyl group is prepared by deprotecting the corresponding compound [I] or [II] in which the substituent R ¹ is a phthalimido lower alkyl group by a conventional method (eg, hydrazine, Sodium hydroxide, methylhydrazine).

[0226] (f Method: substitution reaction) substituted with a substituent R ¹ is a lower alkyl group which is an amino-lower alkyl group compound [I] or [II], the substituent R ¹ is a halogenated lower alkyl It can be produced by reacting the corresponding compound [I] or [II] which is a group with an amine which may be substituted with a lower alkyl group (eg, ammonia, methylamine, dimethylamine).

(Method g: Deprotection reaction of amino group) Substituent R
¹ and / or R ² is an amino group or a mono-lower alkylamino group (e.g., methylamino group) compound is a substituent containing a [I] or [II], the substituent R ¹ and / or R ² Protection The corresponding compound [I] or [II], which is a substituent containing a protected amino group (as a protecting group, for example, a benzyloxycarbonyl group, a benzyl group, a tert-butoxycarbonyl group) is deprotected by a conventional method ( For example, iodotrimethylsilane, palladium-carbon / hydrogen, palladium-carbon / formic acid, hydrogen bromide /
Acetic acid, trifluoroacetic acid, formic acid).

(Method h: Reductive amination reaction) Substituent R ¹
And / or R ² is an amino group substituted with a lower alkyl group, an aryl lower alkyl group or a cyclo lower alkyl group (eg, a dimethylamino group, a diethylamino group,
Compound [I] or [II] which is a substituent containing a benzylamino group or a cyclohexylamino group corresponds to the substituent R ¹ and / or R ² is a substituent containing a primary or secondary amino group. Compound [I] or [II]
And a lower alkanal, an aryl lower alkanal (eg, formaldehyde, benzaldehyde) or a cyclo lower alkanone (eg, cyclohexanone) with a reducing agent (eg, sodium borohydride, sodium triacetoxyborohydride, cyanoborohydride). It can be produced by reacting in the presence of sodium).

(Method i: Cyanoguanidinization reaction) The substituent R ¹ has the formula:

[0230]

[Chemical 95]

The compound [I] which is the formula (where the symbols have the same meaning as described above) is the compound [Ic] or a salt thereof and diphenylcyanocarboxylic imidate (diphen).
yl cyanocarbonimidate) to give a substituent R ¹
Has the formula:

[0232]

[Chemical 96]

(However, the symbols have the same meanings as described above.)
And then converting the compound to a compound [31]
It can be produced by reacting with.

(Method j: N-nitrovinylation reaction) The substituent R ¹ has the formula:

[0235]

[Chemical 97]

(However, the symbols have the same meanings as described above.)
Compound [I] which is a compound [Ic] or a salt thereof is reacted with 1,1-bis (methylthio) -2-nitroethylene (1,1-bis (methylthio) -2-nitroethylene). , The substituent R ¹ has the formula:

[0237]

[Chemical 98]

(However, the symbols have the same meanings as described above.)
And then converting the compound to a compound [31]
It can be produced by reacting with.

[0239] (k Method: guanidino reduction) substituents ^{R 1} or ^{R 3} is a substituent containing a guanidino group compound [I] is a substituent ^{R 1} or ^{R 3} is a primary or secondary amino group The corresponding compound [I], which is a substituent contained, and 1
H-pyrazole-1-carboxamidine and a base (eg, triethylamine, diisopropylethylamine)
It can be produced by reacting in the presence of.
1H-pyrazole-1-carboxamidine may be protected with an appropriate protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group), and after the reaction, the protecting group may be removed by a conventional method.

(Method l: N-biscyanovinylation reaction) The substituent R ¹ has the formula:

[0241]

[Chemical 99]

(However, the symbols have the same meanings as described above.)
The compound [I] which is a compound [Ic] or a salt thereof is reacted with (bis (methylthio) methylene) propanedinitrile [(CH ₃ S) ₂ C = C (CN) ₂ ] to cause substitution. Group R ¹
Has the formula:

[0243]

[Chemical 100]

(However, the symbols have the same meanings as above)
And then converting the compound to a compound [31]
It can be produced by reacting with.

(Method m: N-cyclobutenylation reaction) The substituent R ¹ has the formula:

[0246]

[Chemical 101]

(However, the symbols have the same meanings as described above.)
Compound [I] which is a compound [Ic] or a salt thereof is reacted with 3,4-diethoxy-3-cyclobutene-1,2-dione, and the substituent R ¹ has the formula:

[0248]

[Chemical 102]

(However, the symbols have the same meanings as described above.)
And then converting the compound to a compound [31]
It can be produced by reacting with.

(Method n: N-carbamoylation reaction) The substituent R ¹ has the formula:

[0251]

[Chemical 103]

(However, the symbols have the same meanings as described above.)
The compound [I] is a compound [Ic] or a salt thereof, and a compound of the formula [32]: (R ⁴¹ ) (R ⁴² ) N═C═O [32] (where the symbols have the same meanings as described above). It can be produced by reacting with a compound represented by

(Method o: N-thiocarbamoylation reaction) The substituent R ¹ has the formula:

[0254]

[Chemical 104]

(However, the symbols have the same meanings as described above.)
The compound [I] is a compound [Ic] or a salt thereof, and a compound of the formula [33]: (R ⁴¹ ) (R ⁴² ) N = C = S [33] (where the symbols have the same meanings as described above). It can be produced by reacting with a compound represented by

(Method p: O-carbamoylation reaction) The compound [I] in which the substituent R ¹ is a substituent containing a carbamoyloxy group, a (mono- or di-) lower alkylcarbamoyloxy group, is a substituent It can be produced by reacting the corresponding compound [I] in which R ¹ is a substituent having a hydroxyl group with the compound [31] in the presence of a phosgene equivalent and a base. Alternatively, it can also be produced by reacting the corresponding compound [I] in which the substituent R ¹ is a substituent containing a hydroxyl group with the corresponding carbamoyl halide in the presence of a base.

(Method q: C-alkenylation reaction) Substituent-
The compound [I] or [II] in which Z-R ¹ is a lower alkenoyl group (for example, 4-pentenoyl group) can be prepared by converting the corresponding compound [I] or [II] in which the substituent -Z-R ¹ is an acetyl group. Can be produced by reacting with an allyl halide (eg, allyl bromide) in the presence of a base (eg, lithium diisopropylamide, lithium hexamethyldisilazide).

(Method r: aldol-reduction reaction) Substituent-
Compound [I] or [I] wherein Z-R ¹ is a butyryl group
[I] is obtained by reacting the corresponding compound [I] or [II] in which the substituent —Z—R ¹ is an acetyl group with acetaldehyde in the presence of a base (eg, lithium diisopropylamide, lithium hexamethyldisilazide). , 3-hydroxybutyryl group, and after converting the hydroxyl group on the substituent to a reactive group (for example, a methanesulfonyloxy group),
It can be produced by reduction.

[0259] (s Method: Reduction reaction) substituent R ³ is a substituent containing an amino group compound [I], the corresponding compound substituent R ³ is a substituent containing a nitroso group [I]
By a conventional method (as the reducing agent, for example,
Palladium-carbon / hydrogen, zinc / acetic acid).

(Method t: Reduction Reaction of Hydroxyl Group) Compounds [I] and [II] in which ring A is an unsubstituted benzene ring or a starting compound thereof is a corresponding compound in which ring A is a benzene ring substituted with a hydroxyl group. I], [II] or a raw material compound thereof and a trifluoromethanesulfonylating agent (for example, trifluoromethanesulfonic acid anhydride) are reacted to convert the hydroxyl group into a trifluoromethanesulfonyloxy group, and then a reducing agent (for example, palladium acetate / It can be produced by reacting with formic acid / triphenylphosphine / triethylamine).

[A method] to [G method] or (a
The object compound [I] of the present invention obtained by the methods (1) to (t) can be converted into a pharmacologically acceptable salt, if desired. Conversion to a pharmacologically acceptable salt may be performed according to a method known to those skilled in the art.

The above target compound [I] and synthetic intermediate [I]
I] and / or the starting material compound, each intermediate compound is not limited to those shown in the above-mentioned sentence or the chemical reaction formula, as long as it does not adversely affect the reaction.
Those salts or their reactive derivatives can also be used appropriately. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium, salts with an organic base such as pyridine, triethylamine and diisopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like. Salts with inorganic acids, organic acids such as acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid Of salt.

Further, in the production of the object compound and the starting compound of the present invention, when the starting compound or each intermediate has a functional group, a protecting group other than those exemplified above may be appropriately used unless the reaction is affected. It is possible.

In the present invention, examples of the alkyl include linear or branched ones having 1 to 16 carbon atoms, and particularly ones having 1 to 8 carbon atoms. Examples of lower alkyl or lower alkoxy include linear or branched ones having 1 to 6 carbon atoms, and particularly ones having 1 to 4 carbon atoms. Further, the lower alkanoyl includes a straight or branched one having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms, and the cycloalkyl means
Examples thereof include those having 3 to 20 carbon atoms, and particularly those having 3 to 12 carbon atoms. Examples of cyclo lower alkyl include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. The alkenyl includes those having 2 to 16 carbon atoms, especially those having 2 to 10 carbon atoms, and the lower alkenyl includes those having 2 to 8 carbon atoms, especially those having 2 to 4 carbon atoms. Can be mentioned. Examples of the alkylene include linear or branched ones having 1 to 16 carbon atoms, and particularly 1 to 10 carbon atoms, and lower alkylene refers to linear ones having 1 to 8 carbon atoms, especially 1 to 6 carbon atoms. And branched chains.
Further, examples of the halogen atom include fluorine, chlorine, bromine and iodine.

[0265]

Experimental Example Experimental Example 1 ( ¹²⁵ I-apamine binding inhibitory action) Experimental animal species; Guinea pig, strain; Hartley, sex;
Male, age: 4 weeks or older 2. Sample preparation Prepare sample with buffer (3) (5 mM Tris-HCl, 5.4 mM KCl, 0.1% B
SA (bovine serum albumin); pH 7.
Dissolve in 4). However, the slightly soluble sample is dissolved in dimethyl sulfoxide (DMSO) and then diluted with the buffer solution (3). 3. Experimental procedure Hugues et al. (Life Sciences [Life
Sciences] 31, 437-443, 1982) and Catterall et al. (Journal of Biological Chemistr
y] Volume 254, pages 11379-11387, 1979). A. Preparation of Membrane Specimen Remove the mucosa of the isolated colon of guinea pig and use buffer (1) (4
After homogenizing in 0 mM Tris-HCl, 8% sucrose; pH 7.4), centrifuge (16000 × g, 20 min),
The supernatant is further centrifuged (130000 xg, 60 min). Suspend the obtained precipitate in buffer solution (1), and use 33%, 40%
Centrifuge after stacking on sucrose (160000 × g, 90 min)
To do. The 8/33% layer was collected and buffered (2) (5 mM Tris-HCl;
After suspension in pH 7.4), further centrifugation (160000 × g, 60 m
in) Buffer solution (3) (5 mM Tris-HCl, 5.4 mM KCl, 0.1%) so that the protein concentration of the obtained precipitate is 500 μg / ml
Suspend in BSA; pH 7.4) and store frozen in liquid nitrogen. B. Add the membrane preparation (10 μg / ml), ¹²⁵ I-apamine (10 pM) and the sample in the binding experiment buffer (3), and heat the mixture at 4 ° C. for 60 minutes.
After filtering with a cell harvester, ¹²⁵ I on the filter paper is measured with a γ-counter, and the inhibition rate (IC50 value) of the sample for specific binding of ¹²⁵ I-apamine is calculated. The amount of ¹²⁵ I-apamine bound in the presence of 100 nM apamin is defined as non-specific binding.

The results are shown in Table 1 below.

[0267]

[Table 1]

Experimental Example 2 (Acetylcholinesterase (A
ChE) inhibitory action) 1. Sample preparation 0.1% BSA (bovine serum albumin);
Dissolve in distilled water containing pH 7.4). However, the sparingly soluble compound is dissolved in dimethyl sulfoxide (DMSO) and then diluted with distilled water containing 0.1% BSA. 2. Experimental procedure AChE activity was measured by the method of Ellman et al. (Biochem. Pharmac
ol., 7, 88-95, 1961). 12 mM in 1.8 ml of 110 mM (final concentration; 100 mM) phosphate buffer (pH 7.4)
(Final concentration: 0.3 mM) 5,5'-dithiobis- (2-nitrobenzoic a
cid) Add 50 μl, 2-4 U / ml AChE 50 μl, and sample 50 μl in this order, and incubate for a certain period of time (25 ° C, 3-60 minutes). Then, add 50 μl of 20 mM (final concentration; 0.5 mM) acetylthiocholine iodide, mix well, and immediately measure the absorbance at 412 nm. Using the change in absorbance per unit time (△ E / min) as an index for enzyme activity, the inhibition rate (I
C50 value) is calculated. All measurements are performed in the presence of 0.1% BSA. The results are shown in Table 2 below.

The results are shown in Table 2 below.

[0270]

[Table 2]

Experimental Example 3 (Guinea pig defecation promoting action) 1. Experimental species: Guinea pig, Strain: Hartley, Gender:
Male, age: 4-5 weeks, group: 6-10 cases 2. Sample preparation Dissolve the sample in distilled water. However, 0.5% CMC for poorly soluble samples
Suspend with (carboxymethyl cellulose). The dose volume is 5 ml / kg. 3. Experimental procedure Two animals are housed in individual cages, acclimatized for 2-3 days, and then used for experiments. Clonidine (30 μg / kg, i.
p.), and 15 minutes after that, the test drug is administered intraperitoneally (i.
p.) or orally (po). 1 after administration of study drug
Record the number of stools excreted in each cage (2) by 1 hour. The minimum dose of the test drug that shows an increase in the number of feces compared to the control group (clonidine + test drug solvent) is the effective dose in this test system.

The results are shown in Tables 3 and 4 below.

[0273]

[Table 3]

[0274]

[Table 4]

From Experimental Example 1, the object compound [I] of the present invention was obtained.
Have been shown to have SK channel blockade.

From Experimental Example 2, the object compound [I] of the present invention was obtained.
It was shown that there is a compound having both an SK channel blocking action and an acetylcholinesterase inhibiting action.

From Experimental Example 3, the object compound [I] of the present invention was obtained.
Has been shown to be useful in the treatment and prevention of constipation.

[0278]

[Examples] Specific examples (Examples) of the target compound [I] of the present invention synthesized by the above-mentioned methods are shown below, but the present invention is not limited thereto.

The compounds described in the following Examples and Reference Examples are
Unless otherwise specified to be an optically active substance, it means a pair of enantiomers having a relative configuration of the compound, that is, a racemate. On the other hand, when there is an indication that it is an optically active substance, it means that it is a compound having one of the three-dimensional configurations among the racemates having the relative configurations of the compounds shown in the table or named.

Specifically, for example, (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 'without any indication that the compound is optically active.
-Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- (2-pyridyl) -1-piperazinyl] carbonyl-
When it is described as spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1R, 2R (S), 4R)
-2'-ethyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4- [4- (2-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] and (1S, 2S (R), 4S) -2′-ethyl -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4-
(2-Pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is shown as a racemic body, and in particular, there is an indication that it is an optically active substance. The case means that the compound has one of the three configurations. In the description of the configuration of the named compound, for example, (1R ^* ,
2R ^* (S ^* ), 4R ^* ) of 2R ^* (S ^* ) (S ^* )
Represents the configuration at the 1-position of the tetrahydroisoquinoline ring, which is the substituent at the 2-position of the cyclohexane ring. (The same applies hereinafter.) In addition, for example, the general formula [A]:

[0281]

[Chemical 105]

(However, the symbols have the same meanings as described above)
In the case of notation, the general formula [B]:

[0283]

[Chemical formula 106]

(However, the symbols have the same meanings as described above.)
And a compound represented by the general formula [C]:

[0285]

[Chemical formula 107]

(However, the symbols have the same meanings as described above.)
Represents a racemate consisting of a compound represented by
It represents a compound having one of the configurations of [B] or [C].

Further, the units of MS and IR measurement values are:
Unless otherwise specified, they are “m / z” and “cm ⁻¹ ”, respectively.

Example 1 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 2 (5)) 660
0.22 ml of oxalyl chloride and 1 drop of dimethylformamide are added to a solution of 25 mg of methylene chloride in 25 ml of ice, and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off from the reaction solution to remove excess oxalyl chloride. The residue was dissolved in 25 ml of methylene chloride, and 1 ml of triethylamine was added under ice cooling.
A solution of 682 mg of 1,2-pyridylpiperazine in 10 ml of methylene chloride is added dropwise. After stirring at room temperature for 30 minutes, water is added and the solvent is distilled off from the reaction solution. Ethyl acetate is added, the mixture is washed with water, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the residue was subjected to NH-silica gel column chromatography (Chromatorex NH DM1020).
Fuji Silysia Chemical Ltd. (FUJI SILYSI
A)) (ethyl acetate: n-hexane = 1: 1), and recrystallized from ethanol to give (1R ^* , 2R).
^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- (2-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (782 mg, yield 9
3%) as crystals. Melting point 115-117 ° C, MS (FAB) m / z: 69
8, IR (Nujol) cm ^-1 : 1640,159
0,1510. (2) The trihydrochloride of the compound obtained in (1) above is obtained as crystals by treating the compound obtained in (1) above with a hydrochloric acid-ethanol solution. Melting point 180-183
° C.

Example 2 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxy-
Example 1 By the same treatment as in 1), (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2.
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4- [4- [N
-(2-Pyridyl) -N-methylcarbamoylmethyl]
-1-Piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained as an amorphous powder. MS (FAB) m / z; 770 (M + H), IR (Nu
jol) cm ⁻¹ ; 1670, 1640. (2) The compound obtained in (1) above and twice its equivalent fumaric acid are dissolved in water and freeze-dried to obtain the difumarate salt of the compound obtained in (1) above as a powder. MS (FAB) m / z; 770 (M + H). (3) 1. The compound obtained in the above (1) is dissolved in ethanol and the compound obtained in the above (1) and 1.5 times equivalent amount of fumaric acid, and recrystallized from ethanol and diisopropyl ether. 5 Fumarate is obtained as crystals. Melting point 172-174 [deg.] C.

Example 3-21 (1) The corresponding starting material compound was prepared as Example 1 (1) or Example 2.
By treating in the same manner as in (1), the compounds shown in Table 5 are obtained. (Note that the unit of MS measurement value in the table is "m / z". In the table, Me represents a methyl group,
Et is an ethyl group, n-Pr is an n-propyl group, n-Bu
Represents an n-butyl group, and Ac represents an acetyl group. same as below. )

[0291]

[Table 5]

[0292]

[Table 6]

[0293]

[Table 7]

[0294]

[Table 8]

(2) The compound obtained in (1) above is treated in the same manner as in Example 1 (2), Example 2 (2) or Example 2 (3) to give the following salt. Compound 3 (2): 3 of the compounds obtained in Example 3 (1)
Hydrochloride. Melting point 174-176 [deg.] C. (decomposition). Compound 4 (2): 2 of the compound obtained in Example 4 (1)
Fumarate. Lyophilized powder, MS (ESI) m / z; 7
14 (M + H), IR (Nujol) cm ^-1 ; 323
0,1694. Compound 5 (2): Compound 2 obtained in Example 5 (1)
Fumarate. Lyophilized powder, MS (APCI) m / z;
712 (M + H), IR (Nujol) cm ⁻¹ ; 17
01, 1635. Compound 6 (2): Compound 2 obtained in Example 6 (1)
Fumarate.

Example 22 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 2 (5)) 150
82 mg of 2- [N- (2-pyridyl) -N-acetylamino] ethylpiperazine, 0.065 ml of diethyl cyanophosphonate, 69 mg of triethylamine and 2 ml of dimethylformamide are combined and stirred at room temperature overnight. Aqueous sodium hydrogen carbonate solution is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 10: 1).
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [2- [N-
(2-Pyridyl) -N-acetylamino] ethylpiperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (120 mg, yield 56%) is obtained as an oil. MS (APCI) m / z; 783 (M + H), IR (n
eat) cm ⁻¹ ; 1665, 1635. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder. MS (APCI) m / z; 783 (M + H).

Examples 23-51 (1) The corresponding starting materials were treated in the same manner as in Example 22 (1) to give the compounds shown in Table 6.

[0298]

[Table 9]

[0299]

[Table 10]

[0300]

[Table 11]

[0301]

[Table 12]

[0302]

[Table 13]

[0303]

[Table 14]

[0304]

[Table 15]

[0305]

[Table 16]

[0306]

[Table 17]

(2) Implementation of the compound obtained in (1) above
The following salt was obtained by treating in the same manner as in Example 2 (2).
It Compound 23 (2): Compound obtained in Example 23 (1)
2 fumarate. Lyophilized powder, MS (APCI) m /
z; 799 (M + H), IR (Nujol) cm ^-1;
1705, 1635, 1612. Compound 24 (2): Compound obtained in Example 24 (1)
2 fumarate. Lyophilized powder, MS (APCI) m /
z; 811 (M + H), IR (Nujol) cm ^-1;
1640. Compound 25 (2): Compound obtained in Example 25 (1)
3 fumarate. Freeze-dried powder, MS (ESI) m /
z; 799 (M + H), IR (Nujol) cm^{− 1};
1641, 1460. Compound 26 (2): Compound obtained in Example 26 (1)
2 fumarate. Compound 27 (2): Compound obtained in Example 27 (1)
2 fumarate. Compound 28 (2): Compound obtained in Example 28 (1)
3 fumarate. Compound 29 (2): Compound obtained in Example 29 (1)
2.5 fumarate. Compound 30 (2): Compound obtained in Example 30 (1)
3 fumarate. Amorphous powder, IR (neat)
cm^-12605, 1711, 1640. Compound 32 (2): Compound obtained in Example 32 (1)
2 fumarate. Compound 33 (2): Compound obtained in Example 33 (1)
2 fumarate. Compound 34 (2): Compound obtained in Example 34 (1)
2 fumarate. Compound 35 (2): Compound obtained in Example 35 (1)
2 fumarate. Compound 36 (2): Compound obtained in Example 36 (1)
2.5 fumaric acid mixture. Compound 37 (2): Compound obtained in Example 37 (1)
2 fumarate. Compound 38 (2): Compound obtained in Example 38 (1)
2 fumarate. Compound 39 (2): Compound obtained in Example 39 (1)
2 fumarate. Compound 40 (2): Compound obtained in Example 40 (1)
2.5 fumarate. Amorphous powder, IR (nea
t + chloroform) cm^-11706, 1639. Compound 43 (2): Compound obtained in Example 43 (1)
2 fumarate. Compound 44 (2): Compound obtained in Example 44 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 741.5 (M + H), IR (neat + black)
Loholm) cm^-11703.

Example 52 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 2 (5)) 200
mg, 2-amino-4-piperazinyl pyridine 77.4
mg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 103.8 mg, 1-hydroxybenzotriazole 70.6 mg and dimethylformamide 4 ml are combined and stirred at room temperature overnight. Aqueous sodium hydrogen carbonate solution is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate.
After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '.
-Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- (2-Aminopyridin-4-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline] (171 mg, yield 67
%) As an amorphous powder. MS (APCI) m / z; 713 (M + H), IR (n
ujol) cm ⁻¹ ; 1599. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder. IR (neat + chloroform) cm ⁻¹ ; 1638.

Examples 53-163 (1) The corresponding starting materials are treated in the same manner as in Example 52 (1) to give the compounds shown in Table 7.

[0310]

[Table 18]

[0311]

[Table 19]

[0312]

[Table 20]

[0313]

[Table 21]

[0314]

[Table 22]

[0315]

[Table 23]

[0316]

[Table 24]

[0317]

[Table 25]

[0318]

[Table 26]

[0319]

[Table 27]

[0320]

[Table 28]

[0321]

[Table 29]

[0322]

[Table 30]

[0323]

[Table 31]

[0324]

[Table 32]

[0325]

[Table 33]

[0326]

[Table 34]

[0327]

[Table 35]

[0328]

[Table 36]

[0329]

[Table 37]

[0330]

[Table 38]

[0331]

[Table 39]

(2) Implementation of the compound obtained in (1) above
The following salt was obtained by treating in the same manner as in Example 2 (2).
It Compound 53 (2): Compound obtained in Example 53 (1)
2 fumarate. Compound 54 (2): Compound obtained in Example 54 (1)
2 fumarate. Compound 56 (2): Compound obtained in Example 56 (1)
2 fumarate. Amorphous powder, IR (neat +
Chloroform) cm^-11710, 1637. Compound 57 (2): Compound obtained in Example 57 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 756 (M + H), IR (neat + chloropho
Rum) cm^-11707, 1635. Compound 58 (2): Compound obtained in Example 58 (1)
2 fumarate. Compound 59 (2): Compound obtained in Example 59 (1)
2 fumarate. Compound 60 (2): Compound obtained in Example 60 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 769 (M + H), IR (neat + chloropho
Rum) cm^-11703, 1639. Compound 61 (2): Compound obtained in Example 61 (1)
2 fumarate. Compound 62 (2): Compound obtained in Example 62 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 740 (M + H), IR (neat + chloropho
Rum) cm^-11706, 1637. Compound 63 (2): Compound obtained in Example 63 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 726 (M + H), IR (neat + chloropho
Rum) cm^-11705, 1612. Compound 64 (2): Compound obtained in Example 64 (1)
2 fumarate. Compound 65 (2): Compound obtained in Example 65 (1)
2 fumarate. Compound 66 (2): Compound obtained in Example 66 (1)
2 fumarate. Lyophilized powder, MS (APCI) m /
z; 783.6 (M + H), IR (Nujol) cm
^-11706, 1637. Compound 67 (2): Compound obtained in Example 67 (1)
2 fumarate. Lyophilized powder, MS (APCI) m /
z; 783 (M + H), IR (Nujol) cm ^-1;
1705, 1641. Compound 68 (2): Compound obtained in Example 68 (1)
2 fumarate. Compound 69 (2): Compound obtained in Example 69 (1)
2 fumarate. Compound 70 (2): Compound obtained in Example 70 (1)
2 fumarate. Amorphous powder, MS (APCI)
m / z; 799.8 (M + H), IR (neat + black)
Loholm) cm^-11703, 1640. Compound 71 (2): Compound obtained in Example 71 (1)
2 fumarate. Compound 74 (2): Compound obtained in Example 74 (1)
2 fumarate. Compound 75 (2): Compound obtained in Example 75 (1)
2 fumarate. Compound 76 (2): Compound obtained in Example 76 (1)
2 fumarate. Compound 135 (2): Compound obtained in Example 135 (1)
Compound monofumarate. Lyophilized powder, MS (APCI)
m / z; 606 (M + H), IR (Nujol) cm
^-11702, 1635. Compound 136 (2): Compound obtained in Example 136 (1)
Compound monofumarate. Lyophilized powder, MS (APCI)
m / z; 583 (M + H), IR (Nujol) cm
^-11706, 1637. Compound 137 (2): Compound obtained in Example 137 (1)
Compound monofumarate. Lyophilized powder, MS (APCI)
m / z; 565.6 (M + H), IR (Nujol) c
m^-11631. Compound 138 (2): Compound obtained in Example 138 (1)
Compound monofumarate. Lyophilized powder, MS (APCI)
m / z; 681.6 (M + H), IR (Nujol) c
m^-11707, 1633. Compound 139 (2): Compound obtained in Example 139 (1)
Compound monofumarate. Freeze-dried powder, MS (ACPI)
m / z; 726 (M + H), IR (Nujol) cm
^-11634.

Example 164 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-acetyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4- [2- (N
-Benzyloxycarbonylamino) ethyl] aminocarbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (compound obtained in Example 72 (1)) (2.47 g) in tetrahydrofuran (30 ml) is added with borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution) (35.55 ml), and the mixture is stirred for 3 days. Methanol and 10% hydrochloric acid are added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated, ethyl acetate is added, the mixture is washed with saturated aqueous sodium hydrogen carbonate solution, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to give (1R
^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [2- (N-benzyloxycarbonyl) Amino) ethyl] aminomethyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (1.32 g, 56% yield) is obtained. MS (APC
I): 715 (M + H), IR (neat) cm ⁻¹ :
3366, 2931, 1609. (2) The compound (494 mg) obtained in the above (1), triethylamine (80 mg) and acetyl chloride (60 mg) are added to methylene chloride (10 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.05) to obtain (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '. -Ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [2- (N-
Benzyloxycarbonylamino) ethyl] -N-acetylaminomethyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (427 mg, yield 82
%). MS (ESI): 757 (M + H), IR (Nujo
l) cm- ¹ : 1718, 1633.

Example 165 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2
-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
0.25 ml of trimethylsilane iodide is added to a solution of 351.1 mg of (2′H) -isoquinoline] (compound obtained in Example 78 (1)) in 5 ml of acetonitrile, and the mixture is stirred at room temperature for 1 hour. 10% Hydrochloric acid is added to the reaction solution, which is washed with diisopropyl ether. The aqueous layer is made alkaline with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 2.
(1R ^* , 2R ^* ) by purification with (00: 10: 1)
(S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2--
(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl))
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] (209.6 mg, yield 69%) is obtained as crystals. Melting point 178-180 ° C, M
S (APCI) m / z; 887 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a foam. MS (APCI) m / z; 887.5 (M + H), IR
(Neat + chloroform) cm ⁻¹ ; 1704,16
33.

Examples 166-199 (1) The corresponding starting materials were treated in the same manner as in Example 165 (1) to give compounds shown in Table 8.

[0336]

[Table 40]

[0337]

[Table 41]

[0338]

[Table 42]

[0339]

[Table 43]

[0340]

[Table 44]

[0341]

[Table 45]

[0342]

[Table 46]

(2) Implementation of the compound obtained in (1) above
The following salt was obtained by treating in the same manner as in Example 2 (2).
It Compound 166 (2): Compound obtained in Example 166 (1)
Compound 2 fumarate. Compound 167 (2): Compound obtained in Example 167 (1)
Compound 2 fumarate. Compound 168 (2): Compound obtained in Example 168 (1)
Compound monofumarate. Compound 169 (2): Compound obtained in Example 169 (1)
Compound monofumarate. Compound 170 (2): Compound obtained in Example 170 (1)
Compound monofumarate. Compound 171 (2): Compound obtained in Example 171 (1)
Compound monofumarate. Compound 172 (2): Compound obtained in Example 172 (1)
Compound monofumarate. Compound 173 (2): Compound obtained in Example 173 (1)
Compound monofumarate. Compound 174 (2): Compound obtained in Example 174 (1)
Compound monofumarate. Compound 175 (2): Compound obtained in Example 175 (1)
Compound monofumarate. Compound 176 (2): Compound obtained in Example 176 (1)
Compound monofumarate. Compound 177 (2): Compound obtained in Example 177 (1)
Compound monofumarate. Compound 178 (2): Compound obtained in Example 178 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 887 (M + H), IR (neat + black)
Loholm) cm^-11705, 1698, 1633. Compound 179 (2): Compound obtained in Example 179 (1)
Compound 2 fumarate. Powder, MS (APCI) m / z;
954 (M + H), IR (Nujol) cm^-1; 17
03, 1634, 1573. Compound 180 (2): Compound obtained in Example 180 (1)
Compound monofumarate. Compound 181 (2): Compound obtained in Example 181 (1)
Compound 2 fumarate. Powder, MS (APCI) m / z;
931 (M + H), IR (Nujol) cm^-1; 16
36,1572. Compound 182 (2): Compound obtained in Example 182 (1)
Compound monofumarate. Compound 183 (2): Compound obtained in Example 183 (1)
Compound monofumarate. Compound 184 (2): Compound obtained in Example 184 (1)
Compound monofumarate. Compound 185 (2): Compound obtained in Example 185 (1)
Compound monofumarate. Compound 186 (2): Compound obtained in Example 186 (1)
Compound monofumarate. Compound 187 (2): Compound obtained in Example 187 (1)
Compound monofumarate. Compound 188 (2): Compound obtained in Example 188 (1)
Compound monofumarate. Compound 189 (2): Compound obtained in Example 189 (1)
Compound monofumarate. Compound 190 (2): the compound obtained in Example 190 (1)
Compound monofumarate. Compound 191 (2): Compound obtained in Example 191 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
825.6 (M + H), IR (Nujol) cm ^-1;
1653, 1637. Compound 192 (2): Compound obtained in Example 192 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
785.6 (M + H), IR (Nujol) cm ^-1;
1653. Compound 193 (2): Compound obtained in Example 193 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
729.5 (M + H), IR (Nujol) cm ^-1;
1652. Compound 194 (2): Compound obtained in Example 194 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
757.6 (M + H), IR (Nujol) cm ^-1;
3347, 1693, 1645. Compound 195 (2): Compound obtained in Example 195 (1)
Compound monofumarate. Compound 196 (2): Compound obtained in Example 196 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
887 (M + H), [α]_D-39.59 ° (c1, eta
Noor). Compound 197 (2): Compound obtained in Example 197 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
887 (M + H), [α]_D+ 40 ° (c 1, ethanol
Le). Compound 198 (2): Compound obtained in Example 198 (1)
Compound monofumarate. Amorphous powder, MS (APC
I) m / z; 903.7 (M + H), IR (Nujo
l) cm^-1: 1639. Compound 199 (2): Compound obtained in Example 199 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
887.9 (M + H), IR (Nujol) cm ^-1;
3406, 1634, 1573.

Example 200 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2
-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- (4-pyridyl) piperazine-
1-yl] carbonyl-spiro [cyclohexane-1,1 '
(2′H) -isoquinoline] (Compound obtained in Example 79 (1)) 190 mg, 10% Palladium-carbon 380
mg and 10 ml of ethanol together, under a hydrogen atmosphere,
Subjected to atmospheric pressure catalytic reduction. After 16 hours, the catalyst is filtered off and washed with methanol. The filtrate and washings are combined and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 200: 10: 1) to obtain (1R ^* , 2R ^* (S ^* ), 4R ^* )-.
2 '-[3- (methylamino) propionyl] -3', 4 '
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (4-pyridyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -Isoquinoline] (128 mg, 77% yield) is obtained as an amorphous powder. NMR (CDCl ₃ ) δ: 0.78
(3H, t, J = 7.1), 2.49 (3H, s),
3.41 (1H, d, J = 9.7), 3.66 (3H,
s), 3.86 (3H, s), 3.88 (3H, s), 3.
98 (3H, s), 6.42 (1H, s), 6.56 (1
H, s), 6.60 (1H, s), 7.57 (1H,
s). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a foam. MS (APCI) m / z; 755.6 (M + H), IR
(Neat + chloroform) cm ⁻¹ : 1704, 16
39,1515.

Examples 201 to 212 (1) The corresponding starting materials are treated in the same manner as in Example 200 (1) to give the compounds shown in Table 9.

[0346]

[Table 47]

[0347]

[Table 48]

[0348]

[Table 49]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 201 (2): difumarate of the compound obtained in Example 201 (1). Compound 202 (2): The difumarate salt of the compound obtained in Example 202 (1). Compound 203 (2): difumarate of the compound obtained in Example 203 (1). Compound 204 (2): the difumarate salt of the compound obtained in Example 204 (1). Compound 205 (2): The difumarate salt of the compound obtained in Example 205 (1). Compound 206 (2): The difumarate salt of the compound obtained in Example 206 (1). Compound 207 (2): difumarate of the compound obtained in Example 207 (1). Compound 208 (2): The difumarate salt of the compound obtained in Example 208 (1). Compound 209 (2): difumarate salt of the compound obtained in Example 209 (1). Compound 210 (2): The difumarate salt of the compound obtained in Example 210 (1). Compound 211 (2): difumarate of the compound obtained in Example 211 (1). Compound 212 (2): The difumarate salt of the compound obtained in Example 212 (1).

Example 213 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2
-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- (2-pyridyl) piperazine-
1-yl] carbonyl-spiro [cyclohexane-1,1 '
(2′H) -isoquinoline] (compound obtained in Example 41 (1)) 60 mg, 10% palladium-carbon 60 m
g, ammonium formate 85 mg, and methanol 6 ml are combined and heated under reflux for 1 hour. The catalyst is filtered off, washed with methanol, the filtrate and washings are combined and the solvent is distilled off.
The residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 200: 1).
(1R ^* , 2R by purifying with 0: 1)
^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-
2- (2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (2-pyridyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (41 mg, yield 80
%) As an amorphous powder. NMR (CDCl
₃ ) δ: 0.79 (3H, t, J = 7.1), 2.53
(3H, s), 3.70 (3H, s), 3.86 (3H,
s), 3.88 (3H, s), 3.97 (3H, s), 6.
45 (1H, s), 6.56 (1H, s), 6.58 (1
H, s), 7.55 (1H, s). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a foam. MS (APCI) m / z; 755 (M + H), IR (n
eat + chloroform) cm ⁻¹ : 1700, 163
5,1593.

Examples 214-253 (1) The corresponding starting materials were treated in the same manner as in Example 213 (1) to give compounds shown in Table 10.

[0352]

[Table 50]

[0353]

[Table 51]

[0354]

[Table 52]

[0355]

[Table 53]

[0356]

[Table 54]

[0357]

[Table 55]

[0358]

[Table 56]

[0359]

[Table 57]

(2) Implementation of the compound obtained in (1) above
The following salt was obtained by treating in the same manner as in Example 2 (2).
It Compound 214 (2): Compound obtained in Example 214 (1)
Compound 2.5 fumarate. Amorphous powder, MS (A
PCI) m / z; 755.6 (M + H), IR (nea)
t + chloroform) cm^-1: 1701, 1629, 1
593. Compound 215 (2): Compound obtained in Example 215 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 756.4 (M + H), IR (neat +
Chloroform) cm^-1: 1705, 1629. Compound 216 (2): Compound obtained in Example 216 (1)
Compound 2 fumarate. Compound 217 (2): Compound obtained in Example 217 (1)
Compound 2 fumarate. Compound 218 (2): Compound obtained in Example 218 (1)
Compound 2 fumarate. Compound 219 (2): Compound obtained in Example 219 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 827.7 (M + H), IR (neat +
Chloroform) cm^-1: 1739, 1704, 163
5. Compound 220 (2): Compound obtained in Example 220 (1)
Compound 2 fumarate. Compound 221 (2a): Obtained in Example 221 (1a)
Difumarate of the compound. Compound 221 (2b): Obtained in Example 221 (1b)
Difumarate of the compound. Compound 222 (2): Compound 222 obtained in Example 222 (1)
Compound 2 fumarate. Powder, MS (APCI) m / z;
770.6 (M + H), IR (Nujol) cm ^-1:
3353, 3135, 1615. Compound 223 (2): Compound obtained in Example 223 (1)
Compound 2 fumarate. Compound 224 (2): Compound obtained in Example 224 (1)
Compound 2 fumarate. Compound 225 (2): Compound obtained in Example 225 (1)
Compound 2 fumarate. Compound 226 (2): Compound obtained in Example 226 (1)
Compound 2 fumarate. Compound 227 (2): Compound obtained in Example 227 (1)
Compound 2 fumarate. Compound 228 (2): Compound obtained in Example 228 (1)
Compound 2 fumarate. Compound 229 (2): Compound obtained in Example 229 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 809.4 (M + H), IR (neat +
Chloroform) cm^-1: 1704, 1632. Compound 230 (2): Compound obtained in Example 230 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 809.4 (M + H), IR (neat +
Chloroform) cm^-1: 1704, 1631, 158
9. Compound 231 (2): Compound obtained in Example 231 (1)
Compound 2 fumarate. Compound 232 (2): Compound obtained in Example 232 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 809 (M + H), IR (neat + black)
Loholm) cm^-1: 1703, 1631. Compound 233 (2): Compound obtained in Example 233 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 838 (M + H), IR (neat + black)
Loholm) cm^-1: 1705, 1633, 1571. Compound 234 (2): Compound obtained in Example 234 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 852 (M + H), IR (neat + black)
Loholm) cm^-1: 1703, 1633, 1586. Compound 235 (2): Compound obtained in Example 235 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 873 (M + H), IR (Nujol) c
m^-1: 3396, 1654. Compound 236 (2): Compound obtained in Example 236 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 838 (M + H), IR (Nujol) c
m^-1: 3395, 1631. Compound 237 (2): Compound obtained in Example 237 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 880 (M + H), IR (Nujol) c
m^-1: 3405, 1632. Compound 238 (2): Compound obtained in Example 238 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 900 (M + H), IR (Nujol) c
m^-1: 3399, 1634. Compound 239 (2): Compound obtained in Example 239 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 741.5 (M + H), IR (neat +
Chloroform) cm^-1: 3129, 1703, 162
7. Compound 240 (2): Compound obtained in Example 240 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 866 (M + H), IR (Nujol) c
m^-1: 3409, 1633. Compound 241 (2): Compound obtained in Example 241 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 811 (M + H), IR (Nujol) c
m^-1: 3132, 1635. Compound 242 (2): Compound obtained in Example 242 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 851 (M + H), IR (neat + black)
Loholm) cm^-1: 3126,1631. Compound 243 (2): Compound obtained in Example 243 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 824 (M + H), IR (neat + black)
Loholm) cm^-1: 3130, 1633. Compound 244 (2): Compound obtained in Example 244 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 872 (M + H), IR (Nujol) c
m^-1: 3398. Compound 245 (2): Compound obtained in Example 245 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 852 (M + H), IR (Nujol) c
m^-1: 3329, 1637. Compound 246 (2): Compound obtained in Example 246 (1)
Compound 2 fumarate. Amorphous powder, MS (APC
I) m / z; 839 (M + H), IR (Nujol) c
m^-1: 1638. Compound 247 (2): Compound obtained in Example 247 (1)
Compound 2 fumarate. Compound 248 (2): Compound obtained in Example 248 (1)
Compound monofumarate. Compound 249 (2): Compound obtained in Example 249 (1)
Compound monofumarate. Amorphous powder, MS (APC
I) m / z; 825.7 (M + H), IR (Nujo
l) cm^-1: 1636, 1597, 1576. Compound 250 (2): Compound obtained in Example 250 (1)
Compound monofumarate. Compound 251 (2): Compound obtained in Example 251 (1)
Compound monofumarate. Melting point 216-220 ° C (decomposition),
MS (APCI) m / z; 783.5 (M + H), IR
(Nujol) cm^-11652, 1634. Compound 252 (2): Compound obtained in Example 252 (1)
Compound monofumarate. Amorphous powder, MS (APC
I) m / z; 811 (M + H), [α]_D-39.79 °
(C1.0, ethanol). Compound 253 (2): Compound obtained in Example 253 (1)
Compound monofumarate. Amorphous powder, MS (APC
I) m / z; 811 (M + H), [α]_D+ 39 ° (c
1.0, ethanol).

Example 254 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2
-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- (4-pyrimidyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] (compound obtained in Example 85 (1)) 330 mg acetic acid 6 ml solution, hydrogen bromide-acetic acid (HBr—AcOH) 2 ml acetic acid 6 ml solution was added dropwise at room temperature, Stir for 2 hours at the same temperature. Add diisopropyl ether and remove the supernatant. A saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform.
After drying the organic layer with sodium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 200: 10:
By purifying in 1), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2 '-[3- (methylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- (4-pyrimidyl) piperazine-
1-yl] carbonyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (110 mg, yield 39%)
As an amorphous powder. MS (APCI) m / z; 756 (M + H), IR (n
ujol) cm ⁻¹ : 1636, 1587. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a foam. MS (APCI) m / z; 756.6 (M + H), IR
(Neat + chloroform) cm ⁻¹ : 1704, 16
34,1589.

Example 255 (1) The corresponding starting material compound was treated in the same manner as in Example 254 (1) to give the compounds shown in Table 11.

[0363]

[Table 58]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 255 (2): difumarate of the compound obtained in Example 255 (1). Amorphous powder, MS (APC
I) m / z; 886 (M + H), IR (Nujol) c
m- ¹ : 3395, 1632.

Example 256 (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Reference Example 2 (5) 255 mg,
4-Piperazino-1-methylpyridinium bromide / hydrobromide (compound obtained in Reference Example 18 (2)) 22
1 mg and 235 mg of triethylamine are dissolved in 3 ml of dimethylformamide, 0.12 ml of diethyl cyanophosphonate is added, and the mixture is stirred at room temperature for 4 hours. The solvent is distilled off, and the residue is purified by NH-silica gel column (chloroform: methanol = 25: 1). The product is dissolved in water to give a strongly basic anion exchange resin IRA-400.
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 'by lyophilizing the product through (Cl) (Organo Co., Ltd.).
-Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [ 4-
(1-Methyl-4-pyridinio) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)-
Isoquinoline] chloride (190 mg, 55% yield) is obtained as a powder. MS (ESI) m / z: 712.3 (M ⁺ ), IR (N
ujol) cm ⁻¹ : 1633, 1653.

Examples 257-261 The corresponding starting materials were treated in the same manner as in Example 256 to give compounds shown in Table 12.

[0367]

[Table 59]

Example 262 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [4- (2-methoxycarbonyl-4-pyridyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] (compound obtained in Example 57 (1))
370 mg, sodium hydroxide 121.1 mg, methanol 6.3 ml, and water 3.2 ml are combined and stirred at room temperature for 16 hours. The solvent is distilled off from the reaction solution, dissolved in an aqueous sodium hydroxide solution, washed with ethyl acetate, the aqueous layer is neutralized with hydrochloric acid, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'. -Dihydro-6 ', 7'-dimethoxy-
2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4- (2-
Carboxyl-4-pyridyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)-
Isoquinoline] (317 mg, yield 87%) is obtained as an amorphous powder. MS (FAB): 742 (M + H), IR (Nujo
l) cm ^<-1> : 1638. (2) The compound (198 mg) obtained in (1) above is dissolved in a mixed solvent of ethanol (5 ml) and water (1 ml), and sodium hydroxide (11 mg) is added to the mixture.
Stir for 0 minutes. By distilling off the solvent and recrystallizing with a mixed solvent of methanol-isopropyl alcohol, (1R
^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (2-carboxyl-4 -
Pyridyl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline].
The sodium salt (117 mg, 57% yield) is obtained as crystals. Melting point 217-220 [deg.] C.

Example 263 (1) By treating the corresponding starting material compound in the same manner as in Example 262 (1), the compounds shown in Table 13 are obtained.

[0370]

[Table 60]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 263 (2): difumarate of the compound obtained in Example 263 (1).

Example 264 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-piperazinylcarbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (compound obtained in Example 55 (1)) and 30 mg of triethylamine in 5 ml of methylene chloride were added to N-methyl-N- (pyridine-) prepared from 2- (methylamino) pyridine and phosgene.
50 mg of 2-yl) carbamoyl chloride is added, and the mixture is stirred at room temperature for 3 hours. After distilling off the solvent, ethyl acetate was added,
The extract is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform:
Methanol: 28% aqueous ammonia = 2000: 100:
By purifying in 5), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2'-ethyl-3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-[[4- [N- (2-pyridyl) -N-methylcarbamoyl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '( 2'H) -isoquinoline] (122 mg, 66% yield) is obtained as an amorphous powder. MS (APCI): 755 (M + H), IR (Nujo
l) cm < ^-1 >: 1659, 1640. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder.

Example 265 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-piperazinylcarbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (the compound obtained in Example 55 (1)) 302 mg, pyrazolyl-1-carboxamidine 86 mg, and diisopropylethylamine 75 mg are dissolved in dimethylformamide 10 ml, and the mixture is stirred at room temperature for 34 hours. Add 21 mg of pyrazolyl-1-carboxamidine and stir at 80 ° C. for 14 hours. The solvent was distilled off, and the residue was purified by NH-silica gel column chromatography to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-
Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[[4-Amidinopiperazin-1-yl] carbonyl]
-Spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (222 mg, 69% yield) is obtained as an amorphous powder. MS (APCI): 663 (M + H), IR (Nujo
1) cm < ^-1 >: 1639,1609. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder.

Example 266 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- (4-nitroso-1-piperazinyl) carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Example 73 (1)) 978 mg 590 mg of zinc powder is added to 50 ml of a 50% aqueous solution of acetic acid under ice-cooling. After stirring at the same temperature for 30 minutes, the mixture is stirred at room temperature for 2 hours. The reaction mixture is ice-cooled, made alkaline with 40% aqueous sodium hydroxide solution, water is added, the mixture is extracted with chloroform, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '.
-Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
(4-Amino-1-piperazinyl) carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (912 mg, yield 95.3%) is obtained as a powder. MS (APCI): 636 (M + H), IR (Nujo)
l) cm ^<-1> : 1634. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder. MS (A
PCI): 636 (M + H), IR (Nujol) cm
^-1 : 1705, 1636.

Example 267 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [4- (2-aminopyridin-4-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Example 52) Compound obtained in (1)) 23
60.8 mg of acetyl chloride is added to a 9 ml solution of 0 mg of pyridine under ice cooling, and the mixture is stirred at the same temperature for 3.5 hours. After distilling off the solvent, ethyl acetate was added and washed with saturated saline,
Dry with sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 150: 5: 1) to obtain (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'- Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-
2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4-
(2-acetamino-4-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline] (189 mg, yield 78
%) As an amorphous powder. MS (APCI): 755 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder. MS (A
PCI): 755 (M + H), IR (Nujol) cm
^-1 : 1638.

Example 268 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-(4-pentenyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-2 -(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- (4-Pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (compound obtained in Example 76 (1)) 3
To a solution of 71 mg of ethanol in 30 ml, 10% of palladium-carbon (300 mg) is added and subjected to atmospheric pressure catalytic reduction under hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was evaporated, and the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-
2'-pentyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4- [4- (4-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)
-Isoquinoline] (315 mg, yield 85%) is obtained as a foam. MS (APCI): 740 (M + H), IR (Nujo
l) cm < ^-1 >: 1639,1592. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a lyophilized powder.

Example 269 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4-
(2-Methoxycarbonyl-4-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] (compound obtained in Example 77 (1)) 250 mg of tetrahydrofuran 5 m
1 solution under ice cooling, a suspension of calcium borohydride (Ca (BH ₄ ) ₂ ) prepared from 59 mg of calcium chloride and 40 mg of sodium borohydride in tetrahydrofuran (S. Daluge et al, J. Org. Chem. , 43, 2311 (1978))
Add. The mixture is stirred at 0 ° C. for 3 hours, ice water is added to stop the reaction, and the solvent is evaporated. After extraction with ethyl acetate, it is dried over sodium sulfate. After distilling off the solvent, thin layer chromatography (chloroform: methanol = 19:
By purifying in 1), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-
Methylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- (2-hydroxymethyl-4)
-Pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (150 mg, 57% yield) is obtained as an amorphous powder. MS (APCI): 919 (M + H). (2) The compound obtained in the above (1) is used in Example 200.
By performing the same processing as (1), (1R ^* , 2R ^* (S
^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4) -Tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4-
(2-Hydroxymethyl-4-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] is obtained as an amorphous powder. MS (APCI): 785.7 (M + H). (3) The compound obtained in (2) above is treated in the same manner as in Example 2 (2) to obtain the difumarate salt of the compound obtained in (2) above. MS (APCI): 785.
7 (M + H).

Example 270 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-
Methylamino) propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- [1- (4-pyridylmethyl) 1H-pyrazolo [3,4-d]
Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline]
(Compound obtained in Example 165 (1)) 500 mg,
To a solution of 63 μl of acetaldehyde and 93 μl of acetic acid in 10 ml of methylene chloride, 179 mg of sodium triacetoxyborohydride (NaBH (OAc) ₃ ) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. 10% Hydrochloric acid is added to the reaction solution to terminate the reaction, the organic layer is extracted with 10% hydrochloric acid, the aqueous layer is made alkaline with potassium carbonate and extracted with chloroform.
The chloroform layer is washed with water and saturated saline and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 500: 10: 1).
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-ethyl-N-methylamino) propionyl] -3', 4 '
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-[[4- [1- (4 -Pyridylmethyl) 1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl] -spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (428 mg, yield 83 %). MS (APCI): 915.5 (M + H), IR (ne
at) cm ⁻¹ : 1638. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as an amorphous powder.

Example 271 (1) By treating the corresponding starting material compound in the same manner as in Example 270 (1), the compounds shown in Table 14 are obtained.

[0380]

[Table 61]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 271 (2): monofumarate of the compound obtained in Example 271 (1).

Example 272 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-benzyloxycarbonyl-N-methylamino) propionyl] -3', 4 ' -Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4- [4-
126 mg of (1-tert-butoxycarbonyl-2-imidazolinyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (compound obtained in Example 144 (1)) 126 mg of chloride 0.4 ml of trifluoroacetic acid is added to a 3 ml solution of methylene, and the mixture is stirred at room temperature for 24 hours. The solvent was evaporated, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated brine and dried over sodium sulfate. The solvent was distilled off and the residue was purified by NH-silica gel column chromatography (chloroform: methanol = 20: 1) to obtain (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3--
(N-benzyloxycarbonyl-N-methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,6 7-dimethoxy-1-isoquinolyl) -4-
[4- (2-Imidazolinyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline] (106 mg, 94% yield) is obtained as an amorphous powder. MS (APCI): 880 (M + H), IR (Nujo
l) cm ⁻¹ : 3200-3500, 1700, 163
5,1612. (2) By treating the compound obtained in (1) above in the same manner as in Example 213, (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2 '-[3- (methylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [4- (2-
Imidazolinyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (72 mg, 90% yield) is obtained as an amorphous powder. MS (APCI): 746.6 (M + H), IR (Nu
jol) cm ⁻¹ : 1635, 1611. (3) By treating the compound obtained in (2) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 272 (3): monofumarate of the compound obtained in Example 272 (2). Amorphous powder, MS (APC
I): 746.7 (M + H), IR (neat + chloroform) cm < ^-1 >: 3414, 1638, 1569.

Example 273 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (1-benzyl-2-imidazolyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H ) -Isoquinoline] (compound obtained in Example 187 (1)) 200 mg, 10%
Palladium-carbon 200 mg, ammonium formate 20
0 mg and 10 ml of methanol are combined and heated under reflux for 2 hours. After cooling the reaction solution, the catalyst is filtered off and the filtrate is distilled off. The residue is dissolved in chloroform and dried over sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to give (1
R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (2-imidazolyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '
(2′H) -isoquinoline] (91 mg, yield 51%)
To get MS (APCI) m / z; 744 (M + H), IR (N
ujol) cm ⁻¹ ; 3700-3100, 1634,
1567,1512. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a powder. MS (APCI) m / z; 744.6 (M + H), IR
(Nujol) cm ^-1 ; 3388, 3140, 163
5,1570.

Example 274 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4- [4- (3-methyl-3H-
1,2,3-triazolo [4,5-d] pyrimidine-7
-Yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline]
(Compound obtained in Example 161 (1)) 223 mg,
A mixture of 568 mg of diisopropylethylamine, 1.18 g of N- (3-bromopropyl) phthalimide and 10 ml of dimethylacetamide is stirred at 100 ° C for 1 hour. Further, 1.36 g of N- (3-bromopropyl) phthalimide is added and stirred at 120 ° C. for 5 hours. After cooling the reaction mixture, ethyl acetate is added, the mixture is washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and silica gel column chromatography (chloroform: methanol = 5)
(1α, 4β) -2 ′ by purification with 0: 1)
-(3-phthalimidopropyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- (3-methyl-3H-1,2,3-triazolo [4,5-d] Pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (200 mg, yield 65%) is obtained as crystals. Melting point 229-230 ° C, MS (FAB): 694 (M +
H), IR (Nujol) cm ⁻¹ : 1711,165
1. (2) To a mixture of 139 mg of the compound obtained in (1) above, 10 ml of ethanol, and 10 ml of tetrahydrofuran, add 150 mg of hydrazine hydrate, and heat and reflux for 4 hours. After cooling the reaction solution, the precipitated crystals are filtered off and the filtrate is distilled off. The residue was subjected to NH-silica gel column chromatography (chloroform: methanol = 5: 1), and then
Neutral silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 200: 10:
By purifying in 1), (1α, 4β) -2′-
(3-Aminopropyl) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-4- [4- [3-methyl-3
H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (118 mg, yield 100%) as an amorphous powder. MS (APCI): 564 (M + H), IR (neat
+ Chloroform) cm ^{- 1} : 3370, 1643. (3) By treating the compound obtained in (2) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (2) above is obtained as a powder. MS (APCI): 564 (M + H), IR (Nujo)
l) cm < ^-1 >: 3387, 1633, 1598.

Examples 275 to 277 The corresponding starting materials are treated in the same manner as in Example 274 (1) to give the compounds shown in Table 15.

[0386]

[Table 62]

Examples 278-288 (1) The corresponding starting materials were treated in the same manner as in Example 274 (2) to give the compounds shown in Table 16.

[0388]

[Table 63]

[0389]

[Table 64]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 278 (2): monofumarate of the compound obtained in Example 278 (1). Powder, MS (APCI): 65
9.5 (M + H), IR (Nujol) cm ⁻¹ : 16
37,1571. Compound 279 (2): monofumarate of the compound obtained in Example 279 (1). Powder, MS (APCI): 67
3.5 (M + H), IR (Nujol) cm ^-1 : 16
37,1571. Compound 280 (2): monofumarate of the compound obtained in Example 280 (1). Amorphous powder, MS (APC
I): 687 (M + H), IR (neat + chloroform) cm < ^-1 >: 3416, 1635, 1571. Compound 281 (2): monofumarate of the compound obtained in Example 281 (1). Powder, MS (APCI): 59
1.5 (M + H), IR (Nujol) cm ^-1 : 33
81, 1629, 1573. Compound 282 (2): monofumarate of the compound obtained in Example 282 (1). Amorphous powder, MS (APC
I): 640.4 (M + H), IR (neat + chloroform) cm ⁻¹ : 3417, 1634, 1573. Compound 283 (2): monofumarate of the compound obtained in Example 283 (1). Powder, MS (APCI): 684
(M + H), IR (Nujol) cm ⁻¹ : 3384,
1632, 1613, 1573. Compound 284 (2): 1-fumarate salt of the compound obtained in Example 284 (1). Powder, MS (APCI): 654
(M + H), IR (Nujol) cm ⁻¹ : 3378,
1617, 1573. Compound 285 (2): monofumarate of the compound obtained in Example 285 (1). Powder, MS (APCI): 640
(M + H), IR (Nujol) cm ⁻¹ : 3375,
1614,1573. Compound 286 (2): 1-fumarate salt of the compound obtained in Example 286 (1). Powder, MS (APCI): 664
(M + H), IR (Nujol) cm ⁻¹ : 3383,
2225, 1633, 1573. Compound 287 (2): monofumarate of the compound obtained in Example 287 (1). Powder, MS (APCI): 719
(M + H), IR (Nujol) cm ⁻¹ : 3387,
1628,1573. Compound 288 (2): monofumarate of the compound obtained in Example 288 (1). Powder, MS (APCI): 654
(M + H), IR (Nujol) cm ⁻¹ : 3385,
1625,1573.

Example 289 (1) (1α, 4β) -2 ′-(3-aminopropyl)
-3 ', 4'-dihydro-6', 7'-dimethoxy-4
-[4- [1- (2-chlorophenylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-
Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (Example 279
160 mg of the compound obtained in (1) and 0.5 ml of 37% formalin aqueous solution are added to a mixed solvent of 5 ml of tetrahydrofuran and 2 ml of acetic acid, and 28.8 mg of sodium borohydride is added little by little under ice cooling. After stirring for 1 hour at the same temperature, saturated aqueous sodium hydrogen carbonate solution is added little by little to make the mixture alkaline, and extracted with chloroform. The extract is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 10:
By purifying in 1), (1α, 4β) -2′-
(3-Dimethylaminopropyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- [1- (2-
Chlorophenylmethyl) -1H-pyrazolo [3,4-
d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)
-Isoquinoline] (104 mg, 62% yield) is obtained as an amorphous powder. MS (APCI): 701 (M + H), IR (Nujo
l) cm < ^-1 >: 1642, 1570. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a powder. MS (APCI): 701.6 (M + H), IR (Nu
jol) cm ⁻¹ : 3396, 1635, 1573.

Examples 290-291 (1) The corresponding starting material compound (the compound obtained in Example 278 (1) or Example 280 (1)) was prepared in Example 289.
By treating in the same manner as in (1), compounds shown in Table 17 are obtained.

[0393]

[Table 65]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 290 (2): monofumarate of the compound obtained in Example 290 (1). Powder, MS (APCI): 68
7.6 (M + H), IR (Nujol) cm ⁻¹ : 17
00, 1635. Compound 291 (2): monofumarate of the compound obtained in Example 291 (1). Amorphous powder, MS (APC
I): 715.5 (M + H), IR (neat + chloroform) cm ⁻¹ : 3425, 1637, 1571.

Example 292 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Compound obtained in Example 162 (1)) 283 m
217 mg of bromoacetyl chloride was slowly added dropwise to a suspension of g of triethylamine (140 mg) in methylene chloride under ice cooling. After stirring at the same temperature for 30 minutes, the solvent is distilled off. Ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give (1α, 4β) -2′-bromoacetyl-.
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (357 mg, yield 100%) is obtained as an amorphous powder. MS (APCI): 738 (M + H), IR (Nujo)
l) cm ^<-1> : 1635. (2) 100 mg of the compound obtained in the above (1), 50%
1 ml of an aqueous dimethylamine solution is added to 2 ml of acetonitrile, and the mixture is stirred at room temperature for 20 hours. After the reaction solution was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 10: 1) to give (1α, 4β) -2 ′-(N, N−).
Dimethylaminoacetyl) -3 ', 4'-dihydro-
6 ', 7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 ′ (2′H) -isoquinoline] (57 mg, yield 63%) is obtained as an amorphous powder. MS (APCI): 701 (M + H), IR (Nujo
l) cm ^<-1> : 1635. (3) By treating the compound obtained in (2) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (2) above is obtained as a powder. MS (APCI): 701.5 (M + H), IR (Nu
jol) cm ⁻¹ : 1639, 1572.

Example 293 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Compound obtained in Example 162 (1)) 149m
g, 1,3-dibromopropane 2.44 g, diisopropylethylamine 310 mg dimethylacetamide 5
The ml solution is stirred at 120 ° C. for 1.5 hours. After cooling the reaction mixture, saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and silica gel column chromatography (chloroform: methanol = 50:
By purifying in 1), (1α, 4β) -2′-
(3-Bromopropyl) -3 ', 4'-dihydro-
6 ', 7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 ′ (2′H) -isoquinoline] (122 mg, yield 69%) is obtained as an amorphous powder. (2) The compound obtained in (1) above is converted into acetonitrile 3
ml and 40% methylamine aqueous solution 1 ml, and the mixture is stirred at room temperature for 13 hours. After distilling off the reaction solution, silica gel column chromatography (chloroform: methanol: 2)
By purifying with 8% aqueous ammonia = 500: 10: 1, (1α, 4β) -2 ′-(3-methylaminopropyl) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy- 4- [4- [1- (2-chlorophenylmethyl))
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (78
mg, yield 68%) as an amorphous powder. MS (APCI): 687 (M + H), IR (Nujo)
l) cm ^<-1> : 1639. (3) By treating the compound obtained in (2) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (2) above is obtained as an amorphous powder. MS (APCI): 687 (M + H), IR (Nujo)
1) cm < ^-1 >: 3417, 1634, 1571.

Example 294 (1) (1α, 4β) -2 ′-[3- (dimethylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-
Dimethoxy-4- [4- (2-amino-4-pyridyl) -1
-Piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Example 137
250 mg of the compound obtained in (1), 141 mg of benzaldehyde and 25 ml of toluene are combined, and a dehydrator is attached and the mixture is heated under reflux for 6 hours. After cooling the reaction solution, the solvent is distilled off. The residue is dissolved in 10 ml of ethanol, and 42 mg of sodium borohydride is added under ice cooling. After stirring overnight at room temperature, the solvent was distilled off from the reaction solution, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. After extraction with ethyl acetate, the extract is washed with saturated brine and dried over sodium sulfate. The solvent was distilled off and silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 100: 1).
(1α, 4β) -2′-by purification with 0: 1)
(3-Dimethylaminopropionyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- (2-benzylamino-4-pyridyl) -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 '(2'H)-
Isoquinoline] (77 mg, yield 29%) is obtained as an amorphous powder. MS (APCI): 655 (M + H), IR (Nujo)
l) cm < ^-1 >: 3340, 1628. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as an amorphous powder. MS (APCI): 655 (M + H), IR (neat
+ ^{Chloroform) cm} - 1: 3408,1633,16
08.

Example 295 (1) (1α, 4β) -2 ′-(4-aminobutyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] (Example 280
(Compound obtained in (1)) 444 mg, sodium hydrogencarbonate 271 mg, dioxane 15 ml, and water 15 ml are vigorously stirred, and benzyloxycarbonyl chloride 0.12 ml is added dropwise under ice cooling. After stirring at room temperature for 30 minutes, the mixture is diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10:
1: 0.1) to obtain (1α, 4β)-
2 '-[4- (benzyloxycarbonylamino) butyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl]-
1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (479 m
g, 90% yield). MS (APCI) m / z; 821 (M + H), IR (n
ujol) cm ⁻¹ ; 1636, 1715. (2) 184 mg of the compound obtained in (1) above, 5 ml of dimethylformamide, and 1 ml of tetrahydrofuran are combined, and under cooling with ice, 53.8 mg of sodium hydride is added, and the mixture is stirred for 1 hour. Add 0.042 ml of methyl iodide and stir at room temperature for 3 hours. The mixture is diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give (1α, 4β).
-2 '-[4- (N-benzyloxycarbonyl-N-methylamino) butyl] -3', 4'-dihydro-6 ',
7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (132.8 mg, 71% yield) is obtained. MS (APCI) m / z; 835.5 (M + H), IR
(Nujol) cm < ^-1 >; 1637, 1698. (3) By treating 125.5 mg of the compound obtained in (2) above in the same manner as in Example 165 (1), (1)
α, 4β) -2 '-[4- (Methylamino) butyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] (91.4 mg,
Yield 86.9%) is obtained as an amorphous powder. MS (APCI) m / z; 701 (M + H), IR (N
ujol) cm ⁻¹ ; 1639, 3419. (4) The compound obtained in (3) above is treated in the same manner as in Example 2 (2) to obtain the monofumarate salt of the compound obtained in (3) above. MS (APCI) m / z; 701.5 (M + H), IR
(Nujol) cm ^-1 ; 3425, 1641, 157.
2.

Example 296 (1) (1α, 4β) -2 ′-(3-aminopropyl)
-3 ', 4'-dihydro-6', 7'-dimethoxy-4
-[4- [1- (2-chlorophenylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-
Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (Example 279
1.14 g of the compound obtained in (1) and 441 mg of diphenylcyanocarbimidate are placed in a mixed solvent of 6 ml of methylene chloride and 18 ml of isopropyl alcohol, and the mixture is stirred at room temperature for 18 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the adduct (1α,
4β) -2 ′-[3- (Cyanimide-phenoxymethyleneamino) propyl] -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (1.4 g, 100% yield) is obtained. MS (APC
I) m / z; 817 (M + H), IR (Nujol) c
m- ¹ ; 2185, 1734, 1635. (2) 463 mg of the compound obtained in (1) above, 5 ml of isopropyl alcohol, and 5 ml of aqueous ammonia are combined and heated at 100 ° C. for 6 hours in a sealed tube. After cooling the reaction mixture, saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol:
(1α, 4β) -2 ′-[3- (2-cyanoguanidino) propyl] -3 ′, 4′-dihydro-by purification with 28% aqueous ammonia = 20: 1: 0.1).
6 ', 7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 ′ (2′H) -isoquinoline] (396 mg, yield 94%) is obtained. MS (APCI) m / z; 740 (M + H), IR (N
ujol) cm ⁻¹ ; 3325, 3175, 2169,
1635. (3) The monofumarate of the compound obtained in (2) above is obtained by treating the compound obtained in (2) above in the same manner as in Example 2 (2). Powder, MS (APCI) m /
z; 740 (M + H), IR (Nujol) cm ⁻¹ ;
3333, 2174, 1705, 1635.

Examples 297-303 (1) The corresponding starting materials were treated in the same manner as in Example 296 (1) (2) to give the compounds shown in Table 18.

[0401]

[Table 66]

[0402]

[Table 67]

[0403]

[Table 68]

(2) Implementation of the compound obtained in (1) above
The following salt was obtained by treating in the same manner as in Example 2 (2).
It Compound 297 (2): Compound obtained in Example 297 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
754 (M + H), IR (Nujol) cm^-132
80, 2167, 1705. Compound 298 (2): Compound obtained in Example 298 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
768 (M + H), IR (Nujol) cm^-121
65, 1706, 1636. Compound 299 (2): Compound obtained in Example 299 (1)
Compound 0.5 fumarate. Powder, MS (APCI) m /
z; 779 (M + H), IR (Nujol) cm ^-1;
2164, 1574. Compound 300 (2): Compound obtained in Example 300 (1)
Compound 0.5 fumarate. Powder, MS (APCI) m /
z; 751 (M + H), IR (Nujol) cm ^-1;
2175, 1576. Compound 301 (2): Compound obtained in Example 301 (1)
Compound 0.5 fumarate. Powder, MS (APCI) m /
z; 765 (M + H), IR (Nujol) cm ^-1;
2167, 1576. Compound 302 (2): Compound obtained in Example 302 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
721.5 (M + H), IR (Nujol) cm ^-1;
3343, 2173, 1701. Compound 303 (2): Compound obtained in Example 303 (1)
Compound monofumarate. Powder, MS (APCI) m / z;
968.6 (M + H), IR (Nujol) cm ^-1;
2166, 1703, 1629.

Example 304 (1) (1α, 4β) -2 ′-(3-aminopropyl)
-3 ', 4'-dihydro-6', 7'-dimethoxy-4
-[4- [1- (2-chlorophenylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-
Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (Example 279
A mixed solution of 528 mg of the compound obtained in (1) and 260 mg of 1,1-bis (methylthio) -2-nitroethylene in 5 ml of tetrahydrofuran and 10 ml of isopropyl alcohol is stirred at room temperature for 22 hours, and then heated under reflux for 3 hours. . The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give the adduct (1α,
4β) -2 ′-[3- (1-methylthio-2-nitro-vinylamino) propyl] -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (574 mg, 93% yield) is obtained. MS (ESI) m / z; 790.4 (M + H), IR
(Nujol) cm < ^-1 >; 1638,3480. (2) A mixed solution of 148 mg of the compound obtained in (1) above in 3 ml of dioxane, 3 ml of isopropanol and 1 ml of an aqueous dimethylamine solution is stirred at room temperature for 18 hours. By distilling off the solvent and purifying the residue by NH-silica gel column chromatography (chloroform),
(1α, 4β) -2 ′-[3- (1-dimethylamino-
2-Nitro-vinylamino) propyl] -3 ', 4'-
Dihydro-6 ', 7'-dimethoxy-4- [4- [1-
(2-chlorophenylmethyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] -1-piperazinyl]
Carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (124 mg, 84% yield). MS (ESI) m / z; 787.4 (M + H), IR (N
ujol) cm ⁻¹ ; 1637,3463. (3) By treating the compound obtained in (2) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (2) above is obtained as a powder. MS (ESI) m
/ Z; 809 (M + Na), 787 (M + H), IR
(Nujol) cm ^-1 ; 1699, 1617, 157.
0.

Examples 305-312 (1) The corresponding starting materials were treated in the same manner as in Examples 304 (1) (2) to give the compounds shown in Table 19.

[0407]

[Table 69]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 305 (2): monofumarate of the compound obtained in Example 305 (1). Powder, MS (ESI) m / z; 7
95 (M + Na), 773 (M + H), IR (Nujo
1) cm < ^-1 >; 1701, 1623, 1573. Compound 306 (2): monofumarate of the compound obtained in Example 306 (1). Powder, MS (ESI) m / z; 7
81 (M + Na), 759 (M + H), IR (Nujo
1) cm < ^-1 >; 1699, 1614, 1574. Compound 307 (2): dicitrate salt of the compound obtained in Example 307 (1). Powder, MS (ESI) m / z; 7
96.5 (M-H), IR (Nujol) cm - 1; 1
724, 1665, 1610. Compound 308 (2): the dicitrate salt of the compound obtained in Example 308 (1). Powder, MS (ESI) m / z; 7
92 (M + Na), 770 (M + H), IR (Nujo
1) cm < ^-1 >; 1720,1610. Compound 309 (2): dicitrate salt of the compound obtained in Example 309 (1). Powder, MS (ESI) m / z; 7
82 (M-H), IR (Nujol) cm ^-1 ; 172
5,1612. Compound 310 (2): citrate salt of the compound obtained in Example 307 (1). Compound 311 (2): citrate salt of the compound obtained in Example 308 (1). Compound 312 (2): Citrate salt of the compound obtained in Example 309 (1).

Example 313 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 ′-[3- (methylamino) propionyl] -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) In a solution of 10.0 g of the compound obtained in (1)) and 1.71 g of triethylamine in 100 ml of methylene chloride, propanoyloxymethylcarbonochloridate (propanoyloxymethylcarbo) was added.
nochlordate: FJLundet et al, Synth
esis (1990) 1159.) 2.50 g methylene chloride 30 m
1 solution is added dropwise under ice cooling. After stirring at the same temperature for 1 hour, the mixture is stirred at room temperature for 1 hour. The reaction solution is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent is evaporated. By purifying the residue by silica gel column chromatography (chloroform: methanol = 50: 1), (1R ^* , 2R ^* (S ^* ), 4R ^* )-
2 '-[3- [N- (propionyloxymethyloxycarbonyl) -N-methylamino] propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [4- [1-
(4-Pyridylmethyl) -1H-pyrazolo [3,4-
d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)
-Isoquinoline] (6.90 g, 60% yield) is obtained as crystals. Melting point 160-161 ° C, MS (APCI): 1017.
5 (M + H), IR (Nujol) cm ⁻¹ : 175
5,1721,1641. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a powder. MS (APCI): 1017 (M + H), IR (Nuj
ol) cm ⁻¹ : 3397, 1751, 1708, 16
35.

Example 314 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) 0.55 g of the compound obtained in (1) and 0.1 ml of triethylamine in 8 ml of methylene chloride,
A solution of 128 mg of 2- (chloromethyloxycarbonyloxy) -pyridine in 2 ml of methylene chloride is added dropwise under ice cooling. After stirring at 4 ° C for 20 minutes, ethyl acetate is added, washed with water and saturated saline, and dried over magnesium sulfate. After distilling off the solvent, the residue is azeotropically distilled with toluene. (2) Residue obtained in (1) above, cesium carbonate 1.1
1g, Molecular Sieves 3A (MS3A) 1.1
1 g, propionic acid 0.185 ml, acetonitrile 1
Heat 5 ml of the mixture to reflux for 6 hours. After cooling the reaction solution, ethyl acetate is added and the insoluble matter is filtered through Celite. The filtrate is washed with water and saturated saline and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give (1R ^* ,
2R ^* (S ^* ), 4R ^* )-2 '-[3- [N- (propionyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) 1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-
Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (430 mg, yield 68%: the compound obtained in Example 313 (1)) is obtained as crystals. Melting point 160-161 [deg.] C.

Example 315 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3-
(Methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- [3-methyl-3H-1,
2,3-Triazolo [4,5-d] pyrimidin-7-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (obtained in Example 241 (1)) Compound) 250 mg, cesium carbonate 512 mg, molecular sieves 3A (MS
3A) To 460 mg of powder and 8 ml of acetonitrile, 0.03 ml of chloromethyl chloroformate was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Pivalic acid 12 was added to the reaction solution.
Add 6 mg and heat to reflux for 4 hours. After cooling the reaction solution, inorganic substances are filtered off and washed with ethyl acetate. After evaporating the filtrate,
It is dissolved in ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate.
After the solvent was distilled off, the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give (1R ^* , 2R ^*
(S ^* ), 4R ^* )-2 '-[3- [N- (pivaloyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-6 ', 7'- Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4
-[4- [3-Methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (215 mg, yield 72
%) As an amorphous powder. MS (APCI): 969 (M + H), IR (Nujo)
l) cm ⁻¹ : 1746, 1721, 1639, 159
7. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a powder. MS (APCI): 969 (M + H), IR (Nujo)
l) cm < ^-1 >: 3133, 1713, 1635.

Examples 316-361 (1) Corresponding starting material compounds were obtained from Examples 313 (1), 314.
By treating in the same manner as (1) (2) or 315 (1), the compounds shown in Table 20 are obtained.

[0413]

[Table 70]

[0414]

[Table 71]

[0415]

[Table 72]

[0416]

[Table 73]

[0417]

[Table 74]

[0418]

[Table 75]

[0419]

[Table 76]

[0420]

[Table 77]

[0421]

[Table 78]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 316 (2): difumarate salt of the compound obtained in Example 316 (1). Compound 317 (2): The difumarate salt of the compound obtained in Example 317 (1). Compound 318 (2): The difumarate salt of the compound obtained in Example 318 (1). Compound 319 (2): difumarate of the compound obtained in Example 319 (1). Compound 320 (2): The difumarate salt of the compound obtained in Example 320 (1). Powder, MS (APCI): 92
8.6 (M + H), IR (Nujol) cm ⁻¹ : 31
31, 1707, 1636. Compound 321 (2): difumarate of the compound obtained in Example 321 (1). Powder, MS (APCI): 85
9.5 (M + H), IR (Nujol) cm ⁻¹ : 31
35, 1705, 1657. Compound 322 (2): The difumarate salt of the compound obtained in Example 322 (1). Powder, MS (APCI): 91
3.5, (M + H), IR (Nujol) cm ⁻¹ : 1
747, 1714, 1667, 1637. Compound 323 (2): difumarate of the compound obtained in Example 323 (1). Powder, MS (APCI): 984
(M + H), IR (Nujol) cm ⁻¹ : 3131,
1710, 1637. Compound 324 (2): The difumarate salt of the compound obtained in Example 324 (1). Compound 325 (2): The difumarate salt of the compound obtained in Example 325 (1). Powder, [α] _D −33.8 ° (c
1.0, ethanol). Compound 326 (2): difumarate salt of the compound obtained in Example 326 (1). Powder, [α] _D −34.39 °
(C1.0, ethanol), MS (APCI): 92
9.4 (M + H), IR (Nujol) cm ⁻¹ : 31
33, 1708, 1635. Compound 327 (2): difumarate of the compound obtained in Example 327 (1). Compound 328 (2): difumarate salt of the compound obtained in Example 328 (1). Powder, MS (APCI): 957
(M + H), IR (Nujol) cm ⁻¹ : 3131,
1706, 1637. Compound 329 (2): difumarate salt of the compound obtained in Example 329 (1). Powder, MS (APCI): 101
0 (M + H), IR (Nujol) cm ⁻¹ : 313
5,1708,1634. Compound 330 (2): The difumarate salt of the compound obtained in Example 330 (1). Powder, MS (APCI): 104
5 (M + H), IR (Nujol) cm < ^-1 >: 313
3,1709,1633. Compound 331 (2): difumarate of the compound obtained in Example 331 (1). Compound 332 (2): difumarate of the compound obtained in Example 332 (1). Powder, [α] _D + 40.2 ° (c
1.0, ethanol), MS (APCI): 969 (M
+ H), IR (Nujol) cm ^-1 : 3081,17
49, 1713, 1666. Compound 333 (2): The difumarate salt of the compound obtained in Example 333 (1). Powder, [α] _D + 29 ° (c0.
5, ethanol), MS (APCI): 1045 (M +
H). Compound 334 (2): difumarate of the compound obtained in Example 334 (1). Amorphous powder, [α] _D -3
8.8 ° (c1.0, ethanol), MS (APC
I): 1045.5 (M + H), IR (Nujol) c
m- ¹ : 1745, 1714, 1665, 1639. Compound 335 (2): The difumarate salt of the compound obtained in Example 335 (1). Powder, [α] _D -43.0 ° (c
1.0, ethanol), MS (APCI): 969.5.
(M + H), IR (Nujol) cm ⁻¹ : 3084,
1714, 1637. Compound 336 (2): The difumarate salt of the compound obtained in Example 336 (1). Compound 337 (2): The difumarate salt of the compound obtained in Example 337 (1). Powder, [α] _D −37.24 °
(C1.0, ethanol), MS (APCI): 104
5.5 (M + H), IR (Nujol) cm ⁻¹ : 31
29, 1710, 1635. Compound 338 (2): The difumarate salt of the compound obtained in Example 338 (1). Powder, [α] _D + 40.2 ° (c
1.0, ethanol), MS (APCI): 1078
(M + H). Compound 339 (2): difumarate of the compound obtained in Example 339 (1). Powder, [α] _D + 17.9 ° (c
1.0, ethanol), MS (APCI): 1045
(M + H). Compound 340 (2): The difumarate salt of the compound obtained in Example 340 (1). Compound 341 (2): difumarate of the compound obtained in Example 341 (1). Powder, MS (APCI): 99
6.6 (M + H), IR (Nujol) cm ⁻¹ : 31
33, 1711, 1633. Compound 342 (2): difumarate of the compound obtained in Example 342 (1). Compound 343 (2): difumarate of the compound obtained in Example 343 (1). Powder, MS (APCI): 107
8.7 (M + H), IR (Nujol) cm ⁻¹ : 31
30, 1711, 1633. Compound 344 (2): The difumarate salt of the compound obtained in Example 344 (1). Powder, MS (APCI): 106
5.5 (M + H), IR (Nujol) cm ⁻¹ : 31
28, 1710, 1633. Compound 345 (2): The difumarate salt of the compound obtained in Example 345 (1). Powder, MS (APCI): 107
1.5 (M + H), IR (Nujol) cm ^-1 : 31
30, 1710, 1633. Compound 346 (2): The difumarate salt of the compound obtained in Example 346 (1). Amorphous powder, MS (APC
I): 1031 (M + H), IR (neat + chloroform) cm ⁻¹ : 1715, 1635. Compound 347 (2): difumarate salt of the compound obtained in Example 347 (1). Powder, MS (APCI): 103
1 (M + H), IR (Nujol) cm ⁻¹ : 170
7,1653,1636. Compound 348 (2): The difumarate salt of the compound obtained in Example 348 (1). Powder, MS (APCI): 100
3 (M + H), IR (Nujol) cm < ^-1 >: 341
5,1757,1707,1651. Compound 350 (2): The difumarate salt of the compound obtained in Example 350 (1). Powder, MS (APCI): 102
9 (M + H), IR (Nujol) cm ^-1 : 340
9, 1710, 1634. Compound 351 (2): difumarate of the compound obtained in Example 351 (1). Powder, MS (FAB): 968
(M + H), IR (Nujol) cm ⁻¹ : 3429,
1752, 1711, 1633. Compound 352 (2): difumarate of the compound obtained in Example 352 (1). Powder, MS (APCI): 93
8.7 (M + H), IR (Nujol) cm ⁻¹ : 31
32, 1700, 1635. Compound 353 (2): difumarate of the compound obtained in Example 353 (1). Powder, MS (APCI): 980
(M + H), IR (Nujol) cm ⁻¹ : 1712,
1634. Compound 354 (2): The difumarate salt of the compound obtained in Example 354 (1). Powder, MS (APCI): 982
(M + H), IR (Nujol) cm ⁻¹ : 1711
1633. Compound 355 (2): The difumarate salt of the compound obtained in Example 355 (1). Powder, MS (APCI): 996
(M + H), IR (Nujol) cm ⁻¹ : 3419,
1711, 1635. Compound 356 (2): The difumarate salt of the compound obtained in Example 356 (1). Powder, MS (APCI): 101
0 (M + H), IR (Nujol) cm ⁻¹ : 171
0,1631. Compound 357 (2): The difumarate salt of the compound obtained in Example 357 (1). Powder, MS (APCI): 982
(M + H), IR (Nujol) cm ⁻¹ : 3129,
1710, 1635. Compound 358 (2): The difumarate salt of the compound obtained in Example 358 (1). Powder, MS (APCI): 102
2.6 (M + H), IR (Nujol) cm ⁻¹ : 31
28, 1711, 1635. Compound 359 (2): The difumarate salt of the compound obtained in Example 359 (1). Powder, MS (APCI): 100
8.8 (M + H), IR (Nujol) cm ⁻¹ : 34
25, 1711, 1633. Compound 360 (2): The difumarate salt of the compound obtained in Example 360 (1). Powder, MS (APCI): 99
6.7 (M + H), IR (Nujol) cm ⁻¹ : 34
31, 1713, 1634. Compound 361 (2): dicitrate salt of the compound obtained in Example 361 (1). Powder, MS (APCI): 842
(M + H), IR (Nujol) cm ^-1 : 3362,
2610, 1732, 1634.

Example 362 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) 2 mg in a solution of 200 mg of the compound obtained in (1)) and 57 mg of triethylamine in 8 ml of methylene chloride.
-(Chloromethyloxycarbonyloxy) pyridine 1
A solution of 33 mg of methylene chloride in 2 ml is added dropwise under ice cooling. After stirring at 4 ° C for 30 minutes, ethyl acetate is added, the mixture is washed with water and saturated brine, dried over magnesium sulfate, and the solvent is evaporated. Tetrabutylammonium iodide (tetra)
butyllammonium iodide) 166m
g, cesium carbonate 367 mg, and ethanol 52 mg in a suspension, the above crude product dimethylformamide 7
Add ml solution and stir vigorously at room temperature while bubbling carbon dioxide. After 2 hours, 367 mg of cesium carbonate and 208 mg of ethanol were added, and the mixture was further stirred at 50-60 ° C for 4 hours. Ethyl acetate is added to the reaction solution, which is washed with water and saturated saline and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1).
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- [N-
(Ethoxycarbonyloxymethyloxycarbonyl)
-N-methylamino] propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (167 mg, yield 43%) is obtained as amorphous powder. MS (APCI): 1033.5 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a powder. MS (APCI): 1033.6 (M + H), IR (N
ujol) cm ⁻¹ : 3131, 1757, 1710.

Examples 363-367 (1) The corresponding starting materials were treated in the same manner as in Example 362 (1) to give the compounds shown in Table 21.

[0425]

[Table 79]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 363 (2): difumarate of the compound obtained in Example 363 (1). Powder, MS (APCI): 104
7.6 (M + H), IR (Nujol) cm ⁻¹ : 34
10, 3129, 1758, 1710. Compound 364 (2): The difumarate salt of the compound obtained in Example 364 (1). Powder, MS (APCI): 108
7.5 (M + H), IR (Nujol) cm ⁻¹ : 34
08, 3129, 1752, 1710. Compound 365 (2): the difumarate salt of the compound obtained in Example 365 (1). Powder, MS (APCI): 101
9.4 (M + H), IR (Nujol) cm ⁻¹ : 34
09, 3131, 1761, 1709. Compound 366 (2): The difumarate salt of the compound obtained in Example 366 (1). Powder, MS (APCI): 104
7.5 (M + H), IR (Nujol) cm ⁻¹ : 31
27,1751,1715. Compound 367 (2): The difumarate salt of the compound obtained in Example 367 (1). Powder, MS (APCI): 107
3.5 (M + H), IR (Nujol) cm ^-1 : 31
28, 1753, 1710.

Example 368 (1) triphosgene 446 mg methylene chloride 10 ml
In solution, 4-hydroxymethyl-5-methyl-1,3
-Dioxole-2-one (M. Alpegani
et al, Synthetic Communicat
ion, 22, 1277 (1992)) 583 mg of salt
A 5 ml solution of methylene chloride is added dropwise under ice cooling. Then,
Isopropylethylamine 585 mg of methylene chloride 5
Slowly add the ml solution. Stir at the same temperature for 2.5 hours
After that, excess phosgene is degassed. (1R^*, 2R
^*(S^*), 4R^*) -2 '-[3- (Methylamino) propio
Nyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy
Ci-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-pi
Perazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (in Example 165 (1)
Obtained compound) 1.00 g, diisopropylethyl acetate
A solution of 291 mg of min in 5 ml of methylene chloride was cooled with ice,
Add dropwise to the above reaction solution. After 5 minutes, add ice water and add the solvent.
Distill off. Dissolve the residue in ethyl acetate, water, saturated carbonated water.
After washing with sodium hydroxide solution, dry it with sodium sulfate.
It After evaporation of the solvent, silica gel column chromatography
Purify with (chloroform: methanol = 30: 1)
By, (1R ^*, 2R^*(S^*), 4R^*) -2 '-[3
-[N-[(5-methyl-2-oxo-1,3-dioki
Sole-4-yl) methyloxycarbonyl] -N-me
Cylamino] propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-tetrahydro-6,7-dimethoxy-1-iso
Quinolyl) -4- [4- [1- (4-pyridylmethyl))
-1H-pyrazolo [3,4-d] pyrimidin-4-i
]-1-Piperazinyl] carbonyl-spiro [cyclo
Hexane-1,1 '(2'H) -isoquinoline] (27
3 mg, yield 23%) is obtained as an amorphous powder. MS (APCI): 1043.5 (M + H), IR (N
ujol) cm^-1: 1817, 1736, 1703
1635. (2) The compound obtained in (1) above is referred to as Example 2 (2).
By performing the same processing, the compound obtained in (1) above
The difumarate of the product is obtained as a powder. MS (APCI): 1043.5 (M + H), IR (N
ujol) cm^-1: 3131, 1815, 1704.

Examples 369-377 (1) The corresponding starting materials were treated in the same manner as in Example 368 (1) to give compounds shown in Table 22.

[0429]

[Table 80]

[0430]

[Table 81]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 369 (2): The difumarate salt of the compound obtained in Example 369 (1). Powder, [α] _D + 48.19 °
(C1.0, ethanol), MS (APCI): 967
(M + H), IR (Nujol) cm ⁻¹ : 3133,
1817, 1706. Compound 370 (2): The difumarate salt of the compound obtained in Example 370 (1). Powder, [α] _D −49.4 ° (c
1.0, ethanol), MS (APCI): 967.6.
(M + H), IR (Nujol) cm ⁻¹ : 3133,
1818, 1706. Compound 371 (2): difumarate of the compound obtained in Example 371 (1). Powder, MS (APCI): 967
(M + H), IR (Nujol) cm ⁻¹ : 3133,
1817, 1705. Compound 372 (2): difumarate of the compound obtained in Example 372 (1). Powder, MS (APCI): 110
5.5 (M + H), IR (Nujol) cm < ^-1 >: 34
04, 1821, 1759, 1704, 1651. Compound 373 (2): difumarate salt of the compound obtained in Example 373 (1). Powder, MS (APCI): 108
5.6 (M + H), IR (Nujol) cm ⁻¹ : 34
09, 3132, 1811, 1703. Compound 374 (2): The difumarate salt of the compound obtained in Example 374 (1). Powder, MS (APCI): 105
7 (M + H), IR (Nujol) cm ⁻¹ : 181
9, 1703, 1652. Compound 375 (2): the difumarate salt of the compound obtained in Example 375 (1). Powder, MS (APCI): 107
1 (M + H), IR (Nujol) cm ⁻¹ : 339
1,1816,1701,1635. Compound 376 (2): difumarate salt of the compound obtained in Example 376 (1). Powder, MS (APCI): 107
1 (M + H), IR (Nujol) cm ^-1 : 340
7,1703,1636. Compound 377 (2): The difumarate salt of the compound obtained in Example 377 (1). Amorphous powder, MS (APC
I): 994.7 (M + H), IR (neat + chloroform) cm ⁻¹ : 1820, 1704, 1667, ¹
639.

Example 378 (1) 4-acetoxybenzyl alcohol 337 mg,
Di (2-pyridyl) carbonate (AK Ghosh
et al, Tetrahedron Letter
1991, 32 (34) 4251. ) 292 mg and triethylamine 205 mg were added to methylene chloride 5 ml,
Stir overnight at room temperature. Into the reaction mixture, (1R ^* , 2R
^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2-
(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl))
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
665 mg of 1 ′ (2′H) -isoquinoline] (the compound obtained in Example 165 (1)) is added, and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated, ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine. After drying over sodium sulfate and evaporating the solvent, silica gel column chromatography (chloroform: methanol = 50: 1)
By purification with (1R ^* , 2R ^* (S ^* ), 4R ^* )-
2 '-[3- [N- (4-acetoxybenzyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-
Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H-pyrazolo
[3,4-d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (697 mg, yield 86.1%) as amorphous powder obtain. MS (APCI): 1079.6 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a powder. MS (APCI): 1079.6 (M + H), IR (N
ujol) cm ⁻¹ : 1759, 1698, 1650.

Examples 379-385 (1) The corresponding starting materials were treated in the same manner as in Example 378 (1) to give compounds as shown in Table 23.

[0434]

[Table 82]

[0435]

[Table 83]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 379 (2): The difumarate salt of the compound obtained in Example 379 (1). Powder, MS (APCI): 114
1.5 (M + H), IR (Nujol) cm ⁻¹ : 16
98, 1634. Compound 380 (2): The difumarate salt of the compound obtained in Example 380 (1). Powder, MS (APCI): 112
1.6 (M + H), IR (Nujol) cm ⁻¹ : 31
25,1751,1700,1635. Compound 381 (2): difumarate of the compound obtained in Example 381 (1). Amorphous powder, MS (APC
I): 1109.6 (M + H), IR (neat + chloroform) cm ⁻¹ : 1759, 1700, 1637. Compound 382 (2): difumarate salt of the compound obtained in Example 382 (1). Powder, MS (APCI): 115
5.6 (M + H), IR (Nujol) cm ⁻¹ : 34
09, 3127, 1762, 1701, 1635. Compound 383 (2): difumarate salt of the compound obtained in Example 383 (1). Amorphous powder, MS (APC
I): 1151.7 (M + H), IR (neat + chloroform) cm ⁻¹ : 1757, 1693, 1640. Compound 384 (2): The difumarate salt of the compound obtained in Example 384 (1). Powder, MS (APCI): 115
1.6 (M + H), IR (Nujol) cm ⁻¹ : 31
29, 1711, 1635. Compound 385 (2): difumarate of the compound obtained in Example 385 (1). Powder, MS (APCI): 112
1.7 (M + H), IR (neat + chloroform) c
m- ¹ : 1746,1693.

Example 386 (1) 2-Benzoyloxymethylbenzoic acid chloride 1
Into a solution of 08 mg of methylene chloride in 7 ml, (1R ^* , 2R ^*
(S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2--
(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (1-propyl-1H-pyrazolo [3,4-d] pyrimidine-4- Iyl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (compound obtained in Example 236 (1)) (300 mg) and triethylamine (0.074 ml) in methylene chloride (1.5 ml) were added dropwise under ice cooling.
Stir for 30 minutes at the same temperature. The reaction mixture is added to ice water, extracted with methylene chloride, the organic layer is dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 4: 1) to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '.
-[3- [N- (2-benzoyloxymethylbenzoyl)
-N-methylamino] propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-
Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- [1-Propyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (380
mg, yield 99%) as an amorphous powder. MS (APCI): 1076 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the difumarate salt of the compound obtained in (1) above is obtained as a powder. MS (APCI): 1076 (M + H), IR (Nuj
ol) cm ⁻¹ : 1714, 1631.

Examples 387-399 (1) The corresponding starting materials were treated in the same manner as in Example 386 (1) to give compounds shown in Table 24.

[0439]

[Table 84]

[0440]

[Table 85]

[0441]

[Table 86]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 387 (2): The difumarate salt of the compound obtained in Example 387 (1). Powder, MS (APCI): 101
4 (M + H), IR (Nujol) cm ^-1 : 312
9, 1711, 1631. Compound 388 (2): The difumarate salt of the compound obtained in Example 388 (1). Powder, MS (APCI): 109
0 (M + H), IR (Nujol) cm ⁻¹ : 171
5,1629,1572. Compound 389 (2): The difumarate salt of the compound obtained in Example 389 (1). Powder, MS (APCI): 112
5 (M + H), IR (Nujol) cm ^-1 : 312
3,1713,1628,1573. Compound 390 (2): The difumarate salt of the compound obtained in Example 390 (1). Powder, MS (APCI): 112
5 (M + H), IR (Nujol) cm ^-1 : 312
4,1713,1630. Compound 391 (2): difumarate salt of the compound obtained in Example 391 (1). Powder, MS (APCI): 104
9 (M + H), IR (Nujol) cm ⁻¹ : 342
1,1715,1629. Compound 392 (2): difumarate of the compound obtained in Example 392 (1). Powder, MS (APCI): 113
8 (M + H), IR (Nujol) cm ⁻¹ : 343
1,1716,1632. Compound 393 (2): difumarate of the compound obtained in Example 393 (1). Powder, MS (APCI): 112
5 (M + H), IR (Nujol) cm ^-1 : 347
4,1722,1633. Compound 394 (2): The difumarate salt of the compound obtained in Example 394 (1). Powder, MS (APCI): 115
8.5 (M + H), IR (Nujol) cm ⁻¹ : 34
47,1721,1635. Compound 395 (2): The difumarate salt of the compound obtained in Example 395 (1). Powder, MS (APCI): 99
9.5 (M + H), IR (Nujol) cm ⁻¹ : 34
32, 1760, 1635. Compound 396 (2): The difumarate salt of the compound obtained in Example 396 (1). Powder, MS (APCI): 107
5.6 (M + H), IR (Nujol) cm ⁻¹ : 34
14, 1759, 1707. Compound 397 (2): the difumarate salt of the compound obtained in Example 397 (1). Powder, MS (APCI): 111
7.7 (M + H), IR (Nujol) cm ⁻¹ : 34
12, 3129, 1751, 1706. Compound 398 (2): difumarate salt of the compound obtained in Example 398 (1). Powder, MS (APCI): 113
7.6 (M + H), IR (Nujol) cm ⁻¹ : 34
13, 1707. Compound 399 (2): difumarate salt of the compound obtained in Example 399 (1). Amorphous powder, MS (APC
I): 1105.7 (M + H), IR (neat + chloroform) cm ⁻¹ : 1759, 1705, 1681.

Example 400 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) (Compound obtained in (1)) 200 mg of formic acid 2
0.21 ml of acetic anhydride is added to the ml solution under ice cooling, and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated, the residue is diluted with ethyl acetate and the solution is poured into 10% aqueous potassium carbonate solution. The aqueous layer is extracted with ethyl acetate, the organic layers are combined, washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1) to give (1R ^* ,
2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-formyl-N-
Methylamino) propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-
[4- [1- (4-pyridylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (179 mg, yield 87%) is obtained as an amorphous powder. MS (APCI): 915 (M + H), IR (Nujo
l) cm < ^-1 >: 1732, 1668. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a powder. MS (APCI): 915 (M + H), IR (Nujo
l) cm < ^-1 >: 3411, 1704, 1659.

Example 401 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) 21 μl of ethyl chlorocarbonate was added to a mixture of 200 mg of the compound obtained in (1) 2 ml of ethyl acetate and 62 mg of potassium carbonate in 2 ml of water under ice cooling. After stirring for 1.5 hours at the same temperature, dilute with ethyl acetate,
The organic layer is washed with water and saturated saline. After drying over sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1) to give (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3 -(N-Ethoxycarbonyl-N-methylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (212 mg, 98% yield) is obtained as an amorphous powder. MS (APCI): 959.5 (M + H), IR (Nu
jol) cm < ^-1 >: 1694. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a powder. MS (APCI): 959 (M + H), IR (Nujo)
l) cm < ^-1 >: 1691, 1632.

Example 402 (1) (1R^*, 2R^*(S^*), 4R^*) -2 '-[3- (Met
Luamino) propionyl] -3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahi
Doro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1-
Propyl-1H-pyrazolo [3,4-d] pyrimidin-4-y
] -1-Piperazinyl] carbonyl-spiro [cyclohexa]
N-1,1 '(2'H) -isoquinoline] (Example 236
(Compound obtained in (1)) 500 mg and triethylami
Solution in 0.13 ml of methylene chloride in 10 ml of ice
Below, add 83 μl of butyl chlorocarbonate. 1 hour at the same temperature
After stirring, the solvent was distilled off, ethyl acetate was added to the residue, water,
Wash with saturated saline. After drying over sodium sulfate, remove the solvent
The residue was distilled off and the residue was subjected to silica gel column chromatography.
Purify with (chloroform: methanol = 20: 1)
By, (1R^*, 2R^*(S ^*), 4R^*) -2 '-[3-
(N-butoxycarbonyl-N-methylamino) propyi
Onyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimeth
Xy-1-isoquinolyl) -4- [4- [1-propyl-1H-pi
Lazolo [3,4-d] pyrimidin-4-yl] -1-piperazini
Lu] carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (560 mg, 100% yield)
Obtained as morphus powder. MS (APCI): 938.6 (M + H), IR (Nu
jol) cm^-1: 1697, 1637. (2) The compound obtained in (1) above is referred to as Example 2 (2).
By performing the same processing, the compound obtained in (1) above
The difumarate of the product is obtained as a powder. MS (APCI): 938.7 (M + H), IR (Nu
jol) cm^-1: 3428, 3132, 1700, 1
635.

Example 403 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1--
(4-Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Example 165) (Compound obtained in (1)) 800 mg, t-butoxycarbonylglycine 190 mg, triethylamine 0.38 ml, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride 233 mg, 1-
A mixture of 183 mg of hydroxybenzotriazole and 20 ml of methylene chloride is stirred at room temperature for 13 hours. The reaction mixture is diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate.
After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1) to give (1R ^* ,
2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-tert-butoxycarbonylaminoacetyl-N-methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy -2- (2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H-pyrazolo [3, 4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (978 mg, 100% yield) is obtained as an amorphous powder. MS (APCI): 1044.5 (M + H), IR (N
ujol) cm ⁻¹ : 1711. (2) To a solution of 961 mg of the compound obtained in (1) above in 5 ml of methylene chloride, 5 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 15 hours. The solvent is distilled off, and a 10% aqueous potassium carbonate solution is added to make it alkaline. After extraction with chloroform, the organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol:
By refining with 28% ammonia water = 20: 1: 0.1), (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 ′-[3-
(N-Aminoacetyl-N-methylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2
-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline] (846 mg, yield 96%)
As an amorphous powder. MS (APCI): 944.5 (M + H), IR (Nu
jol) cm ⁻¹ : 3373, 1635. (3) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a powder. MS (APCI): 944 (M + H), IR (Nujo)
l) cm < ^-1 >: 3398, 1633, 1573.

Example 404 (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Reference Example 12)
The compound obtained in (4) is treated in the same manner as in Example 52 (1) to give (1α, 4β) -3 ′, 4′-dihydro.
-6 ', 7'-dimethoxy-4- [4- [1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1
-Piperazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] is obtained as an amorphous powder. MS (APCI) m / z; 627 (M + H).

Example 405 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
1.226 g of 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 16 (1))
And triethylamine 2.915 g of methylene chloride 10 ml, under ice cooling, chloroacetyl chloride 0.51 ml of methylene chloride 10 ml.
Add the ml solution dropwise and stir at the same temperature for 2 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated. Silica gel column chromatography of the residue (chloroform: methanol = 50: 1)
By purification with (1α, 4β) -2′-chloroacetyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 ′ (2 'H) -isoquinoline] 1.35 g is obtained as an oil. MS (APCI) m / z; 472 (M + H), IR (n
eat) cm ⁻¹ ; 1727, 1661. (2) 1.334 g of the compound obtained in (1) above was added to 20
It is dissolved in ml of acetonitrile, 10 ml of 50% dimethylamine aqueous solution is added, and the mixture is stirred at room temperature overnight. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1α, 4β) -2 ′-(N, N-dimethylaminoacetyl) -3 ′, 4. '-Dihydro-6', 7'-
Dimethoxy-4-benzyloxycarbonyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline]
1.34 g are obtained as an oil. MS (APCI) m / z; 481 (M + H), IR (n
EAT) cm ^-1 ; 1731, 1658, 1651, 16
33. (3) 1.32 g of the compound obtained in the above (2) was dissolved in 20 ml of methanol to obtain 10% palladium-carbon 263.
Add mg and hydrogenate at atmospheric pressure. After 24 hours, the catalyst was filtered off and the solvent was distilled off to give (1α, 4β) -2′-
(N, N-Dimethylaminoacetyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4-carboxyl-
0.99 g of spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained. Melting point 223-235 [deg.] C. (decomposition), MS (APCI) m /
z; 391 (M + H), IR (Nujol) cm ^-1 ; 1
671. (4) By treating the compound obtained in (3) above in the same manner as in Example 52 (1), (1α, 4β) -2 ′-(N,
N-dimethylaminoacetyl) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-4- [4- [1- (3-methylbenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1
-Piperazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] is obtained as a crystalline powder. Melting point 116-118 ° C, MS (APCI) m / z; 68
1 (M + H). (5) The compound obtained in (4) above is treated in the same manner as in Example 2 (2) to obtain the monofumarate of the compound obtained in (4) above. MS (APCI) m / z; 681 (M + H), IR (N
ujol) cm ⁻¹ ; 3407, 1650, 1634.

Example 406 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Compound obtained in Reference Example 16 (1)) 2.77
To a solution of g (7 mmol) in 30 ml of tetrahydrofuran, 30 ml of formalin aqueous solution and 4.45 g of sodium triacetoxyborohydride are added under ice cooling, and the mixture is stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate is added to the reaction solution, extraction is performed with ethyl acetate, the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol = 20:
By purification in 1), (1α, 4β) -2′-methyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4
2.76 g of -benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as a resinous material. MS (APCI) m / z; 410 (M + H), IR (n
eat) cm ⁻¹ ; 1727, 1608. (2) 2.76 g of the compound obtained in (1) above is dissolved in 30 ml of ethanol, 400 mg of palladium hydroxide is added, and hydrogenation is carried out under a hydrogen atmosphere of 3 atm. Water was added to the reaction solution, the catalyst was filtered off, and then the solvent was distilled off,
(1α, 4β) -2′-methyl-3 ′, 4′-dihydro-
6 ', 7'-dimethoxy-4-carboxyl-spiro
[Cyclohexane-1,1 ′ (2′H) -isoquinoline]
1.87 g are obtained. Melting point 199 ° C, MS (APCI) m / z; 320 (M +
H), IR (Nujol) cm ^-1 ; 3385,172
2, 1611. (3) By treating the compound obtained in (2) above in the same manner as in Example 52 (1), (1α, 4β) -2′-methyl-3 ′, 4′-dihydro-6 ′, 7 ′. -Dimethoxy-4- [4--
(3-Methyl-3H-1,2,3-triazolo [4,5-
d] pyrimidin-7-yl) -1-piperazinyl] carbonyl
-Spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained as a crystalline powder. Melting point 189-191 ° C, MS (APCI) m / z; 52
1 (M + H).

Example 407 (1) 3 ', 4'-dihydro-6', 7'-dihydroxy-4,4-diethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] ( 14.767 g of the compound obtained in Reference Example 13 (1)), 27.03 g of potassium carbonate, 15.64 ml of ethyl iodide and 60 ml of dimethylacetamide were combined and cooled under ice-cooling 30.
Min, room temperature 1 hour, 100 ° C. for 3 hours, then room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give 2′-ethyl-3 ′, 4′-dihydro-6 ′,
17.81 g of 7'-diethoxy-4,4-diethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained as an oil. MS (APCI) m / z; 462 (M + H), IR (n
eat) cm ⁻¹ ; 1730. (2) 17.79 g of the compound obtained in (1) above, 7.75 g of sodium hydroxide, 30 ml of ethanol and 30 ml of water are combined, and the mixture is stirred at room temperature for 5 hours and then heated under reflux for 13 hours. The reaction solution was ice-cooled and 10% hydrochloric acid was added to pH 1-2.
After that, the solvent is distilled off. 200 ml of pyridine in the residue
Is added and the mixture is heated under reflux for 3 hours. After cooling the reaction solution, the solvent is distilled off and toluene is azeotropically distilled. Dissolve the residue in water, 10%
After adjusting the pH to 7 with an aqueous sodium hydroxide solution and salting out with sodium chloride,
Extract with chloroform. The organic layer is washed with a small amount of saturated saline, dried over sodium sulfate, and then the solvent is distilled off. The residue was crystallized with a mixed solvent of isopropyl alcohol-ethyl acetate to give (1α, 4β) -2′-
Ethyl-3 ', 4'-dihydro-6', 7'-diethoxy-4-carboxyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] 3.26 g is obtained. Melting point 203-213 (decomposition) MS (APCI) m / z; 362 (M + H), IR (n
eat) cm ⁻¹ ; 1715, 1735. (3) By treating the compound obtained in (2) above in the same manner as in Example 52 (1), (1α, 4β) -2′-ethyl-3 ′, 4′-dihydro-6 ′, 7 ′. -Diethoxy-4- [4--
[1- (2-pyridylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] -1-piperazinyl] carbonyl
-Spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained as an amorphous powder. MS (APCI) m / z; 639 (M + H).

Example 408 (1) 3,4-dihydro-6,7-dimethoxy-2-
(3-Dibenzylaminopropyl) -1 '-[4- (3-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) piperazin-1-yl] carbonyl- Spiro [isoquinoline-1 (2H), 4'-piperidine] (compound obtained in Reference Example 23 (7)) 579 mg, 5% palladium carbon 116 mg, ammonium formate 980 mg, tetrahydrofuran 10 ml, methanol 20 ml A mixture for 2.5 hours. Heat to reflux. The catalyst is filtered off and the filtrate is concentrated. A 10% aqueous potassium carbonate solution is added to the residue, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by neutral silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to give 3,4-dihydro-6,7-dimethoxy-2- (3.
-Aminopropyl) -1 '-[4- (3-methyl-3H-1,
2,3-triazolo [4,5-d] pyrimidin-7-yl)
Piperazin-1-yl] carbonyl spiro [isoquinoline-1 (2H), 4′-piperidine] 357 mg (81
%). MS (APCI): 565 (M + H), IR (neat) cm ^-1 :
3373, 1639. (2) Triethylamine 75 was added to a solution of 139 mg of the compound obtained in the above (1) in 3 ml of dimethylformamide.
mg and Nt-butoxycarbonyl-N'-benzyloxycarbonyl-1H-pyrazole-1-carboxamidine
(See International Publication WO2000078723) is added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is diluted with ethyl acetate and washed with water and saturated saline. After drying the organic layer with sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give 3,4-dihydro-6,7-dimethoxy-2-.
[3- (N-t-butoxycarbonyl-N'-benzyloxycarbonyl) guanidinopropyl] -1 '-[4- (3-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidine -7-yl) piperazin-1-yl] carbonyl-spiro [isoquinoline-1 (2H), 4'-piperidine] 190
Obtaining mg (92%). MS (APCI): 841 (M + H), IR (nujol) cm ^-1 :
3325, 1722. (3) To a solution of 175 mg of the compound obtained in (2) above in 1 ml of methylene chloride, 1 ml of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated, chloroform is added, and the mixture is washed with 10% aqueous potassium carbonate solution and saturated brine. After drying over sodium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (chloroform:
Methanol: ammonia water = 20: 1: 0.1) to give 3,4-dihydro-6,7-dimethoxy-2- [3- (N-benzyloxycarbonyl) guanidinopropyl] -1′-. [4- (3-methyl-3H-1,2,3
-Triazolo [4,5-d] pyrimidin-7-yl) piperazin-1-yl] carbonyl-spiro [isoquinoline-1
(2H), 4'-piperidine] 162 mg (quantitative) is obtained. MS (APCI): 841 (M + H), IR (nujol) cm ^-1 :
3375, 1634. (4) 150 mg of the compound obtained in the above (3), 10%
A mixture of 30 mg of palladium on carbon and 5 ml of methanol was added to 3-
Catalytic hydrogenation is carried out under a hydrogen atmosphere of 4 atm. The catalyst is filtered off from the reaction solution, an ethanol solution of hydrogen chloride is added to the filtrate, and the solvent is distilled off. The residue was filtered with a mixed solvent of ethanol / ether to give 3,4-dihydro-6.
7-dimethoxy-2- (3-guanidinopropyl)-
1 '-[4- (3-methyl-3H-1,2,3-triazolo
[4,5-d] Pyrimidin-7-yl) piperazin-1-yl] carbonyl-spiro [isoquinoline-1 (2H), 4 ′
-111 mg of piperidine] -hydrochloride is obtained as a powder. MS (APCI): 607 (M + H), IR (nujol) cm ^-1 :
3327, 1650.

Examples 409-447 By treating the corresponding starting materials in the same manner as in Example 52 (1), the compounds shown in Table 25 are obtained.

[0453]

[Table 87]

[0454]

[Table 88]

[0455]

[Table 89]

[0456]

[Table 90]

[0457]

[Table 91]

Examples 448-472 (1) The corresponding starting materials were treated in the same manner as in Example 274 (2) to give the compounds shown in Table 26.

[0459]

[Table 92]

[0460]

[Table 93]

[0461]

[Table 94]

[0462]

[Table 95]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 468 (2): monofumarate of the compound obtained in Example 468 (1). MS (APCI) 679 (M + H), IR (Nujol)
1633. Compound 469 (2): monofumarate of the compound obtained in Example 469 (1). MS (APCI) 653 (M + H), IR (Nujol)
1633. Compound 470 (2): monofumarate of the compound obtained in Example 470 (1). MS (APCI) 653 (M + H), IR (Nujol)
1634. Compound 471 (2): monofumarate of the compound obtained in Example 471 (1). MS (APCI) 653 (M + H), IR (Nujol)
1632. Compound 472 (2): monofumarate of the compound obtained in Example 472 (1). MS (APCI) 609 (M + H), IR (Nujol)
1629.

Examples 473-486 Corresponding starting compounds were prepared according to Example 274 (2) and Example 2.
By treating in the same manner as (2), compounds shown in Table 27 are obtained.

[0465]

[Table 96]

[0466]

[Table 97]

Examples 487-488 (1) The corresponding starting compounds were treated in the same manner as in Example 293 (1) (2) to give the compounds shown in Table 28.

[0468]

[Table 98]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 488 (2): monofumarate of the compound obtained in Example 488 (1). MS (APCI) 654 (M + H), IR (nujol) c
m ^-1 : 3373, 1628.

Example 489 (1α, 4β) -2 ′-(3-aminopropyl) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-4- [4-
[1- (2-nitrobenzyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (compound obtained in Example 283 (1)) 2
To a solution of 00 mg and 0.3 ml of cyclohexanone in methylene chloride, 94 mg of sodium triacetoxyborohydride is added and stirred for 13 hours at room temperature. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 20: 1: 0.1) to give (1α, 4β) -2 ′-(3-cyclohexylaminopropyl) -3 ′, 4 ′. -Dihydro-6 ', 7'-
Dimethoxy-4- [4- [1- (2-nitrobenzyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl] -1
-Piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 201 mg (89%)
As an amorphous powder. MS (APCI): 766 (M + H), IR (nujol) cm ^-1 : 1640,
1571.

Examples 490-503 (1) The corresponding starting materials were treated in the same manner as in Example 489 to give the compounds shown in Table 29.

[0472]

[Table 99]

[0473]

[Table 100]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 490 (2): monofumarate of the compound obtained in Example 490 (1). Amorphous powder, MS (APCI) 72
6 (M + H), IR (nujol) cm ^-1 1573. Compound 491 (2): monofumarate of the compound obtained in Example 491 (1). Amorphous powder, MS (APCI) 76
8 (M + H), IR (nujol) cm ^-1 1643. Compound 494 (2): 1-fumarate salt of the compound obtained in Example 494 (1). Amorphous powder, MS (APCI) 76
8 (M + H), IR (nujol) cm ^-1 1635. Compound 495 (2): monofumarate of the compound obtained in Example 495 (1). Amorphous powder, MS (APCI) 74
0 (M + H), IR (nujol) cm ^-1 1634. Compound 496 (2): monofumarate of the compound obtained in Example 496 (1). Amorphous powder, MS (APCI) 78
8 (M + H), IR (nujol) cm ^-1 1704. Compound 497 (2): monofumarate of the compound obtained in Example 497 (1). Amorphous powder, MS (APCI) 78
0 (M + H), IR (nujol) cm ^-1 1635. Compound 498 (2): monofumarate of the compound obtained in Example 498 (1). Amorphous powder, MS (APCI) 78
2 (M + H), IR (nujol) cm ^-1 1705. Compound 499 (2): monofumarate of the compound obtained in Example 499 (1). Amorphous powder, MS (APCI) 74
0 (M + H), IR (nujol) cm ^-1 1635. Compound 500 (2): monofumarate of the compound obtained in Example 500 (1). Amorphous powder, MS (APCI) 75
4 (M + H), IR (nujol) cm ^-1 1635. Compound 501 (2): monofumarate of the compound obtained in Example 501 (1). Amorphous powder, MS (APCI) 76
8.4 (M + H), IR (nujol) cm ^-1 1635. Compound 502 (2): monofumarate of the compound obtained in Example 502 (1). Amorphous powder, MS (APCI) 75
4.4 (M + H), IR (nujol) cm ^-1 1635. Compound 503 (2): monofumarate of the compound obtained in Example 503 (1). Amorphous powder, MS (APCI) 72
6 (M + H), IR (nujol) cm ^-1 1574.

Examples 504 to 636 (1) The corresponding starting materials were treated in the same manner as in Example 52 (1) to give compounds as shown in Table 30.

[0476]

[Table 101]

[0477]

[Table 102]

[0478]

[Table 103]

[0479]

[Table 104]

[0480]

[Table 105]

[0481]

[Table 106]

[0482]

[Table 107]

[0483]

[Table 108]

[0484]

[Table 109]

[0485]

[Table 110]

[0486]

[Table 111]

[0487]

[Table 112]

[0488]

[Table 113]

[0489]

[Table 114]

[0490]

[Table 115]

[0491]

[Table 116]

[0492]

[Table 117]

[0493]

[Table 118]

[0494]

[Table 119]

[0495]

[Table 120]

[0496]

[Table 121]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 539 (2): monofumarate of the compound obtained in Example 539 (1). MS (APCI) 681 (M + H), IR (nujo
l) cm ⁻¹ : 3407, 1650, 1634. Compound 540 (2): monofumarate of the compound obtained in Example 540 (1). Amorphous powder, MS (APCI) 668
(M + H), IR (nujol) 1638, 1573. Compound 541 (2): monofumarate of the compound obtained in Example 541 (1). Amorphous powder, MS (APCI) 712
(M + H), IR (nujol) 1641, 1573. Compound 542 (2): monofumarate of the compound obtained in Example 542 (1). Amorphous powder, MS (APCI) 685
(M + H), IR (nujol) 1638, 1573. Compound 543 (2): monofumarate of the compound obtained in Example 543 (1). Amorphous powder, MS (APCI) 703
(M + H), IR (nujol) 1643, 1627. Compound 544 (2): monofumarate of the compound obtained in Example 544 (1). Amorphous powder, MS (APCI) 667
(M + H), IR (nujol) 1643, 1573. Compound 545 (2): monofumarate of the compound obtained in Example 545 (1). Amorphous powder, MS (APCI) 657
(M + H), IR (nujol) 1639, 1574. Compound 546 (2): monofumarate of the compound obtained in Example 546 (1). Amorphous powder, MS (APCI) 692
(M + H), IR (nujol) 1642, 1573. Compound 547 (2): monofumarate of the compound obtained in Example 547 (1). Amorphous powder, MS (APCI) 712
(M + H), IR (nujol) 1641, 1573. Compound 548 (2): monofumarate of the compound obtained in Example 548 (1). Amorphous powder, MS (APCI) 673
(M + H), IR (nujol) 1641, 1574. Compound 549 (2): monofumarate of the compound obtained in Example 549 (1). Amorphous powder, MS (APCI) 668
(M + H), IR (nujol) 1640, 1573. Compound 550 (2): monofumarate of the compound obtained in Example 550 (1). Amorphous powder, MS (APCI) 673
(M + H), IR (nujol) 1643, 1573. Compound 551 (2): monofumarate of the compound obtained in Example 551 (1). Amorphous powder, MS (APCI) 745 /
747 (M + H), IR (nujol) 1640, 1573. Compound 552 (2): monofumarate of the compound obtained in Example 552 (1). Amorphous powder, MS (APCI) 673
(M + H), IR (nujol) 1703, 1641. Compound 553 (2): monofumarate of the compound obtained in Example 553 (1). Amorphous powder, MS (APCI) 645
(M + H), IR (nujol) 1641, 1573. Compound 554 (2): monofumarate of the compound obtained in Example 554 (1). Amorphous powder, MS (APCI) 659
(M + H), IR (nujol) 1699, 1641. Compound 555 (2): monofumarate of the compound obtained in Example 555 (1). Amorphous powder, MS (APCI) 697
(M + H). Compound 574 (2): monofumarate of the compound obtained in Example 574 (1). Amorphous powder, MS (APCI) 6
55 (M + H), IR (nujol) 1705, 1634. Compound 575 (2): monofumarate of the compound obtained in Example 575 (1). Amorphous powder, MS (APCI) 6
11 (M + H), IR (nujol) 1704, 1634. Compound 581 (2): monofumarate of the compound obtained in Example 581 (1). Amorphous powder, IR (nujol) 17
05, 1636, MS (ESI) 669 (M + H). Compound 582 (2): monofumarate of the compound obtained in Example 582 (1). Amorphous powder, IR (nujol) 17
04, 1635, MS (ESI) 625 (M + H). Compound 594 (2): monofumarate of the compound obtained in Example 594 (1). MS (APCI): 583 (M + H), IR (Nujo
l) cm ⁻¹ : 1703, 1633. Compound 605 (2): monofumarate of the compound obtained in Example 605 (1). Amorphous powder, MS (APCI)
641 (M + H), IR (nujol) 1705, 1636. Compound 606 (2): monofumarate of the compound obtained in Example 606 (1). Amorphous powder, MS (APCI)
597 (M + H), IR (nujol) 1704, 1634.

Example 637 (1α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-4- [4- [1- (3-ethoxyphenylmethyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] (compound obtained in Example 633 (1)) 150 mg, tetrahydrofuran 3 ml, acetic acid 0.3 ml, formalin aqueous solution 41 μl, triacetoxy sodium borohydride 78 mg was added, and the mixture was stirred at room temperature. Two
Stir for hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried, and the solvent is distilled off. The residue was purified by NH-silica gel (chloroform: methanol = 20: 1) and lyophilized to give (1α, 4β) -3 ′, 4′-dihydro-
6'-ethoxy-2'-methyl-4- [4- [1- (3-
Ethoxyphenylmethyl) -1H-pyrazolo [3,4-d]
133 mg (86.7%) of pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] are obtained. MS (APCI): 624 (M + H), IR (nujol) (cm ^-1 ): 344
5, 1640, 1570, 1460, 1375, 1000.

Examples 638 to 640 The corresponding starting compounds were treated in the same manner as in Example 637 to give the compounds shown in Table 31.

[0500]

[Table 122]

Example 641 (1α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-4- [4- [1- (3-ethoxyphenylmethyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (compound obtained in Example 633 (1)) (150 mg) in acetonitrile (3 ml) was added with diisopropylethylamine (129 µl) and chloroacetyl chloride (39 µl) under ice cooling and the mixture was stirred for 2 hours. After adding 1 ml of a dimethylamine aqueous solution to the reaction solution, the mixture is stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, water,
The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 9: 1) and freeze-dried with t-butyl alcohol to give (1α, 4β) -3 ′, 4′-dihydro-6′-ethoxy. -2'-dimethylaminoacetyl-4- [4- [1-
(3-Ethoxyphenylmethyl) -1H-pyrazolo [3,4
94 mg (55%) of -d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] as a powder are obtained. MS (APCI): 695 (M + H), IR (nujol) cm ^-1 : 3465, 1635,
1570, 1460, 1000.

Examples 642-647 The corresponding starting materials were treated in the same manner as in Example 641, to give compounds as shown in Table 32.

[0503]

[Table 123]

Example 648 (1α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-4- [4- [1- (6-ethyl-2-pyridylmethyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1
-Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (Example 636 (1)
Compound obtained in 1.) 150 mg of dimethylacetamide 5
174 mg of potassium carbonate and 101 of ethyl iodide were added to the ml solution.
Add μl and stir at 100 ° C. for 2 hours. After cooling the reaction solution, ethyl acetate is added. The organic layer is washed with water, washed with saturated saline and dried, and then the solvent is distilled off. The residue was purified by NH-silica gel (ethyl acetate: hexane = 1: 1 → 4: 1),
By freeze-drying with t-butyl alcohol, (1
α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-
2'-Ethyl-4- [4- [1- (6-ethyl-2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 124
mg (79%) is obtained as an amorphous powder. MS (APCI): 623 (M + H), IR (nujol) cm ^-1 : 164
0,1570.

Example 649 The corresponding starting material compound was treated in the same manner as in Example 648 to give (1α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-2′-ethyl-4- [4- [1- (6-ethyl-
2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained as an amorphous powder. . MS (APCI): 623 (M + H).

Examples 650-661 The corresponding starting materials were treated in the same manner as in Example 52 (1), to give compounds as shown in Table 33.

[0507]

[Table 124]

[0508]

[Table 125]

Examples 662 to 667 The corresponding starting materials were treated in the same manner as in Example 648 to give the compounds shown in Table 34.

[0510]

[Table 126]

Examples 668-673 The corresponding starting materials were treated in the same manner as in Example 637 to give the compounds shown in Table 35.

[0512]

[Table 127]

Examples 674-685 The corresponding starting materials were treated in the same manner as in Example 641, to give compounds as shown in Table 36.

[0514]

[Table 128]

[0515]

[Table 129]

Example 686 (1) (1α, 4β) -2 ′-(3-aminopropyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline] (compound obtained in Example 283 (1)) 100 mg, chloroform 2 ml, water 1 ml, sodium hydrogen carbonate 37 mg, and methyl chlorocarbonate 17
The mixture with μl is stirred for 1 hour under ice cooling. Chloroform was added to the reaction solution, washed with water, dried over sodium sulfate, and the solvent was distilled off. Silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1:
(1α, 4β) -2′-by purification with 0.1)
(3-methoxycarbonylaminopropyl) -3 ',
4'-dihydro-6 ', 7'-dimethoxy-4- [4-
[1- (2-nitrobenzyl) -1H-pyrazolo [3,4-
94 mg of d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] are obtained as amorphous powder. MS (APCI): 742 (M + H), IR (nujol) cm ^-1 : 3328, 1718,
1637. (2) The compound obtained in (1) above is treated in the same manner as in Example 2 (2) to obtain the monofumarate salt of the compound obtained in (1) above. MS (APCI): 742 (M + H), IR (nujol) cm ^-1 : 1713, 1635.

Examples 687-695 (1) The corresponding starting materials were treated in the same manner as in Example 686 (1) to give the compounds shown in Table 37.

[0518]

[Table 130]

[0519]

[Table 131]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 687 (2): 1-fumarate salt of the compound obtained in Example 687 (1). Amorphous powder, MS (APCI) 6
98 (M + H), IR (nujol) 1702, 1636. Compound 693 (2): The difumarate salt of the compound obtained in Example 693 (1). Amorphous powder, MS (APCI) 75
7 (M + H), IR (Nujol) 1707, 1635, 1607.

Example 696 (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro-
6 ', 7'-Dimethoxy-4- [4- [1- (2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 ′ (2′H) -isoquinoline] (compound obtained in Example 282 (1)) (250 mg) was dissolved in methylene chloride, and ethoxyacetic acid (55 μl), 1-ethyl-3- (3-dimethyl Aminopropyl) carbodiimide hydrochloride (112 mg), 1-hydroxybenzotriazole (78 mg) and triethylamine (81 μl) were added,
Stir at room temperature for 18 hours. Saturated sodium hydrogen carbonate (20m
l) is added and the mixture is extracted with ethyl acetate, the organic layer is washed with water and saturated brine, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (chloroform: methanol: aqueous ammonia = 190: 10: 1) to obtain (1α, 4β) -2 ′-[3- (ethoxyacetamide). Propyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- [1- (2-pyridylmethyl) -1H-pyrazolo [3,4-d]
Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 179 mg (6
3%) as an amorphous powder. MS (APCI) 726 (M + H), IR (nujol) cm ^-1 : 3415, 1653,
1637.

Examples 697-709 (1) The corresponding starting materials were treated in the same manner as in Example 696 to give compounds shown in Table 38.

[0523]

[Table 132]

[0524]

[Table 133]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 697 (2): monofumarate of the compound obtained in Example 697 (1). Amorphous powder, MS (APCI) 75
6 (M + H), IR (nujol) 1705, 1636. Compound 698 (2): monofumarate of the compound obtained in Example 698 (1). Amorphous powder, MS (APCI) 78
6 (M + H), IR (nujol) 1711, 1636. Compound 699 (2): monofumarate of the compound obtained in Example 699 (1). Amorphous powder, MS (APCI) 78
2 (M + H), IR (nujol) 1667, 1643. Compound 700 (2): monofumarate of the compound obtained in Example 700 (1). Amorphous powder, MS (APCI) 78
4 (M + H), IR (nujol) 1718, 1635. Compound 701 (2): monofumarate of the compound obtained in Example 701 (1). Amorphous powder, MS (APCI) 71
2 (M + H), IR (nujol) 1701, 1635. Compound 702 (2): monofumarate of the compound obtained in Example 702 (1). Amorphous powder, MS (APCI) 74
2 (M + H), IR (nujol) 1711, 1634. Compound 703 (2): monofumarate of the compound obtained in Example 703 (1). Amorphous powder, MS (APCI) 74
0 (M + H), IR (nujol) 1744, 1715. Compound 704 (2): monofumarate of the compound obtained in Example 704 (1). Amorphous powder, MS (APCI) 73
8 (M + H), IR (nujol) 1636, 1573.

Example 710 (1) (1α, 4β) -2 ′-[3- (2-hydroethoxy) carbonylaminopropyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)- Isoquinoline] (compound obtained in Example 704 (1)) 95 mg in a solution of methylene chloride in 2 ml of triethylamine 19 under ice cooling.
mg and triphosgene 18 mg are added and stirred for 1 hour.
Then, 0.5 ml of dimethylamine aqueous solution is added, and the mixture is stirred for another hour. The reaction solution is diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated. Silica gel column chromatography of the residue
(Chloroform: methanol: ammonia water = 20:
1: 0.1) to obtain (1α, 4β) -2 ′
-[3- (2-Dimethylaminocarboxyethoxy) carbonylaminopropyl] -3 ', 4'-dihydro-6',
7'-Dimethoxy-4- [4- [1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 34 mg of '(2'H) -isoquinoline] is obtained as an amorphous powder. MS (APCI): 843 (M + H), IR (Nujol) cm ^-1 : 1702,
1637. (2) The compound obtained in (1) above is treated in the same manner as in Example 2 (2) to obtain the monofumarate salt of the compound obtained in (1) above. MS (APCI): 843 (M + H), IR (Nujol) cm ^-1 : 1704,
1633.

Example 711 (1α, 4β) -2 ′-(3-acetoxyacetylaminopropyl) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- (2 -Pyridylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] (Example 707
To a solution of 172 mg of the compound obtained in (1) in 2 ml of methanol was added 0.17 ml of 4M aqueous sodium hydroxide solution, and 1
Stir for hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give (1α, 4β) -2 ′-(3-hydroxyacetylaminopropyl) -3 ′, 4'-dihydro-6 ',
7'-Dimethoxy-4- [4- [1- (2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '-(2'H) -isoquinoline] 122
mg is obtained as an amorphous powder. MS (APCI): 698 (M + H), IR (Nujol) cm ^-1 : 1649,
1573.

Examples 712-713 (1) The corresponding starting materials were treated in the same manner as in Example 710 to give the compounds shown in Table 39.

[0529]

[Table 134]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 712 (2): monofumarate of the compound obtained in Example 712 (1). Amorphous powder, MS (APCI) 79
9 (M + H), IR (nujol) 1698, 1632. Compound 713 (2): monofumarate of the compound obtained in Example 713 (1). Amorphous powder, MS (APCI) 76
9 (M + H), IR (nujol) 1704, 1633.

Examples 714-733 (1) The corresponding starting materials were treated in the same manner as in Examples 296 (1) and (2) to give the compounds shown in Table 40.

[0532]

[Table 135]

[0533]

[Table 136]

[0534]

[Table 137]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 714 (2): monofumarate of the compound obtained in Example 714 (1). Powder, MS (APCI) 779 (M + H), IR (nuj
ol) cm ^-1 : 2167, 1705, 1635. Compound 715 (2): monofumarate of the compound obtained in Example 715 (1). Powder, MS (APCI) 735 (M + H), IR (nuj
ol) cm ^-1 : 2166, 1733, 1635. Compound 716 (2): monofumarate of the compound obtained in Example 716 (1). Amorphous powder, IR (nujol) 21
68, MS (ESI) 720 (M + H). Compound 717 (2): monofumarate of the compound obtained in Example 717 (1). Amorphous powder, IR (nujol) 21
68, MS (ESI) 765 (M + H). Compound 718 (2): monofumarate of the compound obtained in Example 718 (1). Amorphous powder, IR (nujol) 21
68, MS (ESI) 765 (M + H). Compound 719 (2): monofumarate of the compound obtained in Example 719 (1). Amorphous powder, IR (nujol) 21
67, MS (ESI) 738 (M + H). Compound 720 (2): monofumarate of the compound obtained in Example 720 (1). Amorphous powder, IR (nujol) 21
67, MS (ESI) 756 (M + H). Compound 721 (2): monofumarate of the compound obtained in Example 721 (1). Amorphous powder, IR (nujol) 21
67, MS (APCI) 710 (M + H). Compound 722 (2): monofumarate of the compound obtained in Example 722 (1). Amorphous powder, IR (nujol) 21
67, MS (APCI) 710 (M + H). Compound 723 (2): monofumarate of the compound obtained in Example 723 (1). Amorphous powder, IR (nujol) 21
67, MS (APCI) 726 (M + H). Compound 724 (2): monofumarate of the compound obtained in Example 724 (1). Amorphous powder, IR (nujol) 21
67, MS (APCI) 726 (M + H). Compound 725 (2): monofumarate of the compound obtained in Example 725 (1). Amorphous powder, IR (nujol) 21
67, MS (APCI) 721 (M + H). Compound 726 (2): monofumarate of the compound obtained in Example 726 (1). Amorphous powder, MS (APCI) 83
3 (M + H), IR (nujol) cm ^-1 3277, 2166, 1636, 1701. Compound 727 (2): monofumarate of the compound obtained in Example 727 (1). Amorphous powder, MS (APCI) 79
1 (M + H), IR (nujol) cm ^-1 3271, 2169, 1699, 1682, 1
635. Compound 728 (2): monofumarate of the compound obtained in Example 728 (1). Amorphous powder, MS (APCI) 80
7 (M + H), IR (nujol) cm ^-1 3299, 2164, 1706, 1636, 1
610. Compound 729 (2): monofumarate of the compound obtained in Example 729 (1). Amorphous powder, MS (APCI) 79
3 (M + H), IR (nujol) cm ^-1 3272, 2167, 1699, 1633. Compound 730 (2): monofumarate of the compound obtained in Example 730 (1). Amorphous powder, MS (APCI) 80
7 (M + H), IR (nujol) cm ^-1 3278, 2166, 1705, 1631. Compound 731 (2): monofumarate of the compound obtained in Example 731 (1). Amorphous powder, MS (APCI) 77
9 (M + H), IR (nujol) cm ^-1 3287, 2167, 1705. Compound 732 (2): monofumarate of the compound obtained in Example 732 (1). Amorphous powder, MS (APCI) 75
9 (M + H), IR (Nujol) 2167, 1708, 1637. Compound 733 (2): monofumarate of the compound obtained in Example 733 (1). Amorphous powder, MS (APCI) 81
2, 814 (M + H), IR (Nujol) 2165, 1635.

Examples 734-737 (1) The corresponding starting materials were treated in the same manner as in Examples 304 (1) (2) to give the compounds shown in Table 41.

[0537]

[Table 138]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 734 (2): monofumarate of the compound obtained in Example 734 (1). Amorphous powder, IR (nujol) 17
00, 3395, MS (ESI) 754 (M + H). Compound 735 (2): 1 citrate salt of the compound obtained in Example 735 (1). MS (APCI) 793.5 (M + H), IR (Nujol) 1719, 1613. Compound 736 (2): 1 citrate salt of the compound obtained in Example 736 (1). MS (APCI) 767.5 (M + H), IR (Nujo
l) 1721, 1613. Compound 737 (2): the monocitrate salt of the compound obtained in Example 737 (1). MS (APCI) 767.5 (M + H), IR (Nujo
l) 1719, 1611.

Example 738 (1) (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- ( 2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
Cyclohexylthioisocyanate (44 μl) was added to a solution of (2′H) -isoquinoline] (compound obtained in Example 283 (1)) (200 mg) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated and then purified by basic silica gel chromatography (chloroform) to give (1α, 4β) -2 ′-[3- (N-cyclohexylthioureido) propyl] -3 ′, 4′-dihydro- 6 ', 7'-dimethoxy-4
-[4- [1- (2-Chlorophenylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 240 mg
(100%) is obtained as an amorphous powder. MS (APCI) 825 (M + H), IR (nujol) cm ^-1 : 3331, 2175,
1716, 1699, 1683, 1636. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a colorless amorphous powder. MS (APCI) 825 (M + H), IR (nujol) cm ^-1 : 3274, 1706,
1635.

Examples 739-741 (1) The corresponding starting materials were treated in the same manner as in Example 738 (1) to give compounds as shown in Table 42.

[0541]

[Table 139]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 739 (2): monofumarate of the compound obtained in Example 739 (1). Amorphous powder, MS (APCI) 79
9 (M + H), IR (nujol) cm ^-1 3343, 1706, 1636, 1612. Compound 740 (2): monofumarate of the compound obtained in Example 740 (1). Amorphous powder, MS (APCI) 79
9 (M + H), IR (nujol) cm ^-1 3265, 1702, 1635, 1611. Compound 741 (2): monofumarate of the compound obtained in Example 741 (1). Amorphous powder, MS (APCI) 75
7 (M + H), IR (nujol) cm ^-1 3341, 1707, 1635, 1612.

Example 742 (1) (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- ( 2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
To a solution of (2′H) -isoquinoline] (compound obtained in Example 283 (1)) (200 mg) in tetrahydrofuran (5 ml), butyl isocyanate (40 μl) was added, and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction solution, by purifying with basic silica gel chromatography (chloroform),
(1α, 4β) -2 '-[3- (N-n-butylureido) propyl]-
3 ', 4'-Dihydro-6', 7'-dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1 201 mg (88%) of -piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as amorphous powder. MS (APCI) 783 (M + H), IR (nujol) cm ^-1 : 3347, 1716,
1636. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a colorless amorphous powder. MS (APCI) 783 (M + H), IR (nujol) cm ^-1 : 3358, 1705,
1637.

Example 743 (1) By treating the corresponding starting material compound in the same manner as in Example 742 (1), (1α, 4β) -2 ′-[3- (N-ethylureido) propyl] -3 ′ , 4'-Dihydro-6 ', 7'-dimethoxy-4-
[4- [1- (2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d]
Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained as an amorphous powder. MS (APCI) 755 (M + H). (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as an amorphous powder. MS (APCI) 755 (M + H), IR (nujol) cm ^-1 3346, 1703, 16
36, 1612.

Example 744 (1) (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- [1- ( 2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (compound obtained in Example 283 (1)) (200 mg) in methylene chloride (5 ml) was added with acetyl chloride (25 μl) and triethylamine (60 μl) under ice cooling. Stir at room temperature for 18 hours. The reaction solution was concentrated and then purified by basic silica gel chromatography (chloroform) to give (1α, 4β) -2 ′-[3- (acetamide).
Propyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- [1
-(2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 191 mg ( 90%) as an amorphous powder. MS (APCI) 726 (M + H), IR (nujol) cm ^-1 : 1698, 1636. (2) The monofumarate of the compound obtained in (1) above is obtained as a colorless amorphous powder by treating the compound obtained in (1) above in the same manner as in Example 2 (2). MS (APCI) 726 (M + H), IR (nujol) cm ^-1 : 3273, 1705,
1635.

Example 745 (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro
-6 ', 7'-Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [ Cyclohexane-1,1 '(2'H)
-Isoquinoline] (compound obtained in Example 283 (1))
To a solution of (1.0 g) in methylene chloride (5 ml) and isopropanol (5 ml) was added 3,4-diethoxy-3-cyclobutene-1,2.
-Add dione (272 mg) and stir at room temperature for 24 hours. After concentrating the reaction solution, it was purified by silica gel chromatography (chloroform: methanol = 20: 1).
(1α, 4β) -2 '-[3- (3-ethoxy-3-cyclobutene-1,2-
Dione-4-yl) aminopropyl] -3 ', 4'-dihydro-6', 7 '
-Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl]
Carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 1.13 g (96%) is obtained as an amorphous powder. MS (APCI) 808 (M + H), IR (nujol) cm ^-1 : 3213, 1801,
1705, 1607.

Example 746 (1) (1α, 4β) -2 ′-[3- (3-ethoxy-3-cyclobutene
-1,2-dione-4-yl) aminopropyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-4- [4- [1- (2-nitrophenylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Example 745) ( 200 m
To a solution of g) in tetrahydrofuran (2 ml) and isopropanol (4 ml) is added an aqueous dimethylamine solution (2 ml), and the mixture is stirred at room temperature for 18 hours. The reaction solution was concentrated and then purified by basic silica gel chromatography (chloroform) to give (1α, 4β) -2 ′-[3- (3-dimethylamino-
3-Cyclobutene-1,2-dione-4-yl) aminopropyl]-
3 ', 4'-Dihydro-6', 7'-dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1 170 mg (85%) of -piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as amorphous powder. MS (APCI) 807 (M + H), IR (nujol) cm ^-1 : 1793, 1668,
1636. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a colorless amorphous powder. MS (APCI) 807 (M + H), IR (nujol) cm ^-1 : 3387, 3246,
1795, 1707, 1637.

Examples 747-748 (1) The corresponding starting materials were treated in the same manner as in Example 746 (1) to give compounds as shown in Table 43.

[0549]

[Table 140]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 747 (2): monofumarate of the compound obtained in Example 747 (1). Amorphous powder, MS (APCI) 79
3 (M + H), IR (nujol) cm ^-1 3246, 1799, 1707. Compound 748 (2): monofumarate of the compound obtained in Example 748 (1). Amorphous powder, MS (APCI) 77
9 (M + H), IR (nujol) cm ^-1 3328, 3197, 1801, 1635.

Example 749 (1α, 4β) -2 ′-(3-aminopropyl) -3 ′, 4′-dihydro
-6 ', 7'-Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [ Cyclohexane-1,1 '(2'H)
-Isoquinoline] (compound obtained in Example 283 (1))
A solution of (1.0 g) in tetrahydrofuran (2 ml) and isopropanol (10 ml) was added to (bis (methylthio) methylene) propanedinitrile [(CH ₃ S) ₂ C = C (CN) ₂ ] (273
(mg) and then heated to reflux for 8 hours. The reaction solution was concentrated and then purified by silica gel chromatography (chloroform: methanol = 30: 1) to give (1α, 4β)-
2 '-[3- (1-Methylthio-2,2-dicyanoethyleneamino) propyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- [1-
(2-Nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 1.17 g ( 99%) as an amorphous powder. MS (APCI) 806 (M + H), IR (nujol) cm ^-1 : 2204, 1733,
1717, 1699, 1635.

Example 750 (1) (1α, 4β) -2 ′-[3- (1-methylthio-2,2-dicyanoethyleneamino) propyl] -3 ′, 4′-dihydro-6 ′, 7 ′ -Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ' (2′H) -isoquinoline] (compound obtained in Example 749) 200 mg acetonitrile (5 ml) solution, dimethylamine aqueous solution (5 ml)
Add and heat in a sealed tube at 100 ° C for 30 minutes. The reaction solution was concentrated and then purified by silica gel chromatography (chloroform: methanol = 50: 1) to give (1α, 4β)-
2 '-[3- (1-Amino-2,2-dicyanoethyleneamino) propyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- [1- (2-nitro Phenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
268 mg (72%) of -yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as amorphous powder. MS (APCI) 775 (M + H), IR (nujol) cm ^-1 : 2199, 2173,
1631. (2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the monofumarate of the compound obtained in (1) above is obtained as a colorless amorphous powder. MS (APCI) 825 (M + H), IR (nujol) cm ^-1 : 2200,2174,17
01,1635.

Examples 751 to 752 (1) The corresponding starting materials were treated in the same manner as in Example 750 (1) to give compounds as shown in Table 44.

[0554]

[Table 141]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 751 (2): monofumarate of the compound obtained in Example 751 (1). Amorphous powder, MS (APCI) 80
3 (M + H), IR (nujol) cm ^-1 3264, 2200, 2176, 1707, 16
36. Compound 752 (2): monofumarate of the compound obtained in Example 752 (1). Amorphous powder, MS (APCI) 78
9 (M + H), IR (nujol) cm ^-1 3264, 2200, 2176, 1707, 163
6.

Examples 753-779 (1) The corresponding starting materials (the compounds obtained in Reference Example 15 (2)) are treated in the same manner as in Example 52 (1) to give the compounds shown in Table 45.

[0557]

[Table 142]

[0558]

[Table 143]

[0559]

[Table 144]

[0560]

[Table 145]

(2) By treating the compound obtained in (1) above in the same manner as in Example 2 (2), the following salt is obtained. Compound 776 (2): monofumarate of the compound obtained in Example 776 (1). Amorphous powder, MS (APCI) 68
2 (M + H), IR (nujol) cm ^-1 3855, 3629, 3395. Compound 777 (2): monofumarate of the compound obtained in Example 777 (1). Amorphous powder, MS (APCI) 68
7 (M + H), IR (nujol) cm ^-1 3416, 1705, 1636. Compound 778 (2): 1-fumarate salt of the compound obtained in Example 778 (1). Amorphous powder, MS (APCI) 65
9 (M + H), IR (nujol) cm ^-1 3407, 1706, 1636. Compound 779 (2): monofumarate of the compound obtained in Example 779 (1). Amorphous powder, MS (APCI) 65
9 (M + H), IR (nujol) cm ^-1 3406, 1705, 1635.

Example 780 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 ′-[3-
(N-methyl-N-benzyloxycarbonylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
Example 52 Using spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] -4-carboxylic acid (the compound obtained in Reference Example 1 (10)) and 4,6-dimethyl-2-piperazinylpyridine By performing the same processing as (1),
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- (N-
Methyl-N-benzyloxycarbonylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy -1-isoquinolyl) -4-
[4- (4,6-dimethylpyridin-2-yl) -1-
Piperazinyl] carbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] is obtained as an amorphous powder. MS (APCI) 917 (M + H), IR (Nujol) 1701, 1635, 1605. (2) The compound obtained in the above (1) was used in Example 165.
By performing the same processing as (1), (1R ^* , 2R
^* (S ^* ), 4R ^* )-2 '-[3- (N-methyl-amino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (4,6-dimethylpyridin-2-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H ) -Isoquinoline] as an amorphous powder. MS (APCI) 783 (M + H), IR (Nujol) 1635, 1605. (3) The monofumarate of the compound obtained in (2) above is obtained by treating the compound obtained in (2) above in the same manner as in Example 2 (2). MS (APCI) 783 (M + H), IR (Nujol) 1634, 1606.

Example 781 (1) (1α, 4β) -2 ′-(3-aminopropyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (compound obtained in Example 477) (500 mg) is dissolved in dichloromethane, and triethylamine is added. Separately adjusted under ice cooling (5-methyl-1,
3-Dioxolen-2-one-4-yl) -methyl p-
Nitrophenyl carbonate 270mg (J. Alexande
r and L.Kans, US 5,466,811.), and after stirring for 1 hour and 30 minutes, 10 ml of water is added to the reaction solution. The organic layer is separated, washed with 10 ml of saturated sodium hydrogen carbonate and dried over sodium sulfate. After distilling off the solvent, the residue was subjected to column chromatography (chloroform / methanol = 30: 1 to 20:
By purification in 1), (1α, 4β) -2 ′-[3-
[N- (5-methyl-2-oxo-1,3-dioxole-4
-Yl) methyloxycarbonylamino] propyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- [1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (355 mg, yield 57%) is obtained as an amorphous powder. MS (APCI): 657 (parent compound form), IR (Nujol)
cm ^-1 : 1816, 1717, 1633. (2) The compound obtained in (1) above is treated in the same manner as in Example 2 (2) to obtain the difumarate salt of the compound obtained in (1) above. MS (APCI) 813 (M + H) (prodrug form), IR (Nujol) 181
7, 1708, 1638.

Examples 782-816 The corresponding starting materials were treated in the same manner as in Example 52 (1) to give compounds as shown in Table 46.

[0565]

[Table 146]

[0566]

[Table 147]

[0567]

[Table 148]

[0568]

[Table 149]

[0569]

[Table 150]

[0570]

[Table 151]

[0571]

[Table 152]

[0572]

[Table 153]

Example 817 The corresponding starting material compound was treated in the same manner as in Example 52 (1) to give the compounds shown in Table 47.

[0574]

[Table 154]

[0575]

[Table 155]

[0576]

[Table 156]

[0577]

[Table 157]

[0578]

[Table 158]

[0579]

[Table 159]

[0580]

[Table 160]

[0581]

[Table 161]

[0582]

[Table 162]

[0583]

[Table 163]

[0584]

[Table 164]

[0585]

[Table 165]

[0586]

[Table 166]

[0587]

[Table 167]

[0588]

[Table 168]

[0589]

[Table 169]

[0590]

[Table 170]

[0591]

[Table 171]

[0592]

[Table 172]

[0593]

[Table 173]

[0594]

[Table 174]

[0595]

[Table 175]

Example 938 (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-4- [4- [1- (3-methylbenzyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Compound of Example 583 (1)) 0.030 ml of chloroacetyl chloride is added dropwise to a dichloromethane solution of 185 mg and 0.056 ml of triethylamine under ice cooling, and the mixture is stirred for 30 minutes. A 40% aqueous solution of methylamine is added to the reaction solution under ice cooling, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure. The obtained residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia solution = 200: 1).
0: 1) and freeze-dried with tert-butanol to give (1α, 4β) -3 ′, 4′-
Dihydro-6 ', 7'-dimethoxy-2'-(N-methyl) aminoacetyl-4- [4- [1- (3-methylbenzyl) -1H-pyrazolo [3,4-d] pyrimidine-
4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (125 mg, 60% yield) is obtained as an amorphous powder. MS (APCI) 667 (M + H).

Examples 939 to 945 The corresponding starting compounds were treated in the same manner as in Example 938 to give the compounds shown in Table 48.

[0598]

[Table 176]

Reference Example 1 (1) Diethyl malonate 300 g, acrylic acid tert
-Butyl 624 g tetrahydrofuran 1.5 L and
Hydroxylation to a solution of tert-butyl alcohol (1.5 L)
2.62 g of potassium was added under ice cooling and stirred overnight at room temperature.
It The solvent was distilled off under reduced pressure from the reaction solution, and the residue was diluted with diethyl ether.
Teru 4.5L was added, water (1.5L x 2) and saturated food
Wash with 1.5 L of brine and dry over anhydrous sodium sulfate
It By distilling off the solvent under reduced pressure, 4,4-biseth
Ditert-butyl xycarbonylpimelate as an oil
Get as. This product can be used for the next reaction without purification.
There is. (2) 1.2 L formic acid solution of the compound obtained in (1) above
Is stirred overnight at room temperature and heated at reflux for a further 2 hours. reaction
Formic acid was distilled off from the liquid, and diethyl ether was added to the residue at 750 m.
l is added and the precipitated crystals are collected by filtration. The resulting crystals are
Wash with 450 ml of isopropyl ether and wash with 4,4-bi
Sethoxycarbonylpimelic acid (557 g, yield 98
% (From diethyl malonate)) as crystals. Melting point 120 [deg.] C. (3) 100 g of the compound obtained in the above (2), Ogizari
Suspension of 104 g of chloride and 400 ml of methylene chloride
Add 0.03 ml of dimethylformamide to the suspension and add 5
Stir for hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was diluted
Add 200 ml of methoxyethane and homogenize the solution.
Latrilamine 119 g, potassium carbonate 114 g, acetic acid
Stir vigorously in a solution consisting of 1.2 L of ethyl and 1 L of water.
With stirring, add dropwise at 0-5 ° C over 40 minutes. below freezing
After stirring for 20 minutes at room temperature for 1 hour at room temperature, the organic layer is separated,
Saturated saline solution 0.5 L, 10% hydrochloric acid 1 L, saturated saline solution 0.
5 L, saturated sodium hydrogen carbonate solution 1 L, saturated saline
Wash in order of 0.5 L. Dry the organic layer with sodium sulfate
Dry and evaporate the solvent under reduced pressure. The crystals obtained are ethyl acetate
By recrystallizing with N, N'-di (3,4-dimme
Toxyphenethyl) -4,4-bisethoxycarbonyl
Pimelic acid diamide (196 g, yield 95%) as crystals
Get it. Melting point 85-86 [deg.] C. (4) 200 g of the compound obtained in (3) above and Oki
A solution of 97.2 g of phosphorus chlorochloride in 1 L of acetonitrile was added to 3
Heat to reflux for hours. After distilling off the solvent under reduced pressure from the reaction solution,
Dissolve the residue in 400 ml of 10% hydrochloric acid and add 60% ethyl acetate.
Wash with 0 ml. 1 more wash solution (ethyl acetate solution)
Extract with 100 ml of 0% hydrochloric acid, and extract with 10% hydrochloric acid solution described above.
After combining with the washing solution, dilute with 500 ml of water. below freezing
After adding 500 g of potassium carbonate to make it basic,
Extract with 700 ml of Loform and 300 ml of saturated saline.
After washing and drying with sodium sulfate, the solvent is distilled off under reduced pressure.
By recrystallizing the residue with isopropanol (5 times)
, (1R^*, 2R^*) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (3,4-dihydro-
6,7-dimethoxy-1-isoquinolyl) -4,4-bi
Suethoxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (184 g, yield 95
%) As crystals. Melting point 116-118 [deg.] C. (5) Compound 178 g obtained in the above (4), diisoprene
1.7 L of methylene chloride containing 77.6 g of ropylethylamine
To the solution, 73.8 g of acetyl bromide in dichloromethane 15
The 0 ml solution is added dropwise at -5 to 0 ° C over 2 hours. Water 1
L was added, the organic layer was separated, and saturated aqueous sodium hydrogen carbonate solution was added.
Wash the solution with saturated brine, dry over sodium sulfate, and dissolve.
The medium is distilled off under reduced pressure. The crystals obtained are methylene chloride 100
By recrystallizing with a mixed solvent of ml-ethyl acetate 1 L,
, (1R^*, 2R^*) -2'-Acetyl-3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (3,4-
Dihydro-6,7-dimethoxy-1-isoquinolyl)-
4,4-bisethoxycarbonyl-spiro [cyclohex
Sun-1,1 '(2'H) -isoquinoline] (168
g, yield 88%) as crystals. Melting point 163-165 [deg.] C. (6) 340 g of ethanol obtained in the above (5)
1360 ml, 2-methoxyethanol 1360 ml
And a suspension consisting of 1360 ml of tetrahydrofuran
And 30.4 g of sodium borohydride at room temperature for 1 hour
Add over and stir for 4 hours. In addition, sodium borohydride
Add 10.1 g of sium at room temperature over 20 minutes, then for 30 minutes
Stir. 2 L of solvent was distilled off under reduced pressure, and water was added while stirring.
4 L is added dropwise at room temperature. After stirring overnight, the precipitated crystals are filtered.
By collecting and drying (1R^*, 2R^*(S^*))
-3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4,4-bis-ene
Toxycarbonyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (271 g, 81% yield)
Is obtained as a crystal. Melting point 146-147 [deg.] C. (7) 271 g of the compound obtained in (6) above and a bird
A solution of 66 g of ethylamine in 1.3 L of methylene chloride was added with
A solution of 59 g of acrylic acid chloride in 350 ml of methylene chloride
Is added dropwise at −5 to 0 ° C. over 3 hours and stirred for 30 minutes
It 1 L of water was added and the separated organic layer was saturated with sodium hydrogencarbonate.
Rinse solution and saturated saline solution, wash with sodium sulfate
Dry and evaporate the solvent under reduced pressure. Dissolve the residue in chloroform
Dissolve and filter through 540 g NH silica gel. Concentrate the filtrate
And recrystallized with ethyl acetate to give (1R^*, 2
R^*(S^*))-2'-acryloyl-3 ', 4'-di
Hydro-6 ', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4,4-bisethoxycarbonyl
-Spiro [cyclohexane-1,1 '(2'H) -iso
Quinoline] (208 g, yield 79%) was obtained as crystals.
It Melting point 150-151 [deg.] C. (8) 181 g of the compound obtained in (7) above and 40%
A 2 L solution of acetonitrile containing 820 ml of a chillamine aqueous solution.
Is stirred overnight at room temperature and the solvent is evaporated under reduced pressure. Acetic acid residue
Dissolve in ethyl, saturated aqueous sodium bicarbonate and
Wash with saturated brine, dry over sodium sulfate, and reduce the solvent.
Remove by pressure. The residue was washed with ethyl acetate-diisopropyl ether.
By recrystallizing with (2: 1)^*, 2R
^*(S^*))-2 '-[3- (Methylamino) propioni
]]-3 ', 4'-dihydro-6', 7'-dimethoxy
-2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4,4-bi
Suethoxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (141 g, yield 89
%) As crystals. Melting point 119-121 [deg.] C. (9) Ethanol of 119 g of the compound obtained in (8) above
67.5 g of sodium hydroxide in a 675 ml suspension.
Add a 137 ml solution of water and heat to reflux for 45 minutes. reaction
The liquid is ice-cooled, diluted with 600 ml of water, and 700 ml of solvent is added.
After evaporation, 675 ml dioxane is added. Chlorocarbonate
33.2 g of sodium chloride was added dropwise under ice cooling and stirred for 30 minutes.
It About 130 ml of concentrated hydrochloric acid was added to the reaction mixture under ice cooling to adjust the pH to 4
Adjust to -5. 400 ml of solvent was distilled off under reduced pressure and at room temperature
Stir overnight. The precipitated crystals are collected by filtration, then washed with water and diethyl ether.
After washing with a filter and drying (1R^*, 2R
^*(S ^*))-2 '-[3- (N-methyl-N-benzyl
Luoxycarbonylamino) propionyl] -3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dime
Toxy-1-isoquinolyl) -4,4-biscarboxy
Ruspiro [cyclohexane-1,1 '(2'H) -i
Soquinoline] (156 g) is obtained. (10) Dicarboxylic acid compound 20 obtained in the above (9)
A solution of 0 g of pyridine in 2 L is heated under reflux for 2.5 hours. reaction
After cooling the liquid, the solvent was distilled off under reduced pressure and the residue was converted to chloroform.
Dissolve. With 500 ml of water and 500 ml of saturated saline
After washing and drying with sodium sulfate. The solvent was distilled off under reduced pressure,
Crystallize with 1 L of acetone with stirring. The resulting crystals are
Dissolve the solvent in vacuum and remove the solvent under reduced pressure.
Dissolve in 1 L and stir. The precipitated crystals are collected by filtration and dried
By doing (1R^*, 2R^*(S^*), 4R^*) −
2 '-[3- (N-methyl-N-benzyloxycarbo
Nylamino) propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-tetrahydro-6,7-dimethoxy-1-iso
Quinolyl) -spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] -4-carboxylic acid (145 g, yield
Ratio 77%: Compound 1 (10a)) is obtained as crystals. Compound 1 (10a): melting point 181-183 ° C. The mother liquor was collected, the solvent was distilled off, and the silica gel column chromatography was performed.
By purifying with a matography, (1R^*, 2R^*
(S^*), 4S^*) -2 '-[3- (N-methyl-N-beta)
Nyloxycarbonylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -spiro [cyclohexyl
Xan-1,1 '(2'H) -isoquinoline] -4-ca
Rubonic acid (15 g, yield 8%: compound 1 (10b))
Obtained as crystals. Compound 1 (10b): melting point 118-120 ° C.

Reference Example 2 (1) (1R ^* , 2R ^* (S ^* ))-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-)
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 1 (6)) 3.0
g, and 1.56 g of diisopropylethylamine, to a 50 ml solution of 1,2-dichloroethane, a solution of 1.19 g of acetyl bromide in 10 ml of dichloroethane was added dropwise at 0 ° C. over 3 hours, and the mixture was stirred for 1 hour. Silica gel 1.
Add 5 g and stir overnight at room temperature. The silica gel is filtered off and washed with chloroform-methanol (5: 1).
The combined filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and recrystallized from isopropyl alcohol-diisopropyl ether to give (1R ^* , 2R ^* (S ^* ))-2′-acetyl- 3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (2.6 g, yield 81%)
Is obtained as a crystal. The mother liquor was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 → 1: 1) to obtain the same compound (374 mg, 12%). Melting point 142-144 [deg.] C. (2) To a suspension of 50.0 g of the compound obtained in (1) above in 600 ml of ethanol, sodium hydroxide (30.0
300 g of an aqueous solution of 7 g) is added, and the mixture is heated under reflux for 22 hours. After cooling, it is neutralized with ice-cooled 10% hydrochloric acid, and the solvent is distilled off under reduced pressure. Furthermore, toluene is azeotropically distilled. The residue is suspended in 1 L of pyridine and heated under reflux for 2 hours. After distilling off the solvent,
The residue was separated and purified by silica gel column chromatography (chloroform: methanol = 35: 1 to 5: 1) to give a highly polar compound (1R ^* , 2R ^* (S ^* ), 4R ^* )-.
2'-acetyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] -4-carboxylic acid (30.6 g, yield 72%:
Compound 2 (2a)) and low polarity compound (1R ^* , 2R)
^* (S ^* ), 4S ^* )-2'-acetyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] -4-carboxylic acid (4.0 g, yield 9.5%: compound 2 (2b)) is obtained, respectively. Compound 2 (2a): melting point 202-205 ° C. Compound 2 (2b): amorphous powder, MS (FA
B): 567 (M + H), IR (Nujol) c
m- ¹ : 3360, 1720, 1640, 1610. (3) 2.0 g of the compound obtained in Reference Example 2 (2a) above
0.67 g of lithium aluminum hydride was gradually added to a suspension of 100 ml of tetrahydrofuran in
Heat to reflux for minutes. 2 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution under ice cooling, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 120: 1).
By purifying (0: 1 → 80: 10: 1),
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-hydroxymethyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (1.45 g, 77% yield) is obtained as an amorphous powder. (4) To a solution of 0.44 ml of oxalyl chloride in 45 ml of methylene chloride, a solution of 0.54 g of dimethyl sulfoxide in 10 ml of methylene chloride was added dropwise at -78 ° C, and the mixture was stirred for 10 minutes. A solution of 1.37 g of the compound obtained in (3) above in 15 ml of methylene chloride is added dropwise at -78 ° C, and the mixture is stirred at -78 ° C for 15 minutes and at -45 ° C to -30 ° C for 2 hours. 2.58 ml of triethylamine was added dropwise at -45 ° C, and 1 at 0 ° C.
Stir for hours. After adding saturated aqueous ammonium chloride solution under ice cooling, the mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine. By drying over sodium sulfate and evaporating the solvent under reduced pressure, (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy. -2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-Dimethoxy-1-isoquinolyl) -4-formyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (1.30 g, yield 96%) is obtained as an amorphous powder. (5) 1.1 g of the compound obtained in the above (4) and 2-
To a solution of 11 ml of methyl-2-butene and 110 ml of tert-butyl alcohol, 1.7 g of sodium chlorite in a phosphate buffer solution (pH 7, 50 ml) is added dropwise at room temperature, and the mixture is stirred for 30 minutes. Add water, extract with chloroform four times, and dry over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 4).
(0: 100: 1) to give (1
R ^* , 2R ^* (S ^* ), 4R ^* )-2'-ethyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] -4-carboxylic acid (0.85 g, yield 69%) is obtained as crystals. Melting point 124-126 [deg.] C. (6) The compound obtained in Reference Example 2 (2b) is converted to the above (3)
By processing in the same manner as in (4) and (4), (1R ^* , 2
R ^* (S ^* ), 4S ^* )-2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-Isoquinolyl) -4-formyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained.
To a solution of 389 mg of the present compound in 6 ml of ethanol, 369 mg of silver nitrate is added at 0 ° C. At the same temperature, a solution of 264 mg of potassium hydroxide in 3 ml of water was added dropwise and washed with 3 ml of water. After stirring at room temperature for 2 hours, it is filtered through Celite. After washing with ethanol, the filtrate and washings are distilled off. Add water to the residue 1
After neutralization with 0% hydrochloric acid, chloroform-methanol (4:
The mixture is extracted with the mixed solvent of 1), the organic layer is dried over sodium sulfate, and then the solvent is distilled off. By purifying the residue by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 200: 50: 2),
(1R ^* , 2R ^* (S ^* ), 4S ^* )-2'-ethyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] -4-carboxylic acid (260 mg, yield 65 %) As crystals. Melting point 136-140 [deg.] C.

Reference Example 3 (1) (1R^*, 2R^*(S^*), 4R^*) -2 '-[3-
(N-methyl-N-benzyloxycarbonylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-teto
Lahydro-6,7-dimethoxy-1-isoquinolyl)-
Spiro [cyclohexane-1,1 '(2'H) -isoki
Norrin] -4-carboxylic acid (obtained in Reference Example 1 (10a)
Compound) 40g of tetrahydrofuran 240ml suspension
The solution was allowed to stand at room temperature for 5 minutes, and oxalyl chloride 7.51 was added.
g of tetrahydrofuran 40 ml solution was added dropwise, and then 15 minutes
Stir for a while. Reduces solvent and excess oxalyl chloride
It is distilled off under pressure and 240 ml of tetrahydrofuran are added.
While stirring the solution under ice-cooling, triethylamine 6.53
g of tetrahydrofuran 40 ml solution was added dropwise, and 30 minutes
Stir for a while. The precipitated triethylamine hydrochloride is filtered off
Then, the filtrate is evaporated under reduced pressure to remove the acid chloride.
Obtained as rufus powder. (2) (4R) -4-isopropyloxazolidine-2
-ON 8.33 g tetrahydrofuran 240 ml solution
, N-butyllithium (1.47M, n-hexane dissolved
Liquid) was added dropwise at -60 ° C over 20 minutes, and then at -60 ° C for 2 minutes.
Stir for 0 minutes. Of the acid chloride obtained in (1) above
Tetrahydrofuran 280 ml solution at -60 ° C 40
Add dropwise over a period of 1 minute, and cool with ice at -60 to -5 ° C for 1 hour.
Stir under 1 hour. Saturated ammonium chloride water under ice cooling
Add 100 ml of solution and stir for 10 minutes. 100m of water
1 is added and the organic layer is separated. Wash with saturated saline and
Dry with sodium acidate. The solvent was distilled off under reduced pressure, and the residue was
Neutral silica gel column chromatography (silica gel
 60N (neutral, spherical) 37561-79 (Kanto
(Gaku)) (Chloroform: Acetonitrile = 5: 1 to 2:
1, chloroform: methanol = 5: 1)
Divided into polar compound 3 (2a) and highly polar compound 3 (2b)
Let go. Furthermore, a low-polarity compound 3 (2a) was added to NH silica gel
Column chromatography (ChromatorexN
H DM1020 Fuji Silysia Chemical Ltd. (FUJIS
ILYSIA)) (ethyl acetate: hexane = 1: 1 to 1
2: 1) to obtain (1R^*, 2R
^*(S^*), 4R^*) -2 '-[3- (N-methyl-N-be
Nyloxycarbonylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-[((4R)-
Isopropyl-2-oxo-3-oxazolinyl) carboni
] -Spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] (16.01 g, yield 34.8%: compound
Object 3 (2a)) is obtained as an amorphous powder. High polarity
Alumina gel chromatography of compound 3 (2b)
(Aluminum oxide 90 1.01097 (Mel
)) (Chloroform: ethyl acetate: n-hexane =
1: 2: 5) to give (1S^*, 2S^*(R
^*), 4S^*) -2 '-[3- (N-methyl-N-benzyl
Luoxycarbonylamino) propionyl] -3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dime
Toxy-1-isoquinolyl) -4-[((4R) -isop
Ropyl-2-oxo-3-oxazolinyl) carbonyl]-
Spiro [cyclohexane-1,1 '(2'H) -isoki
Norrin] (13.05 g, yield 28%: compound 3 (2
b)) is obtained as an amorphous powder. (3) Compound 3 (2a) 13.0 obtained in the above (2)
To a solution of 5 g of methanol in 260 ml, potassium hydroxide
Add 100 ml of 9.94 g aqueous solution dropwise at room temperature over 40 minutes.
Down. Stir at room temperature for 20 minutes and heat to reflux for 40 minutes
It After cooling the reaction solution, methanol was distilled off under reduced pressure, and water (1
00 + 31 (washing in) ml) and add diethyl ether.
4 times with a mixed solvent of 78 ml of ethyl acetate and 16 ml of ethyl acetate
To wash. Neutralize with about 12.5 ml of 10% hydrochloric acid under ice cooling.
Then, add 18 ml of 10% aqueous sodium hydroxide solution and add a base.
Sex Diethyl ether 45m and ethyl acetate 9
Wash twice with ml of mixed solvent. Under ice cooling, with 10% hydrochloric acid
Neutralize. (Adjust to pH = 7.) Natri chloride in the aqueous layer
Dissolve and saturate 60 g of sodium with 110 ml of ethyl acetate
Extract 3 times and wash with saturated brine. With sodium sulfate
After drying, the solvent is distilled off under reduced pressure. Diethyl ether residue
By recrystallizing with 93 ml, the optically active substance (-)-
(1R^*, 2R^*(S^*), 4R^*) -2 '-[3- (N-me
Tyl-N-benzyloxycarbonylamino) propio
Nyl] -3 ', 4'-dihydro-6', 7'-dimethoxy
Ci-2- (2-ethyl-1,2,3,4-tetrahydro
-6,7-Dimethoxy-1-isoquinolyl) -spiro
[Cyclohexane-1,1 '(2'H) -isoquinoli
] -4-Carboxylic acid (9.71 g, yield 24%: compound
The product 3 (3a)) is obtained as crystals. Compound 3 (2b)
By the same treatment as above, the optically active substance (+)-
(1R ^*, 2R^*(S^*), 4R^*) -2 '-[3- (N-me
Tyl-N-benzyloxycarbonylamino) propio
Nyl] -3 ', 4'-dihydro-6', 7'-dimethoxy
Ci-2- (2-ethyl-1,2,3,4-tetrahydro
-6,7-Dimethoxy-1-isoquinolyl) -spiro
[Cyclohexane-1,1 '(2'H) -isoquinoli
] -4-Carboxylic acid (7.64 g, yield 19%: compound
The product 3 (3b)) is obtained as crystals. Compound 3 (3a): melting point 144-145 ° C., [α]_D
²⁵−26.5 ° (c1.0, chloroform), 99.
9% ee (from HPLC). Compound 3 (3b): melting point 146-147 ° C., [α]_D
²⁵+ 26.5 ° (c1.0, chloroform), 99.
6% ee (from HPLC). (HPLC conditions; SUMICHIRAL OA-310
0, 20 mM-ammonium acetate / methanol).

Reference Example 4 (1) (1R ^* , 2R ^* )-2′-acetyl-3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2- (3,
4-dihydro-6,7-dimethoxy-1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Compound obtained in Reference Example 1 (5) ) 10.0 g to 100 m
Heat to reflux for 7 hours with 1 liter of methyl iodide. After cooling the reaction solution, the precipitated crystals were collected, collected by filtration, and washed with ethyl acetate to give 2'-acetyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-methyl-). Three
4-Dihydro-6,7-dimethoxy-isoquinolinium-1-yl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] iodide (10.2 g, yield 84) %) As a mixture of diastereomers. Melting point 171-173 [deg.] C. (decomposition), MS (ESI): 651 (M +), IR (Nuj
ol) cm ⁻¹ : 1743, 1727, 1629, 16
01. (2) 9.0 g of the diastereomer mixture obtained in (1) above is dissolved in 180 ml of ethanol, and 0.438 g of sodium borohydride is added under ice cooling. Same temperature 30
After stirring for a minute, 10% hydrochloric acid is added. The reaction solvent is evaporated, ethyl acetate is added, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. By distilling off the solvent and recrystallizing it with a mixed solvent of ethyl acetate-isopropyl ether, (1R ^* , 2S ^* )-
2'-acetyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (7.38)
g, yield 98%) as crystals. Melting point 165.5-167.5 ° C, MS (ESI): 65
3 (M + H), IR (Nujol) cm ⁻¹ : 173
9, 1721. (3) 7.0 g of the compound obtained in (2) above, 4.3 g of sodium hydroxide, 86 ml of ethanol and 43 of water
Mix and heat to reflux for 2 days. After cooling the reaction solution,
After neutralization with 1M hydrochloric acid, the solvent is distilled off. Pyridine 1 in the residue
Add 00 ml and heat to reflux for 4 hours. After distilling off the solvent, chloroform is added, washed with water and dried over sodium sulfate. By purifying by silica gel column chromatography (chloroform: methanol = 5: 1 to 1: 1), (1
R ^* , 2S ^* (S ^* ), 4R ^* )-2'-acetyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (3.43 g, yield 58%: Compound 4 (3a)) and (1R ^* , 2S ^* (R ^* ), 4S ^* )-2'-acetyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-methyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (0.96 g, yield 16%: compound 4 (3
b)) is obtained as a crystal. Compound 4 (3a): melting point 235-237 ° C. (decomposition), M
S (ESI): 553 (M + H), IR (Nujol)
cm- ¹ : 1713, 1597. Compound 4 (3b): melting point 218-220 ° C. (decomposition), M
S (ESI): 553 (M + H), IR (Nujol)
cm < ^-1 >: 3400, 1732, 1710. (4) 1.0 g of the compound 4 (3a) obtained in the above (3)
0.3 ml of oxalyl chloride was added dropwise to a solution of methylene chloride in 30 ml of methylene chloride under ice cooling, and 1 ml of dimethylformamide was added.
Add dropwise and stir at room temperature for 2 hours. The solvent is distilled off from the reaction solution, ethanol is added under ice cooling, the mixture is stirred at room temperature for 30 minutes, and then the solvent is distilled off. Ethyl acetate is added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent is evaporated. By silica gel column chromatography (chloroform: methanol = 10:
By purifying in 1), (1R ^* , 2S ^* (R ^* ), 4
R ^* )-2'-acetyl-3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-methyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-ethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (1.08
g, 100% yield) as an amorphous foam. MS (ESI): 581 (M + H), IR (Nujo
l) cm < ^-1 >: 1726, 1628. (5) To a suspension of 2.77 g of lithium aluminum hydride in 40 ml of tetrahydrofuran, a solution of 8.47 g of the compound obtained in (4) above in 40 ml of tetrahydrofuran was added dropwise while heating under reflux. After heating under reflux for 3 hours,
Under ice cooling, 2.8 ml of sodium hydroxide and 5.6 ml of water are sequentially added dropwise. After stirring the mixture for 2 hours at room temperature, chloroform is added and the insoluble matter is filtered off. After the chloroform solution was dried over sodium sulfate, the solvent was distilled off (1R
^* , 2S ^* (R ^* ), 4R ^* )-2'-ethyl-3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-hydroxymethyl-spiro [cyclohexane-1, 1 '(2'H) -isoquinoline] (8.50 g) is obtained as a crude product. The crude product is used in the next step without purification. MS (APCI): 525 (M + H), IR (Nujo
1) cm < ^-1 >: 3541. (6) To a solution of 2.55 ml of oxalyl chloride in 70 ml of methylene chloride, 2.8 ml of dimethyl sulfoxide is added dropwise at -78 ° C. After stirring for 15 minutes at the same temperature, 7.65 g of the compound obtained in (5) above was added to methylene chloride 30.
Add the ml solution dropwise. After stirring at -45 to -35 ° C for 2 hours, 14.9 ml of triethylamine was added dropwise at -45 ° C. After stirring at 0 ° C. for 2 hours, ethyl acetate was added, the mixture was washed with saturated saline and dried over sodium sulfate. After distilling off the solvent, a methylene chloride-isopropyl ether mixed solvent was added to remove insoluble substances, and crystallization was carried out with isopropyl ether to give (1R ^* , 2S ^* (R ^* ), 4R ^* )-2 '.
-Ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-formyl -Spiro [cyclohexane-1,1 '(2'H)
-Isoquinoline] (5.25 g, 69% yield) is obtained as crystals. Melting point 137-139 [deg.] C., MS (FAB): 523 (M +
H), IR (Nujol) cm < ^-1 >: 1726. (7) To a solution of 975 mg of silver nitrate in 10 ml of water, 1.0 g of the compound obtained in the above (6) and 77 of potassium hydroxide.
A mixed solution of 3 mg, 40 ml of ethanol and 10 ml of water was added dropwise under ice cooling. After stirring at room temperature for 3 hours, the insoluble matter is filtered through Celite, the filtrate is neutralized with hydrochloric acid, and the solvent is evaporated. The residue is dissolved in chloroform, dried over sodium sulfate, and the solvent is distilled off. By crystallization with a mixed solvent of ethanol-ethyl acetate, (1R ^* , 2S ^* (R ^* ), 4R ^* )-
2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4
-Carboxyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (0.65 g, yield 63
%) As crystals. Melting point 197-199 [deg.] C. (decomposition), MS (APCI): 5
39 (M + H), IR (Nujol) cm ^-1 : 338
8,1717. (8) By treating the compound 4 (3b) obtained in (3) above in the same manner as in (4) to (7) above, (1R ^* ,
2S ^* (R ^* ), 4S ^* )-2'-ethyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-methyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained.

Reference Example 5 (1) (1R ^* , 2R ^* (S ^* ))-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-)
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 1 (6)) 5.0
g, paraformaldehyde 2.4 g, acetic acid 25 ml, trifluoroacetic acid 4.56 g, tetrahydrofuran 50 m
The mixture of 1 is stirred at room temperature for 1 hour. Then, under ice cooling, 2.42 g of sodium borohydride was added little by little, and the mixture was stirred at room temperature for 2 days. After the reaction solution was distilled off under reduced pressure,
Ethyl acetate is added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1R ^* , 2R ^* (S ^* ))-2′-methyl-3 ′, 4′-dihydro-. 6 ', 7'-dimethoxy-
2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-dimethoxy-1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (2.82 g, yield 5
5.2%) as an amorphous foam. MS (APCI): 639 (M + H), IR (Nujo
l) cm ^<-1> : 1725. (2) 2.63 g of the compound obtained in the above (1), 50%
Sodium hydroxide 9.9 ml and ethanol 25 ml
The mixture is stirred overnight at room temperature and then heated under reflux for 18 hours. After cooling the reaction solution, it is neutralized with hydrochloric acid and the solvent is distilled off.
After extraction with hot chloroform and drying over sodium sulfate, the solvent was distilled off to give (1R ^* , 2R ^* (S ^* )).
-2'-methyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4,4-biscarboxyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (2.83 g) is obtained as a crude product. The crude product is used in the next step without purification. MS (APCI): 583 (M + H), IR (Nujo)
l) cm < ^-1 >: 3388, 1732. (3) A mixture of 1.87 g of the compound obtained in (2) above, 371 mg of pyridine / hydrochloride, and 20 ml of pyridine is heated under reflux for 1.5 hours. After cooling the reaction solution, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain (1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '. -Methyl-3 ', 4'-dihydro-6', 7'-dimethoxy-
2- (2-ethyl-1,2,3,4-tetrahydro-
6,7-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H)
Isoquinoline] (1.58 g, yield 91%: compound 5
(3a)) and (1R ^* , 2R ^* (S ^* ), 4S ^* )-2 '
-Methyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl -Spiro [cyclohexane-1,1 '(2'
H) -isoquinoline] (0.15 g, yield 8.6%: compound 5 (3b)). Compound 5 (3a): MS (APCI): 539 (M +
H), IR (neat + chloroform) cm ⁻¹ : 34
00-3300, 1709. Compound 5 (3b): MS (APCI): 539 (M +
H), IR (Nujol) cm ⁻¹ : 3400, 170
7.

Reference Example 6 (1) (1R^*, 2R^*(S^*))-3 ', 4'-jihi
Doro-6 ', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4,4-bisethoxycarbonyl
-Spiro [cyclohexane-1,1 '(2'H) -iso
Quinoline] (compound obtained in Reference Example 1 (6)) 3.0
0 g of diisopropylethylamine 4.34 g of chloride
Propionic acid bromide in a 60 ml solution of ethylene under ice cooling.
2.16 ml methylene chloride 20 ml solution over 2 hours
And drip. After stirring overnight at room temperature, add water and then react.
Distill off. Add ethyl acetate and add saturated sodium bicarbonate.
Wash with aqueous sodium chloride solution, water and saturated saline solution, and wash with sodium sulfate.
To dry. After distilling off the solvent, NH-silica gel column
By purification by chromatography (ethyl acetate)
, (1R^*, 2R^*(S^*))-2'-Propionyl
-3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4,4-bis-ene
Toxycarbonyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (1.59 g, yield 48.
6%) as crystals. Melting point 138 ° C, MS (APCI): 681 (M + H),
IR (Nujol) cm ^-1: 1749, 1725, 1
639. (2) The compound obtained in (1) above, 2.02 g of tetra
Hydrofuran in 80 ml solution under argon flow for 10
Add 3.00 ml of M borane-dimethyl sulfide complex
Then, the mixture is stirred at 60 ° C. for 3 hours. After cooling the reaction solution,
The solution is added little by little and stirred at room temperature for 1 hour. Next
Then, 15 ml of 5M hydrochloric acid / ethanol was added dropwise to 1.5.
Heat to reflux for hours. After cooling, the solvent was distilled off and the residue was saturated charcoal.
Add sodium hydrogen carbonate aqueous solution and extract with chloroform
And dried over sodium sulfate. After distilling off the solvent, silica
Gel column chromatography (chloroform: methano)
: 28% ammonia water = 20: 1: 0.1)
By doing, (1R^*, 2R^*(S^*))-2'-
n-propyl-3 ', 4'-dihydro-6', 7'-di
Methoxy-2- (2-ethyl-1,2,3,4-tetra
Hydro-6,7-dimethoxy-1-isoquinolyl)-
4,4-bisethoxycarbonyl-spiro [cyclohex
Sun-1,1 '(2'H) -isoquinoline] (966m
g, yield 48.8%) as an amorphous foam.
It MS (APCI): 667 (M + H), IR (Nujo
l) cm^-1: 1727. (3) Referential Example 839 mg of the compound obtained in (2) above
By processing in the same manner as 1 (9) and (10),
(1R^*, 2R^*(S^*), 4R^*) -2'-n-propyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl
-Spiro [cyclohexane-1,1 '(2'H) -iso
Quinoline] (361 mg, yield 63.7%: compound 6
(3a)) and (1R^*, 2R^*(S^*), 4S^*) -2 '
-N-propyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-teto
Lahydro-6,7-dimethoxy-1-isoquinolyl)-
4-carboxyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (154 mg, 21
%: Compound 6 (3b)) as amorphous powder
Get it. Compound 6 (3a): MS (APCI): 567 (M +
H), IR (Nujol) cm^-1: 3600,353
0,1699. Compound 6 (3b): MS (APCI): 567 (M +
H), IR (Nujol) cm^-1: 1715,169
9.

Reference Example 7 (1) (1R^*, 2R^*(S^*))-3 ', 4'-jihi
Doro-6 ', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4,4-bisethoxycarbonyl
-Spiro [cyclohexane-1,1 '(2'H) -iso
Quinoline] (compound obtained in Reference Example 1 (6)) 8.0
g and 16 ml of benzyl chlorocarbonate at 75 ° C.
Stir for 4 hours. After cooling the reaction solution, ethyl acetate was added,
Wash with saturated aqueous sodium hydrogen carbonate solution and saturated saline
After that, the solvent is distilled off. Repeat this operation 4 times
Gel column chromatography (n-hexane → n-he
Xan: Ethyl acetate = 1: 1 → Ethyl acetate → Chloroform
Frame: methanol = 10: 1)
(1R^*, 2R^*(S^*))-2'-Benzyloxyca
Lubonyl-3 ', 4'-dihydro-6', 7'-dimeth
Xy-2- (2-ethyl-1,2,3,4-tetrahydr
B-6,7-dimethoxy-1-isoquinolyl) -4,4
-Bisethoxycarbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] (7.35 g, yield
Yield 75.7%) as an amorphous powder. MS (APCI): 759 (M + H), IR (Nujo
l) cm^-11724,1696. (2) The compound obtained in (1) above is used in Reference Example 1 (9).
By treating in the same manner as (10) and (10), (1R^*, 2
R^*(S^*), 4R^*) -2'-Benzyloxycarbonyl
-3 ', 4'-dihydro-6', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-dimethoxy-1-isoquinolyl) -4-carboxy
Ruspiro [cyclohexane-1,1 '(2'H) -i
Soquinoline] (4.92 g, yield 77.6%: compound 7
(2a)) and (1R^*, 2R^*(S ^*), 4S^*) -2 '
-Benzyloxycarbonyl-3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-tetrahydro-6,7-dimethoxy-1-iso
Quinolyl) -4-carboxyl-spiro [cyclohexa]
-1, -1 '(2'H) -isoquinoline] (1.20
g, yield 18.9%: Compound 7 (2b))
Obtained as morphus powder. Compound 7 (2a): MS (ESI): 659 (M +
H), IR (Nujol) cm^-1: 1694. Compound 7 (2b): MS (ESI): 659 (M +
H), IR (Nujol) cm^-1: 1703. (3) Compound 7 (2a) 2.06 obtained in (2) above
g, 5M hydrochloric acid-ethanol solution 10 ml and ethanol
20 ml of the solution are combined and stirred at room temperature for 24 hours. solvent
Is distilled off, neutralized with saturated aqueous sodium hydrogen carbonate solution, and then vinegar.
After extraction with ethyl acetate and washing with saturated brine, the organic layer was washed with sodium sulfate.
Dry with thorium. By distilling off the solvent, crude
Product (1R^*, 2R^*(S^*), 4R^*) -2'-Benzyl
Xycarbonyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-2- (2-ethyl-1,2,3,4-teto
Lahydro-6,7-dimethoxy-1-isoquinolyl)-
4-ethoxycarbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] (2.08 g, yield
Yield 97%) as an amorphous powder. MS (APCI): 687 (M + H), IR (Nujo)
l) cm^-1: 1720, 1695. (4) 2.06 g and 1 of the compound obtained in (3) above
0% palladium-carbon 2.06 g ethanol 40 ml
In addition, it is subjected to atmospheric pressure catalytic reduction in a hydrogen atmosphere. Remove catalyst
The filtrate was evaporated and the residue was combined with diisopropyl ether.
By crystallization, (1R^*, 2R^*(S^*), 4R^*) −
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-ethoxycarl
Bonyl-spiro [cyclohexane-1,1 '(2'H)
-Isoquinoline] (1.23 g, 74% yield) as crystals
Get it. Melting point 140-142 ° C, MS (APCI): 553 (M
+ H), IR (Nujol) cm^-1: 3345, 17
20. (5) 0.80 g of the compound obtained in (4) above
0.59 ml of acrylic acid chloride in 16 ml of ren solution
And 1.0 ml of triethylamine are sequentially added dropwise at room temperature for 2
Stir for hours. Wash the reaction mixture with water and dry over sodium sulfate.
It The solvent was distilled off and the residue was subjected to silica gel column chromatography.
Purified with Raffy (chloroform: methanol = 35: 1)
By manufacturing, (1R^*, 2R^*(S^*), 4R^*) −
2'-acryloyl-3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinoli
) -4-Ethoxycarbonyl-spiro [cyclohexa]
-1, -1 '(2'H) -isoquinoline] (0.834
g, yield 95%) as an amorphous powder. MS (APCI): 607 (M + H), IR (Nujo
l) cm^-1: 1719, 1645, 1609. (6) 0.91 g of the aceto compound obtained in the above (5)
50% dimethylamine aqueous solution in 10 ml nitrile solution
Add 3 ml and stir at room temperature for 12 hours. Evaporate the solvent
The residue on silica gel column chromatography (chromatography).
Rhoholm: Methanol: 28% Ammonia water = 200
(0:40:10) to give (1R ^*, 2R^*
(S^*), 4R^*) -2 '-[3- (Dimethylamino) p
Ropionyl] -3 ', 4'-dihydro-6', 7'-di
Methoxy-2- (2-ethyl-1,2,3,4-tetra
Hydro-6,7-dimethoxy-1-isoquinolyl) -4
-Ethoxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (0.81 g, yield 8
3%) as crystals. Melting point 154-156 [deg.] C., MS (APCI): 652 (M
+ H), IR (Nujol) cm^-1: 1713,16
49. (7) Add 790 mg of the compound obtained in (6) above to ethanol.
Suspended in a mixed solvent of 10 ml of methanol and 3 ml of methanol
Then, add 4 ml of 10% sodium hydroxide aqueous solution, and add
Stir for 2 hours at warm temperature. Neutralize with 10% hydrochloric acid under ice-cooling, then use as solvent
Distill off. The residue is extracted with chloroform and the solvent is distilled off.
By doing (1R^*, 2R^*(S^*), 4R^*) -2'-
[3- (dimethylamino) propionyl] -3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl
Ru-1,2,3,4-tetrahydro-6,7-dimetoki
Ci-1-isoquinolyl) -4-carboxyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoli
Amorphous (850 mg, yield quant.)
Obtained as a powder. MS (APCI): 624 (M + H), IR (Nujo)
l) cm^-1: 1706, 1656, 1640. (8) The compound 7 (2b) obtained in the above (2) is added to the above.
By performing the same processing as (3) to (7), (1R^*，
2R^*(S^*), 4S^*) -2 '-[3- (Dimethylami
No) propionyl] -3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinoli
) -4-carboxyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] is obtained.

Reference Example 8 (1) (1R ^* , 2R ^* )-2′-acetyl-3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2- (3,
4-dihydro-6,7-dimethoxy-1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Compound obtained in Reference Example 1 (5) ) 10.0 g was dissolved in 630 ml of ethanol and 70 ml of acetic acid to obtain platinum oxide (Pt).
100 mg of O ₂ ) is added and subjected to atmospheric pressure catalytic reduction under hydrogen atmosphere. The catalyst is filtered off, the filtrate is evaporated, the residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over sodium sulfate, and then the solvent is distilled off. The residue was crystallized from diethyl ether and recrystallized from ethanol to give (1
R ^* , 2R ^* (S ^* ))-3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-acetyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (8.45 g, 84% yield) is obtained as crystals. Melting point 146-149 ° C, MS (FAB): 639 (M +
H), IR (Nujol) cm ^-1 : 3280,174
0, 1725, 1620, 1610. (2) To a solution of 4.0 g of the compound obtained in the above (1) and 2.5 g of triethylamine in 40 ml of methylene chloride, 1.70 g of acrylic acid chloride is added dropwise under ice cooling. After stirring at room temperature for 2 hours, the reaction solution is washed with an aqueous sodium hydroxide solution and dried over sodium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to give (1
R ^* , 2R ^* (S ^* ))-2'-acryloyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Acetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline] (4.09 g, yield 94%) is obtained as crystals. Melting point 162-165 ° C, MS (APCI): 693 (M
+ H). (3) To a solution of 200 mg of the compound obtained in (2) above in 2 ml of acetonitrile, 50% dimethylamine aqueous solution 1
Add ml and stir overnight at room temperature. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) and crystallized with diisopropyl ether to give (1R ^* , 2R ^* (S ^* ))-2 '-[3- (Dimethylamino) propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-acetyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (174 mg, yield 81%) is obtained as crystals.
Melting point 154-156 ° C, MS (APCI): 738 (M
+ H). (4) To a solution of 2.0 g of the compound obtained in (3) above in 20 ml of ethanol, a 1% aqueous solution of 10% sodium hydroxide is added.
Add 0 ml and heat to reflux for 18 hours. After cooling the reaction solution, the solvent is distilled off, the residue is acidified with hydrochloric acid and then washed with chloroform. The aqueous layer was neutralized with ammonia, the solvent was distilled off, the residue was extracted with chloroform-methanol (5: 1) to remove inorganic substances, and then the solvent was distilled off to give a crude product (1R ^* , 2R ^* (S ^* ))-2 '-[3
-(Dimethylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-acetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl ) -4,4-Biscarboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (2.42 g) is obtained. MS (ESI): 680 (MH). (5) 2.4 g of the crude product obtained in (4) above was combined with 25 ml of pyridine and 0.813 g of pyridine hydrochloride to obtain 2
Heat to reflux for hours. After cooling the reaction solution, the solvent is distilled off, chloroform is added and the insoluble matter is filtered off. The filtrate was distilled off, and the residue was purified by NH-silica gel column chromatography (chloroform → methanol) to give (1R
^* , 2R ^* (S ^* ))-2 '-[3- (dimethylamino) propionyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-acetyl-1,2,3,3
4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (1.34 g, yield 78% (from the compound obtained in the above (3))) is obtained as an amorphous powder. MS (ESI): 636 (M-H), IR (Nujo)
l) cm ^<-1> : 1640.

Reference Example 9 (1) 24.9 ml of n-butyllithium (1.6Mn-hexane solution) was added dropwise to a solution of 4.44 g of diisopropylamine in 25 ml of tetrahydrofuran under ice cooling. After stirring at the same temperature for 30 minutes, the solution was stirred at -78 ° C for (1
R ^* , 2R ^* (S ^* ), 4R ^* )-2'-acetyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Reference Example 2 (2) Compound 2 (2a) obtained by
4.52 g of tetrahydrofuran in 25 ml of solution are added dropwise. After stirring for 2 hours at −20 to −30 ° C., 9.65 g of allyl bromide is added dropwise at −78 ° C. After stirring at 0 ° C for 1 hour, the mixture is neutralized with 10% hydrochloric acid at the same temperature. After evaporating tetrahydrofuran, the mixture is extracted with chloroform and dried over sodium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (chloroform: methanol = 50: 1 to 1: 1).
(1R ^* , 2R by purifying with 10: 1)
^* (S ^* ), 4R ^* )-2 '-(4-pentenoyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (4.22 g, 87% yield) is obtained as a foam. MS (APCI): 607 (M + H), IR (Nujo
l) cm ^<-1> : 1609. (2) A solution of 3.94 g of the compound obtained in (1) above in 70 ml of tetrahydrofuran is added dropwise while heating a refluxing solution of 1.23 g of lithium aluminum hydride in 70 ml of tetrahydrofuran. After the reaction solution was heated under reflux for 2 hours, 1.2 ml of water, 1.8 ml of 10% sodium hydroxide aqueous solution, and 0.6 ml of water were sequentially added under ice cooling. After stirring at room temperature overnight, it is dried over sodium sulfate and the solvent is distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 → chloroform: methanol: 28% aqueous ammonia = 10: 2: 0.1) to give (1R ^* , 2R ^* (S ^* ), 4R. ^* )-2'-
(4-pentenyl) -3 ', 4'-dihydro-6',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-hydroxymethyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (2.75 g,
Yield 73%) is obtained as a foam. MS (APCI): 579 (M + H), IR (Nujo
l) cm < ^-1 >: 3525. (3) By treating the compound obtained in (2) above in the same manner as in Reference Example 2 (4), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2 '-(4-pentenyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4-formyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained. MS (APCI): 577 (M + H), IR (Nujo
l) cm ^<-1> : 1721. (4) By treating the compound obtained in (3) above in the same manner as in Reference Example 2 (5), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2 '-(4-pentenyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained. MS (APCI): 593 (M + H), IR (Nujo)
l) cm ^<-1> : 1702.

Reference Example 10 (1) 10.5 ml of n-butyllithium (1.6Mn-hexane solution) was added dropwise to a solution of 1.87 g of diisopropylamine in 19 ml of tetrahydrofuran under ice cooling. After stirring at the same temperature for 30 minutes, this solution was mixed with (1R ^* , 2R
^* (S ^* ), 4R ^* )-2'-acetyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-
1.90 g of 1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound 2 (2a) obtained in Reference Example 2 (2))
In tetrahydrofuran (19 ml) at -78 ° C. After stirring for 2 hours at -20 to -30 ° C, 1.90 ml of acetaldehyde is added dropwise at -78 ° C. After stirring at 0 ° C for 3 hours, the mixture is neutralized at the same temperature with 1M-hydrochloric acid. After evaporating tetrahydrofuran, the mixture is extracted with chloroform and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1).
~ 5: 1) to give (1R ^* , 2R
^* (S ^* ), 4R ^* )-2 '-(3-hydroxy) butyryl-3', 4'-dihydro-6 ', 7'-dimethoxy-2
-(2-Ethyl-1,2,3,4-tetrahydro-6,
7-Dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (1.62 g, 79% yield) is obtained as a foam. MS (ESI): 609 (M + H), IR (Nujo
l) cm < ^-1 >: 1711, 1610. (2) 888 mg of the compound obtained in the above (1), 1 ml of ethanol and N, N-dimethylaminopyridine 35
To a solution of 10 mg of methylene chloride in 10 ml, 418 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform:
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-(3-hydroxy) butyryl-3', 4'-dihydro-6 by purification with methanol = 50: 1 to 20: 1). ', 7'
-Dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)
-4-ethoxycarbonyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] (893 mg, yield 96%) is obtained as an amorphous powder. MS (APCI): 639 (M + H), IR (nea
t) cm < ^-1 >: 3465, 1720, 1613. (3) To a solution of 692 mg of the compound obtained in (2) above and 219 mg of triethylamine in 20 ml of methylene chloride, 167 μl of methanesulfonyl chloride is added under ice cooling, and the mixture is stirred at the same temperature for 1 hour. After the solvent is distilled off, ethyl acetate is added, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give (1R ^* , 2R
^* (S ^* ), 4R ^* )-2 '-(3-methanesulfonyloxy) butyryl-3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3 , 4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4
-Ethoxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (726 mg, yield 9
3%) as an amorphous powder. MS (ESI): 717 (M + H), IR (neat)
cm- ¹ : 1719, 1639. (4) A suspension of 427 mg of lithium aluminum hydride in 7 ml of tetrahydrofuran is heated under reflux, and a solution of 714 mg of the compound obtained in (3) above in 7 ml of tetrahydrofuran is added dropwise to this solution. The reaction solution is heated under reflux for 2 hours, and then 0.3 ml of water, 0.45 ml of 10% aqueous sodium hydroxide solution and 0.15 ml of water are sequentially added under ice cooling.
After stirring at room temperature for 3 hours and drying over sodium sulfate, the solvent is distilled off. By repeating the same operation again to complete the reaction, (1R ^* , 2R ^* (S ^* ), 4R ^* )-2′-n
-Butyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-hydroxy Methyl-spiro [cyclohexane-1,1 '
(2′H) -isoquinoline] (595 mg) is obtained as an oil. MS (APCI): 567 (M + H), IR (nea
t) cm < ^-1 >: 3524, 1609. (5) By treating the compound obtained in (4) above in the same manner as in Reference Example 2 (4), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2'-n-butyl-3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-formyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] is obtained. MS (APCI): 565 (M + H), IR (nea)
t) cm ^<-1> : 1719. (6) By treating the compound obtained in (5) above in the same manner as in Reference Example 2 (5), (1R ^* , 2R ^* (S ^* ), 4
R ^* )-2'-n-butyl-3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained. MS (APCI): 581 (M + H), IR (Nujo
l) cm ^<-1> : 1695.

Reference Example 11 (1) (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-acryloyl-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2- Ethyl-1,2,3,4-tetrahydro-
6,7-Dimethoxy-1-isoquinolyl) -4-ethoxycarbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline] (compound obtained in Reference Example 7 (5)) 1.0 g in acetonitrile 20 ml solution,
Add benzylamine (3.54 g) and heat to reflux for 36 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 2000: 25: 10).
(1R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-(3-benzylamino) propionyl-3', 4'-dihydro-6 ',
7'-dimethoxy-2- (2-ethyl-1,2,3,4
-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-ethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (0.60
g, 51% yield) as crystals. Melting point 83-85 ° C, MS (APCI): 714 (M +
H), IR (Nujol) cm ^-1 : 1717,164
3. (2) 0.055 ml of benzyl chlorocarbonate is added to a solution of 248 mg of the compound obtained in (1) above and 0.098 ml of triethylamine in 5 ml of methylene chloride, and the mixture is stirred at room temperature for 2 hours. The reaction solution was distilled off, ethyl acetate was added,
After washing with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
Dry with sodium sulfate. By distilling off the solvent, the crude product (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-
[3- (N-benzyl-N-benzyloxycarbonylamino) propionyl] -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4-ethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] 295
get mg. (3) Crude product 29 obtained in (2) above
5 mg of methanol 20 ml and ethanol 20 ml
Dissolved in a mixed solvent of 10% sodium hydroxide aqueous solution 1
Add 0 ml and stir at room temperature for 10 hours. In addition, 60
After stirring at 0 ° C for 1 hour, the mixture is neutralized with 10% hydrochloric acid under ice cooling and the alcohol is distilled off. After extraction with chloroform and drying over sodium sulfate, the solvent was distilled off to give (1R ^* , 2R ^*
(S ^* ), 4R ^* )-2 '-[3- (N-benzyl-N-
Benzyloxycarbonylamino) propionyl]-
3 ', 4'-dihydro-6', 7'-dimethoxy-2-
(2-ethyl-1,2,3,4-tetrahydro-6,7
285 mg of crude product of -dimethoxy-1-isoquinolyl) -4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained.

Reference Example 12 (1) 3,4-dimethoxyphenethylamine 20.4
g, 14.9 g of 4,4-bisethoxycarbonylcyclohexanone and 200 g of polyphosphoric acid are combined, and the mixture is heated and stirred at 130 ° C. for 40 minutes. After cooling the reaction solution, it is neutralized by pouring it into a saturated aqueous solution of sodium hydrogen carbonate. The organic layer is extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate.
The solvent was distilled off, and the residue was triturated with diethyl ether to give 3 ', 4'-dihydro-6', 7 '.
-Dimethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (6.98 g, yield 31.5%) is obtained as crystals. Melting point 103-104 ° C, MS (APCI): 406 (M
+ H), IR (Nujol) cm ^-1 : 3306, 17
35, 1715. (2) Compound 998 mg obtained in the above (1), diisopropylethylamine 413 mg, methylene chloride 20 m
0.42 ml of benzyl chlorocarbonate is added to the mixed solution of 1 under ice cooling, and the mixture is stirred at room temperature for 3 hours and then heated under reflux for 3 hours.
The solvent is distilled off from the reaction solution, ethyl acetate is added, the mixture is washed with 10% hydrochloric acid and saturated saline, and then dried over sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 2) to give 2′-benzyloxycarbonyl-3 ′, 4 ′.
-Dihydro-6 ', 7'-dimethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1'
(2′H) -isoquinoline] (1.34 g, yield 100
%) As crystals. Melting point 101-102 ° C, MS (APCI): 540 (M
+ H), IR (Nujol) cm ⁻¹ : 1727, 17
02, 1609. (3) 75.0 g of the compound obtained in (2) above, 55.6 g of sodium hydroxide, 400 ml of ethanol, 40 parts of water
The 0 ml mixture is stirred for 16 hours at room temperature and then heated to reflux for 6 hours. The reaction solution is cooled, the solvent is concentrated, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, the organic layer is washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure and recrystallized from ethyl acetate-diisopropyl ether to give 2'-benzyloxycarbonyl-3 ',
4'-dihydro-6 ', 7'-dimethoxy-4,4-biscarboxyl-spiro [cyclohexane-1,1'
(2'H) -isoquinoline] (72.0 g, yield 100
%) As crystals. Melting point 181-182 ° C, MS (ESI): 481 (M-
H), IR (Nujol) cm ^-1 : 1749, 170
3, 1669, 1611. (4) A mixture of 72.0 g of the compound obtained in (3) above and 500 ml of pyridine is heated under reflux for 5 hours. After cooling the reaction solution, the solvent is distilled off. 500 ml of the residue is methanol
And 3.0 g of 10% palladium-carbon are added, and catalytic reduction is performed under a hydrogen atmosphere at atmospheric pressure. After completion of the reaction, the catalyst is filtered off and the solvent is distilled off from the filtrate. Pyridine 50 in the residue
Add 0 ml and heat to reflux for 16 hours. Evaporate the solvent,
By crystallization with ethanol, (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
Carboxyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (21.3 g, yield 50
%) As crystals. Melting point 238-241 ° C, MS (APCI): 306 (M
+ H), IR (Nujol) cm ⁻¹ : 1616.

Reference Example 13 (1) A solution of 54.0 g of dopamine hydrochloride, 69.0 g of 4,4-bisethoxycarbonylcyclohexanone and 28.8 g of triethylamine in 570 ml of ethanol was stirred at 50 ° C. for 20 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration to give 3 ', 4'-dihydro-
6 ', 7'-dihydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1'(2'H)
-Isoquinoline] (78.6 g, yield 73.1%) is obtained as crystals. Melting point 180-181 ° C, MS (APCI): 378 (M
+ H), IR (Nujol) cm ^-1 : 3475,17
19, 1620. (2) 1000 ml of methylene chloride containing 68.0 g of the compound obtained in (1) above and 91.1 g of triethylamine
78.3 g of chlorotrimethylsilane are added dropwise to the solution at 4 ° C. After stirring for 1 hour at room temperature, 1M citric acid aqueous solution 50
0 ml is poured, the organic layer is separated, the organic layer is washed with water and then dried over sodium sulfate. By distilling off the solvent and triturating the residue with ethyl acetate-n-hexane,
3 ′, 4′-dihydro-6 ′, 7′-ditrimethylsilyloxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (86.4 g) as a powder obtain. (3) To the crude product obtained in (2) above, 46.5 g of diisopropylethylamine and 1000 of methylene chloride.
Add 3 ml of benzyl chlorocarbonate (61.4 g) at 4 ° C.
The solution is added dropwise over 0 minutes, the solution is stirred at room temperature for 20 hours, and then the solvent is distilled off. Ethyl acetate is added to the residue, washed with a 1M aqueous citric acid solution and water, and then dried over sodium sulfate. The solvent is distilled off, 600 ml of acetonitrile is added to the residue, and 47% aqueous hydrogen fluoride is added at 4 ° C. After stirring at the same temperature for 30 minutes, the mixture is stirred at room temperature for another 30 minutes and neutralized with sodium hydrogen carbonate powder. The mixture is concentrated, the reaction solution is poured into 1 L of water, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 1: 1) to give 2′-benzyloxycarbonyl-3 ′, 4′-dihydro-6 ′, 7'-dihydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] (73.0 g, yield 69
%) As crystals. Melting point 132-133 ° C, MS (APCI): 512 (M
+ H), IR (Nujol) cm ⁻¹ : 3430, 33
75, 1746, 1725, 1690, 1620. (4) Add 73.0 g of the compound obtained in (3) above to 4 ° C.
Below, add portionwise into a suspension of 12.6 grams of 60% sodium hydride in 500 ml of dimethylformamide. After stirring at room temperature for 30 minutes, the reaction solution was added with methyl iodide 50.
7 g are dropped. After stirring at room temperature for 17 hours, the reaction solution is concentrated, poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the organic layer is washed with water and saturated saline and then dried over sodium sulfate. The solvent was distilled off, and silica gel column chromatography (n-hexane: ethyl acetate =
4 ') and purified by 2'-benzyloxycarbonyl-3', 4'-dihydro-6 ', 7'-dimethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1' ( 2'H) -isoquinoline]
(75.0 g, yield 97%: compound obtained in Reference Example 12 (2)) is obtained as crystals. Melting point 101-102 ° C, MS (APCI): 540 (M
+ H), IR (Nujol) cm ⁻¹ : 1727, 17
02, 1609.

Reference Example 14 (1) 3 ', 4'-dihydro-6', 7'-dimethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] ( 3.97 g of the compound obtained in Reference Example 12 (1), 1.52 g of triethylamine, and 80 ml of methylene chloride were added to a solution of 809 ml of methylene chloride under ice-cooling, and 1.09 g of methylene chloride 2 was added.
Add 0 ml solution dropwise. After stirring for 20 minutes at the same temperature, water 100
Add ml and stir for 1.5 hours at room temperature. The organic layer is separated and dried over sodium sulfate. NH-silica gel 10
After adding g, the mixture is filtered, and the filtrate is distilled off.
2'-acryloyl-3 ', 4'-dihydro-6',
7'-dimethoxy-4,4-bisethoxycarbonyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (4.56 g, yield 99%) is obtained as crystals. Melting point 134-134.5 ° C, MS (APCI): 460
(M + H), IR (Nujol) cm ⁻¹ : 1725,
1661. (2) To a solution of 4.14 g of the compound obtained in (1) above in 40 ml of acetonitrile is added 15 ml of 50% aqueous dimethylamine solution, and the mixture is stirred at room temperature for 13 hours. The reaction solution is evaporated, saturated brine is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is extracted with 5% hydrochloric acid. The aqueous layer is made alkaline with potassium carbonate (solid) and then extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by NH-silica gel column chromatography (ethyl acetate → chloroform: methanol = 50: 1) to give 2 ′-[3- (dimethylamino) propionyl] -3 ′, 4′-dihydro. -6 ', 7'-Dimethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1'(2'H)
-Isoquinoline] (4.13 g, 91% yield) is obtained as an oil. MS (APCI): 505 (M + H), IR (nea)
t) cm < ^-1 >: 1728, 1657.

The compound can be converted to the dihydrochloride by a conventional method. Melting point 208-209.5 [deg.] C. (3) To a solution of 3.74 g of the compound obtained in (2) above in 20 ml of ethanol is added a solution of 2.96 g of sodium hydroxide in 20 ml of water, and the mixture is heated under reflux for 2.5 hours. Under ice cooling, 6.8 ml of concentrated hydrochloric acid is added, and the solvent is distilled off. Methanol is added to the residue, and inorganic substances are removed by decantation. Methanol was distilled off, 30 ml of pyridine was added, and 4
Heat to reflux for hours. After cooling the reaction solution, the solvent is distilled off, water is added, and the insoluble matter is filtered off. By purification by non-ionic adsorption resin (trade name: HP-20, manufactured by Mitsubishi Kasei) packed column chromatography, 2 '-[3- (dimethylamino) propionyl] -3', 4'-dihydro-.
6 ′, 7′-Dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (2.88 g, 96% yield: cis-trans mixture) is obtained as an amorphous powder. MS (APCI): 405 (M + H), IR (nea)
t) cm < ^-1 >: 1712,1652,1609.

Reference Example 15 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
Treat 7′-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (compound obtained in Reference Example 12 (4)) in the same manner as in Reference Example 14 (1). Thus, (1α, 4β) -2′-acryloyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4-carboxyl-spiro [cyclohexane-
1,1 ′ (2′H) -isoquinoline] is obtained as an amorphous powder. MS (ESI): 358 (MH), IR (Nujo)
l) cm < ^-1 >: 1718, 1635. (2) The compound obtained in (1) above is used as Reference Example 14 (2).
By performing the same process as in (1α, 4β) -2′-
[3- (Dimethylamino) propionyl] -3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1'(2'H) -isoquinoline] is obtained as an amorphous powder. MS (ESI): 403 (MH), IR (Nujo)
1) cm < ^-1 >: 1700,1637.

Reference Example 16 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 12 (4)) 1 g, benzyl alcohol 531 mg, 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide / hydrochloride 942 mg, 1-
Hydroxybenzotriazole 664 mg, triethylamine 662 mg, N, N-dimethylaminopyridine 4
0 mg and 20 ml of dimethylformamide are combined and stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4-. Benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] (1.16 g, 90% yield) is obtained as crystals. Melting point 89-90 ° C, MS (APCI) m / z; 396
(M + H), IR (Nujol) cm ⁻¹ ; 1713,
3317. (2) 1.14 g of the compound obtained in the above (1), N-
7.73 g of (3-bromopropyl) phthalimide, 3.73 g of diisopropylethylamine and 10 ml of N, N-dimethylacetamide are combined and stirred at 120 ° C. for 4 hours. After cooling the reaction mixture, water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give (1α, 4
β) -2 ′-(3-phthalimidopropyl) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (1.41 g, yield 8
4%). MS (APCI) m / z; 583 (M + H), IR (N
ujol) cm ⁻¹ ; 1711, 1770. (3) 5.15 g of the compound obtained in (2) above and 10%
Palladium-carbon 700 mg, ammonium formate 2
A mixture of 7.87 g and 100 ml of methanol is heated under reflux for 6 hours. After cooling the reaction solution, the catalyst is filtered off and the filtrate is distilled off. Water is added to the residue and extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 1 → 20:
By purifying in 1), (1α, 4β) -2′-
(3-phthalimidopropyl) -3 ', 4'-dihydro-6', 7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (3.98 g, yield 91%). MS (ESI) m / z; 491 (MH), IR (Nu
jol) cm < ^-1 >; 1709, 1770, 3370.

Reference Example 17 (1) To a suspension of 19.8 g of allopurinol in 59 ml of N, N-dimethylaniline, 296 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 2 hours and 30 minutes. After cooling the reaction solution, excess phosphorus oxychloride is distilled off under reduced pressure and water is added. Extract 5 times with ethyl acetate and wash twice with 200 ml saturated saline,
After drying over sodium sulfate, the solvent is distilled off under reduced pressure. The residue was triturated in diethyl ether and collected by filtration to give 4-
Chloro allopurinol (16.7 g, 74%) is obtained as crude crystals. 18 g of the crude crystals of dimethylformamide 1
In a 00 ml solution, 14.7 g of ethyl 1-piperazinecarboxylate and diisopropylethylamine 1
A solution of 8.4 g of dimethylformamide in 10 ml is added dropwise at room temperature, and the mixture is stirred for 15 hours. 300 ml of water is added to the reaction solution, and the mixture is stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration and washed with 200 ml of water and 50 ml of diisopropyl ether. 200 ml of ethyl acetate was added to crush the crystals,
By collecting by filtration, 4- (4-ethoxycarbonyl-
1-Piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (21.6 g, yield 82%) is obtained as crystals. Melting point 245-247 [deg.] C. (2) Allopurinol 10.88 g, ethyl 1-piperazinecarboxylate 37.96 g, 1,1,1,
35.44 ml of 3,3,3-hexamethyldisilazane and 1.06 g of ammonium sulfate are combined and stirred under heating at 140 ° C. for 29 hours. Methanol 1 in the reaction mixture under ice cooling
50 ml is dropped, and the precipitated crystals are collected by filtration. Methanol 5
The crystals were washed with 0 ml of a saturated aqueous solution of sodium hydrogen carbonate and water and dried to give 4- (4-ethoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4].
-D] pyrimidine (18.33 g, yield 83%: compound obtained in the above (1)) is obtained. Melting point 247 ° C, MS (APCI) m / z; 277 (M
+ H), IR (Nujol) cm ^-1 ; 3196, 31
15, 1699. (3) 20 g of the compound obtained in (1) or (2) above
Then, 12.4 g of lithium hydroxide is added to a 500 ml solution of dimethylformamide containing 13.1 g of 4-chloromethylpyridine · hydrochloride and stirred at room temperature for 6 hours. Water 1.6
L, 200 ml of saturated saline and 200 ml of saturated aqueous sodium hydrogen carbonate solution are added, and the mixture is extracted 3 times with ethyl acetate. The organic layer is washed twice with saturated saline and dried over sodium sulfate. Recrystallization from isopropyl alcohol gave 1- (4-pyridylmethyl) -4- (4-ethoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (17.7 g, yield 66). %)
Is obtained as a crystal. Melting point 123-124 [deg.] C. (4) 20 g of the compound obtained in (3) above and 20.6 g of potassium hydroxide in 300 ml of ethanol-60 m of water
The suspension of 1 is heated under reflux for 3 hours and 30 minutes. The solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. Wash with saturated saline and dry over sodium sulfate. The solvent was distilled off under reduced pressure and recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 1- (4-pyridylmethyl) -4.
-(1-Piperazinyl) -1H-pyrazolo [3,4-
d] Pyrimidine (12.2 g, yield 76%) is obtained as crystals. Melting point 121 [deg.] C.

Reference Example 18 (1) To a solution of 1.01 g of 4-bromopyridine and 5 ml of methyl iodide in 10 ml of acetonitrile was added dropwise 0.81 ml of triethylamine at room temperature. After stirring overnight at room temperature, the precipitated crystals were collected by filtration to give 1-methyl-4.
1.35 g of a mixture of -bromopyridinium iodide and triethylamine hydrochloride are obtained as crude product. (2) To a solution of 1.12 g of N- (benzyloxycarbonyl) piperazine and 525 mg of triethylamine in 15 ml of acetonitrile, a suspension of 1.24 g of the crude product obtained in the above (1) in 20 ml of acetonitrile was added dropwise at room temperature. After stirring for 5 hours, the solvent is distilled off. The residue is dissolved in water, treated with carbon powder, washed with diethyl ether, and the solvent is evaporated. The residue is dissolved in 12 ml of acetic acid, 5 ml of 25% hydrogen bromide-acetic acid is added to this solution, and the mixture is stirred at room temperature for 2 hours. Add 100 ml of diisopropyl ether dropwise,
The precipitated crystals are collected by filtration. 4-piperazinyl-1 by washing with isopropyl alcohol and ethanol
-Methylpyridinium bromide / hydrobromide (1.0
1 g, yield 62.3%) are obtained as crystals. Melting point 267-276 [deg.] C. (decomposition), MS (ESI) m /
z: 178 (M ⁺ ).

Reference Example 19 (1) N- (2-bromoethyl) phthalimide 46.9
A mixture of 8 g, 38.66 ml of triethylamine, 300 ml of acetonitrile and 48.88 g of 1-benzyloxycarbonylpiperazine is heated under reflux for 22 hours. After cooling the reaction solution, 570 ml of 1 M hydrochloric acid is added, and the mixture is heated under reflux for 3 hours. After cooling the reaction mixture, it is made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried over sodium sulfate. By distilling off the solvent and recrystallizing from ethanol, N- (2- (4-benzyloxycarbonyl-1-
Piperazinyl) ethyl) phthalimide (35.09g)
Is obtained as a crystal. Melting point 89.5-90.5 [deg.] C. (2) 52.75 g of the compound obtained in (1) above, 13.42 g of hydrazine hydrate and 600 ml of ethanol are combined and heated under reflux for 2 hours. The precipitate is filtered off and the filtrate is concentrated. The residue is made alkaline with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic layer is dried over sodium sulfate, and the solvent is evaporated. Hydrochloric acid-methanol was added to the residue, the solvent was evaporated, and the residue was recrystallized from a mixed solvent of methanol-diethyl ether to give 1- (2-aminoethyl) -4-benzyloxycarbonylpiperazine dihydrochloride ( 43.03 g) are obtained as crystals. Melting point 174-174.5 [deg.] C. (3) 29.95 g of the hydrochloride obtained in (2) above is returned to a free state, 300 ml of ethyl formate is added, and the mixture is heated under reflux for 19 hours. By distilling off the solvent, 1- (2-formylaminoethyl) -4-benzyloxycarbonylpiperazine (25.67 g) was obtained. (4) To a solution of 25.67 g of the formyl compound obtained in (3) above in 500 ml of tetrahydrofuran is added 35.2 ml of borane-dimethyl sulfide complex, and the mixture is heated under reflux for 15 hours. The reaction solution is cooled and 100 ml of methanol is added dropwise.
After heating for 0 minutes, 250 ml of 2M hydrochloric acid-methanol is added dropwise and the mixture is heated under reflux for 3 hours. After cooling the reaction solution, the solvent was distilled off,
By recrystallizing with a mixed solvent of methanol-diethyl ether, 1- (2-methylaminoethyl) -4-benzyloxycarbonylpiperazine (28.63 g) is obtained. Melting point 190-190.5 [deg.] C. (5) 3.5 g of the compound obtained in (4) above, 1.48 g of picolinic acid, 2.45 of diethyl cyanophosphonate
g, 4.05 g of triethylamine and 35 ml of dimethylformamide are combined and stirred at room temperature for 5 hours. After distilling off the solvent, ethyl acetate was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate,
The solvent is distilled off. The residue was purified by NH-silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give 1- (2-N-methyl-N-picolinoylaminoethyl) -4-benzyloxycarbonylpiperazine ( 3.64 g) is obtained as an oil. MS (ESI) m / z: 383 (M + H), IR (ne
at) cm < ^-1 >: 1699, 1634. (6) The compound obtained in the above (5) (3.6 g), 10% palladium-carbon (500 mg) and ethanol (50 ml) are combined and subjected to hydrogenation under atmospheric pressure at atmospheric pressure. After removing the catalyst by filtration, the filtrate was evaporated and recrystallized from methanol to obtain 1- (2-N-methyl-N-picolinoylaminoethyl) piperazine (3.74 g) as crystals. Melting point 225-227 [deg.] C (decomposition). (7) 1.51 g of the compound obtained in the above (5), Lawesson's reagent 1.
13 g and 30 ml of dimethylformamide are combined and heated under reflux for 6 hours. After cooling the reaction solution, the solvent is distilled off, ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol = 80: 1) to give 1- [2- (N-methyl-N-thiopicolinoylamino) ethyl] -4-benzyl. Oxycarbonylpiperazine (1.36 g) is obtained as an oil. MS (APCI) m / z: 399 (M + H), IR (n
ujol) cm ^-1 : 1700. (8) 1.34 g of the compound obtained in the above (7) and acetic acid 7
ml, hydrogen bromide-acetic acid 13 ml mixture is stirred at room temperature for 3 hours. Add diisopropyl ether and discard the supernatant. The residue is dissolved in water and washed with ethyl acetate, and the aqueous layer is made alkaline with aqueous ammonia. After extraction with chloroform, the organic layer is dried over sodium sulfate, and the solvent is evaporated to give 1- [2- (N-methyl-N-thiopicolinoylamino) ethyl] piperazine (923 mg) as an oil. . MS (APCI) m / z: 265 (M + H), IR
(Neat) cm ^-1 : 3280.

Reference Example 20 (1) To a solution of 5.0 g of 2-aminopyridine in 31 ml of tetrahydrofuran was added dropwise an n-hexane solution of n-butyllithium (1.6 M) at -78 ° C. The reaction solution is heated to 0 ° C., stirred for 5 minutes, cooled to −78 ° C., and then 5.5 ml of ethyl bromoacetate is added dropwise. The reaction solution is heated to -20 ° C and stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution is added at -78 ° C and the mixture is diluted with ethyl acetate. The temperature is raised to room temperature, the two layers are separated, the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1).
Purification in 1) and filtration of the crystals with diisopropyl ether give 2- (bromoacetylamino) pyridine (4.72 g) as crystals. Melting point 248-250 <0> C (decomposition). (2) A solution of 4.2 g of the compound obtained in (1) above, 5.0 g of 1-benzyloxycarbonylpiperazine and 2.52 g of triethylamine in 50 ml of acetonitrile is stirred at room temperature for 4 hours. The solvent was concentrated, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine,
Dry with sodium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and the crystals were collected by filtration with diisopropyl ether to give 2-[(4-benzyloxycarbonylpiperazin-1-yl). ) Acetylamino] pyridine (6.80 g) is obtained as crystals. Melting point 78-80 [deg.] C. (3) In a solution of 3.54 g of the compound obtained in (2) above in 50 ml of tetrahydrofuran, under cooling with ice, borane-dimethyl sulfide complex (2M tetrahydrofuran solution) 2
Add 0 ml dropwise. After stirring for 18 hours at room temperature, a solution of 7.2 g of oxalic acid in 80 ml of methanol is added dropwise under ice cooling. The mixture is heated under reflux for 2 hours, the solvent is distilled off after cooling. Ethyl acetate is added, washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated. By purifying the residue by silica gel column chromatography (chloroform: methanol = 100: 1), 2- [2- (4
-Benzyloxycarbonylpiperazin-1-yl) ethylamino] pyridine (3.42 g) is obtained. MS (DI = EI) m / z: 340 (M ⁺ ), IR (n
eat) cm ⁻¹ : 3380, 1700, 1603. (4) To 1.70 g of the compound obtained in (3) above, 593 mg of pyridine and 30 ml of methylene chloride, a solution of 470 mg of acetyl chloride in 5 ml of methylene chloride was added dropwise under ice cooling. After stirring for 1 hour at room temperature, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate and evaporated to remove 2- [N -(2- (4-Benzyloxycarbonylpiperazin-1-yl) ethyl) -N-acetylamino] pyridine (1.92 g) is obtained as an oil. (5) 3.9 g of the compound obtained in (4) above, 1.0 g of 10% palladium-carbon and 50 ml of ethanol are combined and hydrogenated under atmospheric pressure. After removing the catalyst by filtration, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 80: 20:
By purification in 1), 2- [N- (2- (piperazin-1-yl) ethyl) -N-acetylamino] pyridine (2.15 g) is obtained as an oil. (6) To the methanol solution of the compound obtained in the above (5), twice fumaric acid was added, the solvent was distilled off, and the residue was crystallized with ethanol and diisopropyl ether to give 2
-[N- (2- (piperazin-1-yl) ethyl) -N-
Acetylamino] pyridine difumarate is obtained. Melting point 153-155 [deg.] C.

Reference Example 21 1.36 g of 3-bromopyridine, 3.71 of piperazine
g, 1.24 g of sodium t-butoxide, trisdibenzylideneacetone palladium complex (Pd ₂ (dba)
₃ ) 158 mg, tri-o-toluylphosphine 105 m
g and 60 ml of toluene are combined and heated and stirred under an argon stream for 4 days. The reaction solution was evaporated, and the residue was subjected to silica gel column chromatography (chloroform: methanol:
Purify with 28% aqueous ammonia = 200: 10: 1), and
M hydrochloric acid-ethanol solution was added and evaporated, and the residue was recrystallized with a mixed solution of methanol-ethyl acetate to give 3
-Piperazinopyridine dihydrochloride (759 mg) is obtained as crystals. Melting point 247-250 [deg.] C (decomposition).

Reference Example 22 (1) A solution of 4-chloro-5-amino-6-methylaminopyrimidine 24.59 g, acetic acid 120 ml and water 740 ml was added to a solution of sodium nitrite 21.39 g and water 100 ml.
Is added dropwise at 3 ° C. After stirring at the same temperature for 40 minutes, the mixture is extracted with ethyl acetate. The aqueous layer is made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, and the solvent was distilled off to give 7-
Chloro-3-methyl-3H-1,2,3-triazolo
[4,5-d] pyrimidine (16.02 g) is obtained. The compound is dissolved in 80 ml of dimethylacetamide, 17.48 g of 1-benzylpiperazine is added dropwise under ice cooling, and subsequently 18.31 g of diisopropylamine is added dropwise. After stirring at the same temperature for 1 hour, ethyl acetate is added, washed with water, dried over sodium sulfate, and the solvent is evaporated. The residue was crystallized from diisopropyl ether to give 7- (4-benzylpiperazin-1-yl) -3-methyl-3H-1,2,3.
-Triazolo [4,5-d] pyrimidine (28.16 g,
Yield 59%) as crystals. Melting point 91-92 [deg.] C. (2) A mixture of 28 g of the compound obtained in (1) above, 5.6 g of 10% palladium-carbon, 57 g of ammonium formate, and 560 ml of methanol is heated under reflux for 1.5 hours.
After cooling the reaction solution, the catalyst is filtered off and the filtrate is distilled off. A 10% aqueous potassium carbonate solution is added to the residue, and the mixture is extracted with chloroform. The organic layer is washed with water, washed with saturated saline and dried over sodium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to give 7- (1-piperazinyl) -3-methyl-3H-1,2,3-triazolo.
[4,5-d] pyrimidine (17.68 g, yield 89%)
Is obtained as a crystal. Melting point 95-96 [deg.] C.

Reference Example 23 (1) 3,4-Dihydroxyphenethylamine / hydrochloride 1.0 g, 1-carboethoxy-4-piperidone 1.0
83 g, triethylamine 535 mg, ethanol 15
Add to ml and heat to reflux for 13 hours. After cooling, add an ethanol solution of hydrogen chloride and concentrate. By recrystallizing the residue from a mixed solution of methanol and ethanol, 1′-ethoxycarbonyl-3,4-dihydro-6,7-dihydroxy-spiro [isoquinoline-1 (2H), 4′-piperidine] · hydrochloride 1 0.64 g (91%) are obtained as crystals. Melting point 285-286 (decomposition). (2) In a mixture of 5.0 g of the compound obtained in the above (1) and 100 ml of dimethylformamide, potassium was added under ice cooling.
Add 5.401 g of tert-butoxide and stir for 10 minutes.
Then, 2 ml of methyl iodide is added dropwise and stirred for 1.5 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to give 1′-ethoxycarbonyl-3,4.
2.89 g of -dihydro-6,7-dimethoxy-spiro [isoquinoline-1 (2H), 4'-piperidine] are obtained. MS (APCI): 335 (M + H), IR (neat) cm ^-1 :
1694, 1609. (3) To a solution of 1.0 g of the compound obtained in (2) above in 20 ml of methylene chloride, 1.26 ml of triethylamine was added, and 0.36 ml of acrylic acid chloride was added under ice cooling, and the mixture was stirred for 2 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and the solvent was distilled off to give 1'-ethoxycarbonyl-. 2-acryloyl-3,4-dihydro-6,7-dimethoxy-spiro
[Isoquinoline-1 (2H), 4'-piperidine] 1.18
get g. (4) The compound obtained in (3) above is dibenzylamine.
Add 5 ml and stir at 150 ° C. for 3 hours. After cooling the reaction solution, it is diluted with ethyl acetate and 10% hydrochloric acid is added. The precipitate is filtered off, the filtrate is made alkaline with potassium carbonate, extracted with ethyl acetate, the organic layer is washed with water and saturated brine, dried over sodium sulfate and the solvent is distilled off. The residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1′-ethoxycarbonyl-3,4-dihydro-6,7-dimethoxy-2.
-(3-Dibenzylaminopropionyl) -spiro [isoquinoline-1 (2H), 4'-piperidine] 1.30 g (7
4%) as an oil. MS (APCI): 586 (M + H), IR (neat) cm ^-1 :
1735, 1693. (5) To a suspension of 247 mg of sodium borohydride in 10 ml of tetrahydrofuran was added 1.1 ml of trifluoroborane / diethyl ether complex under ice cooling, and the mixture was stirred for 15 minutes. A solution of 1.27 g of the compound obtained in (4) above in 10 ml of tetrahydrofuran is added dropwise under ice cooling, and then the mixture is heated under reflux for 1.5 hours. 10 ml of 10% hydrochloric acid is added to the reaction solution, heated under reflux for 2 hours, and stirred at room temperature for 12 hours. Tetrahydrofuran is distilled off and the mixture is made alkaline with potassium carbonate. After extraction with ethyl acetate, the organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 1′-ethoxycarbonyl-3,4-dihydro-6,7-dimethoxy-2-.
(3-Dibenzylaminopropyl) -spiro [isoquinoline-1 (2H), 4'-piperidine] 717 mg (58
%) As an oil. MS (APCI): 572 (M + H), IR (neat) cm ^-1 :
1697, 1694. (6) 697 mg of the compound obtained in (5) above, 7 ml of ethylene glycol, and 7 ml of 50% aqueous potassium hydroxide solution are combined and heated under reflux for 3 hours. After cooling the reaction solution, it is diluted with water and extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to give 3,4-dihydro-6,7-dimethoxy-2- (3-dibenzylaminopropyl). -565 mg of spiro [isoquinoline-1 (2H), 4'-piperidine] are obtained. MS (APCI): 500 (M + H), IR (neat) cm ^-1 :
3327. (7) To a solution of 535 mg of the compound obtained in (6) above in 10 ml of methylene chloride, 127 mg of triphosgene is added,
Under ice-cooling, 0.3 ml of triethylamine is added dropwise. At the same temperature, 15
After stirring for a minute, the solvent is distilled off. 10m methylene chloride on the residue
l, triethylamine 0.3 ml, 1- (3-methyl-
235 mg of 3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) piperazine is added, and the mixture is stirred at room temperature for 13 hours. The reaction solution is concentrated and diluted with ethyl acetate, then water,
The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to column chromatography on neutral silica gel (chloroform: methanol = 100: 1).
By purification with 3,4-dihydro-6,7-dimethoxy-2- (3-dibenzylaminopropyl)-
1 '-[4- (3-methyl-3H-1,2,3-triazolo
[4,5-d] Pyrimidin-7-yl) piperazin-1-yl] carbonyl spiro [isoquinoline-1 (2H), 4 ′
-Piperidine] to obtain 595 mg (75%). MS (APCI): 745 (M + H), IR (neat) cm ^-1 :
1643.

Reference Example 24 (1) 2'-benzyloxycarbonyl-3 ', 4'-
Dihydro-6 ', 7'-dihydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1'
(2′H) -isoquinoline] (compound obtained in Reference Example 13 (3)) In 20.0 g of dimethylformamide 140 ml, 4
At 60 ° C, 3.44 g of 60% sodium hydride is added, and the mixture is stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. Cool the reaction to 4 ° C,
After dropwise adding 15.2 g of ethyl iodide, the mixture is stirred at the same temperature for 1 hour. After stirring at room temperature for another 17 hours, the reaction solution is poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated.
By crystallization with a mixed solvent of diisopropyl ether-hexane, 2'-benzyloxycarbonyl-
3 ', 4'-dihydro-6', 7'-diethoxy-4,
4-bisethoxycarbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] 19.7 g (88.
8%). Melting point 88.4-89.1 ℃, MS (APCI) m / z: 568 (M + H), IR (nujo
l) cm ^-1 : 1725, 1703, 1611. (2) 19.7 g of the compound obtained in (1) above, 13.9 g of sodium hydroxide, 90 ml of water and 9 parts of ethanol.
0 ml of the mixture is stirred at room temperature for 15 hours and then heated under reflux for 5 hours. The reaction solution is cooled, concentrated, and acidified with hydrochloric acid.
After extraction with ethyl acetate, the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated. By crystallizing the residue with a mixed solvent of diisopropyl ether-hexane, 2'-
Benzyloxycarbonyl-3 ', 4'-dihydro-
6 ', 7'-diethoxy-4,4-biscarboxyl-
16.14 g (90.9%) of spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] are obtained. Melting point 175-176 ° C, MS (ESI) m / z: 510 (MH), IR
(nujol) cm ^-1 : 1747, 1705, 1669, 1609. (3) 16.13 g of the compound obtained in (2) above is dissolved in 120 ml of pyridine and heated under reflux for 15 hours. After cooling the reaction solution, pyridine was distilled off, and then azeotropic distillation with toluene was performed to completely remove pyridine, thereby obtaining 2'-benzyloxycarbonyl-3 ', 4'-dihydro-6', 7'-diethoxy-4. -Carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] is obtained as a crude product. (4) Methanol 120 is added to the compound obtained in (3) above.
ml, 10% palladium-carbon (700 mg), and hydrogenated under atmospheric pressure. After the catalyst is filtered off, it is washed with warm methanol and warm dimethylformamide. The filtrates are combined, distilled off, dissolved in 120 ml of pyridine and heated under reflux for 15 hours. After cooling the reaction solution, pyridine was distilled off and the residue was crystallized with ethanol to give (1α, 4β) -3 ′, 4′-dihydro-
6 ', 7'-diethoxy-4-carboxyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline]
5.26 g (50.0%) are obtained as crystals. Melting point 197-198 ℃, MS (APCI) m / z: 334 (M + H), IR
(nujol) cm ^-1 : 3549, 3314, 1642. (5) 2.2 g of the compound obtained in (4) above was dissolved in 33 ml of dimethylformamide to give 2.58 of cesium carbonate.
g, and 863 μl of benzyl bromide, and the mixture is stirred at room temperature for 2 hours. After distilling off the solvent, the reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic layer is washed with water, washed with saturated saline, and dried over sodium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography (chloroform-chloroform / methanol = 20: 1) to give (1α, 4β) -3 ', 4'-dihydro-.
2.80 g (quantitative) of 6 ', 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1'(2'H) -isoquinoline] are obtained as a yellow oil. MS (APCI) m / z: 424 (M + H), IR (neat) cm-1: 17
27, 1607. (6) 2.80 g of the compound obtained in (5) above and N- (2
-Bromoethyl) phthalimide (23.5 g), diisopropylethylamine (12.0 g) and dimethylformamide (5 ml) are combined and stirred at 130 ° C for 3 hours. After cooling the reaction solution, 50 ml of ethyl acetate is added and the precipitate is filtered off. The filtrate was evaporated, ethyl acetate was added, and the mixture was washed with water and saturated saline,
Dry with sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform / methanol / ammonia = 19: 1: 0.1) to give (1α, 4β) -2 ′-(2-phthalimidoethyl) -3. 2.55 g of ', 4'-dihydro-6', 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline]
(82.7%) is obtained as a yellow oil. MS (APCI) m / z: 597 (M + H), IR (neat) cm ^-1 : 17
73, 1714, 1607. (7) 2.14 g of hydrazine hydrate is added to a mixture of 20 ml of tetrahydrofuran and 20 ml of ethanol containing 2.55 g of the compound obtained in (6) above. 16 at room temperature
After stirring for an hour, the reaction mixture is poured into saturated sodium bicarbonate and extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / ammonia = 9: 1: 0.1) to give (1α, 4β) -2 ′-(2-aminoethyl)-
3 ', 4'-dihydro-6', 7'-diethoxy-4-
Benzyloxycarbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline] 1.64 g (82.
3%) as a pale yellow oil. MS (APCI) m / z: 467 (M + H), IR (neat) cm ^-1 : 17
27,1684,1653,1606. (8) To a solution of 1.64 g of the compound obtained in (7) above in 30 ml of tetrahydrofuran is added 6 ml of acetic acid and 3 ml of an aqueous formalin solution. Then 665 mg of sodium borohydride are added at 4 ° C. over 30 minutes. After stirring for 16 hours at room temperature, the reaction solution is concentrated and azeotropically distilled with toluene. 100 ml of saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with chloroform. The organic layer is a saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform / methanol / ammonia = 20:
1: 0.1) to obtain (1α, 4β) -2 ′
-(2-Dimethylaminoethyl) -3 ', 4'-dihydro-6', 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] 1.42 g (81.7%) is obtained as a colorless oil. MS (APCI) m / z: 495 (M + H), IR (neat) cm ^-1 : 17
29, 1606. (9) Dissolve 1.42 g of the compound obtained in (8) above in 30 ml of methanol, and add 10% palladium on carbon (300 m).
g and put in a hydrogenation reaction at atmospheric pressure. The catalyst is filtered off, the catalyst is washed with methanol and water, the filtrates are combined and the solvent is distilled off. The residue was crystallized from a mixed solvent of ethyl acetate-diethyl ether to give (1α, 4β) -2 ′-(2-
Dimethylaminoethyl) -3 ', 4'-dihydro-
6 ', 7'-diethoxy-4-carboxyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline]
1.09 g (93.9%) are obtained as crystals. Melting point 111.9-112 ° C, MS (APCI) m / z: 405 (M
+ H), IR (nujol) cm ^-1 : 3385, 1737, 169
3,1607.

Reference Example 25 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7′-Dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] (Compound obtained in Reference Example 16 (1)) 1.226 g (3.
2 mmol) and 2.915 g (28.8 mmol) of triethylamine in 10 ml of methylene chloride under ice-cooling.
A solution of 51 ml (6.4 mmol) of methylene chloride in 10 ml is added dropwise, and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. After washing the organic layer with saturated saline,
Glauber's salt is dried and the solvent is distilled off. The residue was subjected to silica gel column chromatography (chloroform: methanol = 50:
By purifying in 1), (1α, 4β) -2′-chloroacetyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 ′ (2'H) -isoquinoline] 1.35 g is obtained as an oil. MS (APCI) 472 (M + H), IR (neat) cm ^-1 : 1727,
1661. (2) 1.334 g of the compound obtained in (1) above was added to 20
Dissolve it in ml of acetonitrile, add 10 ml of 50% dimethylamine aqueous solution, and stir at room temperature overnight. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1α, 4β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′. , 7'-dimethoxy-4
1.34 g of -benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as an oil. MS (APCI) 481 (M + H), IR (neat) cm ^-1 : 1731
1658,1651,1633. (3) 1.32 g of the compound obtained in (2) above is dissolved in 20 ml of methanol, 263 mg of 10% palladium-carbon is added, and hydrogenation is carried out at atmospheric pressure. After 24 hours, the catalyst was filtered off and the solvent was distilled off to give (1α, 4β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′, 7′-
0.99 g of dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as crystals. Melting point 233-235 ℃ (decomposition) MS (APCI) 391 (M + H), IR
(nujol) cm ⁻¹ : 1671.

Reference Example 26 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
1.53 g of 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 24 (5)),
By performing the same processing as in Reference Example 25 (1), (1α,
4β) -2'-chloroacetyl-3 ', 4'-dihydro-6', 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 1.86 g As an oil. MS (APCI) m / z 500 (M + H), IR (neat) cm ^-1 : 17
29,1661, 1644,1608. (2) By treating 1.85 g of the compound obtained in (1) above in the same manner as in Reference Example 25 (2), (1α, 4
β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′, 7′-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], 1.84 g is obtained as an oil. MS (APCI) m / z 509 (M + H), IR (neat) cm ^-1 : 17
29, 1656, 1635, 1609. (3) By treating 1.83 g of the compound obtained in (2) above in the same manner as in Reference Example 25 (3), (1α, 4
β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′, 7′-diethoxy-4-carboxyl-
768 mg of spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained as an amorphous powder. MS (APCI) m / z 419 (M + H), IR (nujol) cm ^-1 : 3
397, 1651, 1610.

Reference Example 27 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-diethoxy-4-
Benzyloxycarbonyl-spiro [cyclohexane-1,
1 ′ (2′H) -isoquinoline] (compound obtained in Reference Example 24 (5)) (1.49 g) in tetrahydrofuran (15 ml) and acetic acid (5 ml) was added with formalin aqueous solution (590 μl) and triacetoxyborohydride. Sodium (895mg) is added under ice cooling and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate is added to the reaction solution, extraction is performed with ethyl acetate, the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated. By purifying the residue by silica gel column chromatography (chloroform: methanol = 50: 1),
(1α, 4β) -2'-methyl-3 ', 4'-dihydro-6', 7'-diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 1.6 g (100%) is obtained as an oil. MS (APCI) 438 (M + H), IR (neat) cm ^-1 : 1727, 1608. (2) 1.59 g of the compound obtained in (1) above is dissolved in ethanol (20 ml), palladium carbon (300 mg) is added, and hydrogenation is carried out under a hydrogen atmosphere at normal pressure. After removing the catalyst by filtration, the solvent was distilled off to give (1α, 4β) -2′-methyl-3 ′, 4′-
1.1 g (90%) of dihydro-6 ′, 7′-diethoxy-4-carboxy-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] are obtained as crystals. Melting point 235 ° C.

Reference Example 28 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-diethoxy-4-
Benzyloxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] (compound obtained in Reference Example 24 (5)) (1.35 g) in dimethylacetamide (7 ml), 2-bromoethanol (7.0 ml), diisopropylethylamine (16.7 ml) Add and heat to 100 ° C. After 3 hours, the reaction solution is poured into water (200 ml) and extracted with ethyl acetate. The organic layer is washed with water and dried over sodium sulfate, and the solvent is distilled off.
The residue was purified by silica gel column chromatography (chloroform: ethanol = 50: 1) to give (1
α, 4β) -2 '-(2-hydroxyethyl) -3', 4'-dihydro-6 ',
7'-Diethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 1.45 g (100%) is obtained as an oil. MS (APCI) 468 (M + H), IR (neat) cm ^-1 : 3446, 1727, 1
606. (2) The compound (1.44 g) obtained in (1) above is dissolved in ethanol (38 ml), palladium carbon (480 mg) is added, and hydrogenation is carried out under a hydrogen atmosphere at normal pressure. After filtering off the catalyst, by distilling off the solvent, (1α, 4β) -2 '-(2-hydroxyethyl) -3', 4'-dihydro-6 ', 7'-diethoxy-4-carboxyl- 1.1 g (98%) of spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as amorphous powder. MS (APCI) 378 (M + H), IR (neat) cm ^-1 : 3335, 1713, 1
607.

Reference Example 29 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 12 (4)) 824 mg, ethyl iodide 1.08 ml and potassium carbonate 1. 119 g was added to 8 ml of dimethylformamide, and the mixture was stirred at room temperature for 1 hour and then at 100 ° C. for 2 hours. After cooling the reaction solution, ethyl acetate is added and the mixture is washed with water. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 300: 10: 1) to give (1α, 4β) -2′-ethyl-3 ′, 4′-dihydro-6 ′, 7 ′. 1.08 g of -dimethoxy-4-ethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as an oil. MS (APCI) m / z: 362 (M + H). (2) 1.08 g of the compound obtained in (1) above is dissolved in 10 ml of methanol, 4.1 ml of 2M aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature overnight. 2M hydrochloric acid 4.
1 ml is added and the solvent is distilled off. The residue is dissolved in 20 ml of ethanol and the precipitate is filtered off with Celite. The filtrate is concentrated, dissolved in chloroform and the insoluble matter is removed by filtration through Celite. The solvent is distilled off, and a concentrated hydrochloric acid-ethanol mixed solution is added and distilled off. The residue was crystallized in a mixed solvent of ethanol-isopropyl alcohol-ether to give (1α, 4
β) -2′-ethyl-3 ′, 4′-dihydro-6 ′,
539 mg of 7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] .hydrochloride is obtained as crystals. Melting point 254-259 [deg.] C (decomposition).

Reference Example 30 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 12 (4)) was used in Reference Example 29 (1).
By the same treatment as described above, (1α, 4β) -2′-propyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4-propyloxycarbonyl-spiro [cyclohexane-1,1 ′ ( 2'H) isoquinoline] is obtained as an oil. MS (APCI): 390 (M + H), IR (neat) cm ^-1 : 1727, 1607. (2) The compound obtained in the above (1) was used in Reference Example 29.
By performing the same processing as (2), (1α, 4β)-
2'-propyl-3 ', 4'-dihydro-6', 7'-
Dimethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] .hydrochloride is obtained as crystals. Melting point 266-270 [deg.] C.

Reference Example 31 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
2.77 g of 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (compound obtained in Reference Example 16 (1))
To a solution of (7 mmol) in 30 ml of tetrahydrofuran, 30 ml of formalin aqueous solution and 4.45 g of sodium triacetoxyborohydride are added under ice cooling, and the mixture is stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give (1α, 4β) -2′-methyl-3 ′,
4'-dihydro-6 ', 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline] 2.76 g (96.4%) is obtained as an amorphous powder. MS (APCI) 410 (M + H), IR (neat) cm ^-1 : 1727,
1608. (2) 2.76 g of the compound obtained in (1) above is dissolved in 30 ml of ethanol, 400 mg of palladium hydroxide is added, and hydrogenation is carried out under a hydrogen atmosphere of 3 atm. Water was added to the reaction solution, the catalyst was filtered off, and the solvent was distilled off to give (1
α, 4β) -2'-methyl-3 ', 4'-dihydro-
6 ', 7'-dimethoxy-4-carboxyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline]
1.87 g are obtained as crystals. Melting point 199 ° C. MS (APCI) 320 (M + H), IR (neat) cm
^-1 : 3385, 1722, 1611.

Reference Example 32 (1) (1α, 4β) -3 ′, 4′-dihydro-6 ′,
7'-Dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] (Compound obtained in Reference Example 16 (1)) 5.587
g, N- (2-bromoethyl) phthalimide 35.89
g and 18.26 g of diisopropylethylamine are added to 10 ml of dimethylacetamide, and the mixture is stirred at 130 ° C. for 10 hours. Further, 13.50 g of N- (2-bromoethyl) phthalimide is added, and the mixture is stirred at 130 ° C. for 10 hours. After cooling the reaction solution, ethyl acetate is added and the mixture is washed with water. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to give (1α, 4β) -2 ′-(2-phthalimidoethyl).
-3 ', 4'-dihydro-6', 7'-dimethoxy-4
7.14 g of -benzyloxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as a pale yellow amorphous powder. MS (APCI) m / z 569 (M + H), IR (neat + CHCl3) cm ^-1 :
1712, 1772. (2) Dissolve 7.09 g of the compound obtained in (1) above in 30 ml of ethanol and 30 ml of tetrahydrofuran,
Add 6.24 g of hydrazine hydrate and stir at room temperature for 7 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution,
Extract with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was purified by neutral silica gel column chromatography (chloroform: methanol: aqueous ammonia = 200: 10: 1) to give (1α, 4β) -2 ′-(2-aminoethyl) -3 ′, 4′-. 4.91 g of dihydro-6 ', 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1'(2'H) -isoquinoline] are obtained as pale yellow crystals. Melting point 84-85 ° C, MS (APCI) m / z 639 (M + H), IR
(neat + CHCl3) cm ^-1 : 3373, 1726. (3) Dissolve 4.88 g of the compound obtained in (2) above in 100 ml of tetrahydrofuran and 20 ml of acetic acid, and cool under ice cooling.
Add 10 ml of 5% formalin aqueous solution. Then, 2.10 g of sodium borohydride is added over 20 minutes, and the mixture is stirred at the same temperature for 30 minutes and at room temperature for 4 hours. The reaction solution is distilled off, azeotropically distilled with toluene, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated. The residue was subjected to neutral silica gel column chromatography (chloroform: methanol: aqueous ammonia = 200: 1).
(1α, 4β) -2 ′-(2
-Dimethylaminoethyl) -3 ', 4'-dihydro-
There is obtained 4.81 g of 6 ', 7'-dimethoxy-4-benzyloxycarbonyl-spiro [cyclohexane-1,1'(2'H) -isoquinoline] as a pale yellow oil. MS (APCI) m / z 467 (M + H), IR (neat + CHCl3) cm
^-1 : 1728. (4) 4.78 g of the compound obtained in the above (3), 10%
Palladium-carbon (500 mg) is put in ethanol (80 ml) and hydrogenated under normal pressure. The reaction solution is filtered, the catalyst is washed with methanol and water, the filtrate and the washing solution are combined and dried under reduced pressure. By crystallizing the residue from ethyl acetate,
(1α, 4β) -2 '-(2-Dimethylaminoethyl)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
Carboxyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] 3.37 g is obtained as colorless crystals. Melting point 231-233 ° C (decomposition), MS (APCI) m / z 37
7 (M + H), IR (neat + CHCl3) cm ^-1 : 1683.

Reference Example 33 (1) 25.98 g of m-methoxyphenethylamine and 150 ml of 47% hydrobromic acid were combined and heated at 120 to 130 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was azeotropically distilled with ethanol, and then crystallized with a mixed solvent of isopropanol and ether to give 3-hydroxyphenethylamine / hydrobromide 3
4.1 g (90.9%) are obtained. Melting point 118-120 ° C. (2) The compound (34.08 g) obtained in the above (1), 4,4-bisethoxycarbonylcyclohexanone (90.7 g), triethylamine (43.5 g) and ethanol (300 ml) are combined to give 50-6.
Heat at 0 ° C for 64 hours. The precipitate was collected by filtration and washed with ethanol and ether to give 3 ', 4'-dihydro-
6'-hydroxy-4,4-bisethoxycarbonyl-
34.95 g (62%) of spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] are obtained as crystals. Melting point 188.5-190 ° C. (3) 43.73 g of the compound obtained in (2) above is dissolved in 500 ml of methylene chloride, 67.5 ml of triethylamine is added, and the mixture is ice-cooled. 39.43 g of chlorotrimethylsilane was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 26 hours. A 10% aqueous citric acid solution is added to the reaction solution, the organic layer is separated, the organic layer is washed with water and saturated brine, dried, and the solvent is evaporated. By triturating the residue with a mixed solvent of isopropyl ether-hexane, 3 ', 4'-dihydro-6'-trimethylsilyloxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1' (2 ' H) -isoquinoline] 34.88 g are obtained as crude product. (4) The crude product obtained in (3) above is treated with methylene chloride 40
Dissolve in 0 ml, add 28 ml of diisopropylethylamine, add 27.4 g of benzyl chlorocarbonate dropwise under ice cooling, and stir at room temperature for 8 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with water, 5% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated to give 2'-benzyloxycarbonyl-. 3 ', 4'-dihydro-6'-
54.44 g of trimethylsilyloxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as a crude product. (5) The crude product obtained in the above (4) is dissolved in 250 ml of acetonitrile, and 47% hydrofluoric acid aqueous solution is added under ice cooling. The mixture is stirred at the same temperature for 30 minutes, sodium hydrogen carbonate is added to the reaction solution to adjust the pH to 6, and then the mixture is concentrated. Ethyl acetate and water are added to the residue, the pH is adjusted to 4 with citric acid, and the organic layer is separated. The organic layer is washed with water and saturated saline and then dried, and the solvent is distilled off. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give 2'-benzyloxycarbonyl-
3 ', 4'-dihydro-6'-hydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,
28.4 g (71.2%) of 1 '(2'H) -isoquinoline] are obtained as crystals. The mother liquor was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) and recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 5.78 g (14.5%). Melting point 123-124 ° C. (6) 26.18 g of the compound obtained in the above (5) was dissolved in 60 ml of dimethylformamide, to which 14.7 g of potassium carbonate and 8.5 ml of ethyl iodide were added to give 50-
Warm at 60 ° C. for 5 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then dried, and the solvent is distilled off. 27.65 g of the obtained residue was put into 100 ml of ethanol and 100 ml of water without purification, 21.1 g of sodium hydroxide was further added, and the mixture was stirred at room temperature for 14 hours. Then, the mixture is heated under reflux for 7 hours and the reaction solution is concentrated. Under ice cooling, 10% hydrochloric acid is added to the residue to make it acidic. Extract with ethyl acetate, wash with saturated brine, dry, and evaporate the solvent. By crystallizing the residue with isopropyl ether, 2'-benzyloxycarbonyl-3 ',
4'-dihydro-6'-ethoxy-4,4-biscarboxyl-spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] 23.91 g (96.9%) are obtained as crystals. Melting point 184-185 [deg.] C. (7) 21.4 g of the compound obtained in (6) above and 230 ml of pyridine are combined and heated under reflux for 5.5 hours. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, 10% hydrochloric acid,
After washing with saturated saline and drying, the solvent is distilled off. 400 ml of methanol and 2 g of 5% palladium-carbon were added to the residue,
Perform catalytic hydrogenation at room temperature and atmospheric pressure. The catalyst is filtered off from the reaction solution and the filtrate is concentrated. Add 200 ml of pyridine to the residue 24
Heat to reflux for hours. The solvent is distilled off and the solution is azeotropically distilled with toluene. The residue is dissolved in methanol, treated with carbon powder, and the solvent is distilled off. By recrystallizing the residue with ethyl acetate, (1
α, 4β) -3 ′, 4′-dihydro-6′-ethoxy-4
-Carboxyl-spiro [cyclohexane-1,1 '
(2'H) -isoquinoline] 6.04 g (44.7%) is obtained as crystals. Melting point 209-211.5 [deg.] C.

Reference Example 34 (1) 3-methoxyphenethylamine 25.5 g and 4,4
-Bisethoxycarbonylcyclohexanone 68.5 g
250 g of polyphosphoric acid is added to the mixture of, and stirred at 120 ° C. (external temperature) for 40 minutes. 500 ml of water in the reaction mixture,
Add 500 ml of saturated saline solution to dissolve, and extract with chloroform. The organic layer is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue is neutral silica gel (hexane: ethyl acetate = 4: 1 to ethyl acetate)
By purification with 3 ', 4'-dihydro-6'-
Methoxy-4,4-bisethoxycarbonyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline]
23.32 g (36.8%) are obtained as crystals. Melting point 81-83 [deg.] C. (2) 12.4 ml of benzyl chlorocarbonate was added dropwise to a methylene chloride solution of 21.76 g of the compound obtained in (1) above and 11.24 g of diisopropylethylamine, and the mixture was stirred at room temperature for 1.5 hours and then for 2.5 hours. Heat to reflux. After cooling the reaction mixture, it is concentrated and ethyl acetate is added to the residue for dilution. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated. Residue, ethanol 100ml, water 1
Sodium hydroxide 23.1 was added to a mixture of 00 ml under ice cooling.
g, and the mixture is stirred at room temperature for 16 hours and then heated under reflux for 7 hours. The reaction solution is concentrated, acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated. By crystallizing the residue with isopropyl ether, 3 ', 4'-dihydro-6'-methoxy-2'-benzyloxycarbonyl-4,4-biscarboxyl-spiro [cyclohexane-1,1'(2'H ) -Isoquinoline] 24.5 g (9
3.3%) as crystals. Melting point 193-194 [deg.] C. (3) The compound obtained in the above (3) is used in Reference Example 33.
By performing the same processing as in (7), (1α, 4β) −
3 ′, 4′-Dihydro-6′-methoxy-4-carboxyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline] is obtained as crystals. (Yield 51.5%) Melting point 201-205 ° C.

Reference Example 35 (1) (1α, 4β) -3 ′, 4′-dihydro-6′-methoxy-4-carboxyl-spiro [cyclohexane->
1,1 '(2'H) -isoquinoline] (Reference Example 34 (3)
1.70 ml of sulfuryl chloride was added dropwise to a solution of 3.0 g of the compound obtained in step 3) in 30 ml of acetic acid, and the mixture was stirred at room temperature for 2 hours. 20 ml of acetic acid and 0.8 of sulfuryl chloride
Add 8 ml and stir at room temperature for 4 hours. The reaction solution is concentrated,
The residue is azeotroped with toluene. Methanol is added to the residue and evaporated. Saturated aqueous sodium hydrogen carbonate is added, the mixture is extracted with ethyl acetate, the organic layer is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent is evaporated. By purifying the residue by neutral silica gel column chromatography (chloroform: methanol: aqueous ammonia = 50: 1: 0.1),
(1α, 4β) -3 ′, 4′-dihydro-5′-chloro-
6'-methoxy-4-methoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 2.
09 g are obtained as crystals. Melting point 113-115 [deg.] C. (2) A mixture of 2.05 g of the compound obtained in (1) above, 20 ml of ethanol, 20 ml of water and 12.7 g of sodium hydroxide is stirred at room temperature for 7 hours. The reaction solution was cooled to 10 under ice cooling.
Acidify with% hydrochloric acid and evaporate the solvent. The residue is purified by reverse phase column chromatography (ODS-S-50B, water-water: acetonitrile = 7: 1), the obtained crystals are dissolved in dioxane, hydrogen chloride / dioxane is added, and the solvent is evaporated. By triturating the residue with a mixed solvent of dioxane-ethyl acetate, (1α, 4β) -3 ′, 4′-
Dihydro-5'-chloro-6'-methoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H)-
Isoquinoline] 2.88 g is obtained as a colorless powder. (Although about 3 mol of sodium chloride was contained, it was used as it was in the next step) MS (APCI): 310/312 (M + H), IR (nujol) cm ^-1 :
1743, 1736, 1703.

Reference Example 36 (1) 3 ', 4'-dihydro-6', 7'-dihydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] ( Reference example 1
3 (1) (compound obtained in (1)) 14.767 g, potassium carbonate 27.03 g, ethyl iodide 15.64 ml and dimethylacetamide 60 ml are combined and cooled under ice-cooling 30.
Min, room temperature for 1 hour, 100 ° C. for 3 hours, and then overnight at room temperature. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent is evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 2'-ethyl-3 ', 4'-dihydro-6', 7 '.
17.81 g of -diethoxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] are obtained as an oil. MS (APCI) 462 (M + H), IR (neat) cm ^-1 : 1730. (2) 17.79 g of the compound obtained in (1) above, 7.75 g of sodium hydroxide, 30 ml of ethanol, 30 ml of water
After stirring for 5 hours at room temperature, the mixture is heated under reflux for 13 hours. The reaction solution is ice-cooled and adjusted to pH 1-2 with 10% hydrochloric acid, and then the solvent is distilled off. 200 ml of pyridine is added to the residue, and the mixture is heated under reflux for 3 hours. After cooling the reaction solution, the solvent is distilled off and toluene is azeotropically distilled. The residue is dissolved in water, adjusted to pH 7 with 10% aqueous sodium hydroxide solution, salted out with sodium chloride, and extracted with chloroform. The organic layer is washed with a small amount of saturated saline, dried over sodium sulfate, and then the solvent is distilled off. The residue was crystallized from a mixed solvent of isopropanol-ethyl acetate to give (1α, 4
β) -2'-ethyl-3 ', 4'-dihydro-6',
7'-Diethoxy-4-carboxyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 3.26
g are obtained as crystals. Melting point 203-213 [deg.] C (decomposition). MS (APCI) 362 (M + H), IR
(nujol) cm ⁻¹ : 1715, 1735.

Reference Example 37 (1) 2'-benzyloxycarbonyl-3 ', 4'-
Dihydro-6'-hydroxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H)
-Isoquinoline] (compound obtained in Reference Example 33 (5)) 1.40 ml of triethylamine was added to a solution of 40 ml of methylene chloride in 2.03 g, and 1.74 g of trifluoromethanesulfonic anhydride was chlorinated at -10 to -20 ° C. A 10 ml solution of methylene is added dropwise. After stirring the reaction solution for 1 hour,
Wash with water, 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dry and evaporate the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 7) to give 2′-benzyloxycarbonyl-3 ′,
4'-dihydro-6'-trifluoromethanesulfonyloxy-4,4-bisethoxycarbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline] 2.
57 g (quantitative) are obtained. MS (APCI): 628 (M + H), IR (neat) cm ^-1 : 1730, 1490,
1420. (2) To a solution of 2.55 g of the compound obtained in (1) above in 20 ml of dimethylformamide was added 1.7 ml of triethylamine, 27 mg of palladium acetate, 63 mg of triphenylphosphine, 313 μl of formic acid in an argon stream, and the mixture was heated at 60 ° C.
Stir for 3 hours, pour the reaction solution into ice water, and extract with ethyl acetate. The organic layer is washed with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent is evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 7) to give 2'-benzyloxycarbonyl-3 ', 4'-dihydro-4,4-bisethoxycarbonyl-spiro [cyclohexane-1. ，
1 '(2'H) -isoquinoline] 1.69 g (86.8
%). MS (APCI): 480 (M + H), IR (neat) cm ⁻¹ : 1730,1
715, 1450. (3) 19.31 g of the compound obtained in the above (2) was added to 100 ml of ethanol, 100 ml of water and 16.
The mixture is combined with 1 g and stirred at room temperature for 13 hours, and then heated under reflux for 7 hours. The reaction mixture was cooled and then concentrated, and the residue was cooled to 10% with ice.
Acidify with hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer is washed with saturated brine and dried, and the solvent is evaporated. By crystallizing with isopropyl ether, 2'-benzyloxycarbonyl-3 ', 4'-dihydro-4,4-
Biscarboxyl-spiro [cyclohexane-1,1 '
16.16 g (94.7%) of (2'H) -isoquinoline] is obtained as crystals. Melting point 199-200 [deg.] C. (4) The compound obtained in (3) above was used in Reference Example 33.
By performing the same processing as in (7), (1α, 4β) −
3 ', 4'-Dihydro-4-carboxyl-spiro [cyclohexane-1,1'(2'H) -isoquinoline] is obtained as crystals. Melting point 221.5-223.5 [deg.] C. Reference Examples 38-42 The corresponding starting compounds are treated in the same manner as in Reference Example 17 (3) to give the compounds shown in Table 49.

[0637]

[Table 177]

Reference Examples 43-47 The corresponding starting materials were treated in the same manner as in Reference Example 17 (4) to give the compounds shown in Table 50.

[0639]

[Table 178]

Reference Example 48 (1) 4- (4-Ethoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (Compound obtained in Reference Example 17 (1) or (2)) 84 .2
A mixture of g, 170.9 g of potassium hydroxide, 600 ml of water, and 600 ml of ethanol is heated under reflux for 5 hours. After cooling, 600 ml of the solvent is distilled off under reduced pressure, and concentrated hydrochloric acid is added to make the solution acidic. After distilling off the solvent under reduced pressure, the residue and water 1000
102.4 g of sodium hydrogen carbonate and 99.7 g of di-tert-butyl dicarbonate are added to a mixture of 100 ml of dioxane and 1000 ml of dioxane under ice cooling, and the mixture is stirred at room temperature for 12 hours. At room temperature, add 80 g of sodium hydroxide and add 3
Stir for hours. Concentrated hydrochloric acid is added to neutralize, and the precipitate is collected by filtration. After washing with water and recrystallizing with ethanol,
4- (4-tert-butoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (7
5.35 g, yield 81.2%) are obtained as crystals. Melting point 230-231 ° C, MS (APCI) 305 (M +
H), IR (Nujol) 1690. (2) 75 g of dimethylformamide of 75 g of the compound obtained in (1) above and 75 m of tetrahydrofuran
2.37 g of sodium hydride is added to the suspension of 1 and stirred at room temperature for 1 hour and 30 minutes. Under ice cooling, 7.8 ml of 3-methylbenzyl chloride is added dropwise, and the mixture is stirred at room temperature for 3 hours. The reaction solution is added to water and extracted with ethyl acetate. The organic layer is separated, washed with saturated brine and dried over sodium sulfate. After distilling off the solvent under reduced pressure, it was recrystallized from isopropanol to give 4- (4-tert-butoxycarbonyl-1-piperazinyl) -1- (3-methylbenzyl).
-1H-Pyrazolo [3,4-d] pyrimidine (9.6
g, yield 48%) as crystals. Melting point 130-131 ° C, MS (APCI) 409 (M +
H), IR (Nujol) 1691, 1681. (3) To a suspension of 9.58 g of the compound obtained in (2) above in 58 ml of methanol, 58 ml of 4N hydrogen chloride dioxane solution is added at room temperature, and the mixture is stirred for 16 hours. Add 100 ml of ethyl acetate and stir at room temperature for 1 hour. The precipitated crystals are collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 60 ° C. to give 1- (3-methylbenzyl) -4.
-(1-Piperazinyl) -1H-pyrazolo [3,4-
d] Pyrimidine dihydrochloride (9.06 g, quantitative yield) is obtained as crystals. Melting point 254-256 ° C, MS (APCI) 309 (M +
H).

Reference Example 49-60 The corresponding starting materials are treated in the same manner as in Reference Example 48 (2) to give the compounds shown in Table 51.

[0642]

[Table 179]

[0643]

[Table 180]

Reference Examples 61-72 The corresponding starting compounds were treated in the same manner as in Reference Example 48 (3) to give the compounds shown in Table 52.

[0645]

[Table 181]

[0646]

[Table 182]

Reference Example 73 (1) To a solution of 10.0 g of ethylpyridine in 50 ml of acetic acid was added 10.6 ml of a 30% aqueous hydrogen peroxide solution at room temperature, and the mixture was heated under reflux for 24 hours. After cooling to room temperature, 3.4 ml of dimethyl sulfide is added and stirred for 1 hour, and the reaction solution is concentrated under reduced pressure. In a solution of the residue obtained and 11.6 g of cyanotrimethylsilane in 90 ml of dichloromethane,
Dimethylaminocarbamic acid chloride 10.7 at room temperature
A 25 ml solution of 25 ml of dichloromethane is added dropwise over 10 minutes, and the mixture is stirred for 24 hours. At room temperature, 10% aqueous potassium carbonate solution is added and stirred for 10 minutes. The organic layer is separated and extracted twice with 100 ml dichloromethane. The combined organic layers are washed with 50 ml of saturated saline and dried over sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by flash silica gel column chromatography (chloroform) to give 2-cyano-6-ethylpyridine (9.45 g, yield 81.1%) as a pale yellow oil. MS (APCI) 133 (M + H), IR (Ne
at) 2236. (2) 9.44 g of the compound obtained in (1) above is dissolved in 50 ml of 6N hydrochloric acid and heated under reflux for 24 hours. After concentrating under reduced pressure, the resulting residue is pulverized in acetonitrile and then collected by filtration to obtain crude crystals of 6-ethylpicolinic acid hydrochloride, which is used in the next reaction without further purification. (3) 10N at room temperature in a suspension of 13.4 g of the compound obtained in (2) above in 200 ml of tetrahydrofuran.
Borane dimethyl sulfide complex of 19.3 ml of dimethyl sulfide solution is added dropwise over 10 minutes, and the mixture is heated under reflux for 6 hours. After cooling to room temperature, 100 ml of 1N sodium hydroxide aqueous solution is added, and the mixture is stirred for 15 minutes. Ethyl acetate 30
After extracting twice with 0 ml, 200 ml of water and saturated saline solution 2
Wash with 00 ml and dry over sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by flash silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 6-ethyl-2-hydroxymethylpyridine (7.07 g, yield 72.2% ( 2 strokes)) as an oil. MS (APCI) 138 (M + H), I
R (Neat) 3244, 1736. (4) 4.54 ml of diethylazodicarboxylate was added dropwise to a solution of 7.56 g of triphenylphosphine in 200 ml of tetrahydrofuran at −78 ° C., and the mixture was stirred for 5 minutes. At −78 ° C., 4.35 g of the compound obtained in (3) above, 1.40 g of neopentylamine, and 8.77 g of the compound obtained in Reference Example 38 (1) were added,
Stir for 15 minutes at 78 ° C and for 17 hours at room temperature. After concentration under reduced pressure, the residue was subjected to flash silica gel column chromatography (chloroform → chloroform: methanol = 2).
Purify at 0: 1) and evaporate the solvent under reduced pressure. To a solution of the obtained residue in 40 ml of methanol, 40 ml of 4N hydrogen chloride dioxane solution is added at room temperature, and the mixture is stirred for 17 hours.
150 ml of ethyl acetate was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give 1- (6
-Ethyl-2-pyridylmethyl) -4- (1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine 3
The hydrochloride salt (6.15 g, yield 49.3%) is obtained as crystals. Melting point 228 ° C, MS (APCI) 324 (M +
H), IR (Nujol) 3281, 1985, 173.
3, 1635.

Reference Examples 74-91 The corresponding starting materials were treated in the same manner as in Reference Example 73 (4) to give the compounds shown in Table 53.

[0649]

[Table 183]

[0650]

[Table 184]

[0651]

[Table 185]

Reference Example 92 (1) 500 mg of thiopropionamide and 1,3-
A solution of 748 mg of dichloro-2-propanone in 10 ml of dimethylformamide is heated under reflux for 3 hours. After evaporating the solvent under reduced pressure, the residue is dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure,
By purification by silica gel column chromatography (hexane: ethyl acetate = 7: 3), 4-chloromethyl-2-ethylthiazole (458 mg, yield 50.
5%) as an oil. MS (APCI) 162 /
163 (M + H), IR (Neat) 3109. (2) Dimethylacetamide 6 containing 3.0 g of the compound obtained in Reference Example 38 (1) and 1.65 g of lithium hydroxide
2.07 g of the compound obtained in (1) above is added to a 0 ml suspension at room temperature, and the mixture is stirred for 16 hours. Water is added to the reaction solution, extracted with ethyl acetate, washed twice with saturated saline solution, and dried with sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:
By purifying with methanol = 80: 1), 4-
(4-tert-butoxycarbonyl-1-piperazinyl)
-1- (2-ethyl-4-thiazolylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidine (2.33 g, 55% yield) is obtained as an oil. MS (APCI) 430
(M + H), IR (Neat) 1682. (3) By treating 2.31 g of the compound obtained in (2) above in the same manner as in Reference Example 38 (3), 1- (2-
Ethyl-4-thiazolylmethyl) -1H-pyrazolo [3,4-d] pyrimidine trihydrochloride (2.21 g, yield 94%) is obtained as crystals. Melting point 210-211 ° C, M
S (APCI) 330 (M + H), IR (Neat + chloroform) 1633, 1613.

Reference Examples 93-102 The corresponding starting materials are treated in the same manner as in Reference Example 92 (2) to give the compounds shown in Table 54.

[0654]

[Table 186]

[0655]

[Table 187]

Reference Examples 103 to 112 The corresponding starting materials are treated in the same manner as in Reference Example 48 (3) to give the compounds shown in Table 55.

[0657]

[Table 188]

[0658]

[Table 189]

Reference Example 113 (1) 8.85 g of 6-bromopicolinic acid and concentrated sulfuric acid 2
A 270 ml solution of methanol in ml is heated to reflux for 12 hours. After concentration under reduced pressure, the residue is dissolved in chloroform and dried over sodium sulfate. After evaporating the solvent under reduced pressure, 1.9 g of lithium borohydride was slowly added to 240 ml of a tetrahydrofuran solution of the resulting residue under ice cooling, and the mixture was cooled with ice to 5 ml.
Stir for 3 minutes at room temperature for 3 hours. Add the reaction mixture to ice water, and
Acidify with N hydrochloric acid and stir for 30 minutes. Basify with saturated aqueous sodium hydrogen carbonate solution, extract with ethyl acetate, and dry over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 6-bromo-2-hydroxymethylpyridine (7.
5 g, 91% yield) is obtained as a colorless oil. (2) By treating 5.96 g of the compound obtained in (1) above and 8.77 g of the compound obtained in Reference Example 38 (1) in the same manner as in Reference Example 39 (4), 1- (6-bromo) 2-Pyridylmethyl) -4- (4-tert-butoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (9.0 g, 66% yield) is obtained as crystals. Melting point 126-128 ° C, MS (APCI) 4
75 (M + H), IR (Nujol) 1683. (3) After slowly dissolving 1.80 g of sodium in 210 ml of ethanol, the compound 7.0 obtained in (2) above
g and the mixture is heated to reflux for 3 days. The solvent is evaporated under reduced pressure, water is added, and the mixture is extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography and recrystallized from chloroform-diethyl ether to give 1-
(6-ethoxy-2-pyridylmethyl) -4- (4-te
rt-Butoxycarbonyl-1-piperazinyl) -1H-
Pyrazolo [3,4-d] pyrimidine (5.0 g, yield 7
7%) as crystals. Melting point 130-132 ° C, MS
(APCI) 440 (M + H), IR (Nujol) 1688. (4) By treating 5.0 g of the compound obtained in (3) above in the same manner as in Reference Example 38 (3), 1- (6-ethoxy-2-pyridylmethyl) -4- (1-piperazinyl). -1H-Pyrazolo [3,4-d] pyrimidine trihydrochloride (5.1 g, yield quantitative) is obtained as crystals. Melting point 200 ° C, MS (APCI) 340 (M + H), IR (Nujol) 16
43, 1633.

Reference Example 114 (1) To a solution of the compound (20.58 g) obtained in Reference Example 96 in 80 ml of methanol and 80 ml of tetrahydrofuran was added 3.0 g of palladium carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. . After filtering the reaction mixture, the catalyst is washed with methanol and the filtrate is concentrated. The obtained residue was purified by NH silica gel column chromatography (chloroform: hexane = 1: 1) and then pulverized in diisopropyl ether to give 1- (3-aminobenzyl) -4- (4-tert-butoxycarbonyl). -1-Piperazinyl) -1H-pyrazolo [3,4-d]
Pyrimidine (18.49 g, 96% yield) is obtained as a powder. MS (APCI) 410 (M + H). (2) 1.5 ml of formic acid in 3.0 ml of acetic anhydride under ice cooling
Is added dropwise, and the mixture is stirred at 60 ° C. for 1 hour. Tetrahydrofuran 60m of the compound 5.0g obtained in (1) above in a 10ml tetrahydrofuran solution of the reaction solution under ice cooling.
1 is added dropwise and stirred for 1 hour. The reaction mixture is made basic with saturated aqueous sodium hydrogen carbonate solution and the tetrahydrofuran is distilled off. After extraction with ethyl acetate, the extract is washed with water and saturated saline and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crushed in diisopropyl ether to give 1- (3-formylaminobenzyl).
-4- (4-tert-Butoxycarbonyl-1-piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (5.15 g, 96% yield) is obtained as a powder. MS (AP
CI) 438 (M + H). (3) 150 mg of the compound obtained in the above (2) and 0.137 ml of iodoethane are added to a suspension of 16 mg of sodium hydride (60%) in 0.5 ml of tetrahydrofuran at room temperature, and the mixture is stirred for 30 minutes. In the reaction solution,
At room temperature, 0.5 ml of tetrahydrofuran and 33 mg of sodium hydride are added, and the mixture is stirred for 2 hours. Ice water is added to the reaction mixture, which is extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was triturated in diisopropyl ether to give 1- (3- (N-ethyl-N-formylamino) benzyl) -4- (4-tert-butoxycarbonyl-1. -Piperazinyl) -1H-pyrazolo [3,4-d] pyrimidine (142 mg, 89% yield)
As a powder. MS (APCI) 466 (M +
H). (4) 132 mg hydrochloric acid 2 of the compound obtained in (3) above
The ml solution is heated to reflux for 1 hour. The reaction solution is diluted with ice water and made basic with potassium carbonate. After extraction with chloroform, the extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1- (3-ethylaminobenzyl) -4-.
(1-Piperazinyl) -1H-pyrazolo [3,4-d]
Pyrimidine (98 mg, quantitative yield) is obtained as an oil. MS (APCI) 338 (M + H).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/505 A61K 31/505 31/506 31/506 31/519 31/519 31/52 31/52 31 / 53 31/53 A61P 1/00 A61P 1/00 25/00 25/00 43/00 111 43/00 111 C07B 53/00 C07B 53/00 G C07D 401/14 C07D 401/14 471/04 106 471 / 04 106C 107 107E 473/34 361 473/34 361 487/04 143 487/04 143 146 146 // C07M 7:00 C07M 7:00 (72) Inventor Akihiko Ishida 10-16-1, Tokiwa, Saitama City, Saitama Prefecture 415 (72) Hiroyuki Taniguchi 208 Koizumi, Ageo City, Saitama Prefecture (72) Yuichi Onoda Yu 38 Onuma, Kuma City, Saitama Prefecture F-Term (Reference) 4C050 AA01 BB05 BB06 CC08 EE04 EE05 FF01 GG04 HH02 HH03 HH04 4C 063 AA01 AA03 AA05 BB01 BB09 CC17 CC29 CC34 CC43 DD12 DD14 DD15 DD17 EE01 4C065 AA04 BB05 BB06 CC01 DD03 EE02 HH01 JJ08 KK09 LL01 PP19 QQ04 4C0 GA607 GA01 ZA16C08 GA1607A02 AA04 BC30 BC50 BC64 GA07 CB01 GAA07 AA03 AA03 AA02 AA03 AB26 AC81

Claims (37)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, ring A is an optionally substituted benzene ring, R
¹⁰ is a hydrogen atom or a group represented by -Z-R ¹ ,
R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, and Z is
A group represented by CH ₂ — or —CO—, R ² is a hydrogen atom or an optionally substituted heterocyclic group, and B is And R ³ is an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group, Y 3
Represents a group represented by —CH ₂ — or —CO—) or a pharmaceutically acceptable salt thereof. 2. A benzene ring optionally substituted with a group selected from a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group, a halogen atom, an amino group, and a lower alkylenedioxy group, R ¹⁰ is a hydrogen atom or a group represented by —Z—R ¹ , R ¹ is (1) a hydrogen atom, (2) a lower alkyl group optionally substituted with a group selected from the following, (i) halogen Atom, (ii) optionally protected hydroxyl group, (iii) lower alkyl group; cyclo lower alkyl group; aryl lower alkyl group;
Lower alkoxycarbonyl group; acyl group; 1-amino-
2-nitrovinyl group; 1- (mono- or di-) lower alkylamino-2-nitrovinyl group; 1-amino-2,
2-dicyanovinyl group; 1- (mono- or di-) lower alkylamino-2,2-dicyanovinyl group; 3-aminocyclobut-3-en-1,2-dione-4-yl group; 3- A group selected from (mono- or di-) lower alkylamino-cyclobut-3-en-1,2-dione-4-yl group; and a group capable of being enzymatically or chemically metabolized in vivo to be removed. Selected from an optionally substituted amino group, (iv) lower alkyl group, cyclo lower alkyl group and cyano group, optionally substituted guanidino group, (v) lower alkyl group and cyclo lower alkyl group A ureido group optionally substituted with a group, and (vi) a thioureido group optionally substituted with a group selected from a lower alkyl group and a cyclo lower alkyl group, or (3) lower alkenyl, Z is -CH ₂ - group represented by or -CO-, ^{R 2} is (1)
A hydrogen atom, or (2) a heterocyclic group which may be substituted with a group selected from the following, (i) a lower alkyl group,
(Ii) lower alkoxy group, (iii) optionally protected hydroxyl group, (iv) halogen atom, (v) lower alkylenedioxy group, and (vi) acyl group, R ³ is selected from (1) Optionally substituted with an amino group, (i) an oxo group, an optionally protected amino group, a (mono- or di-) lower alkylamino group, an aryl lower alkylimidazolylthio group, and a pyridylamino group ( The pyridyl moiety of the pyridylamino group may be substituted with a lower alkyl group, which may be substituted with a lower alkyl group, (ii) an acyl group, (iii) a lower alkyl group. An optionally substituted nitrogen-containing heterocyclic group and an amino group which may be substituted with a lower alkyl group, and (iv) a lower alkyl group, a lower group A nitrogen-containing heterocyclic group which may be substituted with a group selected from an alkoxy group, an aryl lower alkyl group, an optionally protected hydroxyl group, and an amino group, or (2) a group selected from the following: Optionally a nitrogen-containing aliphatic heterocyclic group, (i) nitroso group,
(Ii) optionally protected amino group, (iii) oxo group, oxide group, lower alkyl group, cyano lower alkyl group, cyclo lower alkyl lower alkyl group (the carbon atom on the cyclo lower alkyl group is substituted with a sulfur atom) , A pyrrolidinylcarbonyl lower alkyl group, a halogeno lower alkyl group, a lower alkylthio lower alkyl group, an aryl lower alkyl group (the aryl portion of the aryl lower alkyl group is a lower alkyl group, a lower alkoxy group, (mono -Or di-) lower alkylamino group, lower alkoxy lower alkyl group, halogen atom, trihalogenomethyl group, trihalogenomethoxy group, nitro group, and may be substituted with a group selected from cyano group),
Thienyl lower alkyl group (the thienyl part of the thienyl lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group), furyl lower alkyl group (the furyl part of the furyl lower alkyl group is a lower alkyl group) And (mono- or di-) may be substituted with a group selected from lower alkylamino lower alkyl group), imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group is a lower alkyl group, Hydroxy group, (mono-
Or di-) may be substituted with a group selected from a lower alkylamino group and a lower alkoxy lower alkyl group), a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group (the pyrimidinyl portion of the pyrimidinyl lower alkyl group is a lower alkyl group) May be substituted),
Pyridazinyl lower alkyl group, pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group is a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkoxy lower alkyl group, a (mono- or di-) lower alkylamino group, a lower alkoxy group. Carbonyl group, (mono-
Or di-) lower alkylcarbamoyl group, (mono- or di-) lower alkylamino lower alkyl group, optionally substituted with a group selected from hydroxy lower alkyl group, oxo group and oxide group), a carboxyl group,
Lower alkoxycarbonyl group, halogen atom, hydroxy lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, aryl lower alkoxy lower alkyl group (wherein the aryl part of the aryl lower alkoxy lower alkyl group is substituted with a halogen atom, ), An amino group-protecting group, an amino group which may be substituted with a lower alkyl group, a cyclo-lower alkyl group, an N-pyridyl-N-lower alkylcarbamoyl group,
Lower alkenyl group, halogeno lower alkenyl group, and aryl group (the aryl group is a trifluoromethyl group,
A lower alkoxy group and a nitrogen-containing heterocyclic group which may be substituted with a group selected from a group selected from a nitro group) (which may form an onium salt on the nitrogen) And (iv) an oxo group, a pyridyl group, an imino group, a pyrazolyl group (the pyrazolyl group may be substituted with a group selected from a lower alkyl group and a benzyl group), a carbamoyl group (the carbamoyl group is a pyridyl group. And a lower alkyl group may be substituted), a thiocarbamoyl group (the thiocarbamoyl group may be substituted with a group selected from a pyridyl group and a lower alkyl group), an amino group (the amino group). The group is N-lower alkyl-N-pyridylcarbamoyl group, lower alkylcarbamoyl group, pyridylcarbamoyl group, lower alkyl group. Group, an amino-protecting group, a pyridylcarbonyl group, a pyridylthiocarbonyl group, a pyridyl group, and a group selected from a 1-cyanoimino-1-pyridylmethyl group). The compound according to claim 1, which is a lower alkyl group which may be substituted. 3. A “group capable of being enzymatically or chemically metabolized in vivo to be removed” in R ¹ has the formula: (In the formula, R ⁵ is represented by the formula: (In the formula, R ⁵¹ represents a hydrogen atom or a lower alkyl group, R ^51
52 is a lower alkyl group which may be substituted with a carboxyl group, a cyclo lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group or an aryl group, R ⁵³ is a lower alkyl group or an aryl group, and R ⁵⁴ and R ⁵⁵ are the same or Differently selected from a hydrogen atom, a lower alkanoyloxy group, an arylcarbonyloxy group, a lower alkoxycarbonyloxy group, a lower alkanoyloxymethyloxy group, a halogen atom and a lower alkyl group, R ⁵⁶ is a hydrogen atom, a lower alkanoyloxy lower alkyl Group or arylcarbonyloxy lower alkyl group, m is 0 or 1, R ⁵⁷ is an optionally protected amino group, lower alkoxy group, carbamoyloxy group,
(Mono- or di-) lower alkylcarbamoyloxy group or acyl group, p is 1 or 2, R ⁵⁸ is lower alkoxy group, acyl group, carbamoyloxy group or (mono- or di-) lower alkylcarbamoyloxy group,
The compound according to claim 2, wherein q represents a group represented by 1) or 2). 4. R ² is of the formula: (In the formula, ring A is a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group, a halogen atom, an amino group,
And a benzene ring which may be substituted with a group selected from a lower alkylenedioxy group, R ²¹ represents a hydrogen atom or a lower alkyl group, and W represents a group represented by —CH ₂ — or —CO—). The compound according to claim 3, which is a group. 5. The compound according to claim 3, wherein R ² is a hydrogen atom. 6. The heterocyclic group for R ² is monocyclic or 2
A nitrogen-containing heterocyclic group in R ^3, the nitrogen-containing aliphatic heterocyclic group in R ³ is a monocyclic 4- to 8-membered nitrogen-containing aliphatic heterocyclic group, and the nitrogen-containing heterocyclic group in R ³ . The compound according to claim 3, wherein is a monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group. 7. The heterocyclic group for R ² is 1, 2, 3,
4-tetrahydroisoquinolyl group, 3,4-dihydroisoquinolyl group or isoquinolyl group, wherein the nitrogen-containing aliphatic heterocyclic group in R ³ is azetidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidyl group, A piperazinyl group, an azepinyl group, a diazepinyl group, an azeosynyl group or a diazeosynyl group,
The aryl group in R ¹ or R ³ is a phenyl group, a naphthyl group, an anthryl group or a phenanthryl group,
The nitrogen-containing heterocyclic group for R ³ is a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an imidazolyl group, an imidazolinyl group, a pyrazolyl group, a pyridyl group,
Dihydropyridyl group, pyridazinyl group, pyrimidinyl group, tetrahydropyrimidinyl group, pyrazinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group,
Piperidyl group, piperazinyl group, triazinyl group, morpholinyl group, indolyl group, quinolyl group, isoquinolyl group, purinyl group, 1H-indazolyl group, quinazolinyl group, cinnolinyl group, quinoxalinyl group, phthalazinyl group, pteridinyl group, pyrazolopyrimidinyl group, tria The compound according to claim 3, which is a zolopyrimidinyl group, an imidazopyrimidinyl group, a pyrazolopyridyl group, a triazolopyridyl group or an imidazopyridyl group. 8. R ¹ is of the formula: embedded image (In the formula, R ⁴ is a hydrogen atom or a lower alkyl group, and n is 1
Represents an integer of 6 to 6),
The compound of 4, 5, 6 or 7. 9. A prodrug of the compound according to claim 8. 10. The group R in the compound according to claim 8.
A compound in which the bonding nitrogen atom of ⁴ is further substituted with a group which can be removed by being metabolized enzymatically or chemically in vivo. 11. The group R in the compound according to claim 8.
⁴ bonded nitrogen atoms have the formula: (In the formula, R ⁵ is represented by the formula: (In the formula, R ⁵¹ represents a hydrogen atom or a lower alkyl group, R ^51
52 is a lower alkyl group which may be substituted with a carboxyl group, a cyclo lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group or an aryl group, R ⁵³ is a lower alkyl group or an aryl group, and R ⁵⁴ and R ⁵⁵ are the same or Differently selected from a hydrogen atom, a lower alkanoyloxy group, an arylcarbonyloxy group, a lower alkoxycarbonyloxy group, a lower alkanoyloxymethyloxy group, a halogen atom and a lower alkyl group, R ⁵⁶ is a hydrogen atom, a lower alkanoyloxy lower alkyl Group or arylcarbonyloxy lower alkyl group, m is 0 or 1, R ⁵⁷ is an optionally protected amino group, lower alkoxy group, carbamoyloxy group,
(Mono- or di-) lower alkylcarbamoyloxy group or acyl group, p is 1 or 2, R ⁵⁸ is lower alkoxy group, acyl group, carbamoyloxy group or (mono- or di-) lower alkylcarbamoyloxy group,
q represents a group represented by 1 or 2) and a compound further substituted with a group represented by). 12. R ⁵ is of the formula: (In the formula, R ⁵¹ represents a hydrogen atom or a lower alkyl group, R ^51
52 is a group represented by a lower alkyl group optionally substituted with a carboxyl group, a cyclo lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group or an aryl group), and the compound according to claim 11. 13. A ring A having the same or different 2 selected from a lower alkoxy group and an optionally protected hydroxyl group.
Benzene ring optionally substituted with a group, R ¹⁰ is-
Z ¹ is a group represented by R ¹ , wherein R ¹ is a hydrogen atom or a lower alkyl group, Z is a group represented by —CH ₂ —, R ² is a lower alkyl group, an acyl group, a lower alkoxy group and protected. 1,2,3,4-tetrahydroisoquinolyl group which may be substituted with a group selected from a hydroxyl group, and a lower group in which R ³ is (1) (mono- or di-) lower alkylamino group Alkyl group-substituted amino group or (2)
Substituted with a group selected from a piperazinyl group optionally substituted with a group selected from the following, (i) a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, an oxo group, an oxide group and a hydroxy lower alkyl group. Optionally a monocyclic nitrogen-containing heterocyclic group (which may form an onium salt on the nitrogen), and (i
i) an N-pyridyl-N-lower alkylcarbamoyl group,
The compound according to claim 2, which is a lower alkyl group which may be substituted with a group selected from an oxo group, an imino group, an amino group and a pyridyl group, and Y is a group represented by -CO-. 14. Ring A is the same or different 2 selected from a lower alkoxy group and an optionally protected hydroxyl group.
Benzene ring optionally substituted with a group, R ¹⁰ is-
A group represented by Z-R ¹ , wherein R ¹ is a lower alkyl group substituted with a (mono- or di-) lower alkylamino group, Z is a group represented by —CH ₂ — or —CO—, R ²
May be substituted with (1) a hydrogen atom, or (2) a group selected from a lower alkyl group, an acyl group, a lower alkoxy group and an optionally protected hydroxyl group, 1, 2,
3,4-tetrahydroisoquinolyl group, R ³ is amino group, lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, hydroxy lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, aryl lower Alkyl group (the aryl portion of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with an oxide group) ), A thienyl lower alkyl group, a lower alkylamino group, a halogenobenzyloxy lower alkyl group, a lower alkenyl group, a cyclo lower alkyl group, and an aryl group (the aryl group is selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group. Substitute with a group A piperazinyl group substituted with a monocyclic or bicyclic nitrogen-containing heterocyclic group and Y is a group represented by —CO—, which may be substituted with a group selected from Item 2. The compound according to Item 2. 15. Ring A is of the formula: (Wherein R ⁸ represents a lower alkoxy group), R ¹⁰ is a group represented by —Z—R ¹ , and R ^{1 is}
Is a lower alkyl group substituted with a (mono- or di-) lower alkylamino group, Z is a group represented by -CO-, R ²
Has the formula: (In the formula, R ²¹ represents a hydrogen atom or a lower alkyl group, W represents a group represented by —CH ₂ — or —CO—, and R ²² represents a lower alkoxy group), R ³ is selected from the following. A piperazinyl group substituted with a group, (1) a lower alkyl group, a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group) A pyrazolopyrimidinyl group (2)
An imidazopyridyl group substituted with a lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and (3) a lower alkyl group or aryl A triazolopyrimidinyl group substituted with a lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and Y is a group represented by -CO-. The compound according to 2. 16. Ring A is of the formula: (Wherein R ⁸ represents a lower alkoxy group), R ¹⁰ is a group represented by —Z—R ¹ , and R ^{1 is}
Is 1- (mono- or di-) lower alkylamino-2-
A lower alkyl group substituted with an amino group which may be substituted with a nitrovinyl group, a group in which Z is -CH _2- ,
Pyra substituted with R ² as a hydrogen atom and R ³ with a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a nitro group, a halogen atom or a lower alkyl group) A piperazinyl group substituted with a zolopyrimidinyl group, Y is-
The compound according to claim 2, which is a group represented by CO-. 17. Ring A having the same or different 2 selected from a lower alkoxy group and an optionally protected hydroxyl group.
Benzene ring optionally substituted with a group, R ¹⁰ is-
Z ¹ is a group represented by R ¹ , wherein R ¹ is an amino group-substituted lower alkyl group (the amino group of the amino group-substituted lower alkyl group is removed by being metabolized enzymatically or chemically in the lower alkyl group and in vivo). Substituted with a group capable of being), Z
Is a group represented by —CH ₂ — or —CO—, R ² is (1) a hydrogen atom, or (2) a group selected from a lower alkyl group, an acyl group, a lower alkoxy group and an optionally protected hydroxyl group. 1, 2, which may be replaced with
3,4-tetrahydroisoquinolyl group, R ³ is amino group, lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, hydroxy lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, aryl lower Alkyl group (the aryl portion of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with an oxide group) ), A thienyl lower alkyl group, a lower alkylamino group, a halogenobenzyloxy lower alkyl group, a lower alkenyl group, a cyclo lower alkyl group, and an aryl group (the aryl group is selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group. Substitute with a group A piperazinyl group substituted with a monocyclic or bicyclic nitrogen-containing heterocyclic group and Y is a group represented by —CO—, which may be substituted with a group selected from Item 2. The compound according to Item 2. 18. Ring A is of the formula: (Wherein R ⁸ represents a lower alkoxy group), R ¹⁰ is a group represented by —Z—R ¹ , and R ^{1 is}
Is an amino group-substituted lower alkyl group (the amino group of the amino group-substituted lower alkyl group is substituted with a lower alkyl group and a group capable of being enzymatically or chemically metabolized in vivo). A group represented by CO-, wherein R ² has the formula: (In the formula, R ²¹ represents a hydrogen atom or a lower alkyl group, W represents a group represented by —CH ₂ — or —CO—, and R ²² represents a lower alkoxy group), R ³ is selected from the following. A piperazinyl group substituted with a group, (1) a lower alkyl group, a pyridyl lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group) A pyrazolopyrimidinyl group (2)
An imidazopyridyl group substituted with a lower alkyl group or an aryl lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and (3) a lower alkyl group or aryl A triazolopyrimidinyl group substituted with a lower alkyl group (the aryl part of the aryl lower alkyl group may be substituted with a halogen atom or a lower alkyl group), and Y is a group represented by -CO-. The compound according to 2. 19. A compound represented by the general formula [Ih]: (In the formula, R ⁸¹ , R ⁸² , and R ⁸³ are the same or different and are selected from a hydrogen atom, a lower alkoxy group, an optionally protected hydroxyl group and a halogen atom, and R ¹⁰ is a hydrogen atom or —Z—R ¹ And Z is -CH
A group represented by _2- or -CO-, R ¹ is (1) a hydrogen atom, (2) a lower alkyl group optionally substituted with a group selected from the following, (i) a halogen atom, (ii) protected Optionally substituted hydroxyl group, (iii) lower alkyl group; cyclo lower alkyl group; aryl lower alkyl group; lower alkoxycarbonyl group; acyl group; 1-amino-2-nitrovinyl group; 1- (mono- or di-) lower Alkylamino-2-nitrovinyl group; 1-amino-2,2-dicyanovinyl group; 1- (mono- or di-) lower alkylamino-2,2-dicyanovinyl group; 3-aminocyclobut-3-ene -1,2-dione-4-yl group; 3-
(Mono- or di-) lower alkylamino-cyclobut-3-en-1,2-dione-4-yl group; and a group selected from a group capable of being enzymatically or chemically metabolized and removed in vivo. An optionally substituted amino group, (i
v) a guanidino group which may be substituted with a group selected from a lower alkyl group, a cyclo lower alkyl group and a cyano group, and (v) an ureido which may be substituted with a group selected from a lower alkyl group and a cyclo lower alkyl group. Group, and (vi) a thioureido group which may be substituted with a group selected from a lower alkyl group and a cyclo lower alkyl group, or (3) a lower alkenyl group, and R ³⁰ is an oxo group, an oxide group, a lower alkyl group , Cyano lower alkyl group, cyclo lower alkyl lower alkyl group (the carbon atom on the cyclo lower alkyl group may be substituted with a sulfur atom), pyrrolidinylcarbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl Group, aryl lower alkyl group (aryl moiety of the aryl lower alkyl group Is a lower alkyl group, a lower alkoxy group, a halogen atom, a trihalogenomethyl group, a trihalogenomethoxy group, a nitro group, or a group selected from a cyano group), a thienyl lower alkyl group (the thienyl lower alkyl group). The thienyl portion of the group may be substituted with a halogen atom), furyl lower alkyl group, imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group may be substituted with a lower alkyl group) ), A pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group, a pyridazinyl lower alkyl group, a pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with a lower alkyl group or an oxide group),
Carboxyl group, lower alkoxycarbonyl group, halogen atom, hydroxy lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, aryl lower alkoxy lower alkyl group (the aryl part of the aryl lower alkoxy lower alkyl group is substituted with a halogen atom) Optionally)), a protecting group for an amino group, an amino group optionally substituted with a lower alkyl group,
Cyclo lower alkyl group, N-pyridyl-N-lower alkylcarbamoyl group, lower alkenyl group, halogeno lower alkenyl group, and aryl group (the aryl group is a group selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group. Represents a spiroisoquinoline derivative represented by a nitrogen-containing heterocyclic group (which may form an onium salt on nitrogen) optionally substituted with a group selected from A pharmacologically acceptable salt. 20. R ³⁰ is of the formula: embedded image (In the formula, D ¹ and D ² are the same or different and are a group represented by -N = or -CH =, and ^one of E ¹ and E ² is-
A group represented by N =, the other group represented by -N = or -CH =, R ³¹ represents a hydrogen atom, an oxo group, an oxide group, a lower alkyl group, a cyano lower alkyl group, a cyclo lower alkyl lower alkyl group (The carbon atom on the cyclo lower alkyl group may be substituted with a sulfur atom), pyrrolidinylcarbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl group, aryl lower alkyl group (the aryl lower alkyl group) The aryl part of is a lower alkyl group, a lower alkoxy group, a halogen atom, a trihalogenomethyl group, a trihalogenomethoxy group,
Optionally substituted with a group selected from a nitro group and a cyano group), a thienyl lower alkyl group (the thienyl portion of the thienyl lower alkyl group may be substituted with a halogen atom), a furyl lower alkyl group, imidazolyl Lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group may be substituted with a lower alkyl group), pyrazolyl lower alkyl group, pyrimidinyl lower alkyl group, pyridazinyl lower alkyl group, pyridyl lower alkyl group ( The pyridyl portion of the pyridyl lower alkyl group may be substituted with a lower alkyl group or an oxide group), a carboxyl group,
Lower alkoxycarbonyl group, halogen atom, hydroxy lower alkyl group, carboxyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, aryl lower alkoxy lower alkyl group (wherein the aryl part of the aryl lower alkoxy lower alkyl group is substituted with a halogen atom, ), An amino group-protecting group, an amino group which may be substituted with a lower alkyl group, a cyclo-lower alkyl group, an N-pyridyl-N-lower alkylcarbamoyl group,
Lower alkenyl group, halogeno lower alkenyl group, and aryl group (the aryl group is a trifluoromethyl group,
The compound according to claim 19, which is a group represented by a lower alkoxy group and a group selected from a group selected from a nitro group). 21. R ³⁰ is of the formula: embedded image And R ³¹ in the above formula is a lower alkyl group, a pyridyl lower alkyl group (the pyridyl portion of the pyridyl lower alkyl group may be substituted with a lower alkyl group), a thiazolyl lower alkyl group ( The thiazolyl moiety of the thiazolyl lower alkyl group may be substituted with a lower alkyl group) or a phenyl lower alkyl group (the phenyl moiety of the phenyl lower alkyl group may be substituted with a lower alkyl group). 20
The described compound. 22. (1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (1-methylamino-2-nitrovinylamino) propyl] -4
-[4- [1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazine-
1-yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2 '
-[3- (1-Amino-2-nitrovinylamino) propyl] -4- [4- [1- (2-nitrobenzyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α,
4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (N-normalbutylureido) propyl] -4- [4- [1- (2-nitrobenzyl)- 1
H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α,
4β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (N-ethylureido) propyl]-
4- [4- [1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-3 ', 4'-dihydro-6', 7'-dimethoxy-
2 '-[3- (3-Dimethylamino-3-cyclobuten-1,2-dione-4-yl) aminopropyl] -4-
[4- [1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2 '
-[3- (3-methylamino-3-cyclobutene-1,
2-dione-4-yl) aminopropyl] -4- [4-
[1- (2-nitrobenzyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline], (1α, 4β) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-2'-[3
-(3-amino-3-cyclobutene-1,2-dione-
4-yl) aminopropyl] -4- [4- [1- (2-
Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-2'-[3- (1-amino-
2,2-Dicyanovinylamino) propyl] -4- [4
-[1- (2-Nitrobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-2 '
-[3- (1,3-dimethyl-2-cyanoguanidino)
Propyl] -4- [4- [1- (2-nitrobenzyl)
-1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-2 '-[3- (N-isopropylamino)
Propyl] -4- [4- [1- (2-nitrobenzyl)
-1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-2 '-(N, N-dimethylaminoacetyl) -4- [4- [1- (2-nitrobenzyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2′-ethyl-4- [4- [1- (3-methylbenzyl) -1H-pyrazolo [3,4-d] pyrimidine -4-
Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -3 ′, 4′-dihydro-6 ′, 7′-
Dimethoxy-2′-methyl-4- [4- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane- 1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ′, 4′-dihydro-
6 ', 7'-dimethoxy-2'-[3- (N-ethoxycarbonylamino) propyl] -4- [4- [1- (2
-Bromobenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4β ) -3 ', 4'-Dihydro-6', 7'-dimethoxy-2 '-[3- (N-ethoxycarbonylamino) propyl] -4- [4- [1-
(2-Chlorobenzyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -3 ′, 4′-
Dihydro-6 ', 7'-dimethoxy-2'-[3- (N
-Ethoxycarbonylamino) propyl] -4- [4-
[1- (2-cyanobenzyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline], (1α, 4β) -3 ′,
4'-dihydro-6 ', 7'-diethoxy-2'-methyl-4- [4- [1- (3-nitrobenzyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4
β) -3 ′, 4′-dihydro-6 ′, 7′-diethoxy-2′-methyl-4- [4- [1- (3-chlorobenzyl) -1H-pyrazolo [3,4-d] pyrimidine -4-
Yl] piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
Or a pharmaceutically acceptable salt thereof. 23. (1α, 4β) -3 ′, 4′-Dihydro-6 ′, 7′-dimethoxy-2 ′-[3- (N, N-dimethylamino) propionyl] -4- [4- ( 1- (3
-Methylbenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4β ) -3 ', 4'-Dihydro-6', 7'-dimethoxy-2 '-[3- (N, N-dimethylamino) propionyl] -4- [4- (1- (3-
Methoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -3 ', 4'-dihydro-6', 7'-dimethoxy-2 '-[2- (N, N-dimethylamino) ethyl] -4- [4- (1- (6-methylpyridine-2- Ilmethyl) -1H-pyrazolo [3,4
-D] pyrimidin-4-yl) piperazin-1-yl]
Carbonyl-spiro [cyclohexane-1,1 '(2'
H) -isoquinoline], (1α, 4β) -3 ′, 4′-
Dihydro-6 ', 7'-diethoxy-2'-[2-
(N, N-Dimethylamino) ethyl] -4- [4- (1-
(6-Methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-3 ', 4'-dihydro-6', 7'-diethoxy-
2 '-(N, N-dimethylaminoacetyl) -4- [4-
(1- (3-methylbenzyl) -1H-pyrazolo [3,
4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′
(2′H) -isoquinoline], (1α, 4β) -3 ′,
4'-dihydro-6 ', 7'-dimethoxy-4- [4-
(1- (3-Ethoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6'-methoxy-4- [4-
(1- (3-Ethoxybenzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
2 '-(N-methylaminoacetyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- (1-
(3-Ethoxybenzyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) isoquinoline], (1α, 4β) -2 ′-(N-methylaminoacetyl) -3 ′, 4′-dihydro-6 ′,
7'-dimethoxy-4- [4- (1- (3-trifluoromethoxybenzyl) -1H-pyrazolo [3,4-d]
Pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) isoquinoline], (1α, 4β) -2 ′-(N-methylaminoacetyl) -3 ′, 4'-dihydro-6 ', 7'-
Dimethoxy-4- [4- (1- (6-ethylpyridine-
2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) isoquinoline], (1α, 4β) -3 ', 4'-dihydro-
6 ', 7'-dimethoxy-4- [4- (1- (6-n-
Propylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) isoquinoline], (1α, 4β) -2'
-(N, N-Dimethylaminoacetyl) -3 ', 4'-dihydro-6'-ethoxy-4- [4- (1- (6-ethoxypyridin-2-ylmethyl) -1H-pyrazolo [3,4 -D] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 ′ (2′H) isoquinoline], or a pharmacologically acceptable salt thereof. 24. (1α, 4β) -2′-methyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- (3-Methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-diethoxy-4-
[4- (1- (3-ethoxyphenylmethyl) -1H-
Pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4
β) -2′-methyl-3 ′, 4′-dihydro-6 ′,
7'-diethoxy-4- [4- (1- (6-methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -2 ′-(N,
N-dimethylaminoacetyl) -3 ', 4'-dihydro-6'-methoxy-4- [4- (1- (6-methylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-
d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -3 ′, 4′-
Dihydro-6 ', 7'-dimethoxy-4- [4- (1-
(6-Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-3 ', 4'-dihydro-6', 7'-diethoxy-4
-[4- (1- (6-Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -2′-methyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- (1- (6-ethylpyridin-2-ylmethyl) -1H-pyrazolo [ 3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
2'-methyl-3 ', 4'-dihydro-6', 7'-diethoxy-4- [4- (1- (6-ethylpyridine-2
-Ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1α, 4β) -2′-ethyl-3 ′, 4 ′
-Dihydro-6 ', 7'-dimethoxy-4- [4- (1
-(6-Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], (1α, 4β)
-2'-dimethylaminoacetyl-3 ', 4'-dihydro-6', 7'-diethoxy-4- [4- (1- (6-
Ethylpyridin-2-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine-1
-Yl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], (1α, 4β)-
3 ', 4'-dihydro-6', 7'-dimethoxy-4-
[4- (1- (2-ethylthiazol-4-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-
Yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
(1α, 4β) -2′-dimethylaminoacetyl-
3 ', 4'-dihydro-6'-ethoxy-4- [4-
(1- (6-methylpyridin-2-ylmethyl) -1H
-Pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4
β) -2′-dimethylaminoacetyl-3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-4- [4- (1-
(2-Methylthiazol-4-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazin-1-yl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], or a pharmaceutically acceptable salt thereof. 25. 2 '-[3- (Methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-
2- (2-ethyl-1,2,3,4-tetrahydro-6,7
-Dimethoxy-1-isoquinolyl) -4- [4- [1-
(4-Pyridylmethyl) -1H-pyrazolo [3,4-
d] Pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H)-
Isoquinoline], 2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-
1-isoquinolyl) -4- [4- [1- (2-pyridylmethyl) -1
H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], 2 '-[3- (methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2-
(2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (3-pyridylmethyl))
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-[3- (methylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy
-2- (2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (4-n-butyl-4)
H-imidazo [4,5-b] pyrimidin-7-yl)-
1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], 2'-[3- (methylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1) , 2,3,4-tetrahydro-6,
7-Dimethoxy-1-isoquinolyl) -4- [4- (3-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro
[Cyclohexane-1,1 '(2'H) -isoquinoline], 2'-
[3- (Methylamino) propionyl] -3 ′, 4′-dihydro-6 ′, 7′-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1 -Isoquinolyl) -4-
[4- (1-n-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline],
2 '-[3- (Methylamino) propionyl] -3', 4'-dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,
4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)-
4- [4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H ) -Isoquinoline], 2 '-[3- (methylamino) propionyl]
-3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl
-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (3-methylphenylmethyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-[3- (methylamino)
Propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy
-2- (2-Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- (1-n-butyl-
1H-pyrazolo [3,4-d] pyrimidin-4-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-(3-aminopropyl) -3', 4'-dihydro-6 ', 7'-dimethoxy-4- [4- [1- (2-pyridylmethyl)- 1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-
1,1 '(2'H) -isoquinoline], 2'-(3-aminopropyl) -3 ', 4'-dihydro-6', 7'-
Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline],
2 '-[3- (2-cyano-3,3-dimethylguanidino) propyl] -3', 4'-dihydro-6 ', 7'-
Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4
-Yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline],
2 '-[3- (1-dimethylamino-2-nitro-vinylamino) propyl] -3', 4'-dihydro-6 ',
7'-dimethoxy-4-[[4- [1- (2-chlorophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl]-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-(3-aminopropyl) -3 ′, 4 ′
-Dihydro-6 ', 7'-dimethoxy-4- [4- [1
-(2-Bromophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], 2 '-[3- [N- (propionyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], 2'
-[3- [N- (pivaloyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3 ',
4'-dihydro-6 ', 7'-dimethoxy-2- (2-
Ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-
Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-
Spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- [N- (pivaloyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3 ′, 4′- Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
Isoquinolyl) -4- [4- (3-methyl-3H-1,2,2
3-triazolo [4,5-d] pyrimidin-7-yl) -1
-Piperazinyl] carbonyl-spiro [cyclohexane-1,
1 '(2'H) -isoquinoline], 2'-[3- [N- (cyclopropylcarbonyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3 ', 4'
-Dihydro-6 ', 7'-dimethoxy-2- (2-ethyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4- Pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], 2 ′-[3- (Pivaloyloxymethyloxycarbonylamino) propyl] -3 ', 4'-dihydro-
6 ', 7'-Dimethoxy-4- [4- [1- (2-nitrophenylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane -1,1 '(2'H) -isoquinoline], (1α, 4β) -3', 4'-dihydro-6 ',
7'-dimethoxy-4- [4- [1- (3-nitrobenzyl)-
1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′
(2'H) -isoquinoline], (1α, 4β) -2'-dimethylaminoacetyl-3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4- [1- (3-methyl Benzyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2 ′
H) -isoquinoline], (1α, 4β) -2′-methyl-
3 ', 4'-dihydro-6', 7'-dimethoxy-4- [4-
(3-Methyl-3H-1,2,3-triazolo [4,5-
d] pyrimidin-7-yl) -1-piperazinyl] carbonyl
-Spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1α, 4β) -2'-ethyl-3', 4'-dihydro-
6 ', 7'-Diethoxy-4- [4- [1- (2-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane- 1,1 '(2'H) -isoquinoline], or a pharmacologically acceptable salt thereof. 26. (1R ^* , 2R ^* (S ^* ), 4R ^* )-2'-
[3- (Methylamino) propionyl] -3 ', 4'-dihydro-6', 7'-dimethoxy-2- (2-ethyl-1,
2,3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4-
Iyl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 ′ (2′H) -isoquinoline], (1
R ^* , 2R ^* (S ^* ), 4R ^* )-2 '-[3- [N- (propionyloxymethyloxycarbonyl) -N-methylamino] propionyl] -3', 4'-dihydro-
6 ', 7'-dimethoxy-2- (2-ethyl-1,2,
3,4-Tetrahydro-6,7-dimethoxy-1-isoquinolyl) -4- [4- [1- (4-pyridylmethyl)
-1H-Pyrazolo [3,4-d] pyrimidin-4-yl] -1-piperazinyl] carbonyl-spiro [cyclohexane-1,1 '(2'H) -isoquinoline], (1
α, 4β) -2'-methyl-3 ', 4'-dihydro-6',
7'-dimethoxy-4- [4- (3-methyl-3H-1,2,2
3-triazolo [4,5-d] pyrimidin-7-yl) -1-piperazinyl] carbonyl-spiro [cyclohexane-1 ,,
1 '(2'H) -isoquinoline], or a pharmaceutically acceptable salt thereof. 27. The general formula [II-A]: [Chemical 18] (In the formula, ring A is an optionally substituted benzene ring, R
¹⁰Is a hydrogen atom or -Z-R¹Is a group represented by
R¹Is a hydrogen atom, an optionally substituted lower alkyl group
Or an optionally substituted lower alkenyl group, Z is-
CH_TwoA group represented by -or -CO-, R^TwoIs a hydrogen atom
Or an optionally substituted heterocyclic group, R ⁶Is hydrogen
Represents a child, a lower alkyl group or a benzyl group)
Or a salt thereof, and a compound of the general formula [16]: R^Three-H [16] (In the formula, R^ThreeIs an optionally substituted amino group or
Represents an optionally substituted nitrogen-containing aliphatic heterocyclic group)
By reacting with the indicated compound or a salt thereof, if desired
Characterized in that the product is a pharmacologically acceptable salt
General formula [Ia]: [Chemical 19] (However, the symbols have the same meaning as above)
A process for producing a compound or a pharmaceutically acceptable salt thereof. 28. General formula [II-c]: (In the formula, ring A is an optionally substituted benzene ring, R ²
Is a hydrogen atom or an optionally substituted heterocyclic group, R
⁶ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a salt thereof, and a compound represented by the general formula [9]: XZR ¹ [9] (wherein R ¹ is a hydrogen atom or a substituted An optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, Z is a group represented by —CH ₂ — or —CO—, and X is a leaving group) or a salt thereof. After reaction, the compound of the general formula [II-b]: (Where the symbols have the same meaning as described above), and then the product [II-b] and the general formula [16]: R ³ —H [16] (wherein R ³ is substituted) (Representing an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof, and reacting the product with a pharmacologically acceptable salt if desired. Wherein the general formula [Ie] is: (However, the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 29. General formula [If]: embedded image (In the formula, ring A is an optionally substituted benzene ring, R ²
Is a hydrogen atom or an optionally substituted heterocyclic group, R
³ represents an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof, and a compound represented by the general formula [9]: XZR ¹ [ 9] (In the formula, R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, Z is a group represented by —CH ₂ — or —CO—, and X is a A compound represented by a leaving group) or a salt thereof is reacted with the compound to form a pharmacologically acceptable salt, if desired, and represented by the general formula [I-e]: (However, the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 30. A compound represented by the general formula [II-c]: (In the formula, ring A is an optionally substituted benzene ring, R ²
Is a hydrogen atom or an optionally substituted heterocyclic group, R
⁶ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a salt thereof;
6]: a compound represented by R ³ —H [16] (in the formula, R ³ represents an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group) or a salt thereof. To react with the general formula [I
-F]: (Where the symbols have the same meanings as described above), and then the product [If] and general formula [9]: XZR ¹ [9] (wherein R ¹ represented by groups represented by or -CO-, X represents a leaving group) _- a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, Z is -CH 2 is A compound of the general formula [I-e]: embedded image characterized by reacting a compound or a salt thereof with the product to form a pharmacologically acceptable salt if desired. (However, the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 31. A compound represented by the general formula [Ie]: (In the formula, ring A is an optionally substituted benzene ring, R ¹
Is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, and Z is -CH.
A group represented by _2- or -CO-, R ² is a hydrogen atom or an optionally substituted heterocyclic group, R ³ is an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic group A compound represented by a heterocyclic group) or a salt thereof is reduced, and the product is optionally converted into a pharmacologically acceptable salt. [Formula [Ib]] (However, the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 32. The general formula [Ic]: [Chemical 30] (In the formula, ring A is an optionally substituted benzene ring, R^Four
Is a hydrogen atom or a lower alkyl group, n is an integer of 1 to 6,
Z is -CH_TwoA group represented by -or -CO-, R ^TwoIs water
An elementary atom or an optionally substituted heterocyclic group, B is [Chemical 31] A group represented by R^ThreeIs an optionally substituted amino group
Or an optionally substituted nitrogen-containing aliphatic heterocyclic group, Y
Is -CH_TwoRepresents a group represented by -or -CO-)
Or a salt thereof, and a compound of the general formula [17]: [Chemical 32] (In the formula, X¹Is a leaving group, R⁵¹Is a hydrogen atom or a lower atom
Rukiru group, R⁵²Is substituted with a carboxyl group
Good lower alkyl, cyclo lower alkyl, lower alkyl
Coxy group, cyclo lower alkoxy group or aryl group
Represented by the formula) or a salt thereof,
If desired, the product may be characterized as a pharmaceutically acceptable salt.
General formula [Id₁]: [Chemical 33] (However, the symbols have the same meaning as above)
A process for producing a compound or a pharmaceutically acceptable salt thereof. 33. General formula [Ic]: [Chemical 34] (In the formula, ring A is an optionally substituted benzene ring, R^Four
Is a hydrogen atom or a lower alkyl group, n is an integer of 1 to 6,
Z is -CH_TwoA group represented by -or -CO-, R ^TwoIs water
An elementary atom or an optionally substituted heterocyclic group, B is [Chemical 35] A group represented by R^ThreeIs an optionally substituted amino group
Or an optionally substituted nitrogen-containing aliphatic heterocyclic group, Y
Is -CH_TwoRepresents a group represented by -or -CO-)
Or a salt thereof, and a compound of the general formula [18]: [Chemical 36] (In the formula, X¹Is a leaving group, R⁵¹Is a hydrogen atom or a lower atom
Rukiru group, X^TwoRepresents a halogen atom)
With a compound of the general formula [Id₇]: [Chemical 37] (However, the symbols have the same meaning as above)
And then the product [Id₇] And the general formula
[19]: R⁵²-COOH [19] (In the formula, R⁵²May be substituted with a carboxyl group
Lower alkyl group, cyclo lower alkyl group, lower alcohol
Represents an oxy group, a cyclo-lower alkoxy group or an aryl group.
Reaction) with a compound represented by
More characterized in that the product is a pharmacologically acceptable salt
Of the general formula [Id₁]: [Chemical 38] (However, the symbols have the same meaning as above)
A process for producing a compound or a pharmaceutically acceptable salt thereof. 34. General formula [II-B]: (In the formula, ring A is an optionally substituted benzene ring, R
¹⁰ is a hydrogen atom or a group represented by -Z-R ¹ ,
R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, and Z is
A group represented by CH ₂ — or —CO—, R ² represents a hydrogen atom or an optionally substituted heterocyclic group) or a salt thereof, and a compound represented by the general formula [16]: R ³ —H [16] The compound represented by the formula (wherein R ³ represents an optionally substituted amino group or an optionally substituted nitrogen-containing aliphatic heterocyclic group), or a salt thereof, in the presence of a phosgene equivalent. The compound of the general formula [I-g]: embedded image (However, the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 35. The general formula [II-A]: [Chemical 41] (In the formula, ring A is an optionally substituted benzene ring, R
¹⁰Is a hydrogen atom or -Z-R¹Is a group represented by
R¹Is a hydrogen atom, an optionally substituted lower alkyl group
Or an optionally substituted lower alkenyl group, Z is-
CH_TwoA group represented by -or -CO-, R^TwoIs a hydrogen atom
Or an optionally substituted heterocyclic group, R ⁶Is hydrogen
Represents a child, a lower alkyl group or a benzyl group)
A spiroisoquinoline derivative or a salt thereof. 36. A compound represented by the general formula [II-B]: (In the formula, ring A is an optionally substituted benzene ring, R
¹⁰ is a hydrogen atom or a group represented by -Z-R ¹ ,
R ¹ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group, and Z is
A spiroisoquinoline derivative represented by a group represented by CH ₂ — or —CO—, R ² represents a hydrogen atom or an optionally substituted heterocyclic group, or a salt thereof. 37. A compound represented by the general formula [28]: (In the formula, D ¹ and D ² are the same or different and are a group represented by -N = or -CH =, and ^one of E ¹ and E ² is-
A group represented by N =, the other group represented by -N = or -CH =, R ³¹ represents a hydrogen atom, an oxo group, an oxide group, a lower alkyl group, a cyano lower alkyl group, a cyclo lower alkyl lower alkyl group (The carbon atom on the cyclo lower alkyl group may be substituted with a sulfur atom), pyrrolidinyl carbonyl lower alkyl group, halogeno lower alkyl group, lower alkylthio lower alkyl group, aryl lower alkyl group (the aryl lower alkyl group) The aryl moiety of is derived from a lower alkyl group, a lower alkoxy group, a (mono- or di-) lower alkylamino group, a lower alkoxy lower alkyl group, a halogen atom, a trihalogenomethyl group, a trihalogenomethoxy group, a nitro group, and a cyano group. It may be substituted with a selected group), a thienyl lower alkyl group (the The thienyl portion of the lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group, a furyl lower alkyl group (the furyl portion of the furyl lower alkyl group is a lower alkyl group and a (mono- or di- -) Optionally substituted with a group selected from lower alkylamino lower alkyl group), imidazolyl lower alkyl group, thiazolyl lower alkyl group (the thiazolyl portion of the thiazolyl lower alkyl group is a lower alkyl group, a hydroxy group, (mono- Or di-) may be substituted with a group selected from a lower alkylamino group and a lower alkoxy lower alkyl group), a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group (the pyrimidinyl portion of the pyrimidinyl lower alkyl group is a lower alkyl group) May be substituted), Ridajiniru lower alkyl group, a pyridyl pyridyl moiety of the lower alkyl group (said pyridyl lower alkyl group is a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkoxy-lower alkyl group, (mono- - or di -) lower alkylamino group,
Substituted with a group selected from a lower alkoxycarbonyl group, a (mono- or di-) lower alkylcarbamoyl group, a (mono- or di-) lower alkylamino lower alkyl group, a hydroxy lower alkyl group, an oxo group and an oxide group. ), A carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a hydroxy lower alkyl group, a carboxyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an aryl lower alkoxy lower alkyl group (the aryl part of the aryl lower alkoxy lower alkyl group is Optionally substituted with a halogen atom), an amino group-protecting group, an amino group optionally substituted with a lower alkyl group, a cyclo lower alkyl group, an N-pyridyl-N-lower alkylcarbamoyl group, a lower alkenyl group, Lower halogeno A compound or a salt thereof represented by a lukenyl group and an aryl group (the aryl group represents a group selected from a trifluoromethyl group, a lower alkoxy group, and a nitro group) , The general formula [29]: (Wherein G represents an amino-protecting group) or a salt thereof is reacted with the product to form a salt if desired, and the compound is represented by the general formula [III]: (However, symbols have the same meanings as described above), or a method for producing a salt thereof.