CN1074214A - The preparation method of isoquinoline sulfone amide derivative - Google Patents

The preparation method of isoquinoline sulfone amide derivative Download PDF

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CN1074214A
CN1074214A CN 92115101 CN92115101A CN1074214A CN 1074214 A CN1074214 A CN 1074214A CN 92115101 CN92115101 CN 92115101 CN 92115101 A CN92115101 A CN 92115101A CN 1074214 A CN1074214 A CN 1074214A
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CN1028638C (en
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日高弘义
石川智彦
荻原正敏
井上勗
内藤贤治
佐久间修
汤浅雅之
森田正
利冈佶
梅泽勋
稻叶隆之
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Tobishi Pharmaceutical Co Ltd
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Abstract

The invention relates to the preparation method of isoquinoline sulfone amide derivative.The step that this method comprises sees specification sheets for details.
Said isoquinoline sulfone amide derivative has vascular smooth muscle relaxation usefulness, and platelet aggregation suppresses usefulness and to the inhibition usefulness of protein kinase A, myosin light chain kinase, protein kinase C and calmodulin dependent protein kinase ii, but little to the effect of cardiac stimulant function.

Description

The preparation method of isoquinoline sulfone amide derivative
The present invention relates to have the loose active compound of vessel smooth muscle, Preparation Method And The Use.
The existing narration of quinoline compound with vessel smooth muscle relaxation activity is as Japanese Patent office prospectus (KOKAI), JP-60-81168,61-126026,61-271221,61-293914,62-103066 and 63-211267; With U.S. Pat 4456757,4525589,4560755,4634770,4678783,4709032 and 4798897.
In the described compound of above-mentioned reference, some has gratifying smooth muscle relaxation activity, but has the problem that relates to toxicity, organ specificity and security.
Therefore, the purpose of this invention is to provide novel cpd, they have gratifying smooth muscle relaxation activity, hypotoxicity, the security of good organ specificity and height.
More particularly, the invention provides the compound that a kind of chemical formula I is represented:
Figure 921151012_IMG6
Y represents N in the formula, H 3C-N or CH;
R 1The expression hydrogen atom, the optional low alkyl group that replaces, formyl radical, halogeno-benzene propargyl, optional aralkyl that replaces or the optional phenyl that replaces; And
(1) R 2Represent a group by chemical formula II representative:
Figure 921151012_IMG7
In the formula, R 3Represent hydrogen atom, the optional low alkyl group that replaces, formyl radical, halogeno-benzene propargyl, optional aralkyl that replaces or the optional phenyl that replaces; Or R 1And R 3The formation low-grade alkylidene connects together;
R 4Represent hydrogen atom or low alkyl group;
R 5Represent hydrogen atom, halogen atom, nitro, low alkyl group, the optional hydroxyl that replaces, the optional N substituted-amino that replaces, the optional carboxyl that replaces, the low alkyl group that polyfluoro replaces, cyano group, methylol, methylthio group, methanesulfinyl or methylsulfonyl;
R 6Represent hydrogen atom, halogen atom or lower alkoxy; Or
R 5And R 6Connect together and form rudimentary alkylene dioxo base;
R 7Represent hydrogen atom or lower alkoxy;
X represents vinylene or ethynyl;
Ar represents phenyl, naphthyl or a heterocyclic radical;
M is 1～3 integer; And
W represents low-grade alkylidene, optional phenylene that replaces or the optional phenylene-low-grade alkylidene that replaces; Perhaps
(2) R 2A group representing chemical formula III to represent:
Figure 921151012_IMG8
In the formula, R 10Represent hydrogen atom, nitro, the optional amino that replaces, the optional hydroxyl that replaces, low alkyl group, or halogen atom; Perhaps R 1And R 10The formation low-grade alkylidene connects together;
R 11Represent hydrogen atom, hydroxyl or lower alkoxy;
R 12And R 13Each represents a hydrogen atom, or common representative=0;
The same connotation that Ar tool chemistry formula II is limited;
N is 1～3 integer; And
A representative=CR 14R 15Or=NR 14; R wherein 14Represent hydrogen atom, the optional hydroxyl that replaces, optional substituted-phenyl, acyl group, substituted carbonyl, optional substituted alkoxycarbonyl replaces carbamyl, optional substituted-amino, arylsulfonyl, sweet-smelling alkane sulfonyl, aralkyl, or a heterocyclic radical; And
R 15Represent hydrogen atom or lower alkoxy, perhaps R 15And R 14Common be alkylene dioxo base or be=O;
And provide the non-toxic salt of compound shown in the quaternary ammonium salt of compound shown in the chemical formula I and the formula I.
The present invention also provides a kind of technology, preparation R 2Be the chemical formula I representative compound of group shown in the chemical formula II, this technology comprises that step is as follows:
(1) compound of compound of representing with chemical formula IV and formula (V) expression reacts:
Figure 921151012_IMG9
Y in the formula, W, R 1And R 3It is identical with the top implication that limits,
Figure 921151012_IMG10
B representative-CH in the formula 2Hal or-COR 4, other symbols limit according to claim 1;
And washability ground
(2) the made compound of reduction step (1), and/or randomly
(3) with step (1) or (2) made alkylation or formylation.
The present invention especially provides the technology of compound shown in a kind of formula I, the R in this compound 2Be the group that formula II is represented, comprise that step is:
(1) with the compound of formula VI and formula (VII) but compound or its response derivative or salt carry out instead
Figure 921151012_IMG11
Wherein, all symbols are the same implication that limits previously in formula VI and (VII); Selectively
(2) alkylation that step (1) is made.
The present invention further provides a kind of preparation technology of compound of formula I representative, in this compound, according to claim 1, R wherein 2Be the group that formula III is represented, comprise that step is:
(1) make the compound of formula (VIII) and the compound of formula (VII), but or its response derivative or salt react:
Figure 921151012_IMG12
Wherein, interior all symbols of formula (VII) and formula (VIII) are all with top qualification;
And selectively carry out the one or more steps in following step (2)～(8),
(2) hydrolysis generates free hydroxyl or an amino;
(3) with hydroxyl or amino protecting group deprotection;
(4) with the earbalkoxylation of hydroxyl or amino acidylate or replacement;
(5) with hydroxyl or aminoalkyl groupization;
(6) with carbonyl amination or hydroxylation;
(7) nitroreduction is become amino;
(8) with the acetal carbonylation.acelat
The present invention also provides the pharmaceutical compositions that comprises above-claimed cpd.
In definition of the present invention, the optional low alkyl group that replaces comprises the low alkyl group that does not replace and replace." low alkyl group " refers to contain at the most the alkyl of seven carbon atoms, and the person is good to contain the four carbon atom at the most.Unsubstituted low alkyl group comprises the low alkyl group of straight chain and side chain, for example is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl and heptyl.
At R 1And R 3Definition in, the low alkyl group of replacement comprises optional substituted-amino low alkyl group, as 2-aminoethyl and 3-aminopropyl, N, N-dimethylaminopropyl, 4-piperidyl low alkyl group such as 4-piperidines propyl group, morpholino low alkyl group such as morpholino ethyl and piperidino-(1-position only) low alkyl group such as piperidino-(1-position only) ethyl.The halogeno-benzene propargyl comprises fluorine, chlorine, bromine and phenyl-iodide propargyl, being good to the chlorobenzene propargyl.The optional aralkyl that replaces comprises unsubstituting aromatic alkyl, and for example phenyl lower alkyl such as benzyl and styroyl also comprise such as the substituted-phenyl low alkyl group to methoxybenzyl.The optional phenyl that replaces comprises substituted-phenyl as 3, the 4-dimethoxy phenyl.By R 1And R 3The alkylidene group that forms for example is methylene radical, ethylidene or propylidene.
R 4The same qualification of low alkyl group.
R 5Halogen atom be fluorine, chlorine, bromine or iodine; Chlorine preferably.
R 5Low alkyl group be defined as above.
R 5Optional substituted hydroxy comprise hydroxyl and substituted hydroxy, for example lower alkoxy such as methoxyl group, oxyethyl group or propoxy-.
R 5Optional N substituted-amino be amino or lower alkyl amino, as dimethylamino.
R 5Optional replacement carboxyl comprise carboxyl itself and replace carboxyl, lower alkoxycarbonyl for example, as methoxycarbonyl, the ethoxycarbonyl and the third oxygen carbonyl.
R 5Polyfluoro replace low alkyl group, for example be trifluoromethyl.
R 6Halogen atom such as R 5Defined in.
R 6Lower alkoxy such as R 5Defined in.
R 5And R 6The rudimentary alkylene dioxo base that forms for example is a methylene-dioxy, ethylenedioxy, 1, the 3-two inferior third dioxy bases, 1, the 2-two inferior third dioxy base or its analogue, preferably ethylenedioxy.
R 7Lower alkoxy such as R 5Defined in.
The low-grade alkylidene of W for example is methylene radical, ethylidene, trimethylene or tetramethylene.
The phenylene of W for example is 1,2-phenylene or 1,3-phenylene.The phenylene low-grade alkylidene of W, for example be 1,2 phenylene-or 1,3 phenylene-low alkyl group as 1,2-or 1, the inferior styrene of 3-.The optional substituting group of phenylen moiety for example is a lower alkoxycarbonyl, weevil oxygen carbonyl.
The heterocyclic radical of Ar for example is a pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, and pyrryl such as 2-pyrryl or 3-pyrryl, sulfinyl such as 2-sulfinyl or 3-sulfinyl, perhaps furyl such as 2-furyl or 3-furyl.
As R 10Optional substituted-amino comprise free amino group and substituted-amino.In substituted-amino, substituent example has low alkyl group such as methyl, ethyl, propyl group or as above other low alkyl group of defined, and replaces sulfo group such as isoquinoline 99.9 sulfo group, naphthalene sulfo group, first sulfo group, toluene sulfo group.Therefore, substituted-amino for instance, be isoquinoline sulfonaide, N-low alkyl group isoquinoline sulfonaide such as N-sulfonyloxy methyl amine, naphthalene sulfonylamide, N-low alkyl group naphthalene sulfonylamide such as N-methylnaphthalene sulphonamide, Toluidrin, N-low alkyl group Toluidrin, N-methyl Toluidrin, toluol sulfonamide, perhaps N-low alkyl group Toluidrin such as N-methyl Toluidrin.Substituted-amino is phthalic imidine also.
As R 10Substituted hydroxy comprise ester, ether and protected hydroxyl.Ester has the sulfonyloxy of replacement such as isoquinoline 99.9 sulfonyloxy, tosyloxy or naphthalene sulfonyl oxygen base, perhaps lower alkanoyloxy such as acetoxyl group, propionyloxy or butyryl acyloxy for instance.Ether is lower alkoxy such as methoxyl group, oxyethyl group or propoxy-for instance; Aralkoxy such as benzyloxy; Lower alkanoyloxy-lower alkoxy such as acetoxyl group methoxyl group; Perhaps heterocycle-lower alkoxy such as 2-pyridyl methoxyl group or 4-pyridyl methoxyl group.
As R 10Low alkyl group be as above defined person.As R 10Halogen be as above defined person.As R 10Lower alkoxy for as above to R 5The defined person.As R 10Halogen for as above to R 5The defined person.As Ar 2Heterocyclic radical, be imidazolyl such as 4-imidazolyl for instance.
As R 14Substituted hydroxy, be the lower alkoxy of ether such as top defined for instance, perhaps optional aralkyl that replaces such as phenyl take up an official post phenyl-low alkyl group of choosing generation such as benzyl, hydrocinnamyl, 4-methyl-benzyl, 3, the 4-dichloro benzyl, perhaps ester group, for example lower alkanoyloxy such as acetoxyl group or propionyloxy.
As R 14Substituted-phenyl, for example be lower alkyl phenyl such as 3-aminomethyl phenyl, the lower alkoxy benzyl is as 2,3-or 4-p-methoxy-phenyl, a halo or dihalogenated phenyl such as 4-chloro-phenyl-, 3,4-dichlorophenyl.
As R 14Acyl group, be acyl phenyl such as benzoyl for instance, perhaps aromatic alkyl carbonyl such as benzyloxycarbonyl group or phenyl propyl carbonyl.
Substituted alkoxycarbonyl R 14, be phenyl-lower alkoxycarbonyl such as benzyloxycarbonyl, perhaps tert-butoxycarbonyl for instance.
Substituted carbonyl is aryl carbonyl such as phenylcarbonyl group, perhaps aromatic alkyl carbonyl such as benzyloxycarbonyl group for instance.
Substituted-amino R 14Be low-grade alkyl amino for instance, optional aralkylamine or the N that replaces, the rudimentary aryl alkyl amino of N-, for example methylamino, benzylamino, 3,4-dichloro benzyl amino, N, N-methyl-benzyl amino or N, N-methyl 3,4-two chloro amidos.
Aryl sulfonyl R 14For instance, be benzyl alkylsulfonyl, isoquinolinesulfonylcompounds.
Aralkyl alkylsulfonyl R 14For instance, be benzyl alkylsulfonyl or phenyl propyl alkylsulfonyl.
Aralkyl R 14Be benzyl or phenyl propionyl for instance.
Heterocyclic radical R 14For instance, be pyridyl such as 2-pyridyl, perhaps pyrimidyl such as 2-pyrimidyl.
Because in the The compounds of this invention nitrogen-atoms is arranged, thus quaternary ammonium salt can be formed, or salt such as non-toxic salt.For generating quaternary ammonium salt, compound of the present invention is for example reacted with methyl-iodide.Salt of the present invention is preferably non-toxic salt, for example inorganic acid salt example hydrochloric acid salt, vitriol, nitrate, phosphoric acid salt, hydrogen bromide salt, iodine hydrohalogenic acid salt etc., and organic acid salt such as Citrate trianion, acetate, oxalate, tartrate, sulfonate such as mesylate, esilate, benzene sulfonate, fumarate, maleate, malate etc.
In producing an embodiment of The compounds of this invention, the compound that makes logical as mentioned above formula IV representative reacts with the compound of general formula (V) representative as mentioned above.
In the preferable embodiment of this scheme, make wherein R 1And R 3Represent the logical formula IV representative compound of hydrogen atom to react, and after reaction, the intermediate product of gained is derived, for example alkylation or formylation is to introduce R 1And/or R 3
Under a kind of particular case, make general formula (IV ')
Figure 921151012_IMG13
The compound of the same general formula of isoquinoline sulfonaide (V) representative of representative reacts, and when needed, with the intermediate product reduction of gained.Reaction in the medium such as methyl alcohol, dimethyl formamide, tetrahydrofuran (THF), methyl-sulphoxide, diglyme, benzene, is carried out under 0 ℃ to 100 ℃ temperature, for instance at room temperature to carry out to good.Reduction is used such as sodium borohydride, lithium aluminium hydride, carries out under 0 ℃ to 60 ℃ temperature, at room temperature to carry out to good.R 1And/or R 3Introducing, can use R 1And/or R 3Halogenide, i.e. Hal-R 1Or Hal-R 2Carry out, remove hydrogen halide simultaneously.Use alkylene halogen, just generate wherein R 1And R 3The compound that key connects.For introducing formyl radical, intermediate product in the presence of acetic anhydride, is reacted with formic acid.Above-mentioned each reaction all in for example chloroform, N,N-DIMETHYLACETAMIDE, dimethyl formamide or other aprotonic solvent, is carried out under about 0 ℃ to 100 ℃ temperature, at room temperature to carry out to good.
In another embodiment of producing The compounds of this invention, make the compound reaction of the same general formula of compound (VII) of logical formula VI.In preferable embodiment, make R in the logical formula VI 3Be the compound reaction of the same general formula of the compound of hydrogen atom (VII), and after reaction, with the alkylation of gained intermediate product, to introduce R 3
In specific embodiment, make general formula (VI ')
Middle R 16Be the compound reaction of the same general formula of optional substituent compound (VII) on the phenyl moiety W, make by general formula (I-a)
Figure 921151012_IMG15
The compound of representative.
This is reflected at as in the media such as pyridine, dimethyl formamide, acetonitrile, dioxan, tetrahydrofuran (THF), methylene dichloride, chloroform, carries out under 0 ℃ to 40 ℃ temperature, to carry out to good under 20 ℃ to 30 ℃ temperature.
Notice that (I is a) with introducing substituent R to make product 1And/or R 3Compound reaction.Can introduce R 1And/or R 3Compound for example be R 1Or R 3Halide-containing, i.e. Hal-R 1Or Hal-R 3, wherein Hal represents a halogen atom.
This for example is reflected in the media such as tetrahydrofuran (THF), dimethyl formamide, dioxan, methylene diethyl ether, methyl alcohol, ether such as ether, chloroform, ethyl acetate, can in reaction process, neutralize such as pyridine, the dimethyl aminopyridine such as tertiary amine carry out in the presence of the alkali of generation hydrogen halide.Such alkali also has N-methyl piperidine or triethylamine, perhaps mineral alkali such as saleratus, potassium hydroxide, yellow soda ash, sodium hydroxide or the like.
R wherein 3For the raw material (VI) of hydrogen atom can make general formula (VIII)
Figure 921151012_IMG16
The same general formula of the compound of representative (IX)
The compound of representative reacts and prepares.
For example, for making intermediate product (VI '), can make general formula (VIII ')
Figure 921151012_IMG17
The same general formula of the compound of representative (IX ')
Figure 921151012_IMG18
The compound reaction of representative.
These reactions can introduced R together basically 1And R 3The same terms under carry out.
Produce in the embodiment of The compounds of this invention (I) at another, make the compound reaction of the same general formula of compound (VII) of general formula (VIII).
Raw material (VIII) can be through general formula (X)
Figure 921151012_IMG19
Middle R 17Be the same general formula of the compound of hydrogen atom or low alkyl group (XI)
Figure 921151012_IMG20
The compound of representative reacts and makes.
When carrying out this reaction, R in the compound that makes (VIII) 12And R 13Common formation=O.This compound generates wherein R through reduction 12And R 13Be the compound of hydrogen atom.
In specific embodiment, (X a) to make general formula
Figure 921151012_IMG21
(XI a) for representative and the same general formula of amino protected known compound tyrosine
Figure 921151012_IMG22
Representative and the wherein protected piperazine of nitrogen-atoms reaction make that (VIII a) by general formula
Figure 921151012_IMG23
The intermediate product of representative.
Then, (VIII a) again with the condensation of isoquinoline 99.9 SULPHURYL CHLORIDE, makes by general formula (XII) to make this intermediate product
The compound of representative.
Then, can carry out the following modification of this compound (XII), to produce some The compounds of this invention:
(2a) isoquinolinesulfonylcompounds is removed in hydrolysis, makes the hydroxyl free on the benzyl ring;
(3a) make the piperazine ring deprotection;
(4a) make free hydroxyl acidylate and alkylation;
(4a) make piperazine nitrogen-atoms acidylate partly;
(5a) make the sulfonamido alkylation.
For preparing other compound of the present invention, can use Histidine, phenylalanine to wait and replace tyrosine, and/or can use piperidines to wait to replace piperazine.In addition, also can use the alkylating compound of N-replace N-protected compound (II a), and/or can use compound (II a) in the protected compound of hydroxyl.Compound (VIII a) or (XII) can change into the carbonyl structure that is connected on the methene chain through reduction.Ortho position part on the benzyl ring can link to each other with amino via alkylidene chain, forms ring structure.Use piperidines to replace piperazine, piperidines partly can be changed into the corresponding section that on its 4th, has ethylidene ether structure.After the sulfonic acid condensation, acetal (8a) can be by carbonylation, and carbonyl (6a) can change into hydroxyl or amino, hydroxyl (4b) or amino acylable, or hydroxyl (5b) or amino can be obtained some compounds required for the present invention by alkylation.
Being reflected in the medium such as tetrahydrofuran (THF), dioxan, methylene dichloride or other aprotonic solvents of compound (X) and (XI) carried out under about 0～40 ℃ temperature, to carry out to good under 20～30 ℃.
Compound (VII) and (VIII) be reflected at such as methylene dichloride, chloroform, dimethyl formamide or other aprotonic solvents, having in the presence of alkali such as the triethylamine etc., under about 0～40 ℃ temperature, carry out, under 20～30 ℃, to carry out to good.
The hydrolysis of step (2) in the solvent such as methyl alcohol, tetrahydrofuran (THF), the two mixture, methyl-sulphoxide or the like, is carried out having in the presence of alkali such as sodium hydroxide, the potassium hydroxide etc.
The protection again of step (3) is carried out in solvent such as methyl alcohol, ethanol, chloroform, ethyl acetate etc.
The acidylate of step (4) in solvent such as chloroform, tetrahydrofuran (THF), pyridine or its equivalent, is carried out having in the presence of alkali such as the triethylamine.
The alkylation of step (5) is carried out in solvent such as dimethyl formamide, tetrahydrofuran (THF), ethyl acetate, methyl alcohol, methylene dichloride or its mixture.
The hydroxylation of step (6) in protonic solvent such as methyl alcohol or ethanol, is carried out in the presence of reductive agent such as sodium borohydride or sodium cyanoborohydride.The amination of step (6) forms the back in imines and carries out under with hydroxylated condition.Nitroreduction in the step (7), at solvent such as alcohol for example in methyl alcohol or the ethanol, nationality uses and drapes over one's shoulders palladium on noble metal catalyst such as the carbon and make the catalytic hydrogenation of catalyzer and carry out.
Hydroxyacetone is to the conversion of oxidation, and the acidic hydrolysis in the nationality aqueous solution carries out.
Embodiment
Now further illustrate the present invention, but the present invention is not limited to the following example with the following example.
Among many embodiment, fusing point adopts capillary type Yamato MP-21 fusing point survey meter (Yamato Kagaku, Japan) to measure; Nuclear magnetic resonance spectrum ( 1H-NMR) use JEOLJNM-FX200(Nippon Denshi, Japan) nuclear magnetic resonance analyser measures; (Nippon Denshi Japan) measures the mensuration of molecular weight with JMS-D300 type mass spectrograph; Infrared absorption spectrum (IR) is then used IRA-1 type instrument Nippon Bunko Kogyo, Japan) measure.
Reference example 1.1-(N-carbobenzoxy-(Cbz)) histidyl-)-the 4-phenylpiperazine
With 7.13g N, N '-two benzyloxy carbonyl Histidine, 3.00g4-phenylpiperazine and 16.1g N-hydroxybenzotriazole are dissolved in the 100ml tetrahydrofuran (THF), add the DCC(dicyclohexylcarbodiimide of 3.84g in mixture), whole in stirring at room three hours.The filtering insolubles, concentrating under reduced pressure filtrate adds 200ml ethyl acetate reformation crystallization to enriched material, and it is leached.Leach thing and wash in succession, dried over mgso, concentrating under reduced pressure with 20% wet chemical and saturated sodium-chloride water solution.The gained residue is dissolved in 60ml methyl alcohol, add 10% ammonium hydroxide-methanol solution, and after stirring at room 30 minutes, decompression concentrated solution gets residue, then it being carried out silica gel chromatography separates, with chloroform/methanol (50: 1～10: 1) wash-out, get the colourless amorphous title compound of 6.61g.
1H-NMR（CDCl 3，δ PPm）：2.81-3.20（6H，m），3.40-3.82（4H，m），4.95（1H，m），5.09（2H，s），5.78（1H，d，J＝8.3HZ），6.80-6.97（4H，m），7.20-7.30（2H，m），7.34（5H，s），7.55（1H，s）。
Reference example 2.1-(N-(tertbutyloxycarbonyl) histidyl-)-the 4-phenylpiperazine
With 6.61g 1-(N-(carbobenzoxy-(Cbz)) histidyl-)-the 4-phenylpiperazine is dissolved in 80ml methyl alcohol; add the catalyzer that 4g carbon drapes over one's shoulders 5% palladium to this solution under ice-cooled; under the nitrogen atmosphere in stirring at room mixture 20 hours, leaching filtrate, concentrating under reduced pressure gets the 4.26g residue then.Residue is dissolved in the 80ml dimethyl formamide, adds 6.8g tert.-butoxy carboxylic acid anhydride and 10ml triethylamine in succession to this solution, stirring at room mixture 90 minutes.Add the 200ml ethyl acetate to reaction mixture, use the saturated sodium-chloride water solution washed twice, dried over mgso, leaching filtrate.The decompression liquid filtrate of contracting gets residue, then it is dissolved in 100ml methyl alcohol, adds the 20ml10% aqueous sodium hydroxide solution to gained solution, in room temperature whole mixture is stirred 30 minutes.Reaction mixture is evaporated to 1/3 of original volume, each uses twice of 80ml chloroform extraction enriched material after adding 150ml water, the chloroform phase of dried over mgso gained, filter, concentrating under reduced pressure, the gained residue is coated onto on the silicagel column, with chloroform/methanol (50: 1～20: 1) wash-out, gets the colourless amorphous title compound of 4.53g.
1H-NMR（CDCl 3，δ PPm）：1.43（9H，s），2.80-3.22（6H，m），3.40-3.83（4H，m），4.87（1H，m），5.46（1H，br），6.86-6.93（4H，m），7.23-7.31（2H，m），7.57（1H，s）。
Reference example 3.1-(2-(t-butoxycarbonyl amino)-3-imidazoles-4(5)-Ji-propyl group)-4-benzene piperazine
Under ice-cooled the solution of 1.3g lithium aluminium hydride in the 38ml tetrahydrofuran (THF) is added to the solution of 4.56g aluminum chloride in the 38ml ether, and under ice-cooled, stirred the mixture 20 minutes.Drip 4.53g1-(N-(tertbutyloxycarbonyl) histidyl-to mixture)-solution of 4-benzene piperazine in the 51ml tetrahydrofuran (THF); ice-cooled down with its stirring one hour; add the 20ml25% wet chemical to reaction mixture, add the 100ml chloroform subsequently and get suspension.Make the flocculating aids filtering suspension liquid with silica and get filtrate.Silica with the washing of the chloroform solution of 20% methyl alcohol after, compile filtrate and carry out concentrating under reduced pressure and get residue.Residue is coated onto on the silicagel column, gets the colourless non-crystalline state title compound of 3.1g with chloroform/methanol (40: 1～10: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：1.44（9H，s），2.33（1H，dd，J＝7.3，12.2Hz），2.47（1H，dd，J＝7.8，12.2Hz），2.64（4H，m），2.93（2H，m），3.20（4H，m），3.97（1H，m），5.10（1H，br），6.81-6.97（4H，m），7.21-7.30（2H，m），7.58（1H，s）。
Embodiment 1.N-1-(1-(5-isoquinolinesulfonylcompounds) imidazoles-4(5)-Ji-methyl)-the 2-(4-Phenylpiperazinyl) ethyl }-the 5-isoquinoline sulfonaide
3.1g reference example 3 gained amorphous compounds are dissolved in the 10ml ethyl acetate, add the ethyl acetate solution of the 4N hydrochloric acid of 16ml, stirring at room mixture 30 hours, and evaporated under reduced pressure to this solution.Add 70ml tetrahydrofuran (THF) and 30ml chloroform to residue, form suspension, add 6g isoquinoline 99.9 SULPHURYL CHLORIDE and 30ml triethylamine in it, stirring at room adds water 150ml after 18 hours, with the whole mixture of 70ml chloroform extraction.The dried over mgso extraction liquid, concentrating under reduced pressure gets residue, and the gained residue is coated onto on the silicagel column, and chloroform/methanol (80: 1～60: 1) wash-out gets the colourless amorphous title compound of 1.86g.
IR（KBr）cm -1：1618，1600，1490，1380，1325，1210，1170，1132，1073;
1H-NMR（CDCl 3，δ PPm）：2.00-2.34（6H，m），2.59-2.81（6H，m），3.39（1H，m），6.74-6.89（3H，m），7.04（1H，d，J＝1.5Hz），7.19-7.29（3H，m），7.69（1H，t，J＝7.3Hz），7.80（1H，t，J＝7.8Hz），7.93（1H，d，J＝1.5Hz），8.21（1H，d，J＝8.3Hz），8.34（1H，d，J＝8.3Hz），8.38-8.46（3H，m），8.52（1H，dd，J＝1.0，7.3Hz），8.69（1H，d，J＝6.3Hz），8.77（1H，d，J＝6.3Hz），9.36（1H，s），9.39（1H，s）。
Embodiment 2.N-(the 1-(imidazoles-4(5)-Ji-methyl)-2-(4-benzene piperazinyl) ethyl)-the 5-isoquinoline sulfonaide
Embodiment 1 gained amorphous compound 250mg is dissolved in the mixed solution of 1ml tetrahydrofuran (THF) and 5ml methyl alcohol, adds 1ml4N sodium hydroxide to this solution.Behind the stirring at room miscellany 10 minutes, add 20ml water, use the mixed solution extracting twice of 10ml chloroform and 2ml Virahol then to mixture.Dried over mgso extraction liquid and concentrating under reduced pressure get residue, and the gained residue is coated onto on the silicagel column, with chloroform/methanol (20: 1) and chloroform/methanol/triethylamine (20: 1: 0.2) wash-out, get the colourless amorphous title compound of 163mg.
IR（KBr）cm -1：1615，1600，1490，1448，1320，1225，1153，1130;
1H-NMR（CDCl 3，δ PPm）2.06-2.44（6H，m），2.67-2.90（5H，m），3.02（1H，dd，J＝5.4，10.0Hz），3.25（1H，m），6.74-6.90（4H，m），7.19-7.33（2H，m），7.54（1H，s），7.74（1H，t，J＝7.8Hz），8.24（1H，d，J＝7.8Hz），8.47（1H，d，J＝6.4Hz），8.52（1H，dd，J＝1.0，7.32Hz），8.70（1H，d，J＝5.9Hz），9.38（1H，s）。
Embodiment 3.N-1-(1-(5-isoquinoline 99.9 sulphonyl) imidazoles-4(5)-Ji-methyl)-2-(benzene piperazine) ethyl }-N-methyl-5-isoquinoline sulfonaide
Embodiment 1 gained amorphous compound 1.45g is dissolved in the 20ml dimethyl formamide, adds 60% sodium hydride and the 0.2ml methyl iodide of 120mg in succession to this solution, and simultaneously ice-cooled, ice-cooled stirring adds 30ml water after 30 minutes.With 30ml ethyl acetate extraction reaction mixture, wash extraction liquid with saturated sodium-chloride water solution afterwards, dried over mgso, concentrating under reduced pressure gets residue, the gained residue is applied to silicagel column, and chloroform/methanol (80: 1) wash-out gets the colourless amorphous title compound of 616mg.
IR（KBr）cm -1：1618，1600，1490，1380，1320，1210，1170，1140，1080;
1H-NMR（CDCl 3，δ PPm）2.35-2.47（6H，m），2.64（1H，dd，J＝7.8，14.6Hz），2.80（3H，s），2.85-2.97（5H，m），4.36（1H，m），6.82-6.89（3H，m），7.08（1H，d，J＝1.5Hz），7.21-7.29（2H，m），7.61（1H，t，J＝7.3Hz），7.75（1H，t，JJ＝7.8Hz），7.87（1H，d，J＝1.5Hz），8.14（1H，d，J＝7.8Hz），8.25-8.29（2H，m），8.37-8.45（3H，m），8.64（1H，d，J＝5.9Hz），8.76（1H，d，J＝6.3Hz），9.31（1H，s），9.35（1H，s）。
Embodiment 4.N-(the 1-(imidazoles-4(5)-Ji-methyl)-the 2-(4-Phenylpiperazinyl) ethyl)-N-methyl-5-isoquinoline 99.9 sulfanilamide (SN)
450mg must be dissolved in the mixed solution of 2ml tetrahydrofuran (THF) and 10ml methyl alcohol in the amorphous compound of embodiment 3, add the sodium hydroxide of 1ml4N to this solution.After room temperature was stirred 10 minutes, by this reaction mixture of same step process that is set forth in embodiment 2, the result obtained colourless amorphous this title compound of 299mg.
IR（KBr）Cm -1：1595，1490，1448，1320，1225，1150，1128;
1H-NMR（CDCl 3，δ PPm）：2.45-2.65（6H，m），2.89（3H，s），2.90-3.08（6H，m），4.37（1H，m），6.68（1H，s），6.82-6.90（3H，m），7.20-7.32（3H，m），7.64（1H，t，J＝7.8Hz），8.14（1H，d，J＝7.8Hz），8.31（1H，d，J＝6.3Hz），8.46（1H，dd，J＝1.0，7.3Hz），8.62（1H，d，J＝5.9Hz），9.29（1H，s）。
Reference example 4.N-(tert-butoxycarbonyl)-3,4-benzyloxy phenenyl L-Ala benzyl ester
With 21.12g N-(tert-butoxycarbonyl) DOPA is dissolved in the 200ml dimethyl formamide, add 50g bromotoluene and 40g salt of wormwood after, in room temperature this mixture was stirred 40 hours.After adding the 400ml sodium chloride aqueous solution, with this mixture of 500ml ethyl acetate extraction, extraction liquid washs secondary with saturated sodium-chloride water solution, with dried over mgso, filtration and concentrating under reduced pressure.Hexane added make this title compound crystallization in the gained residue, then with it washing, filtration and dry and obtain the 30.0g clear crystal.
1H-NMR（CDCl 3，δ PPm）：1.42（9H，s），2.99（2H，d，J＝14.14Hz），4.59（1H，m），4.98（1H，brd），5.05（2H，s），5.07（2H，s），5.11（2H，s），6.56（1H，dd，JJ＝2.0，7.8Hz），6.71（1H，d，J＝2.0Hz），6.79（1H，d，J＝7.8Hz），7.20-7.50。
Reference example 5.N-(tert-butoxycarbonyl)-3,4-benzyloxy phenenyl L-Ala
30.0g must be dissolved in 600ml methyl alcohol in the crystal of embodiment 4, add the sodium hydroxide of 65ml10% after, in room temperature this mixture was stirred 20 hours, add 1000ml water.With concentrated hydrochloric acid this reaction mixture is transferred to PH4, uses 800ml chloroform extraction 2 times.This extract makes this title compound crystallization with dried over mgso and concentrating under reduced pressure, then with it filtration, obtains the 25.2g clear crystal with hexane wash.
1H-NMR（CDCl 3，δ PPm）：1.40（9H，s），3.02（2H，m），4.49（1H，brs），4.88（1H，brs），5.11（4H，s），6.68（1H，dd，J＝2.0，7.8Hz），6.76（1H，d，J＝2.0Hz），6.74（1H，d，J＝7.8Hz），7.23-7.45（10H，m）。
Reference example 6.1-(N-(tert-butoxycarbonyl)-3,4-benzyloxy phenenyl alanyl)-the 4-phenylpiperazine
Must be in the 5.67g crystal in the reference example 5,1.9gN-phenylpiperazine and 1.53gN-hydroxybenzotriazole are dissolved in the 80ml methylene dichloride, add 2.4gDCC after, in room temperature this reaction mixture was stirred 18 hours.The gained insolubles is leached, and wash with ethyl acetate.The filtrate decompression that merges is concentrated and obtain residue, then it is imposed on silicagel column and obtain colourless amorphous this title compound of 6.39g with hexane/ethyl acetate (2: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：1.44（9H，s），2.39（1H，m），2.76-3.10（6H，m），3.30（1H，m），3.61（2H，m），4.78（1H，m），5.03（2H，s），5.14（2H，s），5.42（1H，brd，J＝8.3Hz），6.69（1H，dd，J＝2.0，8.3Hz），6.79-6.91（5H，m），7.20-7.48（12H，m）。
Reference example 7.1-2-(N-(tert-butoxycarbonyl amino))-3-(3, the 4-benzyloxy phenenyl) propyl group }-the 4-phenylpiperazine
3.66g must be dissolved in the 50ml tetrahydrofuran (THF) in the colourless amorphous compound of reference example 6,, this mixture be stirred 90 minutes, add water to this mixture and finish until foaming with ice-cooled along with the ice-cooled 700mg lithium aluminium hydride that adds.Then the 80ml trichloromethane being added in this reaction mixture and forming suspension, is that flocculating aids makes this suspension filtered with the elimination insolubles then with silica gel.The filtrate of gained is obtained residue through concentrating under reduced pressure, it is imposed on silicagel column and obtains colourless amorphous this title compound of 2.67g with hexane/ethyl acetate (3: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：1.43（9H，s），2.24（2H，m），2.53（4H，m），2.79（2H，m），3.16（4H，m），3.90（1H，m），4.58（1H，brs），5.13（2H，s），5.16（2H，s），6.70（1H，dd，J＝2.0，8.3Hz），6.80-6.93（5H，m），7.20-7.46（12H，m）。
Reference example 8.1-(2-amino-3-(3,4-benzyloxy phenenyl) propyl group)-the 4-phenylpiperazine
4.35g must be dissolved in the amorphous compound in the reference example 7 in the 20ml ethyl acetate, behind the hydrochloric acid in ethyl acetate of adding 30ml4N, this mixture be stirred 1 hour in room temperature.This reaction mixture is depressurized concentrated, and with sodium bicarbonate aqueous solution alkalization, with 80ml chloroform extraction 2 times, extraction liquid is with dried over mgso and concentrating under reduced pressure.The gained residue is imposed on silicagel column and is obtained colourless amorphous this title compound of 1.64g with trichloromethane/methyl alcohol (100: 1 to 30: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：2.27-2.68（8H，m），3.10-3.20（5H，m），5.10（2H，brs），5.14（2H，s），5.17（2H，s），6.73（1H，dd，J＝2.0，8.3Hz），6.81-6.94（5H，m），7.22-7.46（12H，m）。
Embodiment 5.N-1-((3, the 4-benzyloxy phenenyl) methyl)-2-(4-Phenylpiperazinyl) ethyl }-the 5-isoquinoline sulfonaide
Must be dissolved in 640mg in the 15ml methylene dichloride in the amorphous compound in the reference example 8, add 1ml triethylamine and 350mg5-isoquinoline 99.9 SULPHURYL CHLORIDE along with ice-cooled to this solution, after 1 hour, add 50ml water with ice-cooled stirring again, with this mixture secondary of 50ml chloroform extraction.The fluid of will coming together obtains residue with dried over mgso and concentrating under reduced pressure, and it is imposed on silicagel column and obtains colourless amorphous this title compound of 470mg with hexane/ethyl acetate (1: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：2.08-2.24（6H，m），2.64-2.91（6H，m），3.30（1H，m），5.08（2H，s），5.10（2H，s），6.51（1H，dd，J＝2.0，8.3Hz），6.63（1H，d，J＝2.0Hz），6.71（1H，d，J＝8.3Hz），6.76-6.89（3H，m），7.21-7.43（12H，m），7.67（1H，t，J＝7.8Hz），8.18（1H，d，J＝8.3Hz），8.44（2H，m），8.67（1H，d，J＝5.9Hz），9.34（1H，s）。
Embodiment 6.N-1-((3, the 4-benzyloxy phenenyl) methyl)-2-(4-Phenylpiperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Must be dissolved in 470mg in the 8ml dimethyl formamide in the amorphous compound among the embodiment 5, the sodium hydride from ice-cooled order to this solution and the 0.1ml methyl-iodide that add 30mg60% along with, mix along with ice-cooled stirring after 2 hours, add saturated sodium-chloride water solution, with this mixture of 50ml ethyl acetate extraction.The collection fluid is washed with saturated sodium-chloride water solution, obtains a residue with dried over mgso and concentrating under reduced pressure, and it is imposed on silicagel column and obtains colourless amorphous this title compound of 413mg with hexane/ethyl acetate (1: 1) wash-out.
1H-NMR（CDCl 3，δ PPm）：2.34（1H，dd，J＝6.35，13.2Hz），2.42-2.60（5H，m），2.65（1H，dd，J＝7.3，14.2Hz），2.81（1H，dd，J＝6.4，14.2Hz），2.86（3H，s），2.99（4H，m），4.22（1H，m），5.03（2H，s），5.10（2H，s），6.54（1H，dd，J＝2.0，8.3Hz），6.61（1H，d，J＝2.0Hz），6.63（1H，d，J＝8.3Hz），6.82-6.90（3H，m），7.19-7.53（13H，m），8.05（1H，d，J＝8.3Hz），8.24（1H，dd，J＝1.0，7.3Hz），8.30（1H，d，J＝5.9Hz），8.60（1H，d，J＝5.9Hz），9.24（1H，d，J＝1.0Hz）。
Embodiment 7.N-{1-((3, the 4-dihydroxy phenyl) methyl)-2-(4-Phenylpiperazinyl) ethyl }-N-methyl-isoquinoline sulfonaide
310mg must be dissolved in 2ml1 in the amorphous compound among the embodiment 6, in the 2-ethane dithiol, add 1ml boron trifluoride/ether to this solution, in stirring at room after 18 hours, add saturated sodium bicarbonate aqueous solution again, extract this reaction mixture secondary with the mixed solution of trichloromethane and methyl alcohol (10: 1).With the extraction liquid dried over mgso, concentrating under reduced pressure and obtain a residue imposes on silicagel column with it and with trichloromethane/methyl alcohol (80: 1-20: 1) wash-out and obtain colourless amorphous this title compound of 148mg.
IR（KBr）Cm -1：1600，1495，1448，1328，1230，1155，1130;
1H-NMR（CDCl 3，δ PPm）：2.41（1H，dd，J＝10.25，14.65Hz），2.50-2.98（7H，m），3.01（3H，s），3.17（4H，m），4.06（1H，m），6.12（1H，dd，J＝20，8.3Hz），6.20（1H，d，J＝8.3Hz），6.28（1H，d，J＝2.0Hz），6.82-6.95（3H，m），7.26（2H，m），7.62（1H，t，J＝7.8Hz），8.09（1H，d，J＝6.8Hz），8.13（1H，d，J＝9.3Hz），8.30（1H，d，J＝6.8Hz），8.41（1H，d，J＝4.9Hz），9.25（1H，s）。
Embodiment 8.N-1-((3, the 4-dihydroxy phenyl) methyl)-2-(4-Phenylpiperazinyl) ethyl }-the 5-isoquinoline sulfonaide
Obtain colourless amorphous this title compound by the amorphous compound of embodiment 7 described step process gained in embodiment 5.
IR（KBr）Cm -1：1610，1600，1490，1445，1320，1220，1150，1128;
1H-NMR（CDCl 3，δ PPm）：2.30-2.60（6H，m），2.74-3.02（6H，m），3.36（1H，m），6.15（1H，d，J＝8.3Hz），6.33（1H，d，J＝8.3Hz），6.36（1H，s），6.76-6.90（3H，m），7.19-7.29（2H，m），7.65（1H，t，J＝7.8Hz），8.16（1H，d，J＝8.3Hz），8.33（1H，d，J＝6.5Hz），8.39（1H，d，J＝7.3Hz），8.51（1H，d，J＝5.5Hz），9.28（1H，s）。
Reference example 9.6,7-benzyloxy-3-((4-Phenylpiperazinyl) methyl)-1,2,3,4-tetrahydroisoquinoline
The amorphous compound of 100g gained in reference example 8 is dissolved in the 2ml tetrahydrofuran (THF), adds the formalin of 0.25ml37% to this solution.After room temperature is stirred 30 minutes, the hydrochloric acid of 600mg12N is added in this mixture, then it was stirred 2 hours in room temperature.After adding saturated sodium bicarbonate aqueous solution, this reaction mixture is extracted 2 times with the 20ml trichloromethane.With the extraction liquid dried over mgso, concentrating under reduced pressure imposes on it silicagel column and obtains colourless amorphous this title compound of 585mg with trichloromethane/methyl alcohol (100: 1) wash-out to obtain a residue.
1H-NMR（CDCl 3，δ PPm）：2.28-2.38（8H，m），3.02（1H，m），3.21（4H，m），3.95（2H，s），5.11（4H，s），6.63（1H，s），6.68（1H，s），6.80-6.95（3H，m），7.20-7.46（12H，m）。
Embodiment 9.6,7-benzyloxy-2-(5-isoquinoline 99.9 sulphonyl)-3-((4-Phenylpiperazinyl) methyl)-1,2,3,4-tetrahydroisoquinoline
The amorphous compound that 580mg reference example 9 is obtained is dissolved in the 10ml methylene dichloride, in this solution with ice-cooled adding 1ml triethylamine and 400mg5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl.This mixture was at room temperature stirred 2 hours, and after adding 20ml water, with 10ml chloroform extraction secondary.With the extraction liquid dried over mgso, and under reduced pressure concentrate, then it is imposed on a silicagel column, and, obtain colourless non-crystalline state title compound 610mg with hexane/ethyl acetate (1: 1) wash-out to obtain a kind of residue.
1H-NMR（CDCl 3，δ PPm）：2.31（1H，dd，J＝7.8，11.6Hz），2.43（1H，dd，J＝6.8，11.6Hz），2.53（4H，m），2.70（1H，dd，J＝2.0，16.2Hz），2.87（1H，dd，J＝4.2，16.2Hz），3.05（4H，m），4.26（1H，d，J＝15.6Hz），4.48（1H，d，J＝15.6Hz），4.49（1H，m），5.06（2H，s），5.07（2H，s），6.56（1H，s），6.60（1H，s），6.80-6.90（3H，m），7.20-7.95（12H，m），7.64（1H，t，J＝7.8Hz），8.15（1H，d，J＝7.81Hz），8.37（1H，d，J＝5.9Hz），8.48（1H，dd，J＝1.0，7.3Hz），8.64（1H，d，J＝6.4Hz），9.30（1H，d，J＝1.0Hz）。
Embodiment 10.6,7-dihydroxyl-2-(5-isoquinoline 99.9 sulphonyl)-3-((4-Phenylpiperazinyl) methyl)-1,2,3, the 4-tetrahydroisoquinoline
Add 2ml1 in the amorphous compound that obtains in the 314mg embodiment 9,2-ethylene dithiol phenol and 1ml boron trifluoride/ether stir mixture 18 hours in room temperature.After adding saturated sodium bicarbonate aqueous solution, mixed solution extractive reaction mixture secondary with trichloromethane and methyl alcohol (1: 1), with the extract dried over mgso, and it is concentrated down in decompression, obtain a kind of residue, then it is imposed on silicagel column, and, obtain the colourless amorphous title compound of 213mg with trichloromethane/methyl alcohol (50: 1 to 20: 1) wash-out.
IR（KBr）Cm -1：1610，1600，1490，1445，1320，1225，1150，1130;
1H-NMR（CDCl 3，δ PPm）：2.35-2.80（8H，m），3.11（4H，m），4.24（1H，d，J＝16.1Hz），4.40（1H，d，J＝16.1Hz），4.55（1H，m），6.45（2H，s），6.80-6.90（3H，m），7.20-7.28（2H，m），7.67（1H，t，J＝7.8Hz），8.14（1H，d，J＝8.5Hz），8.40（1H，d，J＝6.3Hz），8.50（1H，dd，J＝1.0，7.3Hz），8.59（1H，d，J＝6.4Hz），9.25（1H，d，J＝1.0Hz）。
Reference example 10.1-(N-(tertbutyloxycarbonyl)-p-nitrophenyl alanyl)-the 4-phenylpiperazine
7.03 gram p-nitrophenyl L-Ala are suspended in 70ml1, in the 4-dioxan, and in suspension, add aqueous sodium hydroxide solution and the 7.5g di-tert-butyl dicarbonic acid ester of 28ml10%, this mixture was stirred 30 minutes in room temperature.The hydrochloric acid of 200ml water and 7ml12N is added in this reaction mixture, with the 150ml ethyl acetate it is extracted then, extract is washed with saturated sodium-chloride water solution, use dried over mgso, and under reduced pressure concentrate.The residue that obtains is dissolved in the 150ml tetrahydrofuran (THF), and in this solution, adds 6.0g N-phenylpiperazine and 5.5g hydroxybenzotriazole, and add 7.6gDCC again.After stirring 3 hours under the room temperature, filter this reaction mixture to remove insolubles, filtrate is concentrated down in decompression, the residue of gained is dissolved in the 200ml ethyl acetate.With this solution successively with 10% wet chemical and saturated sodium-chloride water solution washing, use dried over mgso, and under reduced pressure concentrate to obtain a kind of residue, then it is imposed on a silicagel column and use hexane/ethyl acetate (2: 1) wash-out, obtain the pale yellow crystals of 11.1g title compound.
1H-NMR（CDCl 3，δ PPm）：1.40（9H，s），2.83-3.20（6H，m），3.37（1H，m），3.57-3.70（3H，m），3.84（1H，m），4.92（1H，m），5.40（1H，d，J＝8.3Hz），6.85-6.95（3H，m），7.24-7.32（2H，m），7.38（2H，d，J＝8.8Hz），8.16（2H，d，J＝8.8Hz）。
Embodiment 11.1-(N-(5-isoquinoline 99.9 sulphonyl)-p-nitrophenyl alanyl)-the 4-phenylpiperazine
Be dissolved in the 100ml ethyl acetate with reference to the crystal 11.0g that obtains in the example 10, add 100ml14N be dissolved in hydrochloric acid in the ethyl acetate after, this reaction mixture was stirred under room temperature 1 hour, and under reduced pressure concentrated.In residue, add the 200ml saturated sodium bicarbonate, with this mixture secondary of 100ml chloroform extraction.With the extraction liquid dried over mgso, and under reduced pressure concentrate to obtain a residue, it is imposed on a silicagel column, (80: 1-10: 1) wash-out obtains unhindered amina with trichloromethane/methyl alcohol.This unhindered amina is dissolved in the 100ml methylene dichloride, in this solution, adds 8.5g5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 20ml triethylamine in turn.This reaction mixture was stirred under room temperature 18 hours, add entry after, with 100ml chloroform extraction secondary.Extract is concentrated to obtain a kind of residue down with dried over mgso and in decompression, it is imposed on a silicagel column,, obtain the title compound of 9.66g clear crystal with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.
Fusing point: 184-188 ℃ (decomposition)
IR（KBr）Cm -1：1660，1600，1520，1420，1345，1325，1230，1150，1135;
1H-NMR（CDCl 3，δ PPm）：2.72-3.06（6H，m），3.20-3.61（4H，m），4.46（1H，m），6.06（1H，br），6.83（2H，d，J＝7.8Hz），6.94（1H，t，J＝7.3Hz），7.10（2H，t，J＝8.8Hz），7.29（2H，m），7.56（1H，t，J＝7.8Hz），8.22-8.29（2H，m），8.71（1H，d，J＝6.3Hz），9.26（1H，s）。
Embodiment 12.1-(N-(5-isoquinoline 99.9 sulphonyl)-N-methyl-p-nitrophenyl alanyl)-the 4-phenylpiperazine
The crystal that obtains among the 5.87g embodiment 11 is dissolved in the 60ml dimethyl formamide, with ice-cooled sodium hydride and the 1.5ml methyl-iodide that in this solution, adds 500mg60% successively.After 2 hours, in this mixture, add water with ice-cooled stirring, use the 150ml ethyl acetate extraction then.Wash extract with saturated sodium-chloride water solution.Also under reduced pressure concentrate with dried over mgso, it is imposed on a silicagel column,, obtain the yellow amorphous title compound of 5.93g with trichloromethane/methyl alcohol (100: 1) wash-out to obtain a residue.
IR（KBr）Cm -1：1640，1600，1535，1445，1340，1225，1150，1125;
1H-NMR（CDCl 3，δ PPm）：2.60（1H，dd，J＝4.9，12.7Hz），2.83（1H，m），2.92-3.06（3H，m），3.06（3H，s），3.40（1H，dd，J＝7.8，13.2Hz），3.46-3.63（2H，m），3.70-3.88（2H，m），5.23（1H，dd，J＝4.9，9.8Hz），6.82（2H，d，J＝7.8Hz），6.91（1H，t，J＝7.3Hz），7.22-7.30（4H，m），7.73（1H，t，J＝7.8Hz），8.07（2H，d，J＝8.8Hz），8.25（1H，d，J＝8.3Hz），8.36（1H，dd，J＝1.0，7.3Hz），8.48（1H，d，J＝6.4Hz），8.71（1H，d，J＝6.4Hz），9.37（1H，d，J＝1.0Hz）。
Embodiment 13.1-(to amino-N-(5-isoquinoline 99.9 sulphonyl)-N-methyl-prop aminoacyl)-the 4-phenylpiperazine
The amorphous compound that obtains among the 6.08g embodiment 12 is dissolved in the 70ml methyl alcohol, in this solution, adds hydrochloric acid and the 30ml water of 5ml12N, and then the carbon that adds 5g5% carries palladium.This mixture in stirring 30 minutes in nitrogen atmosphere under the room temperature, is filtered to remove insolubles, filtrate is concentrated down in decompression, in this residue, add the 150ml saturated sodium bicarbonate aqueous solution, with this mixture secondary of 200ml chloroform extraction.Use the dried over mgso extract, and under reduced pressure concentrate, then it is imposed on a silicagel column, and, obtain the yellow amorphous title compound of 3.32g with trichloromethane/methyl alcohol (50: 1) wash-out to obtain a residue.
IR（KBr）Cm -1：1635，1600，1495，1445，1325，1220，1150，1125;
1H-NMR（CDCl 3，δ PPm）：2.47-2.56（2H，m），2.87-3.22（4H，m），3.14（3H，s），3.33-3.75（4H，m），5.14（1H，dd，J＝4.9，9.8Hz），6.50（2H，d，J＝8.3Hz），6.80-6.92（5H，m），7.22-7.34（2H，m），7.69（1H，t，J＝7.8Hz），8.20（1H，d，J＝8.3Hz），8.36（1H，dd，J＝1.5，7.3Hz），8.40（1H，d，J＝5.9Hz），8.68（1H，d，J＝6.4Hz），9.34（1H，s）。
Embodiment 14.
3.75g crystal according to preparation among the step process embodiment 11 described in the embodiment 13 obtains 2.17g1-(to amino-N-(5-isoquinoline 99.9 sulphonyl) phenyl alanyl)-yellow crystals of 4-phenylpiperazine.
IR（KBr）Cm -1：1635，1600，1495，1440，1320，1225，1155，1135;
1H-NMR（CDCl 3，δ PPm）：2.41（1H，m），2.59-3.07（6H，m），3.17（1H，m），3.33（1H，m）3.51（1H，m），4.35（1H，m），5.95（1H，d，J＝9.3Hz），6.38（2H，d，J＝8.3Hz），6.75（2H，d，J＝8.3Hz），6.78（2H，d，J＝7.8Hz），6.91（1H，t，J＝7.3Hz），7.22-7.30（2H，m），7.60（1H，t，J＝8.3Hz），8.12（1H，d，J＝8.3Hz），8.30-8.35（2H，m），8.71（1H，d，J＝5.9Hz），9.30（1H，s）。
Embodiment 15.1-(N-(5-isoquinoline 99.9 sulphonyl)-to (tolysulfonyl amino) phenyl alanyl)-the 4-phenylpiperazine
The crystal that 200mg embodiment 14 is obtained is dissolved in the 5ml pyridine, with the ice-cooled 90mg Tosyl chloride that adds in this solution, this mixture is followed ice-cooled stirring 1 hour, and pour in the 30ml saturated sodium bicarbonate aqueous solution.With this mixture secondary of 15ml chloroform extraction, and, concentrate to obtain a residue down, it is imposed on a silicagel column,, obtain the 128mg title compound with trichloromethane/methyl alcohol (80: 1 to 50: 1) wash-out in decompression with the extraction liquid dried over mgso.
IR（KBr）Cm -1：1635，1600，1335，1225，1155，1090;
1H-NMR（CDCl 3，δ PPm）：2.30（3H，s），2.65-2.80（4H，m），2.83-3.04（2H，m），3.17-3.50（4H，m），4.33（1H，m），6.14（1H，d，J＝9.3Hz），6.70-6.83（6H，m），6.93（1H，t，J＝7.3Hz），6.77（1H，s），7.17（2H，d，J＝8.3Hz），7.26-7.36（2H，m），7.59（1H，t，J＝7.3Hz），7.59（2H，d，J＝8.3Hz），8.13（1H，d，J＝7.8Hz），8.30（2H，m），8.64（1H，br），9.31（1H，br）。
Embodiment 16.
Remove and use the crystal that obtains among 200mg5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and the 300mg embodiment 14, and carry out outside the wash-out with trichloromethane/methyl alcohol (40: 1 to 20: 1), repeat the same steps as described in the embodiment 15, acquisition 372mg1-(N-(5-isoquinoline 99.9 sulphonyl)-to (5-isoquinoline 99.9 sulfonamido) phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）Cm -1：1630，1600，1340，1225，1155，1135;
1H-NMR（CDCl 3，δ PPm）：2.35-3.07（9H，m），3.30（1H，m），4.26（1H，m），6.67-6.84（6H，m），6.89-6.96（2H，m），7.23（2H，t，J＝8.8Hz），7.52（1H，t，J＝7.8Hz），7.54（1H，t，J＝7.8Hz），7.98（1H，d，J＝7.8Hz），8.07（1H，d，J＝8.3Hz），8.25（1H，d，J＝6.8Hz），8.31-8.36（2H，m），8.54（1H，d，J＝6.3Hz），8.65（2H，d，J＝6.4Hz），9.17（1H，s），9.26（1H，s），10.06（1H，s）。
Embodiment 17.
Remove the crystal that will obtain among 200mg1-naphthalic sulfonic chloride and the 360mg embodiment 14 and be used as raw material, and carry out outside the wash-out with trichloromethane/methyl alcohol (80: 1 to 50: 1), repeat the same steps as described in the embodiment 15, acquisition 385mg1-(N-(5-isoquinoline 99.9 sulphonyl)-to (1-naphthalene sulfonyl amino) phenyl alanyl)-the 4-phenylpiperazine.
1H-NMR（CDCl 3，δ PPm）：2.40-2.74（6H，m），2.80-3.04（3H，m），3.33（1H，m），4.24（1H，m），6.68-6.82（6H，m），6.92（1H，t，J＝7.3Hz），7.12（1H，d，J＝9.3Hz），7.26-7.57（5H，m），7.65（1H，m），7.78（1H，d，J＝8.3Hz），7.88（1H，d，J＝7.8Hz），7.99（1H，d，J＝8.3Hz），8.16（1H，dd，J＝1.0，7.3Hz），8.21（1H，dd，J＝1.0，7.3Hz），8.36（1H，d，J＝5.9Hz），8.65（1H，d，J＝6.4Hz），8.77（1H，d，J＝8.8Hz），9.22（1H，s），9.88（1H，s）。
Embodiment 18.
The crystal that removes the gained in embodiment 14 with 0.07ml methylsulfonyl chloride and 360mg is as raw material, and carry out outside the wash-out with trichloromethane/methyl alcohol (50: 1 to 30: 1), repeat the same steps as described in the embodiment 15, the 1-(N-(5-isoquinoline 99.9 sulphonyl) of acquisition 356mg-to (methanesulfonamido) phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1635，1600，1330，1225，1150;
1H-NMR（CDCl 3，δ ppm）：2.38（1H，m），2.72（3H，s），2.70-2.90（6H，m），3.04-3.21（3H，m），3.42（1H，m），4.39（1H，m），6.78（2H，d，J＝7.8Hz），6.88（1H，t，J＝7.3Hz），6.92（2H，d，J＝8.3Hz），7.00（2H，d，J＝8.3Hz），7.20-7.30（3H，m），7.62（1H，t，J＝7.8Hz），8.16（1H，d，J＝8.3Hz），8.32（1H，dd，J＝1.0，7.3Hz），8.42（1H，d，J＝5.9Hz），8.69（1H，d，J＝6.4Hz），9.15（1H，s），9.31（1H，s）.
Embodiment 19.1-(N-(5-isoquinoline 99.9 sulphonyl)-to methanesulfonamido-N-aminomethyl phenyl alanyl)-the 4-phenylpiperazine
The amorphous compound that 700mg is derived from embodiment 13 is dissolved in the pyridine of 7ml, then along with the ice-cooled methylsulfonyl chloride that adds 0.13ml in this solution, along with ice-cooled mixture is stirred 1 hour, pours in the saturated sodium bicarbonate aqueous solution of 50ml.With this mixture 30ml chloroform extraction secondary.Extract is also under reduced pressure concentrated with dried over mgso.The residue that obtains is imposed on silicagel column,, obtain the title compound of 790mg with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.
IR（KBr）cm -1：1635，1595，1325，1220，1145;
1H-NMR（CDCl 3，δ ppm）：2.48-2.59（2H，m），2.83（3H，s），2.85-3.10（3H，m），3.12（3H，s），3.22（1H，dd，J＝9.8，13.2Hz），3.44-3.80（4H，m），5.16（1H，dd，J＝5.4，9.8Hz），6.80-6.93（4H，m），7.04（4H，s），7.26（2H，t，J＝8.3Hz），7.72（1H，t，J＝7.8Hz），8.23（1H，d，J＝8.3Hz），8.35（1H，dd，J＝1.0，7.3Hz）8.42（1H，d，J＝5.9Hz），8.68（1H，d，J＝5.9Hz），9.36（1H，s）.
Embodiment 20.
The amorphous compound that derives from embodiment 13 except that 1-naphthalic sulfonic chloride and 700mg with 360mg is used as raw material, and with outside trichloromethane/methyl alcohol (100: 1) wash-out, repetition is in the same step described in the embodiment 19, obtains 1-(N-(5-isoquinoline 99.9 sulphonyl)-N-methyl of 770mg-to (1-naphthalene sulfonyl amino) phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1635，1595，1440，1330，1220，1150，1120;
1H-NMR（CDCl 3，δ ppm）：2.42（1H，dd，J＝4.9，12.7Hz），2.63（1H，m），2.85-3.17（4H，m），3.07（3H，s），3.32-3.73（4H，m），5.04（1H，dd，J＝5.4，10.3Hz），6.73-6.96（7H，m），7.05（1H，br），7.30-7.41（3H，m）7.54-7.70（3H，m），7.88（1H，d，J＝7.8Hz），7.95（1H，d，J＝8.3Hz），8.12（1H，dd，J＝1.0，7.3Hz），8.16（1H，d，J＝8.3Hz），8.27（1H，dd，J＝1.5，7.3Hz），8.37（1H，d，J＝6.3Hz），8.62-8.68（2H，m），9.32（1H，s）.
Embodiment 21.
The 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl that removes use 320mg is as sulphonating agent, use 500mg to derive from the pyridine of amorphous compound among the embodiment 13,5ml and use trichloromethane/methyl alcohol (80: 1 to 50: 1) as outside the eluent, repeat the same step described in the embodiment 19, the 1-(N-(5-isoquinoline 99.9 sulphonyl) of acquisition 498mg-to (5-isoquinoline 99.9 sulfonamido)-N-aminomethyl phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1640，1595，1330，1225，1155，1135.
1H-NMR（CDCl 3，δ ppm）：2.44（1H，dd，J＝4.9，13.2Hz），2.61（1H，m），2.85-3.26（5H，m），3.05（3H，s），3.40-3.70（3H，m），5.06（1H，dd，J＝4.9，9.8Hz），6.77（2H，d，J＝8.8Hz），6.79-6.97（5H，m），7.31（2H，t，J＝7.3Hz），7.53（1H，t，J＝8.3Hz），7.63（1H，t，J＝8.8Hz），8.08（1H，d，J＝8.3Hz），8.20（1H，d，J＝8.3Hz），8.27-8.32（2H，m），8.37（2H，d，J＝6.4Hz），8.64（1H，d，J＝6.4Hz），8.67（1H，d，J＝6.4Hz），9.29（1H，s），9.34（1H，s）
Embodiment 22.
Remove and use the Tosyl chloride of 300mg as sulphonating agent, 700mg derives from the amorphous compound of embodiment 13, outside the 10ml pyridine and trichloromethane/methyl alcohol (100: 1) as eluent, repeat the same steps as described in the embodiment 19,1-(N-(5-isoquinoline 99.9 sulphonyl)-N-methyl of acquisition 812mg-to (tolysulfonyl amino) phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1635，1595，1440，1325，1220，1150;
1H-NMR（CDCl 3，δ ppm）：2.32（3H，s），2.50（1H，dd，J＝4.9，12.7Hz），2.68（1H，m），2.90-3.03（4H，m），3.10（3H，s），3.29（1H，m），3.42-3.73（3H，m），5.12（1H，dd，J＝5.4，9.8Hz），6.79-6.97（7H，m），7.17（2H，d，J＝8.3Hz），7.28（2H，t，J＝7.3Hz），7.61（2H，d，J＝8.3Hz），7.69（1H，t，J＝7.8Hz），8.21（1H，d，J＝8.3Hz），8.31（1H，dd，J＝1.5，7.3Hz），8.40（1H，d，J＝5.9Hz），8.65（1H，d，J＝6.4Hz），9.35（1H，s）.
Embodiment 23.1-N-(5-isoquinoline 99.9 sulphonyl)-to (N '-(5-isoquinoline 99.9 sulphonyl)-N '-methylamino-)-N-methyl-phenyl alanyl }-the 4-phenylpiperazine
Product among the 306mg embodiment 21 is dissolved in the dimethyl formamide of 5ml, add the sodium hydride of 25mg60% and the hydrogen iodide of 0.1ml along with ice-cooled to this solution, with this mixture with ice-cooled stirring 1 hour, after adding the 30ml saturated sodium-chloride, this mixture ethyl acetate extraction of 30ml, wash extract with saturated sodium-chloride water solution, use dried over mgso, and under reduced pressure concentrate.The residue of gained is imposed on a silicagel column, and with trichloromethane/methyl alcohol (80: 1) wash-out, obtain the title compound of 266mg.
IR（KBr）cm -1：1640，1600，1445，1340，1225，1150，1130;
1H-NMR（CDCl 3，δ ppm）：2.41-2.61（2H，m），2.83-3.09（3H，m），3.07（6H，s），3.27（1H，dd，J＝10.7，13.2Hz），3.43（1H，m），3.56-3.71（3H，m）5.18（1H，dd，J＝4.4，10.7Hz），6.80-6.91（3H，m），6.94（2H，d，J＝8.8Hz），7.00（2H，d，J＝8.8Hz），7.21-7.30（2H，m），7.60（1H，t，J＝7.8Hz），7.73（1H，t，J＝7.8Hz），7.98（1H，d，J＝5.9Hz），8.14-8.23（3H，m），8.36（1H，d，J＝8.4Hz），8.40（1H，d，J＝5.9Hz），8.46（1H，d，J＝6.4Hz），8.69（1H，d，J＝6.4Hz），9.29（1H，s），9.37（1H，s）.
Embodiment 24.
The product 594mg that removes embodiment 19 is dissolved in the dimethyl formamide of 6ml, and outside this solution adds the methyl-iodide of the sodium hydride of 60mg60% and 0.1ml, repeat the same steps as described in the embodiment 23, acquisition 450mg1-(N-(5-isoquinoline 99.9 sulphonyl)-to (N '-methylsulfonyl-N '-methylamino-) N-aminomethyl phenyl alanyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1635，1595，1445，1335，1225，1150，1140;
1H-NMR（CDCl 3，δ ppm）：2.36（1H，m），2.50（1H，dd，J＝3.9，12.2Hz），2.64（3H，s），2.81（1H，m），2.96-3.16（2H，m），3.11（3H，s），3.16（3H，s），3.31（1H，dd，J＝10.7，12.7Hz），3.37-3.62（3H，m），3.78（1H，m），5.20（1H，dd，J＝4.4，10.7Hz），6.80（2H，d，J＝7.8Hz），6.88（1H，t，J＝7.3Hz），7.12（2H，d，J＝8.8Hz），7.21-7.31（4H，m），7.74（1H，t，J＝7.8Hz），8.24（1H，d，J＝7.8Hz），8.38（1H，dd，J＝1.0，7.3Hz），8.47（1H，d，J＝6.4Hz），8.71（1H，d，J＝6.4Hz），9.37（1H，s）.
Embodiment 25.
The product that removes 587mg embodiment 20 is dissolved in the dimethyl formamide of 6ml, and also use outside trichloromethane/methyl alcohol (100: 1) wash-out to the sodium hydride of this solution interpolation 50mg60% and the methyl-iodide of 0.1ml, repeat embodiment 23 described same steps as, acquisition 490mg1-N-(5-isoquinoline 99.9 sulphonyl)-the N-methyl-to (N '-methyl-N '-(1-naphthalene sulfonyl) amino) the phenyl alanyl }-the 4-phenylpiperazine.
IR（KBr）cm -1：1640，1600，1440，1330，1220，1150，1125;
1H-NMR（CDCl 3，δ ppm）：2.47（1H，dd，J＝4.4，12.7Hz），2.53（1H，m），2.80-3.07（3H，m），3.07（3H，s），3.08（3H，s），3.27（1H，dd，J＝10.3，12.7Hz），3.38（1H，m），3.51-3.65（3H，m），5.17（1H，dd，J＝4.4，10.3Hz），6.81（2H，d，J＝8.8Hz），6.88（1H，t，J＝7.3Hz），6.98（4H，s），7.24（2H，dd，J＝7.3，8.8Hz），7.38-7.57（3H，m），7.72（1H，d，J＝7.3Hz），7.88（1H，d，J＝7.8Hz），8.01（1H，d，J＝8.3Hz），8.04（1H，d，J＝7.3Hz），8.23（1H，d，J＝8.3Hz），8.32-8.37（2H，m），8.46（1H，d，J＝5.9Hz），8.68（1H，d，J＝6.3Hz），9.36（1H，s）.
Embodiment 26.
The product that removes 650mg embodiment 22 is dissolved in the 10ml dimethyl formamide, add the sodium hydride of 60mg60% and the methyl-iodide of 0.1ml to this solution, and with outside trichloromethane/methyl alcohol (100: 1) wash-out, repeat embodiment 23 described same steps as, acquisition 603mg1-N-(5-isoquinoline 99.9 sulphonyl)-the N-methyl-to (N '-methyl-N '-(tolysulfonyl) amino) the phenyl alanyl }-the 4-phenylpiperazine.
IR（KBr）cm -1：1640，1600，1440，1335，1220，1145;
1H-NMR（CDCl 3，δ ppm）：2.37（3H，s），2.52（1H，dd，J＝4.9，12.7Hz），2.55（1H，m），2.80-3.10（3H，m），2.99（3H，s），3.11（3H，s），3.28（1H，dd，J＝10.3，12.7Hz），3.40（1H，m），3.50-3.68（3H，m），5.20（1H，dd，J＝4.9，10.3Hz），6.81（2H，d，J＝8.3Hz），6.88（1H，t，J＝7.3Hz），6.98（2H，d，J＝8.8Hz）7.05（2H，d，J＝8.8Hz），7.18（2H，d，J＝8.3Hz），7.24（2H，dd，J＝7.3，8.3Hz），7.37（2H，d，J＝8.3Hz），7.73（1H，t，J＝7.8Hz），8.23（1H，d，J＝8.3Hz），8.36（1H，dd，J＝1.0，7.8Hz），8.46（1H，d，J＝6.4Hz），8.70（1H，d，J＝6.4Hz）9.36（1H，s）.
Reference example 11.1-(N-carbobenzoxy-(Cbz) tyrosyl)-and the 4-(tertbutyloxycarbonyl) piperazine
With the N-benzyloxycarbonyl tyrosine of 21.31g and the N-(tert-butoxycarbonyl of 11.79g) piperazine is dissolved in the mixed solvent of 200ml methylene dichloride and 100ml ethyl acetate, adds the DCC of 14g in solution.After at room temperature stirring 40 hours, sedimentary insolubles is leached, and this filtrate is under reduced pressure concentrated, the residue of gained is imposed on a silicagel column and with hexane/ethyl acetate (1: 1) wash-out, obtain the colourless amorphous title compound of 23.9g.
1H-NMR（CDCl 3，δ ppm）：1.45（9H，s），2.80-3.02（4H，m），3.14-3.39（4H，m），3.49（2H，m），4.83（1H，m），5.08（1H，d，J＝12Hz），5.10（1H，d，J＝12Hz），5.69（1H，d，J＝8.8Hz），6.17（1H，br），6.72（2H，d，J＝8.8Hz），7.01（2H，d，J＝8.3Hz），7.34（5H，s）.
Embodiment 27.1-(N, adjacent two (5-isoquinoline 99.9 sulphonyl) tyrosyls)-4-(tert-butoxycarbonyl) piperazine
The amorphous compound that 1.00g is derived from reference example 11 is dissolved in the methyl alcohol of 20ml, and the carbon that adds 500mg5% in this solution carries palladium, and this mixture was stirred 5 hours under room temperature in nitrogen atmosphere.After removing by filter insolubles, under reduced pressure filtrate is concentrated.In the residue of gained, add 30ml tetrahydrofuran (THF), the 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl of 630mg and the triethylamine of 1.4ml in turn, under room temperature, this mixture was stirred 50 hours, add behind the water 100ml with 50ml chloroform extraction secondary.Extract is also under reduced pressure concentrated with dried over mgso.Residue with gained imposes on a silicagel column then, with trichloromethane/methyl alcohol (50: 1 to 25: 1) wash-out, obtains the yellow amorphous title compound of 1.38g.
1H-NMR（CDCl 3，δ ppm）：1.45（9H，s），2.53-3.18（10H，m），4.29（1H，m），6.05（1H，d，J＝9.3Hz），6.61（2H，d，J＝8.8Hz），6.85（2H，d，J＝8.8Hz），7.62（1H，t，J＝7.8Hz），7.66（1H，t，J＝7.8Hz），8.19（2H，d，J＝7.8Hz），8.26-8.31（3H，m），8.52（1H，d，J＝5.9Hz），8.69（1H，d，J＝5.9Hz），8.84（1H，d，J＝6.4Hz），9.33（1H，s），9.43（1H，s）
Embodiment 28.1-(N, adjacent two (5-isoquinoline 99.9 sulphonyl) tyrosyls) piperazine
The amorphous compound of 366mg embodiment 27 preparations is dissolved in the 3ml trichloromethane, adds hydrochloric acid/ethyl acetate of the 3N of 5ml to this solution.After at room temperature stirring 1 hour, this mixture is under reduced pressure concentrated, and in the residue of gained, add the 50ml saturated sodium bicarbonate aqueous solution.With the mixed extractant solvent secondary of this mixture,, under reduced pressure concentrate then, obtain the crude preparation by using of the colourless amorphous title compound of 301mg the extract dried over mgso with 30ml trichloromethane/methyl alcohol (5: 1).
1H-NMR（CDCl 3，δ ppm）：2.11（1H，m），2.35（1H，m），2.43（2H，m），2.70-2.83（4H，m），2.90（1H，m），3.09（1H，m），4.30（1H，t，J＝7.4Hz），6.65（2H，d，J＝8.3Hz），6.88（2H，d，J＝8.3Hz），7.62（1H，dd，J＝7.3，8.3Hz），7.64（1H，t，J＝7.8Hz），8.17（1H，d，J＝8.3Hz），8.24-8.31（4H，m），8.52（1H，d，J＝5.9Hz），8.68（1H，d，J＝6.3Hz），8.83（1H，d，J＝6.4Hz），9.32（1H，s），9.43（1H，s）.
Embodiment 29.1-carbobenzoxy-(Cbz)-4-(N-(5-isoquinoline 99.9 sulphonyl) tyrosyl) piperazine
The crude product that 620mg is derived from embodiment 28 is dissolved in the methylene dichloride of 10ml, adds 0.29ml benzyloxycarbonyl chlorine and 3.04ml triethylamine to this solution successively along with ice-cooled., after 2 hours the 40ml saturated sodium-chloride water solution is added in this reaction mixture with ice-cooled stirring, then this mixture is used 20ml chloroform extraction secondary, this extract is also under reduced pressure concentrated to obtain residue with dried over mgso.This residue is dissolved in the 6ml methyl alcohol, after adding the aqueous sodium hydroxide solution of 2ml1N,, use dried over mgso this mixture reflux 2 hours, and under reduced pressure concentrated.The residue that obtains is imposed on a silicagel column,, obtain the title compound of 336mg clear crystal with trichloromethane/methyl alcohol (80: 1 to 50: 1) wash-out.
Fusing point: 137-141 ℃
IR（KBr）cm -1：1700，1630，1510，1417，1318，1218，1148，1128;
1H-NMR（CDCl 3-CD 3OD，δ ppm）：2.60-2.77（2H，m），2.80-3.55（8H，m），4.25（1H，t，J＝7.8Hz），5.10（1H，s），5.12（1H，s），6.29，6.74（Total 2H，each d，each J＝8.3Hz），6.60，7.01（Total 2H，each d，each J＝8.3Hz），7.35（5H，s），7.60（1H，t，J＝7.8Hz），8.15（1H，d，J＝8.3Hz），8.26（1H，d，J＝7.8Hz），8.29（1H，d，J＝5.9Hz），8.57（1H，d，J＝5.9Hz），9.25（1H，s）.
Embodiment 30.
Repetition obtains yellow amorphous 1-(N-(5-isoquinoline 99.9 sulphonyl) tyrosyl in the same steps as described in the embodiment 29)-4-phenylacetyl piperazine.
IR（KBr）cm -1：1620，1510，1435，1320，1228，1152，1130;
1H-NMR(DMSO-d 6, δ PPm): 2.20-3.45(10H, m), and 3.67, the total 2H of 370(, every s), 4.32, the total 1H of 4.82(, every m), 6.45,6.65(total 2H, every d, every J=8.3Hz), 6.82, the total 2H of 7.00(, every d, every J=8.3Hz), 7.13-7.39(5H, m), 7.60-7.74(1H, m), 8.13-8.42(3H, m), 8.64(1H, d, J=5.9Hz), 9.18(1H, br), 9.39(1H, br).
Embodiment 31.
Repeat and identical step described in the embodiment 29 acquisition 1-(N-(5-isoquinoline 99.9 sulphonyl)-tyrosyl)-4-(3-phenylpropyl alcohol acyl) clear crystal of piperazine.
Fusing point: 172-178 ℃
IR（KBr）cm -1：1630，1510，1440，1320，1225，1150，1128;
1H-NMR（CDCl 3-CD 3OD，δ ppm）：2.50-3.47（14H，m），4.26（1H，t，J＝7.3Hz），6.32（2H，d，J＝8.3Hz），6.62（2H，d，J＝8.3Hz），7.15-7.34（5H，m），7.62（1H，t，J＝7.8Hz），8.17（1H，d，J＝7.8Hz），8.24-8.33（2H，m），8.58（1H，d，J＝5.4Hz），9.26（1H，s）.
Embodiment 32.1-(N, adjacent two (5-isoquinoline 99.9 sulphonyl) tyrosyls)-4-(3-hydrocinnamyl) piperazine
The crude product and the 95mg3-hydrocinnamyl bromine that 301mg are derived from embodiment 28 are dissolved in the 5ml dimethyl formamide, add 66mg salt of wormwood and 72mg sodium iodide again in this solution., after 7 hours the 30ml saturated sodium-chloride is added in the reaction mixture of using the 40ml ethyl acetate extraction subsequently 80 ℃ of stirrings, this extract with the washing of 30ml saturated sodium-chloride water solution, is used dried over mgso, and under reduced pressure concentrate.The residue that obtains is imposed on a silicagel column, and, obtain the yellow amorphous title compound of 216mg with trichloromethane/methyl alcohol (40: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.60-1.95（6H，m），2.06-2.29（2H，m），2.53-3.20（8H，m），4.28（1H，m），5.98（1H，d，J＝9.3Hz），6.64（2H，d，J＝8.3Hz），6.86（2H，d，J＝8.3Hz），7.14-7.35（5H，m），7.59（1H，t，J＝7.8Hz），7.62（1H，t，J＝7.8Hz），8.12（1H，d，J＝8.3Hz），8.23-8.29（4H，m），8.52（1H，d，J＝5.9Hz），8.68（1H，d，J＝6.4Hz），8.82（1H，d，J＝6.4Hz），9.28（1H，s），9.42（1H，s）.
Embodiment 33.1-(N-(5-isoquinoline 99.9 sulphonyl) tyrosyl)-and the 4-(3-hydrocinnamyl) piperazine
The amorphous compound 216mg that derives from embodiment 32 is dissolved in the 3ml methyl alcohol, adds the potassium hydroxide aqueous solution of 0.6ml2N to this solution.With this mixture reflux 10 hours, after adding the 30ml saturated sodium-chloride water solution, with the mixed extractant solvent secondary of 20ml trichloromethane/methyl alcohol (5: 1).With this extract dried over mgso, and under reduced pressure concentrate, the residue of gained is imposed on a silicagel column, and, obtain the colourless amorphous title compound of 74mg with trichloromethane/methyl alcohol (40: 1 to 10: 1) wash-out.
IR（KBr）cm -1：1630，1510，1440，1320，1230，1150，1128;
1H-NMR（CDCl 3，δ ppm）：1.65-1.83（2H，m），2.00-2.37（6H，m），2.57-2.80（4H，m），3.02-3.42（4H，m），4.31（1H，m），6.30（2H，d，J＝8.3Hz），6.41（1H，d，J＝9.3Hz），6.65（2H，d，J＝8.3Hz），7.15-7.37（5H，m），7.60（1H，t，J＝7.8Hz），8.16（1H，d，J＝8.3Hz），8.23-8.33（2H，m），8.58（1H，br），9.33（1H，br）.
Reference example 12.1-(N-(tert-butoxycarbonyl) tyrosyl)-the 4-phenylpiperazine
With 19.7g N-(tert-butoxycarbonyl) tyrosine, 12.5gN-phenylpiperazine and 16.1g N-hydroxybenzotriazole are dissolved in the 100ml tetrahydrofuran (THF), in this solution, splash into the solution of 18.7g DCC in the 50ml tetrahydrofuran (THF) with ice-cooled, the time of splashing into is 20 minutes, and this mixture was stirred 1 hour.This reaction mixture is filtered to remove insolubles, then this insolubles is washed with the 300ml ethyl acetate, filtrate is merged, under reduced pressure concentrate.The residue that obtains is dissolved in the 500ml ethyl acetate, this solution with saturated sodium bicarbonate aqueous solution washing 3 times, with saturated sodium-chloride water solution washing 1 time, is used dried over mgso, under reduced pressure concentrate.The residue of gained is imposed on a silicagel column, and with ethyl acetate/hexane (1: 2 to 1: 1) wash-out to collect required part, then this part is merged, and under reduced pressure concentrates.The residue that obtains is dissolved in the 100ml ethyl acetate, makes this solution in refrigerator, retain a night, filter then to remove insolubles.Filtrate is under reduced pressure concentrated, and with the benzene azeotropic distillation, drying under reduced pressure obtains colourless amorphous title compound.
IR（KBr）cm -1：1700，1620，1220;
1H-NMR（DMSO·d 6，δ ppm）：1.33（9H，s），2.6-3.1（6H，m），3.4-3.7（4H，m），4.55（1H，m），6.64（2H，d，J＝8.2Hz），6.80（1H，t，J＝7.3Hz），6.90（2H，d，J＝7.9Hz），7.02（2H，d，J＝8.2Hz），7.22（2H，dd，J＝7.3，7.9Hz），9.16（1H，s）.
Reference example 13.1-(2-(tert-butoxycarbonyl amino)-3-(p-hydroxybenzene) propyl group)-the 4-phenylpiperazine
In 50 minutes, in the solution of 230ml tetrahydrofuran (THF), splash into the solution of 28.0g aluminum chloride in the 230ml ether along with ice-cooled to the 8.0g lithium aluminum hydride, and after 15 minutes, in the solution of gained, splash into the solution of 40.0g amorphous compound in the 230ml tetrahydrofuran (THF) that derives from reference example 12,15 minutes time.Make this reaction mixture be in room temperature, and after adding the 300ml tetrahydrofuran (THF), stirred 25 minutes.Filter this mixture to remove the insolubles that washs with tetrahydrofuran (THF) subsequently.The filtrate that merges is under reduced pressure concentrated, the residue of gained is imposed on a silicagel column, the part that under reduced pressure is concentrated subsequently with collection with trichloromethane/methyl alcohol (20: 1) wash-out.Then the 100ml ethyl acetate is added to and makes the product crystallization in the residue.This product is filtered so that collect, and again with mother liquor washing 5 times, with normal hexane washing 3 times, drying under reduced pressure obtains 24.1g clear crystal title compound then again.
Fusing point: 199-202 ℃ (decomposition)
1H-NMR（DMSO-d 6，δ ppm）：1.33（9H，s），2.2-2.8（8H，m），3.09（4H，brs），3.72（1H，m），6.5-7.0（7H，m），7.20（2H，t，J＝8.3Hz），9.10（1H，s）;
IR（KBr）cm -1：1690，1500，1230.
Reference example 14.1-(2-amino-3-(p-hydroxybenzene) propyl group)-the 4-phenylpiperazine
Derive from the solution of hydrochloric acid in ethyl acetate 30 minutes that drips 215ml4N in the suspension of crystal in the 100ml ethyl acetate of reference example 13 to 23.6g, stir after 90 minutes, under reduced pressure excessive hydrochloric acid is removed from reaction mixture.After the extraction of 200ml water, with of the aqueous hydrochloric acid extraction of isolating ethyl acetate layer with 50ml1N.Water layer is merged and is neutralized to PH with solid-state sodium bicarbonate is 7.4, collects the crystal of gained, and water and benzene washing are dry under decompression in moisture eliminator with Vanadium Pentoxide in FLAKES, obtains the title compound 16.9g of clear crystal.
Fusing point:＞270 ℃;
IR（KBr）cm -1：1600，1470，1230;
1H-NMR（DMSO-d 6，δ ppm）：2.2-3.5（13H，m），6.7-6.8（3H，m），6.90（2H，d，J＝8.3Hz），7.07（2H，d，J＝8.3Hz），7.19（2H，t，J＝7.6Hz），8.00（2H，brs），9.41（1H，brs）.
Embodiment 34.N-{ 1-(to (5-isoquinoline 99.9 sulfonyloxy) benzyl-2-(4-Phenylpiperazinyl) ethyl }-5-isoquinoline sulfonaide
In the suspension of crystal in the 700ml tetrahydrofuran (THF) of the 22.96g that derives from reference example 14,, dripped the 103ml triethylamine then 30 minutes with the ice-cooled 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl that in 5 minutes, adds 51.01g.After reaction mixture is heated to room temperature, it is poured in the frozen water of 460ml, with it all with the chloroform extraction of 920ml and 230ml.The extract that merges is washed with saturated sodium-chloride water solution, use dried over mgso, under reduced pressure be concentrated to drying.The amorphous residue of gained is imposed on a silicagel column,, obtain the yellow amorphous title compound of 45.5g with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.
IR（KBr）cm -1：1600，1500，1130;
1H-NMR（CDCl 3，δ ppm）：2.0-3.0（12H，m），3.30（1H，m），5.51（1H，brs），6.7-7.8（11H，m），8.20（1H，d，J＝8.2Hz），8.28（2H，d，J＝7.7Hz），8.4-8.5（2H，m），8.53（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz）8.81（1H，d，J＝6.1Hz），9.35（1H，s），9.42（1H，s）.
Embodiment 35.N-1-(to (5-isoquinoline 99.9 sulfonyloxy) benzyl)-2-(4-Phenylpiperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Derive to 25.0g and to divide three parts to add the sodium hydride of 1.64g60% in the solution of amorphous compound in the 200ml dimethyl formamide among the embodiment 34, splashed into the 3.14ml methyl-iodide after 5 minutes again 2 minutes, this reaction mixture was stirred 1 hour.This reaction mixture to going in the 400ml frozen water, is extracted its integral body with 200ml, 200ml and 100ml ethyl acetate again.The extract that merges with saturated sodium-chloride water solution washing 3 times, use dried over mgso, concentrate down, the residue of gained is imposed on a silicagel column, use trichloromethane/methyl alcohol (100: 1) wash-out again, obtain the amorphous title compound of 20.0g yellow in decompression.
1H-NMR（CDCl 3，δ ppm）：2.30（1H，dd，J＝6.8，12.2Hz），2.39-2.52（5H，m），2.68（1H，dd，J＝7.3，14.2Hz），2.86（3H，s），2.89-3.01（5H，m），4.18（1H，m），6.61（2H，d，J＝8.3Hz），6.83-6.92（5H，m），7.26（2H，t，J＝7.8Hz），7.57（1H，t，J＝7.8Hz），7.60（1H，t，J＝7.8Hz），8.10（1H，d，J＝8.3Hz），8.23-8.28（3H，m），8.33（1H，dd，J＝1.0，7.3Hz），8.56（1H，d，J＝5.9Hz），8.58（1H，d，J＝5.9Hz），8.83（1H，d，J＝5.9Hz），9.27（1H，s），9.41（1H，d，J＝1.0Hz）
IR（KBr）cm -1：1620，1500，1370，1325，1130
Embodiment 36.N-(1-(is to hydroxybenzyl)-2-(4-Phenylpiperazinyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
The aqueous sodium hydroxide solution that adds 240ml methyl alcohol, 60ml tetrahydrofuran (THF) and 29ml2N in embodiment 35 among the amorphous compound 17.7g that obtains with this mixture reflux 150 minutes, is poured in the saturated sodium-chloride water solution then.With 200ml chloroform extraction 3 times of this mixture, wash extract with saturated sodium-chloride water solution, use dried over mgso, under reduced pressure concentrate.The residue that obtains is imposed on a silicagel column,, from eluate, obtain the yellow amorphous product of 10.9g with trichloromethane/methyl alcohol (50: 1) wash-out.In this product, add 54ml ethanol, this mixture was stirred under room temperature 1 hour, formed crystal at ice-cooled following 30 minutes, collect this crystal then, with mother liquor washing 3 times, with benzene washing 2 times, drying under reduced pressure, the title compound 8.2g of acquisition light yellow crystal.
Fusing point: 210 ℃;
1H-NMR（CDCl 3，δ ppm）：2.49（1H，dd，J＝6.8，9.8Hz），2.52-2.77（7H，m），2.95（1H，dd，J＝4.4，14.2Hz），3.02（3H，s），3.14（4H，t，J＝4.9Hz），4.03（1H，m），6.26（2H，d，J＝8.3Hz），6.61（2H，d，J＝8.8Hz），6.86（1H，t，J＝6.8Hz），6.91（2H，d，J＝7.3Hz），7.27（2H，t，J＝7.8Hz），7.60（1H，t，J＝7.3Hz），8.11（1H，d，J＝5.9Hz），8.14（1H，d，J＝6.4Hz），8.33（1H，dd，J＝1.0，7.3Hz），8.47（1H，d，J＝6.3Hz），9.27（1H，s）;
IR（KBr）cm -1：1600，1510，1445，1320，1205，1150，1125.
Embodiment 37.
Amorphous compound alkaline hydrolysis according to making in the step described in the embodiment 36 in embodiment 34 obtains colourless amorphous N-(1-(is to hydroxybenzyl)-2-(4-Phenylpiperazinyl) ethyl)-the 5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：2.25-2.55（6H，m），2.65（1H，dd，J＝13.7，6.85Hz），2.79（1H，dd，J＝13.7，6.85Hz），2.82-3.0（4H，m），3.37（1H，quintet，J＝6.85Hz），6.42（2H，d，J＝8.57Hz），6.69（2H，d，J＝8.57Hz），6.84（2H，d，J＝8.57Hz），6.85（1H，t，J＝8.57Hz），7.26（2H，t，J＝8.57Hz），7.69（1H，t，J＝7.42Hz），8.22（1H，d，J＝7.99Hz），8.38（1H，d，J＝6.28Hz），8.43（1H，dd，J＝7.42，1.0Hz），8.59（1H，d，J＝6.28Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 38.N-(1-(is to methoxybenzyl)-2-(4-Phenylpiperazinyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
1.51g is derived from the mixed solvent of dimethyl formamide/tetrahydrofuran (THF) (1: 1) that crystal among the embodiment 36 is dissolved in 20ml, down along with stirring the sodium hydride that in this solution, adds 140mg60%, continue to stir 30 minutes ice-cooled.After forming foam, add the 490mg methyl-iodide, at room temperature mixture is further stirred a night.After adding ice,, wash extract, with dried over mgso and under reduced pressure concentrated with saturated sodium-chloride water solution with 50ml ethyl acetate extraction 3 times of this reaction mixture.The residue that obtains is imposed on a silicagel column, and, obtain the light brown buttery title compound of 1.55g with trichloromethane/methyl alcohol (100: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：2.45（1H，dd，J＝7.1，13.8Hz），2.6（5H，m），2.65（1H，m），2.88（1H，s），2.95（3H，s），3.05（4H，m），3.74（3H，s），4.2（1H，m），6.5（2H，d，J＝8.5Hz），6.9（5H，m），7.25（2H，m），7.55（1H，t，J＝7.5Hz），8.07（1H，d，J＝7.5Hz），8.22（1H，d，J＝6.4Hz），8.56（1H，d，J＝6.4Hz），9.22（1H，s）;
IR（KBr）cm -1：1600，1510，1320，1240，1150，1130.
Embodiment 39.
Except that with the 1-(2-pyrimidyl) the piperazine dihydrochloride is used for the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and the embodiment 34, obtain colourless amorphous N-{ 1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-2-((4-(2-pyrimidyl) piperazinyl) ethyl }-5-isoquinoline sulfonaide
1H-NMR（CDCl 3，δ ppm）：1.8-1.96（2H，m），1.96-2.24（4H，m），2.8（1H，dd，J＝13.7，6.85Hz），2.92（1H，dd，J＝13.7，4.57Hz），3.0-3.47（5H，m），5.49（1H，br），6.47（1H，t，J＝4.57Hz），6.70（2H，d，J＝8.57Hz），6.94（2H，d，J＝8.57Hz），7.64（1H，t，J＝7.42Hz），7.70（1H，t，J＝7.42Hz），8.17-8.35（5H，m），8.37-8.48（2H，m）8.52（1H，d，J＝5.71Hz），8.68（1H，d，J＝6.28Hz），8.82（1H，d，J＝6.28Hz）9.37（1H，s），9.42（1H，d，J＝1.0Hz）.
Embodiment 40.
The amorphous compound of Processing Example 39 as described in example 37 above, obtain N-1-(is to hydroxybenzyl)-2-(4-(2-pyrimidyl) piperazinyl) ethyl-the 5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：2.05-2.55（6H，m），2.66（1H，dd，J＝13.13，6.85Hz），2.82（1H，dd，J＝13.13，6.28Hz），3.2-3.7（5H，m），6.42（2H，d，J＝7.99Hz），6.46（1H，t，J＝4.57Hz），6.72（2H，d，J＝7.99Hz），7.68（1H，t，J＝7.42Hz），8.20（1H，d，J＝8.57Hz），8.27（2H，d，J＝4.57Hz），8.35-8.50（2H，m），8.57（1H，d，J＝5.71Hz），9.31（1H，s）
Embodiment 41.
The amorphous compound of Processing Example 39 as described in example 35 above obtains colourless amorphous N-{ 1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-2-(4-(2-pyrimidyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
1H-NMR(CDCl 3, δ ppm): 2.15-2.36(5H, m), 2.44(1H, dd, J=13.7,6.85Hz), 2.71(1H, dd, J=13.13,6.85Hz), 2.8-2.95(1H, m), 2.87(3H, s), 3.56(4H, m), 4.17(1H, quintet, J=6.85Hz), 6.48(1H, t, J=4.85Hz), 6.63(2H, d, J=9.14Hz), 6.92(2H, d, J=9.14Hz), 7.58(1H, t, J=6.85Hz), 7.61(1H, t, J=6.85Hz), 8.13(1H, d, J=7.42Hz), 8.18-8.38(6H, m), 8.56(1H, d, J=6.28Hz), 8.58(1H, d, J=6.28Hz), 8.84(1H, d, J=6.28Hz), 9.28(1H, s), 9.42(1H, d, J=1.0Hz)
Embodiment 42.
The amorphous compound of Processing Example 41 as described in example 36 above, obtain colourless amorphous N-1-(is to acrinyl)-2-(4-(2-pyrimidyl) piperazinyl) ethyl-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1585，1510，1355，1325，1255，1130;
1H-NMR（CDCl 3，δ ppm）：2.4-2.65（6H，m），2.70（1H，dd，J＝13.13，6.28Hz），2.97（1H，dd，J＝13.13，5.71Hz），3.03（3H，s），3.77（4H，t，J＝4.57Hz），4.04（1H，m），6.28（2H，d，J＝8.57Hz），6.49（1H，t，J＝5.14Hz），6.62（2H，d，J＝8.57Hz），7.62（1H，t，J＝7.42Hz），8.11（1H，d，J＝6.28Hz），8.15（1H，d，J＝7.42Hz），8.30（2H，d，J＝5.14Hz），8.32（1H，dd，J＝7.42，1.0Hz），8.48（1H，d，J＝6.28Hz），9.28（1H，s）.
Embodiment 43.
Except that with the N-(tert-butoxycarbonyl) phenylalanine is used for the N-(tert-butoxycarbonyl) the tyrosine position, repeat the same steps as described in reference example 12-14 and embodiment 34 and 35, obtain faint yellow amorphous N-(1-benzyl-2-(4-Phenylpiperazinyl) ethyl)-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1595，1490，1300，1220，1120;
1H-NMR(CDCl 3, δ ppm): 2.45(1H, dd, J=6.6,13Hz), 2.7(1H, dd, J=8,13Hz), 2.55(5H, m), 3.0(5H, m), 4.3(1H, m), 6.84, the total 3H of 6.9(, m), 7.0(5H, brs), 7.25(2H, m), 7.5(1H, t, J=7.5Hz), 8.05(1H, d, J=8Hz), 8.2(1H, d, J=7.5Hz), 8.05(1H, d, J=8Hz), 8.2(1H, d, J=7.5Hz), 8.3(1H, d, J=8Hz), 8.55(1H, d, J=6.1Hz), 9.23(1H, s).
Embodiment 44.
Except that with the N-(2-pyridyl) piperazine is used for the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and the embodiment 34, obtain yellow amorphous N-{ 1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl-2-(4-(2-pyridyl) piperazinyl) ethyl }-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1615，1590，1480，1430，1370，1310，1150，1130;
1H-NMR（CDCl 3，δ ppm）：1.93-2.21（6H，m），2.77（1H，dd，J＝7.3，14.2Hz），2.83-3.00（3H，m），3.02-3.19（2H，m），3.29（1H，m），5.46（1H，br），6.47（1H，d，J＝8.8Hz），6.62（1H，dd，J＝4.9，7.3Hz），6.69（2H，d，J＝8.8Hz），6.92（2H，d，J＝8.8Hz），7.44（1H，ddd，J＝1.0，8.8，7.3Hz），7.64（1H，t，J＝7.8Hz），7.70（1H，dd，J＝7.3，8.3Hz），8.13（1H，dd，J＝1.0，4.9Hz），8.22（1H，d，J＝8.3Hz），8.28（2H，d，J＝7.3Hz），8.43（2H，m），8.53（1H，d，J＝5.9Hz），8.67（1H，d，J＝6.3Hz），8.81（1H，d，J＝5.9Hz），9.35（1H，d，J＝1.0Hz），9.42（1H，s）.
Embodiment 45.
As product in Processing Example 44 described in the embodiment 35, acquisition N-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-2-(4-(2-pyridyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1590，1480，1430，1370，1310，1130;
1H-NMR（CDCl 3，δ ppm）：2.23-2.50（6H，m），2.69（1H，dd，J＝7.3，14.2Hz），2.86（3H，s），2.88（1H，dd，J＝14.2，10.2Hz），3.30（4H，m），4.18（1H，m），6.55-6.65（4H，m），6.90（2H，d，J＝8.8Hz），7.47（1H，ddd，J＝1.0，7.3，8.8Hz），7.58（1H，dd，J＝7.3，8.3Hz），7.60（1H，t，J＝7.8Hz），8.11（1H，d，J＝8.3Hz），8.17（1H，dd，J＝1.0，4.9Hz），8.22-8.27（3H，m），8.33（1H，dd，J＝1.0，7.3Hz），8.56（1H，d，J＝5.9Hz），8.58（1H，d，J＝5.9Hz），8.84（1H，d，J＝6.4Hz），9.28（1H，s），9.41（1H，s）.
Embodiment 46.
The product of Processing Example 45 as described in example 36 above, obtain N-1-(is to acrinyl)-2-(4-(2-pyridyl) piperazinyl) ethyl-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1590，1475，1445，1320，1230，1150，1125;
1H-NMR（CDCl 3，δ ppm）：2.48（1H，dd，J＝3.4，9.4Hz），2.50-2.75（6H，m），2.95（1H，dd，J＝4.9，14.7Hz），3.02（3H，s），3.49（4H，t，J＝4.9Hz），4.06（1H，m），6.27（2H，d，J＝8.3Hz），6.62（2H，d，J＝8.3Hz），6.61-6.66（2H，m），7.43（1H，ddd，J＝1.0，7.3，8.8Hz），7.61（1H，dd，J＝7.3，8.3Hz），8.10-8.16（2H，m），8.19（1H，dd，J＝1.0，4.3Hz），8.32（1H，dd，J＝1.0，7.3Hz），8.48（1H，d，J＝6.4Hz），9.28（1H，s）.
Embodiment 47.
Except that with chloro-phenyl-between N-() piperazine is used for the position of N-phenylpiperazine, repeat the same steps as described in reference example 12-14 and the embodiment 34-36, obtain light yellow amorphous N-2-(chloro-phenyl-between 4-() piperazinyl)-1-(is to acrinyl) ethyl)-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1590，1320，1230，1130;
1H-NMR（CDCl 3，δ ppm）：2.5（1H，dd，J＝12.0，10Hz），2.5-2.8（2H，m），2.6-2.7（4H，m），2.95（1H，dd，J＝4.5，13.8Hz），3.0（3H，s），3.15（4H，m），4.0（1H，m），6.22（2H，d，J＝8.0Hz），6.55（2H，d，J＝8.0Hz），6.77（1H，dd，J＝8.5，2.2Hz），6.8（1H，d，J＝8.0Hz），6.85（1H，d，J＝2.2Hz），7.16（1H，t，J＝8.0Hz），7.6（1H，t，J＝7.8Hz），8.1（1H，d，J＝6.1Hz），8.15（1H，d，J＝8.1Hz），8.3（1H，d，J＝7.3Hz），8.45（1H，d，J＝6.4Hz），9.28（1H，s）.
Embodiment 48.
Except that with N-(to fluorophenyl) piperazine is used for the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and the embodiment 34, obtain colourless amorphous N-{ 2-(4-(is to fluorophenyl) piperazinyl)-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl) ethyl) }-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1500，1370，1320，1210，1130，860，820;
1H-NMR（CDCl 3，δ ppm）：2.0-2.3（5H，m），2.4-2.9（6H，m），3.3（1H，m），6.6-6.75（4H，m），6.85-7.0（4H，m），7.65（1H，t，J＝8.1Hz），7.7（1H，t，J＝8.4Hz），8.2（1H，d，J＝8.3Hz），8.3（1H，d，J＝7.8Hz），8.4（1H，d，J＝6.3Hz），8.4（1H，d，J＝6.1Hz），8.5（1H，d，J＝6.1），8.65（1H，d，J＝6.1Hz），8.8（1H，d，J＝6.3Hz），9.3（1H，s），9.4（1H，s）.
Embodiment 49.
The amorphous compound that derives from embodiment 48 is methylated by the step described in the embodiment 35, obtain light yellow amorphous N-{ 2-(4-(is to fluorophenyl) piperazinyl)-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1620，1510，1370，1330，1210，1140
1H-NMR（CDCl 3，δ ppm）：2.3（1H，dd，J＝12.1，6.5Hz），24.5（4H，m），2.4-2.6（1H，m），2.67（1H，dd，J＝13.8，7.8Hz），2.75-3.0（5H，m），4.17（1H，m），6.63（2H，d，J＝8.6Hz），6.7-7.0（6H，m），7.57（1H，t，J＝8.0Hz），7.60（1H，t，J＝7.6Hz），8.1（1H，d，J＝8.0Hz），8.2-8.35（4H，m），8.55（1H，d，J＝5.4Hz），8.56（1H，d，J＝8.1Hz），8.83（1H，d，J＝6.3Hz），9.27（1H，d，J＝0.7Hz），9.40（1H，d，J＝1.0Hz）
Embodiment 50.
According to the step described in the embodiment 36, the 160mg amorphous compound that derives among the embodiment 49 is dissolved in the 2ml methyl alcohol, to the sodium hydroxide of this solution adding 0.5ml2N, with this reaction mixture refluxed heating 2 hours, chloroform extraction 3 times were used in cooling.Extract is purified with trichloromethane/methyl alcohol (100: 2) on a silicagel column, the light yellow amorphous N-of acquisition 103mg 1-(is to acrinyl)-2-(4-(is to fluorophenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1500，1320，1230，1150，1130，820;
1H-NMR（CDCl 3，δ ppm）：2.4-2.6（2H，m），2.6-2.8（1H，m），2.8-3.0（1H，m），2.75（4H，m），3.05（1H，m），3.1（1H，m），6.3（2H，d，J＝8.3Hz），6.67（2H，d，J＝8.3Hz），6.87（2H，dd，J＝8.3，10.1Hz），6.95（2H，t，J＝8.3Hz），7.6（1H，dd，J＝7.6，8.0Hz），8.12（1H，d，J＝9.0Hz），8.13（1H，d，J＝6.1Hz），8.3（1H，d，J＝7.3Hz），8.5（1H，d，J＝6.1Hz），9.25（1H，s）.
Embodiment 51.
Except that with tolyl between N-() piperazine is used for the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and the embodiment 34-36, obtain light yellow amorphous N-{ 1-(to acrinyl)-2-(tolyl between 4-() piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1600，1440，1320，1210，1190，1150，1120;
1H-NMR(CDCl 3, δ ppm): 2.30(3H, s), 2.55(4H, m), 2.96(1H, dd, J=11.6,7.1Hz), 2.5-2.9(3H, m), 2.9(3H, s), 3.1(4H, m), 4.3(1H, m), and 6.8(2H, d, J=8.3Hz), 7.0(2H, d, J=8.3Hz), 7.0-7.15(3H, m), 7.3(1H, m), 7.55(1H, t, J=7.8Hz), 8.1(1H, d, J=7.8Hz), 8.2-8.3(2H, complex spike 8.58(1H, d, J=6.1Hz), 9.25(1H, s).
Embodiment 52.
Except that with the N-(p-methoxyphenyl) piperazine is used for the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and the embodiment 34 successively, obtain yellow amorphous N-{ 1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl-2-(4-(p-methoxyphenyl) piperazinyl) ethyl }-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1615，1500，1360，1130;
1H-NMR（CDCl 3，δ ppm）：1.96-2.22（6H，m），2.39-2.52（2H，m），2.52-2.67（2H，m），2.77（1H，dd，J＝7.3，14.2Hz），2.90（1H，dd，J＝4.4，14.2Hz），3.27（1H，m），3.76（3H，s），5.50（1H，br），6.70（4H，d，J＝8.8Hz），6.82（2H，d，J＝8.8Hz），6.94（2H，d，J＝8.8Hz），7.65（1H，t，J＝7.8Hz），7.70（1H，t，J＝7.3Hz），8.21（1H，d，J＝8.3Hz），8.29（2H，d，J＝7.8Hz），8.40-8.43（2H，m），8.53（1H，d，J＝5.9Hz），8.68（1H，d，J＝6.4Hz），8.81（1H，d，J＝5.9Hz），9.36（1H，s），9.42（1H，s）.
Embodiment 53.
With the amorphous compound of methyl-iodide, obtain yellow amorphous N-{ 1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-2-(4-(p-methoxyphenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide according to the step process embodiment 52 described in the embodiment 35.
IR（KBr）cm -1：1665，1615，1505，1365，1320，1130;
1H-NMR（CDCl 3，δ ppm）：2.30（1H，dd，J＝6.8，12.2Hz），2.37-2.51（5H，m），2.68（1H，dd，J＝7.3，14.2Hz），2.85（3H，s），2.78-2.97（5H，m），3.77（3H，s），4.16（1H，m），6.62（2H，d，J＝8.3Hz），6.82（4H，s），6.90（2H，d，J＝8.3Hz），7.57（1H，t，J＝7.8Hz），7.60（1H，t，J＝7.8Hz），8.11（1H，d，J＝8.3Hz），8.23-8.28（3H，m），8.33（1H，dd，J＝1.0，7.3Hz），8.56（1H，d，J＝6.4Hz），8.58（1H，d，J＝6.4Hz），8.83（1H，d，J＝5.9Hz），9.27（1H，d，J＝1.0Hz），9.41（1H，d，J＝1.0Hz）.
Embodiment 54.
Make amorphous compound from embodiment 53 according to the step alkaline hydrolysis described in the embodiment 36, obtain N-1-(is to acrinyl)-2-(4-(p-methoxyphenyl) piperazinyl) ethyl-yellow crystals of N-methyl-5-isoquinoline sulfonaide.
Fusing point: 157-160 ℃ (decomposition)
IR（KBr）cm -1：1615，1510，1445，1320，1305，1240，1125;
1H-NMR（CDCl 3，δ ppm）：2.46-2.74（7H，m），2.88-3.02（5H，m），3.00（3H，s），3.77（3H，s），4.06（1H，m），6.30（2H，d，J＝8.3Hz），6.65（2H，d，J＝8.3Hz），6.83（2H，d，J＝9.3Hz），6.88（2H，d，J＝9.3Hz），7.57（1H，dd，J＝7.3，8.3Hz），8.12（1H，d，J＝8.3Hz），8.13（1H，d，J＝6.4Hz），8.32（1H，dd，J＝1.0，7.3Hz），8.50（1H，d，J＝6.4Hz），9.26（1H，s）.
Embodiment 55.
Make amorphous compound from embodiment 52 according to step alkaline hydrolysis described in the embodiment 37, obtain N-1-(is to acrinyl)-2-(4-(p-methoxyphenyl) piperazinyl) ethyl-yellow crystals of 5-isoquinoline sulfonaide.
Fusing point: 200-208 ℃ (decomposition)
IR（KBr）cm -1：1615，1590，1510，1450，1340，1230，1150，1130，1025;
1H-NMR（CDCl 3，δ ppm）：2.20-2.44（6H，m），2.58-2.82（6H，m），3.33（1H，m），3.77（3H，s），5.55（1H，br），6.47（2H，d，J＝8.3Hz），6.76（2H，d，J＝8.3Hz），6.78（2H，d，J＝6.8Hz），6.83（2H，d，J＝6.8Hz），7.70（1H，t，J＝7.8Hz），8.21（1H，d，J＝8.3Hz），8.40（1H，d，J＝6.4Hz），8.44（1H，dd，J＝1.0，7.3Hz），8.64（1H，d，J＝6.4Hz），9.34（1H，s）.
Embodiment 56.
Except that with the N-(2-methoxyphenyl) piperazine is used in the N-phenylpiperazine position, repeat the same steps as described in reference example 12-14 and embodiment 34 and 35 successively, acquisition N-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-2-(4-(2-methoxyphenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide, make this compound of 800mg according to step alkaline hydrolysis described in the embodiment 36, the light yellow amorphous N-of acquisition 504mg 1-(is to acrinyl)-2-(4-(2-methoxyphenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1590，1500，1320，1230，1130;
1H-NMR（CDCl 3，δ ppm）：2.5（1H，dd，J＝13.8，10.0Hz），2.55-2.8（2H，m），2.9-3.0（1H，m），2.7（4H，m），3.0（4H，m），3.05（3H，s），3.86（3H，s），4.0（1H，m），6.23（2H，d，J＝8.3Hz），6.57（2H，d，J＝8.3Hz），6.8-7.1（4H，m），7.6（1H，t，J＝8.0Hz），8.14（1H，d，J＝6.1Hz），8.16（1H，d，J＝7.9Hz），8.35（1H，dd，J＝7.4，1.0Hz），9.30（1H，s）.
Embodiment 57.
To derive from 1-(2-amino-3-(is to the hydroxyphenyl) propyl group of reference example 14)-4-phenylpiperazine crystal is according to the step of embodiment 34 and the reaction of 1-naphthalene sulfonyl base chlorine; the product that so obtains is handled with methyl-iodide according to the step described in the embodiment 35, obtain colourless amorphous N-methyl-N-1-(is to α-naphthalene sulfonyl base oxygen) phenyl)-the 2-(4-Phenylpiperazinyl) ethyl-α-naphthalene sulfonylamide.
1H-NMR(CDCl 3, δ ppm): 2.26(1H, dd, J=12.56,6.85Hz), 2.42(4H, m), 2.48(1H, dd, J=12.56,6.85Hz), 2.68(1H, dd, J=14.85,6.85Hz), 2.84(1H, dd, J=14.85,6.85Hz), 2.85(3H, s), 2.92(4H, m), 4.12(1H, quintet, J=6.85Hz), 6.56(2H, d, J=8.0Hz), 6.78-6.92(5H, m), 7.26(2H, t, J=8.0Hz), 7.42(2H, t, J=8.0Hz), 7.46-7.58(2H, m), 7.68(1H, dt, J=8.0,1.0Hz), 7.77-7.90(2H, m), 7.90-8.07(3H, m), 8.12(1H, d, J=8.57Hz), 8.17(1H, dd, J=8.57,1.0Hz), 8.45(1H, m), 8.84(1H, d, J=9.14Hz)
Embodiment 58.
The amorphous compound that embodiment 57 is obtained obtains colourless amorphous N-(1-(is to acrinyl)-2-(4-Phenylpiperazinyl according to the step alkaline hydrolysis described in the embodiment 36) ethyl)-N-methyl-α-naphthalene sulfonylamide.
IR（KBr）cm -1：1595，1315，1310，1225，1150，1120;
1H-NMR(CDCl 3, δ ppm): 2.37(1H, dd, J=13.70,6.85Hz), 2.47(4H, m), 2.55(1H, dd, J=13.70,6.85Hz), 2.72(1H, dd, J=14.28,6.85Hz), 2.85(1H, dd, J=14.28,6.85Hz), 2.89(3H, s), 2.97(4H, m), 4.27(1H, quintet, J=6.85Hz), 5.10(1H, br), 6.57(2H, d, J=7.99Hz), 6.78-6.89(3H, m), 6.91(2H, d, J=7.99Hz), 7.25(2H, t, J=7.99Hz), 7.43(1H, t, J=7.42Hz), 7.50-7.63(2H, m), 7.86(1H, dd, J=7.99,1.0Hz), 7.98(1H, d, J=7.42Hz), 8.22(1H, dd, J=7.42,1.0Hz), 8.56(1H, dd, J=7.99,1.0Hz).
Reference example 15.1-(2-amino-3-(is to hydroxyl) phenyl) propyl group }-4-carbobenzoxy-(Cbz) piperazine
With the 1-(N-tertbutyloxycarbonyl tyrosyl of 1.41g according to the step described in the reference example 11 preparation)-the 4-(carbobenzoxy-(Cbz)) piperazine is dissolved in the 5.6ml anhydrous ethyl acetate,, down along with stirring the hydrogenchloride in ethyl acetate 2 minutes that drips 11.25ml4N to this solution this reaction mixture was stirred under room temperature 2 hours ice-cooled.After this reaction is finished, down solvent evaporation is fallen, added the sodium bicarbonate aqueous solution of 20ml5% to residue in decompression.With this mixture 30ml, use the mixed extractant solvent of trichloromethane/methyl alcohol (9: 1) of 20ml then, wash extract with saturated sodium-chloride water solution, with dried over mgso and filtration.
Filtrate is evaporated to obtain a kind of colourless foam down in decompression.This foam is imposed on a silicagel column,, obtain the colourless amorphous title compound of about 700mg with trichloromethane/methyl alcohol (6: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：2.2-2.8（8H，m），3.19（1H，m），3.50（7H，brs），5.13（2H，s），6.71（2H，d，J＝8.5Hz），7.02（2H，d，J＝8.5Hz），7.35（5H，s）.
Embodiment 59.N-2-(4-carbobenzoxy-(Cbz) piperazinyl)-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl)-ethyl }-the 5-isoquinoline sulfonaide
The amorphous compound that obtains in the 680mg reference example 15 is dissolved in the 18ml anhydrous tetrahydro furan, add 1.27g5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl to this solution, dripped the 3.20ml triethylamine 1 minute along with stirring down in ice-cooled then, this mixture was stirred under room temperature 150 minutes.Dilute this reaction mixture with the 50ml trichloromethane, and wash with water, with this washing lotion 20ml chloroform extraction.The organic extract that merges is washed with saturated sodium chloride aqueous solution, use dried over mgso, filter this filtrate of vapourisation under reduced pressure.The residue that obtains is imposed on a silicagel column,, obtain the light yellow amorphous title compound of 987mg with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）cm -1：1700，1620，1500，1370，1230，1130;
1H-NMR（CDCl 3，δ ppm）：1.8-2.2（6H，m），2.7-3.4（7H，m），5.05（2H，s），5.36（1H，brs），6.67（2H，d，J＝8.4Hz），6.89（2H，d，J＝8.4Hz），7.2-7.4（5H，m），7.62（1H，d，J＝7.7Hz），7.69（1H，d，J＝7.7Hz），8.2-8.5（5H，brs），8.52（1H，d，J＝6.2Hz），8.68（1H，d，J＝6.2Hz），8.81（1H，d，J＝5.9Hz），9.34（1H，s），9.41（1H，s）.
Embodiment 60.N-2-(4-carbobenzoxy-(Cbz) piperazinyl)-1-(to (5-isoquinoline 99.9 sulphonyl oxygen) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The amorphous compound that obtains among the 852mg embodiment 59 is dissolved in the 8.5ml anhydrous dimethyl formamide, along with stirring the sodium-chlor that adds 59mg60% down to this solution ice-cooled, add 113 μ l methyl-iodides again, with this reaction mixture along with ice-cooled stirring 2 hours.After adding the 30ml frozen water, ethyl acetate with 30ml, 20ml and 20ml extracts this reaction mixture, the extract that merges is washed with saturated sodium chloride aqueous solution, use dried over mgso, filter and under reduced pressure concentrate, the residue that obtains is imposed on a silicagel column,, obtain the light yellow amorphous title compound of 679mg with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）cm -1：1700，1620，1500，1370，1240，1130;
1H-NMR（CDCl 3，δ ppm）：2.23（5H，brs），2.3-2.9（3H，m），2.83（3H，s），3.25（4H，brs），4.09（1H，m），5.11（2H，s），6.60（2H，d，J＝8.7Hz），6.86（2H，d，J＝8.7Hz），7.34（5H，brs），7.5-7.7（2H，m），8.12（1H，d，J＝8.2Hz），8.1-8.3（4H，m），8.56（2H，m），8.84（1H，d，J＝6.1Hz），9.29（1H，s），9.41（1H，s）.
Embodiment 61.N-{ 2-((4-benzenesulfonyl) piperazinyl)-1-(to (5-isoquinolinesulfonylcompounds oxygen) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Add the solution of hydrogen iodide in acetate of 3ml30% in the amorphous compound that obtains in the 480mg embodiment 60, under room temperature, this mixture was stirred 80 minutes.Then the 50ml ether is added this mixture, stir this mixture then.Collect resulting throw out,, obtain the clear crystal of 567mg N-{ 1-(to (5-isoquinolinesulfonylcompounds oxygen) benzyl)-2-piperazinyl-ethyl }-N-methyl-5-isoquinoline sulfonaide HBr with ether washing, drying under reduced pressure.
1H-NMR（DMSO-d 6+D 2O，δ ppm）：3.06（3H，s），3.46（12H，brs），4.24（1H，brs），6.08（2H，d，J＝8.5Hz），6.74（2H，d，J＝8.5Hz），7.93（2H，m），8.25（1H，d，J＝6.7Hz），8.35（1H，d，J＝7.3Hz），8.5-8.8（5H，m），9.05（1H，d，J＝6.4Hz），9.86（2H，brs）.
The crystal that 550mg is obtained like this is suspended in the 10ml anhydrous tetrahydro furan, after ice-cooled stirring, adds 84 μ l benzene sulfonyl chlorides and 767 μ l triethylamines in this suspension, and this reaction mixture was stirred under room temperature 140 minutes.Then 30ml trichloromethane and 20ml water are added in this reaction mixture, after these layers are separated, with 20ml chloroform extraction waterbearing stratum.Trichloromethane is also laminated, with the saturated sodium-chloride water solution washing, with dried over mgso and filtration.With the filtrate vapourisation under reduced pressure, the resistates of gained is imposed on a silicagel column, with trichloromethane/methyl alcohol (100: 1) wash-out, obtain the light yellow amorphous title compound of 331mg.
IR（KBr）cm -1：1620，1500，1440，1330，1170;
1H-NMR（CDCl 3，δ ppm）：2.1-2.5（6H，m），2.5-2.8（6H，m），2.78（3H，s），4.05（1H，m），6.60（2H，d，J＝8.7Hz），6.83（2H，d，J＝8.7Hz），7.37（1H，t，J＝7.8Hz），7.5-7.8（6H，m），7.98（1H，d，J＝7.9Hz），8.1-8.3（4H，m），8.49（1H，d，J＝6.1Hz），8.55（1H，d，J＝6.1Hz），8.84（1H，d，J＝6.1Hz），9.17（1H，s），9.42（1H，s）
Embodiment 62.N-2-((4-benzenesulfonyl) piperazinyl)-1-(is to hydroxybenzyl)-ethyl }-N-methyl-5-isoquinoline sulfonaide
The amorphous compound that obtains among the 221ml embodiment 61 is dissolved in the mixing solutions of 2.69ml methyl alcohol and 0.66ml tetrahydrofuran (THF), in this solution, adds the sodium chloride aqueous solution of 0.33ml2N.With this reaction mixture refluxed heating 3.5 hours, in this mixture, add the aluminum chloride aqueous solution of 30ml trichloromethane and 20ml10%, formed layer is separated.With this waterbearing stratum of 20ml chloroform extraction, trichloromethane is also laminated, with the saturated sodium-chloride water solution washing, with dried over mgso and filtration.Filtrate in decompression evaporation down, is imposed on a silicagel column with the residue that obtains,, obtain the colourless amorphous title compound of 146mg with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）cm -1：1620，1510，1440，1320，1160;
1H-NMR（CDCl 3，δ ppm）：2.3-2.5（2H，m），2.60（4H，brs），2.6-2.8（2H，m），2.95（3H，s），3.01（4H，brs），3.92（1H，brs），6.21（2H，d，J＝8.2Hz），6.51（2H，d，J＝8.2Hz），7.4-7.8（6H，m），8.03（1H，d，J＝6.1Hz），8.09（1H，d，J＝8.2Hz），8.24（1H，dd，J＝1.2，7.3Hz），8.40（1H，d，J＝5.8Hz），8.68（1H，brs），9.23（1H，brs）.
Reference example 16. adjacent benzyls-N-carbobenzoxy-(Cbz) tyrosine
The adjacent phenyl of 27.25g-N-carbobenzoxy-(Cbz) tyrosine methyl ether is dissolved in the mixed solvent of 185ml ethanol and 122ml tetrahydrofuran (THF), in this solution, adds 5.8g lithium chloride and 5.2g sodium borohydride down ice-cooled.At room temperature this reaction mixture was stirred 18 hours, behind the interpolation 500ml saturated sodium-chloride water solution, with 300ml chloroform extraction secondary.Extract is also under reduced pressure concentrated with dried over mgso, obtain the clear crystal of 25.4g title compound.
1H-NMR（CDCl 3，δ ppm）：2.79（2H，d，J＝7.4Hz），3.51-3.79（2H，m），3.89（1H，m），4.93（1H，br），5.04（2H，s），5.08（2H，s），6.90（2H，d，J＝8.6Hz），7.11（2H，d，J＝8.6Hz），7.26-7.46（5H，m）.
Reference example 17.1-(2-benzyloxycarbonyl amino-3-(is to benzyl oxy phenyl) propyl group)-and the 4-(tertbutyloxycarbonyl) piperazine
The crystal that obtains in the 5.6g reference example 16 is dissolved in the 70ml tetracol phenixin, add the 4.5g triphenyl phosphine after, with this mixture reflux 20 hours.Reaction mixture is filtered to remove insolubles, under reduced pressure will filter molten concentrating.The residue of gained is imposed on a silicagel column, and with hexane/ethyl acetate (6: 1) wash-out, obtains 4.96g2-benzyloxycarbonyl amino-3-(benzyl oxy phenyl) clear crystal of propyl chloride.
1H-NMR(CDCl 3, δ PPm): 2.76-2.90(2H, m), 3.56-3.80(2H, m), 4.39(1H, m), 5.03(2H, s), 5.05, the total 2H of 5.13(, every s), 6.85, the total 2H of 6.89(, every d, every J=8.3Hz), 7.00, the total 2H of 7.09(, every d, every J=8.3Hz), 7.23-7.45(5H, m).
With above-mentioned crystal of 4.1g and 2.23gN-(tertbutyloxycarbonyl) piperazine is dissolved in the 40ml dimethyl formamide, adds 1.8g methyl-iodide and 1.66g salt of wormwood to this solution, this mixture was stirred 3 hours in 120 ℃.After adding the 100ml saturated sodium-chloride water solution,, reach this extract under reduced pressure concentrated with dried over mgso with 60ml chloroform extraction reaction mixture secondary.The residue of gained is imposed on a silicagel column, and, obtain the colourless amorphous title compound of 2.69g with hexane/ethyl acetate (2: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.45（9H，s），2.22-2.49（6H，m），2.82（2H，m），3.36（4H，m），3.94（1H，m），4.83（1H，br），8.03（2H，s），5.09（2H，s），6.88（2H，d，J＝8.3Hz），7.06（2H，d，J＝8.3Hz），7.30-7.45（5H，m）.
Embodiment 63.N-2-(4-(tertbutyloxycarbonyl) piperazinyl)-1-(to (5-isoquinolinesulfonylcompounds oxygen) benzyl)-ethyl } the 5-isoquinoline sulfonaide
The amorphous compound that obtains in the 1.6g reference example 17 is dissolved in the 25ml methyl alcohol, and adds the palladium on the carbon of being stated from of 1.0g5% to this solution.This mixture was stirred in nitrogen atmosphere 20 hours, and filter to remove insolubles.Filtrate is concentrated down in decompression.The residue of gained is dissolved in the 30ml tetrahydrofuran (THF), at ice-cooled 2.8g5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and the 4ml triethylamine of in solution, adding down.After stirring 3 hours under the room temperature, in reaction mixture, add 100ml water, with this mixture secondary of 70ml chloroform extraction,, and under reduced pressure concentrate the extract dried over mgso.The residue of gained is imposed on a silicagel column, and, obtain yellow amorphous title compound 1.27g with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.40（9H，s），1.75-2.18（6H，m），2.15-3.07（6H，m），3.27（1H，m），5.35（1H，br），6.67（2H，d，J＝8.3Hz），6.90（2H，d，J＝8.3Hz），7.65（1H，t，J＝7.8Hz），7.69（1H，t，J＝7.8Hz），8.21（1H，d，J＝8.3Hz），8.27-8.32（2H，m），8.37-8.41（2H，m），8.53（1H，d，J＝6.4Hz），8.69（1H，d，J＝6.9Hz），8.82（1H，d，J＝6.4Hz），9.36（1H，s），9.43（1H，s）.
Embodiment 64.
The amorphous compound that obtains among the 940mg embodiment 63 is dissolved in the mixed solvent of dimethyl formamide of 7.5ml tetrahydrofuran (THF) and 7.5ml, at ice-cooled sodium hydride and the 0.11ml methyl-iodide that in this solution, adds 67mg60% down successively, under room temperature, this mixture was stirred 1 hour.After adding the 30ml saturated sodium-chloride water solution,, this extract is washed with saturated sodium-chloride water solution, with dried over mgso and under reduced pressure concentrated with 40ml ethyl acetate extraction reaction mixture.The residue of gained is imposed on a silicagel column; and with trichloromethane/methyl alcohol (60: 1) wash-out, obtain the yellow amorphous N-of 723mg { 2-(4-(tertbutyloxycarbonyl) piperazinyl)-(to (5-isoquinolinesulfonylcompounds oxygen) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：1.44（9H，s），2.21（5H，m），2.40（1H，dd，J＝6.9，12.6Hz），2.15（1H，dd，J＝7.4，14.3Hz），2.83（1H，dd，J＝6.9，14.3Hz），2.84（3H，s），3.17（9H，m），4.12（1H，m），6.60（2H，d，J＝8.8Hz），6.86（2H，d，J＝8.8Hz），7.58（1H，t，J＝7.8Hz），7.63（1H，t，J＝7.8Hz），8.13（1H，d，J＝8.3Hz），8.21-8.30（4H，m），8.56（1H，d，J＝6.9Hz），8.57（1H，d，J＝5.9Hz），8.84（1H，d，J＝5.9Hz），9.29（1H，s），9.42（1H，s）.
Embodiment 65.
Add the spirit of salt in the ethyl acetate of being dissolved in of 10ml4N in the amorphous compound that in 720mg embodiment 64, obtains, this mixture was stirred under room temperature 1 hour, and concentrated down in decompression.In this mixture, add the 30ml saturated sodium bicarbonate aqueous solution, reaction mixture is extracted secondary with the mixed solvent of 20ml trichloromethane/Virahol (5: 1).With the extract dried over mgso, and under reduced pressure be concentrated into driedly, obtain the yellow amorphous N-{ 1-(to (5-isoquinolinesulfonylcompounds oxygen) benzyl) ethyl-2-piperazinyl } of 620mg-N-methyl-5-isoquinoline sulfonaide
1H-NMR（CDCl 3，δ ppm）：2.18-2.28（5H，m），2.37（1H，dd，J＝7.3，12.7Hz），2.63（4H，m），2.66（1H，dd，J＝7.3，14.8Hz），2.83（3H，s），2.86（1H，dd，J＝5.4，14.8Hz），4.13（1H，m），6.61（2H，d，J＝8.8Hz），6.89（2H，d，J＝8.8Hz），7.59（1H，t，J＝7.8Hz），7.63（1H，t，J＝7.8Hz），8.12（1H，d，J＝8.3Hz），8.23-8.35（4H，m），8.56（1H，d，J＝5.9Hz），8.58（1H，d，J＝6.4Hz），8.83（1H，d，J＝6.9Hz），9.29（1H，s），9.42（1H，s）.
Embodiment 66.
The amorphous compound that obtains among the 620mg embodiment 65 is dissolved in the 10ml methylene dichloride, with ice-cooled 0.29ml chloroformic acid benzyl ester and the 0.4ml triethylamine of in this solution, adding.With ice-cooled this reaction mixture was stirred 2 hours, behind the interpolation 40ml saturated sodium-chloride water solution, with 20ml chloroform extraction secondary.With the extraction liquid dried over mgso, and under reduced pressure concentrate, the residue of gained is imposed on a silicagel column, with trichloromethane/methyl alcohol (60: 1) wash-out, obtain the light yellow amorphous product of 660mg, it demonstrates 1The H-NMR spectrum is identical with the compound of embodiment 60.
Embodiment 67.
650mg must be dissolved in the 6ml methyl alcohol by this amorphous compound in embodiment 66, in this solution, add the aqueous sodium hydroxide solution of 2ml1N again.With this mixture reflux 2 hours, and after adding the saturated sodium chloride aqueous solution of 30ml, with 200ml trichloromethane/Virahol (5: 1) mixed extractant solvent 2 times.This extraction liquid is also under reduced pressure concentrated with dried over mgso, again the residue of this gained is imposed on the silicagel column and with trichloromethane/methyl alcohol (80: 1-50: 1) wash-out, the result obtain the yellow amorphous N-(2-(4-benzyloxycarbonyl piperazinyl) of 386mg-1-(right-acrinyl) ethyl)-N-methyl-S-isoquinoline sulfonaide.
IR（KBr）cm -1：1693，1510，1425，1320，1235，1120;
1H-NMR（CDCl 3，δ ppm）：2.39-2.55（6H，m），2.64（1H，dd，J＝6.4，12.7Hz），2.87（1H，dd，J＝4.4，14.6Hz），2.97（3H，s），3.44（4H，m），4.03（1H，m），5.13（2H，s），6.28（2H，d，J＝8.3Hz），6.62（2H，d，J＝8.3Hz），7.36（5H，s），7.39（1H，dd，J＝7.3，7.8Hz），8.09（1H，d，J＝5.9Hz），8.13（1H，d，J＝7.8Hz），8.26（1H，d，J＝7.3Hz），8.48（1H，d，J＝5.9Hz），9.27（1H，s）.
Embodiment 68.
Pressing on the step described in the embodiment 65 must remove in the protecting group of the part of the piperazine in the amorphous compound among the embodiment 63; and this intermediate product that will slough protecting group is by the step process described in embodiment 66 and 67, the result obtain N-(2-(4-benzyloxycarbonyl piperazinyl)-1-(right-acrinyl) ethyl)-the 5-isoquinoline sulfonaide.
IR（KBr）cm -1：1670，1510，1425，1320，1230，1150，1125，993;
1H-NMR（CDCl 3，δ ppm）：2.07-2.23（4H，m），2.30（1H，dd，J＝6.3，13.2Hz），2.39（1H，dd，J＝7.8，13.2Hz），2.62（1H，dd，J＝6.8，14.2Hz），2.76（1H，dd，J＝6.4，14.2Hz），3.00-3.38（5H，m），5.09（2H，s），6.41（2H，d，J＝8.3Hz），6.69（2H，d，J＝8.8Hz），7.33（5H，s），7.68（1H，dd，J＝7.3，8.3Hz）8.21（1H，d，J＝8.3Hz），8.35（1H，d，J＝5.9Hz），8.40（1H，dd，J＝1.0，7.3Hz），8.61（1H，d，J＝5.9Hz），9.34（1H，s）.
Embodiment 69.
Be repeated on the same step described in the embodiment 68 except that replacing the chloroformic acid benzyl ester with the phenyl propionyl chloride, the result obtain N-1-(is right-acrinyl)-2-(4-(3-hydrocinnamyl) piperazinyl) ethyl-the 5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1510，1445，1320，1150，1130，993;
1H-NMR（CDCl 3，δ ppm）：2.00-2.20（4H，m），2.26（1H，dd，J＝5.9，12.7Hz），2.36（1H，dd，J＝7.8，12.7Hz），2.46-2.60（2H，m），2.62-2.77（2H，m）2.83-3.00（2H，m），3.00-3.41（5H，m），5.24（1H，br），6.43（2H，d，J＝8.3Hz），6.71（2H，d，J＝8.3Hz），7.13-7.34（5H，m），7.69（1H，dd，J＝7.3，8.3Hz），8.20（1H，d，J＝7.8Hz），8.34（1H，d，J＝5.9Hz），8.40（1H，dd，J＝1.0，7.3Hz），8.63（1H，br），9.12（1H，br）.
Embodiment 70.
Except that replacing being repeated on the same step described in the embodiment 68 chloroformic acid benzyl ester with phenylcarbimide, the result obtains yellow amorphous N-(1-(right-acrinyl)-2-(4-phenylamino carbonyl piperazine base) ethyl)-the 5-isoquinoline sulfonaide.
1H-NMR（CDCl 3+CD 3OD，δ ppm）：2.37（1H，dd，J＝8.8，14.2Hz），2.65（1H，dd，J＝5.4，13.7Hz），2.73-3.20（4H，m），3.40-3.95（7H，m），6.12（2H，d，J＝8.3Hz），6.50（2H，d，J＝8.3Hz），7.05（1H，m），7.25-7.38（4H，m），7.67（1H，dd，J＝7.8，8.3Hz），8.21（1H，d，J＝7.8Hz），8.31（1H，d，J＝6.8Hz），8.53（1H，br），9.23（1H，br）.
Embodiment 71.
Except that replacing with benzyl mustard oil the chloroformic acid benzyl ester, repeat and the same step described in the embodiment 68, the result obtain yellow amorphous N-(2-(4-benzylaminocarbonyl piperazinyl)-1-(right-acrinyl) ethyl)-the 5-isoquinoline sulfonaide.
1H-NMR（CDCl 3-CD 3OD，δ ppm）：2.40-2.71（2H，m），2.76-3.23（4H，m），3.40-3.80（7H，m），4.39（2H，s），6.08（2H，d，J＝8.3Hz），6.46（2H，d，J＝8.3Hz），7.20-7.38（5H，m），7.63（1H，t，J＝7.8Hz），8.17（1H，d，J＝8.3Hz），8.29（2H，d，J＝6.9Hz），8.52（1H，br），9.23（1H，br）.
Embodiment 72.
200mg must be dissolved in the 5ml trichloromethane by this amorphous compound in embodiment 67, and in this solution, add 1ml methyl alcohol, with the ice-cooled solution of diazomethane in ether that adds again.This reaction mixture was stirred 90 minutes, concentrate then.The residue of gained imposed on the silicagel column and with trichloromethane/methyl alcohol (80: 1 to 50: 1) wash-out, the result obtain 103mgN-(2-(4-benzyloxycarbonyl piperazinyl)-1-(right-methoxy-benzyl) ethyl)-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1692，1508，1420，1320，1235，1120;
1H-NMR（CDCl 3，δ ppm）：2.32-2.45（5H，m），2.53-2.65（2H，m），2.78-2.90（1H，m）2.92（3H，s），3.37（4H，m），3.73（3H，s），4.16（1H，m），5.11（2H，s），6.50（2H，d，J＝8.3Hz）6.82（2H，d，J＝8.3Hz），7.35（5H，s），7.55（1H，t，J＝7.8Hz），8.09（1H，d，J＝8.3Hz），8.18（1H，d，J＝6.4Hz），8.22（1H，d，J＝7.3Hz），8.55（1H，d，J＝6.4Hz），9.24（1H，s）.
Embodiment 73.
Press the product of the step process embodiment 68 of embodiment 72, the result obtain N-(2-(4-phenyloxycarbonyl piperazinyl)-1-(right-methoxybenzyl) ethyl)-5-isoquinoline 99.9 sulfanilamide (SN).
1H-NMR（CDCl 3，δ ppm）：1.97-2.17（4H，m），2.19（1H，dd，J＝4.4，13.7Hz），2.28（1H，dd，J＝6.8，13.7Hz），2.70（1H，dd，J＝6.8，14.2Hz），2.82（1H，dd，J＝5.4，14.2Hz），3.03（2H，m），3.15（2H，m），3.34（1H，m），3.74（3H，s），5.07（2H，s），5.36（1H，br），6.59（2H，d，J＝8.8Hz），6.85（2H，d，J＝8.3Hz），7.27-7.37（5H，m），7.68（1H，dd，J＝7.3，7.8Hz），8.18（1H，d，J＝8.3Hz），8.39（1H，d，J＝5.9Hz），8.42（1H，dd，J＝1.0，7.8Hz），8.67（1H，d，J＝5.9Hz），9.33（1H，s）.
Embodiment 74.N-2-(4-benzoyl-piperazine base)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The middle crystal that 764mg is obtained in embodiment 61 is suspended in the 7ml tetrahydrofuran (THF), adds the 135ml Benzoyl chloride to this suspensoid again, and after 5 minutes along with ice-cooled adding 1.1ml triethylamine, stirred this mixture 1 hour.After adding trichloromethane and water, with this reaction mixture extraction 3 times, wash this extraction liquid with the 30ml trichloromethane with saturated sodium-chloride water solution, also under reduced pressure be concentrated into drying with dried over mgso.The lurid residue of 0.82g gained is imposed on silicagel column and uses trichloromethane/methyl alcohol (100: 1) wash-out, and the result obtains colourless amorphous this title compound of 198mg.
IR（KBr）cm -1：1620，1370，1130;
1H-NMR（CDCl 3，δ ppm）：2.2-2.8（10H，m），2.84（3H，s），3.1-3.7（4H，m），4.14（1H，m），6.61（2H，d，J＝8.6Hz），6.85（2H，d，J＝8.6Hz），7.3-8.6（14H，m），8.84（1H，d，J＝5.8Hz），9.30（1H，s），9.43（1H，s）.
Embodiment 75.N-(2-(4-benzoyl-piperazine base)-1-(is right-acrinyl) and ethyl)-N-methyl-5-isoquinoline sulfonaide
To adding 4ml methyl alcohol in the amorphous compound of the 349mg among the embodiment 74, the sodium hydroxide of 1ml tetrahydrofuran (THF) and 0.5ml2N, reflux added trichloromethane, water and sodium-chlor after 2 hours in this reaction mixture.With this reaction mixture of 30ml chloroform extraction 3 times, wash this extraction liquid with saturated sodium-chloride water solution, again with dried over mgso and under reduced pressure concentrate, the result obtains 0.25g xanchromatic oil.This oil is imposed on silicagel column and uses trichloromethane/methyl alcohol (50: 1) wash-out, and the result obtains colourless amorphous this title compound of 145mg.
IR（KBr）cm -1：1610，1440，1120;
1H-NMR（CDCl 3，δ ppm）：2.6-2.9（8H，m），2.99（3H，s），3.2-3.9（4H，m），4.00（1H，m），6.25（2H，d，J＝8.5Hz），6.56（2H，d，J＝8.5Hz），7.41（5H，s），7.59（1H，t，J＝7.9Hz），8.08（1H，d，J＝6.1Hz），8.15（1H，d，J＝7.9Hz），8.25（1H，d，J＝7.9Hz），8.46（1H，d，J＝6.1Hz），9.29（1H，s）
Embodiment 76.
Except that replacing the Benzoyl chloride with middle crystal among the 470mg embodiment 61 and 113mg benzyl SULPHURYL CHLORIDE; repeat in turn and the same step described in the embodiment 74 and 75, the result obtain the colourless amorphous N-of 116mg (2-(4-benzyl alkylsulfonyl piperazinyl)-1-(right-acrinyl) ethyl)-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1320，1150;
1H-NMR（CDCl 3，δ ppm）：2.3-2.9（8H，m），2.94（3H，s），3.0-3.2（4H，m），4.03（1H，m），4.20（2H，s），6.26（2H，d，J＝8.2Hz），6.56（2H，d，J＝8.2Hz），7.40（5H，s），7.60（1H，t，J＝7.9Hz），8.07（1H，d，J＝6.4Hz），8.15（1H，d，J＝7.9Hz），8.22（1H，d，J＝7.9Hz），8.46（1H，d，J＝6.4Hz），9.29（1H，s）.
Embodiment 77.
Except that replacing the Benzoyl chloride with middle crystal among the 382mg embodiment 61 and 133mg5-isoquinoline 99.9 sulfanilamide (SN) HCl; repeat the same step described in embodiment 74 and 75 in turn, the result obtain colourless amorphous N-1-(is right-acrinyl)-2-(4-(5-isoquinolinesulfonylcompounds) piperazinyl) ethyl-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1610，1320，1150;
1H-NMR（CDCl 3，δ ppm）：2.3-2.8（8H，m），2.90（3H，s），3.0-3.2（4H，m），3.95（1H，m），6.29（2H，d，J＝8.6Hz），6.53（2H，d，J＝8.6Hz），7.50（1H，t，J＝7.9Hz），7.75（1H，t，J＝7.9Hz），8.0-8.1（2H，m），8.17（1H，d，J＝7.9Hz），8.26（1H，d，J＝7.9Hz），8.3-8.5（2H，m），8.53（1H，d，J＝6.1Hz），8.70（1H，d，J＝6.1Hz），9.19（1H，s），9.39（1H，s）.
Embodiment 78.
Except that replace 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl with α-naphthalic sulfonic chloride, repeat successively and the same step described in the embodiment 59 and 60, the result obtain colourless amorphous N-2-(4-carbobenzoxy-(Cbz) piperazinyl)-1-(is right-(α-naphthalene sulfonyl oxygen base) benzyl) ethyl-N-methyl-α-naphthalene sulfanilamide (SN).
IR（KBr）cm -1：1700，1365，1130，860，765;
1H-NMR(CDCl 3, δ ppm): 2.05-2.25(5H, m), 2.41(1H, dd, J=13.13,6.85Hz), 2.55-2.8(2H, m), 2.84(3H, s), 3.05-3.25(4H, m), 4.05(1H, quintet, J=6.85Hz), 5.11(2H, s), 6.57(2H, d, J=8.57Hz), 6.82(2H, d, J=8.57Hz), 7.25-7.60(9H, m), 7.60-8.20(8H, m), 8.42(1H, m), 8.82(1H, d, J=7.99Hz).
Embodiment 79.
By the step of embodiment 62 make amorphous compound alkaline hydrolysis in embodiment 78, result obtain colourless amorphous N-(2-(4-benzyloxycarbonyl piperazinyl)-1-(right-acrinyl) ethyl)-N-methyl-α-naphthalene sulfonylamide.
IR（KBr）cm -1：1695，1670，1310，1240，1120;
1H-NMR（CDCl 3，δ ppm）：2.15-2.4（5H，m），2.48（1H，dd，J＝12.56，7.42Hz），2.6-2.85（2H，m），2.87（3H，s），3.15-3.35（4H，m），4.20（1H，quintet，J＝6.85Hz），5.10（2H，s），5.13（1H，br），6.58（2H，d，J＝7.99Hz），6.89（2H，d，J＝7.99Hz），7.33（5H，s），7.44（1H，t，J＝7.42Hz），7.47-7.63（2H，m），7.8-7.93（1H，m），7.99（1H，d，J＝7.99Hz），8.15（1H，dd，J＝6.85，1.0Hz），8.45-8.6（1H，m）.
Embodiment 80.N-{ 1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl-high piperazinyl of 2-(4-phenyl) ethyl }-5-isoquinoline sulfonaide.
Except that with 1-(2-amino-3-(right-hydroxyphenyl) propyl group)-the high piperazine of 4-phenyl replaces 1-(2-amino-3-(right-hydroxyphenyl) propyl group)-the 4-phenylpiperazine, repeat and the same step described in the embodiment 34, the result obtains yellow amorphous this title compound
IR（KBr）cm -1：1620，1600，1365，1135;
1H-NMR（CDCl 3，δ ppm）：2.10-2.36（7H，m），2.63（1H，dd，J＝6.8，13.7Hz），2.76（1H，dd，J＝4.9，13.7Hz），2.99-3.29（6H，m），6.53（2H，d，J＝8.3Hz），6.60（2H，d，J＝8.8Hz），6.64（1H，t，J＝7.3Hz），6.80（2H，d，J＝8.8Hz），7.17（1H，t，J＝8.8Hz），7.62（1H，t，J＝7.8Hz），7.66（1H，t，J＝7.8Hz），8.18（1H，d，J＝8.3Hz），8.26（2H，d，J＝7.3Hz），8.37-8.38（2H，m），8.53（1H，d，J＝5.9Hz），8.67（1H，d，J＝6.4Hz），8.82（1H，d，J＝5.9Hz），9.33（1H，s），9.42（1H，s）.
Embodiment 81.
The step process of pressing embodiment 35 must be in the amorphous compound among the embodiment 80, and the result obtains yellow amorphous N-{ 1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-high piperazinyl of 2-(4-phenyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1620，1600，1500，1365，1135;
1H-NMR（CDCl 3，δ ppm）：1.70（2H，m），2.37（1H，dd，J＝8.8，11.7Hz），2.40-2.65（6H，m），2.76（1H，dd，J＝4.9，13.7Hz），2.84（3H，s），3.23-3.42（4H，m），3.98（1H，m），6.51-6.65（5H，m），6.77（2H，d，J＝8.3Hz），7.16（2H，t，J＝7.8Hz），7.54（1H，dd，J＝7.3，8.3Hz），7.59（1H，t，J＝7.8Hz），8.08（1H，d，J＝7.8Hz），8.18-8.26（4H，m），8.55（1H，d，J＝5.9Hz），8.55（1H，dd，J＝1.0，6.3Hz），8.84（1H，d，J＝6.3Hz），9.26（1H，s），9.41（1H，d，J＝1.0Hz）.
Make amorphous compound alkaline hydrolysis in embodiment 80 and 81 by step described in the embodiment 36, the result obtains following two kinds of compounds:
Embodiment 82.N-(1-(right-the acrinyl)-high piperazinyl of 2-(4-phenyl) ethyl)-the 5-isoquinoline sulfonaide
Yellow crystals;
Fusing point: 170-178 ℃ (decomposition)
IR（KBr）cm -1：1615，1600，1505，1365，1320，1205，1155，1130;
1H-NMR（CDCl 3，δ ppm）：1.79（2H，m），2.44（1H，dd，J＝8.3，13.7Hz），2.50-2.72（7H，m），3.23（1H，m），3.30-3.45（4H，m），6.24（2H，d，J＝8.3Hz），6.51（2H，d，J＝8.3Hz），6.66（2H，d，J＝8.3Hz），6.68（1H，t，J＝7.3Hz），7.23（2H，dd，J＝7.3，8.3Hz），7.64（1H，t，J＝7.8Hz），8.19（1H，d，J＝7.8Hz），8.27（1H，d，J＝6.4Hz），8.34（1H，dd，J＝1.0，7.3Hz），8.53（1H，d，J＝6.4Hz），9.33（1H，brs）.
Embodiment 83.N-(1-(right-the acrinyl)-high piperazinyl of 2-(4-phenyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
Yellow noncrystal.
IR（KBr）cm -1：1615，1600，1500，1360，1320，1210，1150，1125;
1H-NMR（CDCl 3，δ ppm）：1.93（2H，m），2.40（1H，dd，J＝9.8，14.2Hz），2.56（1H，dd，J＝8.8，12.7Hz），2.70（2H，m），2.80-2.92（4H，m），3.00（3H，s），3.46-3.53（4H，m），3.85（1H，m），6.19（2H，d，J＝8.3Hz），6.51（2H，d，J＝8.3Hz），6.65（1H，t，J＝7.3Hz），6.69（2H，d，J＝8.3Hz），7.21（2H，dd，J＝7.3，8.8Hz），7.58（2H，t，J＝7.3Hz），8.07（1H，d，J＝6.4Hz），8.12（1H，d，J＝8.3Hz），8.27（1H，dd，J＝1.0，7.3Hz），8.45（1H，d，J＝5.9Hz），9.27（1H，s）
Reference example 18.N-tertbutyloxycarbonyl-4-hydroxyl piperazine
7.14g4-piperidone-hydrate oxyhydroxide is dissolved in 50ml dimethyl formamide and the 10ml water, and at room temperature adds 25ml diisopropylethylamine and 9.5g azodicarbonic acid di tert butyl carbonate, again this reaction mixture was stirred 4 hours along with stirring to this solution.After adding entry and using sodium-chlor saturated, with this reaction mixture of 300ml chloroform extraction.With this extraction liquid of dried over mgso, and vapourisation under reduced pressure, the result obtains the 9.6g residue, then it is dissolved in the 100ml ethanol.Along with stirring and in this solution, adding the 1.83g sodium borohydride down ice-cooled, under similarity condition, stirred this mixture 90 minutes, at room temperature stirred then 30 minutes.After adding saturated sodium chloride aqueous solution, this reaction mixture is alkalized with sodium bicarbonate, use the 600ml chloroform extraction again 2 times.Extraction liquid is with dried over mgso and vapourisation under reduced pressure, the residue of gained imposed on silicagel column and with hexane/ethyl acetate (2: 1) wash-out, the result obtains colourless amorphous this title compound of 8.03g.
1H-NMR（CDCl 3，δ ppm）：1.35-1.6（2H，m），1.45（9H，s），1.75-1.95（2H，m），3.03（2H，ddd，J＝13.13，10.28，4.00Hz），3.75-3.95（3H，m）.
Reference example 19.4-(is right-the methyl benzyloxy) and piperidines
2.0g must be dissolved in the amorphous compound in the reference example 18 in the 20ml dimethyl formamide, in ice-bath, add the sodium hydride of 0.48g60% to this solution.After shifting out by ice-bath, at room temperature stirred this reaction mixture 30 minutes, and add 1.54g right-methyl-benzyl chlorine after, stirred again 18 hours.This reaction mixture is inclined on ice, saturated and with 150ml chloroform extraction 2 times with sodium-chlor.This extraction liquid is with dried over mgso and vapourisation under reduced pressure, the gained residue imposed on silicagel column and with hexane/ethyl acetate (5: 1) wash-out, the result obtain 1.27g uncle N--butoxy carbonyl-4-right-methyl benzyloxy piperidines.This compound is dissolved in the 3ml ethyl acetate, and after at room temperature adding the solution of hydrogenchloride in ethyl acetate of 12ml3N, and then stirred 17 hours, down solvent evaporation is fallen in decompression then.The gained residue is water-soluble, and this solution alkalized with sodium bicarbonate, saturated and with twice of 200ml chloroform extraction with sodium-chlor.This extraction liquid also under reduced pressure falls solvent evaporation with dried over mgso, and the result obtains colourless amorphous this title compound of 830mg.
1H-NMR(CDCl 3, δ ppm): 1.55-1.8(2H, m), 1.9-2.15(2H, m), 2.34(3H, s), 2.81(2H, ddd, J=13.13,10.28,4.00Hz), 3.17(2H, ddd, J=11.42,7.42,4.00Hz), 3.56(1H, septet, J=3.71Hz), 4.50(2H, s), 5.01(1H, brs), 7.14(2H, d, J=7.99Hz), 7.22(2H, d, J=7.99Hz).
Reference example 20.N-uncle-butoxy carbonyl-neighbour-(2-methoxy ethoxy methyl) L-Tyrosine methyl ester
13.39g uncle N--butoxy carbonyl L-Tyrosine methyl ester is dissolved in 65ml tetrahydrofuran (THF) and the 65ml dimethyl formamide, and adds the sodium hydride of 1.9g60%, in ice bath, stir simultaneously to this solution.After in ice bath, taking out, at room temperature stirred this mixture 30 minutes, behind ice-cooled adding 5.4g methoxy ethoxy methyl chloride, stir and made it be warmed to room temperature in 15 minutes.This reaction mixture is inclined on ice, saturated and with twice of 800ml chloroform extraction with sodium-chlor.This extraction liquid down falls solvent evaporation with dried over mgso and in decompression, the residue of gained is imposed on silicagel column and with hexane/ethyl acetate (4: 1) wash-out, the result obtains colourless amorphous this title compound of 13.85g.
1H-NMR（CDCl 3，δppm）：1.46（9H，s），3.02（2H，m），3.37（3H，s），3.5-3.6（2H，m），3.71（3H，s），3.75-3.85（2H，m），4.54（1H，m），4.95（1H，m），5.24（2H，s），6.96（2H，d，J＝9.71Hz），7.04（2H，d，J＝9.71Hz）.
Reference example 21.2-(N-uncle-butoxy carbonyl amino)-1-chloro-3-(right-(2-methoxy ethoxy methoxyl group) phenyl) propane
13.85g must be dissolved in the amorphous compound in the reference example 20 in 90ml ethanol and the 60ml tetrahydrofuran (THF), add 3.11g lithium chloride and 2.77g sodium borohydride along with in ice bath, stirring to this solution.After in ice bath, taking out, this mixture was stirred under room temperature 16 hours, add saturated sodium-chloride water solution after, this reaction mixture alkalized with sodium bicarbonate and with 800ml chloroform extraction 2 times.This extraction liquid dried over mgso, and under reduced pressure solvent evaporation is fallen, the result obtains 11.73g uncle N--butoxy carbonyl-neighbour-(2-methoxy ethoxy methyl) junket ammonia alcohol.This compound is dissolved in the 120ml tetracol phenixin, and in this solution, adds the 10g triphenyl phosphine.With this mixture reflux 3 hours, and and then 80 ℃ of reheat 17 hours.Reduction vaporization falls solvent, and the residue of gained is imposed on silicagel column and uses the hexane/ethyl acetate wash-out then with trichloromethane/methyl alcohol (100: 1), and the result obtains colourless amorphous this title compound of 7.22g.
1H-NMR（CDCl 3，δ ppm）：1.43（9H，s），2.75-2.9（2H，m），3.38（3H，s），3.4-3.65（4H，m），3.75-3.9（2H，m），4.08（1H，m），4.79（1H，m），5.26（2H，s），6.99（2H，d，J＝9.71Hz），7.16（2H，d，J＝9.71Hz）.
Reference example 22.N-uncle 2-(-butoxy carbonyl amino)-3-(he right-(2-methoxy ethoxy methoxyl group) phenyl }-4-(is right-the methyl benzyloxy) and piperidines
Must be dissolved in 1.56g in the 25ml dimethyl formamide in the amorphous compound in the reference example 21, adding 0.83g in this solution must be in the amorphous compound in the reference example 19,0.67g salt of wormwood and 0.67g sodium iodide, then this mixture was stirred 2 hours in 100 ℃, after adding saturated sodium-chloride water solution, use 150ml chloroform extraction 2 times.This extraction liquid falls with dried over mgso and with solvent removed under reduced pressure.The residue of gained is imposed on silicagel column and uses trichloromethane/methyl alcohol (100: 1) wash-out, and the result obtains colourless amorphous this title compound of 490mg.
1H-NMR（CDCl 3，δ ppm）：1.42（9H，s），1.5-1.75（3H，m），1.75-2.0（2H，m），2.0-2.3（3H，m），2.33（3H，s），2.55-2.95（4H，m），3.25-3.5（1H，m），3.38（3H，s），3.5-3.65（2H，m），3.75-3.95（3H，m），4.49（2H，s），4.64（1H，m），5.25（2H，s），6.96（2H，d，J＝9.71Hz），7.09（2H，d，J＝9.71Hz），7.14（2H，d，J＝9.71Hz），9.23（2H，d，J＝9.71Hz）.
Embodiment 84.N-{ 1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-2-(4-(right-methyl benzyloxy) piperidino-(1-position only) } ethyl-5-isoquinoline sulfonaide
490mg must be dissolved in the amorphous compound in the reference example 22 in the 1ml ethyl acetate, and at room temperature with stirring the solution of hydrogenchloride in ethyl acetate that adds 5ml3N to this solution.Again this reaction mixture was stirred 1 hour.After solvent evaporation fallen, the residue of gained with the sodium bicarbonate aqueous solution alkalization, made this mixture saturated with sodium-chlor more again, with the small amount of methanol washing, with 100ml chloroform extraction 2 times.Extraction liquid is with dried over mgso and solvent evaporated, and obtains a residue, and it contains N-(2-amino-3-(right-hydroxyphenyl)) propyl group-4-(is right-the methyl benzyloxy) piperidines.This residue is dissolved in the 7ml tetrahydrofuran (THF), and at room temperature adds 545mg5-isoquinoline 99.9 sulfahydantoin chlorine HCl and 450mg triethylamine to this solution with stirring.This reaction mixture was stirred 18 hours, make it alkalization, and it is extracted 2 times with the 100ml trichloromethane with sodium bicarbonate aqueous solution.This extraction liquid falls solvent with dried over mgso and reduction vaporization, and the gained residue is imposed on silicagel column and obtains colourless amorphous this title compound of 572mg with trichloromethane/methyl alcohol (30: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.0-1.33（3H，m），1.33-1.54（1H，m），1.59-1.88（2H，m），1.88-2.25（4H，m），2.33（3H，s），2.71（1H，dd，J＝14.28，6.85Hz），2.91（1H，dd，J＝14.28，4.57Hz），3.18（2H，m），4.34（2H，s），6.68（2H，d，J＝9.14Hz），6.90（2H，d，J＝9.14Hz），7.14（4H，s），8.13（1H，t，J＝7.42Hz），8.18（1H，t，J＝7.42Hz），9.19（1H，d，J＝7.42Hz），8.27（2H，d，J＝7.42Hz），8.40（1H，dd，J＝7.99，1.0Hz），8.44（1H，d，J＝6.85Hz），8.52（1H，d，J＝6.28Hz），8.68（1H，d，J＝6.28Hz），8.81（1H，d，J＝6.28Hz），9.34（1H，s），9.41（1H，s）.
Embodiment 85.N-1-(is right-acrinyl)-2-(4-(right-methyl benzyloxy) piperidino-(1-position only)) ethyl }-isoquinoline sulfonaide
400mg must be dissolved in the amorphous compound among the embodiment 84 in 2.5ml methyl alcohol and the 2.5ml tetrahydrofuran (THF), add the sodium hydroxide solution of 4ml1N, with this mixture reflux 2 hours to this solution.After the cooling, this mixture dilute with water is used the citric acid acidifying, with the sodium bicarbonate alkalization, uses the 100ml chloroform extraction again 2 times then.This extraction liquid dried over mgso, and reduction vaporization falls solvent.The gained residue is imposed on silicagel column and obtains colourless amorphous this title compound of 172mg with trichloromethane/methyl alcohol (20: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.2-1.75（4H，m），1.85-2.15（2H，m），2.2-2.58（4H，m），2.32（3H，s），2.58-2.85（2H，m），3.15-3.4（2H，m），4.41（2H，s），4.8（2H，br），6.42（2H，d，J＝9.14Hz），6.68（2H，d，J＝9.14Hz），7.14（2H，d，J＝7.42Hz），7.19（2H，d，J＝7.42Hz），7.67（1H，t，J＝7.42Hz），8.19（1H，d，J＝7.42Hz），8.33-8.50（2H，m），8.58（1H，d，J＝6.28Hz），9.33（1H，s）.
Embodiment 86.
Remove with N-{ 2-(tert-butoxycarbonyl amino)-3-(right-(2-methoxy ethoxy methoxyl group) phenyl) propyl group }-4-(3,4-dichloride base benzyloxy) piperidines replace N-2-(tert-butoxycarbonyl amino)-3-(is right-(2-methoxy ethoxy methoxyl group) phenyl) propyl group-4-(is right-the methyl benzyloxy) outside the piperidines, be repeated on the same step described in the embodiment 84 and obtain colourless amorphous N-1-(right-5-isoquinoline 99.9 sulfonyloxy) phenyl)-2-(4-(3,4-dichloro-benzyloxy) piperidino-(1-position only)) ethyl-the 5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：0.95-1.17（1H，m），1.17-1.34（2H，m），1.34-1.91（2H，m），1.91-2.30（4H，m），2.72（1H，dd，J＝13.13，7.42Hz），2.89（1H，dd，J＝13.13，4.57Hz），3.20（2H，m），4.33（2H，s），6.68（2H，d，J＝9.14Hz），6.92（2H，d，J＝9.14Hz），7.10（1H，dd，J＝9.14，1.71Hz），7.36（1H，d，J＝1.71Hz），7.38（1H，d，J＝9.14Hz），7.64（1H，t，J＝7.42Hz），7.68（1H，t，J＝7.42Hz），8.20（1H，d，J＝7.42Hz），8.28（2H，d，J＝7.42Hz），8.39（1H，dd，J＝7.42，1.0Hz），8.43（1H，d，J＝6.28Hz），8.53（1H，d，J＝6.28Hz），8.69（1H，d，J＝6.28Hz），8.80（1H，d，J＝6.28Hz），9.35（1H，s），9.42（1H，s）;
IR（KBr）cm -1：1615，1375，1130，860.
Embodiment 87.
Will be in embodiment 86 amorphous compound of gained obtain by the step alkaline hydrolysis among the embodiment 85 colourless amorphous N-1-(is right-acrinyl)-2-(4-(3,4-dichloro-benzyloxy) piperidino-(1-position only)-the 5-isoquinoline sulfonaide.
IR（KBr）cm -1：1615，1375，1130，860;
1H-NMR（CDCl 3，δ ppm）：1.2-1.8（4H，m），1.9-2.2（2H，m），2.2-2.6（4H，m），2.62（1H，dd，J＝14.28，6.85Hz），2.75（1H，dd，J＝14.28，6.28Hz），3.29（2H，m），4.33（2H，br），4.39（2H，s），6.38（2H，d，J＝8.57Hz），6.67（2H，d，J＝8.57Hz），7.12（1H，dd，J＝8.57，1.71Hz），7.38（1H，d，J＝8.57Hz），7.39（1H，d，J＝1.71Hz），7.67（1H，t，J＝7.42Hz），8.20（1H，d，J＝7.42Hz），8.37（1H，d，J＝6.28Hz），8.40（1H，dd，J＝7.42，1.0Hz），8.58（1H，d，J＝6.28Hz），9.32（1H，s）.
Reference example 23.
Except that replacing N-tert-butoxycarbonyl-neighbour-(2-methoxy ethoxy methyl) L-Tyrosine methyl ester with N-benzyloxycarbonyl-neighbour-benzyl L-Tyrosine methyl ester, be repeated on the same step described in the reference example 21 and obtain colourless amorphous 2-benzyloxycarbonyl amino-3-(right-the benzyloxy phenyl)-n-propyl chloride.
1H-NMR（CDCl 3，δ ppm）：2.7-2.95（2H，m），3.49（1H，dd，J＝11.42，3.43Hz），3.63（1H，dd，J＝11.42，4.00Hz），4.13（1H，m），5.00（1H，m），5.04（2H，s），5.10（2H，s），6.92（2H，d，J＝7.99Hz），7.15（2H，d，J＝7.99Hz），7.3-7.5（5H，m）.
In this amorphous compound of such acquisition, add the N-phenylpiperazine, and be repeated on the same step described in the reference example 21 and obtain colourless amorphous 1-2-(benzyloxycarbonyl amino)-3-(is right-the benzyloxy phenyl) propyl group-the 4-phenylpiperazine.
1H-NMR（CDCl 3，δ ppm）：2.34（2H，d，J＝6.85Hz），2.4-2.7（4H，m），2.75-3.0（2H，m），3.14（4H，t，J＝5.14Hz），3.99（1H，m），4.90（1H，m），5.04（2H，s），5.10（2H，s），6.75-7.0（5H，m），7.09（2H，d，J＝8.57Hz），7.2＝7.5（12H，m）
Embodiment 88.N-1-((right-benzyloxy) benzyl)-2-(4-Phenylpiperazinyl) ethyl-5-isoquinoline sulfonaide
The 4-phenylpiperazine that the 1-that 500mg is obtained in reference example 23 replaces is dissolved in the 1ml acetate, and adds the solution of hydrogen bromide in acetate of 2ml30% to this solution, and this mixture was stirred 10 minutes and was poured on ice.After adding saturated aqueous sodium thiosulfate, this reaction mixture is alkalized with saturated sodium bicarbonate aqueous solution, and with twice of 150ml chloroform extraction.This extraction liquid dried over sodium sulfate, and reduction vaporization falls solvent imposes on silicagel column with the gained residue and obtains 235mg1-{ 2-amino-3-(is right-benzyloxy phenyl) propyl group }-4-phenylpiperazine with trichloromethane/methyl alcohol (30: 1) wash-out.This compound of 235mg is dissolved in the 5ml tetrahydrofuran (THF), and at room temperature adds 195mg5-isoquinolinesulfonylcompounds chlorine HCl and 178mg triethylamine with stirring to this solution.Then this mixture was stirred 16 hours.After adding saturated sodium-chloride water solution, make this reaction mixture alkalization, use the 150ml chloroform extraction again 2 times with sodium bicarbonate.The extraction liquid dried over mgso, reduction vaporization falls solvent again, the gained residue is imposed on silicagel column use trichloromethane/methyl alcohol (50: 1) wash-out again and obtain the colourless amorphous N-of 280mg { 1 ((4-benzyloxy) benzyl)-2-(4-Phenylpiperazinyl) ethyl }-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：2.1-2.5（6H，m），2.7-3.0（6H，m），3.37（1H，m），4.99（2H，s），5.5（1H，br），6.71（2H，d，J＝8.57Hz），6.81（3H，t，J＝8.57Hz），6.90（2H，d，J＝8.57Hz），7.24（2H，t，J＝8.57Hz），7.3-7.5（5H，m），7.68（1H，t，J＝7.42Hz），8.17（1H，d，J＝7.99Hz），8.43（1H，d，J＝6.28Hz），8.46（1H，d，J＝6.85Hz），8.67（1H，d，J＝6.28Hz），9.32（1H，s）.
Embodiment 89.N-2-(4-(3,4-dichloro-benzyloxy) piperidino-(1-position only))-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
1.70g must be dissolved in the amorphous compound among the embodiment 86 in the 10ml dimethyl formamide, and add the 93mg sodium hydride, stir again after 10 minutes and remove ice bath with in ice is molten, stirring to this solution.At room temperature this reaction mixture was stirred 4 hours, after adding the 150ml ethyl acetate, wash three times and use these washing lotions of 50ml ethyl acetate extraction with water.Merge each extraction liquid and, use dried over mgso, and reduction vaporization falls solvent with the saturated sodium-chloride water solution washing.The gained residue is imposed on silicagel column, and (silica gel: Fuji Debison Kagaku, BW-820MH), the eluant solution of the methyl alcohol with 1% in trichloromethane restrains colourless amorphous this title mixture and obtain 1.3.
IR（CHCl 3）cm -1：2920，2810，1618，1583，1563，1450，983，902;
1H-NMR（CDCl 3，δ ppm）：1.30-1.52（2H，m），1.60-1.78（2H，m），1.95-2.12（2H，m），2.15-3.00（6H，m），2.84（3H，s），3.31（1H，m），4.10（1H，m），4.42（2H，s），6.58（2H，brd，J＝8.5Hz），6.87（2H，brd，J＝8.5Hz），7.14（1H，dd，J＝8.3，1.9Hz），7.39（1H，d，J＝8.3Hz），7.41（1H，d，J＝1.9Hz），7.53-7.65（2H，m），8.11（1H，d，J＝8.3Hz），8.28-8.31（3H，m），8.32（1H，dd，J＝7.5，1.2Hz），8.54（1H，brd，J＝6.1Hz），8.57（1H，d，J＝6.1Hz），8.83（1H，d，J＝6.1Hz），9.28（1H，d，J＝1.0Hz），9.41（1H，d，J＝1.0Hz）.
Embodiment 90.N-2-(4-(3,4-dichlorophenoxy) piperidino-(1-position only))-1-(is right-acrinyl) and ethyl }-N-methyl-5-isoquinoline sulfonaide
1.04g must be dissolved in the amorphous compound among the embodiment 89 in the 10ml methyl-sulphoxide, add the solution of 152mg sodium hydroxide in 2ml water to this solution again, this mixture was stirred 2 hours in 80 ℃.After adding the 150ml ethyl acetate, with this reaction mixture twice of 100ml water washing, and with these washing lotions of 50ml ethyl acetate extraction.Each ethyl acetate layer is merged, wash with saturated sodium-chloride water solution.Fall solvent with dried over sodium sulfate and vapourisation under reduced pressure.With the gained residue impose on silicagel column and with 1% methyl alcohol in trichloromethane eluant solution and obtain colourless amorphous this title compound of 650mg.
1H-NMR（CDCl 3，δ ppm）：1.50-1.67（2H，m），1.75-1.94（2H，m），2.15-2.30（2H，m），2.40-2.96（6H，m），3.00（3H，s），3.39（1H，m），3.96（1H，m），4.47（2H，s），6.26（2H，brd，J＝8.5Hz），6.61（2H，brd，J＝8.5Hz），6.90-7.10（1H，br），7.16（1H，dd，J＝8.3，1.9Hz），7.41（1H，d，J＝8.3Hz），7.44（1H，d，J＝1.9Hz），7.60（1H，dd，J＝8.0，7.5Hz），8.09（1H，brd，J＝6.1Hz），8.14（1H，brd，J＝8.0Hz），8.31（1H，dd，J＝7.5，1.2Hz），8.47（1H，d，J＝6.1Hz），9.28（1H，brs）.
Embodiment 91.N-2-(4-(3,4-dichloro-benzyloxy) piperidines)-1-(is right-methoxy-benzyl) and ethyl }-N-methyl-5-isoquinoline sulfonaide
350mg must be dissolved in the amorphous compound among the embodiment 90 in the 10ml dimethyl formamide, stir methyl-iodide to this solution adding 82.8mg with ice bath.This mixture was stirred 30 minutes, and after removing ice bath, at room temperature stirred again 2 hours.Add the 100ml ethyl acetate to this reaction mixture, and with this mixture of 50ml water washing three times.With each washing lotion of 50ml ethyl acetate extraction, wash each ethyl acetate layer with water.Each ethyl acetate layer is merged, with the saturated sodium-chloride water solution washing, use dried over mgso, reduction vaporization falls solvent again.The gained residue is imposed on silicagel column and with 1% the eluant solution of methyl alcohol in trichloromethane, the result obtains colourless amorphous this title compound of 297mg.
IR（CHCl 3）cm -1：2910，2835，1615，1585，1322，1125，986;
1H-NMR（CDCl 3，δ ppm）：1.38-1.60（2H，m），1.69-1.85（2H，m），2.06-2.22（2H，m），2.36（1H，dd，J＝13.0，7.3Hz），2.51-2.76（4H，m），2.88（1H，m），2.93（3H，s），3.34（1H，m），3.73（3H，s），4.13（1H，m），4.44（2H，s），6.50（2H，dm，J＝8.8Hz），6.83（2H，dm，J＝8.8Hz），7.14（1H，dd，J＝8.0，1.9Hz），7.40（1H，d，J＝8.0Hz），7.43（1H，d，J＝1.9Hz），7.56（1H，dd，J＝8.3，7.3Hz），8.08（1H，brd，J＝8.3Hz），8.29（1H，dd，J＝7.3，1.2Hz），8.55（1H，d，J＝6.3Hz），9.23（1H，brs）
Embodiment 92.
Except that with 1-(2-amino-3-(right-hydroxyphenyl) propyl group)-the 4-Phenylpiperidine replaces 1-(2-amino-3-(right-hydroxyphenyl) phenyl)-the 4-phenylpiperazine, be repeated on the same step described in embodiment 34 and 35 successively and obtain colourless amorphous N-1-(is right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-2-(4-Phenylpiperidine subbase) ethyl-N-methyl-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：1.15-1.75（4H，m），1.80-2.10（2H，m），2.20-2.50（3H，m），2.60-2.80（2H，m），2.80-3.05（3H，m），2.86（3H，s），4.13（1H，d，J＝6.85Hz），6.62（2H，d，J＝7.99Hz），6.91（2H，d，J＝7.99Hz），7.12（2H，dd，J＝6.85，1.0Hz），7.16-7.40（3H，m），7.58（1H，t，J＝7.42Hz），7.61（1H，t，J＝7.42Hz），8.11（1H，d，J＝7.42Hz），8.26（3H，dd，J＝6.85，1.0Hz），8.36（1H，dd，J＝7.42，1.0Hz），8.56（1H，d，J＝6.28Hz），8.59（1H，d，J＝6.28Hz），8.83（1H，d，J＝6.28Hz），9.28（1H，s），9.41（1H，d，J＝1.0Hz）.
Embodiment 93.
Make amorphous compound in embodiment 92 obtain colourless amorphous N-(1-(right-acrinyl)-2-(4-Phenylpiperidine subbase by the step alkaline hydrolysis among the embodiment 36) ethyl)-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1615，1515，1325，1125;
1H-NMR（CDCl 3，δ ppm）：1.55-1.95（5H，m），2.22（2H，dt，J＝6.28，1.7Hz），2.35-2.60（3H，m），2.70（1H，dd，J＝12.56，5.71Hz），2.8-3.25（3H，m），3.06（3H，s），3.98（1H，m），6.23（2H，d，J＝8.57Hz），6.59（2H，d，J＝8.57Hz），7.15-7.40（5H，m），7.62（1H，t，J＝7.42Hz），8.10（1H，d，J＝6.85Hz），8.16（1H，d，J＝7.42Hz），8.35（1H，dd，J＝7.42，1.0Hz），8.47（1H，d，J＝6.28Hz），8.29（1H，s）
Embodiment 94.
Remove propyl group with 1-(2-amino-3-(right-hydroxyphenyl))-4,4-ethylenedioxy piperidines replaces 1-(2-amino-3-(right-hydroxyphenyl) propyl group)-the 4-phenylpiperazine outside, be repeated on the same step described in embodiment 34 and 35 successively and obtain colourless amorphous N-{ 2-(4,4-ethylenedioxy piperidino-(1-position only))-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：1.4-1.6（4H，m），2.22（1H，dd，J＝12.56，6.85Hz），2.25-2.5（5H，m），2.6-2.8（1H，m），2.8-2.95（1H，m），2.84（3H，s），3.90（4H，s），4.11（1H，q，J＝6.85Hz），6.61（2H，d，J＝8.57Hz），6.89（2H，d，J＝8.57Hz），7.61（1H，t，J＝7.42Hz），7.63（1H，t，J＝7.42Hz），8.12（1H，d，J＝7.42Hz），8.26（2H，d，J＝7.42Hz），8.27（1H，d，J＝7.42Hz），8.35（1H，d，J＝7.42Hz），8.57（1H，d，J＝6.28Hz），8.58（1H，d，J＝6.28Hz），8.84（1H，d，J＝6.28Hz），9.29（1H，s），9.42（1H，s）.
Embodiment 95.N-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-2-(4-oxo-piperidine subbase) ethyl }-N-methyl-5-isoquinoline sulfonaide
Must be dissolved in the product 2.57g of embodiment 94 in the hydrochloric acid of 50ml3N, after reflux cooled off in 6 hours then, make this reaction mixture alkalization, use the 200ml chloroform extraction again 2 times with saturated sodium bicarbonate aqueous solution.With the extraction liquid dried over mgso, and reduction vaporization falls solvent, the gained residue imposed on silicagel column and with trichloromethane/methyl alcohol (50: 1) wash-out, the result obtains colourless amorphous this title compound of 2.22g.
1H-NMR（CDCl 3，δ ppm）：2.1-2.25（4H，m），2.31（1H，dd，J＝13.13，6.85Hz），2.4＝2.65（6H，m），2.65-2.85（1H，m），2.79（3H，s），4.10（1H，q，J＝6.85Hz），6.52（2H，d，J＝7.71Hz），6.78（2H，d，J＝7.71Hz），7.49（1H，t，J＝7.42Hz），7.55（1H，t，J＝7.42Hz），8.05（1H，d，J＝7.99Hz），8.10-8.20（3H，m），8.20（1H，d，J＝7.42Hz），8.46（1H，d，J＝6.28Hz），8.48（1H，d，J＝6.28Hz），8.76（1H，d，J＝6.28Hz），9.20（1H，s），9.34（1H，s）.
Embodiment 96.N-2-(4-(N '-benzyl-N '-methylamino) piperidino-(1-position only))-1-(right-(5-isoquinoline 99.9 acyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The product of 1.0g embodiment 95 is dissolved in the 15ml methyl alcohol, at room temperature adds 270mg benzyl methylamine and 120mg cyano group sodium borohydride, and then this reaction mixture was stirred 18 hours with stirring to this solution.After adding saturated sodium bicarbonate aqueous solution, this reaction mixture is extracted 2 times with the 150ml trichloromethane.This extraction liquid dried over mgso, and reduction vaporization falls solvent places the gained residue on the silicagel column and with trichloromethane/methyl alcohol (30: 1) wash-out, the result obtains colourless amorphous this title compound of 380mg.
1H-NMR（CDCl 3，δ ppm）：1.0-1.45（2H，m），1.45-1.65（1H，m），1.65-2.0（3H，m），2.13（3H，s），2.15-2.45（3H，m），2.5-2.9（4H，m），2.84（3H，s），3.49（3H，s），4.07（1H，q，J＝6.85Hz），6.61（2H，d，J＝7.99Hz），6.89（2H，d，J＝7.99Hz），7.28（5H，s），7.58（1H，t，J＝7.42Hz），7.60（1H，t，J＝7.42Hz），8.11（1H，d，J＝7.99Hz），8.25（1H，d，J＝6.28Hz），8.26（2H，d，J＝7.42Hz），8.34（1H，dd，J＝7.42，1.0Hz），8.55（1H，d，J＝6.28Hz），8.57（1H，d，J＝6.28Hz），8.83（1H，d，J＝6.28Hz），9.26（1H，s），9.41（1H，s）.
Embodiment 97.N-2-(4-(N-benzyl-N-methylamino) piperidino-(1-position only))-1-(is right-acrinyl) and ethyl }-N-methyl-5-isoquinoline sulfonaide
380mg must be dissolved in the amorphous compound among the embodiment 96 in 2ml tetrahydrofuran (THF) and the 2ml methyl alcohol, to the aqueous sodium hydroxide solution of this solution adding 4ml1N, with this reaction mixture refluxed heating 3 hours, cooling then.Reaction mixture is poured in the water, again with the sodium bicarbonate alkalization, washed back 100ml chloroform extraction 2 times with small amount of methanol with the citric acid acidifying.This extraction liquid dried over mgso, and reduction vaporization places the gained residue silicagel column and obtains colourless amorphous this title compound of 147mg with trichloromethane/methyl alcohol (20: 1) wash-out to remove solvent.
1H-NMR（CDCl 3，δ ppm）：1.35-1.95（4H，m），1.95-2.25（2H，m），2.19（3H，s），2.3-2.7（4H，m），2.75-3.15（3H，m），3.01（3H，s），3.57（2H，s），3.95（1H，m），6.25（2H，d，J＝8.3Hz），6.58（2H，d，J＝8.55Hz），7.2-7.4（5H，m），7.60（1H，t，J＝7.57Hz），8.11（1H，d，J＝5.86Hz），8.12（1H，d，J＝8.06Hz），8.32（1H，d，J＝7.33Hz），8.46（1H，d，J＝6.35Hz），9.28（1H，s）.
Embodiment 98.
Except that replacing repeating to be set forth in the same step of embodiment 96 and 97 successively the benzyl methylamine with benzylamine, the result obtain colourless amorphous N-2-(4-benzylamino) piperidino-(1-position only))-1-(is right-acrinyl) ethyl-N-methyl-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：1.2-1.6（2H，m），1.7-2.0（2H，m），2.0-2.3（2H，m），2.35-2.7（4H，m），2.7-3.5（3H，m），3.0（3H，s），3.83（2H，s），3.95（1H，m），6.24（2H，d，J＝7.99Hz），6.56（2H，d，J＝7.99Hz），7.32（5H，m），7.59（1H，t，J＝7.42Hz），8.10（1H，d，J＝6.28Hz），8.12（1H，d，J＝7.42Hz），8.30（1H，d，J＝7.42Hz），8.46（1H，d，J＝6.28Hz），9.26（1H，s）.
Embodiment 99.N-2-(4-hydroxy piperidine subbase)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
200mg must be dissolved in the amorphous compound among the embodiment 95 in the 5ml methyl alcohol, at room temperature with stirring the 35.2mg sodium borohydride be divided into several parts of these solution of ground adding, stir this mixture 2 hours, revaporization removes solvent.The gained residue is imposed on silicagel column and uses trichloromethane/methyl alcohol (100: 4) wash-out, and the result obtains this title compound of the light yellow oily of 116mg.
IR（KBr）cm -1：1620，1500，1370，1320，1130，860;
1H-NMR（CDCl 3，δ ppm）：1.2-1.4（2H，m），1.5-1.8（4H，m），1.9-2.1（2H，m），2.25（1H，dd，J＝12.6，7.3Hz），2.4（1H，dd，J＝12.7，7.1Hz），2.7（1H，dd，J＝13.8，7.0Hz），2.8-2.95（1H，m），2.55（1H，brs），2.83（3H，s），3.55（1H，m），4.1（1H，m），6.6（2H，d，J＝8.5Hz），6.87（2H，d，J＝8.5Hz），7.6（1H，t，J＝8.3Hz），7.63（1H，t，J＝7.8Hz），8.12（1H，d，J＝8.3Hz），8.23（1H，d，J＝5.1Hz），8.26（1H，d，J＝5.1Hz），8.3（1H，dd，J＝1.2，3.3Hz），8.54（1H，d，J＝4.1Hz），8.57（1H，d，J＝4.1Hz），8.83（1H，d，J＝6.1Hz），9.28（1H，s），9.4（1H，s）.
Embodiment 100.N-2-(4-hydroxy piperidine subbase)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
150mg must be dissolved in 3ml methyl alcohol in the oil among the embodiment 99, the aqueous sodium hydroxide solution that adds 1ml10% to this solution, with this reaction mixture refluxed heating 2 hours then reduction vaporization remove solvent, with the citric acid acidifying of gained residue, again with sodium bicarbonate alkalization, with the 20ml trichloromethane with this mixture extraction 3 times.The extraction liquid dried over mgso, reduction vaporization falls solvent again, and the gained residue is through silica gel system thin-layer chromatography, and separates with trichloromethane/methyl alcohol (20: 1), and the result obtains colourless amorphous this title compound 87mg.
IR（KBr）cm -1：1610，1510，1320，1150，1125;
1H-NMR（CDCl 3，δ ppm）：1.4-1.7（2H，m），1.8-2.0（2H，m），2.1-2.4（4H，m），2.3-2.6（1H，m），2.7（1H，dd，J＝12.7，4.8Hz），2.8（1H，dd，J＝14.6，4.7Hz），2.95（1H，dd，J＝12，2.5Hz），2.99（3H，s），3.7（1H，m），3.9（1H，m），6.15（2H，d，J＝8.3Hz），6.5（2H，d，J＝8.3Hz），7.6（1H，t，J＝7.6Hz），8.0（1H，d，J＝6.1Hz），8.15（1H，d，J＝8.3Hz），8.33（1H，dd，J＝7.3，1.0Hz），8.4（1H，d，J＝6.1Hz），9.24（1H，s）.
Embodiment 101.N-(1-(right-acrinyl)-2-(4-hydroxy piperidine subbase) ethyl)-N-methyl-5-isoquinoline sulfonaide
100mg must be dissolved in the amorphous compound among the embodiment 100 in 5ml ethyl acetate/methanol (1: the 1) mixture, add the excessive solution of diazomethane in ether, this mixture is put a whole night in room temperature to this solution.Reduction vaporization falls the solvent in this mixture, and the gained residue is separated through silica gel system thin-layer chromatography and with trichloromethane/methyl alcohol (20: 1), and the result obtains colourless amorphous this title compound of 80.4mg.
IR（KBr）cm -1：1510，1320，1240，1150，1120，1030;
1H-NMR（CDCl 3，δ ppm）：1.3-1.5（2H，m），1.7-2.0（4H，m），2.0-2.3（2H，m），2.35（1H，dd，J＝13.0，7.1Hz），2.55（1H，dd，J＝10.0，6.9Hz），2.62（1H，dd，J＝10.3，7.3Hz），2.89（1H，dd，J＝14.8，6.3Hz），2.6-2.75（1H，m），2.93（3H，s），3.6（1H，m），4.12（1H，m），3.73（3H，s），6.5（2H，d，J＝8.7Hz），6.84（1H，d，J＝8.7Hz），7.56（1H，t，J＝8.0Hz），8.1（1H，d，J＝8.3Hz），8.2（1H，d，J＝6.1Hz），8.3（1H，d，J＝7.3Hz），8.55（1H，d，J＝6.1Hz），9.24（1H，s）.
Embodiment 102.N-(1-(right-acetoxyl benzyl)-2-(4-acetoxyl piperidino-(1-position only)) ethyl)-N-methyl-5-isoquinoline sulfonaide
230mg must be dissolved in the 2ml pyridine in the amorphous compound among the embodiment 100, add the 1ml diacetyl oxide, this reaction mixture is put a whole night in room temperature to this solution.Add the 20ml frozen water to this mixture, this mixture was stirred 1 hour and used 20ml ethyl acetate extraction 2 times.Extraction liquid washs with saturated sodium-chloride water solution, uses dried over mgso, and reduction vaporization removes solvent.The gained residue is imposed on silicagel column and obtains colourless amorphous this title compound of 234.3mg with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）cm -1：1760，1730，1360，1320，1240，1215，1200，1030;
1H-NMR（CDCl 3，δ ppm）：1.58（3H，s），2.03（3H，s），2.30（3H，s），2.91（3H，s），1.4-1.8（4H，m），2.2-2.9（4H，m），4.2（1H，m），4.7（1H，m），6.77（2H，d，J＝6.6Hz），6.8（2H，d，J＝6.6Hz），7.5（1H，t，J＝8.0Hz），8.1（1H，d，J＝8.1Hz），8.2（1H，d，J＝7.4Hz），8.29（1H，d，J＝6.1Hz），8.57（1H，d，J＝6.1Hz），9.27（1H，s）.
Embodiment 103.
Except that replace with synthetic N-in a similar fashion { 2-(tert-butoxycarbonyl amino)-3-(right-(2-methoxy ethoxy methoxyl group) phenyl) propyl group }-4-acetoxyl piperidines N-{ 2-(t-butoxycarbonyl amino)-3-(right-(2-methoxy ethoxy methoxyl group) phenyl) propyl group }-4-(right-the methyl benzyloxy) the piperidines, repeat the same step described in the embodiment 84, the result obtains colourless amorphous N-{ 2-(4-acetoxyl piperidino-(1-position only))-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ ppm）：0.8-1.05（1H，m），1.2-1.55（3H，m），1.6-2.15（5H，m），1.99（3H，s），2.15-2.33（1H，m），2.73（1H，dd，J＝13.13，6.85Hz），2.89（1H，dd，J＝13.13，4.57Hz），3.22（1H，m），4.51（1H，m），5.43（1H，br），6.70（2H，d，J＝8.57Hz），6.91（1H，d，J＝8.57Hz），7.66（1H，t，J＝7.42Hz），7.68（1H，d，J＝7.42Hz），8.20（1H，d，J＝7.42Hz），8.30（2H，d，J＝7.42Hz），7.39（1H，dd，J＝7.42，1.0Hz），8.42（1H，d，J＝6.28Hz），8.53（1H，d，J＝6.29Hz），8.70（1H，d，J＝6.28Hz），8.81（1H，d，J＝6.28Hz），9.34（1H，s），9.43（1H，s）.
Embodiment 104.N-{ 2-(4-hydroxy piperidine subbase)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-5-isoquinoline sulfonaide
1.5g must be dissolved in the product among the embodiment 103 in the 8ml methyl alcohol, add the aqueous sodium hydroxide solution of 8ml1N, this mixture was stirred 2 hours to this solution, add water after, with 100ml chloroform extraction 2 times.This extraction liquid washs, removes solvent with dried over mgso and reduction vaporization with saturated sodium-chloride water solution.The gained residue is imposed on silicagel column, and with trichloromethane/methyl alcohol (30: 1) wash-out, the result obtains colourless amorphous this title compound of 800mg.
1H-NMR（CDCl 3，δ ppm）：0.6-0.9（1H，m），1.05-1.3（1H，m），1.3-1.5（2H，m），1.5-1.9（3H，m），1.9-2.2（2H，m），2.2-2.4（1H，m），2.72（1H，dd，J＝13.70，6.85Hz），2.89（1H，dd，J＝1.82，4.57Hz），3.19（1H，m），3.46（1H，m），6.72（2H，d，J＝8.57Hz），6.72（2H，d，J＝8.57Hz），7.66（1H，t，J＝7.42Hz），7.69（1H，t，J＝7.42Hz），8.21（1H，d，J＝7.99Hz），8.29（2H，d，J＝7.42Hz），8.41（1H，d，J＝7.99Hz），8.44（1H，d，J＝6.28Hz），8.53（1H，d，J＝6.28Hz），8.69（1H，d，J＝6.28Hz），8.81（1H，d，J＝6.28Hz），9.35（1H，s），9.42（1H，s）.
Embodiment 105.N-3,4-dichloro benzyl-N-(1-(right-hydroxybenzyl)-2-(4-hydroxy piperidine subbase) ethyl)-the 5-isoquinoline sulfonaide
400mg must be dissolved in the 5ml dimethyl formamide in the amorphous compound of embodiment 104, down add 130mg3 with stirring to this solution ice-cooled, the sodium hydride of 4-dichlorobenzyl chloride and 28mg60% makes this mixture heat to room temperature and stirred 18 hours.After adding saturated sodium-chloride water solution, use this reaction mixture of 100ml chloroform extraction 2 times, this extraction liquid washs, falls solvent with dried over mgso and reduction vaporization with saturated sodium-chloride water solution.The gained residue is imposed on silicagel column; and obtain 228mg N-(3, the 4-dichloro benzyl with trichloromethane/methyl alcohol (30: 1) wash-out)-N-2-(4-hydroxy piperidine subbase)-1-(right-(5-isoquinolinesulfonylcompounds oxygen base) benzyl) ethyl }-the 5-isoquinoline sulfonaide
The 228mg above-claimed cpd is dissolved in the 1.5ml methyl alcohol, add the aqueous sodium hydroxide solution of 1ml1N to this solution, with the cooling then in 3 hours of this mixture reflux, behind the dilute with water, again with the sodium bicarbonate alkalization, use 100ml chloroform extraction 2 times with the citric acid acidifying.This extraction liquid dried over mgso, and solvent evaporated impose on the gained residue silicagel column and obtain colourless amorphous this title compound of 162mg with trichloromethane/methyl alcohol (20: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.2-1.6（2H，m），1.6-2.0（3H，m），2.0-2.2（2H，m），2.4-2.9（5H，m），3.5（1H，m），4.21（1H，q，J＝6.08Hz），4.44（1H，d，J＝16.36Hz），4.66（1H，d，J＝16.11Hz），6.51（2H，d，J＝8.55Hz），6.79（2H，d，J＝8.55Hz），7.17（1H，dd，J＝8.30，1.96Hz），7.25（1H，d，J＝8.06Hz），7.33（1H，d，J＝1.96Hz），7.57（1H，t，J＝7.57Hz），8.12（1H，d，J＝8.3Hz），8.25（1H，d，J＝6.10Hz），8.33（1H，dd，J＝7.32，0.98Hz），8.50（1H，d，J＝5.86Hz），9.21（1H，s）.
Embodiment 106.N-(1-(right-acrinyl)-2(4-hydroxy piperidine subbase) ethyl)-and N-is right-methyl-benzyl-5-isoquinoline sulfonaide
Remove with 4-methyl chloride replacement 3, outside the 4-dichlorobenzyl chloride, repeat the same step described in the embodiment 105, the result obtains colourless amorphous this title compound.
1H-NMR（CDCl 3+CD 3OD，δ ppm）：1.2-1.55（2H，m），1.55-2.15（5H，m），2.33（3H，s），2.33-2.85（5H，m），3.5（1H，m），3.98（1H，q，J＝6.59Hz），4.52（1H，d，J＝15.63Hz），4.78（1H，d，J＝15.62Hz），6.36（2H，d，J＝8.05Hz），6.66（2H，d，J＝8.06Hz），7.08（2H，d，J＝7.56Hz），7.29（2H，d，J＝7.57Hz），7.60（1H，t，J＝7.57Hz），8.12（1H，d，J＝8.06Hz），8.28（1H，d，J＝6.10Hz），8.39（1H，d，J＝7.32Hz），8.48（1H，d，J＝6.35Hz），9.20（1H，s）.
Embodiment 107.N-2-(4-hydroxy piperidine subbase)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Must handle with methyl-iodide by the step of embodiment 89 in the amorphous compound among the embodiment 103, and this intermediate product obtain by the step alkaline hydrolysis among the embodiment 104 with embodiment 99 in same product.
1H-NMR（CDCl 3，δ ppm）：1.20-1.42（2H，m），1.68（2H，m），2.01（2H，m），2.22（1H，dd，J＝7.3，13.2Hz），2.40（1H，dd，J＝7.3，13.2Hz），2.43-2.60（2H，m），2.66（1H，dd，J＝6.8，13.7Hz），2.84（3H，S），2.85（1H，dd，J＝6.4，13.7Hz），3.58（1H，m），4.10（1H，m），6.61（2H，d，J＝8.8Hz），6.88（2H，d，J＝8.8Hz），7.59（1H，t，J＝7.8Hz），7.63（1H，t，J＝7.8Hz），8.12（1H，d，J＝8.3Hz），8.23-8.35（4H，m），8.55（1H，d，J＝6.4Hz），8.58（1H，d，J＝6.4Hz），8.83（1H，d，J＝5.9Hz），9.29（1H，s），9.42（1H，s）
Reference example 24.1-(N-benzyloxycarbonyl tyrosyl)-the 4-phenylpiperazine
12.3gN-carbobenzoxy-(Cbz) tyrosine and 6.6g N-phenylpiperazine are dissolved in the 150ml methylene dichloride, and add 8.4g DCC, this mixture was stirred 5 hours in room temperature to this solution.Filter sedimentary insolubles, this filtrate decompression is concentrated, the gained residue is imposed on silicagel column, and also (1: 1-1: 2) wash-out, the result obtains colourless amorphous this title compound of 10.5g with hexane/ethyl acetate.
1H-NMR（CDCl 3，δ ppm）：2.63（1H，m），2.88-3.24（6H，m），3.48（1H，m），3.68（2H，m），4.88（1H，m），5.07（1H，d，J＝12.7Hz），5.11（1H，d，J＝12.7Hz），5.34（1H，br），5.67（1H，d，J＝8.8Hz），6.71（2H，d，J＝8.3Hz），6.84（2H，d，J＝8.3Hz），6.90（1H，t，J＝7.3Hz），7.04（2H，d，J＝8.3Hz），7.26（2H，t，J＝7.3Hz），7.34（5H，s）.
Embodiment 108.1-(N, neighbour-two (5-isoquinolinesulfonylcompounds)-tyrosyls)-4-phenylpiperazine
4.59g must be dissolved in 50ml methyl alcohol in the amorphous compound in the reference example 24, add the palladium that 3g5% is stated from carbon, in nitrogen atmosphere, this mixture be stirred 17 hours in room temperature to this solution.Filter the insolubles of gained, this filtrate decompression is concentrated and a residue, it is suspended in the trichloromethane.Add 5.7g5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 10ml triethylamine to this suspensoid successively with ice-cooled, in room temperature this mixture was stirred 3 hours then.After adding 200ml water, with this mixture of 100ml chloroform extraction 2 times, with this extraction liquid with dried over mgso and concentrating under reduced pressure.The gained residue imposed on silicagel column and with trichloromethane/methyl alcohol (80: 1-30: 1) wash-out and obtain amorphous this title compound of 5.46g yellow.
1H-NMR（CDCl 3，δ ppm）：2.50-2.90（7H，m），2.92-3.17（2H，m），3.24（1H，m），4.32（1H，m），5.99（1H，br），6.65（2H，d，J＝8.8Hz），6.80（2H，d，J＝7.8Hz），6.89（2H，d，J＝8.8Hz），6.94（1H，t，J＝7.3Hz），7.29（2H，dd，J＝7.3，8.3Hz），7.51（1H，t，J＝7.8Hz），7.59（1H，dd，J＝7.3，8.3Hz），8.09-8.31（5H，m），8.50（1H，d，J＝6.4Hz），8.69（1H，d，J＝5.9Hz），8.81（1H，d，J＝5.9Hz），9.28（1H，s），9.39（1H，s）.
Embodiment 109.1-(N, neighbour-two (5-isoquinolinesulfonylcompounds)-N-methyl tyrosyls)-4-phenylpiperazine
2.27g must be dissolved in the amorphous compound of embodiment 108 in the 30ml dimethyl formamide, add the sodium hydride of 160mg60% and the methyl-iodide of 0.3ml to this solution successively, this mixture be stirred 90 minutes along with ice-cooled with ice-cooled.After adding 80ml water, with this reaction mixture of 100ml ethyl acetate extraction, this extraction liquid is with the washing of 80ml saturated sodium-chloride water solution, with dried over mgso and concentrating under reduced pressure.The gained residue is imposed on silicagel column and uses trichloromethane/methyl alcohol (60: 1) wash-out, and the result obtains yellow amorphous this title compound of 1.8g.
1H-NMR（CDCl 3，δ ppm）：2.45（1H，dd，J＝4.6，13.1Hz），2.63（1H，m），2.82-3.07（4H，m），3.03（3H，s），3.13-3.29（2H，m），3.43-3.65（4H，m），5.11（1H，dd，J＝4.6，10.3Hz），6.76（2H，d，J＝8.6Hz），6.85（2H，d，J＝8.0Hz），6.88（1H，t，J＝8.6Hz），7.29（2H，dd，J＝8.0，8.6Hz），7.49（1H，dd，J＝8.3，7.3Hz），7.70（1H，dd，J＝8.3，7.3Hz），8.16（1H，dd，J＝1.0，7.3Hz），8.21（2H，d，J＝8.3Hz），8.30（1H，dd，J＝1.0，7.3Hz），8.41（1H，d，J＝6.4Hz），8.51（1H，d，J＝6.4Hz），8.68（1H，d，J＝6.4Hz），8.80（1H，d，J＝6.4Hz），9，36（1H，s），9.40（1H，s）.
Embodiment 110.1-(N-(5-isoquinolinesulfonylcompounds)-N-methyl tyrosyl)-the 4-phenylpiperazine
Must be suspended in the 20ml methyl alcohol in the 1.15g of embodiment 109 amorphous compound, add the aqueous sodium hydroxide solution of 2ml2N, with this mixture reflux 90 minutes to this solution.After adding 100ml water, use this reaction mixture of 50ml chloroform extraction 2 times, this extraction liquid dried over mgso, and concentrating under reduced pressure.The gained residue is imposed on silicagel column and uses trichloromethane/methyl alcohol (80: 1 to 50: 1) wash-out, and the result obtains colourless amorphous this title compound of 820mg.
IR（KBr）cm -1：1638，1590，1440，1326 1150;
1H-NMR（CDCl 3，δ ppm）：2.56（1H，dd，J＝5.4，12.7Hz），2.61（1H，m），2.90-3.22（3H，m），3.15（3H，s），3.43（1H，m），3.51-3.71（4H，m），5.13（1H，dd，J＝5.9，9.8Hz），5.53（1H，br），6.62（2H，d，J＝8.8Hz），6.84（2H，d，J＝7.8Hz），6.89（1H，t，J＝7.3Hz），6.90（2H，d，J＝8.3Hz），7.26（2H，t，J＝7.8Hz），7.70（1H，dd，J＝7.3，8.3Hz），8.21（1H，d，J＝8.3Hz），8.32（1H，dd，J＝1.0，7.3Hz），8.38（1H，d，J＝5.9Hz），8.66（1H，d，J＝5.9Hz），9.33（1H，br）.
Embodiment 111.
The product of embodiment 108 is pressed step alkaline hydrolysis described in the embodiment 110, and the result obtains yellow amorphous 1-(N-(5-isoquinolinesulfonylcompounds) tyrosyl)-the 4-phenylpiperazine.
IR（KBr）cm -1：1630，1590，1510，1440，1325，1220，1150，1128;
1H-NMR（CDCl 3-CD 3OD，δ ppm）：2.60（1H，m），2.72-2.77（2H，m），2.88（4H，m），3.10-3.43（3H，m），4.37（1H，t，J＝7.8Hz），6.40（2H，d，J＝8.3Hz），6.72（2H，d，J＝8.3Hz），6.83（2H，d，J＝7.8Hz），6.91（1H，t，J＝7.3Hz），7.27（2H，dd，J＝7.8，8.3Hz），7.63（1H，dd，J＝7.3，8.3Hz），8.17（1H，d，J＝8.3Hz），8.30（1H，dd，J＝1.0，7.3Hz），8.38（1H，d，J＝6.4Hz），8.60（1H，d，J＝6.4Hz），9.24（1H，s）.
The high piperazine of reference example 25.N-benzyloxycarbonyl
In the 230ml dimethyl formamide, add high piperazine of 25g and 5.4g sodium bicarbonate with being stirred in ice-cooled time, add 25ml water then to drip 10g benzyloxycarbonyl chlorine then, at room temperature this mixture is stirred a whole night.After reduction vaporization falls dimethyl formamide, use this reaction mixture of 100ml chloroform extraction 3 times, this extraction liquid falls solvent with dried over mgso and reduction vaporization.The gained residue is imposed on silicagel column also obtains the light yellow solution of 9g with trichloromethane/methyl alcohol (9: 1) wash-out liquid.
IR（KBr）cm -1：1695，1420;
1H-NMR（CDCl 3，δ ppm）：1.8（2H，m），2.8-3.0（4H，m），3.4-3.65（4H，m），5.15（2H，s），7.4（5H，s）.
Reference example 26.1-(N-(tert-butoxycarbonyl)-N-methyl) tyrosyl-high piperazine of 4-carbobenzoxy-(Cbz)
1.0gN-tert-butoxycarbonyl-N-methyltyrosine is dissolved in the 70ml methylene dichloride, at room temperature adds the high piperazine of 793mgN-benzyloxycarbonyl, and after once adding 837mg DCC, in room temperature this mixture is stirred a whole night again along with stirring.Reduction vaporization falls solvent, and benzene is added the gained residue.Filter insolubles, also (6: 4-6: 5) wash-out, the result obtains 1.06g and has this title compound of flaxen buttery with hexane/ethyl acetate this filtrate to be imposed on silicagel column again.
The acetyl derivatives of this compound has following characteristic:
IR（KBr）Cm -1：1760，1695，1215，1200;
1H-NMR(CDCl 3, δ PPm): 1.3,1.4(is 9H altogether, every s), 1.85(1H, m), 2.3(3H, s), 2.82(3H, brs), 2.7-2.9(2H, m), 3.0-3.8(8H, m), 5.15(2H, brs), 7.0(2H, d, J=8.3Hz), 7.35(5H, brs).
Reference example 27.1-3 '-(right-the acetoxyl phenyl)-2 ' (N-(tert-butoxycarbonyl)-N-methylamino) propyl group }-the high piperazine of 4-benzyloxycarbonyl
The 3.56g of institute must be dissolved in the product in the reference example 26 in the 60ml anhydrous tetrahydro furan, along with stirring and ice-cooledly adding the solution of borane in tetrahydrofuran (THF) of 20ml1.0M to this solution, this mixture is stirred a whole night in room temperature.Reduction vaporization falls solvent, and the gained residue is dissolved in the 10ml pyridine.Add the 5ml diacetyl oxide to this solution, this mixture is placed a whole night in room temperature.After on the rocks, this mixture was stirred 30 minutes, and with 60ml chloroform extraction 2 times.Extraction liquid washs with saturated sodium-chloride water solution, falls solvent with dried over mgso and reduction vaporization.The gained residue is imposed on silicagel column and obtains light yellow amorphous this title compound of 2.0g with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）Cm -1：1760，1690，1215，1200;
1H-NMR(CDCl 3, δ PPm): 1.25,1.27(is 9H altogether, each is s), 1.6-1.9(2H, m), 2.27(3H, s), 2.4-2.8(11H, m), 3.4-3.6(4H, m), 5.13(2H, brs), 6.97(2H, d, J=8.6Hz), 7.1(2H, d, J=8.6Hz), 7.25 7.33(is 5H altogether, each is s).
Embodiment 112.N-(1-(is to the acetoxyl the benzyl)-high piperazinyl of 2-(4-benzyloxycarbonyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
1 gram is dissolved in 28 milliliters of methylene dichloride by the amorphous compound that reference example 27 obtains, and add 2 milliliter 2 earlier to this solution while stirring in room temperature, the 6-lutidine adds the sulphonate of 2 milliliters of t-butyldimethylsilyl trifluoromethanes again, and reaction mixture was stirred 16 hours.After adding ice, reaction mixture is extracted secondary, washs extraction liquid with saturated sodium-chloride water solution with 70 milliliters of ethyl acetate, again with dried over mgso and vapourisation under reduced pressure with the removal solvent.The solution of tetrabutylammonium fluoride in tetrahydrofuran (THF) with 20 milliliters of tetrahydrofuran (THF)s and 4.28 milliliter of 1.0 volumetric molar concentration was added in the residue of gained while stirring, this reaction mixture of stirring at room 40 minutes.After on the rocks,, wash extraction liquid, desolvate to remove with dried over mgso and vapourisation under reduced pressure again with saturated sodium-chloride water solution with this reaction mixture secondary of 70 milliliters of chloroform extractions.The gained residue is added on the silicagel column and with trichloromethane/methyl alcohol (95: 5-90: 10) wash-out, obtain 723 milligrams of 1-(3 '-(to the acetoxyl phenyl)-2 '-(N-methylamino-) propyl group)-the high piperazine of 4-benzyloxycarbonyl.
1H-NMR（CDCl 3，δ PPm）：1.8（2H，m），2.3（3H，s），2.48（3H，d，J＝2.0Hz），2.35-3.8（9H，m），3.4-3.6（4H，m），5.1（2H，s），7.0（2H，d，J＝8.5Hz），7.2（2H，brd，J＝8.5Hz），7.35（5H，s）。
723 milligrams of above-claimed cpds are dissolved in 25 milliliters of dimethyl formamides, adding 564 milligrams of 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl again, at room temperature mixture are stirred a night then with in this mixture, adding 401 milligrams of triethylamines under ice-cooled while stirring.After adding water, with 70 milliliters of ethyl acetate reaction mixture is extracted secondary, wash extraction liquid with saturated sodium-chloride water solution again, use dried over mgso, vapourisation under reduced pressure desolvates to remove.Be added to the residue that obtains on the silicagel column and usefulness trichloromethane/methyl alcohol (100: 1) wash-out, obtain 796 milligrams of faint yellow amorphous title compounds.
1H-NMR(CDCl 3, δ PPm): 1.7(2H, m), 2.3(3H, s), 2.7-2.8(8H, m), 2.90 2.91(is 3H altogether, every s), 3.3-3.55(4H, m), 4.1(1H, m), 5.1(2H, s), 6.7(2H, d, J=8.3Hz), 6.9(2H, d, J=8.3Hz), 7.34,7.36(is 5H altogether, every s), 7.53,7.55(is 1H altogether, every t, J=7.6Hz), 8.1(1H, d, J=6.1Hz), 8.18(2H, d, J=6.5Hz), 8.55(1H, d, J=6.1Hz), 9.25(1H, s).
Embodiment 113.N-(the high piperazinyl of 2-(4-benzyloxycarbonyl)-1-(is to hydroxybenzyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
400 milligrams of amorphous compounds that obtain in embodiment 112 are dissolved in 10 ml methanol, in solution, add 2 milliliter 10% sodium hydroxide, this mixture was stirred 10 minutes.With this reaction mixture of aqueous citric acid solution acidifying, with the saturated sodium bicarbonate aqueous solution alkalization, use 50 milliliters of chloroform extraction secondaries more then.With the extraction liquid dried over mgso, vapourisation under reduced pressure is to remove solvent.Be added to the gained residue on the silicagel column and usefulness trichloromethane/methyl alcohol (100: 2) wash-out, obtain 339 milligrams of colourless amorphous title compounds.
IR（KBr）Cm -1：1700，1330，1210，1150，1120;
1H-NMR(CDCl 3, δ PPm): 1.8(2H, m), and 1.37,1.38(is 1H altogether, every dd, J=10.0,13.8Hz), 1.55(1H, dd, J=13.8,9.8Hz), 2.75(4H, m), 2.7-3.0(2H, m), 3.0(3H, s), 3.5(4H, m), 3.8(1H, m), 5.13(2H, s), 6.17(2H, d, J=8.0Hz), 6.50,6.51(is 2H altogether, every d, J=8.0Hz), 7.49,7.50(is 1H altogether, every t, J=7.7Hz), 8.03(1H, d, J=6.1Hz) 8.13(1H, d, J=7.8Hz), 8.23(1H, d, J=7.1Hz), 6.43(1H, d, J=6.1Hz), 9.24(1H, s), 7.35(5H, s).
Embodiment 114.
220 milligrams of amorphous compounds that obtain in embodiment 113 are dissolved in 2 milliliters of acetate, in solution, add 6 milliliter 25% the solution of hydrogen bromide in acetate, at room temperature stirred this mixture 20 minutes.40 milliliters of anhydrous diethyl ethers are added to form white precipitate in the reaction mixture, with saturated sodium bicarbonate aqueous solution it is alkalized then, and with 20 milliliters of trichloromethane/Virahols (5: 1) extraction secondary.The extraction liquid dried over mgso, and vapourisation under reduced pressure desolvates to remove, the gained residue is added on the silicagel column also with trichloromethane/methyl alcohol (20: 80-30: 70) wash-out obtains the high piperazinyl ethyl of 67 milligrams of N-(1-(is to hydroxyl) benzyl-2-)-N-methyl-5-isoquinoline sulfonaide light yellow oil.
1H-NMR（CDCl 3，δ ppm）：1.75（2H，m），2.3-3.0（12H，m），2.93（3H，s），3.96（1H，m），6.3（2H，d，J＝8.3Hz），6.6（2H，d，J＝8.3Hz），7.6（1H，t，J＝8.1Hz），8.1（1H，d，J＝5.3Hz），8.12（1H，d，J＝8.3Hz），8.2（1H，d，J＝7.4Hz），8.45（1H，d，J＝6.1Hz），9.26（1H，s）.
Reference example 28.1-benzyloxycarbonyl-4-(N-tert-butoxycarbonyl tyrosyl) high piperazine
15.29 gram N-tert-butoxycarbonyl tyrosine and the high piperazine of 12.73 gram N-benzyloxycarbonyl are dissolved in 280 milliliters of tetrahydrofuran (THF)s, in this solution, add 8.09 gram I-hydroxybenzotriazole hydrates and 11.77 gram DCC, stirred reaction mixture 16 hours while stirring in room temperature.The vapourisation under reduced pressure reaction mixture adds benzene to remove solvent in residue, filter insolubles and wash with benzene.Merge each benzene layer and under reduced pressure steam and remove.The gained residue is added on the silicagel column, and, obtains the colourless amorphous title compound of 26.42 grams with trichloromethane/methyl alcohol (100: 1) wash-out.
1H-NMR(CDCl 3, δ PPm): 1.41(9H, s), 1.5-2.0(2H, m), 2.75-3.05(2H, m), 3.05-3.7(8H, m), 4.67(1H, m), 5.10,5.12(is 2H altogether, every s), 5.25(1H, m), 6.0(1H, br), and 6.68,6.72(is 2H altogether, every d, J=8.57Hz), 7.02,7.03(is 2H altogether, every d, J=8.57Hz), 7.32,7.34(is 5H altogether, every s).
Embodiment 115.N-{ 2-((5-benzyloxycarbonyl) high piperazinyl)-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl) ethyl }-5-isoquinoline sulfonaide
The amorphous compound that obtains in the 3.0 gram reference examples 28 is dissolved in 20 milliliters of tetrahydrofuran (THF)s, adds the solution of borane in tetrahydrofuran (THF) of 24 milliliter of 1 volumetric molar concentration, under room temperature and nitrogen atmosphere, mixture was stirred 15 hours to this solution.After reaction is finished,, and in the gained residue, add 3 gram saleratus under reduced pressure with the solvent evaporate to dryness.In this mixture of stirring at room 30 minutes, use 200 milliliters of chloroform extraction secondaries again.Extraction liquid obtains 1-benzyloxycarbonyl-4-(2-(tert-butoxycarbonyl amino)-3-(p-hydroxybenzene with dried over mgso and under reduced pressure concentrated) propyl group) high piperazine.
This compound is dissolved in 6 milliliters of ethyl acetate, in solution, adds the solution of 30 milliliter of 4 centinormal 1 hydrogenchloride in ethyl acetate, in this mixture of stirring at room 30 minutes.The vapourisation under reduced pressure reaction mixture with saturated sodium bicarbonate aqueous solution alkalization gained residue, is used 200 milliliters of chloroform extraction secondaries again.The extraction liquid dried over mgso, vapourisation under reduced pressure desolvates to remove, and obtains 2.43 gram 1-(2-amino-3-(p-hydroxybenzene) propyl group)-the high piperazine of 4-benzyloxycarbonyl.
This intermediate is dissolved in 65 milliliters of tetrahydrofuran (THF)s, in solution, adds 4.03 gram 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 8.9 milliliters of triethylamines while stirring in room temperature, and stirred this mixture 16 hours.After adding saturated sodium bicarbonate solution, with this mixture secondary of 300 milliliters of chloroform extractions, extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.Be added to the gained residue on the silicagel column and usefulness trichloromethane/methyl alcohol (20: 1) wash-out, obtain the colourless amorphous title compound of 2.26 grams.
1H-NMR(CDCl 3, δ PPm): 1.43(2H, m), 2.2(6H, m), 2.73(2H, m), 2.9-3.4(5H, m), 5.07(2H, s), 5.34(1H, br), 6.62(2H, d, J=8.57Hz), and 6.84,6.86(is 2H altogether, every d, J=8.57Hz), 7.32,7.33(is 5H altogether, every s), 7.63(1H, t, J=8.28Hz), 7.67(1H, m), 8.16(1H, t, J=8.28Hz), 7.67(1H, m), 8.16(1H, t, J=7.42Hz), 8.22-8.45(4H, m), 8.53(1H, d, J=6.28Hz), 8.66(1H, dd, J=6.57,1.0Hz), 8.82(1H, d, J=6.28Hz), 9.31 9.34(is 1H altogether, every s), 9.42(1H, s).
Embodiment 116.
The products that obtain among the 1.0 gram embodiment 115 are dissolved in 5 ml methanol and the 5 milliliters of tetrahydrofuran (THF)s, in solution, add 10 milliliter of 1 centinormal 1 sodium hydroxide, with this mixture reflux 2 hours, cooling then.With citric acid acidifying reaction mixture, with the sodium bicarbonate alkalization, the insolubles that produces is dissolved in the methyl alcohol again., with the extraction liquid drying, and under reduced pressure concentrate this solution extraction secondary with 100 milliliters of trichloromethanes with sal epsom.The gained residue is added on the silicagel column, and with trichloromethane/methyl alcohol (20: 1) wash-out.Obtain 458 milligrams of colourless amorphous N-the high piperazinyl of 2-(4-(benzyloxycarbonyl)-1-(is to hydroxybenzyl) ethyl-the 5-isoquinoline sulfonaide
1H-NMR（CDCl 3，δ ppm）：1.72（2H，brs），2.3-2.9（8H，m），3.1-3.7（5H，m），5.12（2H，s），6.27（2H，d，J＝7.32Hz），6.57（2H，d，J＝7.32Hz），7.6（1H，br），7.33（6H，s），7.63（1H，t，J＝7.57Hz），8.17（1H，d，J＝8.3Hz），8.33（2H，d，J＝7.08Hz），8.52（1H，brs），9.28（1H，brs）.
Embodiment 117.N-{ 1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-high piperazinyl ethyl of 2-}-5-isoquinoline sulfonaide
Add the solution of 6 milliliter of 30% hydrogen bromide in acetate in room temperature along with stirring in the product that in 1.0 gram embodiment 115, obtains, mixture was further stirred 24 hours.After adding 100 milliliters of ether, reaction mixture is stirred 30 minutes generation salt, then by filtering, again with ether washing and dry in moisture eliminator with its collection.This salt is soluble in water, with sodium bicarbonate this solution that alkalizes, use 100 milliliters of chloroform extraction secondaries again.With the extraction liquid drying, vapourisation under reduced pressure desolvates to remove, and obtains 830 milligrams of colourless amorphous title compounds with sal epsom.
1H-NMR（CDCl 3，δ ppm）：1.37（2H，m），2.1-2.9（12H，m），3.22（1H，m），6.62（2H，d，J＝8.79Hz），6.87（2H，d，J＝8.54Hz），7.64（1H，t，J＝7.82Hz），7.66（1H，t，J＝7.82Hz），8.18（1H，d，J＝8.31Hz），8.23-8.36（3H，m），8.40（1H，d，J＝6.35Hz），8.53（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.11Hz），8.81（1H，d，J＝6.35Hz），9.33（1H，s），9.42（1H，s）.
Embodiment 118.N-1-(right-(5-isoquinoline 99.9 sulfonyloxy) benzyl)-high piperazinyl of 2-(4-(3-phenyl propionyl)) ethyl }-the 5-isoquinoline sulfonaide
The amorphous compound that 420 milligrams of embodiment 117 are obtained is dissolved in 6 milliliters of methylene dichloride, adds 125 milligrams of 3-phenyl propionyl chlorides and 100 milligrams of triethylamines in room temperature along with stirring to this solution, and mixture was stirred 17 hours.With saturated sodium bicarbonate aqueous solution quaternization mixture, and with 50 milliliters of chloroform extraction secondaries.Extraction liquid is also evaporated to remove solvent with dried over mgso.Be added to the gained residue on the silicagel column and usefulness trichloromethane/methyl alcohol (30: 1) wash-out, obtain 400 milligrams of colourless amorphous title compounds.
1H-NMR(CDCl 3, δ PPm): 1.46(2H, m), 1.9-2.4(6H, m), 2.4-2.6(2H, m), 2.6-2.82(2H, m), 2.82-2.98(2H, m), 2.98-3.12(1H, m), 3.12-3.33(3H, m), 3.4(1H, t, J=6.28Hz), 6.61,6.63(2H altogether, every d, J=8.57Hz), 6.82,6.85(2H altogether, every d, J=8.57Hz), 7.1-7.35(5H, m), 7.64(1H, t, J=8.28Hz), 7.66(1H, t, J=8.28Hz), 8.1-8.45(5H, m), 8.52(1H, d, J=6.28Hz), 8.67(1H, dd, J=6.28,1.0Hz), 8.82(1H, d, J=6.28Hz), 9.33,9.34(1H altogether, every s), 9.42(1H, s).
Embodiment 119.N-1-(is to hydroxybenzyl)-the high piperazinyl of 2-(4-(3-phenyl propionyl)) ethyl }-the 5-isoquinoline sulfonaide
The amorphous compound that 400 milligrams of embodiment 118 are obtained is dissolved in 2 milliliters of tetrahydrofuran (THF)s of 2 ml methanol, adds 4 milliliter of 1 centinormal 1 sodium hydroxide in solution, with the cooling then in 3 hours of mixture reflux.With this reaction mixture of citric acid acidifying, generate insolubles with the sodium bicarbonate alkalization again, then it is dissolved in the small amount of methanol, with 50 milliliters of chloroform extraction secondaries.Extraction liquid is desolvated to remove with dried over mgso and vapourisation under reduced pressure.Be added to the gained residue on the silicagel column and usefulness trichloromethane/methyl alcohol (30: 1) wash-out, obtain 230 milligrams of colourless amorphous title compounds.
1H-NMR(CDCl 3, δ PPm): 1.64(2H, m), 2.3-2.85(10H, m), 2.96(2H, t, J=8.3Hz), 3.15-3.6(5H, m), 6.31,6.35(is 2H altogether, every d, J=8.30Hz), 6.57,6.61(is 2H altogether, every d, J=8.30Hz), 7.1-7.4(5H, m), 7.65(1H, t, J=8.06Hz), 8.19(1H, d, J=8.23Hz), 8.25-8.4(2H, m), 8.55(1H, d, J=6.28Hz), 9.32(1H, s).
Reference example 29.1-benzyloxycarbonyl-4-(N-tert-butoxycarbonyl-adjacent methyl) the high piperazine of tyrosyl
The amorphous compounds that 5.0 gram reference examples 28 are obtained are dissolved in 25 milliliters of tetrahydrofuran (THF)s and the 25 milliliters of dimethyl formamides, are adding 0.41 to solution and restrain 60% sodium hydride along with stirring down with ice-cooled, then mixture are warming to room temperature and stir 30 minutes.After adding 1.43 gram methyl-iodides, reaction mixture was stirred 16 hours, behind the interpolation saturated sodium-chloride water solution, with 300 milliliters of chloroform extraction secondaries.With the extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column, and, obtains the colourless amorphous title compound of 3.76 grams with trichloromethane/methyl alcohol (100: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：1.41（9H，s），1.65-2.0（2H，m），2.8-3.05（2H，m），3.05-3.65（8H，m），3.77（3H，s），5.68（1H，m），5.10（2H，s），5.23（1H，m），6.79（2H，d，J＝8.3Hz），7.11（2H，d，J＝8.54Hz），7.33（5H，s）.
Reference example 30.1-(N-tert-butoxycarbonyl-adjacent methyl) tyrosyl-high piperazine of 4-phenyl acetyl
The amorphous compound that 1.02 grams are obtained in reference example 29 is dissolved in 25 ml methanol, after carrying palladium with adding 250 milligram of 5% carbon to this solution in ice-cooled, mixture is warming to room temperature, carries out 6 hours catalytic reductions.Again catalyzer is filtered out and uses methanol wash, evaporate this methanol solution and obtain 800 milligrams of (N-tert-butoxycarbonyl-adjacent methyl) high piperazines of tyrosyl.
400 milligrams of these compounds are dissolved in 6 milliliters of methylene dichloride, in solution, add 195 milligrams of phenyl Acetyl Chloride 98Min.s and 190 milligrams of triethylamines, in this mixture of stirring at room 24 hours.With saturated sodium bicarbonate aqueous solution quaternization mixture, and with 100 milliliters of chloroform extraction secondaries, with the extraction liquid dried over mgso, and vapourisation under reduced pressure desolvates to remove.The residue that obtains is added on the silicagel column, and, obtains 433 milligrams of colourless amorphous title compounds with trichloromethane/methyl alcohol (50: 1) wash-out.
1H-NMR(CDCl 3, δ PPm): 1.41(9H, s), 1.6-2.0(2H, m), 2.7-3.75(12H, m), 3.77, the total and 3H of 3.78(, every s), 4.65(1H, m), 5.13,5.24(is 1H altogether, every d, J=9.14Hz), 6.78,6.79(is 2H altogether, every d, J=9.71Hz), 7.08,7.11(is 2H altogether, every d, J=9.71Hz), 7.28(5H, m).
Embodiment 120.1-(N-(5-isoquinoline 99.9 sulphonyl)-adjacent methyl) tyrosyl-high piperazine of 4-phenyl acetyl
433 milligrams of amorphous compounds that obtain in reference example 30 are dissolved in 1 milliliter of ethyl acetate, in solution, add the solution of 4 milliliter of 4 centinormal 1 hydrogenchloride in ethyl acetate, after 30 minutes, under reduced pressure solvent evaporation is fallen in stirring at room.In the gained residue, add saturated sodium bicarbonate aqueous solution, with 50 milliliters of trichloromethanes with this solution extraction secondary.Extraction liquid is also under reduced pressure concentrated with dried over mgso.In the gained residue, add 6 milliliters of tetrahydrofuran (THF)s while stirring in room temperature, and 275 milligrams of 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 1.2 milliliters of triethylamines, mixture was further stirred 18 hours, with saturated sodium bicarbonate aqueous solution this reaction mixture that alkalizes, and with 50 milliliters of chloroform extraction secondaries, with the extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column, and, obtains the colourless amorphous title compound of 439 grams with trichloromethane/methyl alcohol (30: 1) wash-out.
1H-NMR(CDCl 3, δ PPm): 1.5-1.9(2H, m), 2.4-2.9(3H, m), 2.9-4.0(9H, m), 3.67,3.68,3.70(is 3H altogether, every s), 4.18(1H, m), 6.18(1H, m), 6.25-6.5(2H, m), 6.7(2H, m), 7.28(5H, m), and 7.54,7.56(is 1H altogether, every t, J=7.81Hz), 8.09(1H, t, J=7.81Hz), 8.15-8.3(2H, m), 8.63(1H, m), 9.22,9.26(is 1H altogether, every s).
Embodiment 121.1-(N, adjacent dimethyl-N-(5-isoquinoline 99.9 sulphonyl)) tyrosyl-high piperazine of 4-phenyl acetyl
4.39 milligrams of amorphous compounds that obtain in embodiment 120 are dissolved in 2.5 milliliters of tetrahydrofuran (THF)s and the 2.5 milliliters of dimethyl formamides, with the sodium hydride that in solution, adds 30 milligram 60% in ice-cooled, then this mixture is warming to room temperature and stirred 30 minutes.After adding 110 milligrams of methyl-iodides, reaction mixture was further stirred 16 hours.After adding saturated sodium-chloride water solution, reaction mixture is extracted secondary with 50 milliliters of trichloromethanes, with extraction liquid with dried over mgso and vapourisation under reduced pressure with the removal solvent.Be added to the gained residue on the silicagel column and usefulness trichloromethane/methyl alcohol (30: 1) wash-out, obtain 348 milligrams of colourless amorphous title compounds.
1H-NMR(CDCl 3, δ PPm): 1.5-2.0(2H, m), 2.2-4.0(12H, m), 3.03,3.07,3.08,3.19(is 3H altogether, every s), 3.71,3.73,3.75(3H altogether, every s), 4.9(1H, m), 6.5-6.78(2H, m), 6.78-7.0(2H, m), 7.26(5H, m), 7.68(1H, m), 8.1-8.33(2H, m), 8.42(1H, m), 8.66(1H, m), 9.32(1H, m).
The high piperazine of embodiment 122.1-benzyloxycarbonyl-4-(N, neighbour-two (5-isoquinoline 99.9 sulphonyl) tyrosyl)
The amorphous compound that 6.44 grams are obtained in reference example 28 is dissolved in 6 milliliters of ethyl acetate, adds the solution of 60 milliliter of 4 centinormal 1 hydrogenchloride in ethyl acetate in room temperature along with stirring in this solution, stirs this mixture 3 hours.Under reduced pressure concentrate this reaction mixture, behind the adding benzene, under reduced pressure concentrate again, obtain amorphous 1-benzyloxycarbonyl-high piperazine/hydrochloride of 4-tyrosyl.
In this intermediate, add 130 milliliters of tetrahydrofuran (THF)s and 7.88 gram 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 18 milliliters of triethylamines, this mixture was stirred 18 hours in room temperature.With saturated sodium bicarbonate aqueous solution this reaction mixture that alkalizes, and with 700 milliliters of chloroform extraction secondaries, with the extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column, and, obtains the colourless amorphous title compound of 5.50 grams with trichloromethane/methyl alcohol (30: 1) wash-out.
1H-NMR(CDCl 3, δ PPm): 1.65(2H, m), 2.4-3.8(10H, m), 4.17(1H, m), 5.1(2H, m), 6.02(1H, d, J=9.52Hz), 6.47,6.51(2H altogether, every d, J=8.55Hz), 6.75(2H, d, J=8.55Hz), 7.29,7.33(is 5H altogether, every s), 7.58,7.60(is 1H altogether, every t, J=8.06Hz), 8.1-8.3(5H, m), 8.52(1H, d, J=6.11Hz), 8.64(1H, d, J=6.10Hz), 8.84(1H, d, J=5.37Hz), 9.29(1H, s), 9.41(1H, s).
Embodiment 123.1-benzyloxycarbonyl-4-(N-(5-isoquinoline 99.9 sulphonyl) tyrosyl) high piperazine
The amorphous compounds that 5.50 gram embodiment 122 are obtained are dissolved in 30 ml methanol and the 30 milliliters of tetrahydrofuran (THF)s, add 60 milliliter of 1 centinormal 1 sodium hydroxide to this solution, with the cooling then in 2 hours of mixture reflux.With this reaction mixture of citric acid acidifying, alkalize with sodium bicarbonate then, insolubles with small amount of methanol dissolving gained, use 400 milliliters of trichloromethanes with this solution extraction secondary again, the extraction liquid dried over mgso, and vapourisation under reduced pressure is added to the gained residue on the silicagel column with except that desolvating, with trichloromethane/methyl alcohol (20: 1) wash-out, obtain the colourless amorphous title compound of 3.1 grams.
1H-NMR（CDCl 3+CD 3OD，δ ppm）：1.82（2H，m），2.48（1H，m），2.68（1H，dt，J＝6.85，5.71Hz），3.1-3.8（8H，m），4.16（1H，m），5.12，5.13（Total 2H，each s），6.14，6.17（Total 2H，each d，J＝8.55Hz），6.52，6.53（Total 2H，each d，J＝8.55Hz），7.33，7.35（Total 5H，each s），7.61（1H，m），8.16（1H，d，J＝8.06Hz），8.2-8.45（2H，m），8.53（1H，d，J＝6.11Hz），9.21（1H，s）.
Reference example 31.
According to step process N-benzyloxycarbonyl tyrosine in the reference example 28 and the high piperazine of N-tert-butoxycarbonyl, obtain colourless amorphous 1-(N-benzyloxycarbonyl) tyrosyl-high piperazine of 4-tert-butoxycarbonyl.
1H-NMR(CDCl 3, δ ppm): 1.42,1.44(is 9H altogether, every s), 1.6-2.0(2H, m), 2.7-3.8(10H, m), 4.75(1H, m), 5.04(1H, d, J=11.42Hz), 5.13(1H, d, J=11.42Hz), 5.5(1H, m), 6.72(2H, m), 7.02(2H, m), 7.34(5H, s).
The adjacent ethanoyl of reference example 32.1-(-N-benzyloxycarbonyl) tyrosyl-high piperazine of 4-tert-butoxycarbonyl
690 milligrams of amorphous compounds that obtain in reference example 31 are dissolved in 7 milliliters of pyridines, in this solution, add 3.5 ml acetic anhydride along with stirring, this mixture was further stirred 18 hours in room temperature.Reaction mixture poured in the saturated aqueous sodium hydroxide solution alkalizes, with 100 milliliters of trichloromethanes with this mixture extraction secondary.Wash extraction liquid with saturated sodium-chloride water solution, use dried over mgso again, vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column,, obtains 670 milligrams of colourless amorphous title compounds with trichloromethane/methyl alcohol (100: 1) wash-out.
1H-NMR(CDCl 3, δ ppm): 1.41,1.43(is 9H altogether, every s), 1.5-2.0(2H, m), 2.28(3H, s), 2.8-3.7(10H, m), 4.7(1H, m), 5.05(1H, d, J=11.4Hz), 5.13(1H, d, J=11.4Hz), 5.52(1H, m), 6.99(2H, d, J=7.42Hz), 7.21(2H, d, J=7.42Hz), 7.34(5H, s).
The adjacent acetyl of reference example 33.1-(-N-benzyloxycarbonyl) high piperazine tyrosyl-4-(3-phenyl propyl)
670 milligrams of amorphous compounds that obtain in reference example 32 are dissolved in 2 milliliters of ethyl acetate, in solution, add the solution of 7 milliliter of 3 centinormal 1 hydrogenchloride in ethyl acetate in room temperature along with stirring, this mixture was further stirred 30 minutes, alkalize with sodium bicarbonate aqueous solution, saturated with sodium-chlor, use 100 milliliters of ethyl acetate extraction secondaries again.Extraction liquid sulphur magnesium drying, and vapourisation under reduced pressure obtain the adjacent acetyl of 460 milligrams of 1-(-N-benzyloxycarbonyl) the high piperazine of tyrosyl.
This compound is dissolved in 6 milliliters of dimethyl formamides, in solution, adds 150 milligrams of salt of wormwood, 160 milligrams of sodium iodides and 210 milligrams of 1-bromo-3-phenyl-propanes while stirring, this mixture was stirred 20 hours in room temperature.After adding saturated sodium-chloride water solution, reaction mixture is extracted secondary with 100 milliliters of trichloromethanes, the extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column, and trichloromethane/methyl alcohol (100: 1) wash-out obtains 430 milligrams of colourless amorphous title compounds.
1H-NMR（CDCl 3，δ ppm）：1.5-2.0（6H，m），2.26（3H，s），2.3-2.7（6H，m），2.9-3.8（6H，m），4.84（1H，m），5.03（1H，d，J＝11.99Hz），5.12（1H，d，J＝11.99Hz），5.6（1H，m），6.97（2H，dd，J＝8.57，1.0Hz），7.1-7.3（7H，m），7.33（5H，s）.
Reference example 34.1-(3-phenyl propyl)-the high piperazine of 4-tyrosyl
430 milligrams of amorphous compounds that obtain in reference example 33 are dissolved in 5 ml methanol, in solution, add 120 milligrams of salt of wormwood while stirring, reaction mixture was stirred 70 hours in room temperature.Add after the saturated sodium-chloride water solution, with this reaction mixture of citric acid acidifying, and with 100 milliliters of chloroform extraction secondaries.The extraction liquid dried over mgso, and vapourisation under reduced pressure is to remove solvent.The gained residue is added on the silicagel column, uses trichloromethane/methyl alcohol (100: 1) wash-out again, obtain 395 milligrams of 1-(N-benzyloxycarbonyl) tyrosyl-4-(3-phenyl propyl) high piperazine.
This compound is dissolved in 15 ml methanol, with in solution, adding 0.05 milliliter of concentrated hydrochloric acid in ice-cooled and 150 milligram of 5% carbon carries palladium.After reaction mixture is warming to room temperature, in nitrogen atmosphere, carried out catalytic reduction 8 hours.The suction strainer carbon-containing palladium catalyst is used methanol wash.Filtrate is merged, and vapourisation under reduced pressure adds saturated sodium-chloride water solution to remove solvent in the gained residue.With sodium bicarbonate aqueous solution this mixture that alkalizes, add small amount of methanol and make sedimentary insolubles dissolving, with 80 milliliters of trichloromethanes with the mixture extraction secondary.Extraction liquid dried over mgso, and vapourisation under reduced pressure to be to remove solvent is added to the gained residue on the silicagel column and with trichloromethane/methyl alcohol (20: 1) wash-out, obtains 180 milligrams of colourless amorphous title compounds.
1H-NMR(CDCl 3, δ PPm): 1.75(4H, m), 2.3-2.8(10H, m), 2.92(1H, m), 3.1-3.8(4H, m), 3.86(1H, q, J=6.28Hz), and 6.65,6.66(is 2H altogether, every d, J=8.57Hz), 6.99,7.00(is 2H altogether, every d, J=8.57Hz), 7.1-7.35(5H, m).
Embodiment 124.1-(N-(S-isoquinoline 99.9 sulphonyl) tyrosyl)-and the 4-(3-phenyl propyl) high piperazine
The amorphous compound that 180 milligrams of reference examples 34 are obtained is dissolved in 4 milliliters of tetrahydrofuran (THF)s, adds 137 milligrams of 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 0.2 milliliter of triethylamine while stirring in room temperature in solution, and this mixture was stirred 15 hours.After adding saturated sodium-chloride water solution, with sodium bicarbonate quaternization mixture, the interpolation small amount of methanol will precipitate insolubles makes oily, uses 50 milliliters of trichloromethanes with the mixture extraction secondary again.Extraction liquid desolvates to remove with dried over mgso and vapourisation under reduced pressure.The gained residue is added on silicagel column and the preparation of lamina chromatosheet, and, obtains 130 milligrams of colourless amorphous title compounds with trichloromethane/methyl alcohol (10: 1) wash-out.
1H-NMR(CDCl 3+ CD 3OD, δ PPm): 1.76(4H, m), 2.3-2.8(10H, m), 3.1-3.7(4H, m), 4.22(1H, m), and 6.17,6.19(is 2H altogether, every d, J=8.57Hz), 6.53,6.56(is 2H altogether, every d, J=8.57Hz), 7.1-7.4(5H, m), 7.57,7.59(is 1H altogether, every t, J=8.28Hz), 8.12(1H, d, J=8.28Hz), 8.15-8.35(2H, m), 8.53(1H, dd, J=6.28,1.0Hz), 9.18(1H, s).
Reference example 35.1-(N-tert-butoxycarbonyl)-p-nitrophenyl alanyl)-and the 4-(p-methoxyphenyl) piperazine
With 9.00 gram N-(tert-butoxycarbonyls)-the p-nitrophenyl L-Ala is dissolved in 120 milliliters of tetrahydrofuran (THF)s, 100 milliliters of methylene dichloride and the 100 milliliters of trichloromethanes, order is added 7.68 gram N-(p-methoxyphenyls in solution) dihydrochloride of piperazine and the monohydrate of 4.44 gram N-hydroxybenzotriazoles and 20 milliliters of triethylamines and 6 gram DCC, stir this mixture 18 hours in room temperature.Under reduced pressure reaction mixture is concentrated to 1/3rd of original volume, behind the wet chemical of 200 milliliter 2.5% of interpolation, with 200 milliliters of chloroform extraction secondaries.The extraction liquid dried over mgso, and under reduced pressure concentrate and make the product crystallization, use methanol wash, obtain 10.75 and restrain the clear crystal title compounds.
1H-NMR（CDCl 3，δ ppm）：1.40（9H，s），2.73（1H，m），2.87-3.00（3H，m），3.04（1H，dd，J＝6.3，13.2Hz），3.17（1H，dd，J＝7.3，13.2Hz），3.35（1H，m），3.55-3.70（2H，m），3.77（3H，s），3.84（1H，m），4.92（1H，m），5.4（1H，d，J＝8.8Hz），6.83（4H，s），7.38（2H，d，J＝8.8Hz），8.16（2H，d，J＝8.8Hz）.
Reference example 36.1-(N-(tert-butoxycarbonyl)-p-aminophenyl alanyl)-and the 4-(p-methoxyphenyl) piperazine
The crystal that 10.75 grams are obtained in reference example 35 is dissolved in the mixed solvent of 100 milliliters of tetrahydrofuran (THF)s and 20 ml methanol, adds 5 grams, 5% carbon and carry palladium in this solution, in room temperature and nitrogen atmosphere mixture is stirred 2 hours.After insolubles filtered, concentrated filtrate under reduced pressure was added to the gained residue that (200: 1-100: 1) wash-out obtains the colourless amorphous title compound of 10.08 grams on the silicagel column and with trichloromethane/methyl alcohol.
1H-NMR（CDCl 3，δ ppm）：1.43（9H，s），2.42（1H，m），2.75-3.00（4H，m），3.13（1H，m），3.43（1H，m），3.57（1H，m），3.63-3.73（2H，m），3.76（3H，s），4.78（1H，m），5.43（1H，br），6.59（2H，d，J＝8.3Hz），6.82（4H，s），6.98（2H，d，J＝8.3Hz）.
Reference example 37.1-(3-(p-aminophenyl)-2-(tert-butoxycarbonyl amino) propyl group)-and the 4-(p-methoxyphenyl) piperazine
2.54 gram lithium aluminum hydrides are suspended in 75 milliliters of tetrahydrofuran (THF)s, with in suspension, adding the solution of 8.91 gram aluminum chloride in 75 milliliters of ether in ice-cooled, also restrain the solution of amorphous compound in 100 milliliters of tetrahydrofuran (THF)s that reference examples 36 obtain with dropping in 20 minutes 10.08 down ice-cooled.Under similarity condition, this mixture was stirred 1 hour, add the less water stopping of reaction after, 70 milliliter of 30% wet chemical and 200 milliliters of trichloromethanes are added in the reaction mixture, use silica gel to filter to remove insolubles then as flocculating aids.With the solution washing insolubles of 20% methyl alcohol in trichloromethane, filtrate is merged, under reduced pressure concentrate.200 milliliters of saturated sodium bicarbonate aqueous solutions are added in the residue, with 100 milliliters of chloroform extraction mixture secondaries, the extraction liquid dried over mgso, and under reduced pressure concentrate, the gained residue is added on the silicagel column, (100: 1 wash-outs obtain the colourless amorphous title compound of 7.72 grams with trichloromethane/methyl alcohol.
1H-NMR（CDCl 3，δ ppm）：1.43（9H，s），2.30（2H，d，J＝6.8Hz），2.48-2.68（4H，m），2.78（2H，t，J＝6.3Hz），3.06（4H，t，J＝4.9Hz），3.76（3H，s），3.86（1H，m），4.59（1H，br），6.62（2H，d，J＝8.3Hz），6.82（2H，d，J＝9.3Hz），6.89（2H，d，J＝9.3Hz），6.98（2H，d，J＝8.3Hz）.
Reference example 38.1-(2-tert-butoxycarbonyl amino)-3-(is to the phthalimide phenyl) propyl group)-the 4-(p-methoxyphenyl) piperazine
The amorphous compound that 7.0 gram reference examples 37 are obtained is dissolved in 70 milliliters of trichloromethanes, adds 2.66 gram Tetra hydro Phthalic anhydrides in this solution.With mixture reflux 1 hour, under reduced pressure concentrate, adds 100 milliliters of toluene after, further reflux 2 hours.Under reduced pressure solvent evaporation is fallen, the gained residue is added on the silicagel column and (100: 1-50: 1) wash-out obtains 8.91 gram clear crystal title compounds with trichloromethane/methyl alcohol.
1H-NMR（CDCl 3，δ ppm）：1.45（9H，s），2.37（2H，d，J＝6.8Hz），2.51-2.71（4H，m），2.96（2H，d，J＝5.4Hz），3.09（4H，t，J＝4.9Hz），3.77（3H，s），4.01（1H，m），4.66（1H，br），6.83（2H，d，J＝9.3Hz），6.90（2H，d，J＝9.3Hz），7.36（4H，s），7.79（2H，dd，J＝3.4，5.4Hz），7.96（2H，dd，J＝3.4，5.4Hz）.
Embodiment 125.N-2-(4-p-methoxyphenyl) piperazinyl)-1-(is to the phthalimide benzyl) ethyl }-the 5-isoquinoline sulfonaide
The crystal that 8.91 grams are obtained in reference example 38 is dissolved in 50 milliliters of ethyl acetate, adds the solution of 100 milliliter of 4 centinormal 1 hydrogenchloride in ethyl acetate in this solution, at room temperature mixture is stirred 1 hour.Under reduced pressure reaction mixture is concentrated, in residue, add 200 milliliters of saturated sodium bicarbonate aqueous solutions, with this mixture secondary of 100 milliliters of 20% methyl alcohol/chloroform extractions.The extraction liquid dried over mgso, and under reduced pressure concentrate, crystallization goes out not have aminocompound.This crystal is suspended in 120 milliliters of tetrahydrofuran (THF)s, after restraining 5-isoquinoline 99.9 SULPHURYL CHLORIDE HCl and 20 milliliters of triethylamines with in suspension, adding 5.0 in ice-cooled, being warming to room temperature, mixture was stirred 2 hours.After adding 200 ml waters, collect the crystallization that generates.With 100 milliliters of chloroform extraction filtrate secondaries, extraction liquid dried over mgso, under reduced pressure concentrate, obtain residue.Order has the crystalline residue with methyl alcohol, ethyl acetate and hexane wash, obtains 6.49 gram clear crystal title compounds.
Fusing point: 204-211 ℃ (decomposition)
IR（KBr）cm -1：1710，1510，1370，1235，1150，1130;
1H-NMR（CDCl 3，δ ppm）：2.03-2.33（6H，m），2.46-2.59（2H，m），2.59-2.72（2H，m），2.85（1H，dd，J＝7.3，13.7Hz），3.10（1H，dd，J＝4.4，13.7Hz），3.41（1H，m），3.77（3H，s），5.63（1H，br），6.73（2H，d，J＝9.3Hz），6.83（2H，d，J＝9.3Hz），7.20（2H，d，J＝8.8Hz），7.29（2H，d，J＝8.8Hz），7.74（1H，t，J＝8.3Hz），7.80（2H，dd，J＝3.4，5.4Hz），7.96（2H，dd，J＝3.4，5.4Hz），8.24（1H，d，J＝8.3Hz），8.48-8.52（2H，m），8.72（1H，d，J＝6.4Hz），9.36（1H，s）.
Embodiment 126.N-2-(4-(p-methoxyphenyl) piperazinyl)-1-(is to the phthalimide benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The crystal that 4.71 gram embodiment 125 are obtained is dissolved in 70 milliliters of dimethyl formamides, adding 500 milligram of 60% sodium hydride and 1 milliliter of methyl-iodide with ice-cooled order down in solution, under similarity condition mixture is stirred 3 hours.Add the less water termination reaction, after adding 200 milliliters of saturated aqueous ammonium chlorides, with this mixture secondary of 100 milliliters of chloroform extractions.Extraction liquid also under reduced pressure concentrates with dried over mgso.In the gained residue, add 50 ml acetic anhydride and 1.2 gram sodium acetates, this mixture was stirred 1 hour, under reduced pressure be concentrated to driedly then, the gained residue is dissolved in 200 milliliters of ethyl acetate at 80 ℃.Order with 100 milliliters of saturated sodium bicarbonate aqueous solutions and 100 milliliters of saturated sodium-chloride water solution washings, is used dried over mgso with this solution, under reduced pressure concentrates again.The gained residue is added on the silicagel column, and, obtains 4.84 gram clear crystal title compounds with trichloromethane/methyl alcohol (100: 1) wash-out.
Fusing point: 170-172 ℃
IR（KBr）cm -1：1710，1610，1510，1375，1300，1235，1145，1125;
1H-NMR（CDCl 3，δ ppm）：2.48（1H，dd，J＝7.3，13.2Hz），2.50-2.63（4H，m），2.66（1H，dd，J＝7.3，13.2Hz），2.82（1H，dd，J＝6.8，14.2Hz），2.86-2.96（4H，m），2.97（3H，s），3.02（1H，dd，J＝6.8，14.2Hz），3.77（3H，s），4.32（1H，m），6.84（4H，s），7.15（2H，d，J＝8.8Hz），7.22（2H，d，J＝8.8Hz），7.61（1H，t，J＝7.3Hz），7.81（2H，dd，J＝2.9，5.4Hz），7.97（2H，dd，J＝2.9，5.4Hz），8.13（1H，d，J＝8.3Hz），8.31（2H，d，J＝6.4Hz），8.60（1H，d，J＝6.3Hz），9.23（1H，s）.
Embodiment 127.
The crystal that 1.5 gram embodiment 125 are obtained were suspended in 30 milliliters of ethanol, add 3 milliliters of hydrazine hydrates in this suspension, with mixture reflux 1 hour.Behind the aqueous sodium hydroxide solution of interpolation 10%, with 30 milliliters of chloroform extraction reaction mixture secondaries.The extraction liquid dried over mgso, under reduced pressure concentrate and generate crystallization, with the mixed solvent washing of ethyl acetate and methyl alcohol, the N-of acquisition 1.14 gram light yellow crystal the 1-(PAB)-2-(4-p-methoxyphenyl) piperazinyl) ethyl }-the 5-isoquinoline sulfonaide.
Fusing point: 210-211 ℃
IR（KBr）cm -1：1615，1510，1330，1245，1225，1150，1130，1025;
1H-NMR（CDCl 3，δ ppm）：2.12-2.34（6H，m），2.53-2.72（5H，m），2.85（1H，dd，J＝4.9，14.2Hz），3.31（1H，m），3.52（2H，br），3.77（3H，s），5.48（1H，br），6.43（2H，d，J＝8.3Hz），6.75（2H，d，J＝9.3Hz），6.77（2H，d，J＝8.3Hz），6.83（2H，d，J＝9.3Hz），7.70（1H，t，J＝7.8Hz），8.20（1H，d，J＝8.3Hz），8.44（1H，d，J＝6.4Hz），8.47（1H，dd，J＝1.0，7.3Hz），8.68（1H，d，J＝6.4Hz），9.35（1H，s）.
Embodiment 128.
The crystal that 4.64 gram embodiment 126 are obtained were suspended in 80 milliliters of ethanol, add 8 milliliters of hydrazine hydrates in suspension, with mixture reflux 90 minutes.After adding 100 milliliter 10% sodium hydroxide,,, and under reduced pressure concentrate the extraction liquid dried over mgso with 80 milliliters of chloroform extraction reaction mixture secondaries.The residue that obtains is added on the silicagel column, and with trichloromethane/methyl alcohol (100: 1-50: 1) wash-out, obtain 3.29 the gram yellow amorphous N-the 1-(PAB)-2-(4-(p-methoxyphenyl) piperazinyl) ethyl-N-methyl-5-isoquinoline sulfonaide.
IR（KBr）cm -1：1620，1510，1315，1235，1150，1125;
1H-NMR（CDCl 3，δ ppm）：2.43（1H，dd，J＝6.8，13.2Hz），2.53-2.66（6H，m），2.85（1H，dd，J＝6.4，14.2Hz），2.87-2.94（4H，m），2.92（3H，s），3.50（2H，br），3.77（3H，s），4.20（1H，m），6.34（2H，d，J＝8.3Hz），6.75（2H，d，J＝8.3Hz），6.84（4H，s），6.56（1H，t，J＝7.3Hz），8.09（1H，d，J＝8.3Hz），8.24（1H，d，J＝6.3Hz），8.31（1H，dd，J＝1.0，7.3Hz），8.56（1H，d，J＝5.9Hz），9.25（1H，d，J＝1.0Hz）.
Embodiment 129.
500 milligrams of amorphous compounds that obtain in embodiment 128 are dissolved in 5 milliliters of pyridines, in this solution, adding 305 milligrams of 5-isoquinoline 99.9 SULPHURYL CHLORIDE chlorine HCl with ice-cooled time, under similarity condition, mixture was stirred 20 minutes, then stirring at room 1 hour.After adding 30 milliliters of saturated sodium bicarbonate aqueous solutions, reaction mixture is extracted secondary with 20 milliliters of trichloromethanes, the extraction liquid dried over mgso, and under reduced pressure concentrate.The gained residue is added on the silicagel column; use trichloromethane/methyl alcohol (50: 1) wash-out again, obtain 665 milligrams of amorphous N-of yellow { 1-(right-(5-isoquinolinesulfonylcompounds benzyl))-2-(4-(p-methoxyphenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
IR（KBr）Cm -1：1615，1510，1325，1225，1150，1130;
1H-NMR（CDCl 3，δ ppm）：2.34（1H，dd，J＝7.3，12.7Hz），2.45-2.61（6H，m），2.79-2.94（5H，m），2.90（3H，s），3.77（2H，s），4.04（1H，m），6.55（2H，d，J＝8.3Hz），6.70（2H，d，J＝8.3Hz），6.83（4H，s），7.57（2H，t，J＝7.8Hz），8.08-8.15（3H，m），8.28-8.35（2H，m），8.40（1H，d，J＝6.4Hz），8.50（1H，d，J＝5.3Hz），8.64（1H，d，J＝6.4Hz），9.29（1H，s），9.31（1H，d，J＝1.0Hz）.
Embodiment 130.
The crystal that 200 milligrams of embodiment 127 are obtained is dissolved in 3 milliliters of pyridines, with in this solution, adding 130 milligrams of 5-isoquinoline 99.9 SULPHURYL CHLORIDE 1/2 hydrosulfates in ice-cooled, down mixture was being stirred 20 minutes with ice-cooled, then stirring at room 1 hour, after adding 30 milliliters of saturated sodium bicarbonate aqueous solutions, with 20 milliliters of chloroform extraction secondaries.The extraction liquid dried over mgso, and under reduced pressure concentrate, the gained residue is added on the silicagel column, (50: 1-25: 1) wash-out obtains 270 milligrams of amorphous N-of yellow { 1-(right-(5-isoquinoline 99.9 sulfonamido benzyl))-2-(4-p-methoxyphenyl) piperazinyl) ethyl }-5-isoquinoline sulfonaide with trichloromethane/methyl alcohol.
IR（KBr）cm -1：1615，1505，1330，1230，1150，1125;
1H-NMR（CDCl 3，δ ppm）：2.16-2.33（6H，m），2.49-2.81（6H，m），3.28（1H，m），3.76（3H，s），6.69（2H，d，J＝8.3Hz），6.73（2H，d，J＝9.3Hz），6.79（2H，d，J＝8.3Hz），6.82（2H，d，J＝9.8Hz），7.61（1H，t，J＝7.8Hz），7.67（1H，t，J＝7.8Hz），8.16（1H，d，J＝8.3Hz），8.19（1H，d，J＝8.3Hz），8.34-8.48（4H，m），8.62（2H，d，J＝6.4Hz），9.33（1H，s），9.35（1H，s）.
Embodiment 131.N-1-(right-(N-5-isoquinoline 99.9 sulphonyl)-N-(methylamino-) benzyl)-4-(4-(p-methoxyphenyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The amorphous compound that 503 milligrams of embodiment 129 are obtained is dissolved in 8 milliliters of dimethyl formamides, with sodium hydride and 0.1 milliliter of methyl-iodide of adding 50 milligram 60% in ice-cooled in this solution, down mixture is stirred 1 hour ice-cooled.After adding 30 milliliters of saturated sodium-chloride water solutions, with 30 milliliters of ethyl acetate extraction reaction mixtures, extraction liquid washs with saturated sodium-chloride water solution, uses dried over mgso, and under reduced pressure concentrates.The residue that obtains is added on the silicagel column,, obtains 488 milligrams of yellow non-crystalline state title compounds with trichloromethane/methyl alcohol (100: 1) wash-out.
IR（KBr）cm -1：1610，1505，1340，1320，1235，1145，1125，;
1H-NMR（CDCl 3，δ ppm）：2.32（1H，dd，J＝6.4，13.2Hz），2.41-2.56（5H，m），2.73-2.98（6H，m），2.88（3H，s），3.23（3H，s），3.77（3H，s），4.31（1H，m），6.82（4H，s），6.89（2H，d，J＝8.3Hz），7.01（2H，d，J＝8.3Hz），7.63（1H，t，J＝7.8Hz），7.64（1H，t，J＝7.8Hz），8.02（1H，d，J＝5.9Hz），8.13（1H，d，J＝8.3Hz），8.19（1H，d，J＝8.3Hz），8.23（1H，d，J＝7.3Hz），8.34（1H，d，J＝6.3Hz），8.40-8.47（2H，m），8.60（1H，d，J＝5.9Hz），9.28（1H，s），9.29（1H，s）.
Embodiment 132.N-1-(to (4-picolyl oxygen base) benzyl)-2-(4-(2-pyrimidyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
The amorphous compound that 100 milligrams of embodiment 42 are obtained is dissolved in the mixture of 10 milliliters of anhydrous tetrahydro furan/anhydrous dimethyl formamides (1: 1), in solution, add the hydrochloride of 34.8 milligrams of 4-pyrmethyl chloride, add 24 milligrams of triethylamines then, in this mixture of stirring at room 30 minutes.After adding 10 milligram 60% sodium hydride, mixture is stirred a night in room temperature, add 20 gram water after, with twice of 20 milliliters of chloroform extraction.Extraction liquid is washed with saturated sodium-chloride water solution, use dried over mgso, and vapourisation under reduced pressure is to remove solvent.The residue that obtains is added on the silicagel column, obtains 73 milligrams of colourless non-crystalline state title compounds with trichloromethane/methyl alcohol (100: 1) extraction.
NMR(CDCl 3) δ PPm:2.45(4H, complex spike), 2.5-2.75(2H, complex spike) and, 2.95(3H, s), 3.65(4H, complex spike), 4.22(1H, complex spike), 5.0(2H, s), 6.49(1H, t, J=4.26Hz), 6.6(2H, d, J=8.0Hz), 6.9(2H, d, J=8.0Hz), 7.4(2H, brd), 7.6(1H, t, J=8.3Hz), 8.11(1H, d, J=8.3Hz), 8.23(1H, d, J=6.64Hz), 8.3(2H, d, J=4.26Hz), 8.37(1H, dd, J=1.0,6.6Hz), 8.57(1H, d, J=6.6Hz), 8.65(2H, brd), 9.25(1H, d, J=1.0Hz).
Embodiment 133.N-1-(right-(2-picolyl oxygen base) benzyl)-2-(4-(2-pyrimidyl) piperazinyl) ethyl }-N-methyl-S-isoquinoline sulfonaide
Except the hydrochloride of the 2-pyrmethyl chloride of using same amount replaces repeating the same step described in the embodiment 132 hydrochloride of 4-pyrmethyl chloride, obtain 74.4 milligrams of colourless non-crystalline state title compounds.
NMR(CDCl 3) δ PPm:2.45(4H, complex spike), 2.5-2.9(2H, complex spike) and, 2.98(3H, s), 3.75(4H, complex spike), 4.2(1H, complex spike), 5.13(2H, s), 6.46(1H, t, J=4.8Hz), 6.65(2H, d, J=8.0Hz), 6.9(2H, d, J=8.0Hz), 7.15(1H, complex spike), 7.58(2H, t, J=6.9Hz), 7.75(1H, complex spike), 8.1(1H, d, J=8.0Hz), 8.2-8.35(2H, complex spike), 8.3(1H, d, J=4.8Hz), 8.58(1H, d, J=6.6Hz), 8.6(1H, brs), 9.25(1H, s).
Embodiment 134.N-{ 1-(right-(right-(4-picolyl oxygen base) phenyl)-2-(4-(2-pyridyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Except the product that uses embodiment 46 replaces repeating embodiment 132 described same steps the amorphous compound of embodiment 42 acquisitions, the productive rate with 53.5% obtains colourless non-crystalline state title compound.
NMR(CDCl 3) δ PPm:2.5(4H, complex spike), 2.5-2.75(2H, complex spike) and, 2.95(3H, s), 3.38(4H, complex spike), 4.22(1H, complex spike), 5.0(2H, s), 6.58(2H, d, J=8.6Hz), 6.6(2H, t, J=5.7Hz), 6.9(2H, d, J=8.6Hz), 7.35-7.5(4H, complex spike), 7.58(1H, t, J=7.8Hz), 8.07(1H, d, J=8.1Hz), 8.17(1H, brd), 8.23(1H, d, J=6.1Hz), 8.35(1H, dd, J=1.0,7.4Hz), 8.57(1H, d, J=6.1Hz), 8.63(1H, brd), 8.63(1H, d, J=5.8Hz), 9.2(1H, d, J=1.0Hz).
Embodiment 135.N-1-(is to (2-picolyl oxygen base) benzyl)-2-(4-(2-pyridyl) piperazinyl) ethyl }-N-methyl-5-isoquinoline sulfonaide
Except the product that uses embodiment 46 replaces repeating embodiment 133 described same steps the amorphous compound of embodiment 42 acquisitions, the productive rate with 59.5% obtains colourless non-crystalline state title compound.
NMR(CDCl 3) δ PPm:2.5(4H, complex spike), 2.5-2.9(2H, complex spike) and, 2.95(3H, s), 3.38(4H, complex spike), 4.22(1H, complex spike), 5.12(2H, s), 6.55-6.65(2H, complex spike), 6.54(2H, d, J=8.6Hz), 6.9(2H, d, J=8.6Hz), 7.2-7.25(1H, complex spike), 7.4-7.7(4H, complex spike), 7.65-7.8(1H, complex spike), 8.1(1H, d, J=7.7Hz), 8.2(1H, brd), 8.27(1H, d, J=6.6Hz), 8.3(1H, d, J=6.6Hz), 8.57(1H, d, J=6.3Hz), 8.6(1H, brs), 9.73(1H, s).
Embodiment 136.N-(2-amino-ethyl)-N-(2-(4-benzyloxycarbonyl piperazinyl)-1-(is to methoxy-benzyl) ethyl)-the 5-isoquinoline sulfonaide
The product that 1.0 gram embodiment 73 are obtained is dissolved in 5 milliliters of tetrahydrofuran (THF)s, in solution, add 685 milligrams of triphenyl phosphines and 340 milligrams of N-tert-butoxycarbonyl thanomins, in ice bath, splash into the solution of 530 milligrams of diisopropyl azo-2-carboxylic acids in 3 milliliters of tetrahydrofuran (THF)s then while stirring.After removing ice bath, in room temperature mixture was stirred 3 hours, and pour in the water, with sodium bicarbonate this mixture that alkalizes, with 150 milliliters of chloroform extractions 2 times.With the extraction liquid dried over mgso, vapourisation under reduced pressure falls solvent.The oil that obtains is dissolved in 2 milliliters of ethyl acetate, in this solution, add the solution of 30 milliliter of 4 centinormal 1 hydrochloric acid in ethyl acetate, in room temperature mixture was stirred 30 minutes, after adding 100 milliliter of 1 centinormal 1 hydrochloric acid, with ethyl acetate washing reaction mixture secondary, with the sodium bicarbonate aqueous layer that alkalizes, use 150 milliliters of chloroform extraction secondaries again.With the extraction liquid dried over mgso, vapourisation under reduced pressure removes and desolvates, and the oil that obtains is added on the silicagel column, with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.Obtain 400 milligrams of colourless non-crystalline state title compounds.
IR（KBr）cm -1：1701，1514，1325，1248，1135，763，601;
NMR（CDCl 3）δ ppm：1.99（2H，brs），2.15-2.40（5H，m），2.55-2.80（3H，m），2.90-3.10（2H，m），3.20-3.70（6H，m），3.73（3H，s），4.98（1H，m），5.10（2H，s），6.54（2H，d，J＝8.55Hz），6.77（2H，d，J＝8.55Hz），7.33（5H，s），7.62（1H，dd，J＝8.06，7.57Hz），8.14（1H，d，J＝8.06Hz），8.34（1H，d，J＝6.10Hz），8.39（1H，d，J＝7.57Hz），8.63（1H，d，J＝6.10Hz），9.28（1H，s）.
Embodiment 137.N-(2-(4-benzyloxycarbonyl piperazinyl-1-is to methoxy-benzyl) ethyl)-the N-(2-dimethylaminoethyl)-the 5-isoquinoline sulfonaide
The product that 6.08 gram embodiment 73 are obtained is dissolved in 30 milliliters of tetrahydrofuran (THF)s, in solution, add 5.0 gram triphenyl phosphines and 1.42 gram N, the N-dimethylethanolamine drips the solution of 3.21 gram diisopropyl azo-2-carboxylic acids in 10 milliliters of tetrahydrofuran (THF)s then while stirring in ice bath.After removing ice bath, reaction mixture was stirred 3 hours,, use 100 milliliter of 1 centinormal 1 hcl as extraction agent again with the ethyl acetate dilution in room temperature.With the sodium bicarbonate extraction liquid that alkalizes, and with 100 milliliters of chloroform extraction secondaries, with the extraction liquid dried over mgso, vapourisation under reduced pressure removes and desolvates.The oil that obtains is added on the silicagel column,, obtains the colourless non-crystalline state title compound of 4.99 grams with trichloromethane/methyl alcohol (200: 1 to 100: 1) wash-out.
IR（KBr）cm -1：1703，1514，1327，1247，1135，600;
NMR（CDCl 3）δ ppm：2.10-2.45（5H，m），2.26（6H，s），2.45-2.85（5H，m），3.20-3.65（6H，m），3.73（3H，s），4.00（1H，m），5.10（2H，s），6.53（2H，d，J＝8.79Hz），6.83（2H，d，J＝8.79Hz），7.34（5H，s），7.56（1H，dd，J＝8.05，7.57Hz），8.10（1H，d，J＝8.05Hz），8.31（1H，d，J＝6.10Hz），8.35（1H，d，J＝7.57Hz），8.59（1H，d，J＝6.10Hz），9.25（1H，s）.
Embodiment 138.N-(2-acetoxyl ethyl)-N-(2-(4-benzyloxycarbonyl piperazinyl)-1-(is to methoxy-benzyl) ethyl)-the 5-isoquinoline sulfonaide
The product that 1.0 gram embodiment 73 are obtained is dissolved in 5 milliliters of tetrahydrofuran (THF)s, add 220 milligrams-acetate glycol ester and 685 milligrams of triphenyl phosphines to replace N-tert-butoxycarbonyl thanomin according to embodiment 136 described steps to solution, obtain 600 milligrams of colourless non-crystalline state title compounds.
NMR（CDCl 3）δ ppm：2.04（3H，s），2.20-2.45（5H，m），2.60-2.80（3H，m），3.20-3.40（4H，m），3.45-3.73（2H，m），3.74（3H，s），4.04（1H，m），4.27（2H，t，J＝6.84Hz），5.10（2H，s），6.54（2H，d，J＝8.55Hz），6.82（2H，d，J＝8.55Hz），7.34（5H，s），7.59（1H，dd，J＝8.05，7.57Hz），8.13（1H，d，J＝8.05Hz），8.30（1H，d，J＝6.10Hz），8.36（1H，d，J＝7.57Hz），9.27（1H，s）.
Embodiment 139.N-(2-(4-benzyloxycarbonyl piperazinyl)-1-(is to methoxybenzyl) ethyl)-the N-(2-hydroxyethyl)-the 5-isoquinoline sulfonaide
The amorphous compound that 600 milligrams of embodiment 138 are obtained is dissolved in 6 ml methanol and the 3 milliliters of tetrahydrofuran (THF)s, adds 6 milliliter of 1 centinormal 1 aqueous sodium hydroxide solution to this solution and in room temperature mixture is stirred 2 hours.The dilute with water reaction mixture, and, wash extraction liquid with saturated sodium-chloride water solution again with 50 milliliters of chloroform extraction secondaries, use dried over mgso, and vapourisation under reduced pressure desolvates to remove.The oil that obtains is added on the silicagel column,, obtains 403 milligrams of colourless non-crystalline state title compounds with trichloromethane/methyl alcohol (100: 1 to 50: 1) wash-out.
IR（KBr）cm -1：1701，1514，1433，1332，1249，1136;
NMR（CDCl 3）δ ppm：2.10-2.25（3H，m），2.25-2.50（4H，m），2.50-2.70（1H，m），3.10-3.45（5H，m），3.55-3.75（2H，m），3.76（3H，s），4.00-4.20（2H，m），5.08（2H，s），about 5.4（1H，br），6.70（2H，d，J＝8.79Hz），6.79（2H，d，J＝8.79Hz），7.32（5H，s），7.73（1H，dd，J＝8.30，7.32Hz），8.22（1H，d，J＝8.3Hz），8.50（1H，d，J＝7.32Hz），8.63（1H，d，J＝6.10Hz），8.72（1H，d，J＝6.10Hz），9.34（1H，s）.
Embodiment 140.N-2-(4-(3,4-dichloro benzyl amino)-piperidino-(1-position only))-1-(is to methoxy-benzyl) ethyl }-N-methyl-5-isoquinoline sulfonaide.
Solution in dimethyl formamide/tetrahydrofuran (THF) (1: 1) carries out alkaline hydrolysis to the amorphous compound that will obtain in embodiment 94 with methyl-iodide and yellow soda ash, methylate, and with 3 equivalent concentration hydrochloric acid refluxs heating, obtain colourless amorphous N-1-(is to methoxy-benzyl)-2-(4-oxo-piperidine subbase) ethyl-N-methyl-5-isoquinoline sulfonaide.
NMR（CDCl 3）δ ppm：2.37（4H，t，J＝5.99Hz），2.40-2.90（8H，m），2.94（3H，s），3.74（3H，s），4.23（1H，m），6.51（2H，d，J＝8.55Hz），6.83（2H，d，J＝8.55Hz），7.55（1H，dd，J＝8.32，7.50Hz），8.10（1H，d，J＝8.32Hz），8.19（1H，d，J＝7.50Hz），8.19（1H，d，J＝6.10Hz），8.55（1H，d，J＝6.10Hz），9.25（1H，s）.
3.34 these compounds of gram are dissolved in 30 ml methanol, add 1.89 grams 3 in solution, 4-dichloro benzyl amine and 0.6 milliliter of acetate stir mixture 3 hours in room temperature.In ice bath with the cooling of this reaction mixture, add 450 milligrams of cyano group sodium borohydrides after, followed the ice bath cooling and stirring 30 minutes, then stirring at room 1 hour.With sodium bicarbonate quaternization mixture, use 150 milliliters of chloroform extraction secondaries again, with the extraction liquid dried over mgso, vapourisation under reduced pressure is to remove solvent, resulting oil is added on the silicagel column, (100: 1-50: 1) wash-out obtains the colourless amorphous title compound of 2.78 grams with trichloromethane/methyl alcohol.
IR（KBr）cm -1：1514，1327，1249，1157，1130，826，600;
NMR（CDCl 3）δ ppm：1.05-1.40（2H，m），1.60-2.15（4H，m），2.30-2.90（8H，m），2.93（3H，s），3.73（5H，s），4.13（1H，m），6.49（2H，d，J＝8.79Hz），6.83（2H，d，J＝8.79Hz），7.15（1H，dd，J＝8.20，1.95Hz），7.38（1H，d，J＝8.20Hz），7.44（1H，d，J＝1.95Hz），7.56（1H，dd，J＝8.06，7.57Hz），8.08（1H，d，J＝8.06Hz），8.19（1H，d，J＝6.35Hz），8.29（1H，d，J＝7.57Hz），8.55（1H，d，J＝6.35Hz），9.23（1H，s）.
Embodiment 141.N-(2-{ 4-(N-(3,4 dichloro benzyls)-N-methylamino) piperidino-(1-position only) }-1-(is to methoxy-benzyl) ethyl)-N-methyl-5-isoquinoline sulfonaide
The amorphous compounds that obtain among the 1.62 gram embodiment 140 are dissolved in 10 milliliters of tetrahydrofuran (THF)s and the 10 milliliters of dimethyl formamides, in solution, adding 115 milligram 60% sodium hydride while stirring with ice-cooled time, under same temperature, made mixture reaction 5 minutes, also used ice-cooled again in 15 minutes at room temperature reaction then.After adding 405 milligrams of methyl-iodides, under same temperature, make this mixture reaction 5 minutes, at room temperature reacted then 2 hours, pour in the water again.With 200 milliliters of these mixtures of ethyl acetate extraction, wash extraction liquid with saturated sodium-chloride water solution again, use dried over mgso, vapourisation under reduced pressure desolvates to remove.The oil that obtains is added on the silicagel column, and (200: 1-100: 1) wash-out obtains 880 milligrams of colourless amorphous title compounds with trichloromethane/methyl alcohol.
IR（KBr）cm -1：1514，1329，1249，1157，1131，826，600;
NMR（CDCl 3）δ ppm：1.10-2.10（6H，m），2.14（3H，s），2.20-3.00（7H，m），2.93（3H，s），3.46（2H，s），3.73（3H，s），4.12（1H，m），6.51（2H，d，J＝8.55Hz），6.85（2H，d，J＝8.55Hz），7.15（1H，dd，J＝8.30，1.71Hz），7.37（1H，d，J＝8.30Hz），7.42（1H，d，J＝1.71Hz），7.56（1H，t，J＝7.82Hz），8.08（1H，d，J＝7.82Hz），8.20（1H，d，J＝6.11Hz），8.30（1H，d，J＝7.82Hz），8.56（1H，d，J＝6.11Hz），9.23（1H，s）.
Reference example 39.4-chlorine cinnamyl alcohol
25.9 grams are dissolved in 250 ml methanol chloro-cinnamic acid, in this solution, add 1.5 milliliters of vitriol oils, and with mixture reflux 2 hours.Reaction mixture is poured on ice, with sodium bicarbonate this mixture that alkalizes, with 1000 milliliters of chloroform extraction secondaries.Wash extraction liquid with saturated sodium-chloride water solution, use dried over mgso again, vapourisation under reduced pressure is added to the gained residue on the silicagel column to remove solvent, and with hexane/ethyl acetate (10: 1) wash-out, obtains 26.5 grams to the chloro-cinnamic acid methyl esters.
This compound is dissolved in 250 milliliters of toluene,, mixture was stirred 2 hours with the ice-cooled solution of diisobutyl aluminium hydride in toluene that in this solution, adds 200 milliliter of 1.5 volumetric molar concentration down while stirring.Reaction mixture is poured on ice, uses the concentrated hydrochloric acid acidifying, again with 700 milliliters of benzene extraction secondaries.Wash extraction liquid with saturated sodium-chloride water solution, use dried over mgso, vapourisation under reduced pressure is added to the gained residue on the silicagel column to remove solvent again, and with hexane/ethyl acetate (4: 1) wash-out, obtains 21.0 gram clear crystal title compounds.
1H-NMR（CDCl 3，δ ppm）：4.33（2H，brs），6.33（1H，dt，J＝17.1，5.7Hz），6.59（1H，dt，J＝17.1，2.0Hz），7.29（4H，s）.
Reference example 40.N-4-chlorine cinnamyl-1, the 2-phenylenediamine
The crystal that 11.9 gram reference examples 39 are obtained are dissolved in 120 milliliters of trichloromethanes, add 10.1 gram thionyl chloride in ice bath while stirring in solution, remove ice bath after, mixture was stirred 1 hour, allow temperature of reaction raise simultaneously and reach room temperature.Vapourisation under reduced pressure falls trichloromethane and excessive thionyl chloride, adds benzene in residue, and vapourisation under reduced pressure falls solvent.The gained residue is added on the silicagel column, and, obtains 1 1.3 gram clear crystal 4-chlorine cinnamyl chlorine with hexane/ethyl acetate (15: 1) wash-out
1H-NMR（CDCl 3，δ ppm）：4.23（2H，dd，J＝6.3，1.0Hz），6.29（1H，dt，J＝16.6，6.9Hz），6.62（1H，dt，J＝16.6，1.0Hz），7.30（4H，s）.
With 19.6 grams 1, the 2-phenylenediamine is dissolved in 300 milliliters of dimethyl formamides, and 4-chlorine cinnamyl chlorine crystal and 12.5 gram salt of wormwood in that room temperature prepares above solution adds 11.3 grams while stirring stir mixture 48 hours under similarity condition.After adding water and sodium-chlor, with 1000 milliliters of trichloromethanes reaction mixture is extracted secondary, with the extraction liquid drying, vapourisation under reduced pressure is to remove solvent with sal epsom.The gained residue is added on the silicagel column, and, obtains 12.85 gram clear crystal title compounds with hexane/ethyl acetate (3: 1) wash-out.
1H-NMR（CDCl 3，δ ppm）：3.4（3H，brs），3.93（2H，dd，J＝5.71，1.0Hz），6.36（1H，dt，J＝16.0，5.71Hz），6.59（1H，dt，J＝16.0，1.0Hz），6.68-6.9（4H，m），7.28（4H，s）.
Embodiment 142.N-(2-(4-chlorine cinnamyl amino) phenyl)-the 5-isoquinoline sulfonaide
The crystal that 12.85 gram reference examples 40 are obtained are dissolved in 200 milliliters of pyridines, add the hydrochloride of 15.1 gram 5-isoquinoline 99.9 SULPHURYL CHLORIDE in ice bath while stirring in solution, remove ice bath after, make mixture room temperature reaction 18 hours.Reaction mixture is poured on ice, with sodium bicarbonate alkalization, and with 1000 milliliters of chloroform extraction secondaries.Extraction liquid dried over mgso, vapourisation under reduced pressure are fallen solvent to form soluble hardly crystal.Add trichloromethane to this crystal, whole reflux, cooling is collected resulting crystal by suction strainer then, and with the trichloromethane washing, drying under reduced pressure obtains 17.23 gram clear crystal title compounds again.
Fusing point: 205-208 ℃ (decomposition)
IR（KBr）cm -1：1600，1320，1150，1135;
1H-NMR（CDCl 3+CD 3OD，δ ppm）：3.73（2H，dd，J＝5.62，1.46Hz），6.04（1H，dt，J＝15.8，5.37Hz），6.27-6.35（2H，m），6.42（1H，dt，J＝16.11，1.46Hz），6.58（1H，d，J＝7.81Hz），7.04（1H，ddd，J＝8.30，6.10，2.93Hz），7.25（2H，d，J＝9.03Hz），7.31（2H，d，J＝9.03Hz），7.63（1H，dd，J＝8.06，7.33Hz），8.17（1H，dd，J＝7.32，0.98Hz），8.30（1H，dd，J＝7.57，1.23Hz），8.47（1H，dd，J＝6.35，1.02Hz），8.55（1H，d，J＝6.35Hz），9.25（1H，d，J＝0.98Hz）.
Embodiment 143.N-(2-(4-chloro cinnamyl amino) phenyl)-N-methyl-5-isoquinoline sulfonaide
Embodiment 142 gained crystal 3 80mg are dissolved in 6ml methyl alcohol, and to the diethyl ether solution of this solution adding 10ml diazomethane, temperature is a room temperature, stirs down to add, and mixture stirred 18 hours.Remove solvent under reduced pressure and get a kind of oily matter, it is coated onto uses hexane/ethyl acetate (1: 1) wash-out on the silicagel column then, get its acetic ester, carry out recrystallization, obtain 270mg title compound clear crystal with hexane/ethyl acetate.
Fusing point: 149-151 ℃;
INFRARED SPECTRUM IR(KBr) cm -1: 1595,1325,1125,830,745;
The nuclear-magnetism and the spectrum of shaking 1H-NMR(CDCl 3, δ PPm): 3.24(3H, s), 3.87(2H, m), 4.81(1H, t, J=5.71Hz), 6.13(1H, dt, J=19.14,5.71Hz), 6.25-6.40(2H, m), 6.53(1H, dt, J=19.4,1.0Hz), 6.67(1H, d, J=8.57Hz), 7.05-7.18(1H, m), 7.28(4H, s), 7.67(1H, t, J=7.42Hz), 8.19(1H, d, J=7.42Hz), 8.28(1H, d, J=6.28Hz), 8.32(1H, dd, J=7.42,1.0Hz), 8.51(1H, d, J=6.28Hz), 9.30(1H, d, J=1.0Hz).
Embodiment 144.1-(4-chlorine cinnamyl)-and the 4-(5-isoquinolinesulfonylcompounds)-1,2,3, the 4-tetrahydroquinoxaline
The crystal 5 .0g that embodiment 142 is obtained is dissolved in the 75ml dimethyl formamide, adds 4.6g salt of wormwood and 2.19g1 in stirring at room in this solution, and the 2-ethylene dibromide stirred the mixture 60 hours.Reaction mixture is poured in the water, saturated with sodium-chlor, use twice of 400ml chloroform extraction then.With the dried over mgso extraction liquid, solvent is removed in underpressure distillation.The residue that obtains is coated onto on the silicagel column, uses hexane/ethyl acetate (2: 1) wash-out then, get yellow amorphous title compound 3.32g with chloroform/methanol (400: 1).
IR（KBr）cm -1：1600，1340，1150，1130，660;
1H-NMR（CDCl 3，δ PPm）：2.68（2H，t，J＝5.71Hz），3.49（2H，dd，J＝6.28，1.0Hz），3.89（2H，t，J＝5.71Hz），5.43（1H，dt，J＝15.42，6.28Hz），6.10（1H，dt，J＝15.42，1.0Hz），6.48（1H，dd，J＝7.99，1.0Hz），6.75（1H，dt，J＝7.99，1.0Hz），7.09（2H，d，J＝7.99Hz），7.12（1H，dt，J＝7.99，1.0Hz），7.31（2H，d，J＝7.99Hz），7.54（1H，dd，J＝7.99，1.0Hz），7.59（1H，t，J＝7.99Hz），7.77（1H，d，J＝6.28Hz），7.94（1H，d，J＝7.99Hz），8.30（1H，d，J＝6.28Hz），8.38（1H，dd，J＝7.99，1.0Hz），9.03（1H，d，J＝1.0Hz）。
Embodiment 145.
Repeat the same processing step of embodiment 142, difference is with N-(3-(3-pyridyl) allyl group)-1, the 2-phenylenediamine replaces N-(4-chlorine cinnamyl)-1, the 2-phenylenediamine obtains brown amorphous N-{ 2-(3-(3-pyridyl) allyl amino) phenyl }-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ PPm）：2.2（1H，br），3.78（2H，dd，J＝5.14，1.0Hz），4.85（1H，br），6.14（1H，dt，J＝15.99，5.14Hz），6.33（2H，d，J＝4.57Hz），6.42（1H，dt，J＝15.99，1.0Hz），6.58（1H，d，J＝7.42Hz），6.98-7.15（1H，m），7.26（1H，dd，J＝7.42，4.57Hz），7.59（1H，t，J＝7.42Hz），7.65（1H，dt，J＝7.42，1.0Hz），8.16（1H，d，J＝7.99Hz），8.30（1H，d，J＝6.85Hz），8.35-8.53（3H，m），8.56（1H，d，J＝6.28Hz），9.32（1H，s）。
Embodiment 146.
According to the processing step Processing Example 145 gained amorphous compounds of embodiment 143, obtain N-{ 2-(3-(3-pyridyl) allyl amino) phenyl }-N-methyl-5-isoquinoline sulfonaide.
1H-NMR（CDCl 3，δ PPm）：3.24（3H，s），3.92（2H，t，J＝4.57Hz），4.90（1H，t，J＝5.71Hz），6.26（1H，dt，J＝15.42，5.14Hz），6.32（2H，d，J＝4.57Hz），6.58（1H，dt，J＝15.42，1.0Hz），6.62-6.74（2H，m），7.05-7.20（1H，m），7.26（1H，dd，J＝7.99，4.57Hz），7.6-7.75（1H，m），8.21（1H，d，J＝7.99Hz），8.28（1H，d，J＝6.85Hz），8.32（1H，d，J＝6.28Hz），8.47（1H，dd，J＝5.71，1.0Hz），8.51（1H，d，J＝6.28Hz），8.58（1H，d，J＝1.7Hz），9.31（1H，s）。
Reference example 41.2-amino-3-(4-chlorine cinnamyl amino) pyridine
To cinnamoyl chloride chlorine and 13.5g2, the 3-diamino-pyridine is dissolved in the 220ml dimethyl formamide with 7.71g, adds 8.6g salt of wormwood in this solution, in stirring at room mixture 50 hours, adds behind the 300ml water with twice of 200ml chloroform extraction.With concentrating under reduced pressure behind the dried over mgso extraction liquid, the gained residue is coated onto on the silicagel column, chloroform/methanol (100: 1～50: 1) wash-out, the yellow crystals of 4.52g title compound.
1H-NMR（CDCl 3，δ PPm）：3.38（1H，br），3.92（2H，m），4.20（2H，br），6.31（1H，dt，J＝16.1，5.9Hz），6.59（1H，dt，J＝16.1，1.5Hz），6.71（1H，dd，J＝4.9，7.8Hz），6.86（1H，dd，J＝1.5，7.8Hz），7.29（4H，s），7.63（1H，dd，J＝1.5，4.9Hz）。
Embodiment 147.3-(4-chlorine cinnamyl amino)-and 2-(5-isoquinoline 99.9 sulfonamido) pyridine
41 gained crystal 4 .52g are dissolved in the 50ml pyridine with reference to example, add the hydrochloride of 5-isoquinoline 99.9 SULPHURYL CHLORIDE of 5.8g and the Dimethylamino pyridine of 3g in this solution, in stirring at room mixture 18 hours, add behind the 150ml water with twice of 80ml chloroform extraction.Extract and concentrating under reduced pressure with dried over mgso, the gained residue is coated onto also uses chloroform/methanol (100: 1) wash-out on the silicagel column, the gained crystal washs with ethyl acetate, obtains the yellow crystals of 1.2g title compound.
Fusing point: 211-217 ℃ (decomposition);
IR（KBr）cm -1：1595，1550，1345，1285，1250，1105;
1H-NMR（CDCl 3，δ PPm）：3.89（2H，m），5.45（1H，t，J＝5.9Hz），6.12（1H，dt，J＝16.1，5.4Hz），6.45（1H，d，J＝16.1Hz），6.51-6.62（2H，m），6.92（1H，brs），7.21（2H，d，J＝8.8Hz），7.29（2H，d，J＝8.8Hz），7.64（1H，dd，J＝7.3，8.3Hz），8.12（1H，d，J＝8.3Hz），8.45（1H，dd，J＝1.0，7.3Hz），8.64（1H，d，J＝5.9Hz），8.69（1H，d，J＝5.9Hz），9.31（1H，s）。
Reference example 42.4-amino-3-(4-chlorine cinnamyl amino) methyl benzoate
With 3 of 5.0g, the 4-diamino-methyl benzoate is dissolved in the 40ml dimethyl formamide, adds 2.07g salt of wormwood and 1.87g to cinnamoyl chloride chlorine in this solution, react according to the processing step of reference example 40, the light brown oily thing of 2.0g title compound.
NMR（CDCl 3）δ PPm：3.85（3H，s），3.94（2H，brd），6.35（1H，dt，J＝5.86，15.8Hz），6.59（1H，d，J＝5.8Hz），6.7（1H，d，J＝8.02Hz），7.28（4H，s），7.4（1H，d，J＝1.4Hz），7.46（1H，dd，J＝1.4，8.0Hz）。
Embodiment 148.4-(5-isoquinoline 99.9 sulfonamido)-and 3-(4-chlorine cinnamyl amino) methyl benzoate
1.8g reference example 42 gained oily matter are dissolved in the 18ml pyridine, the 5-isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride that adds 1.29g in this solution, add the fashionable ice-cooled stirring of using, processing step treating mixture according to embodiment 142, get residue, be coated onto it on silicagel column and usefulness chloroform/methanol (100: 1) wash-out, get the pale yellow crystals of 1.28g title compound.
Fusing point: 143-145 ℃ (distilling when being higher than melting temperature);
NMR（CDCl 3）δ PPm：3.78（2H，brd），3.82（3H，s），6.0（1H，dt，J＝5.86，15.87Hz），6.4（1H，d，J＝15.8Hz），6.45（1H，d，J＝8.3Hz），7.05（1H，dd，J＝1.8，8.3Hz），7.2-7.3（5H，brs），7.60（1H，t，J＝7.6Hz），8.15（1H，d，J＝8.3Hz），8.29（1H，dd，J＝1.2，7.3Hz），8.43（1H，d，J＝6.1Hz），8.61（1H，d，J＝6.1Hz），9.3（1H，d，J＝1.2Hz）。
Reference example 43.N-cinnamyl-1, the 2-phenylenediamine
O-Phenylene Diamine 3.24g is dissolved in the 30ml dimethyl formamide, adds 2.07g salt of wormwood and 1.52g cinnamyl chloride in this solution, in room temperature mixture is stirred and spend the night.Use 100ml and twice extractive reaction mixture of 50ml chloroform after adding 100ml water, wash extraction liquid with saturated sodium-chloride water solution, dried over mgso, solvent is removed in underpressure distillation.The gained residue is coated onto on the silicagel column, with the chloroform wash-out, gets the light brown crystal of 2.0g title compound.
Fusing point: 59-66 ℃ (decomposition);
NMR(CDCl 3) δ PPm:3.3(2H, brs), 3.93(2H, brd), and 6.4(1H, d and t, J=5.6,16.1Hz), and 6.1-6.45(4H, complex spike), 5.2-5.7(5H, complex spike).
Embodiment 149.N-(2-cinnamyl amino) phenyl-5-isoquinoline sulfonaide
43 gained crystal 1.8g are dissolved in the 18ml pyridine with reference to example, add 1.83g isoquinoline 99.9 SULPHURYL CHLORIDE hydrochloride in this solution, stirring at room mixture 18 hours.Use the 80ml chloroform with the reaction mixture extracting twice after adding water 50ml, with saturated common salt solution washing extraction liquid, dried over mgso, solvent is removed in underpressure distillation.The gained residue is coated onto on the silicagel column, with chloroform/methanol (100: 1) wash-out, gets the light red crystal of 2.40g title compound.
Fusing point: 181-185 ℃;
NMR(CDCl 3) δ PPm:3.75(2H, brd), 4.55(1H, brs), 6.05(1H, d and t, J=5.6,16.1Hz), 6.35(2H, brd), 6.45(1H, d, J=16.1Hz), 6.63(1H, d, J=8.3Hz), 7-7.13(1H, complex spike), 7.25-7.4(5H, complex spike), 7.6(1H, t, J=8.2Hz), 8.15(1H, d, J=8.3Hz), 8.31(1H, dd, J=1.0,8.2Hz), 8.4(1H, d, J=6.6Hz), 8.65(1H, d, J=6.6Hz), 9.3(1H, d, J=1.0Hz).
Reference example 44.N-(4-chlorine cinnamyl)-1, the 3-phenylenediamine
The 3.24g mphenylenediamine is dissolved in the 40ml dimethyl formamide, in this solution, add 2.07g salt of wormwood and 1.87g to cinnamoyl chloride chlorine, processing step by reference example 40 reacts this mixture, the gained residue is coated onto on the silicagel column, with n-hexane/ethyl acetate (3: 1～2: 1) wash-out, obtain the light brown oily thing of 1.70g title compound.
NMR(CDCl 3) δ PPm:3.65(2H, brs), 3.90(2H, dd, J=1.4,5.6Hz), 6.0-6.2(3H, complex spike), 6.3(1H, dd, J=5.6,15.9Hz), 6.56(1H, dd, J=1.4,15.9Hz), 6.97(1H, t, J=8.1Hz), 7.3(4H, s).
Embodiment 150.N-(3-(4-chlorine cinnamyl amino) phenyl)-the 5-isoquinoline sulfonaide
Reference example 44 gained oily matter 1.7g are dissolved in the 18ml pyridine, add 5-isoquinoline 99.9 SULPHURYL CHLORIDE-hydrochloride of 1.99g in this solution, and ice-cooled stirring down repeats embodiment 142 described same processing steps, gets the light brown oily thing of 1.45g title compound.
NMR(CDCl 3) δ PPm:3.8(2H, brd), 3.92(1H, brs), 6.15(1H, d and t, J=5.6,15.9Hz), 6.25(1H, brs), 6.35(2H, brd), 6.49(1H, d, J=15.9Hz), 6.92(1H, t, J=8.1Hz), 7.3(4H, s), 7.51(1H, t, J=8.3Hz), 8.1(1H, d, J=8.3Hz), 8.35(1H, dd, J=1.0,8.3Hz), 8.45(1H, d, J=6.1Hz) 8.65, (1H, d, J=6.4Hz), and 9.3(1H, d, J=1.0Hz).
Embodiment 151.N-2-(is to chlorine cinnamyl amino) phenyl }-the N-(2-hydroxyethyl)-the 5-isoquinoline sulfonaide
Embodiment 142 gained crystal 1.5g are dissolved in the 8ml tetrahydrofuran (THF), add 1.32g triphenylphosphine and 420mg ethylene glycol-acetate in this solution under ice bath stirs, and also splash into the solution of 1.01g diisopropyl azodiformate in the 2ml tetrahydrofuran (THF).Make mixture be raised to room temperature after removing ice bath, stirred 3 hours,, use twice of the 2N hcl as extraction agent of 70ml then with ethyl acetate dilution.Water alkalizes with sodium bicarbonate, uses 150ml chloroform extraction twice again, dried over mgso, and solvent is removed in underpressure distillation.The residual oily matter of gained is dissolved in 20ml methyl alcohol and the 20ml tetrahydrofuran (THF), and the 1N aqueous sodium hydroxide solution in this solution adding 20ml at room temperature reacted 2 hours.The dilute with water reaction mixture, each uses 100ml and 50ml chloroform extraction twice, the dry extraction liquid of magnesium chloride, solvent is removed in underpressure distillation.Residual oily matter is coated onto on the silicagel column, and chloroform/methanol (100: 1～50: 1) wash-out gets the 1.59g title compound, is the armorphous thing of yellow.
IR（KBr）cm -1：1603，1516，1491，1342，1161，1139，835，758，604，509;
NMR（CDCl 3）δ PPm：3.09（1H，m），3.29（1H，ddd，J＝13.43，4.64，3.18Hz），3.47（1H，m），3.75（1H，m），3.85（2H，m），4.33（1H，ddd，J＝13.43，8.30，4.15Hz），5.12（1H，m），6.16（1H，dt，J＝15.87，5.62Hz），6.23（1H，dd，J＝8.06，1.47Hz），6.40（1H，td，J＝7.33，1.47Hz），6.55（1H，d，J＝16.11Hz），6.76（1H，d，J＝8.54Hz），7.15（1H，t，J＝8.30Hz），7.29（4H，s），7.63（1H，t，J＝8.30Hz），8.18（1H，d，J＝8.30Hz），8.28（1H，d，J＝8.30Hz），8.28（1H，d，J＝6.35Hz），8.52（1H，d，J＝6.3Hz），9.31（1H，s）。
Embodiment 152.N-(2-(is to chlorine cinnamyl amino) phenyl)-N-(2-diformazan aminoethyl)-the 5-isoquinoline sulfonaide
Embodiment 142 gained crystal 2 .0g are dissolved in the 10ml tetrahydrofuran (THF), under stirring, ice bath adds 1.75g triphenylphosphine and 520mg N in this solution, the N-dimethylethanolamine, and be dissolved in solution in the 3ml tetrahydrofuran (THF) to wherein splashing into the 1.3g diisopropyl azodiformate.Rise to room temperature after removing ice bath, stirred 3 hours, then with ethyl acetate dilution, with twice of 100ml2N hcl as extraction agent.Use 200ml chloroform extracting twice again behind the sodium bicarbonate aqueous solution alkalization extraction liquid.This extraction liquid dried over mgso, solvent is removed in underpressure distillation, and residual oily matter is coated onto on the silicagel column, and chloroform/methanol (100: 1) wash-out gets the yellow amorphous title compound of 1.35g.
IR（KBr）cm -1：：1603，1521，1491，1458，1329，1160，1137，834，749，601，507;
NMR（CDCl 3）δ PPm：2.19（6H，s），2.15-2.55（2H，m），3.19（1H，dt，J＝12.69，4.15Hz），3.56（2H，m），4.35（1H，m），5.78（1H，m），5.89（1H，dt，J＝15.87，5.37Hz），6.30-6.55（3H，m），6.64（1H，dd，J＝7.81，1.71Hz），7.09（1H，td，J＝7.81，1.71Hz），7.23（2H，d，J＝9.03Hz），7.30（2H，d，J＝9.03Hz），7.57（1H，dd，J＝8.30，7.57Hz），8.11（1H，d，J＝8.30Hz），8.24（1H，d，J＝7.57Hz），8.40（1H，d，J＝6.35Hz），8.53（1H，d，J＝6.35Hz），9.26（1H，s）。
Embodiment 153 to 171.
In embodiment 153 to 171, adopt following general reaction formula.
Figure 921151012_IMG25
Embodiment 153.(n=2, aryl=4-chloro-phenyl-) N-(2-(4-chloro-α methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
7.30g the N-(2-aminoethyl)-the 5-isoquinoline sulfonaide is dissolved in 150ml methyl alcohol, adds 6.30g in this solution to the chlorine benzylidene-acetone, stirred the mixture under the room temperature 36 hours.After adding the 1.32g sodium tetraborate, the frozen water cooling stirred the mixture 30 minutes.Decompression is concentrated into reaction mixture half of original volume down, and after adding the 300ml ethyl acetate, washes with water three times.Water 100ml ethyl acetate extraction, the extraction liquid water washs as mentioned above.Ethyl acetate is compiled mutually, used the saturated sodium-chloride water solution washed twice, dried over mgso is filtered, and solvent is removed in underpressure distillation.Residue silicagel column purifying (silica gel: 200g; Eluent: contain 5% methyl alcohol in the chloroform), gets the colourless amorphous title compound of 6.78g, reclaim residual raw materials simultaneously.
1H-NMR（CDCl 3，δ PPm）：1.06（3H，d，J＝6.6Hz），1.8-2.8（2H，br），2.57-2.64（2H，m），2.96（2H，t，J＝5.7Hz），3.06（1H，dq，J＝7.8，6.6Hz），5.79（1H，dd，J＝15.8，7.8Hz），6.24（1H，d，J＝15.8Hz），7.19（2H，dm，J＝8.8Hz），7.25（2H，dm，J＝8.8Hz），7.67（1H，dd，J＝8.0，7.6Hz），8.28（1H，dt，J＝8.0，1.0Hz），8.42-8.46（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）。
Embodiment 154.(n=2, aryl=phenyl) N-(2-(Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ PPm）：2.0-3.0（2H，br），2.59-2.66（2H，m），2.98（2H，t，J＝5.5Hz），3.09（1H，dq，J＝8.0，6.6Hz），5.80（1H，dd，J＝15.9，8.0Hz），6.28（1H，d，J＝15.9Hz），7.28（5H，brs），7.66（1H，dd，J＝8.3，7.3Hz），8.17（1H，brd，J＝8.3Hz），8.43（1H，dd，J＝7.3，1.2Hz），8.44（1H，d，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）。
Embodiment 155.(n=2, aryl=2,4 difluorobenzene base)
N-(2-(2,4-two fluoro-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR(CDCl 3, δ ppm): 1.06(3H, d, J=6.4Hz), 1.3-2.2(2H, br), 2.57-2.67(2H, m), 2.96(2H, t, J=5.6Hz), 3.04(1H, dq, J=8.0,6.4Hz), 5.81(1H, dd, J=16.1,8.0Hz), 6.35(1H, d, J=16.1Hz), 6.79(1H, d, J=8.3Hz and 1H, ddd, J=17.6,8.8,2.0Hz), 7.30(1H, ddd, J=14.9,8.3,2.0Hz), 7.69(1H, dd, J=8.3,7.3Hz), 8.29(1H, dt, J=8.3,1.0Hz), 8.42-8.47(2H, m), 8.70(1H, d, J=6.1Hz), 9.35(1H, d, J=1.0Hz).
Embodiment 156.(n=2, aryl=2,4 dichloro benzene base)
N-(2-(2,4-two chloro-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.07（3H，d，J＝6.6Hz），1.5-2.5（2H，br），2.58-2.65（2H，m），2.97（2H，t，J＝5.5Hz），3.09（1H，dq，J＝8.0，6.6Hz），5.75（1H，dd，J＝15.8，8.0Hz），6.58（1H，d，J＝15.8Hz），7.18（1H，dd，J＝8.5，2.0Hz），7.28（1H，d，J＝8.5Hz），7.35（1H，d，J＝2.0Hz），7.68（1H，dd，J＝8.0，7.3Hz），8.18（1H，td，J＝8.0，1.0Hz），8.42-8.47（2H，m），8.70（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 157.(n=2, aryl=3-chloro-phenyl-)
N-(2-(3-chloro-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.06（3H，d，J＝6.6Hz），1.3-2.4（2H，br），2.56-2.63（2H，m），2.97（2H，t，J，5.6Hz），3.06（1H，dq，J＝7.8，6.6Hz），5.80（1H，dd，J＝15.9，7.8Hz），6.22（1H，d，J＝15.9Hz），7.10-7.26（4H，m），7.68（1H，dd，J＝8.1，7.5Hz），8.18（1H，dt，J＝8.1，1.0Hz），8.42-8.47（2H，m），8.70（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 158.(n=2, aryl=2-nitrophenyl)
N-(2-(alpha-methyl-2-nitro cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Light yellow amorphous;
1H-NMR（CDCl 3，δ ppm）：1.08（3H，d，J＝6.4Hz），1.3-2.6（2H，br），2.61-2.67（2H，m），2.99（2H，t，J＝5.6Hz），3.09（1H，dq，J＝7.8，6.4Hz），5.73（1H，dd，J＝15.6，7.8Hz），6.73（1H，d，J＝15.6Hz），7.36-7.56（3H，m），7.68（1H，dd，J＝8.3，7.3Hz），7.92（1H，dd，J＝7.9，1.2Hz），8.42-8.47（2H，m），8.67（1H，d，J＝6.1Hz），9.31（1H，d，J＝1.0Hz）.
Embodiment 159.(n=2, aryl=4-nitrophenyl)
N-(2-(Alpha-Methyl-4-nitro cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Light yellow amorphous;
1H-NMR（CDCl 3，δ ppm）：1.10（3H，d，J＝6.6Hz），1.4-2.6（2H，br），2.60-2.67（2H，m），2.99（2H，t，J＝5.5Hz），3.14（1H，dq，J＝7.6，6.6Hz），6.05（1H，dd，J＝15.9，7.6Hz），6.38（1H，d，J＝15.9Hz），7.40（2H，dm，J＝8.8Hz），7.69（1H，dd，J＝8.3，7.5Hz），8.14（2H，dm，J＝8.8Hz），8.23（1H，brd，J＝8.3Hz），8.43-8.48（2H，m），8.68（1H，d，J＝6.1Hz），9.36（1H，d，J＝1.0Hz）.
Embodiment 160.(n=2, aryl=4-aminomethyl phenyl)
N-(2-(α, 4-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.05（3H，d，J＝6.6Hz），2.0-2.5（2H，br），2.33（3H，s），2.56-2.64（2H，m），2.96（2H，t，J＝5.9Hz），3.05（1H，m），5.73（1H，dd，J＝15.9，7.8Hz），6.24（1H，d，J＝15.9Hz），7.09（2H，brd，J＝8.3Hz），7.16（2H，brd，J＝8.3Hz），7.67（1H，t，J＝8.0Hz），8.17（1H，brd，J＝8.0Hz），8.43（1H，d，
Embodiment 161.(n=2, aryl=3,4-methylenedioxyphenyl)
N-(2-(Alpha-Methyl-3,4-methylene-dioxy cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.04（3H，d，J＝6.3Hz），2.56-2.63（2H，m），2.95（2H，t，J＝5.6Hz），3.05（1H，dq，J＝8.0，6.3Hz），5.60（1H，dd，J＝15.9，8.0Hz），6.95（2H，s），6.18（1H，d，J＝15.9Hz），6.70（1H，dd，J＝7.5，1.5Hz），6.73（1H，d，J＝7.5Hz），6.79（1H，d，J＝1.5Hz），7.68（1H，dd，J＝8.1，7.5Hz），8.19（1H，brd，J＝8.1Hz），8.42-8.46（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 162.(n=2, aryl=2-pyridyl)
N-2-(1-methyl-3-(2-pyridyl)-2-acrylic-amino) ethyl }-the 5-isoquinoline sulfonaide
1H-NMR（CDCl 3，δ ppm）：1.07（3H，d，J＝6.6Hz），1.5-4.0（2H，br），2.62（2H，dt，J＝5.7，5.7Hz），2.97（2H，t，J＝6.4Hz），3.06（1H，dq，J＝5.6，6.6Hz），6.35（1H，d，J＝5.6Hz），6.37（1H，s），7.12（1H，dddd，J＝7.8，5.0，2.0，1.0Hz），7.21（1H，d，J＝7.8Hz），7.62（1H，td，J＝7.8，2.0Hz），7.68（1H，dd，J＝8.0，7.3Hz），8.18（1H，brd，J＝8.0Hz），8.44（1H，d，J＝7.3Hz），8.45（1H，d，J＝7.3Hz），8.52（1H，ddd，J＝5.0，2.0，1.0Hz），8.67（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 163.(n=2, aryl=4-pyridyl)
N-2-(1-methyl-3-(4-pyridyl)-2-acrylic-amino) ethyl }-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.09（3H，d，J＝6.3Hz），1.2-1.9（2H，br），2.59-2.65（2H，m），2.98（2H，t，J＝6.0Hz），3.12（1H，dq，J＝7.3，6.3Hz），6.06（1H，dd，J＝15.9，7.3Hz），6.26（1H，d，J＝15.9Hz），7.14（2H，dd，J＝6.1，1.5Hz），7.69（1H，dd，J＝8.1，7.5Hz），8.19（1H，brd，J＝8.1Hz），8.42-8.47（2H，m），8.51（2H，dd，J＝6.1，1.5Hz），8.68（1H，d，J＝6.3Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 164.(n=2, aryl=2-thienyl)
N-2-(1-methyl-3-(2-thienyl)-2-acrylic-amino) ethyl }-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.05（3H，d，J＝6.6Hz），1.2-2.5（2H，br），2.56-2.64（2H，m），2.93-3.05（3H，m），5.65（1H，dd，J＝15.6，8.0Hz），6.41（1H，d，J＝15.6Hz），6.85（1H，dd，J＝3.7，2.4Hz），6.94（1H，dd，J＝4.9，3.7Hz），7.13（1H，dd，J＝4.9，2.4Hz），7.68（1H，dd，J＝8.3，7.5Hz），8.19（1H，brd，J＝8.3Hz），8.42-8.46（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 165.(n=2, aryl=2-furyl)
N-2-(3-(2-furyl)-1-methyl-2-acrylic-amino) ethyl }-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.04（3H，d，J＝6.4Hz），1.3-1.5（2H，br），2.59（2H，td，J＝6.0，4.9Hz），2.95（2H，t，J＝6.0Hz），2.98（1H，dq，J＝7.8，6.4Hz），5.75（1H，dd，J＝15.9，7.8Hz），6.10（1H，d，J＝15.9Hz），6.16（1H，d，J＝3.2Hz），6.35（1H，dd，J＝3.2，1.9Hz），7.32（1H，d，J＝1.9Hz），7.68（1H，dd，J＝8.3，7.5Hz），8.19（1H，brd，J＝8.3Hz），8.42-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 166.(n=2, aryl=4-fluorophenyl)
N-(2-(4-fluoro-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.06（3H，d，J＝6.4Hz），1.3-2.0（2H，br），2.57-2.63（2H，m），2.95（2H，t，J＝5.5Hz），3.05（1H，dq，J＝8.0，6.4Hz），5.72（1H，dd，J＝15.9，8.0Hz），6.25（1H，d，J＝15.9Hz），6.98（2H，tm，J＝8.7Hz），7.20-7.27（2H，m），7.68（1H，dd，J＝8.1，7.3Hz），8.18（1H，brd，J＝8.1Hz），8.42-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 167.(n=2, aryl=4-bromophenyl)
N-(2-(4-bromo-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.06（3H，d，J＝6.4Hz），1.3-2.2（2H，br），2.56-2.63（2H，m），2.95（2H，t，J＝5.7Hz），3.05（1H，dq，J＝8.0，6.4Hz），5.79（1H，dd，J＝15.9，8.0Hz），6.22（1H，d，J＝15.9Hz），7.13（2H，dm，J＝8.5Hz），7.41（2H，dm，J＝8.5Hz），7.68（1H，dd，J＝8.3，7.4Hz），8.19（1H，brd，J＝8.3Hz），8.42-8.46（2H，m），8.69（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 168.(n=2, aryl=4-isopropyl phenyl)
N-(2-(4-sec.-propyl-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.05（3H，d，J＝6.6Hz），1.24（6H，d，J＝6.8Hz），1.5-2.5（2H，br），2.56-2.63（2H，m），2.80-3.05（3H，m），5.74（1H，dd，J＝15.9，8.0Hz），6.24（1H，d，J＝15.9Hz），7.16（2H，d，J＝8.6Hz），7.20（2H，d，J＝8.6Hz），7.66（1H，dd，J＝8.3，7.3Hz），8.17（1H，brd，J＝8.3Hz），8.43（1H，dd，J＝7.3，1.0Hz），8.44（1H，d，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 169.(n=2, aryl=4-methoxyphenyl)
N-(2-(4-methoxyl group-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.05（3H，d，J＝6.4Hz），1.5-2.5（2H，br），2.56-2.63（2H，m），2.96（2H，t，J＝5.6Hz），3.02（1H，dq，J＝8.0，6.4Hz），3.81（3H，s），5.64（1H，dd，J＝15.9，8.0Hz），6.21（1H，d，J＝15.9Hz），6.83（2H，dm，J＝8.8Hz），7.20（2H，dm，J＝8.8Hz），7.67（1H，dd，J＝8.3，7.3Hz），8.19（1H，brd，J＝8.3Hz），8.44（1H，dd，J＝7.3，1.2Hz），8.44（1H，d，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 170.(n=2, aryl=4-hydroxyphenyl)
N-(2-(4-hydroxyl-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 70-73 ℃;
1H-NMR（CDCl 3，δ ppm）：1.06（3H，d，J＝6.4Hz），2.61（2H，brt，J＝5.7Hz），3.00（2H，brt，J＝5.7Hz），3.05（1H，dq，J＝8.0，6.4Hz），3.3-3.5（3H，br），5.61（1H，dd，J＝15.9，8.0Hz），6.19（1H，d，J＝15.9Hz），6.75（2H，brd，J＝8.5Hz），7.10（2H，brd，J＝8.5Hz），7.65（1H，dt，J＝8.3，7.3Hz），8.16（1H，brd，J＝8.3Hz），8.40-8.46（2H，m），8.59（1H，d，J＝6.1Hz），9.32（1H，d，J＝1.0Hz）.
Embodiment 171.(n=3, aryl=phenyl)
N-(3-(Alpha-Methyl cinnamyl amino) propyl group)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.27（3H，d，J＝6.6Hz），1.50-1.60（2H，m），1.6-2.5（2H，br），2.60-2.67（2H，m），3.01-3.09（2H，m），3.24（1H，dq，J＝7.8，6.6Hz），5.91（1H，dd，J＝15.9，7.8Hz），6.40（1H，d，J＝15.9Hz），7.30（5H，m），7.68（1H，dd，J＝8.0，7.3Hz），8.18（1H，brd，J＝8.0Hz），8.43（1H，dd，J＝7.3，1.2Hz），8.47（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz），9.36（1H，d，J＝1.0Hz）.
Embodiment 172 to 188.
In embodiment 172 to 188, adopt following general reaction formula.
Figure 921151012_IMG26
Embodiment 172.(n=2, m=1, aryl=4-chloro-phenyl-)
N-(2-(4-chlorine cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
N-(2-aminoethyl with 2.01g)-the 5-isoquinoline sulfonaide is dissolved in the 30ml methyl alcohol, adds 1.60g in this solution to chlorocinnamaldehyde, stirring at room mixture one hour.Stirred the mixture 30 minutes behind the ice-cooled adding of the part 350mg sodium tetraborate.The washing reaction mixture that water continues after the adding ethyl acetate three times is used saturated common salt solution washing twice, dried over mgso then.Filtering mixt, solvent is removed in underpressure distillation.With silicagel column purifying residue (silica gel 80g, eluent: chloroform contains 5% methyl alcohol),, get 2.30g title compound clear crystal with benzene/hexane (1: 1) washing gained crystal.
Fusing point: 120-123 ℃;
1H-NMR（CDCl 3，δ ppm）：1.8-3.5（2H，br），2.64-2.70（2H，m），2.97-3.03（2H，m），3.14（2H，dd，J＝6.1，1.2Hz），6.00（1H，dt，J＝15.9，6.1Hz），6.32（1H，d，J＝15.9Hz），7.21（2H，dd，J＝8.8，2.4Hz），7.28（2H，dd，J＝8.8，2.4Hz），7.69（1H，dd，J＝8.3，7.4Hz），8.19（1H，dd，J＝8.3，1.0Hz），8.42-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 173.(n=2, m=1, aryl=phenyl)
N-(2-cinnamyl aminoethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.8-2.8（2H，br），2.64-2.69（2H，m），2.97-3.03（2H，m），3.14（1H，dd，J＝6.3，1.2Hz），6.02（1H，dt，J＝15.9，6.3Hz），6.46（1H，dt，J＝15.9，1.2Hz），7.30（5H，s），7.68（1H，dd，J＝8.1，7.3Hz），9.18（1H，dt，J＝8.1，1.0Hz），8.42-8.48（2H，m），8.70（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 174.(n=2, m=1, aryl=4-diformazan aminophenyl)
N-(2-(4-diformazan ammonia cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：2.65（2H，brs），2.70（2H，dd，J＝6.1，4.9Hz），2.96（6H，s），3.02（2H，dd，J＝6.1，4.9Hz），3.14（2H，dd，J＝6.6，1.0Hz），5.81（1H，dt，J＝15.9，6.5Hz），6.27（1H，brd，J＝15.9Hz），6.66（2H，brd，J＝8.8Hz），7.20（2H，brd，J＝8.8Hz），7.68（1H，dd，J＝8.0，7.5Hz），8.18（1H，dt，J＝8.0，1.0Hz），8.44（1H，d，J＝6.0Hz and 1H，d，J＝7.5Hz），8.71（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 175.(n=2, m=1, aryl=4-fluorophenyl)
N-(2-(4-fluoro cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.5-2.5（2H，br），2.63-2.69（2H，m），2.97-3.02（2H，m），3.12（2H，dd，J＝6.1，1.2Hz），5.94（1H，dt，J＝15.9，6.1Hz），6.33（1H，d，J＝15.9Hz），7.00（2H，ddd，J＝8.6，8.6，2.2Hz），7.27（2H，ddd，J＝8.6，5.3，2.2Hz），7.69（1H，dd，J＝8.2，7.6Hz），8.19（1H，brd，J＝8.2Hz），8.42-8.48（2H，m），8.70（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 176.(n=2, m=1, aryl=4-bromo phenyl)
N-(2-(4-bromo phenyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 124-127 ℃;
1H-NMR（CDCl 3，δ ppm）：2.0-3.5（2H，br），2.64-2.69（2H，m），2.97-3.03（2H，m），3.13（2H，dd，J＝6.1，1.0Hz），6.01（1H，dt，J＝15.9，6.3Hz），6.30（1H，d，J＝15.9Hz），7.14（2H，dm，J＝8.6Hz），7.41（2H，dm，J＝8.6Hz），7.68（1H，dd，J＝8.3，7.5Hz），8.18（1H，brd，J＝8.3Hz），8.43-8.47（2H，m），8.68（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 177.(n=2, m=1, aryl=4-isopropyl phenyl)
N-(2-(4-sec.-propyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.24（6H，d，J＝7.1Hz），2.0-2.3（2H，br），2.63-2.69（1H，m），2.87（1H，q，J＝7.1Hz），2.97-3.03（2H，m），3.13（1H，dd，J＝6.3，1.2Hz），5.97（1H，dt，J＝15.9，6.3Hz），6.33（1H，brd，J＝15.9Hz），7.16（2H，dm，J＝8.3Hz），7.23（2H，dm，J＝8.3Hz），7.67（1H，dd，J＝8.3，7.3Hz），8.17（1H，d，J＝8.3Hz），8.43-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 178.(n=2, m=1, aryl=4-methoxyphenyl)
N-(2-(4-methoxyl group cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 92-95 ℃;
1NMR（CDCl 3，δ ppm）：2.0-3.0（2H，br），2.63-2.69（2H，m），2.97-3.06（2H，m），3.11（2H，dd，J＝6.3，1.2Hz），3.81（3H，s），5.88（1H，dt，J＝15.9，6.3Hz），6.30（1H，d，J＝15.9Hz），6.84（2H，dm，J＝8.8Hz），7.23（2H，dm，J＝8.8Hz），7.68（1H，dd，J＝8.3，7.5Hz），8.19（1H，brd，J＝8.3Hz），8.42-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 179.(n=2, m=1, aryl=4-trifluoromethyl)
N-(2-(4-trifluoromethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.5-2.5（2H，br），2.66-2.72（2H，m），2.98-3.04（2H，m），3.19（2H，dd，J＝6.1，1.2Hz），6.14（1H，dt，J＝15.9，6.1Hz），6.41（1H，d，J＝15.9Hz），7.39（2H，brd，J＝8.3Hz），7.56（2H，brd，J＝8.3Hz），7.69（1H，dd，J＝8.3，7.3Hz），8.20（1H，brd，J＝8.3Hz），8.42-8.48（2H，m），8.70（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 180.(n=2, m=2, aryl=4-trifluoromethyl)
N-2-(5-(4-trifluoromethyl)-2,4-pentadiene amino) ethyl }-the 5-isoquinoline sulfonaide
Light yellow amorphous;
1H-NMR（CDCl 3，δ ppm）：1.0-2.5（2H，br），2.61-2.67（2H，m），2.96-3.05（2H，m），3.08（2H，dd，J＝6.3，1.0Hz），5.69（1H，dt，J＝15.0，6.3Hz），6.19（1H，dd，J＝15.0，10.0Hz），6.48（1H，d，J＝15.7Hz），6.75（1H，dd，J＝15.7，10.0Hz），7.47（2H，brd，J＝8.3Hz），7.57（2H，brd，J＝8.3Hz），7.72（1H，dd，J＝8.3，7.3Hz），8.20（1H，dt，J＝8.3，1.0Hz），8.43-8.48（2H，m），8.72（1H，d，J＝6.1Hz），9.36（1H，d，J＝1.0Hz）.
Embodiment 181.(n=2, m=3, aryl=4-trifluoromethyl)
N-2-(7-(4-fluoroform phenyl)-2,4,6-heptantriene amino) ethyl }-the 5-isoquinoline sulfonaide
Light yellow amorphous;
1H-NMR（CDCl 3，δ ppm）：2.0-3.5（2H，br），2.61-2.67（2H，m），2.95-3.01（2H，m），3.07（2H，dd，J＝6.3，1.0Hz），5.59（1H，dt，J＝14.6，6.3Hz），6.05-6.22（1H，m），6.29-6.34（2H，m），6.55（1H，d，J＝15.6Hz），6.81-6.93（1H，m），7.47（2H，brd，J＝8.3Hz），7.55（2H，brd，J＝8.3Hz），7.71（1H，dd，J＝8.3，7.3Hz），8.21（1H，brd，J＝8.3Hz），8.43-8.48（2H，m），8.72（1H，d，J＝6.1Hz），9.37（1H，d，J＝1.0Hz）.
Embodiment 182. (n=2, m=1, aryl=4-(2-methoxyethoxy) methoxyphenyl) N-{ 2-(4-(2-methoxyethoxy) methoxyl group cinnamyl amino) ethyl }-5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.8-2.7（2H，br），2.63-2.69（2H，m），2.96-3.02（2H，m），3.11（2H，dd，J＝6.4，1.2Hz），3.37（3H，s），3.53-3.58（2H，m），3.80-3.85（2H，m），5.27（2H，s），5.90（1H，dt，J＝15.9，6.4Hz），6.30（1H，d，J＝15.9Hz），6.99（2H，dm，J＝8.8Hz），7.23（2H，dm，J＝8.8Hz），7.68（1H，dd，J＝8.3，7.3Hz），8.19（1H，dt，J＝8.3，1.0Hz），8.42-8.47（2H，m），8.70（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 183.(n=2, m=1, aryl=4-hydroxyphenyl)
N-(2-(4-hydroxyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 156-159 ℃;
1H-NMR（DMSO-d 6，δ ppm）：2.44（2H，brt，J＝6.3Hz），2.88（2H，brt，J＝6.3Hz），3.01（2H，brd，J＝6.1Hz），3.39（3H，br），5.83（1H，dt，J＝15.9，6.1Hz），6.20（1H，d，J＝15.9Hz），6.70（2H，brd，J＝8.3Hz），7.14（2H，brd，J＝8.3Hz），7.81（1H，t，J＝7.8Hz），8.34-8.46（3H，m），8.68（1H，d，J＝6.1Hz），9.46（1H，d，J＝1.0Hz）.
Embodiment 184.(n=2, m=1, aryl=1-naphthyl)
N-2-(3-(1-naphthyl)-2-acrylic-amino) ethyl }-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 135-138 ℃;
1H-NMR（CDCl 3，δ ppm）：1.5-4.0（2H，br），2.68-2.73（2H，m），3.01-3.06（2H，m），3.26（1H，dd，J＝6.3，1.5Hz），6.00（1H，dt，J＝15.6，6.3Hz），7.10（1H，d，J＝15.6Hz），7.43-7.51（4H，m），7.61（1H，dt，J＝8.3，7.3Hz），7.78（1H，dd，J＝7.1，2.7Hz），7.83-7.89（1H，m），7.97-8.02（1H，m），8.07（1H，brd，J＝8.3Hz），8.44（1H，dd，J＝7.3，1.0Hz），8.44（1H，d，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），9.27（1H，d，J＝1.0Hz）.
Embodiment 185.(n=2, m=1, aryl=3,4,5 ,-trimethoxyphenyl) N-(2-(3,4,5-trimethoxy cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.5-2.6（2H，br），2.65-2.71（2H，m），2.97-3.03（2H，m），3.15（2H，dd，J＝6.3，1.2Hz），3.85（3H，s），3.88（6H，s），5.97（1H，dt，J＝15.9，6.3Hz），6.31（1H，d，J＝15.9Hz），6.55（2H，s），7.69（1H，dd，J＝8.3，7.5Hz），8.20（1H，brd，J＝8.3Hz），8.43（1H，brd，J＝6.1Hz），8.46（1H，dd，J＝7.5，1.2Hz），8.70（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 186.(n=2, m=1, aryl=4-methoxycarbonyl phenyl)
N-(2-(4-methoxycarbonyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 110-113 ℃
1H-NMR（CDCl 3，δ ppm）：1.2-2.0（2H，br），2.65-2.70（2H，m），2.97-3.02（2H，m），3.17（2H，dd，J＝5.9，1.2Hz），3.92（3H，s），6.15（1H，dt，J＝15.9，5.9Hz），6.41（1H，d，J＝15.9Hz），7.36（2H，dm，J＝8.3Hz），7.69（1H，dd，J＝8.3，7.3Hz），7.98（2H，dm，J＝8.3Hz），8.19（1H，brd，J＝8.3Hz），8.43（1H，brd，J＝6.1Hz），8.46（1H，dd，J＝7.3，1.5Hz），8.71（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 187.(n=2, m=1, aryl=4-carboxyl phenyl)
N-(2-(4-carboxyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Clear crystal;
Fusing point: 239-240 ℃ (decomposition);
1H-NMR（DMSO-d 6，δ ppm）：2.49（2H，brt，J＝6.3Hz），2.91（2H，brt，J＝6.3Hz），3.13（2H，brd，J＝5.7Hz），3.0-4.0（3H，br），6.24（1H，dt，J＝16.1，5.7Hz），6.44（1H，d，J＝16.1Hz），7.44（2H，brd，J＝8.3Hz），7.82（1H，dd，J＝8.3，7.3Hz），7.88（2H，brd，J＝8.3Hz），8.36（1H，dd，J＝7.3，1.2Hz），8.42（1H，brd，J＝8.3Hz），8.44（1H，brd，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.46（1H，d，J＝1.0Hz）
Embodiment 188.(n=3, m=1, aryl=phenyl)
N-(3-cinnamyl aminopropyl)-the 5-isoquinoline sulfonaide
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.5-2.2（2H，br），1.59（2H，tt，J＝5.6，5.6Hz），2.66（2H，t，J＝5.6Hz），3.06（2H，t，J＝5.6Hz），3.30（2H，dd，J＝6.1，1.5Hz），6.21（1H，dt，J＝15.9，6.1Hz），6.52（1H，d，J＝15.9Hz），7.21-7.40（5H，m），7.67（1H，dd，J＝8.3，7.5Hz），8.18（1H，d，J＝8.3Hz），8.43（1H，dd，J＝7.5，1.2Hz），8.44（1H，d，J＝6.1Hz），8.63（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Embodiment 189.N-2-(3-(4-chloro-phenyl-)-2-propynyl amino) ethyl }-5-isoquinoline sulfonaide (compound 189-I);
N-2-(two-(3-(4-chloro-phenyl-)-2-propynyl) amino) ethyl }-5-isoquinoline sulfonaide (compound 189-II);
N-(3-(4-chloro-phenyl-)-2-propynyl)-and N-(2-(rubigan)-third block of amino of 2-) ethyl)-5-isoquinoline sulfonaide (compound 189-III);
(compound 189-I)
The N-(2-aminoethyl of dissolving 1.90g in the 10ml dimethyl formamide)-and 3-rubigan-2-propynyl muriate of 5-isoquinoline sulfonaide and 1.39g, add 1.38g salt of wormwood, stirring at room mixture 24 hours in this solution.In reaction mixture impouring 100ml ethyl acetate, the saturated sodium-chloride water solution washed twice is used in the water washing that continues three times then, and dried over mgso is filtered, and solvent is removed in underpressure distillation.Separating obtained residue is also used silicagel column purifying (silica gel 100g; Eluent: the chloroform that contains 5% methyl alcohol).With its crystallization, obtain the compound 189-I of 855mg from ether-hexanes mixtures, be colourless crystallization, the compound 189-III of the compound 189-II of 220mg and 214mg is colourless amorphous thing.
Compound 189-I
Clear crystal;
Fusing point: 120-123 ℃;
1H-NMR（CDCl 3，δ ppm）：1.30-1.80（2H，br），2.74-2.80（2H，m），3.00-3.05（2H，m），3.39（1H，s），7.26（4H，s），7.69（1H，dd，J＝8.3，7.3Hz），8.20（1H，dt，J＝8.3，1.0Hz），8.42（1H，dt，J＝6.1，1.0Hz），8.46（1H，dd，J＝7.3，1.2Hz），8.70（1H，d，J＝6.1Hz），9.36（1H，d，J＝1.0Hz）.
Compound 189-II
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：2.69-2.74（2H，m），3.01-3.09（2H，m），3.43（4H，s），5.48（1H，t，J＝5.0Hz），7.27（4H，dm，J＝9.0Hz），7.30（4H，dm，J＝9.0Hz），7.68（1H，dd，J＝8.3，7.3Hz），8.20（1H，brd，J＝8.3Hz），8.42（1H，brd，J＝6.1Hz），8.47（1H，dd，J＝7.3，1.2Hz），8.66（1H，d，J＝6.1Hz），9.35（1H，d，J＝1.0Hz）.
Compound 189-III
Colourless amorphous;
1H-NMR（CDCl 3，δ ppm）：1.58（1H，br），3.02（2H，t，J＝6.0Hz），3.55（2H，t，J＝6.0Hz），3.64（2H，s），4.50（2H，s），6.81（2H，dm，J＝8.8Hz），7.15（2H，dm，J＝8.8Hz），7.27（2H，dm，J＝9.0Hz），7.31（2H，dm，J＝9.0Hz），7.66（1H，dd，J＝8.3，7.3Hz），8.13（1H，brd，J＝8.3Hz），8.48（1H，dd，J＝7.3，1.2Hz），8.57（1H，brd，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.26（1H，d，J＝1.0Hz）.
Embodiment 190.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Figure 921151012_IMG29
The product 1.50g of embodiment 172 is dissolved in the 10ml chloroform, in this solution, adds the 3ml methyl iodide under the room temperature, stirred the mixture 40 minutes.At once under reduced pressure steam unnecessary methyl iodide, purifying gained residue on silicagel column (silica gel 50g, eluent: the chloroform that contains 5% methyl alcohol), obtain colourless amorphous title compound 720mg.
1H-NMR（CDCl 3，δ ppm）：1.4-2.1（1H，br），1.95（3H，s），2.37（2H，t，J＝5.5Hz），2.92-3.00（3H，m），5.97（1H，dt，J＝15.9，6.6Hz），6.34（1H，d，J＝15.9Hz），7.25（2H，dm，J＝8.8Hz），7.28（2H，dm，J＝8.8Hz），7.68（1H，dd，J＝8.3，7.8Hz），8.19（1H，brd，J＝8.3Hz），8.44（1H，brd，J＝6.1Hz），8.45（1H，dd，J＝7.8，1.5Hz），8.69（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 191.1-(4-chlorine cinnamyl)-and the 4-(5-isoquinolinesulfonylcompounds) piperazine
Figure 921151012_IMG30
The product 1.31g of embodiment 172 is dissolved in the 3ml dimethyl formamide, adds 644mg1 under the room temperature in this solution, and 2-ethylene dibromide and 1.13g Anhydrous potassium carbonate stirred the mixture 24 hours.After adding the 100ml ethyl acetate, successively with each water of ethyl acetate layer and saturated sodium-chloride water solution washed twice, dried over mgso.Filtering solution, reduction vaporization, purifying gained residue on the silicagel column (silica gel 50g, eluent: the chloroform that contains 5% methyl alcohol), get the colourless amorphous title compound of 356mg, reclaim remaining raw material simultaneously.
1H-NMR（CDCl 3，δ ppm）：2.53（4H，brt，J＝4.9Hz），3.10（2H，dd，J＝6.6，1.2Hz），3.20（4H，brt，J＝4.9Hz），6.07（1H，dt，J＝15.9，6.6Hz），6.43（1H，d，J＝15.9Hz），7.24（4H，s），7.72（1H，dd，J＝8.1，7.3Hz），8.22（1H，brd，J＝8.1Hz），8.37（1H，dd，J＝7.3，1.2Hz），8.55（1H，brd，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），9.34（1H，d，J＝1.0Hz）.
Embodiment 192.N-ethyl-N-(2-(4-chloro-N-ethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Figure 921151012_IMG31
Repeat embodiment 191 described processing steps, different is that what to be used as the N-alkylating reagent is the product of 1.31g embodiment 172 and the iodic ether of 2.14g, obtains the colourless amorphous title compound of 720mg.
1H-NMR（CDCl 3，δ ppm）：0.99（3H，t，J＝7.1Hz），1.05（3H，t，J＝7.1Hz），2.53（2H，q，J＝7.1Hz），2.61（2H，t，J＝7.8Hz），3.19（2H，dd，J＝6.5，1.2Hz），3.33-3.43（4H，m），6.12（1H，dt，J＝15.9，6.5Hz），6.32（1H，d，J＝15.9Hz），7.26（4H，s），7.62（1H，dd，J＝8.1，7.3Hz），8.14（1H，dd，J＝8.1Hz），8.35（1H，dd，J＝7.3，1.2Hz），8.42（1H，brd，J＝6.1Hz），8.66（1H，d，J＝6.1Hz），9.31（1H，d，J＝1.0Hz）.
Embodiment 193.N-(2-(4-chloro-N-formyl radical cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Figure 921151012_IMG32
Mix 3ml formic acid and 3ml acetic anhydride under the K temperature, in this mixture, add the product of 1.41g embodiment 172, stirred the mixture one hour.Ice-cooled 50ml ethyl acetate and the 30ml saturated aqueous sodium carbonate of adding in reaction mixture down stirs the mixture, after the termination of bubbling, ethyl acetate layer is washed with water 2 times successively, with the saturated sodium-chloride water solution washing once, dried over mgso, filter reduction vaporization.(silica gel 60g, eluent: the chloroform that contains 2% methyl alcohol), get colourless amorphous title compound 1.49g, be the mixture of two kinds of isomer (3: 2) to purifying gained residue on silicagel column.
1H-NMR（CDCl 3，δ ppm）：3.07-3.16（2H，m），3.39-3.47（2H，m），3.90（0.6 x 2H，dd，J＝6.3，1.0Hz），4.03（0.4 x 2H，dd，J＝6.3，1.0Hz），5.93（0.6H，dt，J＝15.9，6.3Hz），6.01（0.4H，dt，J＝15.9，6.3Hz），6.40（0.4H，d，J＝15.9Hz），6.44（0.6H，d，J＝15.9Hz），7.20（0.6 x 2H，d，J＝8.8Hz），7.21（0.4 x 2H，d，J＝8.8Hz），7.26（0.6 x 2H，d，J＝8.8Hz），7.27（0.4 x 2H，d，J＝8.8Hz），7.61（0.6H，dd，J＝8.0，7.6Hz），7.64（0.4H，dd，J＝8.0，7.6Hz），8.05（0.6H，s），8.09（0.4H，s），8.16（0.6H，brd，J＝8.0Hz），8.17（0.4H，brd，J＝8.0Hz），8.33-8.42（2H，m），8.60（0.4H，d，J＝6.1Hz），8.65（0.6H，d，J＝6.1Hz），9.33（1H，d，J＝1.0Hz）.
Embodiment 194.N-2-(4-chloro-N-(4-oxybenzene methyl) cinnamyl amino) ethyl }-the 5-isoquinoline sulfonaide
The product of 0.2g embodiment 172 and 0.13g are dissolved in the 10ml methyl alcohol oxybenzene formaldehyde, add 60mg sodium cyanoborohydride and two acetate in this solution, stirred the mixture under the room temperature two days.The concentrating under reduced pressure reaction mixture is used 20ml ethyl acetate extraction three times behind the adding saturated sodium-chloride water solution.Compile extraction liquid, with the sodium-chlor washing, dried over mgso is filtered concentrating under reduced pressure.Purifying gained residue on the silicagel column (silica gel 10g, eluent: the chloroform that contains 2% methyl alcohol), get the colourless amorphous title compound of 150mg.
1H-NMR（CDCl 3，δ ppm）：2.50（2H，brt），2.90（2H，brt），3.10（2H，d，J＝6.6Hz），3.35（2H，s），6.06（1H，dt，J＝15.6，6.6Hz），6.35（1H，d，J＝15.9Hz），6.75（2H，d，J＝8.5Hz），6.97（2H，d，J＝8.5Hz），7.30（4H，s），7.65（1H，t，J＝8.0Hz），8.15（1H，d，J＝8.0Hz），8.37-8.41（2H，m），8.63（1H，d，J＝6.0Hz），9.32（1H，s）.
Embodiment 195.2-methyl-5-(2-(4-chloro-N, N-dimethyl cinnamyl amino) ethyl) and sulfamyl } the isoquinoline 99.9 diiodide
Embodiment 172 product 83mg are dissolved in the 2.0ml dimethyl formamide, add 1.0ml methyl iodide, stirring at room mixture 4 hours in this solution.Remove unnecessary methyl iodide and dimethyl formamide under reduced pressure, the crystallization in 5ml methyl alcohol/chloroform (1: 5) mixed solution of gained residue.Gained coarse crystallization body is recrystallize in methyl alcohol/chloroform (1: 5) mixed solution, gets the light yellow title compound crystal of 78mg.
Fusing point: 199-200 ℃;
1H-NMR（DMSO-d 6，δ ppm）：3.09（6H，s），3.43（4H，brs），4.16（2H，d，J＝7.0Hz），4.53（3H，s），6.48（1H，dt，J＝15.9，7.0Hz），6.89（1H，d，J＝15.9Hz），7.58（2H，dm，J＝9.4Hz），7.61（2H，dm，J＝9.4Hz），8.21（1H，t，J＝7.9Hz），8.72-8.78（2H，m），8.90-8.99（3H，m），10.22（1H，brs）.
Embodiment 196.2-methyl-5-N-methyl-N-(2-(4-chloro-N, N-dimethyl cinnamyl amino) ethyl) and sulfamyl } the isoquinoline 99.9 iodide
Embodiment 172 product 83mg are dissolved in the 2.0ml dimethyl formamide, add 1.0ml methyl iodide and 83mg anhydrous sodium carbonate, stirring at room mixture 4 hours in the solution.Remove unnecessary methyl iodide and dimethyl formamide under reduced pressure, add and stir this mixture after 10ml methyl alcohol/chloroform (1: 5) mixed solution, remove by filter insolubles.Concentrating under reduced pressure filtrate adds 10ml methyl alcohol/chloroform (1: 5) mixed solution to be settled out insolubles, then with its filtering in the enriched material.Repeating twice should concentrate and filtration step, got the yellow amorphous title compound of 145mg.
1H-NMR（DMSO-d 6，δ ppm）：2.97（3H，s），3.15（6H，s），3.50-3.70（2H，m），3.70-3.80（2H，m），4.21（2H，d，J＝7.3Hz），4.54（3H，s），6.54（1H，dt，J＝15.6，7.3Hz），6.93（1H，d，J＝15.6Hz），7.48（2H，brd，J＝8.5Hz），7.63（2H，brd，J＝8.5Hz），8.23（1H，t，J＝7.9Hz），8.75-8.85（3H，m），8.99（1H，d，J＝7.1Hz），10.22（1H，brs）.
This isoquinoline compound is different with the compound of embodiment 174, can handle with the excessive methyl iodide that is dissolved in the dimethyl formamide by present embodiment, gets corresponding compounds, and wherein the nitrogen-atoms on the isoquinoline 99.9 ring is methylated, becomes quaternary nitrogen atoms.
Embodiment 197.N-(2-(4-chlorine cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
The product 2.00g of embodiment 172 is suspended in the 20ml methyl alcohol, adds the 1ml concentrated hydrochloric acid and makes suspension become clear, and ice-cooled stirring formed crystal in 10 minutes.Filter and collect crystal,, get the corresponding dihydrochloride clear crystal of 1.65g with the mixed solution recrystallization of 20ml methyl alcohol and 3ml water.
Fusing point: 205-208 ℃;
1H-NMR（DMSO-d 6，δ ppm）：2.90-3.05（2H，m），3.10-3.20（2H，m），3.65-3.75（2H，m），4.3-4.9（br），6.33（1H，dt，J＝16.1，7.1Hz），6.76（1H，d，J＝16.1Hz），7.45（4H，s），8.00（1H，dd，J＝8.3，7.5Hz），8.54（1H，dd，J＝7.5，1.2Hz），8.64（1H，brd，J＝8.3Hz），8.71（1H，brd，J＝6.4Hz），8.80（1H，br），8.82（1H，d，J＝6.4Hz），9.39（1H，brs），9.79（1H，brs）.
Embodiment 198.N-(2-(Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Repeat embodiment 194 described processing steps, different is to adopt the product of embodiment 154 to make raw material, gets corresponding dihydrochloride clear crystal.
Fusing point: 80-85 ℃;
1H-NMR（DMSO-d 6，δ ppm）：1.40（3H，d，J＝6.5Hz），2.89（2H，m），3.16（2H，brt，J＝6.5Hz），3.91（1H，m），5.0-6.0（br），6.19（1H，dd，J＝16.1，7.5Hz），6.71（1H，d，J＝16.1Hz），7.39（5H，m），7.97（1H，dd，J＝8.0，7.6Hz），8.51-8.82（5H，m），9.44（2H，br），9.76（1H，d，J＝1.0Hz）
Embodiment 199.N-(2-(4-chloro-Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Repeat embodiment 194 described same processing steps, different is to adopt the product of embodiment 153 to make raw material, gets corresponding dihydrochloride, is white hygroscopic powder.
1H-NMR（DMSO-d 6，δ ppm）：1.40（3H，d，J＝6.5Hz），2.85-3.96（2H，m），3.10-3.20（2H，m），3.80-4.00（1H，m），5.1-6.1（br），6.23（1H，dd，J＝15.9，8.5Hz），6.72（1H，d，J＝15.9Hz），7.44（4H，s），7.99（1H，dd，J＝8.2，7.4Hz），8.54（1H，dd，J＝7.4，1.2Hz），8.64（1H，brd，J＝8.2Hz），8.72（1H，brd，J＝6.4Hz），8.80（1H，br），8.82（1H，d，J＝6.4Hz），9.48（2H，brs），9.80（1H，brs）.
Embodiment 200.N-(2-(4-cinnamyl bromide base amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Use embodiment 176 products to make raw material, repeat embodiment 194 described same processing steps, get corresponding dihydrochloride clear crystal.
Fusing point: 195-200 ℃;
1H-NMR（DMSO-d 6，δ ppm）：2.90-3.10（2H，brs），3.2-3.3（2H，m），3.65-3.75（2H，brs），6.35（1H，dt，J＝16.0，7.1Hz），6.76（1H，d，J＝16.0Hz），7.38（2H，d，J＝8.5Hz），7.57（2H，d，J＝8.5Hz），8.10（1H，t，J＝7.6Hz），8.67（1H，d，J＝7.6Hz），8.78（1H，d，J＝7.6Hz），8.90（1H，brs），9.05（1H，brs），10.0（1H，s）.
Embodiment 201.N-(2-cinnamyl aminoethyl)-1/2 fumarate of 5-isoquinoline sulfonaide
Embodiment 173 product 303mg are dissolved in the 5ml ethyl acetate, add the solution that the 89ml fumaric acid is dissolved in 2ml methyl alcohol under the room temperature in this solution, stir the mixture 30 minutes to separate out crystallization, filter and collect crystallization and, get the corresponding 1/2 fumarate white crystal of 312mg with the ethyl acetate washing.
Fusing point: 153-156 ℃;
1H-NMR（DMSO-d 6，δ ppm）：2.69（2H，brt，J＝6.3Hz），3.00（2H，brt，J＝6.3Hz），3.34（2H，brd，J＝6.1Hz），5.0-8.0（3H，br），6.16（1H，dt，J＝16.0，6.1Hz），6.51（1H，d，J＝16.0Hz），6.54（1H，s），7.23-7.3（2H，m），7.34-7.40（3H，m），7.82（1H，dd，J＝8.1，7.5Hz），8.36（1H，dd，J＝7.5，1.0Hz），8.42（1H，brd，J＝8.1Hz），8.44（1H，brd，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.47（1H，d，J＝1.0Hz）.
Embodiment 202.N-(2-(Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide 1/2 fumarate
Adopt the product of embodiment 154 to make raw material, repeat embodiment 198 described same process steps, get 1/2 fumarate clear crystal accordingly.
Fusing point: 162-167 ℃;
1H-NMR（DMSO-d 6，δ ppm）：1.02（3H，d，J＝6.4Hz），2.49（2H，brt，J＝6.6Hz），2.5-5.7（3H，br），2.93（2H，brt，J＝6.6Hz），3.17（1H，dd，J＝7.9，6.4Hz），5.91（1H，dd，J＝16.1，7.9Hz），6.35（1H，d，J＝16.1Hz），6.55（1H，s），7.32（5H，m），7.79（1H，dd，J＝8.0，7.3Hz），8.34（1H，dd，J＝7.3，1.2Hz），8.39（1H，brd，J＝8.0Hz），8.43（1H，brd，J＝6.1Hz），8.69（1H，d，J＝6.1Hz），9.45（1H，d，J＝1.0Hz）.
Embodiment 203.N-(2-(4-chloro-Alpha-Methyl cinnamyl amino) ethyl)-L-(+ of 5-isoquinoline sulfonaide)-tartrate
6.60g embodiment 153 products are dissolved in the 50ml ethyl acetate, add 2.38g L-(+ in this solution)-tartrate is dissolved in the solution that methyl alcohol becomes, to generate crystallization, filter collections and with the ethyl acetate washing, get corresponding L-(+)-the tartrate clear crystal.
Fusing point: 125-130 ℃;
1H-NMR（DMSO-d 6，δ ppm）：1.14（3H，d，J＝6.3Hz），2.64（2H，brt，J＝6.5Hz），2.98（2H，brt，J＝6.5Hz），3.45（1H，dd，J＝8.0，6.3Hz），3.5-4.7（6H，br），4.13（2H，s），6.03（1H，dd，J＝15.9，8.0Hz），6.49（1H，d，J＝15.9Hz），7.41（4H，s），7.81（1H，dd，J＝8.0，7.3Hz），8.36（1H，brd，J＝8.0Hz），8.41（1H，d，J＝6.1Hz），8.42（1H，brd，J＝7.3Hz），8.69（1H，d，J＝6.1Hz），9.46（1H，d，J＝1.0Hz）.
Embodiment 204.N-(2-aminoethyl)-N-(2-third osmanthus base aminoethyl)-5-isoquinoline sulfonaide trihydrochloride
With 1.10g embodiment 173 gained amorphous compounds, 1.18g triphenylphosphine and 0.73g2-(t-butoxycarbonyl amino) ethanol is dissolved in the 15ml tetrahydrofuran (THF), the limit is with ice-cooled, the limit drips to this solution and a kind ofly is dissolved in the solution that the 5ml tetrahydrofuran (THF) is become by the 0.78g diethyl azodiformate, meter drips 15ml, then in stirring at room mixture 4 hours.Add the 0.39g triphenylphosphine with ice-cooled back to reaction mixture once more, and drip the 0.26g diethyl azodiformate and be dissolved in the solution that the 3ml tetrahydrofuran (THF) is become, in stirring at room reaction mixture one hour.Concentrating under reduced pressure reaction mixture, gained residue are coated onto on the silicagel column and with chloroform/methanol (19: 1) wash-out, get the shallow tangerine look of 0.99g non-crystalline state product.This product is dissolved in 20ml methyl alcohol, to the ethyl acetate solution of this solution adding 7.7ml4N hydrochloric acid, this mixture of stirring at room 3 hours.The reduction vaporization reaction mixture removes and desolvates, and forms solid to wherein adding ethyl acetate again.This solid is collected in filtration, with ethyl acetate and normal hexane it is washed, and decompression is dry down, gets the colourless hygroscopic powder of 0.97g title compound.
NMR（D 2O）δ ppm：3.2-3.5（4H，m），3.7-4.0（6H，m），6.1-6.3（1H，m），6.82（1H，d，J＝15.9Hz），7.44（5H，s），8.15（1H，t，J＝7.6Hz），8.1-8.3（3H，m），9.09（1H，d，J＝7.0Hz），9.7（1H，s）.
The amino butyl of embodiment 205.N-(4-)-N-(2-(4-chlorine cinnamyl amino) ethyl)-5-isoquinoline sulfonaide trihydrochloride
To crystal, 0.226g4-(tert-butoxycarbonyl amino by 0.4g embodiment 172 gained) butanols and 0.445g triphenylphosphine be dissolved in the solution that the 5ml tetrahydrofuran (THF) formed, under with ice-cooled condition, add 0.295g azodicarbonic acid diethyl ester while stirring and be dissolved in the solution that the 2ml tetrahydrofuran (THF) is formed.At room temperature make this mixture leave standstill, and reduction vaporization, a kind of residue obtained.Then this residue is coated onto on the silicagel column, and, obtains 2.8g oily matter with methyl alcohol/chloroform (2: 98) wash-out.Be dissolved in the solution of 1ml methyl alcohol to this oily matter, add 4N hydrochloric acid/ethyl acetate, to generate throw out.Then, collect this throw out after filtration, with ethyl acetate washcoated and dry it, make the compound described in the 0.2g colourless powder shape title.
NMR（D 2O）δ PPm：1.70（4H，brs），2.95（2H，m），3.30（2H，m），3.55（2H，m），3.77（2H，m），3.89（2H，dd，J＝7.3Hz），6.15（1H，dt，J＝15.8，7.3Hz），6.76（1H，d，J＝15.8Hz），7.35（4H，s），8.11（1H，t，J＝8.0Hz），8.6-8.8（2H，m），8.98（1H，d，J＝7.0Hz），9.75（1H，s）。
Embodiment 206.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-(2-(4-piperidyl) ethyl)-the 5-isoquinoline sulfonaide
The limit is with ice-cooled, the amorphous compound that the limit makes in by 0.39g embodiment 190,0.145g piperidines ethanol and 0.265g triphenylphosphine are dissolved in the solution that the 5ml tetrahydrofuran (THF) formed, interpolation is dissolved in the solution that the 2ml tetrahydrofuran (THF) is become by the 0.245g diethyl azodiformate, then mixture was at room temperature stirred 1 hour, and reduction vaporization it, remove and to desolvate.After adding the 30ml ethyl acetate, with 5ml1N hydrochloric acid with mixture extraction three times.With sodium bicarbonate extraction liquid is alkalized, and with 10ml ethyl acetate extraction three times.Organic layer is carried out drying and solvent evaporated with sal epsom.The residual residual of gained is coated onto on the aluminum oxide chromatographic column, and with the chloroformic solution wash-out that contains 1% methyl alcohol, obtains compound described in the title of 180mg colorless oil.
NMR（CDCl 3）δ ppm：0.87-1.05（2H，m），1.30-1.45（5H，m），1.85（1H，brs），2.21（3H，s），2.33（2H，m），2.51（2H，t，J＝7.6Hz），2.89（2H，m），3.08（2H，d，J＝6.6Hz），3.30（2H，t，J＝7.8Hz），3.42（2H，t，J＝7.3Hz），6.09（1H，dt，J＝15.8，6.6Hz），6.41（1H，d，J＝15.8Hz），7.26（4H，s），7.65（1H，dd，J＝8.0，8.6Hz），8.15（1H，d，J＝8.0Hz），8.4（1H，d，J＝8.6Hz），8.40（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz），9.31（1H，s）.
The oily matter of gained like this is dissolved in the 1ml methyl alcohol, and to the ethyl acetate solution that wherein adds 0.3ml4N hydrochloric acid, and then add the 30ml ether, obtain the corresponding trihydrochloride of colourless powder shape.
Embodiment 207.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-(2-morpholino ethyl)-5-isoquinoline sulfonaide trihydrochloride
To amorphous embodiment 190 gained compounds, 0.377g2-N-morpholino ethanol and 1 by 1g: the 25g triphenylphosphine is dissolved in the solution that the 5ml tetrahydrofuran (THF) formed, under with ice-cooled condition, drip while stirring by the 0.835g diethylazodicarboxylate and be dissolved in the solution that the 2ml tetrahydrofuran (THF) is formed, and mixture was stirred 2 hours.After removing solvent under reduced pressure, in residue, add the 20ml ethyl acetate, and with this mixed solution of 10ml1N hcl as extraction agent three times.Extract alkalizes with sodium bicarbonate, and with 10ml ethyl acetate extraction 3 times.Make the extraction liquid dried over mgso, and reduction vaporization, desolvate to remove.The gained residue is applied on the silicagel column, and, obtains a kind of oily matter with methanol/ethyl acetate (10: 90) wash-out.
NMR（CDCl 3）δ ppm：2.18（3H，s），2.28-2.33（4H，m），2.4（2.6（4H，m），3.07（2H，d，J＝6.6Hz），3.4-3.6（8H，m），6.07（1H，dt，J＝15.9，6.6Hz），6.40（1H，d，J＝15.9Hz），7.26（4H，s），7.63（1H，dd，J＝8.0，7.1Hz），8.14（1H，d，J＝8.0Hz），8.42（1H，d，J＝7.1Hz），8.42（1H，d，J＝7.1Hz），8.42（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz），9.31（1H，s）.
The oily matter of gained like this is dissolved in 4ml methyl alcohol, and adds the ethyl acetate solution of 2ml4N hydrochloric acid, remove solvent then under reduced pressure, the products therefrom ethyl alcohol recrystallization makes the colourless crystalline state title compound of 0.67g.
Fusing point: 172-176 ℃;
NMR（D 2O）δ ppm：3.04（3H，s），3.2-3.6（8H，m），3.8-4.1（10H，m），6.18（1H，dt，J＝15.9，7.0Hz），6.76（1H，d，J＝15.9Hz），7.22（4H，s），8.09（1H，dd，J＝7.6，8.2Hz），8.52（1H，d，J＝7.6Hz），8.65-8.75（2H，m），8.87（1H，d，J＝7.0Hz），9.74（1H，s）.
Embodiment 208.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-(2-piperidino-(1-position only) ethyl)-the 5-isoquinoline sulfonaide
Under with ice-cooled condition, to be dissolved in the solution that the 5ml tetrahydrofuran (THF) formed by 0.39g embodiment 190 gained amorphous compounds, 0.145g1-piperidines ethanol and 0.369g triphenylphosphine in, drip the 0.245g diethylazodicarboxylate while stirring and be dissolved in the solution that the 2ml tetrahydrofuran (THF) is become.Mixture was stirred 2 hours, remove solvent under reduced pressure, the gained residue is dissolved in the 30ml ethyl acetate, and with 10ml 1N hcl as extraction agent 3 times.Water is alkalized with sodium bicarbonate, use 10ml ethyl acetate extraction 3 times,, and remove solvent under reduced pressure the organic extract liquid dried over mgso.The gained residue is applied on the silicagel column, and with the chloroformic solution wash-out of 2% methyl alcohol, obtains the described compound of title of 0.37g colorless oil.
NMR（CDCl 3）δ ppm：1.3-1.5（6H，m），2.20（3H，s），2.20-2.30（4H，m），2.39（2H，t，J＝7.1Hz），2.55（2H，t，J＝7.1Hz），3.08（2H，d，J＝6.8Hz），3.46（4H，q，J＝7.1Hz），6.09（1H，dt，J＝15.9，6.8Hz），6.40（1H，d，J＝15.9Hz），7.25（4H，s），7.63（1H，dd，J＝7.3，8.1Hz），8.14（1H，d，J＝8.1Hz），8.43（1H，d，J＝7.3Hz），8.43（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz），9.31（1H，s）.
Be dissolved in the solution of 3ml methyl alcohol to above-mentioned gained oily matter, add the ethyl acetate solution of 0.5ml4N hydrochloric acid, and remove the solvent in the whole solution under reduced pressure.In concentrated solution, add ether, generate meal, filter then and collect this meal, obtain the corresponding trihydrochloride of 0.35g colourless powder shape.
NMR（D 2O）δ ppm：1.3-2.0（6H，m），2.8-3.0（2H，m），3.05（3H，s），3.3-3.6（6H，m），3.8-4.1（6H，m），6.25（1H，dt，J＝15.8，8.0Hz），6.80（1H，d，J＝15.8Hz），7.25（4H，s），8.13（1H，t，J＝8.0Hz），8.60（1H，d，J＝8.0Hz），8.68-8.78（2H，m），8.95（1H，d，J＝7.0Hz），9.70（1H，s）.
Embodiment 209.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-the N-(2-dimethyl aminoethyl)-the 5-isoquinoline sulfonaide
Under with ice-cooled condition, be dissolved in the solution that the 2ml tetrahydrofuran (THF) is formed to being dissolved in the solution that the 5ml tetrahydrofuran (THF) is formed by 1.0g embodiment 190 gained amorphous compounds, 0.267g2-dimethylaminoethanol and 0.982g triphenylphosphine, dripping while stirring by the 0.652g diethylazodicarboxylate.After 2 hours, the concentrating under reduced pressure reaction mixture to remove tetrahydrofuran (THF), is dissolved in the 10ml ethyl acetate with the gained residue, and with 10ml1N hcl as extraction agent 3 times.Make the water layer alkalization with sodium bicarbonate, use 10ml ethyl acetate extraction 3 times; And organic layer carried out drying with sal epsom, remove solvent under reduced pressure.Then the gained residue is coated on the silicagel column, and with the chloroformic solution wash-out of 3% methyl alcohol, the described compound of title of 0.77g colorless oil.
NMR（CDCl 3），δ ppm：2.11（6H，s），2.20（3H，s），2.38（2H，t，J＝7.3Hz），2.54（2H，t，J＝7.3Hz），3.08（2H，d，J＝6.6Hz），3.38-3.50（4H，m），6.08（1H，dt，J＝15.8，6.6Hz），6.40（1H，d，J＝15.8Hz），7.26（4H，s），7.63（1H，dd，J＝8.1，7.5Hz），8.14（1H，d，J＝8.1Hz），8.40-8.45（2H，m），8.68（1H，d，J＝6.1Hz），9.31（1H，s）.
To be dissolved in the solution that 5ml methyl alcohol become by gained oily matter like this in, add the ethyl acetate solution of 1.4ml4N hydrochloric acid, and after removing solvent under reduced pressure, in the gained enriched material, add ether, produce Powdered thing, then it is collected after filtration and drying, obtained the corresponding Powdered trihydrochloride of 0.7g.
NMR（D 2O）δ ppm：2.96（6H，s），3.03（3H，s），3.4-3.6（4H，m），3.9-4.1（6H，m），6.17（1H，dt，J＝15.9，7.0Hz），6.73（1H，d，J＝15.9Hz），7.19（4H，s），8.01（1H，t，J＝8.0Hz），8.54（1H，d，J＝8.0Hz），8.70（2H，m），8.91（1H，d，J＝8.0Hz），9.78（1H，s）.
Embodiment 210.N-(2-piperidino-(1-position only) ethyl)-N-(2-(N-methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Press the step described in the embodiment 190, the non-crystalline state product of gained in the Processing Example 173 makes N-(2-(N-methyl cinnamyl amino)-ethyl)-the 5-isoquinoline sulfonaide.
NMR（CDCl 3）δ ppm：1.95（3H，s），2.37（2H，t，J＝5.7Hz），2.93-3.00（4H，m），6.00（1H，dt，J＝15.8，6.6Hz），6.38（1H，d，J＝15.8Hz），7.31（5H，s），7.68（1H，dd，J＝8.3，7.3Hz），8.18（1H，d，J＝8.3Hz），8.43-8.47（2H，m），8.69（1H，d，J＝6.1Hz），9.34（1H，s）.
Under with ice-cooled condition, to be dissolved in the solution that the 5ml tetrahydrofuran (THF) formed by 0.476g above-claimed cpd, 0.193g1-piperidines ethanol and 0.524g triphenylphosphine in, add while stirring by the 0.348g diethylazodicarboxylate and be dissolved in the solution that the 2ml tetrahydrofuran (THF) is become, make mixture leave standstill 3 hours then, and remove solvent under reduced pressure.In enriched material, add the 30ml ethyl acetate, and with 10ml1N hydrochloric acid with mixture extraction three times.Make the extraction liquid alkalization with sodium bicarbonate, and it is extracted 3 times with the 10ml ethyl acetate.The dried over mgso ethyl acetate solution, and remove solvent under reduced pressure.The gained residue is applied on the silicagel column, and carries out wash-out, obtain the described compound of title of 0.44g colorless oil with the chloroformic solution of 5% methyl alcohol.
NMR（CDCl 3）δ ppm：1.3-1.5（6H，m），2.20（3H，s），2.20-2.30（4H，m），2.41（2H，t，J＝6.8Hz），2.53（2H，t，J＝6.3Hz），3.09（2H，d，J＝6.6Hz），3.4-3.55（4H，m），6.10（1H，dt，J＝15.8，6.6Hz），6.45（1H，d，J＝15.8Hz），7.2-7.4（5H，m），7.61（1H，dd，J＝8.0，7.5Hz），8.11（1H，d，J＝8.0Hz），8.4-8.5（2H，m），8.66（1H，d，J＝6.1Hz），9.29（1H，s）.
In this oily matter that is dissolved in 5ml methyl alcohol, add the ethyl acetate solution of 0.8ml4N hydrochloric acid, and remove solvent under reduced pressure.Add the 50ml ether, obtain a kind of throw out, filtration this throw out of collection and drying, the corresponding trihydrochloride of 0.4g colourless powder shape obtained.
NMR（D 2O）δ ppm：1.6-2.0（6H，m），2.7-2.9（2H，m），3.04（3H，s），3.4-3.6（6H，m），3.9-4.1（6H，m），6.25（1H，dt，J＝15.8，8.0Hz），6.86（1H，d，J＝15.8Hz），7.40（5H，s），8.14（1H，t，J＝8.0Hz），8.6-8.7（3H，m），9.0（1H，d，J＝7.0Hz），9.72（1H，s）.
Embodiment 211.N-anisyl-N-(2-(4-chlorine cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
The crystallisate, 0.276g pmethoxybenzyl alcohol and the 0.524g triphenyl phosphorus that make among the 0.4g embodiment 172 are dissolved in the 10ml tetrahydrofuran (THF),, drip while stirring by the 0.404g diisopropyl azo-2-carboxylic acid and be dissolved in the solution that the 2ml tetrahydrofuran (THF) is become with ice-cold this solution.Reaction mixture is warmed to room temperature, and makes its standing over night, remove solvent then under reduced pressure.The gained residue is dissolved in the 30ml ethyl acetate, and this mixed solution is extracted 2 times with 30ml1N hydrochloric acid.Extract alkalizes with sodium bicarbonate, and with 30ml ethyl acetate extraction 2 times.Wash ethyl acetate solution with water, use dried over mgso, and remove solvent under reduced pressure.The gained residue is applied on the silicagel column, and carries out wash-out, obtain the described compound of title of 0.22g colorless oil with the chloroformic solution of 1% methyl alcohol.
NMR（CDCl 3）δ ppm：2.61（2H，t，J＝6.6Hz），3.14（2H，d，J＝6.1Hz），3.34（2H，t，J＝6.6Hz），3.74（3H，s），4.43（2H，s），6.0（1H，dt，J＝15.9，6.1Hz），6.30（1H，d，J＝15.9Hz），6.75（2H，d，J＝8.8Hz），7.08（2H，d，J＝8.8Hz），7.26（4H，s），7.66（1H，dd，J＝8.3，7.3Hz），8.17（1H，brd，J＝8.3Hz），8.39-8.49（2H，m），8.69（1H，d，J＝6.1Hz），9.3（1H，s）.
Embodiment 212.N-(2-(4-chlorine cinnamyl amino) ethyl)-N-styroyl-5-isoquinoline sulfonaide
Repeat the step described in the embodiment 211, difference is to replace pmethoxybenzyl alcohol with the 0.146g phenylethyl alcohol, obtains the described compound of title of 0.37g colorless oil.
NMR（CDCl 3）δ ppm：1.4（1H，brs），2.75-2.90（4H，m），3.27（2H，d，J＝6.1Hz），3.4-3.6（4H，m），6.10（1H，dt，J＝15.9，6.1Hz），6.39（1H，d，J＝15.9Hz），6.59-7.05（2H，m），7.1-7.2（3H，m），7.26（4H，s），7.65（1H，dd，J＝8.3，7.6Hz），8.15（1H，d，J＝8.3Hz），8.38（2H，t，J＝6.1Hz），8.63（1H，d，J＝6.1Hz），9.28（1H，s）.
Embodiment 213.N-benzyl-N-(2-(4-chlorine cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Repeat the step described in the embodiment 211, but replace pmethoxybenzyl alcohol, make the described compound of title of 0.3g colorless oil with the 0.162g phenylcarbinol.
NMR（CDCl 3）δ ppm：2.0（1H，brs），2.6（2H，t，J＝6.6Hz），3.15（2H，d，J＝6.1Hz），3.40（2H，t，J＝6.6Hz），4.50（2H，s），6.0（1H，dt，J＝15.8，6.1Hz），6.30（1H，d，J＝15.8Hz），7.15-7.25（9H，m），7.66（1H，dd，J＝8.0，7.6Hz），8.16（1H，d，J＝8.0Hz），8.4-8.5（2H，m），8.70（1H，d，J＝6.1Hz），9.31（1H，s）.
Embodiment 214.N-(2-(4-chlorine cinnamyl amino) ethyl)-N-methyl-5-isoquinoline sulfonaide
Repeat the step described in the embodiment 211, but replace pmethoxybenzyl alcohol, make the described compound of title of 0.3g colorless oil with 48mg methyl alcohol.
NMR（CDCl 3）δ ppm：1.5（1H，brs），2.86（2H，t，J＝6.2Hz），2.88（3H，s），3.3-3.4（4H，m），6.15（1H，dt，J＝15.8，6.1Hz），6.43（1H，d，J＝15.8Hz），7.27（4H，s），7.69（1H，dd，J＝8.3，7.3Hz），8.18（1H，d，J＝8.3Hz），8.38（1H，d，J＝7.3Hz），8.50（1H，d，J＝6.3Hz），8.67（1H，d，J＝6.3Hz），9.31（1H，s）.
Reference example 45.N-(3, the 4-Dimethoxyphenyl)-the 5-isoquinoline sulfonaide
With 3.06g3, the 4-dimethoxyaniline is dissolved in the 30ml pyridine, with ice-cooled this solution, and repeatedly adds 5.28g5-isoquinoline 99.9 SULPHURYL CHLORIDE-hydrochloride while stirring on a small quantity in this solution, then mixture was stirred 30 minutes, and continue at room temperature to stir to spend the night.After removing pyrido interpolation 20ml water under reduced pressure, this mixture is with 50ml chloroform/Virahol (10: 1) extracting twice.The dried over mgso extraction liquid also removes solvent under reduced pressure.Add 20ml benzene/chloroform (3: 1) in the gained residue, heated mixt is also collected a little then, obtains the described compound of 5.64g colorless oil title.
Fusing point: 195-197 ℃;
NMR（CDCl 3）δ ppm：3.67（3H，s），3.77（3H，s），6.3（1H，dd，J＝8.5，2.7Hz），6.5-6.6（3H，complex），7.61（1H，t，J＝8.3Hz），8.2（1H，d，J＝8.3Hz），8.3（1H，dd，J＝1.3，7.3Hz），8.4（1H，d，J＝6.1Hz），8.7（1H，d，J＝6.4Hz），9.36（1H，d，J＝1.3Hz）.
Reference example 46.N-(3, the 4-Dimethoxyphenyl)-N-(2-phthalimide ethyl)-the 5-isoquinoline sulfonaide
Gained crystallisate in the 500mg reference example 45 is dissolved in 7ml dimethyl formamide and the 4ml tetrahydrofuran (THF), with ice-cooled it, the sodium hydride that in this solution, adds 70mg60% while stirring, this mixture was stirred 20 minutes, and after adding 406mg bromoethyl phthalimide, whole mixture backflow was stirred 6 hours.After adding the 10ml frozen water,, use the dried over mgso extraction liquid then, and remove solvent under reduced pressure with 30ml ethyl acetate extraction reaction mixture.The gained residue is coated on the silicagel column, and carries out wash-out, make the described compound of 320mg colourless crystallization shape title with chloroform/methanol (100: 1).
Fusing point: 197-201 ℃;
NMR（CDCl 3）δ ppm：3.80（3H，s），3.88（3H，s），3.7-3.78（2H，complex），3.75-4.0（2H，complex），6.67（1H，s），6.68（1H，s），6.73（1H，s），7.57（1H，t，J＝7.57Hz），7.73（4H，s），8.0（1H，dd，J＝1.0，8.3Hz），8.05（1H，d，J＝7.3Hz），8.24（1H，dd，J＝1.0，7.57Hz），8.44（1H，brd），9.1（1H，brs）.
Reference example 47.N-(3, the 4-Dimethoxyphenyl)-the N-(2-amino-ethyl)-the 5-isoquinoline sulfonaide
The crystallisate that makes in the 517mg reference example 46 is dissolved in 5ml methyl alcohol and the 5ml chloroform, in this solution, adds the 60mg hydrazine hydrate, and mixture was refluxed 3 hours.Filtering crystalline soluble substance, and with filtrate evaporated under reduced pressure, remove and desolvate.After adding the 10ml ethyl acetate, filtering insolubles therefrom, reduction vaporization then produces the described compound of title of the little yellow oily of 420mg.
NMR（CDCl 3）δ ppm：2.76（2H，t，J＝6.1Hz），3.60（3H，s），3.75（2H，t，J＝6.1Hz），3.83（3H，s），6.48（1H，s），6.46（1H，d，J＝9.2Hz），6.63（1H，d，J＝9.2Hz），7.61（1H，t，J＝7.5Hz），8.18（1H，d，J＝8.0Hz），8.25（1H，dd，J＝1.3，8.3Hz），8.5（1H，d，J＝6.1Hz），9.3（1H，d，J＝1.3Hz）.
Embodiment 215.N-(3, the 4-Dimethoxyphenyl)-N-(2-(4-chlorine cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Prepared oily matter in the 320mg reference example 47 is dissolved in the 6ml dimethyl formamide, in this solution, adds 200mg salt of wormwood and 150mg cinnamoyl chloride chlorine, and at room temperature mixture is stirred and spend the night.After adding 20ml water, with 30ml chloroform extraction reaction mixture.Extraction liquid uses the magnesium chloride drying with the saturated sodium-chloride water solution washing, and removes solvent under reduced pressure.The gained residue is applied on the silicagel column, and, makes the described compound of 90mg colourless crystallization shape title with chloroform/methanol (100: 1) wash-out.
NMR（CDCl 3）δ ppm：2.75（2H，t，J＝6.1Hz），3.36（1H，d，J＝6.1Hz），3.6（3H，s），3.74（2H，d，J＝6.1Hz），3.82（3H，s），6.15（1H，d，and dt，J＝15.6，6.1Hz），6.42（1H，d，J＝15.6Hz），6.5（1H，s），6.61（1H，d，J＝8.1Hz），6.48（1H，d，J＝6.1Hz），7.3（4H，brs），7.63（1H，t，J＝8.1Hz），8.16（1H，d，J＝6.1Hz），8.17（1H，d，J＝8.1Hz），8.3（1H，dd，J＝1.0，6.1Hz），8.5（1H，d，J＝6.1Hz），9.3（1H，d，J＝1.0Hz）.
Embodiment 216.N-{ 2-(two (4-chlorine cinnamyl) amino) ethyl }-5-isoquinoline sulfonaide
In embodiment 215, before with the chloroform/methanol wash-out, use chloroform to carry out wash-out, make the described compound of the colourless non-crystalline state title of 100mg.
NMR（CDCl 3）δ ppm：2.66（2H，t，J＝6.2Hz），3.25（4H，d，J＝6.2Hz），3.52（3H，s），3.75（2H，t，J＝6.2Hz），3.71（3H，s），6.1（2H，d and t，J＝15.6，6.2Hz），6.3（1H，d，J＝5.6Hz），6.4（1H，s），6.4（2H，d，J＝15.6Hz），6.45（1H，d，J＝5.6Hz），7.3（8H，s），7.51（1H，t，J＝8.1Hz），8.14（1H，d，J＝6.1Hz），8.16（1H，d，J＝8.1Hz），8.2（1H，dd，J＝1.0，6.1Hz），8.45（1H，d，J＝6.1Hz），9.3（1H，d，J＝1.0Hz）.
Prepare following compounds as mentioned above.
Embodiment 217.N-(2-(4-methoxyl group-Alpha-Methyl cinnamyl amino)-ethyl)-5-isoquinoline sulfonaide dihydrochloride
Colourless non-crystalline state.
IR（KBr）cm -1：3420，3200-2300，1720，1605，1345，1280;
UMR（D 2O）δ ppm：1.59（3H，d，J＝6.71Hz），3.19（2H，brt.），3.38（2H，brt），4.01（3H，s），4.16（1H，m），6.28（1H，dd，J＝15.9，8.9Hz），6.83（1H，d，J＝15.9Hz），7.51（2H，d，J＝8.4Hz），7.94（2H，d，J＝8.4Hz），8.10（1H，brt），8.64（1H，d，J＝8.6Hz），8.76（2H，brt），8.99（1H，d，J＝7.0Hz），9.72（1H，s）.
Embodiment 218.N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Colourless noncrystalline shape.
IR（KBr）cm -1＝3420，3150-2300，1715，1605，1345，1285;
NMR（D 2O）δppm＝1.59（3H，α，J＝6.4Hz），2.94（3H，s），3.44（4H，brs），3.99（3H，s），4.31（1H，m），6.37（1H，dd，J＝16.2，8.7Hz），6.89（1H，d，J＝16.2Hz），7.54（2H，d，J＝8.1Hz），8.08（2H，d，J＝8.1Hz），8.10（1H，brt），8.67（1H，d，J＝8.5Hz），8.75（2H，brt），8.96（1H，d，J＝7.0Hz），9.74（1H，s）.
Embodiment 219.N-(2-(4-methoxyl group-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
NMR（CDCl 3）δppm：1.07（3H，d，J＝6.6Hz），1.85（3H，s），2.3-2.5（2H，m），2.91（2H，t，J＝6.0Hz），2.95-3.10（1H，m），3.80（3H，s），5.86（1H，dd，J＝6.0Hz），2.95-3.10（1H，m），3.80（3H，s），5.86（（1H，dd，J＝16.1，7.3Hz），6.24（1H，d，J＝16.1Hz），6.84（2H，d，J＝8.8Hz），7.24（2H，d，J＝8.8Hz），7.68（1H，dd，J＝7.3，8.0Hz），8.20（1H，α，J＝8.0Hz），8.4-8.5（2H，m），8.66（1H，d，J＝6.1Hz），9.34（1H，s）.
Embodiment 220.N-(2-methylamino ethyl) N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
NMR（CDO 3）δppm：1.9-2.2（1H，br），2.23（3H，s），2.35（3H，s），2.59（2H，t.J＝6.6Hz），2.80（2H，t，J＝6.1Hz），3.12（2H，α，J＝6.6Hz），3.4-5.5（4H，m），6.10（（1H，dt，J＝15.9，6.6Hz），6.44（（1H，d，J＝15.9Hz），7.26（4H，s），7.66（1H，t，J＝15.9，6.6Hz），6.44（1H，d，J＝15.9Hz），7.26（4H，s），7.66（1H，t，J＝7.8Hz），8.17（1H，d，J＝7.8Hz），8.40（1H，d，J＝7.8Hz），8.46（1H，d，J＝6.1Hz），8.67（1H，d，J＝6.1Hz），9.32（1H，s）.
Embodiment 221.N-(2-methylamino ethyl)-N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide trihydrochloride
Colourless noncrystalline shape.
NMR（D 2O）δppm：2.80（3H，s），3.05（3H，s），3.4-3.6（4H，m），3.9-4.1（6H，m），6.17（1H，d.t，J＝15.9，7.2Hz），6.74（1H，d，J＝15.9Hz），7.18（4H，s），8.10（1H，t，J＝7.9Hz），8.53（1H，d，J＝7.9Hz），8.6-8.8（2H，m），8.93（1H，d，J＝7.0Hz），9.77（1H，s）.
Embodiment 222.N-(2-hydroxyethyl)-N-(2-(4-methoxyl group-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline.
NMR（CDCl 3）δppm：1.29（3H，d，J＝6.6Hz），2.30（3H，s），2.7-3.0（2H，m），3.2-3.4（5H，m），3.80（3H，s），3.8-3.9（2H，m），6.04（1H，dd，J＝16.1，7.8Hz），6.40（1H，d，J＝16.1Hz），6.86（2H，d，J＝16.1，7.8Hz），6.40（1H，d，J＝16.1Hz），6.86（2H，d，J＝8.7Hz），7.32（2H，d，J＝8.7Hz），7.32（2H，d，J＝8.7Hz），7.68（1H，dd，J＝8.0，7.3Hz），8.19（1H，d，J＝8.0Hz），8.25（1h，d，J＝7.3Hz），8.58（1H，d，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），9.33（1H，s）.
Embodiment 223.N-(2-(methoxyl group) ethyl)-N-(2-(N-methyl-4-methoxyl group-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
NMR（CDCl 3）δppm：1.12（3H，d.J＝6.6Hz），2.18（3H，s），2.4-2.65（2H，m），3.1（3H，s），3.10-3.20（1H，m），3.35-3.60（6H，m），3.81（3H，s），5.93（1H，d，d，J＝16.1，7.3Hz），6.31（1H，d，J＝16.1Hz），6.85（2H，d，J＝8.7Hz），7.62（1H，dd，J＝7.6，8.1Hz），8.13（1H，d，J＝8.1Hz），8.35-8.45（2H，m），8.67（1H，d，J＝6.1Hz），9.30（1H，s）.
Embodiment 224.N-(2-(4-chlorine cinnamyl amino) ethyl)-the N-(2-dimethyl aminoethyl)-5-isoquinoline sulfonaide trihydrochloride
Colourless non-crystalline state.
IR（KBr）cm -1：3420，2700，1340，1150，840，590
NMR（D 2O）δppm：2.99（6H，s），3.33（2H，t，J＝6.8Hz），3.55（2H，t，J＝6.8Hz），3.8-4.0（6H，m），6.18（1H，dt，J＝16.2，6.7Hz），6.76（1H，d，J＝16.2Hz），7.32（4H，s），8.12（1H，t，J＝8.0Hz），8.6-8.8（3H，m），8.97（1H，d，J＝7.0Hz），9.74（1H，s）.
Embodiment 225.N-(2-(4-chlorine cinnamyl amino) ethyl)-N-(2-methylamino ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
NMR（D 2O）δppm：3.26（2H，brt），3.92（4H，brt），5.04（2H，s），6.1-6.3（1H，m），6.77（1H，d，J＝15.6Hz），7.38（4H，s），7.68（1H，t，J＝6.7Hz），8.0-8.3（2H，m），8.57（1H，d，J＝5.8Hz），8.7-8.9（3H，m），9.02（1H，d，J＝7.3Hz），9.80（1H，s）.
Embodiment 226.N-2-(4-chlorine cinnamyl amino) ethyl)-the N-(2-pyridylmethyl)-5-isoquinoline sulfonaide tri hydrochloride
Faint yellow non-crystalline state.
IR（KBr）cm -1：3420，2800，1350，1150，590;
NMR（D 2O）δppm：3.12（2H，brt），3.8-4.0（4H，m），4.96（2H，s），6.0-6.2（1H，m），6.70（1H，d，J＝15.7Hz），7.37（4H，brq），7.93（1H，t，J＝6.3Hz），8.16（2H，brt），8.54（1H，d，J＝5.8Hz），8.61（1H，d，J＝8.5Hz），8.7-8.8（2H，m），8.83（1H，s），9.01（1H，d，J＝6.7Hz），9.76（1H，s）.
Embodiment 227.N-(2-(4-chlorine cinnamyl amino) ethyl)-the N-(3-pyridylmethyl)-5-isoquinoline sulfonaide trihydrochloride
Faint yellow non-crystalline state.
IR（KBr）cm -1：3420，2800，1350，1150，590;
NMR（D 2O）δppm：3.12（2H，brt），3.8-4.0（4H，m），4.96（2H，s），6.0-6.2（1H，m），6.70（1H，d，J＝15.7Hz），7.37（4H，brq），7.93（1H，t，J＝6.3Hz），8.16（2H，brt），8.54（1H，d，J＝5.8Hz），8.61（1H，d，J＝6.7Hz），9.76（1H，s）.
Embodiment 228.N-(2-(3,4-dimethoxy-Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Yellow non-crystalline state.
HMR（D 2O）δppm：1.56（3H，d，J＝6.7Hz），3.1-3.2（2H，m），3.35-3.45（2H，m），3.84（3H，s），3.91（3H，s），4.0-4.5（1H，m），6.0（1H，dd，J＝15.6，9.0Hz），6.64（1H，d，J＝15.6Hz），6.92（3H，s），8.07（1H，t，J＝8.0Hz），8.60（1H，d，J＝8.0Hz），8.73（1H，d，J＝8.0Hz），8.73（1H，d，J＝6.7Hz），8.95（1H，d，J＝6.7Hz），9.68（1H，s）.
Embodiment 229.N-(2-(Alpha-Methyl-3,4,5-trimethoxy cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
NMR（D 2O）δppm：1.65（3H，d，J＝6.4Hz），3.2-3.5（4H，m），3.84（3H，s），3.91（6H，s），4.1-4.3（1H，m），6.13（1H，dd，J＝14.1，8.8Hz），6.70（1H，d，J＝14.1Hz），6.67（2H，s），8.16（1H，t，J＝8.0Hz），8.17（1H，d，J＝8.0Hz），8.75-8.85（2H，m），9.02（1H，t，J＝8.0Hz），8.17（1H，d，J＝8.0Hz），8.75-8.85（2H，m），9.02（1H，d，J＝7.0Hz），9.80（1H，s）.
Embodiment 230.N-(2-dimethyl aminoethyl)-N-(2-(N-methyl-3,4,5-trimethoxy cinnamyl amino) ethyl-5-isoquinoline sulfonaide
Colorless oil.
NMR（CDCL 3）δppm：2.12（6H，s），2.22（3H，s），2.39（2H，t，J＝6.8Hz），3.10（2H，d，J＝6.6Hz），3.4-3.5（4H，m），3.84（3H，s），3.87（6H，s），6.06（1H，dt，J＝1.6，6.6Hz），6.40（1H，d，J＝16Hz），6.61（2H，s），7.64（1H，t，J＝7.4Hz），8.15（1H，d，J＝7.4Hz），8.44（2H，m），8.68（1H，d，J＝6.1Hz），9.32（1H，s）.
Embodiment 231.N-(2-dimethyl aminoethyl)-N-(2-(N-methyl-3,4,5-trimethoxy cinnamyl amino) ethyl)-5-isoquinoline sulfonaide trihydrochloride
Yellow non-crystalline state.
NMR（D 2O）δppm：3.00（6H，s），3.08（3H，s），3.80（3H，s），3.82（6H，s），3.5-4.1（10H，m），6.1（1H，m），6.51（2H，s），6.68（1H，d，J＝16Hz），8.0（1H，t，J＝16Hz），8.5（2H，m），8.7（2H，m），9.55（1H，s）.
Embodiment 232.N-(2-(4-chlorine cinnamyl amino) ethyl)-and N-(3,4,5-trimethoxy benzyl)-5-isoquinoline sulfonaide dihydrochloride
Colourless non-crystalline state.
IR（KBr）cm -1＝3420，2920，1330，1130，590;
NMR（DMSO-d 6）δppm：2.99（2H，brs），3.55（6H，s），3.56（3H，s），3.68（4H，brs），4.47（2H，s），6.2-6.4（1H，m），6.76（1H，d，J＝15.9Hz），7.45（4H，s），7.95（1H，t，J＝7.9Hz），8.54（1H，d，J＝7.6Hz），8.6-8.7（2H，m），8.78（1H，d，J＝6.3Hz），9.48（2H，brs），9.73（1H，s）.
Embodiment 233.N-cyano methyl-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
IR（KBr）cm -1＝2250，1718，1280;
NMR（CDCl 3）δppm＝1.16（3H，d，J＝6.6Hz），2.23（3H，s），2.65-2.8（2H，m），3.35（1H，m），3.43（2H，t，J＝5.6Hz），3.91（3H，s），4.63（2H，s），6.23（1H，dd，J＝15.9，7.1Hz），6.46（1H，d，J＝15.9Hz），7.39（2H，d，J＝8.3Hz），7.73（1H，t，J＝8.3Hz），7.98（2H，d，J＝8.3Hz），8.25（1H，d，J＝8.3Hz），8.4-8.5（2H，m），8.70（1H，d，J＝6.1Hz），9.36（1H，s）.
Embodiment 234.N-cyano methyl-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Colourless non-crystalline state.
IRC（KBr）cm -1＝1718，1280;
NMR（CDCl 3）δppm：1.14（3H，d，J＝6.6Hz），2.10（6H，s），2.21（3H，s），2.37（2H，t，J＝7.3Hz），2.45-2.65（2H，m），3.22（1H，m），3.35-3.50（4H，m），3.91（3H，s），6.21（1H，dd，J＝1.59，6.8Hz），6.42（1H，d，J＝1.59Hz），8.15（1H，t，J＝7.7Hz），8.7-8.85（3H，m），8.99（1H，d，J＝7.0Hz），9.76（1H，s）.
Embodiment 235.N-(2-dimethyl aminoethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino)-ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
IRC（KBr）cm -1：1718，1280;
NMR（CDCl 3）δppm：1.14（3H，d，J＝6.6Hz），2.10（6H，s），2.21（3H，s），2.37（2H，t，J＝7.3Hz），2.45-2.65（2h，m），3.22（1H，m），3.35-3.50（4H，m），3.91（3H，s），6.21（1H，dd，J＝15.9，6.8Hz），6.42（1H，d，J＝15.9Hz），7.38（2H，d，J＝8.3Hz），7.63（1H，t，J＝7.9Hz），7.98（2H，d，J＝8.3Hz），8.14（1H，d，J＝7.9Hz），8.4-8.5（2H，m），8.67（1H，d，J＝6.4Hz），9.31（1H，s）.
Embodiment 236.N-(2-dimethyl aminoethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide trihydrochloride
Colourless non-crystalline state.
NMR（D 2O）δppm：1.53（3H，d，J＝6.7Hz），2.95（9H，s），3.3-3.6（4H，m），3.9-4.0（4H，m），4.0（3H，s），4.25（1H，m），6.30（1H，m），6.75（1H，d，J＝16.0Hz），7.37（2H，brs），7.81（2H，brs），8.04（1H，t，J＝8.1Hz），8.55（2H，m），8.65（1H，d，J＝7.0Hz），9.60（1H，s）.
Embodiment 237.N-(2-morpholino ethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
IR（KBr）cm -1：1720，1280;
NMR（CDCl 3）δppm：1.15（3H，d，J＝6.4Hz），2.21（3H，s），2.25-2.7（2H，m），3.1-3.3（1H，m），3.4-3.6（8H，m），3.91（3H，s），6.20（1H，dd，J＝16.1，7.3Hz），6.42（1H，d，J＝16.1Hz），7.38（2H，d，J＝8.3Hz），7.63（1H，t，J＝7.8Hz），8.42（1H，d，J＝7.8Hz），8.42（1H，d，J＝7.1Hz），8.67（1H，d，J＝7.1Hz），9.32（1H，s）.
Embodiment 238.N-(2-morpholino ethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl-5-isoquinoline sulfonaide trihydrochloride
Colourless non-crystalline state.
NMR（D 2O）δppm：1.55（3H，d，J＝6.8Hz），3.00（3H，s），3.2-3.7（8H，m），3.8-4.1（8H，m），4.0（3H，s），4.24（1H，m），6.35（1H，m），6.76（1H，d，J＝16Hz），7.40（2H，brs），7.82（2H，brs），8.06（1H，t，J＝7.5Hz），8.5-8.75（3H，m），8.80（1H，d，J＝7.0Hz），9.63（1H，s）.
Embodiment 239.N-(2-amino-ethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colorless oil.
IR（KBr）cm -1：1718，1280;
NMR（CDCl 3）δppm：1.13（3H，d，J＝6.6Hz），2.19（3H，s），2.6（2H，m），2.86（2H，brs），3.22（1H，m），3.37（4H，t，J＝6.9Hz），3.91（3H，s），6.20（1H，dd，J＝16.0，6.9Hz），6.42（1H，d，J＝16.0Hz），7.39（2H，d，J＝8.3Hz），8.14（1H，d，J＝8.1Hz），8.38（1H，d，J＝8.1Hz），8.45（1H，d，J＝6.1Hz），8.68（1H，d，J＝6.1Hz），9.31（1H，s）.
Embodiment 240.N-(2-amino-ethyl)-N-(2-(4-methoxycarbonyl-N, alpha-alpha-dimethyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide trihydrochloride
Colourless non-crystalline state.
NMR（D 2O）δppm：1.53（3H，d，J＝6.4Hz），2.96（3H，s），3.3-3.5（4H，m），3.8-4.0（4H，m），4.0（3H，s），4.2（1H，m），6.3（1H，m），6.76（1H，d，J＝15.9Hz），7.35（2H，d，J＝8.0Hz），7.78（2H，brs），803（1H，t，J＝7.9Hz），8.6（2H，m），8.66（1H，d，J＝6.7Hz），8.85（1H，d，J＝6.7Hz），9.58（1H，s）.
Embodiment 241.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-methoxycarbonyl methyl-5-isoquinoline sulfonaide dihydrochloride
Yellow non-crystalline state.
IR（KBr）cm -1：3420，2650，1750，1350，1150，840，590;
NMR（D 2O）δppm：3.05（3H，s），3.51（2H，brs），3.61（3H，s），3.89（2H，brs），4.06（2H，d，J＝7.3Hz），4.45（2H，s），6.2-6.4（1H，m），6.85（1H，d，J＝15.6Hz），7.34（4H，brq），8.12（1H，t，J＝8.0Hz），8.6-8.8（3H，m），8.95（1H，d，J＝7.0Hz），9.79（1H，s）.
Embodiment 242.N-carboxyl methyl-N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
The light brown non-crystalline state.
IR（KBr）cm -1：3420，1620，1330，1140，590：
NMR（DMSO-d6）δppm：2.43（3H，s），2.89（2H，brt），3.3-3.6（4H，m），3.91（2H，s），6.2-6.4（1H，m），6.67（1H，d，J＝15.8Hz），7.45（4H，brq），7.85（1H，t，J＝8.0），8.3-8.5（3H，m），8.71（1H，d，J＝6.2Hz），9.49（1H，s）.
Embodiment 243.N-(2-(N-carboxyl methyl-4-chlorine cinnamyl amino) ethyl)-N-methyl-5-isoquinoline sulfonaide
Faint yellow non-crystalline state.
IR（KBr）cm -1：3400，1630，1320，1140，590;
NMR（DMSO-d6）δppm：2.75（2H，brt），2.79（3H，s），3.2-3.4（6H，m），6.1-6.3（1H，m），6.50（1H，d，J＝16.2Hz），7.39（4H，brq），7.83（1H，t，J＝7.8Hz），8.3-8.5（3H，m），8.68（1H，d，J＝6.1Hz），9.48（1H，s）.
Embodiment 244.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-methyl-5-isoquinoline sulfonaide dihydrochloride
The light brown non-crystalline state.
IR（KBr）cm -1：3420，2670，1350，1140，830，590;
NMR（D 2O）δppm：3.00（3H，s），3.04（3H，s），3.51（2H，brs），3.66（2H，brs），4.10（2H，brd），6.2-6.4（1H，m），6.90（1H，d，J＝15.9Hz），7.39（4H，brq），8.15（1H，t，J＝8.0Hz），8.6-8.8（3H，m），9.08（1H，d，J＝6.3Hz），9.80（1H，s）.
Embodiment 245.N-formamyl-N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Colourless non-crystalline state.
IR（KBr）cm -1：3420，2670，1680，1350，1150，840，590;
NMR（D 2O）δppm：3.04（3H，s），3.4-3.7（2H，m），3.89（2H，brt），4.06（2H，brt），4.29（2H，s），6.2-6.4（1H，m），6.86（1H，d，J＝7.0Hz），9.80（1H，s）.
Embodiment 246.N-(2-(4-chlorine cinnamyl amino) ethyl)-N-((5-methyl-4-imidazolyl) methyl)-5-isoquinoline sulfonaide-hydrochloride
Faint yellow non-crystalline state.
IR（KBr）cm -1：3420，3020，1350，1150，830，590;
NMR（D 2O）δppm：2.49（3H，s），3.52（4H，brs），4.10（2H，brd），4.70（2H，s），6.1-6.3（1H，m），6.83（1H，d，J＝15.8Hz），7.34（4H，s），8.10（1H，d，J＝8.0Hz），8.6-8.8（3H，m），8.83（1H，s），8.95（1H，d，J＝7.0Hz），9.81（1H，s）.
Embodiment 247.N-(2-(4-chloro-N-methoxycarbonyl methyl cinnamyl amino) ethyl)-N-methyl-5-isoquinoline sulfonaide dihydrochloride
Yellow non-crystalline state.
IR（KBr）cm -1：3420，2620，1750，1350，1140，840，590;
NMR（D 2O）δppm：3.07（3H，s），3.73（4H，brt），3.89（3H，s），4.2（2H，brd），4.37（2H，s），6.2-6.4（1H，m），6.89（1H，d，J＝16.0Hz），7.32（4H，brq），8.14（1H，t，J＝7.9Hz），8.6-8.8（3H，m），9.04（1H，d，J＝7.0Hz），9.83（1H，s）.
Embodiment 248.N-(2-(N-carbamyl ylmethyl-4-chlorine cinnamyl amino)-ethyl)-N-methyl-5-isoquinoline sulfonaide dihydrochloride
Faint yellow non-crystalline state.
IR（KBr）cm -1：3400，1690，1350，1140，830，590;
NMR（D 2O）δppm：3.05（3H，s），3.5-3.8（4H，m），4.1-4.2（2H，m），4.23（2H，s），6.2-6.4（1H，m），6.91（1H，d，J＝15.9Hz），734（4H，brq），8.11（1H，t，J＝7.0Hz），8.6-8.8（3H，m），9.00（1H，d，J＝7.0Hz），9.80（1H，s）.
Embodiment 249.N-(2-(4-chloro-N-cyano methyl cinnamyl amino) ethyl)-N-methyl-5-isoquinoline sulfonaide dihydrochloride
The light brown non-crystalline state.
IR（KBr）cm -1：3420，2570，1350，1140，830，590;
NMR（DMSO-d6）δppm：2.80（2H，brt）2.89（3H，s），3.3-3.5（4H，m），3.89（2H，s），6.1-6.3（1H，m），6.64（1H，d，J＝15.8Hz），7.43（4H，brq），8.09（1H，t，J＝8.0Hz），8.63（1H，d，J＝7.6Hz），8.7-8.9（3H，m），9.98（1H，s）.
Embodiment 250.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-morpholino carbonyl methyl-5-isoquinoline sulfonaide
Colorless oil.
IR（KBr）cm -1：1660，1330，1130;
NMR（D 2O）δppm：2.17（3H，s），2.57（2H，t，J＝6.3Hz），3.06（2H，d，J＝6.3Hz），3.39（4H，brs），3.5-3.7（6H，m），4.41（2H，s），6.06（1H，dt，J＝15.9，6.3Hz），6.40（1H，d，J＝15.9Hz），7.27（4H，s），7.66（1H，t，J＝8.0Hz），8.15（1H，d.J＝8.3Hz），8.43（1H，d，J＝6.4Hz），8.54（1H，d，J＝8.0Hz），8.66（1H，d，J＝6.4Hz），9.30（1H，s）.
Embodiment 251.N-2-(N-(2-amino-ethyl)-4-chlorine cinnamyl amino) ethyl }-N-methyl-5-isoquinoline sulfonaide trihydrochloride
Colourless non-crystalline state.
IR（KBr）cm -1：3420，2950，1490，1350，1140，590;
NMR（D 2O）δppm：3.05（3H，s）3.5-3.8（8H，m），4.20（2H，brd），6.2-6.4（1H，m），6.05（1H，d，J＝15.9Hz），7.37（4H，brq），8.16（1H，t，J＝7.9Hz），8.6-8.8（3H，m），9.07（1H，d，J＝7.0Hz），9.84（1H，s）.
Embodiment 252.N-(2-(4-chloro-N-methyl cinnamyl amino)-ethyl)-N-(2-(1-piperazinyl) ethyl)-5-isoquinoline sulfonaide four hydrochlorides
Colourless non-crystalline state.
IR（KBr）cm -1：3420，2660，1460，1350，1150，590;
NMR（D 2O）δppm：3.04（3H，s），3.3-3.7（12H，m），3.8-4.1（6H，m），6.0-6.2（1H，m），6.73（1H，d，J＝15.9Hz），7.18（4H，s），8.11（1H，t，J＝7.9Hz），8.53（1H，d，J＝7.3Hz），8.6-8.8（2H，m），8.89（1H，d，J＝6.9Hz），9.78（1H，s）.
Embodiment 253.N-(2-(4-chloro-N-methyl cinnamyl amino) ethyl)-N-(2-(4-methyl isophthalic acid-piperazinyl) ethyl-5-isoquinoline sulfonaide four hydrochlorides
Colourless non-crystalline state.
IR（KBr）cm -1：3420，2660，1460，1140，590;
NMR（D 2O）δppm：3.02（3H，s），3.3-3.7（12H，m），3.8-4.1（6H，m），6.1-6.3（1H，m），6.74（1H，d，J＝16.0Hz），7.19（4H，s），8.11（1H，t，J＝7.9Hz），8.55（1H，d，J＝7.0Hz），8.5-8.8（2H，m），8.90（1H，d，J＝7.0Hz），9.79（1H，s）.
Embodiment 254.N-(2-(3-methoxyl group-Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide dihydrochloride
Faint yellow crystallization.
Fusing point 115-118 ℃;
IR（KBr）cm -1：3420，3200-2600，1605，1350，1162，1150;
NMR（DMSO-d6）δppm：1.40（3H，d，J＝6.4Hz），2.90-3.0（2H，m），3.15-3.25（2H，m），3.78（3H，s），3.80-4.0（1H，m），6.22（1H，dd，J＝15.9，8.8Hz），6.70（1H，d，J＝15.9Hz），6.85-7.05（3H，m），7.30（1H，t，J＝7.9Hz），7.30（1H，br，disappears in D 2O），8.0（1H，d，J＝7.9Hz），8.04（1H，d，J＝7.3Hz），8.59（1H，d，J＝7.3Hz），8.68（1H，d，J＝7.9Hz），8.82（2H，s），8.91（1H，m，disappears in D 2O），9.60（2H，br，disappears in D 2O），9.88（1H，s）.
Embodiment 255.N-(2-(4-hydroxymethyl-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless crystallization.
IR（KBr）cm -1：1620，1326，1160，1139，831，761，598;
NMR（CDCl 3）δppm：1.07（3H，d，J＝6，35Hz），near1.95（3H，br），2.60（2H，t，J＝6.0Hz），2.96（2H，m），3.05（1H，m），4.68（2H，s），5.78（1H，dd，J＝15.87，7.82Hz），6.27（1H，d，J＝8.30Hz），7.67（1H，dd，J＝8.30，7.32Hz），8.18（1H，d，J＝8.30Hz），8.40（1H，d，J＝6.11Hz），8.44（1H，d，J＝7.32Hz），8.61（1H，d，J＝6.11Hz），9.32（1H，s）.
Embodiment 256.N-(2-(Alpha-Methyl-4-methyl sulfo-cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
IR（KBr）cm -1：1618，1493，1324，1160，1138，1094，830，807，760，598;
NMR（CDCl 3）δppm：105（3H，d，J＝6.35Hz），2.48（3H，s），2.60（2H，m），2.96（2H，t，J＝6.10Hz），3.03（1H，m），5.75（1H，dd，J＝15.87，7.81Hz），6.22（1H，d，J＝15.87Hz），7.18（4H，s），7.67（1H，dd，J＝8.30，7.32Hz），8.17（1H，d，J＝8.30Hz），8.43（1H，d，J＝6.10Hz），8.44（1H，d，J＝7.32Hz），8.68（1H，d，J＝6.10Hz），9.34（1H，s）.
Embodiment 257.N-(2-(Alpha-Methyl-4-methyl sulfinyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
IR（KBr）cm -1;1618，1326，1160，1138，1089，1041，831，762，599;
NMR（CDCl 3）δppm：1.11（3H，d，J＝6.59Hz），2.0-4.0（2H，br），2.65（2H，m），2.73（3H，s），3.00（2H，t，J＝5.62Hz），3.15（1H，m），5.96（1H，dd，J＝16.11，7.81Hz），6.36（1H，d，J＝16.11Hz），7.42（2H，d，J＝8.30Hz），7.58（2H，d，J＝8.30Hz），7.68（1H，dd，J＝8.31，7.32Hz），8.10（1H，d，J＝8.30Hz），7.68（1H，dd，J＝8.31，7.32Hz），8.19（1H，d，J＝8.31Hz），8.44（1H，d，J＝6.1Hz），8.44（1H，d，J＝7.32Hz），8.67（1H，d，J＝6.10Hz），9.35（1H，s）.
Embodiment 258.N-(2-(Alpha-Methyl-4-methyl sulphonyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
IR（KBr）cm -1;1310，1149，1090，960，832，765，599，542;
NMR（CDCl 3）δppm：1.09（3H，d，J＝6.35Hz），2.62（2H，m），2.98（2H，t，J＝5.62Hz），3.05（3H，s），3.10（1H，m），6.02（1H，dd，J＝15.87，7.57Hz），6.37（1H，d，J＝15.87Hz），3.05（3H，s），3.10（1H，m），6.02（1H，dd，J＝15.87，7.57Hz），6.37（1H，d，J＝15.87Hz），7.44（2H，d，J＝8.30Hz），7.69（1H，dd，J＝8.06，7.57Hz），7.85（2H，d，J＝8.30Hz），8.20（1H，d，J＝8.06Hz），8.44（1H，d，J＝6.35Hz），8.45（1H，d，J＝7.57Hz），8.67（1H，d，J＝6.35Hz），9.36（1H，s）.
Embodiment 259.N-(2-(4-cyano group-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless needle-like.
Fusing point: 62-65 ℃;
IR（KBr）cm -1;2230，1620，1322，1140，600;
NMR（CDCl 3）δppm：1.08（3H，d，J＝6.3Hz），2.57-2.65（2H，m），2.9-3.0（2H，m），3.0-3.2（1H，m），5.98（1H，dd，J＝15.9，7.8Hz），6.33（1H，d，J＝15.9Hz），7.36（2H，d，J＝8.3Hz），7.58（2H，d，J＝8.3Hz），7.69（1H，t，J＝8.0Hz），8.20（1H，d，J＝8.0Hz），8.40-8.50（2H，m），8.69（1H，d，J＝6.1Hz），9.36（1H，s）.
Embodiment 260.N-(2-(4-formamyl-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless needle-like.
Fusing point: 66-70 ℃;
IR（KBr）cm -1;3450，1662，1610，1320，1160，1140;
NMR（CDCl 3）δppm：1.08（3H，d，J＝6.4Hz），2.61（2H，K），2.90-3.20（3H，m），5.93（1H，dd，J＝16.1，7.8Hz），6.32（1H，d，J＝16.1Hz），7.32（2H，d，J＝8.3Hz），7.66（1H，t，J＝8.3Hz），7.74（2H，d，J＝8.3Hz），8.18（1H，d，J＝8.3Hz），7.74（2H，d，J＝8.3Hz），8.18（1H，d，J＝8.3Hz），8.40-8.50（2H，m），8.67（1H，d，J＝6.1Hz），9.34（1H，s）.
Embodiment 261.N-(2-(4-ethanamide-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
IR（KBr）cm -1;3300-2800，1670，1600，1538，1320，1160，1140;
NMR(CDCl 3) δ ppm:1.03(3H, d, J=6.6Hz), 2.16(3H, s), 2.55-2.65(2H, m), 2.90-3.10(3H, m), 5.68(1H, dd, J=15.9,8.1Hz), 6.20(1H, d, J=15.9Hz), 7.17(2H, d, J=8.5Hz), 7.44(2H, d, J=8.5Hz), 7.66(1H, dd, J=8.3,7.3Hz), 8.44(1H, d, J=7.3Hz), 7.66(1H, s, d D 2Disappear among the O), 8.16(1H, d, J=8.3Hz), and 8.44(1H, c, J=7.3Hz), and 8.44(1H, d, J=6.1Hz), and 8.61(1H, d, J=6.1Hz), 9.31(1H, s).
Embodiment 262.N-(2-(3-nitro-3-methoxyl group-Alpha-Methyl cinnamyl amino) ethyl)-5-isoquinoline sulfonaide-hydrochloride
Colourless crystallization.
Fusing point: 159-163 ℃;
IR（KBr）cm -1：3450，3150-2600，1530，1330，116-，1140;
NMR(DMSO-d6) δ ppm:1.34(3H, d, J=6.6Hz), 2.75-3.0(2H, m), 3.02-3.20(2H, m), 3.90(3H, s), 3.90-4.10(1H, m), 6.30(1H, dd, J=15.6,8.6Hz), 6.57(1H, d, J=15.6Hz), 7.26(1H, d, J=7.8Hz), 7.32(1H, d, J=7.8Hz), 7.83(1H, t, J=7.8Hz), 8.35-8.45(3H, m), 8.52(1H, brs is at D 2Disappear among the O), 8.7(1H, d, J=6.1Hz), and 9.25(2H, brs is at D 2Disappear among the O), 9.47(1H, s)
Embodiment 263.N-(2-(2-methoxyl group-Alpha-Methyl cinnamyl amino) ethyl)-the 5-isoquinoline sulfonaide
Colourless non-crystalline state.
IR（KBr）cm -1：1490，1463，1326，1244，1160，1138，755，599;
NMR（CDCl 3）δppm：1.05（3H，d，J＝6.35Hz），2.6（2H，m），2.96（2H，t，J＝5.62Hz），3.04（1H，m），3.82（3H，s），5.79（1H，dd，J＝16.12，7.94Hz），6.85（1H，brd，J＝8.06Hz），6.90（1H，brt，J＝7.57Hz），7.21（1H，m），7.31（1H，dd，J＝16.12，7.94Hz），6.85（1H，brd，J＝8.06Hz），6.90（1H，brt，J＝7.57Hz），7.21（1H，m）7.31（1H，dd，J＝7.57，（1.71Hz），7.66（1H，dd，J＝8.06，7.57Hz），8.16（1H，t，J＝8.06Hz），8.44（2H，m），8.67（1H，d，J＝6.35Hz），9.33（1H，s）.
Embodiment 264.
For further confirming the practicality of the invention described above compound, carried out following test.
Vascular smooth muscle relaxation effect (V.R.ED 50)
Rabbit is killed in bloodletting, takes out the dorsal mesentery artery, is cut into spirrillum, prepares banded sample according to a conventional method.Frothing in Krebs-Henseleit solution blasts the oxygen that contains 5% carbonic acid gas, above-mentioned sample is loaded produce certain strain, hangs in this solution.In solution, add Repone K, sample is shunk, with the strain that keeps being scheduled to.Thereafter, increase progressively adding compound to be tried.Wait to try the loose activity of compound with ED 50(μ M) expression also, makes strain relaxation to only there being Repone K to have 50% o'clock of strain down (meter work 100%), used compound concentration.
Inhibition (the P.A. of platelet aggregation effect; IC 50)
(1) preparation of washing platelet
Obtain blood from healthy human body, make it to mix with 0.38% Trisodium Citrate of 1/10th volumes, and with mixture with 700 * G centrifugal treating 10 minutes, make and be rich in hematoblastic blood plasma (PRP).In this PRP, add the ACD solution (2.2% Trisodium Citrate, 0.8% citric acid and 2.2% glucose are newly joined before the use) of sixth volume, and with mixture with 1500 * G centrifugal treating 10 minutes, make the thrombocyte microsphere.Then, the thrombocyte microsphere is suspended in improvement HEPES-Tyrode solution (135mM NaCl, 2.7mMKCl, 1mM MgCl 2, 0.1mg/ml glucose, 20mM HEPES, PH7.4).In this suspension, add the ACD solution of sixth volume, and whole suspension is with the further centrifugal treating of 1500 * G 5 minutes, to produce the thrombocyte microsphere.This thrombocyte microsphere is suspended in the HEPES Tyrode solution of improvement then, makes about 3 * 10 5The washed platelet suspension of/μ l.
(2) measurement of platelet aggregation effect
In 270 μ l washing platelet suspension, add 3 μ l and wait to try compound and be dissolved in the solution that suitable medium is become with different concns, and with this mixture 37 ℃ of following preincubation 2 minutes.Behind the 20 μ g/ml collagen solutions that add 30 μ l, (HEMA Tracer 601, Niko Bioscience produces) measures absorbancy with 4 passage aggegation analysers.
Wait to try the mensuration of compound effect
As a comparison, use not contain and waits that the test(ing) medium that tries compound carries out above-mentioned steps, measure and add the extinction amount before the collagen and add maximum extinction amount after the collagen, and the difference of getting these two kinds of extinction amounts is as 100% aggegation.
Treat examination compound measurement interpolation collagen extinction amount before and add collagen maximum extinction amount afterwards, and compare, determine restraining effect per-cent with simultaneous test.To produce 50% and inhibitingly wait to try compound concentration with IC 50Expression.
The inhibition of calmodulin dependency phosphodiesterase
(1) calmodulin dependency phosphodiesterase (Ca 2+PDE) preparation
With DEAE-gelose column chromatography purification calmodulin dependency phosphodiesterase Ca from rat brain 2+PDE.
(2) preparation of calmodulin
With the calmodulin inhibitor W-7 affinity post calmodulin of from the calf brain, purifying.
(3) Ca 2+The active measurement of PDE
Contain 20 μ l500mM tris-HCl(PH8.0 in the reaction mixture), 20 μ l50mM MgCl 2, 20 μ l2mM CaCl 2(or 10mM EGTA), 20 μ l1mg/ml bovine serum albumin(BSA)s, PDE, 200mg calmodulin, treat test agent and make cumulative volume reach the distilled water of 200 μ l.The 4 μ M of interpolation 20 μ l in this mixture ( 3H)-and cGMP(2.5 μ Ci/ml), in this mixture of 30 ℃ of following incubations 15 minutes, heating 3 to 5 minutes in boiling water then with termination reaction, and was cooled off in ice-water bath.20 μ g5 '-phosphonucleases (snake venom) are added in this mixture, and again with this mixture 30 ℃ of following incubations 10 minutes.After adding about 2ml water, sample is coated onto on the cation exchange resin column (Biorad AGAG50W-X4), with absorption ( 3H)-guanosine-, and sample washing water that again will about 2ml are added on the post.With about 20ml water post is washed, and with absorbed ( 3H)-the guanosine-3N NH of 3ml 4OH carries out wash-out, directly receives effluent with phial.Measure radioactivity through adding 10ml emulsification scintillation solution (ACS-II AMERSHAM) afterwards, uses scintillometer LS7500(Beckmann).Enzymic activity under existing with calmodulin does 0%, and will with μ M be unit wait that trying compound produces 50% concentration that suppresses and be expressed as IC 50
The results are shown in following table.
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
1
2 47
3
4 12 53
5
6
7 1.6 13
8 1.8 51
9
10 6.4 37
11 59
12
13 1.2 15
14
15 43
16
17
18
19 22 20
20 1 23
21
22 1.8
23 0.25 66
24 8.3 63
25 0.55 70
26 10
27
28
29 7.6 73
30
31 24±7.0
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
32
33 21
34 1.8
35 6.9
36 0.81 10.5
37 4.4 29
38 8.1
39
40 4.7
41 1.8 10
42 6.2
43 0.36 3.8
44
45 7.5
46 4 36
47 0.39 18
48 3.9 6.5
49 0.92
50 0.67 70 11
51 0.17 38
52 9.9
53 1.3
54 1.7
55 8.6
56 1.2 39
57 0.75 50
58 0.25 63
59
60 10
61 10
62 2.3
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
63
64
65
66
67 2.2 3.6
68 3.3±1.4 6
69 14
70
71 14 93
72 4 6.2
73 14 21
74 2.8
75 9.7
76 2.9
77 1.4
78 1.8
79 5.5
80 2.4 13
81 1.7 32
82 0.86 33
83 0.39 24
84 43
85 75
86 13 24
87 1.7 1.9
88 4.3 14
89
90 0.33 3.4
91 1.1 10
92 63
93 0.31 3.4
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
94
95
96
97 39
98 22
99 2.8 61
100 95
101 29
102 24
103
104
105 5.4 12
106 8.9 28
107
108 1.2 10
109 0.59 1.3
110 3.8 9.3
111 7.0 77
112
113 0.88 20 1.2
114 54 100
115
116 1.5
117
118
119 11 51
120 19±3.0
121
122
123 4.8 22
124 11
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
125 9.2
126 10
127 39
128 1.8
129 0.82
130 13
131 1.5
132
133
134
135
136
137
138
139
140
141
142 6.8 1.1
143 0.82 1.5
144 1.8 1.0
145 12
146 2.8
147 1.2 42
148
149
150
151
152
153 1.5 25
154 60
155 4.1 55
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
156 4.4 19 19
157 3.2 36 8.6
158 17 21
159 5.1 24 92
160 1.8 56
161 4.7
162 35
163 31
164 4.1
165 11
166 1.4 90
167 1.2 52
168 3.6 26
169 4.6
170 5.2
171 5.4
172 1.0 51 9.4
173
174 11
175 2.0 13
176 1.2 55 8.5
177 2.7 56 24
178 2.4 50
179 2.8 51 7.8
180 1.8 4.8
181 8.4 38 4.7
182 17
183 2.8
184 2.8 12
185 0.21
186
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
187
188 4
189-I 0.22 2.7
189-II 0.20
189-III 0.29 1.0
190 0.19
191 1.9 26
192 0.12 84
193 3.2 12
194 80
195
196
197
198
199
200
201 3.2
202 1.3
203
204
205
206
207
208
209
210
211
212
213
214
EXAMPLE V .R. (ED 50) P.A. (IC 50) Ca 2+PDE (IC 50)
Numbering (μ M) (μ M)
215
216
Test-results shows, other compound of the invention described above has the platelet aggregation restraining effect, also have restraining effect to protein kinase A, myosin light chain kinase, protein kinase C, calmodulin deopendent protein kinase I1, cyclic amp dependency phosphodiesterase etc., but little to the influence of cardiac stimulant function.
As by the The above results finding, The compounds of this invention has smooth muscle relaxation as mentioned above, thereby can be used as vasodilator or cerebral circulation improves medicine; Because The compounds of this invention has the platelet aggregation restraining effect, so can be used as thrombotic preventive or therapeutical agent.In addition, because The compounds of this invention is inhibited to various kinases, so can be used as antineoplastic agent.Above-claimed cpd toxicity is low, thus the useful as drug preparation.

Claims (2)

1, by the compound of logical formula I representative or the preparation method of its quaternary ammonium salt or other salt, formula I is:
Y represents N or H in the formula 3C-N;
R 1Represent a hydrogen atom, an optional low alkyl group that replaces, a formyl radical, a fontanel for phenyl propargyl, an optional aralkyl that replaces or any phenyl that replaces; And
R 3Represent a hydrogen atom, an optional low alkyl group that replaces, a formyl radical, a halogenophenyl propargyl, an optional aralkyl that replaces or the optional phenyl that replaces; Perhaps R 1And R 3Low-grade alkylidene of common formation;
R 4Represent a hydrogen atom or a low alkyl group;
R 5Represent a hydrogen atom, halogen atom, nitro, low alkyl group, any substituted hydroxy, one choose the amino that on nitrogen, replaces, optional carboxyl, a polyfluoro low alkyl group, a cyano group, a methylol, a cyano group, a methylol, methyl thio group, methylsulfinyl or a methyl sulphonyl that replaces wantonly;
R 6Represent a hydrogen atom, halogen atom or a lower alkoxy; Perhaps
R 5And R 6Rudimentary alkylene dioxo base of common formation;
R 7Represent a hydrogen atom or a lower alkoxy;
X represents a vinylene or an ethynylene;
Ar represents a phenyl, a naphthyl or a heterocyclic radical;
M represents 1 to 3 integer; Simultaneously
W represents a low-grade alkylidene, an optional phenylene that replaces or optional phenylene one low-grade alkylidene that replaces;
This method comprises the following steps:
(1) compound of the compound that makes logical formula IV representative and general formula (V) representative reacted 30 minutes to 36 hours in 0 ℃ to 40 ℃, and logical formula IV with (V) is:
Figure 921151012_IMG2
Y, W, R in the logical formula IV 1And R 3Definition the same; B representative-CH in the general formula (V) 2-Hal or=CO-R, Ar, R 5, R 6, R 7, X and m definition the same; And randomly
(2) in 0 ℃ to 25 ℃, with 30 minutes to 2 hours the time chien shih step (1) in prepared compound reduction, and/or randomly
(3) in 0 ℃ to 40 ℃, with 30 minutes to 48 hours the time chien shih step (1) or (2) in prepared alkylation or formylation, and/or
(4) above-mentioned prepared compound is changed into quaternary ammonium salt or other salt.
2, by the compound of logical formula I representative or the preparation method of quaternary ammonium salt or other salt, formula I is:
Figure 921151012_IMG3
Wherein the definition of each symbol is identical with the definition of each symbol in claim 1 formula I; This method comprises the following steps:
(1) compound of the compound of logical formula VI representative and general formula (VII) representative or its derivative that can react or salt were reacted 2 to 20 hours in 0 ℃ to 40 ℃, formula VI and formula (VII) are respectively:
Figure 921151012_IMG4
Figure 921151012_IMG5
Each symbol in its formula of (VI) and (VII) is all identical with the definition of each symbol in claim 1 formula I, and randomly
(2) in 0 ℃ to 40 ℃, with 2 to 20 hours the time chien shih step (1) in prepared alkylation, and/or
(3) make the above-mentioned compound that makes change into quaternary ammonium salt or other salt.
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