CN1742013A - Pyrazolopyrimidine compound and method for producing the same - Google Patents

Pyrazolopyrimidine compound and method for producing the same Download PDF

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CN1742013A
CN1742013A CN 200480002601 CN200480002601A CN1742013A CN 1742013 A CN1742013 A CN 1742013A CN 200480002601 CN200480002601 CN 200480002601 CN 200480002601 A CN200480002601 A CN 200480002601A CN 1742013 A CN1742013 A CN 1742013A
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amino
low alkyl
alkyl group
group
low
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CN100345853C (en
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高室严
关根康雄
坪井康范
能城广司
谷口弘之
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Mitsubishi Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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Abstract

The present invention provides a novel pyrazolopyrimidine compound of the formula [I]: wherein R' is (A) a substituted aryl group, (B) an optionally substituted nitrogen-containing aliphatic heteromonocyclic group, (C) a substituted cyclo-lower alkyl group, (D) an optionally substituted amino group, or (E) a substituted heteroaryl group, R<2> is (a) an optionally substituted heteroaryl group or (b) an optionally substituted aryl group, Y is a single bond, a lower alkylene group or a lower alkenylene group, Z is a group of the formula: -CO-, -CH2-, -S02- or a group of the formula[II]: Q is a lower alkylene group, and q is an integer of 0 or 1 or a pharmaceutically acceptable sait thereof, which has a small conductance potassium channel (SK channel) blocking activity and is useful as a medicament and a process for preparing the same.

Description

Pyrazolopyrimidine compound and preparation method thereof
Technical field
The present invention relates to a kind of new Pyrazolopyrimidine compound and preparation method thereof, this Pyrazolopyrimidine compound is led potassium channel (SK) to little electricity and is had the active and useful as drug of blocking-up.
Background technology
Ca 2+Activated potassium (K) passage comprises at least three seed categories: big electricity is led potassium channel (BK), middle electricity leads potassium channel (IK) and little electricity is led potassium channel.These passages are because of Ca in the cell 2+The rising of level and being activated.Although BK and IK passage are to Ca in the variation of membrane voltage and the cell 2+The rising of level is responsive, but the SK passage is not too responsive to the variation of membrane voltage.In addition, the SK passage is characterised in that, this passage has 6 to 20pS low conductivity for single passage, and apamin is had higher susceptibility.The SK passage does not exist only in for example excitable cell such as neurocyte and myocyte, and being present in for example cell of other kind such as liver cell or hemocyte, it can undertake the various kinds of cell function of the release, Muscle contraction and the secretion that comprise chemokine.
Apamin is known selectivity SK channel blocker, report this reagent activated the gastrointestinal peristalsis function (S.A.Waterman and M.Costa, J.Physiology 477,459-468,1994; N.Spencer etc., J.Physiology 517,889-898,1999), improved cognition/acquistion defective (S.Ikonen etc., Eur.J.Pharmacol.347,13-21,1998; C.Ghelardini etc., Br.J.Pharmacol.123,1079-1084,1998), and in mouse pressure swim test, reduced the dead time (N.Galeotti etc., Br.J.Pharmacol.126,1653-1659,1999).In addition, according to reports, the specific receptors of apamin is present in Skeletal Muscle Cell, and this reagent use the symptom that alleviated the patient who suffers from the myotonic muscular dystrophy (J.F.Renaud etc., Nature 319,678-680,1986; M.I.Behrens etc., Muscle ﹠amp; Nerve 17,1264-1270,1994).In addition, according to reports, under the conditionality overexpression of SK subtype (SK3), mouse demonstrates the paradoxical breathing reaction (C.T.Bond etc., Science 289,1942-1946,2000) to hypoxia.
As having the active compound of SK carrier frequency channel break, two (benzoglyoxaline) compounds are disclosed respectively in international monopoly publication WO00/01676, WO97/48705, U.S. Patent No. 5866562 and WO02/79189, for example 1,1 '-(α, α '-p-Xylol)-3,3 '-(α, α '-m-xylene)-two (benzoglyoxalines); Cyclophane (cyclophan) compound, for example 7,18-diaza-3,4 (1,4)-hexichol-1,6 (1,4)-two quinoline-ring 18 virtues (acyclooctadecaphan) 3 trifluoro-acetate hydrates; Crosslinked two quinoline compounds, for example 1, two (2-methyl-quinolyl-4)-[1,4]-diazepines (diazepane) of 4-and have hexanaphthene-1,1 ' (2 ' H)-spiral shell isoquinoline 99.9 compound partly.
Summary of the invention
The object of the invention provides a kind of new Pyrazolopyrimidine compound and its preparation method, and this Pyrazolopyrimidine compound can be used as and has the active medicine of excellent SK carrier frequency channel break.
The present invention relates to Pyrazolopyrimidine compound or its pharmacologically acceptable salt of a kind of general formula [I]:
Figure A20048000260100171
R wherein 1Be
(A) have substituent aryl,
(B) optionally have substituent nitrogenous aliphatic heteromonocyclic group,
(C) have substituent ring type low alkyl group,
(D) optionally have substituent amino, or
(E) have substituent heteroaryl,
R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl,
Y is singly-bound, low-grade alkylidene or lower alkenylene,
Z be the group shown in the following chemical formula :-CO-,-CH 2-,-SO 2-or
Figure A20048000260100172
Q is a low-grade alkylidene, and q is integer 0 or 1.
R in compound [I] 1Be that (A) has under the situation of substituent aryl, this substituting group can be 1～3 identical or different group, and described substituting group is selected from:
(i) hydroxyl; (ii) halogen atom; (iii) low alkyl group; (iv) amino; this amino optionally has one or two substituting group that is selected from following group: optionally have low alkyl group, lower alkoxy-low alkyl group, the amino low-grade alkane acidyl of hydroxyl substituent, this amino low-grade alkane acidyl optionally has the group shown in low alkyl group, lower alkoxycarbonyl and the following general formula as substituting group:
Wherein, R 31It is low alkyl group in described amino part, (single or two low alkyl groups) amino low alkyl group, (single or two low alkyl groups) carbamyl, the low-grade alkane acidyl that optionally has hydroxyl substituent, the ring type lower alkylcarbonyl, lower alkoxy-low-grade alkane acidyl, lower alkoxy-lower alkoxycarbonyl, ring type low alkyl group-low alkyl group, the low alkyl group alkylsulfonyl, optionally has (single or two low alkyl groups) amino as substituent aryl lower alkyl, rudimentary enoyl-(alkenoyl), optionally has low alkyl group as substituent thiocarbamyl, the heteroaryl carbonyl, has nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group, has nitrogenous aliphatic heteromonocyclic group as substituent low-grade alkane acidyl, optionally has (single or two low alkyl groups) amino at aryl moiety as substituent aryl sulfonyl; Group shown in the following general formula:
Figure A20048000260100182
Wherein, R 32Be lower alkoxy and optionally have low alkyl group as substituent nitrogenous aliphatic heteromonocyclic group; (v) optionally have the substituent lower alkoxy that is selected from following group: optionally have be selected from low alkyl group and aryl lower alkyl group as substituent amino, optionally have a heteroaryl of low-grade alkyl substituent and optionally have the nitrogenous aliphatic heteromonocyclic group of low-grade alkyl substituent; (vi) optionally has a substituent amino-low alkyl group that is selected from following group: the low alkyl group that optionally has hydroxyl substituent; low-grade alkane acidyl; (single or two low alkyl groups) amino-low alkyl group; (single or two low alkyl groups) amino-lower alkoxycarbonyl; lower alkoxy-low-grade alkane acidyl; (single or two low alkyl groups) carbamyl; lower alkoxy-lower alkoxycarbonyl; lower alkoxy-low alkyl group; the ring type lower alkylcarbonyl; aryl lower alkyl; the ring type low alkyl group; ring type low alkyl group-low alkyl group; have nitrogenous aliphatic heteromonocyclic group as the group shown in substituent lower alkoxycarbonyl and the following general formula:
Figure A20048000260100191
Wherein, R 33It is amino, (single or two low alkyl groups) amino or (single or two low alkyl groups) amino-low-grade alkyl amino; (vii) have nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group, described low alkyl group optionally has the substituting group that is selected from following group: hydroxyl, optionally have low alkyl group, lower alkoxy-low alkyl group and a carbamyl of hydroxyl substituent; (viii) optionally has a substituent carbamyl that is selected from following group: low alkyl group, (single or two low alkyl groups) amino-low alkyl group, have the substituent low alkyl group of heteroaryl and have nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group; (ix) optionally has the nitrogenous aliphatic heteromonocyclic group (described nitrogenous aliphatic heteromonocyclic group can be connected to aryl moiety by the Sauerstoffatom key) of low-grade alkyl substituent; (x) nitro; (xi) optionally has (single or two low alkyl groups) amino substituent ring type lower alkoxy; (xii) group that optionally has and be selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group is as substituent low-grade alkylidene; (xiii) the one or more groups that optionally have and be selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group are as substituent low-grade alkynyl; (xiv) optionally has (single or two low alkyl groups) amino substituent low alkyl group sulfenyl; (xv) optionally has (single or two low alkyl groups) amino substituent ring type low alkyl group-lower alkoxy in ring type low alkyl group part.
R in compound [I] 1Be that (B) optionally has under the situation of substituent nitrogenous aliphatic heteromonocyclic group, described substituting group can be the one or more groups that are selected from following group: low alkyl group; Has the substituent low-grade alkane acidyl of nitrogenous aliphatic heteromonocyclic group; (single or two low alkyl groups) amino-low-grade alkane acidyl; Lower alkoxy-low alkyl group; (single or two low alkyl groups) amino-low alkyl group; The ring type low alkyl group; Heteroaryl; Nitrogenous aliphatic heteromonocyclic group optionally comprises one or more pairs of keys and optionally has the one or more substituting groups that are selected from following group: low alkyl group, lower alkoxy-low alkyl group, carbamyl and low-grade alkane acidyl-amino in the ring of this nitrogenous aliphatic heteromonocyclic group; And optionally has the one or more substituent amino that is selected from following group: low alkyl group, (single or two low alkyl groups) amino, ring type low alkyl group-carbonyl, rudimentary enoyl-, hetero-aromatic ring base carbonyl, lower alkoxy-low alkyl group, low-grade alkane acidyl and nitrogenous aliphatic heteromonocyclic group.
R in compound [I] 1Be that (C) has under the situation of substituent ring type low alkyl group, this substituting group can be selected from the one or more groups in the following group: (i) optionally have the substituent amino that is selected from following group: low alkyl group; (single or two low alkyl groups) amino-low-grade alkane acidyl; has the substituent low-grade alkane acidyl of nitrogenous aliphatic heteromonocyclic group; (single or two low alkyl groups) amino-low alkyl group; low-grade alkane acidyl; the ring type lower alkylcarbonyl; rudimentary enoyl-; the heteroaryl carbonyl; optionally have one or more halogen atoms as substituent aryl carbonyl; low alkyl group-thiocarbamyl; elementary alkoxy carbonyl; the ring type low alkyl group; group shown in the following general formula:
Figure A20048000260100201
Wherein, R 34Be (single or two low alkyl groups) amino, ring type low alkyl group-low alkyl group and low alkyl group alkylsulfonyl; (ii) optionally has the substituent amino-low alkyl group that is selected from following group: the low alkyl group that optionally has hydroxyl substituent, (single or two low alkyl groups) amino-low-grade alkane acidyl, has the substituent low-grade alkane acidyl of nitrogenous aliphatics heteromonocyclic group, has the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group, (single or two low alkyl groups) amino-low alkyl group, has the substituent low alkyl group of heteroaryl, lower alkoxy-low alkyl group, low-grade alkane acidyl, heteroaryl carbonyl (heteroaryl moieties of described group optionally has low-grade alkyl substituent), the ring type lower alkylcarbonyl, aryl lower alkyl, the ring type low alkyl group, ring type low alkyl group-low alkyl group, the low alkyl group alkylsulfonyl, elementary alkoxy carbonyl, single or two low alkyl group carbamyl, optionally have be selected from halogen atom and lower alkoxy group as substituent aryl carbonyl, lower alkoxy-low-grade alkane acidyl and low-grade alkane acidyl; (iii) optionally has the one or more substituent nitrogenous aliphatics heteromonocyclic group that is selected from following group: hydroxyl, low alkyl group, low-grade alkane acidyl and lower alkoxy-low alkyl group; (iv) has the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group (described nitrogenous aliphatics heteromonocyclic group optionally condenses with phenyl ring and optionally has a substituting group that is selected from following group: low alkyl group, carbamyl (or thiocarbamyl), hydroxyl, lower alkoxy-low alkyl group, low-grade alkane acidyl and (single or two low alkyl groups) amino); (v) single or two low-grade alkyl amino-lower alkoxies; (vi) optionally have the one or more substituent carbamyl that is selected from following group: have the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group, described low alkyl group optionally has low-grade alkyl substituent; (single or two low alkyl groups) amino; And low alkyl group.
R in compound [I] 1Be that (D) optionally has under the situation of substituent amino, described substituting group can be a low alkyl group.
R in compound [I] 1Be that (E) has under the situation of substituent heteroaryl, described substituting group can be the group that is selected from following group: (i) optionally have the one or more substituent amino-low alkyl group that is selected from low alkyl group and lower alkoxy-low alkyl group; (ii) optionally has the substituent amino that is selected from following group: ring type lower alkylcarbonyl, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, rudimentary enoyl-, (single or two low alkyl groups) thiocarbamyl, (single or two low alkyl groups) carbamyl and low alkyl group; (iii) optionally has the substituent carbamyl that is selected from following group: low alkyl group, have the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group and (single or two low alkyl groups) amino-low alkyl group; (iv) optionally have one or more halogen atoms as substituent low alkyl group; (v) (single or two low alkyl groups) amino-lower alkoxy; (vi) oxo group; (group shown in the vii) following general formula:
Wherein, ring A is nitrogenous aliphatic heteromonocyclic group, and this nitrogenous aliphatic heteromonocyclic group optionally has low-grade alkyl substituent and optionally condenses Y with phenyl ring aBe singly-bound, low-grade alkylidene or lower alkenylene, p is integer 0 or 1.
R in compound [I] 2Be that (a) optionally has under the situation of substituent heteroaryl, described substituting group can be 1～3 identical or different group, and described group is selected from low alkyl group, lower alkoxy and (single or two low alkyl groups) amino.R in compound [I] 2Be that (b) optionally has under the situation of substituent aryl; described substituting group can be 1～3 identical or different group, and described group is selected from low alkyl group, halogen atom, halogenated lower alkoxy, (single or two low alkyl groups) amino, lower alkoxy, nitro, lower alkoxy-low alkyl group, hydroxyl, low-grade alkane acidyl and elementary alkoxy carbonyl.
R 1And R 2In the example of aryl comprise 6 yuan to 10 yuan the monocycle or the aryl of dicyclo, for example phenyl and naphthyl.
R 1And R 2In the example of nitrogenous aliphatic heteromonocyclic group comprise the nitrogenous aliphatic heteromonocyclic group (described cyclic group optionally comprises one or more pairs of keys in ring) of 4 yuan to 8 yuan (preferred 5 yuan or 6 yuan), for example azetidinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl, azatropylidene base, diazepine base, azecine (azeocinyl), two azecines (diazeocinyl), 3-pyrrolinyl or morpholinyl.
R 1And R 2In the example of heteroaryl comprise having list or the bicyclic heteroaryl that is selected from least one heteroatomic 5 yuan to 14 yuan (preferred 5 yuan to 10 yuan) in nitrogen-atoms, sulphur atom and the Sauerstoffatom.This heteroaryl can be: nitrogenous heteroaryl, described nitrogenous heteroaryl is selected from pyrryl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyridyl, dihydropyridine base, pyrazinyl, pyrimidyl, tetrahydro-pyrimidine base, furan pyrimidyl (furopyrimidinyl), pyridazinyl, imidazolidyl, indyl, quinolyl, isoquinolyl, purine radicals, 1H-indazolyl, quinazolyl, cinnolinyl, quinoxalinyl, 2 base and pteridyl; The heteroaryl of perhaps oxygen containing heteroaryl or sulfur-bearing, the heteroaryl of described oxygen containing heteroaryl or sulfur-bearing is selected from furyl, pyranyl, thienyl, benzofuryl and benzo thienyl.
The low-grade alkylidene among the Y and the example of lower alkenylene comprise alkylidene group (for example methylene radical, ethylidene or propylidene) with 1 to 8 carbon atom and the alkenylene (for example vinylidene or propenylidene) with 2 to 8 carbon atoms respectively.
In the target compound of the present invention [I], preferred embodiment is following compound (1) or compound (2), and in compound (1), Y is singly-bound, low-grade alkylidene or lower alkenylene, and Z is-CO-R 2Be have the group that is selected from low alkyl group, lower alkoxy and halogen atom as substituent phenyl, have the substituent heteroaryl of lower alkoxy or have the heteroaryl of low-grade alkyl substituent, and q is an integer 0; In compound (2), Y is a singly-bound, and Z is-CH 2-, R 2Be lower alkoxyphenyl, and q is an integer 0.
In the target compound of the present invention [I], preferred example is following compound: in this compound, and R 1Be that (a) has the substituent phenyl that is selected from following group: (i) lower alkoxy, this lower alkoxy has the substituting group that is selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group, (ii) low alkyl group, this low alkyl group has the substituting group that is selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group, (iii) amino, this amino has the substituting group that is selected from following group: low alkyl group, the ring type lower alkylcarbonyl, (single or two low alkyl groups) amino-low alkyl group, lower alkoxy-elementary alkoxy carbonyl, has the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group, low-grade alkane acidyl and rudimentary enoyl-; (b) have the substituent ring type low alkyl group that is selected from following group: (i) amino low alkyl group, this amino low alkyl group optionally has the substituting group that is selected from following group: low alkyl group, hydroxy lower alkyl, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, ring type lower alkylcarbonyl and lower alkoxy-low alkyl group; The nitrogenous aliphatic heteromonocyclic group that (ii) optionally has hydroxyl substituent; (iii) amino, this amino has the substituting group that is selected from following group: low alkyl group, ring type lower alkylcarbonyl, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, heteroaryl carbonyl, low alkyl group alkylsulfonyl and low alkyl group-thiocarbamyl; Or (c) has a substituent nitrogenous aliphatic heteromonocyclic group that is selected from following group: (i) low alkyl group; (ii) amino, this amino optionally has the substituting group that is selected from low alkyl group, (single or two low alkyl groups) amino-low alkyl group and ring type lower alkylcarbonyl; The nitrogenous aliphatic heteromonocyclic group that (iii) has low-grade alkyl substituent, R 2Be to have the substituent phenyl that is selected from halogen atom and lower alkoxy, have the heteroaryl of low-grade alkyl substituent or have the substituent heteroaryl of lower alkoxy, and Q is a methylene radical.
In above-mentioned preferred compound [I], further preferred compound is following compound: the general formula in this compound: R 1-(O) q-Y-Z-is 4-(single or two low-grade alkyl amino-low alkyl groups) benzoyl; 4-(pyrrolidyl-low alkyl group) benzoyl; 4-(two low-grade alkyl amino-lower alkoxy) benzoyl; 3-(two low-grade alkyl amino-lower alkoxy)-4-(two low-grade alkyl amino-lower alkoxy) benzoyl; 4-(piperidino-(1-position only)-lower alkoxy) benzoyl; 4-[N-low alkyl group-N-(two low-grade alkyl amino-low alkyl group)-amino] benzoyl; 4-[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group)-amino] benzoyl; Rudimentary enoyl--the N-of 4-[N-(two low-grade alkyl amino-low alkyl group)-amino] benzoyl; 4-[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-(lower alkoxy-elementary alkoxy carbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-low-grade alkane acidyl-N-(pyrrolidyl-low alkyl group) amino] benzoyl; [1-(low alkyl group) piperidin-4-yl]-carbonyl; 4-[N-low alkyl group-N-(two low-grade alkyl amino-low alkyl group) amino]-piperidino carbonyl; 4-[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino]-piperidino carbonyl; 4-[4-(two low alkyl group) piperidino-(1-position only)]-the piperidino-(1-position only) carbonyl; [1-(low alkyl group) piperidin-4-yl] low-grade alkane acidyl; [1-(low alkyl group) piperidin-4-yl] rudimentary enoyl-; 4-(two low-grade alkyl amino-low alkyl group) cyclohexyl-carbonyl; 4-(single or two low-grade alkyl aminos) cyclohexyl-carbonyl; 4-[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group) amino]-cyclohexyl-carbonyl; Rudimentary enoyl--the N-of 4-[N-(two low-grade alkyl amino-low alkyl group)-amino] cyclohexyl-carbonyl; 4-[N-heteroaryl carbonyl-N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; 4-[N-low alkyl group sulfo-carbamyl-N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; 4-[N-(two low-grade alkyl amino-low alkyl group)-N-(low alkyl group alkylsulfonyl) amino] cyclohexyl-carbonyl; 4-[[N-low alkyl group-N-(hydroxy lower alkyl) amino] low alkyl group] cyclohexyl-carbonyl; 4-[[N-low alkyl group-N-(lower alkoxy-low alkyl group) amino] low alkyl group] cyclohexyl-carbonyl; 4-[[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group) amino]-low alkyl group] cyclohexyl-carbonyl; 4-[[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] low alkyl group] cyclohexyl-carbonyl; 4-(pyrrolidyl)-cyclohexyl-carbonyl; 4-(hydroxyl pyrrolidine base) cyclohexyl-carbonyl; Or 4-(piperidino-(1-position only)) cyclohexyl-carbonyl, and, R 2Be to have one or two the substituent phenyl that is selected from oxyethyl group and fluorine atom; The ethoxy pyridine base; Propyl group pyridyl or propyl group thiazolyl.
In the above-mentioned further preferred compound [I] of the present invention, particularly preferred example is following compound: in this compound, and R 2Be 3-phenelyl, 6-propyl group pyridine-2-base, 6-ethoxy pyridine-2-base, 2-propyl group-1,3-thiazoles-4-base or 3-oxyethyl group-2-fluorophenyl.
The particularly preferred examples of the compound include the following compounds or a pharmaceutically acceptable Salt: 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [2 - (dimethylamino) ethoxy] benzoyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [2 - (1 - piperidinyl) ethoxy Yl] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - (dimethylaminomethyl) benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (diethylamino) benzoyl] piperazine-1 - Yl]-1H-pyrazolo - [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (1 - methyl-pyrrolidinyl) Benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - [N-(cyclopropylcarbonyl)-N-[2 - (dimethylamino) ethyl] - amino] benzoyl] piperazine Triazine-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-[(2 - methyl oxy Ethoxy) carbonyl]-N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazole And [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-isobutyl-N-[2 - (dimethylamino) Ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [(1 - propyl-piperidin-4 - yl) carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - Ethoxy-benzyl) -4 - [4 - [3 - (1 - isopropyl-piperidin-4 - yl) propionyl]-piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans 4 - (dimethylaminomethyl) cyclohexyl]-carbonyl Yl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans 4 - (1 - Pyrrolidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-phenyl Methyl) -4 - [4 - [(E) -3 - (1 - isopropyl-piperidin-4 - yl) acryloyl]-piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [3 - (dimethylamino) -2,2 - dimethyl-propoxy Yl] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl Yl] -4 - [4 - [4 - [3 - (dimethylamino) -2,2 - dimethyl-propoxy] benzoyl] piperazin-1 - yl]-1H- Pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-acetyl-N-[2 - (1 - pyrrolidin- Yl) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-phenyl Methyl) -4 - [4 - [4 - [N-acetyl-N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (ethylamino methyl) benzoic Benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [(trans-4 - Piperidino cyclohexyl) carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [[trans 4 - ((3S) -3 - hydroxy-1 - pyrrolidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazole And [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [N-acetyl-N-[2 - (dimethylaminoethyl Yl) ethyl] amino] - cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy Methyl-phenyl) -4 - [4 - [[trans-4 - [N-(2 - furoyl)-N-[2 - (dimethylamino) ethyl] amino] Ring Hexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [[trans-4 - [N-(crotonic acid)-N-[2 - (dimethylamino) ethyl] amino] cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [N-(methyl Carbamoyl-ylthio)-N-[2 - (dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [4 - [N - Pakistan Soybean acyl-N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans 4 - (1 - pyrrolidinyl) cyclohexyl] Carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl Yl] -4 - [4 - [[trans 4 - (1 - pyrrolidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans 4 - (diethyl aminomethyl) cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans- 4 - [N-isopropyl-N-(2 - methoxyethyl) aminomethyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazol Pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [4 - [2,2 - dimethyl- -3 - (two Methylamino) propoxy] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl Pyridin-2 - yl) methyl] -4 - [4 - [[trans 4 - (propylamino) cyclohexyl] carbonyl] - piperazin-1 - yl]-1H-pyrazol Pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [[trans 4 - (propylamino) Cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl Yl] -4 - [4 - [[trans 4 - (1 - piperidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans 4 - (1 - piperidinyl) cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [[trans-4 - (1 - Piperidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [[trans 4 - (ethylamino) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [3 - [2 - (diisopropylamino) ethoxy] -4 - [3 - (dimethyl-amino Yl) -2,2 - (dimethyl) propoxy] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - Ethoxy-benzyl) -4 - [4 - [4 - [N-(cyclopropane carbonyl)-N-[2 - (dimethylamino) ethyl] amino] piperidine Piperidino-carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - (3,3 - dimethyl-piperidino) piperidino carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-ethyl-N-[2 - (dimethylamino) ethyl] Amino] piperidino-carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - Yl) methyl] -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-ethyl amino] methyl] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans-4 - [[N-( uncle Butyl)-N-[2 - (methoxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans-4 - [[N-(t-butyl Yl)-N-[2 - (methoxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy- yl) Ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - C -1,3 - Thiazol-4 - yl) methyl] -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy) - ethyl] amino] Methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (hydroxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazine Triazine-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans- 4 - [N-[2 - (dimethylamino) ethyl]-N-(methanesulfonyl) amino] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans- 4 - [N-[2 - (dimethylamino) ethyl]-N-(methanesulfonyl) amino] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [[trans- 4 - [N-[2 - (dimethylamino) ethyl]-N-(methanesulfonyl) amino] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans- 4 - [[N-[2 - (dimethylamino) ethyl]-N-pivaloyl amino] methyl] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans-4 - [[N- (ring Propane-carbonyl)-N-[2 - (dimethylamino) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [N-[2 - (dimethyl- Amino) ethyl]-N-propionylamino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [(trans-4 - piperidin-1 - cyclohexyl) carbonyl] - piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [[trans-4 - [[N-(t- Ding Yl)-N-[2 - (methoxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [4 - (ethylamino) benzoyl] piperazine -1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [4 - [N-acetyl- -N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine. ...
When The compounds of this invention [I] at R 1And/or R 2On substituting group in when having unsymmetrical carbon, owing to have described unsymmetrical carbon in this substituting group, therefore this compound can exist with its steric isomer (diastereomer, optical isomer) form, and the present invention also comprises these steric isomers and its mixture.
Compound of the present invention [I] or its pharmacologically acceptable salt demonstrate significant antagonistic activity for apamin in CBA, apamin is considered to SK channel blocker selectively.For example; to show with result that method identical described in the WO02/079189 (experiment 1) is tested; one of compound of the present invention 1-(3-phenetole methyl)-4-[4-[4-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine demonstrates excellent inhibition apamin bonded activity (IC 50: 0.05 μ M).Therefore, compound [I] or its pharmacologically acceptable salt can be used as the SK channel blocker, it is applicable to and treats and/or prevents the disease that relates to the SK passage, for example gastrointestinal motility disorders (for example constipation, irritable bowel syndrome, gastroesophageal reflux disease, postoperative ileus), central nervous system disorder (for example memory and learning disorder, it comprises Alzheimer (Arzheimer ' s disease), dysthymia disorders), emotional handicap, myotonic dystrophy or sleep apnea.
In addition, The compounds of this invention demonstrates hypotoxicity as medicine, and is safe.
The compounds of this invention [I] can use clinically with free form or with its pharmaceutical acceptable salt.The pharmacologically acceptable salt of compound [I] comprises the inorganic acid salt that forms with mineral acid, for example hydrochloride, vitriol, phosphoric acid salt or hydrobromate; Or the organic acid salt that forms with organic acid, for example oxalate, Citrate trianion, mesylate, benzene sulfonate, tosylate or maleate.In addition, when The compounds of this invention [I] had carboxyl etc. in its molecule, the example of its pharmacologically acceptable salt comprised the salt that forms with alkali, for example an alkali metal salt (for example sodium salt, sylvite) or alkaline earth salt (for example calcium salt).
The salt of compound [I], its salt or its intermediate or its intermediate comprises molecule inner salt or its adducts and its solvate or hydrate.
Can use compound of the present invention [I] or its pharmacologically acceptable salt with oral or parenteral form, and compound of the present invention [I] or its pharmacologically acceptable salt can be mixed with the conventional medicament preparation, for example tablet, granule, microgranules, capsule, pulvis, injection or inhalation.
The dosage of The compounds of this invention [I] or its pharmacologically acceptable salt can change with route of administration and patient's age, body weight and state.For example, when with the injection formulations administration, be generally about 0.0001 to 1mg/kg/ day, preferred about 0.001 to 0.1mg/kg/ day.For example, when with oral preparation drug administration, be generally about 0.001 to 100mg/kg/ day, preferred 0.01 to 10mg/kg/ day.
Embodiment
Can prepare Pyrazolopyrimidine compound of the present invention [I] with following method.
Method A:
In the compound of the present invention [I], following formula [I-A] compound can make by making the reaction of following formula [II] compound or its salt and following formula [III] compound or its salt, and described formula [I-A] compound is:
Figure A20048000260100281
Z wherein aBe chemical formula :-CO-,-SO 2-or=group shown in the C=N-CN, other symbol definition is same as described above, and described formula [II] compound is:
Figure A20048000260100291
Symbol definition wherein is same as described above, and described formula [III] compound is:
R 1-(O) q-Y-Z a-OR 3 [III]
Wherein, R 3Be hydrogen atom, low alkyl group or phenmethyl, other symbol is identical with above-mentioned definition.
Work as R 3When being hydrogen atom, can be in solvent in the presence of condensing agent, exist or do not exist under the situation of activator and alkali and carry out above-mentioned reaction.The example of this solvent comprises any solvent that does not disturb this reaction, for example methylene dichloride, chloroform, N, dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), diox, toluene, benzene, 1,2-ethylene dichloride, 1-Methyl-2-Pyrrolidone and 1,2-glycol dimethyl ether etc.
Described condensing agent comprises: for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (WSCHCl), azido-diphenyl phosphate (DPPA), carbonyl dimidazoles (CDI), diethyl phosphorocyanidate (DEPC), DIC (DIPCI), phosphofluoric acid benzotriazole-1-base-oxygen base-tripyrrole Wan Ji phosphonium salt (PyBOP), the two triazoles of carbonyl, N-carbodicyclo hexylimide-N '-propoxy-methylated polystyrene (PS-carbodiimide), N-oxyethyl group-carbonyl-2-oxyethyl group-1,2-dihydroquinoline (EEDQ), phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea salt (HATU), phosphofluoric acid 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea salt (HBTU), phosphofluoric acid bromine tripyrrole Wan Ji phosphonium salt (PyBroP), Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea salt (TBTU), chlorine metaantimmonic acid chloro-1,1,3,3-tetramethyl-urea salt (ACTU) etc.
The example of described activator comprises I-hydroxybenzotriazole (HOBt), 1-N-Hydroxysuccinimide (HOSu), dimethyl aminopyridine (DMAP), 1-hydroxyl-7-azepine benzotriazole (HOAt), hydroxyphthalimide (HOPht), Pentafluorophenol (Pfp-OH), I-hydroxybenzotriazole-6-sulfonamido methylated polystyrene (PS-HOBt) etc.
Described alkali comprises for example pyridine, triethylamine, diisopropyl ethyl amine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0]-7-undecylene (DBU) etc.
In the aforesaid method, the compound with respect to every mole [III], the usage quantity of compound [II] can be 0.3 to 10 mole, preferred 0.5 to 2 mole.With respect to per 1 mole compound [II] or [III], the usage quantity of condensing agent can be 1 to 10 mole, preferred 1.5 to 4 moles.With respect to per 1 mole compound [II] or [III], the usage quantity of described alkali can be 1 to 10 mole, preferred 2 to 4 moles.With respect to per 1 mole compound [II] or [III], the usage quantity of described activator can be 1 to 10 mole, preferred 1.5 to 4 moles.Described reaction can be carried out at-20 to 80 ℃, and preferably this temperature is 0 to 30 ℃.
Correspondingly, when the R3 in the compound [III] is hydrogen atom, reaction method A in order to preparation compound [I-A] can carry out by the following method: compound [III] is located to be converted into reactive derivatives (for example carboxylic acid halides, mixed acid anhydride) at its carboxyl etc., in described solvent or under solvent-free situation, in the presence of alkali, make this reactive derivatives and compound [II] reaction then.
R in compound [III] 3During for low alkyl group or phenmethyl, this reaction method A also can carry out by the following method: with the acidolysis or the hydrogenation of for example hydrolysis of traditional method, use hydrochloric acid, formic acid, trifluoroacetic acid etc., this compound [III] is converted into corresponding carboxylic acid (sulfonic acid or imino-acid) compound, and makes this carboxylic acid cpd and compound [II] reaction with aforesaid method.
In addition, the R in compound [III] 3During for low alkyl group or phenmethyl, this reaction method A also can carry out by the following method: in solvent or under solvent-free situation, make ester cpds [II] and compound [III] direct reaction in the presence of alkali.The example of described solvent comprises any solvent that does not disturb this reaction, for example methylene dichloride, chloroform, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox, toluene, benzene, 1,2-ethylene dichloride, 1-Methyl-2-Pyrrolidone, methyl alcohol, ethanol and Virahol etc.Described alkali comprises for example triethylamine, diisopropyl ethyl amine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] undecylene (DBU), dimethyl aminopyridine (DMAP) etc.
In the aforesaid method, with respect to every mole compound [II], the usage quantity of compound [III] can be 0.3 to 10 mole, preferred 0.5 to 2 mole.With respect to per 1 mole compound [II] or [III], the usage quantity of described alkali can be 1 to 10 mole, preferred 1 to 4 mole.This reaction can be carried out at 25 to 150 ℃, and preferably this temperature is 60 to 100 ℃.
Method B:
In the compound of the present invention [I], following formula [I-B] compound (is that Z in the compound [I] is-CH 2The compound in-time) can make by make the reaction of compound [II] or its salt and following formula [IV] aldehyde cpd (lower alkanols alkanal or aryl-lower alkanols alkanal) in solvent, in the presence of reductive agent, described formula [I-B] compound is:
Figure A20048000260100311
Wherein symbol definition is same as described above, and described formula [IV] aldehyde cpd is:
R 1-(O) q-Y-CHO [IV]
Wherein symbol definition is same as described above.
The example of described solvent comprises any solvent that does not disturb this reaction, for example methylene dichloride, chloroform, 1,2-ethylene dichloride, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, diox, toluene, benzene, methyl alcohol, ethanol, Virahol, acetate etc.Described reductive agent comprises for example the triethyl ammonium methyl of macroporosity-polystyrene cyano group hydroborate (MP-Cyanoborohydride), sodium borohydride, triacetyl oxygen base sodium borohydride, cyano group sodium borohydride etc.With respect to per 1 mole compound [II], the usage quantity of this reductive agent can be 1 to 10 mole, preferred 1 to 4 mole.This reaction can be carried out at-20 to 100 ℃, and preferably this temperature is 0 to 40 ℃.
Method C:
In the The compounds of this invention [I], following formula [I-C] compound can make by making following formula [V] carboxylic acid cpd or its salt and following formula [VI] amine compound or its reactant salt, and described formula [I-C] compound is:
Figure A20048000260100312
Wherein, R 11For optionally having the substituent amino that is selected from following group: low alkyl group, (single or two low alkyl groups) amino-low alkyl group and have the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group, Z aBe chemical formula :-CO-,-SO 2-or=group shown in the C=N-CN, other symbol definition is same as described above, and described formula [V] carboxylic acid cpd is:
Figure A20048000260100321
Wherein symbol definition is same as described above, and described formula [VI] amine compound is:
R 11-H [VI]
R wherein 11Define same as described above.This reaction can be in solvent in the presence of condensing agent, under the situation that has or do not exist activator and alkali, carry out.The example of described solvent, condensing agent, activator and alkali comprises solvent, condensing agent, activator and the alkali that exemplifies among the method A.
With respect to per 1 mole compound [VI], the usage quantity of compound [V] can be 0.5 to 3 mole, preferred 1 to 2 mole.With respect to per 1 mole compound [V] or [VI], the usage quantity of condensing agent can be 1 to 10 mole, preferred 1.5 to 4 moles.With respect to per 1 mole compound [V] or [VI], the usage quantity of described alkali can be 1 to 10 mole, preferred 2 to 4 moles.With respect to per 1 mole compound [V] or [VI], the usage quantity of described activator can be 1 to 10 mole, preferred 1.5 to 4 moles.This reaction can be carried out at-20 to 80 ℃, and preferably this temperature is 0 to 30 ℃.
Method D:
In the The compounds of this invention [I], following formula [I-D] compound can make by following formula [VII] compound and following formula [VIII] compound or its salt are reacted, perhaps can make by making the reaction of following formula [II] compound or its salt and following formula [IX] compound, described formula [I-D] compound is:
Figure A20048000260100322
Wherein, R 12Be optionally to have substituent nitrogenous aliphatic heteromonocyclic group or optionally have substituent amino, other symbol definition is same as described above, and described formula [VII] compound is:
Wherein, W 2Be reactive residue, other symbol definition is same as described above, and described formula [VIII] compound is:
Wherein, symbol definition is same as described above, and described formula [II] compound is:
Figure A20048000260100332
Wherein, symbol definition is same as described above, and described formula [IX] compound is:
Figure A20048000260100333
Wherein symbol definition is same as described above.
Can in solvent, in the presence of alkali, carry out from compound [VII] and [VIII] or from the reaction of compound [II] and [IX] preparation compound [I-D].Described solvent comprises any solvent that does not disturb this reaction, for example chloroform, methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), diox, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, dimethyl sulfoxide (DMSO), toluene etc.Described alkali comprises for example triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine etc.With respect to per 1 mole compound [VII] or [IX], the usage quantity of compound [VIII] or [II] can be 0.8 to 3 mole, preferred 1 to 1.5 mole.With respect to per 1 mole compound [II] or [IX], the usage quantity of described alkali can be 1 to 4 mole, preferred 2 to 3 moles.This reaction can be carried out at 25 to 150 ℃, preferably carries out at 60 to 120 ℃.
Simultaneously, compound [IX] can make by making compound [II] and the reaction of following formula [X] compound (phosgene, phosgene precursor, phosgene equivalent etc.), and described formula [X] compound is:
Wherein, W 1And W 2It is reactive residue.
In addition, can make compound [IX] by making compound [VIII] and compound [X] reaction.In the compound [X], W 1Or W 2The reactive residue of representative can be halogen atom, phenoxy group, p-nitrophenyl oxygen base, lower alkoxy or nitrogenous fragrant heteromonocyclic group (5 yuan or 6 yuan of heteroaryls for example comprising at least one nitrogen-atoms are as pyridyl).
Can in solvent, in the presence of alkali, be prepared the reaction of compound [VII] or [IX].Described solvent and alkali comprise from compound [VII] and [VIII] or the solvent and the alkali that use from the reaction of compound [II] and [IX] preparation compound [I-D].Described phosgene precursor is for example triphosgene, trichloromethylchloroformate (phosgene dimer) etc.Described phosgene equivalent for example comprise p-nitrophenyl chloroformate ester, diethyl carbonate, 1,1 '-carbonyl dimidazoles, chloroformic acid diphenyl ester, diethyl carbonate, N, N '-two succinimido carbonic ether, two pyridines-2-base carbonic ether etc.
With respect to per 1 mole compound [II] or [VIII], the usage quantity of compound [X] can be 0.2 to 4 mole, preferred 0.4 to 2 mole.With respect to per 1 mole compound [II] or [VIII], the usage quantity of described alkali can be 3 to 6 moles, preferred 3 to 4 moles.This reaction can be carried out at-4 to 40 ℃, preferably carries out at 0 to 30 ℃.
Above-mentionedly can also under the situation of not separating intermediate compound [VII] or [IX], carry out via the reaction that compound [VII] or [IX] prepare compound [I-D] from compound [V].
Target compound of the present invention [I] also can be by at the R of intramolecularly with the above-mentioned compound that obtains [I] 1In substituting group be converted into other the required substituting group in the scope of the invention and make.Can select the intramolecularly conversion method according to the substituent kind of target, for example can carry out intramolecularly and transform with following method (a) to (e).
Method (a):
For target compound of the present invention [I] at R 1In have a following substituent situation: this substituting group contains and has substituent lower alkoxy, and this target compound [I] can prepare by the following method: in the presence of alkali (for example sodium hydride, salt of wormwood), make at R 1In have the substituent compound [I] that contains hydroxyl and have corresponding substituent elementary alkyl halide reaction; Or in appropriate solvent, in the presence of triphenylphosphine and sec.-propyl azodicarboxylate, make at R 1In have the substituent compound [I] that contains hydroxyl and have corresponding substituent low-level chain triacontanol reaction.
Method (b):
For target compound of the present invention [I] at R 1In have following substituent situation: this substituting group contains low-grade alkyl amino, this target compound [I] can prepare by the following method: in the presence of alkali, make to have the substituent respective compound [I] and corresponding elementary alkyl halide reaction that contains primary amino or secondary amino group in appropriate solvent.
Method (c):
For target compound of the present invention [I] at R 1In have the substituent situation that low alkyl group amido etc. for example contains amido, this target compound [I] can prepare by the following method: by with the described identical mode of aforesaid method A, make at R 1In have the substituent respective compound [I] that contains primary amino or secondary amino group and corresponding carboxylic acid or the reaction of thiocarboxylic acid compound.
Method (d):
For at R 1In have the situation of following substituent target compound of the present invention [I]: this substituting group contains the group shown in the following general formula:
Figure A20048000260100351
Wherein, R 13Be hydrogen atom or low alkyl group, R 14And R 15Be can interosculate to form the low alkyl group of cyclic group, n is integer 1 or 2, and this target compound [I] can prepare by the following method: in the presence of alkali, make to have at R in appropriate solvent 1In contain primary amino or secondary amino group substituent respective compound [I] and following formula [X '] compound reaction, products therefrom and formula [XI] amine compound is reacted, described formula [X '] compound is:
Figure A20048000260100352
Wherein, X 1And X 2Be halogen atom, other symbol definition is same as described above, and described formula [XI] compound is:
(R 14)(R 15)NH [XI]
Wherein symbol definition is same as described above.Simultaneously, also this reaction can carried out in single reactor under the situation of not separating intermediate.
Method (e):
For at R 1In have the situation of following substituent target compound of the present invention [I]: this substituting group contains the group shown in the following general formula:
Figure A20048000260100353
Wherein, m is integer 5 or 6, and this target compound [I] can prepare by the following method: in the presence of alkali, make to have to contain amino substituent respective compound [I] and following formula [XII] compound reaction in appropriate solvent, described formula [XII] compound is:
X 3-(CH 2) m-X 4 [XII]
Wherein, X 3And X 4Be halogen atom, other symbol definition is same as described above.
When carrying out aforesaid method A to C and method (a) to (e), when raw material or intermediate compound have functional group, can carry out the protection of functional group and deprotection subsequently according to ordinary method in case of necessity.
The intermediate compound [II] that is used to prepare target compound of the present invention [I] can obtain by the following method: for example; according to the described following method of WO02/79189; compound [XIII] and compound [XIV] are reacted with preparation compound [II-A]; make this product and compound [XV] reaction with preparation compound [II-B], and from products therefrom, remove amino protecting group (G) with traditional method.
Figure A20048000260100361
In the above-mentioned synoptic diagram, G is an amino protecting group, and other symbol definition is same as described above.
Can carry out solvent being arranged or do not have solvent, existence or do not exist under the situation of activator and additive in order to the reaction process of preparation compound [II-A].Described solvent comprises any solvent that does not disturb this reaction, for example dimethylbenzene, chloroform etc.The example of described activator comprises hexamethyldisilazane, N, the two trimethyl silyl ethanamides of O-, chlorine trimethyl silane.Described additive comprises ammonium sulfate, chlorine trimethyl silane, Triethylammonium chloride salt, pyridine hydrochloride salt, triethylamine etc.
Can react by the compound that in appropriate solvent, in the presence of dewatering agent or alkali, makes compound [II-A] and low-level chain triacontanol or have formula [XV] leavings group and prepare compound [II-B]:
R 2-Q-X 5 [XV]
Wherein, X 5Be hydroxyl or leavings group, other symbol definition is same as described above.The example of described solvent comprises any solvent that does not disturb this reaction, for example methylene dichloride, chloroform, 1,2-ethylene dichloride, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-methyl-pyrrolidone, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1,4-dioxane, toluene, benzene etc.Be used for wherein X 5The dewatering agent that is the compound of hydroxyl comprises for example combination of azodicarboxy acid diesters and trisubstituted phosphine or phosphorane etc.Be used for wherein X 5The alkali that is the compound of leavings group (for example halogen atom, low alkyl group sulfonyloxy or aryl-sulfonyl oxygen) comprises for example alkali metal hydroxide (for example lithium hydroxide), alkalimetal hydride, alkaline carbonate, alkali metal lower salt, LDA (LDA) etc.
In the above-claimed cpd [II-B], amino protecting group G comprises for example phenmethyl, elementary alkoxy carbonyl, and this protecting group can be removed with ordinary method.
Can be by making compound [II] and following formula [XVI] compound or for example corresponding carboxylic acid halides (for example acyl chlorides) reaction of its reactive derivatives; and from products therefrom, remove protecting group or the ester residue prepares intermediate compound of the present invention [V] according to ordinary method, described formula [XVI] compound is:
R 16-COOH [XVI]
Wherein, R 16Be to have the carboxyl of protected or esterification as substituent phenyl.
Also can be by at the R of intramolecularly with the above-mentioned compound that obtains 1And/or R 2In substituting group be converted into that other required substituting group prepares target compound of the present invention [I] and raw material of the present invention [III] or [IV] in the scope of the invention.The method of described conversion can be selected according to required substituent kind, and described method comprises for example O-alkylation, reductive amination etc.
If necessary, can the The compounds of this invention [I] that obtain in aforesaid method A to D or the method (a) to (e) be converted into its pharmacologically acceptable salt with ordinary method.
This specification sheets and claim in full in, " low alkyl group " or " lower alkoxy " is meant the straight chain with 1 to 6 carbon atom, preferred 1 to 4 carbon atom or the alkyl or the alkoxyl group of branched chain." low-grade alkane acidyl " is meant to have 2 to 7 carbon atoms, the straight chain of preferred 2 to 5 carbon atoms or the alkyloyl of branched chain." ring type low alkyl group " is meant the cycloalkyl with 3 to 8 carbon atoms, preferred 3 to 6 carbon atoms." low-grade alkenyl " is meant to have 2 to 8 carbon atoms, the straight chain of preferred 2 to 4 carbon atoms or the alkenyl of branched chain." low-grade alkynyl " is meant to have 2 to 8 carbon atoms, the straight chain of preferred 2 to 4 carbon atoms or the alkynyl of branched chain." low-grade alkylidene " is meant to have 1 to 6 carbon atom, the straight chain of preferred 1 to 5 carbon atom or the alkylidene group of branched chain." lower alkenylene " is meant to have 2 to 8 carbon atoms, the straight chain of preferred 2 to 4 carbon atoms or the alkenylene of branched chain.In addition, " halogen atom " is meant fluorine, chlorine, bromine or iodine atom." rudimentary enoyl-" is meant to have 2 to 8 carbon atoms, the straight chain of preferred 3 to 6 carbon atoms or the enoyl-of branched chain." heteroaryl " is meant to have at least one heteroatomic 5 to the 14 yuan of heteroaryl that is selected from nitrogen-atoms, sulphur atom or the Sauerstoffatom, particularly comprises at least one nitrogen-atoms as heteroatomic 5 to 10 yuan monocycle or bicyclic heteroaryl.
Illustrate in greater detail the present invention by the following example and reference example, but should not be construed the present invention only limits to this.
Embodiment 1
To 4-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl] amino] ethyl benzoate (106mg; The compound that obtains in the reference example 11) adds 2N sodium hydroxide solution (21 μ L) in ethanol (3mL) solution, and at room temperature stir the mixture and spend the night.Add 2NHCl (42 μ L) to reaction mixture, and this mixture is concentrated to obtain thick carboxylic acid cpd.Add methylene dichloride (2mL), 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3 successively to this compound, 4-d] pyrimidine dihydrochloride (105mg, be described in the compound of WO02/79189), I-hydroxybenzotriazole (51.7mg), triethylamine (124.5 μ L) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (73.4mg), and at room temperature stirred the mixture 19 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.With flash column chromatography at NH-silica gel (Chromatorex NH silica gel; Fuji SiliciaChemical Ltd.; solvent: ethyl acetate: chloroform=1: 0 → 0: 1) go up the crude product of purifying gained to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (127mg, productive rate: amorphous powder 84%).MS (APCI; The atmospheric pressure chemical ionization mass spectrum) m/z:597[M+H] +
Embodiment 2
To anti-4-(1-pyrrolidyl) hexahydrobenzoic acid hydrochloride (26mg; The compound that obtains in the reference example 87 (2)) adds methylene dichloride (3.5mL), 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3 successively, 4-d] pyrimidine dihydrochloride (30mg), contain the N of 0.5M I-hydroxybenzotriazole, dinethylformamide (219 μ L) solution, triethylamine (35.6 μ L) and N-carbodicyclo hexylimide-N '-propoxy-methyl-polystyrene (310.4mg, PS-Carbodiimide, 0.94mmol/g; And use parallel synthesizer (Quest 210 ArgonautTechnology); Argonaut Technology) in stirring at room mixture 24 hours.The triethyl ammonium methylated polystyrene carbonate from macroporosity to reaction mixture (120mg, the MP-Carbonate 3.04mmol/g that add; Argonaut Technology), and in stirring at room mixture 3 hours.Isolate liquid level from reaction mixture, and use chloroform and methanol wash cull successively.Merge liquid level and elutant and concentrated with centrifugal concentrator.With high performance liquid chromatography (HPLC, XTerra PerpMS C18 post; Waters Inc., solvent: 10mM volatile salt: the crude product of purifying gained methyl alcohol=1: 1 → 5: 95), to obtain 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(1-pyrrolidyl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (27mg, productive rate: amorphous powder 71%).
MS(APCI)m/z：518[M+H] +
IR(Nujol)cm -1；1634，1596，1555，1459
Embodiment 3
To 4-[2-(dimethylamino) oxyethyl group] benzoate hydrochlorate (66mg, the compound that obtains in the reference example 78 (2)) adds methylene dichloride (2mL), 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3 successively, 4-d] pyrimidine dihydrochloride (100mg), I-hydroxybenzotriazole (49.3mg), triethylamine (118.6 μ L) and 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride (70mg), and in stirring at room mixture 17 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, separate and concentrated organic layer.With flash column chromatography NH-silica gel (solvent: ethyl acetate: chloroform=1: 0 → 0: 1) go up crude product that purifying obtains to obtain 1-(3-phenetole methyl)-4-[4-[4-[2-(dimethylamino) oxyethyl group] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (103mg, productive rate: amorphous powder 69%).MS(APCI)m/z：530[M+H] +
Embodiment 4
(1) ice-cooled following to 1-(3-phenetole methyl)-4-piperazine-1-yl]-1H-pyrazolo [3,4-d] drip chlorination terephthalic acid monomethyl ester's (970mg) methylene dichloride (10mL) solution in methylene dichloride (20mL) suspension of pyrimidine dihydrochloride (2g) and triethylamine (2.18mL), and in stirring at room mixture one day.The dilute with water reaction mixture also stirred 30 minutes.Isolate dichloromethane layer and use the chloroform extraction aqueous layer.Combined chloroform layer and dichloromethane layer with the saturated brine washing, are used anhydrous sodium sulfate drying, and are concentrated.With flash column chromatography at silica gel (Biotage Flush 40M; Solvent: ethyl acetate: normal hexane=1: 1) go up this crude product of purifying to obtain 1-(3-phenetole methyl)-4-[4-[4-(methoxycarbonyl) benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d]-pyrimidine (2.4g, productive rate: amorphous powder 98%).MS(APCI)m/z：501[M+H] +
(2) ethanol/tetrahydrofuran (THF) of the compound (2.4g) that obtains to above-mentioned steps (1) (1: 1,25mL) be added dropwise to 10% aqueous sodium hydroxide solution (10mL) in the suspension, and in stirring at room mixture 19 hours.Use the chloroform diluted reaction mixture, with 10% aqueous citric acid solution neutralization, and with chloroform extraction (2 times).With this extract with saturated brine washing, with anhydrous sodium sulfate drying and concentrated.In the thick carboxylic acid cpd (50mg) that obtains, add N successively, the N of N-diethyl ethylenediamine (35.8mg), 0.5M I-hydroxybenzotriazole, dinethylformamide (308 μ L) solution, N-carbodicyclo hexylimide-N '-propoxy-methylated polystyrene (328mg, PS-Carbodiimide 0.94mmol/g).Use parallel synthesizer (Quest 210) at room temperature to stir the mixture 24 hours.To reaction mixture add macroporosity triethyl ammonium methylated polystyrene carbonate (MP-carbonate 3.04mmol/g, 120mg), and in stirring at room mixture 1 hour.Isolate liquid level and use chloroform and this resin of methanol wash successively.Merge elutant and reaction soln and concentrated.With high performance liquid chromatography (XTerra PrepMS C18 post; solvent: 10mM volatile salt: methyl alcohol=80: 20 5: 95) crude product that obtains of purifying is to obtain 1-(3-phenetole methyl)-4-[4-[4-[2-(diethylin) ethyl carbamyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (15.6mg, productive rate: amorphous powder 19%).MS(APCI)m/z：585[M+H] +
(3) compound that dissolving above-mentioned steps (2) obtains in ethanol (1mL), and to wherein adding 2N hydrochloric acid (16 μ L).Evaporating mixture desolvates to remove; and resistates dissolved in water; lyophilize is to obtain 1-(3-phenetole methyl)-4-[4-[4-[2-(diethylin) ethyl carbamyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine hydrochloride amorphous powder.MS(APCI)m/z：585[M+H] +
Embodiment 5
(1) with embodiment 1 in identical method handle the compound that obtains in the reference example 1 (3); thereby obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[3-(dimethylamino) propionyl] N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine amorphous powder.
(2) mixture that the compound (131mg) that obtains in the above-mentioned steps (1) and 24.2mg fumaric acid are formed dissolves in water; and lyophilize is to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[3-(dimethylamino) propionyl]-N-[2-(dimethylamino) ethyl] amino] benzoyl]-piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine fumarate powder.
MS(APCI)m/z：628[M+H] +
Embodiment 6
To the 4-[N-[(2-methoxy ethoxy) carbonyl]-N-[2-(dimethylamino) ethyl] amino] phenyl aldehyde (90mg, the compound that obtains in the reference example 97) adds tetrahydrofuran (THF) (1.5mL), 1-(3-phenetole methyl)-4-(1-piperazinyl)-1H-pyrazolo [3 successively, 4-d] pyrimidine dihydrochloride (100mg), triethylamine (90 μ L), acetate (73 μ L) and macroporosity triethyl ammonium methylated polystyrene cyano group hydroborate (MP-Cyanoborohydride 2.04mmol/g, Argonaut Technology).Use parallel synthesizer (MiniBlock; Mettler Toledo) this mixture of jolting at room temperature is 18 hours.Separate this reaction mixture, and wash remaining resin (3 times) with tetrahydrofuran (THF).Merge elutant and reaction soln and concentrated.With flash column chromatography at silica gel (solvent: ethyl acetate: chloroform=1: 00: 1) go up crude product that purifying obtains) carbonyl to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[(2-methoxy ethoxy]-N-[2-(dimethylamino) ethyl] amino] phenmethyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (159mg, productive rate: amorphous powder 38%).MS(APCI)m/z：617[M+H] +
Embodiment 7 to 83
With with embodiment 1 or embodiment 1 and 4 (2) in identical method handle corresponding raw material to obtain down the compound shown in the tabulation 1.
Table 1 (No.1)
*: hydrochloride
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Table 1 (No.2)
Figure A20048000260100431
*: hydrochloride
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Table 1 (No.3)
Figure A20048000260100441
*: hydrochloride
Me: methyl, Et: ethyl
Table 1 (No.4)
Figure A20048000260100451
Me: methyl, Et: ethyl
Table 1 (No.5)
Figure A20048000260100461
*: hydrochloride
Me: methyl, Et: ethyl
Table 1 (No.6)
Figure A20048000260100471
*: hydrochloride
Me: methyl, Et: ethyl
Table 1 (No.7)
Me: methyl, Et: ethyl
Table 1 (No.8)
Me: methyl, Et: ethyl
Table 1 (No.9)
Figure A20048000260100501
Me: methyl, Et: ethyl
Table 1 (No.10)
Me: methyl, Et: ethyl
Table 1 (No.11)
Figure A20048000260100521
Me: methyl, Et: ethyl
Table 1 (No.12)
Figure A20048000260100531
Me: methyl, Et: ethyl
Table 1 (No.13)
Figure A20048000260100541
*: hydrochloride, Me: methyl, Et: ethyl, Boc: tert-butoxycarbonyl
Table 1 (No.14)
Figure A20048000260100551
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 84 to 92
With with embodiment 2 in identical method handle corresponding raw material, thereby obtain down the compound shown in the tabulation 2.
Table 2
Figure A20048000260100561
Me: methyl, Et: ethyl
Embodiment 93 to 129
With with embodiment 3 or embodiment 3 and 5 (2) in identical method handle corresponding raw material, thereby obtain down the compound shown in the tabulation 3.
Table 3 (No.1)
Figure A20048000260100571
*: fumarate
Me: methyl, Et: ethyl
Table 3 (No.2)
Figure A20048000260100581
*: fumarate
Me: methyl, Et: ethyl, nPr: n-propyl
Table 3 (No.3)
Figure A20048000260100591
Me: methyl, Et: ethyl, nPr: n-propyl
Table 3 (No.4)
Figure A20048000260100601
*: fumarate
Me: methyl, Et: ethyl, nPr: n-propyl
Table 3 (No.5)
*: fumaric acid
Me: methyl, Et: ethyl, nPr: n-propyl
Table 3 (No.6)
Figure A20048000260100621
Me: methyl, Et: ethyl
Embodiment 130 to 133
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 4 with method identical described in embodiment 4 and 5 (2).
Table 4
Figure A20048000260100631
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 134 to 139
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 5 with method identical described in the embodiment 6.
Table 5
Figure A20048000260100641
Me: methyl, Et: ethyl
Embodiment 140 to 181
With with embodiment 1 to 6 in the described identical method of any embodiment handle corresponding raw material, thereby obtain down the tabulation 6 shown in compound.
Table 6 (No.1)
Table 6 (No.2)
Figure A20048000260100661
Table 6 (No.3)
Table 6 (No.4)
*: hydrochloride
Table 6 (No.5)
Table 6 (No.6)
Figure A20048000260100701
Table 6 (No.7)
Figure A20048000260100711
Table 6 (No.8)
Embodiment 182 to 341
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 7 with method identical described in embodiment 1 or embodiment 1 and 4 (3).
Table 7 (No.1)
Figure A20048000260100731
Me: methyl, Et: ethyl
Table 7 (No.2)
Figure A20048000260100741
Me: methyl, nPr: n-propyl
Table 7 (No.3)
Figure A20048000260100751
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.4)
Figure A20048000260100761
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.5)
*: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.6)
Figure A20048000260100781
*: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.7)
*: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.8)
Figure A20048000260100801
*: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.9)
Figure A20048000260100811
*: hydrochloride, * *: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.10)
Figure A20048000260100821
*: hydrochloride, * *: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.11)
Figure A20048000260100831
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.12)
Figure A20048000260100841
*: hydrochloride
Me: methyl, Et: ethyl, nBu: normal-butyl
Table 7 (No.13)
Figure A20048000260100851
*: hydrochloride
Me: methyl, Et: ethyl, Boc: tert-butoxycarbonyl
Table 7 (No.14)
Figure A20048000260100861
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.15)
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.16)
Figure A20048000260100881
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.17)
Figure A20048000260100891
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.18)
Figure A20048000260100901
*: hydrochloride,
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.19)
Figure A20048000260100911
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, nBu: normal-butyl
Table 7 (No.20)
Figure A20048000260100921
*: hydrochloride, * *: dihydrochloride
Me: methyl, Et: ethyl
Table 7 (No.21)
Figure A20048000260100931
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.22)
Figure A20048000260100941
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.23)
Figure A20048000260100951
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 7 (No.24)
Figure A20048000260100961
*: hydrochloride
Me: methyl, Et: ethyl
Table 7 (No.25)
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 7 (No.26)
*: hydrochloride
Me: methyl
Embodiment 342
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 8 with method identical described in the embodiment 2.
Table 8
Figure A20048000260100991
Me: methyl, Et: ethyl
Embodiment 343 to 365
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 9 with method identical described in embodiment 3 or embodiment 3 and 4 (3).
Table 9 (No.1)
Figure A20048000260101001
Me: methyl, Et: ethyl, nPr: n-propyl
Table 9 (No.2)
Figure A20048000260101011
Me: methyl, Et: ethyl, nPr: n-propyl
Table 9 (No.3)
*: dihydrochloride
Me: methyl, Et: ethyl
Table 9 (No.4)
Figure A20048000260101031
*: dihydrochloride, Me: methyl, Et: ethyl
Table 9 (No.5)
*: dihydrochloride, Me: methyl
Embodiment 366
To 4-[N-ethanoyl-N-[2-(1-pyrrolidyl) ethyl] amino] add trifluoroacetic acid (0.2mL) in methylene dichloride (0.2mL) solution of t-butyl perbenzoate (37mg, the compound that obtains in the reference example 107), and this mixture of jolting at room temperature a day.Concentrate this reaction mixture and with resistates successively with chloroform, 4N HCl-diox and chloroform component distillation, to obtain 4-[N-ethanoyl-N-[2-(1-pyrrolidyl) ethyl] amino] the benzoate hydrochlorate.With handling product and 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3 with embodiment 3 described identical methods; 4-d] the pyrimidine dihydrochloride; use then with embodiment 4 (3) described identical methods the product of gained is handled; to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-ethanoyl-N-[2-(1-pyrrolidyl) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (15mg, productive rate: amorphous powder 21%).MS(APCI)m/z：597[M+H] +
Embodiment 367 to 380
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 9.1 with method identical described in the embodiment 366.
Table 9.1 (No.1)
*: hydrochloride
Me: methyl, Et: ethyl
Table 9.1 (No.2)
*: hydrochloride
Me: methyl, Et: ethyl
Table 9.1 (No.3)
Me: methyl, Et: ethyl
Embodiment 381
(1) in 4-hydroxy-benzoic acid (1.06g), adds methylene dichloride (30mL), 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3,4-d] pyrimidine dihydrochlorides (3.02g), I-hydroxybenzotriazole (1.25g), triethylamine (3.7mL) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (1.78g) successively.In stirring at room mixture 17 hours.Use the chloroform diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer, and this organic layer evaporation is desolvated to remove.With flash column chromatography silica gel (solvent: chloroform: methyl alcohol=50: 1) go up resistates that purifying obtains to obtain 1-(3-phenetole methyl)-4-[4-(4-hydroxy benzoyl) piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (2.70g, productive rate: amorphous powder 80%).MS(APCI)m/z：459[M+H] +
(2) at ice-cooled compound (250mg), the 3-dimethylamino-2 that obtains to above-mentioned steps (1) down, drip diisopropyl azo-2-carboxylic acid (330mg) in tetrahydrofuran (THF) (4.0mL) solution of 2-dimethyl-1-propyl alcohol (215mg) and triphenylphosphine (429mg), and in the stirring at room mixture overnight.With methylene dichloride (4mL) diluted reaction mixture, and with Zeo-karb (ISOLUTE SCX; IST Ltd., solvent: methyl alcohol: methylene dichloride=1: 1 1N ammonia/methyl alcohol) handle.With flash column chromatography at silica gel (solvent: chloroform: methyl alcohol=10: 1) go up the crude product that purifying obtains; handle this product to obtain 1-(3-phenetole methyl)-4-[4-[4-[3-(dimethylamino)-2 with the method identical then with embodiment 4 (3); 2-dimethyl propoxy-] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (257mg, productive rate: amorphous powder 78%).MS(APCI)m/z：572[M+H] +
Embodiment 382 to 403
Handling corresponding raw material, thereby obtain down the compound shown in the tabulation 10 with method identical described in the embodiment 381.
Table 10 (No.1)
Figure A20048000260101081
*: hydrochloride
Me: methyl, Et: ethyl
Table 10 (No.2)
Figure A20048000260101091
*: hydrochloride
Me: methyl, Et: ethyl
Table 10 (No.3)
Figure A20048000260101101
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 10 (No.4)
Figure A20048000260101102
*: hydrochloride
Me: methyl, nPr: n-propyl
Embodiment 404
(1) employing is handled respective compound to obtain 1-(3-phenetole methyl)-4-[4-[4-[[1-(tert-butoxycarbonyl) piperazine-4-yl with embodiment 381 described identical methods] the oxygen base] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (34mg, productive rate: amorphous powder 61%).MS(APCI)m/z：642[M+H] +
(2) in methyl alcohol (0.5mL) solution of the compound (34mg) that above-mentioned steps (1) obtains, add 4NHCl-diox (0.1mL), and in the stirring at room mixture overnight.Evaporating this reaction mixture desolvates to remove.Water-soluble and the lyophilize with the resistates of gained is to obtain 1-(3-phenetole methyl)-4-[4-[4-(4-piperidines oxygen base) benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (27mg, productive rate: amorphous powder 79%).MS(APCI)m/z：542[M+H] +
Embodiment 405 to 406
With handling corresponding raw material, to obtain down the compound shown in the tabulation 11 with embodiment 404 described identical methods.
Table 11
Figure A20048000260101111
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 407
With handling 4-[[N-ethyl-N-(tert-butoxycarbonyl) with embodiment 1 identical method] amino methyl] methyl benzoate (230mg; the compound that obtains in the reference example 81); to obtain 1-(3-phenetole methyl)-4-[4-[4-[[N-ethyl-N-(tert-butoxycarbonyl) amino methyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (330mg, 2 step productive rates: amorphous powder 70%).MS(APCI)m/z：600[M+H] +
(2) in diox (2mL) solution of the compound (330mg) that above-mentioned steps (1) obtains, add 4N HCl-diox (4mL), and in stirring at room mixture 6 hours.Add Di Iso Propyl Ether (6mL) to reaction mixture, after the stirring, remove supernatant liquid (repeating this washing procedure once more).With throw out water-soluble (2mL) and to wherein adding saturated sodium bicarbonate (3mL) and chloroform (3mL).After leaving standstill, isolate organic layer and it is concentrated.With flash column chromatography at NH-silica gel (Purif 8Hi-flush/L, MORITEX Inc.; Solvent: normal hexane: the crude product that purification obtains ethyl acetate=65: 35 → 0: 100) is to obtain 1-(3-phenetole methyl)-4-[4-[4-(ethylamino methyl) benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (121mg, productive rate: amorphous powder 44%).MS(APCI)m/z：500[M+H] +
(3) in water (the 500 μ L) suspension of the compound (110mg) that above-mentioned steps (2) obtains, add 2N HCl (220 μ L); and this mixture of lyophilize; to obtain 1-(3-phenetole methyl)-4-[4-[4-(ethylamino methyl) benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d]-pyrimidine dihydrochloride amorphous powder.MS(APCI)m/z：500[M+H] +
Embodiment 408 to 415
With handling corresponding raw material, to obtain down the compound shown in the tabulation 12 with embodiment 407 described identical methods.
Table 12
Figure A20048000260101131
*: dihydrochloride, * * *: tri hydrochloride
Me: methyl, Et: ethyl
Embodiment 416
In the dichloromethane solution of compound (50mg) that embodiment 415 obtains and triethylamine (50mg), add Acetyl Chloride 98Min. (10mg), and in stirring at room mixture 18 hours.With the saturated sodium bicarbonate solution diluted reaction mixture and use chloroform extraction.Evaporating this extract desolvates to remove; and with high performance liquid chromatography (solvent: 10mM volatile salt: the crude product that obtains of purifying methyl alcohol=80: 20 → 5: 95); and use with the described identical method of embodiment 4 (3) handle gained product (1-(3-phenetole the methyl)-anti-4-[N-ethanoyl-N-[2-of 4-[4-[[(dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine); with obtain 1-(3-phenetole methyl)-anti-4-of 4-[4-[[(N-ethanoyl-N-[2-(dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (20mg, productive rate: amorphous powder 40%).MS(APCI)m/z：577[M+H] +
Embodiment 417 to 421
With handling corresponding raw material, to obtain down the compound shown in the tabulation 13 with embodiment 416 described identical methods.
Table 13
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 422
In tetrahydrofuran (THF) (1mL) suspension of the compound (40mg) that embodiment 410 obtains, add salt of wormwood (35mg) and iodoethane (9 μ L) successively, and in the stirring at room mixture overnight.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer and it is concentrated.With high performance liquid chromatography (solvent: 10mM volatile salt: the crude product that obtains of purifying methyl alcohol=80: 20 → 5: 95), then to handle the product that obtains with embodiment 4 (3) described identical methods, thereby obtain amorphous powder 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(N-ethyl-N-methylamino) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (13mg, productive rate: 31%).MS(APCI)m/z：506[M+H] +
Embodiment 423 to 424
With handling corresponding raw material, to obtain down the compound shown in the tabulation 14 with embodiment 422 described identical methods.
Table 14
Figure A20048000260101151
*: dihydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, iPr: sec.-propyl
Embodiment 425
(1) adds triethylamine (44 μ L) and chloroacetyl chloride (9 μ L) in methylene dichloride (1mL) suspension of the compound that in embodiment 411, obtains (50mg) successively, under ice-cooled, stirred the mixture 2 hours.At ice-cooled tetrahydrofuran (THF) (0.3mL) solution that adds the 2M dimethyl amine down to mixture, and in the stirring at room mixture overnight.With chloroform (3mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (5mL).After the stirring, isolate organic layer and it is concentrated.(solvent: 10mM volatile salt: methyl alcohol=80: 20 5: 95) crude product that obtains of purifying is to obtain amorphous powder 1-(3-phenetole methyl)-anti-4-[N of 4-[4-[[with high performance liquid chromatography, N-(dimethyl glycyl) amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (20.4mg, productive rate: 40%).MS (ESI (electro-spray ionization mass spectrum)) m/z:549[M+H] +
(2) use with the described identical methods of embodiment 4 (3) and handle the compound that above-mentioned steps (1) obtain; to obtain amorphous powder 1-(3-phenetole methyl)-anti-4-[N of 4-[4-[[; N-(dimethyl-glycyl) amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (21.5mg, productive rate: 93%).MS(APCI)m/z：549[M+H] +
Embodiment 426 to 433
With handling corresponding raw material, to obtain down the compound shown in the tabulation 15 with embodiment 425 described identical methods.
Table 15 (No.1)
Figure A20048000260101161
*: dihydrochloride
Me: methyl, Et: ethyl
Table 15 (No.2)
Figure A20048000260101171
Me: methyl
Et: ethyl
Embodiment 434
(1) in tetrahydrofuran (THF) (1mL) suspension of the compound (40mg) that embodiment 411 obtains, adds N,N-DIMETHYLACETAMIDE (0.2mL), 1 successively, 5-two iodopentanes (16.6 μ L) and yellow soda ash (28mg).Stirred the mixture 23 hours at 70 ℃.After the cooling, with chloroform (3mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (5mL).After the stirring, isolate organic layer and it is concentrated.With high performance liquid chromatography (solvent: 10mM volatile salt: methyl alcohol=80: 20 5: 95) crude product that obtains of purifying is to obtain 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(piperidino) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (12.9mg, productive rate: 34%).MS(ESI)m/z：532[M+H] +
(2) use with the described identical methods of embodiment 4 (3) and handle the compound that above-mentioned steps (1) obtain, to obtain 1-(3-phenetole methyl) the anti-4-of 4-[4-[[(piperidino) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (15.4mg, productive rate: quantitatively) amorphous powder.MS(APCI)m/z：532[M+H] +
Embodiment 435
With handling corresponding raw material, to obtain down the compound shown in the tabulation 16 with embodiment 434 described identical methods.
Table 16
*: fumarate
Et: ethyl
Embodiment 436 to 442
With handling corresponding raw material, to obtain down the compound shown in the tabulation 17 with embodiment 407 described identical methods.
Table 17 (No.1)
*: dihydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 17 (No.2)
Figure A20048000260101191
*: dihydrochloride,
Et: ethyl, nPr: n-propyl, iPr: sec.-propyl
Embodiment 443 to 500
With handling corresponding raw material, to obtain down compound shown in the tabulation 18 with embodiment 3 described identical methods.
Table 18 (No.1)
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, iPr: sec.-propyl
Table 18 (No.2)
Figure A20048000260101211
*: dihydrochloride
Me: methyl, Et: ethyl
Table 18 (No.3)
Figure A20048000260101212
Et: ethyl
Table 18 (No.4)
*: dihydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 18 (No.5)
Figure A20048000260101231
*: hydrochloride
Me: methyl, Et: ethyl
Table 18 (No.6)
Figure A20048000260101241
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 18 (No.7)
Figure A20048000260101251
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 18 (No.8)
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl
Table 18 (No.9)
*: hydrochloride
Me: methyl, Et: ethyl, nPr: n-propyl, iPr: sec.-propyl
Table 18 (No.10)
Me: methyl, Et: ethyl, nPr: n-propyl
Table 18 (No.11)
Figure A20048000260101291
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 501 to 567
With handling corresponding raw material, to obtain down compound shown in the tabulation 19 with embodiment 1 described identical method.
Table 19 (No.1)
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.2)
Figure A20048000260101311
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.3)
Figure A20048000260101321
Me: methyl, Et: ethyl
Table 19 (No.4)
Me: methyl, Et: ethyl
Table 19 (No.5)
Figure A20048000260101341
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.6)
Figure A20048000260101351
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.7)
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.8)
Figure A20048000260101362
*: hydrochloride
Et: ethyl, n-Pr: n-propyl
Table 19 (No.9)
Figure A20048000260101371
*: hydrochloride
Me: methyl, Et: ethyl
Table 19 (No.10)
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.11)
Figure A20048000260101391
*: dihydrochloride
Me: methyl, Et: ethyl
Table 19 (No.12)
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.13)
Figure A20048000260101411
* hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 19 (No.14)
Figure A20048000260101412
Et: ethyl
Embodiment 568 to 577
With handling corresponding raw material, to obtain down the compound shown in the tabulation 20 with embodiment 381 described identical methods.
Table 20 (No.1)
*: hydrochloride
Me: methyl, Et: ethyl
Table 20 (No.2)
Figure A20048000260101422
*: hydrochloride
Me: methyl, Et: ethyl
Table 20 (No.3)
Figure A20048000260101431
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 578 to 616
With handling corresponding raw material, to obtain down compound shown in the tabulation 21 with embodiment 366 identical methods.
Table 21 (No.1)
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 21 (No.2)
Figure A20048000260101451
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 21 (No.3)
Figure A20048000260101461
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl, i-Bu: isobutyl-
Table 21 (No.4)
Figure A20048000260101471
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 21 (No.5)
Figure A20048000260101481
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 21 (No.6)
Figure A20048000260101491
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 617
(1) use with embodiment 3 described identical methods handle anti-4-[N-methyl-N-(tert-butoxycarbonyl) amino methyl] hexahydrobenzoic acid (compound that obtains in the reference example 239), to obtain amorphous powder 1-(3-phenetole the methyl)-anti-4-[N-methyl-N-of 4-[4-[[(tert-butoxycarbonyl) amino methyl] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine.MS(APCI)m/z：592[M+H] +
(2) use with the described identical methods of embodiment 404 (2) and handle the compound that above-mentioned steps (1) obtain, to obtain amorphous powder 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(methylamino methyl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride.MS(APCI)m/z：492[M+H] +
Embodiment 618
(1) use 3 described identical methods processing 4-[[2-(dimethylamino) ethyls with embodiment] amino]-3-tolyl acid hydrochloride (compound that reference example 251 obtains); to obtain amorphous powder 1-(3-phenetole methyl)-4-[4-[3-methyl-4-[2-(dimethylamino) ethylamino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine.MS(APCI)m/z：543[M+H] +
(2) at 1 of the ice-cooled compound (50mg) that obtains to above-mentioned steps (1) down, 2-ethylene dichloride (1mL) solution adds acetaldehyde (10 μ L), acetate (10 μ L) and sodium triacetoxy borohydride (29mg) successively.In the stirring at room mixture overnight.Further add acetaldehyde (10 μ L), acetate (10 μ L) and sodium triacetoxy borohydride (29mg) successively to reaction mixture.In the stirring at room mixture overnight.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.Concentrate this extract and use high performance liquid chromatography (solvent: 10mM volatile salt: purification resistates methyl alcohol=80: 20 → 5: 95).With handling the product that obtains with embodiment 4 (3) described identical methods; to obtain amorphous powder 1-(3-phenetole methyl)-4-[4-[3-methyl-4-[N-ethyl-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (22mg, productive rate: 37%).MS(APCI)m/z：571[M+H] +
Embodiment 619 to 629
With handling corresponding raw material, to obtain down the compound shown in the tabulation 22 with embodiment 618 described identical methods.
Table 22 (No.1)
Figure A20048000260101501
*: hydrochloride, Et: ethyl, i-Pr: sec.-propyl, i-Bu: isobutyl-
Table 22 (No.2)
Figure A20048000260101511
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl, i-Bu: isobutyl-
Embodiment 630
(1) at 0 ℃ to 1-(3-phenetole methyl)-4-(piperidino)-1H-pyrazolo [3,4-d] add N in methylene dichloride (1.2mL) solution of pyrimidine dihydrochloride (60mg), N-diisopropyl ethyl amine (85 μ L) and chloroformic acid 4-nitro phenyl ester (49mg), and in stirring at room mixture 2.5 hours.With chloroform (1mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (1.5mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, use dried over sodium sulfate, and filter.Concentrate this filtrate and use column chromatography at silica gel (solvent: normal hexane: ethyl acetate=9: 10: 10) go up the purification resistates, to obtain amorphous powder 1-(3-phenetole methyl)-4-[4-[(4-nitro-phenoxy) carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (72mg, productive rate: 100%).MS(APCI)m/z：504[M+H] +
(2) N of the compound solution (25mg) that obtains to above-mentioned steps (1) in room temperature, add N in dinethylformamide (1.5mL) solution, N-diisopropylethylamine (51 μ L) and 4-(1-pyrrolidyl) piperidines (65mg), and stirred the mixture 4 hours at 70 ℃.After the cooling, with chloroform (1mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (1.5mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, use dried over sodium sulfate, and filter.Concentrate this filtrate and use column chromatography at silica gel (solvent: chloroform: methyl alcohol=10: 0 85: 15) go up the purification resistates, to obtain amorphous powder 1-(3-phenetole methyl)-4-[4-[[4-(1-pyrrolidyl) piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (19mg, productive rate: 73%).MS(APCI)m/z：519[M+H] +
(3) use with the described identical methods of embodiment 4 (3) and handle the compound (19mg) that above-mentioned steps (2) obtain, to obtain amorphous powder 1-(3-phenetole methyl)-4-[4-[[4-(1-pyrrolidyl) piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride.MS(APCI)m/z：519[M+H] +
Embodiment 631 to 632
With handling corresponding raw material, to obtain down the compound shown in the tabulation 23 with embodiment 630 described identical methods.
Table 23
Figure A20048000260101521
The * dihydrochloride
Et: ethyl
Embodiment 633
(1) use 1 described identical method processing 4-[[1-(tert-butoxycarbonyl amino methyl)-1-cyclopropyl with embodiment] methoxyl group] methyl benzoate (compound that reference example 235 obtains; 245mg); to obtain 1-(3-phenetole methyl)-4-[4-[4-[[1-(tert-butoxycarbonyl amino methyl)-1-cyclopropyl] methoxyl group] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (380mg, productive rate: colourless liquid 98%).MS(APCI)m/z：642.5[M+H] +
(2) use with the described identical method of embodiment 404 (2) handle the compound (100mg) that obtains in the above-mentioned steps (1) to obtain 1-(3-phenetole methyl)-4-[4-[4-[[1-(amino methyl)-1-cyclopropyl] methoxyl group] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (crude product); and use with embodiment 618 (2) described identical methods and handle product; to obtain 1-(3-phenetole methyl)-4-[4-[4-[[1-(dimethylamino methyl)-1-cyclopropyl] methoxyl group] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (33mg, productive rate: amorphous powder 34%).MS(APCI)m/z：570[M+H] +
Embodiment 634 to 636
With handling corresponding raw material, to obtain down the compound shown in the tabulation 24 with embodiment 633 described identical methods.
Table 24
Figure A20048000260101531
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 637
With handling 1-(3-phenetole methyl)-4-[4-[3-methyl-4-[2-(dimethylamino) ethylamino with embodiment 416 described identical methods] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (compound that obtains among the embodiment 618 (1)); to obtain 1-(3-phenetole methyl)-4-[4-[3-methyl-4-[N-ethanoyl-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (26mg, productive rate: amorphous powder 42%).MS(APCI)m/z：585[M+H] +
Embodiment 638 to 650
With handling corresponding raw material, to obtain down compound shown in the tabulation 25 with embodiment 637 identical methods.
Table 25 (No.1)
Figure A20048000260101541
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 25 (No.2)
Figure A20048000260101551
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 25 (No.3)
Figure A20048000260101552
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 651
(1) uses with embodiment 1 described identical method and handle anti-4-(methoxymethoxy) hexahydrobenzoic acid ethyl ester (compound that reference example 237 obtains, 2.0g), to obtain 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(methoxymethoxy) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (2.88g, productive rate: amorphous powder 78%).MS(APCI)m/z：509[M+H] +
Add concentrated hydrochloric acid (2.0mL) and water (0.2mL) in ethanol (20mL) suspension of the compound (2.8g) that (2) in above-mentioned steps (1), obtains, and stirred the mixture 1 hour at 80 ℃.Use the ether diluted reaction mixture, and by filtering the crystal that collection obtains, to obtain 1-(3-phenetole methyl)-anti-4-hydroxy-cyclohexyl of 4-[4-[() carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (2.81g, productive rate: clear crystal 99%).MS(APCI)m/z：465[M+H] +
Add 2-(dimethylamino) diethylaluminum monochloride hydrochloride (80mg) and sodium hydride (60% mineral oil dispersion liquid in toluene (0.5mL) suspension of the compound (50mg) that (3) in above-mentioned steps (2), obtains, 50mg), and at 100 ℃ stirred the mixture 2 days.Add entry and use the chloroform extraction mixture to reaction mixture.The vacuum concentration extraction liquid, with flash column chromatography at silica gel (solvent: ethyl acetate) go up the purification resistates, use then with embodiment 4 (3) described identical methods and handle the product that obtains, to obtain 1-(3-phenetole the methyl)-anti-4-[2-of 4-[4-[[(dimethylamino) oxyethyl group] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (14mg, productive rate: amorphous powder 24%).MS(APCI)m/z：536[M+H] +
Embodiment 652
With handling 4-[(2S with embodiment 1 described identical method)-2-(tert-butoxycarbonyl amino)-4-methyl pentyloxy] methyl benzoate (compound that reference example 285 obtains; 256mg); to obtain 1-(3-phenetole methyl)-4-[4-[4-[(2S)-2-(tert-butoxycarbonyl amino)-4-methyl pentyloxy] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (400mg, productive rate: colorless oil 99%).MS(APCI)m/z：659[M+H] +
(2) tetrahydrofuran (THF) (3mL) solution at the ice-cooled compound (50mg) that obtains to above-mentioned steps (1) down adds sodium hydride (60% mineral oil dispersion liquid; 10mg), and stirred the mixture 0.5 hour.Drip methyl-iodide (55mg) to mixture, and in stirring at room mixture 3 hours.Add entry and use the ethyl acetate extraction mixture to reaction mixture.Concentrated extract also uses flash column chromatography at NH silica gel (solvent: normal hexane: ethyl acetate=9: 11: 9) go up the purification resistates; to obtain 1-(3-phenetole methyl)-4-[4-[4-[(2S)-2-[N-methyl-N-(tert-butoxycarbonyl) amino]-4-methyl pentyloxy] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (35mg, productive rate: colorless oil 67%).MS(APCI)m/z：672[M+H] +
(3) use with the described identical method of embodiment 404 (2) handle the compound that obtains in the above-mentioned steps (2) to obtain 1-(3-phenetole methyl)-4-[4-[4-[(2S)-2-(methylamino)-4-methyl pentyloxy] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (15mg, productive rate: amorphous powder 46%).MS(APCI)m/z：572[M+H] +
Embodiment 653
With handling corresponding raw material, to obtain down the compound shown in the tabulation 26 with embodiment 652 described identical methods.
Table 26
Figure A20048000260101571
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 654
(1) at-60 ℃ of methylene dichloride (5mL) solution that drip dimethyl sulfoxide (DMSO) (4.55g) with times of 15 minutes to methylene dichloride (50mL) solution of oxalyl chloride (4.48mL).Drip anti-4-(hydroxymethyl) hexahydrobenzoic acid methyl esters (compound that reference example 238 obtains to this mixture with 30 minutes times; 5.9g) methylene dichloride (30mL) solution.Stirred the mixture 1 hour in identical temperature, and at-60 ℃ to wherein dripping triethylamine (16.7mL).Stirred the mixture 30 minutes and stirred 1 hour in identical temperature at 0 ℃.Use the chloroform diluted reaction mixture, and water, 5% citric acid solution, water and saturated brine washing successively.With anhydrous sodium sulfate drying organic layer and vacuum concentration, to obtain anti-4-formyl radical hexahydrobenzoic acid methyl esters (5.32g, productive rate: oily matter 91%).
(2) compound (500mg) that obtains to above-mentioned steps (1) and methylene dichloride (10mL) solution of 3-dimethylamino propylamine (600mg) add sodium triacetoxy borohydride (983mg) and acetate (353mg) successively, and at room temperature stir the mixture 5 days.Use saturated sodium bicarbonate solution neutralization reaction mixture carefully, and with chloroform extraction mixture (2 times).This extraction liquid of vacuum concentration, and with flash column chromatography silica gel (solvent: chloroform: methyl alcohol: 28% ammonia soln=9: 1: 0.1) go up the purification resistates to obtain anti-4-[3-(dimethylamino) third amino methyl] hexahydrobenzoic acid methyl esters (293mg, productive rate: oily matter 32%).MS(APCI)m/z：257[M+H] +
(3) add chloroform (0.5mL) solution and the pyridine (67 μ L) of 2 furoyl chloride (68 μ L) at chloroform (0.5mL) solution of the ice-cooled compound (92mg) that in above-mentioned steps (2), obtains down, and in stirring at room mixture one day.Add saturated sodium bicarbonate solution to reaction mixture, and with chloroform extraction mixture (3 times).Merge organic layer and vacuum concentration.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=9: 11: 1) go up to purify the crude product that obtains to obtain anti-4-[[N-(2-furancarbonyl)-N-[3-(dimethylamino) propyl group] amino] methylcyclohexanecarboxylic acid methyl esters (102mg, productive rate: oily matter 75%).MS(APCI)m/z：373[M+H] +
(4) use with the described identical method of embodiment 1 and handle the compound that obtains in the above-mentioned steps (3); to obtain 1-(3-phenetole methyl)-anti-4-[N-of 4-[4-[[(2-furancarbonyl)-N-[3-(dimethylamino) propyl group] amino methyl] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine hydrochloride amorphous powder.MS(APCI)m/z：657[M+H] +
Embodiment 655 to 670
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27 with embodiment 654 described identical methods.
Table 27 (No.1)
Figure A20048000260101591
*: hydrochloride
Me: methyl, Et: ethyl
Table 27 (No.2)
Figure A20048000260101601
*: hydrochloride
Me: methyl, Et: ethyl
Table 27 (No.3)
Figure A20048000260101611
*: hydrochloride
Me: methyl, Et: ethyl
Table 27 (No.4)
Figure A20048000260101612
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 671 to 703
With with the foregoing description 404,407,617 and 652 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.1.
Table 27.1 (No.1)
Figure A20048000260101621
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.1 (No.2)
*: hydrochloride, * *: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.1 (No.3)
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.1 (No.4)
*: hydrochloride
Me: methyl, n-Pr: n-propyl
Embodiment 704 to 712
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.2 with embodiment 1 described identical method.
Table 27.2 (No.1)
*: dihydrochloride
Me: methyl, Et: ethyl
Table 27.2 (No.2)
Figure A20048000260101671
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 713
(1) uses compound (730mg) and the 4-piperidone monohydrate hydrochloride (1.05g) that obtains with the described identical method Processing Example 630 (1) of embodiment 630 (2), to obtain 1-(3-phenetole methyl)-4-[4-[[4-oxo-piperidine-1-yl] carbonyl] piperidines-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (654mg, productive rate: amorphous powder 97%).MS(APCI)m/z：464[M+H] +
(2) use with the described identical methods of embodiment 6 and handle the compound (50mg) that obtains in the above-mentioned steps (1), to obtain 1-(3-phenetole methyl)-4-[4-[[4-(dimethylamino) piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (15.6mg, productive rate: amorphous powder 30%).MS(APCI)m/z：493[M+H] +
(3) use the method identical to handle the compound (13.8mg) that obtains in the above-mentioned steps (2) with embodiment 4 (3), to obtain 1-(3-phenetole methyl)-4-[4-[[4-(dimethylamino) piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (15.9mg, productive rate: amorphous powder 99.6%).MS(APCI)m/z：493[M+H] +
Embodiment 714
With with the described identical method Processing Example 441 of embodiment 6 in the compound (50mg) that obtains, to obtain 1-(3-phenetole methyl)-anti-4-of 4-[4-[[(N-ethyl-N-n-propyl amino) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (59.3mg; Productive rate: amorphous powder 64%).MS(APCI)m/z：534[M+H] +
Embodiment 715
(1) adds pyridine (6mL) and 1-(3-phenetole methyl)-4-piperazine-1-base-1H-pyrazolo [3 at ice-cooled following methylene dichloride (20mL) solution to 4-fluorobenzene SULPHURYL CHLORIDE (2.1g), 4-d] pyrimidine dihydrochloride (3g), and in stirring at room mixture 16 hours.With chloroform (20mL) diluted reaction mixture.To wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, use anhydrous sodium sulfate drying, and filter.Concentrate this filtrate; and with chromatography silica gel (solvent: normal hexane: ethyl acetate=1: 11: 3) go up the purification resistates to obtain 1-(3-phenetole methyl)-4-[4-(4-fluorobenzene alkylsulfonyl) piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (3.2g, productive rate: amorphous powder 88%).MS(APCI)m/z：497[M+H] +
(2) use with the described identical method of reference example 1 (1) and handle the compound (100mg) that obtains in the above-mentioned steps (1); to obtain 1-(3-phenetole methyl)-4-[4-[4-[[2-(dimethylamino) ethyl] amino] benzenesulfonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (91mg, productive rate: amorphous powder 80%).MS(APCI)m/z：565[M+H] +
Embodiment 716
With with the described identical method Processing Example 715 (2) of embodiment 416 and embodiment 4 (3) in the compound (57mg) that obtains; to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-ethanoyl-N-[2-(dimethylamino) ethyl] amino] benzenesulfonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (51mg, productive rate: amorphous powder 75%).MS(APCI)m/z：607[M+H] +
Embodiment 717
With with the described identical method Processing Example 441 of embodiment 422 (2) in the compound that obtains, use then with embodiment 4 (3) described identical methods and handle the product that obtains, to obtain 1-(3-phenetole the methyl)-anti-4-[N-of 4-[4-[[(2-dimethylamino) ethyl-N-propyl group] amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (3.4mg, productive rate: amorphous powder 6.5%).MS(ESI)m/z：577[M+H] +
Embodiment 718
With handling corresponding raw material, to obtain 1-(3-phenetole methyl)-4-[4-[[4-[[2-(dimethylamino) ethyl with embodiment 713 described identical methods] amino] piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine.With handling product (53mg) with embodiment 416 described identical methods, to obtain 1-(3-phenetole methyl)-4-[4-[[4-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl] amino] piperidines-1-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride (23mg, productive rate: amorphous powder 34%).MS(APCI)m/z：604[M+H] +
Embodiment 719
(1) add phenylbenzene cyano group carbon imines (1.56g) to the methylene dichloride (5mL) of 4-piperidinyl piperidine (1.0g) and Virahol (15mL) solution, and in stirring at room mixture 24 hours.With ethyl acetate (20mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (30mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, with the saturated brine washing, use anhydrous sodium sulfate drying, and filter.Concentrate this filtrate and with column chromatography silica gel (solvent: chloroform: methyl alcohol=9: 15: 1) go up the purification resistates obtaining N-cyano group-1,4-two piperidines-1 '-carbonyl imido acid phenyl ester (2.5g, productive rate: quantitative) amorphous powder.MS(APCI)m/z：313[M+H] +
Add sodium hydride (14.4mg) and 1-(2-fluoro-3-methylbenzene methyl)-4-[4-(piperidino) piperidines-1-yl in tetrahydrofuran (THF) (3mL) solution of the compound (70mg) that (2) in above-mentioned steps (1), obtains] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (60mg), and stirred the mixture 24 hours at 100 ℃.With chloroform (3mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (5mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, use anhydrous sodium sulfate drying, filter and concentrate.(Purif 8 at silica gel with column chromatography, Hi-flash/M, solvent: chloroform: methyl alcohol=100: 0 85: 15) go up the purification resistates to obtain 1-(2-fluoro-3-methylbenzene methyl)-4-[4-[1,4 '-two piperidines-1 '-Ji (cyanoimino) methyl]-1H-pyrazolo [3,4-d] pyrimidine (77.4mg, productive rate: amorphous powder 95%).MS(APCI)m/z：545[M+H] +
Embodiment 720
(1) uses the compound (282mg) that obtains with the described identical method Processing Example 407 of embodiment 719 (1); to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[(cyanoimino) (phenoxy group) methyl]-the N-ethyl] amino] methyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (221mg, productive rate: amorphous powder 69%).MS(APCI)m/z：644[M+H] +
(2) acetonitrile solution of the compound (64mg) that obtains to above-mentioned steps (1) adds the dimethyl amine aqueous solution (241 μ L), and stirs the mixture 16 hours at 100 ℃.After the cooling; concentrate this reaction mixture and use column chromatography at silica gel (Purif8; Hi-flash/M; solvent: chloroform: methyl alcohol=100: 0 90: 10) go up the purification resistates) (dimethylamino) methyl to obtain 1-(3-phenetole methyl)-4-[4-[4-[[N-[(cyanoimino]-the N-ethyl] amino] methyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (51mg, productive rate: amorphous powder 86%).MS(APCI)m/z：595[M+H] +
(3) use with the described identical methods of embodiment 4 (3) and handle the compound (51mg) that obtains in the above-mentioned steps (2); to obtain 1-(3-phenetole methyl)-4-[4-[4-[[N-[(cyanoimino) (dimethylamino) methyl]-the N-ethyl] amino] methyl] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine dihydrochloride (45.8mg, productive rate: amorphous powder 80%).MS(APCI)m/z：595[M+H] +
Embodiment 721
With handling corresponding raw material, to obtain 1-(3-phenetole methyl)-4-[4-[4-[2-(dimethylamino) ethylamino with embodiment 366 described identical methods] benzoyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine.To methyl chloride/Virahol of products therefrom (50mg) (1: 1,1mL) add cyano group carbon imido acid diphenyl ester (25mg) in the solution, and stirred the mixture 6 hours at 50 ℃.With chloroform (2mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (2mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer, use anhydrous sodium sulfate drying, filter and concentrate.With column chromatography at silica gel (Purif8; Hi-flash/M; solvent: chloroform: methyl alcohol=100: 0 90: 10) go up the purification resistates to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[2-(dimethylamino) ethyl]-the N-[(2-propoxy-) (cyanoimino) methyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (44.3mg, productive rate: amorphous powder 69%).MS(APCI)m/z：639[M+H] +
Embodiment 722
(1) uses 3 described identical methods processing hexanaphthenes-1 with embodiment, 4-dicarboxylic acid monomethyl ester (1.0g), to obtain 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(methoxycarbonyl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (1.83g, productive rate: amorphous powder 81%).MS(APCI)m/z：507[M+H] +
(2) use with the described identical method in embodiment 4 (2) and (3) and handle compound and the N that obtains in the above-mentioned steps (1); N; N '-triethyl-1; the 2-quadrol; to obtain 1-(3-phenetole the methyl)-anti-4-[N-ethyl-N-[2-of 4-[4-[[(diethylin) ethyl] carbamyl] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine dihydrochloride amorphous powder.MS(ESI)m/z：619[M+H] +
Embodiment 723
With handling 4-(2-dimethylaminoethyl amino) hexahydrobenzoic acid ethyl ester with embodiment 654 (3) and (4) described identical method; to obtain 1-(6-propyl group-2-pyridylmethyl)-4-[4-[[4-[N-naphthoyl-N-[2-(dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine amorphous powder.MS(ESI)m/z：688[M+H] +
Embodiment 724
(1) in tetrahydrofuran (THF) (1.5mL) solution of 6-chlorine pyridazine-3-carboxylic acid, ethyl ester (37mg), add N, N, N '-trimethyl propane-1,3-diamines (46mg), and in the stirring at room mixture overnight.With tetrahydrofuran (THF) (1.5mL) diluted reaction mixture, and to wherein add MP-Isocyanate (the polystyrene methyl isocyanate, 1.43mmol/g, 400mg).Jolting mixture overnight at room temperature.Filter reaction mixture to be removing resin, and extracts filtrate with chloroform/methanol.Concentrate organic layer to obtain thick 6-[N-(3-dimethylaminopropyl)-methylamino]-3-pyridazine carboxylic acid, ethyl ester.MS(ESI)m/z：267[M+H] +
(2) use with embodiment 1 and embodiment 4 (3) described identical methods and handle the compound that obtains in the above-mentioned steps (1), to obtain 1-(3-phenetole methyl)-4-[4-[[6-[N-methyl-N-[3-(dimethylamino) propyl group] amino] pyridazine-3-yl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine hydrochloride amorphous powder.MS(APCI)m/z：559[M+H] +
Embodiment 725
(1) in methylene dichloride (5mL) solution of compound (500mg) that embodiment 22 obtains and N-phenmethyl oxygen base carbonyl-Beta-alanine (291mg), add diethyl phosphorocyanidate (230 μ L), and in the stirring at room mixture overnight.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.The evaporation organic layer desolvates to remove; and with column chromatography silica gel (solvent: chloroform/methanol=10: 1) go up the purification resistates to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[3-[N '-methyl-N '-(phenmethyl oxygen base carbonyl) amino] propionyl]-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine (431mg, productive rate: yellow liquid 61%).MA(APCI)m/z：748[M+H] +
(2) to methyl alcohol (5mL) the suspension reflux of the compound (480mg), ammonium formiate (81mg) and the 10% palladium-charcoal (100mg) that obtain in the above-mentioned steps (1) 2 hours.Filter reaction mixture and vacuum concentrated filtrate.With column chromatography at silica gel (solvent: chloroform/methanol=5: 1) go up the purification resistates; use then with embodiment 4 (3) described identical methods and handle the product that obtains; to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[3-(methylamino) propionyl]-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (390mg, productive rate: yellow liquid 99%).MA(APCI)m/z：614[M+H] +
Embodiment 726
(1) use anti-4-[(2-nitrophenyl with embodiment 1 described identical method processing 4-[) alkylsulfonyl] piperazine-1-yl] hexanaphthene-carboxylate methyl ester (compound that reference example 310 obtains; 1.29g); to obtain 1-(3-phenetole methyl)-anti-4-[4-[(2-nitrophenyl of 4-[4-[[) alkylsulfonyl] piperazine-1-yl] cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo-[3; 4-d] pyrimidine (1.91g, productive rate: yellow liquid 85%).MS(APCI)m/z：718[M+H] +
(2) at room temperature to the N of compound (1.71g), salt of wormwood (658mg) and the thiophenol (270 μ L) that obtain in the above-mentioned steps (1), dinethylformamide (10mL) suspension stirred 4 hours.Water/ethyl acetate diluted reaction mixture, and with Zeo-karb (SCX-2, IST Ltd., solvent: methanol=1: 1 → 1N ammonia/methyl alcohol) treating mixture, to obtain 1-(3-oxyethyl group-phenmethyl)-anti-4-[[4-of 4-[(1-piperazinyl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (1.09g, productive rate: colorless solid 86%).MS(APCI)m/z：533[M+H] +
(3) at 1 of the ice-cooled compound (50mg) that in above-mentioned steps (2), obtains down, 2-ethylene dichloride (1mL) solution adds formaldehyde solution (15 μ L), acetate (11 μ L) and sodium triacetoxy borohydride (30mg) successively, and in the stirring at room mixture overnight.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.The evaporation organic layer desolvates to remove, and with high performance liquid chromatography (solvent: 10mM volatile salt/methyl alcohol) crude product that obtains of purifying is to obtain 1-(3-phenetole the methyl)-anti-4-of 4-[4-[[(4-methylpiperazine-1-yl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine (47mg, productive rate: colorless solid 92%).MS(APCI)m/z：547[M+H] +
Embodiment 727
Methylene dichloride (3mL) solution of the compound (50mg) that obtains to embodiment 725 adds Vinyl chloroformate (10 μ L) and triethylamine (22 μ L), and in the stirring at room mixture overnight.Also use the chloroform extraction mixture with the saturated sodium bicarbonate solution diluted reaction mixture.The evaporation organic layer desolvates to remove; and with column chromatography at silica gel (solvent: chloroform/methanol=10: 1) go up the purification resistates; with handling the product that obtains with embodiment 4 (3) described identical methods; to obtain 1-(3-phenetole methyl)-4-[4-[4-[N-[3-[N '-methyl-N '-(ethoxy carbonyl) amino] propionyl]-N-[2-(dimethylamino) ethyl] amino] benzoyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (17mg, productive rate: amorphous powder 30%).MS(APCI)m/z：686[M+H] +
Embodiment 728 to 738
With with the foregoing description 416,714,715,716 and 717 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.3.
Table 27.3 (No.1)
Figure A20048000260101731
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.3 (No.2)
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 739 to 745
With with embodiment 1,366 and 407 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.4.
Table 27.4 (No.1)
Figure A20048000260101751
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.4 (No.2)
Figure A20048000260101752
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 746 to 749
With with embodiment 3,407 and 434 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.5.
Table 27.5
Figure A20048000260101761
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 750 to 770
With with embodiment 713 and 718 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.6.
Table 27.6 (No.1)
Figure A20048000260101771
*: hydrochloride, * *: dihydrochloride
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl, n-Bu: normal-butyl
Table 27.6 (No.2)
Figure A20048000260101781
*: hydrochloride
Me: methyl, Et: ethyl
Table 27.6 (No.3)
Figure A20048000260101791
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 771 to 798
With with embodiment 720 and 724 in the described identical method of arbitrary embodiment handle corresponding raw material, to obtain down the compound of tabulation shown in 27.7.
Table 27.7 (No.1)
Figure A20048000260101792
Me: methyl, Et: ethyl
Table 27.7 (No.2)
Figure A20048000260101801
*: hydrochloride
Me: methyl, n-Pr: n-propyl
Table 27.7 (No.3)
*: hydrochloride
Me: methyl, Et: ethyl
Table 27.7 (No.4)
Figure A20048000260101821
*: hydrochloride
Me: methyl, n-Pr: n-propyl
Embodiment 799 to 874
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.8 with embodiment 1 described identical method.
Table 27.8 (No.1)
Figure A20048000260101831
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.8 (No.2)
Me: methyl, n-Pr: n-propyl
Table 27.8 (No.3)
Figure A20048000260101851
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.8 (No.4)
Figure A20048000260101861
Me: methyl, Et: ethyl
Table 27.8 (No.5)
Figure A20048000260101871
Me: methyl, Et: ethyl
Table 27.8 (No.6)
Figure A20048000260101881
Me: methyl, Et: ethyl
Table 27.8 (No.7)
Figure A20048000260101891
Me: methyl, Et: ethyl
Table 27.8 (No.8)
Figure A20048000260101901
Me: methyl, n-Pr: n-propyl
Table 27.8 (No.9)
Figure A20048000260101911
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 875
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.9 with embodiment 3 described identical methods.
Table 27.9
Figure A20048000260101921
Me: methyl
Embodiment 876 to 891
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.10 with embodiment 723 described identical methods.
Table 27.10 (No.1)
*: dihydrochloride
Me: methyl, n-Pr: n-propyl
Table 27.10 (No.2)
Figure A20048000260101941
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 892 to 900
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.11 with embodiment 633 or 726 described identical methods.
Table 27.11
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 901 to 908
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.12 with embodiment 366 described identical methods.
Table 27.12
Figure A20048000260101961
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Embodiment 909 to 915
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.13 with embodiment 719 described identical methods.
Table 27.13
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 916
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.14 with embodiment 720 described identical methods.
Table 27.14
Figure A20048000260101981
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 917 to 927
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.15 with embodiment 722 described identical methods.
Table 27.15 (No.1)
Figure A20048000260101991
*: dihydrochloride
Me: methyl, Et: ethyl
Table 27.15 (No.2)
Figure A20048000260102001
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 928 to 939
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.16 with embodiment 723 described identical methods.
Table 27.16 (No.1)
Figure A20048000260102011
*: dihydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Table 27.16 (No.2)
*: dihydrochloride
Me: methyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Embodiment 940 to 941
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.17 with embodiment 727 described identical methods.
Table 27.17
Figure A20048000260102022
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 942 to 947
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.18 with embodiment 630 described identical methods.
Table 27.18
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 948 to 967
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.19 with embodiment 723 or 725 described identical methods.
Table 27.19 (No.1)
Figure A20048000260102041
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.19 (No.2)
Figure A20048000260102051
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 968 to 969
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.20 with embodiment 720 or 727 described identical methods.
Table 27.20
Figure A20048000260102061
*: dihydrochloride
Me: methyl, Et: ethyl
Embodiment 970 to 989
With handling corresponding raw material, to obtain down compound shown in the tabulation 27.21 with embodiment 723 or 724 described identical methods.
Table 27.21 (No.1)
Figure A20048000260102071
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.21 (No.2)
Figure A20048000260102081
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.21 (No.3)
Figure A20048000260102091
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.21 (No.4)
Figure A20048000260102101
*: hydrochloride
Me: methyl, n-Pr: n-propyl
Embodiment 990 to 994
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.22 with embodiment 713 described identical methods.
Table 27.22
Figure A20048000260102111
*: hydrochloride
Me: methyl, Et: ethyl
Embodiment 995 to 1018
Handle corresponding raw material with the method identical, to obtain down the compound shown in the tabulation 27.23 with embodiment 713.
Table 27.23 (No.1)
Figure A20048000260102121
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Table 27.23 (No.2)
Figure A20048000260102131
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Table 27.23 (No.3)
Figure A20048000260102141
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 1019 to 1040
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.24 with embodiment 718 described identical methods.
Table 27.24 (No.1)
Figure A20048000260102151
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.24 (No.2)
Figure A20048000260102161
*: hydrochloride,
Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.24 (No.3)
Figure A20048000260102171
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1041 to 1048
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.25 with embodiment 1 described identical method.
Table 27.25
Figure A20048000260102181
Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 1049 to 1071
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.26 with embodiment 654 described identical methods.
Table 27.26 (No.1)
Figure A20048000260102191
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Table 27.26 (No.2)
Figure A20048000260102201
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl, t-Bu: the tertiary butyl
Table 27.26 (No.3)
Figure A20048000260102211
*: hydrochloride, Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Table 27.26 (No.4)
Figure A20048000260102221
*: hydrochloride, Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Embodiment 1072 to 1074
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.27 with embodiment 416 described identical methods.
Table 27.27
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1075
With with the described identical method Processing Example 726 (2) of embodiment 416 in the compound (45mg) that obtains; with 1-(3-phenetole the methyl)-anti-4-[[4-of 4-[(4-ethanoyl-piperazine-1-yl) cyclohexyl that obtains being yellow oily] carbonyl] piperazine-1-yl]-1H-pyrazolo [3,4-d] pyrimidine.Subsequently; with handling this compound with embodiment 4 (3) described identical methods; to obtain 1-(3-phenetole the methyl)-anti-4-[[4-of 4-[(4-ethanoyl-piperazine-1-yl) cyclohexyl] carbonyl] piperazine-1-yl]-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (39.8mg, productive rate: amorphous powder 78%).
MS(APCI)：575[M+H] +
Embodiment 1076
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.28 with embodiment 1075 described identical methods.
Table 27.28
Figure A20048000260102241
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1077 to 1078
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.29 with embodiment 637 described identical methods.
Table 27.29
Figure A20048000260102242
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1079 to 1081
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.30 with embodiment 407 described identical methods.
Table 27.30
Figure A20048000260102251
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1082 to 1087
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.31 with embodiment 1 or 3 described identical methods.
Table 27.31
Figure A20048000260102261
*: hydrochloride, Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Embodiment 1088 to 1092
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.32 with embodiment 637 described identical methods.
Table 27.32
Figure A20048000260102271
*: hydrochloride, Me: methyl, Et: ethyl
Embodiment 1093 to 1094
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.33 with embodiment 1 described identical method.
Table 27.33
Figure A20048000260102281
*: dihydrochloride, Me: methyl, Et: ethyl
Embodiment 1095 to 1102
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.34 with embodiment 1 described identical method.
Table 27.34 (No.1)
Figure A20048000260102291
*: hydrochloride, Me: methyl, Et: ethyl
Table 27.34 (No.2)
Figure A20048000260102301
*: dihydrochloride, Me: methyl, Et: ethyl
Embodiment 1103 to 1123
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.35 with embodiment 1 or 637 described identical methods.
Table 27.35 (No.1)
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.35 (No.2)
Figure A20048000260102321
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Table 27.35 (No.3)
Figure A20048000260102331
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Embodiment 1124 to 1125
With handling corresponding raw material, to obtain down the compound shown in the tabulation 27.36 with embodiment 723 described identical methods.
Table 27.36
Figure A20048000260102332
*: hydrochloride, Me: methyl, Et: ethyl, n-Pr: n-propyl
Reference example 1
(1) 80 ℃ with 4-ethyl fluoro benzoate (20g), N, dimethyl sulfoxide (DMSO) (200mL) solution stirring of N-dimethyl-ethylenediamine (20g) and salt of wormwood (32.9g) 3 days.After cool to room temperature, add ethyl acetate and water to reaction mixture, and stir the mixture, with ethyl acetate extraction (2 times).Handle organic layer with 10%HCl, to shift basic materials to water layer.Wash water layer with ethyl acetate, to this water layer with 10% sodium hydroxide solution neutralization and with ethyl acetate extraction (3 times).Extraction liquid and vacuum concentration with the anhydrous sodium sulfate drying merging.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=8: 14: 1) go up to purify the crude product that obtains to obtain 4-[[2-(dimethylamino) ethyl] amino] ethyl benzoate (12.45g, productive rate: oily matter 44%).MS(APCI)m/z：237[M+H] +
(2) drip acrylate chloride (2.55mL) at the ice-cooled compound (5g) that obtains to above-mentioned steps (1) down and methylene dichloride (20mL) solution of pyridine (10mL), and in stirring at room mixture 3 hours.Add entry and saturated sodium bicarbonate solution successively to reaction mixture, and stir the mixture, use chloroform extraction.Wash this extraction liquid with saturated brine, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.With flash column chromatography silica gel (solvent: chloroform: methyl alcohol=1: 0 50: 1) go up crude product that purifying obtains to obtain buttery 4-[N-acryl-N-[2-(dimethylamino) ethyl that takes on a red color] amino] ethyl benzoate (1.62g, productive rate: 26%).
(3) mixture that at room temperature compound (1.62g) that obtains in the above-mentioned steps (2) and 50% dimethylamine agueous solution (5mL) is formed in acetonitrile (20mL) stirred 1.5 hours, and the vacuum concentration reaction mixture.With flash column chromatography silica gel (solvent: chloroform: methyl alcohol=1: 0 → 50: 1 → chloroform: methyl alcohol: ammoniacal liquor=25: 1: 0.1) go up crude product that purifying obtains to obtain buttery 4-[N-[3-(dimethylamino) propionyl that takes on a red color]-N-[2-(dimethylamino) ethyl] amino] ethyl benzoate (1.78g, productive rate: 95%).MS(APCI)m/z：336[M+H] +
Reference example 2 to 10
With handling corresponding raw material, to obtain down the compound shown in the tabulation 28 with reference example 1 described identical method.
Table 28
Figure A20048000260102351
Me: methyl, Et: ethyl, nPr: n-propyl, Ph: phenyl
Reference example 11
At the ice-cooled compound (200mg) that obtains to reference example 1 (1) down and methylene dichloride (4mL) the solution dropping pyridine (137 μ L) of cyclopropane carbonyl chloride (115 μ L), and in stirring at room mixture 23 hours.Add entry and saturated sodium bicarbonate solution successively to reaction mixture, and stir the mixture.Use the chloroform extraction mixture, and concentrate this extraction liquid.With flash column chromatography at NH-silica gel (Hi-Flash post; Yamazen, solvent: chloroform: 4-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl of crude product to obtain being yellow oily of last purification gained methyl alcohol=1: 0 → 89: 11)] amino] ethyl benzoate (209mg, productive rate: 81%).MS(APCI)m/z：305[M+H] +
Reference example 12 to 26
With handling corresponding raw material, to obtain down the compound shown in the tabulation 29 with reference example 11 described identical methods.
Table 29 (No.1)
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Table 29 (No.2)
Figure A20048000260102371
Me: methyl, Et: ethyl, tBu: the tertiary butyl
Reference example 27
At room temperature methylene dichloride (4mL) solution stirring of compound (200mg) that reference example 1 (1) is obtained and n-butyl isocyanate (143 μ L) is 23 hours.Further add n-butyl isocyanate (143 μ L) to reaction mixture, and stirred the mixture 17 hours at 50 ℃.Concentrated reaction mixture; and with gel permeation chromatography (JAI Gel-H post; solvent: chloroform) purify the crude product obtain to obtain being yellow resinoid 4-[N-(butyl carbamyl)-N-[2-(dimethylamino) ethyl] amino] ethyl benzoate (179mg, productive rate: 63%).MS(APCI)m/z：336[M+H] +
Reference example 28 to 30
With handling corresponding raw material, to obtain down the compound shown in the tabulation 30 with reference example 27 described identical methods.
Table 30
Me: methyl, Et: ethyl
Reference example 31
Drip chloroacetyl chloride (0.56mL) and N successively at ice-cooled following methylene dichloride (15mL) solution to 4-phenmethyl subcutin (1.5g), N-diisopropylethylamine (1.54mL), and stirred the mixture 1 hour.Add diethylamine (3mL) at uniform temp to reaction mixture, and in stirring at room mixture 12 hours.Add entry (10mL) to reaction mixture, and separate organic layer.With chloroform (5mL) aqueous layer extracted.Merge organic layer and concentrated.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=6: 1 → 3: 1) crude product of going up the purification gained with obtain being brown buttery 4-[N-(N '; the sweet acyl group of N '-diethyl)-and N-phenmethyl amino] ethyl benzoate (2.0g, productive rate: 92%).MS(APCI)m/z：369[M+H] +
Reference example 32 to 35
With handling corresponding raw material, to obtain down the compound shown in the tabulation 31 with reference example 31 described identical methods.
Table 31
Figure A20048000260102391
Me: methyl, Et: ethyl, Ph: phenyl
Reference example 36
(1) methylene dichloride (250mL) solution to 4-acyl radical methyl benzoate (25g) adds N successively, N-dimethyl-ethylenediamine (67g), acetate (87mL) and sodium triacetoxy borohydride (50.6g).In the stirring at room mixture overnight.The vacuum concentration reaction mixture, and to resistates adding unsaturated carbonate potassium solution.Use the ethyl acetate extraction mixture, and use the anhydrous sodium sulfate drying organic layer, again it is carried out vacuum concentration, with 4-[[[2-(dimethylamino) ethyl that obtains colorless oil] amino] methyl] methyl benzoate (31.9g, productive rate: 89%).MS(APCI)m/z：237[M+H] +
(2) drip 3-(dimethylamino) propyl alcohol (14.2mL) to methylene dichloride (300mL) solution of p-nitrophenyl chloroformate ester (18.1g), and in stirring at room mixture 4 hours.Add 4-[[[2-(dimethylamino) ethyl successively to mixture] amino] methyl] methyl benzoate (13.7g) and triethylamine (25mL), and in stirring at room mixture one day.With saturated potassium carbonate solution washing reaction mixture, with anhydrous sodium sulfate drying and vacuum concentration.With flash column chromatography at NH-silica gel (Chromatorex NH silica gel, solvent: ethyl acetate: 4-[[N-[2-(dimethylamino) ethyl of crude product to obtain colorless oil of last purification gained normal hexane=1: 1)]-N-[[3-(dimethylamino) propoxy-] carbonyl] amino] methyl] methyl benzoate (7.97g, productive rate: 38%).MS(APCI)m/z：366[M+H] +
Reference example 37
Methylene dichloride (4mL) solution of the compound (200mg) that obtains to reference example 36 (1) add propionyl chloride (110 μ L) and ice-cooled down to wherein dripping pyridine (137 μ L).In stirring at room mixture 4 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.With column chromatography silica gel (solvent: chloroform: methyl alcohol=100: 0 → 90: 10) go up to purify the crude product that obtains to obtain 4-[[N-propionyl-N-[2-(dimethylamino) ethyl] amino] methyl] methyl benzoate (191mg, productive rate: amorphous powder 78%).MS(APCI)m/z：293[M+H] +
Reference example 38 to 42
With handling corresponding raw material, to obtain down the compound shown in the tabulation 32 with reference example 37 described identical methods.
Table 32
Me: methyl
Reference example 43
To 4-[[[2-(dimethylamino) ethyl] amino] methyl] methyl benzoate (compound that reference example 36 (1) obtains, methylene dichloride 200mg) (4mL) solution add n-butyl isocyanate (143 μ L), and in stirring at room mixture 4 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.With column chromatography silica gel (solvent: chloroform: 4-[[N-(butyl carbamyl)-N-[2-(dimethylamino) ethyl of crude product to obtain light yellow oily of go up purifying and to obtain methyl alcohol=100: 0 → 90: 10)] amino] methyl] methyl benzoate (261mg, productive rate: 92%).MS(APCI)m/z：336[M+H] +
Reference example 44
To 1 of 4-acyl radical methyl benzoate (300mg), 2-ethylene dichloride (6mL) solution adds diethylamine (113 μ L), and ice-cooled following to wherein adding sodium triacetoxy borohydride (581mg) and acetate (261 μ L).In stirring at room mixture 18 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.(solvent: normal hexane: the crude product that purification obtains ethyl acetate=70: 30 → 40: 60) is to obtain buttery 4-(diethylin methyl) methyl benzoate (144mg, productive rate: 60%) at NH-silica gel with flash column chromatography.MS(APCI)m/z：222[M+H] +
Reference example 45 to 59
With handling corresponding raw material, to obtain down the compound shown in the tabulation 33 with reference example 44 described identical methods.
Table 33 (No.1)
Figure A20048000260102421
Me: methyl, Et: ethyl
Table 33 (No.2)
Me: methyl
Reference example 60
To 4-[[2-(dimethylamino) ethyl] amino] ethyl benzoate (compound that reference example 1 (1) obtains, 200mg) 1,2-ethylene dichloride (4mL) solution add isobutyric aldehyde (384 μ L) and ice-cooled down to wherein adding sodium triacetoxy borohydride (448mg) and acetate (145 μ L).In stirring at room mixture 24 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.With column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=80: 20 → 50: 50) 4-[N-[2-(dimethylamino) ethyl of crude product to obtain light yellow oily of go up purifying and to obtain]-the N-isobutylamino] ethyl benzoate (239mg, productive rate: 97%).MS(APCI)m/z：293[M+H] +
Reference example 61 to 66
With handling corresponding raw material, to obtain down the compound shown in the tabulation 34 with reference example 60 described identical methods.
Table 34
Figure A20048000260102441
Me: methyl, Et: ethyl
Reference example 67
To 4-[[2-(dimethylamino) ethyl] amino] ethyl benzoate (compound that reference example 1 (1) obtains, 3.0g) methylene dichloride (30mL) solution add N-(tert-butoxycarbonyl) glycine (2.89g), and ice-cooled down to wherein adding diethyl phosphorocyanidate (2.89mL).In stirring at room mixture 24 hours.With chloroform (20mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (50mL).After the stirring, isolate organic layer, this organic layer is washed, with anhydrous sodium sulfate drying and vacuum concentration with saturated brine.28% ammoniacal liquor=100: 10: 1) and gel permeation chromatography (Nippon BunsekiKogyo use flash column chromatography on the NH-silica gel (solvent: chloroform: methyl alcohol: successively; solvent: the crude product of purifying and obtaining chloroform); to obtain 4-[N-[N '-(tert-butoxycarbonyl) sweet acyl group]-N-[2-(dimethylamino) ethyl] amino] ethyl benzoate (4.2g, productive rate: pale yellow crystals 84%).MS(APCI)m/z：394[M+H] +
Reference example 68
(1) to the N of 4-bromomethyl-benzoic acid methyl ester (22.8g), dinethylformamide (450mL) solution drips the 50% dimethyl amine aqueous solution (27mL), and in stirring at room mixture 3 hours.Reaction mixture is poured into frozen water and used ethyl acetate extraction.Water and saturated brine wash this extraction liquid successively, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.With flash column chromatography at silica gel (solvent: chloroform: methyl alcohol=10: 1) go up crude product that purifying obtains) methyl to obtain brown buttery 4-[(dimethylamino] methyl benzoate (27.5g, productive rate: 99%).MS(APCI)m/z：194[M+H] +
(2) compound (19.2g) that obtains in above-mentioned steps (1) adds concentrated hydrochloric acid (66mL) and water (167mL), and the mixture backflow is spent the night.Reaction mixture is carried out vacuum concentration.Wash the coarse crystal that obtains with ether, to obtain the 4-[(dimethylamino) methyl] benzoate hydrochlorate (19.0g, productive rate: colourless powder 88%).MS(APCI)m/z：179[M+H] +
Reference example 69
(1) to tetracol phenixin (100mL) solution of 6-methylnicotinic acid methyl esters (6.3g) add successively N-bromine succinimide (8.9g) and 2,2 '-Diisopropyl azodicarboxylate (342mg), heating is backflow mixture 6 hours down.After cool to room temperature, add normal hexane (300mL) to reaction mixture, and by removing by filter insoluble substance.Vacuum concentrated filtrate, and with column chromatography at silica gel (solvent: normal hexane: ethyl acetate=10: the 1) crude product of go up purifying and to obtain, and in normal hexane, stirring to obtain 6-(brooethyl) nicotinic acid methyl ester (3.4g, productive rate: clear crystal 35%).
(2) tetrahydrofuran (THF) (5mL) solution of the compound (350mg) that obtains to above-mentioned steps (1) adds the 50% dimethyl amine aqueous solution (3mL), and in stirring at room mixture 10 minutes.Add ethyl acetate to reaction mixture.Water and saturated brine purging compound successively, use anhydrous sodium sulfate drying, and with column chromatography (solvent: chloroform: methyl alcohol=100: 1) purify 6-(dimethylaminomethyl) nicotinic acid methyl ester (276mg, productive rate: 93%) on silica gel to obtain colorless oil.MS(APCI)m/z：195[M+H] +
Reference example 70 to 77
With handling corresponding raw material, to obtain down the compound shown in the tabulation 35 with reference example 69 described identical methods.
Table 35
Figure A20048000260102461
Me: methyl, Et: ethyl
Reference example 78
(1) to the N of 4-nipagin A (15.3g), dinethylformamide (150mL) solution adds 2-dimethyl aminoethyl chloride hydrochloride (15.9g) and salt of wormwood (43.2g) successively, and stirs the mixture at 110 ℃ and to spend the night.Add entry and use the ethyl acetate extraction mixture to reaction mixture.Use saturated sodium bicarbonate solution and water washing organic layer successively, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.With flash column chromatography on silica gel (solvent: chloroform: the crude product of purifying and to obtain methyl alcohol=10: 1), to obtain brown buttery 4-[2-(dimethylamino) oxyethyl group] ethyl benzoate (14.1g, productive rate: 65%).MS(APCI)m/z：238[M+H] +
(2) compound (14.1g) that obtains in above-mentioned steps (1) adds concentrated hydrochloric acid (40mL) and water (100mL) and the mixture backflow is spent the night.This reaction mixture of vacuum concentration and the crystal that obtains with the methanol washing are to obtain 4-[2-(dimethylamino) oxyethyl group] benzoate hydrochlorate (14.1g, productive rate: brown powder 56%).MS(APCI)m/z：210[M+H] +
Reference example 79
With handling corresponding raw material, to obtain down the compound shown in the tabulation 36 with reference example 78 described identical methods.
Table 36
Figure A20048000260102471
Me: methyl
Reference example 80
(1) in ice-cooled down thionyl chloride (1.33mL) to methyl alcohol (30mL), and stirred solution 10 minutes.Add 4-hydroxycinnamic acid (3.0g) to this solution, and in stirring at room mixture 4 days.Concentrated reaction mixture is also used ethyl acetate (50mL) dilution resistates, with saturated sodium bicarbonate solution and saturated brine washing, uses anhydrous sodium sulfate drying successively, and vacuum concentration.Recrystallize resistates from ethyl acetate/normal hexane is to obtain 4-hydroxy-methyl cinnamate (2.86g, productive rate: pale yellow crystals 88%).
Fusing point: 136.5-137 ℃
(2) N of the compound (1.53g) that obtains to above-mentioned steps (1), dinethylformamide (25mL) solution adds hydrochloric acid 3-chloropropyl dimethyl amine salt (1.69g), salt of wormwood (3.12g) and tetrabutylammonium iodide (105mg) successively.Stirred the mixture 17 hours at 80 ℃.After the cooling, add entry (100mL), and extract with ethyl acetate (150mL, 2 times) to reaction mixture.Isolate organic layer, to this organic layer water successively (150mL, 2 times) and saturated brine washing, use anhydrous sodium sulfate drying, and vacuum concentration is to obtain anti-3-[4-[3-(dimethylamino) propoxy-] phenyl] methyl acrylate (2.07g, productive rate: light yellow oil 92%).MS(APCI)m/z：264[M+H] +
Methyl alcohol (15mL) solution of the compound (2.07g) that (3) obtains in above-mentioned steps (2) adds 1N sodium hydroxide solution (15mL), and in stirring at room mixture 15 hours.Concentrated reaction mixture is also used 1N HCl neutralization (pH7) resistates, and to wherein adding methyl alcohol.Stir this mixture and collecting precipitation crystal, to obtain anti-3-[4-[3-(dimethylamino) propionyl] phenyl] vinylformic acid (1.93g, productive rate: clear crystal 98%).Fusing point: 191-193 ℃
Reference example 81
(1) down add tert-Butyl dicarbonate (6.4g) ice-cooled to methylene dichloride (30mL) solution of 4-(amino methyl) methyl benzoate (5.08g), and in stirring at room mixture 24 hours.With methylene dichloride (20mL) diluted reaction mixture, and to wherein adding entry (40mL).After the stirring, isolate organic layer and it is concentrated, to obtain 4-[N-(tert-butoxycarbonyl) amino methyl] methyl benzoate.
(2) tetrahydrofuran (THF) (15mL) solution of the ice-cooled compound (1.5g) that obtains to above-mentioned steps (1) down add sodium hydride (60% mineral oil dispersion liquid, 407mg).In stirring at room mixture 30 minutes.Drip iodoethane (2.26mL) at ice-cooled downhill reaction mixture, and stirred the mixture 1 hour at 60 ℃.After cool to room temperature, with ethyl acetate (10mL) diluted reaction mixture, and to wherein adding entry.After leaving standstill, isolate organic layer and it is concentrated.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=20: 1) go up to purify the product that obtains to obtain 4-[[N-ethyl-N-(tert-butoxycarbonyl)] amino methyl] methyl benzoate (929mg, productive rate: amorphous powder 56%).MS(APCI)m/z：294[M+H] +
Reference example 82
(1) to the N of 4-hydroxy benzaldehyde (610mg), add 2-dimethyl aminoethyl villaumite hydrochlorate (1.08g) and salt of wormwood (2.0g) in dinethylformamide (20mL) solution successively, and in stirring at room mixture 18 hours.Add ethyl acetate to reaction mixture, and water and saturated brine purging compound, anhydrous sodium sulfate drying used.With flash column chromatography silica gel (solvent: chloroform: 4-[2-(the dimethylamino)-oxyethyl group of crude product to obtain light yellow oily of purifying methyl alcohol=20: 1 10: 1) and obtaining] phenyl aldehyde (640mg, productive rate: 66%).MS(APCI)m/z：194[M+H] +
(2) (60% mineral oil dispersion liquid 144mg), and stirred the mixture 30 minutes to add sodium hydride at ice-cooled following tetrahydrofuran (THF) (20mL) solution to the dimethyl phosphine acyl acetic acid tert-butyl ester (807mg).Add tetrahydrofuran (THF) (10mL) solution of the compound (580mg) that obtains in the above-mentioned steps (1) to reaction mixture, and in stirring at room mixture 1 hour.Add frozen water to reaction mixture.Use the ethyl acetate extraction mixture, and wash organic layer, use anhydrous sodium sulfate drying again with saturated brine.With column chromatography silica gel (solvent: chloroform: methyl alcohol=20: 1) go up to purify the crude product that obtains to obtain anti-3-[4-[2-(dimethylamino) oxyethyl group] phenyl] tert-butyl acrylate (920mg, productive rate: quantitatively) clear crystal.MS(APCI)m/z：292[M+H] +
(3) 4N HCl-diox (10mL) solution of the compound (880mg) that obtains in stirring at room above-mentioned steps (2) is 6 hours.Use the ether diluted reaction mixture, and filter the collecting precipitation crystal, and wash this crystal, to obtain anti-3-[4-[2-(dimethylamino) oxyethyl group with ether] phenyl] acrylic acid hydrochloride (750mg, productive rate: clear crystal 91%).MS(APCI)m/z：236[M+H] +
Reference example 83
(1) under-30 ℃ of argon gas atmosphere in 15 minutes time to methyl alcohol (90mL) thionyl chloride (8.7mL), and stirred the mixture 30 minutes at-20 ℃.Add 3-amino-4-methoxybenzoic acid (5.0g) to mixture, and, at room temperature stirred 3 days uniform temp stirred solution 15 minutes.Vacuum concentration reaction mixture and the crystal that obtains with the methanol washing are to obtain 3-amino-4-methoxyl methyl benzoate hydrochloride (6.25g, productive rate: clear crystal 96%).Fusing point: 213-215 ℃, MS (APCI) m/z:182[M+H] +
Tetrahydrofuran (THF) (10mL) suspension of the compound (1.08g) that (2) obtains in above-mentioned steps (1) adds pyridine (2.4mL) and methane sulfonyl chloride (0.56mL), and in stirring at room mixture 30 minutes.Add entry to reaction mixture, and stir the mixture.Use the ethyl acetate extraction mixture.On diatomite, handle this extraction liquid and with its vacuum concentration with column chromatography.With resistates recrystallize from ether/hexane of gained, to obtain 3-sulfonyl methane amino-4-methoxyl methyl benzoate (1.08g, productive rate: crystal 69%).MS(APCI)m/z：258[M+H] +
(3) dimethyl sulfoxide (DMSO) (2mL) solution to the compound (260mg), salt of wormwood (222mg) and the 2-chloroethyl diethylamine hydrochloride (414mg) that obtain in the above-mentioned steps (2) carries out vigorous stirring.Add entry to reaction mixture.After the stirring, use the ethyl acetate extraction mixture.Wash this extraction liquid with saturated brine, filter and vacuum concentration by the NH-silicagel column.With flash column chromatography at NH-silica gel (HI-Flash post; solvent: chloroform: methyl alcohol=1: 0 95: 5) go up the resistates that obtains of purifying and also handle with the HCl/ ethyl acetate; with 3-[N-[2-(diethylin) ethyl that obtains the colourless resin shape]-N-(methane sulfonyl) amino]-4-methoxybenzoic acid hydrochloride (228mg, productive rate: 93%).MS(APCI)m/z：359[M+H] +
Reference example 84
(1) to the N of Vanillin (76.1g), dinethylformamide (500mL) solution adds 4-(2-chloroethyl) morpholine hydrochloride (130g), sodium iodide (7.5g) and salt of wormwood (207g) successively.Stirred the mixture 15 hours at 80 ℃.Reaction mixture is carried out vacuum concentration.Dilute resistates with ethyl acetate,, use anhydrous sodium sulfate drying with the saturated brine washing, and vacuum concentration.Add Di Iso Propyl Ether and filter the crystal that collection obtains to resistates, to obtain 3-methoxyl group-4-(2-morpholine oxyethyl group) phenyl aldehyde (112.6g, productive rate: orange crystal 85%).MS(APCI)m/z：266[M+H] +
(2) (60% mineral oil dispersion liquid 6.4g), and stirred the mixture 0.5 hour to add sodium hydride at ice-cooled following tetrahydrofuran (THF) (150mL) solution to triethyl phosphine acyl acetic acid ester (37.0g).At ice-cooled tetrahydrofuran (THF) (140mL) solution that drips down the compound (40.0g) that obtains in above-mentioned steps (1), and stirred the mixture 2 hours at uniform temp to this mixture.With ethyl acetate (500mL) diluted reaction mixture, with the saturated brine washing, use anhydrous sodium sulfate drying, and vacuum concentration.Add Di Iso Propyl Ether and filter the crystal that collection obtains to precipitated product, to obtain anti-3-[3-methoxyl group-4-(2-morpholine oxyethyl group) phenyl] ethyl propenoate (46.2g, productive rate: orange crystal 91%).MS(APCI)m/z：336[M+H] +
Methyl alcohol (250mL) solution of the compound (43.3g) that (3) obtains in above-mentioned steps (2) adds 2N sodium hydroxide solution (100mL), and in the stirring at room mixture overnight.Vacuum concentration reaction mixture and neutralization.Filter the collecting precipitation crystal and it is dissolved in ethanol.Remove by filter insoluble substance and resulting crystal carried out recrystallize, to obtain anti-3-[3-methoxyl group-4-(2-morpholine oxyethyl group) phenyl] vinylformic acid (34.8g, productive rate: yellow crystals 88%).MS(APCI)m/z：308[M+H] +
Reference example 85
(1)-30 ℃ in 1 hour time to methyl alcohol (1500mL) thionyl chloride (254mL), and in stirring at room mixture 0.5 hour.Add trans cyclohexane-1 to this mixture, 4-dicarboxylic acid (500.0g), and in stirring at room mixture 17 hours.The vacuum concentration reaction mixture also dilutes resistates with chloroform, with saturated sodium bicarbonate solution and saturated brine washing, with anhydrous sodium sulfate drying and vacuum concentration.From the normal hexane crystalline residue, filter and collect, and dry to obtain trans cyclohexane-1,4-dimethyl dicarboxylate (545.0g).MS(APCI)m/z：201[M+H] +
(2) tetrahydrofuran (THF) (1500mL) solution at the ice-cooled compound (150.0g) that obtains to above-mentioned steps (1) down drips the mixture of being made up of 28% sodium methylate-methyl alcohol (149g) solution and water (13.2g).In stirring at room mixture 3.5 hours, and to wherein adding normal hexane (150mL).Filter and collect the throw out that obtains, and add the mixture of concentrated hydrochloric acid (50mL), water (450mL) and chloroform (1000mL).In stirring at room mixture 20 minutes.Isolate chloroform layer and use the chloroform extraction water layer.Merge organic layer, use anhydrous sodium sulfate drying, and vacuum concentration.Crystalline residue from normal hexane is filtered and is collected, and dry, to obtain trans cyclohexane-1,4-mono methyl dicarboxylate (106.0g).MS(ESI)m/z：185[M-H] -
The trimethyl carbinol (1000mL) solution of the compound (100.0g) that (3) obtains in above-mentioned steps (2) adds azido-diphenyl phosphate (155g) and triethylamine (78.6mL).Stirred the mixture 1 hour and under heating, refluxed 17 hours at 60 ℃.After the cooling, ice cold water is poured into reaction mixture and used the ethyl acetate extraction mixture.With saturated sodium bicarbonate solution and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.Resistates is dissolved in methyl alcohol (250mL), and to wherein adding entry (750mL).Under ice-cooled, stirred the mixture 0.5 hour.Filter and collect the throw out that obtains, and water/methyl alcohol (3: 1,1000mL) wash this throw out, and use anhydrous sodium sulfate drying, to obtain anti-4-(tert-butoxycarbonyl amino) hexahydrobenzoic acid methyl esters (117.0g) with normal hexane.MS(APCI)m/z：275[M+NH 4] +
Reference example 86
(1) (234.0g) De diox (500mL) solution adds 4NHCl-diox (500mL) to the compound that obtains to reference example 85, and at room temperature stirs the mixture 19 hours.The vacuum concentration reaction mixture also is suspended in resistates in the ether.Filter the collecting precipitation thing, to obtain anti-4-aminocyclohexane carboxylate methyl ester hydrochloride (121.9g).MS(APCI)m/z：158[M+H] +
(2) methyl alcohol (1000mL) solution of the compound (93.0g) that obtains to above-mentioned steps (1) adds 35% formaldehyde solution (95.4mL), sodium acetate (39.4g) and 10% palladium-charcoal (10g), and at the stirring at room mixture, under normal pressure hydrogen in stirring at room mixture 3.5 hours.(Celite) removes insoluble substance and vacuum concentrated filtrate by diatomite.Add 20% solution of potassium carbonate (500mL) and use the chloroform extraction mixture to resistates.With anhydrous sodium sulphate and the dry organic layer of salt of wormwood, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain anti-4-(dimethylamino) hexahydrobenzoic acid methyl esters (87.3g) ethyl acetate=2: 1) at NH-silica gel with column chromatography.MS(APCI)m/z：186[M+H] +
The diox (300mL) of the compound (27.6g) that (3) obtains in above-mentioned steps (2) and water (100mL) solution add 6N HCl (50mL), and under heating backflow mixture 4 hours.Added the also further backflow mixture of 6N HCl (50mL) 1 hour to reaction mixture.The vacuum concentration reaction mixture, and with resistates with the toluene component distillation.Resistates is suspended in the Di Iso Propyl Ether, and filters and collect the throw out that obtains, with the diisopropyl ether washing, and dry to obtain anti-4-(dimethylamino) hexahydrobenzoic acid (27.5g).MS(APCI)m/z：172[M+H] +
Reference example 87
(1) at 70 ℃ of compounds (10g), 1 that reference example 86 (1) is obtained, the tetrahydrofuran (THF) (300mL) of 4-two butyl iodides (19.2g) and yellow soda ash (16.4g) and N,N-dimethylacetamide (60mL) suspension stirred 20 hours.The vacuum concentration reaction mixture also is dissolved in ethyl acetate/water with it.Separate organic layer, anhydrous sodium sulfate drying is used in water and saturated brine washing, and vacuum concentration.(solvent: ethyl acetate: normal hexane=1: 5) last purification resistates is to obtain anti-4-(1-pyrrolidyl) hexahydrobenzoic acid methyl esters (10.9g) at NH-silica gel with column chromatography.MS(APCI)m/z：212[M+H] +
(2) diox (150mL) solution of the compound (10.9g) that obtains to above-mentioned steps (1) adds 2N aqueous hydrochloric acid (80mL), and stirs the mixture 3 hours at 110 ℃, evaporates simultaneously to remove methyl alcohol.Reaction mixture is carried out vacuum concentration.Resistates is ground and filters collection with ether, to obtain anti-4-(1-pyrrolidyl) hexahydrobenzoic acid hydrochloride (11.1g).MS(APCI)m/z：198[M+H] +
Reference example 88
(1) tetrahydrofuran (THF) (1400mL) of the compound (47.5g) that reference example 86 (1) is obtained, two (2-chloroethyl) ethers (34.5mL), yellow soda ash (77.9g) and sodium iodide (88g) and N,N-dimethylacetamide (280mL) suspension returning are 18 hours.Add two (2-chloroethyl) ethers (23mL) and sodium iodide (22g) to reaction mixture, and backflow mixture 6 hours.The vacuum concentration reaction mixture also is dissolved in ethyl acetate/water with it.Isolate organic layer,, use anhydrous sodium sulfate drying this organic layer water and saturated brine washing, and vacuum concentration.(solvent: ethyl acetate: normal hexane=1: 30 → 1: 5 → 1: 3) last purification resistates is to obtain anti-4-morpholine hexahydrobenzoic acid methyl esters (53.9g) at NH-silica gel with column chromatography.MS(APCI)m/z：228[M+H] +
(2) diox (750mL) solution of the compound (53.8g) that obtains to above-mentioned steps (1) adds 2N aqueous hydrochloric acid (400mL), and stirs the mixture at 110 ℃ and to evaporate simultaneously to remove methyl alcohol in 4 hours.Reaction mixture is carried out vacuum concentration.Be suspended in resistates in the ether and the filtration collection, to obtain anti-4-morpholine hexahydrobenzoic acid hydrochloride (54.8g).MS(APCI)m/z：214[M+H] +
Reference example 89
(1) drip thionyl chloride (6mL) at ice-cooled following methyl alcohol (32mL) suspension to anti-4-(amino methyl) hexahydrobenzoic acid (6.29g), and in the stirring at room mixture overnight.Reaction mixture is carried out vacuum concentration, to obtain anti-4-(amino methyl) hexahydrobenzoic acid methyl ester hydrochloride (8.69g).MS(APCI)m/z：172[M+H] +
Methylene dichloride (400mL) suspension of the compound (8.69g) that (2) obtains in above-mentioned steps (1) adds triethylamine (11.2mL).After at room temperature stirring several minutes, add 35% formaldehyde solution (15.9mL) and sodium triacetoxy borohydride (25.43g), then in stirring at room mixture 2 hours to reaction mixture.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.Water and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration is to obtain anti-4-(dimethylamino methyl) hexahydrobenzoic acid methyl esters (7.42g).MS(APCI)m/z：200[M+H] +
Add 2N aqueous hydrochloric acid (70mL) in diox (140mL) solution of the compound (7.41g) that (3) in above-mentioned steps (2), obtains, mixture was refluxed 3 hours.After the cooling, the vacuum concentration reaction mixture.With resistates and toluene component distillation together and dry to obtain anti-4-(dimethylamino methyl) hexahydrobenzoic acid hydrochloride (8.45g) amorphous powder.MS(APCI)m/z：186[M+H] +
Reference example 90
(1) (60% mineral oil dispersion liquid, tetrahydrofuran (THF) 33.6g) (600mL) suspension drips tetrahydrofuran (THF) (100mL) solution of phosphine acyl acetic acid three ethyl (188.4g) to sodium hydride under ice-cooled.Stirred the mixture 0.5 hour at uniform temp, and to tetrahydrofuran (THF) (100mL) solution that wherein drips pyridine 4-formaldehyde (75.00g).Stirred the mixture 1 hour.Add frozen water (1000mL) and with this mixture of ethyl acetate extraction to reaction mixture.Water, saturated sodium bicarbonate solution and saturated brine washing organic layer are with anhydrous sodium sulfate drying and vacuum concentration.Down resistates is suspended in a small amount of diisopropyl ether ice-cooled.Filter and collect the throw out that obtains,, and be dried to obtain 3-(4-pyridyl) ethyl propenoate (77.53g) with diisopropyl ether and normal hexane washing.MS(APCI)m/z：178[M+H] +
(2) in acetate (280mL) solution of the compound (28.00g) that above-mentioned steps (1) obtains, add platinum oxide (1.80g), and under hydrogen atmosphere in stirring at room mixture 24 hours.Filter reaction mixture is to remove insoluble substance and vacuum concentrated filtrate.The resistates that obtains is dissolved in diox (200mL), and to wherein adding 4N HCl-diox (200mL).Vacuum concentrated mixture also is suspended in resistates in ether/diisopropyl ether.Filter and collect the throw out that obtains,, and be dried to obtain 3-(4-piperidyl) ethyl propionate hydrochloride (33.50g) with the diisopropyl ether washing.MS(APCI)m/z：186[M+H] +
Reference example 91
Add platinum oxide (3.44g) to acetate (500mL) solution of (4-pyridyl) ethyl acetate (50.00g), and under hydrogen atmosphere in room temperature jolting mixture 20 hours.Filter reaction mixture is to remove insoluble substance and vacuum concentrated filtrate.The resistates that obtains is dissolved in diox (200mL), and to wherein adding 4N HCl-diox (400mL).Vacuum concentrated mixture also is suspended in resistates in ether/diisopropyl ether.Filter and collect the throw out that obtains,, and be dried to obtain (4-piperidyl) ethyl acetate hydrochloride (61.80g) with the diisopropyl ether washing.MS(APCI)m/z：172[M+H] +
Reference example 92
(1) ethanol (700mL) solution of the compound that obtains to reference example 90 (70.83g) adds 2-iodopropane (38.2mL) and salt of wormwood (132.3g), and mixture was refluxed 6 hours.Filter reaction mixture is to remove insoluble substance and vacuum concentrated filtrate.With ethyl acetate (800mL) dilution resistates, to this resistates water and saturated brine washing, use anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain 3-(1-sec.-propyl piperidin-4-yl) ethyl propionate (57.13g) ethyl acetate=20: 1 → 9: 1) at NH-silica gel with column chromatography.MS(APCI)m/z：228[M+H] +
(2) diox (1200mL) solution of the compound (57.12g) that obtains to above-mentioned steps (1) adds 2N HCl (600mL), and mixture was refluxed 3 hours.The vacuum concentration reaction mixture and with it Yu the diox component distillation.With gained resistates and ether/diisopropyl ether (1: 1,500mL) grind together.Filter and collect the throw out that obtains, with the diisopropyl ether washing, and dry to obtain 3-(sec.-propyl piperidin-4-yl) propionic salt hydrochlorate (55.36g).MS(APCI)m/z：200[M+H] +
Reference example 93 to 94
With handling corresponding raw material, to obtain down the compound shown in the tabulation 37 with reference example 92 (1) and (2) described identical method.
Table 37
Figure A20048000260102551
Reference example 95
(1) dimethylbenzene (130mL) suspension of compound (5.00g), 4-chloropyridine hydrochloride (3.62g) and triethylamine (10.01mL) that reference example 91 obtains was refluxed 20 hours under heating.After the cooling, filter this reaction mixture to remove insoluble substance and vacuum concentrated filtrate.Dilute resistates with chloroform, this resistates is washed with water, use anhydrous sodium sulfate drying, and vacuum concentration.(solvent: chloroform: the purification resistates is to obtain [1-(4-pyridyl) piperidin-4-yl] ethyl acetate (4.15g) ethyl acetate=4: 1) at NH-silica gel with column chromatography.MS(APCI)m/z：249[M+H] +
(2) diox (200mL) solution of the compound (4.15g) that obtains to above-mentioned steps (1) adds 1N aqueous hydrochloric acid (70mL), and mixture was refluxed 4 hours.Vacuum concentration reaction mixture and lyophilize resistates are to obtain [1-(4-pyridyl) piperidin-4-yl] acetic acid hydrochloride (3.90g).MS(APCI)m/z：221[M+H] +
Reference example 96
(1) the mixture vigorous stirring that iso ethyl nicotinate (1.57g), propionic aldehyde (1.0g) and 10% palladium-charcoal (500mg) is formed in methyl alcohol (20mL) in room temperature under hydrogen atmosphere is 2 hours.Behind argon replaces hydrogen, filter and collect palladium-charcoal and wash this palladium-charcoal with methyl alcohol (100mL).Merge elutant and filtrate and vacuum concentration.Resistates is dissolved in ethanol (20mL), and to wherein adding 4N HCl-diox (20mL).Vacuum concentrated mixture and make resistates from ethanol/ether crystallization to obtain 1-propyl group piperidines-4-carboxylic acid, ethyl ester hydrochloride (1.81g, productive rate: clear crystal 77%).Fusing point: 114-117 ℃
(2) under heating, make the mixture backflow 2 hours that the compound (1.79g) that obtains in the above-mentioned steps (1) and concentrated hydrochloric acid (20mL) form.After the cooling, the vacuum concentration reaction mixture also is added to resistates with ether.Stir the mixture and isolate supernatant liquid.Remove the ether layer in the supernatant liquid, and make resistates crystallization from ethanol/ether, to obtain 1-propyl group piperidines-4-carboxylic acid hydrochloride (1.11g, productive rate: clear crystal 70%).Fusing point 222-224 ℃
Reference example 97
To 4-[[2-(dimethylamino) ethyl] amino] methylene dichloride (4mL) solution of phenyl aldehyde (300mg) adds chloroformic acid 2-methoxyl group ethyl ester (234 μ L), and ice-cooled down to wherein dripping pyridine (252 μ L).Stirred the mixture 2 days at 50 ℃.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution (10mL).After the stirring, isolate organic layer and it is concentrated.With column chromatography at silica gel (solvent: chloroform: methyl alcohol=100: 0 90: 10) go up the purification resistates) carbonyl to obtain the 4-[N-[(2-methoxy ethoxy]-N-[2-(dimethylamino) ethyl] amino] phenyl aldehyde (290mg, productive rate: amorphous powder 63%).MS(APCI)m/z：294[M+H] +
Reference example 98
At room temperature with monomethyl terephthalyl chloride (500mg), N, methylene dichloride (5.0mL) solution stirring of N-dimethyl-ethylenediamine (178mg) and diisopropylethylamine (650mg) is spent the night.Use the ethyl acetate diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer also with this organic layer vacuum concentration.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=9: 1) go up the purification resistates to obtain 4-[[[2-(dimethylamino) ethyl] amino] carbonyl] methyl benzoate (355mg, productive rate: yellow crystals 70%).MS(APCI)m/z：251[M+H] +
Reference example 99
Under argon gas atmosphere, hydride suspension lithium aluminium (1.19g) in tetrahydrofuran (THF) (50mL), and ice-cooled down in 15 minutes time to wherein dripping (1-sec.-propyl piperidin-4-yl) ethyl acetate (compound that reference example 93 (1) obtains, tetrahydrofuran (THF) 6.43g) (50mL) solution.In stirring at room mixture 1.5 hours.Add entry (1.2mL), 2N sodium hydroxide solution (2.4mL) and water (2.4mL) successively at ice-cooled downhill reaction mixture.In stirring at room mixture 2 hours.After adding sal epsom, stirred reaction mixture 10 minutes also filters.Vacuum concentrated filtrate, and with flash column chromatography at NH-silica gel (solvent: normal hexane: ethyl acetate=1: 1) go up 2-(1-sec.-propyl piperidin-4-yl) ethanol (5.09g, the productive rate: 99%) of purification resistates to obtain colorless oil.MS(APCI)m/z：172[M+H] +
Reference example 100
Under argon gas atmosphere, hydride suspension lithium aluminium (3.29g) in tetrahydrofuran (THF) (160mL), and ice-cooled down to wherein add 1-sec.-propyl piperidines-4-carboxylic acid, ethyl ester (compound that reference example 94 (1) obtains, 5.00g).In stirring at room mixture 14 hours.Add entry (3.3mL), 2N sodium hydroxide solution (6.6mL) and water (6.6mL) successively at ice-cooled downhill reaction mixture.In stirring at room mixture 1 hour.After adding sal epsom, stirred reaction mixture 10 minutes also filters.Vacuum concentrated filtrate, and with flash column chromatography at NH-silica gel (solvent: normal hexane: ethyl acetate=1: 1) go up the purification resistates to obtain (1-sec.-propyl piperidin-4-yl) methyl alcohol (3.75g, the productive rate: 99%) of colorless oil.MS(APCI)m/z：158[M+H] +
Reference example 101
Down in the ethanol (80mL) of 1-methyl-2-imidazole formaldehyde (10g) and tetrahydrofuran (THF) (80mL) mixture solution, add sodium borohydride (4.2g) ice-cooled, and in stirring at room mixture 2 hours.The vacuum concentration reaction mixture also is dissolved in chloroform with resistates, with the saturated sodium bicarbonate solution washing, with anhydrous sodium sulfate drying and vacuum concentration.Add diisopropyl ether and filter the crystal that collection obtains to resistates, to obtain (1-methyl isophthalic acid H-imidazoles-2-yl) methyl alcohol (9.9g, productive rate: clear crystal 98%).MS(APCI)m/z：113[M+H] +
Reference example 102
(1) ice-cooled down to the 4-[[(tert-butoxycarbonyl) amino] methyl] methyl benzoate (and the compound that reference example 81 (1) obtains, add in tetrahydrofuran (THF) 2.0g) (20mL) solution sodium hydride (60% mineral oil dispersion liquid, 0.9g).In stirring at room mixture 30 minutes, drip methyl-iodide (2.3mL) to reaction mixture then.In stirring at room mixture 3 hours.Use the ethyl acetate diluted reaction mixture, wash with water, and with its vacuum concentration to obtain 4-[[N-methyl-N-(tert-butoxycarbonyl) amino of yellow oily] methyl] methyl benzoate (1.9g, productive rate: 94%).MS(APCI)m/z：280[M+H] +
(2) in methyl alcohol (5.0mL) solution of the compound (1.5g) that above-mentioned steps (1) obtains, add 4NHCl-diox (10.0mL), and in stirring at room mixture 1 hour.Use the ether diluted reaction mixture, and by filtering the collecting precipitation crystal, to obtain the 4-[(methylamino) methyl] methyl benzoate (0.89g, productive rate: clear crystal 78%).MS(APCI)m/z：180[M+H] +
(3) at the N of 80 ℃ of compound (100mg), 2-(diethylin) diethylaluminum monochloride hydrochloride (160mg) and salt of wormwood (260mg) that obtain in above-mentioned steps (2), dinethylformamide (3.0mL) suspension stirred 3 hours.The dilute with water reaction mixture is also used ethyl acetate extraction.This extraction liquid of vacuum concentration, and with column chromatography silica gel (solvent: chloroform: methyl alcohol=10: 1) go up the purification resistates to obtain 4-[[N-methyl-N-[[2-(diethylin) oxyethyl group of yellow oily] carbonyl] amino] methyl] methyl benzoate (94mg, productive rate: 64%).MS(APCI)m/z：323[M+H] +
Reference example 103
(1) ice-cooled down to methylene dichloride (6.0mL) the solution dropping cyclopropane carbonyl chloride (0.78mL) of the amino furans of 5--2-carboxylate methyl ester (1.0g) and pyridine (1.2mL), and in stirring at room mixture 2 hours.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.With anhydrous sodium sulfate drying extraction liquid and vacuum concentration.With column chromatography at silica gel (solvent: normal hexane: ethyl acetate=3: 1) go up the purification resistates) amino to obtain the 5-[(cyclopropyl carbonyl] furans-2-carboxylate methyl ester (0.82g, productive rate: clear crystal 56%).MS(APCI)m/z：210[M+H] +
(2) at the N of 80 ℃ of compound (200mg), 2-(dimethylamino) diethylaluminum monochloride hydrochloride (275mg) and salt of wormwood (530mg) that obtain in above-mentioned steps (1), dinethylformamide (3.0mL) suspension stirred 3 hours.The dilute with water reaction mixture is also used ethyl acetate extraction.This extraction liquid of vacuum concentration, and with column chromatography silica gel (solvent: chloroform: methyl alcohol=10: 1) go up 5-[N-(cyclopropyl carbonyl)-N-[2-(dimethylamino) ethyl of purification resistates to obtain colorless oil] amino] furans-2-carboxylate methyl ester (196mg, productive rate: 73%).MS(APCI)m/z：281[M+H] +
Reference example 104
(1) in ethanol (50mL) solution of 2-nitrothiophene (nitorthiophen)-4-carboxylic acid (10g), add thionyl chloride (5.0mL) down ice-cooled, and in the stirring at room mixture overnight.The vacuum concentration reaction mixture, and to resistates adding saturated sodium bicarbonate solution.Use the ethyl acetate extraction mixture, and, add iron powder (16g), ammonium chloride (16g), ethanol (100mL) and water (100mL), and mixture was refluxed 2 hours to resistates with this extraction liquid of anhydrous sodium sulfate drying and vacuum concentration.Also filter with the ethyl acetate diluted reaction mixture to remove insoluble substance.With saturated sodium bicarbonate solution and saturated brine wash filtrate, use anhydrous sodium sulfate drying, and vacuum concentration, to obtain brown buttery 5-aminothiophene-3-carboxylic acid, ethyl ester (6.34g, productive rate: 65%).MS(APCI)m/z：172[M+H] +
(2) methylene dichloride (50mL) solution stirring of compound (5.62g), tert-Butyl dicarbonate (15.8g), pyridine (6.4mL) and 4-(dimethylamino) pyridine (0.4g) that obtains in above-mentioned steps (1) in room temperature is 3 hours.Wash reaction mixture with water, use anhydrous sodium sulfate drying, and vacuum concentration.Add cesium carbonate (22g) and ethanol (50mL) to resistates, and stir the mixture at 80 ℃ and to spend the night.Filter reaction mixture is to remove insoluble substance and dilute with water filtrate.Filter and collect the crystal that obtains, to obtain the 5-[(tert-butoxycarbonyl) amino] thiophene-3-carboxylic acid, ethyl ester (6.07g, productive rate: brown crystal 68%).MS(APCI)m/z：272[M+H] +
(3) at the N of 80 ℃ of compound (1.5g), 2-(dimethylamino) diethylaluminum monochloride hydrochloride (1.5g) and salt of wormwood (3.0g) that obtain in above-mentioned steps (2), dinethylformamide (15mL) suspension stirred 3 hours.The dilute with water reaction mixture is also used ethyl acetate extraction.The vacuum concentration extraction liquid, and with column chromatography silica gel (solvent: chloroform: methyl alcohol=50: 1) go up the purification resistates to obtain brown buttery 5-[N-(tert-butoxycarbonyl)-N-[2-(dimethylamino) ethyl] amino] thiophene-3-carboxylic acid, ethyl ester (1.53g, productive rate: 81%).MS(APCI)m/z：343[M+H] +
(4) compound that obtains in above-mentioned steps (3) adds methyl alcohol (5.0mL) and 4N HCl-diox (10.0mL), and in stirring at room mixture 3 hours.The vacuum concentration reaction mixture with the saturated sodium bicarbonate solution neutralization, and is used chloroform extraction.With anhydrous sodium sulfate drying extraction liquid and vacuum concentration.With column chromatography silica gel (solvent: chloroform: methyl alcohol=10: 1) go up the purification resistates to obtain brown buttery 5-[[2-(dimethylamino) ethyl] amino] thiophene-3-carboxylic acid, ethyl ester (0.75g, productive rate: 56%).MS(APCI)m/z：243[M+H] +
(5) in the ice-cooled compound (50mg) that in above-mentioned steps (4), obtains down and the dichloromethane solution dripping acetyl chloride (24mg) of pyridine (33mg), and in the stirring at room mixture overnight.Add saturated sodium bicarbonate solution to reaction mixture, and use the chloroform extraction mixture.With anhydrous sodium sulfate drying extraction liquid and vacuum concentration.With column chromatography silica gel (solvent: normal hexane: ethyl acetate=1: 1) go up the purification resistates to obtain 5-[N-ethanoyl-N-[2-(dimethylamino) ethyl of yellow oily] amino] thiophene-3-carboxylic acid, ethyl ester (46mg, productive rate: 79%).MS(APCI)m/z：285[M+H] +
Reference example 105
Spend the night at 60 compounds (50mg) that reference example 104 (4) is obtained and chloroform (3mL) solution stirring of n-butyl isocyanate (31mg).Add saturated sodium bicarbonate solution to reaction mixture, and use chloroform extraction.With anhydrous sodium sulfate drying extraction liquid and vacuum concentration.With column chromatography silica gel (solvent: normal hexane: ethyl acetate=1: 1) go up 5-[N-(butyl carbamyl)-N-[2-(dimethylamino) ethyl of purification resistates to obtain yellow oily] amino] thiophene-3-carboxylic acid, ethyl ester (58mg, productive rate: 82%).MS(APCI)m/z：342[M+H] +
Reference example 106
Add methylene dichloride (3.0mL), N successively to 5-(ethoxy carbonyl) thiophene-2-carboxylic acid (250mg), N-dimethyl-ethylenediamine (100mg), I-hydroxybenzotriazole (205mg), triethylamine (610mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (290mg).In the stirring at room mixture overnight.Use the chloroform diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer also with this organic layer vacuum concentration.With flash column chromatography NH-silica gel (solvent: ethyl acetate) go up the purification resistates to obtain 5-[[[2-(dimethylamino) ethyl] amino] carbonyl] thiophene-2-carboxylic acid ethyl ester (160mg, productive rate: brown crystal 53%).MS(APCI)m/z：271[M+H] +
Reference example 107
(1) stirred one day at 120 ℃ of mixtures the 4-fluorobenzoic acid tert-butyl ester (2.14g) and 1-(2-amino-ethyl) tetramethyleneimine (1mL) composition.After the cooling, add entry to reaction mixture, and with ethyl acetate extraction mixture (2 times).With the centrifugal concentrator concentrated extract and with flash column chromatography NH silica gel (solvent: normal hexane: ethyl acetate=8: 14: 1) on the purification resistates to obtain buttery 4-[[2-(1-pyrrolidyl) ethyl] amino] t-butyl perbenzoate (1.62g, productive rate: 51%).MS(APCI)m/z：291[M+H] +
(2) at the ice-cooled compound (96mg) that obtains to above-mentioned steps (1) down and chloroform (1mL) the solution adding Acetyl Chloride 98Min. (47 μ L) of pyridine (67 μ L), and in stirring at room mixture one day.Use the chloroform diluted reaction mixture, and wash this mixture with saturated sodium bicarbonate solution.With this elutant of chloroform extraction (2 times), combining extraction liquid also concentrates by centrifugal.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=4: 12: 3) 4-[N-ethanoyl-N-[2-(1-pyrrolidyl) ethyl of resistates to obtain colorless oil of go up purifying and to obtain] amino] t-butyl perbenzoate (37mg, productive rate: 33%).MS(APCI)m/z：333[M+H] +
Reference example 108
(1) bathes methylene dichloride (15mL) solution that drips dimethyl sulfoxide (DMSO) (3.3mL) under the cooling to methylene dichloride (120mL) solution of oxalyl chloride (2.0mL) at dry ice-propanone, and stirred the mixture 10 minutes at uniform temp.Drip compound ((1-sec.-propyl piperazine-4-yl) methyl alcohol) methylene dichloride (30mL) solution (3.00g) that reference example 100 obtains with 15 fens clockwise reaction mixtures.Stirred the mixture 2 hours at uniform temp, and wherein drip triethylamine (13.3mL) with 10 fens clockwise.In stirring at room mixture 1 hour, be poured into saturated sodium bicarbonate solution and use dichloromethane extraction.The vacuum concentration extraction liquid is also used the ethyl acetate extraction water layer.Combining extraction liquid and dichloromethane layer, water and saturated brine washing lotion are used anhydrous sodium sulfate drying, and vacuum concentration is to obtain thick 1-sec.-propyl piperidines-4-formaldehyde (1.96g).MS(APCI)m/z：156[M+H] +
(2) down (60% mineral oil dispersion liquid 1.45g), and stirred the mixture 20 minutes at uniform temp by part adding a sodium hydride to tetrahydrofuran (THF) (50mL) solution of phosphine acyl acetic acid three ethyl (7.96g) ice-cooled.Tetrahydrofuran (THF) (25mL) solution of the compound (5.03g) that in this mixture adding above-mentioned steps (1), obtains.Stirred the mixture 3 hours and dilute at uniform temp with ether.After adding entry, use the ethyl acetate extraction reaction mixture.Water and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the resistates that purification obtains ethyl acetate=9: 1) is to obtain 3-(1-sec.-propyl piperidin-4-yl) ethyl propenoate (6.87g) at NH-silica gel with flash column chromatography.MS(APCI)m/z：226[M+H] +
Ethanol (20mL) solution of the compound (1.01g) that (3) obtains in above-mentioned steps (2) adds 2N sodium hydroxide solution (4.5mL), and in stirring at room mixture 24 hours.Add 2N HCl (9mL) to reaction mixture, and vacuum concentrated mixture.The lyophilize resistates is to obtain 3-(1-sec.-propyl piperidin-4-yl) acrylic acid hydrochloride (1.43g).MS(APCI)m/z：198[M+H] +
Reference example 109
The mixture that parathesin (25.2g), triethyl orthoformate (80g) and trifluoroacetic acid (0.2mL) are formed refluxed 3 hours.After the cooling, the vacuum concentration reaction mixture, and with resistates and ethanol component distillation.Suspension resistates in ethanol (400mL), and to wherein adding sodium borohydride (23g), and mixture was refluxed 3 hours.After the cooling, add ethyl acetate and water to reaction mixture.In stirring at room mixture one day.Isolate organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain 4-(methylamino) ethyl benzoate (12.7g, productive rate: light yellow amorphous powder 46%) ethyl acetate=4: 1) at silica gel with flash column chromatography.MS(APCI)m/z：180[M+H] +
Reference example 110
Diox (100mL) suspension to anti-4-(amino methyl) hexahydrobenzoic acid (8.35g) adds entry (50mL) and 1N sodium hydroxide solution (50mL), then at the ice-cooled tert-Butyl dicarbonate (12.7g) that drips down.In stirring at room mixture 4 hours.The vacuum concentration reaction mixture also dilutes resistates with ethyl acetate, and to wherein adding aqueous citric acid solution with this solution of acidifying (pH3-4).Use the ethyl acetate extraction mixture, water and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.This resistates is ground with normal hexane, filter and collect, and dry to obtain anti-4-(tert-butoxycarbonyl amino methyl) hexahydrobenzoic acid (13.30g, productive rate: crystal 97%).MS(APCI)m/z：256[M-H] -
Reference example 111
(1) at the N of the ice-cooled compound (30.0g) that obtains to reference example 85 down, dinethylformamide (150mL) solution add sodium hydride (60% mineral oil dispersion liquid, 5.60g).Stirred the mixture 0.5 hour at uniform temp, and to wherein adding methyl-iodide (14.5mL) and methyl alcohol (0.15mL) successively.In stirring at room mixture 4 hours.Add saturated ammonium chloride solution and frozen water to reaction mixture, use the ethyl acetate extraction mixture.Water and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.With column chromatography silica gel (solvent: normal hexane: ethyl acetate=10: 1 → 7: 1) go up the purification resistates to obtain anti-4-[N-methyl-N-(tert-butoxycarbonyl) amino] hexahydrobenzoic acid methyl esters (26.3g, productive rate: amorphous powder 83%).MS(APCI)m/z：272[M+H] +
(2) methyl alcohol (300mL) solution of the compound (44.78g) that obtains to above-mentioned steps (1) adds 2N sodium hydroxide solution (100mL), and in stirring at room mixture 6 hours.The vacuum concentration reaction mixture also adds frozen water, ethyl acetate and 10%HCl to resistates.Use the ethyl acetate extraction mixture, water and saturated brine washing organic layer, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.Resistates is suspended in amount of ethyl acetate, and to wherein adding normal hexane.Filter and collect the crystal of separating out, wash several times with normal hexane-diisopropyl ether, and be dried to obtain anti-4-[N-methyl-N-(tert-butoxycarbonyl) amino] hexahydrobenzoic acid (39.20g, productive rate: crystal 92%).MS(APCI)m/z：256[M-H] -
Reference example 112
(1) use with the described identical methods of reference example 69 handle 3-methoxyl group-4-tolyl acids (1g) to obtain buttery 3-methoxyl group-4-[(dimethylamino) methyl] methyl benzoate (792mg, productive rate: 64%).MS(APCI)m/z：224[M+H] +
(2) ethanol (10mL) solution of the compound (792mg) that obtains to above-mentioned steps (1) adds 2N sodium hydroxide solution (2.1mL), and stirs the mixture 2 hours at 60 ℃.After the cooling, add 2N HCl (4.3mL) to reaction mixture.Vacuum concentrated mixture also adds methyl alcohol to resistates.Filtering mixt is to remove insoluble substance and vacuum concentrated filtrate, to obtain 3-methoxyl group-4-[(dimethylamino) methyl] benzoate hydrochlorate (890mg, productive rate: quantitatively) amorphous powder.MS(APCI)m/z：210[M+H] +
Reference example 113
Dimethyl formamide (2mL) solution of the compound (200mg) that obtains to reference example 156 adds the complex compound (60mg) and the salt of wormwood (305mg) of methyl-boron-dihydroxide (132mg), [1, two (diphenylphosphino) ferrocene of 1-] dichloro palladium (II) and methylene dichloride successively.Under argon gas atmosphere, stirred the mixture 3 hours at 115 ℃.With ethyl acetate (10mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer and this organic layer is concentrated with centrifugal concentrator.With column chromatography at silica gel (solvent: chloroform: methyl alcohol=100: 0 → 90: 10) go up the purification resistates) methyl to obtain 3-methyl-4-[(dimethylamino] methyl benzoate (65mg, productive rate: amorphous powder 43%).MS(APCI)m/z：208[M+H] +
Reference example 114
Add the compound (7.7g) that molecular sieve 4A (44.5g) and reference example 86 (1) obtain successively to dimethyl formamide (500mL) suspension of cesium hydroxide (24.5g), and in stirring at room mixture 30 minutes.Add dimethyl aminoethyl chloride hydrochloride (11g) to reaction mixture, and stirred the mixture 22 hours., and wash removing insoluble substance by this reaction mixture of diatomite filtration with ethyl acetate.Merge elutant and filtrate and vacuum concentration.Resistates is dissolved in chloroform (100mL).At ice-cooled chloroform (10mL) solution that adds tert-Butyl dicarbonate (16g) down to this solution, and at room temperature stirred the mixture 1.5 hours.With saturated sodium bicarbonate solution washing reaction mixture, with no dried over sodium sulfate, and vacuum concentration.With column chromatography silica gel (solvent: chloroform: methyl alcohol=100: 0 → 50: 1) go up the purification resistates to obtain anti-4-[N-(tert-butoxycarbonyl)-N-[2-(dimethylamino) ethyl] amino] hexahydrobenzoic acid methyl esters (1.7g, productive rate: amorphous powder 11%).MS(APCI)m/z：329[M+H] +
Reference example 115
Methylene dichloride (10mL) solution at the ice-cooled compound (500mg) that obtains to reference example 90 down adds diethyl ketone (388 μ L), triethylamine (471 μ L) and sodium triacetoxy borohydride (956mg), and in the stirring at room mixture overnight.Use the chloroform diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer and vacuum concentration.With column chromatography silica gel (solvent: chloroform: methyl alcohol=100: 0 → 90: 10) go up the purification resistates to obtain 3-[1-(3-amyl group) piperidin-4-yl] ethyl propionate (130mg).MS(APCI)m/z：256[M+H] +
Reference example 116 to 234
With with above-mentioned reference example 1～115 in the described identical method of arbitrary reference example handle corresponding raw material, thereby obtain down the compound of tabulation shown in 38.
Table 38 (No.1)
Figure A20048000260102651
Me: methyl, Et: ethyl
Table 38 (No.2)
Figure A20048000260102661
Me: methyl, Et: ethyl
Table 38 (No.3)
Me: methyl, Et: ethyl, n-Pr: n-propyl
C-Pr: cyclopropyl, n-Bu: normal-butyl
Table 38 (No.4)
Me: methyl
Table 38 (No.5)
Figure A20048000260102682
Me: methyl
Table 38 (No.6)
Figure A20048000260102691
Me: methyl
Table 38 (No.7)
Me: methyl
Table 38 (No.8)
Me: methyl, Ph: phenyl
Table 38 (No.9)
Figure A20048000260102702
Me: methyl
Table 38 (No.10)
Figure A20048000260102711
Me: methyl
Table 38 (No.11)
Figure A20048000260102721
Me: methyl
Table 38 (No.12)
Figure A20048000260102731
Et: ethyl, i-Pr: sec.-propyl, n-Pr: n-propyl
N-Bu: normal-butyl
Table 38 (No.13)
Figure A20048000260102741
Me: methyl, n-Bu: normal-butyl
Table 38 (No.14)
Figure A20048000260102742
Me: methyl
Table 38 (No.15)
Figure A20048000260102751
Me: methyl
Table 38 (No.16)
Figure A20048000260102752
Me: methyl, Et: ethyl
Table 38 (No.17)
Figure A20048000260102753
Me: methyl, Et: ethyl
Table 38 (No.18)
Figure A20048000260102761
Me: methyl, Et: ethyl
Table 38 (No.19)
Figure A20048000260102762
Table 38 (No.20)
Table 38 (No.21)
Figure A20048000260102772
Table 38 (No.22)
Figure A20048000260102781
Table 38 (No.23)
Figure A20048000260102782
Table 38 (No.24)
Table 38 (No.25)
Figure A20048000260102792
Reference example 235
(1) drips tetrahydrofuran (THF) (7.5mL) solution of 2M borine-dimethyl sulphide ether complexes to tetrahydrofuran (THF) (2.0mL) solution of 1-(carbamyl)-1-cyclopropane-carboxylic acid (500mg), and mixture was refluxed 4 hours.Add 10%HCl and mixture was refluxed 30 minutes to reaction mixture.After the cooling, with saturated sodium bicarbonate solution neutralization reaction mixture, and to wherein adding diox (10mL) and tert-Butyl dicarbonate (1.3g).In stirring at room mixture 3 hours.With ethyl acetate extraction reaction mixture and vacuum concentration extraction liquid.With flash column chromatography at silica gel (solvent: normal hexane: ethyl acetate=3: 1) go up 1-hydroxymethyl-1-(tert-butoxycarbonyl amino methyl) cyclopropane (337mg, the productive rate: 45%) of purification resistates to obtain yellow oily.MS(APCI)m/z：202[M+H]+
(2) tetrahydrofuran (THF) (3.0mL) the solution dropping diisopropyl azo-2-carboxylic acid (510mg) of ice-cooled compound (337mg), 4-methyl hydroxybenzoate (280mg) and the triphenylphosphine (650mg) that obtains to above-mentioned steps (1) down, and in the stirring at room mixture overnight.The vacuum concentration reaction mixture, and with flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=3: 2) go up 4-[[1-(tert-butoxycarbonyl amino methyl) cyclopropyl of purification resistates to obtain yellow oily] methoxyl group] methyl benzoate (515mg, productive rate: 92%).MS(APCI)m/z：353[M+H] +
Reference example 236
Stirred 4 hours at 80 dimethyl sulfoxide (DMSO) (3.0mL) suspension the 4-fluorobenzoic acid tert-butyl ester (300mg), 2-(dimethylamino) ethane thiolate hydrochlorate (420mg) and salt of wormwood (620mg).The dilute with water reaction mixture is also used ethyl acetate extraction.The vacuum concentration extraction liquid also adds 4N HCl-diox (1.5mL) to resistates.In the stirring at room mixture overnight.Use the ether diluted reaction mixture, and by filtering the collecting precipitation crystal, to obtain 4-[2-(dimethylamino) ethylmercapto group] phenylformic acid (380mg, productive rate: clear crystal 99%).MS(APCI)m/z：226[M+H] +
Reference example 237
Add sodium borohydride (2.67g) at-78 ℃ of methyl alcohol (200mL) solution, and stirred the mixture 1 hour at uniform temp to 4-cyclohexanone carboxylic acid ethyl ester (24g).Add entry to reaction mixture, and evaporating mixture is used ethyl acetate extraction again to remove methyl alcohol.Wash organic layer with saturated brine, with this organic layer anhydrous sodium sulfate drying, and vacuum concentration.Drip diisopropylethylamine (50mL) and chloromethyl methyl ether (16mL) at ice-cooled following methylene dichloride (200mL) solution to resistates (20g), and in the stirring at room mixture overnight.Add entry to reaction mixture, and use the ethyl acetate extraction mixture.Concentrate this extraction liquid, (solvent: normal hexane: the purification resistates is to obtain anti-4-(methoxymethoxy) hexahydrobenzoic acid ethyl ester (12.3g, the productive rate: 40%) of colorless oil ethyl acetate=15: 1) at silica gel with flash column chromatography.MS(APCI)m/z：234[M+H] +
Reference example 238
Compound (the trans cyclohexane-1 that dissolving reference example 85 (2) obtains in tetrahydrofuran (THF) (78mL), the 4-mono methyl dicarboxylate, 14.3g), and under-50 ℃ of argon gas atmosphere, in 1 hour time to the tetrahydrofuran (THF) that wherein drips 1.0M borine-tetrahydrofuran complex (100mL) solution.Stirred the mixture 1 hour at-10 ℃.Add entry (160mL) and saturated sodium bicarbonate solution (160mL) at ice-cooled downhill reaction mixture, and with ethyl acetate extraction mixture (4 times).Wash extraction liquid with saturated brine, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.(solvent: chloroform: methyl alcohol=20: 1) last purification resistates is to obtain the anti-4-of buttery (hydroxymethyl) hexahydrobenzoic acid methyl esters (13.25g, productive rate: quantitatively) at silica gel with flash column chromatography.MS(APCI)m/z：173[M+H] +
Reference example 239
(1) ice-cooled down to chloroform (100mL) the solution dripping acetyl chloride (2.69g) of anti-4-(amino methyl) hexahydrobenzoic acid methyl ester hydrochloride (5.86g) and triethylamine (12mL), and in stirring at room mixture 2 hours.Pour reaction mixture into water, and with this mixture of chloroform extraction (2 times).The extraction liquid that is combined with 10%HCl, saturated brine, saturated sodium bicarbonate solution and saturated brine washs successively, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain anti-4-(acetylamino methyl) hexahydrobenzoic acid methyl esters (5.92g, productive rate: amorphous powder 98%) ethyl acetate=1: 1 → 0: 1) at silica gel with flash column chromatography.MS(APCI)m/z：214[M+H] +
(2) dimethyl formamide (50mL) solution at the ice-cooled compound (4.32g) that obtains to above-mentioned steps (1) down adds sodium hydride (60% mineral oil dispersion liquid successively, 1.0g), methyl-iodide (5.91g) and methyl alcohol (5), and in stirring at room mixture 8 hours.Add sodium hydride (60% mineral oil dispersion liquid, 430mg), behind methyl-iodide (1.5mL) and the methyl alcohol (2), stirred the mixture 2 hours.Pour reaction mixture into water and inferior with ethyl acetate extraction (3).Wash this extraction liquid (2 times) with water, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain the anti-4-of buttery (N-methyl-N-acetylamino methyl) hexahydrobenzoic acid methyl esters (3.04g, productive rate: 66%) ethyl acetate=1: 2 → 0: 1) at silica gel with flash column chromatography.MS(APCI)m/z：228[M+H]+
(3) compound (3.03g) that obtains in methyl alcohol/tetrahydrofuran solution (14mL) the hydrolysis above-mentioned steps (2) with 2N sodium hydroxide, the vacuum concentration reaction mixture also neutralizes with dilute hydrochloric acid solution.Use the chloroform extraction mixture, and use the anhydrous sodium sulfate drying extraction liquid, again with its vacuum concentration to obtain thick carboxylic acid cpd (2.67g, 94%).This compound (500mg) was refluxed 2 days under heating in 5N HCl, and concentrated reaction mixture is to obtain thick amino-acid compound.(6mL) is with the mixture that diox (4mL) and tert-Butyl dicarbonate (1.0g) are formed to add the 1N sodium hydroxide solution to this compound.In stirring at room mixture 12 hours.The dilute with water reaction mixture also washs with ether.With in 10% citric acid solution and behind the water layer, use the ethyl acetate extraction mixture.Water and saturated brine wash extraction liquid successively, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration, to obtain the anti-4-[N-methyl-N-of buttery (tert-butoxycarbonyl) amino methyl] hexahydrobenzoic acid (680mg, productive rate: 90%).MS(ESI)m/z：270[M-H] -
Reference example 240
With handling compound (500mg) and sec.-propyl-(2-methoxy ethyl) amine (689mg) that reference example 238 obtains with embodiment 654 (1) and (2) described identical method, to obtain the anti-4-[N-sec.-propyl-N-of buttery (2-methoxy ethyl) amino methyl] hexahydrobenzoic acid methyl esters (445mg, productive rate: 56%).MS(APCI)m/z：272[M+H] +
Reference example 241
(1) add chlorobutanoylchloride (3.95mL) and N in ice-cooled following methylene dichloride (60mL) drips of solution to 4-phenmethyl subcutin (6.0g), N-diisopropylethylamine (6.14mL), and stirred the mixture 12 hours.Use the chloroform diluted reaction mixture, and to wherein adding 10%HCl.Isolate organic layer, water, saturated sodium bicarbonate solution, water and saturated brine wash this organic layer successively, use anhydrous sodium sulfate drying, and vacuum concentration.With flash column chromatography silica gel (solvent: normal hexane: ethyl acetate=4: 1) go up the purification resistates to obtain buttery 4-[N-phenmethyl-N-(4-chlorobutyryl) amino] ethyl benzoate (8.27g, productive rate: quantitatively).MS(APCI)m/z：360/362[M+H] +
(2) under 100 ℃ of argon gas atmosphere with dimethyl sulfoxide (DMSO) (2.5mL) solution stirring of the compound (1.0g), diethylamine (287 μ L) and the sodium iodide (417mg) that obtain in the above-mentioned steps (1) a day.After the cooling, add saturated sodium bicarbonate solution to reaction mixture, and with chloroform extraction mixture (2 times).The vacuum concentration extraction liquid; and with flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=4: 1) go up the purification resistates to obtain buttery 4-[N-phenmethyl-N-[4-(diethylin) butyryl radicals] amino] ethyl benzoate (280mg, productive rate: 25%).MS(APCI)m/z：397[M+H] +
Reference example 242
In argon gas atmosphere and ice-cooled down to 3,4-dihydric ethyl benzoate (500mg), N, methylene dichloride (20mL) solution of N-dimethylethanolamine (565 μ L) and triphenylphosphine (1.51g) drips diisopropyl azo-2-carboxylic acid (1.37mL).In stirring at room mixture one day.Use the ethyl acetate diluted reaction mixture, wash with water and handle so that the basic materials in the ethyl acetate layer is transferred to water layer with 10%HCl.With extracting with water layer and with chloroform/methanol/tetrahydrofuran (THF) (4: 1: 1,2 times) in the saturated sodium bicarbonate solution.With anhydrous sodium sulfate drying extraction liquid and vacuum concentration.With flash column chromatography NH-silica gel (solvent: normal hexane: ethyl acetate=1: 1 → chloroform: methyl alcohol=19: 1) go up the purification resistates to obtain buttery 4-[2-(dimethylamino) oxyethyl group]-3-nipagin A (240mg, productive rate: 35%).MS(APCI)m/z：254[M+H] +
Reference example 243
Ice-cooled down to methylene dichloride (200mL) the solution adding sodium triacetoxy borohydride (18.9g) and the acetate (3.47mL) of 4-subcutin (10g) and 4-(dimethylamino) phenyl aldehyde (9.0g), and in stirring at room mixture 2 days.Add saturated sodium bicarbonate solution to reaction mixture, and extraction chloroform extraction (2 times).The vacuum concentration extraction liquid, and in n-hexane/ethyl acetate grinding residues, to obtain 4-[4-(dimethylamino) phenmethyl amino] ethyl benzoate (11.6g, productive rate: powder 64%).MS(APCI)m/z：299[M+H] +
Reference example 244
(1) chloroform (290mL) solution of 4-(brooethyl) phenyl aldehyde (15.9g) and (1-ethoxy carbonyl ethidine) triphenyl phosphorane (29g) was refluxed 12 hours.After the cooling, concentrated reaction mixture, and with column chromatography silica gel (solvent: chloroform) go up the purification resistates to obtain buttery 3-[4-(brooethyl) phenyl]-ethyl 2-methacrylate (18mg, productive rate: 79%).
(2) add tetrahydrofuran (THF) (5mL) solution of the compound (2.83g) that obtains in the above-mentioned step (1) to water (10mL) drips of solution of tetramethyleneimine (0.89g) and salt of wormwood (1.38g), and in the stirring at room mixture overnight.Use the ethyl acetate diluted reaction mixture, wash with water, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.Resistates is dissolved in ether, and removes by filter insoluble substance.Add oxalic acid (0.9g) to filtrate, and filter and collect the throw out that obtains, to obtain 2-methyl-3-[4-[(1-pyrrolidyl) methyl] phenyl] ethyl propenoate half oxalate (2.67g, productive rate: amorphous powder 83%).
(3) handle the compound (2.2g) that obtains in the above-mentioned steps (2) with ethyl acetate/10% solution of potassium carbonate, and the vacuum concentration ethyl acetate layer.Resistates (2-methyl-3-[4-(tetramethyleneimine-1-yl) aminomethyl phenyl] vinylformic acid) is dissolved in methyl alcohol (10mL), and to wherein adding potassium hydroxide (1.38g).Stirred the mixture 5 hours at 50 ℃.After the cooling, add ethanol (5mL) and filter the crystal that collection obtains to reaction mixture, to obtain 2-methyl-3-[4-[(1-pyrrolidyl) methyl] phenyl] potassium acrylate (1.65g, productive rate: powder 83%).Fusing point: 268 ℃ (dec. (decomposition))
Reference example 245
(1) add cyclopentamine (929mg) to tetrahydrofuran (THF) (5mL) solution of 4-(brooethyl) methyl benzoate (500mg), and in stirring at room mixture 3 hours.With chloroform (5mL) diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.After the stirring, isolate organic layer,, and filter this organic layer anhydrous sodium sulfate drying.Concentrated filtrate and with column chromatography silica gel (solvent: normal hexane: ethyl acetate=9: 1 → 5: 5) on 4-(cyclopentyl amino methyl) methyl benzoate (469mg, the productive rate: 92%) of purification resistates to obtain colorless oil.MS(APCI)m/z：234[M+H] +
(2) use with the described identical methods of reference example 89 (2) and handle the compound (480mg) that obtains in the above-mentioned steps (1), to obtain the 4-[(N-cyclopentyl-N-methylamino of colorless oil) methyl] methyl benzoate (420mg, productive rate: 83%).MS(APCI)m/z：248[M+H] +
Reference example 246
(1) use with reference example 107 (1) described identical methods and handle corresponding raw material, to obtain 4-[[3-(dimethylamino)-2,2-dimethyl-propyl group] amino] t-butyl perbenzoate.
(2) use with the described identical methods of reference example 89 (2) and handle the compound (500mg) that obtains in the above-mentioned steps (1), with the 4-[N-[3-(dimethylamino)-2 that obtains colorless oil, the 2-dimethyl propyl]-the N-ethylamino] t-butyl perbenzoate (468mg, productive rate: 85%).MS(APCI)m/z：335[M+H] +
Reference example 247
With handling the compound (1.00g) that reference example 86 (1) obtains with reference example 89 (2) described identical methods, and use with reference example 81 (1) described identical methods and handle the product that obtains, to obtain anti-4-[N-(the tert-butoxycarbonyl)-N-ethylamino of colorless oil] hexahydrobenzoic acid methyl esters (258.4mg, productive rate: 14%).MS(APCI)m/z：303[M+NH 4] +
Reference example 248
(1) add methyl alcohol (30mL) suspension of acetoin (25g) to methyl alcohol (30mL) solution of propane dinitrile (28.2g), and at ice-cooled (internal temperature: 10 ℃) down to wherein dripping diethylamine (11mL).In stirring at room mixture 3 hours.Pour reaction mixture into frozen water (300mL), and filter and collect the crystal of separating out, to obtain 2-amino-4,5-dimethyl-3-chaff nitrile (28.91g, productive rate: clear crystal 75%).
(2) methylene dichloride (200mL) solution of the compound (13.6g) that obtains to above-mentioned steps (1) adds piperidines (18.9g), and ice-cooled down to the methylene dichloride that wherein drips glyoxylate ethyl chloride (16.3g) (200mL) solution.Stirred the mixture 1.5 hours at 0 ℃.With chloroform (100mL) diluted reaction mixture, and to wherein adding entry (300mL).After the stirring, separate organic layer and use the chloroform extraction water layer.Merge organic layer and, use anhydrous sodium sulfate drying with the saturated brine washing, and filtration.Also (solvent: chloroform: the purification resistates is to obtain [(3-cyano group-4,5-dimethyl furan-2-yl) amino] (oxo) ethyl acetate (17g, productive rate: colourless powder 72%) ethyl acetate=9: 1) at silica gel with column chromatography for concentrated filtrate.Under 60 ℃ of argon gas atmosphere, stirred formic acid (30mL) and diacetyl oxide (30mL) mixture 2 hours, and to wherein adding [(3-cyano group-4,5-dimethyl furan-2-yl) amino] (oxo) ethyl acetate (7.07g).Mixture was refluxed 14 hours.Concentrated reaction mixture, and with column chromatography at silica gel (solvent: chloroform: ethyl acetate=9: 1 → chloroform: methyl alcohol=19: 1) go up the purification resistates to obtain 5,6-dimethyl-4-oxo-3,4-dihydrofuran also [2,3-d] and pyrimidine-2-carboxylic acid, ethyl ester (4.30g, productive rate: colourless powder 61%). fusing point: 180-182 ℃
(3) compound (2.36g) that obtains in the above-mentioned steps (2) is dissolved in N, dinethylformamide (60mL), and to wherein adding dimethylamino ethyl chloride thing hydrochloride (2.16g) and salt of wormwood (4.14g).Stirred the mixture 14 hours at 60 ℃.With chloroform (50mL) diluted reaction mixture, and to wherein adding entry (70mL).After the stirring, isolate organic layer and use the chloroform extraction water layer.Merge organic layer and, use anhydrous sodium sulfate drying with the saturated brine washing, and filtration.Concentrated filtrate also uses column chromatography at silica gel (solvent: chloroform: ethyl acetate: methyl alcohol=6: 2: 1) go up the purification resistates.With handling the product that obtains, to obtain 4-[2-(dimethylamino) oxyethyl group with embodiment 5 (2) described identical methods]-5, the 6-dimethyl furan is [2,3-d] pyrimidine-2-carboxylic acid, ethyl ester fumarate (780mg, productive rate: colourless powder 18%) also.Fusing point: 173-174 ℃
(4) compound (1.44g) that obtains in the above-mentioned steps (3) is dissolved in ethanol (20mL), and to wherein adding 2N sodium hydroxide solution (2.34mL).In stirring at room mixture 2 hours.The vacuum concentration reaction mixture also adds ether to resistates.Filter and collect the crystal that obtains, and with reversed-phase column chromatography method (HP-20 post, solvent: water: methyl alcohol=1: 0 → 1: 1) purify to obtain 4-[2-(dimethylamino) oxyethyl group]-5,6-dimethyl furan also [2,3-d] and pyrimidine-2-carboxylic acid (970mg, productive rate: colourless powder 74%). fusing point 179-180 ℃
Reference example 249
(1) to the N of 5-hydroxyl 2-(hydroxymethyl)-4H-pyrone (1g), dinethylformamide (20mL) solution adds salt of wormwood (1.95g) and bromo-acetic acid tert-butyl (1.37g), and in stirring at room mixture 16 hours.With tetrahydrofuran (THF) (10mL) diluted reaction mixture, and to wherein adding entry and saturated brine.After the stirring, isolate organic layer and use the tetrahydrofuran (THF) aqueous layer extracted.Merge organic layer and, use anhydrous sodium sulfate drying with the saturated brine washing, and filtration.Concentrated filtrate is also used the ether debris, filters and collects to obtain [[6-(hydroxymethyl)-4-oxo-4H-pyrans-3-yl] oxygen base] tert.-butyl acetate (1.49g, productive rate: colourless powder 88%).MS (ESI) m/z:257[M+H] +, fusing point 90-92 ℃.
(2) in methylene dichloride (600mL) solution of the compound (50g) that above-mentioned steps (1) obtains, add Dess-Martin periodinate (1,1,1-three (acetoxyl group)-1, acyl-3 (1H) in the 1-dihydro-1,2-benzo iodine-ketone, 1,1,1-Tris (acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one91.04g), and in stirring at room mixture 5 days.By the diatomite filtration reaction mixture, with ethyl acetate extraction filtrate and concentrated.Collect with ether debris and filtration, to obtain [(6-formyl radical-4-oxo-4H-pyrans-3-yl)-oxygen base] tert.-butyl acetate (17.1g, 34.5%) brown powder.
(3) with and the compound (2.0g) that obtains of the described identical methods processing above-mentioned steps (2) of embodiment 6, to obtain [[4-oxo-6-[(1-pyrrolidyl) methyl]-4H-pyrans-3-yl] the oxygen base] tert.-butyl acetate (1.06g, productive rate: yellow powder 44%).MS (ESI) m/z:310[M+H] +, fusing point 93-94 ℃
(4) add trifluoroacetic acid (2.5mL) at methylene dichloride (5mL) solution of 0 ℃ of compound (700mg) that in above-mentioned steps (3), obtains, and in stirring at room mixture 24 hours.Concentrated reaction mixture, and to wherein adding ethyl acetate and water.After the stirring, isolate water layer and also wash with ethyl acetate once more.The lyophilize water layer is to obtain [[4-oxo-6-[(1-pyrrolidyl) methyl]-4H-pyrans-3-yl] the oxygen base] acetate (820mg, productive rate: colourless powder 99%).MS(ESI)m/z：254[M+H]+
Reference example 250
(1) to [[4-oxo-6-[(1-pyrrolidyl) methyl]-4H-pyrans-3-yl] the oxygen base] tert.-butyl acetate (compound that reference example 249 (2) obtains, toluene solution 12g) adds (1-methoxycarbonyl methylene radical) triphenyl phosphorane (17.36g), and stirs the mixture 3 hours at 60 ℃.Concentrated reaction mixture, and with flash column chromatography silica gel (solvent: normal hexane: ethyl acetate=1: 1) go up the purification resistates to obtain [2-[(1E)-2-(methoxycarbonyl) vinyl]-4-oxo-4H-pyrans-3-yl] the fluoroacetic acid tert-butyl ester (10.99g, productive rate: clear crystal 75%).MS (ESI) m/z:311[M+H] +, fusing point 115-116 ℃
(2) in tetrahydrofuran (THF) (100mL) solution of the compound (8.83g) that above-mentioned steps (1) obtains, add entry (100mL) and 2N sodium hydroxide solution (20.1mL), and in stirring at room mixture 4 hours.After adding HCl (23mL), concentrated reaction mixture also is dissolved in N, dinethylformamide (7mL) with resistates (1.0g).Add N-methylmorpholine (3mL) and Tripyrophosphoric acid (3.9mL) to this solution, and in stirring at room mixture 4 days.Use the ethyl acetate diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution and saturated brine.After the stirring, isolate organic layer and use the ethyl acetate extraction water layer.Merge organic layer, with the saturated brine washing, use anhydrous magnesium sulfate drying, and filter.Concentrated filtrate, and with flash column chromatography silica gel (solvent: chloroform: methyl alcohol=19: 1) go up the purification resistates with obtain [2-[(1E)-2-[(4-methylpiperazine-1-yl) carbonyl] vinyl]-4-oxo-4E-pyrans-3-yl] the fluoroacetic acid tert-butyl ester (450mg, productive rate: yellow crystals 35%).MS (ESI) m/z:379[M+H] +, fusing point 124-125 ℃
(3) add trifluoroacetic acid (2mL) at methylene dichloride (5mL) solution of 0 ℃ of compound (390mg) that in above-mentioned steps (2), obtains, and in stirring at room mixture 5 hours.Concentrated reaction mixture and to wherein adding entry.Freeze-drying solution, with obtain [2-[(1E)-2-[(4-methyl-piperazine-1-yl) carbonyl] vinyl]-4-oxo-4H-pyrans-3-yl] fluoroacetic acid (330mg, productive rate: colourless powder 73%).MS(ESI)m/z：323[M+H] +
Reference example 251
(1) use and reference example 1 (1) the described identical method processing 4-fluoro-3-tolyl acid tert-butyl ester (4g), to obtain buttery 4-[[2-(dimethylamino) ethyl] amino]-the 3-tolyl acid tert-butyl ester (1.3g, productive rate: 24%).MS(APCI)m/z：279[M+H] +
(2) in diox (5mL) solution of the compound (1.3g) that above-mentioned steps (1) obtains, add 4NHCl-diox (5mL) and 5N HCl (3mL), and stirred the mixture 10 minutes at 60 ℃.After the cooling, the vacuum concentration reaction mixture, and resistates is water-soluble, with its lyophilize, to obtain 4-[[2-(dimethylamino) ethyl] amino]-3-tolyl acid dihydrochloride (1.35g, productive rate: amorphous powder 98%).MS(APCI)m/z：223[M+H] +
Reference example 252
(1) under 130 ℃ of argon gas atmosphere with 4,4,4-trifluoroacetic ethyl acetoacetate (23.1g), urea (7.54g) and ethyl orthoformate (18.6g) mixture stirred 1.5 hours.Add dimethylbenzene (100mL) to reaction mixture, and stirred the mixture 17 hours at 140 ℃.Evaporation reaction mixture desolvates to remove, and dilutes resistates with methyl alcohol.Use the active carbon powder treatment soln, vacuum concentration, and in diisopropyl ether, grind to obtain 2-hydroxyl 4-trifluoromethyl-5-pyrimidine carboxylic ethyl ester (20.3g, productive rate: crystal 69%).MS(ESI)m/z：235[M-H] -
(2) phosphoryl chloride (30mL) solution of the compound (5.0g) that obtains in the above-mentioned steps (1) was refluxed 2 hours.Reaction mixture is poured into frozen water and used chloroform extraction.Wash extraction liquid with saturated brine, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.(solvent: normal hexane: the purification resistates is to obtain buttery 2-chloro-4-trifluoromethyl-5-pyrimidine carboxylic ethyl ester (4.3g, productive rate: 80%) ethyl acetate=5: 1) at silica gel with column chromatography.MS (GC-EI (gas-chromatography-electron impact mass spectra)) m/z:254[M +]
Tetrahydrofuran (THF) (3mL) solution of the compound (500mg) that (3) obtains in above-mentioned steps (2) under argon gas atmosphere adds N, N, and tetrahydrofuran (THF) (2mL) solution of N '-trimethylammonium quadrol (421mg), and in stirring at room mixture 1 hour.Use the ethyl acetate diluted reaction mixture, successively with saturated sodium bicarbonate solution, water and saturated brine washing.With anhydrous sodium sulfate drying organic layer and vacuum concentration.With column chromatography silica gel (solvent: chloroform: methyl alcohol=100: 0 50: 1) go up the purification resistates to obtain buttery 2-[N-methyl-N-[2-(dimethylamino) ethyl] amino]-4-trifluoromethyl-5-pyrimidine carboxylic ethyl ester (540mg, productive rate: 77%).MS(APCI)m/z：321[M+H] +
Reference example 253
At 1 of the ice-cooled compound (500mg) that obtains to reference example 86 (1) down, add triethylamine (665 μ L), propionic aldehyde (688 μ L), sodium triacetoxy borohydride (1.68g) and acetate (546 μ L) in 2-ethylene dichloride (10mL) solution.In stirring at room mixture 3 days.Use the chloroform diluted reaction mixture, and to wherein adding saturated sodium bicarbonate solution.Use the chloroform extraction mixture, and the vacuum concentration extraction liquid.Resistates is dissolved in chloroform (6mL), and ice-cooled down to the chloroform that wherein adds tert-Butyl dicarbonate (690mg) (2mL) solution, and in stirring at room mixture 2 hours.The vacuum concentration reaction mixture, and with column chromatography at silica gel (solvent; Chloroform: methyl alcohol=100: 0 → 90: 10) go up the purification resistates to obtain the anti-4-of buttery (dipropyl amino) hexahydrobenzoic acid methyl esters (600mg, productive rate: 78%).MS(APCI)m/z：242[M+H] +
Reference example 254
(1) methyl alcohol (32mL) solution to 4-(3-hydroxyl 1-proyl) methyl benzoate (2g) adds Lin Dela (Lindlar) catalyzer (238mg), and stirs the mixture under the room temperature hydrogen atmosphere 18 hours.Add lindlar catalyst (90mg) to reaction mixture, and stirred the mixture 1 hour.By the diatomite filtration reaction mixture to remove insoluble substance.Vacuum concentrated filtrate, and with column chromatography at silica gel (solvent; Normal hexane: ethyl acetate=100: 0 → 50: 50) go up the purification resistates to obtain 4-(3-hydroxyl-1-propenyl) methyl benzoate (1.5g, productive rate: amorphous powder 75%).MS(APCI)m/z：175[M+H-H 2O] +
(2) tetrahydrofuran (THF) (4mL) solution at the ice-cooled compound (200mg) that obtains to above-mentioned steps (1) down adds triethylamine (218 μ L) and methane sulfonyl chloride (105 μ L), and stirs the mixture 30 minutes.Use the ethyl acetate diluted reaction mixture, and to wherein adding 10% citric acid solution.Use the ethyl acetate extraction mixture, water and saturated brine wash extraction liquid successively, with this extraction liquid anhydrous sodium sulfate drying, and vacuum concentration.Resistates is dissolved in dimethyl formamide (2mL), and to wherein adding 2M dimethyl amine/tetrahydrofuran (THF) (2mL).In stirring at room mixture 2 days.Use the ethyl acetate diluted reaction mixture, with the saturated sodium bicarbonate solution washing, and vacuum concentration.With column chromatography at silica gel (solvent; Chloroform: methyl alcohol=100: 0 → 90: 10) go up the purification resistates to obtain buttery 4-[3-(dimethylamino)-1-propenyl] methyl benzoate (198mg, productive rate: 87%).MS(APCI)m/z：220[M+H] +
Reference example 255
Add tetrahydrofuran (THF) (2.2mL) solution of 2M dimethyl amine to dimethyl formamide (3mL) solution of 4-(3 tosyloxy propyl group) methyl benzoate (500mg), and stirred the mixture 15 hours at 50 ℃.Use the ethyl acetate diluted reaction mixture, with the saturated sodium bicarbonate solution washing, and vacuum concentration.With column chromatography at silica gel (solvent; Chloroform: methyl alcohol=100: 0 90: 10) go up the purification resistates to obtain buttery 4-[3-(dimethylamino) propyl group] methyl benzoate (357mg, productive rate: quantitatively).MS(APCI)m/z：222[M+H] +
Reference example 256
With handling 4-(3-hydroxyl 1-proyl) methyl benzoate, to obtain buttery 4-[3-(1-pyrrolidyl)-1-proyl with reference example 254 (2) described identical methods] methyl benzoate (463mg, productive rate: 91%).MS(APCI)m/z：244[M+H] +
Reference example 257
With handling the 4-fluorobenzoic acid tert-butyl ester, to obtain 4-[2-(dimethylamino) ethyl with reference example 251 described identical methods] benzaminic acid dihydrochloride amorphous powder.MS(APCI)m/z：209[M+H] +
Reference example 258 to 303
With with above-mentioned reference example in the described identical method of arbitrary reference example handle corresponding raw material, to obtain down the compound of tabulation shown in 39.
Table 39 (No.1)
Figure A20048000260102901
*: hydrochloride
Me: methyl, Et: ethyl, n-Pr: n-propyl, Boc: tert-butoxycarbonyl
Table 39 (No.2)
Me: methyl
Table 39 (No.3)
Figure A20048000260102921
*: hydrochloride
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl
Table 39 (No.4)
Figure A20048000260102922
Me: methyl, n-Pr: n-propyl, i-Bu: isobutyl-, t-Bu: the tertiary butyl
Table 39 (No.5)
Figure A20048000260102931
Me: methyl, Et: ethyl, Bzl: phenmethyl,
Boc: tert-butoxycarbonyl
Table 39 (No.6)
Figure A20048000260102941
Me: methyl, Et: ethyl
Table 39 (No.7)
Me: methyl, Et: ethyl
Table 39 (No.8)
Figure A20048000260102951
Me: methyl, Et: ethyl
Table 39 (No.9)
Figure A20048000260102952
Me: methyl, Et: ethyl
Reference example 304
(1) to 6-oxo-1,4,5, acetate (50mL) solution of 6-tetrahydro pyridazine-3-carboxylic acid (20g) adds 25% Hydrogen bromide/acetate (200mL), and at room temperature to wherein dripping dimethyl sulfoxide (DMSO) (22.0g).At room temperature stirred the mixture 3 days.Filter to collect the throw out that obtains, use acetate and water washing successively and 40 ℃ of dried overnight, to obtain 6-oxo-1,6-dihydrogen dazin-3-carboxylic acid (10.55g, productive rate: clear crystal 54%).MS(ESI)m/z：139[M-H]-
(2) in toluene (5mL) solution of the compound (1.0g) that above-mentioned steps (1) obtains, add thionyl chloride (3mL) and two dimethyl formamides down ice-cooled, and stirred the mixture 3 hours at 80 ℃.After the cooling, the vacuum concentration reaction mixture also adds ether to resistates.Filter and collect the crystal that obtains, with ether washing and dry to obtain 6-chloro-1,6-dihydrogen dazin-3-carboxylic acid, ethyl ester (813mg, productive rate: colourless powder 61%).MS(APCI)m/z：187/189[M+H] +
Reference example 305
Ice-cooled following to 4-cyclohexanone carboxylic acid ethyl ester (5g), N, N-dimethyl ethylidene-1, chloroform (50mL) solution of 2-diamines (6.45mL) and acetate (3.36mL) adds sodium triacetoxy borohydride (9.8g), and in the stirring at room mixture overnight.Add saturated sodium bicarbonate solution to reaction mixture.After the stirring, also use chloroform extraction (2 times) with salt of wormwood alkalization mixture.Dry extraction liquid and vacuum concentration.With flash column chromatography at silica gel (Biotage, Flash 75M, solvent: the crude product that purifying obtains chloroform/methanol/ammoniacal liquor=19: 1: 0.3) is to obtain buttery 4-(2-dimethyl aminoethyl amino) hexahydrobenzoic acid ethyl ester (cis-trans-isomer mixture, 6.63g, productive rate: 94%).MS(APCI)m/z：243[M+H] +
Reference example 306
With handling respective compound with the described identical methods of reference example 242, with obtain 4-(3-dimethylamino-2,2-dimethyl propoxy-)-3-nipagin A (MS (APCI) m/z:296[M+H] +).(60% mineral oil dispersion liquid 22.7mg), and stirred the mixture 20 minutes to add sodium hydride in dimethyl formamide (1.5mL) solution of this compound (80mg).Add 4-(2-chloroethyl) morpholine hydrochloride (55.4mg) to this mixture, and in stirring at room mixture one day.The dilute with water reaction mixture is also used chloroform extraction (3 times).The vacuum concentration extraction liquid, and with flash column chromatography at NH-silica gel (solvent: ethyl acetate/normal hexane=5: 95 → 25: 75) go up to purify the product that obtains to obtain buttery 4-(3-dimethylamino-2,2-dimethyl propoxy-)-3-(2-morpholine-4-base oxethyl) ethyl benzoate (53mg, productive rate: 70%).MS(APCI)m/z：409[M+H] +
Reference example 307
To the N of 6-chlorine apellagrin methyl esters (10g), add N in N-dimethyl sulfoxide (DMSO) (15mL) solution, N-dimethyl-ethylenediamine (10mL), and stir the mixture at 75 ℃ and to spend the night.The dilute with water reaction mixture is also used ethyl acetate extraction.The vacuum concentration extraction liquid, and with flash column chromatography at NH-silica gel (solvent: n-hexane/ethyl acetate=1: 1) go up to purify the product that obtains) ethyl to obtain the 6-[(2-dimethylamino] amino-nicotinic acid methyl esters (4.09g, productive rate: yellow liquid 31%).MS(APCI)m/z：224[M+H] +
Reference example 308
(1) to the N of 1-amino-2-methyl-2-propane thiolate hydrochlorate (75mg), dinethylformamide (2mL) solution add sodium hydride (60% mineral oil dispersion liquid, 50mg), and in stirring at room mixture 30 minutes.Add the 4-fluorobenzoic acid tert-butyl ester (50mg) to this mixture, and stirred the mixture 4 hours at 70 ℃.The dilute with water reaction mixture is also used ethyl acetate extraction.The vacuum concentration extraction liquid, and with flash column chromatography at NH-silica gel (solvent: ethyl acetate) go up to purify the product that obtains) sulfenyl to obtain the 4-[(2-amino-1 of colorless oil, 1-dimethyl ethyl] t-butyl perbenzoate (54mg, productive rate: 75%).MS(APCI)m/z：282[M+H] +
(2) use with the described identical methods of embodiment 618 (1) and handle the compound (59mg) that obtains in the above-mentioned steps (1), to obtain the 4-[(2-dimethylamino-1 of yellow oily, 1-dimethyl ethyl) sulfenyl] t-butyl perbenzoate (40mg, productive rate: 62%).MS(APCI)m/z：310[M+H] +
Reference example 309
(1) methyl alcohol (20mL) solution to 4-Thiosalicylic acid (1.5g) adds the vitriol oil (0.5mL) and the mixture backflow is spent the night.Evaporation reaction mixture desolvates to remove, and uses in the saturated sodium bicarbonate solution and resistates.Use the ethyl acetate extraction mixture, and the vacuum concentration extraction liquid, to obtain 4-Thiosalicylic acid methyl esters (1.6g, the productive rate: 99%) of colorless oil.MS(APCI)m/z：167[M-H]-
(2) use with the described identical methods of embodiment 381 and handle the compound (50mg) that obtains in the above-mentioned steps (1), to obtain brown buttery 4-[(3-dimethylamino-2,2-dimethyl propyl) sulfenyl] methyl benzoate (58mg, productive rate: 69%).MS(APCI)m/z：282[M+H] +
Reference example 310
(1) adds a 2-nitrobenzene sulfonyl chloride (10.5g) at 65 ℃ of water (25mL) solution by part, and stirred the mixture 3 hours at 90 ℃ to diethanolamine (5.0g) and yellow soda ash (5.5g).The dilute with water reaction mixture is also used ethyl acetate extraction.The vacuum concentration extraction liquid also adds thionyl chloride (10mL) to resistates.Stirred the mixture 2 hours at 90 ℃.Reaction mixture is poured in the water and is used into the chloroform extraction mixture.The vacuum concentration extraction liquid, and with flash column chromatography at silica gel (solvent: n-hexane/ethyl acetate=4: 1) go up the purification resistates to obtain N, N-two (2-chloroethyl)-2-nitrobenzene sulfonamide (7.1g, productive rate: yellow liquid 46%).MS(APCI)m/z：327/329[M+H] +
(2) use with the described identical methods of embodiment 434 (1) and handle compound (2.0g) and the anti-4-aminocyclohexane carboxylate methyl ester (1.0g) that obtains in the above-mentioned steps (1); with anti-4-[4-(the 2-oil of mirbane alkylsulfonyl) piperazine-1-yl that obtains yellow oily] hexahydrobenzoic acid methyl esters (1.29g, productive rate: 61%).MS(APCI)m/z：412[M+H] +
Reference example 311
With handling anti-4-[N-(tert-butoxycarbonyl)-N-[2-(dimethylamino) ethyl with embodiment 404 (2) described identical methods] amino] the hexahydrobenzoic acid methyl esters (compound that reference example 114 obtains, 2.0g) to obtain anti-4-[N-[2-(dimethylamino) ethyl] amino] hexahydrobenzoic acid methyl esters (1.5g, productive rate: clear crystal 82%).MS(APCI)m/z：229[M+H] +
Reference example 312
With handling respective compound, to obtain 4-[3-(methylamino)-1-proyl with reference example 256 described identical methods] methyl benzoate.Add tert-Butyl dicarbonate at ice-cooled following chloroform (4mL) solution to this compound (227mg), and in the stirring at room mixture overnight.The vacuum concentration reaction mixture and with column chromatography silica gel (solvent: n-hexane/ethyl acetate=8: 1) go up product that purification obtains to obtain 4-[3-(N-methyl-N-tert-butoxycarbonyl amino)-1-proyl] methyl benzoate (225mg, productive rate: clear crystal 86%).MS(APCI)m/z：321[M+NH 4] +
Reference example 313
With handling respective compound with reference example 254 described identical methods, to obtain 4-[3-(methylamino)-suitable 1-propenyl] methyl benzoate, use then with reference example 312 described identical methods and handle this compound (135mg), to obtain 4-[3-(N-methyl-N-tert-butoxycarbonyl amino)-1-propenyl] methyl benzoate (135mg, productive rate: clear crystal 86%).MS(APCI)m/z：323[M+NH 4] +
Reference example 314
With handling respective compound with reference example 255 described identical methods, to obtain 4-[3-(methylamino) propyl group] methyl benzoate, use then with reference example 312 described identical methods and handle this compound (117mg) to obtain 4-[3-(N-methyl-N-tert-butoxycarbonyl amino) propyl group] methyl benzoate (123mg, productive rate: clear crystal 90%).MS(APCI)m/z：325[M+NH 4] +
Reference example 315 to 355
With with above-mentioned reference example in the described identical method of arbitrary reference example handle corresponding raw material, to obtain down the compound of tabulation shown in 40.
Table 40 (No.1)
Figure A20048000260102991
Me: methyl, Boc: tert-butoxycarbonyl
Table 40 (No.2)
Figure A20048000260103001
Me: methyl
Table 40 (No.3)
Figure A20048000260103002
Me: methyl, Et: ethyl
Table 40 (No.4)
Figure A20048000260103011
Me: methyl, Et: ethyl
Table 40 (No.5)
Figure A20048000260103021
Me: methyl
Table 40 (No.6)
Figure A20048000260103031
Me: methyl, Et: ethyl
Table 40 (No.7)
Me: methyl, t-Bu: the tertiary butyl
Reference example 356 to 357
With with above-mentioned reference example in the described identical method of arbitrary reference example handle corresponding raw material, to obtain down the compound of tabulation shown in 41.
Table 41
Figure A20048000260103042
Me: methyl, Et: ethyl, t-Bu: the tertiary butyl

Claims (22)

1. formula [I] compound or pharmaceutically acceptable salt thereof:
Figure A2004800026010002C1
Wherein, R 1Be
(A) have substituent aryl,
(B) optionally have substituent nitrogenous aliphatic heteromonocyclic group,
(C) have substituent ring type low alkyl group,
(D) optionally have substituent amino, or
(E) have substituent heteroaryl,
R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl,
Y is singly-bound, low-grade alkylidene or lower alkenylene,
Z be the group shown in the following chemical formula :-CO-,-CH 2-,-SO 2-or
Figure A2004800026010002C2
Q is a low-grade alkylidene, and q is integer 0 or 1.
2. compound as claimed in claim 1, wherein R 1Be
(A) has 1～3 the substituent aryl that is selected from following group: (i) hydroxyl; (ii) halogen atom; (iii) low alkyl group; (iv) amino; this amino optionally has one or two substituting group that is selected from following group: optionally have low alkyl group, lower alkoxy-low alkyl group, the amino low-grade alkane acidyl of hydroxyl substituent, this amino low-grade alkane acidyl optionally has and is selected from the group shown in low alkyl group, lower alkoxycarbonyl and the following general formula as substituting group:
Figure A2004800026010003C1
Wherein, R 31It is low alkyl group in described amino part, (single or two low alkyl groups) amino low alkyl group, (single or two low alkyl groups) carbamyl, the low-grade alkane acidyl that optionally has hydroxyl substituent, the ring type lower alkylcarbonyl, lower alkoxy-low-grade alkane acidyl, lower alkoxy-lower alkoxycarbonyl, ring type low alkyl group-low alkyl group, the low alkyl group alkylsulfonyl, optionally has (single or two low alkyl groups) amino as substituent aryl lower alkyl, rudimentary enoyl-, optionally has low alkyl group as substituent thiocarbamyl, the heteroaryl carbonyl, has nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group, has nitrogenous aliphatic heteromonocyclic group as substituent low-grade alkane acidyl, optionally has (single or two low alkyl groups) amino at aryl moiety as substituent aryl sulfonyl; Group shown in the following general formula:
Figure A2004800026010003C2
Wherein, R 32Be lower alkoxy and optionally have low alkyl group as substituent nitrogenous aliphatic heteromonocyclic group; (v) optionally have a substituent lower alkoxy that is selected from following group: amino, described amino optionally have be selected from low alkyl group and aryl lower alkyl group as substituting group; The heteroaryl that optionally has low-grade alkyl substituent; And the nitrogenous aliphatic heteromonocyclic group that optionally has low-grade alkyl substituent; (vi) optionally has a substituent amino-low alkyl group that is selected from following group: the low alkyl group that optionally has hydroxyl substituent; low-grade alkane acidyl; (single or two low alkyl groups) amino-low alkyl group; (single or two low alkyl groups) amino-lower alkoxycarbonyl; lower alkoxy-low-grade alkane acidyl; (single or two low alkyl groups) carbamyl; lower alkoxy-lower alkoxycarbonyl; lower alkoxy-low alkyl group; the ring type lower alkylcarbonyl; aryl lower alkyl; the ring type low alkyl group; ring type low alkyl group-low alkyl group; have nitrogenous aliphatic heteromonocyclic group as the group shown in substituent lower alkoxycarbonyl and the following general formula:
Figure A2004800026010003C3
Wherein, R 33It is amino, (single or two low alkyl groups) amino or (single or two low alkyl groups) amino-low-grade alkyl amino; (vii) have nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group, described low alkyl group optionally has the substituting group that is selected from following group: hydroxyl, optionally have low alkyl group, lower alkoxy-low alkyl group and a carbamyl of hydroxyl substituent; (viii) optionally has a substituent carbamyl that is selected from following group: low alkyl group, (single or two low alkyl groups) amino-low alkyl group, have the substituent low alkyl group of heteroaryl and have nitrogenous aliphatic heteromonocyclic group as substituent low alkyl group; (ix) optionally have the nitrogenous aliphatic heteromonocyclic group of low-grade alkyl substituent, described nitrogenous aliphatic heteromonocyclic group can be connected to aryl moiety by the Sauerstoffatom key; (x) nitro; (xi) optionally has (single or two low alkyl groups) amino substituent ring type lower alkoxy; (xii) group that optionally has and be selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group is as substituent low-grade alkylidene; (xiii) the one or more groups that optionally have and be selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group are as substituent low-grade alkynyl; (xiv) optionally has (single or two low alkyl groups) amino substituent low alkyl group sulfenyl; (xv) optionally have (single or two low alkyl groups) amino substituent ring type low alkyl group-lower alkoxy in ring type low alkyl group part,
(B) optionally have substituent nitrogenous aliphatic heteromonocyclic group, described substituting group is selected from: low alkyl group; Has the substituent low-grade alkane acidyl of nitrogenous aliphatic heteromonocyclic group; (single or two low alkyl groups) amino-low-grade alkane acidyl; Lower alkoxy-low alkyl group; (single or two low alkyl groups) amino-low alkyl group; The ring type low alkyl group; Heteroaryl; Nitrogenous aliphatic heteromonocyclic group optionally comprises one or more pairs of keys and optionally has the one or more substituting groups that are selected from following group: low alkyl group, lower alkoxy-low alkyl group, carbamyl and low-grade alkane acidyl-amino in the ring of this nitrogenous aliphatic heteromonocyclic group; And optionally has the one or more substituent amino that is selected from following group: low alkyl group, (single or two low alkyl groups) amino, ring type low alkyl group-carbonyl, rudimentary enoyl-, heteroaryl carbonyl, lower alkoxy-low alkyl group, low-grade alkane acidyl and nitrogenous aliphatic heteromonocyclic group
(C) have substituent ring type low alkyl group, this substituting group is selected from: (i) optionally have the substituent amino that is selected from following group: low alkyl group; (single or two low alkyl groups) amino-low-grade alkane acidyl; has the substituent low-grade alkane acidyl of nitrogenous aliphatic heteromonocyclic group; (single or two low alkyl groups) amino-low alkyl group; low-grade alkane acidyl; the ring type lower alkylcarbonyl; rudimentary enoyl-; the heteroaryl carbonyl; optionally have one or more halogen atoms as substituent aryl carbonyl; low alkyl group-thiocarbamyl; elementary alkoxy carbonyl; the ring type low alkyl group; group shown in the following general formula:
Figure A2004800026010005C1
Wherein, R 34Be (single or two low alkyl groups) amino, ring type low alkyl group-low alkyl group and low alkyl group alkylsulfonyl; (ii) optionally has the substituent amino-low alkyl group that is selected from following group: the low alkyl group that optionally has hydroxyl substituent, (single or two low alkyl groups) amino-low-grade alkane acidyl, has the substituent low-grade alkane acidyl of nitrogenous aliphatics heteromonocyclic group, has the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group, (single or two low alkyl groups) amino-low alkyl group, has the substituent low alkyl group of heteroaryl, lower alkoxy-low alkyl group, low-grade alkane acidyl, heteroaryl moieties optionally has the heteroaryl carbonyl of low-grade alkyl substituent, the ring type lower alkylcarbonyl, aryl lower alkyl, the ring type low alkyl group, ring type low alkyl group-low alkyl group, the low alkyl group alkylsulfonyl, elementary alkoxy carbonyl, one or more groups that single or two low alkyl group carbamyl and optionally having is selected from halogen atom and the lower alkoxy are as substituent aryl carbonyl, lower alkoxy-low-grade alkane acidyl and low-grade alkane acidyl; (iii) optionally has the one or more substituent nitrogenous aliphatics heteromonocyclic group that is selected from following group: hydroxyl, low alkyl group, low-grade alkane acidyl and lower alkoxy-low alkyl group; (iv) have the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group, described nitrogenous aliphatics heteromonocyclic group optionally condenses with phenyl ring and optionally has a substituting group that is selected from following group: low alkyl group, carbamyl or thiocarbamyl, hydroxyl, lower alkoxy-low alkyl group, low-grade alkane acidyl and (single or two low alkyl groups) amino; (v) single or two low-grade alkyl amino-lower alkoxies; (vi) optionally have the one or more substituent carbamyl that is selected from following group: have the substituent low alkyl group of nitrogenous aliphatics heteromonocyclic group, described low alkyl group optionally has low-grade alkyl substituent; (single or two low alkyl groups) amino; And low alkyl group,
(D) optionally have the amino of low-grade alkyl substituent, or
(E) optionally have substituent heteroaryl, described substituting group is selected from: (i) optionally have the one or more substituent amino-low alkyl group that is selected from low alkyl group and the lower alkoxy-low alkyl group; (ii) optionally has the substituent amino that is selected from following group: ring type lower alkylcarbonyl, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, rudimentary enoyl-, (single or two low alkyl groups) thiocarbamyl, (single or two low alkyl groups) carbamyl and low alkyl group; (iii) optionally has the substituent carbamyl that is selected from following group: low alkyl group, have the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group and (single or two low alkyl groups) amino-low alkyl group; (iv) optionally have one or more halogen atoms as substituent low alkyl group; (v) (single or two low alkyl groups) amino-lower alkoxy; (vi) oxo group; (group shown in the vii) following general formula:
Figure A2004800026010006C1
Wherein, ring A is nitrogenous aliphatic heteromonocyclic group, and this nitrogenous aliphatic heteromonocyclic group optionally has low-grade alkyl substituent and optionally condenses Y with phenyl ring aBe singly-bound, low-grade alkylidene or lower alkenylene, p is integer 0 or 1, and
R 2Be that (a) optionally has 1～3 identical or different substituent heteroaryl, described substituting group is selected from low alkyl group, lower alkoxy and (single or two low alkyl groups) amino; Or (b) optionally having 1～3 identical or different substituent aryl, described substituting group is selected from low alkyl group, halogen atom, halogenated lower alkoxy, (single or two low alkyl groups) amino, lower alkoxy, nitro, lower alkoxy-low alkyl group, hydroxyl, low-grade alkane acidyl and elementary alkoxy carbonyl.
3. compound as claimed in claim 2, wherein, R 1And R 2In aryl be phenyl or naphthyl.
4. compound as claimed in claim 2, wherein, R 1And R 2In nitrogenous aliphatics heteromonocyclic group be 4 yuan to 8 yuan nitrogenous aliphatics heteromonocyclic group.
5. compound as claimed in claim 4, wherein, described nitrogenous aliphatic heteromonocyclic group is azetidinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl, azatropylidene base, diazepine base, azecine, two azecines, 3-pyrrolinyl or morpholinyl.
6. compound as claimed in claim 2, wherein, R 1And R 2In heteroaryl be 5 yuan to 10 yuan list or bicyclic heteroaryl.
7. compound as claimed in claim 6, wherein, described heteroaryl is: nitrogenous heteroaryl, described nitrogenous heteroaryl is selected from pyrryl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyridyl, dihydropyridine base, pyrazinyl, pyrimidyl, tetrahydro-pyrimidine base, furan pyrimidyl, pyridazinyl, imidazolidyl, draws diindyl base, quinolyl, isoquinolyl, purine radicals, 1H-indazolyl, quinazolyl, cinnolinyl, quinoxalinyl, 2 base and pteridyl; The heteroaryl of perhaps oxygen containing heteroaryl or sulfur-bearing, the heteroaryl of described oxygen containing heteroaryl or sulfur-bearing is selected from furyl, pyranyl, thienyl, benzofuryl and benzo thienyl.
8. as each described compound in the claim 2 to 7, wherein Y is singly-bound, low-grade alkylidene or lower alkenylene, and Z is-CO-R 2Be have the group that is selected from lower alkoxy, low alkyl group and halogen atom as substituent phenyl, have the substituent heteroaryl of lower alkoxy or have the heteroaryl of low-grade alkyl substituent, and q is an integer 0.
9. as each described compound in the claim 2 to 7, wherein Y is a singly-bound, and Z is-CH 2-, R 2Be lower alkoxyphenyl, and q is an integer 0.
10. compound, wherein R as claimed in claim 8 or 9 1Be
(a) has the substituent phenyl that is selected from following group: (i) lower alkoxy; this lower alkoxy has the substituting group that is selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group; (ii) low alkyl group; this low alkyl group has the substituting group that is selected from (single or two low alkyl groups) amino and nitrogenous aliphatic heteromonocyclic group; (iii) amino; this amino has the substituting group that is selected from following group: low alkyl group; the ring type lower alkylcarbonyl; (single or two low alkyl groups) amino-low alkyl group; lower alkoxy-elementary alkoxy carbonyl; has the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group; low-grade alkane acidyl and rudimentary enoyl-
(b) have the substituent ring type low alkyl group that is selected from following group: (i) amino low alkyl group, this amino low alkyl group optionally has the one or more substituting groups that are selected from the following group: low alkyl group, hydroxy lower alkyl, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, ring type lower alkylcarbonyl and lower alkoxy-low alkyl group; The nitrogenous aliphatic heteromonocyclic group that (ii) optionally has hydroxyl substituent; (iii) amino, this amino has the substituting group that is selected from following group: low alkyl group, (single or two low alkyl groups) amino-low alkyl group, low-grade alkane acidyl, heteroaryl carbonyl, low alkyl group alkylsulfonyl and low alkyl group-thiocarbamyl, or
(c) has the substituent nitrogenous aliphatic heteromonocyclic group that is selected from following group: (i) low alkyl group; (ii) amino, this amino optionally has the substituting group that is selected from low alkyl group, (single or two low alkyl groups) amino-low alkyl group and ring type lower alkylcarbonyl; The nitrogenous aliphatic heteromonocyclic group that (iii) has low-grade alkyl substituent, R 2Be to have the substituent phenyl that is selected from halogen atom and lower alkoxy, have the heteroaryl of low-grade alkyl substituent or have the substituent heteroaryl of lower alkoxy, and Q is a methylene radical.
11. compound as claimed in claim 8, wherein, the general formula radicals R 1-(O) q-Y-Z-is 4-(single or two low-grade alkyl amino-low alkyl groups) benzoyl; 4-(pyrrolidyl-low alkyl group) benzoyl; 4-(two low-grade alkyl amino-lower alkoxy) benzoyl; 3-(two low-grade alkyl amino-lower alkoxy)-4-(two low-grade alkyl amino-lower alkoxy) benzoyl; 4-(piperidino-(1-position only)-lower alkoxy) benzoyl; 4-[N-low alkyl group-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; Rudimentary enoyl--the N-of 4-[N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-(lower alkoxy-elementary alkoxy carbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] benzoyl; 4-[N-low-grade alkane acidyl-N-(pyrrolidyl-low alkyl group) amino] benzoyl; [1-(low alkyl group) piperidin-4-yl] carbonyl; 4-[N-low alkyl group-N-(two low-grade alkyl amino-low alkyl group) amino] the piperidino-(1-position only) carbonyl; 4-[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] the piperidino-(1-position only) carbonyl; 4-[4-(two low alkyl group) piperidino-(1-position only)] the piperidino-(1-position only) carbonyl; [1-(low alkyl group) piperidin-4-yl] low-grade alkane acidyl; [1-(low alkyl group) piperidin-4-yl] rudimentary enoyl-; 4-(two low-grade alkyl amino-low alkyl group) cyclohexyl-carbonyl; 4-(single or two low-grade alkyl aminos) cyclohexyl-carbonyl; 4-[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; Rudimentary enoyl--the N-of 4-[N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; 4-[N-heteroaryl carbonyl-N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; 4-[N-low alkyl group sulfo-carbamyl-N-(two low-grade alkyl amino-low alkyl group) amino] cyclohexyl-carbonyl; 4-[N-(two low-grade alkyl amino-low alkyl group)-N-(low alkyl group alkylsulfonyl) amino] cyclohexyl-carbonyl; 4-[[N-low alkyl group-N-(hydroxy lower alkyl) amino] low alkyl group] cyclohexyl-carbonyl; 4-[[N-low alkyl group-N-(lower alkoxy-low alkyl group) amino] low alkyl group] cyclohexyl-carbonyl; 4-[[N-low-grade alkane acidyl-N-(two low-grade alkyl amino-low alkyl group) amino] low alkyl group] cyclohexyl-carbonyl; 4-[[N-(ring type lower alkylcarbonyl)-N-(two low-grade alkyl amino-low alkyl group) amino] low alkyl group] cyclohexyl-carbonyl; 4-(pyrrolidyl) cyclohexyl-carbonyl; 4-(hydroxyl pyrrolidine base) cyclohexyl-carbonyl; Or 4-(piperidino-(1-position only)) cyclohexyl-carbonyl, and, R 2Be to have one or two the substituent phenyl that is selected from oxyethyl group and fluorine atom; The ethoxy pyridine base; Propyl group pyridyl or propyl group thiazolyl.
12. as claim 10 or 11 described compounds, wherein, R 2Be 3-ethoxyl phenenyl, 6-propyl group pyridine-2-base, 6-ethoxy pyridine-2-base, 2-propyl group-1,3-thiazoles-4-base or 3-oxyethyl group-2-fluorophenyl.
13 A compound or a pharmaceutically acceptable salt thereof, the compound is 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - [2 - (dimethylamino) ethoxy] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] Pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [2 - (1 - piperidinyl) ethoxy] benzoyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (dimethylaminomethyl) Benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - (diethylamino) benzoyl] piperazin-1 - yl]-1H-pyrazolo - [3,4-d] pyrimidine Pyridine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (1 - pyrrolidinyl) benzoyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-(cyclopropylcarbonyl Yl)-N-[2 - (dimethylamino) ethyl] - amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] Pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-[(2 - methoxyethoxy) carbonyl]-N-[2 - (dimethylamino Ylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy Methyl-phenyl) -4 - [4 - [4 - [N-isobutyl-N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazine Triazine-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [(1 - propyl-piperidin-4 - Yl) carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [3 - (1 - Isopropyl-piperidin-4 - yl) propionyl]-piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy- Benzyl) -4 - [4 - [[trans 4 - (dimethylaminomethyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans 4 - (1 - pyrrolidinyl) cyclohexyl] carbonyl] piperazine Triazine-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [(E) -3 - (1 - iso- propyl Piperidin-4 - yl) acryloyl]-piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - [3 - (dimethylamino) -2,2 - dimethyl-propoxy] benzoyl] piperazin-1 - yl]-1H- Pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [4 - [3 - (dimethyl-amino Yl) -2,2 - dimethyl-propoxy] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - Ethoxy-benzyl) -4 - [4 - [4 - [N-acetyl-N-[2 - (1 - pyrrolidinyl) ethyl] amino] benzoyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - [N-acetyl- -N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (ethylamino) benzoyl] piperazin-1 - yl]-1H-pyrazol Pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [(trans-4 - piperidino-cyclohexyl) carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans 4 - ((3S) - 3 - Hydroxy-1 - pyrrolidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - B Oxy phenylmethyl) -4 - [4 - [[trans-4 - [N-acetyl-N-[2 - (dimethylamino) ethyl] amino] - cyclohexyl] Carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans- 4 - [N-(2 - furoyl)-N-[2 - (dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [N-(crotonic acid Yl)-N-[2 - (dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [N-(methyl-thio-carbamoyl Yl)-N-[2 - (dimethylamino) ethyl] amino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [4 - [N-Crotonoyl-N-[2 - (two Methylamino) ethyl] amino] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - Ethoxy-2 - yl) methyl] -4 - [4 - [[trans 4 - (1 - pyrrolidinyl) cyclohexyl] carbonyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans 4 - (1 - pyrrolidinyl Alkyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - Yl) methyl] -4 - [4 - [[trans 4 - (diethyl aminomethyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans-4 - [N-isopropyl-N-(2 - methyl oxygen Yl-ethyl) aminomethyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - Propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [4 - [2,2 - dimethyl-3 - (dimethylamino) propoxy] benzoic Benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl Yl] -4 - [4 - [[trans 4 - (propylamino) cyclohexyl] carbonyl] - piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine Pyridine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [[trans 4 - (propylamino) cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans- 4 - (1 - piperidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - ethoxy- Pyridin-2 - yl) methyl] -4 - [4 - [[trans 4 - (1 - piperidinyl) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl] -4 - [4 - [[trans 4 - (1 - piperidinyl) ring hexyl] Carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans- 4 - (ethylamino) cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy- Benzyl) -4 - [4 - [3 - [2 - (diisopropylamino) ethoxy] -4 - [3 - (dimethylamino) -2,2 - (dimethyl) Propoxy] benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzoic Yl) -4 - [4 - [4 - [N-(cyclopropane carbonyl)-N-[2 - (dimethylamino) ethyl] amino] carbonyl piperidino] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [4 - (3,3 - dimethoxyphenyl Piperidino yl) piperidino carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy- Benzyl) -4 - [4 - [4 - [N-ethyl-N-[2 - (dimethylamino) ethyl] amino] piperidino-carbonyl] piperazine Triazine-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans- 4 - [[N-(t-butyl)-N-ethyl amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[ 2 - (A Oxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy) ethyl yl] Amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-phenyl Methyl) -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy) ethyl] amino] methyl] cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl-1 ,3 - thiazol-4 - yl) methyl Yl] -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy) - ethyl] amino] methyl] cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans-4 - [[N- (tert- Butyl)-N-[2 - (hydroxy) ethyl] amino] methyl] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(6 - propyl-2 - yl) methyl] -4 - [4 - [[trans-4 - [N-[2 - (dimethylamino) ethyl Yl]-N-(methanesulfonyl) amino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - ethoxy-2 - yl) methyl] -4 - [4 - [[trans-4 - [N-[2 - (dimethylamino) ethyl]-N-(methyl Alkylsulfonyl) amino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - [(2 - propyl -1,3 - Thiazol-4 - yl) methyl] -4 - [4 - [[trans-4 - [N-[2 - (dimethylamino) ethyl]-N-(methanesulfonyl) Amino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - propyl-2 - Yl) methyl] -4 - [4 - [[trans-4 - [[N-[2 - (dimethylamino) ethyl]-N-pivaloyl amino] methyl] Ring Hexyl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] - pyrimidine; 1 - [(6 - propyl-2 - yl) methyl Yl] -4 - [4 - [[trans-4 - [[N-(cyclopropane carbonyl)-N-[2 - (dimethylamino) ethyl] amino] methyl] cyclohexyl Yl] carbonyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-benzyl) -4 - [4 - [[trans- 4 - [N-[2 - (dimethylamino) ethyl]-N-propionylamino] cyclohexyl] carbonyl] piperazin-1 - yl]-1H-pyrazol Pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [(trans-4 - piperidin-1 - cyclohexyl) Carbonyl] - piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzonitrile Yl) -4 - [4 - [[trans-4 - [[N-(t-butyl)-N-[2 - (methoxy) ethyl] amino] methyl] cyclohexyl] carbonyl] Piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorobenzyl) -4 - [4 - [4 - (ethylamino Ylmethyl) benzoyl] piperazin-1 - yl]-1H-pyrazolo [3,4-d] pyrimidine; 1 - (3 - ethoxy-2 - fluorophenyl Methyl) -4 - [4 - [4 - [N-acetyl-N-[2 - (dimethylamino) ethyl] amino] benzoyl] piperazine-1 - Yl]-1H-pyrazolo [3,4-d] pyrimidine. ...
14. a method for preparing following formula [I-A] compound, described formula [I-A] compound is:
Figure A2004800026010012C1
Wherein, R 1Be
(A) have substituent aryl,
(B) optionally have substituent nitrogenous aliphatic heteromonocyclic group,
(C) have substituent ring type low alkyl group,
(D) optionally have substituent amino, or
(E) have substituent heteroaryl,
R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl,
Y is singly-bound, low-grade alkylidene or lower alkenylene,
Z aBe chemical formula-CO-,-SO 2-or=group shown in the C=N-CN,
Q is a low-grade alkylidene, and q is integer 0 or 1, and described preparation method comprises makes following formula [II] compound or its salt and following formula [III] compound or its salt reaction, and described formula [II] compound is
Figure A2004800026010012C2
Wherein symbol definition is same as described above, and described formula [III] compound is:
R 1-(O) q-Y-Z a-OR 3[III]
Wherein, R 3Be hydrogen atom, low alkyl group or phenmethyl, other symbol is identical with above-mentioned definition.
15. a method for preparing following formula [I-B] compound, described formula [I-B] compound is:
Figure A2004800026010013C1
R wherein 1Be
(A) have substituent aryl,
(B) optionally have substituent nitrogenous aliphatic heteromonocyclic group,
(C) have substituent ring type low alkyl group,
(D) optionally have substituent amino, or
(E) have substituent heteroaryl,
R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl,
Y is singly-bound, low-grade alkylidene or lower alkenylene,
Q is a low-grade alkylidene, and q is integer 0 or 1, and described method comprises makes following formula [II] compound or its salt and following formula [IV] aldehyde cpd reaction, and described formula [II] compound is
Figure A2004800026010013C2
Wherein symbol definition is same as described above, and described formula [IV] aldehyde cpd is:
R 1-(O) q-Y-CHO [IV]
Wherein symbol definition is same as described above.
16. a method for preparing following formula [I-C] compound, described formula [I-C] compound is:
Figure A2004800026010013C3
Wherein, R 11For optionally having the substituent amino that is selected from following group: low alkyl group, (single or two low alkyl groups) amino-low alkyl group and have the substituent low alkyl group of nitrogenous aliphatic heteromonocyclic group, Z aBe chemical formula-CO-,-SO 2-or=group shown in the C=N-CN, R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl, and Q is a low-grade alkylidene, described preparation method comprises makes following formula [V] carboxylic acid cpd or its salt and following formula [VI] compound or its salt reaction, and described formula [V] carboxylic acid cpd is:
Figure A2004800026010014C1
Wherein symbol definition is same as described above, and described formula [VI] compound is:
R 11-H [VI]
R wherein 11Define same as described above.
17. a method for preparing following formula [I-D] compound is described:
Wherein, R 12Be optionally to have substituent nitrogenous aliphatic heteromonocyclic group or optionally have substituent amino, R 2Be that (a) optionally has substituent heteroaryl or (b) optionally have a substituent aryl, and Q is a low-grade alkylidene, described preparation method comprises makes following formula [VII] compound and following formula [VIII] compound or its salt reaction, perhaps make following formula [II] compound or its salt and following formula [IX] compound reaction, described formula [VII] compound is:
Figure A2004800026010014C3
Wherein, W 2Be reactive residue, other symbol definition is same as described above, and described formula [VIII] compound is:
Wherein symbol definition is same as described above, and described formula [II] compound is:
Wherein symbol definition is same as described above, and described formula [IX] compound is:
Wherein symbol definition is same as described above.
18. a pharmaceutical composition, said composition comprises: as each described compound or pharmaceutically acceptable salt thereof in the claim 1～13 of activeconstituents; And pharmaceutically acceptable carrier that is used for described activeconstituents.
19. one kind prevents and/or treats the method for leading the relevant disease of potassium channel (SK passage) with little electricity, this method comprises that the patient that needs are prevented and/or treated this disease uses each described compound or pharmaceutically acceptable salt thereof in the claim 1～13.
20. method as claimed in claim 19, wherein, described and little electricity is led the relevant disease of potassium channel and is selected from: gastrointestinal motility disorders, central nervous system disorder, emotional handicap, myotonic dystrophy or sleep apnea.
21. method as claimed in claim 20, wherein, described gastrointestinal motility disorders is constipation, irritable bowel syndrome, gastroesophageal reflux disease or postoperative ileus.
22. method as claimed in claim 20, wherein, described central nervous system disorder is memory and learning disorder, and described memory and learning disorder comprise Alzheimer and dysthymia disorders.
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US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
CN108752351A (en) * 2018-09-13 2018-11-06 遵义医学院 It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and the preparation method and application thereof
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CN103002897A (en) * 2010-04-23 2013-03-27 赛特凯恩蒂克公司 Certain amino-pyridazines, compositions thereof, and methods of their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
CN103002897B (en) * 2010-04-23 2017-06-09 赛特凯恩蒂克公司 Specific amino pyridazine class, thing in combination, and its application method
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
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CN109280014A (en) * 2018-09-05 2019-01-29 成都百事兴科技实业有限公司 Trans-4-amino-cyclohexanecarboxylic acid carbethoxy hydrochloride preparation method
CN108752351A (en) * 2018-09-13 2018-11-06 遵义医学院 It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and the preparation method and application thereof

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