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CN100564358C - The method of a kind of preparation 4-(3, the 4-dichlorophenoxy) piperidines - Google Patents

The method of a kind of preparation 4-(3, the 4-dichlorophenoxy) piperidines Download PDF

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CN100564358C
CN100564358C CNB200610110091XA CN200610110091A CN100564358C CN 100564358 C CN100564358 C CN 100564358C CN B200610110091X A CNB200610110091X A CN B200610110091XA CN 200610110091 A CN200610110091 A CN 200610110091A CN 100564358 C CN100564358 C CN 100564358C
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piperidines
dichlorophenoxy
alkyl
hydroxypropyl
carboxylic acid
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CN1907968A (en
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莉莲·阿尔卡雷兹
马克·弗伯
马克·珀迪
布赖恩·斯普林索普
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AstraZeneca AB
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Abstract

The invention provides formula (I) compound: wherein, X is CH 2, O, S (O) 2Or NR 10Y is a key, CH 2, NR 35, CH 2NH, CH 2NHC (O), CH (OH), CH (NHCOR 33), CH (NHSO 2R 34), CH 2O or CH 2S; Z is C (O), or Z also can be S (O) when Y is a key 2R 1For the optional aryl that replaces, the optional heterocyclic radical that replaces or with phenyl ring condensed C 4-6Cycloalkyl; And R 2, R 3, R 4, R 5, R 6, R 7And R 8, R 9, R 10, R 32, R 33, R 34And R 35As definition here; Be chemokine (especially CCR3) active regulator (be used for, for example, treat asthma).The present invention also provides preparation 4-(3, the 4-dichlorophenoxy) method of piperidines, and this 4-(3, the 4-dichlorophenoxy) piperidines can be used as the intermediate of some compound of preparation the present invention.

Description

The method of a kind of preparation 4-(3, the 4-dichlorophenoxy) piperidines
The present invention is a Chinese patent application (denomination of invention: compound; Application number: 03804130.8; The applying date: dividing an application on February 17th, 2003).
The present invention relates to have the piperidine derivative of pharmaceutical activity, the method for preparing these derivatives, the pharmaceutical composition that comprises these derivatives and these derivatives purposes as active therapeutic agent.The present invention also provides preparation 4-(3, the 4-dichlorophenoxy) method of piperidines, and this 4-(3, the 4-dichlorophenoxy) piperidines can be used as the intermediate of some compound of preparation the present invention.
The pharmaceutical activity piperidine derivative is existing open at WO01/62728, WO01/62729 and WO01/62757.
Chemokine is a chemotactic cytokine, is discharged so that scavenger cell, T cell, eosinophil, basophilic leukocyte and neutrophilic granulocyte are attracted to inflammation part by various kinds of cell, and plays a significant role in the maturation of immune system cell.Chemokine plays an important role in the immunity of all kinds of diseases and illness (comprising asthma and complaisance disease and autoimmunization pathology (as rheumatoid arthritis) and atherosclerosis) and inflammatory reaction.These little secretion molecules are members of a growing 8-14kDa protein superfamily, it is characterized by four conservative halfcystine motifs.This chemokine superfamily mainly can be divided into two groups that present the characteristic texture motif, i.e. Cys-X-Cys (C-X-X, or α) and Cys-Cys (C-C, or β) family.According near the cysteine residues the NH-between single amino acids and the sequence similarity inserted distinguish this two families.
The C-X-C chemokine comprises several effective chemoattractant and the activator of neutrophilic granulocyte such as interleukin 8 (IL-8) and neutrophil activation peptide 2 (NAP-2).
The C-C chemokine comprises monocyte and lymphocyte but do not comprise effective chemoattractant of neutrophilic granulocyte, as person monocytic cell's chemotactic protein 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (activation is regulated, normal T cell expressing and secretion), eosinophil chemotactic protein with hugely have a liking for cell inflammatory protein 1 α and 1 β (MIP-1 α and MIP-1 β).
Studies show that the subtribe mediation of the effect of chemokine by the G-protein linked receptor, wherein these acceptors are CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.Can be used for treatment those illnesss and disease as previously mentioned owing to regulate the medicine of these acceptors, so these acceptors are represented the good target of drug development.
Histamine is a kind of basic amine, 2-(4-imidazolyl)-ethamine, by Histidine through the effect of L-Histidine decarboxylase. and form.This material is found in overwhelming majority's tissue of health, but is present in lung, skin and the gi tract with high density.In the inflammatory cell of cell levels such as mastocyte and basophilic leukocyte, store a large amount of histamine.Recognize that at present the threshing of mastocyte and basophilic leukocyte and histamine release subsequently are for being responsible for the basic mechanism of irritated process clinical manifestation.Histamine is by bringing into play its effect to the effect of specific histamine G-protein linked receptor, mainly by three types, and H1, H2 and H3.Histamine H 1 antagonist comprises being used for the treatment of to suffer from the especially patient's of rhinitis and rubella maximum one class medicine of anaphylactic disease.The H1 antagonist can be used to control anaphylaxis, by for example blocking the effect of histamine to the postcapillary venule unstriated muscle, causes vascular permeability, oozes out and decrease in edema.This antagonist also can block the effect of histamine to the H1 acceptor on the c-type pain nerve fiber, causes scratching where it itches and sneezes minimizing.
The known viruse infection can cause pneumonia.Test verified common flu and increase the increase of air flue mucous membrane secretion eosinophil chemotactic protein.The eosinophil chemotactic protein splashes into some signs and the symptom that can simulate common cold in the nose.(referring to, Allergy (1999) such as Greiff L 54(11) 1204-8[Experimental common cold increase mucosal output of eotaxin in atopicindividuals] and Int.Arch.Allergy Immunol. (2000) such as Kawaguchi M 122S1 44[Expression of eotaxin by normal airway epithelial cells after virus A infection].)
Summary of the invention
One aspect of the present invention relates to the compound of formula (I):
Figure C20061011009100041
Wherein:
X is CH 2, O, S (O) 2Or NR 10
Y is a key, CH 2, NR 35, CH 2NH, CH 2NHC (O), CH (OH), CH (NHC (O) R 33), CH (NHS (O) 2R 34), CH 2O or CH 2S;
Z is C (O), or Z also can be S (O) when Y is a key 2
R 1For the optional aryl that replaces, the optional heterocyclic radical that replaces or with phenyl ring condensed C 4-6Cycloalkyl;
R 4Be hydrogen, C 1-6Alkyl is (optional by C 3-6Cycloalkyl substituted) or C 3-6Cycloalkyl;
R 2, R 3, R 5, R 6, R 7And R 8Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl;
M and n are 0 or 1 independently;
R 9Be optional aryl that replaces or the optional heterocyclic radical that replaces;
R 10, R 32And R 35Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl;
R 33And R 34Be C 1-6Alkyl or C 3-6Cycloalkyl;
Aryl and heterocyclic radical part wherein aforementionedly under possible situation, are optionally replaced by following groups: halogen, cyano group, nitro, hydroxyl, oxo S (O) kR 12, OC (O) NR 13R 14, NR 15R 16, NR 17C (O) R 18, NR 19C (O) NR 20R 21, S (O) 2NR 22R 23, NR 24S (O) 2R 25, C (O) NR 26R 27, C (O) R 28, CO 2R 29, NR 30CO 2R 31, C 1-6Alkyl (itself is optional by the replacement of NHC (O) phenyl list), C 1-6Haloalkyl, C 1-6Alkoxyl group (C 1-6) alkyl, C 1-6Alkoxyl group, C 1-6Halogenated alkoxy, C 1-6Alkoxyl group (C 1-6) alkoxyl group, C 1-6Alkylthio, C 2-6Alkenyl, C 2-6Alkynyl, C 3-10Cycloalkyl, methylene radical dioxy base, difluoro methylene dioxy base, phenyl, phenyl (C 1-4) alkyl, phenoxy group, thiophenyl, phenyl (C 1-4) alkoxyl group, morpholinyl, heteroaryl, heteroaryl (C 1-4) alkyl, heteroaryloxy or heteroaryl (C 1-4) alkoxyl group; Wherein any aforementioned phenyl and heteroaryl moieties are optional to be replaced by following groups: halogen, hydroxyl, nitro, S (O) r(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3
K and r are 0,1 or 2 independently;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 26, R 27, R 29And R 30Be hydrogen, C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), C 3-6(itself is optional by halogen, hydroxyl, nitro, NH for cycloalkyl, phenyl 2, NH (C 1-4Alkyl), NH (C 1-4Alkyl) 2, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace);
Perhaps NR 13R 14, NR 15R 16, NR 20R 21, NR 22R 23, NR 26R 27Can form independently and be selected from following 4-7 element heterocycle: (itself is optional by hydroxyl or C for azetidine 1-4Alkyl replaces), tetramethyleneimine, piperidines, nitrogen heterocyclic heptantriene, 1,4-morpholine or 1, the 4-piperazine, the latter is optional by C on its terminal nitrogen atom 1-4Alkyl replaces;
R 12, R 25, R 28And R 31Be C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14Described in ring), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace);
Condition be when X be CH 2And when m and n were 0, then Y was not NR 35
Or its N-oxide compound; Or the solvate of its pharmacologically acceptable salt, solvate or salt.
Preferably, in described compound, X is O; Y is a key, CH 2, NR 35, CH 2NH, CH (OH), CH (NHC (O) R 33), CH (NHS (O) 2R 34) or CH 2O; Z is C (O), or Z also can be S (O) when Y is a key 2R 1Be the optional phenyl that replaces; R 4Be hydrogen or C 1-6Alkyl; R 2, R 3, R 5, R 6, R 7And R 8, when existing, all be hydrogen; M and n are 0 or 1 independently; R 9Be optional aryl that replaces or the optional heterocyclic radical that replaces; R 32And R 35Be hydrogen or C independently 1-6Alkyl; R 33And R 34Be C 1-6Alkyl; Wherein aforementioned phenyl, aryl and heterocyclic radical part under possible situation, optional are replaced by following groups: halogen, cyano group, hydroxyl, oxo, S (O) 2R 12, NR 15R 16, NR 17C (O) R 18, S (O) 2NR 22R 23, NR 24S (O) 2R 25, C (O) NR 26R 27, CO 2R 29, C 1-6Alkyl (itself is optional by the replacement of NHC (O) phenyl list), CF 3, phenyl or heteroaryl; Wherein any aforementioned phenyl and heteroaryl moieties are optional to be replaced by following groups: halogen, C 1-4Alkyl, C 1-4Alkoxyl group or CF 3R 15, R 16, R 17, R 18, R 22, R 23, R 24, R 26, R 27And R 29Be hydrogen, C independently 1-6Alkyl (choose wantonly and replaced) or C by hydroxyl 3-6Cycloalkyl; Perhaps NR 22R 23(itself is optional by hydroxyl or C can to form the azetidine ring 1-4Alkyl replaces); R 12And R 25Be C independently 1-6Alkyl or phenyl; Or its pharmacologically acceptable salt.
Preferably, in described compound, R wherein 1Be phenyl, optional by halogen, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2NH (C 3-6Cycloalkyl), C (O) 2(C 1-4Alkyl), C (O) NH (C 1-4Alkyl) or C (O) NH 2Replace.
Preferably, in described compound, X is O.
Preferably, in described compound, wherein Y is a key.
Preferably, in described compound, wherein Z is C (O).
Preferably, in described compound, wherein m and n are 0.
Preferably, in described compound, R 2, R 3, R 4, R 5, R 6, R 7And R 8, when existing, all be hydrogen.
Preferably, in described compound, R 9Be the optional heterocyclic radical that replaces; Wherein this heterocyclic radical is: thienyl, pyrryl, thiazolyl, pyrazolyl oxazolyl isoxazolyl, imidazolyl, 1,2,5-oxadiazole base, pyridyl, 1,6-dihydropyridine base, pyrimidyl, indyl, indazolyl, 2,3-dihydro-1H-indazolyl, imidazopyridyl, 2,1,3-diazosulfide base, quinoxalinyl, quinolyl, 1,2-dihydroquinoline base, 1, the 4-dihydroquinoline, isoquinolyl, 1,2-dihydro-isoquinoline base, cinnolinyl, 3,4-dihydro phthalazinyl, 2,3-dihydro-4H-1, the 4-benzoxazinyl, 3,4-dihydro-2H-1, the 4-benzoxazinyl, 1,3-dihydro-2H-pseudoindoyl, the method for preparation of pyrazolotriazine base, the pyrazolopyrimidine base, the imidazo benzothiazole, the imidazopyrimidine base, or 2,1,3-Ben Bing oxadiazole base, 1, the 3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, 4,5,6,7-tetrahydrochysene indazole or 2,3-dihydro-1H-benzoglyoxaline; Wherein this heterocyclic radical is replaced by one or more following radicals or does not replace: oxo (under the possible situation), halogen, C 1-4Alkyl, CF 3, C 1-4Alkoxyl group, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2Or OCF 3
The present invention relates to the method for the compound of a kind of preparation formula (I) on the other hand, and this method comprises formula (II) compound:
Figure C20061011009100071
Wherein X, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 32, m and n as defined above, under following various situations, react with following each general formula compound:
(i) when Y be a key, CH 2, NR 35, CH 2NH, CH 2NHC (O), CH (OH), CH (NHCOR 33), CH (NHSO 2R 34), CH 2O or CH 2S, Z are C (O), R 35Be not hydrogen and R 33And R 34In the time of as defined above, under the condition that alkali exists, choose wantonly in the presence of coupling agent and react with formula (IIIa) compound:
L 1-CO-Y-R 9 (IIIa)
R wherein 9As defined above and L 1Be leavings group;
(ii) when Y be NH and Z when being C (O), react with formula (IIIb) compound:
Figure C20061011009100081
R wherein 9As defined above; Or,
(iii) working as Y is that a key and Z are S (O) 2The time, under the condition that alkali exists, react with formula (IIIc) compound:
L 1-S(O) 2-R 9 (IIIc)
R wherein 9As defined above and L 1Be leavings group.
The present invention relates to a kind of pharmaceutical composition on the other hand, comprises formula (I) compound, or its pharmacologically acceptable salt, or its solvate, or the solvate of its salt, and pharmaceutically acceptable adjuvant, diluent or carrier.
Another aspect of the invention relates to formula (I) compound, or its pharmacologically acceptable salt, or its solvate, or the solvate of its salt is used for the treatment of.
The present invention relates to formula (I) compound on the other hand, or its pharmacologically acceptable salt, or its solvate, or the purposes of the solvate of its salt in the medicine that preparation is used for the treatment of.
The present invention relates to a kind of method for the treatment of chemokine mediated diseases state in the Mammals on the other hand, wherein said Mammals suffers from described disease, or be in the danger of described disease, described method comprise to the administration of this treatment of needs treatment significant quantity formula (I) compound, or its pharmacologically acceptable salt, or its solvate, or the solvate of its salt.
The present invention relates to the method for a kind of preparation 4-(3, the 4-dichlorophenoxy) piperidines on the other hand, comprises the steps:
A. 4-hydroxy piperidine and suitable alkali are at room temperature reacted in appropriate solvent; And,
B. with consequent mixture and 1,2-two chloro-4-fluorobenzene are at 50-90 ℃, or heat under the reflux temperature of the solvent that uses.
Detailed Description Of The Invention
The invention provides the compound of formula (I):
Figure C20061011009100091
Wherein:
X is CH 2, O, S (O) 2Or NR 10
Y is a key, CH 2, NR 35, CH 2NH, CH 2NHC (O), CH (OH), CH (NHC (O) R 33), CH (NHS (O) 2R 34), CH 2O or CH 2S;
Z is C (O), or when Y was a key, Z also can be S (O) 2
R 1For the optional aryl that replaces, for the optional heterocyclic radical that replaces or with phenyl ring condensed C 4-6Cycloalkyl;
R 4Be hydrogen, C 1-6Alkyl is (optional by C 3-6Cycloalkyl substituted) or C 3-6Cycloalkyl;
R 2, R 3, R 5, R 6, R 7And R 8Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl;
M and n are 0 or 1 independently;
R 9For the optional aryl that replaces or for choosing the heterocyclic radical that replaces wantonly;
R 10, R 32And R 35Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl;
R 33And R 34Be C 1-6Alkyl or C 3-6Cycloalkyl;
Aryl and heterocyclic radical part wherein aforementionedly under the possible situation, are optionally replaced by following groups: halogen, cyano group, nitro, hydroxyl, oxo, S (O) kR 12, OC (O) NR 13R 14, NR 15R 16, NR 17C (O) R 18, NR 19C (O) NR 20R 21, S (O) 2NR 22R 23, NR 24S (O) 2R 25, C (O) NR 26R 27, C (O) R 28, CO 2R 29, NR 30CO 2R 31, C 1-6Alkyl (itself is optional by the replacement of NHC (O) phenyl list), C 1-6Haloalkyl, C 1-6Alkoxyl group (C 1-6) alkyl, C 1-6Alkoxyl group, C 1-6Halogenated alkoxy, C 1-6Alkoxyl group (C 1-6) alkoxyl group, C 1-6Alkylthio, C 2-6Alkenyl, C 2-6Alkynyl, C 3-10Cycloalkyl, methylene radical dioxy base, difluoro methylene dioxy base, phenyl, phenyl (C 1-4) alkyl, phenoxy group, thiophenyl, phenyl (C 1-4) alkoxyl group, morpholinyl, heteroaryl, heteroaryl (C 1-4) alkyl, heteroaryloxy or heteroaryl (C 1-4) alkoxyl group; Wherein any aforementioned phenyl and heteroaryl moieties are optional by halogen, hydroxyl, nitro, S (O) r(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace;
K and r are 0,1 or 2 independently;
R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 26, R 27, R 29And R 30Be hydrogen, C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), C 3-6(itself is optional by halogen, hydroxyl, nitro, NH for cycloalkyl, phenyl 2, NH (C 1-4Alkyl), NH (C 1-4Alkyl) 2, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2,, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace);
Perhaps NR 13R 14, NR 15R 16, NR 20R 21, NR 22R 23, NR 26R 27Can form the 4-7 element heterocycle independently, described heterocycle is selected from: (itself is optional by hydroxyl or C for azetidine 1-4Alkyl replaces), tetramethyleneimine, piperidines, nitrogen heterocyclic heptantriene, 1,4-morpholine or 1, the 4-piperazine, the latter is optional by C on the nitrogen-atoms endways 1-4Alkyl replaces;
R 12, R 25, R 28And R 31Be C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), cyano group, C 1-4Alkyl, C 1-4Alkoxyl group, C (O) NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The middle ring of describing), CO 2H, CO 2(C 1-4Alkyl), NHC (O) (C 1-4Alkyl), NHS (O) 2(C 1-4Alkyl), C (O) (C 1-4Alkyl), CF 3Or OCF 3Replace);
Condition be when X be CH 2And when m and n were 0, then Y was not NR 35
Or its N-oxide compound; Or the solvate of pharmacologically acceptable salt, solvate or its salt.
Some compound of the present invention can the different isomerization body form (as enantiomorph, diastereomer, geometrical isomer or tautomer) exist.The present invention contain all these isomer with and the mixture of any ratio.
Suitable salt comprises acid salt example hydrochloric acid salt, nicotinium dihydrochloride, hydrobromate, phosphoric acid salt, vitriol, acetate, diacetin, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or tosilate.
Compound of the present invention can solvate (as hydrate) form exist, all these solvates are contained in the present invention.
Halogen comprises fluorine, chlorine, bromine and iodine.
Alkyl group and moieties are straight or branched, and are, for example, and methyl, ethyl, n-propyl, sec.-propyl or the tertiary butyl.Alkyl preferably includes 1-6 carbon atom.
Alkenyl is, for example, and vinyl or allyl group.Alkenyl preferably includes 2-6 carbon atom.
Alkynyl is, for example, and propargyl.Alkynyl preferably includes 2-6 carbon atom.
Cycloalkyl is monocyclic and is, for example, and cyclopropyl, cyclopentyl or cyclohexyl.Cycloalkyl preferably includes 3-6 carbon atom.
The cycloalkyl that is fused to phenyl ring is that for example, two encircle [4.2.0] suffering-1,3,5-triolefin.
Aryl is preferably phenyl or naphthyl.
Heterocyclic radical be fragrance or 5 or 6 Yuans rings of non-fragrance, randomly be fused to one or more other ring, comprise that at least one is selected from the heteroatoms of nitrogen, oxygen and sulphur; Or its N-oxide compound, or its S-oxide compound or S-dioxide.Heterocyclic radical is, for example, furyl, thienyl (being also referred to as methylthio group phenyl (thiophenyl)), pyrryl, 2,5-pyrrolin base, thiazole, pyrazolyl oxazolyl isoxazolyl, imidazolyl, piperidyl, morpholinyl, pyridyl, 1,6-dihydropyridine base is (for example in 6-oxo-1, in the 6-dihydropyridine base section), pyrimidyl, indyl, 2, the 3-indolinyl, benzo [b] furyl (being also referred to as benzfuryl), benzo [b] thienyl (being also referred to as benzothienyl or benzo methylthio group phenyl), 2,3-dihydrobenzo [b] thienyl is (for example 1,1-dioxo-2, in 3-dihydrobenzo [b] the thienyl part), draw the azoles base, benzimidazolyl-, benzotriazole base benzoxazolyl, benzothiazole, 1,2-dihydro-benzothiazole (for example in 1H-benzothiazole-2-ketone-base section), 2, the 3-dihydro-benzothiazole is (for example 2, in 3-dihydro-benzothiazole-2-ketone-base section), 1,2,3-diazosulfide base, imidazopyridyl is (as imidazo [1,2-a] pyridyl), thieno-[3,2-b] pyridine-6-base, 1,2,3-Ben Bing oxadiazole base (is also referred to as benzo [1,2,3] thiadiazoles), 2,1,3-diazosulfide base, the benzo furazan (is also referred to as 2,1,3-Ben Bing oxadiazole base), quinoxalinyl, 3,4-dihydro-1H-2,1-benzothiazine base is (for example in 2-dioxo-3,4-dihydro-1H-2, in the 1-benzothiazine base section), (for example the 1H-pyrazolo [3 for Pyrazolopyridine, 4-b] pyridyl), purine, 3,7-dihydro-purine radicals is (for example 3,7-dihydro-purine-2, in 6-diketone-8-base section), quinolyl, isoquinolyl, 1,2-dihydro-isoquinoline base (for example (perhaps claims 1-oxo-1 at 2H-isoquinoline 99.9-1-ketone-Ji, 2-dihydro-isoquinoline base or 1,2-dihydro-isoquinoline base-1-ketone) in the part), phthalazinyl (for example [1,6] phthalazinyl or [1,8] phthalazinyl), 1,4-dihydro [1,8] phthalazinyl is (for example at 1H-[1, naphthyridine-4-ketone-base section) or the benzothiazine base 8], 4H-benzo [1,4] thiazinyl (for example in 4H-benzo [1,4] thiazine-3-ketone-base section); Or its N-oxide compound (as pyridine N-oxides) or its S-oxide compound or S-dioxide.1,2-dihydropyridine base (1, the another kind of method for numbering serial of 6-dihydropyridine base) also can be present in 2-oxo-1, in the 2-dihydropyridine base section; And 2,3-dihydro-1H-indazolyl also can be present in 3-oxo-2, in 3-dihydro-1H-indazolyl part.
Heterocyclic radical also comprises cinnolinyl, phthalazinyl, 3,4-dihydro phthalazinyl is (for example in 4-oxo-3, in the 4-dihydro naphthyridine base section); benzoxazinyl, 2,3-dihydro-4H-1, the 4-benzoxazinyl is (for example in 3-oxo-2,3-dihydro-4H-1, in the 4-benzoxazine base section), 3,4-dihydro-2H-1, the 4-benzoxazinyl is (for example in 3-oxo-3,4-dihydro-2H-1, in the 4-benzoxazine base section), pseudoindoyl, 1,3-dihydro-2H-pseudoindoyl is (for example 1,3-dioxo-1 is in 3-dihydro-2H-pseudoindoyl part), method for preparation of pyrazolotriazine base (pyrazolo [5,1-c] [1 for example, 2,4] triazinyl), pyrazinyl, pyridazinyl, the 9H-purine radicals, pyrazolopyrimidine base (for example pyrazolo [1,5-a] pyrimidyl), imidazo benzothiazole (imidazo [2,1-b] [1 for example, 3] benzothiazole), 1,2,5-oxadiazole base, imidazopyrimidine base (for example imidazo [1,2-a] pyrimidyl), quinolyl, 1,2-dihydroquinoline base is (for example in 2-oxo-1, in the 2-dihydroquinoline base section) or 2,1,3-Ben Bing oxadiazole base (for example being the 1-oxide compound); Or also can be its N-oxide compound or its S-oxide compound or S-dioxide.Other examples of heterocyclic radical are 1,3-benzothiazole, 2,3-dihydro-1, the 3-benzothiazole is (for example in 2-oxo-2, in the 3-dihydro-1,3-benzothiazole part), 4,5,6,7-tetrahydrochysene indazole, 2,3-dihydro-1H-benzoglyoxaline (for example in 2-oxo-2, in 3-dihydro-1H-benzoglyoxaline part) and 1,4-dihydroquinoline (for example in 4-oxo-1, in the 4-dihydroquinoline part).
Formula (I) or (Ia) the N-oxide compound of compound be, for example, 1-oxygen base-piperidinyl compounds.
Heteroaryl is a fragrant heterocyclic radical.Therefore, it is, furyl for example, thienyl, pyrryl, thiazole, pyrazolyl oxazolyl isoxazolyl, imidazolyl, pyridyl, pyrimidyl, indyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzotriazole base benzoxazolyl, benzothiazole, 1,2,3-diazosulfide base, imidazopyridyl, thieno-[3,2-b] pyridine-6-base 1,2,3-Ben Bing oxadiazole base, 2,1,3-diazosulfide base, benzo furazan base, quinoxalinyl, Pyrazolopyridine, purine, quinolyl, isoquinolyl, phthalazinyl, the benzothiazine base, cinnolinyl, phthalazinyl benzoxazinyl, pseudoindoyl, method for preparation of pyrazolotriazine base pyrazinyl, pyridazinyl, the pyrazolopyrimidine base, the imidazo benzothiazolyl, imidazopyrimidine base quinolyl or 2,1,3-Ben Bing oxadiazole base; Or its N-oxide compound (as pyridine N-oxides), or its S-oxide compound or S-dioxide.
Haloalkyl is for to have the alkyl of one or more (as 1～6) halogen atom, and is, for example, and CF 3Alkoxyalkyl is, for example, and CH 3OCH 2, CH 3CH 2OCH 2Or CH 3CH 2O (CH 2) 2Halogenated alkoxy is for having the alkoxyl group of one or more (as 1～6) halogen atom and being, for example, and OCF 3The alkoxyl group alkoxyl group is, for example, and CH 3OCH 2O, CH 3CH 2OCH 2O or CH 3CH 2O (CH 2) 2O.Phenylalkyl is, for example, and benzyl, benzene second-1-base or benzene second-2-base.The phenyl alkoxyl group is, for example benzyloxy.Heteroarylalkyl is, for example, and pyridylmethyl or Pyrimidylmethyl.Heteroaryloxy is, for example, and pyridyloxy or 2-pyrimidinyl oxy.The heteroaryl alkoxyl group is, for example, and pyridyl methoxyl group or pyrimidyl methoxyl group.
On the one hand, the invention provides formula (I) compound, wherein: X is CH2、O、S(O) 2Or NR10 Y is a key, CH2、NR 35、CH 2NH、CH 2NHC(O)、CH(OH)、CH(NHC(O)R 33)、 CH(NHS(O) 2R 34)、CH 2O or CH2S； Z is C (O), or Z also can be S (O) when Y is a key2；R 1For the optional aryl that replaces, the optional heterocyclic radical that replaces or the C that condenses with phenyl ring4-6Cycloalkyl; R4For hydrogen, C1-6Alkyl is (optional by C3-6Cycloalkyl replaces) or C3-6Cycloalkyl; R2、R 3、 R 5、R 6、R 7And R8Be hydrogen, C independently1-6Alkyl or C3-6Cycloalkyl; M and n are 0 or 1 independently; R9For the optional aryl that replaces or for choosing the heterocyclic radical that replaces wantonly; R10、R 32、R 33And R35Be hydrogen or C independently1-6Alkyl; R34For C1-6Alkyl; Aryl and heterocyclic radical part wherein aforementionedly, in the situation that possible, optionally replaced by following groups: halogen, cyano group, nitro, hydroxyl, oxo, S (O)kR 12、 OC(O)NR 13R 14、NR 15R 16、NR 17C(O)R 18、NR 19C(O)NR 20R 21、S(O) 2NR 22R 23、 NR 24S(O) 2R 25、C(O)NR 26R 27、C(O)R 28、CO 2R 29、NR 30CO 2R 31、C 1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxyl (C1-6) alkoxyl, C1-6Alkylthio group, C2-6Alkenyl, C2-6Alkynyl, C3-10Cycloalkyl, methylene dioxy base, difluoro methylene dioxy base, phenyl, phenyl (C1-4) alkyl, phenoxy group, thiophenyl, phenyl (C1-4) alkoxyl, heteroaryl, heteroaryl (C1-4) alkyl, heteroaryloxy or heteroaryl (C1-4) alkoxyl; Wherein any aforementioned phenyl and heteroaryl moieties are optional is replaced by following groups: halogen, hydroxyl, nitro, S (O)r(C 1-4Alkyl), S (O)2NH 2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、 C(O)NH(C 1-4Alkyl), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3 K and r are 0,1 or 2 independently; R13、R 14、 R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 26、R 27、R 29、R 30And R31Be hydrogen, C independently1-6Alkyl is (optional by halogen, hydroxyl or C3-10The cycloalkyl replacement), CH2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl2、NH(C 1-4Alkyl), NH (C1-4Alkyl)2、S(O) 2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、CO 2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH2、 NH(C 1-4Alkyl), N (C1-4Alkyl)2、S(O) 2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、CO 2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace); Perhaps NR13R 14、 NR 15R 16、NR 20R 21、NR 22R 23、NR 26R 27Can form independently 4-7 element heterocycle, azetidine, pyrrolidines, piperidines, azacyclo-heptantriene, Isosorbide-5-Nitrae-morpholine or Isosorbide-5-Nitrae-piperazine, the latter chooses wantonly by C on nitrogen-atoms endways1-4Alkyl replaces; R12、R 25And R28Be C independently1-6Alkyl is (optional by halogen, hydroxyl or C3-10The cycloalkyl replacement), CH2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl2、NH(C 1-4Alkyl), N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), S (O)2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace) or heterocyclic radical (itself optional halogen, hydroxyl, nitro, NH of being substituted2、NH(C 1-4Alkyl), N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), S (O)2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14Described in ring), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3); Condition be when X be CH2And when m and n are 0 Y for NR35 Or its N-oxide; Or officinal salt, the solvate of solvate or its salt.
On the other hand, the invention provides formula (Ia) compound:
Figure C20061011009100151
Wherein: X is CH2、O、S(O) 2Or NR10；R 1For the optional aryl that replaces or for choosing the heterocyclic radical that replaces wantonly; R4For hydrogen, C1-6Alkyl is (optional by C3-6Cycloalkyl replaces) or C3-6Cycloalkyl; R2、R 3、 R 5、R 6、R 7And R8Be hydrogen, C independently1-6Alkyl or C3-6Cycloalkyl; M and n are 0 or 1 independently; R9For the optional aryl that replaces or for choosing the heterocyclic radical that replaces wantonly; R10For hydrogen or C1-6Alkyl; Aryl and heterocyclic radical part wherein aforementionedly, in the situation that possible, optionally replaced by following groups: halogen, cyano group, nitro, hydroxyl, oxo S (O)kR 12、OC(O)NR 13R 14、NR 15R 16、NR 17C(O)R 18、 NR 19C(O)NR 20R 21、S(O) 2NR 22R 23、NR 24S(O) 2R 25、C(O)NR 26R 27、C(O)R 28、 CO 2R 29、NR 30CO 2R 31、C 1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxyl (C1-6) alkoxyl, C1-6Alkylthio group, C2-6Alkenyl, C2-6Alkynyl, C3-10Cycloalkyl, methylene dioxy base, difluoro methylene dioxy base, phenyl, phenyl (C1-4) alkyl, phenoxy group, thiophenyl, phenyl (C1-4) alkoxyl, heteroaryl, heteroaryl (C1-4) alkyl, heteroaryloxy or heteroaryl (C1-4) alkoxyl; Wherein any aforementioned phenyl and heteroaryl moieties are optional is replaced by following groups: halogen, hydroxyl, nitro, S (O)r(C 1-4Alkyl), S (O)2NH 2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3 K and r are 0,1 or 2 independently; R13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、 R 26、R 27、R 29、R 30And R31Be hydrogen, C independently1-6Alkyl is (optional by halogen, hydroxyl or C3-10The cycloalkyl replacement), CH2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl2、 NH(C 1-4Alkyl), NH (C1-4Alkyl)2、S(O) 2(C 1-4Alkyl), S (O)2NH 2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH2、NH(C 1-4Alkyl), N (C1-4Alkyl)2、S(O) 2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、CO 2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace); Perhaps NR13R 14、NR 15R 16、NR 20R 21、NR 22R 23、NR 26R 27Can form independently 4-7 element heterocycle, azetidine, pyrrolidines, piperidines, azacyclo-heptantriene, Isosorbide-5-Nitrae-morpholine or Isosorbide-5-Nitrae-piperazine, the latter chooses wantonly by C on nitrogen-atoms endways1-4Alkyl replaces; R12、R 25And R28Be C independently1-6Alkyl is (optional by halogen, hydroxyl or C3-10The cycloalkyl replacement), CH2(C 2-6Alkenyl), (itself is optional by halogen, hydroxyl, nitro, NH for phenyl2、NH(C 1-4Alkyl), N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), S (O)2(C 1-4Alkyl), S (O)2NH 2、 S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace) or heterocyclic radical (itself is optional by halogen, hydroxyl, nitro, NH2、NH(C 1-4Alkyl), N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), S (O)2(C 1-4Alkyl), S (O)2NH 2、S(O) 2NH(C 1-4Alkyl), S (O)2N(C 1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2(and these alkyl can form together as above-mentioned R13And R14The ring of middle definition), CO2H、CO 2(C 1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C 1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Replace); Or its N-oxide; Or officinal salt, the solvate of solvate or its salt.
The invention provides formula (I) compound on the other hand wherein: X is O; Y is a key, CH 2, NR 35, CH 2NH, CH (OH), CH (NHC (O) R 33), CH (NHS (O) 2R 34) or CH 2O; Z is C (O), or Z also can be S (O) when Y is a key 2R 1Be the optional phenyl that replaces; R 4Be hydrogen or C 1-6Alkyl; R 2, R 3, R 5, R 6, R 7And R 8When existing, all be hydrogen; M and n are 0 or 1 independently; R 9For the optional aryl that replaces or for choosing the heterocyclic radical that replaces wantonly; R 32And R 35Be hydrogen or C independently 1-6Alkyl; R 33And R 34Be C 1-6Alkyl; Wherein aforementioned phenyl, aryl and heterocyclic radical part under possible situation, optional are replaced by following groups: halogen, cyano group, hydroxyl, oxo, S (O) 2R 12, NR 15R 16, NR 17C (O) R 18, S (O) 2NR 22R 23, NR 24S (O) 2R 25, C (O) NR 26R 27, CO 2R 29, C 1-6Alkyl (itself is optional by the replacement of NHC (O) phenyl list), CF 3, OCF 3, phenyl or heteroaryl; Wherein any aforementioned phenyl and heteroaryl moieties are optional to be replaced by following groups: halogen, C 1-4Alkyl, C 1-4Alkoxyl group or CF 3R 15, R 16, R 17, R 18, R 22, R 23, R 24, R 26, R 27And R 29Be hydrogen, C independently 1-6Alkyl (the optional hydroxyl that is substituted) or C 3-6Cycloalkyl; Perhaps NR 22R 23(itself is optional by hydroxyl or C can to form the azetidine ring 1-4Alkyl replaces); R 12And R 25Be C independently 1-6Alkyl or phenyl; Or its pharmacologically acceptable salt.
On the other hand, R 1Be phenyl, optional by halogen (especially fluorine or chlorine), cyano group, C 1-4Alkyl (especially methyl), C 1-4Alkoxyl group (especially methoxyl group), S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2NH (C 3-6Cycloalkyl), C (O) 2(C 1-4Alkyl), C (O) NH (C 1-4Alkyl) or C (O) NH 2(for example one, two or three) replaces.
On the other hand, R 1Be phenyl, optional by halogen (especially fluorine or chlorine), cyano group, C 1-4Alkyl (especially methyl) or C 1-4Alkoxyl group (especially methoxyl group) (for example one, two or three) replaces.R on the other hand 1Be the optional phenyl that is replaced by one, two or three following groups: fluorine, chlorine, methyl or cyano group.R on the other hand 1Be the optional phenyl that is replaced by one, two or three following groups: fluorine, chlorine or methyl.Therefore, R 1For, for example, 2-methyl-4-chloro-phenyl-, 3-methyl-2,4 dichloro benzene base, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl-or 4-chloro-phenyl-.On the other hand, R 1Be 3, the 4-dichlorophenyl.
X is O on the other hand.
Y is a key on the other hand.
Z is C (O) on the other hand.
M is 0 on the other hand.
N is 0 on the other hand.
M and n are 0 on the other hand.
R on the other hand 4Be hydrogen or C 1-6Alkyl (as methyl).R on the other hand 4Be hydrogen.
R on the other hand 2, R 3, R 5, R 6, R 7And R 8All be hydrogen; And n is 0 on the other hand, and R 2, R 3, R 5And R 6All be hydrogen.
R on the other hand 2, R 3, R 4, R 5, R 6, R 7And R 8When existing, all be hydrogen.
On the other hand, R 9Be the heterocyclic radical of single-or two-phenyl of replacing, unsubstituted heterocyclic or single-or two-replace, substituting group is selected from those of foregoing description.
R on the other hand 9Be the optional heterocyclic radical that replaces, wherein this heterocyclic radical is: thienyl, pyrryl, thiazole, pyrazolyl oxazolyl isoxazolyl, imidazolyl, 1,2,5-oxadiazole base, pyridyl, 1,6-dihydropyridine base is (for example in 6-oxo-1,6-dihydropyridine base or 2-oxo-1, in the 2-dihydropyridine base section), pyrimidyl, indyl, indazolyl, 2,3-dihydro-1H-indazolyl is (for example in 3-oxo-2, in 3-dihydro-1H-indazolyl part), imidazopyridyl is (as imidazo [1,2-a] pyridyl), 2,1,3-diazosulfide base, quinoxalinyl, quinolyl, 1,2-dihydroquinoline base is (for example in 2-oxo-1, in the 2-dihydroquinoline base section), 1, the 4-dihydroquinoline is (for example in 4-oxo-1, in the 4-dihydroquinoline composition), isoquinolyl, 1,2-dihydro-isoquinoline base (for example (perhaps is called 1-oxo-1 at 2H-isoquinoline 99.9-1-ketone-Ji, 2-dihydro-isoquinoline base or 1,2-dihydro-isoquinoline base-1-ketone) in the composition), cinnolinyl, 3,4-dihydro phthalazinyl is (for example in 4-oxo-3, in the 4-dihydro naphthyridine base section), 2,3-dihydro-4H-1, the 4-benzoxazinyl is (for example in 3-oxo-2,3-dihydro-4H-1, in the 4-benzoxazine base section), 3,4-dihydro-2H-1, the 4-benzoxazinyl is (for example in 3-oxo-3,4-dihydro-2H-1, in the 4-benzoxazine base section), 1,3-dihydro-2H-pseudoindoyl is (for example 1,3-dioxo-1, in 3-dihydro-2H-pseudoindoyl part), (for example pyrazolo [5 for the method for preparation of pyrazolotriazine base, 1-c] [1,2,4] triazinyl), (for example pyrazolo [1 for the pyrazolopyrimidine base, 5-a] pyrimidyl), (for example imidazo [2 for the imidazo benzothiazole, 1-b] [1,3] benzothiazole), (for example imidazo [1 for the imidazopyrimidine base, 2-a] pyrimidyl) or 2,1,3-Ben Bing oxadiazole base (for example being the 1-oxide compound), 1, the 3-benzothiazole, 2,3-dihydro-1, the 3-benzothiazole is (for example in 2-oxo-2,3-dihydro-1 is in the 3-benzothiazole composition), 4,5,6,7-tetrahydrochysene indazole or 2,3-dihydro-1H-benzoglyoxaline (for example in 2-oxo-2, in 3-dihydro-1H-benzoglyoxaline composition).
Aryl (as phenyl) or heterocyclic radical R on the other hand 9Do not replaced or replace by one or more following radicals: oxo (under the possible situation), halogen, C 1-4Alkyl, CF 3, C 1-4Alkoxyl group, S (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2Or OCF 3
Work as R on the other hand 9In the time of for heterocyclic radical, it is optional thienyl, the quinolyl, 1 that replaces, 2-dihydroquinoline base, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, imidazo [1,2-a] pyridyl, isoquinolyl or 1,2-dihydro-isoquinoline base; Or 1,2-dihydropyridine ketone, 1,6-dihydropyridine ketone, pyrazolyl, pyrryl or indyl.
R on the other hand 9Be phenyl or heterocyclic radical (being defined Anywhere as above-mentioned), its each group is all chosen wantonly by following groups and is replaced: halogen, hydroxyl, nitro, cyano group, oxo, amino, C 1-4(itself is optional by S (O) for alkyl 2(C 1-4Alkyl) or S (O) 2The phenyl replacement), C 1-4Alkoxyl group, S (O) kR 12{ wherein k is 0,1 or 2 (preferred 2); And R 12Be C 1-4Alkyl, C 1-4Hydroxyalkyl, C 3-7Cycloalkyl (C 1-4Alkyl) (as the cyclopropyl methyl) or phenyl }, C (O) NH 2, NHS (O) 2(C 1-4Alkyl), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl) or S (O) 2N (C 1-4Alkyl) 2(and these alkyl can form together as above-mentioned R 13And R 14The ring of middle definition).
R on the other hand 32Be hydrogen.
R on the other hand 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 26, R 27, R 29, R 30And R 31Be hydrogen, C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl),, (itself is optional by halogen or C for phenyl 1-4Alkyl replaces) or heterocyclic radical (itself is optional by halogen or C 1-4Alkyl replaces); And R 12, R 25And R 28Be C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), (itself is optional by halogen or C for phenyl 1-4Alkyl replaces) or heterocyclic radical (itself is optional by halogen or C 1-4Alkyl replaces).
On the other hand, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 26, R 27, R 29And R 30Be hydrogen, C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), (itself is optional by halogen or C for phenyl 1-4Alkyl replaces) or heterocyclic radical (itself is optional by halogen or C 1-4Alkyl replaces); And R 12, R 25, R 28And R 31Be C independently 1-6Alkyl is (optional by halogen, hydroxyl or C 3-10Cycloalkyl substituted), CH 2(C 2-6Alkenyl), (itself is optional by halogen or C for phenyl 1-4Alkyl replaces) or heterocyclic radical (itself is optional by halogen or C 1-4Alkyl replaces).
R on the other hand 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 26, R 27, R 29And R 30Be hydrogen or C independently 1-6Alkyl; And R 12, R 25, R 28And R 31Be C independently 1-6Alkyl (choose wantonly and replaced) or phenyl by hydroxyl.
R on the other hand 10Be hydrogen.
R on the other hand 35Be hydrogen or C 1-6Alkyl (as methyl); (R for example 35Be hydrogen).
R on the other hand 33Be C 1-6Alkyl (as methyl).
R on the other hand 34Be C 1-6Alkyl (as methyl).
The invention provides formula (I) or (Ia) compound on the other hand, wherein: R 1Be the optional phenyl that is replaced by 2 halogen atoms (as chlorine); X is O; M is 0; N is 0 or 1; R 2, R 3, R 4, R 5, R 6, R 7And R 8All be hydrogen; And R 9Be phenyl, thienyl, quinolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, imidazo [1,2-a] pyridyl or 1,2-dihydro-isoquinoline base, optional by S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3), halogen (for example chlorine or fluorine), NH 2, C 1-4Alkoxyl group is (as OCH 3), cyano group or, under the possible situation, oxo group replaces.
The invention provides formula (I) or (Ia) compound on the other hand, wherein: R 1Be phenyl, optional by 1 or 2 halogen (as chlorine) replacement, or by 1 or 2 halogen (as chlorine) and C 1-4Alkyl (as methyl) replaces; X is O; M is 0; N is 0 or 1; R 2, R 3, R 4, R 5And R 6, and, when existing, R 7And R 8All be hydrogen; And R 9Be phenyl, thienyl, quinolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, imidazo [1,2-a] pyridyl, 1,2-dihydro-isoquinoline base, 1,2-dihydropyridine base, 1,6-dihydropyridine base or pyrazolyl, all groups are optional by S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2(and two alkyl can combine form the azetidine ring), halogen (for example chlorine or fluorine), NH 2, C 1-4Alkyl is (as CH 3), C 1-4Alkoxyl group is (as OCH 3), CF 3, cyano group or, under possible situation, oxo group replaces.
The invention provides formula (I) or (Ia) compound on the other hand, wherein: R 1Be phenyl, optional by 1 or 2 halogen (as chlorine) replacement, and optional by 0 or 1 C 1-6Alkyl (as methyl) replaces; X is O; M is 0; N is 0 or 1; R 2, R 3, R 4, R 5And R 6, and, when existing, R 7And R 8All be hydrogen; And R 9Be phenyl, thienyl, quinolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, imidazo [1,2-a] pyridyl, 1,2-dihydro-isoquinoline base, 1,2-dihydropyridine base, 1,6-dihydropyridine base, pyrazolyl, pyrryl or indyl, all these groups are optional by S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2, halogen (for example chlorine or fluorine), NH 2, C 1-4Alkoxyl group is (as OCH 3), C 1-4Alkyl (as methyl), CF 3, OCF 3, cyano group or, when possible the time, oxo group replaces.
The invention provides formula (I) or (Ia) compound on the other hand, wherein: R 1Be phenyl, optional by 1 or 2 halogen (as chlorine) replacement, and optional by 0 or 1 C 1-6Alkyl (as methyl) replaces; X is O; M is 0; N is 0 or 1; R 2, R 3, R 4, R 5, R 6, R 7And R 8All be hydrogen; And R 9Be phenyl, thienyl, quinolyl, 1,3-benzothiazole, 2,3-dihydro-1,3-benzothiazole, imidazo [1,2-a] pyridyl or 1,2-dihydro-isoquinoline base, all groups are optional by S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3), halogen (for example chlorine or fluorine), NH 2, C 1-4Alkoxyl group is (as OCH 3), C 1-4Alkyl (as methyl), CF 3, OCF 3, cyano group or, when possible the time, oxo group replaces.
The invention provides formula (I) or (Ia) compound, wherein R on the other hand 9Be isoquinolyl, 1-oxo-1,2-dihydro-isoquinoline base, quinolyl, 2-oxo-1,2-dihydroquinoline base, 2-oxo-1,2-dihydropyridine base, 6-oxo-1,6-dihydropyridine base or pyrazolyl; Each group is optional by halogen (as fluorine), C 1-4Alkyl (as methyl or ethyl), CF 3, C 1-4Alkoxyl group (as methoxyl group), S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3), S (O) 2NH 2, S (O) 2NH (C 1-4Alkyl), S (O) 2N (C 1-4Alkyl) 2Or OCF 3Replace.
The invention provides formula (I) or (Ia) compound, wherein R on the other hand 9Be isoquinolyl, 1-oxo-1,2-dihydro-isoquinoline base, quinolyl or 2-oxo-1,2-dihydroquinoline base; Each group is optional by halogen (as fluorine), C 1-4Alkyl (as methyl or ethyl), CF 3, C 1-4Alkoxyl group (as methoxyl group), S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3) or OCF 3Replace.
R on the other hand 9Be 1-oxo-1,2-dihydro-isoquinoline base, optional by halogen (as fluorine), C 1-4Alkyl (as methyl or ethyl), CF 3, C 1-4Alkoxyl group (as methoxyl group), S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3) or OCF 3Replace.Perhaps, R 9Be 2-oxo-1,2-dihydroquinoline base, optional by halogen (as fluorine), C 1-4Alkyl (as methyl or ethyl), CF 3, C 1-4Alkoxyl group (as methoxyl group), S (O) 2(C 1-4Alkyl) (S (O) for example 2CH 3) or OCF 3Replace.
R on the other hand 9For the dihydropyridine base of oxo-replacement (as 6-oxo-1,6-dihydropyridine 3-base, 2-oxo-1,2-dihydropyridine-5-base or 2-oxo-1,2-dihydropyridine-4-yl), the dihydro-isoquinoline base of oxo-replacement is (as 1-oxo-1,2-dihydro-isoquinoline-4-yl), the dihydro phthalazinyl of oxo-replacement is (as 4-oxo-3,4-dihydro naphthyridine-1-yl), pyrazinyl (as pyrazine-4-yl), pyrryl (as pyrroles-3-yl) or indyl (as indol-3-yl), each group is not further replaced or is further replaced by following groups: halogen (as chlorine or fluorine), C 1-4Alkyl (as methyl), CF 3Or C 3-5Cycloalkyl (as cyclopropyl).
R on the other hand 9For the dihydropyridine base of oxo-replacement (as 6-oxo-1,6-dihydropyridine-3-base, 2-oxo-1,2-dihydropyridine-5-base or 2-oxo-1,2-dihydropyridine-4-yl), the dihydro-isoquinoline base of oxo-replacement is (as 1-oxo-1,2-dihydro-isoquinoline base-4-yl) or pyrazinyl (as pyrazine-4-yl), each group is not further replaced or is further replaced by following groups: halogen (as chlorine or fluorine), C 1-4Alkyl (as methyl) or CF 3
Formula (I) or (Ia) examples for compounds be:
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(methylsulfonyl) benzamide;
2-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(methylsulfonyl) benzamide;
4-amino-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-methoxy benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(methylsulfonyl) thiophene-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-flumizole [1,2-a] pyridine-2-carboxylic acid amides also;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3-benzothiazole-6-carboxylic acid amides;
3-cyano group-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-2-(methylsulfonyl) benzamide;
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid amides;
4-amino-N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-the 3-methoxy benzamide;
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxybutyl }-2-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-[(methylamino) alkylsulfonyl] benzamide;
3, two (the acetylamino)-N-{ (2R) of 5--3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
3-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 1H-pyrazole-4-carboxamide;
2-(acetylamino)-5-bromo-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-1,2-dihydropyridine-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-5-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-4-carboxylic acid amides;
2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
2-(acetylamino)-5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
2-(acetylamino)-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino] benzamide;
4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino] benzamide;
2-amino-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-6-oxo-1,6-dihydropyridine-3-carboxylic acid amides;
2-(amino-sulfonyl)-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indazole-3-carboxylic acid amides;
The 1-tertiary butyl-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4,5,6,7-tetrahydrochysene-2H-indazole-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-glyoxal ethyline [1,2-a] pyridine-3-carboxylic acid amides also;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(1H-pyrazole-3-yl) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } cinnoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-hydroxyquinoline-4-carboxylic acid amides;
N-{3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-3-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide;
N-{ (2R)-3-[4-(4-chlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chloro-3-fluorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3,4-two fluorophenoxies) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-N-methyl isophthalic acid-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-N-methyl isophthalic acid H-indazole-3-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-N-methyl-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides;
Phenylformic acid, 3-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino]-, methyl ester;
Propionic acid amide, N-[2-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino] phenyl]-;
Propionic acid amide, N-[2-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino] phenyl]-;
(2S)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-hydroxyl-2-phenyl-acetamides;
2-[2-((2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino)-2-oxo oxyethyl group] benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4-yl] ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-methoxy benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylamino) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } niacinamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } Isonicotinamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(dimethylamino) benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 6-hydroxy nicotinoyl amine;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(1H-indol-3-yl) ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } two ring [4.2.0] sufferings-1,3,5-triolefin-7-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4,7-dimethyl pyrazole [5,1-c] [1,2,4] triazine-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } pyrazine-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-9H-purine-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,7-dimethyl pyrazole [1,5-a] pyrimidine-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(pyrimidine-2-base sulfenyl) ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-fluoro-1H-indoles-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3-benzothiazole-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-phenyl-1,3-oxazole-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-pyridone-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-pyridone-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-benzoglyoxaline-5-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-5-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-Methyl-1H-indole-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-imidazoles-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-Methyl-1H-indole-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-7-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-[(methylamino) alkylsulfonyl] benzamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3, two (methylsulfonyl) benzamide of 4-;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-pyridin-3-yl ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-hydroxyl-1H-indoles-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,5-dimethyl-1H-pyrazole-3-carboxamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(methylsulfonyl)-1H-indoles-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoxaline-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,8-phthalazinyl-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo [2,1-b] [1,3] benzothiazole-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,6-dimethyl-imidazo [1,2-a] pyridine-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo-2,3-dihydro-1H-indazole-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-hydroxyl-1H-indazole-6-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
2-(1H-benzoglyoxaline and 1-1-yl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-methyl isophthalic acid H-pyrazole-3-carboxamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 4-methyl isophthalic acid, 2,5-oxadiazole-3-carboxylic acid amides;
6-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo [1,2-a] pyridine-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-glyoxal ethyline [1,2-a] pyridine-3-carboxylic acid amides also;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo [1,2-a] pyrimidine-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-[(4-methylpyrimidine-2-yl) sulfenyl] ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-hydroxyquinoline-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-8-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-Methylimidazole [1,2-a] pyridine-2-carboxylic acid amides also;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo [1,2-a] pyridine-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,6-phthalazinyl-2-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-5-carboxylic acid amides 1-oxide compound;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-1,6-dihydropyridine-3-carboxylic acid amides;
4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 1H-pyrazole-3-carboxamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-phenyl-1,3-oxazole-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,5-dimethyl-1H-pyrazole-4-carboxamide;
(2R)-2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-phenyl-acetamides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(2-hydroxy phenyl) ethanamide;
(2R)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methylsulfonyl) amino]-the 2-phenyl-acetamides;
(2S)-2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-phenyl-acetamides;
(2S)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methylsulfonyl) amino]-the 2-phenyl-acetamides;
1-{ (R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-o-tolyl-urea;
1-{ (R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-p-methylphenyl-urea;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-2-oxo-1,2-dihydroquinoline-4-carboxylic acid amides;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides;
(2S)-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-2-hydroxyl-2-phenylacetamide;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-((2R)-3-{4-[2-(aminocarboxyl)-3,4-dichlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
3-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino)-alkylsulfonyl]-the 2-methoxy benzamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-sulphonamide acetate;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2,4 difluorobenzene sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amsacrine;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-phenylmethane sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 4-methoxybenzenesulphoismide;
N-(5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl]-the 2-thienyl } methyl) benzamide;
4-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl]-the 4-methyl isophthalic acid, the 3-thiazol-2-yl } ethanamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } thiophene-2-sulphonamide;
4-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl] phenylformic acid;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,5-dimethoxy benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(phenyl sulfonyl) thiophene-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(1,3-oxazole-5-yl) thiophene-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl] thiophene-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-pyridine-2-base thiophene-2-sulphonamide;
5-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3-dimethyl-1H-pyrazoles-4-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,5-dimethyl isoxazole-4-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-diazosulfide 4-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-imidazoles-4-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-4-sulphonamide;
N-{ (2S)-3-[-4 (3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-isoxazole-3-base thiophene-2-sulphonamide;
Methyl 3-[({ (2S) 3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl] the thiophene-2-carboxylic acid ester;
2,6-two chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-methyl benzenesulfonamide;
3-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } propane-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } propane-1-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-sulphonamide;
3-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-methyl benzenesulfonamide;
Methyl 5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl]-2-methyl-3-furoate;
Methyl 5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl]-1-methyl isophthalic acid H-pyrroles-2-carboxylicesters;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,4-dimethoxy benzsulfamide;
5-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } thiophene-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-morpholine-4-yl pyridines-3-sulphonamide;
N-{2-chloro-4-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl] phenyl } ethanamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,3-dihydroxyl quinoxaline-6-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,4-dimethoxy benzsulfamide;
5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino) alkylsulfonyl]-the 2-methoxy benzamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-methyl benzenesulfonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,4-dimethyl-1,3-thiazoles-5-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-hydroxy quinoxaline-6-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } pyridine-3-sulphonamide;
4 '-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } biphenyl-2-sulphonamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,2-dimethyl-1H-imidazoles-4-sulphonamide;
4-ethanoyl-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(methylsulfonyl) benzsulfamide;
2-chloro-4-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy)-piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide;
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3,5-trimethylammonium-1H-pyrazoles-4-sulphonamide;
N-[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamideas;
N-{ (2S)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2S)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2S)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-[(methylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-{[(2-hydroxyethyl) amino] alkylsulfonyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
7-[(cyclopropyl amino) alkylsulfonyl]-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
7-(azetidin-1-base alkylsulfonyl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
7-(amino-sulfonyl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-[(dimethylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-[(3-hydroxy-3-methyl azetidin-1-yl) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(cyclopropyl amino) carbonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-((2R)-2-hydroxyl-3-{4-[4-(methylsulfonyl) phenoxy group] piperidines-1-yl } propyl group)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-((2R)-3-{4-[2-(aminocarboxyl)-4-chlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-[(2R)-and 3-(4-{4-chloro-2-[(methylamino) carbonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
Methyl 5-chloro-2-{[1-((2R)-2-hydroxyl-3-{[(1-oxo-1,2-dihydro iso quinolyl-4) carbonyl] amino } propyl group) piperidin-4-yl] the oxygen base } the benzoic ether acetate;
N-((2R)-3-{4-[2-(amino-sulfonyl)-3,4-dichlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides trifluoroacetate;
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(methylaminos) alkylsulfonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(cyclopropyl amino) alkylsulfonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-{4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-6-(methyl sulphonyl)-1H-indoles-3-carboxylic acid amides;
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methyl sulphonyl)-1H-indoles-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides;
N-((2R)-3-{4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides acetate;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(2-oxo quinoxaline-1 (2H)-yl) ethanamide;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo-3,4-dihydro-quinoxaline-1 (2H)-carboxylic acid amides;
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazoles-4 carboxylic acid amides;
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl }-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-2-methylisoquinolinium-4-carboxylic acid amides;
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-1,2-dihydro-1-toluquinoline-4-carboxylic acid amides;
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides; Or,
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides.
Formula (I) or (Ia) preparation of compound can be by with formula (II) compound:
Figure C20061011009100351
Wherein X, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 32, m and n as defined above:
(i) when Y be a key, CH 2, NR 35, CH 2NH, CH 2NHC (O), CH (OH), CH (NHCOR 33), CH (NHSO 2R 34), CH 2O or CH 2S, Z are C (O), R 35Be not hydrogen and, R 33And R 34As defined above, with formula (IIIa) compound:
L 1-CO-Y-R 9 (IIIa)
R wherein 9As defined above and L 1For leavings group (for example hydroxyl or chlorine leavings group) in the presence of alkali (for example diisopropyl ethyl amine), choose that (for example bromo-three-pyrrole is coughed up alkane Phosphonium hexafluorophosphate, PyBrOP or O-(7-azepine benzo triazol-1-yl)-N at coupling agent wantonly, N, N ', N '-tetramethyl-urea hexafluorophosphate) reacts under the existence; And,
(ii) when Y be NH and Z when being C (O), react with formula (IIIb) compound:
Figure C20061011009100352
R wherein 9As defined above.
(iii) working as Y is that a key and Z are S (O) 2The time, react in the presence of alkali (for example pyridine) with formula (IIIc) compound:
L 1-S(O) 2-R 9 (IIIc)
R wherein 9As defined above and L 1Be leavings group (for example hydroxyl or chlorine leavings group).
Formula (II) compound can be prepared or with formula (IV) compound according to the method for putting down in writing among WO00/58305 or the WO01/77101:
Figure C20061011009100361
Wherein X and R 1As defined above, react with following compound and be prepared:
(i) when m and n be 0, R 2, R 3, R 5And R 6Be hydrogen, and R 4And R 32Suc as formula definition in (I), react with the formula V compound:
Figure C20061011009100362
L wherein 2Be leavings group (for example chlorine or 3-nitrobenzene-sulfonic acid base (nosyloxy) { 3-NO 2-C 6H 4-S (O) 2O-, }), then with ammonia, amine R 32-NH 2Reaction or for example use then with sodium azide reaction, triphenyl phosphine reduces;
(ii) working as m and n is 0, R 2And R 3Be hydrogen and R 4, R 5, R 6And R 32Suc as formula definition in (I), react with formula (VI) compound:
Figure C20061011009100363
P wherein 1And P 2Be suitable protecting group (for example forming phthalic diamide together), perhaps P individually or together 1Or P 2Be R 32, carry out deprotection subsequently, for example work as P 1And P 2When forming phthalic diamide, carry out with hydrazine;
(iii) working as m is 0, and n is 1, R 2And R 3Be hydrogen and R 4, R 5, R 6, R 7, R 8And R 32In the time of suc as formula (I) middle definition, react with formula (VII) compound:
Figure C20061011009100364
P wherein 1And P 2Be suitable protecting group (for example forming phthalic diamide together) or P independently or together 1Or P 2Be R 32Carry out deprotection subsequently, for example work as P 1And P 2When forming phthalic diamide, carry out with hydrazine;
(iv) working as m and n is 1, R 2And R 3Be hydrogen and R 4, R 5, R 6, R 7, R 8And R 32Suc as formula definition in (I), react with formula (VIII) compound:
Figure C20061011009100371
L wherein 2As definition and P in the formula V 1And P 2Be suitable protecting group (for example forming phthalic diamide together) or P independently or together 1Or P 2Be R 32, carry out deprotection subsequently, for example work as P 1And P 2When forming phthalic diamide, carry out with hydrazine;
(v) when m be 1 and n be 0, R 2And R 3Be hydrogen, R 5And R 6Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl, and R 4And R 32Suc as formula definition in (I), react with formula (IX) compound:
Figure C20061011009100372
L wherein 2As definition and P in the formula V 1And P 2Be suitable protecting group (for example forming phthalic diamide together) or P independently or together 1Or P 2Be R 32, carry out deprotection subsequently, for example work as P 1And P 2When forming phthalic diamide, carry out with hydrazine;
(vi) when m be 1 and n be 0, R 2, R 3, R 5And R 6Be hydrogen and R 4And R 32Suc as formula definition in (I), react with formula (X) compound:
Figure C20061011009100373
L wherein 2Be leavings group (for example bromine), then with ammonia, amine R 32-NH 2React or with sodium azide reaction and for example use subsequently, triphenyl phosphine reduces;
(vii) when m be 1 and n be 0, R 2, R 3, R 5And R 6Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl, and R 1, R 4And R 32Suc as formula definition in (I), react with formula (XI) compound:
Figure C20061011009100374
P wherein 1And P 2Be suitable protecting group (for example forming phthalic diamide together) or P independently or together 1Or P 2Be R 32, use hydride reduction (for example using sodium borohydride) then, or add suitable organo-metallic material (R for example 4MgX, wherein X is a halogenide); Or,
(viii) when m be 1 and n be 1, R 2, R 3, R 5, R 6, R 7And R 8Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl, and R 1, R 4And R 32Suc as formula definition in (I), react with formula (XII) compound:
P wherein 1And P 2Be suitable protecting group (for example forming phthalic diamide together) or P independently or together 1Or P 2Be R 32, carry out hydride reduction (for example using sodium borohydride) then, or by adding suitable organo-metallic material (R for example 4MgW, wherein W is a halogenide).
When m be 0 and n be 0, R 2, R 3, R 5And R 6Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl, the preparation of formula (II) compound is carried out according to following method: with formula (XIII) compound:
Figure C20061011009100382
Wherein X and R 1Suc as formula definition in (I), and L 3Be hydrogen or leavings group (for example oxyethyl group, N, O-dimethyl hydroxyl amine), react with formula (XIV) compound:
M——CR 5R 6——CO——L 4 (XIV)
Wherein M represents metal (for example Li or Na) and L 4Be amino (for example ammonium), reset (for example using the phenyl-iodide diacetin, Tetrahedron Letters, 2001,42,1449.) and suitable reduction (for example using sodium borohydride) then, or add suitable organo-metallic (R for example 4MgW, wherein W is a halogenide).
When m is 0, n is 1 and R 2, R 3, R 5, R 6, R 7And R 8Be hydrogen, C independently 1-6Alkyl or C 3-6Cycloalkyl, the preparation of formula (II) compound can be carried out as follows: with formula (XX) compound:
Figure C20061011009100383
Wherein X, R 1And R 4As definition and Z in the following formula (I) is aldehyde protecting group (for example hydroxyl cyanogen or dithian), and formula (XXI) compound:
CR 5R 6＝CR 7R 8——C(O)——L 5 (XXI)
R wherein 5, R 6, R 7And R 8As mentioned above, and L 5For alkoxyl group or amino (for example oxyethyl group or ammonium) react in the presence of alkali (for example LDA or n-butyllithium), group L is removed in hydrolysis then 5, reset (for example using the phenyl-iodide diacetin) and suitable reduction (for example using sodium borohydride), or suitable organo-metallic addition (R for example 4MgW, wherein W is a halogenide).
The formula V compound can prepare in the following manner: with formula (XXII) compound:
Figure C20061011009100391
With peracid (for example metachloroperbenzoic acid) or utilize Sharpless asymmetric Epoxidation condition (J.Am.Chem.Soc.1980,102,5974-5976), then alcohol is activated into leavings group (for example being 3-nitrobenzene-sulfonic acid base (nosyloxy)).
Formula (VI) compound can prepare by following manner:
(a) work as R 5And R 6All be hydrogen, with formula (XXIII) compound:
Figure C20061011009100392
With peracid (for example metachloroperbenzoic acid) or utilize Sharpless asymmetric Epoxidation condition, then, for example, utilize phthalic imidine, 1 by the Mitsunobu reaction, 1-(azo dicarbapentaborane) two piperidines and tributylphosphine react (Tetrahedron Lett.1993,34,1639).
(b) work as R 5And R 6Be hydrogen, C independently 1-6Alkyl or C 3-6In the time of cycloalkyl, with formula (XXIV) compound:
Figure C20061011009100393
P wherein 1And P 2Be suitable protecting group (for example they form phthalic diamide together), perhaps P independently or together 1Perhaps P 2Be R 32, with sulfur ylide (trimethylsulfonium methyl ylide for example, J.Am.Chem.Soc.1965,87,1353-1364); Huo Phosphonium ylide (for example triphenyl phosphonium methyl ylide) reacts; Utilize peracid (for example metachloroperbenzoic acid) to make the alkene of gained carry out epoxidation reaction then.
Formula (VII) compound can be prepared as follows: with formula (XXV) compound:
Figure C20061011009100394
P wherein 1And P 2Be suitable protecting group (for example they form phthalic imidine together), perhaps P independently or together 1Perhaps P 2Be R 32, with sulfur ylide (trimethylsulfonium methyl ylide for example, J.Am.Chem.Soc.1965,87,1353-1364); Huo Phosphonium ylide (for example triphenyl phosphonium methyl ylide) reacts; Utilize peracid (for example metachloroperbenzoic acid) to make the alkene of gained carry out epoxidation reaction then.
Formula (VIII) compound can prepare by following mode: with negatively charged ion (available lithium diisopropylamine is handled ethyl acetate and the obtained) reaction of formula (XXV) compound and ethyl acetate, the ester that obtains of reduction then, or use, for example, the vinyl magnesium Green of alkene is refined and hydroboration subsequently (for example cathecholborane)/oxidation (for example hydrogen peroxide).
Formula (IX) compound can be from formula (XXIV) compound according to being prepared with the same method of compound (VIII).
Formula (X) compound can pass through formula (XXVI) compound:
Figure C20061011009100401
With peracid (for example metachloroperbenzoic acid) reaction, then the primary alconol selectivity is activated into leavings group (for example 3-nitrobenzene-sulfonic acid base) and be prepared.
In addition, formula (I) and (Ia) the available following method of preparation of compound or its improve one's methods and carry out: above-described route, the method or the following embodiment that describe in the art.Above-mentioned intermediate be commercially available maybe can utilize in the art technology or its improve one's methods and be prepared.
The invention provides the method for preparation 4-(3, the 4-dichlorophenoxy) piperidines on the other hand, comprise the steps:
A. with 4-hydroxy piperidine and suitable alkali in suitable solvent at room temperature reaction; And,
B. with the mixture and 1 that produces, 2-two chloro-4-fluorobenzene are together at 50-90 ℃, or heat under the solvent refluxing state of use.
The invention provides the method for preparation 4-(3, the 4-dichlorophenoxy) piperidines on the other hand, comprise 4-hydroxy piperidine and suitable alkali { as basic metal (preferably sodium or potassium) C 1-10Alkoxide is [as C 4-10Tertiary alcohol salt (C for example 4-6Tertiary alcohol salt)], for example potassium tert.-butoxide or potassium 3,7-dimethyl-3-octanol salt } in suitable solvent { as the mixture of ether [for example tetrahydrofuran (THF) or methyl tertbutyl ester], aromatic solvent [as toluene] or these solvents } react in room temperature (10-30 ℃); With the mixture and 1 that produces, 2-two chloro-4-fluorobenzene are together at 50-90 ℃, or heat under the solvent refluxing temperature of use.
On the other hand, the invention provides the method for a kind of preparation 4-(3, the 4-dichlorophenoxy) piperidines, comprise 4-hydroxy piperidine and suitable alkali { as basic metal (preferred sodium or potassium) C 1-10Alkoxide is (as C 4-10Tertiary alcohol salt), C for example 1-6Alkoxide is (as C 4-6Tertiary alcohol salt), potassium tert.-butoxide for example } in suitable solvent as: the mixture of ether [for example tetrahydrofuran (THF) or methyl tertbutyl ester], aromatic solvent [as toluene] or these solvents } react in room temperature (10-30 ℃), and with the mixture that produces at 50-90 ℃, or the reflux temperature of the solvent that uses heating down, and add 1,2-two chloro-4-fluorobenzene.
The example of tertiary alcohol salt is potassium tert.-butoxide and 3,7-dimethyl-3-octanol potassium.
The invention provides the synthetic method of preparation formula (I) and formula (Ia) compound on the other hand.
Here Ding Yi formula (VI), (VII) and (VIII) intermediate be new and these intermediates and preparation method thereof, constituted other feature of the present invention.
Compound of the present invention has the activity as medicine, particularly as Chemokine Receptors (especially CCR3) active regulator, and can be used for treating autoimmunity, inflammatory, hyperplasia or excessively proliferative disease, or immunomodulatory disease (comprising transplant organ or tissue rejection and acquired immune deficiency syndrome (AIDS) (AIDS)).
On the one hand, the example of these diseases is:
(1) occlusive disease of (respiratory tract) air flue comprises: chronic obstructive pulmonary disease (COPD) (as irreversible COPD); Asthma { as segmental bronchus, supersensitivity, endogenous, exogenous or dust asthma, is particularly breathed heavily or inveterate asthma (for example late period asthma or airway hyperreactivity) } for a long time; Bronchitis { as oxyphilous bronchitis }; Acute, supersensitivity, atrophic rhinitis or chronic rhinitis comprise caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca or medicamentous rhinitis; Membranous rhinitis comprises croup, fibrin or pseudomembranous rhinitis or tuberculous rhinitis; The seasonal rhinitis comprises nervous rhinitis's (pollinosis) or vasomotor rhinitis; Sarcoidosis; Farmer's lung and relevant disease; Nasal polyposis; Fibroid lung or idiopathic interstitial pneumonia; The cough-relieving activity; The treatment of chronic cough that airway inflammation is relevant or the cough of iatrogenic inductive;
(2) (bone and joint) sacroiliitis comprises rheumatic arthritis, infective arthritis, autoimmunity sacroiliitis, seronegative spondyloanthropathy (as ankylosing spondylitis, psoriatic arthritis or RD), behcet disease, Sjogren Cotard or Sjogren's syndrome disease;
(3) eosinophilia, uveitis, alopecia areata or the vernal conjunctivitis of (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczematoid dermatitis, seborrheic dermatitis, lichen planus, Phemphigus, blister Phemphigus, epidermolysis bullosa, urticaria, angioderm disease (angiodermas), erythema vasculitis, skin;
(4) the relevant transformation reactions of (gi tract) coeliac disease, rectitis, eosinophilic gastroenteritis, mastocytosis, Crohn disease, ulcerative colitis, supersensitivity enteropathy or food, it is in work away from digestive tube (for example migraine, rhinitis or eczema);
(5) (allograft rejection) following acute and chronic disease: for example transplanting of kidney, heart, liver, lung, marrow, skin or cornea; Or chronic graft versus host disease; And/or
(6) (other tissue or disease) degenerative brain disorder, multiple sclerosis, atherosclerosis, acquired immune deficiency syndrome (AIDS) (AIDS), lupus (as lupus erythematosus or systemic lupus erythematosus), systemic lupus erythematosus, Hashimoto thyroiditis, myasthenia gravis, type i diabetes, nephrotic syndrome, the eosinophilia fascitis, high IgE syndrome, leprosy (as lepromatous leprosy), periodontopathy, malignant cutaneous reticulosis syndrome, the special property sent out thrombocytopenia purpura or the confusion of the menstrual cycle.
The compounds of this invention also is the H1 antagonist and can be used for treating anaphylactic disease.
The compounds of this invention also can be used to control symptom and/or the symptom (for example symptom and/or the symptom of common cold or influenza or other relevant respiratory viral infectionses) that is commonly referred to flu.
According to a further aspect of the invention, provide formula (I) or (Ia) compound, or its pharmacologically acceptable salt or its solvate, the purposes in the method for treatment (comprising prevention) warm-blooded animal (as the people).
According to a further aspect of the invention, provide a kind of in the treatment of this kind of needs warm-blooded animal such as the people in regulate chemokine receptor activity (especially CCR3 receptor active), or the method for antagonism H1, described method comprises formula (I) from significant quantity to described animal or compound (Ia) or its pharmacologically acceptable salt or its solvate of using.
The present invention also provides formula (I) or compound (Ia) or its pharmacologically acceptable salt or its solvate purposes as medicine.
The invention provides the purposes in formula (I) or compound (Ia) or its pharmacologically acceptable salt or its solvate be used for the treatment of (for example regulate chemokine receptor activity (especially CCR3 receptor active) in warm-blooded animal such as people, or antagonism H1) in preparation the medicine on the other hand.
The invention provides formula (I) or compound (Ia) or its pharmacologically acceptable salt or its solvate and be used for the treatment of the purposes in the following disease medicament among warm-blooded animal such as the people in preparation:
(1) occlusive disease of (respiratory tract) air flue comprises: chronic obstructive pulmonary disease (COPD) (as irreversible COPD); Asthma { as segmental bronchus, supersensitivity, endogenous, exogenous or dust asthma, is particularly breathed heavily or inveterate asthma (for example late period asthma or airway hyperreactivity) } for a long time; Bronchitis { as oxyphilous bronchitis }; Acute, supersensitivity, atrophic rhinitis or chronic rhinitis comprise caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca or medicamentous rhinitis; Membranous rhinitis comprises croup, fibrin or pseudomembranous rhinitis or tuberculous rhinitis; The seasonal rhinitis comprises nervous rhinitis's (pollinosis) or vasomotor rhinitis; Sarcoidosis; Farmer's lung and relevant disease; Nasal polyposis; Fibroid lung or idiopathic interstitial pneumonia; The cough-relieving activity; The treatment of chronic cough that airway inflammation is relevant or the cough of iatrogenic inductive;
(2) (bone and joint) sacroiliitis comprises rheumatic arthritis, infective arthritis, autoimmunity sacroiliitis, seronegative spondyloanthropathy (as ankylosing spondylitis, psoriatic arthritis or RD), behcet disease, Sjogren Cotard or Sjogren's syndrome disease;
(3) eosinophilia, uveitis, alopecia areata or the vernal conjunctivitis of (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczematoid dermatitis, seborrheic dermatitis, lichen planus, Phemphigus, blister Phemphigus, epidermolysis bullosa, urticaria, angioderm disease (angiodermas), erythema vasculitis, skin;
(4) the relevant transformation reactions of (gi tract) coeliac disease, rectitis, eosinophilic gastroenteritis, mastocytosis, Crohn disease, ulcerative colitis, supersensitivity enteropathy or food, it is in work away from digestive tube (for example migraine, rhinitis or eczema);
(5) (allograft rejection) following acute and chronic disease: for example transplanting of kidney, heart, liver, lung, marrow, skin or cornea; Or chronic graft versus host disease; And/or
(6) (other tissue or disease) degenerative brain disorder, multiple sclerosis, atherosclerosis, acquired immune deficiency syndrome (AIDS) (AIDS), lupus (as lupus erythematosus or systemic lupus erythematosus), systemic lupus erythematosus, Hashimoto thyroiditis, myasthenia gravis, type i diabetes, nephrotic syndrome, the eosinophilia fascitis, high IgE syndrome, leprosy (as lepromatous leprosy), periodontopathy, malignant cutaneous reticulosis syndrome, the special property sent out thrombocytopenia purpura or the confusion of the menstrual cycle.
Formula (I) or (Ia) compound on the other hand, or its pharmacologically acceptable salt can be used for treating asthma and { as segmental bronchus, supersensitivity, endogenous, exogenous or dust asthma, particularly breathe heavily for a long time or inveterate asthma (for example late period asthma or airway hyperreactivity) }; Or rhinitis { comprises acute, supersensitivity, atrophic rhinitis or chronic rhinitis, as comprises caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca or medicamentous rhinitis; Membranous rhinitis comprises croup, fibrin or pseudomembranous rhinitis or tuberculous rhinitis; The seasonal rhinitis comprises nervous rhinitis's (pollinosis) or vasomotor rhinitis }.
Formula (I) or (Ia) compound on the other hand, or its pharmacologically acceptable salt can be used for treating asthma.
The present invention also provide formula (I) or (Ia) compound or its pharmacologically acceptable salt in the purposes that is used for preparing the medicine that is used for the treatment of asthma or rhinitis.
The present invention also provides a kind of method for the treatment of the chemokine mediated morbid state of warm-blooded animal such as philtrum (especially CCR3 disease states mediated especially asthma), and described method comprises to the formula (I) of the administration significant quantity of this kind of needs treatment or (Ia) compound or its pharmacologically acceptable salt or its solvate.
For with compound of the present invention or its pharmacologically acceptable salt or its solvate treatment warm-blooded animal such as people, particularly regulate Chemokine Receptors (for example CCR3 acceptor) activity or antagonism H1, described composition is mixed with pharmaceutical composition according to the pharmacy standard of standard usually.
Therefore, the invention provides a kind of pharmaceutical composition on the other hand, it comprises formula (I) or compound (Ia) or its pharmacologically acceptable salt or its solvate (activeconstituents) and pharmaceutically acceptable adjuvant, diluent or carrier.The invention provides the described method for compositions of a kind of preparation on the other hand, comprise activeconstituents is mixed with pharmaceutically acceptable adjuvant, diluent or carrier.According to the administering mode difference, pharmaceutical composition preferably includes 0.05～99%w (weight percent), 0.05～80%w more preferably, also more preferably 0.10～70%w, and even the activeconstituents of 0.10～50%w more preferably, all weight percents are based on total composition.
Composition of the present invention carries out administration to the mode that the morbid state of needs treatments can standard, for example by local (as to lung and/or air flue or to skin), per os, rectum or administered parenterally.In order to realize these purposes, The compounds of this invention can mode well known in the art be mixed with, for example, aerosol, dry powder formulations, tablet, capsule, syrup, powder, particle, water-based or oily solution or suspension, (liquid state) but the form of emulsion dispersed powders, suppository, ointment, ointment, drops and aseptic injection water or oil solution or suspension.
Suitable pharmaceutical composition of the present invention is to be suitable for oral unit dosage form, for example tablet or capsule, and it comprises the activeconstituents of 0.1mg～1g.
Pharmaceutical composition of the present invention on the other hand is the form that is suitable for intravenously, subcutaneous or intramuscular administration.
For example, each patient can accept 0.01mgkg -1～100mgkg -1The intravenously of compound, subcutaneous or intramuscular dosage, preferred 0.1mgkg -1～20mgkg -1, composition can every day carries out administration 1～4 time.Intravenously, subcutaneous or intramuscular dosage can carry out administration by the mode of injecting.Perhaps intravenous dosages can be carried out administration by for some time continuous infusion.Perhaps each patient accepts to be equivalent to the day oral dosage of day parenteral dosage, described composition administration every day 1～4 time.
The present invention will be illustrated by following non-limiting example, wherein, and except as otherwise noted:
(i) data of quoting have 1HNMR and with the form of main judgement proton δ value, with respect to providing as 1,000,000/(ppm) of interior target tetramethyl-silicomethane (TMS), described numerical value utilizes deuterium for DMSO-D6 (CD in 300MHz or 400MHz magnetic field 3SOCD 3), methyl alcohol-D4 (CD 3OD) or CDCl 3Measure as solvent (except as otherwise noted);
(ii) mass spectrum (MS) utilizes the probe that directly exposes to carry out with 70 electron-volts electron energy in chemi-ionization (CI) pattern; Wherein the ionization of Xian Shiing is with electron-bombardment (EI) or fast atom bombardment(FAB) (FAB) or electron spray(ES) (ESI) generation; Wherein provide the m/z value, usually only report shows the ion of parent quality, and except as otherwise noted, and the mass ion of citation is a positively charged ion-(M+H) +
(iii) title in embodiment and the method and subhead compound utilize ACD/Index nameprogram version 4.55 to name, and this software is available from Advanced ChemistryDevelopment, Inc;
Unless (iv) in addition by explanation, reversed-phase HPLC utilizes Symmetry, NovaPak or Xterra reverse phase silica gel post to carry out; And
(v) used following abbreviation:
APCI Normal atmosphere CI
DMF N, dinethylformamide
HPLC High pressure liquid chromatography
MTBE Methyl tertiary butyl ether
DMSO Er Jia Ji Ya Sulfone
THF Tetrahydrofuran (THF)
DCM Methylene dichloride
Preparation 1
(2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Step 1:2-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-isoindole-1,3 (2H)-diketone
Figure C20061011009100451
With (R)-2-(oxiranylmethyl radical)-1H-isoindole-1,3 (2H)-diketone (TetrahedronAsymmetry, 1996,7,1641, the 5g) 4-(3, the 4-dichlorophenoxy) of the mixture in the DMF of 50ml ethanol and 15ml-piperidines (6g) processing.With the mixture stirred overnight at room temperature.Vacuum concentrated solution and with residue with twice of methylbenzene azeotropic.Thick material is obtained the subhead compound of yellow oily through chromatography purification (ethyl acetate).
MS(APCI)449/451(M+H) +
1H NMRδ(CDCl 3)7.92-7.81(2H，m)，7.77-7.70(2H，m)，7.30(1H，d)，6.98(1H，t)，6.74(1H，dt)，4.34-4.20(1H，m)，4.09-3.97(1H，m)，3.83(1H，dd)，3.73(1H，dd)，2.93-2.79(1H，m)，2.73-2.60(1H，m)，2.59-2.37(3H，m)，2.31(1H，t)，2.02-1.86(2H，m)，1.86-1.67(2H，m)。
Step 2:(2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100452
With (S)-2-[3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl]-ethanol (100ml) solution of 1H-isoindole-1,3 (2H)-diketone (4g) handles with 20ml one hydrazine hydrate, and the mixture that obtains refluxed 3 hours.To react cooling and filtration.Carry out the title compound (2.5g) of chromatography (ethyl acetate) yellow oily with filtrate evaporation and with product, place after fixing.
MS(APCI)319/321(M+H) +
1H NMRδ(CDCl 3)7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.00(1H，app.sept.)，3.74-3.62(1H，m)，2.94-2.84(1H，m)，2.82(1H，d)，2.72-2.61(1H，m)，2.65(1H，d)；2.60-2.49(1H，m)，2.46-2.21(3H，m)，2.06-1.91(2H，m)，1.90-1.72(2H，m)。
Preparation 2
4-amino-1-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol
Step 1:2-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-1H-isoindole-1,3 (2H)-diketone
With 4-(3, the 4-dichlorophenoxy) piperidines (WO0058305, WO0177101) (4.40g) and 2-(2-oxyethane-2-base ethyl)-1H-isoindole-1,3 (2H)-diketone (J.Med.Chem.1979,22 (6), 631-9.5.00g) mixture in ethanol (50ml) stirred 12 hours at 60 ℃.Cooling mixture is also placed and is spent the night.Filter and collect the crystal that forms, obtain the subhead compound (3.0g) of white solid with cold washing with alcohol and vacuum-drying.
MS(APCI)463/465(M+H) +
1H NMRδ(DMSO)7.90-7.80(4H，m)，7.49(1H，d)，7.25(1H，d)，6.97(1H，dd)，4.53-4.33(2H，m)，3.80-3.69(1H，m)，3.69-3.58(2H，m)，2.77-2.60(2H，m)，2.38-2.17(4H，m)，1.94-1.84(2H，m)，1.85-1.75(1H，m)，1.65-1.50(3H，m)。
Step 2:4-amino-1-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol
With 2-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-mixture heating up of 1H-isoindole-1,3 (2H)-diketone (3.00g) in the ethanol (75ml) and the 35% hydrazine aqueous solution (15ml) refluxed 4 hours.Mixture is cooled down, and vacuum is removed solvent.Residue is ground with warm methylene dichloride.Filter and remove white solid and filtrate is used dried over sodium sulfate.Filtering mixt, evaporating solvent obtain the title compound (2.10g) of yellow oily, are directly used in next step without further purifying.
MS(APCI)333/335(M+H) +
1H NMRδ(CDCl 3)7.29(1H，d)，6.96(1H，d)，6.76(1H，dd)，4.40-4.25(1H，m)，3.95-3.85(1H，m)，3.20-3.00(2H，m)，2.96-2.79(1H，m)，2.78-2.63(1H，m)，2.60-2.45(1H，m)，2.41-2.23(3H，m)，2.10-1.88(2H，m)，1.88-1.70(3H，m)，1.70-1.58(1H，m)。
Preparation 3
1-amino-4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol
Step 1:4-(3, the 4-dichlorophenoxy)-1-(2-oxyethane-2-base ethyl) piperidines
With 4-(3, the 4-dichlorophenoxy) piperidines (WO0058305, WO0177101) (2.00g), 2-(2-bromotrifluoromethane) oxyethane (J.Am.Chem.Soc.1981,103,7520-8) (1.36g) and salt of wormwood (2.2g) mixture in acetone (20ml) stirred 12 hours at 50 ℃.Vacuum is removed solvent.Residue is distributed between water and ethyl acetate.With organic layer water, salt water washing, and through dried over mgso.Mixture filtered and evaporating solvent obtains the subhead compound (2.50g) of yellow oily, be directly used in next step without further purifying.
MS(APCI)316/318(M+H) +
1H NMR δ (CDCl 3) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.27 (1H, d quintets), 3.02-2.95 (1H, m), 2.78 (1H, t), 2.77-2.68 (2H, m), 2.57-2.49 (3H, m), 2.39-2.24 (2H, m), 2.03-1.94 (2H, m), 1.87-1.75 (2H, m), 1.77-1.72 (1H, m), 1.73-1.61 (1H, m).
Step 2:1-amino-4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol
Figure C20061011009100472
In the metal tube of sealing, 4-(3, the 4-dichlorophenoxy)-1-(2-oxyethane-2-base ethyl) piperidines (1.00g) was heated 12 hours at 70 ℃ at the solution of the methyl alcohol (25ml) of 7N ammoniacal liquor.Vacuum is removed solvent, and residue purifying (methanol solution/methylene dichloride of 0～10%7N ammoniacal liquor) on silica gel is obtained the title compound (0.55g) of yellow oily.
MS(APCI)333/335(M+H) +
1H NMR
Figure C20061011009100481
(CDCl 3)7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.36-4.27(1H，m)，3.79-3.70(1H，m)，2.93-2.78(1H，m)，2.76-2.59(5H，m)，2.61-2.50(1H，m)，2.37-2.27(1H，m)，2.03-1.90(2H，m)，1.89-1.76(2H，m)，1.74-1.61(1H，m)，1.54-1.46(1H，m)。
Preparation 4
(2R)-and 1-amino-3-[4-(4-chlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100482
Be prepared according to the method for describing in the preparation 1.
1H NMR δ (CD 3OD) 7.13 (2H, d), 6.80 (2H, d), 4.26 (1H, septets), 3.68-3.59 (1H, m), 2.77-2.65 (2H, m), 2.62 (1H, dd), 2.46 (1H, dd), 2.38-2.24 (4H, m), 1.95-1.85 (2H, m), 1.73-1.61 (2H, m).
Preparation 5
(2R)-and 1-amino-3-[4-(4-chloro-3-fluorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100483
Be prepared according to the method for describing in the preparation 1.
MS(ESI)303/305(M+H) +
1H NMR δ (CD 3OD) 7.32 (1H, t), 6.86 (1H, dd), 6.77 (1H, ddd), 4.40 (1H, quintets), 3.74 (1H, ddd), 2.87-2.75 (2H, m), 2.72 (1H, dd), 2.56 (1H, dd), and 2.50-2.37 (4H, m), 2.08-1.95 (2H, m), 1.85-1.72 (2H, m).
Preparation 6
(2R)-and 1-amino-3-[4-(3,4-two fluorophenoxies) piperidines-1-yl] propan-2-ol
Figure C20061011009100484
Be prepared according to the method for describing in the preparation 1.
MS(ESI)287(M+H) +
1H NMR δ (CD 3OD) 7.14 (1H, dt), 6.87 (1H, ddd), 6.75-6.69 (1H, m), 4.35 (1H, septets), 3.80-3.71 (1H, m), 2.88-2.75 (2H, m), 2.75 (1H, dd), 2.58 (1H, dd), and 2.51-2.34 (4H, m), 2.07-1.94 (2H, m), 1.85-1.71 (2H, m).
Preparation 7
2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol.
Step 1:4-(3, the 4-dichlorophenoxy) piperidines
(50g, (110.9g is in THF 990mmol) (900ml) suspension 494mmol) to be added drop-wise to the potassium tert.-butoxide that stirs under room temperature and the nitrogen atmosphere with the 4-hydroxy piperidine.Mixture heating up refluxed and with dropping 1 in 30 minutes, and 2-two chloro-4-fluorobenzene (98g, 594mmol).With mixture stirring and refluxing 1 hour, cool to room temperature then was with ethyl acetate (500ml) dilution and water (500ml) washing.Organic layer is further used ethyl acetate (500ml) dilution and extract with 1M hydrochloric acid (200ml).Water extract is adjusted to pH＞10 by dropping sodium solution, and with t-butyl methyl ether (750ml) extracting twice.With the organic extract dried over mgso, filtration and vacuum concentration obtain dark-coloured buttery subhead compound, are directly used in next step.
MS(ESI)246/248(M+H) +
1H NMR (CDCl 3)7.31(1H，d)，7.00(1H，d)，6.78(1H，dd)，4.29-4.37(1H，m)，3.15(2H，dt)，2.75(2H，td)，1.97-2.03(2H，m)，1.60-1.70(2H，m)。
Substituting step 1:4-(3, the 4-dichlorophenoxy) piperidines
(50g, 494mmol) the rare slurry in THF (200ml) joins potassium tert.-butoxide under the stirring at room (110.9g 990mmol) in the suspension in THF (650ml), and washs with THF (50ml) with the 4-hydroxy piperidine.The mixture that obtains was stirred 20 minutes under nitrogen atmosphere.Add 1, (98g's 2-two chloro-4-fluorobenzene 594mmol) and with the mixture heating up that obtains refluxed 90 minutes.Reaction mixture is cooled to room temperature and adds entry (500ml).Layering is also removed solvent from organic fraction.Then material is distributed between MTBE and 10% aqueous citric acid solution.Layering and with water layer further use MTBE (2 * 250ml) washing.Water is added 10N NaOH solution alkalize, and product is extracted in the isopropyl acetate (2 * 300ml) to pH＞10.Organism is washed with salt solution (300ml), and dried over mgso is filtered and vacuum concentration obtains dark-coloured buttery subhead compound, is directly used in next step (109.1g, 90%).
Step 2:(2S)-and 1-azido--3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
With (2R)-oxyethane-2-ylmethyl 3-nitrobenzene-sulfonic acid ester (21.1g, DMF 81.3mmol) (300ml) solution with triethylamine (22.6ml 163.0mmol) handles, add then 4-(3, the 4-dichlorophenoxy)-piperidines (20g, 81.3mmol).Mixture is spent the night 60 ℃ of stirrings.In mixture, add sodium azide (16g, 243.9mmol), and with mixture restir 72 hours.With solution vacuum concentration and with residue water (600ml) dilution, with ethyl acetate (1500ml) extraction carefully.With organic layer water (500ml) washed twice, use salt solution (200ml) washing and vacuum concentration to obtain oily matter then.
Step 3:(2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
To be dissolved in from the oily matter that step 2 obtains the wet tetrahydrofuran (THF) (225ml), and (53.3g 203mmol) handles with triphenyl phosphine.To be reflected at 60 ℃ heats and stirred 4 hours.Vacuum is removed solvent, residue is dissolved in the 2N hydrochloric acid (1000ml) again and with water layer with ethyl acetate extraction (3 700ml).With water with the alkalization of 2N sodium hydroxide solution and with dichloromethane extraction (3 1000ml).With the organic layer salt water washing that merges, dried over sodium sulfate is filtered and vacuum concentration.(methanol solution of 8%7N ammoniacal liquor/DCM) obtains the title compound (17g) of yellow oily to thick material through chromatography purification.
MS(APCI)319/321(M+H) +
1H NMR
Figure C20061011009100502
(CDCl 3)7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.0(1H，app.sept.)，3.74-3.62(1H，m)，2.94-2.84(1H，m)，2.82(1H，d)，2.72-2.61(1H，m)，2.65(1H，d)，2.60-2.49(1H，m)，2.46-2.21(3H，m)，2.06-1.91(2H，m)，1.90-1.72(2H，m)。
Preparation 8
(2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Step 1:(2S)-and 1-chloro-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100503
(3.50ml, (10.0g is in ethanol 40.6mmol) (50ml) solution 44.7mmol) to join 4-(3, the 4-dichlorophenoxy) piperidines of stirring with (S)-(+)-Epicholorohydrin.After 20 hours, add entry (50ml).Mixture continue was stirred 2 hours, filter the solid of collecting precipitation then, wash with water and obtained the subhead compound in 2 hours 50 ℃ of vacuum-dryings.
MS(ESI)338/340/342/344(M+H) +
1H NMR
Figure C20061011009100511
(CDCl 3)7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.28-4.33(1H，m)，3.89-3.96(1H，m)，3.54-3.62(3H，m)，2.84-2.92(1H，m)，2.65-2.72(1H，m)，2.45-2.59(3H，m)，2.32-2.36(1H，m)，1.90-2.01(2H，m)，1.77-1.87(2H，m)。
Step 2:(2R)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100512
(1.62g, methyl alcohol 40.6mmol) (200ml) solution joins in the product of abovementioned steps, and after all solids dissolving mixture is stirred 1 hour with sodium hydroxide.The adding ammonia soln (28%, 80ml) and at ambient temperature continue to stir 3 days.Vacuum concentrated solution to 100ml volume be dissolved in then hydrochloric acid (0.5M, 800ml) in, and with extracted with diethyl ether (2 * 200ml).With water extract filter with remove insoluble impurity add then sodium hydroxide regulate alkalescence and with dichloromethane extraction (4 * 200ml), two-phase mixture is filtered with the insoluble impurity of further removal.Organic extract liquid is dry on anhydrous magnesium sulfate, and filtration and pressurization evaporation obtain buttery title compound (10.6g).
MS(APCI)319/321(M+H) +
1H NMRδ(CDCl 3)7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.0(1H，app.sept.)，3.74-3.62(1H，m)，2.94-2.84(1H，m)，2.82(1H，d)，2.72-2.61(1H，m)，2.65(1H，d)，2.60-2.49(1H，m)，2.46-2.21(3H，m)，2.06-1.91(2H，m)，1.90-1.72(2H，m)。
Preparation 9
(2S)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-methyl propan-2-ol
Figure C20061011009100513
Utilize [(2R)-2-methyl oxirane-2-yl] methyl-3-nitro benzene sulfonate to press, be prepared according to the method for describing in preparation 7 (steps 2 and 3).
MS(APCI)333/335(M+H) +
1H NMR
Figure C20061011009100514
(CDCl 3)7.30(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.38-4.30(1H，m)，3.48(2H，s)，2.96-2.78(2H，m)，2.62-2.30(4H，m)，2.00-1.90(2H，m)，1.85-1.72(2H，m)，1.25(3H，s)。
Preparation 10
(2R)-and 1-amino-3-[4-(4-chloro-2-methylphenoxy)-piperidines-1-yl] propan-2-ol
Figure C20061011009100521
Method according to describing in preparation 7 (steps 2 and 3) is prepared from 4-(4-chloro-2-methylphenoxy)-piperidines.
MS(ESI)299/301(M+H) +
1H NMR
Figure C20061011009100522
(CD 3OD) 7.12-7.05 (2H, m), 6.87 (1H, d), 4.39 (1H, septet), and 3.77-3.70 (1H, m), 2.84-2.72 (2H, m), 2.71 (1H, dd), 2.55 (1H, dd), 2.50-2.39 (2H, m), 2.40 (1H, d), 2.39 (1H, d), 2.18 (3H, s), 2.04-1.95 (2H, m), 1.86-1.75 (2H, m).
Preparation 11
6-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2, the 3-dichloro-benzamide
Step 1: 4-[2-(aminocarboxyl)-3,4-dichlorophenoxy] piperidines-1-carboxylic acid tertiary butyl ester
Under nitrogen atmosphere-70 ℃, to the 4-[3 that stirs, 4-dichlorophenoxy] (7.0g in dry THF 20.3mmol) (250ml) solution, drips s-butyl lithium (18ml, the cyclohexane solution of 1.3M) to piperidines-1-carboxylic acid tertiary butyl ester.Solution is continued to stir 30 minutes under this temperature, use solidified carbon dioxide bead (excessive) to handle then.Remove cryostat and with the mixture vigorous stirring simultaneously with being warmed to room temperature in 1 hour.Continue after 1 hour, solution concentration to about 50ml volume, is distributed between sodium hydrogen carbonate solution and ether then.Water further with ether washing (3 *), is acidified to pH4 then and uses dichloromethane extraction (3 *).The extract drying (sal epsom) that merges is also concentrated.With rough carboxylic acid (2.5g, 6.4mmol) usefulness carbonyl-1,1-diimidazole (1.25g, 7.7mmol) methylene dichloride (50ml) solution at 72 hours rough imidazoles things of room temperature treatment, with its vacuum concentration, be dissolved in again in the ethanol (20ml) and and heated 2 hours at 100 ℃ of high pressure with 35% ammoniacal liquor (20ml).Mixture is slowly cooled to room temperature make the title compound crystallization.Crystallized product is filtered and washes with water.Recrystallization obtains subhead compound (1.90g) from ethanol/water.
MS(APCI)289/291(M+H-BOC) +
1H NMR (CDCl 3)7.40(1H，d)，6.83(1H，d)，5.91(1H，s)，5.73(1H，s)，4.52(1H，m)，3.59(2H，m)，3.41(2H，m)，1.86(4H，m)，1.43(9H，s)。
Step 2:2,3-two chloro-6-(piperidin-4-yl oxygen base) benzamide
To the 4-[-[2-(aminocarboxyl)-3 that stirs, 4-dichlorophenoxy] (1.8g in methylene dichloride 4.6mmol) (10ml) solution, adds trifluoroacetic acid (10ml) to piperidines-1-carboxylic acid tertiary butyl ester.After the room temperature 30 minutes, distribute with solution for vacuum concentration and between saturated sodium hydrogen carbonate solution and methylene dichloride.Water layer is further also used ethyl acetate extraction three times three times with dichloromethane extraction.With organic extract drying (Anhydrous potassium carbonate) and the concentrated subhead compound (1.15g) that obtains white solid that merges.
MS(APCI)289/291(M+H) +
1H NMR
Figure C20061011009100533
(CD 3OD)7.49(1H，d)，7.09(1H，d)，4.65(1H，M)，3.15(2H，m)，2.84(2H，m)，2.02(2H，m)，1.82(2H，m)。
Step 3:6-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2, the 3-dichloro-benzamide
Step a: to 2 of stirring, 3-two chloro-6-(piperidin-4-yl oxygen base) benzamide (1.1g, 3.8mmol) dimethyl formamide (10ml) solution in, add triethylamine (1.06ml.7.6mmol) and (2R)-glycidyl-3-nitrobenzene-sulfonic acid ester (1.0g, 3.8mmol), and with mixture 60 ℃ the heating 3 hours.(1.0g 15.2mmol) and with this temperature continues to keep 48 hours to add sodium azide.Mixture vacuum concentration (explosive-proof protector) is almost extremely done, and product is distributed between methylene dichloride and sodium bicarbonate aqueous solution.Water layer is used ethyl acetate extraction then with dichloromethane extraction again.With organic extract drying (Anhydrous potassium carbonate) and the vacuum concentration that merges.
Step b: be dissolved in product in the tetrahydrofuran (THF) (50ml) again and water (5ml) and triphenyl phosphine (2.4g) processing.Mixture was heated 4 hours at 60 ℃, then vacuum concentration.Product is distributed between ethyl acetate and 1N hydrochloric acid.Water extract further with the ethyl acetate washing, is alkalized to pH11 with 48% sodium hydroxide solution then.Water layer is with dichloromethane extraction (3 *), and organic extract drying (Anhydrous potassium carbonate) and the vacuum concentration that merges obtained rough amine product, is directly used in next step (referring to embodiment 132) without further purifying.
Preparation 12
(R)-1-[4-(3,4-two chloro-phenoxy groups)-piperidines-1-yl]-3-methylamino-propan-2-ol
With 4-(3, the 4-dichlorophenoxy)-1-[(2R)-oxyethane-2-ylmethyl] and piperidines (1g, 3.31mmol) and methylamine (2.56ml, 40% H 2O solution, ethanol 33.1mmol) (15ml) solution heated 16 hours in sealed vessel at 60 ℃.Solvent evaporated under reduced pressure and with residue through the rapid column chromatography purifying, obtain title compound (875mg) with the dichloromethane solution wash-out of 8%7M ammoniacal liquor methanol solution.
MS(APCI)333/335(M+H) +
1H NMR
Figure C20061011009100542
(CDCl 3)7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.32-4.26(1H，m)，3.86-3.80(1H，m)，2.91-2.86(1H，m)，2.71-2.65(2H，m)，2.65(1H，dd)，2.56-2.51(2H，m)，2.54(1H，dd)，2.48-2.42(2H，m)，2.46(3H，s)，2.38-2.27(3H，m)。
Preparation 13
(2R)-and 1-amino-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100543
According to the method for describing in the preparation 10, utilize 4-(2,4-two chloro-3-methylphenoxy)-piperidines to be prepared.
MS(APCI)333/335(M+H) +
1H NMR
Figure C20061011009100544
(CD 3OD)7.25(2H，d)，6.94(2H，d)，4.54-4.37(1H，m)，3.88-3.71(1H，m)，3.35-3.24(2H，m)，2.93-2.72(4H，m)，2.72-2.57(1H，m)，2.08-1.90(2H，m)，1.92-1.75(2H，m)。
Preparation 14
(2S)-and 1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100545
According to the method for describing in the preparation 7, utilize (2S)-oxyethane-2-ylmethyl-3-nitrobenzene-sulfonic acid ester to be prepared.
MS(ESI)319/321(M+H) +
1H NMR (CDCl 3)7.30(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.36-4.24(1H，m)，3.75-3.65(1H，m)，2.94-2.78(2H，m)，2.70-2.60(2H，m)，2.59-2.51(1H，m)，2.41-2.25(3H，m)，2.03-1.93(2H，m)，1.87-1.77(2H，m)。
Preparation 15
(2R)-and 1-amino-2-methyl-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol.
Step 1:2-[[(2R)-and 2-methyl oxirane base] methyl]-1H-isoindole-1,3 (2H)-diketone
Figure C20061011009100551
To (2S)-(2-methyl oxirane-2-yl) methyl 3-nitrobenzene-sulfonic acid ester (1.913g, in dry dimethyl formamide (15ml) solution 7mmoles), add potassium phthalimide (1.304g, 7mmoles).Mixture was stirred 5 hours at 50 ℃, be cooled to room temperature then.The mixture that obtains is distributed between ethyl acetate and water.With water with ethyl acetate (2 * 100ml) washings and with the organic extract water that merges (3 * 100ml), the saturated brine washing, dried over sodium sulfate and vacuum concentration obtain rough orange wax.Obtain the subhead compound (0.864g) of white solid through chromatography purification (silicic acid, the isohexane solution of 20% ethyl acetate).
MS(ESI)189(M-CO) +
1H NMR
Figure C20061011009100552
(CDCl 3)7.90-7.85(2H，m)，7.78-7.71(2H，m)，4.02(1H，d)，3.71(1H，d)，2.82(1H，d)，2.62(1H，d)，1.39(3H，s)。
Step 2:
2-[(2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group]-1H-isoindole-1,3 (2H)-diketone
With 4-(3, the 4-dichlorophenoxy) piperidines (0.985g, 4mmoles), 2-[[(2R)-and 2-methyl oxirane base] methyl]-1H-isoindole-1,3 (2H)-diketone (0.869g, 4mmoles) and triethylamine (0.809g, 1.12ml ethanol 8mmoles) (20ml) solution stirred 5 hours at 50 ℃.The solution that obtains is cooled to room temperature and vacuum concentration obtains rough yellow jelly.Flash chromatography (silica gel, the dichloromethane solution of 2% 7N ammoniacal liquor methyl alcohol is as eluent) obtains the subhead compound (1.24g) of yellow oily.
MS(APCI)463/465/467(M+H) +
1H NMR
Figure C20061011009100561
(CDCl 3)7.89-7.85(2H，m)，7.76-7.72(2H，m)，7.30(1H，d)，6.98(1H，d)，6.78(1H，dd)，4.27-4.21(1H，m)，3.88(1H，d)，3.70(1H，d)，3.43(1H，bd s)，2.96-2.81(2H，m)，2.60-2.42(4H，m)，1.95-1.89(2H，m)，1.80-1.70(2H，m)，1.15(3H，s)。
Step 3:
(2R)-and 1-amino-2-methyl-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol
Figure C20061011009100562
To 2-[(2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group]-1H-isoindole-1,3 (2H)-diketone (278mg, in ethanol 0.6mmoles) (5ml) solution, the adding aqueous methylamine solution (the 40%wt. aqueous solution, 6ml).Stirring at room 24 hours, vacuum concentration obtained rough yellow glass shape material then with mixture.This glassy mass is dissolved in the methyl alcohol (2ml), joins in the IsoluteFlash SCX tube (2g), with methyl alcohol (25ml) and 7N ammoniacal liquor methanol solution (25ml) washing.Vacuum concentration ammoniacal liquor methanol solution obtains the title compound (165mg) of yellow glass shape.
MS(ESI)333/335/337(M+H) +
1H NMR (CDCl 3)7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.29-4.21(1H，m)，2.96-2.80(2H，m)，2.60-2.30(4H，m)，2.00-1.90(3H，m)，1.85-1.75(3H，m)，1.13(3H，s)。
Preparation 16
7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
With 1-oxo-7-sulfonic acid-1,2-dihydro-isoquinoline-4-carboxylic acid (5g) joins in the chlorsulfonic acid (25ml).Mixture 100 ℃ of heating 84 hours, slowly is added drop-wise on ice under stirring then.Mixture filtered and residue water and ether washing and drying are obtained light yellow solid 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (7.5g).
MS(APCI)286(M-H) -
1H NMR
Figure C20061011009100565
(DMSO)11.81(1H，d)，8.79(1H，d)，8.48(1H，d)，8.03(1H，d)，7.96(1H，dd)。
Preparation 17
The 7-[(methylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
With 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1g) joins in the methylamine (60ml) and with mixture and stirred 18 hours.Add the concentrated hydrochloric acid acidifying mixture, filter the 7-[(methylamino that obtains to light yellow solid) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.84g).
MS(APCI)283(M+H) +
1H NMR
Figure C20061011009100572
(DMSO)12.93(1H，s)，12.13(1H，d)，9.03(1H，d)，8.61(1H，d)，8.16(1H，d)，8.12(1H，dd)，7.65(1H，q)，2.43(3H，d)。
Preparation 18
1,2-dihydro-7-[[(2-hydroxyethyl) amino] alkylsulfonyl]-1-oxo-4-1-isoquinolinecarboxylic acid
Figure C20061011009100573
With 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1g) joins in the tetrahydrofuran (THF) (3ml) of thanomin (3ml) and with mixture and stirred 18 hours.Add hydrochloric acid with acidifying mixture, filter and obtain 1 of white solid, 2-dihydro-7-[[(2-hydroxyethyl) amino] alkylsulfonyl]-1-oxo-4-1-isoquinolinecarboxylic acid.
MS(APCI)313(M+H) +
1H NMR
Figure C20061011009100574
(DMSO)12.92(5H，s)，12.12(5H，s)，9.01(6H，d)，8.62(6H，s)，8.16(13H，d)，8.13(13H，dd)，7.81(6H，t)，4.67(5H，s)，3.39-3.25(84H，m)，2.81(13H，q)。
Preparation 19
7-[(cyclopropyl amino) alkylsulfonyl]-1,2-dihydro-1-oxo-4-1-isoquinolinecarboxylic acid
Figure C20061011009100575
With 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1g) joins in tetrahydrofuran (THF) (20ml) solution of cyclopropylamine (3ml), and mixture was stirred 18 hours.Add hydrochloric acid with acidifying mixture, filter the 7-[(cyclopropyl amino that obtains white solid) alkylsulfonyl]-1,2-dihydro-1-oxo-4-1-isoquinolinecarboxylic acid.
MS(APCI)307(M-H) -
1H NMR
Figure C20061011009100581
(DMSO) 12.93 (1H, s), 12.13 (1H, d), 9.03 (1H, d), 8.65 (1H, d), 8.16 (1H, d), 8.14 (1H, dd), 8.08 (1H, d), 2.13 (1H, d sextets), 0.48 (2H, td), 0.39-0.34 (2H, m).
Preparation 20
7-(azetidin-1-base alkylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
With 7-(chlorosulfonyl)-1-oxo-1; 2-dihydro-isoquinoline-4-carboxylic acid (1g) joins in the tetrahydrofuran (THF) (5ml) and acetonitrile (5ml) solution of azetidine (0.7ml) and diisopropylethylamine (0.4ml), and mixture is stirred evaporation then in 72 hours.Solid crystallization from methyl alcohol is added hydrochloric acid with acidifying mixture then, filter 7-(azetidin-1-base the alkylsulfonyl)-1-oxo-1 that obtains white solid, 2-dihydro-isoquinoline-4-carboxylic acid.
MS(APCI)309(M+H) +
1H NMR
Figure C20061011009100583
(DMSO) 12.99 (1H, s), 12.21 (1H, d), 9.12 (1H, d), 8.54 (1H, d), 8.20 (1H, d), 8.16 (1H, dd), 3.70 (4H, t), 1.99 (2H, quintets).
Preparation 21
7-(amino-sulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100584
With 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1g) joins in 0.880 ammoniacal liquor (60ml) and with mixture and stirred 18 hours.Concentrated hydrochloric acid is added with acidifying mixture, filter 7-(the amino-sulfonyl)-1-oxo-1 that obtains white solid, 2-dihydro-isoquinoline-4-carboxylic acid.
MS(APCI)269(M+H) +
1H NMR (DMSO)12.91(1H，s)，12.08(1H，d)，8.99(1H，d)，8.68(1H，d)，8.16(1H，dd)，8.14(1H，d)，7.53(2H，s)。
Preparation 22
The 7-[(dimethylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100592
With 7-(chlorosulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.8g) joins in the dimethyl amine (15ml), and mixture was stirred 18 hours.With mixture concentrated hydrochloric acid acidifying, filter the 7-[(dimethylamino that obtains white solid then) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid.
MS(APCI)295(M-H) -
1H NMR (DMSO)12.96(1H，s)，12.19(1H，d)，9.07(1H，d)，8.50(1H，d)，8.18(1H，d)，8.11(1H，dd)，2.65(6H，s)。
Preparation 23
7-[(3-hydroxy-3-methyl azetidin-1-yl) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100594
With 7-(chlorosulfonyl)-1-oxo-1, tetrahydrofuran (THF) (8ml) solution of 2-dihydro-isoquinoline-4-carboxylic acid (1g), diisopropyl ethyl amine (3ml) and 3-methyl azetidin-3-alcohol hydrochloride (0.8g) was 55 ℃ of heating 3 days.With the mixture hcl acidifying, filter then and obtain baby pink solid 7-[(3-hydroxy-3-methyl azetidin-1-yl) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid.
MS(ESI)337(M-H) -
1H NMR
Figure C20061011009100595
(DMSO)12.99(1H，s)，12.22(1H，d)，9.11(1H，d)，8.53(1H，s)，8.21(1H，d)，8.16(1H，dd)，3.61(2H，d)，3.46(2H，d)，1.25(3H，t)。
Preparation 24
4-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2-benzyl chloride nitrile
Step 1:4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100601
With potassium tert.-butoxide (5.57g, 49.68mmol) join 4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester (5.00g, 24.84mmol) the solution of glyme (100ml) in, and with mixture stir added then in 30 minutes 2-chloro-4-fluoro-benzonitrile (7.73g, 49.68mmol).To be reflected at stirred overnight at room temperature and distribution between ethyl acetate (250ml) and water (200ml) then.Separate organic layer, dried over mgso and evaporating solvent.Residue through the flash chromatography purifying, is used ethyl acetate: isohexane (4: 1) wash-out obtains the subhead compound (3.45g) of colorless solid.
MS(ESI)337(M+H) +
1H NMR
Figure C20061011009100602
(CDCl 3) 1.47 (9H, s), 1.72-1.80 (2H, m), 1.90-1.97 (2H, m), 3.37 (2H, ddd), 3.68 (2H, ddd), 4.54 (1H, d quintets), 6.86 (1H, dd), 7.01 (1H, d), 7.57 (1H, d).
Step 2:4-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2-benzyl chloride nitrile
(2.75g adds trifluoroacetic acid (20ml) in methylene dichloride 9.09mmol) (20ml) solution, and mixture was stirred 90 minutes to 4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-carboxylic acid tertiary butyl ester.Evaporating solvent and with residue (2 * 20ml) azeotropic are dissolved in the water (30ml) then, and add sodium hydroxide solution is adjusted to pH11 with toluene.Free alkali is extracted (5 * 100ml) with DCM.Merge organism, dried over sodium sulfate and removal of solvent under reduced pressure obtain dense thick oily matter, and it is dissolved among the DMF (30ml), add (2R)-oxyethane-2-ylmethyl-3-nitrobenzene-sulfonic acid ester (2.35g then, 9.09mmol) and triethylamine (2.54ml, 18.18mmol).With mixture 60 ℃ the heating 4 hours, add then sodium azide (1.36g, 27.27mmol).Continue heating 72 hours at 60 ℃.With reaction mixture cooling and distribution between water (50ml) and ethyl acetate (100ml).Isolate organic layer and removal of solvent under reduced pressure.Residue is dissolved in THF (20ml) and the water (2ml), and the adding triphenyl phosphine (5.90g, 22.72mmol).Mixture 60 ℃ of heating 16 hours, is used ethyl acetate (100ml) dilution then.With solution with 1N HCl (50ml) washing and and isolate water layer, and be adjusted to pH11 with sodium hydroxide.Product is extracted (4 * 100ml) with DCM.Merge organism, and on sodium sulfate dry and removal of solvent under reduced pressure.Residue is obtained the title compound (1.10g) of faint yellow solid through the flash chromatography purifying.
MS(ESI)310(M+H) +
1H NMR
Figure C20061011009100603
(CDCl 3) 7.56 (1H, d), 7.00 (1H, d), 6.85 (1H, dd), 4.42 (1H, septets), 3.73-3.67 (1H, m), 2.93-2.86 (1H, m), 2.86-2.78 (1H, m), 2.71-2.62 (2H, m), 2.61-2.55 (1H, m), 2.45-2.30 (3H, m), 2.06-1.96 (2H, m), 1.91-1.79 (2H, m).
Preparation 25
(2R)-and 1-amino-3-{4-[4-(methylsulfonyl) phenoxy group] piperidines-1-yl } propan-2-ol.
Method according to describing in the preparation 24 is prepared from 1-fluoro-4-(methylsulfonyl) benzene.
Step 1:4-[4-(methylsulfonyl) phenoxy group] piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100612
1H NMR (CDCl 3)1.48(9H，s)，1.74-1.82(2H，m)，1.91-1.99(2H，m)，3.04(3H，s)，3.38(2H，ddd)，3.69(2H，ddd)，4.57-4.62(1H，m)，7.02(2H，d)，7.86(2H，d)。
Step 2:(2R)-and 1-amino-3-{4-[4-(methylsulfonyl) phenoxy group] piperidines-1-yl } propan-2-ol
MS(ESI)329(M+H) +
1H NMR
Figure C20061011009100614
(CDCl 3) 7.85 (2H, d), 7.01 (2H, d), (4.47 1H, septet), and 3.73-3.67 (1H, m), 3.03 (3H, s), 2.95-2.88 (1H, m), 2.86-2.78 (1H, m), 2.72-2.62 (2H, m), 2.61-2.55 (1H, m), 2.45-2.30 (3H, m), 2.08-1.98 (2H, m), 1.92-1.81 (2H, m).
Preparation 26
4-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base) benzonitrile
Figure C20061011009100615
Be prepared from 4-fluorine benzonitrile according to the method for describing in the preparation 24.
Step 1:4-(4-cyano-benzene oxygen) piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100616
MS(ESI)303(M+H) +
1H NMR
Figure C20061011009100617
(CDCl 3)7.58(2H，d)，6.95(2H，d).4.55(1H，m)，3.69(2H，ddd).3.37(2H，ddd)，1.97-1.90(2H，m)，1.80-1.72(2H，m)，1.47(9H，s)。
Step 2:4-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base) benzonitrile
MS(ESI)276(M+H) +
1H NMR
Figure C20061011009100621
(CDCl 3)7.57(2H，d)，6.94(2H，d)，4.46-4.41(1H，m)，3.74-3.68(1H，m)，2.94-2.88(1H，m)，2.83(1H，dd)，2.73-2.66(1H，m)，2.64(1H，dd)，2.61-2.55(1H，m)，2.46-2.30(3H，m)，2.07-1.97(2H，m)，1.91-1.80(2H，m)。
Preparation 27
4-[4-chloro-2-(methoxycarbonyl) phenoxy group] piperidines-1-carboxylic acid tertiary butyl ester
At 0 ℃, with the di-isopropyl azodicarboxylate (5.2ml, 26.8mmol) be added drop-wise to 5-chloro-2-hydroxymethyl benzoic ether (5.0g, 26.8mmol), 4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester (5.4g, 26.8mmol) and triphenyl phosphine (7.02g is in THF 26.8mmol) (200ml) solution.Reaction mixture is warmed to envrionment temperature to spend the night.Removal of solvent under reduced pressure is also ground residue with ether (200ml).Remove by filter the triphenyl phosphine oxide compound and reduce pressure and remove ether.Residue through the flash chromatography purifying, is used ethyl acetate: isohexane (1: 9) wash-out obtains brown buttery title compound (8.1g).
MS(ESI)370(M+H) +
1H NMR
Figure C20061011009100623
(DMSO)1.47(9H，s)，1.79-1.92(4H，m)，3.45-3.54(2H，m)，3.56-3.62(2H，m)，3.89(3H，s)，4.54-4.59(1H，m)，6.92(1H，d)，7.38(1H，dd)，7.77(1H，d)。
Preparation 28
2-{[1-(tert-butoxycarbonyl) piperidin-4-yl] the oxygen base }-the 5-chloro-benzoic acid
Figure C20061011009100624
The aqueous solution (20ml) with 2N sodium hydroxide under 45 ℃ joins 4-[4-chloro-2-(methoxycarbonyl) phenoxy group] (8.1g is in tetrahydrofuran (THF) 22.0mmol) (70ml) solution for piperidines-1-carboxylic acid tertiary butyl ester.With mixture vigorous stirring 3 hours, be adjusted to pH2 with 2N hydrochloric acid then.With product with ethyl acetate extraction and to wash with water organic layer up to washing lotion repeatedly be pH6.Organic layer is also evaporated in dried over mgso.Residue is obtained the title compound (7.5g) of colorless solid with methylbenzene azeotropic.
MS(ESI)356(M+H) +
1H NMR
Figure C20061011009100631
(DMSO)1.47(9H，s)，1.79-1.88(2H，m)，2.03-2.11(2H，m)，3.30(2H，ddd)，3.77-3.85(2H，m)，4.72(1H，m)，7.02(1H，d)，7.49(1H，dd)，8.12(1H，d)，10.91(1H，s)。
Preparation 29
4-(4-chloro-2-methylamino formyl radical-phenoxy group)-piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100632
With bromo-three-Bi Ka Wan Phosphonium hexafluorophosphate (1.57g, 3.37mmol) join 2-{[1-(tert-butoxycarbonyl) piperidin-4-yl of vigorous stirring] the oxygen base-5-chloro-benzoic acid (1.00g, 2.81mmol) and the 40% methylamine aqueous solution 1) is in the mixture of DCM (10ml).Continue to stir 30 minutes, between 1N hydrochloric acid (10ml) and methylene dichloride (10ml), distribute then.Isolate organic layer also with saturated sodium hydrogen carbonate solution (20ml) and water (20ml) washing, then with dried over sodium sulfate and removal of solvent under reduced pressure.Residue through the flash chromatography purifying, is used ethyl acetate: isohexane (1: 1) wash-out obtains the title compound (0.84g) of colorless solid.
MS(ESI)369(M+H) +
1H NMR
Figure C20061011009100633
(CDCl 3)8.17(1H，d)，7.75(1H，s)，7.35(1H，dd)，6.91(1H，d)，4.58(1H，tt)，3.81-3.71(2H，m)，3.29(2H，ddd)，3.00(3H，d)，2.08-1.98(2H，m)，1.82-1.71(2H，m)，1.48(9H，s)。
Preparation 30
4-[2-(aminocarboxyl)-4-chlorophenoxy] piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100634
Utilize ammoniacal liquor to be prepared according to the method for describing in the preparation 29.
MS(ESI)355(M+H) +
1H NMR
Figure C20061011009100641
(CDCl 3)8.18(1H，d)，7.67-7.61(1H，m)，7.40(1H，dd)，6.94(1H，d)，5.83-5.76(1H，m)，4.61(1H，m)，3.84-3.76(2H，m)，3.26(2H，ddd)，2.09-2.01(2H，m)，1.82-1.73(2H，m)，1.47(9H，s)。
Preparation 31
2-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-5-chloro-benzoic acid methyl ester
Figure C20061011009100642
According to preparation 24, the method for describing in the step 2 is from 4-[4-chloro-2-(methoxycarbonyl) phenoxy group] piperidines-1-carboxylic acid tertiary butyl ester is prepared.
MS(ESI)343(M+H) +
1H NMR
Figure C20061011009100643
(CDCl 3)7.75(1H，d)，7.37(1H，dd)，6.92(1H，d)，4.46-4.39(1H，m)，3.89(3H，s)，3.72-3.66(1H，m)，2.93-2.87(1H，m)，2.81(1H，dd)，2.69-2.55(2H，m)，2.63(1H，dd)，2.43-2.31(3H，m)，2.00-1.84(2H，m)，1.67-1.46(2H，m)。
Preparation 32
2-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-5-chloro-N-methyl-benzamide
Figure C20061011009100644
According to preparation 24, the method for describing in the step 2 is prepared from 4-(4-chloro-2-methylamino formyl radical-phenoxy group)-piperidines-1-carboxylic acid tertiary butyl ester.
MS(ESI)342(M+H) +
1H NMRδ(CDCl 3)8.18(1H，d)，7.88(1H，s)，7.34(1H，dd)，6.91(1H，d)，4.54-4.48(1H，m)，3.73-3.67(1H，m)，3.01(3H，d)，2.89-2.83(1H，m)，2.83(1H，dd)，2.68-2.56(2H，m)，2.63(1H，dd)，2.44(1H，dd)，2.39-2.33(1H，m)，2.34(1H，dd)，2.13-2.03(2H，m)，1.94-1.83(2H，m)。
Preparation 33
2-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-the 5-chlorobenzamide
Figure C20061011009100651
According to preparation 24, the method for describing in the step 2 is from 4-[2-(aminocarboxyl)-4-chlorophenoxy] piperidines-1-carboxylic acid tertiary butyl ester is prepared.
MS(ESI)328(M+H) +
1H NMRδ(CDCl 3)8.19(1H，d)，7.75(1H，s)，7.39(1H，dd)，6.93(1H，d)，5.85(1H，s)，4.56-4.48(1H，m)，3.73-3.67(1H，m)，2.93-2.86(1H，m)，2.83(1H，dd)，2.73-2.66(1H，m)，2.63(1H，dd)，2.61-2.54(1H，m)，2.44(1H，dd)，2.37-2.30(1H，m)，2.35(1H，dd)，2.15-2.05(2H，m)，1.90(2H，dtd)。
Preparation 34
4-{3,4-two chloro-2-[(cyclopropyl amino) carbonyl] phenoxy group } piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100652
With 4-[3,4-two chloro-2-(1H-imidazo 1-1-base carbonyl) phenoxy group] (2.0g, cyclopropylamine 4.5mmol) (12ml) solution was 50 ℃ of heating 14 hours for piperidines-1-carboxylic acid tertiary butyl ester (describing in preparation 11 steps 1).With solution for vacuum concentration, between ethyl acetate and 1N hydrochloric acid, distribute then.With organism dry and vacuum concentration on sal epsom.From methylene dichloride: crystallization obtains the title compound (0.64g) of white solid the isohexane.
MS(ESI)429/431(M+H) +
1H NMRδ(DMSO)8.46(1H，d)，7.56(1H，d)，7.17(1H，d)，4.68(1H，m)，3.42-3.27(4H，m)，2.74(1H，m)，1.78(2H，m)，1.55(2H，m)，0.68(2H，m)，0.44(2H，m)。
Preparation 35
6-{[1-(3-amino-2-hydroxypropyl) piperidin-4-yl] the oxygen base }-2,3-two chloro-N-cyclopropyl-phenyl methane amides
Figure C20061011009100653
According to preparation 24, the method for describing in the step 2 is prepared after preparation 34.
MS(ESI)402(M+H) +
1H NMR
Figure C20061011009100661
(CDCl 3)7.35(1H，d)，6.78(1H，d)，5.82(1H，s)，4.40-4.33(1H，m)，3.68(1H，tt)，2.92-2.85(2H，m)，2.85-2.77(2H，m)，2.81(1H，dd)，2.62(1H，dd)，2.42-2.29(3H，m)，2.00-1.89(2H，m)，1.88-1.79(2H，m)，0.89(2H，td)，0.66-0.62(2H，m)。
Preparation 36
4-[3,4-two chloro-2-(chlorosulfonyl) phenoxy groups] piperidines-1-carboxylic acid tertiary butyl ester
Figure C20061011009100662
Under-70 ℃ of nitrogen atmosphere, to stirring 4-[3,4-dichlorophenoxy] (10.0g in dry THF 28.9mmol) (400ml) solution, drips s-butyl lithium (26.7ml, the cyclohexane solution of 1.3M) to piperidines-1-carboxylic acid tertiary butyl ester.Solution is continued to stir 15 minutes under this temperature, sulfurous gas was fed mixture 10 minutes then.Remove cryostat, and mixture was warmed to room temperature 1 hour.Add N-chlorosuccinimide (4.63g, 35mmol), and will be stirring at room 72 hours.With solution for vacuum concentration, and between ethyl acetate and 1N hydrochloric acid, distribute.With organic extract drying (sal epsom) and concentrated.Silica gel column chromatography (ethyl acetate: isohexane/1: 3) obtain title compound (2.40g).
MS(ESI)445(M+H) +
1H NMR
Figure C20061011009100663
(DMSO)7.45(1H，d)，7.03(1H，d)，4.65(1H，m)，3.59(2H，m)，3.33(3H，s)，1.66(4H，m)，1.40(9H，s)。
Preparation 37
2,3-two chloro-6-(piperidin-4-yl oxygen base) benzsulfamide
With 4-[3,4-two chloro-2-(chlorosulfonyl) phenoxy groups] (0.80g 1.8mmol) is dissolved in the methanol solution of 7N ammonia piperidines-1-carboxylic acid tert-butyl ester, and stirring at room 20 minutes, with solution for vacuum concentration, then with methylbenzene azeotropic 1 time.Residue is dissolved in methylene dichloride again: in the trifluoroacetic acid/1: 1 (20ml), and stirring at room 15 minutes.With solution for vacuum concentration, between ethyl acetate and saturated sodium bicarbonate aqueous solution, distribute then.Water is used ethyl acetate extraction (4 times) again, and the organism that merges is dry on Anhydrous potassium carbonate.Vacuum concentration obtains the title compound (0.54g) of white powder.
MS(ESI)325/327(M+H) +
1H NMR
Figure C20061011009100671
(DMSO)7.74(1H，d)，7.34(1H，d)，4.66(1H，m)，2.96(2H，m)，2.55(2H，m)，1.91(2H，m)，1.63(2H，m)。
Preparation 38
2,3-two chloro-N-methyl-6-(piperidin-4-yl oxygen base) benzsulfamide
Figure C20061011009100672
With 4-[3; 4-two chloro-2-(chlorosulfonyl) phenoxy groups] piperidines-1-carboxylic acid tertiary butyl ester (0.70g; 1.8mmol) be dissolved in the 40% methylamine aqueous solution in the solution of water (10ml) and methyl alcohol (10ml), and stirring at room 30 minutes, with solution for vacuum concentration and with methylbenzene azeotropic (4 times).With residue be dissolved in again methylene dichloride/trifluoroacetic acid (1: 1) (20ml) in, and stirring at room 15 minutes.With solution for vacuum concentration, between ethyl acetate and saturated sodium bicarbonate aqueous solution, distribute then.Water is used ethyl acetate extraction (4 times) again, and the organism that merges is dry on Anhydrous potassium carbonate.Vacuum concentration obtains the title compound (0.69g) of white powder.
MS(ESI)339/341(M+H) +
1H NMR
Figure C20061011009100673
(DMSO)7.76(1H，d)，7.35(1H，d)，4.64(1H，m)，2.96(2H，m)，2.54(3H，s)，2.54(2H，m)，1.90(2H，m)，1.61(2H，m)。
Preparation 39
2,3-two chloro-N-cyclopropyl-6-(piperidin-4-yl oxygen base) benzsulfamide
Figure C20061011009100674
With 4-[3,4-two chloro-2-(chlorosulfonyl) phenoxy groups] piperidines-1-carboxylic acid tertiary butyl ester (0.70g 1.8mmol) is dissolved in the cyclopropylamine (8ml), and stirring at room 30 minutes.With solution for vacuum concentration, and with methylbenzene azeotropic (4 times).Residue is dissolved in methylene dichloride again: in the trifluoroacetic acid/1: 1 (20ml), and stirring at room 15 minutes,, between ethyl acetate and saturated sodium bicarbonate aqueous solution, distribute then with solution for vacuum concentration.Water is used ethyl acetate extraction (4 times) again, and the organism that merges is dry on Anhydrous potassium carbonate.Vacuum concentration obtains the title compound (0.70g) of white powder.
MS(ESI)365/367(M+H) +
1H NMR
Figure C20061011009100681
(DMSO)7.78(1H，d)，7.36(1H，d)，4.65(1H，m)，2.97(2H，m)，2.55(2H，m)，2.27(1H，m)，1.89(2H，m)，1.63(2H，m)，0.49(4H，m)；
Preparation 40
6-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2,3-dichlorobenzene sulphonamide
After preparation 37, be prepared according to the method for describing in preparation 7 (steps 2 and 3).
MS(ESI)398/400(M+H) +
Preparation 41
6-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2,3-two chloro-N-methyl benzenesulfonamides
Figure C20061011009100683
After preparation 38, be prepared according to the method for describing in preparation 7 (steps 2 and 3).
MS(ESI)412/414(M+H) +
Preparation 42
6-(1-[(2R)-3-amino-2-hydroxypropyl] piperidin-4-yl } the oxygen base)-2,3-two chloro-N-cyclopropyl-phenyl sulphonamide
Figure C20061011009100684
After preparation 39, be prepared according to the method for describing in preparation 7 (steps 2 and 3).
MS(ESI)438/440(M+H) +
Preparation 43
7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100691
0 ℃ in the 4ml aqueous solution of sodium bicarbonate (500mg) and S-WAT (353mg), add 7-(chlorosulfonyl)-1-oxo-1 in batches, 2-dihydro-isoquinoline-4-carboxylic acid (referring to the preparation 16) (400mg).Reaction is warmed to room temperature, and then 80 ℃ of heating 2 hours.Reaction is cooled to 0 ℃ and be acidified to pH～1 with concentrated hydrochloric acid.Suspension was stirred 15 minutes with the water dilution of 4ml and at 0 ℃, under nitrogen atmosphere, filter then.Wash solid with water twice, and in 45 ℃ of saleratus (280mg) solution (3ml) that join the degassing.Slowly add ethanol up to solution solution slight haze.Add methyl iodide (262 μ l) then, will be reflected at (45-50 ℃) and reflux 5 hours down.To react vacuum concentration, with ethyl acetate extraction and with concentrated hydrochloric acid with aqueous phase as acidified.To be reflected at 0 ℃ and stir 30 minutes and solid collected by filtration, recrystallization obtains the title compound (325mg) of white solid from acetone then.
MS(ESI)266(M-H) -
1H NMR
Figure C20061011009100692
(DMSO)12.97(1H，bs)，12.19(1H，d)，9.07(1H，d)，8.70(1H，d)，8.27(1H，dd)，8.19(1H，d)，3.30(3H，s)。
Preparation 44
6-(methyl sulphonyl)-1H-Indole-3-Carboxylic Acid
Figure C20061011009100693
After preparation 16, utilize the Indole-3-Carboxylic Acid, be prepared according to the method for describing in the preparation 43.
MS(ESI)238(M-H) -
1H NMR
Figure C20061011009100694
(DMSO)12.34(1H，bd s)，12.29(1H，v bd s)，8.31(1H，s)，8.21(1H，d)，8.03(1H，d)，7.69(1H，dd)，3.20(1H，d)。
Preparation 45
6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Be prepared according to following literature method: Liebigs Annalen der Chemie, 1981,5,819-27 and Chemical ﹠amp; Pharmaceutical Bulletin, 1983,31,1277-82.
Step 1:[5-fluoro-2-(methoxycarbonyl) phenyl] the propanedioic acid dimethyl esters
Figure C20061011009100701
(according to the US5189168 preparation)
At 0 ℃, to the 2-of quick stirring bromo-4-fluorobenzoic acid (4.5g) and cupric bromide (I) (175mg) in the suspension at the dimethyl malonic ester of 25ml, add in batches sodium hydride (60% mineral oil, 1.3g).After 10 minutes, reaction is warmed to room temperature, and stirring at room 30 minutes, then 70 ℃ of heating 2 hours.Then solidified is reacted water (80ml) dilution, and with extracted with diethyl ether (3 * 50ml).Water layer is also used ethyl acetate extraction (3 * 100) with the concentrated hydrochloric acid acidifying.The organic layer that merges is dry on sal epsom, filter, vacuum concentration also obtains thick material recrystallization from ether/isohexane the subhead compound (1.9g) of white solid.
1H NMR
Figure C20061011009100702
(DMSO)13.36(1H，bs)，8.05(1H，dd)，7.35(1H，ddd)，7.14(1H，dd)，5.08(1H，s)，3.70(6H，s)。
Step 2:2-(carboxyl methyl)-4-fluorobenzoic acid
Figure C20061011009100703
[5-fluoro-2-(methoxycarbonyl) phenyl] propanedioic acid dimethyl esters (1.80g) suspension in concentrated hydrochloric acid (25ml) was heated 48 hours at 110 ℃.Subhead compound (1.50g) with reaction cooling and filtration collection white solid.
MS(ESI)197(M-H) -
1H NMR
Figure C20061011009100704
(DMSO)7.97(1H，dd)，7.24(1H，dd)，7.20(1H，dd)，3.96(2H，s)。
Step 3:(4Z)-6-fluoro-4-(methoxyl group methylene radical)-1H-different chromene-1,3 (4H)-diketone
Figure C20061011009100705
The mixture of 2-(carboxyl methyl)-4-fluorobenzoic acid (1.40g) in acetate (3ml) and tri-methyl ortho formate (1ml) heated 3 hours at 110 ℃.In this stage, steam and remove the methyl acetate that produces.After finishing, reaction is cooled to 0 ℃.Filter to collect the solid of white, and with cold water and methanol wash (1.32g).
MS(ESI)207(M-Me) -
The different chromene of step 4:6-fluoro-1-oxo-1H--4-carboxylic acid methyl ester
Figure C20061011009100711
In methyl alcohol (20ml) suspension of (4Z)-6-fluoro-4-(methoxyl group methylene radical)-1H-different chromene-1,3 (4H)-diketone (1.30g), slowly add sulfuric acid (1.5ml).Mixture was heated 3 hours at 40-50 ℃.Along with the carrying out of reaction, crystallization goes out the subhead compound.Reaction is cooled to room temperature and filters the collection white solid, and wash with cold methanol.
MS(ESI)222(M+H) +
1H NMR
Figure C20061011009100712
(DMSO)8.49(1H，s)，8.30(1H，dd)，8.25(1H，dd)，7.56(1H，td)，3.87(3H，s)。
Step 5:6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester
Figure C20061011009100713
The different chromene of 6-fluoro-1-oxo-1H--4-carboxylic acid methyl ester (1.53g) and the mixture of ammonium acetate (2.5g) in the 4ml glacial acetic acid were heated 16 hours at 80 ℃.Reaction is cooled to 40 ℃, with water dilution and the solid collected by filtration (1.38g) of 8ml.
MS(ESI)220(M-H) -
1H NMRδ(DMSO)12.00(1H，s)，8.46(1H，dd)，8.32(1H，dd)，8.10(1H，s)，7.44(1H，td)，3.83(3H，s)。
Step 6:6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100714
To 6-fluoro-1-oxo-1, add the aqueous solution (3ml) of sodium hydroxide (1g) in the solution of the methyl alcohol (3ml) of 2-dihydro-isoquinoline-4-carboxylic acid methyl ester (1.3g), and reaction mixture was heated 3 hours at 80 ℃.Reaction is cooled to 20 ℃ also uses the concentrated hydrochloric acid acidifying carefully.Filter to isolate white precipitate, water and methanol wash obtain title compound (1.16g).
MS(ESI)206(M-H) -
1H NMRδ(DMSO)12.85(1H，s)，11.91(1H，d)，8.58(1H，dd)，8.31(1H，dd)，8.09(1H，d)，7.41(1H，td)。
Preparation 46
7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Be prepared according to following literature method: Liebigs Annalen der Chemie, 1981,5,819-27 and Chemical ﹠amp; Pharmaceutical Bulletin, 1983,31,1277-82.
Step 1:[4-fluoro-2-(methoxycarbonyl) phenyl] the propanedioic acid dimethyl esters
Figure C20061011009100721
Utilize 2-bromo-5-fluorobenzoic acid, according to preparation 45, the method for describing in the step 1 is prepared.
MS(ESI)269/237(M-H) -
1H NMRδ(DMSO)7.70(1H，dd)，7.49(1H，td)，7.39(1H，dd)，5.71(1H，s)，3.68(6H，s)。
Step 2:2-(carboxyl methyl)-5-fluorobenzoic acid
Figure C20061011009100722
Utilize [4-fluoro-2-(methoxycarbonyl) phenyl] propanedioic acid dimethyl esters, according to preparation 45, the method for describing in the step 2 is prepared.
MS(ESI)197(M-H) -
1H NMR (DMSO)7.81-7.74(1H，m)，7.62(1H，dd)，7.41-7.35(1H，m)，3.92(2H，s)。
The different chromene of step 3:7-fluoro-1-oxo-1H--4-carboxylic acid methyl ester
Figure C20061011009100731
According to the method for describing in preparation 45 steps 3 and 4, utilize 2-(carboxyl methyl)-5-fluorobenzoic acid to be prepared.
MS(ESI)223(M+H) +
1H NMR
Figure C20061011009100732
(DMSO)8.60(1H，dd)，8.42(1H，s)，7.95(1H，dd)，7.86(1H，ddd)，3.87(3H，s)。
Step 4:7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester
Figure C20061011009100733
Utilize the different chromene of 7-fluoro-1-oxo-1H--4-carboxylic acid methyl ester, according to preparation 45, the method for describing in the step 5 is prepared.
MS(ESI)221(M-H) -
1H NMR (DMSO)12.04(1H，s)，8.82(1H，dd)，8.03(1H，s)，7.91(1H，dd)，7.73(1H，td)，3.83(3H，s)。
Step 5:7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100735
Utilize 7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester, according to preparation 45, the method for describing in the step 6 is prepared.
MS(ESI)206(M-H) -
1H NMR
Figure C20061011009100736
(DMSO)12.81(1H，s)，12.00(1H，d)，8.93(1H，dd)，8.02(1H，d)，7.90(1H，dd)，7.71(1H，td)。
Preparation 47
6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Be prepared according to following literature method: Liebigs Annalen der Chemie, 1981,5,819-27 and Chemical ﹠amp; Pharmaceutical Bulletin, 1983,31,1277-82.
Step 1:2-[2-oxyethyl group-1-(ethoxy carbonyl)-2-oxoethyl]-4-(methylsulfonyl) phenylformic acid
Be prepared according to following literature method: Journal of Organic Chemistry, 1998,63,4116-4119.
At 20 ℃, (1.0g) in the suspension of 50ml propanedioic acid diethyl ester, add sodium ethylate (10.0g) to 2-chloro-4-(methylsulfonyl) phenylformic acid (10.0g) that stirs very fast and cuprous bromide (I) in batches.To be reflected at stirring at room 30 minutes, then 90 ℃ of heating 36 hours.With slurry water (200ml) dilution, add ammoniacal liquor (3ml), and with mixture extracted with diethyl ether (3 * 100ml).Water layer is also used ethyl acetate extraction (3 * 100ml) with the concentrated hydrochloric acid acidifying.The organic layer that merges is dry on sal epsom, filter and vacuum concentration.
MS(ESI)357/311(M-H) -
1H NMRδ(CD 3OD)8.28(1H，d)，8.06(1H，dd)，7.99(1H，d)，5.78(1H，s)，4.20(4H，q)，3.19(3H，s)，1.28(6H，t)。
Step 2:2-(carboxyl methyl)-4-(methylsulfonyl) phenylformic acid
Figure C20061011009100742
Be prepared according to literature method: Journal of Organic Chemistry, 1998,63,4116-4119.
The thick substance dissolves of step 1 in methyl alcohol (200ml), and is slowly added the solution (200ml) of sodium hydroxide (13g).To be reflected at stirring at room 3 hours.Vacuum is removed methyl alcohol.With water layer with extracted with diethyl ether (3 * 100ml), use the concentrated hydrochloric acid acidifying, usefulness sodium-chlor is saturated and with ethyl acetate extraction (3 * 100ml).The organic layer that merges is dry on sal epsom, filter, concentrate and obtain 1/3rd volumes and finished decarboxylation in 3 hours 65 ℃ of heating.Filter and collect the solid (7.1g) that forms.
MS(ESI)257/213(M-H) -
1H NMRδ(DMSO)8.10(1H，d)，7.95(1H，d)，7.93(1H，dd)，4.07(2H，s)，3.28(3H，s)。
Step 3:(4Z)-4-(methoxyl group methylene radical)-6-(methylsulfonyl)-1H-different chromene-1,3 (4H)-diketone
Figure C20061011009100751
Utilize 2-(carboxyl methyl)-4-(methylsulfonyl) phenylformic acid, according to preparation 45, the method for describing in the step 3 is prepared.
MS(ESI)267(M-Me) -
1H NMR
Figure C20061011009100752
(DMSO)8.68(1H，d)，8.32(1H，d)，8.31(1H，s)，7.98(1H，dd)，4.36(3H，s)，3.46(3H，s)。
The different chromene of step 4:6-(methylsulfonyl)-1-oxo-1H--4-carboxylic acid methyl ester
Figure C20061011009100753
Utilize (4Z)-4-(methoxyl group methylene radical)-6-(methylsulfonyl)-1H-different chromene-1,3 (4H)-diketone, according to preparation 45, the method for describing in the step 4 is prepared.
1H NMR
Figure C20061011009100754
(DMSO)9.08(1H，d)，8.56(1H，s)，8.44(1H，d)，8.18(1H，dd)，3.89(3H，s)，3.34(3H，s)。
Step 5:6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester
Figure C20061011009100755
Utilize the different chromene of 6-(methylsulfonyl)-1-oxo-1H--4-carboxylic acid methyl ester, according to preparation 45, the method for describing in the step 5 is prepared.
MS(ESI)280(M-H) -
1H NMR
Figure C20061011009100756
(DMSO)12.23(1H，s)，9.35(1H，d)，8.47(1H，d)，8.17(1H，s)，8.06(1H，dd)，3.86(3H，s)，3.78(3H，s)。
Step 6:6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100761
Utilize 6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester, according to preparation 45, the method for describing in the step 6 is prepared.
MS(ESI)266(M-H) -
1H NMR
Figure C20061011009100762
(DMSO)12.99(1H，s)，12.14(1H，d)，9.45(1H，d)，8.46(1H，d)，8.15(1H，d)，8.04(1H，dd)，3.30(3H，s)。
Preparation 48
(2R)-and 1-amino-3-{4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-yl } propan-2-ol
Figure C20061011009100763
Step 1:4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-carboxylic acid tertiary butyl ester
Under-70 ℃ of nitrogen atmosphere, to the 4-[3 that stirs, 4-dichlorophenoxy] (10.0g in dry THF 28.9mmol) (400ml) solution, drips s-butyl lithium (26.7ml, the cyclohexane solution of 1.3M) to piperidines-1-carboxylic acid tertiary butyl ester.Solution is continued to stir 15 minutes under this temperature, and (3.9ml 43mmol) handles to use dimethyl disulphide then.Solution was stirred 30 minutes under this temperature, remove cryostat then, and the mixture vigorous stirring was warmed to-30 ℃ with 30 minutes simultaneously.Add saturated aqueous ammonium chloride solution (5ml), and mixture is concentrated into about 30ml volume, and between water and ethyl acetate, distribute.Organic extract is dry and concentrated on sal epsom.(13.3g, methylene dichloride 57-86%) (200ml) solution room temperature treatment obtained rough Sulfone in 14 hours with metachloroperbenzoic acid with rough residue.With solution and the vibration of sodium metabisulfite solution, then with organism dry and vacuum concentration on sal epsom.(the ethyl acetate: isohexane) obtain subhead compound (0.65g) of chromatography on silica gel.
MS(ESI)424/426(M+H) +
1H NMR
Figure C20061011009100771
(DMSO)7.88(1H，d)，7.42(1H，d)，4.92(1H，m)，3.52(2H，m)，3.32(3H，s)，3.36-3.27(2H，m)，1.90(2H，m)，1.69(2H，m)，1.40(9H，s)。
Step 2:(2R)-and 1-amino-3-{4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-yl } propan-2-ol
From 4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-carboxylic acid tertiary butyl ester, according to preparation 24, the method for describing in the step 2 is prepared.
MS(ESI)397/399(M+H) +
1H NMR
Figure C20061011009100772
(CDCl 3)7.60(1H，d)，6.94(1H，d)，4.60-4.53(1H，m)，3.73-3.67(1H，m)，3.33(3H，s)，3.02-2.96(1H，m)，2.81(1H，dd)，2.79-2.73(1H，m)，2.64-2.56(1H，m)，2.63(1H，dd)，2.43-2.32(3H，m)，2.11-1.91(4H，m)
Preparation 49
8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Step 1:2-(carboxyl methyl)-6-fluorobenzoic acid
Utilize 2-bromo-6-fluorobenzoic acid, according to preparation 45, the method for describing in the step 1 and 2 is prepared.
MS(ESI)197(M-H) -
1H NMR
Figure C20061011009100774
(DMSO)7.46(1H，td)，7.20(1H，dd)，7.18(1H，d)，3.77(2H，s)。
Step 2:(4Z)-8-fluoro-4-(methoxyl group methylene radical)-1H-different chromene-1,3 (4H)-diketone
Figure C20061011009100775
Utilize 2-(carboxyl methyl)-6-fluorobenzoic acid, according to preparation 45, the method for describing in the step 3 is prepared.
MS(ESI)207(M-Me) -
The different chromene of step 3:8-fluoro-1-oxo-1H--4-carboxylic acid methyl ester
Utilize (4Z)-8-fluoro-4-(methoxyl group methylene radical)-1H-different chromene-1,3 (4H)-diketone, according to preparation 45, the method for describing in the step 4 is prepared.
MS(ESI)222(M+H) +
1H NMRδ(DMSO)8.42(1H，s)，8.34(1H，d)，7.96(1H，td)，7.50(1H，dd)，3.86(2H，s)。
Step 4:8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester
Figure C20061011009100782
Utilize the different chromene of methyl 8-fluoro-1-oxo-1H--4-carboxylicesters, according to preparation 45, the method for describing in the step 5 is prepared.
MS(ESI)220(M-H) -
1H NMR
Figure C20061011009100783
(DMSO)11.86(1H，s)，8.57(1H，d)，8.03(1H，s)，7.80(1H，td)，7.30(1H，dd)，3.82(3H，s)。
Step 5:8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
Figure C20061011009100784
Utilize 8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester, according to preparation 45, the method for describing in the step 6 is prepared.
MS(ESI)206(M-H) -
1H NMRδ(DMSO)12.75(19H，s)，11.76(19H，d)，8.69(22H，d)，8.02(23H，d)，7.78(24H，td)，7.29(22H，dd)。
Embodiment 1
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide.
Stir down; with 2-(methyl sulphonyl) phenylformic acid (0.063g);, (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and N, the mixture of N-diisopropyl ethyl amine (0.1ml) in dry dimethyl formamide (3ml) is cooled to 0 ℃.Add 2-(1H-9-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (0.13g), and mixture stirred 1-2 hour at 0 ℃.Add saturated sodium hydrogen carbonate solution (10ml).With the mixture ethyl acetate extraction.Isolate the washing of organic layer and salt solution, and dry on sodium sulfate.Mixture is filtered and evaporating solvent.The oily matter that obtains through the normal-phase chromatography purifying, is utilized ethanol/methylene as eluent, and utilizes acetonitrile and 0.1% ammonium acetate aqueous solution as eluent through the reversed-phase HPLC purifying, obtain the title compound (0.055g) of white solid.
MS(APCI)501/503(M+H) +
1H NMR
Figure C20061011009100792
(DMSO)8.57(1H，t)，7.96(1H，dd)，7.78(1H，td)，7.69(1H，td)，7.57(1H，dd)，7.49(1H，d)，7.25(1H，d)，6.98(1H，dd)，4.48-4.37(1H，m)，3.85-3.74(1H，m)，3.40-3.25(1H，m)，3.37(3H，s)，3.26-3.13(1H，m)，2.83-2.69(2H，m)，2.44(1H，dd)，2.37-2.26(3H，m)，1.95-1.84(2H，m)，1.65-1.50(2H，m)。
Embodiment 2
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(methylsulfonyl) benzamide
Figure C20061011009100793
According to the method for describing among the embodiment 1, from 2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 4-(methyl sulphonyl) phenylformic acid (0.063g) be prepared.Obtain the title compound (0.038g) of white solid.
MS(APCI)501/503(M+H) +
1H NMR (DMSO)8.69(1H，t)，8.05(4H，dd)，7.49(1H，d)，7.25(1H，d)，6.98(1H，dd)，4.76(1H，brs)，4.43(1H，mult)，3.86-3.78(1H，m)，3.43(1H，dt)，3.26(3H，s)，3.20(1H，dd)，2.79-2.67(2H，m)，2.41-2.24(4H，m)，1.95-1.85(2H，m)，1.66-1.54(2H，m)。
Embodiment 3
2-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(methylsulfonyl) benzamide
According to the method for describing among the embodiment 1, utilizing (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 3-(methylsulfonyl) phenylformic acid (0.074g) be prepared.Obtain the title compound (0.033g) of white solid.
MS(APCI)535/537(M+H) +
1H NMR (DMSO)8.60(1H，t)，8.03(1H，d)，7.93(1H，dd)，7.70(1H，d)，7.49(1H，d)，7.25(1H，d)，6.98(1H，dd)，4.70(1H，brs)，4.47-4.39(1H，m)，3.82-3.74(1H，m)，3.41-3.31(1H，m)，3.29(3H，s)，3.23-3.15(1H，m)，2.80-2.69(2H，m)，2.44-2.25(4H，m)，1.96-1.86(2H，m)，1.65-1.54(2H，m)。
Embodiment 4
4-amino-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-methoxy benzamide
Figure C20061011009100803
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 4-amino-3-methoxybenzoic acid (0.052g) be prepared.Obtain the title compound (0.053g) of white solid.
MS(APCI)468/470(M+H) +
1H NMR
Figure C20061011009100804
(DMSO)8.05(1H，t)，7.49(1H，d)，7.31-7.27(2H，m)，7.25(1H，d)，6.98(1H，dd)，6.60(1H，d)，5.23(2H，s)，4.74(1H，brs)，4.47-4.38(1H，m)，3.80(3H，s)，3.81-3.73(1H，m)，3.38-3.30(1H，m)，3.18-3.09(1H，m)，2.80-2.65(2H，m)，2.36(2H，dd)，2.32-2.22(2H，m)，1.95-1.86(2H，m)，1.66-1.54(2H，m)。
Embodiment 5
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(methylsulfonyl) benzamide
Figure C20061011009100811
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 3-(methylsulfonyl) phenylformic acid (0.063g) be prepared.Obtain the title compound (0.017g) of white solid.
MS(APCI)501/503(M+H) +
1H NMR (DMSO)8.74(1H，t)，8.39(1H，t)，8.18(1H，dt)，8.07(1H，ddt)，7.76(1H，t)，7.49(1H，d)，7.25(1H，d)，6.98(1H，dd)，4.77(1H，brs)，4.47-4.39(1H，m)，3.86-3.78(1H，m)，3.45(1H，dt)，3.26(3H，s)，3.24-3.14(1H，m)，2.80-2.66(2H，m)，2.41-2.24(4H，m)，1.95-1.86(2H，m)，1.65-1.54(2H，m)。
Embodiment 6
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(methylsulfonyl) thiophene-2-carboxylic acid amides.
Figure C20061011009100813
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 5-(methylsulfonyl) thiophene-2-carboxylic acid (0.065g) be prepared.Obtain the title compound (0.039g) of white solid.
MS(APCI)507/509(M+H) +
1H NMR
Figure C20061011009100814
(DMSO)8.85(1H，t)，7.84(2H，dd)，7.49(1H，d)，7.26(1H，d)，6.98(1H，dd)，4.80(1H，brs)，4.47-4.39(1H，m)，3.83-3.75(1H，m)，3.45-3.38(1H，m)，3.38(3H，s)，3.18-3.09(1H，m)，2.79-2.66(2H，m)，2.37-2.22(4H，m)，1.95-1.85(2H，m)，1.65-1.53(2H，m)。
Embodiment 7
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-6-carboxylic acid amides
Figure C20061011009100821
According to the method for describing among the embodiment, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and QUINOLINE-6-CARBOXYLIC ACID (0.054g) be prepared.Obtain the title compound (0.032g) of white solid.
MS(APCI)474/476(M+H) +
1H NMR
Figure C20061011009100822
(DMSO)8.98(1H，dd)，8.68(1H，t)，8.52(1H，d)，8.47(1H，dd)，8.19(1H，dd)，8.08(1H，d)，7.61(1H，dd)，7.49(1H，d)，7.24(1H，d)，6.97(1H，dd)，4.78(1H，brs)，4.48-4.39(1H，m)，3.90-3.82(1H，m)，3.46(1H，dt)，3.31-3.23(1H，m)，2.82-2.70(2H，m)，2.45-2.25(4H，m)，1.96-1.87(2H，m)，1.67-1.55(2H，m)。
Embodiment 8
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid amides acetate
Figure C20061011009100823
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.061g) is prepared.Obtain the acetate (0.10g) of the title compound of white solid.
MS(APCI)496/498(M+H) +
1H NMR
Figure C20061011009100824
(DMSO) 8.36 (1H, t), 8.05 (1H, d), 7.78 (1H, dd), 7.49 (1H, d), 7.25 (1H, d), 7.15 (1H, d), 6.98 (1H, dd), 4.47-4.40 (1H, m), 3.80 (1H, quintet), 3.38 (1H, dt), 3.22-3.14 (1H, m), 2.80-2.67 (2H, m), 2.41-2.25 (4H, m), 1.95-1.86 (2H, m), 1.91 (3H, s), 1.66-1.51 (2H, m).
Embodiment 9
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-flumizole [1,2-a] pyridine-2-carboxylic acid amides also
Figure C20061011009100831
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 6-flumizole also [1,2-a] pyridine-2-carboxylic acids (0.056g) be prepared.Obtain the title compound (0.076g) of white solid.
MS(APCI)481/482(M+H) +
1H NMR
Figure C20061011009100832
(DMSO)8.80-8.78(1H，m)，8.63(1H，t)，8.33(1H，s)，7.68(1H，dd)，7.50(1H，d)，7.52-7.44(1H，m)，7.28(1H，d)，7.00(1H，dd)，4.89(1H，s)，4.52-4.44(1H，m)，3.83-3.74(1H，m)，3.44-3.28(2H，m)，2.83-2.66(2H，m)，2.44-2.23(4H，m)，2.02-1.90(2H，m)，1.82-1.72(2H，m)。
Embodiment 10
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009100833
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.059g) is prepared.Obtain the title compound (0.047g) of white solid.
MS(APCI)490/492(M+H) +
1H NMR
Figure C20061011009100834
(DMSO) 11.59 (1H, d), 8.33 (1H, t), 8.22 (2H, dd), 7.73 (1H, t), 7.54-7.48 (3H, m), 7.26 (1H, d), 6.98 (1H, dd), 4.79 (1H, s), 4.48-4.40 (1H, m), and 3.85-3.76 (1H, m), 3.43.-3.31 (1H, m), (3.14 1H, quintet), and 2.83-2.69 (2H, m), 2.45-2.25 (4H, m), and 1.96-1.87 (2H, m), 1.67-1.55 (2H, m).
Embodiment 11
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3-benzothiazole-6-carboxylic acid amides
According to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.1g) and 1,3-benzothiazole-6-carboxylic acid (0.056g) is prepared.Obtain the title compound (0.066g) of white solid.
MS(APCI)480/482(M+H) +
1H NMR
Figure C20061011009100842
(DMSO) 9.54 (1H, s), 8.67 (1H, d), 8.60 (1H, t), 8.15 (1H, d), 8.02 (1H, dd), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.78 (1H, brs), 4.47-4.39 (1H, m), 3.87-3.79 (1H, m), 3.44 (1H, dt), (3.23 1H, quintet), 2.82-2.68 (2H, m), 2.40 (1H, dd), 2.37-2.23 (3H, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m).
Embodiment 12
3-cyano group-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100843
Be prepared according to the method for describing among the embodiment 1, from (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (0.2g) and 3-cyanobenzoic acid (0.092g).Obtain the title compound (0.050g) of white solid.
MS(APCI)448/450(M+H) +
1H NMR
Figure C20061011009100844
(CDCl 3)8.10(1H，s)，7.79(1H，d)，7.58(1H，t)，7.31(1H，d)，7.00(1H，d)，6.80(1H，t)，6.75(1H，dd)，4.38-4.25(1H，m)，4.00-3.87(1H，m)，3.81-3.68(1H，m)，3.36(1H，dt)，2.98-2.85(1H，m)，2.75-2.63(1H，m)，2.63-2.53(1H，m)，2.48(1H，dd)，2.37(1H，d)，2.32(2H，t)，2.07-1.90(2H，m)，1.90-1.73(2H，m)。
Embodiment 13
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-2-(methylsulfonyl) benzamide
Figure C20061011009100845
According to the method for describing among the embodiment 1, from 4-amino-1-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol (0.26g) and 2-(methyl sulphonyl) phenylformic acid (0.156g) be prepared.Obtain the title compound (0.170g) of white solid.
MS(APCI)515/517(M+H) +
1H NMR (CDCl 3)8.09(1H，dd)，7.65(1H，dd)，7.59(1H，td)，7.53(1H，dd)，7.31(1H，d)，6.99(1H，d)，6.74(1H，dd)，6.74(1H，dd)，4.32-4.23(1H，m)，3.92-3.83(1H，m)，3.83-3.74(1H，m)，3.57-3.46(1H，m)，3.37(3H，s)，2.94-2.85(1H，m)，2.70-2.60(1H，m)，2.60-2.50(1H，m)，2.40(1H，dd)，2.35(1H，dd)，2.32-2.23(1H，m)，2.01-1.89(2H，m)，1.88-1.69(2H，m)，1.67-1.55(2H，m)。
Embodiment 14
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid amides
Figure C20061011009100852
According to the method for describing among the embodiment 1, from 4-amino-1-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol (0.26g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.152g) is prepared.Obtain the title compound (0.105g) of white solid.
MS(APCI)510/512(M+H) +
1H NMR
Figure C20061011009100853
(CDCl 3)7.88(1H，d)，7.71(1H，dd)，7.48-7.39(1H，m)，7.31(1H，d)，7.13(1H，d)，7.00(1H，d)，6.76(1H，dd)，4.36-4.27(1H，m)，3.93-3.83(2H，m)，3.49-3.38(1H，m)，2.97-2.87(1H，m)，2.73-2.53(2H，m)，2.46-2.32(2H，m)，2.36-2.27(1H，m)，2.06-1.91(2H，m)，1.90-1.75(3H，m)，1.66-1.53(1H，m)。
Embodiment 15
4-amino-N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 3-hydroxybutyl }-the 3-methoxy benzamide
Figure C20061011009100854
According to the method for describing among the embodiment 1, from 4-amino-1-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol (0.26g) and 4-amino-3-methoxybenzoic acid (0.130g) be prepared.Obtain the title compound (0.080g) of white solid.
MS(APCI)482/484(M+H) +
1H NMR
Figure C20061011009100861
(CDCl 3) 7.39 (1H, d), 7.31 (1H, d), 7.15 (1H, dd), 7.04 (1H, bs), 7.00 (1H, d), 6.75 (1H, dd), 6.65 (1H, d), 4.29 (1H, septets), 4.08 (2H, bs), 3.90 (3H, s), 3.89-3.75 (2H, m), 3.49-3.36 (1H, m), 2.96-2.85 (1H, m), 2.73-2.61 (1H, m), 2.61-2.50 (1H, m), 2.44-2.34 (2H, m), 2.35-2.23 (1H, m), 2.07-1.90 (2H, m), 1.90-1.71 (2H, m), 1.70-1.48 (2H, m).
Embodiment 16
N-{4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxybutyl }-2-(methylsulfonyl) benzamide
Figure C20061011009100862
According to the method for describing among the embodiment 1, from 1-amino-4-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] fourth-2-alcohol (0.2g) and 2-(methyl sulphonyl) phenylformic acid (0.12g) be prepared.Obtain the title compound (0.090g) of white solid.
MS(APCI)515/517(M+H) +
1H NMR
Figure C20061011009100863
(CDCl 3)8.10(1H，d)，7.67(1H，td)，7.61(1H，td)，7.55(1H，dd)，7.30(1H，d)，6.98(1H，d)，6.73(1H，dd)，6.61(1H，t)，4.33-4.23(1H，m)，4.06(1H，octet)，3.70(1H，ddd)，3.36-3.29(1H，m)，3.37(3H，s)，2.97-2.82(1H，m)，2.78-2.68(1H，m)，2.64(1H，dt)，2.60-2.47(2H，m)，2.38-2.22(1H，m)，2.02-1.41(6H，m)。
Embodiment 17 and 18 compound, setting out from 4-(2,4-two chloro-3-methylphenoxy) piperidines after preparation 13 is prepared according to similar method among the embodiment 1.
(WO00/58305，WO01/77101)。
Embodiment 17
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009100864
The preparation 13 after according to embodiment 1 in the description method be prepared.
MS(APCI)504/506(M+H) +
1H NMR
Figure C20061011009100871
(DMSO) 11.58 (1H, s), 8.31 (1H, t), 8.22 (2H, d), 7.72 (1H, t), 7.56-7.48 (2H, m), 7.35 (1H, d), 7.10 (1H, d), 4.80-4.70 (1H, m), 4.53-4.44 (1H, m), 3.85-3.75 (1H, m), 3.39 (1H, dt), 3.15 (1H, quintets), 2.78-2.64 (2H, m), 2.40 (3H, s), 2.39-2.27 (4H, m), and 1.96-1.83 (2H, m), 1.74-1.61 (2H, m).
Embodiment 18
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide
Figure C20061011009100872
After preparation 13, be prepared according to the method for describing among the embodiment 1.
MS(APCI)515/517(M+H) +
1H NMRδ(CDCl 3)8.10(1H，dd)，7.67(1H，t)，7.62(1H，t)，7.54(1H，dd)，7.19(1H，d)，6.74(1H，d)，6.55(1H，t)，4.41-4.27(1H，m)，4.03-3.89(1H，m)，3.68(1H，ddd)，3.44(1H，dt)，3.36(3H，s)，3.00-2.87(1H，m)，2.80-2.66(1H，m)，2.63-2.51(2H，m)，2.51-2.42(1H，m)，2.47(3H，s)，2.42-2.29(1H，m)，2.03-1.76(4H，m)。
Embodiment 19
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide
Figure C20061011009100873
After preparation 14, be prepared according to the method for describing among the embodiment 1.
MS(APCI)501/503(M+H) +
1H NMRδ(CDCl 3)8.10(1H，dd)，7.68(1H，td)，7.62(1H，td)，7.54(1H，dd)，7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，6.53(1H，t)，4.35-4.22(1H，m)，4.04-3.91(1H，m)，3.68(1H，ddd)，3.45(1H，dt)，3.36(3H，s)，2.98-2.85(1H，m)，2.80-2.66(1H，m)，2.65-2.52(2H，m)，2.46(1H，dd)，2.41-2.28(1H，m)，2.04-1.88(2H，m)，1.87-1.67(2H，m)。
Embodiment 20
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 3-[(methylamino) alkylsulfonyl] benzamide
Figure C20061011009100881
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)516/518(M+H) +
1H NMRδ(CDCl 3)8.25(1H，s)，7.99(1H，d)，7.95(1H，d)，7.55(1H，t)，7.41(1H，t)，7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.95(1H，s)，4.36-4.25(1H，m)，4.16-4.05(1H，m)，3.75(1H，ddd)，3.31(1H，ddd)，3.02-2.90(1H，m)，2.74-2.56(2H，m)，2.68(3H，s)，2.51(1H，dd)，2.37-2.26(1H，m)，2.37(1H，dd)，2.07-1.91(2H，m)，1.91-1.72(2H，m)。
Embodiment 21
3, two (the acetylamino)-N-{ (2R) of 5--3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100882
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)537/539(M+H) +
1H NMRδ(CDCl 3)9.00(2H，s)，7.86(1H，s)，7.66(2H，s)，7.50(1H，s)，7.31(1H，d)，6.99(1H，d)，6.74(1H，dd)，4.42-4.27(1H，m)，4.19-4.03(1H，m)，3.63-3.46(1H，m)，3.42-3.26(1H，m)，3.05-2.91(1H，m)，2.91-2.74(1H，m)，2.75-2.54(4H，m)，2.17-1.96(2H，m)，2.11(6H，s)，1.97-1.79(2H，m)。
Embodiment 22
3-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)480/482(M+H) +
1H NMR δ (CDCl 3) 7.88 (1H, s), 7.78 (1H, d), 7.55-7.45 (2H, m), 7.39 (1H, t), 7.31 (1H, d), 6.99 (1H, d), 6.82 (1H, t), 6.75 (1H, dd), 4.37-4.22 (1H, m), 3.99-3.85 (1H, m), 3.77-3.63 (1H, m), 3.38 (1H, quintets), 2.96-2.83 (1H, m), 2.75-2.63 (1H, m), 2.63-2.51 (1H, m), 2.52-2.24 (3H, m), 2.20 (3H, s), 2.08-1.90 (2H, m), 1.90-1.69 (2H, m).
Embodiment 23
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 1H-pyrazole-4-carboxamide
Figure C20061011009100892
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)413/415(M+H) +
1H NMRδ(CDCl 3)8.02(2H，s)，7.33(1H，d)，7.00(1H，s)，6.95(1H，t)，6.76(1H，d)，4.44-4.33(1H，m)，4.07-3.98(1H，m)，3.74-3.61(1H，m)，3.40(1H，td)，2.98(1H，td)，2.89-2.77(2H，m)，2.62(2H，d)，2.68-2.56(1H，m)，2.18-1.99(2H，m)，1.98-1.82(2H，m)。
Embodiment 24
2-(acetylamino)-5-bromo-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100893
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)558/460/562(M+H) +
1H NMRδ(CDCl 3)10.98(1H，s)，8.52(1H，d)，7.66(1H，s)，7.55(1H，d)，7.32(1H，d)，7.26(1H，s)，7.16-7.05(2H，m)，7.00(1H，s)，6.76(1H，d)，4.42-4.30(1H，m)，4.06-3.94(1H，m)，3.72-3.59(2H，m)，3.43-3.29(1H，m)，2.95(1H，t)，2.75(2H，t)，2.59-2.43(3H，m)，2.19(3H，s)，2.13-1.96(5H，m)，1.96-1.78(3H，m)。
Embodiment 25
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-1,2-dihydropyridine-3-carboxylic acid amides
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)440/442(M+H) +.
1H NMRδ(CDCl 3)9.86(1H，t)，8.61(1H，dd)，7.53(1H，dd)，7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，6.52(1H，t)，4.33-4.24(1H，m)，3.97-3.89(1H，m)，3.70(1H，ddd)，3.44(1H，td)，2.94-2.85(1H，m)，2.73-2.63(1H，m)，2.59-2.50(1H，m)，2.49-2.37(2H，m)，2.30(1H，t)，2.04-1.90(2H，m)，1.87-1.72(2H，m)。
Embodiment 26
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-5-carboxylic acid amides
Figure C20061011009100902
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)490/492(M+H) +
1H NMR
Figure C20061011009100903
(DMSO)11.34(1H，d)，8.46(1H，t)，8.28(1H，d)，7.78(1H，dd)，7.50(1H，t)，7.49(1H，d)，7.25(1H，d)，7.23-7.16(1H，m)，6.98(1H，dd)，6.81(1H，d)，4.72(1H，d)，4.49-4.37(1H，m)，3.87-3.76(1H，m)，3.46-3.35(1H，m)，3.30-3.16(1H，m)，2.83-2.67(2H，m)，2.47-2.23(4H，m)，1.97-1.84(2H，m)，1.68-1.50(2H，m)。
Embodiment 27
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-4-carboxylic acid amides
Figure C20061011009100911
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)474/476(M+H) +
1H NMRδ(CD 3OD)1.69-1.79(m，2H)，1.90-2.00(m，2H)，2.53-2.65(m，4H)，2.84-2.94(m，2H)，3.39(dd，1H)，3.54(dd，1H)，3.99-4.05(m，1H)，4.33-4.40(m，1H)，6.81(dd，1H)，7.03(d，1H)，7.29(d，1H)，7.52(d，1H)，7.59(t，1H)，7.73(t，1H)，8.00(d，1H)，8.15(d，1H)，8.83(d，1H)。
Embodiment 28
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-4-carboxylic acid amides
Figure C20061011009100912
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)462/464(M+H) +
1H NMRδ(CD 3OD)1.82-1.91(m，2H)，2.00-2.13(m，2H)，2.63-2.76(m，4H)，2.96-3.05(m，2H)，3.44(dd，1H)，3.54(dd，1H)，4.04-4.11(m，1H)，4.43-4.50(m，1H)，5.50(s，1H)，6.56(d，1H)，6.90(dd，1H)，7.12(d，1H)，7.32(d，1H)，7.38(d，1H)，7.43(d，1H)，7.63(dd，1H)，8.14(s，1H)。
Embodiment 29
2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100921
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)480/482(M+H) +
1H NMRδ(CDCl 3)11.05(1H，bd s)，8.60(1H，d)，7.52-7.46(2H，m)，7.31(1H，d)，7.08(1H，t)，6.99(1H，d)，6.81(1H，bd s)，6.76(1H，dd)，4.36-4.28(1H，m)，3.96-3.90(1H，m)，3.72-3.64(1H，m)，3.40-3.32(1H，m)，2.94-2.86(2H，m)，2.72-2.58(2H，m)，2.49-2.31(3H，m)，2.20(3H，s)，2.03-1.93(2H，m)，1.89-1.79(2H，m)。
Embodiment 30
2-(acetylamino)-5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100922
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)514/516/518(M+H) +
1H NMRδ(CDCl 3)10.94(1H，bd s)，8.59(1H，d)，7.47(1H，d)，7.43(1H，dd)，7.32(1H，d)，7.00(1H，d)，6.87(1H，bd s)，6.76(1H，dd)，4.36-4.28(1H，m)，3.97-3.90(1H，m)，3.68-3.61(1H，m)，3.38-3.32(1H，m)，2.94-2.88(1H，m)，2.72-2.58(2H，m)，2.50-2.33(3H，m)，2.19(3H，s)，2.05-1.95(2H，m)，1.90-1.80(2H，m)。
Embodiment 31
2-(acetylamino)-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100923
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)514/516/518(M+H) +
1H NMRδ(CDCl 3)11.19(1H，bd s)，8.73(1H，d)，7.42(1H，d)，7.32(1H，d)，7.05(1H，d)，7.00(1H，d)，6.78-6.74(2H，m)，4.36-4.28(1H，m)，3.96-3.88(1H，m)，3.70-3.62(1H，m)，3.38-3.30(1H，m)，2.94-2.88(1H，m)，2.70-2.58(2H，m)，2.49-2.30(3H，m)，2.20(3H，s)，2.04-1.96(2H，m)，1.90-1.78(2H，m)。
Embodiment 32
5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino] benzamide
Figure C20061011009100931
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)550/552/554(M+H) +
1H NMRδ(CDCl 3)7.69(1H，d)，7.52(1H，s)，7.45(1H，d)，7.31(1H，d)，7.00(1H，d)，6.75(1H，dd)，4.36-4.28(1H，m)，3.96-3.90(1H，m)，3.72-3.64(1H，m)，3.36-3.30(1H，m)，3.04(3H，s)，2.95-2.89(1H，m)，2.74-2.56(2H，m)，2.50-2.30(3H，m)，2.05-1.95(2H，m)，1.90-1.88(2H，m)。
Embodiment 33
4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino] benzamide
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)550/552/554(M+H) +
1H NMRδ(CDCl 3)7.75(1H，d)，7.48(1H，d)，7.31(1H，d)，7.09(1H，dd)，7.00(1H，d)，6.75(1H，dd)，4.38-4.28(1H，m)，3.97-3.87(1H，m)，3.72-3.66(1H，m)，3.34-3.28(1H，m)，3.08(3H，s)，2.98-2.90(1H，m)，2.76-2.58(2H，m)，2.50-2.30(3H，m)，2.10-1.94(2H，m)，1.90-1.74(2H，m)。
Embodiment 34
2-amino-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100941
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)472/474/476(M+H) +
1H NMRδ(CDCl 3)7.31(1H，d)，7.27(1H，d)，6.99(1H，d)，6.75(1H，dd)，6.67(1H，d)，6.61(1H，dd)，6.55(1H，t)，5.64(2H，bd s)，4.34-4.24(1H，m)，3.92-3.82(1H，m)，3.68-3.62(1H，m)，3.36-3.29(1H，m)，2.94-2.86(1H，m)，2.70-2.54(2H，m)，2.47-2.29(2H，m)，2.26-2.16(1H，m)，2.04-1.94(2H，m)，1.88-1.78(2H，m)。
Embodiment 35
5-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-6-oxo-1,6-dihydropyridine-3-carboxylic acid amides
Figure C20061011009100942
To (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (150mg, 0.47mmol) and triethylamine (48mg, 66 μ l, 0.47mmol) methylene dichloride (20ml) solution in, add 5-chloro-6-hydroxyl nicotinoyl chlorine (90mg, methylene dichloride 0.47mmol) (10ml) solution.Mixture was obtained solution for vacuum concentration rough oily matter in 3 hours then in stirring at room.Obtain the title compound (150mg, 67%) of flint glass shape through reversed-phase HPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) purifying.
MS(APCI)474/476/478(M+H) +
1H NMRδ(CDCl 3)8.07(1H，d)，8.04(1H，d)，7.31(1H，d)，7.09(1H，bd s)，6.99(1H，d)，6.75(1H，dd)，4.36-4.26(1H，m)，4.00-3.90(1H，m)，3.68-3.58(1H，m)，3.32-3.22(1H，m)，2.96-2.86(1H，m)，2.76-2.58(2H，m)，2.51-2.35(3H，m)，2.04-1.94(2H，m)，1.88-1.76(2H，m)。
Embodiment 36
2-(amino-sulfonyl)-4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzamide
Figure C20061011009100951
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)536/538/540(M+H) +
1H NMRδ(CDCl 3)8.39(1H，d)，7.90(1H，bd s)，7.78(1H，dd)，7.45(1H，d)，7.32(1H，d)，7.00(1H，d)，6.76(1H，dd)，4.38-4.22(2H，m)，3.76-3.62(1H，m)，3.30-3.20(1H，m)，3.10-3.00(1H，m)，2.80-2.68(2H，m)，2.60-2.40(3H，m)，2.10-2.00(2H，m)，1.96-1.86(2H，m)。
Embodiment 37
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indazole-3-carboxylic acid amides
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)463/465(M+H) +
1H NMRδ(CDCl 3)8.43-8.33(2H，m)，7.54(1H，d)，7.43(1H，t)，7.32(1H，d)，6.99(1H，d)，6.75(1H，dd)，4.38-4.28(1H，m)，4.15-4.05(1H，m)，3.75-3.65(1H，m)，3.60-3.48(1H，m)，3.02-2.92(1H，m)，2.80-2.50(4H，m)，2.45-2.37(1H，m)，2.10-1.95(2H，m)，1.90-1.75(2H，m)。
Embodiment 38
The 1-tertiary butyl-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid amides
Figure C20061011009100953
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)483/485(M+H) +
1H NMRδ(CDCl 3)7.31(1H，d)，6.99(1H，d)，6.75(1H，dd)，6.43(1H，bd s)，6.21(1H，s)，4.35-4.25(1H，m)，3.92-3.82(1H，m)，3.70-3.58(1H，m)，3.38-3.28(1H，m)，2.95-2.85(2H，m)，2.70-2.50(2H，m)，2.45-2.30(3H，m)，2.24(3H，s)，2.05-1.90(2H，m)，1.90-1.78(2H，m)，1.67(9H，s)。
Embodiment 39
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4,5,6,7-tetrahydrochysene-2H-indazole-3-carboxylic acid amides
Figure C20061011009100961
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)467/469(M+H) +
1H NMR δ (DMSO) 12.69 (1H, s), 7.83 (1H, bd s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.80 (1H, d), 4.43 (1H, quintets), 3.73 (1H, q), 3.39-3.16 (2H, m), 2.80-2.52 (6H, m), 2.38-2.23 (4H, m), 1.96-1.86 (2H, m), 1.78-1.58 (6H, m).
Embodiment 40
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide
Figure C20061011009100962
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)481/483(M+H) +
1H NMRδ(CDCl 3)8.11(1H，s)，7.32(1H，d)，7.00(1H，d)，6.75(1H，dd)，6.70(1H，bd s)，4.38-4.28(1H，m)，4.00-3.90(1H，m)，3.70-3.60(1H，m)，3.42-3.32(1H，m)，2.98-2.88(1H，m)，2.75-2.58(2H，m)，2.50-2.36(3H，m)，2.10-1.96(2H，m)，1.92-1.76(2H，m)。
Embodiment 41
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-glyoxal ethyline [1,2-a] pyridine-3-carboxylic acid amides also
Figure C20061011009100971
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)477/479(M+H) +
1H NMRδ(CDCl 3)9.40(1H，d)，7.58(1H，d)，7.36-7.30(2H，m)，7.00(1H，d)，6.92(1H，t)，6.76(1H，dd)，6.35(1H，bd s)，4.38-4.28(1H，m)，4.01-3.93(1H，m)，3.82-3.72(1H，m)，3.48-3.40(1H，m)，2.98-2.90(1H，m)，2.75(3H，s)，2.70-2.58(1H，m)，2.54-2.30(4H，s)，2.06-1.96(2H，m)，1.94-1.76(2H，m)。
Embodiment 42
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-(1H-pyrazole-3-yl) benzamide
Figure C20061011009100972
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)489/491(M+H) +
1H NMRδ(CDCl 3)7.84(2H，d)，7.76(2H，d)，7.64(1H，d)，7.34-7.29(2H，m)，7.00(1H，d)，6.75(1H，dd)，6.66(1H，d)，4.45-4.35(1H，m)，4.18-4.08(1H，m)，3.78-3.66(1H，m)，3.52-3.42(1H，m)，3.06-2.96(1H，m)，2.90-2.80(2H，m)，2.75-2.63(3H，m)，2.18-2.03(2H，m)，2.00-1.80(2H，m)。
Embodiment 43
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } cinnoline-4-carboxylic acid amides
Figure C20061011009100973
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)475/477(M+H) +
1H NMRδ(CDCl 3)9.41(1H，s)，8.61(1H，d)，8.38(1H，d)，7.94-7.82(2H，m)，7.33(1H，d)，7.20(1H，bd s)，7.01(1H，d)，6.76(1H，dd)，4.46-4.36(1H，m)，4.18-4.08(1H，m)，3.88-3.78(1H，m)，3.56-3.46(1H，m)，3.06-2.96(1H，m)，2.94-2.78(2H，m)，2.70-2.60(3H，m)，2.03-1.89(4H，m)。
Embodiment 44
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-1,2-dihydroquinoline-4-carboxylic acid amides
Figure C20061011009100981
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)490/492(M+H) +
1H NMRδ(DMSO)8.69(1H，t)，7.74(1H，d)，7.53(1H，t)，7.49(1H，d)，7.34(1H，d)，7.25(1H，d)，7.18(1H，t)，6.98(1H，dd)，6.54(1H，s)，4.50-4.40(1H，m)，3.87-3.77(1H，m)，3.48-3.40(1H，m)，3.28-3.18(1H，m)，2.82-2.70(2H，m)，2.44-2.24(4H，m)，1.97-1.87(2H，m)，1.68-1.56(2H，m)。
Embodiment 45
N-{3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-carboxylic acid amides
Figure C20061011009100982
Utilize 2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)479/481(M+H) +
1H NMRδ(CDCl 3)9.02(1H，t)，8.17-8.14(1H，d)，7.32(1H，d)，7.18-7.12(2H，m)，7.08-7.05(1H，m)，7.00(1H，d)，6.75(1H，dd)，4.42-4.32(1H，m)，4.16-4.06(1H，m)，3.71-3.61(1H，m)，3.49-3.39(1H，m)，3.04-2.94(1H，m)，2.85-2.75(2H，m)，2.71-2.57(3H，m)，2.16-1.98(2H，m)，1.96-1.80(2H，m)。
Embodiment 46
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides
Figure C20061011009100991
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)491/493/495(M+H) +
1H NMRδ(CDCl 3)9.13(1H，d)，8.43(1H，d)，7.91-75(3H，m)，7.32(1H，d)，7.00(1H，d)，6.76(1H，dd)，4.40-4.32(1H，m)，4.08-3.98(1H，m)，3.76-3.66(1H，m)，3.46-3.38(1H，m)，3.00-2.92(1H，m)，2.80-2.66(2H，m)，2.58-2.44(3H，m)，2.14-1.98(2H，m)，1.96-1.80(2H，m)。
Embodiment 47
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles-3-carboxylic acid amides
Figure C20061011009100992
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)462/464/466(M+H) +
1H NMRδ(CDCl 3)9.03(1H，bd s)，8.07-8.04(1H，d)，7.84(1H，s)，7.45-7.41(1H，m)，7.32(1H，d)，7.28-7.22(2H，m)，6.99(1H，d)，6.82(1H，t)，6.74(1H，dd)，4.44-4.34(1H，m)，4.16-4.06(1H，m)，3.78-3.68(1H，m)，3.56-3.44(1H，m)，3.04-2.94(1H，m)，2.92-2.82(2H，m)，2.77-2.65(3H，m)，2.18-1.98(2H，m)，1.98-1.78(2H，m)。
Embodiment 48
N-{ (2R)-3-[4-(4-chlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methylsulfonyl) benzamide
Figure C20061011009100993
After preparation 4, be prepared according to the method for describing among the embodiment 1.
MS(APCI)467/469(M+H) +
1H NMRδ(CD 3OD)8.08(1H，d)，7.79(1H，t)，7.71(1H，t)，7.61(1H，d)，7.26(2H，d)，6.95(2H，d)，4.564.45(1H，m)，4.21-4.08(1H，m)，3.47(2H，d)，3.35(3H，s)，3.22-3.08(2H，m)，3.01-2.77(4H，m)，2.18-2.00(2H，m)，1.99-1.83(2H，m)。
Embodiment 49
N-{ (2R)-3-[4-(4-chlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101001
After preparation 4, be prepared according to the method for describing among the embodiment 1.
MS(APCI)466/468(M+H) +
1H NMRδ(DMSO)11.57(1H，d)，8.30(1H，t)，8.22(2H，d)，7.73(1H，t)，7.58-7.45(2H，m)，7.30(2H，d)，6.97(2H，d)，4.75(1H，s)，4.41-4.29(1H，m)，3.87-3.74(1H，m)，3.46-3.26(1H，m)，3.22-3.07(1H，m)，2.85-2.67(2H，m)，2.41-2.21(4H，m)，2.00-1.84(2H，m)，1.70-1.51(2H，m)。
Embodiment 50
N-{ (2R)-3-[4-(4-chloro-3-fluorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101002
After preparation 5, be prepared according to the method for describing among the embodiment 1.
MS(APCI)474/476(M+H) +
1H NMRδ(CD 3OD)8.25(1H，d)，8.08(1H，d)，7.67(1H，ddd)，7.48(2H，t)，7.21(1H，t)，6.75(1H，d)，6.66(1H，ddd)，4.30(1H，dq)，3.95-3.87(1H，m)，3.45(1H，dd)，3.29-3.24(1H，m)，2.80-2.69(2H，m)，2.45-2.31(4H，m)，1.95-1.86(2H，m)，1.73-1.62(2H，m)。
Embodiment 51
N-{ (2R)-3-[4-(3,4-two fluorophenoxies) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101011
After preparation 6, be prepared according to the method for describing among the embodiment 1.
MS(APCI)458(M+H) +
1H NMR δ (CD 3OD) 8.25 (1H, dd), 8.08 (1H, d), 7.67 (1H, ddd), 7.50-7.46 (2H, m), 7.03 (1H, dt), 6.76 (1H, ddd), 6.63-6.59 (1H, m), 4.24 (1H, the d quintet), 3.94-3.87 (1H, m), 3.45 (1H, dd), 3.26 (1H, dd), 2.74 (2H, d), 2.45-2.30 (4H, m), 1.90 (2H, dt), 1.72-1.61 (2H, m).
Embodiment 52
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-N-methyl isophthalic acid-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101012
After preparation 12, be prepared according to the method for describing among the embodiment 1.
MS(APCI)504/506(M+H) +
1H NMRδ(DMSO)1.25-1.42(m，1H)，1.57-1.73(m，2H)，1.89-2.15(m，3H)，2.26-2.42(m，2H)，2.69-2.85(m，1H)，2.90-3.15(m，4H)，3.63-3.77(m，1H)，3.97-4.09(m，1H)，4.26-4.49(m，1H)，4.79-4.95(m，1H)，6.91-7.01(m，1H)，7.18-7.31(m，2H)，7.45-7.57(m，3H)，7.73(t，1H)，8.23(d，1H)，11.51(s，1H)。
Embodiment 53
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxypropyl-N-methyl isophthalic acid H-indazole-3-carboxylic acid amides
Figure C20061011009101013
After preparation 12, be prepared according to the method for describing among the embodiment 1.
MS(APCI)477/479(M+H) +
1H NMRδ(DMSO)1.36-1.51(m，1H)，1.58-1.67(m，1H)，1.72-1.81(m，1H)，1.86-1.96(m，1H)，2.04-2.21(m，2H)，2.26-2.39(m，2H)，2.71-2.81(m，1H)，3.13(s，3H)，3.49-3.57(m，1H)，3.78-3.93(m，1H)，3.98-4.06(m，1H)，4.31-4.48(m，1H)，4.71-4.83(m，1H)，6.93-7.00(m，1H)，7.16-7.25(m，2H)，7.34-7.43(m，1H)，7.49(d，1H)，7.58(t，1H)，7.95(dd，1H)，13.34-13.49(m，1H)。
Embodiment 54
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-N-methyl-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides
Figure C20061011009101021
After preparation 12, be prepared according to the method for describing among the embodiment 1.
MS(APCI)505/507(M+H) +
1H NMRδ(CD 3OD)1.44-1.55(m，1H)，1.69-1.80(m，2H)，1.93-2.02(m，1H)，2.15-2.24(m，1H)，2.19(d，1H)，2.46-2.60(m，2H)，2.84-2.93(m，1H)，3.20(s，3H)，3.42-3.51(m，1H)，3.75(dd，1H)，3.84(qt，1H)，4.16-4.25(m，1H)，4.35-4.41(m，1H)，6.79(ddd，1H)，7.00(dd，1H)，7.28(dd，1H)，7.72-7.89(m，3H)，8.31(t，1H)。
Embodiment 55
Phenylformic acid, 3-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino]-, methyl ester
Figure C20061011009101022
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)510/512(M+H) +
1H NMRδ(CDCl 3)8.17(1H，t)，7.95(1H，dd)，7.38(1H，t)，7.31(1H，d)，6.98(1H，d)，6.91(1H，t)，6.78-6.68(2H，m)，6.57(1H，d)，4.32-4.20(1H，m)，3.92(2H，d)，3.89(3H，s)，3.80-3.69(1H，m)，3.52-3.40(1H，m)，3.26(1H，dt)，2.87-2.74(1H，m)，2.62-2.39(2H，m)，2.32(1H，dd)，2.28-2.14(2H，m)，2.00-1.84(2H，m)，1.83-1.66(2H，m)。
Embodiment 56
Propionic acid amide, N-[2-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino] phenyl]-
Figure C20061011009101031
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)523/525(M+H) +
1H NMRδ(CDCl 3)7.48(1H，t)，7.31(1H，d)，7.23-7.11(2H，m)，7.05(1H，d)，6.98(2H，d)，6.83-6.71(2H，m)，6.67(1H，d)，4.54(1H，t)，4.31-4.17(1H，m)，3.92(1H，d)，3.79-3.66(1H，m)，3.45(1H，td)，3.22(1H，td)，2.78-2.66(1H，m)，2.61-2.43(1H，m)，2.49(2H，q)，2.37(1H，t)，2.26-2.06(3H，m)，1.98-1.82(2H，m)，1.82-1.64(2H，m)，1.29(3H，t)。
Embodiment 57
Propionic acid amide, N-[2-[[2-[[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl] amino]-the 2-oxoethyl] amino] phenyl]-
Figure C20061011009101032
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)494/496(M+H) +
1H NMRδ(CDCl 3)7.73(2H，dd)，7.32(1H，dd)，7.29-7.21(2H，m)，7.02-6.97(1H，m)，6.97-6.88(1H，m)，6.80-6.71(1H，m)，6.60-6.49(1H，m)，4.36-4.23(1H，m)，4.14(2H，t)，3.89-3.75(1H，m)，3.62-3.48(1H，m)，3.31-3.17(1H，m)，2.94-2.81(1H，m)，2.72-2.59(1H，m)，2.60-2.47(1H，m)，2.43-2.22(3H，m)，2.40(3H，s)，2.05-1.89(2H，m)，1.88-1.72(2H，m)。
Embodiment 58
(2S)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-hydroxyl-2-phenyl-acetamides
Figure C20061011009101041
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)453/455/457(M+H) +
1H NMRδ(CDCl 3)7.44-7.26(6H，m)，6.98(1H，d)，6.74(1H，dd)，6.54(1H，bd s)，5.06(1H，s)，4.34-4.24(1H，m)，3.83-3.73(1H，m)，3.56-3.43(1H，m)，3.32-3.20(1H，m)，2.88-2.80(1H，m)，2.62-2.52(2H，m)，2.33-2.10(3H，m)，2.02-1.90(2H，m)，1.86-1.70(2H，m)。
Embodiment 59
2-[2-((2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino)-2-oxo oxyethyl group] benzamide
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)496/498(M+H) +
1H NMR δ (CDCl 3) 7.97 (1H, d), 7.48 (1H, t), 7.36-7.28 (2H, m), 7.17-7.07 (1H, m), 7.13 (2H, t), 6.99 (1H, s), 6.93 (1H, d), 6.75 (1H, d), 5.99 (1H, s), 4.68 (2H, s), 4.35-4.22 (1H, m), 3.89-3.77 (1H, m), 3.67-3.54 (1H, m), (3.22 1H, quintet), and 2.91-2.79 (1H, m), 2.68-2.46 (2H, m), 2.43-2.20 (3H, m), 2.04-1.88 (2H, m), 1.88-1.71 (2H, m).
Embodiment 60
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4-yl) ethanamide
Figure C20061011009101043
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)508/510(M+H) +
1H NMRδ(CDCl 3)7.31(1H，d)，7.08-7.01(4H，m)，6.99(1H，d)，6.74(1H，dd)，6.53(1H，bd s)，4.69(2H，s)，4.56(2H，q)，4.34-4.24(1H，m)，3.80-3.72(1H，m)，3.52-3.42(1H，m)，3.28-3.18(1H，m)，2.88-2.80(1H，m)，2.63-2.45(4H，m)，2.36-2.21(3H，m)，2.00-1.90(2H，m)，1.86-1.70(2H，m)。
Other examples of the The compounds of this invention that the method for describing in according to embodiment 1 after preparation 7 prepares are presented in the following table.
Embodiment title (M+H) +
61 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-methoxy 452
Yl-benzamide
62 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(methyl 451
Amino) benzamide
63 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } niacinamide 423
64 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } different nicotinoyl 423
Amine
65 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(diformazan 465
Base is amino) benzamide
66 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-(1,3-505 for 2-
Dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide
67 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-hydroxyl 439
Niacinamide
68 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-(1H-475 for 2-
Indol-3-yl) ethanamide
69 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } two rings 448
[4.2.0] suffering-1,3,5-triolefin-7-carboxylic acid amides
70 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4,7-2 492
Methylpyrazole is [5,1-c] [1,2,4] triazine-3-carboxylic acid amides also
71 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } pyrazine-2-424
Carboxylic acid amides
72 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-9H-purine 464
-6-carboxylic acid amides
73 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-6-473
Carboxylic acid amides
74 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,7-2 491
Methylpyrazole is [1,5-a] pyrimidine-6-carboxylic acid amides also
75 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(pyrimidine 470
-2-base sulfenyl) ethanamide
76 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-fluorine 479
-1H-indoles-2-carboxylic acid amides
77 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,3-benzene 479
And thiazole-6-carboxylic acid amides
78 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-phenyl 489
-1,3-oxazole-4-carboxylic acid amides
79 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-hydroxyl 439
Pyridine-2-carboxylic acid amides
80 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo 493
-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid amides
81 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-hydroxyl 439
Pyridine-2-carboxylic acid amides
82 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-benzo 462
Imidazoles-5-carboxylic acid amides
83 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles 461
-5-carboxylic acid amides
84 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-methyl 475
-1H-indoles-2-carboxylic acid amides
85 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-imidazoles 412
-4-carboxylic acid amides
86 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles 461
-6-carboxylic acid amides
87 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-methyl 475
-1H-draws diindyl-3-carboxylic acid amides
88 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1H-indoles 461
-7-carboxylic acid amides
89 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-[(methyl 515
Amino) alkylsulfonyl] benzamide
90 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,4-two 578
(methylsulfonyl) benzamide
91 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-pyridine 437
-3-yl acetamide
92 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-hydroxyl 477
-1H-indoles-2-carboxylic acid amides
93 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,5-diformazan 440
Base-1H-pyrazole-3-carboxamide
94 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(methylsulfonyl 539
Base)-1H-indoles-2-carboxylic acid amides
95 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoxaline 474
-6-carboxylic acid amides
96 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,8-2 474
Azepine naphthyl-2-carboxylic acid amides
97 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo 518
[2,1-b] [1,3] benzothiazole-2-carboxylic acid amides
98 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,6-2 490
Methylimidazole is [1,2-a] pyridine-3-carboxylic acid amides also
99 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo 478
-2,3-dihydro-1H-indazole-4-carboxylic acid amides
100 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo 478
-2,3-dihydro-1H-indazole-6-carboxylic acid amides
101 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(fluoroform 480
Base)-the 1H-pyrazole-4-carboxamide
102 2-(1H-benzoglyoxaline and 1-1-yl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines 476
-1-yl]-the 2-hydroxypropyl } ethanamide
103 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-ethyl 454
-3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid amides
104 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-methyl 426
-1H-pyrazole-3-carboxamide
105 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-methyl 428
-1,2,5-oxadiazole-3-carboxylic acid amides
106 6-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } miaow 496
Azoles is [1,2-a] pyridine-2-carboxylic acid amides also
107 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-methyl 476
Imidazo [1,2-a] pyridine-3-carboxylic acid amides
108 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo 463
[1,2-a] pyrimidine-2-carboxylic acid amides
109 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-[(4-first 484
Yl pyrimidines-2-yl) sulfenyl] ethanamide
110 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-oxo 489
-1,4-dihydroquinoline-2-carboxylic acid amides
111 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } quinoline-8-473
Carboxylic acid amides
112 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-methyl 476
Imidazo [1,2-a] pyridine-2-carboxylic acid amides
113 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } imidazo 462
[1,2-a] pyridine-2-carboxylic acid amides
114 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,6-2 474
Azepine naphthyl-2-carboxylic acid amides
115 N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-benzene 480
Bing oxadiazole-5-carboxylic acid amides 1-oxide compound
Embodiment 116
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-1,6-dihydropyridine-3-carboxylic acid amides
Figure C20061011009101091
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)440/442(M+H) +
1H NMR
Figure C20061011009101092
(CD 3OD) 8.07 (1H, d), 7.99 (1H, dd), 7.39 (1H, d), 7.15 (1H, d), 6.92 (1H, dd), 6.53 (1H, d), 4.52 (1H, septets), 4.09-4.01 (1H, m), 3.49 (1H, dd), 3.34 (1H, d), 3.11-3.02 (2H, m), 2.86-2.67 (4H, m), 2.14-2.03 (2H, m), 1.95 (3H, s), 1.97-1.84 (2H, m).
Embodiment 117
4-chloro-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 1H-pyrazole-3-carboxamide
Figure C20061011009101093
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)447/449(M+H) +
1H NMR
Figure C20061011009101094
(CD 3OD) 7.77 (1H, s), 7.37 (1H, d), 7.09 (1H, d), 6.88 (1H, dd), 4.39 (1H, t), (3.95 1H, quintet), 3.49 (1H, dd), 3.40 (1H, dd), 2.86-2.77 (2H, m), 2.52-2.39 (2H, m), 2.49 (2H, d), 2.06-1.96 (2H, m), 1.85-1.74 (2H, m).
Embodiment 118
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-phenyl-1,3-oxazole-4-carboxylic acid amides
After preparation 7, from 5-phenyl-1,3-oxazole-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)490/492(M+H) +
1H NMR
Figure C20061011009101096
(CD 3OD) 8.12 (1H, s), 8.10-8.08 (2H, m), 7.40-7.35 (3H, m), 7.29 (1H, d), 7.04 (1H, d), 6.81 (1H, dd), 4.39 (1H, septets), 3.95 (1H, quintet), and 3.44-3.33 (2H, m), 2.96-2.87 (2H, m), 2.67-2.55 (4H, m), 2.03-1.93 (2H, m), 1.85 (3H, s), 1.85-1.75 (2H, m).
Embodiment 119
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,5-dimethyl-1H-pyrazole-4-carboxamide
Figure C20061011009101101
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)441/443(M+H) +
1H NMR
Figure C20061011009101102
(CD 3OD) 7.28 (1H, d), 7.00 (1H, d), 6.79 (1H, dd), 4.34-4.26 (1H, m), (3.86 1H, quintet), 3.41 (1H, dd), 3.21 (1H, dd), 2.78-2.67 (2H, m), 2.41-2.30 (4H, m), 2.29 (6H, s), 1.95-1.86 (2H, m), 1.73-1.63 (2H, m).
Embodiment 120
(2R)-2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-phenyl-acetamides
Figure C20061011009101103
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)494/496(M+H) +
1H NMR
Figure C20061011009101104
(CD 3OD) 7.34 (2H, d), 7.29-7.18 (4H, m), 6.99 (1H, t), 6.78 (1H, dd), 5.29 (1H, s), (4.27 1H, septet), and 3.76-3.65 (1H, m), 3.26-3.08 (2H, m), 2.65-2.49 (2H, m), 2.30-2.15 (4H, m), 1.91 (3H, s), 1.90-1.81 (2H, m), 1.69-1.58 (2H, m).
Embodiment 121
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(2-hydroxy phenyl) ethanamide
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)453/455(M+H) +
1H NMR
Figure C20061011009101112
(CD 3OD) 7.28 (1H, d), 7.05-6.97 (3H, m), 6.78 (1H, dd), 6.72-6.67 (2H, m), 4.27 (1H, dq), 3.72 (1H, quintets), 3.43 (2H, dd), 3.21-3.08 (2H, m), 2.68-2.57 (2H, m), 2.32-2.20 (4H, m), 1.90-1.81 (2H, m), 1.69-1.58 (2H, m).
Embodiment 122
(2R)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methylsulfonyl) amino]-the 2-phenyl-acetamides
Figure C20061011009101113
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)530/532(M+H) +
1H NMR
Figure C20061011009101114
(CD 3OD) 7.37 (2H, d), 7.31-7.21 (4H, m), 6.99 (1H, d), 6.78 (1H, dd), 4.96 (1H, s), (4.27 1H, septet), 3.70 (1H, quintets), 3.24 (1H, dd), 3.13 (1H, dd), 2.72 (3H, s), 2.66-2.56 (2H, m), 2.32-2.18 (4H, m), 1.91-1.82 (2H, m), 1.70-1.59 (2H, m).
Embodiment 123
(2S)-2-(acetylamino)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-phenyl-acetamides
Figure C20061011009101115
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)494/496(M+H) +
1H NMR
Figure C20061011009101116
(CD 3OD)7.34(2H，d)，7.30-7.18(4H，m)，6.99(1H，dd)，6.78(1H，ddd)，5.29(1H，s)，4.30-4.23(1H，m)，3.76-3.65(1H，m)，3.17-3.07(2H，m)，2.65-2.48(2H，m)，2.30-2.14(4H，m)，1.92-1.80(2H，m)，1.91(3H，s)，1.68-1.57(2H，m)。
Embodiment 124
(2S)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2-[(methylsulfonyl) amino]-the 2-phenyl-acetamides
Figure C20061011009101121
After preparation 7, be prepared according to the method for describing among the embodiment 1.
MS(APCI)530/5322(M+H) +
1H NMR
Figure C20061011009101122
(CD 3OD) 7.47 (2H, d), 7.40-7.30 (4H, m), 7.08 (1H, d), 6.87 (1H, dd), 5.06 (1H, s), 4.39-4.32 (1H, m), 3.83 (1H, quintets), 3.27 (2H, d), 2.80 (3H, s), 2.73-2.59 (2H, m), 2.38-2.24 (2H, m), 2.28 (2H, d), 1.99-1.89 (2H, m), 1.78-1.67 (2H, m).
Embodiment 125
1-{ (R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-o-tolyl-urea
Figure C20061011009101123
With 5 minutes times with isocyanic acid o-tolyl ester (64ml, 0.51mmol) methylene dichloride (1ml) solution join (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] (0,15g is in methylene dichloride 0.47mmol) (3ml) suspension for propan-2-ol.After 1 hour, add methyl alcohol (1ml), vacuum is removed solvent.Residue is obtained title compound (87mg) through reversed phase chromatography purifying (C8 symmetrical posts).
MS(APCI)452/454(M+H) +
1H NMRδ(DMSO)7.81(1H，d)，7.78(1H，s)，7.50(1H，dd)，7.26(1H，dd)，7.10(1H，t)，7.05(1H，s)，6.99(1H，ddd)，6.86(1H，t)，6.63(1H，t)，4.74(1H，d)，4.49-4.40(1H，m)，3.72-3.63(1H，m)，3.32-3.30(1H，m)，2.99-2.90(1H，m)，2.79-2.67(2H，m)，2.35-2.24(4H，m)，2.18(3H，s)，1.97-1.88(2H，m)，1.69-1.56(2H，m)。
Embodiment 126
1-{ (R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-p-methylphenyl-urea
Figure C20061011009101131
After preparation 1, be prepared according to the method for describing among the embodiment 125.
MS(APCI)452/454(M+H) +
1H NMR
Figure C20061011009101132
(DMSO)8.52(1H，s)，7.55(1H，d)，7.31(2H，d)，7.31(1H，s)，7.07(2H，d)，7.03(1H，d)，6.15(1H，t)，4.82-4.76(1H，m)，4.55-4.45(1H，m)，3.76-3.67(1H，m)，3.36-3.32(1H，m)，3.03-2.95(1H，m)，2.83-2.72(2H，m)，2.40-2.31(4H，m)，2.27(3H，s)，2.03-1.92(2H，m)，1.75-1.61(2H，m)。
Embodiment 127
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101133
After preparation 9, be prepared according to the method for describing among the embodiment 1.
MS(APCI)504/506/508(M+H) +
1H NMR
Figure C20061011009101134
(CD 3OD)8.37(1H，d)，8.18(1H，d)，7.78(1H，t)，7.59(1H，s)，7.58(1H，t)，7.37(1H，d)，7.07(1H，d)，6.86(1H，dd)，4.33-4.28(1H，m)，3.60-3.45(2H，m)，3.04-2.92(2H，m)，2.60-2.45(4H，m)，1.98-1.86(2H，m)，1.72-1.60(2H，m)，1.25(3H，s)。
Embodiment 128
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-2-oxo-1,2-dihydroquinoline-4-carboxylic acid amides
Figure C20061011009101135
After preparation 9, be prepared according to the method for describing among the embodiment 1.
MS(APCI)504/506/508(M+H) +
1H NMR
Figure C20061011009101141
(CDCl 3)7.93(1H，d)，7.53(1H，t)，7.34-7.20(4H，m)，6.98(1H，d)，6.75-6.69(2H，m)，4.32-4.22(1H，m)，3.68-3.40(2H，m)，3.00-2.80(2H，m)，2.70-2.48(4H，m)，2.00-1.86(2H，m)，1.84-1.72(2H，m)，1.26(3H，s)。
Embodiment 129
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-4-oxo-3,4-dihydro naphthyridine-1-carboxylic acid amides
After preparation 9, be prepared according to the method for describing among the embodiment 1.
MS(APCI)505/507/509(M+H) +
1H NMR
Figure C20061011009101143
(CDCl 3)10.18(1H，bs)，9.15(1H，d)，8.44(1H，d)，8.06(1H，bd s)，7.89(1H，t)，7.81(1H，t)，7.31(1H，d)，7.01(1H，d)，6.78(1H，dd)，4.35-4.25(1H，m)，3.58-3.37(2H，m)，3.04-2.82(2H，m)，2.66-2.46(4H，m)，2.06-1.96(2H，m)，1.94-1.80(2H，m)，1.23(3H，s)。
Embodiment 130
(2S)-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-2-hydroxyl-2-phenylacetamide
Figure C20061011009101144
After preparation 9, be prepared according to the method for describing among the embodiment 1.
MS(APCI)467/469/471(M+H) +
1H NMR
Figure C20061011009101145
(CDCl 3)7.46-7.29(6H，m)，6.98(1H，d)，6.78(1H，bd s)，6.75(1H，dd)，5.08(1H，s)，4.28-4.20(1H，m)，3.71(1H，bd s)，3.35-3.20(2H，m)，2.86-2.69(2H，m)，2.53-2.39(2H，m)，2.31(2H，s)，1.97-1.85(2H，m)，1.82-1.70(2H，m)，1.04(3H，s)。
Embodiment 131
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101151
After preparation 10, be prepared according to the method for describing among the embodiment 1.
MS(APCI)470/472(M+H) +
1H NMR
Figure C20061011009101152
(CD 3OD)8.25(1H，d)，8.08(1H，d)，7.67(1H，t)，7.48(2H，t)，7.05-6.96(2H，m)，6.77(1H，d)，4.36-4.25(1H，m)，3.98-3.87(1H，m)，3.45(1H，dd)，3.28(1H，dd)，2.80-2.67(2H，m)，2.49-2.34(4H，m)，2.08(3H，s)，1.98-1.84(2H，m)，1.78-1.64(2H，m)。
Embodiment 132
N-((2R)-3-{4-[2-(aminocarboxyl)-3,4-dichlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101153
To be dissolved in the methylene dichloride again from preparing the 11 rough amine products that obtain, and with diisopropyl ethyl amine (0.85ml) and 1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides (0.40g) is in room temperature treatment.Reaction is stopped with saturated sodium bicarbonate aqueous solution, and, use methylbenzene azeotropic the mixture vacuum concentration.Solid residue is extracted in the methylene chloride, crosses filter solid and chromatography (methylene dichloride: the methanol solution of 7N ammonia/15: 2) obtain the target compound (0.31g) of white solid on silica gel.
MS(APCI)533/535(M+H) +
1H NMR
Figure C20061011009101154
(CD 3OD)8.25(1H，d)，8.12(1H，d)，7.69(1H，m)，7.55(1H，s)，7.49(1H，m)，7.44(1H，d)，7.05(1H，d)，4.20(1H，m)，3.55-2.96(10H，m)，2.25-1.98(4H，m)。
Embodiment 133
3-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide
Figure C20061011009101155
Under 0 ℃ to (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] propan-2-ol (and 0.200g, in 4ml pyridine solution 0.63mmol), add 3-cyano group benzene sulfonyl chloride (0.127g, 0.63mmol).After 30 minutes, reaction is warmed to room temperature and stirred 2 hours.To react vacuum concentration, and residue will be distributed between 10% sodium bicarbonate aqueous solution and ethyl acetate.With organic layer water, salt water washing then, and through dried over mgso.Thick material purifying (methanol solution/methylene dichloride of 0～5%7N ammonia) on silica gel is obtained the title compound (0.120g) of white foam.
MS(ESI)484/486(M+H) +
1H NMR (DMSO)8.22(1H，d)，8.16-8.07(2H，d)，7.82(2H，t)，7.50(1H，d)，7.25(1H，d)，6.97(1H，dd)，4.71(d，1H)，4.47-4.34(1H，m)，3.63-3.51(1H，m)，2.93(1H，dd)，2.71(1H，dd)，2.69-2.55(2H，m)，2.32-2.12(4H，m)，1.95-1.79(2H，m)，1.65-1.45(2H，m)，1.65-1.45(2H，m)。
Embodiment 134
5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amino)-alkylsulfonyl]-the 2-methoxy benzamide
Figure C20061011009101162
After preparation 7, utilize 3-(aminocarboxyl)-4-anisole SULPHURYL CHLORIDE to be prepared according to the method for describing among the embodiment 133.
MS(APCI)531/533(M+H) +
1H NMR (DMSO) 8.20 (1H, d), 7.87 (1H, dd), 7.73 (2H, s), 7.55 (1H, s), 7.49 (1H, d), 7.32 (1H, d), 7.25 (1H, d), 6.97 (1H, dd), 4.67 (1H, d), (4.41 1H, septet), 3.96 (3H, s), 3.58 (1H, q), 2.82 (1H, d), 2.68-2.57 (3H, m), 2.30-2.16 (4H, m), and 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).
Embodiment 135
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-sulphonamide acetate
Figure C20061011009101164
With (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] pyridine (2m1) solution of propan-2-ol (0.15g) handles with 1-oxo-1,2-dihydro-isoquinoline-4-SULPHURYL CHLORIDE (0.11g), and mixture stirred 18 hours in envrionment temperature.Further add SULPHURYL CHLORIDE (0.05g) and stirred evaporating solvent 24 hours.Obtain the title compound (0.06g) of white solid through column chromatography and reversed-phase HPLC (symmetrical C8 post and acetonitrile/0.1% ammonium acetate solution) purifying.
MS(APCI)526/528(M+H) +
1H NMR
Figure C20061011009101171
(DMSO)8.39(1H，d)，8.32(1H，d)，7.95(1H，s)，7.86(1H，ddd)，7.64(1H，t)，7.39(1H，d)，7.11(1H，d)，6.89(1H，dd)，4.45-4.39(1H，m)，3.82-3.75(1H，m)，3.34(1H，s)，2.97(1H，dd)，2.92(1H，dd)，2.81-2.72(2H，m)，2.55-2.42(2H，m)，2.02-1.92(2H，m)，1.95(3H，s，OAc)，1.82-1.72(2H，m)。
Embodiment 136
N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 2,4 difluorobenzene sulphonamide
Figure C20061011009101172
After preparation 7, utilize the 2,4 difluorobenzene SULPHURYL CHLORIDE to be prepared according to the method for describing among the embodiment 133.
MS(APCI)493/495(M+H) +
1H NMR
Figure C20061011009101173
(DMSO) 7.94 (1H, s), 7.86 (1H, td), 7.55 (1H, ddd), 7.49 (1H, d), 7.28 (1H, ddd), 7.25 (1H, d), 6.97 (1H, dd), 4.69 (1H, d), 4.42 (1H, septet), 3.60 (1H, sextets), 2.96 (1H, dd), 2.81 (1H, dd), 2.68-2.58 (2H, m), 2.34-2.16 (4H, m), and 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).
Other examples of the The compounds of this invention for preparing according to embodiment 133 after preparation 7 are listed in the following table.
Embodiment title (M+H) +
137 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } amsacrine 396
138 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } benzsulfamide 458
139 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-472
The phenylmethane sulphonamide
140 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-488
Methoxybenzenesulphoismide
141 N-(5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 597
Base } amino) alkylsulfonyl]-the 2-thienyl } methyl) benzamide
142 4-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 483
Base } benzsulfamide
143 N-{5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } 536
Amino) alkylsulfonyl]-the 4-methyl isophthalic acid, the 3-thiazol-2-yl } ethanamide
144 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } thiophene 464
Fen-2-sulphonamide
145 4-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } ammonia 502
Base) alkylsulfonyl] phenylformic acid
146 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,5-518
The dimethoxy benzsulfamide
147 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 604
Base }-4-(phenyl sulfonyl) thiophene-2-sulphonamide
148 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 531
Base }-5-(1,3-oxazole-5-yl) thiophene-2-sulphonamide
149 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 612
Base }-5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl] thiophene-2-sulphonamide
150 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-(pyrrole 541
Pyridine-2-yl) thiophene-2-sulphonamide
151 5-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 510
Base }-1,3-dimethyl-1H-pyrazoles-4-sulphonamide
152 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,5-477
Dimethyl is oxazole-4-sulphonamide
153 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-516
Diazosulfide-4-sulphonamide
154 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-462
Methyl isophthalic acid H-imidazoles-4-sulphonamide
155 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,1,3-500
Ben Bing oxadiazole-4-sulphonamide
156 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 531
Base }-5-(isoxazole-3-base) thiophene-2-sulphonamide
157 3-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } ammonia 522
Base) alkylsulfonyl] the thiophene-2-carboxylic acid methyl esters
158 2,6-two chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl 526
Propyl group } benzsulfamide
159 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-472
Methyl benzenesulfonamide
160 3-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 492
Base } benzsulfamide
161 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } the third 424
Alkane-2-sulphonamide
162 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } the third 424
Alkane-1-sulphonamide
163 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-5-538
Methyl isophthalic acid-phenyl-1H-pyrazoles-4-sulphonamide
164 3-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 506
Base }-the 2-methyl benzenesulfonamide
165 5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } ammonia 520
Base) alkylsulfonyl]-2-methyl-3-methylfuroate
166 methyl 5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 519
Base } amino) alkylsulfonyl]-1-methyl isophthalic acid H-pyrroles-2-carboxylicesters
167 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3,4-518
The dimethoxy benzsulfamide
168 5-chloro-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 498
Base } thiophene-2-sulphonamide
169 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(544
Quinoline-4-yl) pyridine-3-sulphonamide
170 N-{2-chloro-4-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl 549
Propyl group } amino) alkylsulfonyl] phenyl } ethanamide
171 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,3-542
Dihydroxyl quinoxaline-6-sulphonamide
172 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,4-518
The dimethoxy benzsulfamide
173 5-[({ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } ammonia 531
Base) alkylsulfonyl]-the 2-methoxy benzamide
174 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-472
Methyl benzenesulfonamide
175 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2,4-493
Dimethyl-1,3-thiazoles-5-sulphonamide
176 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-526
Hydroxy quinoxaline-6-sulphonamide
177 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-529
Methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulphonamide
178 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl } pyrrole 459
Pyridine-3-sulphonamide
179 4 '-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 559
Base } biphenyl-2-sulphonamide
180 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1,2-476
Dimethyl-1H-imidazoles-4-sulphonamide
181 4-ethanoyl-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl 500
Propyl group } benzsulfamide
182 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 536
Base }-4-(methylsulfonyl) benzsulfamide
183 2-chloro-4-cyano group-N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy)-piperidines-1-yl]-2-517
Hydroxypropyl } benzsulfamide
184 N-{ (2S)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-2-hydroxyl the third 490
Base }-1,3,5-trimethylammonium-1H-pyrazoles-4-sulphonamide
Embodiment 185
N-[(2R)-3-[4-(3, the 4-dichlorophenoxy)-piperidino]-the 2-hydroxypropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamideas
Figure C20061011009101201
After preparation 7, utilize 4-oxo-1,4-dihydroquinoline-3-carboxylic acid is prepared according to the method for describing among the embodiment 1.
MS(APCI)490/492(M+H) +
1H NMR
Figure C20061011009101211
(DMSO) 10.21 (5H, t), 8.74 (6H, s), 8.26 (6H, dd), 7.74 (10H, ddd), 7.68 (8H, d), 7.49 (11H, d), 7.48-7.44 (11H, m), 7.25 (6H, d), 6.98 (6H, dd), 4.80 (4H, s), (4.44 6H, septet), 3.75 (6H, s), 3.55 (7H, ddd), 3.26-3.19 (20H, m), 2.78-2.68 (12H, m), 2.34 (20H, d), 2.33-2.25 (24H, m), 1.96-1.88 (12H, m), 1.69-1.58 (12H, m).
Embodiment 186
N-{ (2S)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101212
After preparation 10, utilize (2S)-oxyethane-2-ylmethyl-3-nitrobenzene-sulfonic acid ester and 1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)470/472(M+H) +
1H NMR
Figure C20061011009101213
(DMSO) 8.32 (1H, t), 8.22 (2H, d), 7.73 (1H, td), 7.52 (1H, td), 7.52 (1H, s), 7.20 (1H, d), 7.14 (1H, dd), 6.98 (1H, d), 4.38 (1H, septets), 3.81 (1H, quintet), and 3.43-3.36 (1H, m), 3.18-3.11 (1H, m), 2.75-2.63 (2H, m), 2.42-2.28 (4H, m), 2.14 (3H, s), 1.94-1.84 (2H, m), 1.88 (3H, s, OAc), 1.70-1.58 (2H, m).
Embodiment 187
N-{ (2S)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101214
In after preparation 14, utilize 1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides, the method for describing according to embodiment 35 is prepared.
MS(APCI)490/492/494(M+H) +
1H NMR
Figure C20061011009101221
(CD 3OD)8.40(1H，d)，8.21(1H，d)，7.74(1H，t)，7.54(1H，t)，7.50(1H，s)，7.32(1H，d)，7.00(1H，d)，6.76(1H，dd)，4.36-4.24(1H，m)，3.99-3.93(1H，d)，3.73-3.68(1H，d)，3.33-3.28(1H，m)，2.96-2.84(1H，m)，2.75-2.30(5H，m)，2.04-1.94(2H，m)，1.88-1.76(2H，s)。
Embodiment 188
N-{ (2S)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101222
After preparation 15, utilize 1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)504/506/508(M+H) +
1H NMRδ(CD 3OD)8.38(1H，d)，8.19(1H，d)7.80(1H，t)，7.61(1H，t)，7.60(1H，t)，7.38(1H，d)，7.09(1H，d)，6.87(1H，dd)，4.37-4.30(1H，m)，3.64(1H，d)，3.42(1H，d)，3.03-2.83(2H，m)，2.60-2.46(4H，m)，1.96-1.86(2H，m)，1.72-1.60(2H，m)，1.26(3H，s)。
Embodiment 189
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-[(methylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101223
With the 7-[(methylamino) alkylsulfonyl]-1-oxo-1, dimethyl formamide (7ml) the solution N of 2-dihydro-isoquinoline-4-carboxylic acid (0.1g), N-carbonyl dimidazoles (0.06g) is handled, and mixture was heated 45 minutes at 55 ℃.Add (2R)-1-amino-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl] dimethyl formamide (1ml) solution of propan-2-ol (0.11g), and mixture stirred 18 hours in envrionment temperature.Adding 1 drips and evaporating solvent.Utilize reversed-phase HPLC (Symmetry C8 post) to carry out purifying, and obtain the title compound (0.03g) of white solid with acetonitrile/ammonium acetate solution as moving phase.
MS(APCI)583/585(M+H) +
1H NMR
Figure C20061011009101231
(DMSO) 8.59 (1H, s), 8.44 (1H, d), 8.42 (1H, t), 8.04 (1H, dd), 7.73 (1H, s), 7.62 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.79 (1H, s), (4.44 1H, septet), 3.80 (1H, quintets), 3.45-3.37 (1H, m), 3.18-3.11 (1H, m), 2.81-2.69 (2H, m), 2.42 (3H, s), 2.39-2.25 (4H, m), 1.96-1.87 (2H, m), 1.66-1.55 (2H, m).
Embodiment 190
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-{[(2-hydroxyethyl) amino] alkylsulfonyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
After preparation 7, utilize 1,2-dihydro-7-[[(2-hydroxyethyl) amino] alkylsulfonyl]-1-oxo-4-1-isoquinolinecarboxylic acid, be prepared according to the method for describing among the embodiment 189.
MS(APCI)613/615(M+H) +
1H NMR
Figure C20061011009101233
(DMSO) 8.61 (1H, s), 8.42 (1H, d), 8.42 (1H, t), 8.07 (1H, dd), 7.71 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H, septets), 3.81 (1H, quintets), 3.46-3.37 (1H, m), 3.35 (2H, t), 3.18-3.10 (1H, m), 2.80-2.68 (2H, m), 2.80 (2H, t), 2.42-2.25 (4H, m), 1.96-1.87 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).
Embodiment 191
7-[(cyclopropyl amino) alkylsulfonyl]-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101234
After preparation 7, utilize 7-[(cyclopropyl amino) alkylsulfonyl]-1,2-dihydro-1-oxo-4-1-isoquinolinecarboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)609/611(M+H) +
1H NMR
Figure C20061011009101235
(DMSO) 8.64 (1H, s), 8.44 (1H, d), 8.41 (1H, t), 8.07 (1H, dd), 7.72 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.78 (1H, s), 4.44 (1H, septets), (3.81 1H, quintet), and 3.45-3.38 (1H, m), 3.18-3.10 (1H, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 2.15-2.09 (1H, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m), 0.50-0.44 (2H, m), 0.38-0.32 (2H, m).
Embodiment 192
7-(azetidin-1-base alkylsulfonyl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101241
After preparation 7, utilize 7-(azetidin-1-base alkylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)609/611(M+H) +
1H NMR
Figure C20061011009101242
(DMSO) 8.53 (1H, t), 8.52 (1H, d), 8.44 (1H, t), 8.09 (1H, dd), 7.77 (1H, s), 7.50 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.43 (1H, septets), 3.81 (1H, quintets), 3.69 (4H, t), and 3.47-3.37 (1H, m), 3.21-3.10 (1H, m), 2.83-2.68 (2H, m), and 2.40-2.24 (4H, m), 2.05-1.86 (2H, m), 1.97 (2H, quintet), 1.88 (3H, s, OAc), 1.68-1.53 (2H, m).
Embodiment 193
7-(amino-sulfonyl)-N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101243
After preparation 7, utilize 7-(amino-sulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)569/571(M+H) +
1H NMR
Figure C20061011009101244
(DMSO) 8.65 (1H, s), 8.40 (1H, d), 8.39 (1H, t), 8.09 (1H, dd), 7.69 (1H, s), 7.49 (1H, d), 7.50 (2H, s), 7.25 (1H, d), 6.98 (1H, dd), 4.77 (1H, s), 4.44 (1H, septets), 3.85-3.77 (1H, m), 3.41 (1H, dt), 3.14 (1H, dt), 2.81-2.69 (2H, m), 2.41-2.25 (4H, m), 1.96-1.86 (2H, m), 1.67-1.54 (2H, m).
Embodiment 194
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-the 7-[(dimethylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101251
After preparation 7, utilize the 7-[(dimethylamino) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)597/599(M+H) +
1H NMR (DMSO) 8.49 (1H, s), 8.48 (1H, d), 8.43 (1H, t), 8.04 (1H, dd), 7.75 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H, septets), 3.81 (1H, quintet), and 3.46-3.37 (1H, m), 3.18-3.11 (1H, m), 2.82-2.69 (2H, m), 2.64 (6H, s), 2.42-2.26 (4H, m), 1.95-1.86 (2H, m), 1.89 (3H, s, OAc), 1.60 (2H, dt).
Embodiment 195
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-[(-hydroxy-3-methyl azetidin-1-yl) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101253
After preparation 7, utilize 7-[(3-hydroxy-3-methyl azetidin-1-yl) alkylsulfonyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)639/641(M+H) +
1H NMR
Figure C20061011009101254
(DMSO) 8.53 (1H, d), 8.51 (1H, d), 8.45 (1H, t), 8.08 (1H, dd), 7.77 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H, septets), 3.82 (1H, quintets), 3.60 (2H, d), 3.45 (2H, d), 3.45-3.40 (1H, m), 3.19-3.10 (1H, m), and 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 1.96-1.84 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).
Embodiment 196
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(cyclopropyl amino) carbonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101261
After preparation 35, utilize 1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)573/575(M+H) +
1H NMR
Figure C20061011009101262
(CD 3OD)8.25(1H，d)，8.09(1H，d)，7.68(1H，t)，7.49(1H，s)，7.48(1H，t)，7.38(1H，d)，6.97(1H，d)，4.54-4.48(1H，m)，4.03-3.97(1H，m)，3.44(1H，dd)，3.30(1H，dd)，2.90-2.79(2H，m)，2.76-2.58(5H，m)，1.98-1.89(2H，m)，1.87-1.79(2H，m)，1.85(3H，s，OAc)，0.70-0.65(2H，m)，0.52-0.48(2H，m)。
Embodiment 197
N-{ (2R)-3-[4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Utilize 1-oxo-1 after preparation 24,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)481(M+H) +
1H NMR (CD 3OD)8.36(1H，dd)，8.19(1H，d)，7.86(2H，d)，7.77-7.75(2H，m)，7.57(2H，td)，7.12(2H，d)，4.62-4.56(1H，m)，4.07-4.01(1H，m)，3.57(1H，dd)，3.38(1H，dd)，3.08(3H，s)，2.98-2.88(2H，m)，2.66-2.55(4H，m)，2.12-2.04(2H，m)，1.92-1.83(2H，m)。
Embodiment 198
N-((2R)-2-hydroxyl-3-{4-[4-(methylsulfonyl) phenoxy group] piperidines-1-yl } propyl group)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101271
Utilize 1-oxo-1 after preparation 25,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)500(M+H) +
1H NMR
Figure C20061011009101272
(CD 3OD)8.36(1H，dd)，8.19(1H，d)，7.86(2H，d)，7.77-7.75(2H，m)，7.57(2H，td)，7.12(2H，d)，4.62-4.56(1H，m)，4.07-4.01(1H，m)，3.57(1H，dd)，3.38(1H，dd)，3.08(3H，s)，2.98-2.88(2H，m)，2.66-2.55(4H，m)，2.12-2.04(2H，m)，1.92-1.83(2H，m)。
Embodiment 199
N-{ (2R)-3-[4-(4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Utilize 1-oxo-1 after preparation 26,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)447(M+H) +
1H NMR
Figure C20061011009101274
(DMSO)8.31(1H，t)，8.22(2H，d)，7.75-7.71(3H，m)，7.54-7.50(2H，m)，7.12(2H，d)，4.80-4.73(1H，m)，4.56-4.49(1H，m)，3.83-3.77(1H，m)，3.42-3.35(2H，m)，3.18-3.11(1H，m)，2.81-2.71(2H，m)，2.41-2.27(4H，m)，1.98-1.91(2H，m)，1.68-1.59(2H，m)。
Embodiment 200
N-((2R)-3-{4-[2-(aminocarboxyl)-4-chlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101275
Utilize 1-oxo-1 after preparation 33,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)499(M+H) +
1H NMR
Figure C20061011009101281
(CD 3OD)8.25(1H，d)，8.08(1H，d)，7.78(1H，d)，7.67(1H，td)，7.48(1H，t)，7.47(1H，s)，7.35(1H，dd)，7.08(1H，d)，4.56-4.50(1H，m)，3.94-3.89(1H，m)，3.46(1H，dd)，3.27(1H，dd)，2.79-2.70(2H，m)，2.46-2.36(4H，m)，2.03-1.95(2H，m)，1.82-1.73(2H，m)。
Embodiment 201
N-[(2R)-and 3-(4-{4-chloro-2-[(methylamino) carbonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101282
Utilize 1-oxo-1 after preparation 32,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)513(M+H) +
1H NMR
Figure C20061011009101283
(CD 3OD)8.25(1H，d)，8.09(1H，d)，7.67(1H，td)，7.63(1H，d)，7.48(1H，s)，7.48(1H，td)，7.33(1H，dd)，7.07(1H，d)，4.59-4.51(1H，m)，4.01-3.94(1H，m)，3.46(1H，dd)，3.28(1H，dd)，2.91-2.80(2H，m)，2.83(3H，s)，2.66-2.54(4H，m)，2.05-1.94(2H，m)，1.90-1.79(2H，m)。
Embodiment 202
5-chloro-2-{[1-((2R)-2-hydroxyl-3-{[(1-oxo-1,2-dihydro-isoquinoline-4-yl) carbonyl] amino } propyl group) piperidin-4-yl] the oxygen base } the benzoic acid methyl ester acetate
Figure C20061011009101284
Utilize 1-oxo-1 after preparation 31,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)513(M+H) +
1H NMR
Figure C20061011009101291
(CD 3OD)8.25(1H，dd)，8.09(1H，d)，7.67(1H，td)，7.60(1H，d)，7.49(1H，s)，7.48(1H，td)，7.38(1H，dd)，7.06(1H，d)，4.59-4.54(1H，m)，4.05-3.99(1H，m)，3.76(3H，s)，3.45(1H，dd)，3.30(1H，dd)，3.03-2.92(2H，m)，2.79-2.61(4H，m)，2.00-1.86(4H，m)，1.84(3H，s，OAc)。
Embodiment 203
N-((2R)-3-{4-[2-(amino-sulfonyl)-3,4-dichlorophenoxy] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides trifluoroacetate
Figure C20061011009101292
Utilize 1-oxo-1 after preparation 40,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)569/571(M+H) +
1H NMR
Figure C20061011009101293
(CD 3OD)8.26(1H，d)，8.09(1H，d)，7.71(1H，t)，7.62(1H，d)，7.52(1H，s)，7.48(1H，t)，7.18(1H，d)，5.02(1H，s)，4.23-4.15(1H，m)，3.55(1H，t)，3.46-3.33(5H，m)，3.16-3.08(2H，m)，2.26(2H，t)，2.15-2.00(2H，m)。
Embodiment 204
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(methylaminos) alkylsulfonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Utilize 1-oxo-1 after preparation 41,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)583/585(M+H) +
1H NMR
Figure C20061011009101295
(CD 3OD)8.25(1H，d)，8.08(1H，d)，7.69(1H，td)，7.60(1H，d)，7.49(1H，s)，7.48(1H，td)，7.16(1H，d)，4.73-4.68(1H，m)，4.05-3.99(1H，m)，3.44(1H，dd)，3.30(1H，dd)，3.15-3.04(2H，m)，2.78-2.63(4H，m)，2.52(3H，s)，2.07-1.93(4H，m)，1.85(3H，s，OAc)。
Embodiment 205
N-[(2R)-and 3-(4-{3,4-two chloro-2-[(cyclopropyl amino) alkylsulfonyl] phenoxy group } piperidines-1-yl)-the 2-hydroxypropyl]-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101301
Utilize 1-oxo-1 after preparation 42,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)609/611(M+H) +
1H NMRδ(CD 3OD)8.25(1H，d)，8.08(1H，d)，7.68(1H，t)，7.61(1H，d)，7.49(1H，s)，7.47(1H，t)，7.17(1H，d)，4.72-4.65(1H，m)，4.03-3.96(1H，m)，3.44(1H，dd)，3.30(1H，dd)，3.11-2.99(2H，m)，2.73-2.58(4H，m)，2.19-2.13(1H，m)，2.04-1.90(4H，m)，1.83(3H，s，OAc)，0.50-0.43(4H，m)。
Embodiment 206
N-{ (2R)-3-[4-(3-chloro-4-cyano-benzene oxygen) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101302
Utilize 7-(methylsulfonyl)-1-oxo-1 after preparation 24,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)559(M+H) +
1H NMR
Figure C20061011009101303
(CD 3OD)8.78(1H，d)，8.35(1H，d)，8.14(1H，dd)，7.68(1H，s)，7.60(1H，d)，7.12(1H，d)，6.95(1H，dd)，4.56-4.51(1H，m)，4.01-3.95(1H，m)，3.47(1H，dd)，3.28(1H，dd)，3.10(3H，s)，2.94-2.85(2H，m)，2.64-2.52(4H，m)，2.04-1.95(2H，m)，1.86(3H，s)，1.83-1.74(2H，m)。
Embodiment 207
N-{ (2R)-3-{4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-2-hydroxy-2-methyl propyl group }-6-(methyl sulphonyl)-1H-indoles-3-carboxylic acid amides
After preparation 10, utilize 6-(methyl sulphonyl)-1H-Indole-3-Carboxylic Acid, be prepared according to the method for describing among the embodiment 189.
MS(APCI)520/522/524(M+H) +
1H NMR
Figure C20061011009101312
(CD 3OD)8.35(1H，d)，8.19(1H，s)，8.07(1H，d)，7.69(1H，dd)，7.11(1H，d)，7.08(1H，dd)，6.88(1H，d)，4.56-4.48(1H，m)，4.20-4.12(1H，m)，3.57(1H，dd)，3.43(1H，dd)，3.19-3.12(5H，s)，3.03-2.98(2H，m)，2.94(1H，dd)，2.85(1H，m)，2.18(3h，s)，2.16-2.08(2H，m)，2.03-1.94(2H，m)。
Embodiment 208
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methyl sulphonyl)-1H-indoles-3-carboxylic acid amides
Figure C20061011009101313
After preparation 8, utilize 6-(methyl sulphonyl)-1H-Indole-3-Carboxylic Acid, be prepared according to the method for describing among the embodiment 189.
MS(APCI)540/542/544(M+H) +
1H NMR
Figure C20061011009101314
(CD 3OD)8.35(1H，d)，8.34(1H，s)，8.06(1H，d)，7.69(1H，dd)，7.38(1H，d)，7.09(1H，d)，6.87(1H，dd)，4.50-4.43(1H，m)，4.12-4.06(1H，m)，3.57(1H，dd)，3.41(1H，dd)，3.13(3H，s)，3.07-2.99(2H，m)，2.81-2.68(4H，m)，2.12-2.04(2H，m)，1.94-1.82(2H，m)。
Embodiment 209
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101315
Utilize 7-fluoro-1-oxo-1 after preparation 7,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)508/510(M+H) +
1H NMR
Figure C20061011009101321
(DMSO)11.73(1H，s)，8.39-8.26(2H，m)，7.88(1H，dd)，7.64(1H，td)，7.54(1H，s)，7.49(1H，d)，7.25(1H，d)，6.98(1H，dd)，4.79-4.71(1H，m)，4.48-4.38(1H，m)，3.85-3.75(1H，m)，3.46-3.34(1H，m)，3.19-3.09(1H，m)，2.82-2.65(2H，m)，2.43-2.23(4H，m)，1.97-1.84(2H，m)，1.67-1.53(2H，m)。
Embodiment 210
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101322
Utilize 7-fluoro-1-oxo-1 after preparation 10,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)488(M+H) +
1H NMR
Figure C20061011009101323
(DMSO)8.42-8.28(2H，m)，7.88(1H，dd)，7.64(1H，td)，7.55(1H，s)，7.20(1H，d)，7.14(1H，dd)，6.98(1H，d)，4.43-4.33(1H，m)，3.85-3.75(1H，m)，3.45-3.34(1H，m)，3.20-3.08(1H，m)，2.75-2.60(2H，m)，2.42-2.25(4H，m)，2.14(3H，s)，1.94-1.81(2H，m)，1.70-1.56(2H，m)。
Embodiment 211
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101324
Utilize 6-(methylsulfonyl)-1-oxo-1 after preparation 10,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)548(M+H) +
1H NMR (DMSO) 11.98 (1H, s), 8.89 (1H, d), 8.44 (1H, d), 8.42 (1H, t), 8.01 (1H, dd), 7.76-7.72 (1H, m), 7.20 (1H, d), 7.14 (1H, dd), 6.98 (1H, d), 4.77 (1H, d), 4.43-4.34 (1H, m), 3.86-3.77 (1H, m), 3.42 (1H, td), 3.28 (3H, s), (3.17 1H, quintet), and 2.77-2.63 (2H, m), 2.42-2.29 (4H, m), 2.14 (3H, s), 1.95-1.84 (2H, m), 1.71-1.58 (2H, m).
Embodiment 212
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Utilize 6-(methylsulfonyl)-1-oxo-1 after preparation 13,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)581/583(M+H) +
1H NMR
Figure C20061011009101333
(DMSO)11.97(1H，d)，8.89(1H，d)，8.44(1H，d)，8.42(1H，t)，8.01(1H，dd)，7.76-7.72(1H，m)，7.35(1H，d)，7.10(1H，d)，4.80-4.73(1H，m)，4.53-4.44(1H，m)，3.86-3.76(1H，m)，3.42(1H，td)，3.28(3H，s)，3.21-3.12(1H，m)，2.79-2.65(2H，m)，2.40(3H，s)，2.42-2.30(4H，m)，1.95-1.85(2H，m)，1.74-1.61(2H，m)。
Embodiment 213
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101334
Utilize 7-(methylsulfonyl)-1-oxo-1 after preparation 7,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)568/566(M+H) +
1H NMR
Figure C20061011009101341
(DMSO) 8.70 (1H, s), 8.46 (1H, d), 8.16 (1H, dd), 8.10 (1H, t), 7.70 (1H, s), 7.45 (1H, d), 7.18 (1H, d), 6.94 (1H, dd), 4.39 (1H, septets), 3.82 (1H, quintet), 3.42 (1H, dt), 3.30-3.09 (1H, m), 3.22 (3H, s), and 2.82-2.67 (2H, m), 2.45-2.27 (4H, m), 1.99-1.80 (2H, m), 1.89 (3H, s, OAc), 1.72-1.53 (2H, m).
Embodiment 214
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101342
Utilize 7-(methylsulfonyl)-1-oxo-1 after preparation 10,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)548/550(M+H) +
1H NMR
Figure C20061011009101343
(DMSO)8.68(1H，d)，8.48(1H，d)，8.43(1H，t)，8.20(1H，dd)，7.76(1H，s)，7.21(1H，d)，7.15(1H，dd)，6.98(1H，d)，4.84-4.72(1H，m)，4.46-4.31(1H，m)，3.88-3.74(1H，m)，3.49-3.34(1H，m)，3.28(3H，s)，3.22-3.08(1H，m)，2.78-2.60(2H，m)，2.44-2.24(4H，m)，2.14(3H，s)，1.98-1.79(2H，m)，1.74-1.54(2H，m)。
Embodiment 215
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-7-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101344
Utilize 7-(methylsulfonyl)-1-oxo-1 after preparation 13,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)582/584(M+H) +
1H NMR
Figure C20061011009101345
(DMSO) 8.68 (1H, d), 8.47 (1H, d), 8.44 (1H, t), 8.20 (1H, dd), 7.76 (1H, s), 7.35 (1H, d), 7.10 (1H, d), 4.53-4.44 (1H, m), 3.81 (1H, quintets), 3.42 (1H, dt), 3.20-3.09 (1H, m), 2.77-2.65 (2H, m), 2.40 (3H, s), 2.39-2.28 (4H, m), 1.95-1.85 (2H, m), 1.87 (3H, s, OAc), 1.73-1.61 (2H, m).
Embodiment 216
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-(methylsulfonyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101351
Utilize 6-(methylsulfonyl)-1-oxo-1 after preparation 7,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(ESI)568/570(M+H) +
Embodiment 217
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101352
Utilize 6-fluoro-1-oxo-1 after preparation 7,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(APCI)508/510(M+H) +
1H NMR
Figure C20061011009101353
(DMSO) 11.70 (1H, d), 8.34 (1H, t), 8.28 (1H, dd), 8.03 (1H, dd), 7.64 (1H, d), 7.49 (1H, d), 7.38 (1H, td), 7.25 (1H, d), 6.98 (1H, dd), 4.80-4.70 (1H, m), 4.44 (1H, septets), 3.87-3.73 (1H, m), 3.45-3.36 (1H, m), 3.14 (1H, quintets), 2.84-2.66 (2H, m), 2.43-2.21 (4H, m), 1.99-1.84 (2H, m), 1.69-1.51 (2H, m).
Embodiment 218
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101361
Utilize 6-fluoro-1-oxo-1 after preparation 10,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 189.
MS(ESI)488/490(M+H) +
Embodiment 219
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-4-(trifluoromethyl)-1,2-dihydro-pyrimidin-5-carboxylic acid amides
Utilize 2-oxo-4-(trifluoromethyl)-1 after preparation 10,2-dihydro-pyrimidin-5-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(ESI)489/491(M+H) +
Embodiment 220
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-4-(trifluoromethyl)-1,2-dihydro-pyrimidin-5-carboxylic acid amides
Figure C20061011009101363
Utilize 2-oxo-4-(trifluoromethyl)-1 after preparation 13,2-dihydro-pyrimidin-5-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(ESI)523/525(M+H) +
Embodiment 221
N-((2R)-3-{4-[3,4-two chloro-2-(methylsulfonyl) phenoxy groups] piperidines-1-yl }-the 2-hydroxypropyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides acetate
Figure C20061011009101371
Utilize 1-oxo-1 after preparation 48,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)568/570(M+H) +
1H NMR
Figure C20061011009101372
(CD 3OD)8.35(1H，d)，8.18(1H，d)，7.78(1H，t)，7.76(1H，d)，7.58(1H，s)，7.57(1H，t)，7.28(1H，d)，4.87-4.80(1H，m)，4.13-4.07(1H，m)，3.54(1H，dd)，3.40(1H，dd)，3.35(3H，s)，3.16-3.06(2H，m)，2.85-2.69(4H，m)，2.16-2.00(4H，m)，1.94(3H，s)。
Embodiment 222
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides acetate
Figure C20061011009101373
After preparation 7, according to the method for describing among the embodiment 35, utilize 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-acyl chlorides is prepared, and the latter is by obtaining commercially available 6-chloro-4-trifluoromethyl methylnicotinic acid ester then with sodium hydroxide hydrolysis with the thionyl chloride Processing of Preparation).
MS(APCI)508/510(M+H) +
1H NMR (DMSO) 8.35 (1H, t), 7.77 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 6.72 (1H, s), 4.43 (1H, septets), 3.71 (1H, quintet), 3.29 (1H, dt), 3.06 (1H, dt), 2.78-2.66 (2H, m), 2.36-2.24 (4H, m), 1.95-1.86 (2H, m), 1.90 (3H, s), 1.65-1.54 (2H, m).
Embodiment 223
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides acetate
Figure C20061011009101375
Utilize 6-oxo-4-(trifluoromethyl)-1 after preparation 10,6-dihydropyridine-3-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)488/490(M+H) +
1H NMR
Figure C20061011009101381
(DMSO) 8.35 (1H, t), 7.77 (1H, s), 7.20 (1H, s), 7.15 (1H, dd), 6.98 (1H, d), 6.73 (1H, s), 4.42-4.34 (1H, m), 3.72 (1H, quintets), 3.33-3.27 (1H, m), 3.06 (1H, dt), 2.71-2.61 (2H, m), 2.37-2.25 (4H, m), 2.14 (3H, s), 1.93-1.84 (2H, m), 1.91 (3H, s), 1.69-1.58 (2H, m).
Embodiment 224
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid amides
Figure C20061011009101382
Utilize 6-oxo-4-(trifluoromethyl)-1 after preparation 13,6-dihydropyridine-3-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)522/524(M+H) +
1H NMR
Figure C20061011009101383
(DMSO) 8.32 (1H, t), 7.79 (1H, s), 7.35 (1H, d), 7.10 (1H, d), 6.69 (1H, s), (4.49 1H, septet), 3.72 (1H, quintets), 3.30 (1H, dt), 3.07 (1H, dt), 2.74-2.64 (2H, m), 2.40 (3H, s), 2.37-2.25 (4H, m), 1.94-1.84 (2H, m), 1.89 (3H, s), 1.71-1.61 (2H, m).
Embodiment 225
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-(2-oxo quinoxaline-1 (2H)-yl) ethanamide
Figure C20061011009101384
(2-oxo quinoxaline-1-(2H)-yl) acetate is prepared according to the method for describing among the embodiment 1 in utilization after preparation 7.
MS(APCI)505/507(M+H) +
1H NMR
Figure C20061011009101385
(CDCl 3)8.37(1H，s)，7.92(1H，d)，7.61(1H，t)，7.49(1H，d)，7.40(1H，t)，7.32(1H，d)，6.99(1H，d)，6.74(1H，dd)，6.72(1H，bd s)，4.91(2H，m)，4.36-4.26(1H，m)，3.86-3.76(1H，m)，3.52-3.42(1H，m)，3.26-3.18(1H，m)，2.88-2.80(1H，m)，2.63-2.53(2H，m)，2.40-2.26(3H，m)，2.06-1.92(2H，m)，1.87-1.73(2H，m)。
Embodiment 226
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-oxo-3,4-dihydro-quinoxaline-1 (2H)-carboxylic acid amides
Figure C20061011009101391
Utilize 3-oxo-3 after preparation 7,4-dihydro-quinoxaline-1 (2H)-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)505/507(M+H) +
1H NMRδ(CDCl 3)8.26(1H，s)，7.43(1H，d)，7.31(1H，d)，7.19-7.09(1H，m)，6.99(1H，d)，6.94(1H，d)，6.75(1H，dd)，5.72(1H，t)，4.44(2H，s)，4.30-4.22(1H，m)，3.88-3.81(1H，m)，3.58-3.52(1H，m)，3.17-3.11(1H，m)，2.93-2.85(1H，m)，2.67-2.61(1H，m)，2.57-2.53(1H，m)，2.44-2.40(1H，m)，2.36-2.29(2H，m)，2.00-1.90(2H，m)，1.80-1.70(2H，m)。
Embodiment 227
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide
Figure C20061011009101392
After preparation 10, utilize 3-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, be prepared according to the method for describing among the embodiment 1.
MS(APCI)460/462(M+H) +
1H NMR
Figure C20061011009101393
(DMSO)8.41(1H，s)，8.15(1H，t)，7.20(1H，d)，7.14(1H，dd)，6.98(1H，d)，4.42-4.36(1H，m)，3.77-3.71(1H，m)，3.39-3.33(1H，m)，3.10-3.04(1H，m)，2.73-2.63(2H，m)，2.36-2.26(4H，m)，2.14(3H，s)，1.92-1.82(2H，m)，1.70-1.60(2H，m)。
Embodiment 228
N-{ (2R)-3-[4-(2,4-two chloro-3-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide
Figure C20061011009101401
After preparation 13, utilize 3-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, be prepared according to the method for describing among the embodiment 1.
MS(APCI)495/497(M+H) +
1H NMR
Figure C20061011009101402
(DMSO)8.41(1H，s)，8.15(1H，t)，7.34(1H，d)，7.09(1H，dd)，4.50-4.42(1H，m)，3.77-3.71(1H，m)，3.37-3.33(1H，m)，3.10-3.04(1H，m)，2.74-2.64(2H，m)，2.39(3H，s)，2.36-2.26(4H，m)，1.96-1.86(2H，m)，1.69-1.62(2H，m)。
Embodiment 229
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl }-the 2-hydroxypropyl }-1-oxo-1,2-dihydro-2-methylisoquinolinium-4-carboxylic acid amides
Figure C20061011009101403
Utilize 2-methyl isophthalic acid-oxo-1 after preparation 7,2-dihydro-isoquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 1.
MS(APCI)504/506/508(M+H) +
1H NMR
Figure C20061011009101404
(CDCl 3)8.47(1H，d)，8.14(1H，d)，7.70(1H，t)，7.61(1H，s)，7.53(1H，t)，7.33(1H，d)，7.00(1H，d)，6.76(1H，dd)，6.58(1H，bd t)，4.42-4.32(1H，m)，4.06-3.96(1H，m)，3.80-3.70(1H，m)，3.63(3H，s)，3.44-3.34(1H，m)，3.02-2.92(1H，m)，2.78-2.68(2H，m)，2.59-2.45(3H，m)，2.16-2.00(2H，m)，1.96-1.80(2H，m)。
Embodiment 230
N-{ (2R)-3-{4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-1,2-dihydro-1-toluquinoline-4-carboxylic acid amides
Figure C20061011009101411
Utilize 1-methyl-2-oxo-1 after preparation 7,2-dihydroquinoline-4-carboxylic acid is prepared according to the method for describing among the embodiment 1.
MS(APCI)m/z 504/506/508(M+H) +
1H NMR
Figure C20061011009101412
(CDCl 3)7.97(1H，d)，7.62(1H，t)，7.40(1H，d)，7.32(1H，d)，7.28(1H，t)，7.00(1H，d)，6.83(1H，s)，6.76(1H，dd)，6.72(1H，t)，4.39-4.31(1H，m)，4.04-3.94(1H，m)，3.78-3.70(1H，m)，3.72(3H，s)，3.47-3.37(1H，m)，3.00-2.90(1H，m)，2.75-2.67(2H，m)，2.56-2.42(3H，m)，2.10-1.94(2H，m)，1.94-1.78(2H，m)。
Embodiment 231
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Figure C20061011009101413
After preparation 7, utilize 8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)508/510(M+H) +
Embodiment 232
N-{ (2R)-3-[4-(4-chloro-2-methylphenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-8-fluoro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid amides
Utilize 8-fluoro-1-oxo-1 after preparation 10,2-dihydro-isoquinoline-4-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(APCI)488/490(M+H) +
Embodiment 233
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-2-oxo-4-(trifluoromethyl)-1,2-dihydro-pyrimidin-5-carboxylic acid amides
Figure C20061011009101421
Utilize 2-oxo-4-(trifluoromethyl)-1 after preparation 7,2-dihydro-pyrimidin-5-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(EPCI)509/511(M+H) +
Embodiment 234
N-{ (2R)-3-[4-(3, the 4-dichlorophenoxy) piperidines-1-yl]-the 2-hydroxypropyl }-4-methyl-2-oxo-1,2-dihydro-pyrimidin-5-carboxylic acid amides
Utilize 4-methyl-2-oxo-1 after preparation 7,2-dihydro-pyrimidin-5-acyl chlorides is prepared according to the method for describing among the embodiment 35.
MS(EPCI)455/457(M+H) +
Embodiment 235
Pharmacology analysis: calcium current amount [Ca 2+] iMeasure
People's eosinophil
According to preceding method (Hansel etc., J.Immunol.Methods, 1991, 145, 105-110) from the peripheral blood of EDTA anti-freezing, isolate people's eosinophil.Under the room temperature with cell resuspending (5 * 10 6Ml -1) and be loaded in the low potassium solution (LKS of 5 μ M FLUO-3/AM+Pluronic F127 2.2 μ l/ml (Molecular Probes); NaCl 118mM, MgSO 40.8mM, glucose 5.5mM, Na 2CO 38.5mM, KCl 5mM, HEPES 20mM, CaCl 21.8mM BSA 0.1%, pH7.4) one hour.Behind the loading, with cell centrifugal 5 minutes of 200g and with 2.5 * 10 6Ml -1The density resuspending in LKS.Then cell is transferred in the 96 hole FLIPr plates (the polylysine plate of Becton Dickinson, with 5 μ M fibronectin preincubates 2 hours) with 25 μ l/ holes.With plate centrifugal 5 minutes of 200g and with cell with LKS (200 μ l; Room temperature) washed twice.
The embodiment compound is dissolved among the DMSO in advance, and adds to the final concentration of 0.1% (v/v) DMSO.Add A 50The eosinophil chemotactic protein of concentration starts to be measured, and (Sunnyvale U.S.A.) detects fluo-3 fluorescence (l for FluorometricImaging Plate Reader, Molecular Devices to utilize FLIPR Ex=490nm and l Em=520nm) instantaneous increase.
If the increase of eosinophil chemotactic protein (selectivity CCR3 agonist) inductive fluorescence is subjected to the inhibition of the mode of concentration dependence, just think that the embodiment compound is an antagonist.The concentration that suppresses the needed antagonist of 50% fluorescence can be used to be defined as the IC of CCR3 receptor antagonist 50
Embodiment 236
People's eosinophil chemotaxis
According to preceding method (Hansel etc., J.Immunol.Methods, 1991, 145, 105-110) obtain people's eosinophil whole the separation from the peripheral blood of EDTA anti-freezing.Under the room temperature, with cell with 10 * 10 6Ml -1Density be resuspended among the RPMI, this substratum comprises 200IU/ml penicillin, 200 μ g/ml streptomycin sulfates and adds 10%HIFCS.
With eosinophil (700 μ l) and 7 μ l carriers or compound (the 10%DMSO solution of the 100 * final concentration that needs) 37 ℃ of preincubates 15 minutes.Chemotaxis plate (ChemoTx, 3 μ m holes, Neuroprobe) load by following manner: the eosinophil chemotactic protein (at the selectivity CCR3 of this concentration range agonist) that 28 μ l is comprised 0.1～100nM concentration of the embodiment compound of various concentration or solvent joins in the chemotaxis plate lower floor hole.Then filter is placed on the hole, and 25 μ l eosinophil suspension is added to the top of filter.With plate in the humidity incubator with 95% air/5%CO 2Atmosphere is cultivated at 37 ℃ and was made it to take place chemotaxis in 1 hour.
Sucking-off comprises the substratum that does not have migrating cell and discards carefully from filter top.Filter is washed once to remove any adherent cell with the phosphate-buffered salt (PBS) that comprises 5mM EDTA.The migration of centrifugal (centrifugal 5 minutes of room temperature 300 * g) precipitation by filter cell and remove filter, and supernatant is transferred in each hole of 96-orifice plate (Costar).Add the PBS that 28 μ l comprise 0.5%Triton * 100 and freeze/melt the sedimentary cell of cracking by two-wheeled then.Then cell pyrolysis liquid is joined in the supernatant liquor.According to Strath etc., J.Immunol.Methods, 1985, 83, the eosinophil number that 209 method is quantitatively moved by the eosinophil peroxidase activity of measuring in the supernatant liquor.
If the concentration of response eosinophil chemotactic protein moves on to the right side of control curve, just think the people eosinophil chemotactic antagonist of embodiment compound for the mediation of eosinophil chemotactic protein.Under the condition that has or do not have compound to exist, measure the densitometer of the eosinophil chemotactic protein that provides 50% chemotaxis needs and calculate the apparent avidity of compound, or mensuration can be used to measure the compound activity of one group of compound concentration to the eosinophil chemotactic protein of predetermined concentration CCR3.
Embodiment % when 3nM eosinophil chemotactic protein suppresses (1uM compound)
10 106
17 103
45 102
46 105
47 104
52 95
53 105
58 104
132 101
186 104
192 103
197 103
206 99
212 103
215 103
227 103
Embodiment 237
Isolating guinea pig trachea
(referring to for example, Harrison, R.W.S., Carswell, H..& Young，J.M.(1984)EuropeanJ.Pharmacol.，106，405-409.)
Whole tracheae is put to death and taken out to male albefaction Dunkin-Hartley cavy (250g) through cervical dislocation.After removing adherent reticular tissue, tracheae is cut into 6 annular fragments, 3 cartilage bandwidth are respectively arranged, be suspended in then in the 20ml organ culture liquid, described solution comprises the Krebs-Henseleit solution (mM) of following compositions: NaCl 117.6, NaH 2PO 40.9, NaHCO 325.0, MgSO 41.2 KCl 5.4, CaCl 22.6 and glucose 11.1.Damping fluid is remained on 37 ℃ and feed 5%CO 2Oxygen.INDOMETHACIN (2.8 μ M) is joined in the Krebs solution to prevent the development owing to the synthetic smooth muscle tone that causes of ring-oxygenase product.Tracheal ring is suspended between two parallel tungsten filament hooks, and an end connects force transducer such as Ormed bar and the other end is connected organ culture liquid fixed upholder.The isodynamic variation of record on 2-road Sekonic level bed drawing registering instrument.
Experimental program
In the beginning of each experiment, tissue is used the power of 1g, recover to reach stable with 60 minutes starting times up to remaining tonus.Subsequently, each the tissue in 0.5log 10The unit increment is set up cumulative histamine concentration effect (E/[A]) curve.Cleansing tissue and after about 30 minutes adds test-compound or solvent (20%DMSO) then.Hatch second E/[A that carries out histamine after 60 minutes] curve.
Concentration-response is recorded as the peaked per-cent of first curve.
Data analysis
Analyze experiment E/[A] curve data has and do not have the histamine activity (p[A of test-compound under existing with evaluation 50] value).Calculate the avidity (pA of test-compound subsequently with following equation 2) value:
log(r-1)＝log[B]+pA 2
[A] under wherein the r=test compounds exists 50[A] under/no antagonist 50, and [B] is the concentration of test-compound.Find that the embodiment compound is the H1 antagonist.
Embodiment 238
The histamine H1-receptor of The compounds of this invention is estimated by following method in conjunction with activity: (50mM Tris pH7.4 comprises 2mM MgCl measuring damping fluid under the room temperature 2250mM sucrose and 100mMNaCl) in, measure 1nM[3H during 1 hour]-neo-antergan (Amersham, Bucks, product code name TRK 608, concrete active 30Ci/mmol) to recombinant C HO-K1 cell (Euroscreen SA, Brussels from expressing human H1 acceptor, Belgium, product code name ES-390-M) competitiveness of the 2 μ g films that prepare displacement.
Embodiment H1 pKi/[1328_S]
10 8.4
17 8.1
45 7.7
46 8.2
47 8.1
52 8.4
53 8.1
58 7.2
132 6.6
186 7.9
192 8.7
197 6.8
206 6.6
212 7.8
215 7.3
227 7.6

Claims (4)

1. a method for preparing 4-(3, the 4-dichlorophenoxy) piperidines comprises the steps:
A. 4-hydroxy piperidine and suitable alkali are at room temperature reacted in appropriate solvent; And,
B. with consequent mixture and 1,2-two chloro-4-fluorobenzene are at 50-90 ℃, or heat under the reflux temperature of employed solvent,
Wherein said suitable alkali is basic metal C 1-10Alkoxide, and wherein said solvent is the mixture of ether, aromatic solvent or these solvents.
2. the process of claim 1 wherein that basic metal is sodium or potassium.
3. claim 1 or 2 method, wherein suitable alkali is basic metal C 4-10Tertiary alcohol salt.
4. claim 1 or 2 method, wherein suitable alkali is potassium tert.-butoxide or 3,7-dimethyl-3-octanol potassium.
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EP0333027A1 (en) * 1988-03-14 1989-09-20 Hoechst-Roussel Pharmaceuticals Incorporated 4-Pentafluorophenoxypiperidines, a process for their preparation and their use as medicaments

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