CN101056855B - Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient - Google Patents

Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient Download PDF

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CN101056855B
CN101056855B CN2005800389254A CN200580038925A CN101056855B CN 101056855 B CN101056855 B CN 101056855B CN 2005800389254 A CN2005800389254 A CN 2005800389254A CN 200580038925 A CN200580038925 A CN 200580038925A CN 101056855 B CN101056855 B CN 101056855B
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amino
methyl
carbonyl
piperidyls
phenyl
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CN101056855A (en
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高冈义和
柴山史朗
西泽玲奈
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Abstract

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof, (wherein the characters are as defined in the description). The compounds of the general formula (I) have a CCR5 antagonistic activity, so that they are useful in the prevention and/or therapy for CCR5 mediated diseases, for example, various inflammatory diseases (asthma, gastritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis and other inflammatory intestinal failure, etc.), immunologic diseases (autoimmune disease, rejection of transplanted organ (rejection of solid organ transplant graft, rejection of pancreatic islet cell transplant in diabetes, graft-versus-host disease, etc.), immunosuppression, psoriasis, multiple sclerosis, etc.), infectious diseases (human immunodeficiency virus infection, acquired immunodeficiency syndrome, RSV infection, etc.), allergoses (atopic dermatitis, hives, allergicbronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc.), cardiovascular risks (arteriosclerosis, suppression of ischemic reperfusion injury, etc.), acute respiratory distress syndrome, shock caused by bacterial infection, diabetes, cancer metastasis, etc.

Description

Nitogen-contained heterocycle derivant and contain it as the medicine of active component
Technical field
The present invention relates to the nitrogenous Hete rocyclic derivatives for being suitable for medicine and it is related to medicine comprising it as active component.
In order to which the present invention is explained in greater detail, it is related to
(1) compound that formula (I) is represented
Figure G200580038925420070516D000011
(wherein all symbols have implication as described below), its salt, N- oxides, its solvate or its prodrug,
(2) prevent and/or treat the medicine of CCR5- relevant diseases, including compound, its salt, N- oxides, its solvate or its prodrug that formula (I) is represented as active component, and
(3) its preparation method.
Background technology
Known chemotactic factor (CF) is the endogenous alkaline albumen with leukocyte chemotaxis and activation capability and strong heparin-binding ability.At present, it is believed that chemotactic factor (CF) not only with inflammation and immune response when control the infiltration of special leucocyte relevant, and development with lymphocyte under physiological condition and go back to the nest and the migration of blood cell precursors cell and body cell is relevant.
Differentiation, propagation and the death of haemocyte are controlled by different types of chemotactic factor (CF).In vivo, often there is inflammation, occur the breaking up of lymphocyte, maturation etc. in a certain specific site.That is, a variety of required cell migrations are to some specific sites and accumulation wherein is so as to cause a series of inflammation and immune response.Therefore, cell migration is also for phenomenon that immune system is essential in addition to cell differentiation, propagation and death.
The movement of haemocyte in organism, in generating process, by via tire liver by main artery-gonad-middle kidney (aorta-gonad-mesonephros；AGM) hematopoiesis that region starts changes into hematopoiesis lasting in marrow, has been first begin to intravital haemocyte migration.In addition, T cell, thymic dendritic precursor enter in thymus gland from tire liver, marrow, and carry out in thymus gland environment cell differentiation.The T cell for receiving Immune Clone Selection migrates to the second lymphoid tissue and participates in periphery immune response.By capturing antigen, activation, the Langerhans cell of differentiation move to the T cell region of regional nodes, are used as activated dendritic cell Naive T cells.Memory T cell is gone back to the nest is again introduced into lymph node via lymphatic vessel and blood vessel.In addition, B cell, the T cell in small intestine epithelium tissue, gamma delta T cells, NKT cells and BMDC migrate from marrow and without thymus gland, break up to participate in immune response.
Chemotactic factor (CF) deeply participates in the migration of various kinds of cell.The control of chemokine receptors and inflammation and immune response height correlation, its mechanism are expressed in a variety of specific cells in some specific periods for them and are producing the zone-accumulation effector cell of chemotactic factor (CF).
For example, report and show in animal model has such as knocked out CCR5 mouse, play an important role (Transplantation as the CCR5 of chemokine receptors in the rejection of organ transplant or in autoimmune disease etc., Vol.72 (7), 1199-1205 (2001)；Diabetes, Vol.51 (8), 2489-2495 (2002)；Journal of Virology, Vol.77 (1), 191-198 (2003)；Journal of Immunology, Vol.164 (12), 6303-6312 (2000)).Separately have been reported that the danger of some diseases and survival length (the Ref.The Lancet, Vol.357,1758-1761 (2001) of transplant organ occur between the people for comparing the people with nonactive CCR and the CCR5 with wild type；Arthritis＆Rheumatism, Vol.42 (5), 989-992 (1999)；The Lancet, Vol.354,1264-1265 (1999)；EuropeanJournal of Immunogenetics, Vol.29 (6) 525-528 (2002)).Show that CCR5 is related to some diseases, but they in report without reference to antagonizing CCR 5 medicine effect.
At present, the immunosuppressive therapy for disease is provided in fields of implantation.That is, calcineurin inhibitor such as cyclosporine or tacrolimus (FK506) is mainly shared with various immunodepressant such as TOR (rapamycin target spot) inhibitor such as sirolimus (rapamycin), non-specific antiphlogistic as corticosteroid, anti-proliferative drugs imuran, mycophenolate.But it often causes chronic rejection or serious side effects, it is therefore desirable to more existing protracted drug graft survival time and the effective neotype immunosuppressant for reducing side effect.
Anti-inflammatory agent or the medicine of regulation immunologic function are such as applied to treatment autoimmune disease or allergic disease for the inhibited nonsteroidal anti-inflammatory agent (NSAID) of Cycloxygenase (COX), the modifying antirheumatic drug (DMARD) for alleviating disease etc..Medicine is more effective, and its caused side effect is more serious, and the treatment for showing these medicines is not the basic treatment for disease and is only treatment symptom.
Meanwhile, the acquired immunodeficiency syndrome (being hereinafter referred to as " ADIS ") induced by human immunodeficiency virus's (being hereinafter referred to as " HIV ") is in recent years most in the urgent need to one of disease of effective treatment method.Once in the target cell that HIV is main --- infection is completed in CD4- positive cells, HIV is repeated to breed in patient's body, and the T cell of responsible immunologic function can be thoroughly destroyed sooner or later.In the process, immunologic function gradually reduces to cause the panimmunity defect state of an illness such as heating, diarrhoea, lymphadenovaris, it is easy to cause a variety of chance Infective morbidities such as pneumocystis carinii pneumonia (carinii pneumonia).These state of an illness are AIDS onset of disease, it is known they will induce and aggravate the malignant tumours such as Kaposi sarcoma.
As recent prevention and/or treatment AIDS method, following effort has been carried out：As (1) is infected by giving propagation that RTI or protease inhibitors suppress HIV and (2) by giving chemoprophylaxis with immune-enhancing activity or link chance.
It is responsible for the helper cell of central immune system mainly by HIV.From HIV known to 1985 in infection using express on T cell film memebrane protein CD4 (Cell,52, 631 (1985)).CD4 molecules are made up of 433 amino acid residues, find to express in Deiter's cells in its Langerhans' cells in ripe helper cell and macrophage, some B cells, vascular endothelial cell, skin histology, the dendritic cells in GALT, central nervous tissue etc..But, because there is disclosed HIV and non-fully only by CD4 molecules, indicating and there is molecules other in addition to CD4 molecules related to HIV cell.
CCR5, it is RANTES, MIP-1 α and MIP-1 beta receptors, also played a role in (R5) HIV that macrophage tends to (Science,272, 1955 (1996)).
Therefore, HIV material can be competed with CCR5, or thus can combine inhibition of HIV causes virus can not can be described as HIV inhibitor with reference to CCR5 material.
It is also reported that the possibility that CCR5 (is hereinafter referred to as " RSV ") playing a role in infection in respiratory syncytial (syncytiam) virus.
It is reported that CCR5 is expressed in atherosclerosis plaque, it is taken as that chemokine receptor modulators apply also for treating cardiovascular diseases.
As described above, think chemotactic factor (CF) (such as RANTES, MIP-1 α, MIP-1 β, Deng) acceptor especially CCR5 and inflammation, immunological diseases, infectious diseases (such as by/HIV, by rsv infection, etc.) and angiocardiopathy height correlation.For example, it is believed that they are with a variety of inflammatory disease (asthma, ephritis, nephrosis, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, IBD such as ulcerative colitis etc.), immunity disease (autoimmune disease, rejection (the rejection of solid organ in organ transplant, for the rejection for the islet cell transplantation for treating diabetes, graft versus host disease (GVHD) etc.), immunosupress, psoriasis, multiple sclerosis etc.), infectious disease (HIV infections, acquired immune deficiency syndrome, rsv infection etc.), allergic disease (atopic dermatitis, nettle rash, allergic bronchopulmonary aspergillosis, Eosinophilic Gastroenteritis of allergy etc.), cardiovascular disease (artery sclerosis, ischemic damage and reperfusion injury etc.), acute dyspnea syndrome, with the bacterium infection of shock, diabetes, cancer metastasis etc..
Report the amino piperidine derivatives of formula (Z) representative
Figure G200580038925420070516D000041
(wherein R1ZIt is hydrogen atom or C1-12 alkyl, R2ZAnd R3ZIt is each independently hydrogen atom or C1-12 alkyl, XZIt is nitrogen-atoms or oxygen atom, AZIt is
Figure G200580038925420070516D000042
(wherein R4ZBe hydrogen atom, C1-12 alkyl, C3-8 cycloalkyl, aryl, substitution aryl, aryl-C (=O)-or aryl-CH (OH)-, R5ZIt is hydrogen, C1-12 alkyl, C1-4 alkoxies, halogen atom or COR, R6ZIt is hydrogen, C1-12 alkyl or substituted C1-4 alkyl.On condition that the definition of each symbol is only the extracts of part) it is used as the inhibitor of chemokine receptors (with reference to WO02/079186 specification).
To describe the sulfoacid compound represented by formula (W)
(wherein XWIt is-O- ,-S- ,-CH2- or-NR6-, YWIt is C6-10 aryl or C2-9 heteroaryls, R1WIt is selected from：H-, HO-, halogen atom-, the C1-8 alkyl that is optionally replaced by 1-3 fluorine atom etc., R2WAnd R3WIt is selected from：H-, oxo, the C1-8 alkyl optionally replaced by 1-3 fluorine atom etc., R4WIt is selected from：H-, HO-, halogen atom-,-CN etc., R5WIt is C1-8 alkyl, aW is 0-5, and bW is 0-2, and cW is 0-2 and dW is 0-4.But the definition of each symbol is only the extracts of part), its pharmaceutically acceptable salt and prodrug be CCR1 selective antagonists (with reference to WO02/102787 specification).
In addition, 1- (4- pyridine radicals)-bridged piperazine derivatives are described as CCR5 antagonists (referring to US6,391,865 specification).
On the other hand, report thriazaspiro [5.5] undecane derivative, the effect of its quaternary ammonium salt or N- oxides or pharmaceutically acceptable salt regulation chemotactic factor (CF)/chemokine receptors (CCR), therefore, they are used to prevent and/or treat various inflammatory diseases, asthma, allergic dermatitis, nettle rash, anaphylactia (allergic bronchopulmonary aspergillosis or the thermophilic eosin gastroenteritis of anaphylaxis etc.), ephritis, nephrosis, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic damage and reperfusion is disorderly, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, the adjoint shock of bacterium infection, diabetes, autoimmunity disease, rejection in transplant organ, immunosupress, cancer metastasis and Immune Deficiency Syndrome (referring to WO01/040227 specification).
Describe the compound of formula (M) representative
Figure G200580038925420070516D000051
(wherein mM and nM are identical or different, individually 0 or 1 or 2 integer, Alk3MIt is the C1-6 alkylidene chains of chemical bond or straight or branched, R1MAnd R2MIt is identical or different, individually the C1-6 alkyl of hydrogen atom or straight or branched, DMIt is optionally substituted fragrant or miscellaneous aromatic rings, EMIt is optionally substituted C7-10 cycloalkyl, C7-10 cycloalkenyl groups or C7-10 multicyclic aliphatics group) it is CXCR3 conditioning agents (referring to WO03/070242 specification).
Detailed description of the invention
Compound with antagonizing CCR 5 activity is applied to prevent and/or treatment CCR5- relevant diseases.Thus, it is desirable to develop safe CCR5 antagonists.
In order to find to specifically bind chemokine receptors especially CCR5 and there is the compound of antagonistic activity to it, the present inventor has made intensive studies and finally found that the compound that formula (I) is represented can realize these purposes, this completes the present invention.
The present invention relates to
1. the compound that formula (I) is represented
Figure G200580038925420070516D000061
Wherein R1Represent (1)-N (R1A)SO2-R1B、(2)-SO2NR1CR1D、(3)-COOR1E、(4)-OR1F、(5)-S(O)mR1G、(6)-CONR1HR1J、(7)-NR1KCOR1LOr (8) cyano group, wherein m is 0,1 or 2；R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1LHydrogen atom is independently each represented, the alkyl can with substituent, or can have the 3- of substituent to 15- circle heterocycles bases, wherein R1CAnd R1DOr R1HAnd R1JThe nitrogen heterocycle can with substituent is formed together with the nitrogen-atoms that can be connected with them；
X and Y each independently represent chemical bond or comprising interval base of the 1-3 atom as main chain；
Ring A and ring B are identical or different, and the 3- of substituent can be had to 15- members carbocylic radical or heterocyclic radical by each representing；
Ring D is that can have the 3- of substituent to 15- member heterocyclic ring containing nitrogen bases；
R2It is (1) hydrogen atom; (2) there can be the alkyl of substituent; (3) cyano group; (4) can protected hydroxyl; (5) there can be the amino of substituent; (6) oxo group, (7) can have the 3- of substituent to 15- circle heterocycles base or (8)=N-OR6, wherein R6Hydrogen atom or C1-4 alkyl are represented,
Its salt, N- oxides or solvate or its prodrug；
2. according to above-mentioned 1 compound, wherein X and Y are independently each chemical bond or the divalent group containing one or both of following combination：(1)-CR7R8-、(2)-NR9-、(3)-CO-、(4)-O-、(5)-S-、(6)-SO-、(7)-SO2- and (8)-C (=N-OR10)-, wherein R7And R8Each independently represent hydrogen atom, C1-4 alkyl ,-OR11Or phenyl, R9Represent hydrogen atom, C1-4 alkyl or phenyls；R10And R11Each independently represent hydrogen atom or C1-4 alkyl；
3. according to above-mentioned 2 compound, wherein X is chemical bond ,-O- or-CH2-；
4. according to above-mentioned 2 compound, wherein Y is C1-2 alkylidenes；
5. according to above-mentioned 1 compound, its middle ring D is that can have the 5- of substituent to 10- member heterocyclic ring containing nitrogen bases；
6. according to above-mentioned 5 compound, its middle ring D is tropane, pyrrolidines, piperazine or the azepan can with substituent；
7. according to above-mentioned 6 compound, its middle ring D is the piperazine ring can with substituent；
8. according to above-mentioned 1 compound, its middle ring A and ring B, its is identical or different, is individually 5- the or 6- member aromatic rings can with substituent；
9. according to above-mentioned 1 compound, wherein R2It is
Figure G200580038925420070516D000071
Wherein arrow represents the connection site with ring D, R51、R52And R53It is each independent to represent (1) hydrogen atom, (2) there can be the alkyl of substituent, (3) there can be the 3- of substituent to 15- circle heterocycles bases, (4) there can be the C1-4 alkoxies of substituent, (5) can have the phenoxy group of substituent or (6) can the benzyloxy with substituent；
10. according to above-mentioned 1 compound, wherein R2It is
Wherein arrow represents the connection site with ring D, R51And R54Each independent (1) hydrogen atom, (2) of representing can have the alkyl of substituent, (3) there can be the 3- of substituent to 15- circle heterocycles bases, (4) there can be the C1-4 alkoxies of substituent, (5) can have the phenoxy group of substituent or (6) can the benzyloxy with substituent；
11. according to above-mentioned 1 compound, it is represented by formula (Ib)
The implication of wherein all symbols is identical with above-mentioned 1 or 9；
12. according to above-mentioned 9 compound, wherein by R51The alkyl with substituent that represents or can have substituent 3- be to 15- circle heterocycles bases can the aromatic ring yl with substituent；
13. according to above-mentioned 12 compound, wherein the aryl can with substituent is benzene, pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazoles, thiazole, isothiazole, furazan, oxadiazoles or Thiadiazole；
14. according to above-mentioned 12 compound, it is by formula (Ie), (If), (Ig) or (Ih) Suo Shi
Figure G200580038925420070516D000081
Wherein symbol
Figure G200580038925420070516D000082
Represent beta configuration, symbol
Figure G200580038925420070516D000083
Represent α-configuration, beta configuration or its mixture；R56It is the aromatic rings can with substituent；Other symbols have implication as above described in 1 or 9；
15. according to above-mentioned 11 compound, wherein by R51The shown alkyl with substituent is C1-15 alkyl；
16. according to above-mentioned 15 compound, it is selected from：
(1) 5- ({ [butyl (1- { 4- [4- (methyl sulphonyl) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzamides,
(2) 5- [({ butyl [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
(3) 5- ({ [butyl (1- { [6- (4- { [(2- methoxy ethyls) amino] carbonyl } phenoxy group) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzamides
(4) 5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzamides
(5) 5- { [(butyl { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } the chloro- 4- fluorobenzamides of -2-
(6) 2- (5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorophenyls) acetamide
(7) 5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluoro-N-methyl benzamides,
(8) 5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzamides, and
(9) 5- [({ butyl [1- (4- { 4- [(methylamino) sulfonyl] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides；
17. according to above-mentioned 12 compound, wherein by R51The aromatic rings of representative is list-carbocyclic ring or list-heterocycle with armaticity；
18. according to above-mentioned 17 compound, it is selected from：
(1) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) Methanesulfomide
(2) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(3) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(4) N- [4- ({ 5- [(4- { 3- thienyls [(3- thienyls amino) carbonyl] amino } -1- piperidyls) methyl] -2- pyridine radicals } epoxide) phenyl] Methanesulfomide,
(5) the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(6) N- { 4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls] phenyl } Methanesulfomide
(7) 4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls]-N- [2- (4- morpholinyls) ethyl] benzsulfamide
(8) N- (4- { [5- ({ 4- [{ (2,4- difluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(9) 2- chloro-n-methyls -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(10) N- (4- { [5- ({ 4- [({ [the chloro- 3- of 4- (4- morpholinyl carbonyls) phenyl] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(11) the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide
(12) N- (3- fluorophenyls)-N '-(6- methyl -3- pyridine radicals)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] urea,
(13) 2- [4- ({ 4- [[({ the fluoro- 3- of 4- [(methyl sulphonyl) amino] phenyl } amino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide
(14) the fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(15) the fluoro- N- methyl -5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide
(16) 2- [4- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide
(17) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(18) N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide
(19) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide, and
(20) N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N- phenylureas；
19. according to above-mentioned 11 compound, it is selected from：
(1) the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(2) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(3) N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide, and
(4) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide；
20. according to above-mentioned 11 compound, it is selected from：
(1) 5- [({ butyl [1- (4- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
(2) N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) Methanesulfomide
(3) N- (4- { [5- ({ 4- [{ [(4- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(4) N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide, and
(5) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) acetamide；
21. according to above-mentioned 1 compound, it is selected from：
(1) the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(2) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride
(3) N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride
(4) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride
(5) 5- [({ butyl [1- (4- { 2- methyl -4- [[(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2; 4- difluorobenzoyl amine hydrochlorates
(6) N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) methanesulfonamide hydrochloride
(7) N- (4- { [5- ({ 4- [{ [(4- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(8) N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,, and
(9) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) acetamide hydrochloride；
22. a kind of pharmaceutical composition, it contains compound, its salt, N- oxides, its solvate or its prodrug that with good grounds above-mentioned 1 formula (I) represents；
23. according to above-mentioned 22 pharmaceutical composition, it is chemokine receptor anagonists；
24. according to above-mentioned 23 pharmaceutical composition, it is CCR5 antagonists；
25. according to above-mentioned 24 pharmaceutical composition, it is the medicine for treating and/or preventing CCR5 relevant diseases；
26. according to above-mentioned 25 pharmaceutical composition, wherein CCR5 relevant diseases are infectious disease, immunological diseases, inflammatory disease, and/or angiocardiopathy；
27. according to above-mentioned 26 pharmaceutical composition, wherein CCR5 relevant diseases are rejection, multiple sclerosis, inflammatory bowel disease and/or the asthma in human immunodeficiency virus infection, acquired immunodeficiency syndrome, respiratory syncytial virus infection, organ transplant；
28. according to above-mentioned 26 pharmaceutical composition, wherein immunological diseases are the rejections in organ transplant；
29. according to above-mentioned 22 pharmaceutical composition, it is for preventing and/or treating infectious disease, immunological diseases, inflammatory disease and/or the medicine of angiocardiopathy；
30. a kind of medicine, compound, its salt, N- oxides, its solvate or its prodrug represented containing with good grounds above-mentioned 1 formula (I) simultaneously combines the medicines for having one or more to be selected from RTI, protease inhibitors, integrase inhibitor, CCR2 antagonists, CCR3 antagonists, CCR4 antagonists, CCR5 antagonists, CXCR3 antagonists, CXCR4 antagonists, fusion inhibitor, AntiHIV1 RT activity surface antigen antibody and HIV vaccine；
31. a kind of medicine, compound, its salt, N- oxides, its solvate or its prodrug represented containing with good grounds above-mentioned 1 formula (I) simultaneously combines the medicines for having one or more to be selected from immunodepressant, nonsteroidal anti-inflammatory agent, the modifying antirheumatic drug for alleviating disease, steroidal, the enzyme preparation of anti-inflammatory, Chondroprotective agents, T- cytostatics, TNF α inhibitor, prostaglandin synthase inhibitor, IL-1 inhibitor, IL-6 inhibitor, interferon gamma activator, prostanoid, phosphodiesterase inhibitors and metal protease inhibitors；
32. a kind of method prevented or treat CCR5- relevant diseases in mammal body, including give compound, its salt, N- oxides, its solvate or its prodrug for being represented according to above-mentioned 1 formula (I) of mammal effective dose；
33. compound, its salt, N- oxides, its solvate or its prodrug for being represented according to above-mentioned 1 formula (I) are preparing the application in being used to prevent and/or treat the medicine of CCR5- relevant diseases；
34. according to above-mentioned 22 pharmaceutical composition, it is cellular migration inhibition agent；And
35. a kind of method for preparing the compound, its salt, N- oxides, its solvate or its prodrug that are represented according to above-mentioned 1 formula (I).
By R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" alkyl " in " alkyl can with substituent " that represents is such as including (a) C1-15 alkyl such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, myristyl, pentadecyl；(b) C3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.；(c) C2-10 alkenyls such as vinyl, pi-allyl, 2- methacrylics, 2- cyclobutenyls, 3- cyclobutenyls, 3- octenyls etc.；(d) C2-10 alkynyls such as acetenyl, 2-propynyl, 3- hexin bases etc.；(e) C3-10 cycloalkenyl groups such as cyclopropanyl, cyclopentenyl, cyclohexenyl group etc.；(f) C6-14 aryl such as phenyl, naphthyl etc., (g) C7-16 aralkyl such as benzyl, phenylethyl etc.；(h) (C3-8 cycloalkyl)-(C1-4 alkyl) such as cyclohexyl methyl, cyclohexyl-ethyl, Cyclohexylpropyl, 1- methyl isophthalic acids-cyclohexyl methyl, cyclopropylethyl etc..
By R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" 3- to 15- circle heterocycles " in " can have the 3- of substituent to 15- circle heterocycles " for representing includes " 3- to 15- membered unsaturated heterocycles " or " 3- to 15- members saturated heterocyclic ".
" 3- to 15- membered unsaturated heterocycles " is for example including pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, azepine
Figure G200580038925420070516D000131
(azepine), diaza
Figure G200580038925420070516D000132
(diazepine), furans, pyrans, oxa-
Figure G200580038925420070516D000133
(oxepine), thiophene, thiapyran, thia
Figure G200580038925420070516D000134
(thiepine), oxazoles, isoxazoles, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazines, oxygen azepine
Figure G200580038925420070516D000135
(oxazepine), oxygen diaza
Figure G200580038925420070516D000136
Thiadiazoles, thiazine, thiadiazine, sulphur azepine
Figure G200580038925420070516D000137
Sulphur diaza
Figure G200580038925420070516D000138
Indoles, iso-indoles, indolizine, benzofuran, isobenzofuran, benzothiophene, isothiophene, dithia naphthalene, indazole, quinoline, isoquinolin, quinolizine, purine, phthalazines (phthalazine), pyridine of talking endlessly, benzodiazine (naphthyridine), quinoxaline, quinazoline, cinnolines, benzoxazole, benzothiazole, benzimidazole, chromene, benzo oxa-
Figure G200580038925420070516D000139
Benzo oxygen azepine
Figure G200580038925420070516D0001310
Benzo oxygen diaza
Figure G200580038925420070516D0001311
Benzo thia
Figure G200580038925420070516D0001312
Benzothiazepine
Figure G200580038925420070516D0001313
Benzimidazole thiophanate diazaBenzo-azaBenzodiazepine
Figure G200580038925420070516D000143
Benzofuraxan, diazosulfide, BTA, carbazole, B-carboline, acridine, azophenlyene, dibenzofurans, xanthene, dibenzothiophenes, phenthazine, phenoxazine, fen uh thiophene (phenoxathiin), thianthrene, phenanthridines, phenanthroline, perimidine (perimidine), pyrrolin, imidazoline, triazoline, four oxazolines, pyrazoline, dihydropyridine, tetrahydropyridine, dihydro pyrazine, tetrahydrochysene pyrazine, dihydro-pyrimidin, tetrahydropyrimidine, dihydrogen dazin, tetrahydro pyridazine, dihydro azepine
Figure G200580038925420070516D000144
Tetrahydrochysene azepine
Figure G200580038925420070516D000145
Dihydro diaza
Figure G200580038925420070516D000146
Tetrahydrochysene diaza
Figure G200580038925420070516D000147
Dihydrofuran, dihydropyran, dihydro oxa-
Figure G200580038925420070516D000148
Tetrahydrochysene oxa-
Figure G200580038925420070516D000149
Dihydro-thiophene, dihydro thiapyran, dihydro thia
Figure G200580038925420070516D0001410
Tetrahydrochysene thia
Figure G200580038925420070516D0001411
Er Qing Evil diazas
Figure G200580038925420070516D0001412
Si Qing Evil diazas
Figure G200580038925420070516D0001413
Dihydro thiophene diaza
Figure G200580038925420070516D0001414
Tetrahydrochysene thiophene diaza
Figure G200580038925420070516D0001415
Thiodiazoline, dihydro thiazine, dihydro thiadiazine, dihydro sulphur azepine
Figure G200580038925420070516D0001416
Tetrahydrochysene sulphur azepine
Figure G200580038925420070516D0001417
Dihydro sulphur diaza
Figure G200580038925420070516D0001418
Tetrahydrochysene sulphur diaza
Figure G200580038925420070516D0001419
Indoline, isoindoline, Dihydrobenzofuranes, dihydroisobenzofuran, dihydrobenzo thiophene, dihydro isothiophene, dihydro-indazol, EEDQ, tetrahydroquinoline, dihydro-isoquinoline, tetrahydroisoquinoline, dihydro phthalazines, tetrahydrochysene phthalazines, dihydro benzodiazine, tetrahydrochysene benzodiazine, dihydro-quinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydro quinazoline, dihydro cinnolines, tetrahydrochysene cinnolines, benzo thioxane, Er hydrogen benzoxazines, dihydrobenzo thiazine, pyrazine and morpholine, Er hydrogen benzoxazoles, dihydro-benzothiazole, dihydrobenzo imidazoles, dihydrobenzo azepine
Figure G200580038925420070516D0001420
Tetrahydro benzo azepine
Figure G200580038925420070516D0001421
Dihydrobenzo diaza
Figure G200580038925420070516D0001422
Tetrahydro benzo diaza
Figure G200580038925420070516D0001423
Henzodiozepanne, dihydrobenzo oxygen azepine
Figure G200580038925420070516D0001424
Tetrahydro benzo oxygen azepine
Figure G200580038925420070516D0001425
Dihydro carbazole, tetrahydro carbazole, acridan, tetrahydro acridine, dihydro-dibenzo furans, dihydro-dibenzo thiophene, tetrahydrochysene dibenzofurans, tetrahydrochysene dibenzothiophenes, dioxa indane, benzodioxan, chroman, benzo dithiolane, and benzo dithiane ring etc..
" 3- to 15- members saturated heterocyclic " is for example including aziridine, azetidine, azocane, pyrrolidines, imidazoles alkene, triazolidine, four oxazolidines, pyrazolidine, piperidines, piperazine, perhydro pyrimidine, perhydro pyridazine, azepan (perhydroazepinyl
Figure G200580038925420070516D0001426
), perhydro diaza
Figure G200580038925420070516D0001427
Oxirane, azetidine, tetrahydrofuran, oxinane, perhydro oxa-
Figure G200580038925420070516D0001428
Our the third ring, thietane, thiophane, tetrahydrochysene thio-pyrylium, perhydro thia of sulphur
Figure G200580038925420070516D0001429
Si Qing oxazole (oxazolidines), tetrahydrochysene isoxazole (isoxazole alkyls), tetrahydro-thiazoles (thiazolidine), tetrahydrochysene isothiazole (isothiazolidine), tetrahydrochysene furazan, Si Qing oxadiazole (oxadiazoles alkane), Si Qing oxazines, Si Qing oxadiazines, full Qing oxazines, full Qing oxadiazines, thiodiazolidine (thiadiazolidine), tetrahydrochysene thiazine, tetrahydrochysene thiadiazine, perhydro sulphur azepine
Figure G200580038925420070516D0001430
Perhydro sulphur diaza
Figure G200580038925420070516D0001431
Morpholine, thiomorpholine, thioxane, perhydro benzofuran, perhydro isobenzofuran, perhydro benzothiophene, the different hydrogen benzothiophene of perhydro, perhydro indazole, perhydro quinoline, perhydro isoquinolin, perhydro phthalazines, perhydro naphthyridines, perhydro quinoxaline, perhydro quinazoline, perhydro cinnolines, perhydro benzoxazole, perhydro benzothiazole, perhydro benzimidazole, perhydro carbazole, perhydro acridine, perhydro dibenzofurans, perhydro dibenzothiophenes, dioxolanes, dioxane, dithiolane, dithiane,Deng.
" by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1LSubstituent in the alkyl with substituent represented " or " can the 3- with substituent to 15- circle heterocycles base " is for example including (1) nitro,(2) hydroxyl,(3) oxo,(4) thio (thioxo),(5) cyano group,(6) carbamyl,(7) it is selected from (a) hydroxyl,(b) amino,(c) C1-4 alkoxies,(d) by C1-8 alkyl list-or the amino of di-substituted etc.,(e) carboxyl,(f) group of C1-6 alkoxy-carbonyls etc. one or dibasic C1-8 alkyl substitution amino carbonyl (such as,N- methylaminocarbonyls,N- ethyl aminocarbonyls,N- propylaminocarbonyls,N- butylamino carbonyls,N- Cyclohexylmethylamino carbonyls,N,N- Dimethylaminocarbonyls,N- butyl-N- Cyclohexylmethylamino carbonyls,N- cyclohexylaminocarbonyls,Phenyl amino carbonyl,N- (2- methoxy ethyls) amino carbonyl,N- (2- ethoxys) amino carbonyl,N- (2- amino-ethyls) amino carbonyl,N-[2-(N′,N '-dimethylamino) ethyl] amino carbonyl,N- (2- carboxyethyls) amino carbonyl,N- (2- dion es) amino carbonyl etc.),(8) carboxyl,(9) C1-6 alkoxy-carbonyls such as methoxycarbonyl,Ethoxy carbonyl,Propoxycarbonyl,Isopropoxy carbonyl,Butoxy carbonyl,Isobutoxy carbonyl,T-butoxy carbonyl etc.,(10) sulphur (sulfo),(11) halogen atom such as fluorine,Chlorine,Bromine or iodine,(12) C1-6 alkoxies (such as methoxyl group that can be replaced by halogen atom,Ethyoxyl,Propoxyl group,Isopropoxy,Butoxy,Isobutoxy,Sec- butoxy,T-butoxy,Difluoro-methoxy or trifluoro ethoxy),(13) phenoxy group,(14) halogenated phenoxy is such as o-,It is m-,P- chlorophenoxy is o-,It is m-,P- bromobenzene epoxide etc.,(15) C1-6 alkyl sulfides such as methyl sulphur,Ethyl sulphur,Propylthio,Isopropyl sulphur,Butyl sulphur,Tert-butyl sulphur etc.,(16) phenyl sulphur,(17) C1-6 alkyl sulphinyls such as methylsulfinyl,Ethylsulfinyl,Propylsulfenyl,Butylsulfinyl etc.,(18) C1-6 alkyl sulphonyls such as methyl sulphonyl or ethylsulfonyl,Sulfonyl propyl base,Butyl sulfonyl etc.,(19) amino,(20) the rudimentary acylamino-s of C1-6 such as acetyl-amino or propionamido etc.,(21) by alkyl list-or dibasic amino, (implication of " alkyl " is identical with " alkyl " above and can be by oxo,By optional substituent (such as,Alkyl) substitution amino,Carbamoyl,Halogen atom or hydroxyl etc. replace) (such as,Methylamino,Ethylamino,Propylcarbamic,Isopropylamino,Butylamino,Dimethylamino,Diethylamino,Cyclohexylamino,1- carbamoyl -2- Cyclohexylethylaminos,N- butyl-N- Cyclohexylmethylaminos or phenyl amino etc.),(22) C1-8 alkanoyls such as formoxyl or acetyl group,Propiono,Bytyry,Isobutyryl,Cyclohexyl-carbonyl etc.,(23) C6-10 aryl-C1-4 lower acyls such as benzoyl,Benzyloxycarbonyl group,(24) 3- is to 15- circle heterocycles bases,It includes 1-4 selected from the oxygen in addition to carbon,The hetero atom of sulphur or nitrogen,And optionally there are 1-4 to be selected from following substituent：(a) halogen atom such as bromine, chlorine or fluorine, (b) optionally by the substituted hydrocarbon such as oxo or hydroxyl, (implication for being somebody's turn to do " alkyl " is identical with " alkyl " above) such as methyl, ethyl, propyl group, isopropyl, benzyl, cyclohexyl, cyclohexyl methyl or cyclohexyl-ethyl etc., (c) halogenated phenoxy is such as o-, it is m-, p- chlorophenoxy is o-, it is m-, p- bromobenzene epoxide etc., and (d) oxo etc., such as thienyl, furyl, pyrazolyl, THP trtrahydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals, pyrimidine, pyridazinyl, quinolyl, isoquinolyl, '-aziridino, azelidinyl, pyrrolidinyl, pyrrolinyl, pyrrole radicals, imidazolidinyl, piperidyl, morpholinyl, dihydropyridine base, N methyl piperazine base, NEP base etc., (25) C1-10 alkylhalide groups such as difluoromethyl, trifluoromethyl, trifluoroethyl, chloromethyl, dichloromethyl or trichloroethyl etc., (26) oximino, (27) alkoxyimino such as methoxy imido or ethoxy imido etc., (28) alkyl sulfonyl-amino such as Methylsulfonylamino, ethylsulphsulphonylamino or benzylsulphonyl amino etc., or (29) arlysulfonylamino such as phenyl sulfonyl amino or p-toluenesulfonyl amino etc., (30) ring type amidogen carbonyl such as 1- '-aziridinos carbonyl, 1- azelidinyl carbonyls, 1- pyrrolidinylcarbonyls, 1- piperidino carbonyls, N methyl piperazine carbonyl, morpholine carbonyl etc., (31) are by 1 or 2 C1-8 alkyl replaced selected from following substituent：(a) hydroxyl, (b) amino, (c) C1-4 alkoxies, (d) are by C1-8 alkyl list-or dibasic amino, and (e) quilt can have substituent, and (substituent is selected from：(a) hydroxyl,(b) amino,(c) C1-4 alkoxies,(d) by the substituted list-or disubstituted amido such as C1-8 alkyl,(e) carboxyl,(f) C1-6 alkoxy-carbonyls,And can have 1 or 2 substitutions) the substituted amino carbonyl such as C1-8 alkyl,Such as methylol,Ethoxy,Amino methyl,Methoxy,N,N- dimethylaminomethyls,Carbamo, lmethyl,N- methylaminocarbonylmethyls,N,N- dimethylaminocarbonylmethyls etc.,(32) (C1-4 alkoxies)-(C1-4 alkyl) base such as methoxy ethyl etc.,(33) C1-8 alkanoyls epoxide such as formoxyl epoxide,Acetyl group epoxide,Propionyloxy,Butyryl acyloxy,Isobutyl acyloxy or cyclohexyl-carbonyl epoxide etc.,Or benzoyl epoxide,(34) amidino groups,(35) imino group,(36) C1-8 alkyl amidos such as formamide,Acetamide,Trifluoroacetamide,Propionamide,Butyramide,Isobutyramide,Cyclohexylcarbonylamino etc.,(37) benzamido,(38) carbamoylamino,(39) N-C1-4 alkyl-carbamoyls amino such as N- methylcarbamoyls amino,N- ethylaminocarbonyl amino,N- propylcarbamoylaminos,N- isopropylcarbamoyl amino,N- Butylcarbamoyl amino etc.,(40)N,- C1-4 alkyl-carbamoyls amino such as the N of N- bis-,N- formyl-dimethylamino amino,N,N- diethylamino Formylaminos,N,N- dipropylamino Formylaminos,N,N- dibutylamino Formylaminos etc.,(41) C1-3 alkylenedioxy groups such as methylenedioxy or ethylene epoxide etc.,(42)-B(OH)2, (43) epoxy radicals, (44) sulfydryl, (45) sulfinyl, (46) phosphono, (47) sulfamoyl, (48) C1-6 monoalkyls sulfamoyl such as N- Methylsulfamoyls, N- ethylsulfamovls,-propylsulfamov, N- isopropylsulfamoyls base or N- Butylsulfamoyl bases etc., (49) two-C1-4 alkylsulfamoyl groups such as N, N- DimethylsuIfamoyls, N, N- diethyl amino sulfonyls, N, N- dipropyl sulfamoyl or N, N- dibutylamine sulfonyls etc., (50) phenylsufinyl, (51) phenyl sulfonyl, (52) azido, or (implication for being somebody's turn to do " alkyl " is identical with " alkyl " above for (53) alkyl, such as methyl, ethyl, propyl group, isopropyl, vinyl, acetenyl, cyclohexenyl group, phenyl, naphthyl, benzyl, cyclohexyl, cyclohexyl methyl, cyclohexyl-ethyl etc.).The alkyl of substituent " can have " or " can have the 3- of substituent to 15- circle heterocycles base " can have the 1-10 substituents selected from (1)-(53) above.When substituent is two or more, each substituent can be with identical or different.
By by R1CAnd R1DOr R1HAnd R1J" nitrogen heterocycle " in " nitrogen heterocycle can with substituent " that is formed together with the nitrogen-atoms that they are connected is for example including aziridine, azetidine, pyrrolin, pyrrolidines, imidazoline, imidazoles alkene, dihydropyridine, tetrahydropyridine, piperidines, dihydro pyrazine, tetrahydrochysene pyrazine, piperazine, perhydro pyrimidine, perhydro pyridazine, tetrahydrochysene azepinePerhydroazepinyl
Figure G200580038925420070516D000172
Tetrahydrochysene phenodiazine
Figure G200580038925420070516D000173
Perhydro phenodiazine
Figure G200580038925420070516D000174
Si Qing oxazole (oxazolidines), tetrahydro-thiazoles (thiazolidine), Si Qing oxazines, full Qing oxazines, tetrahydrochysene thiazine, perhydro thiazine, morpholine, thiomorpholine ring etc..
By by R1CAnd R1DOr R1HAnd R1J" substituent " in the nitrogen heterocycle of substituent " can have " that is formed together with the nitrogen-atoms that they are connected or by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " identical implication in representative " alkyl can with substituent " or " can have the 3- of substituent to 5- circle heterocycles base ".
The interval base formed by 1-3 continuous backbone atoms is meant by X and Y " comprising interval bases of the 1-3 atom as main chain " represented.Now, it should cause that the atom number of main chain is minimum when calculating " being used as the atomicity of main chain "." having interval base of the 1-3 atom as main chain " containing 1-3 for example including being selected from following divalent group：-CR7R8-、-NR9-、-CO-、-O-、-S-、-SO-、-SO2- and-C (=N-OR10)-(wherein R7And R8It is each independently hydrogen atom, C1-4 alkyl ,-OR11Or phenyl, R9It is hydrogen atom, C1-4 alkyl or phenyls, R10And R11It is each independently hydrogen atom, C1-4 alkyl).Now by R7-R10" the C1-4 alkyl " represented is such as including methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl.Specifically, " there is interval base of the 1-3 atom as main chain " for example including-CR7R8-、-NR9- ,-CO- ,-O- ,-S- ,-C (=N-OR10)-、-NR9CO-、-CONR9-、-NR9COCR7R8- or-CONR9CR7R8- (wherein R7-R10With implication as described above).
It is methylene or ethylidene by Y " the C1-2 alkylidenes " represented.
" 3- to 15- members carbocylic radical " in " can have the 3- of substituent to 15- members carbocylic radical or heterocyclic radical " for being represented by ring A and ring B is such as including " 3- to 15- members cyclic hydrocarbon "." cyclic hydrocarbon " in " 3- to 15- members cyclic hydrocarbon " is for example including " unsaturated cyclic hydrocarbon " or " saturated cyclic hydrocarbons "." saturated cyclic hydrocarbons " are for example including cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, ring tridecyl, ring myristyl or cyclopentadecane base etc., perhydro pentalene, perhydro Azulene, perhydro indenes, Perhydronaphthalene, perhydro heptalene, spiral shell [4.4] octane, spiral shell [4.5] decane, spiral shell [5.5] hendecane, two rings [2.2.1] heptane, two rings [3.1.1] heptane, two rings [2.2.2] octane, adamantane, new adamantane etc.." unsaturated cyclic hydrocarbon " is such as including cycloalkenyl group such as cyclopentene, cyclohexene, cycloheptene, cyclo-octene, cyclopentadiene, cyclohexadiene, cycloheptadiene or cyclo-octadiene, phenyl, cyclopentadiene (pentalene), Azulene, indenes, indane, naphthalene, dihydronaphthalene, naphthane, heptalene, xenyl, as-indacene；S-indacene, acenaphthene, acenaphthylene, fluorenes, phenalene, phenanthrene, anthracene, two rings [2.2.1] hept-2-ene", two rings [3.1.1] hept-2-ene", two rings [2.2.2] oct-2-ene etc..
The implication of " 3- to 15- circle heterocycles base " in " can have the 3- of substituent to 15- members carbocylic radical or heterocyclic radical " for being represented by ring A and ring B with it is above-mentioned by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" 3- to 15- circle heterocycles base " in " can have the 3- of substituent to 15- circle heterocycles base " for representing is identical.
The implication of " substituent " in " can have the 3- of substituent to 15- members carbocylic radical " for being represented by ring A and ring B with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in the alkyl of substituent " can have " that represents or " can have the 3- of substituent to 15- circle heterocycles base " is identical.1-10 substituent may be present in any possible place.When the number of substituent is two or more, each substituent can be with identical or different.
" 5- or 6- members aromatic ring yl " in " 5- the or 6- members aromatic ring yl can with substituent " that is represented by ring A and ring B is for example including benzene, pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans, thiophene oxazole isoxazoles, thiazole, isothiazole, furazan, oxadiazoles or Thiadiazole etc..
By the implication of " substituent " in " 5- the or 6- members aromatic ring yl can with substituent " of ring A and ring B representatives and by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in the alkyl of substituent " can have " that represents or " can have the 3- of substituent to 15- circle heterocycles base " is identical.1-10 substituent may be present in any possible place.When the number of substituent is two or more, each substituent can be with identical or different.
" nitrogen heterocyclic ring " in " can have the 3- of substituent to 15- member heterocyclic ring containing nitrogens base " for being represented by ring D refers to outside carbon atom, at least containing a nitrogen-atoms, can be also containing the 1-3 hetero atoms for being selected from nitrogen, oxygen and sulphur atom." 3- to 15- member heterocyclic ring containing nitrogens " includes " the nitrogenous saturated heterocyclic of 3- to 15- members " and " the nitrogenous unsaturated heterocycle of 3- to 15- members ".
" the nitrogenous unsaturated heterocycle of 3- to 15- members " is for example including pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, indoles, iso-indoles, indazole, purine, benzimidazole, benzo-aza
Figure G200580038925420070516D000191
Benzene phenodiazine
Figure G200580038925420070516D000192
Benzotriazole, carbazole, B-carboline, benzothiazine, phenoxazine, pool pyridine, pyrrolin, imidazoline, triazoline, four oxazolines, dihydropyazolo, dihydropyridine, tetrahydropyridine, dihydro pyrazine, tetrahydrochysene pyrazine, dihydro-pyrimidin, tetrahydropyrimidine, dihydrogen dazin, tetrahydro pyridazine, dihydro azepine
Figure G200580038925420070516D000193
Tetrahydrochysene azepine
Figure G200580038925420070516D000194
Dihydro phenodiazineTetrahydrochysene phenodiazine
Figure G200580038925420070516D000196
Er Yang oxazoles, two Yang isoxazoles, thiazoline, dihydro isothiazole, dihydro furazan, Er Qing oxadiazoles, Er Qing oxazines, Er Qing oxadiazines, Er Qing oxazines, Si Qing oxazines, Er Qing oxadiazines, Si Qing oxadiazines, thiodiazoline, dihydro thiazine, dihydro thiadiazine, dihydro sulphur azepine
Figure G200580038925420070516D000197
Dihydro sulphur diazaTetrahydrochysene sulphur diaza
Figure G200580038925420070516D000199
Indoline, isoindoline, dihydro-indazol, EEDQ, tetrahydroquinoline, dihydro-isoquinoline, tetrahydroisoquinoline, dihydro phthalazines, tetrahydrochysene phthalazines, dihydronaphthridine, Tetrahydronaphthyridderivates, dihydro-quinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydro quinazoline, dihydro cinnolines, tetrahydrochysene cinnolines, Er hydrogen benzoxazine, dihydrobenzo thiazine, pyrazine and morpholine, Er hydrogen benzoxazole, dihydro-benzothiazole, dihydrobenzo imidazoles, dihydrobenzo azepine
Figure G200580038925420070516D0001910
Tetrahydro benzo azepine
Figure G200580038925420070516D0001911
Dihydrobenzo phenodiazine
Figure G200580038925420070516D0001912
Tetrahydro benzo phenodiazineEr hydrogen benzoxazine, tetrahydro benzo phenodiazine
Figure G200580038925420070516D0001914
Dihydro carbazole, tetrahydro carbazole, acridan, tetrahydro acridine.The nitrogenous saturated heterocyclyl of 3- to 15- members, such as including aziridine, azetidine, azocane, pyrrolidines, imidazolidine, triazolidine, four oxazolidines, pyrazolidine, piperidines, piperazine, perhydro pyrimidine, perhydro pyridazine, perhydroazepinyl
Figure G200580038925420070516D0001915
Perhydro phenodiazine
Figure G200580038925420070516D0001916
Si Qing oxazole (oxazolidines), tetrahydrochysene isoxazole (isoxazole alkyls), tetrahydro-thiazoles (thiazolidine), tetrahydrochysene isothiazole (isothiazolidine), tetrahydrochysene furazan, Si Qing oxadiazole (oxadiazoles alkane), Si Qing oxazines, Si Qing oxadiazines, full Qing oxazines, full Qing oxadiazines, thiodiazolidine (thiadiazoles), tetrahydrochysene thiazine, tetrahydrochysene thiadiazine, tetrahydrochysene sulphur azepinePerhydro sulphur azepine
Figure G200580038925420070516D0001918
Perhydro sulphur diaza
Figure G200580038925420070516D0001919
Morpholine, thiomorpholine, perhydro indazole, perhydro quinoline, perhydro isoquinolin, perhydro phthalazines, perhydro naphthyridines, perhydro quinoxaline, perhydro quinazoline, perhydro cinnolines, perhydro benzoxazole, perhydro benzothiazole, perhydro benzimidazole, perhydro carbazole, perhydro acridine,Deng.
The implication of " substituent " in " can have the 3- of substituent to 15- member heterocyclic ring containing nitrogens base " for being represented by ring D can with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in the alkyl of substituent " can have " that represents or " can have the 3- of substituent to 15- circle heterocycles base " is identical or different.Substituent can have 1-10 in the position that may replace.When substituent number is two or more, each substituent can be with identical or different.
" 5- to 10- member heterocyclic ring containing nitrogens base " in " can have the 5- of substituent to 10- member heterocyclic ring containing nitrogens base " for being represented by ring D can enumerate 5- in above-mentioned " 3- to 15- member heterocyclic ring containing nitrogens base " represented by ring D to 10- member heterocyclic ring containing nitrogen bases.For example including pyrrolidines, piperidines, piperazine, perhydroazepinyl
Figure G200580038925420070516D000201
Or tropane etc..
The implication of " substituent " in " can have the 5- of substituent to 10- member heterocyclic ring containing nitrogens base " for being represented by ring D can with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in the alkyl of substituent " can have " that represents or " can have the 3- of substituent to 15- circle heterocycles base " is identical or different.Substituent can have 1-10 in the position that may replace.When substituent number is two or more, each substituent can be with identical or different.
By R2" can protected hydroxyl " represented is can be by " protection group " protection " hydroxyl "." protection group " of hydroxyl for example including (1) C1-6 alkyl (such as; methyl, ethyl, propyl group, isopropyl, butyl, tert-butyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C6-10 aryl such as phenyl or naphthyl etc.；(c) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (d) nitro etc., (2) C6-10 aryl (e.g., phenyl or naphthyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., (3) C7-12 aralkyl (e.g., benzyl, phenylethyl or menaphthyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc.; (4) formoxyl; (5) C1-6 alkyl-carbonyl (e.g., acetyl group or propiono etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., (6) C6-10 aryl-Epoxide carbonyl (e.g., phenyloxycarbonyl or naphthyl Epoxide carbonyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., (7) C6-10 aryl-carbonyl (e.g., benzoyl or naphthyl carbonyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., (8) C7-12 aralkyl-carbonyl (e.g., benzyloxycarbonyl group or phenylethylcarbonyl etc.), it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or propyl group etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., (9) pyrans or furans, it can have 1-4 and be selected from following substituent (a) halogen atom such as chlorine, bromine or fluorine etc.；(b) C1-6 alkyl such as methyl, ethyl or n-propyl etc.；(c) C6-10 aryl such as phenyl or naphthyl etc.；(d) C7-12 aralkyl such as benzyl or phenylethyl etc.；And (e) nitro etc., or (10) three-C1-4 aIkylsilyl groups such as trimethyl silyls or triethylsilyl etc..
By R2" substituent " in " amino can with substituent " that represents includes the alkyl ,-SO can with substituent2R201Or=NR202(wherein R201And R202It is the alkyl can with substituent).The implication of the alkyl of substituent " can have " with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" alkyl can with substituent " represented is identical.The substituent of amino can have 1-2 in the position that may replace.When substituent number is two or more, each substituent can be with identical or different.In addition, by R2The amino of substituent " can have " represented be
Figure G200580038925420070516D000211
(wherein arrow represents the position being connected with ring D, and R51、R52、R53And R54Each is independently hydrogen atom, can have substituent alkyl, can have substituent 3- to 15- circle heterocycles base, can have substituent C1-4 alkoxies, can have substituent phenoxy group or can with substituent benzyloxy.The implication of the alkyl of substituent " can have " and " can have the 3- of substituent to 15- circle heterocycles " and respectively by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1LThe alkyl of substituent " can have " that represents and " can the 3- with substituent to 15- circle heterocycles " be identical." C1-4 alkoxies " in " the C1-4 alkoxies can with substituent " is such as including methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec- butoxy or t-butoxy." substituent " in " the C1-4 alkoxies can with substituent ", " phenoxy group can with substituent " and " benzyloxy can with substituent " is for example including by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in " alkyl can with substituent " that represents etc..
By R2The implication of the alkyl of substituent " can have " that represents with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" alkyl can with substituent " represented is identical.Substituent can have 1-10 in the position that may replace.When substituent number is two or more, each substituent can be with identical or different.By R2The alkyl of substituent " can have " represented be
Figure G200580038925420070516D000221
(wherein arrow represents the position being connected with ring D, and R52And R53It is as defined above)
By R2The implication of " can have the 3- of substituent to 15- circle heterocycles base " for representing with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" can have the 3- of substituent to 15- circle heterocycles base " represented is identical.
By R6" the C1-4 alkyl " represented is such as including methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl.
By R51The implication of the alkyl of substituent " can have " that represents with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" alkyl can with substituent " represented is identical.
By R51Represent " C1-15 alkyl " implication with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" C1-15 alkyl " in " alkyl can with substituent " that represents is identical.
By R51" aromatic ring yl " in " aromatic ring yl can with substituent " that represents refers to by R51Single-, two- or three ring carbon rings or the heterocyclic radical with armaticity in " 3- to 15- circle heterocycles base " in " alkyl " in the alkyl of substituent " can have " that represents and " can the 3- with substituent to 15- circle heterocycles base ".Single-, two- or three ring carbon rings with armaticity are such as including benzene, azulenes, naphthalene, phenanthrene, anthracene nucleus.List with armaticity-, two-or tricyclic heterocyclic base for example including pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazoles, indoles, iso-indoles, benzofuran, isobenzofuran, benzothiophene, isothiophene, indazole, quinoline, isoquinolin, purine, phthalazines, pteridine, naphthyridines, quinoxaline, quinazoline, cinnolines, benzoxazole, benzothiazole, benzimidazole, benzofuraxan, diazosulfide, BTA, carbazole, B-carboline, acridine, azophenlyene, dibenzofurans, dibenzothiophenes, phenanthridines, phenanthroline, perimidinyl ring etc..
By R51The implication of " substituent " in the aromatic ring yl of substituent " can have " that represents with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in the alkyl of substituent " can have " that represents or " can have the 3- of substituent to 15- circle heterocycles base " is identical.Substituent can have 1-10 in the position that may replace.When substituent number is two or more, each substituent can be with identical or different.
By R51" list-carbocyclic ring or single heterocyclic radical with armaticity " represented refers to above-mentioned by R51Represent " aromatic ring yl " it is monocyclic.Such as including benzene, pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazoles, thiazole, isothiazole, furazan, oxadiazoles or Thiadiazole.
By R56The implication of the aromatic ring yl of substituent " can have " that represents with it is above-mentioned by R51" aromatic ring yl can with substituent " represented is identical.
Unless otherwise indicated, the present invention includes all isomers.Such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylidene, alkenylene, alkynylene include straight or branched.In addition, come from double bond, ring and fused rings all isomers (E-, Z-, it is cis-and trans-forms), come from the isomers (R-, S-, α-and beta configuration, enantiomer and diastereomer) that there is asymmetric carbon etc., the optically active substance (D-, L-, d- and l- form) for revolving with light property, the polar compound (more highly polar compound and compared with low pole compound) of chromatographic isolation, equilibrium compound, revolution isomers, be included in the present invention with the mixture and racemic modification of arbitrary proportion.
According to the present invention, symbol
Figure G200580038925420070516D000231
Represent beta configuration and symbol
Figure G200580038925420070516D000232
Represent α-configuration, beta configuration or its mixture.The ratio for α-configuration and beta configuration is not particularly limited in the mixture.
Salt：
The salt of formula (I) compound includes atoxic or pharmaceutically acceptable all salt.On pharmaceutically acceptable salt, preferably hypotoxicity and solvable salt in water.The salt of appropriate formula (I) compound be, for example, and alkali metal (such as potassium, sodium and lithium) formed salt, with the salt of alkaline-earth metal (such as calcium and magnesium) formation, ammonium salt (such as tetramethyl ammonium and 4-butyl ammonium), with organic amine (such as triethylamine, methylamine, dimethylamine, cyclopentamine, benzylamine, phenyl ethylamine, piperidines, MEA, diethanol amine, trihydroxymethylaminomethane, lysine, arginine and N- methyl-D-glucarnines) [such as inorganic acid salt is (such as the salt that is formed and acid-addition salts, hydrochloride, hydrobromate, sulfate, phosphate and nitrate) and acylate is (such as, acetate, trifluoroacetate, lactate, tartrate, oxalates, fumarate, maleate, benzoate, citrate, mesylate, esilate, benzene methanesulfonic acid salt, different thiosulfate, glucuronate salt and gluconate) etc.].The salt of the compounds of this invention also includes solvate and the solvate with above-mentioned alkali (soil) metal salt, ammonium salt, organic amine salt and acid-addition salts.Preferred solvent compound is low toxicity and water-soluble.Appropriate solvate is, for example, the solvate with water and with alcohol solvent (such as ethanol).The compounds of this invention is converted into by hypotoxicity salt or pharmaceutically acceptable salt by known method.
In addition, salt includes quaternary ammonium salt.The quaternary ammonium salt for the compound that formula (I) is represented is the nitrogen of the wherein compound that formula (I) is represented by R0(R0The C1-8 alkyl for being C1-8 alkyl or being substituted by phenyl) quaternized compound.
The salt also includes N- oxides.The compounds of this invention can be converted into N- oxides by known method.The N- oxides are the oxidized compounds of nitrogen of the wherein compound that formula (I) is represented.
Prodrug：
The prodrug of formula (I) compound mean in vivo by with the reaction such as enzyme, hydrochloric acid in gastric juice and be converted into the compound of formula (I) compound.For example; prodrug on formula (I) compound; when formula (I) compound has amino; in compound amino be for example acylated, be alkylated or phosphorylation (such as; wherein the amino of formula (I) compound is acylated (eicosanoylated), alanyl (alanylated), pentyl amino carbonylation by eicosane; (5- methyl -2- oxo -1,3- dioxo amylene (dioxolen) -4- bases) methoxycarbonyl, tetrahydrofuran, pyrrol ylmethyl, oxy acid methyl neopentyl, acetoxymethylated, tert-butylation etc.)；When the compound of formula (1) has hydroxyl; compound hydroxyl therein is for example acylated, is alkylated, phosphorylation or boration (e.g., the hydroxyl of formula (1) compound is carbonylated by acetylating, palmitoylation, propionating, pivaloyl, succinylation, fumarylated, alanyl or dimethylaminomethyl)；When formula (1) compound has carboxyl, the carboxyl be for example esterified or amidatioon (such as, the carboxyl of formula (1) compound is prepared into ethyl ester, phenylester, phenylethylester, carboxymethyl ester, dimethylaminomethyl ester, oxy acid methyl neopentyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5- methyl -2- oxo -1,3- dioxo amylene -4- bases) methyl ester, cyclohexyloxy carbonyl ethyl ester or methyl nitrosourea).These compounds can be prepared with method known per se.The prodrug of formula (1) compound can be hydrate or non-hydrate.The prodrug of formula (1) compound is alternatively the compound for converting an accepted way of doing sth (1) compound in physiological conditions, for example exist " Iyakuhin nokaihatsu; Vol.7 (Bunshi-sekkei); described in pp.163-198 (Hirokawa-Shoten), 1990 ".And formula (1) compound can be also marked (such as with radio isotope3H、14C、35S、125I etc.).
It is preferred that by R in formula (I) of the present invention1, X, Y, ring A, ring B, ring D and R2Representative is defined.Being listed in all symbols in following each preferred group has implication as described above.
It is preferred that R1E.g.-N (R1A)SO2-R1B,-SO2NR1CR1D,-S (O)mR1G,-CONR1HR1J,-NR1KCOR1LDeng, and more preferably such as-N (R1A)SO2-R1B,-SO2NR1CR1D,-S (O)mR1G,-CONR1HR1JDeng.It is preferred that R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1LIt is preferred that being, for example, hydrogen atom or can have alkyl of substituent etc..Preferred R1E.g.-NHSO2CH3,-NHSO2CH2CH3,-SO2NHCH3,-SO2CH3,-CONHCH2CH2OCH3Deng.
It is preferred that X be, for example, chemical bond ,-CR7R8,-NR9,-CO- ,-O- ,-S- ,-SO- ,-SO2- or-C (=N-OR10)-etc..Preferred X is chemical bond ,-O- or-CH2- etc..
It is preferred that Y be, for example, methylene, ethylidene or propylidene etc..It is highly preferred that Y is methylene, ethylidene.Most preferably, Y is methylene.
Preferably, ring A or ring B are, for example, 5- to 10- members carbocylic radical or heterocyclic radical (it refers to 5-s of the above-mentioned 3- into 15- members carbocyclic ring or heterocyclic radical to 10- members carbocylic radical or heterocyclic radical) etc..It is highly preferred that e.g. 5- to the 10- undersaturated carbocylic radicals of member or heterocyclic radical (its refer to above-mentioned 3- to the 5- of 15- members carbocyclic ring or heterocyclic radical to 10- the undersaturated carbocylic radical of member or heterocyclic radical) etc..It is highly preferred that e.g. 5- is to 6- aromatic rings such as benzene, pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans, thiophene , oxazole , isoxazoles, thiazole, isothiazole, furazan, oxadiazoles or Thiadiazole etc..Most preferably, e.g. benzene or pyridine ring etc..Preferably, ring A or ring B substituent are preferably, for example, alkyl, alkoxy, halogen atom, carboxyl, alkyl amide etc., most preferably e.g. alkyl, alkoxy, halogen atom etc. and most preferably such as chlorine atom, methyl or methoxy.
Preferably, ring D is, for example, 5- to 10- member heterocyclic ring containing nitrogens base (it refers to 5-s of the above-mentioned 3- into 15- member heterocyclic ring containing nitrogen bases to 10- member heterocyclic ring containing nitrogens base) etc., and is more preferably, for example, tropane, pyrrolidines, piperidines, perhydroazepinylOr piperazine ring etc., most preferably e.g. piperazine ring.Preferably, ring D does not have substituent or replaced by alkyl, single-C1-4 alkyl aminos or two-C1-4 alkyl aminos etc..It is highly preferred that ring D does not have substituent.
It is preferred that R2Can e.g. have the alkyl of substituent or there can be amino of substituent etc..It is preferred that " substituent " be can have substituent alkyl.Specifically, preferred R2For example it is independently
Figure G200580038925420070516D000252
(wherein arrow represents the position being connected with ring D, each R51、R52、R53And R54It is as defined above) etc..Preferably, R51、R52、R53Or R54E.g. hydrogen atom, can have substituent alkyl or can have the 3- of substituent to 15- heterocyclic radicals.Furthermore it is preferred that wherein R52Or R53It is the compound of hydrogen atom.More preferred R2E.g.
(R55Implication with by R1A、R1B、R1C、R1D、R1E、R1F、R1G、R1H、R1J、R1KAnd R1L" substituent " in " alkyl can with substituent " that represents is identical；N is 0-5, and other symbols are as defined above) etc..It is preferred that R51Can e.g. have alkyl of substituent etc., more preferably be, for example, the C1-15 alkyl can with substituent, the C6-14 aryl or R can with substituent56Deng most preferably e.g. butyl or can having phenyl etc. of substituent.It is preferred that substituent be methyl, methoxyl group, trifluoromethyl, fluorine atom etc., more preferably methyl or fluorine atom.It is preferred that R55E.g. halogen atom, carbamoyl or the amino carbonyl that is replaced by C1-8 alkyl etc., most preferably e.g. fluorine atom, chlorine atom, carbamoyl, N- methylaminocarbonyls etc..It is preferred that n is 1-3.
It is preferred that R56It is the list-carbocylic radical or list-heterocyclic radical with armaticity can with substituent, can more preferably has the benzene of substituent, pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, oxazole isoxazoles, thiazole, isothiazole, furazan, oxadiazoles or Thiadiazole, the phenyl ring most preferably can with substituent.It is preferred that substituent be methyl, methoxyl group, trifluoromethyl, more preferably fluorine atom etc., methyl or fluorine atom.
In the present invention, it is preferred to the compound represented by formula (I) of the combination containing above-mentioned preferred group and ring.
For example, it is preferable to which its middle ring D is piperidines and Y is the compound of methylene, i.e. as the compound representated by formula (Ia)
(wherein, the implication of all symbols as above)；
Its middle ring D is piperidines and Y methylene, R2It is
Figure G200580038925420070516D000263
The compound of (implication of wherein all symbols is as above), i.e. as the compound representated by formula (Ib)
Figure G200580038925420070516D000271
(implication of wherein all symbols is as above)；
Wherein X is that-O-, Y are methylene, and ring A and ring B are independently each the benzene can with substituent, and ring D is piperidines, R2It is
Figure G200580038925420070516D000272
The compound of (implication of wherein all symbols is as above), i.e. as the compound representated by formula (Ic)
Figure G200580038925420070516D000273
(its middle ring A1aWith ring B1aIt is independently each the benzene can with substituent, the implication of other symbols is as above)；
Wherein X is that-O-, Y are methylene, and its middle ring A and ring B are independently each the benzene can with substituent, and ring D is piperidines, R2It is
The compound of (implication of wherein all symbols is as above), i.e. the compound represented by formula (Id)
Figure G200580038925420070516D000275
(implication of wherein all symbols is as above)；
Its middle ring D is tropane ring and Y is methylene, R2It is
Figure G200580038925420070516D000281
The compound of (implication of wherein all symbols is as above), i.e. the compound represented by formula (Ie)
Figure G200580038925420070516D000282
(implication of wherein all symbols is as above)；
Its middle ring D is pyrrolidine ring and Y is methylene, R2It is
Figure G200580038925420070516D000283
The compound of (implication of wherein all symbols is as above), i.e. the compound that formula (If) is represented
Figure G200580038925420070516D000284
(implication of wherein all symbols is as above)；
Its middle ring D is piperazine and Y is methylene, R2It is
The compound that the compound of (implication of wherein all symbols is as above), i.e. formula (Ig) are represented
Figure G200580038925420070516D000291
(implication of wherein all symbols is as above)；
Its middle ring D is perhydroazepinyl
Figure G200580038925420070516D000292
Ring and Y is methylene, R2It is
The compound of (implication of wherein all symbols is as above), i.e., the compound represented by formula (Ih)
Figure G200580038925420070516D000294
(implication of wherein all symbols is as above), its salt, N- oxides, its solvate and its prodrug.
Compound, its salt, N- oxides, its solvate and its prodrug described in preferred embodiment.More preferably：
(1) 5- ({ [butyl (1- { 4- [4- (methyl sulphonyl) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzamides,
(2) 5- [({ butyl [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
(3) 5- ({ [butyl (1- { [6- (4- { [(2- methoxy ethyls) amino] carbonyl } phenoxy group) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzamides
(4) 5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzamides
(5) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) Methanesulfomide
(6) 5- { [(butyl { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } the chloro- 4- fluorobenzamides of -2-
(7) 2- (5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorophenyls) acetamide
(8) 5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluoro-N-methyl benzamides,
(9) 5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzamides
(10) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(11) 5- [({ butyl [1- (4- { 4- [(methylamino) sulfonyl] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
(12) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(13) N- [4- ({ 5- [(4- { 3- thienyls [(3- thienyls amino) carbonyl] amino } -1- piperidyls) methyl] -2- pyridine radicals } epoxide) phenyl] Methanesulfomide,
(14) the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(15) N- { 4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls] phenyl } Methanesulfomide
(16) 4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls]-N- [2- (4- morpholinyls) ethyl] benzsulfamide
(17) N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(18) 2- chloro-n-methyls -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(19) N- (4- { [5- ({ 4- [({ [the chloro- 3- of 4- (4- morpholinyl carbonyls) phenyl] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(20) the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide
(21) N- (3- fluorophenyls)-N '-(6- methyl -3- pyridine radicals)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] urea,
(22) 2- [4- ({ 4- [[({ the fluoro- 3- of 4- [(methyl sulphonyl) amino] phenyl } amino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide
(23) the fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(24) the fluoro- N- methyl -5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide
(25) 2- [4- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide
(26) N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N- phenylureas,
(27) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(28) N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide
(29) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
(30) 5- [({ butyl [1- (4- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
(31) N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) Methanesulfomide
(32) N- (4- { [5- ({ 4- [{ [(4- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(33) N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(34) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) acetamide,
Its salt, N- oxides, its solvate and its prodrug etc..Most preferably：
The fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide
N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
5- [({ butyl [1- (4- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides,
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) Methanesulfomide
N- (4- { [5- ({ 4- [{ [(4- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) acetamide,
Its salt, N- oxides, its solvate and its prodrug etc..
In the present invention,
(1) N- { 4- [(5- { [4- ((3- aminomethyl phenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
(2) N- (the fluoro- 5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide
(3) N- (the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide
(4) N- (the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide
(5) N- [5- ({ [{ 1- [(6- { the chloro- 4- of 2- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- fluorophenyls) amino] carbonyl } amino) -2- fluorophenyls] acetamide
(6) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -3- aminomethyl phenyls } Methanesulfomide
(7) N- { the chloro- 4- of 3- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
(8) 2- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -5- [(methyl sulphonyl) amino] benzamide
(9) 2- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide]-N- methyl -5- [(methyl sulphonyl) amino] benzamide
(10) N- [4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- (methyl sulphonyl) phenyl] Methanesulfomide
(11) N- { 2- [(5- { [4- ((3- aminomethyl phenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -5- [(methyl sulphonyl) amino] phenyl } acetamide
(12) N- (4- { [5- ({ 4- [[[(4- fluorophenyls) amino] (imido) methyl] (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(13) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl sulfenyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(14) the fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -3- azelidinyls } (phenyl) amino] carbonyl } amino) benzamide
(15) N- (4- { [5- ({ (3R) -3- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- pyrrolidinyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(16) N- [the fluoro- 5- of 2- ({ [{ (3S) -1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -3- pyrrolidinyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide
(17) N- (4- { [5- ({ (4R) -4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- perhydroazepinyls
Figure G200580038925420070516D000331
Base } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
(18) N- (4- { [5- ({ (4S) -4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- perhydroazepinylsBase } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
(19) the fluoro- 5- of 2- ({ [(1- { [6- ({ 4- [(methyl sulphonyl) amino] phenyl } sulfonyl) -3- pyridine radicals] methyl } -4- piperidyls) (phenyl) amino] carbonyl } amino) benzamide
(20) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] methyl } phenyl) Methanesulfomide
(21) 2- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide
(22) N- (3- aminomethyl phenyls)-N '-(6- methyl -3- pyridine radicals)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] urea,
(23) N- [1- ({ 6- [4- (ethylsulfonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- (3- fluorophenyls)-N '-(6- methyl -3- pyridine radicals) urea,
(24) N- (3- fluorophenyls)-N- [1- ({ 6- [4- (isopropelsulfonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N '-(6- methyl -3- pyridine radicals) urea,
(25) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] methyl } phenyl) ethyl sulfonamide
(26) the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -3- azelidinyls } amino) carbonyl] amino } benzamide
(27) N- (4- { [5- ({ 4- [{ [(6- ethyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(28) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -6- methyl -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
(29) N- [2- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -5- (methyl sulphonyl) phenyl] acetamide
(30) N- (4- { [5- ({ 4- [{ [(6- ethyl -3- pyridine radicals) amino] carbonyl } (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(31) N- { 2- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] phenyl } acetamide
(32) N- { 2- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) methyl] -5- [(methyl sulphonyl) amino] phenyl } acetamide
(33) N- [4- (5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) phenyl] Methanesulfomide
(34) the fluoro- 5- of 2- ({ [{ 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(35) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) sulfonyl] phenyl } Methanesulfomide
(36) N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (3- aminomethyl phenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(37) N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- aminomethyl phenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(38) the fluoro- 5- of 2- ({ [{ 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- aminomethyl phenyls) amino] carbonyl } amino) benzamide
(39) the fluoro- 5- of N- ethyls -2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(40) the fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl sulfenyl } amino) benzamide
(41) the fluoro- 5- of 2- { [((3- fluorophenyls) { (3S) -1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -3- pyrrolidinyls } amino) carbonyl] amino }-N-methyl-benzamide
(42) N- [5- ({ [{ (4S) -1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- perhydroazepinyls
Figure G200580038925420070516D000351
Base } (phenyl) amino] carbonyl } amino) -2- fluorophenyls] acetamide,
(43) 2- { [5- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide }-N- methyl -5- [(methyl sulphonyl) amino] benzamide
(44) N- [5- ({ [{ 1- [(6- { the chloro- 4- of 2- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- fluorophenyls) amino] carbonyl } amino) -2- fluorophenyls] acetamide
(45) 5- ({ [{ (3R) -1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -3- pyrrolidinyls } (phenyl) amino] carbonyl } amino) -2- fluorobenzamides
(46) N- (the chloro- 4- of 3- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(47) 5- ({ [{ 1- [(6- { 2- (amino carbonyl) -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- fluorophenyls) amino] carbonyl } amino) the fluoro- N-methyl-benzamides of -2-
(48) the fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(49) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] sulfonyl } phenyl) Methanesulfomide
(50) the fluoro- N- methyl -5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide
(51) the fluoro- 5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide
(52) the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino }-N-methyl-benzamide
(53) N- (3- methyl -4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(54) N- (the chloro- 4- of 3- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(55) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) ethyl sulfonamide
(56) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyrazinyls] epoxide } phenyl) Methanesulfomide
(57) N- (4- { [5- ({ (3S) -3- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- pyrrolidinyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(58) N- (4- { [5- ({ (4S) -4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- perhydroazepinyls
Figure G200580038925420070516D000361
Base } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide,
(59) N- (4- { [5- ({ (3R) -3- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- pyrrolidinyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
(60) 2- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide
(61) 2- { [5- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide
(62) 2- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide
(63) N- [4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -3- (methyl sulphonyl) phenyl] Methanesulfomide
(64) N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] methyl } phenyl) Methanesulfomide
(65) N- { 4- [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] phenyl } Methanesulfomide,
(66) N- { 4- [(5- { [4- ((3- aminomethyl phenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide
(67) N- [5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- fluorophenyls) amino] carbonyl } amino) -2- fluorophenyls] acetamide
(68) the fluoro- 5- of 2- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
(69) 5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) -2- fluorobenzamides, and
(70) N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } ethyl sulfonamide, its salt, N- oxides, solvate and prodrug are preferred.
The preparation method of the compounds of this invention：
The compounds of this invention that formula (I) is represented can be prepared by being suitably modified and combining the method for known method, than as described below, method or Comprehensive OrganicTransformations described in embodiment：Method described in A Guide to Functional Group Preparations, 2nd Edition (Richard C.Larock, John Wiley＆Sons Inc, 1999).In following each methods, starting compound can be used with salt.The example of salt includes the salt of above-mentioned formula (I) compound.
In the compound that formula (I) is represented, wherein the interval base adjacent with ring D is-CH2- ,-CO- or-SO2- the compound that can be represented by alkylation, amidatioon or sulfuryl amine formula (1) of compound
(wherein Z is hydroxyl or leaving group (e.g., halogen atom, tolysulfonyl epoxide, mesyloxy, trifluoro-methanesulfonyl oxy etc.), Y1PBe chemical bond or comprising 1 or 2 atom as the interval base of main chain, Y2PIt is-CH2- ,-CO- or-SO2-, R1P、XPRing APWith ring BPImplication respectively with R1, X, ring A it is identical with B.But in R1P、XP、Y1P、Y2P, ring APWith ring BPDuring with carboxyl, hydroxyl, amino or sulfydryl, these groups can be protected.) and formula (2) represent compound
Figure G200580038925420070516D000372
(wherein R2PWith ring DPImplication respectively with R2It is identical with ring D.Work as R2POr DPDuring with carboxyl, hydroxyl, amino or sulfydryl, these groups can be protected.) and prepare, it is necessary to when, then remove protection group.
Known alkylation.For example, can be in organic solvent (e.g., dimethylformamide, dimethyl sulfoxide (DMSO)), in the presence of alkali (e.g., potassium carbonate, sodium carbonate, triethylamine), presence or absence of sodium iodide or KI, in about 0-150 DEG C progress.
Known amidation method.E.g., including following method：
(1) via carboxylic acid halides,
(2) via mixed acid anhydride,
(3) condensing agent is used.
These methods are explained as follows：
(1) for example can be by carboxylic acid and carboxylic acid halides (such as via the method for carboxylic acid halides, oxalyl chloride or thionyl chloride) in organic solvent (e.g., chloroform, dichloromethane, ether or tetrahydrofuran) or without under solvent, in progress under about -20 DEG C to reflux temperature.Then make gained acyl halide derivative and amine in organic solvent (such as, chloroform, dichloromethane, ether or tetrahydrofuran) in, in the presence of alkali (e.g., pyridine, triethylamine, dimethylaniline, dimethyl aminopyridine or diisopropyl ethyl amine etc.), in about 0-40 DEG C reaction.As alternative reaction, gained acyl halide derivative can be reacted in organic solvent (e.g., dioxane, tetrahydrofuran) with amine using aqueous alkali (e.g., sodium acid carbonate, sodium hydroxide) in about -78 to 40 DEG C.
(2) can be by carboxylic acid and carboxylic acid halides (such as via the method for mixed acid anhydride, pivaloyl chloride, paratoluensulfonyl chloride or mesyl chloride) or acid derivative is (such as, Ethyl formate or iso-butyl formate) in organic solvent (such as, chloroform, dichloromethane, ether, tetrahydrofuran) then gained mixed acid anhydride derivative can with amine in organic solvent (e.g., chloroform, dichloromethane, ether or tetrahydrofuran), in about 0-40 DEG C reaction.
(3) using condensing agent reaction for example by carboxylic acid and amine in organic solvent (such as, chloroform, dichloromethane, dimethylformamide, ether or tetrahydrofuran) in or without under solvent, in alkali (such as, pyridine, triethylamine, dimethylaniline, dimethyl aminopyridine or diisopropyl ethyl amine) in the presence of, using condensation reagent (such as, 1, 3- dicyclohexylcarbodiimides (DCC), 1- ethyls -3- [3- (dimethylamino) propyl group] carbodiimide (EDC), 1, 1 '-carbon diimidazole (CDI), the chloro- 1- methylpyridinium iodides of 2- or 1- propane phosphoric acid cyclic anhydrides (PPA)), presence or absence of under 1- hydroxybenzothiazoles (HOBt), in about 0-40 DEG C progress.
In order to obtain preferably result, the reaction of (1), (2) and (3) description can carry out avoiding water in inert gas (such as argon gas, nitrogen).
Known Sulphonylation method.For example, can be by sulfonic acid and carboxylic acid halides (such as, oxalyl chloride or thionyl chloride, phosphorus pentachloride or phosphorus trichloride) in organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, ether or tetrahydrofuran) or under without solvent in about -20 DEG C to reflux temperature react.Then gained sulfonic acid halide derivative can with amine in organic solvent (such as, chloroform, dichloromethane, dimethylformamide, ether or tetrahydrofuran) in, in the presence of alkali (e.g., pyridine, triethylamine, dimethylaniline, dimethyl aminopyridine or diisopropyl ethyl amine) in about 0-40 DEG C reaction.
The method of known deprotection base and it can be carried out such as following method.
Carboxyl-protecting group is such as including methyl, ethyl, pi-allyl, tert-butyl, trichloroethyl, benzyl (Bn) or phenylacetyl group.
Hydroxyl protecting group is for example including methyl, trityl, methoxy (MOM), 1- ethoxyethyl groups (EE), methoxvethoxvmethvl (MEM), 2- oxinanes (THP), trimethyl silyl (TMS), triethylsilyl (TES), tert-butyl dimetylsilyl (TBDMS), tert-butyl diphenylsilyl group (TBDPS), acetyl group (Ac), pivaloyl, benzoyl, benzyl (Bn), p- methoxy-benzyl, allyloxycarbonyl (Alloc) and 2, 2, 2- tri-chloroethoxy base carbonyls (Troc) etc..
Amino protecting group is such as including benzyloxycarbonyl, t-butoxy carbonyl, allyloxycarbonyl (Alloc), 1- methyl isophthalic acids-(4- diphenyl) ethoxy carbonyl (Bpoc), trifluoroacetyl group, 9- fluorenylmethoxycarbonyl groups (Fmoc), benzyl (Bn), p- methoxy-benzyl, benzyloxymethyl (BOM) or 2- (trimethyl silyl) ethoxyl methyl (SEM).
The protection group of sulfydryl is such as including benzyl, methoxy-benzyl, methoxy (MOM), 2- THP trtrahydropyranyls (THP), diphenyl methyl and acetyl group (Ac).
Above-mentioned group is not specially defined on carboxyl, hydroxyl, amino and sulfhydryl protected base, as long as the protection group being capable of easily selectively removing.The method referred to for example, can be according in " T.W.Greene, ProtectiveGroups in Organic Synthesis, John Wiley＆Sons Inc, 1999 " carries out deprotection reaction.
The known reaction for removing decarboxylate, hydroxyl, amino and sulfhydryl protected base, the example is as follows.
(1) with the deprotection reaction of macromolecule alkali for hydrolysis；
(2) deprotection reaction under the conditions of acid；
(3) deprotection reaction of hydrogenolysis is passed through；
(4) deprotection reaction of silicyl；
(5) using the deprotection reaction of metal；And
(6) using the deprotection reaction of metal composite.
These methods will be specifically illustrated below.
(1) for example at about 0-40 DEG C, the deprotection reaction of macromolecule alkali for hydrolysis is carried out using alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), alkaline earth metal hydroxide (such as barium hydroxide and calcium hydroxide), carbonate (such as sodium carbonate and potassium carbonate), its aqueous solution or its mixture (such as methanol/tetrahydrofuran and dioxane etc.) in organic solvent.
(2) for example at about 0-100 DEG C; in organic acid (such as; acetic acid, trifluoroacetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid), the deprotection reaction that carries out in the organic solvent of inorganic acid (e.g., hydrochloric acid and sulfuric acid) or its mixture (such as hydrobromic acid acetic acid) under acid condition.
(3) for example at about 0-200 DEG C, in normal pressure or the hydrogen atmosphere of high pressure or catalyst (such as palladium-carbon in the presence of ammonium formate, palladium black, palladium dydroxide, palladium oxide and Raney's nickel) in the presence of, in solvent [such as ethers (such as tetrahydrofuran, dioxane, dimethoxy-ethane and ether), alcohols (such as methanol and ethanol), benzene class (such as benzene and toluene), ketone (such as acetone and methyl ethyl ketone), nitrile (such as acetonitrile), amide-type (such as dimethylformamide), water, ethyl acetate, acetic acid or its mixing of two or more] the middle deprotection reaction for carrying out passing through hydrogenolysis.
(4) such as the deprotection reaction for carrying out silicyl in organic solvent (such as tetrahydrofuran and acetonitrile) miscible with water using tetrabutyl ammonium fluoride at about 0-40 DEG C.
(5) deprotection reaction of metal is for example used or in acid flux material (such as acetic acid, pH 4.2-7.2 buffer solution and its solution and the mixed solution of organic solvent such as tetrahydrofuran) use in the presence of zinc powder without using ultrasonic wave at about 0-40 DEG C.
(6) metal complex [such as tetrakis triphenylphosphine palladium (0) is used for example at about 0-40 DEG C, two (triphenylphosphine) palladium chlorides (II), acid chloride (II) and three (triphenylphosphine) radium chlorides (I)] in phosphonate reagent (such as triphenylphosphine) in the presence of, in capture reagent such as tri-butyl tin hydride hydrate, triethyl-silicane, dimetone, morpholine, diethylamine and pyrrolidines), organic acid (such as acetic acid, formic acid and 2 ethyl hexanoic acid) and/or acylate (such as 2 ethyl hexanoic acid sodium and 2 ethyl hexanoic acid potassium) in the presence of in organic solvent (such as dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and ethanol), water or its in the mixed solvent carry out the deprotection reaction using metal complex.
Except above-mentioned points, for example also the deprotection can be realized according to T.W.Greene, Protective Groups in OrganicSynthesis, Wiley, New York, the method described in 1999.
Skilled person readily understands that the target compound of the present invention can be prepared by the one of appropriate of these deprotection reactions.
In the compounds of this invention that formula (I) is represented, wherein R2It is the compound of the amino can with substituent, i.e., the compound that formula (I-a) is represented
Figure G200580038925420070516D000411
(wherein R2-1Be can have substituent amino and other symbols have implication same as before) can by reduction amination formula (3) represent compound
Figure G200580038925420070516D000412
The compound that (implication of wherein all symbols is as above) and formula (4) are represented
Figure G200580038925420070516D000413
(wherein R301And R302, its is identical or different, individually hydrogen atom or identical with " substituent " implication in above-mentioned " amino can with substituent ", and the implication of other symbols is as above.Work as R301Or R302With carboxyl, hydroxyl, amino or sulfydryl, these groups can be protected.) and prepare, it is necessary to when, then remove protection group.
The method of reduction amination is known.For example, reducing agent can be used (such as, sodium triacetoxy borohydride or tricyano sodium borohydride) in about 0-40 DEG C in organic solvent (such as, dichloroethanes, dichloromethane or dimethylformamide) in tertiary amine (e.g., triethylamine or diisopropyl ethyl amine) presence or absence of under, acetic acid presence or absence of under carry out.
Protection group can be removed according to the above method.
In the compounds of this invention that formula (I) is represented, wherein R2It is
(implication of wherein all symbols is as above), i.e. the compound that formula (I-d) is represented
The compound that (implication of wherein all symbols is as above) can be represented by using formula (5)
Figure G200580038925420070516D000422
(wherein R51PImplication and R51The implication of identical and other symbols is as described above.Work as R51PDuring with carboxyl, hydroxyl, amino or sulfydryl, these groups can be protected.) with (6) represent compound
R52P-COOH  (6)
(wherein R52PImplication and R52The implication of identical and other symbols is as described above.Work as R52PDuring with carboxyl, hydroxyl, amino or sulfydryl, these groups can be protected.) reaction and prepare, it is necessary to when, then remove protection group.
The reaction is known.For example, can be in the organic solvent containing alkali (e.g., pyridine, triethylamine, dimethylaniline, dimethyl aminopyridine and diisopropyl ethyl amine) in about 20-120 DEG C progress.
Protection group can be removed according to the above method.
In addition, the compound that the compound and formula (7) of formula (5) representative are represented can be used in the compound that formula (I-d) is represented
R52P-NH2    (7)
(symbol therein is as defined above) prepared by the reaction of urea-change, it is necessary to when, then remove protection group.
The reaction is known.For example, can be reacted in organic solvent (e.g., tetrahydrofuran or DMF) in the presence of triphosgene and alkali (e.g., triethylamine) in about 0-40 DEG C.In addition, can be in organic solvent (e.g., dichloromethane or DMF), 1, in the presence of -1H- the imidazoles (CDI) of 1 '-carbonyl two, containing alkali (e.g., triethylamine or N-methylmorpholine) or without alkali, in 0-80 DEG C of reaction.
Protection group can be removed by the above method.
In the compounds of this invention that formula (I) is represented, wherein Y is the compound of methylene, i.e. the compound represented by formula (I-e)
Figure G200580038925420070516D000431
(implication of wherein all symbols is as described above) can be by the compound that is represented by formula (8)
Figure G200580038925420070516D000432
The compound that (implication of wherein all symbols is as above) and (2) formula are represented carry out reduction amination and prepare, it is necessary to when, then remove protection group.
Reduction amination can be carried out by preceding method and protection group can be removed.
In the compound represented by formula (I), wherein at least one nitrogen-atoms is the compound of quaternary ammonium, i.e. formula (I-2) compound
Figure G200580038925420070516D000433
(wherein R1-2、R2-2、X2、Y2, ring A2, ring B2With ring D2Implication respectively with R1、R2, X, Y, ring A, ring B it is identical with ring D, N2It is nitrogen-atoms.But at least one nitrogen-atoms is quaternary ammonium salt, and Q-It is halogen ion) it can be reacted and prepared by formula (I) compound and formula (9) compound
R0-Q  (9)
(wherein RoIt is the C1-8 alkyl or C1-8 alkyl being substituted by phenyl, Q is halogen atom.).
The reaction be it is known, such as can in organic solvent (acetone, dimethylformamide or methyl ethyl ketone) in about 0-40 DEG C progress.
In formula (I) compound, at least one nitrogen-atoms is the compound of N- oxides, i.e. formula (I-3) compound
Figure G200580038925420070516D000434
(wherein R1-3、R2-3、X3、Y3, ring A3, ring B3With ring D3Implication respectively with R1、R2, X, Y, ring A, ring B be identical with ring D and N3It is nitrogen-atoms.On condition that, at least one nitrogen-atoms represents N- oxides.) can be prepared by aoxidizing formula (I) compound.
The oxidation reaction is known, for example can be in organic solvent (such as, dichloromethane, chloroform, benzene, hexane or tert-butanol) in excessive oxidant (hydrogen peroxide, sodium metaperiodate, acetyl nitrous acid, sodium perborate, peroxy acid (such as 3- chloroperoxybenzoic acids or Peracetic acid), (trade name, OXONE is the abbreviation of peroxidating sulfate mono potassium to OXONE.), potassium permanganate or chromic acid etc.) in the presence of in about 20-60 DEG C reaction..
The compounds of this invention can be prepared by these reactions or the reaction being partially improved.
Other initial compounds or compound as reagent are known compound, can be by easily be prepared with reference to known method, such as Comprehensive Organic Transformations：A Guide toFunctional Group Preparations, 2nd Edition (Richard C.Larock, John Willey＆Sons Inc, 1999) or Elmer J.Rauckman et al., J.Org.Chem., vol.41, No.3, method described in 1976, p564-565etc.
In each reaction of this specification, heating response, as it is well known to the skilled in the art, can be carried out in water-bath, oil bath, sand-bath and microwave.
In each reaction of this specification, the solid-phase reagent supported by polymer (for example, polystyrene, polyamide, polypropylene or polyethylene glycol etc.) can be used.
In each reaction of this specification, products therefrom can be purified by routine techniques.For example, for example in environmental pressure or the lower distillation of decompression, by containing the high performance liquid chromatography with silica gel or magnesium silicate, by thin-layer chromatography, by ion exchange resin, by resin, by column chromatography, by washing or passing through recrystallization when being purified.If can be purified after each reaction or dry reaction.
In reaction of this specification using polystyrene, products therefrom can be purified by routine techniques.For example, being purified more than once by using solvent (dimethylformamide, dichloromethane, methanol, tetrahydrofuran, tolyl-acetic acid/toluene etc.) washing.
Toxicity：
Compound, its salt, N- oxides or the solvate or the toxicity of prodrug (be hereinafter referred to as " compound of the invention ") that formula (I) is represented be very low, it is thus regarded that can safety be used as medicinal application.
Medicinal application：
The compounds of this invention has good solubility and trap.And the compounds of this invention has faint inhibitory activity for drug metabolic enzyme.These properties are physics, chemistry and the pharmaceutical properties needed for medicine, and the compounds of this invention has appropriate condition [Ref. (the The Merck Manual ofDiagnosis and Therapy (17 as outstanding medicinethEd), Merck＆Co.)].
It has rated the compounds of this invention by the method described in following a variety of test methods, Biological examples and its method being suitably modified and be suitable for medicine.Yakubutsubioavailability (Hyouka to kaizen no kagaku); the method described in July 6; 1998; Gendaiiryou-sha " etc., which can also easily evaluate the compounds of this invention, has the length of good pharmacokinetic property such as plasma half-life, the stability in intestines and stomach, absorption, the bioavilability of oral formulations etc. by known method for example ".
(I) evaluation test of the inhibitory activity of the compounds of this invention antiradiation drug-metabolic enzyme
(i) people CYP2C9 inhibitory activity is tested
The anti-human CYP2C9 inhibitory activity experiment of the compounds of this invention can be by Sato et al. method (Yakubutsudotai (Xenobio.Metabol.and Dispos.), 16 (2), 115-126 (2001)) evaluated, it the method improve the degree of accuracy of test and/or the sensitivity of test.
(ii) people CYP3A4 inhibitory activity
The anti-human CYP3A4 inhibitory activity of the compounds of this invention can be by Drug Metabolism andDisposition, Vol.28 (12), and the improved method described in 1440-1448 (2000) is evaluated.
For example, preparing by kaliumphosphate buffer (pH7.4) (final concentration：200mM), magnesium chloride hexahydrate (concentration eventually：5mM), substrate (7- benyloxyquinolines (7-BQ), final concentration：40 μM) and expression be microsome (Daiichikagakuyakuhin, final concentration：0.25mg/mL) the reaction solution of composition.100 μ L reaction solutions are suspended in 96 orifice plates, the aqueous solution of the 50 μ L comprising test compound and 0.8% acetonitrile is added, 10 minutes precultures is carried out in 37 DEG C.50 μ L NADPHs (NADPH, 4mM) are added with initiation reaction.The fluorescence intensity in each hole is measured when adding NADPH and after cultivating 30 minutes.The launch wavelength stimulated at wavelength and 530nm at 409nm measures quinolinol.The inhibiting rate (%) of test compound is calculated by following calculation formula, IC is obtained50Value.
Inhibiting rate (%)=[1- { (adding measured value during test compound)
- (blank value)/(control value-blank value) }] × 100
(II) evaluation test of the compounds of this invention toxicity
(i) the single acute toxicity in rat body
Six week old Crj are given by the oral administration of the intravenous administration or single of single：CD (SD) rat test compound.Toxicity can be evaluated with being added without compared with test compound.The basic evaluation of toxicity can be carried out such as by observing performance status or locomitivity.
(ii) the compounds of this invention resists the active evaluation of hERG IKr electric currents
According to Zou et al. (Biophys.J., Vol.74,230-241 (1998)) report, people ether-a-go-go- related genes (hERG) are overexpressed using HEK293 cells, are measured by Patch-clamp techniques through depolarizing the hERG I that the subsequent repolarization pulse of pulse is inducedKrThe maximum total current (max tale current) of electric current.Rate of change (inhibiting rate) is calculated by the maximum total current before and after comparing addition test compound between 10 minutes.Test compound can be evaluated by inhibiting rate and resist hERG IKrThe influence of electric current.
The compounds of this invention has antagonism chemokine receptors especially CCR5 activity in the especially human body of the animal including people, therefore they are applied to prevent and/or treatment CCR5- relevant diseases, for example, various inflammation (asthma, ephritis, nephrosis, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, IBD such as ulcerative colitis, etc.), immunological diseases (autoimmune disease, rejection (the rejection of solid organ transplantation of organ transplant, treat the rejection of the islet cell transplantation in diabetes, GVHD (transplanting-to anti-host disease) etc.), infectious diseases (HIV infections, acquired immune deficiency syndrome, rsv infection, etc.), allergic disease (atopic dermatitis, nettle rash, allergic broncho-pulmonary aspergillosis, anaphylaxis eosinophilia gastroenteritis, etc.), angiocardiopathy (artery sclerosis, ischemic damage and reperfusion is injured, etc.), acute dyspnea syndrome, the shock of microbe satellite infection, diabetes, cancer metastasis etc..
The compounds of this invention has the activity for suppressing cell migration in the especially human body of the animal including people, therefore they are applied to prevent and/or treatment inflammation (asthma, ephritis, nephrosis, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, IBD such as ulcerative colitis, etc.), immunological diseases (autoimmune disease, rejection (the rejection of solid organ transplantation of organ transplant, treat the rejection of the islet cell transplantation in diabetes, GVHD (transplanting-to anti-host disease) etc.), infectious diseases (HIV infections, acquired immune deficiency syndrome, rsv infection, etc.), allergic disease (atopic dermatitis, nettle rash, allergic broncho-pulmonary aspergillosis, anaphylaxis eosinophilia gastroenteritis, etc.), angiocardiopathy (artery sclerosis, ischemic damage and reperfusion is injured, etc.), acute dyspnea syndrome, the shock of microbe satellite infection, diabetes, cancer metastasis etc..
For above-mentioned purpose, the compounds of this invention generally can capapie or partly be administered, and be usually administered orally or parenterally.
For example given dosage is determined depending on age, body weight, symptom, required curative effect, administration route and the length for the treatment of time.In adult, the dosage of 1 people 1 time is usually oral 1mmg-1000mg, can be taken several times daily, and parenteral 1 people, 1 1mg-100mg, can be taken several times daily, or daily 1-24 hours are administered continuously from vein.
As described above, dosage used depends on a variety of situations.Therefore, it can be used sometimes and be below or above dosage defined above.
Using liquid form, the injection of parenteral, liniment or the suppository that during the compounds of this invention for example can be the solid form of oral administration, be administered orally.
The solid form of oral administration includes compressed tablets, pill, capsule, dispersible pulvis and granule.Capsule includes hard shell capsules and soft capsule.
In these solid forms, one or more active components can be with medium (such as lactose, mannitol, glucose, microcrystalline cellulose or shallow lake), adhesive (such as hydroxypropyl cellulose, polyvinylpyrrolidone or Neusilin US2 hydrochlorate), disintegrant (such as cellulose calcium oxyacetate), lubricant (such as magnesium stearate), stabilizer and dissolution aids (such as glutamic acid or aspartic acid) mix, prepared according to the known method in conventional pharmaceutical practice.When needing, the solid form can be surrounded by coating agent (such as sugar, gelatin, hydroxypropyl cellulose or phthalandione HPMC), can also be coated more than 2 layers.In addition, may also comprise absorbable material such as gelatine capsule.
Include pharmaceutically acceptable solution, suspension, emulsion, syrup and elixir for oral liquid form.In these forms, one or more active materials be can dissolve, suspended or be emulsifiable in diluent commonly used in the art (such as purified water, ethanol or its mixture).In addition, the liquid form can also include some additives such as wetting agent, suspending agent, emulsifying agent, sweetener, fumet, spices (aroma), preservative or buffer.
Injection for parenteral includes aseptic aqueous solution, suspension, emulsion and the solid form that can at once dissolve or be suspended in solvent for injection before the use.In parenteral solution, one or more active materials can dissolve, suspend or be emulsifiable in solvent.These solvents include distilled water for injection, salt solution, vegetable oil, glycerine, polyethylene glycol, alcohol such as ethanol or its mixture.Injection can contain some additives such as stabilizer, solution assistant agent (such as glutamic acid, aspartic acid or POLYSORBATE80 (registration mark)), suspending agent, emulsifying agent, console agent, buffer, preservative.It can be sterilized in last step, asepsis can also be used to prepare.The product that sterile solid form is such as freeze-dried can also be prepared into, it is dissolvable in water in aseptic aqueous solution or other injection diluents at once before the use.
The liquid of the parenteral of other forms including external application, paste with it is endermic apply oil, inhalant, spray, suppository and vaginal plug comprising one or more active materials, method known per se can be passed through and prepared.
Spray can include and remove the unexpected other materials of diluent gas, usually using stabilizer such as sodium hydrogensulfite and can assigning buffer such as isotonic buffer agent such as sodium chloride, sodium citrate or the citric acid of isotonicity.
The compounds of this invention can be used together with other medicines, for example, preventing and/or treating the medicine (medicine for particularly preventing and/or treating AIDS) of HIV or for the rejection in organ transplant and/or the medicine of autoimmune disease.In that case, such medicine can mix separately or concurrently to be added in pharmaceutical preparation with pharmacologically acceptable excipient, adhesive, disintegrant, lubricant, stabilizer, solubilizer, diluent etc., as drug composition oral or parenteral so as to prevent and/or treat HIV, the rejection in organ transplant and/or autoimmune disease.
The compounds of this invention can suppress the infection activity for the medicine (medicine particularly for preventing and/or treating AIDS) of other preventions and/or treatment HIV with the HIV of drug resistance.Therefore, its HIV- infected patient that can be additionally used in the drug ineffective for other preventions and/or treatment HIV.Now, although can be used alone the compounds of this invention, it can also be used together with other medicines (the HIV strains now, infected obtain drug resistance) for preventing and/or treating HIV or with other medicines.
Though the compounds of this invention of the invention that includes is with the joint for the medicine for not suppressing HIV but can strengthening the prevention and/or therapeutic action to HIV compared with unitary agent.
For being used to preventing and/or treating vaccine of the example of the other medicines of HIV for RTI, protease inhibitors, chemokine antagonists (such as CCR2 antagonists, CCR3 antagonists, CCR4 antagonists, CCR5 antagonists, CXCR3 antagonists and CXCR4 antagonists), integrase inhibitor, fusion inhibitor, the antibody of HIV surface antigens and HIV to united with the compounds of this invention.
RTI is in particular (1) nucleoside/nucleotide RTI：Zidovudine (zidovudine) (trade name：Retrovir), Didanosine (didanosine) (trade name：Videx (Videx)), zalcitabine (zalcitabine) (trade name：HIVID), stavudine (stavudine) (trade name：Sai Ruite (Zerit)), Lamivudine (lamivudine) (trade name：Epivir), 1592U89 (abacavir) (trade name：ABC (Ziagen)), adefovirdipivoxil (adefovir), adefovir dipivoxil (adefovir dipivoxil), emtricitabine (trade names：) or PMPA (trade names Coviracil：) etc. and (2) non-nucleoside reverse transcriptase inhibitor Tenofovir：NVP (nevirapine) (trade name：The happy life (Viramune) of dimension), delavirdine (delavirdine) (trade name：Rescriptor), efavirenz (efavirenz) (trade name：Sustiva, Stocklin) or capravirine (capravirine) (AG1549) etc..
Protease inhibitors is in particular that indoles draws Wei (indinavir) (trade name：(Crixivan Crixivan)), Li Tuolawei (ritonavir) (trade name：Norvir (Norvir)), Nai Feilawei (nelfinavir) (trade name：Viracept), husky quinoline draws Wei (sequinavir) (trade name：Invirase, Fortovase), An Polawei (amprenavir) (trade name：Agenerase), lopinavir (trade names：Kaletra) or for pula Wei (tipranavir) etc..
It is used as endogenic ligand, its derivative, the antibody of its non-peptides low molecular compound or chemokine receptors of chemokine antagonists, including chemokine receptors.
The endogenic ligand of chemokine receptors is specially MIP-1 α, MIP-1 β, RANTES, SDF-1 α, SDF-1 β, MCP-1, MCP-2, MCP-4, Eotaxin and MDC etc..
The derivative of these endogenic ligands is specially AOP-RANTES, Met-SDF-1 α, Met-SDF-1 β etc..
The antibody specific of chemokine receptors is Pro-140 etc..
CCR2 antagonists are specifically recorded in WO99/07351, WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198, WO00/46199, WO00/69432 or WO00/69815 specification or Bioorg.Med.Chem.Lett.10, in 1803 (2000) etc..
CCR3 antagonists are specifically recorded in DE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835, WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449, WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877, WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172, WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/62814, in WO00/73327 or WO01/09088 etc. specification.
CCR5 antagonists are, for example, TAK-779, SCH-351125 (SCH-C), SCH-417690 (SCH-D), UK-427857, GW873140 (ONO-4128), TAK-220 etc..In addition, including being for example recorded in WO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153, WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239, WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559, WO00/66141, WO00/68203, JP2000309598, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/76933, WO98/25605, WO99/04794, in WO99/38514 specification or Bioorg.Med.Chem.Lett.,11, 2663 (2003), Curr.Med.Chem.Anti-Infective Agents,4, 133 (2005), Current Opinion inPharmacology,4, 447 (2004) or Current Opinion in Investigational Drugs,5, in 851 (2004) etc..
In specification of the CXCR3 antagonists such as being recorded in WO01/16114, WO02/083143, WO02/085862, US6469002 or WO03/101970.
CXCR4 antagonists are, for example, AMD-3100, AMD-070, T-22, KRH-1120, KRH-1636, KRH-2731 or the compound being recorded in WO00/66112 specification.
Integrase inhibitor is equisetin, Temacrazine, PL-2500, V-165, NSC-618929, L-870810, L-708906 analog, S-1360 or 1838 etc..
Fusion inhibitor is specifically T-20 (pentafuside) and T-1249 etc..
The example of above-mentioned combination medicine is intended to illustrate the present invention rather than limited.
The representative instance of the conventional dosage levels of RTI or protease inhibitors in clinical test is write exactly below, it is intended to illustrate the present invention rather than limited.
Zidovudine：100mg capsules, 200mg is per dosage, 3 times a day；
300mg tablets, 300mg is per dosage, twice daily；
Didanosine：25-200mg tablets, 125-200mg is per dosage, twice daily；
Zalcitabine：0.375-0.75mg tablets, 0.75mg is per dosage, 3 times a day；
Stavudine：15-40mg capsules, 30-40mg is per dosage, twice daily；
Lamivudine：150mg tablets, 150mg is per dosage, twice daily；
Abacavir：300mg tablets, 300mg is per dosage, twice daily；
NVP：200mg tablets, 200mg is per dosage, 14 days once a day, then twice daily；
Delavirdine：100mg tablets, 400mg is per dosage, 3 times a day；
Efavirenz：50-200mg capsules, 600mg is per dosage, once a day；
Indinavir：200-400mg capsules, 800mg is per dosage, 3 times a day；
Ritonavir：100mg capsules, 600mg is per dosage, twice daily；
Nelfinavir：250mg tablets, 750mg is per dosage, 3 times a day；
Inverase：200mg capsules, 1,200mg per dosage, 3 times a day；
Amprenavir：50-150mg tablets, 1,200mg per dosage, twice daily.
It is immunodepressant to combine with the compounds of this invention for the other medicines of prevention and/or treating organs naltrindole.
The example of immunodepressant includes tacrolimus (FK506), cyclosporin, sirolimus (rapamycin), corticosteroid, imuran, mycophenolate, FTY-720, endoxan or cell surface ligand antibody etc..
The example of cell surface ligand antibody includes antithymocyte gamma globulin (Atgam), Thymoglobuline (Thymoglobulin), Simulect, Zanapax or Orthoclone etc..
For being combined with the compounds of this invention so as to prevent and/or treat the other medicines e.g. nonsteroidal anti-inflammatory agent of autoimmune disease, alleviate the modifying antirheumatic drug (DMARDs of disease, the modifying antirheumatic drug slowly acted on), steroidal, immunodepressant agent, anti-inflammatory enzyme preparation, Chondroprotective agents, T- cytostatics, , TNF α inhibitor (including protein formulation such as Anti-tnfa antibody), prostaglandin synthase inhibitor, IL-1 inhibitor, IL-6 inhibitor (including the such as anti-IL-6 receptor antibodies of protein formulation), interleukin γ antagonists, prostaglandin, phosphodiesterase inhibitors, metal protease inhibitors etc..
The example of nonsteroidal anti-inflammatory agent includes disalicylic acid,Sodium salicylate,Aspirin,The aluminium porcelain enamelling of aspirin two,Diflonid,Indomethacin,Suprofen,Ufenamate,Guaiazulene,Bufexamac,Felbinac,Diclofenac,Tolmetin sodium,Sulindac,Fenbufen,napmetone,Proglumetacin,Indomethacin gefarnate,Acemetacin,Proglumetacin Maleate,Amfenac sodium,Mofezolac,Etodolac,Brufen,Ibuprofen piconol,Naproxen,Flurbiprofen (flurbiprofen),Axetil Flurbiprofen (flurbiprofen axethyl),Ketoprofen (ketoprofen),Fenoprofen (fenoprofen calcium),tiaprofenen,Olsapozine (oxaprozin),Pranoprofen (pranoprofen),Pranoprofen sodium (loxoprofen sodium),aluminoprofen,Zaltoprofen (zaltoprofen),Mefenamic acid (mefenamic acid),aluminum mefenamate,Tolfenamic Acid (tolfenamic acid),Floctafenine (floctafenine),Recheton (ketophenylbutazone),oxyfenbutazone,Piroxicam (piroxicam),Tenoxicam (tenoxicam),anpiroxicam,Felbinac emulsion (napageln cream),Epirizole (epirizole),Solantal (tiaramidehydrochloride),Tinoridine Hydrochloride (tinoridine hydrochloride),Emorfazone (emorfazone),Analgin (sulpyrine),Antipyrino-caffeinum citricum (Migrenin),Dissipate profit pain (Saridon),SedesG,Aminopropylon N (Amipylo N),Sorbon,Nicotinamide alexipyretic (pyrine systemantipyretics),Paracetamol (acetaminophen),Phenacetin (phenacetin),Fonazine mesylate (dimethothiazine mesylate),(simetride formulation) or antipyrine class alexipyretic (antipyrine system antipyretics) etc..
Alleviate the modifying antirheumatic drug (DMARD of disease, the modifying antirheumatic drug slowly acted on) for example including aurothioglucose (gold thioglucose), sodium aurothiomalate (aurothiomalate sodium), Anranofin (auranofin), Actarit (actarit), Beracilline preparation (D-penicillaminepreparations), Lobenzarit Disodium (lobenzarit disodium), Bucillamine (bucillamine), HCQ (hydroxychloroquine), SASP (salazosulfapyridine), methotrexate (MTX) (methotrexate), or leflunomide (leflunomide) etc..
External application steroid is for example including Clobesol (clobetasol propionate),Acetic acid diflorasone (diflorasone acetate),FA (fluocinonide),monometasone furancarboxylate,betamesone dipropionate,betamesone butyropropionate,betamesone valerate,Difluprednate (difluprednate),Budesonide (budesonide),Diflucortolone Valerate (diflucortolone valerate),Amcinonide (amcinonide),Halcinonide (halcinonide),Dexamethasone (dexamethasone),Propionic acid dexamethasone (dexamethasone propionate),Valeric acid dexamethasone (dexamethasone valerate),(dexamethasone acetate),(hydrocortisoneacetate),(hydrocortisone butyrate),(hydrocortisone acetopropionate),Propionic acid Deprodone (deprodone propionate),Prednisolone valerate acetate (prednisolone valeroacetate),FA (fluocinolone acetonide),Beclomethasone dipropionate (beclometasone dipropionate),triamcinonide acetonide,Flumethasone pivalate (flumethasone pivalate),Prednisolone (prednisolone),Beclomeasone propionate (beclometasone propionate) and fludroxycortide (fludroxycortide) etc..
Interior use or injection steroid are for example including cortisone acetate (cortisone acetate),Hydrocortisone (hydrocortisone),Hydrocortisone sodium phosphate (hydrocortisone sodium phosphate),Hydrocortisone sodium succinate (hydrocortisone sodium succinate),Fludrocortison (fludrocortisoneacetate),Prednisolone (prednisolone),Prednisolone acetate (prednisolone acetate),Prednisolone sodium succinate (prednisolone sodium succinate),Butylacetic acid prednisolone (prednisolone butylacetate),Inflamase (prednisolone sodium phosphate),Acetic acid Halopredone (halopredon acetate),Methylprednisolone (methyl prednisolone),Methylprednisolone acetic acid esters (methyl prednisolone acetate),Methylprednisolone sodium succinate (methylprednisolone sodium succinate),triamicinolon,triamicinolon acetate,triamicinonolon acetonide,Dexamethasone (dexamethasone),DEX A.A (dexamethasone acetate),Dexamethasone sodium phosphate (dexamethasone sodium phosphate),Dexamethasone palmitate (dexamethasone palmitate),Paramethasone acetate (paramethasoneacetate) and betamethasone (betamethasone) etc..
As the steroid of inhalant for example including beclomeasone propionate (beclomethasone propionate), fluticasone propionate (fluticasone propionate), budesonide (budesonide), flunisolide (flunisolide), triamicinolon, ST-126P, ciclesonide (ciclesonide), dexamethasonepalomitionate, monometasone furancarboxylate, Prasterone sulfate (prasteronesulfonate), deflazacort (deflazacort), Methylprednisolone Suleptanate (methylprednisolonesuleptanate) and Urbason Solubile (methylprednisolone sodium succinate) etc..
Anti-inflammatory enzyme preparation is such as including lysozyme chloride (lysozyme chloride), bromelain (bromelain), pronase (pronase), serrapeptase (serrapeptase) or chain kinase-link enzyme (streptokinase-streptodornase).
Chondroprotective agents are such as including hyaluronate sodium (hyaluronate sodium), aminoglucose (glucosamine), chondroitin sulfate (chondroitin sulfate) and glucosaminoglycan polysulfide sour (glucosaminoglycan polysulfate).
TNF α inhibitor is for example including protein formulation such as Anti-tnfa antibody, such as including infliximab (infliximab), adalimumab (adalimumab), Etanercept (etanercept).
Prostaglandin synthase inhibitor is for example including SASP (salazosulfapyridine), mesalazine (mesalazine), Olsalazine (olsalazine), 4-ASA (4-aminosalicylic acid), JTE-522, Anranofin (auranofin), Carprofen (carprofen), diphenpyramid, Flunoxaprofen (flunoxaprofen), fluoroprofen (flurbiprofen), Indomethacin (indomethacin), Ketoprofen (ketoprofen), Lornoxicam (lomoxicam), loxoprofen (loxoprofen), Meloxicam (Meloxicam), olsapozine (oxaprozin), Parsalmide (parsalmide), piperazine Bu Luoxin (piproxen), piroxicam (piroxicam), beta cyclodextrin compound (piroxicambetadex), piroxicam cinnamate (piroxicamcinnamate), antinfan tropine (tropineindomethacinate), Zaltoprofen (zaltoprofen), and pranoprofen (pranoprofen) etc..
IL-1 inhibitor is such as including protein formulation such as people IL-1 receptor antagonists for example including anakinra (anakinra).
IL-6 inhibitor is such as including the such as anti-IL-6 receptor antibodies of protein formulation for example including MRA.
Prostanoid (hereafter simply referred to as " PG ") is such as including PG receptor stimulating agents and PG receptor antagonists.PG acceptors are for example including PGE acceptors (EP1, EP2, EP3 and EP4), PGD acceptors (DP, CRTH2), PGF acceptors (FP), PGI acceptors (IP) or TX acceptors (TP), etc..
The example of phosphodiesterase inhibitors includes, for example, rolipram (rolipram), cilomilast (cilomilast) (trade name：Arino), Bay 19-8004, NIK-616, roflumilast (rofiumilast) (BY-217), Cipamfylline (cipam not lline) (BGL-61063), atizolam (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4386, IC-485, and ONO-6126 as PDE-4 inhibitor etc..
It is, for example, steroid, adrenergic stimulation thing, LTRA, thromboxane synthase inhibitor, thromboxane A for combining with the compounds of this invention for the other medicines for preventing and/or treating other allergic diseases such as asthma2Receptor antagonist, mediator release inhibitor, antihistamine, xanthine derivative, anticholinergic drug, chemokine inhibitors, prostanoid, Forskolin (forskolin), phosphodiesterase inhibitors, elastatinal, metal protease inhibitors, expectorant and antibiotic.
β2Adrenocepter stimulant is for example including Ipratropine (fenoterolhydrobromide),Salbutamol sulfate (salbutamol sulfate),Bricalin (terbutalinesulfate),Formoterol fumarate (formoterol fumarate),Salmeterol xinafoate (salmeterolxinafoate),isoprotenol sulfate,Metaproterenol sulfate (orciprenalin sulfate),The sweet chlorine of sulfuric acid is breathed heavily (chloroprenalin sulfate),Adrenaline (epinephrine),Trimethoquinol Hydrochloride (trimetoquinol hydrochloride),Methanesulfonic acid etoscol (hexoprenalinmesylsulfate),Procaterol Hydrochloride (procaterol hydrochloride),Tulobuterol (tulobuterolhydrochloride),Tulobuterol (tulobuterol),Pirbuterol hydrochloride (pirbuterolhydrochloride),Clenbuterol Hydrochloride (clenbuterol hydrochloride),Mabuterol Hydrochloride (mabuterol hydrochloride),Ritodrine hydrochloride (ritodrine hydrochloride),Bambuterol (bambuterol),Dopexamine hydrochloride (dopexamine hydrochloride),meradrin tartrate,AR-C68397,Levosalbutamol (levosalbutamol),R,R- Formoterols (R,R-formoterol),KUR-1246,KUL-7211,AR-C89855,S-1319.
LTRA is for example including pranlukast hydrate (pranlukast hydrate), montelukast (montelukast), zafirlukast (zafirlukast), Seratrodast (seratrodast), (MCC-847), (KCA-757), (CS-615), (YM-158), (L-740515), (CP-195494), (LM-1484), (RS-635), (A-93178, S-36496, BIIL-284 and ONO-4057 etc..
Thromboxane synthetase inhibitor is such as including ozagrel hydrochloride (ozagrel hydrochloride) and Imitrodast (imitrodast sodium).
Thromboxane A2 receptor antagonist is such as including the bent department (seratrodast) of plug, Leimaquban (ramatroban), domitroban calcium dihydrate (domitroban calcium dihydrate) and KT-2-962.
The example of mediator release inhibitor includes tranilast (tranilast), nasmil (sodiumcromoglicate), anlexanox, Repirinast (repirinast), Ibudilast (ibudilast), Tazanolast (tazanolast), and Pemirolast (pemilolast) sodium etc..
The example of antihistamine includes Ketotifen (ketotifenfumarate), mequitazine (mequitazine), nitrogenSTING (azelastine hydrochloride), Oxatomide (oxatomide), RMI 9918 (terfenadine), emedastine difumarate (emedastinefumarate), epinastine hydrochloride (epinastinehydrochloride), astemizole (astemizole), Ebastine (ebastin), cetirizine hydrochloride (cetirizinehydrochloride), bepotastine (bepotastine), fexofenadine (fexofenadine), lolatadine, deslolatadine, olopatadine hydrochloride (olopatadinehydrochloride), TAK-427, ZCR-2060, NIP-530, mometasone furoate, Mizolastine (mizolastine), BP-294, appropriate many departments are special (andolast), Anranofin, and acribastin etc..
Xanthine derivative is such as including aminophylline (aminophylline), thoeophyline, doxophylline, Cipamfylline (cipamfylline) and diprophilline.
Anticholinergic drug is such as including Ipratropium Bromide (ipratropium bromide), oxitropium bromide (oxitropium bromide), Flutropium Bromide (flutropium bromide), temiverine (temiverine), Tiotropium Bromide (tiotropium bromide) and Revatropate (revatropate (UK-112166)).
Chemokine inhibitors are for example including Suplatast Tosilate (trade name：IPD)) etc..
Elastatinal is such as including (ONO-5046), (ONO-6818), (MR-889), (PBI-1101), (EPI-HNE-4), (R-665), (ZD-0892), (ZD-8321), (GW-311616) and AE-3763.
Expectorant is for example including foeniculated ammonia spirit (foeniculated ammonia spirit), sodium acid carbonate, bromhexine hydrochloride (bromhexine hydrochloride), carbocisteine (carbocisteine), Ambroxol Hydrochloride (ambroxol hydrochloride), it is sustained Ambroxol Hydrochloride (sustained release ambroxolhydrochloride), Methylcysteine Hydrochloride (methylcysteine hydrochloride), acetylcysteine, L- ethyl cysteine hydrochlorides and tyloxapol (tyloxapol) etc..
Antibiotic is for example including Cefuroxime Sodium (cefuroxime sodium), Meropenem trihydrate (meropenem trihydrate), Netilmicin Sulfate (netilmicin sulfate), mensiso (sisomicin sulfate), Ceftibuten (ceftibuten), (PA-1806), (IB-367), TOB (tobramycin), (PA-1420), Doxorubicin (doxorubicin), astromicin sulfate (astromicinsulfate) or hydrochloric acid cefetamet (cefetamet pivoxil hydrochloride) etc..
As the antibiotic of suction such as including (PA-1806), (IB-367), (tobramycin), (PA-1420), Doxorubicin (doxorubicin), astromicin sulfate (astromicin sulfate) or hydrochloric acid cefetamet (cefetamet pivoxil hydrochloride).
The other medicines of prevention and/or the therapeutic action of supplement and/or enhancing the compounds of this invention are not limited to examples detailed above.As for the other medicines of prevention and/or the therapeutic action of supplement and/or enhancing the compounds of this invention, the medicine that will be apparent that based on above-mentioned mechanism is not only also included including the medicine that section has now found that.
The nomenclature of the compounds of this invention is described as follows.
All compounds of this specification description use ACD/Name (registration marks, AdvancedChemistry Development Inc.) or ACD/Name Batch (registration mark, AdvancedChemistry Development Inc.) name or according to IUPAC naming systems name.For example, following formula: compound
Figure G200580038925420070516D000561
It is named as N- [6- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) -3- pyridine radicals] methanesulfonamide hydrochloride
In this manual, " hydrochloride (or dihydrochloride) " means hydrochloride or dihydrochloride, and it does not represent the mixture of hydrochloride and dihydrochloride.In this manual, " dihydrochloride (or tri hydrochloride) " means dihydrochloride or tri hydrochloride, and it does not represent the mixture of dihydrochloride or tri hydrochloride.Shown in this specification in structure " HCl or 2HCl " mean HCl or 2HCl, therefore its HCl and 2HCl mixture for not representing.Shown in this specification in structure " 2HCl or 3HCl " mean 2HCl or 3HCl, therefore its 2HCl and 3HCl mixture for not representing.
Invention effect：
The compounds of this invention represented by formula (I) has antagonism chemokine receptors especially CCR5 activity, therefore they are applied to prevent and/or treatment CCR5- relevant diseases.
The fact that the compounds of this invention has CCR5 antagonistic activities is for example demonstrated by following experiment.Genetic engineering of the overall operation based on basis is so as to preparing cell that gene altimeter reaches and use conventional method.In addition, when evaluating the method for the present invention, in order to evaluate the compounds of this invention, the degree of accuracy of measurement and/or the sensitivity of measurement are demonstrated as follows.Detailed test method has been expressed below.
(I) RANTES combinations CCR5 test is suppressed
(1) CCR5 gene is separated
Human plactnta cDNA is prepared using Marathon cDNA amplification kits (Clontech).Based on GenBank U54994 sequences Design PCR primers hCCR5XbaI-F1：
5′-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3′(SEQ IDNO：1)
And hCCR5XbaI-R1：
5′-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3′(SEQID NO：2).
Using Human plactnta cDNA as masterplate and using Ex Taq (Takara) enter performing PCR react (in 95 DEG C 2 minutes → (in 95 DEG C 30 seconds, in 60 DEG C 45 seconds, in 72 DEG C 1 minute) x35 times).Thus the PCR primer expanded is subjected to 1% agarose gel electrophoresis, purified using QIAquick Gel ExtractionKit (QUIAGEN), is digested with restriction enzyme XbaI.The fragment digested is connected to expression vector using DNA Ligation Kit Ver.2 (Takara) and transduceed into Escherichia coli DH5 α.By preparing plasmid pEF-BOS-bsr/hCCR5, it was confirmed that DNA sequence dna.
(2) culture of Chinese hamster ovary celI
Use Ham ' s F-12 (including hyclone (10%), penicillin (50U/ml) and streptomysin (50mg/ml)) culture CHO-dhfr (-).Blasticidin (5mg/ml) is added into above-mentioned culture medium to cultivate the cell transduceed.
(3) transduce into Chinese hamster ovary celI
Plasmid pEF-BOS-bsr/hCCR5 is transduceed in CHO-dhfr (-) cell using DMRIE-C reagents (Gibco BRL).After 48 hours, culture medium is replaced with into the culture medium comprising 5mg/ml blasticidins stable overexpressing cell is set up to be selected, thus.
(4) chemokine inhibiting (RANTES, MIP-1 α and MIP-1 β) is incorporated into CCR5 test (chemotactic factor (CF) induces Ca ions temporarily elevated activity)
Thus the stable Chinese hamster ovary celI (CCR5/CHO cells) for the overexpression CCR5 set up is suspended in the Ham ' s F-12 culture mediums comprising FBS (10%), with 3.5x104The density of individual cells/well is seeded in 96- orifice plates.After 37 DEG C are cultivated one day, culture supernatant is discarded, Ham ' s F-12 culture mediums (are included into Fura-2AM (5 μM), probenecid (2.5mM) and HEPES (20mM；PH 7.4)) suspended with every part of 80 μ l/ holes, cultivated 1 hour in 37 DEG C under the conditions of lucifuge.With 1x Hanks/HEPES (20mM；PH 7.4) after solution washes twice, the solution is suspended with every part of 100 μ l/ holes.Each test compound is added to the CCR5/CHO cells of the Fura-2AM- connections, after 3 minutes, added thereto through 1xHanks/HEPES (20mM；PH 7.4) solution dilution recombined human CCR5 parts (RANTES, MIP-1 α or MIP-1 β) (PeproTach) to final concentration (Rantes：10nM；MIP-1α：30nM；MIP-1β：30nM).Use the Ca for 96 orifice plates2+The intracellular Ca that detector (Hamamatsu Photonics) measurement is induced by CCR5 part2+The of short duration rise of concentration, the inhibiting rate (%) of test compound is calculated by following calculation formula.
Inhibiting rate=(Ec-Ea)/Ec × 100
Ec：The Ca induced by CCR5 parts2+Of short duration elevated measured value
Ea：Add the Ca induced during test compound by CCR5 parts2+Of short duration elevated measured value
(II) the migration test of CCR5 expression cell (hCCR5-Ba/F3 cells)：
(1) foundation of CCR5 expression cell
(1-A) separates CCR5 gene
CCR5 Gene Isolation method according to above method (I)-(1) carries out the separation
(1-B) cultivates Ba/F3 cells
In carbon dioxide culture apparatus (temperature：37 DEG C, CO2Concentration：5%, humidity：95%) used in and antibiotic (antibiotic-antimycoin) (final concentration is included in RMMI-1640 culture mediums (Gibco BRL) quiescent culture Ba/F3 cells, culture medium：Novocillin (100U/ml), streptomycin sulphate (100 μ g/ml), amphotericin B (0.25 μ g/ml) (Gibco BRL), hyclone (FBS) (10%), 2 mercapto ethanol (55 μM), mouse interleukin-3 (IL-3) (5ng/ml) (Pepro Tech, Inc).The stable overexpressing cell of external source type gene is cultivated in above-mentioned culture medium, blasticidin (Kaken Pharmaceutical) is added thereto to the μ g/ml of final concentration 10.
(1-C) is converted to Ba/F3 cells
The plasmid (pEF-BOS-bsr/hCCR5) for expressing CCR5 digests and linearized through AatII.The plasmid of the linearisation is purified through QIA QIAquick PCR purification kits (QIAGEN), and electroporated (GenePulser (BIO RAD), 960 μ F/250V) enters Ba/F3 cells.With 1,000, the density in the μ l/ holes of 100,10 cells/100 cell is seeded in 96 orifice plates, cultivate 48 hours.Then blasticidin is added thereto to the μ g/ml of final concentration 10, sets up with rear clone blastocidin-resistance cell line and thus the stable clone (hCCR5-Ba/F3 cells) for the allogenic gene for being overexpressed transduction.
The analysis of (1-D) CCR5 expression
By detecting Anti-Human CCR5 antibody (BDPharmingen) FAC Sort (trade names with fluorescence isothiocyanic acid (FITC)-mark, Becton, Dickinson) detect and analyze the expression of CCR5 in the above method (1-C) institute DCRP.Herein, the mouse IgG 2a κ (BDPharmingen) of FITC- marks are used as special-shaped control antibodies.
(2) cell migration is tested
Test compound be have detected for expressing the influence that the Ba/F3 cells of CCR5 resist RANTES, MIP-1 α or MIP-1 β transfer ability.First, culture mediums of the 0.3ml comprising 0 or 3nM chemotactic factor (CF)s (RANTES, MIP-1 α or MIP-1 β) is added separately to the lower opening of the orifice plate (Neuro Probe) of Chemo T × 96.Then, filter (aperture is placed：5 μm), add the 65 previously prepared test compounds of μ l and the mixed solution (1 × 10 of CCR5-Ba/F3 cells5Individual cells/well).When preparing added test compound, using the culture medium dilution comprising 0.1%DMSO so as to obtain on filter final concentration of 0,0.01,0.03,0.1 or 0.3 μM.These cells are in CO2Incubator (37 DEG C, 5%CO2, relative humidity：95%) culture 3 hours in, then remove the culture medium on filter and the cell not migrated.Then, filter is removed, (1,500rpm, 10min, RT) microplate is centrifuged, decantation removes supernatant.Cell on microplate is suspended in 100 μ l phosphate buffers (PBS), its 1/10 part further dilutes through 90 μ l PBS, mobile on blank to carry out fluorescence test, and the test sample as migrating cell number is (final：100 μ l/ holes).
Then, to previously prepared CellTiter-Glo reagents (trade name at room temperature, Promega) it is added in the above-mentioned test sample for migrating cell number in (100 μ l/ holes), it is then slight to mix (300rpm, use IKA-SCHUTTLER MTS42min) to dissolve cell, the mixture was in incubated at room temperature 10 minutes, it is luminous (being detected through counting/second) using wallac ARVO SX 1420MULTILABEL COUNTER (trade name, PerkinElmer) measurements.
Migrating cell number (cell number (naturallyfalling cell numbers) declined naturally) during 0nmol/l chemotactic factor (CF) concentration calculates inhibiting rate of the test compound relative to 0.1%DMSO control groups as background.
The inhibition of metastasis rate (%) of test compound is calculated by equation：
Inhibiting rate=(Ec-Ea)/Ec × 100
Ec：(adding measured value luminous during 0.1%DMSO)
- (the luminescence assays value for declining cell naturally)
Ea：(adding measured value luminous during test compound)-(the luminescence assays value for declining cell naturally)
Preferred embodiment of the present invention
Following preparation embodiment, biological Examples and example of formulations is intended to illustrate the present invention rather than meaning is confined to this.
In chromatographic isolation and TLC, the solvent in bracket represents elution and developing solvent, and the ratio of solvent for use is volume ratio.
NMR is measured1H NMR values.Solvent in NMR brackets represents measurement solvent.
Prepare embodiment
Embodiment 1
N- [6- (4- formvlphenoxvs) pyridin-3-yl] Methanesulfomide
The nitro of { 4- [(5- nitropyridine -2- bases) epoxide] phenyl } methanol is reduced using zinc and acetic acid, gained compound is reacted with mesyl chloride in pyridine, gained compound obtains title compound through manganese dioxide, with following physical data.
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.67；
NMR(CDCl3)：δ 3.04,6.56,7.05,7.29,7.80,7.94,8.08,9.99.
Embodiment 2
N- butyl-N '-(2,4- difluorophenyl)-N- piperidin-4-yl urea hydrochlorides
Triethylamine (1.6ml) and 2,4- difluorophenyl isocyanate (907mg) are added into dimethyl acetamide (13ml) solution of 4- (butylamino) piperidines -1- carboxylic acid tert-butyl esters (1g).The reactant mixture is stirred at room temperature 5 minutes.The saturated aqueous solution of sodium acid carbonate is added into reactant mixture, is extracted with ethyl acetate.Extract is through water and salt water washing, anhydrous sodium sulfate drying, concentration.The ethyl acetate solution (10ml) of 4N hydrogen chloride is added into gained compound (1.28g) ethyl acetate (2ml) solution.Reactant mixture is stirred at room temperature 20 minutes, concentrates.Gained residue is washed through t-butyl methyl ether, is dried to obtain title compound, with following physical data.
TLC：(the dichloromethane: methanol: acetic acid=5: 1: 0.1) of Rf 0.52；
NMR(CD3OD)：δ 0.99,1.34-1.47,1.60-1.71,1.95-2.01,2.08-2.22,3.03-3.13,3.27-3.34,3.44-3.50,4.13,7.00,7.37,8.01.
Embodiment 3
N- [6- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) -3- pyridine radicals] methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D000611
Acetic acid (0.15ml) and Sodium triacetoxyborohydride (116mg) are added into dimethylformamide (1.5ml) solution of compound prepared by compound (95mg) prepared by embodiment 1 and embodiment 2 (80mg).Reactant mixture is stirred at room temperature 18 hours.Reactant mixture is added to the saturated aqueous solution of sodium acid carbonate, is extracted with ethyl acetate.Extract is washed through anhydrous sodium sulfate, concentration.Gained residue is on silica gel through column chromatography eluting (ethyl acetate: methanol=10: 1).Gained compound is dissolved in ethyl acetate, and adds the ethyl acetate solution of 4N hydrogen chloride.Concentrated reaction mixture obtains title compound (115mg), with following physical data.
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.98,1.35-1.48,1.58-1.70,1.95-2.08,2.18-2.34,3.00,3.08-3.20,3.25-3.34,3.57-3.65,4.19,4.34,6.89-7.03,7.09,7.25,7.38,7.60,7.85,8.06.
Embodiment 3 (1) -3 (107)
By the same procedure described in embodiment 3, using corresponding amines and corresponding aldehyde compound, following the compounds of this invention is obtained.
Embodiment 3 (1)
N- { 4- [(6- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } -3- pyridine radicals) epoxide] phenyl } methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.30；
NMR(CD3OD)：δ 0.99,1.30-1.50,1.60-1.80,1.90-2.10,2.20-2.40,2.97,3.20-3.40,3.60-3.70,4.20,4.47,6.92-7.02,7.09-7.12,7.31-7.40,7.47-7.58,8.45.
Embodiment 3 (2)
N- { 4- [4- ({ 4- [{ [(2- hydroxybutyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.89,1.20-1.42,1.55-1.70,2.05-2.17,2.95,3.08-3.28,3.37-3.50,4.21,4.51,7.00,7.02,7.21-7.30,7.41,7.44-7.55.
Embodiment 3 (3)
N- { 4- [4- ({ 4- [butyl ({ [1- (2- hydroxyethyls) -1H- pyrazoles -4- bases] amino } carbonyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } Methanesulfomide dihydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.97,1.31-1.42,1.50-1.72,1.91-2.01,2.15-2.31,2.95,3.10-3.32,3.51-3.60,3.87,4.23,4.30,4.35,7.03,7.06,7.29,7.53,7.98,8.12.
Embodiment 3 (4)
5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluoro-N-methyl benzamide hydrochloride salts
Figure G200580038925420070516D000631
TLC：(the chloroforms: methanol=4: 1) of Rf 0.90；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.10-2.30,2.91,2.95,3.00-3.20,3.20-3.40,3.50-3.60,4.15,4.29,7.02-7.09,7.12,7.29,7.50,7.78.
Embodiment 3 (5)
N- { 4- [4- ({ 4- [{ [(trans -4- hydroxy-cyclohexyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 1.00-1.18,1.21-1.37,1.55-1.68,1.71-1.89,2.04-2.15,2.95,3.04-3.18,3.38-3.54,4.21,4.60,6.98-7.07,7.18-7.23,7.28,7.41,7.45-7.53.
Embodiment 3 (6)
N- [4- (4- { [4- (the dilute base of 3- fourths (butenyl) { [(2- hydroxybutyls) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) phenyl] methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 0.95,1.30-1.58,1.90-2.00,2.07-2.24,2.28-2.38,2.95,3.02-3.35,3.50-3.60,4.12,4.28,5.05,5.11,5.81,7.03,7.06,7.29,7.50.
Embodiment 3 (7)
N- butyl-N '-(2,4- difluorophenyl)-N- (1- { 4- [4- (4- morpholinosulfonyls) phenoxy group] benzyl } -4- piperidyls) urea hydrochloride
TLC：(the dichloromethane: methanol=20: 1) of Rf 0.60；
NMR(CD3OD)：δ 0.99,1.39-1.43,1.60-1.70,2.00-2.05,2.16-2.30,2.94-2.97,3.06-3.28,3.29-3.36,3.52-3.61,3.69-3.72,4.13,4.23,6.90-7.03,7.20,7.23,7.37,7.58,7.78.
Embodiment 3 (8)
N- butyl -2- (2,4- difluorophenyl)-N- [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] acetamide hydrochloride
TLC：(the chloroforms: methanol=10: 1) of Rf 0.41；
NMR(d6-DMSO)：δ 0.92,1.20-1.40,1.40-1.60,1.70-1.90,2.20-2.40,2.90-3.10,2.97,3.15-3.30,3.30-3.50,3.71,4.05-4.30,6.94-7.09,7.12-7.25,7.57,9.34,10.50.
Embodiment 3 (9)
N- { 4- [(5- { [4- (butyl { [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.16；
NMR(CD3OD)：δ 0.96,1.30-1.45,1.50-1.65,1.90-2.05,2.20-2.35,2.98,3.10-3.40,3.50-3.70,4.00,4.20,4.36,7.09-7.16,7.32,7.95,8.06,8.08,8.31.
Embodiment 3 (10)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [4- (methylsulfany (methylsulfanyl)) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.67；
NMR(CD3OD)：δ 1.60-1.79,2.10-2.20,2.51,2.95,3.08-3.20,3.42-3.55,4.22,4.64,6.95,7.02,7.03,7.15-7.31,7.39,7.42.
Embodiment 3 (11)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [3- (methylsulfany) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.67；
NMR(CD3OD)：δ 1.62-1.80,2.12-2.20,2.51,2.95,3.04-3.22,3.42-3.57,4.22,4.64,6.89-7.10,7.17-7.32,7.34-7.49.
Embodiment 3 (12)
The fluoro- N- of N- butyl -2,4- bis- [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] benzamide hydrochloride salt
TLC：(the chloroforms: methanol=10: 1) of Rf 0.41；
NMR(d6-DMSO)：δ 0.70-0.90,1.10-1.30,1.40-1.60,1.75-1.90,2.30-2.55,2.80-3.05,2.96,3.10-3.45,4.00,4.17,7.00,7.01-7.04,7.12,7.19-7.30,7.42,7.57,9.35.
Embodiment 3 (13)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [4- (methylsulfinyl) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.47；
NMR(CD3OD)：δ 1.67-1.83,2.14-2.23,2.84,2.95,3.10-3.21,3.46-3.55,4.23,4.67,6.96,7.00,7.02,7.23,7.28,7.43,7.54,7.84.
Embodiment 3 (14)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [3- (methylsulfinyl) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.47；
NMR(CD3OD)：δ 1.62-1.80,2.14-2.25,2.86,2.95,3.08-3.21,3.47-3.55,4.23,4.66,6.96,7.01,7.02,7.20-7.30,7.42,7.51,7.66,7.70-7.80.
Embodiment 3 (15)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [4- (methyl sulphonyl) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 1.70-1.88,2.14-2.23,2.95,3.10-3.20,3.16,3.46-3.55,4.23,4.64,6.96,7.01,7.02,7.24,7.28,7.43,7.57,8.08.
Embodiment 3 (16)
N- (4- { 4- [(4- { { [(4- fluorophenyls) amino] carbonyl } [3- (methyl sulphonyl) phenyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 1.64-1.80,2.17-2.28,2.95,3.10-3.21,3.19,3.45-3.55,4.23,4.67,6.96,7.01,7.02,7.24,7.28,7.42,7.66,7.78,7.89,8.05.
Embodiment 3 (17)
N- [4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) -3- methoxyphenyls] methanesulfonamide hydrochloride
TLC：(the chloroforms: methanol=10: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.15-2.30,2.99,3.05-3.20,3.20-3.40,3.50-3.60,3.74,4.15,4.25,6.85-6.95,6.99,7.03,7.38,7.43.
Embodiment 3 (18)
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
Figure G200580038925420070516D000661
TLC：(the chloroforms: methanol=10: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.98,1.30-1.45,1.55-1.70,1.95-2.10,2.15-2.35,2.98,3.05-3.20,3.25-3.35,3.50-3.65,4.15,4.34,7.09-7.18,7.33,7.86,8.03,8.28.
Embodiment 3 (19)
5- { [(butyl { 1- [(5- { 4- [(methyl sulphonyl) amino] phenoxy group } -2- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides
TLC：(the chloroforms: methanol=10: 1) of Rf 0.36；
NMR(CD3OD)：δ 0.99,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.40,2.96,3.20-3.40,3.60-3.70,4.20,4.45,7.10,7.15,7.33,7.44-7.50,7.87,8.44.
Embodiment 3 (20)
5- [({ butyl [1- (4- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.34；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.10-2.30,2.99,3.05-3.20,3.20-3.40,3.50-3.60,3.74,4.15,4.25,6.87,6.92,7.03,7.14,7.42,7.85.
Embodiment 3 (21)
5- [({ butyl [1- (4- { the chloro- 4- of 2- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.10-2.30,3.01,3.10-3.20,3.25-3.35,3.50-3.60,4.15,4.28,6.99,7.13,7.14,7.24,7.43,7.50,7.85.
Embodiment 3 (22)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- (2- hydroxyethyls) benzenesulfonamide, hydrochloride
TLC：(the dichloromethane: methanol=10: 1) of Rf 0.69；
NMR(CD3OD)：δ 0.98,1.36-1.43,1.59-1.70,1.98-2.03,2.18-2.30,2.96,3.09-3.30,3.54,3.54-3.61,4.16,4.33,6.90-7.03,7.16,7.20,7.37,7.59,7.86.
Embodiment 3 (23)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- [2- (dimethylamino) ethyl] benzsulfamide dihydrochloride
TLC：(the dichloromethane: methanol=2: 1) of Rf 0.56；
NMR(CD3OD)：δ 0.98,1.33-1.46,1.59-1.70,1.96-2.00,2.20-2.35,2.93,3.05-3.12,3.17-3.30,3.52-3.56,4.18,4.30,6.89-7.03,7.19,7.37,7.61,7.90.
Embodiment 3 (24)
N- { 4- [4- ({ 4- [{ [(2,4- difluorophenyl) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } methanesulfonamide hydrochloride
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.76；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.95,3.05-3.20,3.40-3.55,4.21,4.65,6.85-6.96,6.99-7.04,7.28,7.35-7.40,7.41,7.51-7.58.
Embodiment 3 (25)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- Methyl benzenesulfonyl amine hydrochlorates
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.63；
NMR(CD3OD)：δ 0.98,1.36-1.46,1.59-1.70,1.99-2.04,2.17-2.30,2.53,3.07-3.17,3.24-3.35,3.57-3.61,4.15,4.33,6.89-7.03,7.16,7.20,7.36,7.57,7.83.
Embodiment 3 (26)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N, N- dimethyl benzene sulfonamide hydrochlorides
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.67；
NMR(CD3OD)：δ 0.98,1.34-1.46,1.60-1.70,1.99-2.03,2.19-2.30,2.68,3.09-3.17,3.25-3.36,3.57-3.61,4.16,4.33,6.89-7.03,7.18,7.21,7.36,7.59,7.78.
Embodiment 3 (27)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- (2- methoxy ethyls) benzenesulfonamide, hydrochloride
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.60；
NMR(CD3OD)：δ 0.98,1.34-1.46,1.60-1.70,1.99-2.03,2.19-2.30,3.03,3.09-3.17,3.26,3.26-3.30,3.36,3.56-3.61,4.16,4.33,6.89-7.03,7.14,7.19,7.37,7.57,7.85.
Embodiment 3 (28)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- tetrahydrochysene -2H- pyrans -4- base benzenesulfonamide, hydrochlorides
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.57；
NMR(CD3OD)：δ 0.98,1.36-1.53,1.63-1.68,2.01-2.04,2.21-2.25,3.07-3.37,3.57-3.61,3.81-3.85,4.14,4.33,4.80,6.89-7.03,7.14,7.19,7.36,7.57,7.87.
Embodiment 3 (29)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D000691
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 1.60-1.80,2.12-2.23,2.97,3.11-3.24,3.48-3.58,4.27,4.67,6.95,7.06,7.11,7.21,7.28-7.35,7.48-7.60,7.90,8.18.
Embodiment 3 (30)
N- [5- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) -2- pyridine radicals] methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 0.97,1.34-1.44,1.58-1.68,1.96-2.05,2.15-2,31,3.03-3.18,3.28,3.25-3.33,3.52-3.60,4.17,4.30,6.88-7.04,7.12,7.14,7.37,7.51-7.60,8.10.
Embodiment 3 (31)
5- ({ [butyl (1- { 4- [4- (4- morpholinosulfonyls) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.35,2.96,3.00-3.20,3.20-3.40,3.50-3.60,3.71,4.10,4.33,7.11-7.24,7.59,7.78,7.87.
Embodiment 3 (32)
5- [({ butyl [1- (4- { 4- [(tetrahydrochysene -2H- pyrans -4- bases amino) sulfonyl] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.30,3.10-3.20,3.20-3.40,3.50-3.70,3.80-3.90,4.15,4.33,7.11-7.21,7.60,7.87,7.88.
Embodiment 3 (33)
5- [({ butyl [1- (4- { 2,6- dimethyl -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.34；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.08,2.20-2.30,2.99,3.00-3.20,3.20-3.40,3.50-3.60,4.15,4.26,6.86,7.04,7.14,7.45,7.85.
Embodiment 3 (34)
5- [({ butyl [1- (4- { 4- [methyl (methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.15-2.30,2.99,3.00-3.20,3.20-3.40,3.30,3.50-3.60,4.15,4.30,7.05-7.18,7.45,7.52,7.86.
Embodiment 3 (35)
5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] benzyl } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=10: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.15-2.30,2.91,3.00-3.20,3.20-3.40,3.50-3.60,3.98,4.15,4.27,7.10-7.20,7.34,7.44,7.85.
Embodiment 3 (36)
5- { [(butyl { 1- [(3; 5- dimethyl -1- { 4- [(methyl sulphonyl) amino] phenyl } -1H- pyrazoles -4- bases) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.20；
NMR(CD3OD)：δ 0.98,1.34-1.47,1.60-1.72,1.98-2.10,2.27-2.50,2.39,2.43,3.04,3.12-3.40,3.65-3.75,4.24,4.29,7.15,7.43,7.49,7.87.
Embodiment 3 (37)
5- ({ [(1- { 4- [4- (amino-sulfonyl) phenoxy group] benzyl } -4- piperidyls) (butyl) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.98,1.35-1.47,1.58-1.70,1.97-2.08,2.18-2.32,3.08-3.20,3.23-3.35,3.52-3.63,4.16,4.33,7.10-7.24,7.58,7.64,7.90.
Embodiment 3 (38)
5- [({ butyl [1- (4- { 4- [(methylamino) sulfonyl] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
Figure G200580038925420070516D000721
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.47；
NMR(CD3OD)：δ 0.98,1.32-1.47,1.60-1.71,1.98-2.10,2.20-2.36,2.53,3.08-3.20,3.26-3.35,3.52-3.64,4.18,4.33,7.14,7.16,7.19,7.60,7.83,7.86.
Embodiment 3 (39)
5- [({ butyl [1- (4- { 4- [(dimethylamino) sulfonyl] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 0.98,1.32-1.49,1.59-1.72,1.97-2.09,2.19-2.38,2.68,3.08-3.21,3.23-3.35,3.58-3.64,4.16,4.34,7.14,7.19,7.21,7.60,7.79,7.86.
Embodiment 3 (40)
N- [4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) -3- aminomethyl phenyls] methanesulfonamide hydrochloride
TLC：(the chloroforms: methanol=10: 1) of Rf 0.39；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.10-2.30,2.16,2.96,3.00-3.20,3.20-3.40,3.50-3.60,4.15,4.27,6.91-6.99,7.13,7.20,7.36,7.46.
Embodiment 3 (41)
5- [({ butyl [1- (4- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
White amorphous powder；
TLC：(the chloroforms: methanol=10: 1) of Rf 0.28；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.55-1.70,1.90-2.10,2.10-2.30,2.16,2.96,3.00-3.20,3.20-3.40,3.50-3.60,4.10,4.26,6.91-6.97,7.11-7.20,7.46,7.86.
Embodiment 3 (42)
4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] benzoate hydrochlorate
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.49；
NMR(CD3OD)：δ 0.98,1.35-1.45,1.60-1.70,1.98-2.03,2.20-2.30,3.10-3.34,3.56-3.60,4.16,4.33,7.07,7.14,7.18,7.57,7.86,8.04.
Embodiment 3 (43)
5- { [(butyl { 1- [(6- { the chloro- 4- of 2- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.20-2.40,3.02,3.10-3.25,3.25-3.40,3.50-3.60,4.20,4.35,7.10-7.26,7.43,7.86,8.09,8.26.
Embodiment 3 (44)
5- { [(butyl { 1- [(6- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 0.97,1.33-1.47,1.58-1.71,1.97-2.08,2.20-2.38,3.01,3.07-3.21,3.25-3.35,3.
Figure G200580038925420070516D000731
5-3.65,3.72,4.18,4.35,6.90,7.04-7.19,7.86,8.08,8.29.
Embodiment 3 (45)
5- ({ [butyl (1- { 4- [4- (methyl sulphonyl) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：Rf0.50 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 0.98,1.35-1.48,1.59-1.70,1.98-2.08,2.19-2.34,3.12,3.08-3.21,3.25-3.35,3.55-3.64,4.16,4.34,7.14,7.21,7.22,7.61,7.86,7.95.
Embodiment 3 (46)
4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) phenoxy group] benzoate hydrochlorate
TLC：Rf0.49 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.67-1.80,2.12-2.22,3.12-3.24,3.48-3.55,4.26,4.68,6.95,7.05,7.14,7.22,7.33,7.47-7.60,8.03.
Embodiment 3 (47)
4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -3- methoxy benzoic acid hydrochlorides
TLC：(the chloroforms: methanol=3: 1) of Rf 0.66；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.10-2.35,3.05-3.20,3.25-3.35,3.50-3.60,3.82,4.10,4.28,6.98,7.09,7.15,7.47,7.77,7.75,7.86.
Embodiment 3 (48)
4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -3- chlorobenzoic acid hydrochlorides
TLC：(the chloroforms: methanol=3: 1) of Rf 0.65；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.35,3.05-3.20,3.25-3.35,3.50-3.60,4.10,4.33,7.10-7.17,7.57,7.86,7.95,8.14.
Embodiment 3 (49)
4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -3- nitrobenzoic acid hydrochlorides
TLC：(the chloroforms: methanol=3: 1) of Rf 0.51；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.35,3.00-3.15,3.20-3.35,3.50-3.60,4.15,4.29,7.10-7.20,7.58,7.86,8.20,8.56.
Embodiment 3 (50)
5- [({ butyl [1- (4- { 3- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：Rf0.42 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 0.98,1.32-1.47,1.58-1.70,1.97-2.08,2.17-2.31,2.91,3.06-3.20,3.24-3.35,3.51-3.63,3.86,4.13,4.29,6.57,6.81,7.10,7.14,7.36,7.51,7.86.
Embodiment 3 (51)
5- [({ butyl [1- (4- { the chloro- 4- of 3- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.98,1.32-1.48,1.60-1.72,1.98-2.08,2.12-2.31,3.00,3.08-3.20,3.24-3.35,3.52-3.62,4.15,4.31,7.00,7.10-7.20,7.51-7.59,7.86.
Embodiment 3 (52)
5- ({ [butyl (1- { [6- (4- methoxyphenoxies) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.39；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.70,1.90-2.10,2.20-2.35,3.05-3.20,3.20-3.35,3.50-3.65,3.81,4.20,4.34,6.97-7.20,7.86,8.05,8.31.
Embodiment 3 (53)
4- { [5- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } benzoate hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=3: 1) of Rf 0.63；
NMR(CD3OD)：δ 0.97,1.30-1.45,1.55-1.70,1.85-2.00,2.05-2.20,2.65-2.85,3.20-3.40,4.05,4.10,7.09-7.21,7.89,7.97,8.07,8.23.
Embodiment 3 (54)
N- (4- { 4- [(4- { phenyl [(tetrahydrochysene -2H- pyrans -4- bases amino) carbonyl] amino } -1- piperidyls) methyl] phenoxy group } phenyl) methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 1.24-1.40,1.55-1.75,2.05-2.15,2.95,3.04-3.18,3.34-3.50,3.68-3.84,4.21,4.60,6.98-7.04,7.22,7.28,7.41,7.45-7.56.
Embodiment 3 (55)
5- { [(butyl { 1- [(5- { 4- [(methyl sulphonyl) amino] phenoxy group } -2- pyrazinyls) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.99,1.34-1.48,1.59-1.72,1.98-2.08,2.21-2.38,2.97,3.17-3.38,3.62-3.71,4.18,4.46,7.14,7.18,7.33,7.67,8.24,8.54.
Embodiment 3 (56)
5- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -2- [(methyl sulphonyl) amino] benzoate hydrochlorate
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.96,1.28-1.47,1.59-1.71,1.95-2.06,2.18-2.37,3.02,3.00-3.20,3.24-3.35,3.50-3.61,4.15,4.30,7.08,7.14,7.25,7.51,7.67-7.72,7.86.
Embodiment 3 (57)
2- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzoate hydrochlorate
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.35；
NMR(CD3OD)：δ 0.98,1.31-1.48,1.54-1.71,1.94-2.04,2.12-2.36,3.00,3.00-3.18,3.20-3.35,3.51-3.61,4.15,4.27,6.98,7.08,7.14,7.41-7.52,7.82,7.84.
Embodiment 3 (58)
N- [4- (4- { [4- (butyl { [(3,4- dicyano phenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) phenyl] methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.96,1.31-1.42,1.52-1.64,1.98-2.07,2.21-2.39,2.95,3.04-3.21,3.28-3.35,3.52-3.61,4.19,4.30,7.03,7.06,7.29,7.52,7.79-7.89,8.11.
Embodiment 3 (59)
N- [4- (4- { [4- (butyl { [(4- cyano group -2,5- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) phenyl] methanesulfonamide hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.97,1.35-1.46,1.55-1.68,1.95-2.06,2.19-2.37,2.95,3.08-3.21,3.24-3.38,3.52-3.61,4.18,4.29,7.03,7.06,7.29,7.50,7.60,7.87.
Embodiment 3 (60)
5- ({ [butyl (1- { [6- (4- cyano-benzene oxygens) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=10: 1) of Rf 0.54；
NMR(CD3OD)：δ 0.98,1.36-1.43,1.59-1.67,2.00-2.04,2.21-2.32,2.99-3.18,3.26-3.30,3.56-3.63,4.14,4.36,7.14,7.21,7.33,7.80,7.86,8.06,8.29.
Embodiment 3 (61)
3- ({ [[1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.33；
NMR(CD3OD)：δ 1.63-1.80,2.14-2.23,2.95,3.10-3.22,3.47-3.55,4.23,4.69,7.01,7.03,7.25-7.37,7.40-7.60,7.72.
Embodiment 3 (62)
4- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] benzamide hydrochloride salt
TLC：(the chloroforms: methanol=7: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.50-1.70,1.95-2.10,2.10-2.30,2.95,3.00-3.20,3.20-3.40,3.50-3.60,4.20,4.30,7.02-7.08,7.29,7.47-7.52,7.80.
Embodiment 3 (63)
N- { 4- [4- ({ 4- [butyl ({ [2,4- bis- fluoro- 5- (4- morpholinyl carbonyls) phenyl] amino } carbonyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } methanesulfonamide hydrochloride
TLC：(the chloroforms: methanol=10: 1) of Rf 0.38；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.95-2.05,2.10-2.30,2.95,3.00-3.20,3.20-3.50,3.50-3.70,3.70-3.80,4.10,4.29,7.02-7.08,7.15,7.29,7.46,7.49.
Embodiment 3 (64)
5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- bis- fluoro- N- (2- methoxy ethyls) benzamide hydrochloride salt
TLC：(the chloroforms: methanol=10: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.75,1.90-2.10,2.15-2.35,2.95,3.00-3.20,3.20-3.40,3.50-3.60,3.55,4.13,4.28,7.02-7.08,7.13,7.29,7.49,7.78.
Embodiment 3 (65)
The fluoro- N of 5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- bis-, N- dimethyl benzamide hydrochlorides
TLC：(the chloroforms: methanol=10: 1) of Rf 0.46；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.80,1.90-2.10,2.20-2.30,2.95,2.97,3.05-3.20,3.10,3.25-3.35,3.50-3.60,4.15,4.29,7.02-7.08,7.14,7.29,7.43,7.50.
Embodiment 3 (66)
5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- bis- fluoro- N- (2- hydroxyethyls) benzamide hydrochloride salt
TLC：(the chloroforms: methanol=10: 1) of Rf 0.38；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.10-2.30,2.95,3.05-3.20,3.20-3.40,3.50,3.50-3.60,3.67,4.15,4.27,7.02-7.07,7.13,7.29,7.50,7.81.
Embodiment 3 (67)
N- { 4- [(5- { [4- (butyl { [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -3- chlorphenyls } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.57；
NMR(CD3OD)：δ 0.96,1.30-1.45,1.50-1.65,1.90-2.10,2.20-2.40,3.02,3.10-3.50,3.50-3.65,4.08,4.25,4.37,7.16,7.24-7.26,7.43,8.12,8.16,8.23,8.28.
Embodiment 3 (68)
N- { 4- [(5- { [4- (butyl { [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -3,5- 3,5-dimethylphenyls } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.56；
NMR(CD3OD)：δ 0.96,1.30-1.50,1.50-1.65,1.90-2.05,2.08,2.20-2.40,2.98,3.10-3.40,3.55-3.65,4.06,4.25,4.37,7.05,7.08,8.13,8.16,8.20,8.33.
Embodiment 3 (69)
5- { [(butyl { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CD3OD)：δ 0.97,1.32-1.45,1.58-1.70,1.95-2.07,2.14,2.20-2.40,2.98,3.08-3.21,3.24-3.37,3.55-3.64,4.20,4.36,7.02-7.25,7.86,8.14,8.34.
Embodiment 3 (70)
5- { [(butyl { 1- [(6- { 2; 6- dimethyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.97,1.32-1.45,1.58-1.70,1.95-2.08,2.08,2.21-2.39,2.98,3.08-3.21,3.24-3.35,3.55-3.65,4.20,4.36,7.05,7.08,7.14,7.86,8.14,8.33.
Embodiment 3 (71)
5- [({ 2- butynyls [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.82,2.01-2.12,2.12-2.31,2.95,3.08-3.19,3.52-3.61,4.10,4.29,4.32,7.03,7.06,7.15,7.29,7.51,7.96.
Embodiment 3 (72)
2,4- bis- fluoro- 5- ({ [[1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] (propyl group) amino] carbonyl } amino) benzamide hydrochloride salts
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 0.97,1.62-1.75,1.98-2.08,2.18-2.30,2.95,3.02-3.18,3.21-3.33,3.52-3.60,4.14,4.28,7.03,7.06,7.14,7.29,7.50,7.85.
Embodiment 3 (73)
N- { 4- [4- ({ 4- [butyl ({ [2,4- bis- fluoro- 5- (hydroxymethyl) phenyl] amino } carbonyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } methanesulfonamide hydrochloride
TLC：(the chloroforms: methanol=7: 1) of Rf 0.80；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.75,1.90-2.10,2.20-2.35,2.96,3.05-3.20,3.20-3.40,3.50-3.65,4.20,4.29,4.60,6.97,7.03,7.06,7.29,7.46,7.52.
Embodiment 3 (74)
2,4- bis- fluoro- 5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salts (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 0.93,1.28-1.45,1.60-1.71,1.97-2.08,2.20-2.38,2.98,3.08-3.22,3.25-3.35,3.55-3.64,4.18,4.35,7.09-7.20,7.33,7.86,8.08,8.31.
Embodiment 3 (75)
5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
Figure G200580038925420070516D000811
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.97,1.32,1.28-1.45,1.57-1.70,1.95-2.08,2.21-2.38,3.11,3.08-3.21,3.25-3.35,3.52-3.64,4.18,4.35,7.07-7.17,7.33,7.86,8.08,8.31.
Embodiment 3 (76)
N- (4- { [5- ({ 4- [{ [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] carbonyl } (amyl group) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.92,1.28-1.42,1.52-1.64,1.92-2.04,2.20-2.38,2.98,3.10-3.29,3.52-3.64,4.04,4.24,4.37,7.11,7.16,7.34,8.05,8.12,8.14,8.34.
Embodiment 3 (77)
N- { 4- [(5- { [4- (butyl { [(1- ethyl -1H- pyrazoles -4- bases) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.97,1.28-1.42,1.52,1.50-1.64,1.90-2.02,2.20-2.38,2.98,3.04-3.29,3.51-3.64,4.24,4.30-4.44,7.13,7.16,7.34,8.05-8.16,8.21,8.34.
Embodiment 3 (78)
5- [({ butyl [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
Figure G200580038925420070516D000821
TLC：(the chloroforms: methanol=7: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.55-1.70,2.00-2.10,2.20-2.40,3.05-3.20,3.15,3.25-3.40,3.50-3.70,4.20,4.36,7.14,7.22,7.40,7.86,8.01,8.07,8.29.
Embodiment 3 (79)
2,4- bis- fluoro- 5- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.94,1.30-1.45,1.60-1.75,2.00-2.10,2.15-2.40,3.00-3.20,3.15,3.20-3.40,3.50-3.70,4.15,4.35,7.14,7.22,7.39,7.86,8.01,8.05,8.29.
Embodiment 3 (80)
2,4- bis- fluoro- 5- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.46；
NMR(CD3OD)：δ 0.93,1.30-1.45,1.60-1.75,1.95-2.10,2.13,2.15-2.30,2.98,3.10-3.40,3.55-3.65,4.15,4.34,7.01-7.21,7.86,8.04,8.26.
Embodiment 3 (81)
5- ({ [{ 1- [(6- { 2; 6- dimethyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.93,1.30-1.45,1.60-1.70,2.00-2.10,2.06,2.15-2.30,2.99,3.00-3.40,3.50-3.70,4.10,4.32,7.03,7.08,7.14,7.86,7.98,8.20.
Embodiment 3 (82)
5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.46；
NMR(CD3OD)：δ 0.93,1.30-1.45,1.33,1.60-1.70,2.00-2.10,2.20-2.40,3.00-3.40,3.11,3.50-3.70,4.15,4.34,7.08-7.17,7.32,7.86,8.03,8.28.
Embodiment 3 (83)
5- ({ [{ 1- [(6- { the chloro- 4- of 2- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.75,2.00-2.10,2.15-2.25,3.02,3.05-3.35,3.50-3.70,4.10,4.33,7.14-7.28,7.42,7.86,8.00,8.20.
Embodiment 3 (84)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D000841
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 1.64-1.82,2.11-2.21,3.00,3.10-3.24,3.48-3.57,3.71,4.31,4.67,6.87-7.00,7.02-7.09,7.12,7.20,7.32,7.45-7.59,8.03,8.26.
Embodiment 3 (85)
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyl) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -3- methoxyphenyls) methanesulfonamide hydrochloride (or dihydrochloride)
Amorphous powder；
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 1.67-1.82,2.11-2.24,3.00,3.12-3.24,3.50-3.57,3.71,4.30,4.67,6.84-6.97,7.01-7.08,7.11,7.35,7.48-7.61,8.02,8.24.
Embodiment 3 (86)
5- { [(butyl { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } chloro- 4- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -2-
Figure G200580038925420070516D000851
TLC：(the chloroforms: methanol=10: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.12,2.20-2.40,2.97,3.00-3.20,3.25-3.35,3.50-3.70,4.20,4.33,7.00-7.21,7.32,7.66,8.01,8.24.
Embodiment 3 (87)
5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } chloro- 4- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -2-
TLC：(the chloroforms: methanol=10: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.98,1.33,1.35-1.50,1.60-1.70,1.95-2.10,2.20-2.40,3.10,3.10-3.20,3.20-3.40,3.50-3.65,4.15,4.33,7.08-7.12,7.30-7.34,7.65,7.99,8.24.
Embodiment 3 (88)
5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] -2- methylphenoxies } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.62；
NMR(CD3OD)：δ 0.98,1.33,1.28-1.45,1.59-1.70,1.97-2.08,2.12,2.18-2.34,3.11,3.06-3.20,3.25-3.35,3.52-3.63,4.12,4.33,7.00,7.07,7.13,7.15,7.20,7.86,8.01,8.24.
Embodiment 3 (89)
5- { [(butyl { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：Rf0.53 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 0.97,1.30-1.47,1.58-1.70,1.95-2.07,2.13,2.20-2.37,2.91,2.98,3.04-3.21,3.22-3.35,3.52-3.64,4.18,4.34,7.01-7.24,7.79,8.06,8.27.
Embodiment 3 (90)
5- { [(butyl { 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 0.98,1.33,1.30-1.47,1.59-1.70,1.98-2.05,2.20-2.38,2.91,3.11,3.07-3.21,3.22-3.35,3.52-3.64,4.18,4.35,7.08-7.16,7.32,7.79,8.06,8.29.
Embodiment 3 (91)
5- { [(butyl { 1- [(6- { the chloro- 4- of 2- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 0.97,1.32-1.45,1.58-1.70,1.97-2.05,2.20-2.37,2.91,3.02,3.04-3.21,3.22-3.35,3.51-3.62,4.18,4.34,7.06-7.29,7.42,7.79,8.06,8.23.
Embodiment 3 (92)
5- { [(butyl { 1- [(6- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 0.97,1.32-1.45,1.58-1.70,1.95-2.05,2.19-2.37,2.91,3.00,3.04-3.21,3.22-3.35,3.54-3.62,3.72,4.18,4.34,6.90,7.04-7.17,7.79,8.06,8.27.
Embodiment 3 (93)
2- (5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorophenyls) acetamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D000871
TLC：(the chloroforms: methanol=7: 1) of Rf 0.42；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.50-1.70,1.95-2.10,2.15-2.30,2.97,3.05-3.20,3.20-3.40,3.50-3.60,3.53,4.10,4.33,7.00,7.08-7.14,7.30-7.34,7.97,8.24.
Embodiment 3 (94)
2- [2,4- bis- fluoro- 5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.43；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.55-1.75,1.90-2.10,2.15-2.35,2.97,3.10-3.20,3.20-3.40,3.50-3.60,3.53,4.15,4.33,7.00,7.08-7.14,7.30-7.34,7.99,8.25.
Embodiment 3 (95)
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.98,1.35-1.50,1.65-1.80,1.95-2.10,2.20-2.35,2.91,2.97,3.05-3.20,3.20-3.40,3.55-3.70,4.10,4.34,7.08-7.16,7.32,7.80,8.00,824.
Embodiment 3 (96)
2,4- difluoro-N-methyl -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.43；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.75,1.95-2.10,2.20-2.40,2.91,2.97,3.05-3.20,3.20-3.40,3.50-3.70,4.15,4.34,7.08-7.16,7.32,7.79,8.00,8.24.
Embodiment 3 (97)
5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.33,1.30-1.45,1.60-1.70,1.90-2.10,2.15-2.30,2.91,3.05-3.20,3.10,3.20-3.40,3.50-3.60,4.10,4.33,7.07-7.16,7.32,7.79,7.97,8.24.
Embodiment 3 (98)
2,4- difluoro-N-methyl -5- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.30-1.40,1.60-1.70,1.95-2.05,2.13,2.20-2.40,2.91,2.98,3.05-3.20,3.20-3.40,3.55-3.65,4.15,4.34,7.11-7.21,7.79,8.04,8.26.
Embodiment 3 (99)
N- [4- (4- { [4- (butyl { [(1,5- dimethyl -1H- pyrazoles -4- bases) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) phenyl] Methanesulfomide dihydrochloride
TLC：(the chloroforms: methanol=4: 1) of Rf 0.84；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.80,1.90-2.10,2.10-2.30,2.27,2.95,3.00-3.20,3.20-3.40,3.50-3.60,3.92,4.20,4.29,7.02-7.08,7.31,7.51,7.84.
Embodiment 3 (100)
4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group)-N- [2- (dimethylamino) ethyl] benzsulfamide dihydrochloride
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.98,1.36-1.43,1.60-1.70,1.98-2.02,2.20-2.35,2.94,3.10-3.34,3.56-3.60,4.21,4.34,6.90-7.01,7.18-7.21,7.36,7.62,7.89.
Embodiment 3 (101)
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -1- oxide -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the chloroforms: methanol=4: 1) of Rf 0.54；
NMR(CD3OD)：δ 0.99,1.30-1.50,1.55-1.70,1.95-2.15,2.20-2.40,3.01,3.10-3.40,3.55-3.70,4.15,4.39,7.12-7.21,7.25,7.40,7.81,7.87,8.70.
Embodiment 3 (102)
5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino]-N- [2- (dimethylamino) ethyl] -2,4- difluorobenzamide dihydrochlorides
TLC：(the chloroforms: methanol=10: 1) of Rf 0.17；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.80,1.90-2.10,2.20-2.40,2.95,2.98,3.00-3.20,3.20-3.40,3.50-3.80,4.20,4.29,7.02-7.08,7.17,7.29,7.52,7.91.
Embodiment 3 (103)
5- { [(benzyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 1.97-2.06,2.07-2.22,2.97,3.04-3.18,3.47-3.58,4.30,4.37,4.66,7.04-7.17,7.21-7.45,7.89,8.00,8.24.
Embodiment 3 (104)
4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] -3- methoxyl methyl benzoates (benzoate) hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.58；
NMR(CD3OD)：δ 0.98,1.32-1.44,1.58-1.70,1.95-2.04,2.12-2.30,3.08-3.18,3.22-3.35,3.51-3.61,3.82,3.91,4.14,4.28,6.99,7.09,7.14,7.47,7.67,7.73,7.85.
Embodiment 3 (105)
2,4- bis- fluoro- 5- { [(hexyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.47；
NMR(CD3OD)：δ 0.91,1.30-1.50,1.60-1.70,2.00-2.10,2.20-2.35,2.97,3.00-3.20,3.20-3.40,3.50-3.70,4.10,4.33,7.08-7.18,7.32,7.86,7.98,8.24.
Embodiment 3 (106)
N- [4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) piperidin-1-yl] methyl } phenoxy group) phenyl]-N- (methyl sulphonyl) glycine methyl ester (glycinate) hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 0.96,1.27-1.44,1.55-1.90,2.10-2.20,2.95-3.07,3.08,3.21-3.34,3.53,3.74,4.05,4.46,6.85-7.04,7.03-7.45,7.47.
Embodiment 3 (107)
N- { 4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] piperidin-1-yl } methyl) phenoxy group] phenyl }-N- (methyl sulphonyl) glycine methyl ester hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 0.97,1.32-1.42,1.58-1.68,1.70-1.97,2.12-2.28,2.99-3.12,3.08,3.20-3.35,3.57,3.74,4.02,4.46,6.92-7.04,7.16,7.36,7.47,8.54.
Embodiment 4
5- { [(butyl { 1- [(6- { 4- [(methylamino) carbonyl] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
Figure G200580038925420070516D000911
Methanol (32 μ l) solution of I-hydroxybenzotriazole (46mg), 1- ethyls -3- [3- (dimethylamino) propyl group] carbodiimide hydrochlorides (65mg) and 33% methylamine is added in dimethylformamide (1ml) solution of prepared compound (132mg) into embodiment 3 (53).The reactant mixture is stirred at room temperature 2.5 hours.The saturated aqueous solution of sodium acid carbonate is added into the mixture, is extracted with ethyl acetate.Extract is through anhydrous sodium sulfate drying, concentration.Gained residue is on silica gel through column chromatography eluting (ethyl acetate: methanol=5: 1).Gained compound is dissolved in ethyl acetate, the ethyl acetate solution of 4N hydrogen chloride is added.Concentrated reaction mixture obtains title compound (73mg), with following physical data.
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.97,1.32-1.45,1.58-1.70,1.95-2.08,2.25-2.40,2.92,3.10-3.22,3.27-3.38,3.58-3.64,4.24,4.37,7.13,7.15,7.24,7.86,7.90,8.12,8.33.
Embodiment 4 (1) -4 (9)
By the way that with identical method described in embodiment 4, the compound for replacing preparing in the compound or embodiment 3 (47) that prepare in methylamine and embodiment 3 (53) using corresponding amines obtains following the compounds of this invention.
Embodiment 4 (1)
5- ({ [[1- ({ 6- [4- (amino carbonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (butyl) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.47；
NMR(CD3OD)：δ 0.98,1.35-1.48,1.59-1.70,1.95-2.08,2.19-2.38,3.06-3.22,3.24-3.35,3.55-3.65,4.18,4.36,7.14,7.16,7.23,7.86,7.96,8.05,8.30.
Embodiment 4 (2)
5- { [(butyl { 1- [(6- { 4- [(dimethylamino) carbonyl] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.97,1.34-1.45,1.58-1.70,1.95-2.08,2.20-2.40,3.02-3.22,3.24-3.35,3.52-3.65,4.19,4.36,7.14,7.16,7.25,7.52,7.86,8.09,8.30.
Embodiment 4 (3)
5- [({ butyl [1- ({ 6- [4- (4- morpholinyl carbonyls) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.98,1.32-1.47,1.59-1.70,1.95-2.08,2.20-2.39,3.10-3.20,3.25-3.35,3.45-3.82,4.18,4.36,7.14,7.16,7.25,7.52,7.86,8.08,8.30.
Embodiment 4 (4)
5- ({ [butyl (1- { [6- (4- { [(2- methoxy ethyls) amino] carbonyl } phenoxy group) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
Figure G200580038925420070516D000921
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 0.98,1.35-1.47,1.60-1.70,1.95-2.08,2.20-2.38,3.08-3.21,3.25-3.40,3.57,3.51-3.64,4.16,4.36,7.14,7.16,7.23,7.86,7.90,8.05,8.30.
Embodiment 4 (5)
5- [({ butyl [1- ({ 6- [4- ({ [2- (dimethylamino) ethyl] amino } carbonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorobenzamides dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.35；
NMR(CD3OD)：δ 0.97,1.35-1.45,1.59-1.70,1.94-2.05,2.23-2.40,2.99,3.10-3.22,3.22-3.35,3.40,3.55-3.65,3.78,4.22,4.37,7.14,7.17,7.27,7.86,7.99,8.13,8.34.
Embodiment 4 (6)
5- ({ [butyl (1- { [6- (4- { [(2- methoxy ethyls) amino] carbonyl } -2,6- dimethyl phenoxies) -3- pyridine radicals] methyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 0.97,1.34-1.46,1.57-1.68,1.98-2.08,2.13,2.18-2.35,3.08-3.21,3.22-3.40,3.56,3.51-3.64,4.17,4.33,7.11,7.14,7.62,7.86,8.06,8.22.
Embodiment 4 (7)
5- ({ [(1- { 4- [4- (amino carbonyl) -2- methoxyphenoxies] benzyl } -4- piperidyls) (butyl) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.98,1.32-1.47,1.58-1.70,1.97-2.05,2.12-2.31,3.04-3.18,3.22-3.35,3.51-3.60,3.82,4.15,4.27,6.97,7.09,7.14,7.47,7.53,7.65,7.85.
Embodiment 4 (8)
5- { [(butyl { 1- [4- (2- methoxyl groups -4- { [(2- methoxy ethyls) amino] carbonyl } phenoxy group) benzyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyl amine hydrochlorates
TLC：Rf0.53 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 0.98,1.32-1.47,1.58-1.70,1.95-2.04,2.12-2.30,3.04-3.18,3.22-3.35,3.50-3.61,3.57,3.82,4.14,4.27,6.97,7.09,7.14,7.45,7.47,7.61,7.85.
Embodiment 4 (9)
5- ({ [butyl (1- { 4- [2- methoxyl groups -4- (4- morpholinyl carbonyls) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 0.98,1.32-1.44,1.58-1.70,1.95-2.04,2.12-2.30,3.04-3.17,3.22-3.35,3.47-3.81,3.79,4.14,4.27,6.97,7.05,7.12,7.14,7.20,7.45,7.85.
Embodiment 5
[[4- (4- { [4- (butyl { [(2,4- difluorophenyl) amino] carbonyl } amino) -1- piperidyls] methyl } phenoxy group) phenyl] (methyl sulphonyl) amino] acetic acid hydrochloride
Figure G200580038925420070516D000941
2N sodium hydrate aqueous solutions (0.5ml) are added in methanol (1ml) solution of the compound (80mg) prepared into embodiment 3 (106).Reactant mixture is stirred at room temperature 2.5 hours.1N hydrochloric acid is added into the reactant mixture on ice bath up to the pH of solution is 5, is then extracted with ethyl acetate.Extract is through anhydrous sodium sulfate drying, concentration.Gained residue is on silica gel through column chromatography eluting (dichloromethane: methanol=9: 1).Gained compound is dissolved in the ethyl acetate solution that 4N hydrogen chloride is added in ethyl acetate.Concentrated reaction mixture obtains title compound (64mg), with following physical data.
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.98,1.32-1.45,1.57-1.70,1.92-2.05,2.12-2.31,3.09,3.06-3.20,3.22-3.35,3.51-3.61,4.17,4.30,4.43,6.88-7.05,7.06,7.12,7.36,7.51-7.58.
Embodiment 5 (1)
[{ 4- [4- ({ 4- [({ [5- (amino carbonyl) -2,4- difluorophenyls] amino } carbonyl) (butyl) amino] -1- piperidyls } methyl) phenoxy group] phenyl } (methyl sulphonyl) amino] acetic acid hydrochloride
By method same as Example 5, using the compound prepared in embodiment 3 (107), title compound is obtained.
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.17；
NMR(CD3OD)：δ 0.97,1.30-1.42,1.57-1.70,1.90-2.02,2.11-2.30,2.95-3.10,3.10,3.23-3.40,3.41-3.52,4.16,4.21,4.30,7.01,7.06,7.13,7.48,7.57,7.86.
Embodiment 6 (1) -6 (20)
By method same as Example 3, using the compound prepared in corresponding aldehyde compound alternate embodiment 1 and using the compound prepared in corresponding amine alternate embodiment 2, following compound is obtained.
Embodiment 6 (1)
2- (5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorophenyls) acetamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D000951
TLC：(the chloroforms: methanol=7: 1) of Rf 0.42；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.50-1.70,1.95-2.10,2.15-2.30,2.97,3.05-3.20,3.20-3.40,3.50-3.60,3.53,4.10,4.33,7.00,7.08-7.14,7.30-7.34,7.97,8.24.
Embodiment 6 (2)
2- [2,4- bis- fluoro- 5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.43；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.55-1.75,1.90-2.10,2.15-2.35,2.97,3.10-3.20,3.20-3.40,3.50-3.60,3.53,4.15,4.33,7.00,7.08-7.14,7.30-7.34,7.99,8.25.
Embodiment 6 (3)
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.41；
NMR(CD3OD)：δ 0.98,1.35-1.50,1.65-1.80,1.95-2.10,2.20-2.35,2.91,2.97,3.05-3.20,3.20-3.40,3.55-3.70,4.10,4.34,7.08-7.16,7.32,7.80,8.00,8.24.
Embodiment 6 (4)
2,4- difluoro-N-methyl -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.43；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.75,1.95-2.10,2.20-2.40,2.91,2.97,3.05-3.20,3.20-3.40,3.50-3.70,4.15,4.34,7.08-7.16,7.32,7.79,8.00,8.24.
Embodiment 6 (5)
5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluoro-N-methyls benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.33,1.30-1.45,1.60-1.70,1.90-2.10,2.15-2.30,2.91,3.05-3.20,3.10,3.20-3.40,3.50-3.60,4.10,4.33,7.07-7.16,7.32,7.79,7.97,8.24.
Embodiment 6 (6)
2,4- difluoro-N-methyl -5- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.30-1.40,1.60-1.70,1.95-2.05,2.13,2.20-2.40,2.91,2.98,3.05-3.20,3.20-3.40,3.55-3.65,4.15,4.34,7.11-7.21,7.79,8.04,8.26.
Embodiment 6 (7)
5- { [(butyl { 1- [(6- { the chloro- 4- of 2- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 0.97,1.33,1.30-1.47,1.59-1.70,1.95-2.08,2.20-2.37,3.15,3.05-3.20,3.22-3.35,3.52-3.62,4.18,4.34,7.10-7.28,7.41,7.86,8.05,8.24.
Embodiment 6 (8)
5- ({ [(1- { 4- [4- (amino carbonyl) phenoxy group] benzyl } -4- piperidyls) (butyl) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.40；
NMR(CD3OD)：δ 0.98,1.32-1.49,1.59-1.70,1.95-2.09,2.19-2.38,3.08-3.20,3.27-3.35,3.51-3.65,4.18,4.32,7.07,7.08,7.16,7.57,7.86,7.91.
Embodiment 6 (9)
5- ({ [butyl (1- { 4- [4- (4- morpholinyl carbonyls) phenoxy group] benzyl } -4- piperidyls) amino] carbonyl } amino) -2,4- difluorobenzoyl amine hydrochlorates
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.98,1.31-1.47,1.60-1.70,1.98-2.07,2.15-2.30,3.04-3.20,3.25-3.35,3.50-3.80,4.13,4.31,7.08-7.18,7.48,7.54,7.86.
Embodiment 6 (10)
2- { 5- [({ butyl [1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorophenyls } acetamide hydrochloride
TLC：(the chloroforms: methanol=7: 1) of Rf 0.42；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.75,1.95-2.10,2.10-2.30,2.95,3.05-3.40,3.53,3.55-3.65,4.15,4.28,7.00-7.08,7.28,7.29,7.49.
Embodiment 6 (11)
2- { 5- [({ butyl [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorophenyls } acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.10,2.15-2.30,3.05-3.40,3.15,3.53,3.55-3.65,4.15,4.36,7.00,7.23,7.33,7.40,8.01,8.04,8.29.
Embodiment 6 (12)
2- { 5- [({ butyl [1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2,4- difluorophenyls } acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.42；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.95-2.10,2.15-2.35,3.00-3.40,3.30,3.53,3.55-3.65,4.15,4.37,7.00,7.25,7.33,7.35,7.53,8.06,8.16,8.31.
Embodiment 6 (13)
2- [5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) -2,4- difluorophenyls] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.33；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.33,1.60-1.70,1.90-2.10,2.15-2.35,3.00-3.40,3.10,3.53,3.55-3.65,4.10,4.33,7.00,7.07-7.13,7.32,7.33,7.97,8.24.
Embodiment 6 (14)
2- [2,4- bis- fluoro- 5- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (amyl group) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.45；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.70,1.90-2.10,2.12,2.20-2.40,2.97,3.00-3.40,3.53,3.55-3.65,4.15,4.33,6.96-7.21,7.33,8.01,8.24.
Embodiment 6 (15)
2- [2,4- bis- fluoro- 5- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.39；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.70,1.90-2.10,2.10-2.30,3.00-3.40,3.15,3.53,3.55-3.65,4.15,4.36,7.00,7.22,7.33,7.40,8.01,8.04,8.29.
Embodiment 6 (16)
2- [5- ({ [[1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) -2,4- difluorophenyls] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.44；
NMR(CD3OD)：δ 0.94,1.30-1.50,1.60-1.70,1.90-2.10,2.10-2.30,3.00-3.40,3.30,3.53,3.55-3.65,4.10,4.35,7.00,7.25,7.33,7.37,7.52,8.05,8.16,8.31.
Embodiment 6 (17)
N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 1.62-1.80,2.14-2.03,3.14,3.12-3.25,3.48-3.58,4.30,4.67,6.95,7.16-7.25,7.30-7.40,7.46-7.58,7.96,8.00,8.22.
Embodiment 6 (18)
N- [1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N '-(4- fluorophenyls)-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 1.62-1.80,2.15-2.23,3.12-3.28,3.31,3.49-3.59,4.30,4.68,6.95,7.10,7.18-7.25,7.30-7.40,7.49-7.58,7.98,8.15,8.24.
Embodiment 6 (19)
N- [1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N '-(2,4- difluorophenyl)-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 1.62-1.80,2.15-2.25,3.10-3.30,3.31,3.50-3.60,4.31,4.68,6.84-6.96,7.21,7.30-7.39,7.48-7.60,7.98,8.15,8.24.
Embodiment 6 (20)
5- ({ [butyl (1- { [6- (4- { [(2- methoxy ethyls) amino] carbonyl } -2- methylphenoxies) pyridin-3-yl] methyl } piperidin-4-yl) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 0.97,1.32-1.47,1.60-1.70,1.97-2.04,2.21,2.20-2.37,3.10-3.20,3.21-3.40,3.57,3.50-3.62,4.18,4.34,7.10-7.20,7.72,7.80,7.86,8.06,8.26.
Embodiment 7 (1) -7 (121)
By method same as Example 3, using the compound prepared in corresponding aldehyde compound alternate embodiment 1 and use the compound prepared in corresponding amines alternate embodiment 2, and free form is translated into when needed, obtain following the compounds of this invention.
Embodiment 7 (1)
5- ({ [[1- ({ 6- [2; 6- dimethyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.42；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.80,1.95-2.10,2.17,2.20-2.35,3.00-3.40,3.14,3.50-3.70,4.15,4.33,7.14,7.21,7.74,7.86,8.07,8.18.
Embodiment 7 (2)
5- ({ [[1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.48；
NMR(CD3OD)：δ 0.93,1.30-1.50,1.60-1.80,1.95-2.10,2.20-2.40,3.10-3.40,3.30,3.50-3.70,4.15,4.37,7.14,7.25,7.35,7.53,7.86,8.10,8.16,8.32.
Embodiment 7 (3)
5- [({ butyl [1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2- fluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.35；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.60-1.80,1.95-2.10,2.20-2.40,3.10-3.40,3.30,3.50-3.70,4.15,4.36,7.14,7.25,7.35,7.50,7.53,7.78,8.07,8.16,8.32.
Embodiment 7 (4)
5- [({ butyl [1- ({ 6- [2- methyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] -2- fluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.36；
NMR(CD3OD)：δ 0.97,1.30-1.50,1.55-1.70,1.90-2.10,2.20-2.40,2.26,3.00-3.40,3.14,3.50-3.70,4.20,4.35,7.11-7.30,7.53,7.76-7.85,7.92,8.07,8.24.
Embodiment 7 (5)
2,4- bis- fluoro- 5- { [(hexyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.37；
NMR(CD3OD)：δ 0.98,1.30-1.50,1.60-1.70,1.90-2.05,2.20-2.35,2.97,3.00-3.35,3.50-3.70,4.20,4.34,7.08-7.17,7.32,7.86,8.02,8.24.
Embodiment 7 (6)
2,4- bis- fluoro- 5- { [((2- methyl-benzyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salts (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 1.98-2.20,2.36,2.97,3.04-3.18,3.48-3.57,4.30,4.43,4.57,7.04-7.33,7.85,7.98,8.23.
Embodiment 7 (7)
2,4- bis- fluoro- 5- ({ [[1- ({ 6- [2- methyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.38；
NMR(CD3OD)：δ 0.94,1.30-1.50,1.60-1.80,1.90-2.10,2.26,2.20-2.40,3.05-3.40,3.14,3.50-3.70,4.15,4.33,7.11-7.29,7.81-7.89,7.92,8.03,8.23.
Embodiment 7 (8)
2,4- bis- fluoro- 5- { [({ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salts (or dihydrochloride)
TLC：Rf0.37 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.65-1.80,2.20-2.30,2.98,3.08-3.21,3.50-3.60,3.83,4.34,7.07-7.19,7.33,8.02,8.27,8.38.
Embodiment 7 (9)
N '-(4- fluorophenyls)-N- [1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 1.64-1.80,2.12-2.22,3.17,3.10-3.25,3.48-3.58,3.79,4.27,4.67,6.95,7.12,7.22,7.30-7.38,7.45-7.64,7.93,8.12.
Embodiment 7 (10)
N '-(2,4- difluorophenyl)-N- [1- ({ 6- [2- methyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.65-1.80,2.15-2.28,2.24,3.13,3.12-3.24,3.50-3.58,4.29,4.68,6.85-6.98,7.17,7.26,7.34-7.38,7.48-7.60,7.81,7.91,7.98,8.17.
Embodiment 7 (11)
N '-(2,4- difluorophenyl)-N- [1- ({ 6- [2,6- dimethyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.62-1.80,2.15,2.12-2.23,3.13,3.10-3.24,3.50-3.58,4.27,4.68,6.85-6.98,7.18,7.33-7.37,7.50-7.60,7.73,7.96,8.11.
Embodiment 7 (12)
N '-(2,4- difluorophenyl)-N- [1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 1.64-1.80,2.15-2.24,3.17,3.12-3.25,3.48-3.58,3.79,4.28,4.68,6.85-6.98,7.12,7.33-7.37,7.50-7.60,7.95,8.13.
Embodiment 7 (13)
2,4- bis- fluoro- 5- [({ hexyl [1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] benzamide hydrochloride salts (or dihydrochloride)
TLC：(the chloroforms: methanol=7: 1) of Rf 0.35；
NMR(CD3OD)：δ 0.91,1.25-1.45,1.60-1.75,1.90-2.10,2.20-2.40,3.05-3.40,3.14,3.50-3.70,3.81,4.15,4.35,7.14,7.15,7.38,7.60-7.65,7.86,8.09,8.24.
Embodiment 7 (14)
N '-(4- fluorophenyls)-N- [1- ({ 6- [2- methyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.75；
NMR(CD3OD)：δ 1.63-1.80,2.12-2.23,2.24,3.13,3.10-3.25,3.48-3.57,4.29,4.67,6.95,7.15-7.35,7.47-7.60,7.81,7.91,7.97,8.17.
Embodiment 7 (15)
N- [1- ({ 6- [2,6- dimethyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N '-(4- fluorophenyls)-N- phenylureas hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.75；
NMR(CD3OD)：δ 1.64-1.80,2.15,2.10-2.23,3.13,3.10-3.25,3.48-3.58,4.27,4.67,6.95,7.15-7.25,7.30-7.35,7.48-7.60,7.73,7.97,8.11.
Embodiment 7 (16)
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 0.98,1.32-1.45,1.58-1.70,1.95-2.05,2.24-2.40,2.67,2.99,3.20-3.35,3.60-3.69,4.28,4.43,6.95,7.14,7.22,7.37,7.87,8.20.
Embodiment 7 (17)
The fluoro- 5- of the chloro- 2- of 4- ({ [[1- ({ 6- [2- methyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 0.94,1.30-1.50,1.67-1.80,1.98-2.06,2.26,2.19-2.38,3.10-3.20,3.14,3.25-3.35,3.55-3.65,4.20,4.34,7.21,7.28,7.41,7.83,7.90-7.99,8.06,8.24.
Embodiment 7 (18)
The chloro- 5- of 4- ({ [[1- ({ 6- [2,6- dimethyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (amyl group) amino] carbonyl } amino) -2- fluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 0.94,1.30-1.47,1.65-1.80,1.98-2.08,2.17,2.15-2.35,3.08-3.20,3.13,3.25-3.35,3.55-3.65,4.19,4.33,7.21,7.41,7.74,7.97,8.06,8.18.
Embodiment 7 (19)
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } chloro- 2- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -4-
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 0.98,1.35-1.48,1.62-1.75,1.98-2.08,2.19-2.38,2.97,3.08-3.20,3.25-3.35,3.55-3.63,4.17,4.34,7.09,7.13,7.32,7.42,7.94,8.02,8.27.
Embodiment 7 (20)
5- [({ butyl [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] chloro- 2- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -4-
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.54；
NMR(CD3OD)：δ 0.99,1.38-1.50,1.64-1.75,1.98-2.07,2.20-2.38,3.15,3.08-3.20,3.25-3.35,3.58-3.65,4.18,4.36,7.22,7.40,7.41,7.94,8.02,8.07,8.30.
Embodiment 7 (21)
5- [({ butyl [1- ({ 6- [2- chloro- 4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] chloro- 2- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -4-
TLC：Rf0.55 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 0.99,1.38-1.45,1.64-1.75,1.98-2.07,2.20-2.38,3.08-3.22,3.25-3.35,3.31,3.58-3.65,4.18,4.37,7.25,7.36,7.41,7.53,7.94,8.09,8.16,8.32.
Embodiment 7 (22)
5- [({ butyl [1- ({ 6- [2,6- dimethyl -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] chloro- 2- fluorobenzoyls amine hydrochlorates (or dihydrochloride) of -4-
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 0.98,1.35-1.48,1.62-1.75,1.97-2.08,2.17,2.19-2.38,3.08-3.21,3.14,3.25-3.35,3.52-3.65,4.19,4.33,7.21,7.41,7.73,7.94,8.07,8.18.
Embodiment 7 (23)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyrazinyls] epoxide } phenyl) Methanesulfomide dihydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.70-1.84,2.14-2.23,2.97,3.20-3.35,3.55-3.65,4.40,4.68,6.95,7.17,7.22,7.29-7.38,7.48-7.60,8.19,8.48.
Embodiment 7 (24)
N- (4- { [5- ({ 4- [[(Cyclohexylamino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 0.93-1.15,1.20-1.38,1.49-1.80,2.08-2.18,2.97,3.10-3.21,3.47-3.58,4.28,4.62,7.07,7.12,7.18-7.25,7.33,7.42-7.55,7.98,8.23.
Embodiment 7 (25)
N- [4- ({ 5- [(4- { phenyl [(3- thienyls amino) carbonyl] amino } -1- piperidyls) methyl] -2- pyridine radicals } epoxide) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.64-1.80,2.12-2.20,2.98,3.12-3.26,3.50-3.59,4.32,4.68,6.91,7.10,7.04-7.20,7.27-7.37,7.48-7.60,8.07,8.31.
Embodiment 7 (26)
N- (4- { [5- ({ 4- [(anilinocarbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.62-1.80,2.15-2.24,2.97,3.12-3.23,3.49-3.57,4.27,4.68,6.97-7.14,7.18-7.22,7.28-7.38,7.48-7.60,7.89,8.17.
Embodiment 7 (27)
N- (4- { [5- ({ 4- [[(benzylamino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 1.60-1.78,2.08-2.18,2.97,3.08-3.21,3.48-3.55,4.25,4.29,4.64,7.08,7.10-7.27,7.32,7.40-7.58,8.01,8.27.
Embodiment 7 (28)
N- { 4- [(5- { [4- (phenyl { [(2- phenylethyls) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 1.57-1.73,2.04-2.13,2.67,2.98,3.10-3.22,3.27-3.35,3.48-3.55,4.31,4.60,7.04-7.25,7.34,7.40-7.47,8.06,8.31.
Embodiment 7 (29)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001081
TLC：(the chloroforms: methanol=10: 1) of Rf 0.30；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.20,2.97,3.10-3.25,3.50-3.60,4.29,4.65,6.93-7.13,7.22-7.33,7.53,7.61,7.94,8.21.
Embodiment 7 (30)
N- [4- ({ 5- [(4- { 3- thienyls [(3- thienyls amino) carbonyl] amino } -1- piperidyls) methyl] -2- pyridine radicals } epoxide) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001082
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.55；
NMR(CD3OD)：δ 1.62-1.78,2.11-2.20,2.97,3.12-3.25,3.48-3.58,4.28,4.67,6.95,7.00,7.06,7.11,7.17-7.23,7.31,7.49,7.60,7.90,8.18.
Embodiment 7 (31)
N- (4- { [5- ({ 4- [{ [(3- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.62-1.80,2.12-2.24,2.97,3.12-3.25,3.48-3.58,4.27,4.68,6.72,6.93,7.03-7.35,7.48-7.60,7.89,8.17.
Embodiment 7 (32)
N- (4- { [5- ({ 4- [{ [(2- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.63-1.80,2.18-2.25,2.97,3.12-3.25,3.48-3.58,4.28,4.69,6.98-7.15,7.31,7.35-7.40,7.50-7.62,7.73,7.90,8.17.
Embodiment 7 (33)
N- (4- { [5- ({ 4- [{ [(4- methoxyphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.62-1.80,2.13-2.21,2.97,3.12-3.25,3.48-3.57,3.73,4.27,4.67,6.79,7.05,7.09,7.10,7.28-7.35,7.47-7.58,7.90,8.17.
Embodiment 7 (34)
N- (4- { [5- ({ 4- [{ [(3- methoxyphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.62-1.80,2.13-2.25,2.97,3.12-3.25,3.48-3.57,3.72,4.28,4.67,6.58,6.73,6.94,7.04-7.15,7.29-7.35,7.49-7.60,7.90,8.18.
Embodiment 7 (35)
N- (4- { [5- ({ 4- [{ [(2- methoxyphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：Rf0.48 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.62-1.80,2.15-2.27,2.97,3.12-3.25,3.50-3.60,3.55,4.29,4.71,6.80-6.97,7.05,7.11,7.31,7.37,7.51-7.64,7.91,7.95,8.18.
Embodiment 7 (36)
N- (4- { [5- ({ 4- [{ [(4- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
Amorphous powder；
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.34-1.50,1.80-1.91,2.10-2.20,2.23,2.83-2.98,2.95,3.44,4.43,6.88,6.98-7.10,7.28,7.45-7.57,7.73,7.98.
Embodiment 7 (37)
N- (4- { [5- ({ 4- [{ [(3- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.35-1.50,1.80-1.91,2.08-2.20,2.24,2.84-2.98,2.94,3.44,4.43,6.80,6.87,6.97-7.12,7.26-7.34,7.44-7.58,7.73,7.98.
Embodiment 7 (38)
N- (4- { [5- ({ 4- [{ [(2- aminomethyl phenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.38-1.54,1.84-1.96,1.91,2.10-2.20,2.85-2.98,2.95,3.44,4.43,6.88,6.97,7.02-7.14,7.28,7.35,7.42-7.60,7.73,7.98.
Embodiment 7 (39)
N- (4- { [5- ({ 4- [{ [(4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
White amorphous powder；
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CDCl3)：δ 1.32-1.48,1.80-1.89,2.08-2.20,2.82-2.90,3.01,3.40,4.53,5.83,6.43,6.85,7.08-7.28,7.44-7.55,7.61,8.00.
Embodiment 7 (40)
N- (4- { [5- ({ 4- [{ [(3- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CDCl3)：δ 1.32-1.50,1.80-1.90,2.08-2.20,2.82-2.90,3.01,3.41,4.53,5.85,6.52,6.85,6.94,7.02-7.15,7.19-7.28,7.35,7.44-7.55,7.61,8.01.
Embodiment 7 (41)
N- (4- { [5- ({ 4- [{ [(2- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CDCl3)：δ 1.38-1.53,1.82-1.90,2.08-2.20,2.83-2.92,3.01,3.41,4.53,6.47,6.59,6.85,6.87,7.12,7.18,7.22-7.28,7.42-7.55,7.61,8.01,8.27.
Embodiment 7 (42)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.40；
NMR(CDCl3)：δ 1.30-1.48,1.70-1.80,2.08-2.19,2.81-2.90,3.01,3.41,3.96,4.46,6.26,6.35,6.85,6.92,7.11,7.18-7.28,7.37,7.61,8.01.
Embodiment 7 (43)
The fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
Figure G200580038925420070516D001111
Free form；
White amorphous powder；
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CDCl3)：δ 1.32-1.48,1.80-1.90,2.08-2.20,2.81-2.92,3.00,3.40,4.55,5.86,5.97,6.62-6.77,6.85,7.06,7.11,7.18-7.30,7.34,7.45-7.55,7.61,8.00,8.04.
Hydrochloride (or dihydrochloride)；
White amorphous powder；
TLC：Rf0.45 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.62-1.81,2.12-2.23,2.97,3.12-3.35,3.47-3.58,4.29,4.67,7.07-7.16,7.29-7.36,7.43,7.48-7.58,7.68,7.95,8.22.
Embodiment 7 (44)
The fluoro- N- of 4- { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls }-N- phenylbenzamaides
TLC：(the chloroforms: methanol=7: 1) of Rf 0.58；
NMR(CDCl3)：δ 1.50-1.70,1.85-1.95,2.10-2.30,2.85-2.95,2.98,3.41,4.72,6.75-6.84,6.95-6.98,7.07,7.19-7.25,7.59,7.99.
Embodiment 7 (45)
N- [4- ({ 5- [(4- { phenyl [(3- pyridinylaminos) carbonyl] amino } -1- piperidyls) methyl] -2- pyridine radicals } epoxide) phenyl] Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.40；
NMR(CDCl3)：δ 1.34-1.50,1.80-1.90,2.10-2.20,2.80-2.90,3.00,3.40,4.54,5.87,6.83,7.09,7.18,7.20-7.28,7.45-7.55,7.59,7.91,7.99,8.16,8.20.
Embodiment 7 (46)
N- (4- { [5- ({ 4- [(amino carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.38；
NMR(CDCl3)：δ 1.30-1.44,1.76-1.85,2.08-2.18,2.80-2.88,3.01,3.39,4.20,4.48,6.83,6.90,7.11,7.13-7.18,7.22-7.28,7.35-7.45,7.59,7.98.
Embodiment 7 (47)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (4- methoxyphenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CDCl3)：δ 1.31-1.49,1.77-1.86,2.09-2.18,2.81-2.90,3.01,3.40,3.86,4.50,5.85,6.38,6.84,6.89,6.96,7.08-7.25,7.60,7.99.
Embodiment 7 (48)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- methoxyphenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CDCl3)：δ 1.37-1.51,1.80-1.89,2.08-2.18,2.81-2.90,3.01,3.40,3.83,4.51,5.87,6.38,6.73,6.80,6.84,6.90,6.98,7.08-7.26,7.37,7.60,8.00.
Embodiment 7 (49)
N- (4- { [5- ({ 3- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -8- azabicyclics [3.2.1] octyl- 8- yls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.29；
NMR(CD3OD)：δ 1.90-2.05,2.20-2.30,2.35-2.50,2.60-2.75,2.97,3.85-3.95,4.16,4.55,6.92-6.98,7.06-7.14,7.19-7.24,7.29-7.33,7.36-7.40,7.48-7.58,8.01,8.25.
Embodiment 7 (50)
4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } benzoate hydrochlorate (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.39；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.25,3.10-3.30,3.50-3.60,4.30,4.65,6.92-6.98,7.13,7.19-7.24,7.31-7.34,7.49-7.55,7.96,8.08,8.25.
Embodiment 7 (51)
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyl) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.63；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.30,2.98,3.10-3.30,3.50-3.60,4.31,4.70,6.88-6.92,7.09,7.15,7.32-7.34,7.33,7.51-7.58,8.04,8.29.
Embodiment 7 (52)
N- (4- { [5- ({ 4- [{ [(the fluoro- 4- methoxyphenyls of 3-) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.65-1.82,2.12-2.22,2.98,3.12-3.28,3.48-3.58,3.79,4.32,4.67,6.84-6.96,7.09,7.13-7.22,7.28-7.38,7.45-7.58,8.05,8.30.
Embodiment 7 (53)
N- (4- { [5- ({ 4- [{ [(3- chloro-4-methoxies phenyl) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.68-1.82,2.12-2.22,2.98,3.12-3.28,3.48-3.58,3.81,4.32,4.68,6.92,7.06,7.09,7.16,7.30-7.38,7.45-7.58,8.05,8.30.
Embodiment 7 (54)
N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
Figure G200580038925420070516D001141
Amorphous powder；
TLC：Rf0.48 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.68-1.85,2.12-2.25,2.68,2.97,3.15-3.28,3.50-3.60,4.31,4.71,7.07,7.13,7.29-7.38,7.50-7.62,7.73,8.01,8.25,8.31,8.97.
Embodiment 7 (55)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) acetamide hydrochloride (or dihydrochloride)
Amorphous powder；
TLC：(the chloroforms: methanol=10: 1) of Rf 0.23；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.25,3.10-3.25,3.50-3.60,3.55,4.28,4.70,6.95,7.04-7.10,7.19-7.24,7.31-7.38,7.49-7.55,7.93,8.21.
Embodiment 7 (56)
N- { 4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls] phenyl } Methanesulfomide dihydrochloride
Figure G200580038925420070516D001151
TLC：(the chloroforms: methanol=10: 1) of Rf 0.21；
NMR(CD3OD)：δ 1.70-1.85,2.10-2.25,2.31,2.33,3.03,3.20-3.35,3.55-3.65,4.20,4.70,6.96,7.21-7.25,7.33-7.41,7.50-7.56.
Embodiment 7 (57)
4- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -3,5- dimethyl -1H- pyrazol-1-yls]-N- [2- (4- morpholinyls) ethyl] benzsulfamide tri hydrochloride
Figure G200580038925420070516D001161
TLC：(the chloroforms: methanol=10: 1) of Rf 0.20；
NMR(CD3OD)：δ 1.70-1.85,2.10-2.25,2.34,2.41,3.20-3.40,3.50-3.65,3.80-3.95,4.00-4.15,4.21,4.70,6.96,7.20-7.25,7.35,7.45-7.56,7.75,8.05.
Embodiment 7 (58)
N- { 4- [(5- { [4- ((3,5- dimethyl -4- isoxazoles) { [(4- fluorophenyls) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 1.68-1.88,2.09-2.23,2.20,2.40,2.97,3.12-3.25,3.50-3.60,4.32,4.60,6.99,7.09,7.13,7.25-7.35,8.01,8.25.
Embodiment 7 (59)
N- { 4- [(5- { [4- (1,3- benzothiazol-6-yl { [(4- fluorophenyls) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.68-1.85,2.19-2.28,2.97,3.12-3.25,3.50-3.60,4.30,4.71,6.94,7.07,7.13,7.23,7.32,7.51,8.00,8.15,8.20,8.25,9.46.
Embodiment 7 (60)
N- (4- { [5- ({ 4- [{ [(3,4- difluorophenyl) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 1.64-1.81,2.12-2.22,2.97,3.12-3.25,3.48-3.58,4.29,4.68,6.93,7.02-7.15,7.28-7.35,7.38,7.45-7.58,7.95,8.21.
Embodiment 7 (61)
N- (4- { [5- ({ 4- [[(2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -6- bases amino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.51；
NMR(CD3OD)：δ 1.63-1.80,2.12-2.22,2.97,3.11-3.25,3.48-3.55,4.17,4.29,4.68,6.56,6.66,6.81,7.07,7.12,7.27-7.35,7.45-7.58,7.96,8.22.
Embodiment 7 (62)
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyl) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001171
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.63-1.80,2.12-2.22,2.97,3.12-3.25,3.48-3.58,4.28,4.68,6.85-6.98,7.03-7.08,7.11,7.31,7.53-7.60,7.64,7.89,8.18.
Embodiment 7 (63)
N- (4- { [5- ({ 4- [{ [(3,4- difluorophenyl) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.62-1.80,2.10-2.20,2.97,3.12-3.25,3.48-3.58,4.28,4.68,6.94-7.16,7.31,7.40,7.51,7.61,7.90,8.18.
Embodiment 7 (64)
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (2- methoxyphenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.61-1.83,2.15-2.25,2.97,3.10-3.22,3.48-3.56,3.84,4.28,4.58,6.95,7.05-7.29,7.32,7.46,7.97,8.23.
Embodiment 7 (65)
N- { 4- [(5- { [4- ((4- fluorophenyls) { [(4- fluorophenyls) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.60-1.78,2.12-2.21,2.97,3.10-3.25,3.48-3.58,4.28,4.65,6.95,7.05,7.09,7.19-7.37,7.90,8.17.
Embodiment 7 (66)
N- { 4- [(5- { [4- ((3- fluorophenyls) { [(4- fluorophenyls) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.65-1.85,2.12-2.25,2.97,3.12-3.25,3.48-3.58,4.28,4.65,6.95,7.04-7.20,7.22-7.33,7.30,7.53,7.90,8.17.
Embodiment 7 (67)
N '-(4- chlorphenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
TLC：Rf0.26 (ethyl acetate)；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,3.10-3.30,3.14,3.50-3.60,4.30,4.65,7.17-7.23,7.31-7.39,7.52-7.55,7.90-8.02,8.21.
Embodiment 7 (68)
N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- (3- thienyls) urea hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.29；
NMR(CD3OD)：δ 1.60-1.80,2.05-2.20,3.14,3.15-3.25,3.50-3.60,4.29,4.65,6.97,7.04,7.18-7.27,7.38,7.52,7.61,7.96-8.02,8.23.
Embodiment 7 (69)
2- chloro-n-methyls -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
Figure G200580038925420070516D001191
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.22,2.86,2.97,3.12-3.25,3.49-3.58,4.29,4.67,7.07,7.13,7.25-7.35,7.43,7.46-7.60,7.96,8.22.
Embodiment 7 (70)
The chloro- N of 2-, N- dimethyl -5- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.22,2.86,2.97,3.08,3.12-3.25,3.49-3.58,4.30,4.67,7.08,7.14,7.27-7.36,7.48-7.60,7.99,8.25.
Embodiment 7 (71)
N- (4- { [5- ({ 4- [{ [(the chloro- 3- nitrobenzophenones of 4-) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide
TLC：(the chloroforms: methanol=7: 1) of Rf 0.39；
NMR(CDCl3)：δ 1.40-1.60,1.80-1.90,2.10-2.20,2.80-2.90,2.99,3.46,4.51,4.64,6.08,6.84,7.09,7.21-7.27,7.31-7.41,7.51-7.54,7.61,7.89,8.01.
Embodiment 7 (72)
N- (4- { [5- ({ 4- [({ [4- (methyl sulphonyl) phenyl] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.65-1.85,2.10-2.30,2.97,3.05,3.10-3.30,3.50-3.60,4.29,4.70,7.06,7.11,7.30-7.35,7.32,7.51-7.58,7.77,7.94,8.20.
Embodiment 7 (73)
N- (4- { [5- ({ 4- [({ [3- (methyl sulphonyl) phenyl] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.65-1.85,2.10-2.25,2.98,3.07,3.10-3.30,3.50-3.60,4.31,4.70,7.08,7.15,7.31-7.36,7.44-7.59,8.02,8.02,8.26.
Embodiment 7 (74)
The chloro- 5- of 2- ({ [[1- (4- { 4- [(methyl sulphonyl) amino] phenoxy group } benzyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CD3OD)：δ 1.62-1.79,2.12-2.22,2.95,3.10-3.22,3.45-3.55,4.22,4.67,7.01,7.02,7.25-7.34,7.41,7.46-7.58.
Embodiment 7 (75)
N- (4- { [5- ({ 4- [({ [the chloro- 3- of 4- (4- morpholinyl carbonyls) phenyl] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001211
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CD3OD)：δ 1.65-1.82,2.12-2.22,2.98,3.14-3.35,3.49-3.80,4.31,4.67,7.08,7.14,7.28-7.37,7.45-7.59,8.02,8.27.
Embodiment 7 (76)
The chloro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzoate hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=5: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.64-1.82,2.12-2.25,2.97,3.12-3.24,3.47-3.60,4.29,4.67,7.06,7.11,7.28-7.36,7.41,7.45-7.60,7.82,7.94,8.20.
Embodiment 7 (77)
N '-(the chloro- 3- nitrobenzophenones of 4-)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas
TLC：Rf0.50 (ethyl acetate)；
NMR(CDCl3)：δ 1.35-1.55,1.80-1.90,2.10-2.25,2.90-3.00,3.06,3.44,4.50,6.04,6.93,7.20-7.39,7.31-7.41,7.50-7.53,7.67,7.92-8.05.
Embodiment 7 (78)
2- [4- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide hydrochloride salt
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.53；
NMR(CD3OD)：δ 1.62-1.79,2.12-2.21,2.99,3.08-3.22,3.43-3.57,4.23,4.67,6.95,7.01,7.06,7.22,7.29-7.35,7.32-7.59,7.70.
Embodiment 7 (79)
The fluoro- 5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 1.64-1.81,2.13-2.25,3.14,3.10-3.25,3.50-3.58,4.31,4.67,7.08,7.19,7.30-7.58,7.69,7.95-8.04,8.23.
Embodiment 7 (80)
The fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salt (or dihydrochloride)
Figure G200580038925420070516D001221
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.68-1.85,2.14-2.23,2.97,3.12-3.25,3.50-3.58,4.30,4.65,7.04-7.19,7.25,7.31,7.46,7.51,7.70,7.92,8.23.
Embodiment 7 (81)
The fluoro- 5- of 2- [({ (3- fluorophenyls) [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.68-1.87,2.15-2.25,3.14,3.12-3.25,3.50-3.58,4.31,4.67,7.09,7.12-7.20,7.25,7.37,7.46,7.54,7.71,7.90-8.04,8.23.
Embodiment 7 (82)
The fluoro- 5- of 2- [({ (3- fluorophenyls) [1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] amino } carbonyl) amino] benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.67-1.85,2.15-2.25,3.17,3.12-3.25,3.48-3.58,3.80,4.28,4.65,7.04-7.19,7.25,7.35,7.46,7.50-7.65,7.71,7.95,8.13.
Embodiment 7 (83)
N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001231
White amorphous powder；
TLC：(the chloroforms: methanol=10: 1) of Rf 0.36；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.12,2.97,3.10-3.25,3.45-3.55,4.27,4.65,7.00-7.12,7.30-7.33,7.49-7.55,7.78,7.90,8.18.
Embodiment 7 (84)
N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.31；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.12,2.99,3.10-3.25,3.45-3.55,3.69,4.26,4.65,6.87,6.98-7.08,7.06,7.31-7.34,7.49-7.55,7.78,7.86,8.11.
Embodiment 7 (85)
N- [the fluoro- 5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.53；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.12,3.10-3.25,3.14,3.45-3.55,4.30,4.65,7.00-7.05,7.19,7.31-7.39,7.50-7.55,7.90,7.94-8.02,8.11.
Embodiment 7 (86)
N- [the fluoro- 5- of 2- ({ [[1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
TLC：(the chloroforms: methanol=10: 1) of Rf 0.52；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.12,3.10-3.25,3.17,3.45-3.55,3.79,4.26,4.66,7.00-7.11,7.19,7.31-7.36,7.49-7.63,7.78,7.78,8.11.
Embodiment 7 (87)
The fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 1.69-1.85,2.12-2.25,3.00,3.12-3.25,3.48-3.58,3.70,4.28,4.65,6.87,6.99-7.19,7.25,7.46,7.54,7.71,7.93,8.17.
Embodiment 7 (88)
The fluoro- 5- of 2- ({ [{ 1- [(6- { 2- methoxyl groups -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 1.64-1.81,2.12-2.24,3.00,3.12-3.25,3.48-3.58,3.70,4.28,4.67,6.87,7.00-7.12,7.29-7.35,7.42,7.47-7.58,7.68,7.94,8.18.
Embodiment 7 (89)
The fluoro- 5- of 2- ({ [[1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.44；
NMR(CD3OD)：δ 1.64-1.80,2.12-2.22,3.17,3.12-3.25,3.48-3.58,3.79,4.28,4.67,7.04-7.14,7.29-7.38,7.43,7.48-7.64,7.68,7.94,8.13.
Embodiment 7 (90)
N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride (or tri hydrochloride)
Figure G200580038925420070516D001251
White amorphous powder；
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.70-1.90,2.12-2.25,2.68,2.97,3.12-3.35,3.48-3.60,4.33,4.70,7.08,7.12-7.23,7.25-7.35,7.55,7.73,8.05,8.23-8.34,8.96.
Embodiment 7 (91)
N- (3- fluorophenyls)-N '-(6- methyl -3- pyridine radicals)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] urea dihydrochloride (or tri hydrochloride)
Figure G200580038925420070516D001252
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.70-1.90,2.12-2.25,2.68,3.14,3.12-3.35,3.48-3.60,4.33,4.70,7.12-7.21,7.29,7.38,7.56,7.73,8.00,8.03,8.22-8.36,8.96.
Embodiment 7 (92)
N- (3- fluorophenyls)-N- [1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N '-(6- methyl -3- pyridine radicals) urea dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.70-1.90,2.12-2.25,2.68,3.17,3.12-3.35,3.48-3.60,3.80,4.30,4.70,7.12,7.15-7.23,7.29,7.35,7.51-7.64,7.73,7.99,8.15,8.31,8.96.
Embodiment 7 (93)
N- [the fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.33；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.97,2.97,3.10-3.25,3.40-3.60,4.27,4.65,7.03-7.11,7.29-7.33,7.44-7.54,7.87,8.16.
Embodiment 7 (94)
N- [the fluoro- 5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.41；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.97,3.14,3.15-3.25,3.45-3.55,4.30,4.62,7.03-7.06,7.18,7.31-7.39,7.44-7.54,7.95-8.02,8.22.
Embodiment 7 (95)
N- [the fluoro- 5- of 2- ({ [[1- ({ 6- [2- methoxyl groups -4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.39；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.25,2.97,3.10-3.25,3.17,3.45-3.55,3.79,4.26,4.65,7.03-7.06,7.12,7.31-7.36,7.45-7.63,7.91,8.10.
Embodiment 7 (96)
2- [4- ({ 4- [[({ the fluoro- 3- of 4- [(methyl sulphonyl) amino] phenyl } amino) carbonyl] (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide hydrochloride salt
Figure G200580038925420070516D001271
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.20；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.30,2.97,2.99,3.10-3.20,3.45-3.55,4.23,4.65,6.99-7.04,7.31-7.55,7.69.
Embodiment 7 (97)
The fluoro- N- methyl -5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
Figure G200580038925420070516D001272
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.23,2.89,2.97,3.12-3.25,3.48-3.58,4.29,4.67,7.01-7.15,7.27-7.35,7.40,7.47-7.57,7.61,7.95,8.21.
Embodiment 7 (98)
The fluoro- N- methyl -5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
Figure G200580038925420070516D001281
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.50；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.23,2.89,3.14,3.12-3.25,3.48-3.59,4.30,4.67,7.06,7.18,7.30-7.43,7.47-7.57,7.61,7.94-8.05,8.22.
Embodiment 7 (99)
N '-(6- methyl -3- pyridine radicals)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.70-1.87,2.12-2.24,2.68,3.14,3.17-3.35,3.50-3.60,4.33,4.71,7.18,7.32-7.36,7.38,7.42-7.59,7.72,8.00,8.05,8.27,8.30,8.96.
Embodiment 7 (100)
2- [4- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (phenyl) amino] -1- piperidyls } methyl) phenoxy group] -5- [(methyl sulphonyl) amino] benzamide hydrochloride salt
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.43；
NMR(CD3OD)：δ 1.61-1.80,2.12,2.05-2.22,2.99,3.05-3.21,3.45-3.55,4.23,4.67,6.97-7.08,7.28-7.35,7.35-7.58,7.69,7.77.
Embodiment 7 (101)
N- (3- methyl -4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.68-1.85,2.11,2.12-2.23,2.67,2.97,3.12-3.28,3.50-3.60,4.30,4.71,7.02,7.04,7.15,7.20,7.31-7.38,7.49-7.60,7.73,8.00,8.17,8.22,8.31,8.96.
Embodiment 7 (102)
N- (the chloro- 4- of 3- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.65-1.85,2.12-2.25,2.67,3.01,3.15-3.28,3.48-3.58,4.30,4.72,7.12,7.19-7.28,7.31-7.37,7.41,7.48-7.60,7.74,7.98,8.17,8.30,8.97.
Embodiment 7 (103)
N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) ethyl sulfonamide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.32,1.70-1.85,2.15-2.25,2.68,3.11,3.15-3.28,3.50-3.60,4.33,4.71,7.08,7.14,7.30-7.38,7.50-7.60,7.73,8.07,8.28-8.35,8.96.
Embodiment 7 (104)
N- { 4- [(5- { [4- ((3- aminomethyl phenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.68-1.87,2.12-2.23,2.41,2.68,2.97,3.13-3.28,3.50-3.60,4.31,4.71,7.05-7.18,7.29-7.37,7.43,7.73,8.01,8.13,8.26,8.31,8.96.
Embodiment 7 (105)
The fluoro- 5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.24,2.40,2.97,3.13-3.28,3.48-3.58,4.29,4.67,7.04-7.17,7.28-7.35,7.37-7.47,7.68,7.95,8.21.
Embodiment 7 (106)
The fluoro- N- methyl -5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } benzamide hydrochloride salt (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.65-1.81,2.12-2.22,2.40,2.89,2.97,3.12-3.26,3.48-3.58,4.30,4.67,7.02-7.18,7.28-7.35,7.36-7.44,7.61,7.99,8.25.
Embodiment 7 (107)
N- (the fluoro- 5- of 2- { [((3- aminomethyl phenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.45；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.25,2.12,2.40,2.97,3.10-3.30,3.50-3.60,4.27,4.65,7.00-7.15,7.30,7.31,7.42,7.78,7.90,8.17.
Embodiment 7 (108)
N- (the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.46；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.25,2.13,2.97,3.10-3.30,3.50-3.60,4.28,4.65,6.98-7.17,7.29,7.31,7.54,7.82,7.94,8.20.
Embodiment 7 (109)
N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyrazinyls] epoxide } phenyl) Methanesulfomide tri hydrochloride
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.71-1.88,2.15-2.26,2.68,2.97,3.22-3.35,3.58-3.68,4.42,4.75,7.17,7.29-7.38,7.52-7.62,7.73,8.17,8.20,8.31,8.48,8.97.
Embodiment 7 (110)
The fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino }-N-methyl-benzamide hydrochloride (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.45；
NMR(CD3OD)：δ 1.70-1.85,2.15-2.23,2.89,2.97,3.12-3.25,3.50-3.58,4.30,4.65,7.03-7.19,7.25,7.32,7.42,7.54,7.65,7.99,8.25.
Embodiment 7 (111)
N- (4- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- nitrogen heterocyclic heptyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.42；
NMR(CD3OD)：δ 1.70-2.50,2.67,2.98,3.18-3.35,3.40-3.62,4.37,4.50,7.10,7.16,7.30-7.40,7.48-7.60,7.72,8.12,8.29,8.33,8.96.
Embodiment 7 (112)
N- (4- { [5- ({ (3R) -3- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- pyrrolidinyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 2.40,2.65,2.69,2.98,3.41-3.65,3.80-3.98,4.30-4.72,7.08-7.20,7.28-7.62,7.74,8.14,8.32,8.39,8.51,8.97.
Embodiment 7 (113)
N- (4- { [5- ({ (3S) -3- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- pyrrolidinyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 2.40,2.65,2.69,2.98,3.41-3.65,3.80-3.98,4.30-4.72,7.08-7.20,7.28-7.62,7.74,8.14,8.32,8.39,8.51,8.97.
Embodiment 7 (114)
N- (the fluoro- 5- of 2- { [((3- fluorophenyls) { 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } phenyl) acetamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.29；
NMR(CD3OD)：δ 1.65-1.90,2.00-2.20,2.11,2.12,2.97,3.10-3.30,3.50-3.60,4.27,4.63,6.98-7.06,7.13-7.27,7.53,7.81,7.94,8.17.
Embodiment 7 (115)
N- [5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (3- fluorophenyls) amino] carbonyl } amino) -2- fluorophenyls] acetamide hydrochloride (or dihydrochloride)
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.24；
NMR(CD3OD)：δ 1.32,1.60-1.80,2.10-2.30,2.12,3.08,3.10-3.25,3.50-3.60,4.29,4.70,7.00-7.16,7.25,7.31,7.54,7.81,7.95,8.22.
Embodiment 7 (116)
The fluoro- 5- of 2- ({ [{ 1- [(6- { 2- methyl -4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt (or dihydrochloride)
TLC：Rf0.48 (dichloromethane: methanol=9: 1)；
NMR(CD3OD)：δ 1.68-1.82,2.12,2.09-2.22,2.98,3.12-3.25,3.48-3.59,4.31,4.68,7.01-7.23,7.30-7.37,7.43,7.47-7.58,7.68,8.03,8.27.
Embodiment 7 (117)
5- ({ [{ 1- [(6- { 4- [(ethylsulfonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) -2- fluorobenzoyls amine hydrochlorate (or dihydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.32,1.65-1.82,2.12-2.22,3.10,3.10-3.25,3.49-3.58,4.31,4.68,7.05-7.10,7.13,7.29-7.36,7.43,7.47-7.58,7.68,8.02,8.28.
Embodiment 7 (118)
N- { 4- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] phenyl } ethyl sulfonamide dihydrochloride (or tri hydrochloride)
TLC：(the dichloromethane: methanol=9: 1) of Rf 0.46；
NMR(CD3OD)：δ 1.32,1.72-1.90,2.12-2.25,2.68,3.11,3.18-3.30,3.50-3.60,4.34,4.70,7.07-7.23,7.29,7.33,7.56,7.74,8.10,8.29-8.38,8.97.
Embodiment 7 (119)
2- { [5- ({ 4- [{ [(6- methyl -3- pyridine radicals) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide dihydrochloride (or tri hydrochloride)
TLC：(the chloroforms: methanol=5: 1) of Rf 0.69；
NMR(CD3OD)：δ 1.70-1.90,2.10-2.30,2.68,2.93,3.20-3.40,3.50-3.60,4.41,4.70,7.04,7.33-7.43,7.50-7.60,7.73,7.96,8.17,8.27,8.30,8.54,8.96.
Embodiment 7 (120)
2- [(5- { [4- ((3- fluorophenyls) { [(6- methyl -3- pyridine radicals) amino] carbonyl } amino) -1- piperidyls] methyl } -2- pyridine radicals) epoxide] -5- [(methyl sulphonyl) amino] benzamide dihydrochloride (or tri hydrochloride)
TLC：(the chloroforms: methanol=5: 1) of Rf 0.59；
NMR(CD3OD)：δ 1.70-1.90,2.10-2.30,2.68,2.93,3.20-3.40,3.50-3.70,4.41,4.70,7.03,7.15-7.20,7.30,7.41,7.56,7.74,7.96,8.25-8.35,8.39,8.54,8.97.
Embodiment 7 (121)
2- { [5- ({ 4- [({ [3- (acetyl-amino) -4- fluorophenyls] amino } carbonyl) (3- fluorophenyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } -5- [(methyl sulphonyl) amino] benzamide hydrochloride salt (or dihydrochloride)
TLC：(the chloroforms: methanol=5: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.70-1.90,2.10-2.30,2.12,2.93,3.20-3.40,3.50-3.70,4.37,4.65,6.99-7.10,7.03,7.15-7.20,7.25,7.40,7.54,7.82,7.96,8.15,8.28,8.49.
Embodiment 8
4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide }-N- (2- methoxy ethyls) benzamide hydrochloride salt (or dihydrochloride)
To the N of compound (80mg) prepared by embodiment 7 (50), O- (7- azepine benzos triazol-1-yl)-N is added in dinethylformamide (3ml) solution, N, N ', N '-tetramethylurea cation hexafluorophosphate (84mg), diisopropyl ethyl amine (38 μ l) and 1- methoxy ethyls amine (19 μ l), are stirred overnight.Saturated aqueous solution of sodium bicarbonate is added into reactant mixture, is extracted with ethyl acetate.Organic layer is through anhydrous sodium sulfate drying, concentration.Ethyl acetate solution processing of the gained residue through 4N hydrogen chloride obtains title compound (65mg), with following physical data.
TLC：(the chloroforms: methanol=10: 1) of Rf 0.49；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.25,3.10-3.30,3.30-3.40,3.50-3.60,3.56,4.29,4.70,6.92-6.98,7.11,7.19-7.24,7.31-7.34,7.52-7.55,7.89,7.90,8.20.
Embodiment 8 (1)
N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (4- morpholinyl carbonyls) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls]-N- phenylureas hydrochloride (or dihydrochloride)
1- methoxy ethyl amine is substituted by method same as Example 8, using morpholine, the title compound with following physical data is obtained.
TLC：(the chloroforms: methanol=10: 1) of Rf 0.51；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.25,3.10-3.25,3.40-3.55,3.55-3.80,4.26,4.65,6.92-6.95,7.11,7.19-7.23,7.32-7.34,7.49-7.55,7.94,8.18.
Embodiment 9
N- (4- { [5- ({ 4- [{ [(3- amino -4- chlorphenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride (or tri hydrochloride)
Iron powder (244mg) is added into the acetic acid (10ml) and water (10ml) solution of compound (720mg) prepared by embodiment 7 (71), the mixture is stirred in 40 DEG C 2 hours.Reactant mixture is filtered through Celite (registration mark).After filtrate neutralizes through 1N sodium hydrate aqueous solutions, it is extracted with ethyl acetate.Organic layer is through water and salt water washing, anhydrous sodium sulfate drying, concentration.Gained residue is on silica gel through column chromatography eluting (dichloromethane: methanol=20: 1).The free form is handled with the ethyl acetate solution of 4N hydrogen chloride and obtains title compound (420mg), with following physical data.
TLC：(the chloroforms: methanol=10: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.30,2.97,3.10-3.25,3.50-3.60,4.28,4.70,7.05,7.10,7.15,7.29-7.32,7.30,7.37,7.50-7.55,7.72,7.90,8.17.
Embodiment 10
N- [the chloro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] methanesulfonamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001361
Mesyl chloride (20 μ l) is added in tetrahydrofuran (5ml) mixture to the free form compound (160mg) prepared by embodiment 9 and triethylamine (36 μ l), the mixture is stirred at room temperature and stays overnight.Reactant mixture is extracted through ethyl acetate, anhydrous sodium sulfate drying, concentration.Gained residue is dissolved in tetrahydrofuran (10ml), tetrabutyl ammonium fluoride (146 μ l) is added into the solution.The mixture is stirred in 60 DEG C 3 hours.Water is added into mixture, is extracted with ethyl acetate.Organic layer is through water and salt water washing, anhydrous sodium sulfate drying, concentration.Gained residue is on silica gel through column chromatography eluting (dichloromethane: methanol=20: 1).Ethyl acetate solution processing of the gained compound through 4N hydrogen chloride obtains title compound (35mg), with following physical data.
TLC：(the chloroforms: methanol=10: 1) of Rf 0.48；
NMR(CD3OD)：δ 1.65-1.80,2.10-2.25,2.97,2.97,3.10-3.25,3.50-3.60,4.29,4.70,7.06,7.10-7.15,7.28-7.34,7.52-7.58,7.94,8.21.
Embodiment 11
N- [the chloro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001371
Acetic anhydride (72.4 μ l) is added into pyridine (4ml) solution of the free form compound (160mg) prepared by embodiment 9, the mixture is stirred at room temperature and stays overnight.Reactant mixture is extracted through ethyl acetate, anhydrous sodium sulfate drying, concentration.The methanol solution (506 μ l) of 28% sodium methoxide is added into methanol (4ml) solution of gained residue, is stirred at room temperature 30 minutes.Concentrated reaction mixture, adds water, is extracted with ethyl acetate.Organic layer is through water and salt water washing, through anhydrous sodium sulfate drying, concentration.Ethyl acetate solution processing of the gained residue through 4N hydrogen chloride obtains title compound (64mg), with following physical data.
TLC：Rf0.40 (chloroforms: methanol=10: 1)；
NMR(CD3OD)：δ 1.65-1.80,2.13,2.15-2.25,2.97,3.10-3.35,3.50-3.60,4.30,4.65,7.07,7.12-7.16,7.25-7.34,7.49-7.51,7.68,7.99,8.25.
Embodiment 12
N- [the chloro- 5- of 2- ({ [[1- ({ 6- [4- (methyl sulphonyl) phenoxy group] -3- pyridine radicals } methyl) -4- piperidyls] (phenyl) amino] carbonyl } amino) phenyl] acetamide hydrochloride (or dihydrochloride)
Figure G200580038925420070516D001372
The amine and 1 for obtaining compound (160mg) reduction made from embodiment 7 (77) to the method according to embodiment 9, acetic anhydride (63 μ l) is added in tetrahydrofuran (5ml) solution of -7- alkene of 8- diazabicylos [5.4.0] 11 (34 μ l), flow back the mixture 4 hours.Reactant mixture is poured into water, is extracted with ethyl acetate.Organic layer is through water and salt water washing, anhydrous sodium sulfate drying, concentration.The methanol solution (447 μ l) of 28% sodium methoxide is added into methanol (4ml) solution of gained residue, is stirred at room temperature 30 minutes.Concentrated reaction mixture, adds water, is extracted with ethyl acetate.Organic layer is through water and salt water washing, anhydrous sodium sulfate drying, concentration.Gained residue is on silica gel through column chromatography eluting (ethyl acetate: methanol=20: 1).Ethyl acetate solution processing of the gained compound through 4N hydrogen chloride obtains title compound (89mg), with following physical data.
TLC：(the ethyl acetate: methanol=10: 1) of Rf 0.56；
NMR(CD3OD)：δ 1.60-1.80,2.10-2.25,2.14,3.14,3.15-3.30,3.50-3.60,4.30,4.70,7.15-7.39,7.51-7.55,7.68,7.96,8.00,8.22.
Biological examples
By following experiment demonstrate formula (I) represent compound have antagonism chemokine receptors especially CCR5 activity, and anti-cell migration activity, its also have as highly useful medicine superiority condition.
Biological examples 1
The active testing of antagonizing CCR 5
For example there is the activity of antagonizing CCR 5 by the provable the compounds of this invention of method described in JP-A-2004-256531.
Biological examples 2
Cell migration is tested
For example prove that the compounds of this invention has the activity for suppressing cell migration by following experiment.
PBMC (PMBC) preparation
Will be by using containing liquaemin (final concentration：10U/mL, heparin sodium injection 1000U/mL, Shimizu Pharmaceutical Co., Ltd.) syringe collection people's venous blood (50mL) be stored in 50mL polypropylene conical pipes.(HYCOMED PHARMA are managed to Lymphoprep, Cat.No1019818 16.5mL DPBS (-) (GIBCO is added in), CatNo.14190-136) and blood sample, reverse mixing for several times, is then centrifuged 10 minutes in 3000rpm at room temperature.About 7mLPBMC phases (interphase) are gathered in every 50mL polypropylene conical pipe using pasteur pipet, DPBS (-) to final 50mL is added, centrifuged 10 minutes in 1200rpm at room temperature.Remove after supernatant, residue is dissolved in 50mL DPBS (-).At room temperature in 1500rpm centrifuge cells suspension 3 minutes.Supernatant is removed, 3mL erythrocyte hemolysis buffers (0.8%NH is added thereto4Cl, 0.1%KHCO3, 1mmol/LEDTA) and abundant DL, it is stored at room temperature 2 minutes.30mL DPBS (-) are added into suspension, are centrifuged 3 minutes in 1500rpm at room temperature.Remove supernatant and obtain PBMC.
The culture of human PBMC
Scribble anti-CD3antibody OKT3 (Janssen Pharmaceutical K.K., 1 μ g/mL) 24 orifice plates in 4 DEG C overnight after its through the culture medium ((GIBCO of RPMI 1640, Cat.No.11875-085), 10%FBS (GIBCO, Cat.No.112318-028), 1%PSF (GIBCO, Cat.No.15240-096)) closed 30 minutes in 37 DEG C.By the human PBMC of preparation with 2 × 106Individual cells/well is seeded in the plate for scribbling OKT3, is cultivated 2-3 days in 37 DEG C.PBMC is gathered, with 2 × 106Individual cells/well is seeded in the plate for being not coated with OKT3 but there is people IL2 (5ng/mL), culture.PBMC is passed on for every two or three days.
Use the expression of facs analysis CCR5
The anti-human CD45RO antibody (BD Pharmingen, Cat.No.347967) of the 10 μ LFITC anti-human CCR5 antibody (2D7) (BD Pharmingen, Cat.No.555992) marked and PE marks is added to 1 × 106After in the human PBMC of individual cell culture, dark place stands 15 minutes or after standing 30 minutes on ice, and DPBS (GIBCO) is added thereto and is washed.Cell is suspended in 500 μ L DPBS, and luminous intensity is measured by using FACS.
The in vitro test of cell migration
By 50 μ L5 × 105Human PBMC's suspension (culture medium) of individual cell and the μ L of compound 50 of 2 times of concentration (0-2 μm of ol/L) of final concentration are added to Transwell (coster) upper hole, 300 μ L60nmol/L people MIP-1 β (Pepro tech, Cat.No.300-09) and 2 times of concentration the μ L of compound 300 are added to lower opening.DMSO concentration is 0.01% in upper hole.The solution cultivates 1.5 hours (37 DEG C, 5%CO in CO2gas incubator2, humidity：95%).Extract after the solvent of overhead, 100 μ L20 μm ol/L EDTA/DPBS (-) is added thereto, cultivated 30 minutes in 4 DEG C, centrifuged 5 minutes in 1500rpm.100 μ L solution are transferred in white 96 orifice plates of illuminating from lower opening by liquid relief, cell number is calculated by using Celltiter Glo (Promega) (measurement ATP) measurement, cellular migration inhibition rate by following calculation formula.IC is calculated by the cellular migration inhibition rate of each concentration50Value.On each test compound, n=3 average value is calculated.As a result, the compounds of this invention shows the activity of the cell migration for the people MIP-1 β-induction for hindering people's culture PBMC, IC50It is worth for 0.01 μM or lower.For example, the compound prepared by embodiment 7 (29) shows 0.0012 μM of IC50Value.
Cellular migration inhibition rate=(Ea-Ec)/(Eb-Ec) × 100
Ea：Add measured value during test compound
Eb：There is no measured value during test compound (0.01%DMSO)
Ec：Measured value when not having test compound (0.01%DMSO) and not adding from part to lower floor
Biological examples 3：Monkey hepatomicrosome stability is test
The metabolic stability of the compounds of this invention is for example demonstrated by following experiment.
Monkey hepatomicrosome (final concentration is added into 100mmol/L phosphate buffers (pH7.4 is prepared by 100mmol/L dipotassium hydrogen phosphates and 100mmol/L potassium dihydrogen phosphate aqueous solutions)：1mg/mL) with test compound (final concentration：5 μm of ol/L), the pre-incubation mixed solution 5 minutes.NADPH generation systems (13mmol/L β-NADP are added into the mixture+(final concentration：1.3mmol/L), 33mmol/LG-6-P (final concentrations：3.3mmol/L), 10U/mL G-6-P DH (coming from yeast) (final concentration：0.4U/mL) with 33mmol/L magnesium chloride solution (final concentrations：3.3mmol/L)).When the mixture is cultivated for 37 DEG C, 0 and 30 minute 100 μ L reaction solution of each sampling after starting add acetonitrile (2mL) with terminating reaction (n=2).Add thereto after inner mark solution, stir mixed solution, centrifuged 5 minutes in 3000rpm.Supernatant obtained by 100 μ L is mixed with 100 μ L mobile phase As, is then analyzed with LC/MS/MS.
Analysis LC/MS/MS condition is listed below.
LC conditions：
Post：XTerra RP83.5μm(2.1mmID×50mm)(Waters Corporation)
Column temperature：40℃
Mobile phase A：5mmol/L ammonium acetate solutions/acetonitrile (80/20, V/V)
Mobile phase B：5mmol/L ammonium acetate solutions/acetonitrile (20/80, V/V)
Sample temperature：4℃
The volume injected of sample：5μL
Analysis time：10min
The composition and flow velocity of mobile phase：
Table 1
Time (min) Flow velocity (μ L/min) A (%) B (%)
  0.00   300   95.0   5.0
  1.00   300   95.0   5.0
  1.10   300   5.0   95.0
  5.00   300   5.0   95.0
  5.10   300   95.0   5.0
  10.00   300   95.0   5.0
MS/MS conditions：
Measurement instrument：API3000 (AB/MDS SCIEX companies)
Ioning method：Electron spray ionisation (ESI, positive)
Appropriate monitoring ion is selected for each sample.647.5 (m/z) are as parent ion and 277.0 (m/z) are used as daughter ion for the compound selection for example, prepared in embodiment 7 (83).
The residual rate (%) of the non-variant of test compound in monkey hepatomicrosome is calculated by following calculation formula.
The residual rate (%) of non-variant=
(concentration of test compound at 30 minutes)/(concentration of test compound at 0 minute) × 100
As a result prove, the compounds of this invention is stable in hepatomicrosome intracellular metabolite.For example, the non-variant residual rate of prepare compound is 88% in embodiment 7 (83).
Biological examples 4
Pharmacokinetics test in monkey blood：
For example demonstrate the compounds of this invention by following experiment has good pharmacokinetic property in blood.
5 kinds of test compounds are weighed respectively, are dissolved in and are heated to 50 DEG C of Soltol (trade names；BASFTakeda Vitamins Ltd.) each solution for forming 5mg/mL in/propane diols=7/3.Then each sample that 5 kinds of equivalent of weighing, mixing dilutes 5 times with water for injection and measures into oral administration solution.Stomach enteral is forced to give stump-tailed macaque (male, Hamri Co., Ltd) (n=3) through feeler lever the oral administration solution (1mg/kg).It is fasting state but can be with free water during administration.Using the syringe with heparin upon administration 5, gather 1mL blood samples respectively from scalp vein (superficial cephalic vein) within 15,30 minutes, 1,2,4,6,8 and 24 hours.The sample progress of collection is ice-cold, and blood plasma is obtained within 15 minutes in 3000rpm centrifugations.The blood plasma is in -20 DEG C of storages.By the plasma sample dissolving of -20 DEG C of storages, internal standard substance and acetonitrile (2mL) then are added to plasma sample kind obtained by 100 μ L, stirring is centrifuged 10 minutes in 3000rpm.Gained supernatant is dried through Centrifugal concentrators.Residue is dissolved in 100 μ L mobile phase As, then takes 40 μ L resulting solutions to carry out LC/MS/MS analyses.
The condition of LC/MS/MS analyses is listed below.
LC conditions：
Measurement instrument：Waters 2790(Waters)
Post：YMC-Pack MB-ODS 5μm(2.1mmID×50mm)(YMC)
Column temperature：Room temperature
Flow velocity：200 μ L/ minutes
Mobile phase：20mmol/L ammonium acetate solutions/acetonitrile (1/1, V/V)
MS/MS conditions：
Measurement instrument：QUATTRO Ultima (Micromass companies)
Ioning method：ES+
Capillary voltage：3.20kV
Source temperature：150℃
Desolvation temperature：250℃
Multiplier：650V
Appropriate monitoring ion is selected for each sample.For example it is respectively that the compound prepared in embodiment 6 (17) selects 575.64 (m/z) as parent ion and 262.07 (m/z) as daughter ion, is that the compound prepared in embodiment 7 (54) selects 587.20 (m/z) as parent ion and 227.12 (m/z) as daughter ion.
The transformation of test compound concentration is analyzed by non-room analytic approach using WinNonlin4.0.1 (Pharsight companies) in monkey blood plasma, and calculates AUC.
As a result prove, the compounds of this invention has good pharmacokinetic property in blood.For example, the AUC of the compound prepared in embodiment 6 (17) and 7 (54) is respectively 226ngh/mL and 1150ngh/mL.
Biological examples 5
The measurement of bioavilability (BA)：
For example demonstrating the compounds of this invention by following experiment has good oral formulations trap.
Test compound is weighed, 30%HP- β-CD (trade names are dissolved in；Mitsubishi Corporation) 1mg/mL intravenous administration solution is made.Test compound is weighed, is dissolved in and is heated to 50 DEG C of Soltol (trade names；BASF Takeda Vitamins Ltd.) 3mg/mL solution is formed in/propane diols=7/3.Then dilute 5 times with water for injection and measure into oral administration solution.By the solution (1mg/kg) of intravenous administration stump-tailed macaque (male, Hamri Co., Ltd) (n=3) is given through scalp vein by dosage in single rapid intravenous.Stomach enteral is forced to give stump-tailed macaque (male, Hamri Co., Ltd) (n=3) through feeler lever the oral administration solution (3mg/kg).It is fasting state but can be with free water during administration.Using the syringe with heparin upon administration 5,15,30 minutes, gather 1mL blood samples respectively from scalp vein within 1,2,4,6,8 and 24 hours.The sample progress of collection is ice-cold, and 15 minutes isolated blood plasma is centrifuged in 3000rpm.The blood plasma is in -20 DEG C of storages.By the plasma sample dissolving of -20 DEG C of storages, internal standard substance and acetonitrile (2mL) are then added into plasma sample obtained by 100 μ L, stirring is centrifuged 10 minutes in 3000rpm.Gained supernatant is dried through Centrifugal concentrators.Residue is dissolved in 100 μ L mobile phase As, then takes 40 μ L resulting solutions to carry out LC/MS/MS analyses.
The condition of LC/MS/MS analyses is listed below.
LC conditions：
Measurement instrument：Waters 2790(Waters)
Post：YMC-Pack MB-ODS 5μm(2.1mmID×50mm)(YMC)
Column temperature：Room temperature
Flow velocity：200 μ L/ minutes
Mobile phase：20mmol/L ammonium acetate solutions/acetonitrile (1/1)
MS/MS conditions：
Measurement instrument：QUATTRO Ultima(Micromass)
Ioning method：ES+
Capillary voltage：3.20kV
Source temperature：150℃
Desolvation temperature：250℃
Multiplier：650V
Appropriate monitoring ion is selected for each sample.The compound for example, prepared in embodiment 6 (17) selects 575.64 (m/z) to be used as parent ion and 262.07m/z) as daughter ion (taper voltage (cone current)：35V, collision voltage (collision current)：34eV).
Analyzed in the transformation of monkey internal test compound concentration by non-room analytic approach using WinNonlin 4.0.1 (Pharsight), and calculate AUC.
BA is calculated by following calculation formula.
BA (%)=(AUCp.o./Dosep.o.)/(AUCi.v./Dosei.v.)×100
AUCp.o.：Orally give AUC during test compound
Dosep.o.：The amount of Oral administration of compounds
AUCi.v.：AUC during intravenous administration test compound
Dosei.v.：The amount of intravenous administration compound
As a result demonstrating the compounds of this invention has good oral formulations trap.The BA of the compound for example in embodiment 6 (17) prepared is 42%.
Biological examples 6
Renal allografts model in stump-tailed macaque body for evaluating the compounds of this invention immunosuppressive action：
Stump-tailed macaque (body weight：3-4.5kg) (it is that ABO- is compatible, MHC (MHC)-difference, more specifically, MLR lacks-matched the joint of donor (male)-acceptor (any sex)), two kidneys of acceptor are extracted, by single kidney transplant of donor into acceptor.Tester (the compounds of this invention and/or immunodepressant) is given daily since first 1 day (Day-1) of transplanting day up to determining occur rejection.Effect is evaluated by the survival number of days for comparing transplanted kidney.
The compounds of this invention is given to be combined with the existing immunodepressant (cyclosporine, sirolimus and/or tacrolimus) below in the market treatment consumption.By demonstrating effect compared with individually giving immunodepressant.
(PO) gives the compounds of this invention for example by oral administration, and dosage level is 3,10 or 30mg/kg twice daily.
For example, suspecting rejection occur if the flat rise of plasma creatine edema due to dysfunction of the liver.Especially, it is increased to 8mg/dL when plasma creatine edema due to dysfunction of the liver is flat and then determines rejection occur.
As a result, the compounds of this invention is demonstrated by immunosuppressive action in stump-tailed macaque renal allografts model.
Example of formulations
Example of formulations 1
N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N- phenylureas hydrochloride (10g), calcium carboxymethylcellulose (disintegrant are mixed in a usual manner; 2.0g) magnesium stearate (lubricant; 1.0g) with microcrystalline cellulose (87g); then by punching press, they obtain 1000, each self-contained 10mg active components.
Example of formulations 2
N '-(4- fluorophenyls)-N- [1- ({ 6- [4- (methyl sulphonyl) phenoxy group] pyridin-3-yl } methyl) piperidin-4-yl]-N- phenylureas hydrochloride (10g), mannitol (200g) and distilled water (5L) is mixed in conventional manner.Then by dust-proof filter filtering solution, injected by 5ml portionings in ampoule, 1000 ampoules, each self-contained 10mg active components are obtained through autoclaving.
Industrial applicibility
The compounds of this invention that formula (I) is represented has antagonism chemokine receptors especially CCR5 activity, therefore they are applied to prevent and/or treatment CCR5- relevant diseases, such as inflammation (asthma, ephritis, nephrosis, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, IBD such as ulcerative colitis etc.), immunity disease (autoimmune disease, rejection (the rejection of solid organ in organ transplant, for the rejection for the islet cell transplantation for treating diabetes, graft versus host disease etc.), immunosupress, psoriasis, multiple sclerosis etc.), infectious disease (HIV infections, acquired immune deficiency syndrome, rsv infection etc.), allergic disease (atopic dermatitis, nettle rash, allergic bronchopulmonary aspergillosis, Eosinophilic Gastroenteritis of allergy etc.), cardiovascular disease (artery sclerosis, ischemic damage and reperfusion injury etc.), acute dyspnea syndrome, with the bacterium infection of shock, diabetes, cancer metastasis etc..Therefore, chemokine receptor anagonists, especially CCR5 antagonists are suitable for medicine.
Figure IYZ000001885302700011

Claims (7)

1. the compound or its salt represented by formula (Ib)
Wherein
R1Expression-N (R1A)SO2-R1B, wherein R1ARepresent hydrogen atom, R1BRepresent methyl；
Ring A represents phenyl ring；
X represents-O-,
Ring B represented optionally by methyl substituted pyridine ring,
R51Butyl, phenyl, or thienyl are represented,
R52Represent hydrogen atom,
R53Phenyl is represented, it is optionally selected from the substituent substitution of carbamoyl and halogen atom.
2. compound according to claim 1, it is
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzoyl amine hydrochlorates, or
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides.
3. compound according to claim 1, it is selected from：
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride,
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride,
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride
N- (4- { [5- ({ 4- [{ [(4- fluorophenyls) amino] carbonyl } (3- thienyls) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride
The fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide
The fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide hydrochloride salt
The fluoro- 5- of 2- ({ [{ 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } (phenyl) amino] carbonyl } amino) benzamide dihydrochloride
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) methanesulfonamide hydrochloride
N- (4- { [5- ({ 4- [{ [(2,4- difluorophenyls) amino] carbonyl } (phenyl) amino] -1- piperidyls } methyl) -2- pyridine radicals] epoxide } phenyl) Methanesulfomide dihydrochloride
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzoyl amine hydrochlorates,
5- { [(butyl { 1- [(6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzoyl amine hydrochlorates, and
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides.
4. a kind of pharmaceutical composition, it contains the compound or its salt of formula according to claim 1 (Ib) expression,
Wherein
R1Expression-N (R1A)SO2-R1B, wherein R1ARepresent hydrogen atom, R1BRepresent methyl；
Ring A represents phenyl ring；
X represents-O-,
Ring B represented optionally by methyl substituted pyridine ring,
R51Butyl, phenyl, or thienyl are represented,
R52Represent hydrogen atom,
R53Phenyl is represented, it is optionally selected from the substituent substitution of carbamoyl and halogen atom.
5. the compound or its salt that formula (Ib) is represented is preparing the application in being used to prevent and/or treat the medicine of CCR5- relevant diseases,
Wherein
R1Expression-N (R1A)SO2-R1B, wherein R1ARepresent hydrogen atom, R1BRepresent methyl；
Ring A represents phenyl ring；
X represents-O-,
Ring B represented optionally by methyl substituted pyridine ring,
R51Butyl, phenyl, or thienyl are represented,
R52Represent hydrogen atom,
R53Phenyl is represented, it is optionally selected from the substituent substitution of carbamoyl and halogen atom.
6.5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzoyl amine hydrochlorates, or
5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides.
7. pharmaceutical composition; it includes 5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2; 4- difluorobenzoyl amine hydrochlorates; or 5- { [(butyl { 1- [(2- methyl -6- { 4- [(methyl sulphonyl) amino] phenoxy group } -3- pyridine radicals) methyl] -4- piperidyls } amino) carbonyl] amino } -2,4- difluorobenzamide dihydrochlorides.
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