CN103373971B - As the carbamide compounds of kinases inhibitor - Google Patents
As the carbamide compounds of kinases inhibitor Download PDFInfo
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- CN103373971B CN103373971B CN201210122943.2A CN201210122943A CN103373971B CN 103373971 B CN103373971 B CN 103373971B CN 201210122943 A CN201210122943 A CN 201210122943A CN 103373971 B CN103373971 B CN 103373971B
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- PFDUOZOKFIIZPC-UHFFFAOYSA-N Nc1cc(c(-c(cc2)ccc2NC(Nc(cc(C(F)(F)F)cc2)c2F)=O)ccc2)c2c(OCCN2CCOCC2)n1 Chemical compound Nc1cc(c(-c(cc2)ccc2NC(Nc(cc(C(F)(F)F)cc2)c2F)=O)ccc2)c2c(OCCN2CCOCC2)n1 PFDUOZOKFIIZPC-UHFFFAOYSA-N 0.000 description 1
- YHTMGGHJSLFTGH-UHFFFAOYSA-N O=C(Nc(cc1)ccc1Oc1ncnc2c1nc[n]2Cc1cc(F)ccc1)Nc(cc1)cc(C(F)(F)F)c1Cl Chemical compound O=C(Nc(cc1)ccc1Oc1ncnc2c1nc[n]2Cc1cc(F)ccc1)Nc(cc1)cc(C(F)(F)F)c1Cl YHTMGGHJSLFTGH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a class as the carbamide compounds of kinases inhibitor and pharmaceutical salts thereof; Containing pharmaceutical composition and the application of this compounds as kinases inhibitor of this compounds.
Description
Technical field:
The invention belongs to field of medicaments, relate in particular to new carbamide compounds of a class and preparation method thereof, also relate to this compounds as the application of kinases inhibitor in Therapeutic cancer simultaneously.
Technical background:
Known at present, all there is Ras/Raf/Mek/Erk Signal Transduction Pathways in all eukaryotic cells, Ras/Raf/MEK/ERK path mitogen activated protein kinase (MAPKs) is transmitted by a large amount of cell surface receptor mediate intracellular signal.The factor of major part stimulate cell growth, comprise EGF, PDGF, VEGF and c-KIT, after the receptors bind of cell surface, namely first the mode by receptor tyrosine kinase autophosphorylation activates Ras, Ras activates Raf/MEK/ERK signal transduction pathway again further, brings the signal of somatomedin into nucleus, realizes signal by extracellular to endonuclear transmission, trigger cell biologically, as cell proliferation, differentiation, conversion and apoptosis etc.
All there is the rise of this path in many tumour cells, and Raf is as the Key kinases of in this path, plays its signal transcription regulating effect by the mode relying on or do not rely on Ras.As the kinase whose stream substrates of Raf, the MEK phosphorylated CREB of activation, and ERK is by acting on multiple substrate to regulate cell function.Once this path generation excessive activation, acceleration and the prolongation of cells survival phase of cell proliferation can lead oncogenic formation and development.
Raf, as the Key kinases in this path, has 3 isozymes, is respectively A-Raf, B-Raf and C-Raf, and they are all closely related with the adjustment of cell proliferation, differentiation and vasculogenesis.Known in human tumor cell A-Raf and C-Raf sudden change very rare, B-Raf sudden change then account for 7%.Somatic mutation rate after B-Raf is activated in melanoma up to 50% ~ 70%, 35% is reached in ovarian cancer, 30% is reached in thyroid carcinoma, 10% is reached in colorectal carcinoma, therefore B-RafV600E as treatment human cancer target and day by day receive the concern of investigator, be one of important target spot of current antitumor drug research.
Small molecule kinase inhibitors containing urea structure is just sent to great expectations from the nineties in early days, is used for the treatment of cancer and inflammation.And BAY 43-9006 is as first Raf kinase with ureas structure, the intracellular signaling that Raf/MEK/ERK path can be hindered to mediate on the one hand, the propagation of inhibition tumor cell, direct Tumor suppression growth; On the other hand, the growth of tumour and transfer depend on the formation of new vessel, VEGF and PDGF is important angiogenic factors, Xarelto is just by suppressing the activity of VEGFR (as VEGER-2, VEGER-3) and PDGFR (PDGFR-β) Tyrosylprotein kinase, block tumor-blood-vessel growth, indirect Tumor suppression growth.Have dual antitumor action, therefore it is referred to as multi-kinase inhibitor.
Preclinical study shows, and the animal transplant models of Xarelto to people's tumour has anti-tumor activity widely, comprises colorectal carcinoma, carcinoma of the pancreas, lung cancer, mammary cancer and ovarian cancer, and its antitumor action is relevant with suppression Raf/MEK/ERK path; The anti-tumor activity of Xarelto is observed too in the tumour with Ras or B-Raf transgenation; In addition, in human colon carcinoma (HT-29 and Colo205) and mammary cancer (MDA-MB-231) animal transplant models, Xarelto obviously can suppress the formation of new vessel.
Summary of the invention:
The object of the present invention is to provide shown in general formula (I) as the carbamide compounds of kinases inhibitor, pharmaceutical salts, hydrate and solvate and corresponding isomer, prodrug or chemoprotectant form.
Wherein:
M is independently selected from 0,1,2,3 or 4;
L independently selected from
X is selected from independently selected from O or (CH
2)
n;
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from independently selected from CH or N;
S ring is independently selected from phenyl ring, pyrrole ring;
R
1independently selected from hydrogen, halogen, C
1-8alkyl, halo C
1-8alkyl, C
1-8alkoxyl group, halo C
1-8alkoxyl group, piperazine methyl, methylpiperazine methyl, ethyl piperazidine methyl or morpholine methyl; But when L choosing
time, R
1only select hydrogen, halogen, C
1-8alkyl, halo C
1-8alkyl;
R
2independently be selected from hydrogen, (CH
2)
pr
3;
Aforementioned R
3independently be selected from C
3-10heteroaryl, chloro C
3-10heteroaryl;
R
4independently be selected from hydrogen, halogen, C
1-8alkyl;
R
5independently be selected from (CH
2)
pr
6;
Aforementioned R
6independently be selected from C
1-8alkyl, C
6-14aryl, C
3-10heteroaryl; Described C
6-14aryl or C
3-10heteroaryl can be replaced independently by one or more halogen;
Aforementioned p is independently selected from 0,1,2,3 or 4;
R
7independently be selected from hydrogen, C
3-10heterocyclylalkyl, O (CH
2)
pr
8, NH (CH
2)
pr
9or C
3-8alkynyl, wherein said C
3-8alkynyl is optional further by C
1-8alkoxyl group, two C
1-8alkylamino replaces;
Aforementioned R
8be selected from C
1-8alkoxyl group, C
6-14aryl or C
3-10heterocyclylalkyl; Described C
6-14aryl or C
3-10heterocyclylalkyl is optionally further by C
1-8alkyl replaces;
Aforementioned R
9be selected from C
3-10heterocyclylalkyl, described C
3-10heterocyclylalkyl is optionally further by C
1-8alkyl replaces;
Described p is independently selected from 0,1,2,3 or 4.
When L is selected from
as general formula (I a) shown in:
Wherein:
M is independently selected from 0,1,2,3 or 4;
R
1independently selected from hydrogen, halogen, C
1-8alkyl, halo C
1-8alkyl; Preferably R
1for hydrogen, halogen, C
1-5alkyl, halo C
1-5alkyl, halo C
1-5alkoxyl group; More preferably R
1for hydrogen, Cl, Br, F, methyl, methoxyl group, trifluoromethyl;
R
2independently be selected from hydrogen, (CH
2)
pr
3;
Aforementioned R
3independently be selected from C
3-10heteroaryl, halo C
3-10heteroaryl;
Preferably R
3for C
3-7heteroaryl, halo C
3-7heteroaryl;
More preferably R
3for pyrimidyl, Chloropyrimide base, pyridyl;
Aforementioned p is independently selected from 0,1,2,3 or 4.
When L is selected from
as shown in general formula (Ib):
Wherein:
M is independently selected from 0,1,2,3 or 4;
X is selected from independently selected from O or (CH
2)
n;
Aforementioned n is selected from 0,1,2,3 or 4;
R
1independently selected from hydrogen, halogen, C
1-8alkyl, halo C
1-8alkyl; Preferably R
1for hydrogen, halogen, C
1-5alkyl, halo C
1-5alkyl, halo C
1-5alkoxyl group; More preferably R
1for hydrogen, F, Cl, Br, methyl, methoxyl group, trifluoromethyl;
R
4independently be selected from hydrogen, halogen, C
1-8alkyl; Preferably R
4for hydrogen, F, Cl, Br, C
1-3alkyl; More preferably R
4for hydrogen;
R
5independently be selected from (CH
2)
pr
6;
Aforementioned R
6independently be selected from C
1-8alkyl, C
6-14aryl, C
3-10heteroaryl; Described C
6-14aryl or C
3-10heteroaryl can be replaced independently by one or more halogen;
Preferably R
6independent C
1-5alkyl, C
6-10aryl, C
3-7heteroaryl, described C
6-10aryl or C
3-7heteroaryl is optionally optionally substituted by halogen further;
More preferably R
6independently be selected from methyl, ethyl, phenyl, pyridyl, chlorophenyl, chloro-pyridine base.
Aforementioned p is independently selected from 0,1,2,3 or 4.
When L is selected from
as shown in general formula (Ic):
Wherein:
M is independently selected from 0,1,2,3 or 4;
X is selected from independently selected from O or (CH
2)
n;
Aforementioned n is selected from 0,1,2,3 or 4;
Y is selected from independently selected from CH or N;
S ring is independently selected from phenyl ring, pyrrole ring;
R
1independently selected from hydrogen, halogen, C
1-8alkyl, halo C
1-8alkyl, C
1-8alkoxyl group, halo C
1-8alkoxyl group, piperazine methyl, 4-methylpiperazine methyl, 4-ethyl piperazidine methyl or morpholine methyl; Preferably R
1for hydrogen, halogen, C
1-5alkyl, halo C
1-5alkyl, C
1-5alkoxyl group, halo C
1-5alkoxyl group, piperazine methyl, 4-methylpiperazine methyl, 4-ethyl piperazidine methyl or morpholine methyl; More preferably R
1for hydrogen, Cl, Br, F, C
1-3alkyl, halo C
1-3alkyl, C
1-3alkoxyl group, halo C
1-3alkoxyl group, piperazine methyl, 4-methylpiperazine methyl, 4-ethyl piperazidine methyl or morpholine methyl;
R
4independently be selected from hydrogen, halogen, C
1-8alkyl; Preferably R
4for hydrogen, F, Cl, Br, C
1-3alkyl; More preferably R
4for hydrogen;
R
7independently be selected from hydrogen, C
3-10heterocyclylalkyl, O (CH
2)
pr
8, NH (CH
2)
pr
9or C
3-8alkynyl, described C
3-8alkynyl is optional further by C
1-8alkoxyl group, two C
1-8alkylamino replaces;
Preferably R
7for hydrogen, C
3-8heterocyclylalkyl, O (CH
2)
pr
8, NH (CH
2)
pr
9or C
3-5alkynyl, described C
3-5alkynyl is optional further by C
1-5alkoxyl group, two C
1-5alkylamino replaces;
More preferably R
7for hydrogen, morpholinyl, methylpiperazine base, Pyrrolidine base, O (CH
2)
pr
8, NH (CH
2)
pr
9, 3-methoxypropargyl, 3-dimethylamino proyl;
Aforementioned R
8be selected from C
1-8alkoxyl group, C
6-14aryl or C
3-10heterocyclylalkyl; Described C
6-14aryl or C
3-10heterocyclylalkyl is optionally further by C
1-8alkyl replaces;
Preferably R
8be selected from C
1-5alkoxyl group, C
6-10aryl or C
3-8heterocyclylalkyl, described C
6-10aryl or C
3-18heterocyclylalkyl is optionally further by C
1-3alkyl replaces;
More preferably R
8be selected from methoxyl group, piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned R
9be selected from C
3-10heterocyclylalkyl, described C
3-10heterocyclylalkyl is optionally further by C
1-8alkyl replaces;
Preferably R
9be selected from C
3-8heterocyclylalkyl; Described C
3-8heterocyclylalkyl is optionally further by C
1-5alkyl replaces;
More preferably R
9be selected from piperazinyl, methylpiperazine base, morpholinyl;
Aforementioned p is independently selected from 0,1,2,3 or 4.
A second aspect of the present invention relates to the pharmaceutical composition comprising the compound shown in general formula (I), wherein pharmaceutical composition preferably also comprises auxiliary material, the preferred pharmaceutically useful carrier of described auxiliary material and/or vehicle, wherein said vehicle preferred diluent.
The invention still further relates to comprise in general formula (I) compound and pharmaceutical composition be used for the treatment of or prophylaxis of tumours medicine or as preparation treatment or the application of prophylaxis of tumours.
The invention still further relates to the compound shown in general formula (I) and prepare the purposes in medicine as kinases inhibitor.Described pharmaceutical use, by suppressing Raf/MEK/ERK signal transduction pathway, also blocks tumor neovasculature formation by suppressing vegf receptor, thus reaches the effect for the treatment of tumour.
Above-mentioned tumour is preferably liver cancer, kidney, mammary cancer, lung cancer, nonsmall-cell lung cancer, thyroid carcinoma, bladder cancer, colon and rectum carcinoma, prostate cancer, carcinoma of the pancreas, ovarian cancer, myelomatosis, head and neck cancer, bladder cancer, the too much disease of acute myeloid leukaemic, chronic marrow sample hypercytosis, peritoneal cancer, mesothelioma, myelodysplastic syndrome, cancer of the stomach.
Unless otherwise indicated, the term " halogen " that the present invention uses represents fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.
Unless otherwise indicated, the term " C of the present invention's use
6-14aryl " refer to any from the functional group that simple aromatic nucleus derives or substituting group.Preferred C
6-10aryl, more preferably C
6-8aryl, especially preferably phenyl, suitable embodiment is as phenyl.Described aryl is optionally replaced by one or more substituting group being independently selected from halogen, alkyl, alkoxyl group, nitro or cyano group, is preferably optionally substituted by halogen, and suitable embodiment is as difluorophenyl.
Unless otherwise indicated, the term " C of the present invention's use
3-10heteroaryl " or " halo C
3-10heteroaryl " represent at least comprise the heteroatomic aromatic group that 1 is selected from N, O and S.Preferred heteroaryl is C
3-8heteroaryl or halo C
3-8heteroaryl, is more preferably C
3-7heteroaryl or halo C
3-7heteroaryl.The embodiment of described heteroaryl comprises the above-mentioned group of such as imidazolyl, pyridyl, pyrimidyl, pyrryl, thienyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl and halogen substiuted.More preferably pyridyl, pyrimidyl, pyrryl, triazolyl, especially preferably pyridyl, pyrimidyl, Chloropyrimide.
Unless otherwise indicated, the term " C of the present invention's use
3-10heterocyclylalkyl " represent that at least comprising 1 is selected from the heteroatomic aliphatics group of naphthene base such as N, O and S.Be preferably C
3-8heterocyclylalkyl.The embodiment of described Heterocyclylalkyl comprises such as piperazinyl, methylpiperazine base, morpholinyl, Pyrrolidine base, furyl.
Unless otherwise indicated, the term " C of the present invention's use
1-8alkyl " or " C
1-8alkoxyl group " mean that this group is straight or branched, preferred C
1-5alkyl or C
1-5alkoxyl group.The embodiment of suitable alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl.The embodiment of suitable alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy and tert.-butoxy, pentyloxy.
" the halo C mentioned herein
1-8alkyl " or " halo C
1-8alkoxyl group " refer to that this group is straight or branched, be preferably halo C
1-5alkyl.The embodiment of suitable halogenated alkyl group comprises as trifluoromethyl, trifluoroethyl, difluoromethyl, two fluoro ethyls.
" the two C mentioned herein
1-8alkylamino " be preferably two C
1-5alkylamino, is more preferably two C
1-3alkylamino, the embodiment of suitable two alkylamino radicals comprises dimethylamino, diethylin, dipropyl amino.
Term " the C that the present invention uses
3-8alkynyl " refer to containing a triple bond and straight chain and the branched hydrocarbyl with 3-8 carbon atom, preferred " C
3-5alkynyl ";
Term " the C that the present invention uses
3-8alkynyl is replaced by two alkylamino " refer to C
3-8α position hydrogen atom on alkynyl is by two C
1-8alkylamino replaces.Be preferably two C
1-5the C that alkylamino replaces
3-5alkynyl, suitable embodiment comprises 3-dimethylamino proyl.
Term " the C that the present invention uses
3-8alkynyl is by C
1-8alkoxyl group replaces " refer to C
3-8α position hydrogen atom on alkynyl is by C
1-8alkoxyl group replaces.Be preferably C
1-5the C that alkoxyl group replaces
3-5alkynyl, suitable embodiment comprises 3-methoxypropargyl.
The pharmacy acceptable salt of indication of the present invention is the salt that formula (I) is formed with any acid, and pharmaceutically acceptable acid.Suitable acid comprises mineral acid as phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, Hydrogen bromide and similar acid; Or organic acid is as acetic acid, trifluoroacetic acid, propionic acid, propanedioic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, amygdalic acid, sulfonic acid, tosic acid, methanesulfonic, ethyl sulfonic acid, Phenylsulfonic acid, camphorsulfonic acid, Whitfield's ointment and similar acid.
The isomer of indication of the present invention refers to that one or more stereoisomer forms exist, and comprises various three-dimensional enantiomer, diastereomer, tautomer and geometrical isomer.The present invention includes Formula (I), its steric isomer and pharmaceutically acceptable salt thereof.Compound of the present invention may occur with the active form of the mixture of steric isomer, single stereoisomers or tool.
" solvate " of indication of the present invention is in this article in a conventional sense for representing the mixture of solute (such as the salt of compound, compound) and solvent.If solvent is water, so solvate can be called as hydrate aptly, such as monohydrate, dihydrate, trihydrate etc.
" the chemoprotectant form " of indication of the present invention refers to that wherein one or more reactive functional groups are protected with the compound avoiding occurring undesirable chemical reaction under defined terms (such as, pH, temperature, irradiation, solvent etc.) in this article in a conventional sense.In practice, well-known chemical process can be adopted reversibly to make those otherwise the functional group reacted is not reacted under prescribed conditions.In chemoprotectant form, one or more reactive functional groups is protected or blocking group (also referred to as masked or shelter group or be blocked or blocking group).By protective reaction functional group, can carry out relating to the reaction of other not protected reactive functional groups and not affect protected group; Blocking group usually can be removed in a subsequent step and substantially not affect the remainder of molecule.Meanwhile, the invention discloses the preparation method preparing the compounds of this invention and pharmaceutical salts thereof.
" prodrug " of indication of the present invention relates to when by the compound of the active compound needed for producing time metabolism (such as in vivo).Usually, prodrug is non-activity, or activity is lower than active compound, but can provide favourable process, use or metabolisming property.
Such as, some prodrugs are esters (ester unstable in acceptable metabolism on such as physiology) of active compound.Between metabilic stage, ester group (-C (=O) OR) is cleaved, produces active medicine.This kind of ester can be formed by esterification; the esterification of such as, any hydroxy-acid group (-C (=O) OH) in parent compound, in a suitable manner, protects other reactive group any be present in parent compound in advance; if needed, then carry out protection.
And some prodrugs are by enzyme activation thus generate active compound or generate the compound (such as in ADEPT, GDEPT, LIDEPT etc.) of active compound after further chemical reaction.Such as, prodrug can be sugar derivatives or other glucosides conjugates, or can be amino acid ester derivative.
" pharmaceutical composition " of indication of the present invention refers to, by more than a kind of activeconstituents mixing or the product merging gained, comprise the fixing of activeconstituents and non-fixed combinations.Term " fixed Combination " refers to activeconstituents, and such as formula (I) compound and concomitant medication, be applied to patient with single entities or dosage simultaneously.Term " non-fixed combinations " refers to activeconstituents, such as formula (I) compound and concomitant medication, be applied to patient successively, the wherein this treatment level of significance used as providing two or more compound in patient body with independent entity simultaneously, jointly or without specified time restriction ground.
The invention provides following particular compound:
1-(4-((9-phenmethyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-((9-(pyridine-2-methyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-((9-methyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-((9-(3-benzyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-morpholinyl isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(4-methylpiperazine-1-yl) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-Pyrrolidine base isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the fluoro-5-aminomethyl phenyl of 2-) urea
1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-aminomethyl phenyl of 2-) urea
1-(4-(3-amino-1-(2-morpholine oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-trifluoromethyl of 2-) urea
1-(4-(3-amino-(2-methoxy ethoxy) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-trifluoromethyl of 2-) urea
1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) third is amino) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-methoxypropargyl) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(3-amino-1-(3-dimethylaminopropyne base) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) (-7-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(4-(2-amino-4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine) (-7-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzos [d] oxazole-6-base) urea
1-phenmethyl-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzos [d] oxazole-6-base) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(2-oxo-3-(6-chloropyrimide-4-base)-2,3-dihydrobenzos [d] oxazole-6-base) urea
1-phenmethyl-3-(2-oxo-3-(6-chloropyrimide-4-base)-2,3-dihydrobenzos [d] oxazole-6-base) urea
Unless otherwise indicated, term used herein " the compounds of this invention " refers to compound shown in general formula (I), preferred above-mentioned particular compound, particularly preferably embodiment compound.
Embodiment
Shown in general formula of the present invention (I), compound is prepared by following methods:
1) preparation of compound shown in general formula (Ia):
A, with 2-amino-5-Nitro-phenol for raw material, first make 6-Xiao base benzoxazole-2 (3H)-one (2),
B, obtained 6-Xiao base benzoxazole-2 (3H)-one (3) replaced;
C, obtained 6-An base benzoxazole-2 (3H)-one (4) compound replaced;
D, again with replace aniline reaction obtain target compound.
2) preparation of compound shown in general formula (Ib):
A, with the chloro-9H-purine of 6-for raw material, 9H-purine compound chloro-with the 6-of formula (II) compound formation formula (III);
B, again with the 6-oxo-aniline-9H-purine compound of the replacement of formula (IV) compound formation formula (V);
C, be obtained by reacting target compound with formula (VI) again.
3) when Y is C, the preparation of compound shown in general formula (Ic):
A, with the amino benzenes compounds replaced (V) for raw material, make formula (VII) phenyl ureas compound;
B, formula (IV) 5-bromo-3-aminoisoquinoline analog derivative and formula (VII) phenyl ureas compound are obtained by reacting target compound:
4) when Y is N, the preparation of compound shown in general formula (Ic):
A, with R
1the aniline replaced is raw material, first reacts phenyl ureas compound processed;
B, again with R
77H-pyrrolo-[2, the 3-d] pyrimidine-2-amino reaction replaced, obtains target compound:
Part is abridged explanation:
CDI: be N, N ' carbonyl dimidazoles, DMF:N, dinethylformamide, THF: tetrahydrofuran (THF), EAC: ethyl acetate, Pd (PPH
3)
4: tetra-triphenylphosphine palladium, L-proline:L-proline(Pro).
Embodiment
Embodiment 1:1-(4-((9-phenmethyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
The preparation of steps A: 4-(9-phenmethyl-9H-purine-6-oxygen) aniline
Take the chloro-9H-purine of 244mg 6-to be dissolved in 20ml DMF, add K
2cO
3stir 0.5h, slowly drip 205.2mg toluene(mono)chloride, reaction 20h, pours into reaction solution in frozen water, and regulate PH to 5-6, extraction into ethyl acetate, column chromatography obtains white solid.
Amino-phenol 102mg, Cs
2cO
3652mg, THF/DMF (9ml/3ml), stir-activating 2h, adds step gained compound 122mg, KI and Bu of catalytic amount
4nBr, is warming up to 85 DEG C.TLC monitors basic complete reaction.Add water, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, desolventizing obtains pink solid.
The preparation of step B:1-(4-((9-phenmethyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
0.317g (1mmol) 4-(9-phenmethyl-9H-purine-6-oxygen) aniline is in 100ml tri-neck round-bottomed flask, add 20ml methylene dichloride stirring and dissolving, add 0.243g (1.5mmol) dicarbapentaborane imidazoles (CDI), after stirring at room temperature 2h, add the chloro-3-5-trifluoromethylaniline of 0.234g (1.2mmol) 4-, continue at room temperature to stir, after question response is complete, concentrated, column chromatography for separation, obtains white solid.
1H NMR(CDCl
3，300MHz)δ(ppm)：8.45(s，1H，purine-H)，8.44(s，1H，Ar-H)，8.00～7.99(s，1H，purine-H)，7.66～7.63(d，1H，Ar-H)，7.56～7.53(d，2H，Ar-H)，7.51～7.48(d，1H，Ar-H)，7.38～7.31(m，5H，Ar-H)，7.24～7.21(d，2H，Ar-H)，5.54(s，2H，CH
2)。
ESI-MS m/z:539 [M+H]
+, calculated value: 539.
Embodiment 2:1-(4-((9-(pyridine-2-methyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With 4-(9-(pyridine-2-methyl)-9H-purine-6-oxygen) aniline and the chloro-3-5-trifluoromethylaniline of 4-for raw material, with the preparation method of embodiment 1, obtain white solid.
1H NMR(CDCl
3，500MHz)δ(ppm)：9.18(s，1H，NH)，8.92(s，1H，NH)，8.60(s，1H，purine-H，)，8.48～8.47(d，1H，pyridine-H)，8.39(s，1H，purine-H，)8.11(s，1H，Ar-H)，7.81～7.80(t，1H，pyridine-H)，7.67～7.65(d，1H，Ar-H)，7.62～7.61(d，1H，Ar-H)，7.55～7.52(d，2H，Ar-H)，7.36～7.35(d，1H，pyridine-H)，7.32～7.30(m，1H，pyridine-H)，7.24～7.22(d，2H，Ar-H)，5.64(s，2H，CH
2)。
ESI-MS m/z:540 [M+H]
+, calculated value: 540.
Embodiment 3:1-(4-((9-methyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With 4-(9-methyl-9H-purine-6-oxygen) aniline and 3-trifluoromethyl-4-chloroaniline for raw material, with the preparation method of embodiment 1, obtain light yellow solid.
1H NMR(CDCl
3，500MHz)δ(ppm)：9.20(s，1H，NH)，9.14(s，1H，NH)，8.46(d，2H，purine-H，)，8.12(s，1H，Ar-H)，7.68～7.60(d，2H，Ar-H)，7.55～7.52(d，2H，Ar-H)，7.22～7.19(d，2H，Ar-H)，3.86(s，3H，CH
3)。
ESI-MS m/z:464 [M+H]
+, calculated value: 464.
Embodiment 4:1-(4-((9-(3-benzyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
4-(9-(3-benzyl)-9H-purine-6-oxygen) aniline and the chloro-3-5-trifluoromethylaniline of 4-are raw material, with the preparation method of embodiment 1, obtain light yellow solid.
1HNMR(CDCl
3，500MHz)δ(ppm)：9.18(s，1H，NH)，8.92(s，1H，NH)，8.65(s，1H，purine-H，)，8.47(s，1H，purine-H，)8.11(s，1H，Ar-H)，7.67～7.65(d，1H，Ar-H)，7.62～7.61(d，2H，Ar-H)，7.54～7.52(d，2H，Ar-H)，7.48～7.40(m，1H，Ar-H)，7.23～7.22(d，2H，Ar-H)，7.18～7.13(m，2H，Ar-H)，5.54(s，2H，CH
2)。
ESI-MS m/z:557 [M+H]
+, calculated value: 557.
Embodiment 5:1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
The preparation of steps A: 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea
Under condition of ice bath first by fluoro-for 5.37g (30mmol) 2-5-5-trifluoromethylaniline and 3.03g (30mmol) triethylamine mixed dissolution in the methylene dichloride of 20mL.Again 2.97g (10mmol) triphosgene is dissolved in the methylene dichloride of 20ml, is slowly added dropwise to above-mentioned reaction solution (keeping the temperature of reaction solution between 5 ~ 10 DEG C), dropwises rear continuation and react 0.5h under condition of ice bath.Remove ice bath, 20ml is dissolved with the methylene dichloride mixed solution of 30mmol to aminoboronic acid pinacol ester and 3.03g (30mmol) triethylamine under normal temperature condition and is added dropwise in above-mentioned reaction solution, stirring is spent the night.After reaction terminates, pour 50ml shrend into reaction solution and go out, with dichloromethane extraction (2 × 20ml), use water (40ml), saturated sodium-chloride (40mL) to wash successively, concentrated after anhydrous sodium sulfate drying.Concentrated solution silica gel column chromatography is separated and obtains white powdery solids, is 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea.
The preparation of step B:1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
By 0.6mmol 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4; 4; 5; 5-tetramethyl--1; 3-dioxolane-2-base) phenyl) urea, the bromo-3-aminoisoquinoline of 0.3mmol5-, 0.018mmol tetra-triphenylphosphine palladium, 1ml10% aqueous sodium carbonate, 2ml ethanol and 2ml toluene joins in 25ml bis-neck bottle; after nitrogen protection; be heated to 110 DEG C of backflows; reaction 8h; reduce pressure reaction solution precipitation, adds methylene chloride and water dissolution, after extraction, precipitation; cross post, recrystallization obtains faint yellow solid, fusing point: 152.3 ~ 153.2 DEG C.
1H NMR(DMSO-D6，500MHz)δ(ppm)：9.29(s，1H，NH)，8.91(d，1H，NH)，8.84(s，1H，quinoline-H)，8.65～8.63(d，1H，Ar-H)，7.79～7.78(d，1H，Ar-H)，7.61～7.37(dd，4H，Ar-H)，7.51～7.48(t，1H，quinoline-H)，7.39～7.38(m，1H，quinoline-H)，7.35～7.33(d，1H，Ar-H)，7.20～7.17(t，1H，quinoline-H)，6.62(s，1H，quinoline-H)，5.88(s，2H，NH
2)。
ESI-MS m/z:439 [M-H]
-, calculated value: 439.
Embodiment 6:1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, obtain faint yellow solid target compound.
1H NMR(DMSO-D6，300MHz)δ(ppm)：9.28(s，1H，NH)，8.92(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，7.90～7.88(d，1H，Ar-H)，7.60～7.36(dd，4H，Ar-H)，7.53～7.49(t，1H，Ar-H)，7.41～7.40(m，1H，quinoline-H)，7.33～7.31(d，1H，Ar-H)，7.13～7.10(t，1H，quinoline-H)，6.18(s，1H，quinoline-H)，5.74(s，2H，NH
2)，4.52～4.50(t，2H，CH
2)，2.81～2.80(t，2H，CH
2)，2.54～2.52(m，4H，CH
2)，2.36～2.32(m，4H，CH
2)，2.15(s，3H，CH
3)。
ESI-MS m/z:583 [M+H]
+, calculated value: 583.
Embodiment 7:1-(4-(3-amino-1-morpholinyl isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-morpholinyl isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, obtain faint yellow solid target compound.
1H NMR(DMSO-D6，500MHz)δ(ppm)：9.29(s，1H，NH)，8.93～8.92(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，7.87～7.85(d，1H，Ar-H)，7.60～7.37(dd，4H，Ar-H)，7.53～7.49(t，1H，Ar-H)，7.41～7.40(m，1H，quinoline-H)，7.29～7.28(d，1H，Ar-H)，7.13～7.10(t，1H，quinoline-H)，6.28(s，1H，quinoline-H)，5.64(s，2H，NH
2)，3.85～3.84(t，4H，CH
2)，3.26～3.24(t，4H，CH
2)。
ESI-MS m/z:526 [M+H]
+, calculated value: 526.
Embodiment 8:1-(4-(3-amino-1-(4-methylpiperazine-1-yl) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(4-methylpiperazine-1-yl) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, obtain faint yellow solid target compound.
1H NMR(DMSO-D6，300MHz)δ(ppm)：9.30(s，1H，NH)，8.95～8.94(d，1H，NH)，8.67～8.64(d，1H，quinoline-H)，7.82～7.79(d，1H，Ar-H)，7.60～7.36(dd，4H，Ar-H)，7.55～7.48(t，1H，Ar-H)，7.43～7.40(m，1H，quinoline-H)，7.28～7.26(d，1H，Ar-H)，7.13～7.08(t，1H，quinoline-H)，6.24(s，1H，quinoline-H)，5.62(s，2H，NH
2)，3.27(s，4H，CH
2)，2.58(s，4H，CH
2)，2.28(s，3H，CH
3)。
ESI-MS m/z:539 [M+H]
+, calculated value: 539.
Embodiment 9:1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(3-(4-methylpiperazine-1-yl) propoxy-) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5, obtain faint yellow solid target compound.
1HNMR(DMSO-D6，300MHz)δ(ppm)：9.29(s，1H，NH)，8.92(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，7.92～7.90(d，1H，Ar-H)，7.60～7.35(dd，4H，Ar-H)，7.53～7.50(t，1H，Ar-H)，7.41～7.39(m，1H，quinoline-H)，7.32～7.31(d，1H，Ar-H)，7.13～7.10(t，1H，quinoline-H)，6.18(s，1H，quinoline-H)，5.71(s，2H，NH
2)，4.43～4.40(t，2H，CH
2)，2.70～2.69(m，2H，CH
2)，2.45～2.33(m，8H，CH
2)，2.15(s，3H，CH
3)，1.98～1.95(m，2H，CH
2)。
ESI-MS m/z:597 [M+H]
+, calculated value: 597.
Embodiment 10:1-(4-(3-amino-1-Pyrrolidine base isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-Pyrrolidine base isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, obtain light brown yellow solid target compound.
1HNMR(DMSO-D6，300MHz)δ(ppm)：9.28(s，1H，NH)，8.94～8.93(d，1H，NH)，8.67～8.64(d，1H，quinoline-H)，7.96～7.93(d，1H，Ar-H)，7.59～7.34(dd，4H，Ar-H)，7.52～7.48(t，1H，Ar-H)，7.41～7.40(m，1H，quinoline-H)，7.21～7.18(d，1H，Ar-H)，7.00～6.95(t，1H，quinoline-H)，6.00(s，1H，quinoline-H)，5.37(s，2H，NH
2)，3.71～3.67(s，4H，CH
2)，1.92～1.88(s，4H，CH
2)。
ESI-MS m/z:510 [M+H]
+, calculated value: 510.
Embodiment 11:1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the fluoro-5-aminomethyl phenyl of 2-) urea
With 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-aminoisoquinoline of 5-be raw material, with the preparation method of embodiment 5 step B, obtains light brown yellow solid target compound.
1HNMR(DMSO-D6，500MHz)δ(ppm)：9.18(s，1H，NH)，8.85(d，1H，NH)，8.51(s，1H，quinoline-H)，8.02～8.01(d，1H，Ar-H)，7.79～7.78(d，1H，Ar-H)，7.60～7.36(dd，4H，Ar-H)，7.36～7.34(t，1H，quinoline-H)，7.22～7.19(t，1H，quinoline-H)，7.11～7.10(t，1H，Ar-H)，6.81(m，1H，quinoline-H)，6.65(s，1H，quinoline-H)，5.89(s，2H，NH
2)，2.50(s，3H，CH
3)。
ESI-MS m/z:387 [M+H]
+, calculated value: 387.
Embodiment 12:1-(4-(3-amino-1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-aminomethyl phenyl of 2-) urea (SHP-12)
With 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(2-(4-methylpiperazine-1-yl) oxyethyl group) isoquinoline 99.9 is raw material, with the preparation method of embodiment 5 step B, obtain faint yellow solid target compound.
1HNMR(DMSO-D6，500MHz)δ(ppm)：9.18(s，1H，NH)，8.50(s，1H，NH)，8.02～8.00(d，1H，quinoline-H)，7.90～7.88(d，1H，Ar-H)，7.58～7.32(dd，4H，Ar-H)，7.32～7.30(d，1H，Ar-H)，7.13～7.11(m，1H，quinoline-H)，7.11～7.09(d，1H，Ar-H)，6.82～6.80(m，1H，quinoline-H)，6.20(s，1H，quinoline-H)，5.72(s，2H，NH
2)，4.52～4.50(t，2H，CH
2)，2.81(s，2H，CH
2)，2.66～2.58(m，4H，CH
2)，2.38～2.30(m，4H，CH
2)，2.28(s，3H，CH
3)，2.23(s，3H，CH
3)。
ESI-MS m/z:529 [M+H]
+, calculated value: 529.
Embodiment 13:1-(4-(3-amino-1-(2-morpholine oxyethyl group) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-trifluoromethyl of 2-) urea
With 1-(the fluoro-5-trifluoromethyl of 2-)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(2-morpholine oxyethyl group) isoquinoline 99.9 is raw material, with embodiment 5 synthetic method, obtain faint yellow solid target compound.
1HNMR(DMSO-D6，300MHz)δ(ppm)：9.18(s，1H，NH)，8.50(s，1H，NH)，8.02～8.00(d，1H，quinoline-H)，7.90～7.88(d，1H，Ar-H)，7.58～7.32(dd，4H，Ar-H)，7.32～7.30(d，1H，Ar-H)，7.13～7.11(m，1H，quinoline-H)，7.11～7.09(d，1H，Ar-H)，6.82～6.80(m，1H，quinoline-H)，6.20(s，1H，quinoline-H)，5.72(s，2H，NH
2)，4.52～4.50(t，2H，CH
2)，2.81(s，2H，CH
2)，2.66～2.58(m，4H，CH
2)，2.38～2.30(m，4H，CH
2)。
ESI-MS m/z:570 [M+H]
+, calculated value: 570.
Embodiment 14:1-(4-(3-amino-(2-methoxy ethoxy) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-trifluoromethyl of 2-) urea
With 1-(the fluoro-5-trifluoromethyl of 2-)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(2-methoxy ethoxy) isoquinoline 99.9 is raw material, with embodiment 5 synthetic method, obtain faint yellow solid target compound.
1HNMR(DMSO-D6)δ(ppm)：9.29(s，1H，NH)，8.92(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，7.92～7.91(d，1H，Ar-H)，7.60～7.5(dd，4H，Ar-H)，7.32～7.30(d，1H，Ar-H)，7.13～7.11(m，1H，quinoline-H)，7.11～7.09(d，1H，Ar-H)，6.82～6.80(m，1H，quinoline-H)，6.20(s，1H，quinoline-H)，5.72(s，2H，NH
2)，4.54～4.52(t，2H，CH
2)，3.78～3.76(t，2H，CH
2)，3.36(s，3H，CH
3)。
ESI-MS m/z:515 [M+H]
+, calculated value: 515
Embodiment 15:1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With 1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-aminoisoquinoline of 5-be raw material, with embodiment 5 synthetic method, obtains faint yellow solid target compound.
1HNMR(DMSO-D6，300MHz)δ(ppm)：9.21(s，1H，NH)，9.00(d，1H，NH)，8.86(d，1H，quinoline-H)，8.14(d，1H，Ar-H)，7.90～7.78(d，1H，Ar-H)，7.70～7.66(m，2H，quinoline-H)，7.62～7.59(m，2H，Ar-H)，7.40～7.37(m，2H，Ar-H)，7.34(s，1H，Ar-H)，7.22～7.17(m，1H，quinoline-H)，6.64(m，1H，quinoline-H)，5.92(s，2H，NH
2)。
ESI-MS m/z:457 [M+H]
+, calculated value: 457
Embodiment 16:1-(4-(3-amino-1-(3-(4-methylpiperazine-1-yl) third is amino) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-amino of 5--1-(3-(4-methylpiperazine-1-yl) third is amino) isoquinoline 99.9 is raw material, with embodiment 5 step B synthetic method, obtain faint yellow solid target compound.
1HNMR(DMSO-D6，500MHz)δ(ppm)：9.29(s，1H，NH)，8.91(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，7.92～7.90(d，1H，Ar-H)，7.57～7.55(d，2H，Ar-H)，7.52～7.48(t，1H，quinoline-H)，7.41～7.39(m，1H，Ar-H)，7.34～7.32(d，2H，Ar-H)，7.26～7.24(t，1H，Ar-H)，7.20～7.18(t，1H，quinoline-H)，7.00～6.97(t，1H，quinoline-H)，5.81(s，1H，NH)，5.28(s，2H，NH
2)，3.48～3.44(m，2H，CH
2)，，2.41～2.36(m，10H，CH
2)，2.16(s，3H，CH
3)，1.82～1.76(m，2H，CH
2)。
ESI-MS m/z:596 [M+H]
+, calculated value: 596.
Embodiment 17:1-(4-(3-aminoisoquinoline-5-base) phenyl)-3-(4-((4-methylpiperazine-1-yl) methyl)-3-(trifluoromethyl) phenyl) urea
With 1-(4-((4-methylpiperazine-1-yl) methyl))-3-trifluoromethyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenyl) urea and the bromo-3-aminoisoquinoline of 5-be raw material, with embodiment 5 step B synthetic method, obtain faint yellow solid target compound.
1HNMR(DMSO-D6，500MHz)δ(ppm)：9.03(s，1H，NH)，8.89(s，1H，NH)，8.85(s，1H，quinoline-H)，7.98(s，1H，Ar-H)，7.79(d，1H，Ar-H)，7.65～7.59(m，4H，Ar-H)，quinoline-H)，7.39～7.34(m，3H，Ar-H)，7.20(t，1H，quinoline-H)，6.65(s，1H，quinoline-H)，5.89(s，2H，NH
2)，3.53(s，2H，CH
2)，2.47～2.24(m，8H，CH
2)，2.16(s，3H，CH
3)
ESI-MS m/z:535 [M+H]
+, calculated value: 535.
Embodiment 18:1-(4-(3-amino-1-(3-methoxypropargyl) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenylurea and the bromo-1-of 5-(3-methoxypropargyl) isoquinoline 99.9-3-amino is raw material, with embodiment 5 step B synthetic method, obtain faint yellow solid.
1HNMR(DMSO-D6，500MHz)δ(ppm)：
1H NMR(DMSO-D6)δ(ppm)：9.32(s，1H，NH)，8.93(d，1H，NH)，8.66～8.64(d，1H，quinoline-H)，8.06～8.05(d，1H，Ar-H)，7.63～7.61(m，2H，Ar-H)，7.53～7.49(m，1H，quinoline-H)，7.40～7.38(m，4H，quinoline-H，Ar-H)，7.30～7.27(d，1H，quinoline-H)，6.70(s，1H，Ar-H)，6.05(s，2H，NH
2)，4.50(m，2H，CH
2)，3.43(s，3H，CH
3)。
ESI-MS m/z:509 [M+H]
+, calculated value: 509.
Embodiment 19:1-(4-(3-amino-1-(3-dimethylaminopropyne base) isoquinoline 99.9-5-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3-dioxolane-2-base) phenylurea and the bromo-1-of 5-(3-dimethylaminopropyne base) isoquinoline 99.9-3-amino is raw material, with embodiment 5 step B synthetic method, obtain faint yellow solid.
1HNMR(DMSO-D6)δ(ppm)：9.33(s，1H，NH)，8.94(d，1H，NH)，8.67～8.64(d，1H，quinoline-H)，8.10～8.07(d，1H，Ar-H)，7.63～7.60(m，2H，Ar-H，quinoline-H)，7.54～7.40(m，1H，quinoline-H)，7.40～7.37(dd，4H，Ar-H)，7.30～7.25(d，1H，quinoline-H)，6.67(s，1H，Ar-H)，6.04(s，2H，NH
2)，3.64(m，2H，CH
2)，2.33(s，6H，CH
3)。
ESI-MS m/z:522 [M+H]
+, calculated value: 522.
Embodiment 20:1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) (-7-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
The preparation of steps A 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-iodophenyl) urea
2.97g (10mmol) triphosgene is dissolved in the methylene dichloride of 20ml, under condition of ice bath again by fluoro-for 5.37g (30mmol) 2-5-5-trifluoromethylaniline and 3.03g (30mmol) triethylamine mixed dissolution in the methylene dichloride of 20ml, slowly be added dropwise to above-mentioned reaction solution (keeping the temperature of reaction solution between 5 ~ 10 DEG C), dropwise rear continuation and react 0.5h under condition of ice bath.Remove ice bath, the methylene dichloride mixed solution of the 4-iodobenzene ammonia and 3.03g (30mmol) triethylamine that 20ml are dissolved with 30mmol replacement under normal temperature condition is added dropwise in above-mentioned reaction solution, and stirring is spent the night.After reaction terminates, pour 50mL shrend into reaction solution and go out, with dichloromethane extraction (2 × 20ml), use water (40ml), saturated sodium-chloride (40ml) to wash successively, concentrated after anhydrous sodium sulfate drying.Concentrated solution silica gel column chromatography is separated and obtains white powdery solids.
The preparation of step B 1-(4-(2-amino-7H-pyrroles [2,3-d] pyrimidine) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
By 0.75mmol 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-iodophenyl) urea, 0.5mmol 7H-pyrrolo-[2; 3-d] pyrimidine-2-amino, 0.05mmol cuprous iodide, 1mmol L-PROLINE, 2mmol salt of wormwood; 5mLDMSO is placed in single neck bottle of 50mL, nitrogen protection 110 DEG C reaction 16h.Add water and extraction into ethyl acetate after reaction terminates, get organic layer, precipitation, column chromatography for separation, obtain faint yellow solid.
1HNMR(DMSO-D6)δ(ppm)：9.25(s，1H，NH)，8.87(d，1H，NH)，8.68(s，1H，pyrimidine-H)，8.55～8.53(d，1H，Ar-H)，7.6(m，1H，pyrimidine-H)，7.5(t，1H，Ar-H)，7.61～7.37(dd，4H，Ar-H)，7.4(m，1H，Ar-H)，6.72(s，1H，pyrimidine-H)，5.88(s，2H，NH
2)。
ESI-MS m/z:431 [M+H]
+, calculated value: 431.
Embodiment 21:1-(4-(2-amino-4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine) (-7-base) phenyl)-3-(the fluoro-5-of 2-(trifluoromethyl) phenyl) urea
With 1-(the fluoro-5-of 2-(trifluoromethyl) phenyl)-3-(4-iodophenyl) urea and 4-(4-methylpiperazine-1-yl)-7H-pyrroles [2,3-d] pyrimidine-2-amino is raw material, with the synthetic method of embodiment 20 step B, obtain faint yellow solid.
1HNMR(DMSO-D6)δ(ppm)：9.25(s，1H，NH)，8.87(d，1H，NH)，8.68(s，1H，pyrimidine-H)，8.55～8.53(d，1H，Ar-H)，7.6(m，1H，pyrimidine-H)，7.5(t，1H，Ar-H)，7.61～7.37(dd，4H，Ar-H)，7.4(m，1H，Ar-H)，5.88(s，2H，NH
2)，3.27(s，4H，CH
2)，2.58(s，4H，CH
2)，2.28(s，3H，CH
3)。
ESI-MS m/z:527 [M+H]
+, calculated value: 527.
Embodiment: 22:1-(the chloro-3-trifluoromethyl of 4-)-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzos [d] oxazole-6-base) urea
Steps A: the preparation of 6-nitro benzo [d] oxazolidine-2-ketone
In the round-bottomed flask of 100ml, add 3.08g (20mmol) 2-Amino-5-nitrophenol, 3.24g (10mmol) CDI, anhydrous THF, be heated to 65 DEG C, backflow 5h.After TLC detection raw material reaction is complete, stopped reaction, is spin-dried for solvent and obtains oily matter.Add the hydrochloric acid soln salify of 2M, filter to obtain yellow solid, recrystallized from acetonitrile, obtain brown needle-like crystals.
The preparation of step B:6-nitro benzo [d] 3-(pyridine-2-ylmethyl) oxazolidine-2-ketone
Steps A gains 1.81g (10mmol) is dissolved in the three-necked bottle containing 70ml acetonitrile, reflux, after all dissolving, adds chloromethylpyridine 1ml, 65 DEG C of backflow 8h.TLC detects to reacting completely, and stopped reaction, is spin-dried for solvent, and Virahol (about 150ml) recrystallization, obtains faint yellow needle-like crystal.
The preparation of amino benzo [d] 3-(pyridine-2-ylmethyl) oxazolidine-2-ketone of step C:6-
Step B gains 0.5g (1.8mmol) is dissolved in the round-bottomed flask of the mixed solvent that 40ml ethyl acetate and ethanol are housed, is heated to 60 DEG C.After all dissolving, add tin protochloride 3.0g, reaction solution becomes oyster white from clarification, and after reaction 2h, TLC detects, when raw material point disappears, and stopped reaction, at this moment reaction solution pinkiness.Be cooled to room temperature, regulate PH to neutral or weakly alkaline 7-8, dichloromethane extraction three times (20ml × 3), organic layer Na
2sO
4dried overnight, is spin-dried for solvent and obtains reddish Solid.
The preparation of step D:1-(the chloro-3-trifluoromethyl of 4-)-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzos [d] oxazole-6-base) urea
Step C gains 0.22g (0.9mmol) and CDI 0.21g (1.3mmol) is joined in the three-necked bottle of 50ml; under nitrogen protection condition, add 15ml anhydrous methylene chloride, under room temperature condition, react 12h; TLC detection reaction; when raw material point disappears, solution is white slurry, adds 4-chloro-3-methyl fluoride aniline 0.3g (1.5mmol); solution becomes clear by white slurry; continue reaction 4h, solution adularescent precipitation produces, and solution is pulpous state.Filter, washed with dichloromethane obtains crude product, THF recrystallization, obtains white solid and title compound.
1H NMR(DMSO-d
6，300MHz)δ(ppm)：9.19(s，1H，NH)，8.92(s，1H，NH)，8.49(d，1H，pyridine-H)，8.09(s，1H，Ar-H)，7.83-7.78(t，1H，pyridine-H)，7.64-7.58(m，3H，Ar-H，Benzoxazol-H)，7.43(d，1H，Benzoxazol-H)，7.34-7.30(m，1H，Ar-H)，7.11-7.01(m，2H，Pyridine-H)，5.13(s，2H，CH
2)。
ESI-MS m/z:463 [M+H]
+, calculated value: 463.
Embodiment 23:1-phenmethyl-3-(2-oxo-3-(pyridine-2-base-methyl)-2,3-dihydrobenzos [d] oxazole-6-base) urea
With 2-Amino-5-nitrophenol, chloromethylpyridine and benzylamine for raw material, with the synthetic method of embodiment 22, obtain faint yellow solid.
1H NMR(DMSO-d
6，300MHz)δ(ppm)：8.63(s，1H，NH)，8.49(d，1H，NH)，7.82～7.77(t，1H，pyridine-H)，7.64(s，1H，pyridine-H)，7.41-7.38(d，1H，Benzoxazol-H)，7.35～7.23(m，5H，Ar-H)，6.97(s，2H，Benzoxazo-H)，6.87(s，1H，pyridine-H，)6.63～6.60(d，1H，pyridine-H)，5.10(s，2H，CH
2)，4.29(d，2H，CH
2)。
ESI-MS m/z:375 [M+H]
+, calculated value: 375.
Embodiment: 24:1-(the chloro-3-trifluoromethyl of 4-)-3-(2-oxo-3-(6-chloropyrimide-4-base)-2,3-dihydrobenzos [d] oxazole-6-base) urea
With the chloro-3-5-trifluoromethylaniline of 2-Amino-5-nitrophenol, 4,6-dichloro pyrimidines and 4-for raw material, with the synthetic method of embodiment 22, obtain pale white solid.
1HNMR(DMSO-d
6，300MHz)δ(ppm)：9.36(s，1H，NH)，9.26(s，1H，NH)，9.08(s，1H，Pyrimidine-H)，8.26～8.23(m，2H，Ar-H，Benzoxazol-H)，8.10(s，1H，Ar-H)，7.77(s，1H，Ar-H)，7.63-7.59(m，2H，Benzoxazol-H)，7.25(d，1H，pyrimidine-H)。
ESI-MS m/z:484 [M+H]
+, calculated value: 484.
Embodiment 25:1-phenmethyl-3-(2-oxo-3-(6-chloropyrimide-4-base)-2,3-dihydrobenzos [d] oxazole-6-base) urea
With 2-Amino-5-nitrophenol, 4,6-dichloro pyrimidines and benzylamine for raw material, with the synthetic method of embodiment 22, obtain pale white solid.
1HNMR(DMSO-d
6，300MHz)δ(ppm)：9.07(s，1H，NH)，8.94(s，1H，NH)，8.27～8.18(m，2H，Pyrimidine-H，Benzoxazol-H)，7.79(s，1H，Benzoxazol-H)，7.32～7.27(m，5H，Ar-H)，7.16～7.13(d，1H，Benzoxazol-H)，6.74(s，1H，Pyrimidine-H)，4.32～4.30(d，2H，CH
2)。
ESI-MS m/z:396 [M+H]
+, calculated value: 396.
Embodiment 26: part of compounds anti tumor activity in vitro is tested
Adopt MTT test
1. collect logarithmic phase cell, adjustment concentration of cell suspension, makes cell concn 1 × 10
5left and right, is inoculated in 96 orifice plates respectively, every hole 100ul.
2. put 37 DEG C, 5%CO
2cultivate in incubator and make cell attachment.
3. add the medicine (medicine will process through suitable, as solvability, degerming etc.) of different concns, basis of time experiment needs, and is generally 48 hours.
4. carefully suck supernatant liquor, PBS washs gently, again abandons supernatant.
5. every sky adds the fresh RPMI1640 nutrient solution of 180ul, then adds 20ulMTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4h.
6. stop cultivating, carefully suck nutrient solution in hole.
7. every hole adds 150ul dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on shaking table, crystallization is fully dissolved.
8. the light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument 490nm place.
9. calculate IC
50value, experimental result sees the following form
Part of compounds external activity test result
Embodiment 27:B-raf enzymic activity is tested
The test embodiment of the present invention 13 suppresses the ability of B-raf activity
1), testing compound (embodiment 13), reference compound or water (contrast) mix with containing enzyme (24ng) damping fluid.Control substrate is tested, not enzyme-added in reaction solution.Damping fluid comprises 40mM Hepes/Tris (pH 7.4), 0.8mM EGTA/Tris, 8mM MgCl
2, 1.6mM DTT and 0.008% polysorbas20.
2) 15nM substrate (the un-activation MEK1 of histidine mark) and 1 μM of ATP, incubated at room 30min, is added.
3), hatch end, add 13mM EDTA stopped reaction.
4), after 5min, add the phosphorylation MEK1/2 antibody of Europium chelate mark, add Ulight-subsequently and resist histidine-tagged.
5), after 1h, microplate reader measures fluorescence transfer, and wavelength is λ ex=337nm, λ em=620nm and λ em=665nm.
6), enzyme work is recorded by 665nm and 620nm signal ratio.Test result represents the inhibition percentage for living relative to control group enzyme.Standard suppresses curve object of reference to be Raf-1 inhibitor, is equipped with several concentration to measure its IC in each test
50value.
The inhibition percentage that the embodiment of the present invention 13 is alive relative to control group enzyme
Embodiment 28:VEGFR-2 enzymic activity is tested
The test embodiment of the present invention 17 suppresses the ability of VEGFR-2 activity
1), testing compound (embodiment 17), reference compound or water (contrast) mix with containing enzyme (0.88ng) damping fluid.Control substrate is tested, not enzyme-added in reaction solution.Damping fluid comprises 40mM Hepes/Tris (pH 7.4), 0.8mM EGTA/Tris, 8mM MgCl
2, 1.6mM DTT and 0.008% polysorbas20.
2) 100nM substrate Ulight-CAGAGAIETDKEYYTVKD (JAK1) and 25 μMs of ATP, incubated at room 60min, is added.
3), hatch end, add 13mM EDTA stopped reaction.
4), after 5min, the phosphorylation PT66 antibody of Europium chelate mark is added
5), after 1h, microplate reader measures fluorescence transfer, and wavelength is λ ex=337nm, λ em=620nm and λ em=665nm
6), enzyme work is recorded by 665nm and 620nm signal ratio.Test result represents the inhibition percentage for living relative to control group enzyme.Standard suppresses curve object of reference to be staurosporine, is equipped with several concentration to measure its IC in each test
50value.
The inhibition percentage that the embodiment of the present invention 17 is alive relative to control group enzyme
Embodiment 29: Pharmacokinetic Evaluation
The pharmacokinetics test of the embodiment of the present invention 12 compound
With SD rat for animal subject, application LC/MS/MS method determines the drug level that rat oral gavage to give after embodiment 12 compound not in blood plasma in the same time.The pharmacokinetics behavior of research the compounds of this invention in rat body, evaluates its oral absorption characteristics of pharmacokinetics.
1. testing program:
Test drug: embodiment 12 compound
Experimental animal: healthy SD rat 12 (male, body weight 224 ~ 300g)
2. test method:
1) LC-MS analytical procedure
LC-MS/MS system: the supper-fast liquid phase systems of Shimadzu UFLC 20-AD XR and applying biological system of the U.S.
System company API-5000 triple level Four bar mass spectrometry
Chromatographic column: ACE 5 μ C18,50 × 2.1mm
Moving phase: 0.4% aqueous formic acid (pH 3.2): acetonitrile
Ion pair: 529.4/127.2
2) linear quantitation range: linearity range: 0.5-250ng/mL; Linear dependence (R
2): 0.9960
3. administration and blood sampling scheme
Healthy SD rat 12 (male, body weight 224 ~ 300g), often organizes 3, and before test, fasting is about 16h, freely drinks water; Drug excipient is 10% ethanol, 20%PEG200,70% physiological saline.
Gavage gives embodiment 12 compound, and dosage is 7mg/kg, and administration volume is 5mL/kg.After administration 4h, unification gives feed.Before administration and after administration, 0.17,0.33,0.67,1,2,4,8,24h gets blood 0.3mL through jugular vein intubate, puts in EDTA centrifuge tube, under 4 DEG C of conditions, and the centrifugal 10min separated plasma of 3200g.During sample analysis, all plasma samples are collected and are placed on-20C Refrigerator store.
4. operate: get plasma sample 50uL, add 150uL methanol extraction, suspendible vibration rear centrifugal twice, gets supernatant liquor and carries out LC-MS/MS analysis.Main pharmacokinetic parameter uses WinNonlin (5.3 editions) to calculate according to non-compartment model.
5. pharmacokinetic parameters result
Male SD rat gives the blood pharmacokinetic parameters of embodiment 12 after 7mg/kg embodiment 12 through gavage
Claims (19)
1. compound or pharmaceutically acceptable salt thereof shown in general formula (I) or enantiomer:
Wherein:
M is 0;
L is
wherein
X is O;
R
4be selected from hydrogen, halogen and C
1-8alkyl;
R
5be selected from (CH
2)
pr
6, wherein R
6be selected from C
6-14aryl and C
3-10heteroaryl, described C
6-14aryl or
C
3-10heteroaryl can be replaced independently by one or more halogen, and p is 1;
R
1be selected from hydrogen, halogen, C
1-8alkyl and halo C
1-8alkyl.
2. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 1 or enantiomer, wherein R
1be selected from hydrogen, halogen, C
1-5alkyl and halo C
1-5alkyl.
3. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 2 or enantiomer, wherein R
1be selected from hydrogen, Cl, Br, F, methyl and trifluoromethyl.
4. according to compound or pharmaceutically acceptable salt thereof or enantiomer, the wherein R of the logical formula I in claim 1-3 described in any one
4be selected from hydrogen, F, Cl, Br and C
1-3alkyl.
5. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 4 or enantiomer, wherein R
4for hydrogen.
6. according to compound or pharmaceutically acceptable salt thereof or enantiomer, the wherein R of the logical formula I in claim 1-3 described in any one
6be selected from C
6-10aryl and C
3-7heteroaryl, described C
6-10aryl or C
3-7heteroaryl is optionally optionally substituted by halogen further.
7. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 4 or enantiomer, wherein R
6be selected from C
6-10aryl and C
3-7heteroaryl, described C
6-10aryl or C
3-7heteroaryl is optionally optionally substituted by halogen further.
8. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 6 or enantiomer, wherein R
6be selected from phenyl, pyridyl, chlorophenyl and chloro-pyridine base.
9. the compound or pharmaceutically acceptable salt thereof of logical formula I according to claim 7 or enantiomer, wherein R
6be selected from phenyl, pyridyl, chlorophenyl and chloro-pyridine base.
10. the compound or pharmaceutically acceptable salt thereof of general formula according to claim 1 (I) or enantiomer, wherein said general formula (I) compound is selected from:
1-(4-((9-phenmethyl-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea;
1-(4-((9-(pyridine-2-methyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea; With
1-(4-((9-(3-benzyl)-9H-purine-6-base) oxygen) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea.
11. according to claim 1-3,5 and 7-10 in compound or pharmaceutically acceptable salt thereof described in any one or enantiomer, wherein said pharmaceutical salts is by the compound of described logical formula I and the corresponding salt being selected from mineral acid and organic acid acid and being formed.
12. compound or pharmaceutically acceptable salt thereof according to claim 4 or enantiomers, wherein said pharmaceutical salts be by the compound of described logical formula I to be selected from mineral acid and the corresponding salt that formed of organic acid acid.
13. compound or pharmaceutically acceptable salt thereof according to claim 6 or enantiomers, wherein said pharmaceutical salts be by the compound of described logical formula I to be selected from mineral acid and the corresponding salt that formed of organic acid acid.
14. compound or pharmaceutically acceptable salt thereof according to claim 11 or enantiomers, wherein said mineral acid is selected from phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid and Hydrogen bromide, and described organic acid is selected from acetic acid, trifluoroacetic acid, propionic acid, propanedioic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, amygdalic acid, sulfonic acid, tosic acid, methanesulfonic, ethyl sulfonic acid, Phenylsulfonic acid, camphorsulfonic acid and Whitfield's ointment.
15. compound or pharmaceutically acceptable salt thereofs according to claim 12 or 13 or enantiomer, wherein said mineral acid is selected from phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid and Hydrogen bromide, and described organic acid is selected from acetic acid, trifluoroacetic acid, propionic acid, propanedioic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, amygdalic acid, sulfonic acid, tosic acid, methanesulfonic, ethyl sulfonic acid, Phenylsulfonic acid, camphorsulfonic acid and Whitfield's ointment.
16. 1 kinds of pharmaceutical compositions, it comprises the compound or pharmaceutically acceptable salt thereof of the general formula (I) in claim 1-15 described in any one or enantiomer and pharmaceutically useful carrier or vehicle.
The compound or pharmaceutically acceptable salt thereof of the general formula (I) in 17. claim 1-15 described in any one or enantiomer or the application of pharmaceutical composition according to claim 16 in the medicine for the preparation for the treatment of or prophylaxis of tumours.
18. application according to claim 17, wherein said tumour is melanoma, liver cancer, kidney, mammary cancer, lung cancer, thyroid carcinoma, bladder cancer, colon and rectum carcinoma, prostate cancer, carcinoma of the pancreas, ovarian cancer, head and neck cancer, the too much disease of acute myeloid leukaemic, chronic marrow sample hypercytosis, peritoneal cancer, mesothelioma, myelodysplastic syndrome or cancer of the stomach.
19. application according to claim 18, wherein said tumour is nonsmall-cell lung cancer or myelomatosis.
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